WO2016167545A1 - Soluble microneedle containing ingredient for controlling release of neurotransmitters - Google Patents

Soluble microneedle containing ingredient for controlling release of neurotransmitters Download PDF

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Publication number
WO2016167545A1
WO2016167545A1 PCT/KR2016/003845 KR2016003845W WO2016167545A1 WO 2016167545 A1 WO2016167545 A1 WO 2016167545A1 KR 2016003845 W KR2016003845 W KR 2016003845W WO 2016167545 A1 WO2016167545 A1 WO 2016167545A1
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WO
WIPO (PCT)
Prior art keywords
microneedle
skin
calcium channel
neurotransmitters
release
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PCT/KR2016/003845
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French (fr)
Korean (ko)
Inventor
강내규
이현종
장윤희
김태윤
김기영
심우선
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주식회사 엘지생활건강
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Priority claimed from KR1020150144855A external-priority patent/KR102203633B1/en
Priority claimed from KR1020150159978A external-priority patent/KR102099326B1/en
Application filed by 주식회사 엘지생활건강 filed Critical 주식회사 엘지생활건강
Priority to CN201680019249.4A priority Critical patent/CN107427474A/en
Priority to US15/566,094 priority patent/US10391289B2/en
Priority to PL16780268T priority patent/PL3284506T3/en
Priority to JP2017553096A priority patent/JP6784442B2/en
Priority to EP16780268.5A priority patent/EP3284506B1/en
Publication of WO2016167545A1 publication Critical patent/WO2016167545A1/en
Priority to HK18107180.5A priority patent/HK1247575A1/en
Priority to US16/516,867 priority patent/US11577063B2/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • the present invention relates to soluble microneedles and relates to skin administration systems capable of delivering to the skin a substance that controls the release of neurotransmitters.
  • the stratum corneum of the skin is a brick structure consisting of keratin-rich keratinocytes, and a mortar filled with lipids such as ceramide, fatty acids, or waxes between the keratinocytes. It consists of a structure. This structure acts as a barrier and has a very low material permeability. Only low molecular structure components of 500 Da or less can be delivered into the skin by diffusion, and only substances with good lipid affinity can pass through the skin.
  • the release of neurotransmitters is caused by the formation of a pathway between the two boundaries after the synaptic vesicle and the presynaptic membrane are fused at the nerve terminal containing the neurotransmitter.
  • SNARE proteins a protein complex consisting of the vesicle protein VAMP (synaptobrevin) and the plasma membrane binding proteins Syntaxin 1a and SNAP-25, provide a fundamental force for the fusion of synaptic vesicles with the entire synaptic membrane. .
  • the neurotransmitter excretion pathway is opened by membrane fusion between synaptic vesicles and the synaptic epithelium, t-SNARE and vesicles (a complex of syntaxin 1a protein and SNAP-25 protein attached to the target membrane). This is the result of the operation of v-SNARE attached to the vesicle.
  • t-SNARE a complex of syntaxin 1a protein and SNAP-25 protein attached to the target membrane.
  • calcium channel blocker (Calcium channel blocker) is known to reduce the contraction of the muscle by acting to inhibit the calcium, which is an important factor for contracting the muscle to enter the muscle vascular fiber cells. Facial movements are caused by the contraction of muscles under the skin, allowing different muscles to move different parts of the face.
  • the calcium channel blocker had to be delivered to the muscle layer, so that the simple application of cosmetics had difficulty in absorbing the drug to the muscle layer.
  • Injecting calcium channel blockers into the skin can be limited to use by individuals because they involve pain and require treatment, and side effects can occur because oral administration affects the whole body.
  • the problem to be solved by the present invention is to provide a soluble microneedle excellent skin penetration amount.
  • soluble microneedle It impregnates soluble microneedle with components that have excellent wrinkle improvement by blocking neurotransmission and are applied to skin without pain by microneedle and applied to skin, while microneedles are dissolved by moisture in skin and deliver drugs into skin. To provide a soluble microneedle.
  • the present invention allows the effective needle to be delivered into the skin while the fine needle is dissolved by the water in the skin.
  • the present invention aims to reduce the release of neurotransmitter by the active ingredient delivered into the skin to relax the muscles to improve wrinkles and facial lines and to suppress pain.
  • the present invention is to solve the problem that the solubility is not good in the general cosmetic composition limited the amount of polyphenols used, improve the solubility of polyphenols to provide a skin delivery system that can be applied to the skin.
  • the present invention provides a microneedle comprising a component for controlling the release of neurotransmitter, preferably the microneedle is a soluble microneedle.
  • the component that modulates the release of neurotransmitters may be i) polyphenols or derivatives thereof, ii) calcium channel blockers, or iii) mixtures thereof.
  • the microneedle preferably contains the microneedle containing a component for controlling the release of neurotransmitter, and has a wrinkle improvement effect.
  • the material forming the microneedles may be dissolved or biodegradable in the skin, and the microneedles are dissolved or decayed when the microneedles are applied to the skin, thereby releasing components that control the release of the neurotransmitter, and the release of the neurotransmitter. Ingredients that regulate the ability to be delivered to the skin stably.
  • the components included in the microneedle include polyphenols or derivatives thereof.
  • the present inventors have studied a variety of administration systems, and as mentioned above, any system has a low solubility, and thus the application of the polyphenol to the general cosmetics is limited only by application to the skin.
  • the inventors have made a surprising invention that, after various efforts, by containing polyphenols in the soluble microneedle in the skin, it can effectively reduce the transmission of neurotransmitters to exhibit wrinkle improvement.
  • microneedles must be soluble in the skin, and hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) and vinyl blood to form soluble microneedles.
  • Water-soluble polymers such as a rollidone-vinylacetate copolymer, poly vinyl alcohol, and poly vinyl pyrrolidone; Sugars such as xylose, sucrose, maltose, lactose, trehalose and the like; Or mixtures thereof may be used.
  • 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 forming the microneedle.
  • plasticizer for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone. Or may be used in admixture.
  • polyols such as ethylene glycol, propylene glycol, dipropylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone. Or may be used in admixture.
  • the microneedle of the present invention controls the neurotransmitter discharge, and may contain 0.01 to 10% by weight, more preferably 0.1 to 5% by weight of polyphenol having a wrinkle improvement effect relative to the total weight of the microneedle. have.
  • the microneedle may comprise a high content of polyphenol components and may provide a polyphenol skin delivery system in which the amount delivered to the skin is significantly increased compared to formulations of common cosmetic compositions.
  • the polyphenol component was poorly soluble, so that the amount contained in the cosmetic composition was extremely low, but the microneedle of the present invention was extremely low in water so that it could be delivered to the skin by applying a high content to the microroll needle without precipitation of the polyphenol component.
  • the polyphenols are camphorol, quercetin, myricetin, luteolin, delchinidine, cyanidin, butane, ellagic acid, ampelopsin, hesperydine, aurantinidin, europinidin, pella May be at least one selected from the group consisting of Peargonidin, Malvidin, Peonidin, Peunidin, Petunidin, and Rossinidin, and derivatives thereof. May be any one or more selected from the group consisting of ampelopsin, hesperidin or derivatives thereof.
  • Derivatives of the polyphenols herein are free form (free acid or base form) and all prodrugs, polymorphs, hydrates, solvates, tautomers, steric Unless otherwise specified, isomers include all pharmaceutically acceptable forms as described above and are used in the sense to include all active forms of the compounds.
  • the microneedle containing polyphenols inhibits the formation of SNARE complexes and inhibits membrane fusion. As a result, the microneedles inhibit the release of neurotransmitters such as acetylcholine. Shrinkage can be suppressed.
  • the present invention provides a microneedle patch system for administration (delivery) of polyphenols or derivatives thereof to which the microneedle is attached.
  • microneedles of the present invention can be prepared by a method of manufacturing conventional soluble microneedles in the art, and the production method is not particularly limited.
  • the microneedle manufacturing method of the present invention (S1) is a solution containing a component (for example, calcium channel blocker, polyphenol or derivatives thereof, or mixtures thereof) to control the release of neurotransmitters.
  • Manufacturing step (S2) injecting the solution into the microneedle mold; And (S3) drying and separating the microneedle from the mold.
  • a component for example, calcium channel blocker, polyphenol or derivatives thereof, or mixtures thereof
  • the present invention also provides a method for administering the skin of polyphenols having improved solubility and improved skin delivery, characterized by using the microneedle according to the present invention.
  • the present invention provides a wrinkle improvement use of the microneedle containing the polyphenol having the effect of improving the wrinkles, and control the neurotransmitter discharge.
  • the present invention provides microneedles containing polyphenols and inhibiting SNARE complex formation.
  • the present invention provides a skin wrinkle improvement of the microneedle containing a component for controlling the release of neurotransmitter.
  • the present invention provides a microneedle containing a calcium channel blocker, and has an effect of improving wrinkles or improving facial contour through muscle relaxation. More preferably, the material forming the microneedle is dissolved in the skin to release or disintegrate the calcium channel blocker upon application of the microneedle to the skin, and the calcium channel blocker can be stably delivered to the skin.
  • the inventors have studied a variety of dosage systems and have, after many efforts, contained calcium channel blockers in soluble microneedles in the skin, effectively reducing the delivery of neurotransmitters, inhibiting muscle contraction, and improving skin wrinkles or facial
  • the contours have been improved to create an amazing invention that can produce lifting effects.
  • microneedles must be soluble in the skin, and hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) and vinyl blood to form soluble microneedles.
  • Water-soluble polymers such as a rollidone-vinylacetate copolymer, poly vinyl alcohol, and poly vinyl pyrrolidone; Sugars such as xylose, sucrose, maltose, lactose, trehalose and the like; Or mixtures thereof may be used.
  • 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 forming the microneedle.
  • plasticizer for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone. Or may be used in admixture.
  • polyols such as ethylene glycol, propylene glycol, dipropylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone. Or may be used in admixture.
  • the microneedle of the present invention contains 0.0001 to 20% by weight of calcium channel blocker to the total weight of the microneedle preparation solution, and more preferably 0.001 to control the release of neurotransmitter and control skin muscle contraction. To 5% by weight.
  • a "calcium channel blocker” is also referred to as a calcium antagonist and refers to a substance that blocks calcium from entering the muscle and thereby inhibits muscle contraction.
  • the calcium channel blocker is at least one member of the group consisting of copper gluconate, zinc gluconate, magnesium sulfate, magnesium gluconate and magnesium aspatate.
  • Organometallic compounds selected; At least one dihydropyridine calcium channel blocker selected from the group consisting of amlodipine, lercanidipine, felodipine, nifedipine, nicardipine, isradinine, nisoldipine and pharmaceutically acceptable salts thereof; Phenylalkylamine based calcium channel blockers including verapamil; Benzothiapine-based calcium channel blockers including dithiazem; And N-type calcium channel blockers selected from the group consisting of gabapentinoids and zinconotides; It may be any one or more selected from the group consisting of, any material capable of muscle relaxation by blocking calcium flowing into the calcium channel may be included, and the type is not particularly limited.
  • the calcium channel blocker may preferably use magnesium gluconate.
  • the present invention provides a microneedle patch system, preferably a microneedle patch system for calcium channel blocker administration (for delivery), comprising a component for controlling the release of neurotransmitters to which the microneedle is attached.
  • the present invention also provides a method of skin administration of a component for controlling the release of neurotransmitters with improved skin delivery rate, preferably a method of skin administration of a calcium channel blocker, characterized in using the microneedle according to the invention.
  • the present invention provides a microneedle for facial muscle relaxation and its facial muscle relaxation uses, including a microneedle containing a component for controlling the discharge of the neurotransmitter.
  • the facial muscle relaxation is a concept including the use of improving the wrinkles by inhibiting the muscle contraction of the skin, the use of improving the contour of the face, the use of having a lifting effect by preventing the sagging of the skin.
  • a method of skin administration of a component for controlling the release of neurotransmitters using the microneedle of the present invention preferably a method of skin administration of a calcium channel blocker for wrinkle improvement.
  • the present invention provides a microneedle having a skin wrinkle improvement effect.
  • the present invention provides a microneedle for skin administration, which can improve the skin permeation efficiency of the polyphenol having a wrinkle improvement effect.
  • the present invention also provides a method for administering the skin of a component that modulates the release of neurotransmitter, characterized by using such microneedles.
  • the present invention provides a microneedle having a skin wrinkle improvement effect or facial contour line improvement effect.
  • the present invention can transmit the active ingredient into the skin without pain by the microneedle.
  • the present invention can inhibit the calcium channel of nerve cells to block the release of neurotransmitters to relax the muscles to improve wrinkles and facial lines.
  • the soluble microneedle may be prepared by a solution casting method, and the solution may be cast into a mold to fill a fine mold with a vacuum and / or centrifuge, followed by drying.
  • the material forming the microneedle structure general synthetic and natural water-soluble polymers may be used.
  • Figure 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedle according to the present invention.
  • 3 exemplarily shows a polyphenol having a Botox-like effect of the present invention.
  • Myricetin, delchinidine, cyanidin, camphorol, quercetin, pisetin, butane, luteolin, ellagic acid, EGCG (Epigallocatechin gallate), ampfellopsin, hesperidin and derivatives thereof can be used.
  • Figure 4 shows the results confirmed the inhibition of SNARE formation of camphorol, myricetin, and ampelopsin.
  • Figure 5 is a graph showing the results of comparing the ampelopsin content in pig skin and acceptor solution.
  • Figure 6 is a graph showing the results of confirming the wrinkle improvement effect of the Amfellopsin cream and Amfellopsin microneedle in the human body.
  • Fig. 7 shows the results of confirming the muscle contraction inhibitory effect of camphorol, myricetin, and ampelopsin.
  • Figure 9 shows the results of measuring the inhibitory effect of In Vitro muscle contraction of magnesium gluconate. After incubation of myocytes and neuroblasts in vitro and treatment of magnesium gluconate by concentration, the results show that the number of muscle contractions decreases after 10 minutes.
  • Figure 10 graphically shows the wrinkle improvement index of magnesium gluconate cream and magnesium gluconate microneedle.
  • Soluble Micro Needle is manufactured by solution casting method.
  • the solution is cast into a mold, filled with liquid in a micro mold by vacuum or centrifuge, and then dried. At this time, general synthetic and natural water-soluble polymers are used to form the micro needle structure. .
  • microneedle having the composition of Table 1.
  • Dissolve Hyaluronic acid (Oligo-HA TM), Sodium carboxymethyl cellulose (Na-CMC) and Trehalose in purified water, and then use a solution of Glycerin, PEG-40 hydrogenated castor oil (HCO-40 TM) and Amfellopsin (10% Amfellopsin, DPG 90). %) was added to prepare an amfellopsin solution (DPG: Dipropylene glycol).
  • the prepared polyphenol dispersion solution was cast on a silicone micro needle mold, and then centrifuged at 3,000 rpm for 10 minutes to fill the liquid in the micro mold.
  • the manufacturing process is shown in FIG.
  • the polyphenol was impregnated and compared with a general oil-in-oil type cream as a comparative example.
  • Amphelopsin release from the microneedle prepared above was evaluated using a Franz diffusion cell equipped with pig skin (see FIG. 2).
  • As an aqueous solution (acceptor solution) was used a PBS solution containing 30% by weight of DPG.
  • the cream containing ampelopsin was minimal in permeation through the skin, but the ampoulescin impregnated in the Micro Needle penetrated directly into the skin by the needle, and the permeation amount was higher than that of the cream.
  • Cream containing ampelopsin was about 1ug permeated through the skin, but the amount was small.However, polyphenol impregnated in the microneedle penetrated directly into the skin by the needle, and its permeation amount was 13ug or more, which was 13 times higher than the cream. Skin permeation amount is shown. The result is shown in FIG.
  • ampellopsin-impregnated microneeedle showed more than 5 times better improvement, and it was confirmed that ampelopsin was effectively penetrated into the skin by the microneedle, resulting in a high wrinkle improvement effect.
  • SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis
  • Camperol, myricetin and ampelopsin have all been found to effectively inhibit the SNARE complex in a concentration dependent manner. As a result, it was confirmed that the activity of inhibiting SNARE complex formation at low concentrations of camphorol and ampelopsin was higher than that of myricetin. Inhibition of SNARE formation of myricetin, ampfellopsin (dihydroxymyricetin), camphorol, and A440 was confirmed and shown in FIG. 4. (Cell line: C2C12 (muscle cell) + NG108-15 (nerve cell) condition, concentration: ppm)
  • C2C12 cells were cultured in DMEM medium containing 10% fetal calf serum and 1% antibiotics on plates. Neuroblasts were then further co-cultured on the same plate. After that, when the cell contraction of C2C12 cells starts, measure the number of contractions of C2C12 cells for 30 seconds, remove all the medium, wash them three times with PBS, and add the calf serum-containing medium and 50 ppm of polyphenolic compound for 2 hours. I was. Afterwards, the contraction frequency of C2C12 cells was measured again for 30 seconds to confirm the degree of muscle contraction inhibition.
  • Camperol, myricetin and ampelopsin inhibited the release of neurotransmitters from neurons, reducing the number of C2C12 cell contractions. Among them, the effect of inhibiting the release of amfellopsin and camphorol compared to myricetin was relatively high. The result is shown in FIG.
  • a cosmetic composition comprising ampelopsin of the present invention
  • it may include less than 0.5% (PEG400 5%, based on 70% water) ampelopsin
  • the microneedle manufactured by the method of manufacturing the microneedle of the present invention Amfellopsin content can be increased to around 5% of the microneedle dry weight.
  • a product containing a high concentration of polyphenols can be produced.
  • Soluble microneedle is manufactured by the solution casting method, the solution was cast by casting the mold to the mold by vacuum or centrifuge the liquid was prepared by drying.
  • the magnesium gluconate dispersion solution was cast into a silicone microneedle mold, and then centrifuged at 3000 rpm for 10 minutes to fill the micro mold with liquid. After the solution was filled and dried for 3 hours in a drying oven (70 °C), the microneedle was separated from the silicone mold by using an adhesive film.
  • magnesium gluconate was impregnated into the cream of the general oil-in-water emulsion as an example.
  • magnesium gluconate content of pig skin tissue and acceptor solution over time was measured by Liquid Chromatography. Magnesium gluconate cream was applied to porcine skin or microneedle impregnated with magnesium gluconate was used to compare skin penetration of magnesium gluconate over time.
  • Cream containing magnesium gluconate is less than about 1 ug permeated through the skin, but the amount of magnesium gluconate impregnated in the microneedle penetrates directly into the skin by the needle, and the permeation amount is 20 ug or more, about 20 times or more. It showed a higher skin penetration than the cream. The results are shown in FIG.
  • the present invention can be used for cosmetics, pharmaceuticals for skin wrinkle improvement.
  • the microneedle of the present invention can expect excellent skin wrinkle reduction effect.

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Abstract

The present invention relates to a skin administration system capable of improving the efficiency of skin delivery of an ingredient for controlling release of neurotransmitters and, particularly, to a microneedle containing an ingredient for controlling release of neurotransmitters.

Description

신경전달물질의 배출을 조절하는 성분이 포함된 용해성 마이크로니들Soluble microneedle with ingredients that regulate the release of neurotransmitters
본 출원은 2015년 4월 13일에 출원된 한국특허출원 제10-2015-0052043호, 2015년 11월 13일에 출원된 한국특허출원 제10-2015-0159978호, 2015년 4월 14일에 출원된 한국특허출원 제10-2015-0052575호, 및 2015년 10월 16일에 출원된 한국특허출원 제10-2015-0144855호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.This application is filed in Korean Patent Application No. 10-2015-0052043, filed April 13, 2015, Korean Patent Application No. 10-2015-0159978, filed April 13, 2015, and April 14, 2015. Claims priority based on Korean Patent Application No. 10-2015-0052575, and Korean Patent Application No. 10-2015-0144855, filed October 16, 2015, and all other contents disclosed in the specification and drawings of that application. Is incorporated in this application.
본 발명은 용해성 마이크로니들에 관한 것으로, 신경전달물질의 방출을 제어하는 물질을 피부에 전달할 수 있는, 피부 투여 시스템에 관한 것이다. FIELD OF THE INVENTION The present invention relates to soluble microneedles and relates to skin administration systems capable of delivering to the skin a substance that controls the release of neurotransmitters.
피부를 통하여 약물을 전달하는 것은 이의 사용 편리성으로 인하여, 다양한 분야 및 형태로 사용되고 있다. 이러한 피부를 통과하는 약물은, 주로 피부를 통하여 체순환계(systemic circulation)로 전달시키기 위한 것이나, 이외에도 아토피 치료제, 미백 또는 주름 개선용 화장품 등의 약물은 피부 자체의 기관에 전달시키려는 목적으로 사용되기도 한다. 이런 편리성 및 기능성에도 불구하고, 피부의 구조상 약물을 피부를 통과하여 전달하는 것에는 많은 어려움이 존재하여, 피부를 통과하는 약물을 개발하는 것이 쉽지 않다. 피부의 각질층은, 케라틴이 풍부한 각질세포로 이루어져 있는 브릭(brick) 구조와, 이러한 각질세포 사이를 세라마이드(ceramide), 지방산(fatty acid), 또는 왁스(wax) 등과 같은 지질이 채운 모르타르(mortar) 구조로 이루어져 있다. 이러한 구조는 장벽으로 역할하여 물질 투과성이 아주 낮은 특성을 가지게 된다. 500Da 이하의 저분자 구조 성분들만이 확산 방식에 의해서 피부 내로 전달될 수 있으며, 지질 친화성이 우수한 물질만이 피부를 통과할 수 있다. Delivering drugs through the skin has been used in a variety of fields and forms because of their ease of use. Drugs that pass through the skin are mainly intended for delivery through the skin to the systemic circulation, but in addition to drugs such as atopy treatments, whitening or anti-wrinkle cosmetics may be used for the purpose of delivery to the organs of the skin itself. . Despite these conveniences and functionalities, there are many difficulties in delivering drugs through the skin due to the structure of the skin, and it is not easy to develop drugs that cross the skin. The stratum corneum of the skin is a brick structure consisting of keratin-rich keratinocytes, and a mortar filled with lipids such as ceramide, fatty acids, or waxes between the keratinocytes. It consists of a structure. This structure acts as a barrier and has a very low material permeability. Only low molecular structure components of 500 Da or less can be delivered into the skin by diffusion, and only substances with good lipid affinity can pass through the skin.
한편 신경전달물질의 배출은, 신경전달물질을 함유하는 신경말단에 위치하는 시냅스 소포 (synaptic vesicle)와 시냅스전막(presynaptic membrane)이 융합된 후 두 경계 간의 통로가 형성됨에 의해 발생된다. 소포 단백질 VAMP(synaptobrevin)와 원형질막 결합단백질인 신택신(Syntaxin) 1a, SNAP-25로 이루어진 3종의 단백질 복합체인 SNARE 단백질(SNARE proteins)이 시냅스 소포와 시냅스 전막의 융합에 근원적인 힘을 제공한다. 여기서 시냅스 소포와 시냅스 전막 간의 막 융합에 의해 신경전달물질 배출 통로가 열리는 것은, 표적 막(target membrane)에 부착되어 있는 신택신 1a 단백질과 SNAP-25 단백질 2종의 복합체인 t-SNARE 및 소포(vesicle)에 부착되어 있는 v-SNARE의 작 용에 따른 결과이다. 상기 막 융합 시에는 지질이중층 (lipid bilayer)의 재배열이 일어나게 된다. 생체막들은 서로 강하게 밀어내므로, 이들 막은 자발적으로 융합되지 않고 외부에서 강한 힘이 주어져 막들 간의 반발력을 극복하여야 하는데, 이러한 힘을 제공하는 것이 SNARE 단백질인 것으로 알려졌다. 이와 같이 SNARE 복합체의 형성은 신경전달물질의 배출을 포함하는 세포외 배출작용(exocytosis)의 핵심 현상이다.On the other hand, the release of neurotransmitters is caused by the formation of a pathway between the two boundaries after the synaptic vesicle and the presynaptic membrane are fused at the nerve terminal containing the neurotransmitter. SNARE proteins, a protein complex consisting of the vesicle protein VAMP (synaptobrevin) and the plasma membrane binding proteins Syntaxin 1a and SNAP-25, provide a fundamental force for the fusion of synaptic vesicles with the entire synaptic membrane. . Herein, the neurotransmitter excretion pathway is opened by membrane fusion between synaptic vesicles and the synaptic epithelium, t-SNARE and vesicles (a complex of syntaxin 1a protein and SNAP-25 protein attached to the target membrane). This is the result of the operation of v-SNARE attached to the vesicle. When the membrane is fused, rearrangement of the lipid bilayer occurs. Since the biofilms push strongly against each other, these membranes are not spontaneously fused and have a strong force from outside to overcome the repulsion between the membranes, which is known to provide SNARE protein. As such, the formation of the SNARE complex is a key phenomenon of extracellular exocytosis, including the release of neurotransmitters.
최근 들어 상기 식물성 폴리페놀들이 신경전달물질 배출을 조절하여 보톡스와 유사한 효능을 발휘한다는 점을 이용하여 바르는 형태의 화장품이나 실제 보톡스를 사용할 수 없는 상황에 적용하려는 노력이 존재하나, 대부분의 폴리페놀류는 용해성이 좋지 않아, 화장료 제형 내에 함유시킬 수 있는 양이 제한적이며, 이에 따라 피부 투과량이 매우 낮아 효능을 나타내기 어려운 문제점이 존재하였다.Recently, efforts have been made to apply cosmetics or botox in a situation in which it is not possible to use botox by using the plant polyphenols, which control the neurotransmitter and exhibit similar effects to botox. Due to poor solubility, the amount that can be contained in the cosmetic formulation is limited, and thus there is a problem in that the amount of skin permeation is very low and the efficacy is difficult to be exhibited.
한편, 칼슘 채널 차단제(Calcium channel blocker)는 근육을 수축시키는 중요한 요소인 칼슘이 근육혈관섬유 세포로 들어가지 못하게 억제하는 작용을 하여 근육의 수축을 저하시키는 것으로 알려져 있다. 안면의 움직임은 피부 아래에 놓인 근육의 수축으로 인해 일어나며, 상이한 근육들이 얼굴의 다른 부분들을 움직일 수 있도록 되어 있다.On the other hand, calcium channel blocker (Calcium channel blocker) is known to reduce the contraction of the muscle by acting to inhibit the calcium, which is an important factor for contracting the muscle to enter the muscle vascular fiber cells. Facial movements are caused by the contraction of muscles under the skin, allowing different muscles to move different parts of the face.
이러한 칼슘 채널 차단제가 근육 수축을 저하시키고 이완 효과를 주기 위해서는 약물이 근육층까지 전달되어야 하기 때문에 화장품의 단순 도포로는 근육층까지 약물을 흡수시키기 어려워 그 효과가 미미한 문제가 있었다. In order to reduce the muscle contraction and to relax the muscles, the calcium channel blocker had to be delivered to the muscle layer, so that the simple application of cosmetics had difficulty in absorbing the drug to the muscle layer.
칼슘 채널 차단제를 피부에 주사할 경우 통증을 수반하고, 시술을 받아야 하기 때문에 개인이 사용하는데 제한될 수 있으며, 경구투여할 경우 전신에 영향을 미치게 되므로 부작용이 발생할 수 있다. Injecting calcium channel blockers into the skin can be limited to use by individuals because they involve pain and require treatment, and side effects can occur because oral administration affects the whole body.
주름 및 라인 개선을 위해 칼슘채널 차단제를 화장품에 함유시켜 피부에 전달하려는 시도는 있으나, 아직까지 피부 투과 개선을 고려하고 있지는 않는 실정이다.There are attempts to deliver calcium channel blockers to cosmetics to improve wrinkles and lines to the skin, but there are no considerations for improving skin permeation.
따라서 본 발명이 해결하고자 하는 과제는 피부 투과량이 우수한 용해성 마이크로니들을 제공하고자 한다. Therefore, the problem to be solved by the present invention is to provide a soluble microneedle excellent skin penetration amount.
신경전달을 차단하여 주름개선 효과가 우수한 성분을 용해성 마이크로니들에 함침시켜, 피부에 적용하여 미세바늘에 의해 통증없이 피부 내로 투과되고, 미세바늘이 피부 내 수분에 의해 용해되면서 및 약물을 피부 내로 전달되는 용해성 마이크로니들을 제공하고자 한다.It impregnates soluble microneedle with components that have excellent wrinkle improvement by blocking neurotransmission and are applied to skin without pain by microneedle and applied to skin, while microneedles are dissolved by moisture in skin and deliver drugs into skin. To provide a soluble microneedle.
본 발명은 미세바늘이 피부 내 수분에 의해 용해되면서 유효성분이 피부내로 전달될 수 있도록 한다. The present invention allows the effective needle to be delivered into the skin while the fine needle is dissolved by the water in the skin.
본 발명은 피부내로 전달된 유효성분이 신경전달물질 방출을 차단하여 근육을 이완시켜 주름 및 얼굴 라인을 개선시키고 통증을 억제하고자 한다. The present invention aims to reduce the release of neurotransmitter by the active ingredient delivered into the skin to relax the muscles to improve wrinkles and facial lines and to suppress pain.
본 발명은 일반 화장료 조성물에서 용해성이 좋지 못하여 폴리페놀류의 사용량에 제한이 있었던 문제를 해소하고, 폴리페놀류의 용해도를 향상시켜 피부에 적용할 수 있는 피부 전달 시스템을 제공하고자 한다.The present invention is to solve the problem that the solubility is not good in the general cosmetic composition limited the amount of polyphenols used, improve the solubility of polyphenols to provide a skin delivery system that can be applied to the skin.
상기 과제를 해결하기 위하여, 본 발명은 신경전달물질의 배출을 조절하는 성분을 포함하는 마이크로니들을 제공하며, 바람직하게 상기 마이크로니들은 용해성 마이크로니들이다.In order to solve the above problems, the present invention provides a microneedle comprising a component for controlling the release of neurotransmitter, preferably the microneedle is a soluble microneedle.
상기 신경전달물질의 배출을 조절하는 성분은 i) 폴리페놀 또는 이의 유도체, ii) 칼슘 채널 차단제, 또는 iii) 이들의 혼합물일 수 있다. The component that modulates the release of neurotransmitters may be i) polyphenols or derivatives thereof, ii) calcium channel blockers, or iii) mixtures thereof.
본 발명의 일 실시예에 따르면, 상기 마이크로니들은 바람직하게 본 발명은 신경전달물질의 배출을 조절하는 성분을 함유하며, 주름 개선 효과를 갖는 마이크로니들을 제공한다. 상기 마이크로니들을 형성하는 물질은 피부 내에서 용해되거나 생분해성일 수 있으며, 상기 마이크로니들은 피부 적용 시 마이크로니들이 용해 또는 붕괴됨으로써 신경전달물질의 배출을 조절하는 성분이 방출되며, 상기 신경전달물질의 배출을 조절하는 성분이 안정적으로 피부로 전달할 수 있게 된다.According to one embodiment of the invention, the microneedle preferably contains the microneedle containing a component for controlling the release of neurotransmitter, and has a wrinkle improvement effect. The material forming the microneedles may be dissolved or biodegradable in the skin, and the microneedles are dissolved or decayed when the microneedles are applied to the skin, thereby releasing components that control the release of the neurotransmitter, and the release of the neurotransmitter. Ingredients that regulate the ability to be delivered to the skin stably.
본 발명의 일 실시예에 따르면 상기 마이크로니들에 포함되는 성분은 폴리페놀 또는 이의 유도체를 포함한다.According to an embodiment of the present invention, the components included in the microneedle include polyphenols or derivatives thereof.
본 발명자들은 다양한 투여 시스템을 연구하였으며 어떠한 시스템도 상기 언급한 바와 같이, 폴리페놀은 용해도가 낮아 일반 화장품에 적용하여 피부에 도포하는 것만으로는 적용에 한계가 있었다. 본 발명자들은 여러 노력 끝에 피부 내 용해성(soluble) 마이크로니들 내에 폴리페놀을 함유함으로써 효과적으로 신경전달 물질의 전달을 감소시켜 주름 개선 효과를 나타낼 수 있는 놀라운 발명을 하였다. The present inventors have studied a variety of administration systems, and as mentioned above, any system has a low solubility, and thus the application of the polyphenol to the general cosmetics is limited only by application to the skin. The inventors have made a surprising invention that, after various efforts, by containing polyphenols in the soluble microneedle in the skin, it can effectively reduce the transmission of neurotransmitters to exhibit wrinkle improvement.
위와 같은 과제를 달성하기 위해, 마이크로니들은 피부 내에서 용해성이어야 하며, 용해성 마이크로니들을 형성하기 위해서 히얄루로닉산 (Hyaluronic acid), 소디움-카르복시메틸 셀룰로오스 (Na-CMC, Sodium carboxymethyl cellulose), 비닐피롤리돈-비닐아세테이트 공중합체, 폴리비닐알코올(Poly vinyl alcohol), 및 폴리비닐피릴리돈(Poly vinyl pyrrolidone) 등의 수용성 고분자; 자일로즈(Xylose), 수크로스(Sucrose), 말토오스(Maltose), 락토오스(Lactose), 트레할로스(Trehalose) 등의 당류; 또는 이들의 혼합물이 사용될 수 있다. 특히, 마이크로니들의 피부 투과 강도, 피부 내에서의 용해속도 등을 종합적으로 고려하면 히얄루로닉산 (Oligo-Hyaluronic acid), 소디움-카르복시메틸 셀룰로오스 (Na-CMC, Sodium carboxymethyl cellulose), 및 당류 (saccharide) (더욱 바람직하게는, 트레할로스(Trehalose))의 혼합물이 더욱 바람직하며, 후술하는 글리세린(Glycerine)까지 혼합된 것이 더욱더 바람직하다. 바람직하게, 본 발명에 따른 마이크로니들은 마이크로니들을 형성하는 상기 언급된 성분들 이외에 가소제, 계면활성제, 보존제, 항염제 등을 추가적으로 포함할 수 있다.To achieve this task, microneedles must be soluble in the skin, and hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) and vinyl blood to form soluble microneedles. Water-soluble polymers such as a rollidone-vinylacetate copolymer, poly vinyl alcohol, and poly vinyl pyrrolidone; Sugars such as xylose, sucrose, maltose, lactose, trehalose and the like; Or mixtures thereof may be used. In particular, considering the skin penetration intensity of microneedles and the dissolution rate in the skin, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and sugars (More preferably, a mixture of trehalose) is further preferred, and even more preferably mixed up to glycerin, which will be described later. 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 forming the microneedle.
상기 가소제(plasticizer)로는, 예를 들어, 에틸렌 글리콜(Ethylene glycol), 프로필렌 글리콜(Propylene glycol), 디프로필렌 글리콜(Dipropylene glycole), 뷰틸렌 글리콜(Butylene glycol), 글리세린(Glycerine) 등의 폴리올이 단독으로 또는 혼합하여 사용될 수 있다.As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone. Or may be used in admixture.
바람직하게, 본 발명의 마이크로니들은 신경전달물질 배출을 조절하며, 주름 개선 효과를 갖는 폴리페놀을 마이크로니들 총 중량 대비 0.01 내지 10 중량% 함유하며, 더욱 바람직하게는 0.1 내지 5 중량% 함유할 수 있다. Preferably, the microneedle of the present invention controls the neurotransmitter discharge, and may contain 0.01 to 10% by weight, more preferably 0.1 to 5% by weight of polyphenol having a wrinkle improvement effect relative to the total weight of the microneedle. have.
상기 마이크로니들은 폴리페놀 성분을 고함량 포함할 수 있으며, 피부에 전달되는 양이 일반적인 화장료 조성물의 제형에 비해 월등히 증가된 폴리페놀 피부 전달 시스템을 제공할 수 있다. The microneedle may comprise a high content of polyphenol components and may provide a polyphenol skin delivery system in which the amount delivered to the skin is significantly increased compared to formulations of common cosmetic compositions.
폴리페놀 성분은 용해성이 좋지 못하여 화장료 조성물에 함유되는 양이 극히 적었으나, 본 발명의 마이크로니들은 물의 함량이 극히 적어 폴리페놀 성분의 석출없이 마이크롤니들에 고함량 적용하여 피부에 전달할 수 있다. The polyphenol component was poorly soluble, so that the amount contained in the cosmetic composition was extremely low, but the microneedle of the present invention was extremely low in water so that it could be delivered to the skin by applying a high content to the microroll needle without precipitation of the polyphenol component.
상기 폴리페놀은 캠페롤, 케르세틴, 미리세틴, 루테올린, 델치니딘, 시아니딘, 부테인, 엘라지산, 암펠롭신, 헤스피리딘, 아우란티니딘(Aurantinidin), 유로피니딘(Europinidin), 펠라고니딘(Pelargonidin), 말비딘(Malvidin), 페오니딘(Pheonidin), 페투니딘(Petunidin), 및 로시니딘(Rosinidin) 및 이들의 유도체들로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 바람직하게는 암펠롭신, 헤스페리딘 또는 이의 유도체로 이루어진 군에서 선택된 어느 하나 이상일 수 있다. The polyphenols are camphorol, quercetin, myricetin, luteolin, delchinidine, cyanidin, butane, ellagic acid, ampelopsin, hesperydine, aurantinidin, europinidin, pella May be at least one selected from the group consisting of Peargonidin, Malvidin, Peonidin, Peunidin, Petunidin, and Rossinidin, and derivatives thereof. May be any one or more selected from the group consisting of ampelopsin, hesperidin or derivatives thereof.
본 명세서에서 상기 폴리페놀의 유도체는 유리형태(유리 산 또는 염기 형태) 및 모든 프로드러그(prodrug), 다형체(polymorph), 수화물(hydrate), 용매화물(solvate), 토토머(tautomer), 입체이성질체(stereoisomer) 등 달리 특정하지 않는다면 상기한 바와 같은 모든 약학적으로 허용 가능한 형태를 포함하며, 상기 화합물의 모든 활성 형태를 포함하는 의미로 사용된다. 본 발명의 일 실시예에 따른, 폴리페놀을 함유하는 마이크로니들은 SNARE의 복합체 형성을 저해하여 막융합을 저해하고, 그 결과 신경전달물질, 예를 들어, 아세틸콜린의 방출을 저해하여, 근육세포의 수축을 억제할 수 있다. Derivatives of the polyphenols herein are free form (free acid or base form) and all prodrugs, polymorphs, hydrates, solvates, tautomers, steric Unless otherwise specified, isomers include all pharmaceutically acceptable forms as described above and are used in the sense to include all active forms of the compounds. In accordance with an embodiment of the present invention, the microneedle containing polyphenols inhibits the formation of SNARE complexes and inhibits membrane fusion. As a result, the microneedles inhibit the release of neurotransmitters such as acetylcholine. Shrinkage can be suppressed.
또한, 본 발명은 위와 같은 마이크로니들이 부착되어 있는 폴리페놀 또는 이의 유도체 투여용(전달용) 마이크로니들 패치(patch) 시스템을 제공한다.In addition, the present invention provides a microneedle patch system for administration (delivery) of polyphenols or derivatives thereof to which the microneedle is attached.
본 발명의 마이크로니들은 업계의 통상적인 용해성 마이크로니들을 제조하는 방법으로 제조될 수 있으며, 제조방법은 특별히 제한되지 않는다. The microneedles of the present invention can be prepared by a method of manufacturing conventional soluble microneedles in the art, and the production method is not particularly limited.
예를 들어, 본 발명의 마이크로니들 제조방법은 (S1) 신경전달물질의 배출을펩타조절하는 성분(예를 들어, 칼슘 채널 차단제, 폴리페놀 또는 이의 유도체, 또는 이들의 혼합물)을 포함하는 용액을 제조하는 단계; (S2) 상기 용액을 마이크로니들 몰드에 주입하는 단계; 및 (S3) 건조 하는 단계 및 상기 몰드로부터 마이크로니들을 분리하는 단계를 포함할 수 있다. For example, the microneedle manufacturing method of the present invention (S1) is a solution containing a component (for example, calcium channel blocker, polyphenol or derivatives thereof, or mixtures thereof) to control the release of neurotransmitters. Manufacturing step; (S2) injecting the solution into the microneedle mold; And (S3) drying and separating the microneedle from the mold.
본 발명은 또한 본 발명에 따른 마이크로니들을 이용하는 것을 특징으로 하는 용해도가 향상되고, 피부 전달율이 향상된 폴리페놀의 피부 투여 방법을 제공한다.The present invention also provides a method for administering the skin of polyphenols having improved solubility and improved skin delivery, characterized by using the microneedle according to the present invention.
또한 본 발명은 상기 신경전달물질 배출을 조절하며, 주름 개선 효과를 갖는 폴리페놀을 함유하는 마이크로니들의 주름 개선 용도를 제공한다.In another aspect, the present invention provides a wrinkle improvement use of the microneedle containing the polyphenol having the effect of improving the wrinkles, and control the neurotransmitter discharge.
본 발명의 일 실시예에 따르면, 본 발명은 폴리페놀을 함유하며, SNARE 복합체 형성을 저해하는 마이크로니들을 제공한다.According to one embodiment of the present invention, the present invention provides microneedles containing polyphenols and inhibiting SNARE complex formation.
본 발명의 다른 실시예에 따르면 본 발명은 신경전달물질의 배출을 조절하는 성분이 포함된 마이크로니들의 피부 주름 개선 용도를 제공한다. According to another embodiment of the present invention the present invention provides a skin wrinkle improvement of the microneedle containing a component for controlling the release of neurotransmitter.
또 다른 실시예에 따르면, 본 발명은 칼슘 채널 차단제를 함유하며, 근육 이완 작용을 통해 주름 개선 효과 또는 얼굴 윤곽 개선 효과를 갖는 마이크로니들을 제공한다. 보다 바람직하게, 상기 마이크로니들을 형성하는 물질은 피부 내에서 용해되어 마이크로니들의 피부 적용 시 마이크로니들이 용해 또는 붕괴됨으로써 칼슘 채널 차단제가 방출되며, 상기 칼슘 채널 차단제가 안정적으로 피부로 전달할 수 있게 된다.According to yet another embodiment, the present invention provides a microneedle containing a calcium channel blocker, and has an effect of improving wrinkles or improving facial contour through muscle relaxation. More preferably, the material forming the microneedle is dissolved in the skin to release or disintegrate the calcium channel blocker upon application of the microneedle to the skin, and the calcium channel blocker can be stably delivered to the skin.
본 발명자들은 다양한 투여 시스템을 연구하였으며 여러 노력 끝에 피부 내 용해성(soluble) 마이크로니들 내에 칼슘 채널 차단제를 함유함으로써 효과적으로 신경전달 물질의 전달을 감소시켜 근육의 축소를 저해하고, 피부의 주름 개선 효과 또는 얼굴 윤곽을 개선하여 리프팅 효과를 나타낼 수 있는 놀라운 발명을 하였다. The inventors have studied a variety of dosage systems and have, after many efforts, contained calcium channel blockers in soluble microneedles in the skin, effectively reducing the delivery of neurotransmitters, inhibiting muscle contraction, and improving skin wrinkles or facial The contours have been improved to create an amazing invention that can produce lifting effects.
크림, 로션 등과 같은 화장품 제형에 칼슘 채널 차단제를 함유하여 도포하는 경우, 피부 침투력이 좋지 않아 효과 발현이 제대로 이루어지지 않았고, 주사를 이용하는 경우 가정에서 개인이 적용할 수 없는 단점이 있었다. 본 발명자는 이러한 문제점을 해소하면서 통증없이 간편하게 피부 주름 개선 효과를 얻을 수 있는 방안을 모색한 결과 본 발명을 완성하게 되었다. When applied to the cosmetic formulations such as creams, lotions, etc. containing a calcium channel blocker, the poor skin penetration effect was not achieved properly, when using the injection there was a disadvantage that can not be applied to individuals at home. The present inventors have completed the present invention as a result of finding a way to easily improve the skin wrinkles without pain while solving these problems.
위와 같은 과제를 달성하기 위해, 마이크로니들은 피부 내에서 용해성이어야 하며, 용해성 마이크로니들을 형성하기 위해서 히얄루로닉산 (Hyaluronic acid), 소디움-카르복시메틸 셀룰로오스 (Na-CMC, Sodium carboxymethyl cellulose), 비닐피롤리돈-비닐아세테이트 공중합체, 폴리비닐알코올(Poly vinyl alcohol), 및 폴리비닐피릴리돈(Poly vinyl pyrrolidone) 등의 수용성 고분자; 자일로즈(Xylose), 수크로스(Sucrose), 말토오스(Maltose), 락토오스(Lactose), 트레할로스(Trehalose) 등의 당류; 또는 이들의 혼합물이 사용될 수 있다. 특히, 마이크로니들의 피부 투과 강도, 피부 내에서의 용해속도 등을 종합적으로 고려하면 히얄루로닉산 (Oligo-Hyaluronic acid), 소디움-카르복시메틸 셀룰로오스 (Na-CMC, Sodium carboxymethyl cellulose), 및 당류 (saccharide) (더욱 바람직하게는, 트레할로스(Trehalose))의 혼합물이 더욱 바람직하며, 후술하는 글리세린(Glycerine)까지 혼합된 것이 더욱더 바람직하다. 바람직하게, 본 발명에 따른 마이크로니들은 마이크로니들을 형성하는 상기 언급된 성분들 이외에 가소제, 계면활성제, 보존제, 항염제 등을 추가적으로 포함할 수 있다.To achieve this task, microneedles must be soluble in the skin, and hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) and vinyl blood to form soluble microneedles. Water-soluble polymers such as a rollidone-vinylacetate copolymer, poly vinyl alcohol, and poly vinyl pyrrolidone; Sugars such as xylose, sucrose, maltose, lactose, trehalose and the like; Or mixtures thereof may be used. In particular, considering the skin penetration intensity of microneedles and the dissolution rate in the skin, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and sugars (More preferably, a mixture of trehalose) is further preferred, and even more preferably mixed up to glycerin, which will be described later. 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 forming the microneedle.
상기 가소제(plasticizer)로는, 예를 들어, 에틸렌 글리콜(Ethylene glycol), 프로필렌 글리콜(Propylene glycol), 디프로필렌 글리콜(Dipropylene glycole), 뷰틸렌 글리콜(Butylene glycol), 글리세린(Glycerine) 등의 폴리올이 단독으로 또는 혼합하여 사용될 수 있다.As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone. Or may be used in admixture.
바람직하게, 본 발명의 마이크로니들은 신경전달 물질의 방출을 제어하고, 피부 근육 수축을 제어할 수 있는 칼슘 채널 차단제를 마이크로니들 제조 용액 총 중량 대비 0.0001 내지 20 중량% 함유하며, 더욱 바람직하게는 0.001 내지 5 중량% 함유한다.Preferably, the microneedle of the present invention contains 0.0001 to 20% by weight of calcium channel blocker to the total weight of the microneedle preparation solution, and more preferably 0.001 to control the release of neurotransmitter and control skin muscle contraction. To 5% by weight.
본 명세서에서 사용된 "칼슘 채널 차단제"는 칼슘 길항제라고도 하며, 칼슘이 근육 내로 유입되는 것을 차단하여 근육 수축을 억제하는 물질을 의미한다. 상기 칼슘 채널 차단제는 쿠퍼글루코네이트(copper gluconate), 징크글루코네이트(zinc gluconate), 마그네슘설페이트(Magnesium Sulfate), 마그네슘글루코네이트(magnesium gluconate) 및 마그네슘아스파테이트(magnesium aspatate)로 이루어진 군에서 1종 이상 선택되는 유기 금속 화합물; 암로디핀, 레르카니디핀, 펠로디핀, 니페디핀, 니카르디핀, 이스라디핀, 니솔디핀 및 이의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 어느 하나 이상의 디하이드로피리딘계 칼슘 채널 차단제; 베라파밀을 포함하는 페닐알킬아민계 칼슘 채널 차단제; 디티아젬을 포함하는 벤조티아핀계 칼슘 채널 차단제; 및 가바펜티노이드(gabapentinoid) 및 징코노티드(zinconotide) 로 이루어진 군에서 선택된 N-타입 칼슘채널 차단제; 로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 칼슘 채널으로 유입되는 칼슘을 차단하여 근육 이완 작용을 할 수 있는 물질이라면 모두 포함될 수 있으며, 종류는 특별하게 제한되지 않는다. As used herein, a "calcium channel blocker" is also referred to as a calcium antagonist and refers to a substance that blocks calcium from entering the muscle and thereby inhibits muscle contraction. The calcium channel blocker is at least one member of the group consisting of copper gluconate, zinc gluconate, magnesium sulfate, magnesium gluconate and magnesium aspatate. Organometallic compounds selected; At least one dihydropyridine calcium channel blocker selected from the group consisting of amlodipine, lercanidipine, felodipine, nifedipine, nicardipine, isradinine, nisoldipine and pharmaceutically acceptable salts thereof; Phenylalkylamine based calcium channel blockers including verapamil; Benzothiapine-based calcium channel blockers including dithiazem; And N-type calcium channel blockers selected from the group consisting of gabapentinoids and zinconotides; It may be any one or more selected from the group consisting of, any material capable of muscle relaxation by blocking calcium flowing into the calcium channel may be included, and the type is not particularly limited.
상기 칼슘 채널 차단제는 바람직하게 마그네슘글루코네이트를 이용할 수 있다.The calcium channel blocker may preferably use magnesium gluconate.
또한, 본 발명은 위와 같은 마이크로니들이 부착되어 있는 신경전달물질의 배출을 조절하는 성분이 포함된 마이크로니들 패치 시스템, 바람직하게 칼슘 채널 차단제 투여용(전달용) 마이크로니들 패치(patch) 시스템을 제공한다.In addition, the present invention provides a microneedle patch system, preferably a microneedle patch system for calcium channel blocker administration (for delivery), comprising a component for controlling the release of neurotransmitters to which the microneedle is attached. .
본 발명은 또한 본 발명에 따른 마이크로니들을 이용하는 것을 특징으로 하는, 피부 전달율이 향상된 신경전달물질의 배출을 조절하는 성분의 피부 투여 방법, 바람직하게 칼슘 채널 차단제의 피부 투여 방법을 제공한다.The present invention also provides a method of skin administration of a component for controlling the release of neurotransmitters with improved skin delivery rate, preferably a method of skin administration of a calcium channel blocker, characterized in using the microneedle according to the invention.
또한 본 발명은 상기 신경전달물질의 배출을 조절하는 성분이 포함된 마이크로니들을 포함하는, 얼굴 근육 이완용 마이크로니들 및 이의 얼굴 근육 이완 용도를 제공한다. In another aspect, the present invention provides a microneedle for facial muscle relaxation and its facial muscle relaxation uses, including a microneedle containing a component for controlling the discharge of the neurotransmitter.
상기 얼굴 근육 이완용은 피부의 근육 수축을 억제하여 주름을 개선하는 용도, 얼굴의 윤곽을 개선하는 용도, 피부의 처짐을 방지하여 리프팅 효과를 갖는 용도를 포함하는 개념이다.The facial muscle relaxation is a concept including the use of improving the wrinkles by inhibiting the muscle contraction of the skin, the use of improving the contour of the face, the use of having a lifting effect by preventing the sagging of the skin.
본 발명의 일 실시예에 따르면, 본 발명의 마이크로니들을 이용하는 신경전달물질의 배출을 조절하는 성분의 피부 투여 방법, 바람직하게 주름 개선용 칼슘 채널 차단제의 피부 투여 방법을 제공한다. According to an embodiment of the present invention, there is provided a method of skin administration of a component for controlling the release of neurotransmitters using the microneedle of the present invention, preferably a method of skin administration of a calcium channel blocker for wrinkle improvement.
본 발명은 피부 주름 개선 효과를 갖는 마이크로니들을 제공한다. The present invention provides a microneedle having a skin wrinkle improvement effect.
본 발명은 주름 개선 효과를 갖는 폴리페놀의 피부 투과 효율을 향상시킬 수 있는, 피부 투여용 마이크로니들을 제공한다. 본 발명은 또한 이러한 마이크로니들을 이용하는 것을 특징으로 하는 신경전달 물질의 배출을 조절하는 성분의 피부 투여 방법을 제공한다.The present invention provides a microneedle for skin administration, which can improve the skin permeation efficiency of the polyphenol having a wrinkle improvement effect. The present invention also provides a method for administering the skin of a component that modulates the release of neurotransmitter, characterized by using such microneedles.
본 발명은 피부 주름 개선 효과 또는 얼굴 윤곽 라인 개선 효과를 갖는 마이크로니들을 제공한다. The present invention provides a microneedle having a skin wrinkle improvement effect or facial contour line improvement effect.
본 발명은 미세바늘에 의해 통증 없이 피부내로 유효성분을 투과시킬 수 있다. The present invention can transmit the active ingredient into the skin without pain by the microneedle.
본 발명은 신경세포의 칼슘 채널을 억제하여 신경전달물질 방출을 차단하여 근육을 이완시켜 주름 및 얼굴 라인을 개선시킬 수 있다.The present invention can inhibit the calcium channel of nerve cells to block the release of neurotransmitters to relax the muscles to improve wrinkles and facial lines.
본 명세서에 첨부되는 다음의 도면들은 본 발명의 바람직한 실시예를 예시하는 것이며, 전술한 발명의 내용과 함께 본 발명의 기술사상을 더욱 이해시키는 역할을 하는 것이므로, 본 발명은 그러한 도면에 기재된 사항에만 한정되어 해석되어서는 아니 된다.The following drawings, which are attached to this specification, illustrate preferred embodiments of the present invention, and together with the contents of the present invention serve to further understand the technical spirit of the present invention, the present invention is limited to the matters described in such drawings. It should not be construed as limited.
도 1은 본 발명에 따른 마이크로니들을 제조하는 여러 방법 중 일 예를 보여주는 도면이다. 용해성 마이크로니들은 solution casting 방법으로 제조될 수 있으며, solution을 mold에 casting하여 진공 및/또는 centrifuge로 미세 mold에 액을 채운후 건조하여 제조할 수 있다. 마이크로니들 구조체를 형성하는 material은 일반적인 합성 및 천연 수용성 고분자가 사용될 수 있다.1 is a view showing an example of several methods for manufacturing a microneedle according to the present invention. The soluble microneedle may be prepared by a solution casting method, and the solution may be cast into a mold to fill a fine mold with a vacuum and / or centrifuge, followed by drying. As the material forming the microneedle structure, general synthetic and natural water-soluble polymers may be used.
도 2는 본 발명에 따른 마이크로니들의 약물 방출 거동을 평가하기 위한 Franz diffusion cell을 나타낸다. Figure 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedle according to the present invention.
도 3은 본 발명의 보톡스 유사 효과를 갖는 폴리페놀을 예시적으로 나타낸 것이다. 미리세틴, 델치니딘, 시아니딘, 캠페롤, 케르세틴, 피세틴, 부테인, 루테올린, 엘라지산, EGCG(Epigallocatechin gallate), 암펠롭신, 헤스페리딘 및 이의 유도체들이 이용될 수 있다. 3 exemplarily shows a polyphenol having a Botox-like effect of the present invention. Myricetin, delchinidine, cyanidin, camphorol, quercetin, pisetin, butane, luteolin, ellagic acid, EGCG (Epigallocatechin gallate), ampfellopsin, hesperidin and derivatives thereof can be used.
도 4는 캠페롤, 미리세틴, 및 암펠롭신의 SNARE 형성 저해 확인 결과를 나타낸다. (Cell line: C2C12(근육세포)+NG108-15(신경세포) 조건, 농도: ppm)Figure 4 shows the results confirmed the inhibition of SNARE formation of camphorol, myricetin, and ampelopsin. (Cell line: C2C12 (muscle cell) + NG108-15 (nerve cell) condition, concentration: ppm)
도 5는 돼지 피부 및 acceptor solution 내 암펠롭신 함량을 비교한 결과를 나타낸 그래프이다. Figure 5 is a graph showing the results of comparing the ampelopsin content in pig skin and acceptor solution.
도 6은 인체를 대상으로 암펠롭신 크림과 암펠롭신 마이크로니들의 주름개선 효과를 확인한 결과를 나타낸 그래프이다. Figure 6 is a graph showing the results of confirming the wrinkle improvement effect of the Amfellopsin cream and Amfellopsin microneedle in the human body.
도 7은 캠페롤, 미리세틴, 및 암펠롭신의 근수축 억제 효과를 확인한 결과를 나타낸다.Fig. 7 shows the results of confirming the muscle contraction inhibitory effect of camphorol, myricetin, and ampelopsin.
도 8은 마그네슘글루코네이트 크림 및 마그네슘글루코네이트 마이크로니들의 돼지 피부 및 acceptor solution 내에서 마그네슘글루코네이트 함량을 확인한 그래프이다.8 is a graph confirming magnesium gluconate content in pig skin and acceptor solution of magnesium gluconate cream and magnesium gluconate microneedle.
도 9는 마그네슘글루코네이트의 In Vitro 근수축 저해 효과 측정 결과를 나타낸 것이다. In vitro에서 근세포와 신경아세포를 공동 배양하고 마그네슘 글루코네이트를 농도별로 처리하고 난 뒤 10분 후 근수축 횟수가 줄어드는 결과를 관찰한 결과를 나타낸다. Figure 9 shows the results of measuring the inhibitory effect of In Vitro muscle contraction of magnesium gluconate. After incubation of myocytes and neuroblasts in vitro and treatment of magnesium gluconate by concentration, the results show that the number of muscle contractions decreases after 10 minutes.
도 10은 마그네슘글루코네이트 크림과 마그네슘글루코네이트 마이크로니들의 주름 개선 지수를 그래프로 나타낸 것이다.Figure 10 graphically shows the wrinkle improvement index of magnesium gluconate cream and magnesium gluconate microneedle.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다. Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<Soluble Micro Needle 제조><Soluble Micro Needle Manufacturing>
Soluble Micro Needle은 solution casting 방법으로 제조되며, solution을 mold에 casting하여 진공 혹은 centrifuge로 미세 mold에 액을 채운 후 건조하여 제조하고 이때 Micro Needle 구조체를 형성하는 material은 일반적인 합성 및 천연 수용성 고분자를 사용하였다.Soluble Micro Needle is manufactured by solution casting method. The solution is cast into a mold, filled with liquid in a micro mold by vacuum or centrifuge, and then dried. At this time, general synthetic and natural water-soluble polymers are used to form the micro needle structure. .
<SNARE형성 억제 폴리페놀 Microneedle 제조><Preparation of SNARE Formation Polyphenol Microneedle>
하기 표 1의 조성을 갖는 마이크로니들을 제조하였다. Hyaluronic acid (Oligo-HA™), Sodium carboxymethyl cellulose (Na-CMC) 및 Trehalose를 정제수에 용해한 후 Glycerin, PEG-40 hydrogenated castor oil (HCO-40™) 및 암펠롭신 용액(암펠롭신 10%, DPG 90%)을 첨가하여, 암펠롭신 용액을 제조하였다 (DPG: Dipropylene glycol). 제조한 폴리페놀 분산 용액을 Silicone Micro Needle mold에 casting 한 후, 3,000 rpm에서 10분간 centrifugation 하여 미세 mold에 액을 충진하였다.To prepare a microneedle having the composition of Table 1. Dissolve Hyaluronic acid (Oligo-HA ™), Sodium carboxymethyl cellulose (Na-CMC) and Trehalose in purified water, and then use a solution of Glycerin, PEG-40 hydrogenated castor oil (HCO-40 ™) and Amfellopsin (10% Amfellopsin, DPG 90). %) Was added to prepare an amfellopsin solution (DPG: Dipropylene glycol). The prepared polyphenol dispersion solution was cast on a silicone micro needle mold, and then centrifuged at 3,000 rpm for 10 minutes to fill the liquid in the micro mold.
용액 충진 후 건조 오븐 (70℃ )에서 3시간 동안 건조하고, 접착 필름을 이용하여 Micro Needle을 silicone mold로부터 분리하였다. 하기 표 1의 함량은 중량%로 나타냈다.After the solution was filled and dried in a drying oven (70 ° C.) for 3 hours, the micro needle was separated from the silicone mold using an adhesive film. The content of Table 1 is expressed in weight percent.
제조과정은 도 1에 나타냈다. The manufacturing process is shown in FIG.
Figure PCTKR2016003845-appb-T000001
Figure PCTKR2016003845-appb-T000001
<SNARE형성 억제 폴리페놀 수중유화제형(Oil-in-Water) 크림 제조><Preparation of SNARE Formation Polyphenol Oil-in-Water Cream>
Microneedle에 함침된 폴리페놀의 피부 투과량을 비교하기 위하여, 비교예로 일반적인 수중유화제형의 크림에 폴리페놀의 함침하여 비교하였다.In order to compare the skin permeation amount of the polyphenol impregnated with the microneedle, the polyphenol was impregnated and compared with a general oil-in-oil type cream as a comparative example.
Figure PCTKR2016003845-appb-T000002
Figure PCTKR2016003845-appb-T000002
<약물 방출 거동><Drug Release Behavior>
돼지 피부를 장착한 Franz diffusion cell을 이용하여 위에서 제조한 마이크로니들로부터의 암펠롭신 방출을 평가하였다 (도 2 참조). 수용액(acceptor solution)으로는 30 중량%의 DPG가 함유된 PBS 용액을 사용하였다.Amphelopsin release from the microneedle prepared above was evaluated using a Franz diffusion cell equipped with pig skin (see FIG. 2). As an aqueous solution (acceptor solution) was used a PBS solution containing 30% by weight of DPG.
즉, Franz diffusion cell을 이용하여, 시간에 따른 돼지피부 조직 및 acceptor solution의 암펠롭신 함량을 Liquid Chromatography를 이용하여 측정하였다. In other words, using a Franz diffusion cell, the ampelopsin content of the pig skin tissue and acceptor solution over time was measured using Liquid Chromatography.
암펠롭신을 포함한 크림은 피부를 통해 투과되는 양이 미미하였으나, Micro Needle에 함침된 암펠롭신은 Needle에 의해 피부로 직접 투과하여 그 투과량이 크림 대비 높은 피부 투과량을 나타내었다. The cream containing ampelopsin was minimal in permeation through the skin, but the ampoulescin impregnated in the Micro Needle penetrated directly into the skin by the needle, and the permeation amount was higher than that of the cream.
암펠롭신을 포함한 크림은 피부를 통해 투과되는 양이 약 1ug으로 그 양이 미미하였으나, Microneedle에 함침된 폴리페놀은 Needle에 의해 피부로 직접 투과하여 그 투과량이 13ug 이상으로 약 13배 이상 크림 대비 높은 피부 투과량을 나타내었다. 그 결과를 도 5에 나타냈다.Cream containing ampelopsin was about 1ug permeated through the skin, but the amount was small.However, polyphenol impregnated in the microneedle penetrated directly into the skin by the needle, and its permeation amount was 13ug or more, which was 13 times higher than the cream. Skin permeation amount is shown. The result is shown in FIG.
<주름 개선 효과><Wrinkle improvement effect>
암펠롭신 크림과 암펠롭신이 함침된 Microneedle을 눈가 주름에 12주간 매일 처리하여, 주름 개선 정도를 실리콘 모사판(silicone replica) 및 주름 영상 분석 방법으로 통해 확인하였다. (N=20)Ampelopsin cream and Ampelopsin-impregnated Microneedle were treated daily for 12 weeks on the wrinkles of the eyes, and the degree of wrinkle improvement was confirmed by a silicone replica and a wrinkle image analysis method. (N = 20)
암펠롭신 크림에 비해 암펠롭신이 함침된 Microneeedle에서 5배 이상 우수한 개선효과를 보였으며, 이는 암펠롭신이 Microneedle에 의해 피부내로 효과적으로 침투하여, 주름 개선 효과가 높게 나타난 것을 확인하였다. 이러한 결과는 도 6에 나타냈다.Compared to ampellopsin cream, ampellopsin-impregnated microneeedle showed more than 5 times better improvement, and it was confirmed that ampelopsin was effectively penetrated into the skin by the microneedle, resulting in a high wrinkle improvement effect. These results are shown in FIG.
<SNARE complex 형성 저해 실험>Inhibition of SNARE complex formation
암펠롭신, 캠페롤, 미리세틴 등 폴리페놀의 SNARE 복합체 형성 저해 여부를 확인하기 위해, SDS-PAGE (Sodium dodecyl sulfate-polyacrylamide gel electrophoresis) 분석을 수행하였다. SNARE 단백질인 SNAP25, SynH3, Vps 단백질을 1:1:1의 몰 농도로 혼합했을 때 형성되는 복합체가, 1 - 50 ppm의 농도로 폴리페놀 화합물 첨가에 의해 억제되는지를 확인하였다. 각각의 단백질을 1ml 튜브에 점적한 후 폴리페놀 화합물을 넣어 혼합 후 실온에서 30분간 반응시켰다. 이 후 12% SDS-PAGE상에서 전기영동하여 SNARE 복합체 형성 여부를 확인하였다.Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis was performed to determine whether the polyphenols such as ampelopsin, camphorol and myricetin inhibit SNARE complex formation. It was confirmed whether the complex formed when the SNARE25, SynH3, and Vps proteins, SNARE proteins, were mixed at a molar concentration of 1: 1: 1 was inhibited by the addition of a polyphenol compound at a concentration of 1-50 ppm. Each protein was dropped into a 1 ml tube, and then mixed with a polyphenol compound, followed by reaction at room temperature for 30 minutes. Thereafter, electrophoresis on 12% SDS-PAGE confirmed the formation of SNARE complexes.
캠페롤, 미리세틴, 암펠롭신 모두 농도 의존적으로 SNARE 복합체를 효과적으로 저해하는 것이 확인되었다. 실험결과 미리세틴에 비해 캠페롤과 암펠롭신이 낮은 농도에서 SNARE 복합체 형성 억제 능력이 활발한 것을 확인할 수 있었다. 미리세틴, 암펠롭신(디하이드록시미리세틴), 캠페롤, A440의 SNARE 형성 저해 효과를 확인하여 도 4에 나타냈다. (Cell line: C2C12(근육세포)+NG108-15(신경세포) 조건, 농도: ppm)Camperol, myricetin and ampelopsin have all been found to effectively inhibit the SNARE complex in a concentration dependent manner. As a result, it was confirmed that the activity of inhibiting SNARE complex formation at low concentrations of camphorol and ampelopsin was higher than that of myricetin. Inhibition of SNARE formation of myricetin, ampfellopsin (dihydroxymyricetin), camphorol, and A440 was confirmed and shown in FIG. 4. (Cell line: C2C12 (muscle cell) + NG108-15 (nerve cell) condition, concentration: ppm)
<근수축 억제 실험>Muscle contraction suppression experiment
C2C12세포를 플레이트에 10% 태아 송아지 혈청과 1% 항생물질이 들어간 DMEM배지에서 배양하였다. 이후 신경아세포를 같은 플레이트에 추가적으로 공동 배양하였다. 이후 C2C12세포의 세포 수축이 시작할 때 30초간 C2C12 세포의 수축횟수를 측정하고, 배지를 모두 제거한 후 PBS로 3회 세정한 후 송아지 혈청이 들어있지 않은 배지와 폴리페놀 화합물 50ppm을 넣고 2시간 동안 반응시켰다. 이후 C2C12 세포의 수축횟수를 다시 30초간 측정하여 근 수축 억제 정도를 확인할 수 있었다.C2C12 cells were cultured in DMEM medium containing 10% fetal calf serum and 1% antibiotics on plates. Neuroblasts were then further co-cultured on the same plate. After that, when the cell contraction of C2C12 cells starts, measure the number of contractions of C2C12 cells for 30 seconds, remove all the medium, wash them three times with PBS, and add the calf serum-containing medium and 50 ppm of polyphenolic compound for 2 hours. I was. Afterwards, the contraction frequency of C2C12 cells was measured again for 30 seconds to confirm the degree of muscle contraction inhibition.
캠페롤, 미리세틴, 암펠롭신이 신경세포로부터의 신경전달물질의 배출을 억제하여 C2C12 세포의 수축 횟수를 감소시키는 결과를 확인할 수 있었다. 이 중 암펠롭신과 캠페롤이 미리세틴에 비해 방출을 저해하는 효과가 상대적으로 높게 측정되었다. 그 결과는 도 7에 나타냈다.Camperol, myricetin and ampelopsin inhibited the release of neurotransmitters from neurons, reducing the number of C2C12 cell contractions. Among them, the effect of inhibiting the release of amfellopsin and camphorol compared to myricetin was relatively high. The result is shown in FIG.
본 발명의 암펠롭신을 포함하는 화장료 조성물을 제조하는 경우, 0.5% 미만(PEG400 5%, 물 70% 기준)의 암펠롭신을 포함할 수 있으나, 본 발명의 마이크로니들 제조방법으로 제조된 마이크로니들은 암펠롭신 함유량을 마이크로니들 건조중량 대비 5% 내외로 증가시킬 수 있다. 따라서 고농도의 폴리페놀을 함유하는 제품을 제조할 수 있다.When preparing a cosmetic composition comprising ampelopsin of the present invention, it may include less than 0.5% (PEG400 5%, based on 70% water) ampelopsin, the microneedle manufactured by the method of manufacturing the microneedle of the present invention Amfellopsin content can be increased to around 5% of the microneedle dry weight. Thus, a product containing a high concentration of polyphenols can be produced.
<Soluble Microneedle 제조><Soluble Microneedle Manufacturing>
Soluble microneedle은 solution casting 방법으로 제조되며, solution을 mold에 casting하여 진공 혹은 centrifuge로 미세 mold에 액을 채운 후 건조하여 제조하였다. Soluble microneedle is manufactured by the solution casting method, the solution was cast by casting the mold to the mold by vacuum or centrifuge the liquid was prepared by drying.
Microneedle 구조체를 형성하는 material은 일반적인 합성 및 천연 수용성 고분자가 사용되었다. As the material for forming the microneedle structure, general synthetic and natural water-soluble polymers were used.
<마그네슘글루코네이트가 함침된 soluble microneedle 제조><Preparation of Soluble Microneedle Impregnated with Magnesium Gluconate>
Figure PCTKR2016003845-appb-T000003
Figure PCTKR2016003845-appb-T000003
Oligo-HA(Hyaluronic acid), Na-CMC(Sodium carboxymethyl cellulose) 및 Trehalose를 정제수에 용해한 후 Glycerin, HCO-40 및 마그네슘글루코네이트를 첨가하여, 마그네슘글루코네이트 용액을 제조하였다. (DPG: Dipropylene glycol)After dissolving Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and Trehalose in purified water, Glycerin, HCO-40 and magnesium gluconate were added to prepare a magnesium gluconate solution. (DPG: Dipropylene glycol)
제조한 마그네슘글루코네이트 분산 용액을 silicone microneedle mold에 casting 한 후, 3000rpm에서 10분간 centrifugation 하여 미세 mold에 액을 충진하였다. 용액 충진 후 건조 오븐(70℃)에서 3시간 동안 건조하고, 점착 필름을 이용하여 microneedle을 silicone mold로부터 분리해 냈다. The magnesium gluconate dispersion solution was cast into a silicone microneedle mold, and then centrifuged at 3000 rpm for 10 minutes to fill the micro mold with liquid. After the solution was filled and dried for 3 hours in a drying oven (70 ℃), the microneedle was separated from the silicone mold by using an adhesive film.
<마그네슘글루코네이트가 함침된 수중유화제형 크림>Oil-in-water emulsion impregnated with magnesium gluconate
Figure PCTKR2016003845-appb-T000004
Figure PCTKR2016003845-appb-T000004
Microneedle에 함침된 마그네슘글루코네이트의 피부 투과량을 비교하기 위하여, 실시예로 일반적인 수중유화제형의 크림에 마그네슘글루코네이트를 함침하여 비교하였다.In order to compare the skin permeation amount of magnesium gluconate impregnated in the microneedle, magnesium gluconate was impregnated into the cream of the general oil-in-water emulsion as an example.
<약물 방출 거동><Drug Release Behavior>
Franz diffusion cell을 이용하여, 시간에 따른 돼지피부 조직 및 acceptor solution의 마그네슘글루코네이트 함량을 Liquid Chromatography를 이용하여 측정하였다. 돼지피부에 마그네슘글루코네이트 크림을 도포하거나, 마그네슘글루코네이트가 함침된 Microneedle을 부착하여 시간에 따른 마그네슘글루코네이트의 피부 투과량을 비교하였다. Using a Franz diffusion cell, the magnesium gluconate content of pig skin tissue and acceptor solution over time was measured by Liquid Chromatography. Magnesium gluconate cream was applied to porcine skin or microneedle impregnated with magnesium gluconate was used to compare skin penetration of magnesium gluconate over time.
마그네슘글루코네이트를 포함한 크림은 피부를 통해 투과되는 양이 약 1ug 이하로 그 양이 미미하였으나, Microneedle에 함침된 마그네슘글루코네이트는 Needle에 의해 피부로 직접 투과하여 그 투과량이 20ug 이상으로 약 20배 이상 크림 대비 높은 피부 투과량을 나타내었다. 결과는 도 8에 나타냈다. Cream containing magnesium gluconate is less than about 1 ug permeated through the skin, but the amount of magnesium gluconate impregnated in the microneedle penetrates directly into the skin by the needle, and the permeation amount is 20 ug or more, about 20 times or more. It showed a higher skin penetration than the cream. The results are shown in FIG.
<In Vitro 근 수축 저해 효과>In Vitro muscle contraction inhibitory effect
도 9에서 확인할 수 있듯이, 마그네슘글루코네이트를 처리하는 경우, 마그네슘글루코네이트의 농도가 증가할수록 근육 수축 횟수가 현저히 감소되는 경향을 나타내는 것을 확인하였다. As can be seen in Figure 9, when treated with magnesium gluconate, it was confirmed that the increase in the concentration of magnesium gluconate showed a tendency to significantly reduce the number of muscle contractions.
<주름 개선 효과><Wrinkle improvement effect>
마그네슘글루코네이트 크림과 마그네슘글루코네이트가 함침된 Microneedle을 눈가 주름에 12주간 매일 처리하여, 주름 개선 정도를 실리콘 모사판(silicone replica) 및 주름 영상 분석 방법을 통해 확인하였다. (N=20)Magnesium gluconate cream and Magnesium gluconate-impregnated Microneedle was treated daily for 12 weeks on the wrinkles around the eyes, and the degree of wrinkle improvement was confirmed by using a silicone replica and a wrinkle image analysis method. (N = 20)
도 10에서 확인할 수 있듯이, 마그네슘글루코네이트 크림에 비해 마그네슘글루코네이트가 함침된 Microneeedle에서 2~3배 이상 우수한 개선효과를 보였으며, 이는 마그네슘글루코네이트가 Microneedle에 의해 피부 내로 효과적으로 침투하여, 주름 개선 효과가 높게 나타난 것을 확인하였다. As can be seen in Figure 10, compared with magnesium gluconate creams showed an improvement of more than two to three times in the magnesium gluconate-impregnated microneeedle, which effectively penetrates the skin by the microneedle, wrinkle improvement effect Was found to be high.
본 발명은 피부 주름 개선을 위한 화장품, 약학 용도로 이용될 수 있다. The present invention can be used for cosmetics, pharmaceuticals for skin wrinkle improvement.
본 발명의 마이크로니들은 우수한 피부 주름 감소 효과를 기대할 수 있다.The microneedle of the present invention can expect excellent skin wrinkle reduction effect.

Claims (13)

  1. 신경전달물질의 배출을 조절하는 성분을 함유하는 마이크로니들. Microneedles containing ingredients that regulate the release of neurotransmitters.
  2. 제1항에 있어서, 상기 신경전달물질의 배출을 조절하는 성분은 i) 폴리페놀 또는 이의 유도체, ii) 칼슘 채널 차단제, 또는 iii) 이들의 혼합물인 것을 특징으로 하는, 마이크로니들. The microneedle of claim 1, wherein the component that modulates the release of neurotransmitters is i) polyphenols or derivatives thereof, ii) calcium channel blockers, or iii) mixtures thereof.
  3. 제2항에 있어서, 상기 폴리페놀 또는 이의 유도체는 캠페롤, 케르세틴, 미리세틴, 루테올린, 델치니딘, 시아니딘, 부테인, 엘라지산, 암펠롭신, 헤스피리딘, 아우란티니딘, 유로피니딘, 펠라고니딘, 말비딘, 페오니딘, 페투니딘, 및 로시니딘 및 이들의 유도체들로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는 마이크로니들. The method of claim 2, wherein the polyphenol or derivatives thereof are camphorol, quercetin, myricetin, luteolin, delcinidine, cyanidin, butane, ellagic acid, ampfellopsin, hesperidin, aurantinidine, eurofini. Microneedle, characterized in that any one or more selected from the group consisting of dine, pelagonidine, malbidine, peonidine, petronidine, and rosinidine and derivatives thereof.
  4. 제3항에 있어서, 상기 폴리페놀은 암펠롭신, 헤스페리딘 또는 이의 유도체인 것을 특징으로 하는 마이크로니들.The microneedle of claim 3, wherein the polyphenol is ampelopsin, hesperidin or a derivative thereof.
  5. 제1항에 있어서, 상기 마이크로니들은 마이크로니들 총 중량 대비 0.01 내지 10 중량%의 폴리페놀 또는 이의 유도체를 함유하는 것을 특징으로 하는 마이크로니들.The microneedle of claim 1, wherein the microneedle contains 0.01 to 10% by weight of polyphenol or a derivative thereof based on the total weight of the microneedle.
  6. 제2항에 있어서, 상기 칼슘 채널 차단제는 쿠퍼글루코네이트(copper gluconate), 징크글루코네이트(zinc gluconate), 마그네슘설페이트(Magnesium Sulfate), 마그네슘글루코네이트(magnesium gluconate) 및 마그네슘아스파테이트(magnesium aspatate)로 이루어진 군에서 1종 이상 선택되는 유기 금속 화합물; The method of claim 2, wherein the calcium channel blocker is copper gluconate, zinc gluconate, magnesium sulfate, magnesium gluconate, and magnesium aspatate. Organometallic compounds selected from the group consisting of one or more;
    암로디핀, 레르카니디핀, 펠로디핀, 니페디핀, 니카르디핀, 이스라디핀, 니솔디핀 및 이의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 어느 하나 이상의 디하이드로피리딘계 칼슘 채널 차단제;At least one dihydropyridine calcium channel blocker selected from the group consisting of amlodipine, lercanidipine, felodipine, nifedipine, nicardipine, isradinine, nisoldipine and pharmaceutically acceptable salts thereof;
    베라파밀을 포함하는 페닐알킬아민계 칼슘 채널 차단제; Phenylalkylamine based calcium channel blockers including verapamil;
    디티아젬을 포함하는 벤조티아핀계 칼슘 채널 차단제; 및 Benzothiapine-based calcium channel blockers including dithiazem; And
    가바펜티노이드(gabapentinoid) 및 징코노티드(zinconotide) 로 이루어진 군에서 선택된 N-타입 칼슘채널 차단제; 로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는, 마이크로니들. N-type calcium channel blockers selected from the group consisting of gabapentinoids and zinconotides; Microneedle, characterized in that any one or more selected from the group consisting of.
  7. 제6항에 있어서, 상기 칼슘 채널 차단제는 마그네슘글루코네이트인 것을 특징으로 하는 마이크로니들. 7. The microneedle of claim 6, wherein the calcium channel blocker is magnesium gluconate.
  8. 제1항에 있어서, 상기 마이크로니들은 피부 내에서 용해되는 것을 특징으로 하는 마이크로니들.The microneedle of claim 1, wherein the microneedle is dissolved in the skin.
  9. 제1항에 있어서, 마이크로니들을 형성하는 물질은 히얄루로닉산 (Hyaluronic acid), 소디움-카르복시메틸 셀룰로오스, Na-CMC(Sodium carboxymethyl cellulose), 비닐피롤리돈-비닐아세테이트 공중합체, 폴리비닐알코올(Poly vinyl alcohol), 폴리비닐피릴리돈(Poly vinyl pyrrolidone), 당 또는 이들의 혼합물인 것을 특징으로 하는 마이크로니들.The material of claim 1, wherein the material forming the microneedle is hyaluronic acid, sodium-carboxymethyl cellulose, sodium carboxymethyl cellulose (Na-CMC), vinylpyrrolidone-vinylacetate copolymer, or polyvinyl alcohol ( Poly vinyl alcohol), poly vinyl pyrrolidone, microneedle, characterized in that the sugar or a mixture thereof.
  10. 제9항에 있어서, 상기 마이크로니들은 마이크로니들을 형성하는 물질 이외에 가소제(plasticizer)를 추가로 포함하는 것을 특징으로 하는 마이크로니들.10. The microneedle of claim 9, wherein the microneedle further comprises a plasticizer in addition to the material forming the microneedle.
  11. 제1항 내지 제10항 중 어느 한 항에 따른 마이크로니들을 포함하는, 피부 주름 개선용 마이크로니들.A microneedle for improving skin wrinkles, comprising the microneedle according to any one of claims 1 to 10.
  12. 제1항 내지 제10항 중 어느 한 항에 따른 마이크로니들을 이용하여 피부 주름을 개선하는 것을 특징으로 하는, 신경전달물질의 배출을 조절하는 성분의 피부 투여 방법.Claim 1 to 10, characterized in that to improve the wrinkles of the skin using the microneedle according to any one of claims 1 to 10, the method of skin administration of a component for controlling the release of neurotransmitters.
  13. 신경전달물질의 배출을 조절하는 성분이 포함된 마이크로니들의 피부 주름 개선 용도.Skin wrinkle improvement for microneedles containing ingredients that regulate the release of neurotransmitters.
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