KR102525628B1 - Soluble microneedle patch for alpha lipoic acid delivery - Google Patents
Soluble microneedle patch for alpha lipoic acid delivery Download PDFInfo
- Publication number
- KR102525628B1 KR102525628B1 KR1020150170108A KR20150170108A KR102525628B1 KR 102525628 B1 KR102525628 B1 KR 102525628B1 KR 1020150170108 A KR1020150170108 A KR 1020150170108A KR 20150170108 A KR20150170108 A KR 20150170108A KR 102525628 B1 KR102525628 B1 KR 102525628B1
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- KR
- South Korea
- Prior art keywords
- microneedles
- alpha
- lipoic acid
- skin
- microparticles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
본 발명은 알파-리포산을 안정하게 함침하고, 피부 내로 효과적으로 전달함으로써, 우수한 효과를 발휘할 수 있는 알파-리포산의 피부 투여 시스템에 관한 것으로서, 알파-리포산을 포함하는 미세바늘인 것을 기술적 특징으로 한다. 본 발명은 또한, 상기 미세바늘을 적용하는 것을 특징으로 하는 알파-리포산의 피부 투여 방법을 제공한다.The present invention relates to a system for administering alpha-lipoic acid to the skin, which can exhibit excellent effects by stably impregnating alpha-lipoic acid and effectively delivering it into the skin, and is characterized by microneedles containing alpha-lipoic acid. The present invention also provides a method for skin administration of alpha-lipoic acid, characterized in that the microneedles are applied.
Description
본 발명은 미세바늘 및 미세바늘의 제조 방법에 관한 것이다.The present invention relates to microneedles and methods of making microneedles.
일반적으로 미세바늘(microneedle)은 생체 내 약물, 백신 등의 활성 물질의 전달, 체내 분석물질의 검출 및 생검(biopsy)에 사용된다. 미세바늘을 이용한 약학적 또는 화장학적 활성 성분의 전달은 혈관 또는 림프관과 같은 생체 순환계가 아닌 피부를 통한 활성 물질의 전달을 목적으로 한다.In general, microneedles are used for delivery of active substances such as drugs and vaccines in vivo, detection of analytes in the body, and biopsy. The purpose of delivery of pharmaceutically or cosmetically active ingredients using microneedles is to deliver active substances through the skin rather than through a biological circulatory system such as blood vessels or lymphatic vessels.
이러한 미세바늘을 이용하는 방법으로는 미세바늘이 부착된 롤러(roller) 등의 미세바늘 장치(device)를 사용하여 피부에 일정 수 이상의 구멍을 형성한 후 약물을 덧바르는 형태, 미세바늘 표면에 활성성분(유효성분)을 코팅함으로써 피부 천공과 동시에 활성성분이 투여되도록 하는 형태 등이 일반적으로 이용되고 있다.As a method of using these microneedles, a microneedle device such as a roller to which microneedles are attached is used to form a certain number of holes in the skin and then reapplying drugs, active ingredients on the surface of the microneedles Forms in which the active ingredient is administered simultaneously with skin puncture by coating (active ingredient) are generally used.
일반적으로 화장품 제제에 있어 피부의 표면에서 작용하여 그 효과를 나타내는 색조 화장품과는 달리 양모, 육모, 탈모 방지, 주름 개선, 미백, 피부 보습, 제모, 피부 영양 등의 효과는 피부 표면에서의 작용보다는 경피 및 진피와 같은 피부 내부에서 작용하여 그 효과를 나타내게 된다.In general, unlike color cosmetics that act on the surface of the skin in cosmetic preparations and show their effects, the effects of hair growth, hair growth, hair loss prevention, wrinkle improvement, whitening, skin moisturizing, hair removal, and skin nutrition are more effective than skin surface action. It acts inside the skin, such as the dermis and dermis, to show its effect.
한편, 알파-리포산(Thioctic acid, Alpha Lipoic acid, α-Lipoic acid)은 항산화, 항염 효과 외에, 글루타치온(glutathione)과 비타민 C, E 등의 생성을 촉진하고, 세포 내 에너지 증가제(대한민국 등록특허 제10-0427637호), 지방세포 분화 억제(The Journal of Biological Chemistry, vol. 278, No. 37, 2003, 34823-34833), 혈관 내 지질류 증가 억제(대한민국 공개특허 제10-2004-0067312호)로 혈관 질환의 예방 및 치료제로서, 그리고 체중 감소용 식품, 비만치료 식품으로도 주목받고 있다.On the other hand, alpha-lipoic acid (Thioctic acid, Alpha Lipoic acid, α-Lipoic acid), in addition to antioxidant and anti-inflammatory effects, promotes the production of glutathione and vitamins C and E, and increases intracellular energy (registered patent in Korea). 10-0427637), inhibition of adipocyte differentiation (The Journal of Biological Chemistry, vol. 278, No. 37, 2003, 34823-34833), inhibition of lipid increase in blood vessels (Korean Patent Publication No. 10-2004-0067312 ), it is attracting attention as a preventive and therapeutic agent for vascular diseases, as well as a food for weight loss and obesity treatment.
그러나 수용액에 대해서는 낮은 용해성을 가지며, 일광하에서나 시간 경과에 따라 티올(thiol)로 결합 분리되어 변취 및 변색되는 문제를 가지고 있어, 화장품 성분으로 사용하기에 어려움이 있다.However, it has low solubility in aqueous solutions, and has problems of deodorization and discoloration due to debonding to thiol under sunlight or over time, making it difficult to use as a cosmetic ingredient.
본 발명이 해결하고자 하는 과제는 난용성 성분, 특히 알파-리포산을 용해성 미세바늘에 안정하게 함침하여, 알파-리포산을 효과적으로 피부 내로 전달하는 시스템, 이러한 시스템을 제조하는 방법 및 이러한 시스템을 이용하여 알파-리포산을 피부에 투여하는 화장학적 방법을 제공하는 것이다.The problem to be solved by the present invention is a system for stably impregnating poorly soluble components, particularly alpha-lipoic acid, into soluble microneedles to effectively deliver alpha-lipoic acid into the skin, a method for manufacturing such a system, and alpha using such a system. - To provide a cosmetic method of administering lipoic acid to the skin.
따라서, 본 발명은 알파-리포산을 포함하는 용해성 미세바늘을 제공한다.Accordingly, the present invention provides soluble microneedles comprising alpha-lipoic acid.
또한, 본 발명은 알파-리포산을 함유하는 마이크로파티클을 포함하는 용해성 미세바늘을 제공한다.In addition, the present invention provides soluble microneedles comprising microparticles containing alpha-lipoic acid.
또한, 본 발명은 상기 미세바늘을 포함하는 미세바늘 패치를 제공한다.In addition, the present invention provides a microneedle patch including the microneedles.
또한, 본 발명은 알파-리포산을 포함하는 미세바늘의 제조 방법을 제공한다.In addition, the present invention provides a method for preparing microneedles containing alpha-lipoic acid.
또한, 본 발명은 상기 미세바늘을 적용하는 것을 특징으로 하는 알파-리포산을 안정하게 함침하고, 알파-리포산을 피부 내로 효과적으로 전달하는 알파-리포산의 화장학적 피부 투여 방법을 제공한다.In addition, the present invention provides a method for cosmetic skin administration of alpha-lipoic acid that stably impregnates alpha-lipoic acid and effectively delivers alpha-lipoic acid into the skin, characterized by applying the microneedles.
상기 과제를 해결하기 위하여, 본 발명은 알파-리포산(alpha-lipoic acid)을 포함하는 용해성 미세바늘을 제공하며, 보다 바람직하게, 상기 미세바늘을 형성하는 물질은 피부 내에서 용해되어 미세바늘의 피부 적용 시 미세바늘이 용해 또는 붕괴됨으로써 알파-리포산이 피부 내로 방출되게 된다.In order to solve the above problems, the present invention provides soluble microneedles containing alpha-lipoic acid, and more preferably, the substance forming the microneedles is dissolved in the skin of the microneedles. Upon application, the microneedles dissolve or collapse, releasing alpha-lipoic acid into the skin.
본 발명자들은 오랜 기간 연구 끝에 용해성 미세바늘 내에 알파-리포산을 함침시켜 알파-리포산이 효과적으로 피부 내로 전달될 수 있다는 사실뿐만 아니라 알파-리포산의 변취 및 변색 문제를 원천적으로 해결할 수 있음을 확인하고 본 발명을 완성하게 되었다. 보다 구체적으로, 용해성 미세바늘 내에 알파-리포산을 함침시켜 알파-리포산의 낮은 용해도, 변색 및 변취 문제를 극복하며, 피부 내부에 직접적으로 작용하여 피부 자극이 완화되고 유효성분의 효과가 보다 효과적임을 확인하였다.After a long period of research, the present inventors confirmed that by impregnating alpha-lipoic acid into soluble microneedles, not only the fact that alpha-lipoic acid can be effectively delivered into the skin, but also the problem of discoloration and discoloration of alpha-lipoic acid can be fundamentally solved, and the present invention has completed More specifically, alpha-lipoic acid was impregnated into soluble microneedles to overcome the problems of low solubility, discoloration and odor of alpha-lipoic acid, and it was confirmed that skin irritation was alleviated and the effect of active ingredients was more effective by directly acting on the inside of the skin. did
또한, 본 발명은 알파-리포산을 용해성 미세바늘 내에 안정하게 함침시키기 위하여 알파-리포산이 함유된 마이크로파티클(microparticle)을 포함하는 용해성 미세바늘을 제공할 수 있으며, 보다 바람직하게는, 상기 미세바늘을 형성하는 물질은 피부 내에서 용해되어 미세바늘의 피부 적용시 미세바늘이 용해 또는 붕괴됨으로써 미세바늘의 내부에 포함된 마이크로파티클이 신속하게 피부 내로 나오게 되며, 마이크로파티클로부터 알파-리포산을 방출하게 된다.In addition, the present invention can provide soluble microneedles containing alpha-lipoic acid-containing microparticles in order to stably impregnate alpha-lipoic acid into soluble microneedles, and more preferably, the microneedles The material to form is dissolved in the skin, and when the microneedles are applied to the skin, the microneedles dissolve or collapse, so that the microparticles contained inside the microneedles quickly come out into the skin, and alpha-lipoic acid is released from the microparticles.
본 명세서에서 사용되는 용어, "피부 자극 완화"란, 피부 자극 물질에 의하여 발생하여 피부에 나타나는 가려움, 따끔거림, 화끈거림 등의 자극감과 홍반 및 부종 등의 염증성 자극 반응을 예방, 완화, 및 치료하는 것을 의미한다.As used herein, the term "skin irritation relief" means prevention, relief, and treatment of irritation sensations such as itching, stinging, and burning caused by skin irritants and inflammatory stimulation reactions such as erythema and edema. means to do
본 발명에서 상기 알파-리포산(alpha-lipoic acid)은 지방산의 일종이며, 분자식은 C8H14O2S2, 분자량은 206.32이다. 하기 화학식 1의 구조식으로 표시되는 화합물이라면 알파-리포산을 함유한 시료에서 분리된 알파-리포산, 인공적으로 합성된 알파-리포산, 상업적으로 유통되고 있는 알파-리포산을 모두 포함할 수 있다.In the present invention, the alpha-lipoic acid is a kind of fatty acid, the molecular formula is C 8 H 14 O 2 S 2 , and the molecular weight is 206.32. Any compound represented by the structural formula of Formula 1 may include alpha-lipoic acid isolated from a sample containing alpha-lipoic acid, artificially synthesized alpha-lipoic acid, and commercially available alpha-lipoic acid.
[화학식 1][Formula 1]
본 발명자들은 다양한 투여 시스템을 연구하였으며 어떠한 시스템도 상기 알파-리포산의 여러 가지 문제점을 동시에 해결하기 쉽지 않았다. 본 발명자들은 여러 노력 끝에 미세바늘에 알파-리포산을 함침함으로써 알파-리포산의 변색, 변취 문제를 원척적으로 해결하고, 효과적으로 피부 내로 전달할 수 있는 놀라운 발명을 하였다.The present inventors have studied various administration systems, and none of the systems are easy to solve the various problems of alpha-lipoic acid at the same time. After many efforts, the present inventors have made a surprising invention that can completely solve the problem of discoloration and odor of alpha-lipoic acid and effectively deliver it into the skin by impregnating alpha-lipoic acid into microneedles.
본 명세서에서 사용되는 용어, "함침"은 알파-리포산이 미세바늘에 함유될 수 있는 형태를 의미할 수 있으며, 바람직하게는 i) 미세바늘을 형성하는 용해성 물질과 함께 알파-리포산을 함유, ii) 알파-리포산을 함유한 마이크로파티클을 미세바늘에 포함 또는 iii) 미세바늘에 구멍을 내어 상기 구멍 내에 알파-리포산을 함유할 수 있다. 상기 i), ii) 또는 iii)의 형태로 미세바늘을 제조하는 경우, 난용성 물질인 알파리포산이 피부 내로 효과적으로 침투할 수 있으며, 특히 i) 또는 ii) 의 형태로 미세바늘을 제조하는 경우, 알파-리포산의 낮은 용해도, 변색 및 변취 문제를 원천적으로 해결할 수 있다.As used herein, the term "impregnation" may refer to a form in which alpha-lipoic acid can be contained in microneedles, preferably i) containing alpha-lipoic acid together with soluble substances forming microneedles, ii ) microparticles containing alpha-lipoic acid may be included in microneedles or iii) microneedles may be punctured to contain alpha-lipoic acid in the pores. When the microneedles are prepared in the form of i), ii) or iii), alpha-lipoic acid, which is a poorly soluble substance, can effectively penetrate into the skin, and in particular, when the microneedles are prepared in the form of i) or ii), The problem of low solubility, discoloration and odor of alpha-lipoic acid can be fundamentally solved.
따라서, 미세바늘을 형성하는 물질이 생체 내에서 용해되어 미세바늘에 함유된 알파-리포산이 피부 내로 효과적으로 방출되는 것이 가장 바람직하다.Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the alpha-lipoic acid contained in the microneedles is effectively released into the skin.
본 발명의 바람직한 일양태에서, 상기 미세바늘을 형성하는 물질은 피부 내에서 용해되어 미세바늘의 피부 적용시 미세바늘이 용해 또는 붕괴됨으로써 미세바늘의 내부에 포함된 알파-리포산이 피부 내부에 효과적으로 침투할 수 있다.In a preferred embodiment of the present invention, the material forming the microneedles is dissolved in the skin, and the microneedles dissolve or collapse when the microneedles are applied to the skin, so that the alpha-lipoic acid contained in the microneedles effectively penetrates into the skin. can do.
본 발명에서 상기 미세바늘은 바람직하게는 피부 내에서 용해성일 수 있으며, 용해성 미세바늘을 형성하기 위해서 예를 들어, 히알루론산(Hyaluronic acid), 소듐-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 미세바늘의 피부 투과 강도, 피부 내에서의 용해 속도 등을 종합적으로 고려하면 히알루론산(Hyaluronic acid), 소듐-카르복시메틸 셀룰로오스(Na-CMC, Sodium carboxymethyl cellulose), 및 당류(saccharide)(바람직하게는 트레할로스(Trehalose))의 혼합물이 바람직하며, 글리세린(Glycerin)까지 혼합된 것이 더욱 바람직하다.In the present invention, the microneedles may preferably be soluble in the skin, and to form soluble microneedles, for example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) , water-soluble polymers such as vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used. In particular, considering the skin penetration strength of the microneedle and the dissolution rate in the skin comprehensively, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (preferably is preferably a mixture of trehalose), and more preferably a mixture of glycerin.
바람직하게는, 본 발명의 미세바늘은 미세바늘을 형성하는 상기 성분들 이외에 가소제, 계면활성제, 보존제, 항염제 등을 추가적으로 포함할 수 있다.Preferably, the microneedles of the present invention may additionally include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like in addition to the above components forming the microneedles.
상기 가소제(plasticizer)로는, 예를 들어, 에틸렌글리콜(Ethylene glycol), 프로필렌글리콜(Propylene glycol), 디프로필렌글리콜(Dipropylene glycole), 부틸렌글리콜(Butylene glycol), 글리세린(Glycerin) 등의 폴리올이 단독으로 또는 혼합하여 사용될 수 있다.As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin are used alone. or may be used in combination.
또한, 본 발명의 일양태에 따른 미세바늘에서, 상기 알파-리포산과 함께 마이크로파티클을 형성하는 물질은 미세바늘 제조 과정에서 알파-리포산이 석출되지 않도록 안정하게 포접할 수 있어야 한다.In addition, in the microneedles according to one embodiment of the present invention, the material forming the microparticles together with the alpha-lipoic acid must be stably incorporated so that the alpha-lipoic acid does not precipitate during the microneedle manufacturing process.
이러한 마이크로파티클을 형성하는 물질로는 폴리(락트산), 폴리(락타이드), 폴리(글리코라이드), 폴리(락타이드-코-글리코라이드), 폴리안하이드라이드, 폴리오쏘에스테르, 폴리에테르에스테르, 폴리카프로락톤, 모노-메톡시 폴리에틸렌글리콜-폴리카프로락톤 (MPEG-PCL), 폴리에스테르아마이드, 폴리(부티르 산), 폴리(발레르 산), 폴리우레탄, 또는 이들의 공중합체와 같은 생분해성 고분자; 및 셀룰로오스, 폴리아크릴레이트, 에틸렌-비닐아세테이트 중합체, 아크릴 치환 셀룰로오스 아세테이트, 비-분해성 폴리우레탄, 폴리스티렌, 폴리비닐 클로라이드, 폴리비닐 플루오라이드, 폴리(비닐 이미다졸), 클로로설포네이트 폴리올레핀(chlorosulphonate polyolefins), 폴리에틸렌 옥사이드 또는 이들의 공중합체와 같은 비-생분해성 고분자가 단독으로 또는 혼합하여 사용될 수 있으나, 본 발명은 이에 한정되는 것은 아니다.Materials that form these microparticles include poly(lactic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester, Biodegradable polymers such as polycaprolactone, mono-methoxy polyethyleneglycol-polycaprolactone (MPEG-PCL), polyesteramides, poly(butyric acid), poly(valeric acid), polyurethanes, or copolymers thereof. ; and cellulose, polyacrylates, ethylene-vinylacetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins , polyethylene oxide or non-biodegradable polymers such as copolymers thereof may be used alone or in combination, but the present invention is not limited thereto.
알파-리포산의 안정한 포접 및 피부 내에서의 방출성 등을 종합적으로 고려할 때, 상기 고분자로는 바람직하게는 폴리(락트산), 폴리(락타이드), 폴리(글리코라이드), 폴리(락타이드-코-글리코라이드), 모노-메톡시 폴리에틸렌글리콜-폴리카프로락톤(MPEG-PCL) 또는 이들의 혼합물일 수 있으며, 더욱 바람직하게는 폴리(락트산), 폴리(락타이드), 폴리(글리코라이드), 및 폴리(락타이드-코-글리코라이드) 중 어느 하나 이상과 모노-메톡시 폴리에틸렌글리콜-폴리카프로락톤(MPEG-PCL)의 혼합물일 수 있다.Considering the stable inclusion of alpha-lipoic acid and release in the skin, the polymer is preferably poly(lactic acid), poly(lactide), poly(glycolide), poly(lactide-co -glycolide), mono-methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) or mixtures thereof, more preferably poly(lactic acid), poly(lactide), poly(glycolide), and It may be a mixture of at least one of poly(lactide-co-glycolide) and mono-methoxy polyethylene glycol-polycaprolactone (MPEG-PCL).
상기 마이크로파티클은 본 발명의 목적을 달성할 수 있는 한 매트릭스(matrix) 타입일 수 있으며, 레저보어(reservoir) 타입일 수도 있다.The microparticles may be of a matrix type or a reservoir type as long as the object of the present invention can be achieved.
본 발명에서 사용할 수 있는 마이크로파티클은 본 발명이 속한 분야에서 잘 알려진 다양한 방법들로 제조될 수 있다. 예를 들어, 용매 교환법(Solvent exchange method), 용매 증발법(Solvent evaporation method), 멤브레인 투과법 (Membrane dialysis method), 분무 건조법(Spray drying method) 등을 이용하여 본 발명에서 이용할 수 있는 마이크로파티클을 제조할 수 있다. 예를 들어, 문헌 Journal of Controlled Release 70 (2001) 1-20 및 International Journal of PharmTech Research, 3(2011) 1242-1254 에 기재된 방법들이 이용될 수 있다. 바람직하게는 일반적인 emulsification and solvent evaporation 방법에 의해 제조될 수 있다.Microparticles that can be used in the present invention can be prepared by various methods well known in the field to which the present invention belongs. For example, microparticles usable in the present invention can be obtained by using a solvent exchange method, a solvent evaporation method, a membrane dialysis method, a spray drying method, and the like. can be manufactured For example, methods described in Journal of Controlled Release 70 (2001) 1-20 and International Journal of PharmTech Research, 3(2011) 1242-1254 can be used. Preferably, it can be prepared by a general emulsification and solvent evaporation method.
바람직하게, 본 발명에 따른 마이크로파티클의 직경은 0.01 내지 10 μm 일 수 있다. 마이크로파티클 크기가 10 μm 초과이면 미세바늘에 함침 시 니들의 강도가 약해져 피부투과가 어려워진다. 본 발명에 따른 마이크로파티클의 직경은 레이저광산란(LLS) 방법에 의해 측정될 수 있으며, 예를 들어, Malvern 사의 Zetasizer 2000 TM을 이용해 측정된다.Preferably, the diameter of the microparticles according to the present invention may be 0.01 to 10 μm. If the microparticle size exceeds 10 μm, the strength of the needle becomes weak when impregnated into the microneedle, making it difficult to penetrate the skin. The diameter of the microparticles according to the present invention can be measured by a laser light scattering (LLS) method, for example, using a Zetasizer 2000 TM from Malvern.
바람직하게, 본 발명의 마이크로파티클은 알파-리포산을 마이크로파티클 총 중량 대비 0.01 내지 25 중량% 함유할 수 있으며, 더욱 바람직하게는 0.1 내지 10 중량% 함유할 수 있다. 또한, 본 발명의 미세바늘은 이러한 마이크로파티클을 미세바늘 총 중량 대비 0.05 내지 20 중량% 함유하는 것이 바람직하며, 더욱 바람직하게는 0.1 내지 10 중량% 함유할 수 있다.Preferably, the microparticles of the present invention may contain 0.01 to 25% by weight of alpha-lipoic acid, more preferably 0.1 to 10% by weight, based on the total weight of the microparticles. In addition, the microneedles of the present invention preferably contain 0.05 to 20% by weight of these microparticles, more preferably 0.1 to 10% by weight, based on the total weight of the microneedles.
본 발명에 따른 미세바늘의 길이는 특정 크기에 한정되는 것은 아니나, 최상의 효과를 발휘할 수 있도록, 중앙에서 절단한 미세바늘의 삼각형 단면을 기준으로 0.05 mm 내지 2.5 mm 일 수 있고, 바람직하게는 0.1 mm 내지 2 mm 일 수 있으며, 더욱 바람직하게는 0.2 mm 내지 1.5 mm 일 수 있다. 0.05 mm 미만인 경우 알파-리포산이 기저층에 미치지 못하며, 2.5 mm 를 초과하는 경우 진피층 깊이 손상을 줄 수 있어 바람직하지 않다.The length of the microneedle according to the present invention is not limited to a specific size, but may be 0.05 mm to 2.5 mm based on the triangular cross section of the microneedle cut from the center, preferably 0.1 mm, so as to exert the best effect. to 2 mm, more preferably 0.2 mm to 1.5 mm. If it is less than 0.05 mm, alpha-lipoic acid does not reach the basal layer, and if it exceeds 2.5 mm, it may cause damage to the depth of the dermal layer, which is not preferable.
본 발명에서 상기 알파-리포산은 미세바늘 총 중량 대비 0.001 내지 5 중량% 포함될 수 있으며, 바람직하게는 0.01 내지 3 중량% 포함될 수 있고, 더욱 바람직하게는 0.1 내지 1 중량% 포함될 수 있다. 0.001 중량% 미만으로 포함되는 경우 유효한 효과를 발휘하지 못할 수 있고, 5 중량% 초과로 포함되는 경우 고온에서 경시에 의한 변색 가능성이 있을 수 있다.In the present invention, the alpha-lipoic acid may be included in 0.001 to 5% by weight, preferably 0.01 to 3% by weight, more preferably 0.1 to 1% by weight, based on the total weight of the microneedles. When included in less than 0.001% by weight, effective effects may not be exhibited, and when included in more than 5% by weight, there may be a possibility of discoloration due to aging at high temperatures.
본 발명에서, 상기 알파-리포산은 미세바늘의 제조 과정에서 알파-리포산이 변색 또는 변취가 일어나지 않도록 안정하게 함침될 수 있다. 종래 피부에 도포하는 크림 제형 등에서는 민감한 알파-리포산을 포함하기 위하여 무수제형으로 안정화를 시도하거나 사이클로덱스트린, 리포좀 등의 다양한 방법들을 이용하였으나 안정성에 한계가 있었으나, 본 발명의 경우 미세바늘 내에 함침시킴으로서 이러한 문제를 원천적으로 해결하였다.In the present invention, the alpha-lipoic acid may be stably impregnated so that the alpha-lipoic acid does not discolor or change odor during the manufacturing process of the microneedles. In conventional cream formulations applied to the skin, stabilization was attempted with an anhydrous formulation to include sensitive alpha-lipoic acid, or various methods such as cyclodextrin and liposome were used, but there were limitations in stability. This problem has been fundamentally solved.
본 발명에 따른 미세바늘을 피부에 적용하는 경우, 변색, 변취 등의 문제를 가지고 있는 알파-리포산을 종래 다른 피부 투여 시스템과 비교하여 피부 투과량을 현저하게 향상시킬 수 있다.When the microneedle according to the present invention is applied to the skin, alpha-lipoic acid, which has problems such as discoloration and odor, can be significantly improved in skin permeation compared to other conventional skin administration systems.
또한, 본 발명에 따른 미세바늘은 피부 미백 용도로 사용할 수 있다.In addition, the microneedles according to the present invention can be used for skin whitening.
또한, 본 발명은 상기 미세바늘을 포함하는 미세바늘 패치를 제공하며, 상기 패치는 알파-리포산 투여용(또는 전달용)일 수 있다.In addition, the present invention provides a microneedle patch including the microneedles, and the patch may be used for alpha-lipoic acid administration (or delivery).
본 발명에서 상기 패치는 상기 본 발명의 알파-리포산이 함침된 미세바늘이 하나 이상 부착되어 있으며 상기 미세바늘이 부착되어 있는 면이 피부에 부착될 수 있도록 제작된 시트를 의미할 수 있다. 상기 시트의 크기는 특정 크기에 한정되는 것은 아니며, 피부에 흡수될 알파-리포산의 양 또는 부착 부위에 따라 적절하게 조절할 수 있다. 또한, 피부에 부착할 수 있는 시트의 면에는 하나 이상, 바람직하게는 다수의 미세바늘이 부착될 수 있다.In the present invention, the patch may refer to a sheet to which one or more microneedles impregnated with the alpha-lipoic acid of the present invention are attached and the surface to which the microneedles are attached can be attached to the skin. The size of the sheet is not limited to a specific size, and may be appropriately adjusted according to the amount of alpha-lipoic acid to be absorbed into the skin or the attachment site. In addition, one or more, preferably a plurality of microneedles may be attached to the surface of the sheet attachable to the skin.
또한, 패치의 피부에 부착될 수 있는 면에도 알파-리포산을 함유시켜 미세바늘에 의해 형성된 구멍에 알파-리포산이 침투할 수 있도록 할 수 있으며, 알파-리포산의 변색, 변취 문제를 해결하기 위하여 알파-리포산은 미세바늘에 함침시키는 것이 바람직하다.In addition, alpha-lipoic acid can be contained on the surface of the patch that can be attached to the skin so that alpha-lipoic acid can penetrate into the hole formed by the microneedles, and alpha-lipoic acid can solve the problem of discoloration and odor. - It is preferable to impregnate the microneedles with lipoic acid.
또한, 본 발명은 알파-리포산 및 피부 내 용해성 물질을 혼합하는 단계를 포함하는 알파-리포산을 포함하는 미세바늘의 제조 방법을 제공한다.In addition, the present invention provides a method for preparing microneedles containing alpha-lipoic acid, which includes mixing alpha-lipoic acid and a skin-soluble substance.
상기 방법은 알파-리포산을 미세바늘에 함침시킴으로써 제조할 수 있으며, 상기 함침은 이에 한정되는 것은 아니지만, 바람직하게는 i) 미세바늘을 형성하는 용해성 물질과 함께 알파-리포산을 함유, ii) 알파-리포산을 함유하는 마이크로파티클을 미세바늘에 포함 또는 iii) 미세바늘에 구멍을 내어 상기 구멍 내에 알파-리포산을 함유할 수 있다. 상기 i) 또는 ii)의 형태로 미세바늘을 제조하는 경우, 알파-리포산의 변색, 변취 등의 문제를 해결하면서 피부 내로 효과적으로 침투할 수 있으며, 특히 ii)의 형태인 경우 알파-리포산을 보다 안정하게 미세바늘 내에 함침할 수 있고 투여량 조절에 용이할 수 있다.The method can be prepared by impregnating alpha-lipoic acid into microneedles, but the impregnation is preferably, but not limited to, i) containing alpha-lipoic acid together with soluble substances forming microneedles, ii) alpha- microparticles containing lipoic acid may be included in microneedles or iii) microneedles may be punctured to contain alpha-lipoic acid in the pores. When the microneedles are prepared in the form of i) or ii), they can effectively penetrate into the skin while solving problems such as discoloration and odor of alpha-lipoic acid. In particular, in the form of ii), alpha-lipoic acid is more stable It can be impregnated into microneedles easily and it can be easy to adjust the dosage.
상기 알파-리포산을 미세바늘에 함침시키는 방법 중에서 ii) 형태, 즉 알파-리포산을 함유하는 마이크로파티클을 미세바늘에 포함하는 미세바늘의 제조 방법에 대하여 설명한다.Among the methods of impregnating microneedles with alpha-lipoic acid, a method for preparing microneedles in the form of ii), that is, microneedles containing microparticles containing alpha-lipoic acid, will be described.
본 발명에서 알파-리포산을 포함하는 미세바늘을 제조하기 위하여, S1) 마이크로파티클을 형성하는 고분자와 함께 알파-리포산을 용해하여 마이크로파티클을 형성하는 단계; S2) 미세바늘의 구조를 형성하는 피부 내 용해성 물질과 상기 마이크로파티클을 함께 미세바늘 형성용 몰드(mold)에 채워 혼합하는 단계; 및 S3) 상기 몰드를 가온하고 이를 건조한 후 분리하는 단계를 거칠 수 있다.In the present invention, in order to prepare microneedles containing alpha-lipoic acid, S1) forming microparticles by dissolving alpha-lipoic acid together with a polymer that forms microparticles; S2) filling a mold for forming microneedles with a soluble material in the skin and the microparticles that form the structure of the microneedles and mixing them; and S3) heating the mold, drying it, and separating the mold.
본 발명에서 상기 마이크로파티클을 형성하는 물질로는 폴리(락트산), 폴리(락타이드), 폴리(글리코라이드), 폴리(락타이드-코-글리코라이드), 폴리안하이드라이드, 폴리오쏘에스테르, 폴리에테르에스테르, 폴리카프로락톤, 모노-메톡시 폴리에틸렌글리콜-폴리카프로락톤 (MPEG-PCL), 폴리에스테르아마이드, 폴리(부티르 산), 폴리(발레르 산), 폴리우레탄, 또는 이들의 공중합체와 같은 생분해성 고분자; 및 셀룰로오스, 폴리아크릴레이트, 에틸렌-비닐아세테이트 중합체, 아크릴 치환 셀룰로오스 아세테이트, 비-분해성 폴리우레탄, 폴리스티렌, 폴리비닐 클로라이드, 폴리비닐 플루오라이드, 폴리(비닐 이미다졸), 클로로설포네이트 폴리올레핀(chlorosulphonate polyolefins), 폴리에틸렌 옥사이드 또는 이들의 공중합체와 같은 비-생분해성 고분자가 단독으로 또는 혼합하여 사용될 수 있다.Materials forming the microparticles in the present invention include poly(lactic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, poly etheresters, polycaprolactone, mono-methoxy polyethyleneglycol-polycaprolactone (MPEG-PCL), polyesteramides, poly(butyric acid), poly(valeric acid), polyurethanes, or copolymers thereof; biodegradable polymers; and cellulose, polyacrylates, ethylene-vinylacetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins , polyethylene oxide or non-biodegradable polymers such as copolymers thereof may be used alone or in combination.
본 발명에서 상기 피부 내 용해성 물질은 예를 들어, 히알루론산(Hyaluronic acid), 소듐-카르복시메틸 셀룰로오스(Na-CMC, Sodium carboxymethyl cellulose), 비닐피롤리돈-비닐아세테이트 공중합체, 폴리비닐알코올(Poly vinyl alcohol), 및 폴리비닐피롤리돈(Poly vinyl pyrrolidone) 등의 수용성 고분자; 자일로즈(Xylose), 수크로스(Sucrose), 말토오스(Maltose), 락토오스(Lactose), 트레할로스(Trehalose) 등의 당류; 또는 이들의 혼합물이 사용될 수 있다.In the present invention, the soluble substance in the skin is, for example, hyaluronic acid (Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (Poly vinyl alcohol), and water-soluble polymers such as polyvinylpyrrolidone (Poly vinyl pyrrolidone); sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used.
또한, 본 발명은 본 발명에 따른 미세바늘을 적용하는 것을 특징으로 하는 알파-리포산을 피부 내로 효과적으로 전달하는 알파-리포산의 화장학적 피부 투여 방법을 제공한다.In addition, the present invention provides a method for cosmetic skin administration of alpha-lipoic acid, which effectively delivers alpha-lipoic acid into the skin, characterized by applying the microneedles according to the present invention.
본 명세서에서 상기 용어, "적용"은 본 발명에 따른 미세바늘을 피부에 부착 또는 본 발명에 따른 미세바늘 패치를 피부에 부착하는 것을 모두 포함하는 용어이다.In the present specification, the term "application" includes both attaching the microneedles according to the present invention to the skin or attaching the microneedle patch according to the present invention to the skin.
본 발명은 알파-리포산의 효과적인 피부전달을 통해 우수한 효과를 나타낼 수 있는 알파-리포산의 투여 시스템의 제조 방법을 제공한다. 본 발명은 또한 이러한 미세바늘을 적용하는 것을 특징으로 하는 알파-리포산의 피부 투여 방법을 제공한다.The present invention provides a method for preparing an alpha-lipoic acid administration system capable of exhibiting excellent effects through effective skin delivery of alpha-lipoic acid. The present invention also provides a method for skin administration of alpha-lipoic acid, characterized by applying such microneedles.
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 한정하여 해석되어서는 안 된다.
도 1은 본 발명에 따른 미세바늘을 제조하는 여러 방법 중 일 예를 보여주는 도면이다.
도 2는 본 발명에 따른 미세바늘의 약물 방출 거동을 평가하기 위한 Franz diffusion cell을 나타낸다.
도 3은 실시예 1 및 비교예 1의 알파-리포산 피부 투과량을 나타낸 그래프이다.
도 4는 본 발명에 따른 미세바늘의 피부색 개선 효과를 나타낸 그래프이다. (푸른색 : 실시예 1, 붉은색 : 비교예 1)The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the contents of the above-described invention, so the present invention is limited to those described in the drawings. should not be construed as limiting.
1 is a view showing one example of several methods for manufacturing microneedles according to the present invention.
Figure 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedles according to the present invention.
Figure 3 is a graph showing the alpha-lipoic acid skin permeation amount of Example 1 and Comparative Example 1.
4 is a graph showing the skin color improvement effect of the microneedles according to the present invention. (Blue: Example 1, Red: Comparative Example 1)
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 aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
<알파-리포산을 함유한 마이크로파티클(microparticle)의 제조><Preparation of microparticles containing alpha-lipoic acid>
본 발명자들은 알파-리포산이 함유된 마이크로파티클을 제조하기 위하여, 마이크로파티클을 제조하기 위한 일반적인 emulsification and solvent evaporation 방법에 의해 제조하였으며, 파티클(particle)의 매트릭스(matrix)는 생분해성 고분자(Poly lactic acid, poly caprolactone, etc) 및 cellulose 등을 사용하여 제조하였다.In order to prepare microparticles containing alpha-lipoic acid, the present inventors prepared them by a general emulsification and solvent evaporation method for preparing microparticles, and the matrix of the particles is a biodegradable polymer (Poly lactic acid). , poly caprolactone, etc) and cellulose.
이때, 파티클 크기는 10 μm 초과하면, 미세바늘에 함침시 니들의 강도가 약하기 때문에 피부 투과가 어려워, 10 μm 이하가 바람직하다.At this time, if the particle size exceeds 10 μm, it is difficult to penetrate the skin because the strength of the needle is weak when impregnated into the microneedles, so it is preferably 10 μm or less.
본 발명자들은 알파-리포산을 함유하는 마이크로파티클을 제조하기 위하여 먼저, 폴리(락트산)(Poly lactic acid, PLA) 10g 과 모노-메톡시 폴리에틸렌글리콜-폴리 카프로락톤(MPEG-PCL) diblock copolymer 10g을 메틸렌 클로라이드(Methylene Chloride) 100g에 녹인 후 알파-리포산 3g을 혼합하여 폴리머-알파-리포산 용액을 제조하였다.In order to prepare microparticles containing alpha-lipoic acid, the present inventors first mixed 10 g of poly(lactic acid) (Poly lactic acid, PLA) and 10 g of mono-methoxy polyethylene glycol-poly caprolactone (MPEG-PCL) diblock copolymer with methylene After dissolving in 100 g of chloride (Methylene Chloride), 3 g of alpha-lipoic acid was mixed to prepare a polymer-alpha-lipoic acid solution.
정제수 500ml에 폴리 비닐 알코올(PVA) 2.5g을 용해하여, PVA 수용액을 제조하였다. 그 이후, PVA 수용액 500ml을 700rpm으로 교반하면서, 폴리머-알파-리포산 용액을 첨가하여, oil-in-water emulsion solution을 제조하였다. 이때, 700rpm으로 24시간 교반하면서, 유기용매인 메틸렌 클로라이드가 증발하고 안정한 알파-리포산 마이크로파티클이 제조되었다.A PVA aqueous solution was prepared by dissolving 2.5 g of polyvinyl alcohol (PVA) in 500 ml of purified water. Thereafter, an oil-in-water emulsion solution was prepared by adding a polymer-alpha-lipoic acid solution while stirring 500 ml of the PVA aqueous solution at 700 rpm. At this time, while stirring at 700 rpm for 24 hours, methylene chloride, an organic solvent, evaporated and stable alpha-lipoic acid microparticles were prepared.
Rotary evaporator를 이용하여 잔류하는 메틸렌 클로라이드를 완전히 제거하면서, 알파-리포산 함량이 전체 3%가 되도록 유기용매와 함께 물을 증발시켜 농축시켰다.While completely removing residual methylene chloride using a rotary evaporator, the mixture was concentrated by evaporating water along with the organic solvent so that the alpha-lipoic acid content was 3%.
액체 크로마토그래피(Liquid chromatography)로 분석한 결과, 알파-리포산의 함량은 2.9%로 확인되었으며, Particle size analyzer로 분석한 결과 마이크로파티클의 평균 크기는 450nm 이었다.As a result of analysis by liquid chromatography, the content of alpha-lipoic acid was confirmed to be 2.9%, and as a result of analysis by particle size analyzer, the average size of microparticles was 450 nm.
<용해성 미세바늘의 제조><Preparation of soluble microneedles>
용해성 미세바늘은 solution casting 방법으로 제조되며, solution 을 몰드 (mold)에 캐스팅(casting) 하여 진공 혹은 원심분리로 미세 몰드에 액을 채운 후 건조하여 제조하였다.Soluble microneedles are prepared by a solution casting method, and the solution is cast into a mold, filled with a liquid in a micromold by vacuum or centrifugal separation, and then dried.
미세바늘 구조체를 형성하는 물질은 일반적인 합성 및 천연 수용성 고분자가 사용되었다.As the material forming the microneedle structure, general synthetic and natural water-soluble polymers were used.
<알파-리포산을 함유하는 마이크로파티클이 포함된 용해성 미세바늘 제조(실시예 1)><Preparation of soluble microneedles containing microparticles containing alpha-lipoic acid (Example 1)>
(단위: 중량%)Example 1
(Unit: % by weight)
알파-리포산을 함유하는 마이크로파티클을 포함하는 용해성 미세바늘을 제조하기 위하여 Oligo-HA(Hyaluronic acid), Na-CMC(Sodium carboxymethyl cellulose), 트레할로스(Trehalose), 글리세린(Glycerin) 및 알파-리포산 함유 마이크로파티클(3%)을 정제수에 용해한 후 용액을 제조하였다. 제조한 용액을 실리콘 미세바늘 몰드에 캐스팅(casting) 한 후, 3000 rpm 에서 10 분간 원심분리하여 미세 몰드에 액을 충진하였다. 용액 충진 후 건조 오븐(70℃)에서 3시간 동안 건조하고, 접착 필름을 이용하여 미세바늘을 실리콘 몰드로부터 분리해 냈다(실시예 1).Oligo-HA (hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose), trehalose, glycerin, and alpha-lipoic acid-containing microneedles to prepare soluble microneedles containing microparticles containing alpha-lipoic acid A solution was prepared after dissolving the particles (3%) in purified water. The prepared solution was cast in a silicon microneedle mold, and then centrifuged at 3000 rpm for 10 minutes to fill the micromold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedles were separated from the silicon mold using an adhesive film (Example 1).
<알파-리포산 함유 크림 제조(비교예 1)><Preparation of cream containing alpha-lipoic acid (Comparative Example 1)>
(단위: 중량%)Comparative Example 1
(Unit: % by weight)
미세바늘에 함침된 유효성분과 수중유 크림에 적용한 유효성분을 비교하기 위하여 알파-리포산이 함유된 크림을 제조하였다.In order to compare the active ingredient impregnated with microneedles and the active ingredient applied to the oil-in-water cream, a cream containing alpha-lipoic acid was prepared.
상기 표 2와 같이 원료 1 내지 5 및 원료 6 내지 11을 75℃ 내지 80℃로 가열, 용해하고 호모믹서 5500rpm으로 교반 후 냉각하여, 55℃에서 원료 12 및 13을 넣은 후 호모믹서 5500rpm으로 교반 후 실온까지 냉각하여 제조하였다(비교예 1).As shown in Table 2, raw materials 1 to 5 and raw materials 6 to 11 are heated and dissolved at 75 ° C to 80 ° C, stirred at 5500 rpm with a homomixer, cooled, and after adding raw materials 12 and 13 at 55 ° C, stirred at 5500 rpm with a homomixer. It was prepared by cooling to room temperature (Comparative Example 1).
<< 실험예Experimental example 1> 1>
경시 안정성 확인Check stability over time
본 발명자들은 실시예 1 및 비교예 1을 0℃, 실온, 40℃, 50℃ 항온 조건에서 4주간 보관하여 샘플의 석출 및 변색 등의 안정성을 확인하였다.The inventors of Example 1 and Comparative Example 1 were stored at constant temperature conditions of 0°C, room temperature, 40°C, and 50°C for 4 weeks to confirm stability such as precipitation and discoloration of the samples.
상기 표 3의 결과에서 알 수 있듯이, 실시예 1의 경우, 비교예 1에 비해 저온과 고온에서 모두 양호한 결과를 나타냈다.As can be seen from the results of Table 3, in the case of Example 1, compared to Comparative Example 1, both low and high temperatures showed good results.
<< 실험예Experimental example 2> 2>
피부 자극 개선 효과Skin irritation improvement effect
본 발명자들은 실시예 1 및 비교예 1을 각각 팔 안쪽에 매일 2주간, 미세바늘은 1시간씩 부착하고, 크림은 도포를 하여 피부 자극 정도를 확인하였다(N=20).The present inventors attached Example 1 and Comparative Example 1 to the inside of the arm every day for 2 weeks, microneedles for 1 hour, and applied the cream to confirm the degree of skin irritation (N = 20).
실시예 1 이 비교예 1 보다 피부 자극이 더 작게 나타나는 것은 실제 사용에서 크림은 장시간 도포되어 있는 반면, 미세바늘은 단시간(1시간) 사용 후 제거하기 때문에 피부에 접촉되는 시간이 짧기 때문인 것으로 판단되었다.Example 1 shows less skin irritation than Comparative Example 1 because the cream is applied for a long time in actual use, while the microneedles are removed after a short time (1 hour), so it was judged that the contact time with the skin is short. .
* 피부 자극 지수가 0.2 이상인 경우 피부 자극이 있다고 판단하고 있으며, 보통 기능성 화장품의 경우 피부 자극은 0.05 내지 0.1 수준이다.* If the skin irritation index is 0.2 or more, it is judged that there is skin irritation, and in the case of normal functional cosmetics, skin irritation is at the level of 0.05 to 0.1.
<< 실험예Experimental example 3> 3>
약물 방출 거동drug release behavior
본 발명자들은 Franz diffusion cell을 이용하여, 시간에 따른 돼지피부 조직 및 acceptor solution 의 알파-리포산 함량을 액체 크로마토그래피(Liquid Chromatography)를 이용하여 측정하였다. 돼지 피부에 실시예 1을 부착 및 비교예 1을 도포(시간: 2시간, 온도: 32℃)하여 돼지 피부 내에 침투하여 녹게 한 후, 미세바늘 및 크림을 제거하였다.The present inventors measured the alpha-lipoic acid content of porcine skin tissue and acceptor solution over time using a Franz diffusion cell using liquid chromatography. After attaching Example 1 and applying Comparative Example 1 to pig skin (time: 2 hours, temperature: 32 ° C.) to penetrate and melt into pig skin, the microneedles and cream were removed.
실시예 1 및 비교예 1에 의해 알파-리포산이 흡수된 돼지 피부를 franz diffusion cell에 넣어(도 2), 시간에 따른 알파-리포산의 피부 투과량을 비교하였다.The pig skin in which alpha-lipoic acid was absorbed in Example 1 and Comparative Example 1 was put into a Franz diffusion cell (FIG. 2), and the skin permeation amount of alpha-lipoic acid over time was compared.
그 결과, 도 3에 나타낸 것과 같이 비교예 1은 피부를 통해 투과되는 양이 미미하였으나, 미세바늘에 함침된 알파-리포산은 니들에 의해 피부로 직접 투과하여 그 투과량이 약 25μg 이상으로 약 25배 이상 크림 대비 높은 피부 투과량을 나타내었다.As a result, as shown in FIG. 3, Comparative Example 1 had an insignificant amount of permeation through the skin, but the alpha-lipoic acid impregnated into the microneedles directly penetrated into the skin by the needle, and the permeation amount was about 25 μg or more, about 25 times. It showed a higher amount of skin permeation compared to the ideal cream.
<< 실험예Experimental example 4> 4>
색차계를color difference meter 이용한 멜라닌 지수 측정 Measurement of melanin index using
본 발명자들은 실시예 1 및 비교예 1을 눈가 부위에 6주간 매일 처리하여, 색차계(MPA-580)를 이용하여 멜라닌 지수 측정을 통해 피부색 개선 정도를 평가하였고, 멜라닌 지수를 각 시점별로 평가한 결과를 하기 표 5 및 도 4에 나타내었다. (N=20)The present inventors treated Example 1 and Comparative Example 1 daily for 6 weeks on the eye area, evaluated the degree of skin color improvement through measuring the melanin index using a color difference meter (MPA-580), and evaluated the melanin index at each time point. The results are shown in Table 5 and FIG. 4 below. (N=20)
그 결과, 비교예 1에 비해 실시예 1에서 약 2배 가량 우수한 개선효과를 보였으며, 이는 알파-리포산이 미세바늘에 의해 피부 내로 효과적으로 침투하여, 피부 미백 효과가 높게 나타난 것을 확인하였으며, 각 시점별 멜라닌 지수 분석 결과 실시예 1을 사용한 시험군이 비교예 1을 사용한 시험군에 비해 멜라닌 지수가 감소한 것을 확인하였다.As a result, compared to Comparative Example 1, Example 1 showed an improvement effect about 2 times superior, which confirmed that alpha-lipoic acid effectively penetrated into the skin by microneedles, and the skin whitening effect was high, and at each time point As a result of star melanin index analysis, it was confirmed that the melanin index of the test group using Example 1 was reduced compared to the test group using Comparative Example 1.
Claims (13)
상기 미세바늘을 형성하는 물질은 히알루론산 또는 이의 염; 카르복시메틸 셀룰로오스 또는 이의 염; 당; 및 가소제로 이루어진 군으로부터 선택되는 2종 이상을 포함하는 것이고,
상기 마이크로파티클은 폴리(락트산), 폴리(락타이드), 폴리(글리코라이드), 폴리(락타이드-코-글리코라이드), 모노-메톡시 폴리에틸렌글리콜-폴리카프로락톤(MPEG-PCL) 및 이들의 혼합물로 이루어진 군에서 선택되는 1 이상의 고분자로 형성되어 포함되는 것이고,
상기 알파-리포산은 석출되지 않도록 상기 마이크로파티클 내에 안정하게 포접되어 있는 것인, 수용해성 미세바늘.(i) a substance that forms microneedles; And (ii) a water-soluble microneedle containing microparticles containing alpha-lipoic acid,
The material forming the microneedles is hyaluronic acid or a salt thereof; carboxymethyl cellulose or a salt thereof; sugar; And it includes two or more selected from the group consisting of plasticizers,
The microparticles include poly(lactic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), mono-methoxy polyethylene glycol-polycaprolactone (MPEG-PCL), and the like. It is formed and included in one or more polymers selected from the group consisting of mixtures,
The alpha-lipoic acid is stably encapsulated in the microparticles so as not to precipitate, the water-soluble microneedles.
상기 미세바늘을 형성하는 물질은 피부 내에서 용해되는 것을 특징으로 하는 미세바늘.According to claim 1,
Microneedles, characterized in that the material forming the microneedles is dissolved in the skin.
상기 알파-리포산은 미세바늘 총 중량 대비 0.001 내지 5 중량% 포함된 것을 특징으로 하는 미세바늘.According to claim 1,
The alpha-lipoic acid is microneedles, characterized in that contained 0.001 to 5% by weight relative to the total weight of the microneedles.
상기 미세바늘은 알파-리포산의 피부 투과량을 향상시키는 것을 특징으로 하는 미세바늘.According to claim 1,
The microneedles are microneedles, characterized in that to improve the skin permeation amount of alpha-lipoic acid.
상기 미세바늘은 피부 미백용인 것을 특징으로 하는 미세바늘.According to claim 1,
The microneedles are characterized in that the microneedles for skin whitening.
상기 마이크로파티클의 직경은 0.01 내지 10 μm 인 것을 특징으로 하는 미세바늘.According to claim 1,
Microneedles, characterized in that the diameter of the microparticles is 0.01 to 10 μm.
S2) 미세바늘을 형성하는 물질과 상기 마이크로파티클을 함께 미세바늘 형성용 몰드(mold)에 채워 혼합하는 단계; 및
S3) 상기 몰드를 가온하고 이를 건조한 후 분리하는 단계를 포함하는 제1항에 따른 미세바늘의 제조 방법.S1) forming microparticles by dissolving alpha-lipoic acid together with a polymer that forms microparticles;
S2) filling and mixing a material for forming microneedles and the microparticles together in a mold for forming microneedles; and
S3) The method of manufacturing the microneedles according to claim 1, comprising the step of heating the mold, drying it, and separating it.
Claims 1, 2, 5 to 7 and 10 of the alpha-lipoic acid delivered into the skin, characterized in that the application of the microneedles according to any one of claims for cosmetic purposes. Cosmetic dermal administration methods.
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