KR20160132296A - Dermal delivery method of physiologically active ingredient using nanodiamond - Google Patents
Dermal delivery method of physiologically active ingredient using nanodiamond Download PDFInfo
- Publication number
- KR20160132296A KR20160132296A KR1020150064876A KR20150064876A KR20160132296A KR 20160132296 A KR20160132296 A KR 20160132296A KR 1020150064876 A KR1020150064876 A KR 1020150064876A KR 20150064876 A KR20150064876 A KR 20150064876A KR 20160132296 A KR20160132296 A KR 20160132296A
- Authority
- KR
- South Korea
- Prior art keywords
- active substance
- skin
- physiologically active
- biologically active
- nanodiamond
- Prior art date
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Abstract
Description
본 발명은 나노다이아몬드를 이용한 생리 활성물질의 경피 전달 방법에 관한 것으로서, 나노다이아몬드 표면에 친수성 생리활성 물질과 소수성 생리활성 물질을 동시에 부착 및 가용화한 후 이를 피부 표면에 도포하여 생리활성 물질을 피부 내부로 전달하는 방법에 관한 것이다. The present invention relates to a transdermal delivery method of a physiologically active substance using nanodiamonds, in which a hydrophilic physiologically active substance and a hydrophobic physiologically active substance are simultaneously adhered and solubilized on the surface of a nanodiamond, As shown in FIG.
피부는 조직학적으로 표피, 진피, 피하지방 등으로 구성되어 있으며, 두께는 부위, 연령 및 성별에 따라 다르다. 다양한 피부조건이 존재하지만, 이러한 피부들은 각각 외부로부터의 장벽기능 및 기타 생리학적 기능 등의 역할을 수행하고 있다. 각질층은 상대적으로 소수성(hydrophobicity)이 높은 불용성 단백질 케라틴이 고밀도로 집적되어 있는 케라틴화된 사멸세포(keratinized dead cell)가 지질의 얇은 층인 세포간 지질 이중층(intercellular lipid bilayer)을 사이에 두고 적층되어 있는 구조로서, 지질과 불용성 단백질이 풍부한 매트릭스의 독특한 계층적 구조가 외부 환경 유래의 다양한 화합물을 포함한 화학적 요인에 대한 불투과적 성질을 만든다. 특히 친수성 생리활성물질은 각질층의 이러한 소수성 다중 구조로 인해 투과되는 것이 매우 어려운 실정이다. Skin is histologically composed of epidermis, dermis, subcutaneous fat, etc. The thickness varies according to site, age and sex. Although there are various skin conditions, each of these skins functions as barrier function and other physiological functions from the outside. The stratum corneum is composed of keratinized dead cells with a high density of insoluble protein keratins with relatively high hydrophobicity and intercellular lipid bilayers, which are thin layers of lipids (intercellular lipid bilayer) As a structure, a unique hierarchical structure of the matrix rich in lipids and insoluble proteins creates an impermeable property to chemical factors including various compounds derived from the external environment. In particular, it is very difficult to transmit a hydrophilic physiologically active substance due to the hydrophobic multi-structure of the stratum corneum.
따라서, 일반적으로 건강한 피부에서 각질을 통한 물질의 수송, 특히 친수성 생리활성물질의 피부 투과는 피부의 여러 가지 보호작용으로 인해 쉽게 이루어지지 않으며, 투과된다고 하여도 매우 낮은 농도만 투과될 뿐이다. 화장료의 경우, 화장료에 포함된 생리활성물질이 그 효능을 나타내기 위해서는 피부의 최외각층인 각질층을 통과하여야만 하며, 친수성 생리활성물질의 경우 이러한 각질층의 소수성 다중 구조 및 이로 인한 장벽 기능으로 인해, 화장료에 포함된 생리활성물질이 그 기능을 충분히 나타내지 못하는 문제점을 가진다. Thus, in general, the permeation of substances through the keratinous substances in healthy skin, especially the skin permeation of hydrophilic physiologically active substances, is not easily achieved due to various protective actions of the skin, and even if they are permeated, they are only transmitted at very low concentrations. In the case of cosmetics, the physiologically active substance contained in the cosmetic must pass through the horny layer, which is the outermost layer of the skin, in order to exhibit its effect. Due to the hydrophobic multi-structure of the horny layer and the barrier function of the horny layer, The physiologically active substance contained in the composition does not sufficiently exhibit its function.
피부를 통한 생리활성분자의 피부투과 경로는 일반적으로 각질층, 모낭과 피지선, 한선(땀샘)등 3가지로 나눌 수 있다. 그러나 피부 장벽으로서의 각질층에 대한 직접적인 투과(transcellular pathway)는 용이하지 않으며 세포간 지질층을 통한 투과(intercellular pathway)가 상대적으로 효율적인 것으로 알려져 있다. 이는 비극성 지질들로 이루어져 있는 세포간 지질층 경로를 이용한 것으로 극성 물질은 세포간 지질층을 거의 투과할 수 없지만 소수성(hydrophobicity)물질들의 투과는 용이하다. 그러나 각질층을 투과하여도 각질층 하부에서의 용해도 및 각종 분해 효소들에 의해 생리활성분자의 흡수는 제한적이며 특히 친수성 생리활성물질은 각질층의 이러한 소수성 다중 구조로 인해 투과되는 것이 매우 어려운 실정이다. Skin permeation pathways of physiologically active molecules through the skin can be generally divided into three types: horny layer, hair follicle, sebaceous gland, and glandular glands. However, the transcellular pathway to the stratum corneum as a skin barrier is not easy and the intercellular pathway is known to be relatively efficient. It uses an intercellular lipid layer pathway consisting of nonpolar lipids. Polar substances can hardly penetrate intercellular lipid layers, but hydrophobic substances are easily permeable. However, even when the horny layer is permeated, the absorption of physiologically active molecules is limited by the solubility in the lower part of the stratum corneum and various kinds of degrading enzymes, and in particular, it is very difficult to transmit the hydrophilic physiologically active substance due to the hydrophobic multi-structure of the horny layer.
현재까지 화장료에 포함된 생리활성물질의 경피 전달을 위하여 사용되는 시스템은 주로 계면활성제, 지질, 고분자 등의 소재로 활성물질을 함유하는 소포체를 만들어 적용하는 것이며, 특히, 지질 성분은 생체막의 구성 성분으로서 생리활성물질의 피부 친화력 증진 및 피부 흡수 개선을 통하여 경피투과를 촉진시킬 수 있어 다른 소재보다 우선적으로 활용되고 있다. The system used for the transdermal delivery of physiologically active substances contained in cosmetics up to now is mainly to make an endoplasmic reticulum containing an active substance as a material such as a surfactant, a lipid and a polymer, and in particular, As a result, the transdermal permeation can be promoted by improving the skin-affinity of the physiologically active substance and improving the skin absorption.
특히, 화장품 제형에 가장 많이 응용되고 있는 소포체인 리포좀은 생체막과 가장 유사한 단층 또는 다층의 지질이중막으로 된 구조물로서 수십나노미터의 너비를 갖는 세포간 지질층의 투과가 용이하며 친수성 물질을 포함하는 생리 활성분자의 피부 전달이 용이한 경피 전달 시스템 중의 하나로 이용되고 있다. 그러나 막 자체의 물리화학적 불안정성, 낮은 유화 안정성 무엇보다도 약물의 포집 효율과 약물 자체의 안정성 유지 효율이 매우 낮고 피부 침투율 또한 좋지 않아 결과적으로는 효능이 매우 제한적일 수 밖에 없는 실정이다. Particularly, the liposome, which is the most widely used endoplasmic reticulum in cosmetic formulations, is a structure having a monolayer or multilayered lipid membrane which is most similar to a biomembrane. It is easy to permeate an intercellular lipid layer having a width of several tens of nanometers and a physiological substance And is used as one of transdermal delivery systems which facilitate the skin transfer of active molecules. However, physicochemical instability of the membrane itself, low emulsification stability, and above all, the efficiency of capturing the drug and the stability of the drug itself are very low, and the penetration rate of the skin is not good, and as a result, the efficacy is inevitably limited.
따라서 리포좀을 포함하는 생리활성분자를 담지, 피부 투과를 향상시키고자 하는 담지체는 담지체 자체의 안정화 및 상기 담지물질의 안정화를 최대한 유지할 수 있어야 하며 조성, 입자크기, 입자의 표면전하, 제타 전위 크기, pH등 담지체의 특성을 최적화할 필요가 있으며 궁극적으로는 피부 적용 시, 안전성을 확보함과 동시에 생리활성분자에 의한 효능 향상이 보장되어야 한다. Therefore, the carrier which carries the liposome-containing physiologically active molecule to improve the skin permeability should be able to maintain the stability of the carrier itself and the stability of the carrier substance to the maximum, and the composition, particle size, surface charge of particles, zeta potential It is necessary to optimize the characteristics of the carrier such as size, pH, etc. Ultimately, safety of the skin should be ensured and improvement of the efficacy by the physiologically active molecule should be ensured.
따라서 다양한 연구를 통해 활성물질의 피부 투과를 촉진하는 피부 투과 촉진제들이 보고되어 왔으며, 이들의 투과 촉진은 크게 세포간 지질 이중층(Intercellular lipid bilayer)에 작용, 세포간 결합에 관여하는 데스모좀(desmosome) 및 관련 단백질에 작용, 각질세포 내부 구조에 직접 작용하는 기작으로 나눌 수 있다. 세포간 지질 이중층에 대한 전달 촉진인자(delivery enhancer)의 작용은 주로 지질 이중층의 구조를 느슨하게 하여, 활성물질의 전달을 용이하게 하는 기작으로 많은 수의 피부 투과 촉진제가 이러한 기능을 통해 전달을 촉진하는 것으로 알려져 있다. 일부 피부 투과 촉진제의 경우, 각질세포의 세포간 결합에 관여하는 데스모좀 및 관련 단백질에 작용하여, 각질 세포간 결합을 분리하거나 느슨하게 하여 세포간 간격을 늘리는 기작을 통해 전달을 촉진하는 것으로 알려져 있다. 다른 피부 투과 촉진제의 경우, 각질세포 내부에 침투하여 케라틴을 변성시키거나 내부구조에 영향을 미쳐 트랜스셀룰라 루트(transcellular route)를 통한 전달을 용이하게 하는 기작을 통해 전달을 촉진하는 것으로 알려져 있다. Therefore, skin permeation accelerators have been reported to promote the penetration of active substances through various studies. Their permeation enhancement mainly acts on the intercellular lipid bilayer, desmosome involved in intercellular binding, And related proteins, and mechanisms that directly affect the keratinocyte internal structure. The action of the delivery enhancer on the intercellular lipid bilayer mainly loosens the structure of the lipid bilayer and facilitates the delivery of the active substance. Thus, a large number of skin permeation enhancers facilitate delivery through these functions . Some skin penetration enhancers are known to act on desmosomes and related proteins involved in the intercellular binding of keratinocytes, thereby promoting transmission through mechanisms that increase or decrease intercellular spacing by separating or loosening the keratinocyte interactions. Other skin permeation enhancers are known to penetrate keratinocytes to denature keratin or to affect internal structure and facilitate delivery through a mechanism that facilitates delivery through the transcellular route.
피부 투과 촉진제는 필연적으로 피부 최외각층인 각질층의 구조를 변경시켜 생리활성 물질의 피부 투과를 촉진하는 것이다. 하지만, 이로 인해 대부분의 피부 투과 촉진제의 경우, 피부 세포에 대한 세포 독성이 높고 도포시 피부 작열감 및 홍반을 유발하는 등의 피부 자극 유발 가능성이 매우 높은 문제점을 가진다. The skin penetration enhancer inevitably changes the structure of the stratum corneum, which is the outermost layer of the skin, thereby promoting skin permeation of the physiologically active substance. However, most of the skin penetration enhancers have a high cytotoxicity to skin cells and a high possibility of inducing skin irritation such as skin burning and erythema upon application.
한편, 폭발반응에 의한 나노 다이아몬드의 생성은 가스 대기하, 예를 들면, 이산화탄소(CO2) 또는 물(H2O) 또는 다른 액체상 환원제 조건하에서 밀폐된 금속 챔버내에서 이루어지는데 이때 사용하는 폭발물질로는 2,4,6-트리니트로톨루엔(TNT)/1,3,5-트리니트로트리아자시클로헥산(헥소겐 또는 RDX(Research Development Explosive) 라고도 함)이 일정한 비율로 섞여진 상태에서 폭발반응으로 얻어진다. On the other hand, the generation of nanodiamonds by an explosion reaction occurs in a closed metal chamber under a gas atmosphere, for example under the conditions of carbon dioxide (CO 2) or water (H 2 O) or other liquid phase reducing agent. , 4,6-trinitrotoluene (TNT) / 1,3,5-trinitrotriazacyclohexane (also referred to as hexogen or RDX (Research Development Explosive)) are blended at a constant ratio.
말하자면 DND는 폭발성이 있는 트리니트로톨루엔(T.N.T)과 백색 결정성 비수용성 폭발성분인 RDX(Research department explosive)를 일정비율 예를 들면 각기 수십% 중량비로 혼합된 상태의 폭발물질이 반응할 때 순간적으로 발생된 고온 고압 분위기에서 조성물의 탄소성분이 다이아몬드 결정상의 핵(탄소 SP3 구조) 생성하여 일정한 크기로 핵이 성장하게 되고 또한, 흑연(SP2 구조) 표면에는 C, O, H, N로 이루어진 단수 및 복수의 작용기들이 존재한다. 이의 대표적인 작용기로는 COOH, C=O, NH2, CHO,OH, NO2, -C-O-C- 등이 다수가 있는 것으로 알려져 있다. That is to say, DND is instantaneously generated when explosive substances such as explosive substances (TNT) and RDX (Research department explosive), which are white crystalline non-aqueous explosive substances, are mixed at a certain ratio, for example, (Carbon SP3 structure) on the diamond crystal phase, and the nucleus grows to a certain size, and the surface of the graphite (SP2 structure) has a single and a plurality of C, O, H and N Lt; / RTI > The representative functional groups thereof are known to have a large number of COOH, C = O, NH2, CHO, OH, NO2, and -C-O-C-.
여러 연구에 의하면 DND는 생체내에서 독성이 거의 없고 및 구조체의 안정성으로 인하여 생체적합성을 가지며, 또한, 입경이 매우 작은 수nm 크기와 비표면적이 250m2/g~450m2/g으로 통상 다이아몬드 대비 약 수십배 내지 수백 배로 크며 그 표면에는 다수의 친수성 작용기를 포함하고 있는 등 독특한 전기적, 화학적, 광학적 특징을 나타내어 광범위한 산업 분야에 활용될 수 있다. According to various studies, DND is biocompatible due to the lack of toxicity in the living body and the stability of the structure. In addition, the DND has a small particle size of several nm and a specific surface area of 250 to 250 m 2 / g to 450 m 2 / To several hundred times as large as the surface, and its surface contains many hydrophilic functional groups. Thus, it has unique electrical, chemical and optical characteristics and can be used in a wide range of industrial fields.
본 발명은 피부 자극이나 독성 없이 생리활성 물질을 피부 내부로 전달할 수 있는 방법을 제공하는 것이다. The present invention provides a method for transferring a physiologically active substance into the skin without irritating the skin or toxicity.
본 발명은 피부 내부로 전달하기 어려운 친수성 생리활성 물질을 피부 내부로 용이하게 침투시키는 방법을 제공하는 것이다. The present invention provides a method for easily infiltrating a hydrophilic physiologically active substance, which is difficult to transfer into the skin, into the skin.
상술한 목적을 달성하기 위한 본 발명의 하나의 양상은 According to one aspect of the present invention for achieving the above object,
소수성 피부 생리활성 물질, 친수성 피부 생리활성 물질 및 나노다이아몬드를 용매에 넣어 혼합하는 가용화 단계 ; 및 가용화된 상기 용액을 피부에 도포하는 단계를 포함하는 생리활성 물질의 경피 전달 방법에 관계한다. A step of solubilizing a hydrophobic skin biologically active substance, a hydrophilic skin biologically active substance and a nanodiamond in a solvent; And applying the solubilized solution to the skin. The present invention also relates to a method for transdermal delivery of a physiologically active substance.
다른 양상에서, 본 발명은 소수성 피부생리활성 물질, 친수성 피부 생리활성 물질 및 나노다이아몬드를 용매에 넣어 혼합하는 가용화 단계, 가용화된 상기 용액으로부터 나노다이아몬드 복합체를 분리 및 건조시키는 단계 및 상기 나노다이이몬드 복합체를 용액에 분산시켜 피부에 도포하는 단계를 포함하는 생리활성 물질의 경피 전달 방법에 관계한다. In another aspect, the present invention provides a method for preparing a nanodiamond composite, comprising: solubilizing a hydrophobic skin biologically active substance, a hydrophilic skin biologically active substance and a nanodiamond in a solvent; separating and drying the nanodiamond composite from the solubilized solution; To a skin, and then applying it to the skin. The present invention also relates to a method for transdermal delivery of a physiologically active substance.
본 발명의 방법은 소수성 생리활성 물질의 가용화와 동시에 친수성 생리활성 물질을 함께 담지할 수 있어 피부 각질층의 투과가 어려운 친수성 생리활성물질이 소수성 물질과 함께 피부에 전달됨으로서 피부투과율을 개선시킬 수 있다. The method of the present invention can simultaneously support solubilization of the hydrophobic physiologically active substance and simultaneously support the hydrophilic physiologically active substance so that the hydrophilic physiologically active substance which is difficult to permeate the horny layer of the skin is transferred to the skin together with the hydrophobic substance,
본 발명의 방법은 피부 자극이나 독성 없이 생리활성 물질을 피부 내부로 전달 할 수 있다. The method of the present invention can deliver the physiologically active substance into the skin without skin irritation or toxicity.
본 발명의 방법은 나노다이아몬드 복합체를 사용하여 피부투과가 어려운 친수성 활성물질의 피부 투과를 개선함과 동시에 나노다이아몬드 자체는 피부 표면에 남아 보습 효과를 통해 피부의 건조함을 개선할 수 있다. The method of the present invention improves skin permeation of a hydrophilic active material that is difficult to penetrate through the skin by using a nano diamond composite, and at the same time, the nano diamond itself remains on the surface of the skin to improve the dryness of the skin through moisturizing effect.
본 발명은 나노다이아몬드 표면의 작용기에 대응하는 분자수준으로 상당한 양의 생리활성물질을 담지할 수 있으므로 피부 생리활성 물질의 효과를 장시간에 걸쳐 제공할 수 있다. Since the present invention can support a considerable amount of physiologically active substance at a molecular level corresponding to the functional group of the surface of the nano diamond, the effect of the skin biologically active substance can be provided for a long time.
본 발명은 항산화제 효능, 주름감소, 멜라닌 생성 감소, 피부 염증 완화, 피부 자외선 차단, 피부 건조함 개선, 탈모예방등을 목적으로 하는 스킨, 로션, 에센스, 크림, 팩등의 화장용 조성물로도 적용할 수 있다. The present invention is also applicable to cosmetic compositions such as skins, lotions, essences, creams and packs for the purpose of antioxidant efficacy, wrinkle reduction, reduction of melanin production, skin irritation relief, skin ultraviolet shielding, skin dryness improvement, hair loss prevention can do.
도 1은 폭발형 나노다이아몬드의 표면 구조를 도시한 것이다.
도 2의 a는 상기 가용화 단계에 의해 소수성 생리활성 물질이 나노 다이아몬드 표면 기능기에 결합된 것을 보여주는 모식도이고, 도 2의 b는 친수성 생리활성물질(비타민 C)과 소수성 생리활성 물질(유제놀)이 랜덤하게(일정한 질서나 순서없이, 임의로) 결합되어 있음을 보여주는 모식도이다.
도 3은 나노다이아몬드를 사용하지 않고 소수성 생리활성 물질 Eugenol과 친수성 생리활성 물질 vitamin C을 물에 혼합한 것이고
도 4는 여기에 나노다이아몬드를 넣은 후 혼합시킨 용액이다.
도 5는 실시예 1에서 제조한 ND-COOH의 FT-IR 이다.
도 6은 실시예 2에서 제조한 ND- Eugenol-vitamin C는 FT-IR이다.
도 7은 실시예 3에서 제조한 ND-Glutathione - Hesperidine - Eugenol의 FT-IR 이미지이다.
도 8은 실험 1의 피부 투과실험을 공초점 현미경으로 촬영한 것이다.
도 9는 실험 1의 피부 투과실험을 정량적 값으로 측정한 것이다. 1 shows the surface structure of an explosive nanodiamond.
FIG. 2 (a) is a schematic diagram showing that the hydrophobic physiologically active substance is bound to the surface functional group of the nanodiamid by the solubilization step, and FIG. 2 (b) shows a hydrophilic bioactive substance (vitamin C) and a hydrophobic physiologically active substance (Random order, random order, random order).
FIG. 3 is a graph showing a comparison between a hydrophobic physiologically active substance Eugenol and a hydrophilic physiologically active substance vitamin C in water without using nano-diamonds
FIG. 4 shows a solution prepared by mixing nanodiamond with nanodiamond.
5 is FT-IR of ND-COOH prepared in Example 1. Fig.
6 shows the ND-Eugenol-vitamin C prepared in Example 2 as FT-IR.
7 is an FT-IR image of ND-Glutathione-Hesperidine-Eugenol prepared in Example 3. Fig.
8 is a photograph of a skin permeation experiment of Experiment 1 taken with a confocal microscope.
FIG. 9 is a graph showing a quantitative measurement of skin permeation experiment of Experiment 1. FIG.
본 발명은 나노 다이아몬드를 이용하여 소수성 생리활성 물질과 친수성 생리활성 물질을 가용화하여 피부에 전달하는 방법에 관한 것이다. The present invention relates to a method for solubilizing a hydrophobic physiologically active substance and a hydrophilic physiologically active substance using nano-diamonds and delivering the same to the skin.
본 발명의 생리활성 물질의 경피 전달 방법은 가용화 단계 및 피부 도포 단계를 포함한다. The transdermal delivery method of the physiologically active substance of the present invention includes a solubilization step and a skin application step.
상기 가용화 단계는 소수성 피부생리활성 물질, 친수성 피부 생리활성 물질 및 나노다이아몬드를 용매에 넣어 혼합하는 단계를 포함한다. The solubilizing step includes mixing a hydrophobic skin biologically active substance, a hydrophilic skin biologically active substance and a nanodiamond in a solvent.
도 1은 폭발형 나노다이아몬드의 표면 구조를 도시한 것이다. 도 2의 a는 상기 가용화 단계에 의해 소수성 생리활성 물질이 나노 다이아몬드 표면 기능기에 결합된 것을 보여주는 모식도이고, 도 2의 b는 친수성 생리활성물질(비타민 C)과 소수성 생리활성 물질(유제놀)이 랜덤하게(일정한 질서나 순서없이, 임의로) 결합되어 있음을 보여주는 모식도이다. 1 shows the surface structure of an explosive nanodiamond. FIG. 2 (a) is a schematic view showing that a hydrophobic physiologically active substance is bound to a surface functional group of a nanodiamid by the solubilizing step, and FIG. 2 (b) shows a hydrophilic bioactive substance (vitamin C) and a hydrophobic physiologically active substance (Random order, random order, random order).
도 1을 참고하면, 폭발형 나노다이아몬드는 표면에 COOH, C=O, NH2, CHO,OH, NO2,-C-O-C- 등의 기능기가 존재한다. 1, explosive nanodiamonds have functional groups such as COOH, C = O, NH2, CHO, OH, NO2, and -C-O-C- on the surface thereof.
상기 나노 다이아몬드의 표면 기능기는 Carboxyl, Lactone, Hydroxy, Phenol, Thiol, Amine 중 어느 하나 이상으로 표면 개질될 수 있다. The surface functional group of the nano-diamond may be surface-modified with at least one of Carboxyl, Lactone, Hydroxy, Phenol, Thiol and Amine.
상기 나노 다이아몬드 입자 1개의 평균크기는 10 이상 100nm 이하이며, 입자 하나에 부착된 상기 기능기의 개수가 10,000개 이상 1,000,000개 이하일 수 있다. 따라서, 상기 나노다이아몬드는 매우 많은 양의 생리활성 물질과 결합이 가능하다. The average size of the nanodiamond particles is 10 or more and 100 nm or less, and the number of the functional groups attached to one particle may be 10,000 or more and 1,000,000 or less. Therefore, the nanodiamond can bind with a very large amount of physiologically active substance.
본 발명에서는 상기 나노다이아몬드 표면 기능기에 링커(linker)를 부착하여 상기 기능기의 개수를 증폭시킬 수 있다. 상기 링커로는 alkylamine, arylamine, 당, 항산화물질, 단백질, 펩티드, 핵산 또는 SiCH계 화합물을 사용할 수 있다. 상기 링커는 기능기에 공유결합될 수 있다. In the present invention, a linker may be attached to the surface functional group of the nanodiamonds to amplify the number of functional groups. As the linker, alkylamine, arylamine, sugar, antioxidant, protein, peptide, nucleic acid or SiCH compound can be used. The linker may be covalently attached to the functional group.
본 발명에서 상기 생리활성 물질은 피부 개선에 영향을 미치는 공지된 물질을 제한 없이 사용할 수 있다. In the present invention, the physiologically active substance may be any known substance that affects skin improvement.
상기 피부 생리 활성물질은 유기물질, 무기물질 또는 이들을 모두 포함할 수 있다. 상기 나노다이아몬드 표면의 기능기(10,000~1,000,000개)에 분자수준의 서로 다른 종류의 생리활성 물질이 상당량 부착될 수 있다. The skin physiologically active substance may include an organic substance, an inorganic substance, or both. A large amount of different kinds of physiologically active substances at the molecular level can be attached to the functional groups (10,000 to 1,000,000) of the surface of the nano diamond.
상기 유기물질은 비타민, 지질, 단백질, 펩타이드, 플라보노이드, 핵산, 천연물질군일 수 있다. The organic material may be a vitamin, a lipid, a protein, a peptide, a flavonoid, a nucleic acid, a natural substance group.
상기 무기물질은 탄소에 Si, S, P가 결합된 탄소실리콘계, 탄소황화물계, 탄소인화물계 화합물질들을 포함할 수 있다. The inorganic material may include carbon-silicon-based, carbon-sulfide-based, carbon-phosphide-based compound materials in which Si, S, and P are bonded to carbon.
좀 더 구체적으로, 상기 피부 생리활성 물질은 유제놀, 아스코르빅산, 비타민A, 비타민B, 비타민C, 비타민E, 비타민K, 비타민P, 하이드로퀴논, 헤스페리딘, 글루타치온, EGCG, 레티놀, 아데노신, 히알루론산, 탄닌산, 펩타이드,폴리페놀,플라보노이드와 이들의 유도체로 이루어진 군으로부터 선택될 수 있다.More specifically, the skin biologically active substance may be selected from the group consisting of eugenol, ascorbic acid, vitamin A, vitamin B, vitamin C, vitamin E, vitamin K, vitamin P, hydroquinone, hesperidin, glutathione, EGCG, retinol, adenosine, Lactic acid, tannic acid, peptides, polyphenols, flavonoids and derivatives thereof.
상기 생리 활성물질의 분자량은 2 ~ 500,000이하 일 수 있고, 바람직하게는 2~500 이하일 수 있다. The molecular weight of the physiologically active substance may be 2 to 500,000 or less, preferably 2 to 500 or less.
친수성 생리활성 물질이라 함은 친수성이며 피부개선효과가 우수한 물질을 말하는 것으로서, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 알려진 것이면 특별한 제한은 없으나, 예를 들면 알부틴, 아데노신, 비타민 C 및 그 친수성 유도체들, 이를 제외한 비타민 B3, 비타민 B5, 비타민 H 등 각종 친수성 비타민 및 그 유도체, 아세틸글루코사민, 마데카소사이드를 포함한 센텔라아시아티카 추출물, 셀레늄 아스파테이트, 각종 식물추출물 및 각종 펩타이드 성분들 또는 2 성분 이상의 혼합물일 수 있다. The hydrophilic physiologically active substance refers to a substance which is hydrophilic and has an excellent skin improving effect, and is not particularly limited as long as it is known to those skilled in the art. For example, arbutin, adenosine, vitamin C and Its hydrophilic derivatives, various hydrophilic vitamins and derivatives thereof such as vitamin B3, vitamin B5 and vitamin H, acetylglucosamine, Centella asiatica extract including maddicoside, selenium aspartate, various plant extracts and various peptide components or It may be a mixture of two or more components.
소수성 생리활성 물질은 소수성 특성이 우세한 물질로서, 유제놀, Retinol, ASTAXANTHIN,CAFFEIC ACID,CARNOSIC ACID,CATECHIN, COENZYME-Q10, CURCUMIN, ELLAGIC ACID, FERULIC ACID, IDEBENONE, ISOFLAVONE, LINOLEIC ACID,LIPOIC ACID, LYCOPENE, OLEANOLIC ACID,PHLORETIN, QUERCETIN, RESVERATROL, SQUALANE, SQUALENE, TANNIC ACID,VITAMIN A,VITAMIN B VITAMIN E , VITAMIN F, CHOLESTEROL, PHYTOSPHINGOSINE, SQUALENE, GLYCOSPHINGOLIPID, BETA-SITOSTEROL, LAURIC ACID, LECITHIN 일 수 있다. The hydrophobic physiologically active substance is a substance having a hydrophobic property predominantly and is a substance having hydrophobic properties such as eugenol, Retinol, ASTAXANTHIN, CAFFEIC ACID, CARNOSIC ACID, CATECHIN, COENZYME-Q10, CURCUMIN, ELLAGIC ACID, FERULIC ACID, IDEBENONE, ISOFLAVONE, LINOLEIC ACID, LIPOIC ACID, LYCOPENE , OLEANOLIC ACID, PHLORETIN, QUERCETIN, RESVERATROL, SQUALANE, SQUALENE, TANNIC ACID, VITAMIN A, VITAMIN B VITAMIN E, VITAMIN F, CHOLESTEROL, PHYTOSPHINGOSINE, SQUALENE, GLYCOSPHINGOLIPID, BETA-SITOSTEROL, LAURIC ACID, LECITHIN.
본 발명에서 소수성 생리활성 물질과 친수성 생리활성 물질에 대한 어떤 제한이 있는 것은 아니며, 상기 소수성 생리활성 물질은 분배계수를 기준으로 피부각질층 투과가 용이한 물질이고, 상기 친수성 생리활성 물질은 피부 각질층 투과가 어려운 물질 일 수 있다. 예를 들면, 상기 소수성 생리활성 물질은 분배계수(log P 값)가 1~3으로 피부각질층 투과가 용이한 물질이고, 상기 친수성 생리활성 물질은 피부 각질층 투과가 어려운 물질(분배계수(log P 값)가 1 미만인 것)일 수 있다. In the present invention, there is no limitation on the hydrophobic physiologically active substance and the hydrophilic physiologically active substance, and the hydrophobic physiologically active substance is a substance that permits permeation of the horny layer on the basis of the distribution coefficient, and the hydrophilic physiologically active substance is the horny layer permeable Can be a difficult substance. For example, the hydrophobic physiologically active substance has a distribution coefficient (log P value) of 1 to 3 and is easily permeable to the skin horny layer. The hydrophilic physiologically active substance is a substance hardly permeable to the horny layer of the skin ) Is less than 1).
상기 소수성 피부생리활성 물질 또는 친수성 피부 생리활성 물질은 항산화, 주름개선, 미백, 보습 또는 탈모예방 활성을 가지는 것을 사용할 수 있다. The hydrophobic skin biologically active substance or the hydrophilic skin biologically active substance may be one having antioxidative, wrinkle-improving, whitening, moisturizing or hair-loss-preventing activity.
상기 주름개선 활성을 갖는 생리활성 물질은 피부 세포 성장인자, 단백질 또는 펩타이드군, 레티놀, 레티닐팔미테이트, 아데노신 및 폴리에톡실레이티드레틴아미드의 군에서 선택된 것일 수 있다. The physiologically active substance having the wrinkle-improving activity may be selected from the group of skin cell growth factor, protein or peptide group, retinol, retinyl palmitate, adenosine and polyethoxylated retinamide.
상기 미백 활성을 갖는 생리활성 물질은 알부틴, 아스코르빅산, 에칠아스코르빌에텔, 아스코르빌글루코사이드, 니아신아마이드, 아스코빌포스페이트, 비사보롤, 미백펩타이드군으로부터 선택된 것일 수 있다. The physiologically active substance having the whitening activity may be selected from the group consisting of arbutin, ascorbic acid, erucic ascorbic acid, ascorbyl glucoside, niacinamide, ascorbyl phosphate, bisabolol, whitening peptide.
상기 용매는 물, 에탄올 또는 물과 에탄올의 혼합액, 또는 완충용액들인 것일 수 있다. The solvent may be water, ethanol, or a mixture of water and ethanol, or buffer solutions.
상기 가용화 단계는 상기 소수성 피부생리활성 물질과 상기 친수성 피부 생리활성 물질의 농도 또는 소수성 정도, 나노다이아몬드 함량에 따라 pH를 제어할 수 있다. In the solubilizing step, the pH can be controlled according to the concentration or hydrophobicity of the hydrophobic skin biologically active substance and the hydrophilic skin biologically active substance, and the content of the nanodiamond.
예를 들면, 상기 기용화 단계는 pH를 3~10, 바람직하게는 5~8, 더욱 바람직하게는 6~7 일 수 있다. For example, the vaporization step may have a pH of 3 to 10, preferably 5 to 8, more preferably 6 to 7.
상기 가용화 단계는 상기 용액을 소정 시간 동안 강하게 교반할 수 있다. 예를 들면, 상기 혼합시간은 24 시간일 수 있다 Said solubilizing step can stir the solution vigorously for a predetermined period of time. For example, the mixing time may be 24 hours
상기 혼합단계는 초음파를 추가로 사용하여 혼합용액을 (강하게) 혼합할 수 있다. The mixing step may (strongly) mix the mixed solution by further using ultrasonic waves.
본 발명의 가용화 단계는 계면활성제 등의 첨가제 없이 혼합물을 적정 pH 조건에서 교반하는 것으로 수행될 수 있다. The solubilization step of the present invention can be carried out by stirring the mixture at an appropriate pH condition without additives such as a surfactant.
상기 가용화 단계에서 첨가되는 나노다이아몬드 입자 : 친수성 생리활성 물질 : 소수성 생리활성 물질의 중량비(또는 몰비)는 적절한 범위에서 혼합될 수 있다. The weight ratio (or molar ratio) of the nanodiamond particles: hydrophilic physiologically active substance: hydrophobic physiologically active substance added in the solubilization step may be mixed in an appropriate range.
상기 방법은 상기 나노다이아몬드를 2000ppm 이상 첨가할 수 있다. 좀 더 구체적으로는 상기 나노다이아몬드를 용매 대비 0.001~20중량% 첨가할 수 있다. The method may include adding at least 2000 ppm of the nanodiamond. More specifically, the nano-diamonds may be added in an amount of 0.001 to 20 wt% relative to the solvent.
상기 생리활성 물질의 함량은 표면 개질된 나노다이아몬드 중량의 5~30% 일 수 있다. 한편, 나노다이아몬드 표면에 링커를 이용하여 기능기의 개수가 증가된 경우 상기 생리활성 물질의 함량은 표면 개질된 나노다이아몬드 중량의 0.1~1,000% 범위가 될 수 있다. The amount of the physiologically active substance may be 5 to 30% of the weight of the surface-modified nanodiamond. On the other hand, when the number of functional groups is increased by using a linker on the surface of the nano diamond, the content of the physiologically active substance may be in the range of 0.1 to 1,000% of the weight of the surface-modified nano diamond.
도 2를 참고하면, 본 발명의 가용화 단계를 거치면 친수성 생리 활성 물질과 소수성 생리활성 물질이 나노다이아몬드와의 비공유결합을 통해 용매에 균일하게 혼합되어 존재한다. Referring to FIG. 2, the hydrophilic physiologically active substance and the hydrophobic physiologically active substance are uniformly mixed in a solvent through non-covalent bonding with the nanodiam under the solubilizing step of the present invention.
상기 가용화 단계는 소수성 피부 생리활성 물질과 친수성 피부 생리활성 물질이 나노 다이아몬드의 표면 기능기에 동시에 비공유결합되는 단계이다. The solubilization step is a step in which the hydrophobic skin biologically active substance and the hydrophilic skin biologically active substance are concurrently bonded to the surface functional group of the nanodiamond.
상기 나노다이아몬드와 피부생리활성물질의 비공유결합은 수소결합, 정전기적인력에 의한 결합, 반데르바알스 결합일 수 있다. The non-covalent bonding of the nanodiamond and the skin biologically active substance may be a hydrogen bond, a bond by an electrostatic attractive force, or a van der Waals bonding.
본 발명에서 사용하는 용어인 “가용화”는 서로 용해되지 않는 친수성 생리활성 물질과 소수성 생리활성 물질이 친수성 또는 소수성 용매에 균일하게 섞여 존재하는 상태를 나타내는 용어로 사용한다. 또한, 본 발명에서는 상기 생리활성 물질이 (무기물질인 경우) 용매에 용해되지 않고도 입자 상태로 분산되어 있는 경우도 “가용화”로 표시한다. 본 발명의 나노다이아몬드는 가용화 단계를 거치더라도 용해되지 않고 용매에 분산된다. As used herein, the term " solubilization " is used to refer to a state in which a hydrophilic physiologically active substance which is not mutually soluble and a hydrophobic physiologically active substance are uniformly mixed in a hydrophilic or hydrophobic solvent. In the present invention, the physiologically active substance (in case of an inorganic substance) is also referred to as " solubilized " when it is dispersed in a particle state without being dissolved in a solvent. The nanodiamonds of the present invention are dispersed in a solvent without dissolving even after the solubilization step.
본 발명자들은 서로 용해되지 않는 친수성과 소수성의 생리활성 물질이 가용화되는 것이 나노다이아몬드에 의한 것임을 알고 본 발명을 제출하게 되었다. The inventors of the present invention have found that the solubilization of hydrophilic and hydrophobic physiologically active substances which are not soluble in each other is caused by nanodiamonds.
좀 더 구체적으로, 본 발명자들은 생리활성물질과 나노다이아몬드의 표면에 존재하는 기능기 및 나노다이아몬드 표면 수분층간의 상호작용에 의해 상기 생리활성물질들을 가용화한다고 판단하고 있다. More specifically, the inventors of the present invention have determined that the physiologically active substances are solubilized by interaction between the physiologically active substance and functional groups existing on the surface of the nanodiamonds and the surface water layer of the nanodiamonds.
상기 소수성 및 친수성 생리활성 물질은 상기 나노 다이아몬드 입자 표면에 존재하는 10,000개 이상 1,000,000개 이하의 기능기에 의해 분자단위로 결합되어 존재할 수 있다. The hydrophobic and hydrophilic physiologically active substance may exist in a molecular unit by binding with 10,000 to 1,000,000 or less functional groups present on the surface of the nanodiamond particles.
도 2의 b는 상기 혼합단계에 의해 소수성 및 친수성 생리활성 물질의 분자들이 나노 다이아몬드 표면 기능기에 랜덤하게(일정한 질서나 순서없이, 임의로) 결합되어 있음을 보여주는 개념도이다. FIG. 2 (b) is a conceptual diagram showing that molecules of the hydrophobic and hydrophilic physiologically active substance are randomly bonded (random order, random order, or the like) to the nanodiamond surface functional group by the mixing step.
도 2를 참고하면, 나노다이아몬드 표면에 10,000개 이상 1,000,000개 이하의 기능기가 존재하고 있는데, 이들 기능기의 일부에 소수성 생리활성 물질(20)이 결합되고, 나머지 일부에 친수성 생리활성 물질이 결합될 수 있다. 즉, 수많은 친수성 생리활성 분자들과 소수성 생리활성 분자들이 하나의 나노다이아몬드 입자에 동시에 담지되어 존재할 수 있다. 나노다이아몬드 입자 1개당 결합되는 피부생리활성 물질의 몰 범위가 최대 1× 10-4mol/g ~ 1× 10-2mol/g의 범위일 수 있다. Referring to FIG. 2, there are 10,000 to 1,000,000 functional groups on the surface of a nano diamond. Hydrophobic physiologically active substance 20 is bound to a part of these functional groups, and a hydrophilic physiologically active substance is bound to the remaining part . That is, a large number of hydrophilic bioactive molecules and hydrophobic bioactive molecules may be present simultaneously on one nanodiamond particle. The molar range of the skin biologically active substance bound per nanodiamond particle may be in the range of 1 x 10-4 mol / g to 1 x 10-2 mol / g at the maximum.
본 발명자들은 도 2와 같이, 하나의 나노다이아몬드 입자에 수십 내지 수십만 개의 소수성 생리활성 분자와 친수성 생리활성 분자가 동시에 결합되고도 안정적으로 유지되는 것은 나노다이아몬드 표면에 존재하는 10,000개 이상 1,000,000개 이하의 기능기와 이들 기능기가 가지는 활성 에너지 때문으로 이해하고 있다. As shown in FIG. 2, the present inventors have found that when a single nanodiamond particle has tens to hundreds of thousands of hydrophobic biologically active molecules and hydrophilic bioactive molecules bound to each other at the same time and stably maintained, And the active energy of these functional groups.
도 3은 나노다이아몬드를 사용하지 않고 소수성 생리활성 물질 Eugenol과 친수성 생리활성 물질 vitamin C을 물에 혼합한 것이고 도 4는 여기에 나노다이아몬드를 넣은 후 혼합시킨 용액이다. FIG. 3 shows a mixture of hydrophobic physiologically active substance Eugenol and a hydrophilic physiologically active substance vitamin C in water without using nano-diamonds, and FIG. 4 shows a solution prepared by adding nanodiamond thereto.
도 3은 소수성 물질인 Eugenol의 방울들이 섞이지 않고 유리병의 바닥에 가라앉은 것이 확연히 구분되었으나, 도 4의 경우에는 나노다이아몬드를 통해서 소수성 생리활성 물질과 친수성 생리활성 물질이 균일하게 혼합되어 존재함을 확인할 수 있다. FIG. 3 clearly shows that droplets of Eugenol, which is a hydrophobic substance, do not mix and sink to the bottom of a glass bottle. However, in FIG. 4, a hydrophobic physiologically active substance and a hydrophilic physiologically active substance are mixed uniformly through the nanodiamond Can be confirmed.
본 발명의 가용화 방법은 상기 생리활성 물질의 분자구조나 활성 변형 없이 안정적으로 나노다이아몬드에 담지할 수 있다. The solubilization method of the present invention can stably support the physiologically active substance on the nanodiamond without any molecular structure or active deformation.
본 발명은 상기 가용화된 용액에 화장료를 첨가하여 화장료 조성물을 제조할 수 있다. In the present invention, a cosmetic composition can be prepared by adding a cosmetic to the solubilized solution.
상기 화장료는 유연 화장수(스킨), 영양 화장수(밀크 로션), 영양 크림, 맛사지 크림 또는 엣센스일 수 있다. The cosmetic may be a soft lotion (skin), a nutritional lotion (milk lotion), a nutritional cream, a massage cream or essence.
상기 화장료는 미백제, 보습제, 산화방지제, 자외선 흡수제, 계면 활성제, 증점제, 알콜류, 보존제, 겔화제, 향, 충전제 또는 염료를 포함할 수 있다. The cosmetic may contain a whitening agent, a moisturizing agent, an antioxidant, an ultraviolet absorber, a surfactant, a thickener, an alcohol, a preservative, a gelling agent, an incense, a filler or a dye.
상기 방법은 상기 가용화된 용액 또는 화장료 조성물을 젤 또는 에멀젼 형태로 제조할 수 있다. The method may make the solubilized solution or cosmetic composition in the form of a gel or an emulsion.
상기 방법은 상기 가용화된 용액을 건조시켜 분말형태로 제조할 수 있다. The method may be carried out by drying the solubilized solution to obtain a powder form.
본 발명은 상기 가용화된 용액이나 상기 화장료 조성물을 피부에 도포하는 단계를 포함한다. The present invention includes a step of applying the solubilized solution or the cosmetic composition to the skin.
상기 피부도포 단계는 상기 나노다이아몬드 표면에 비공유 결합된 친수성 생리활성 물질과 소수성 생리활성 물질을 방출(release)하는 단계와 각각의 피부 표피층 틈을 통해 피부 내부로 상기 친수성 유기물질과 소수성 유기물질이 함께 침투하는 단계를 포함할 수 있다. The skin applying step may include releasing a hydrophilic bioactive material and a hydrophobic bioactive material that are not covalently bonded to the surface of the nanodiamond and a step of releasing the hydrophilic organic material and the hydrophobic organic material into the skin through the skin skin layer gap Penetration step.
상기 방출 단계는 상기 나노다이아몬드의 기능기와 비공유 결합된 친수성 생리활성 물질 및 소수성 생리활성 물질이 피부의 pH 변화에 의해 상기 기능기와 분리되어 피부로 침투할 수 있다. In the releasing step, the hydrophilic physiologically active substance and the hydrophobic physiologically active substance that are not covalently bonded to the functional group of the nanodiamper may be separated from the functional group by the pH change of the skin, and penetrate into the skin.
상기 방출 단계는 상기 나노다이아몬드의 기능기와 비공유 결합된 친수성 생리활성 물질 및 소수성 생리활성 물질의 농도차에 의해 상기 기능기로부터 분리되어 피부로 침투할 수 있다. 또한, 상기 친수성 생리활성 물질 및 소수성 생리활성 물질은 땀 등의 체액이나 체액에 함유된 염분의 농도에 의해 나노다이아몬드로부터 분리되어 피부로 침투될 수 있다. The release step may be separated from the functional group by the difference in the concentration of the hydrophilic bioactive material and the hydrophobic bioactive material, which are not covalently bonded to the functional group of the nanodiamond, and penetrate into the skin. In addition, the hydrophilic physiologically active substance and the hydrophobic physiologically active substance can be separated from the nanodiamond and penetrate into the skin by the concentration of saline contained in a body fluid such as sweat or body fluids.
상기 피부 도포 단계에서 피부 생리활성 물질은 피부 내부로 침투하지만, 상기 나노다이아몬드는 피부 표면에 그대로 잔존한다. In the skin application step, the skin physiologically active substance penetrates into the skin, but the nanodiamides remain on the surface of the skin.
이하에서, 실시예를 들어 본 발명에 대하여 더욱 상세하게 설명할 것이나, 이들은 단지 본 발명의 바람직한 구현예를 예시하기 위한 것으로, 실시예가 본 발명의 범위를 제한하는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples, but they should be construed as merely illustrative of preferred embodiments of the present invention, and the examples do not limit the scope of the present invention.
실시예1Example 1
ND-ND- COOH의Of COOH 제조 Produce
나노리소스의 입자분산 공정을 이용하여 제조한 평균 입자 크기가 50nm인 잘 분산된 나노다이아몬드 10g을 황산과 질산을 부피비 3:1로 한 600ml에 넣어 140℃에서 12시간 반응시켰다. 반응 후 여액의 휘발과 비산을 막기 위해 얼음조를 사용하여 약 30분 희석시킨 후 원심분리 시켰다. 원심분리는 pH가 중성이 될 때까지 약10회 반복하였다. 이렇게 해서 얻은 분산된 나노다이아몬드를 건조시켰다. 건조는 오븐에서 100℃에서 10시간 시키거나 별도로 증발농축기를 이용하여 수분을 제거하였다. 상기에서 얻은 입자를 FT-IR을 통해 ND-COOH임을 확인하였다(도 5). 10 g of finely dispersed nanodiamonds having an average particle size of 50 nm prepared by using a nanodevice particle dispersion process were placed in 600 ml of sulfuric acid and nitric acid at a volume ratio of 3: 1 and reacted at 140 ° C for 12 hours. After the reaction, the filtrate was diluted with an ice bath for about 30 minutes to prevent volatilization and scattering, and then centrifuged. The centrifugation was repeated about 10 times until the pH became neutral. The thus-obtained dispersed nanodiamonds were dried. Drying was carried out in an oven at 100 ° C for 10 hours or separately by using an evaporator to remove moisture. The particles thus obtained were confirmed to be ND-COOH through FT-IR (FIG. 5).
ND-ND- EugenolEugenol - vitamin - vitamin C 의Of C 제조 Produce
실시예 1에서 제조된 나노다이아몬드 2g을 탈이온수 900mL에 넣은 후 초음파를 사용하여 60분간 분산시킨 후, 상온이 될 때까지 방치하였다. 0.25N NaOH 용액을 사용하여 pH를 7로 적정한 후, 순서에 상관없이 친수성 생리활성 물질 Vitamin C 100mg, 소수성 생리활성 물질 Eugenol 100mg을 넣어 10분 동안 교반한 후, 1000mL이 되도록 탈이온수를 가하였다.10,000 rpm에서 10분 동안 원심분리를 시켜 고체와 액체를 분리하였으며 이를 1회 세척하여 분말상의 ND- Eugenol-vitamin C을 제조하였다. 2 g of the nanodiamond prepared in Example 1 was placed in 900 ml of deionized water, dispersed for 60 minutes by using ultrasonic waves, and left to stand at room temperature. After adjusting the pH to 7 with 0.25N NaOH solution, 100 mg of hydrophilic physiologically active substance Vitamin C and 100 mg of hydrophobic physiologically active substance Eugenol were added thereto, stirred for 10 minutes, and then deionized water was added to 1000 mL. The solid and liquid were separated by centrifugation at 10,000 rpm for 10 minutes and washed once to prepare ND-Eugenol-vitamin C powder.
제조한 ND- Eugenol-vitamin C는 FT-IR 을 이용하여 complex의 활성물질 존재 유무를 확인하였다(도 6). The ND-Eugenol-vitamin C thus prepared was confirmed by using FT-IR to determine the existence of an active substance in the complex (FIG. 6).
실시예Example 3 3
ND-ND- GlutathioneGlutathione - - HesperidineHesperidine - - EugenolEugenol 의 제조 Manufacturing
실시예 1에서 제조된 나노다이아몬드 2g을 탈이온수 900mL에 넣은 후 초음파를 사용하여 60분간 분산시킨 후, 상온이 될 때까지 방치하였다. 0.25N NaOH 용액을 사용하여 pH를 7로 적정한 후, 순서에 상관없이 친수성 생리활성 물질 Glutathione 2mg, 소수성 생리활성 물질 Hesperidin 0.2mg, Eugenol 100mg을 넣어 10분 동안 교반한 후, 1000mL이 되도록 탈이온수를 가하였다. 10,000 rpm에서 10분 동안 원심분리를 시켜 고체와 액체를 분리하였으며 이를 1회 세척하여 분말상의 ND-Glutathione - Hesperidine - Eugenol을 제조하였다. 2 g of the nanodiamond prepared in Example 1 was placed in 900 ml of deionized water, dispersed for 60 minutes by using ultrasonic waves, and then allowed to stand at room temperature. After adjusting the pH to 7 with 0.25N NaOH solution, add 2 mg of hydrophilic physiologically active substance Glutathione, 0.2 mg of hydrophobic physiologically active substance Hesperidin and 100 mg of Eugenol for 10 minutes, irrespective of the order. After stirring for 10 minutes, deionized water . The solid and liquid were separated by centrifugation at 10,000 rpm for 10 minutes and washed once to prepare powdered ND-Glutathione-Hesperidine-Eugenol.
제조한 ND-Glutathione - Hesperidine - Eugenol는 FT-IR을 이용하여 이용하여 complex의 활성물질 존재 유무를 확인하였다(도 7). The ND-Glutathione-Hesperidine-Eugenol thus prepared was confirmed by using FT-IR to determine the existence of an active substance in the complex (FIG. 7).
실시예Example 4: 공유 결합을 이용한 ND- 4: ND- COOHCOOH 형광 유도체( Fluorescent derivatives ( FluoresceinFluorescein )의 합성 ) Synthesis of
ND-COOH 1g을 SOCl2 30mL과 무수DMF 0.15mL의 혼합액에 가한 후, 초음파를 사용하여 완전히 분산시켰다. 홉합액을 70℃에서 24시간 동안 가온한 후, 잔여분의 SOCl2는 저온 및 감압 조건에서 증류하여 제거하였다.1 g of ND-COOH was dissolved in SOCl 2 And 0.15 mL of anhydrous DMF, followed by thorough dispersion using ultrasonic waves. After the hop mixture was heated at 70 ° C. for 24 hours, the residual SOCl 2 was removed by distillation at low temperature and under reduced pressure.
상기 반응으로 얻어진 ND-COCl2는 초음파를 이용하여 무수 DMSO에 완전히 혼합시켰으며 여기에 0.3mL의 pyridine과 5g의 ethylenediamine을 가하였다. 혼합액을 24시간 동안 상온에서 교반하여 반응시키고 진공 장치를 이용하여 DMSO를 제거한 후, 탈이온수로 원심분리하여(10,000rpm, 10분)반응물을 세척하였으며 이 과정을 5번 반복하였다. The ND-COCl 2 obtained by the above reaction was thoroughly mixed with anhydrous DMSO using ultrasonic waves, and 0.3 mL of pyridine and 5 g of ethylenediamine were added thereto. The reaction mixture was stirred at room temperature for 24 hours, and then the reaction solution was washed with deionized water (10,000 rpm, 10 minutes) to remove DMSO by using a vacuum device. This procedure was repeated five times.
상기 반응에서 얻어진 ND-CONH-(CH2)2-NH2 1g을 0.1M sodium bicarbonate 용액에 가한 후, 여기에 형광물질인 Fluorescein 5g을 다시 가하고 24시간 동안 상온에서 교반하였다. 교반 후, 탈이온수로 원심분리하여(10,000rpm, 10분) 반응물을 세척하였으며 이 과정을 5번 반복하였다. 1 g of ND-CONH- (CH 2 ) 2 -NH 2 obtained in the above reaction was added to 0.1 M sodium bicarbonate solution, and 5 g of fluorescent material Fluorescein was added thereto again and stirred at room temperature for 24 hours. After stirring, the reaction product was centrifuged (10,000 rpm, 10 minutes) with deionized water, and the reaction was repeated five times.
피부 도포Skin application
앞에서 제조된 가용액 용액을 0.5 mL 정도 피부에 도포하였다. 0.5 mL of the prepared solution was applied to the skin.
비교예Comparative Example 1 One
실시예 1에서 나노다이아몬드를 첨가하지 않고 소수성 생리활성 물질 Eugenol과 친수성 생리활성 물질 vitamin C을 물에 넣고 교반하였다(함량 조건은 실시예 1과 동일함). In Example 1, the hydrophobic physiologically active substance Eugenol and the hydrophilic physiologically active substance vitamin C were added to water and stirred without adding nanodiamonds (the content conditions were the same as in Example 1).
도 3은 소수성 물질인 Eugenol의 방울들이 섞이지 않고 유리병의 바닥에 가라앉은 것이 확연히 구분되었으나, 도 4의 경우에는 나노다이아몬드를 통해서 소수성 생리활성 물질과 친수성 생리활성 물질이 균일하게 혼합되어 존재함을 확인할 수 있다. FIG. 3 clearly shows that droplets of Eugenol, which is a hydrophobic substance, do not mix and sink to the bottom of a glass bottle. However, in FIG. 4, a hydrophobic physiologically active substance and a hydrophilic physiologically active substance are mixed uniformly through the nanodiamond Can be confirmed.
실험 Experiment 1 ; 나노다이아몬드의One ; Nano-diamond 피부 skin 비투과Non-transmission 실험 Experiment
상기 ND-COOH의 피부 조직 내 침투 (경피흡수) 여부를 확인하기 위하여 공시된 가이드라인에 따라 경피흡수 실험을 수행하였다(Test Guideline 428 : Skin absroption: in vitro Method, OECD, Paris, (2004), 생체외 피부흡수시험 가이드라인, 한국식품의약품안전청 (2010)). 경피 흡수 실험은 porcine skin (돼지 피부)를 이용하였으며 준비된 피부를 수직형의 확산셀(Franz diffusion cell, Logan FDC-6, Logan instrument Corp. Somerset, NJ, USA)의 도너 (donor)과 리셉터 (receptor) 사이에 표피가 위로 (donor 방향으로) 향하게 하고 진피는 아래로 (receptor 방향으로) 장착하였다. 리셉터에 PBS 용액 (phosphate-buffered saline, pH 7.4, 32℃)을 채우고 돼지 피부가 PBS 용액과 평형상태가 되도록 1시간 동안 방치하였다. 이후, 상기 실시예 4에서 제조된 ND-COOH 형광 유도체를 0.5mL의 물에 분산하여 피부에 도포하고 하였다. 각 12, 24, 48 시간 후 피부조직을 회수하여 탈이온수로 세척 한 후, 10 % Formaldehyde에 18시간 동안 보관함으로서 피부 조직을 고정하였다. 고정한 후, 마이크롬 냉동박절기(Microm HM520 cryostat, Thermo)를 이용하여 동결절편(Cryosection)(14 μm)을 제조한 뒤, 이를 유리 슬라이드 위에 올려 제작하였다. 제작된 슬라이드는 10분 동안 PBS 완충용액으로 절편을 세척하고 0.2 mM DAPI 용액에 7분 간 노출하여 조직 내 세포핵을 염색하였다. 염색된 조직을 다시 10분 간 3번씩 PBS 완충용액으로 세척한 후, 중첩배지(mounting media)를 이용하여 슬라이드에 고정한 후에 공초점 현미경으로 관찰하였고 그 결과를 도 8에 나타내었다. In order to confirm the penetration of ND-COOH into the skin tissue (percutaneous absorption), percutaneous absorption experiments were conducted according to the published guidelines (Test Guideline 428: Skin Absorption: in vitro Method, OECD, Paris, In vitro skin absorption test guidelines, Korea Food & Drug Administration (2010)). Percutaneous absorption experiments were performed using porcine skin (pig skin), and the prepared skin was treated with a donor and receptor of a vertical diffusion cell (Franz diffusion cell, Logan FDC-6, Logan instrument Corp., Somerset, NJ, USA) ) With the epidermis facing up (toward the donor) and the dermis down (towards the receptor). The receptor was filled with PBS solution (phosphate-buffered saline, pH 7.4, 32 ° C) and allowed to stand for 1 hour to allow the pig skin to equilibrate with the PBS solution. Thereafter, the ND-COOH fluorescent derivative prepared in Example 4 was dispersed in 0.5 mL of water and applied to the skin. After 12, 24, and 48 hours, the skin tissues were collected, washed with deionized water, and fixed in 10% formaldehyde for 18 hours. After fixation, frozen sections (14 μm) were prepared using Microm HM520 cryostat (Thermo) and mounted on glass slides. The prepared slides were washed with PBS buffer solution for 10 minutes and exposed to 0.2 mM DAPI solution for 7 minutes to stain nuclei in the tissue. The stained tissue was again washed with PBS buffer three times for 10 minutes, fixed on a slide using mounting media, and observed with a confocal microscope. The results are shown in FIG.
또한 각 6, 12, 18, 24, 30, 36, 48 시간에서 리셉터의 시료를 회수하여 형광측정 장비를 이용 리셉터에 투과된 형광물질의 형광값을 측정함으로서 정량적 값을 구하여 이를 도 9에 나타내었다. A sample of the receptor was recovered at 6, 12, 18, 24, 30, 36, and 48 hours, and the fluorescence value of the fluorescent material transmitted through the receptor was measured using a fluorescence measuring device to obtain a quantitative value, .
도 8과 도 9을 참고하면, 음성대조군인 형광물질(Fluorescein)은 피부를 투과 하였으나 ND에 결합된 Fluorescein은 피부를 투과하지 않는 것을 확인 할 수 있었다. Referring to FIGS. 8 and 9, it was confirmed that the fluorescence substance (Fluorescein), which is a negative control, penetrated through the skin, but Fluorescein bound to ND did not permeate through the skin.
이상에서, 본 발명의 바람직한 구현예에 대하여 상세하게 설명하였으나, 이들은 단지 설명의 목적을 위한 것으로 본 발명의 보호 범위가 이들로 제한되는 것은 아니다. While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments.
Claims (26)
가용화된 상기 용액을 피부에 도포하는 단계를 포함하는 생리활성 물질의 경피 전달 방법.A step of solubilizing a hydrophobic skin biologically active substance, a hydrophilic skin biologically active substance and a nanodiamond in a solvent; And
And applying the solubilized solution to the skin.
가용화된 상기 용액으로부터 나노다이아몬드 복합체를 분리 및 건조시키는 단계 ; 및
상기 나노다이이몬드 복합체를 용액에 분산시켜 피부에 도포하는 단계를 포함하는 생리활성 물질의 경피 전달 방법.A step of solubilizing a hydrophobic skin biologically active substance, a hydrophilic skin biologically active substance and a nanodiamond in a solvent; And
Separating and drying the nanodiamond complex from the solubilized solution; And
And dispersing the nano-diamonds complex in a solution and applying the dispersion to the skin.
각각의 피부 표피층 틈을 통해 피부 내부로 상기 친수성 유기물질과 소수성 유기물질이 함께 침투하는 단계를 포함하는 것을 특징으로 하는 생리활성 물질의 경피 전달 방법.The method of claim 1 or 2, wherein the skin applying step comprises: releasing a hydrophilic bioactive material and a hydrophobic bioactive material that are not covalently bonded to the surface of the nanodiamond; And
Wherein the hydrophilic organic material and the hydrophobic organic material penetrate into the skin through the skin skin layer gaps, respectively.
[26] The method of claim 24, wherein the releasing step separates the functional group from the functional group by a difference in concentration of the hydrophilic bioactive material and the hydrophobic bioactive material not covalently bonded to the functional group of the nanodiamond, Percutaneous delivery method.
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| KR101875407B1 (en) * | 2017-09-22 | 2018-07-06 | 나노다이아랩(주) | Method of preparing cosmetic composition comprising dispersed Astaxanthin |
| WO2020036266A1 (en) * | 2018-08-17 | 2020-02-20 | 이강현 | Nanoliposome preparation method using horse oil and nanodiamonds and composition thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| HK1257465A2 (en) * | 2018-06-22 | 2019-10-18 | Master Dynamic Ltd | Skin hydration composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100305309A1 (en) * | 2009-05-28 | 2010-12-02 | Northwestern University | Nanodiamond particle complexes |
| TWI414309B (en) * | 2009-07-13 | 2013-11-11 | Univ Nat Chiao Tung | Medicine and carrier comprising nanodiamond, method for preparing the same and use thereof |
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2015
- 2015-05-08 KR KR1020150064876A patent/KR101876282B1/en active IP Right Grant
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2016
- 2016-05-09 WO PCT/KR2016/004784 patent/WO2016182277A2/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101875407B1 (en) * | 2017-09-22 | 2018-07-06 | 나노다이아랩(주) | Method of preparing cosmetic composition comprising dispersed Astaxanthin |
| WO2019059661A1 (en) * | 2017-09-22 | 2019-03-28 | 나노다이아랩 주식회사 | Method for preparing cosmetic composition having biologically active substance dispersed therein |
| WO2020036266A1 (en) * | 2018-08-17 | 2020-02-20 | 이강현 | Nanoliposome preparation method using horse oil and nanodiamonds and composition thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016182277A2 (en) | 2016-11-17 |
| WO2016182277A3 (en) | 2017-01-12 |
| KR101876282B1 (en) | 2018-07-10 |
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