KR102647264B1 - Composition for drug delivery comprising nanoparticle carrying telomerase activator and composition for preventing, improving or treating hair loss - Google Patents
Composition for drug delivery comprising nanoparticle carrying telomerase activator and composition for preventing, improving or treating hair loss Download PDFInfo
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- KR102647264B1 KR102647264B1 KR1020240008793A KR20240008793A KR102647264B1 KR 102647264 B1 KR102647264 B1 KR 102647264B1 KR 1020240008793 A KR1020240008793 A KR 1020240008793A KR 20240008793 A KR20240008793 A KR 20240008793A KR 102647264 B1 KR102647264 B1 KR 102647264B1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Abstract
본 발명은 텔로머라제 활성화제와 나노 입자를 포함하는 약물 전달용 조성물 및 이를 포함하는 탈모 예방, 개선 또는 치료용 조성물에 관한 것으로서, 보다 구체적으로는 텔로머라제 활성을 증가시키는 식물 추출물 성분 TA-65 및 그의 유도체, 텔로머라제 활성화 화합물 GPC 및 그의 유도체 등의 약물이 봉입된 나노 리포좀, 나노 실리카 입자, 혹은 나노 버블 조성물로서 모공의 재생 및 성장을 촉진하는 효능이 있는 조성물에 관한 것이다.The present invention relates to a composition for drug delivery containing a telomerase activator and nanoparticles and a composition for preventing, improving or treating hair loss containing the same. More specifically, it relates to a plant extract component TA- that increases telomerase activity. 65 and its derivatives, telomerase activating compound GPC and its derivatives, etc., are encapsulated with drugs such as nano-liposomes, nano-silica particles, or nano-bubble compositions that are effective in promoting the regeneration and growth of pores.
Description
본 발명은 텔로머라제 활성화제와 나노 입자를 포함하는 약물 전달용 조성물 및 이를 포함하는 탈모 예방, 개선 또는 치료용 조성물에 관한 것으로서, 보다 구체적으로는 텔로머라제 활성을 증가시키는 식물 추출물 성분 TA-65 및 그의 유도체, 텔로머라제 활성화 화합물 GPC 및 그의 유도체 등의 약물이 봉입된 나노 리포좀, 나노 실리카 입자, 혹은 나노 버블 조성물로서 모공의 재생 및 성장을 촉진하는 효능이 있는 조성물에 관한 것이다.The present invention relates to a composition for drug delivery containing a telomerase activator and nanoparticles and a composition for preventing, improving or treating hair loss containing the same. More specifically, it relates to a plant extract component TA- that increases telomerase activity. 65 and its derivatives, telomerase activating compound GPC and its derivatives, etc., are encapsulated with drugs such as nano-liposomes, nano-silica particles, or nano-bubble compositions that are effective in promoting the regeneration and growth of pores.
탈모는 일반적으로 두피의 굵고 검은 머리털이 빠지는 것을 의미한다. 탈모의 원인은 다양하지만 유전적인 원인과 남성 호르몬인 안드로겐(androgen)이 중요한 인자로 생각되고 있다. 그 중에서 60-70% 정도로 큰 비율을 차지하고 있는 남성형 탈모증(androgenic alopecia)은 테스토스테론(testosterone)이 5-알파 환원 효소(5-alpha reductase, SRD5A)에 의해서 디하이드로테스토스테론(dihydrotestosterone, DHT)로 전환되고, 과다하게 생성된 디하이드로테스토스테론이 모유두 진피 세포(dermal papilla cell, DPC)의 남성호르몬 수용체(androgenic receptor, AR)에 결합하여 세포 사멸(apoptosis)을 유발시켜, 모발의 소형화로 인해 탈모가 진행되는 것이다. 5-알파 환원 효소 중 모낭의 모유두와 외측모근초에 주로 분포하는 제 2형 5-알파 환원 효소(5-alpha reductase type 2, SRD5A2) 자체가 많이 발현되어 있는 남성이나 제 2형 5-알파 환원 효소의 활성도가 높은 사람이 디하이드로테스토스테론의 양이 일반 남성보다 상대적으로 많기 때문에 탈모의 발생 가능성이 커지는 것이다. 따라서, 남성형 탈모증의 치료 핵심은 제 2형 5-알파 환원 효소의 양이나 활성도를 낮춰 테스토스테론이 디하이드로테스토스테론으로의 전환을 막는데 있다. Hair loss generally refers to the loss of thick, black hair from the scalp. There are various causes of hair loss, but genetic causes and androgen, a male hormone, are considered important factors. Among them, androgenic alopecia, which accounts for a large proportion of about 60-70%, is caused by testosterone being converted to dihydrotestosterone (DHT) by 5-alpha reductase (SRD5A). , Excessively produced dihydrotestosterone binds to the androgenic receptor (AR) of dermal papilla cells (DPC), causing cell death (apoptosis), which leads to hair loss due to hair miniaturization. will be. Among the 5-alpha reductases, type 2 5-alpha reductase type 2 (SRD5A2), which is mainly distributed in the dermal papilla and lateral hair root sheath of hair follicles, is highly expressed in men or type 2 5-alpha reductase. People with high enzyme activity have a relatively higher amount of dihydrotestosterone than ordinary men, which increases the possibility of hair loss. Therefore, the key to treating male pattern baldness is to prevent the conversion of testosterone to dihydrotestosterone by lowering the amount or activity of type 2 5-alpha reductase.
텔로미어(telomere)는 염색체의 끝 부분에서 발견되는 DNA hexamer (TTAGGG) 서열이 반복된 구조의 DNA이며, 염색체의 구조와 기능을 안정화시키는 기능을 수행하는 것으로 알려져 있다. 텔로미어의 길이는 세포가 염색체의 DNA 복제를 반복하면서 단축된다. 텔로미어의 길이가 일정한 길이 이하로 단축되면 세포는 더 이상 성장할 수 없는 노화의 상태로 들어간다. 세포의 텔로미어 길이는 세포의 노화의 정도를 나타내는 마커로 사용될 수 있다. 텔로미어의 길이는 생명체의 나이가 들어갈수록 단축되고, 스트레스, 흡연, 공해, 운동부족, 비만 등에 의해서도 짧아진다. 또한 텔로미어의 길이가 짧아질수록 심혈관질환을 비롯한 다양한 노인성 질환의 발생빈도가 증가한다고 알려져 있다. 세포의 노화가 인체의 조직과 기관의 노화를 유도하는 것으로 볼 수 있다.Telomere is a DNA structure with repeated DNA hexamer (TTAGGG) sequences found at the ends of chromosomes, and is known to perform the function of stabilizing the structure and function of chromosomes. The length of telomeres is shortened as cells repeat the replication of chromosomal DNA. When the length of telomeres is shortened below a certain length, cells enter a state of aging in which they can no longer grow. The telomere length of a cell can be used as a marker to indicate the degree of cell aging. The length of telomeres shortens as an organism ages, and is also shortened by stress, smoking, pollution, lack of exercise, and obesity. Additionally, it is known that as the length of telomeres gets shorter, the incidence of various geriatric diseases, including cardiovascular disease, increases. Aging of cells can be seen as inducing aging of tissues and organs of the human body.
텔로머라제(telomerase)는 텔로미어(telomere)의 3' 말단에 텔로미어 반복서열의 첨가를 촉매하는 효소 단백질로 DNA 복제 및 다양한 세포 외부의 스트레스에 의하여 단축되는 텔로미어를 복구하는 역할을 한다. 텔로머라제 발견 이후 대부분의 과학자들의 관심은 암 연구 분야에서 텔로머라제의 역할에 집중되었다. 암세포가 계속 성장하기 위해서는 텔로머라제가 필요하기 때문에 텔로머라제 발현이 암을 유발하는 것으로 생각하기도 했다. 그러나 텔로머라제 유전자 조작 마우스를 이용한 최근의 연구는 텔로머라제 고수준의 발현이 암을 발생시키지 않고 오히려 노화에 따른 인체기능을 회복(재생, Rejuvenation)시킨다는 것을 보여주었다.Telomerase is an enzyme protein that catalyzes the addition of telomere repeat sequences to the 3' end of telomeres. It plays a role in repairing telomeres shortened by DNA replication and various external stresses. Since the discovery of telomerase, most scientists' attention has focused on its role in cancer research. Because telomerase is required for cancer cells to continue to grow, telomerase expression was thought to cause cancer. However, recent research using telomerase genetically modified mice has shown that high-level expression of telomerase does not cause cancer, but rather restores (rejuvenation) the body's functions due to aging.
텔로머라제 유전자가 없는 유전자 녹아웃 마우스(gene-knockout mice)는 생식능력이 없고, 골다공증, 당뇨, 신경손상 등 노화와 관련된 증상들이 나타나고 일반 마우스보다 노화가 빨리 진행된다는 것이 확인되었다. 반면에 독시사이클린을 경구로 투여할 때만 텔로머라제를 발현하는 유전자조작 마우스에 노화가 진행된 후 독시사이클린을 투여하여 텔로머라제를 고수준으로 발현시키면 노화로 인해 약화된 뇌 기능, 생식능력, 비장, 간, 장 등의 장기들의 기능이 회복되는 것이 나타났다. 이뿐만 아니라 모공의 성장 및 재생을 유도하여 발모가 다시 일어난다는 사실도 확인되었다. 이 결과들은 텔로머라제의 활성화가 모공의 성장을 유도하는 모공 줄기세포를 성장 및 재생함으로써 노화된 모공이 재생되는 변화가 일어난다는 사실을 보여주는 것이다. It was confirmed that gene-knockout mice without the telomerase gene have no reproductive ability, show aging-related symptoms such as osteoporosis, diabetes, and nerve damage, and age faster than regular mice. On the other hand, if doxycycline is administered to genetically engineered mice that express telomerase only when doxycycline is administered orally, and then doxycycline is administered to express telomerase at a high level after aging, the weakened brain function, reproductive capacity, spleen, liver, The function of organs such as intestines was found to be restored. In addition, it was confirmed that hair growth occurs again by inducing the growth and regeneration of pores. These results show that activation of telomerase causes changes in the regeneration of aged pores by growing and regenerating pore stem cells that induce pore growth.
그러나 텔로머라제의 활성이 다양한 노화 현상의 역전을 가능하게 한다는 유전자 조작 동물(gene-engineered animals) 연구의 결과들은 사람에게 직접 사용할 수 있는 텔로머라제 활성화 물질의 탐색을 가속하였고 그 결과 다양한 텔로머라제 활성화 물질이 발견되었다.However, the results of research on gene-engineered animals showing that the activity of telomerase enables the reversal of various aging phenomena has accelerated the search for telomerase activating substances that can be directly used in humans, resulting in the development of various telomerase agents. The first activating substance was discovered.
텔로머라제를 활성화하는 물질(텔로머라제 활성화제)의 종류는 물질의 원천에 따라 2 종류로 분류할 수 있다. 첫째는 텔로머라제 활성화 효능을 가진 식물의 추출물질 및 그의 유도체이며 둘째는 화합물들이다.Types of substances that activate telomerase (telomerase activators) can be classified into two types depending on the source of the substance. The first is plant extracts and their derivatives with telomerase activation effect, and the second is compounds.
식물의 성분인 싸이클로아스트라제놀 및 그의 유도체; Astragalus 속의 식물의 성분인 싸이클로아스트라제놀(cycloastragenol, 약칭은 CAG이며, 화학식은 C30H50O5)은 TAT2 혹은 GRN665 라는 이름으로 불리기도 한다. TA-65는 미국 TA Science사가 Astragalus 속의 식물에서 특허등록된 방법으로 추출하고 정제한 싸이클로아스트라제놀이 포함된 텔로머라제 활성화제이다. 그 외 식물유래의 텔로머라제 활성화물질은 대두 유래의 Genistein, Centella asiatica의 추출물, Olive-pomace oil 유래의 Maslinic acid 등이 있다.Cycloastrazenol and its derivatives, which are plant components; Cycloastragenol (abbreviated as CAG, chemical formula C 3 0H 50 O 5 ), a component of the Astragalus genus plant, is also called TAT2 or GRN665. TA-65 is a telomerase activator containing cycloastragenol extracted and purified by TA Science, USA, from plants of the genus Astragalus using a patented method. Other plant-derived telomerase activating substances include Genistein from soybeans, Centella asiatica extract, and Maslinic acid from olive-pomace oil.
텔로머라제를 활성화하는 화합물로 발견된 물질 중에서 C3-(L)-valyl-cycloastragenol(US 9,913,852 B2) 등은 싸이클로아스트라제놀의 유도체이다.Among the substances discovered as compounds that activate telomerase, C3-(L)-valyl-cycloastragenol (US 9,913,852 B2) is a derivative of cycloastragenol.
한편, N-propyl-5-(2-thienyl)isoxazole-3-carboxamide(US 2009/0143451 Al)와 다양한 유도체들이 텔로머라제의 발현을 증가시키는 화합물로 보고되었다. N-propyl-5-(2-thienyl)isoxazole-3-carboxamide의 유도체 중 하나인 구아니디노펜틸페닐아이소옥사졸카복사마이드, (Guanidinopentyl phenylisoxazolecarboxamide, 화학식; C16H21N5O2, 약칭은 GPC)이 있으며, 이는 대표적인 텔로머라제 활성화 화합물로 알려져 있고, 분자구조식은 아래와 같다.Meanwhile, N-propyl-5-(2-thienyl)isoxazole-3-carboxamide (US 2009/0143451 Al) and various derivatives have been reported as compounds that increase telomerase expression. Guanidinopentyl phenylisoxazolecarboxamide, one of the derivatives of N-propyl-5-(2-thienyl)isoxazole-3-carboxamide, (chemical formula; C 16 H 21 N 5 O 2 , abbreviated name) GPC) is known as a representative telomerase activating compound, and its molecular formula is as follows.
[분자구조식][Molecular structure]
상기 보고된 텔로머라제 활성화제를 이용하여 노화로 인해 약화된 뇌 기능, 생식능력, 비장, 간, 장 등의 장기들의 기능이 회복되고, 면역 활성 등 생체 기능의 향상에 관하여 보고한 논문과 특허는 있지만 동 물질들을 모공에 전달하여 모공의 세포를 활성화하여 탈모 개선 및 발모 효능을 보고한 것은 없었으며, 본 발명의 출원인은 텔로머라제 활성화 물질을 이용하여 탈모방지 효능이 있는지에 대한 연구, 개발을 진행하였다.Papers and patents reporting on the use of the telomerase activator reported above to restore brain function weakened due to aging, reproductive ability, and the function of organs such as the spleen, liver, and intestines, and to improve biological functions such as immune activity. However, there has been no report on hair loss improvement and hair growth efficacy by delivering these substances to the pores and activating the cells of the pores, and the applicant of the present invention has conducted research and development on whether telomerase activating substances have an anti-hair loss effect. proceeded.
본 발명의 목적은 텔로머라제 활성화제를 이용하여 노화로 인해 완전한 휴지기에 들어가 발모가 중단된 노화된 모공의 재성장을 유도함으로써 발모를 재개하도록 나노 버블, 나노리포좀, 나노입자 등을 이용한 약물전달용 조성물, 또는 이의 제조방법 및 이를 유효성분으로 포함하는 탈모 예방, 개선 또는 치료용 조성물을 제공하는 데에 그 목적이 있다.The purpose of the present invention is to deliver drugs using nanobubbles, nanoliposomes, nanoparticles, etc. to resume hair growth by using a telomerase activator to induce regrowth of aged pores where hair growth has stopped due to complete resting phase due to aging. The purpose is to provide a composition, a method for producing the same, and a composition for preventing, improving, or treating hair loss containing the same as an active ingredient.
본 발명은 탈모 치료용 약물로서 텔로머라제 활성화물질이 봉입된 나노 입자 및 이를 함유하는 탈모 개선 또는 치료용 조성물을 제공하는 데에 있다.The present invention aims to provide nanoparticles encapsulated with a telomerase activator as a drug for treating hair loss, and a composition containing the same for improving or treating hair loss.
보다 구체적으로는 본 발명의 목적은 텔로머라제 활성을 증가시키는 식물 추출물 성분 TA-65 및 그의 유도체, 텔로머라제 활성화 화합물 GPC 및 그의 유도체 등의 약물이 봉입된 나노 리포좀, 나노 실리카 입자, 혹은 나노 버블 조성물로서 모공의 재생 및 성장을 촉진하는 효능이 있는 조성물을 제공하는 데에 있다.More specifically, the object of the present invention is to provide nano liposomes, nano silica particles, or nano drugs encapsulated with drugs such as the plant extract ingredient TA-65 and its derivatives, the telomerase activating compound GPC and its derivatives, which increase telomerase activity. The aim is to provide a composition that is effective in promoting the regeneration and growth of pores as a bubble composition.
본 발명은 텔로머라제 활성화제가 봉입된 나노리포좀 결합체 혹은 메조포러스 실리카 나노입자 결합체 혹은 나노 버블 결합체에 관한 것이다.The present invention relates to a nanoliposome conjugate, mesoporous silica nanoparticle conjugate, or nanobubble conjugate encapsulated with a telomerase activator.
상기 텔로머라제 활성화 물질은 세포의 텔로머라제 발현을 증가시키거나 혹은 텔로미어 합성 효소 활성을 증가시키는 텔로머라제 활성화 물질로서 식물유래의 추출물 성분인 TA-65, 화합물 중에서는 GPC로 이루어진 군 중에서 1종 이상 선택되어 포함된 것으로 탈모의 개선 또는 치료용 조성물에 관한 것이다.The telomerase activating substance is a telomerase activating substance that increases telomerase expression in cells or increases telomere synthase activity. TA-65, a plant-derived extract component, and GPC as a compound are selected from the group 1. It relates to a composition for improving or treating hair loss, which includes a selection of more than one species.
본 발명에서는 TA-65와 GPC를 각각 0.2mg/L ~ 2g/L 농도로 나노버블, 나노리포좀, 나노실리카 용액을 조성할 수 있다.In the present invention, nanobubbles, nanoliposomes, and nanosilica solutions can be formed with TA-65 and GPC at concentrations of 0.2 mg/L to 2 g/L, respectively.
또한 상기 모공재생 촉진용 약물은 텔로머라제의 발현 혹은 효소 활성을 증가시키는 효능이 있는 것일 수 있다. Additionally, the drug for promoting pore regeneration may have the effect of increasing the expression or enzyme activity of telomerase.
상기 나노 리포좀은 레시틴, 콜레스테롤 및 양이온성 혹은 음이온성, 혹은 양쪽이온성의 인지질을 포함할 수 있다.The nano liposome may contain lecithin, cholesterol, and cationic, anionic, or zwitterionic phospholipids.
상기 나노 버블은 전기, 초음파, 압력 등 다양한 방법으로 생성된 50nm에서 500nm 크기의 기포로서 모공 안으로 들어갈 수 있는 크기가 바람직하지만 그보다 큰 것도 포함할 수 있다. The nanobubbles are bubbles with a size of 50nm to 500nm created by various methods such as electricity, ultrasound, and pressure. It is preferable that the nanobubbles are large enough to enter the pores, but they can also be larger.
상기 실리카 나노입자는 2nm~50nm 크기의 공동(empty porous)을 가지는 메조다공성 실리카 나노구(MSN, Mesoporous Silica Nanosphere)이며 균일한 공동의 크기와 부피를 가지는 M41S 계열의 실리카 나노입자 중에서 육방정계모양의 (hexagonal)의 MCM-41 (Mobile Crystalline Material-41)이나, 실리카 나노입자의 조성 및 구조는 다양할 수 있다. 본 발명에서는 미국 Sigma-Aldrich사에서 구매한 100nm MCM-41 나노입자를 실리카 나노입자로 사용하였다.The silica nanoparticles are mesoporous silica nanospheres (MSN, Mesoporous Silica Nanosphere) having empty porous with a size of 2 nm to 50 nm. Among the M41S series silica nanoparticles with uniform cavity size and volume, the silica nanoparticles have a hexagonal shape. (hexagonal) of MCM-41 (Mobile Crystalline Material-41), but the composition and structure of silica nanoparticles may vary. In the present invention, 100nm MCM-41 nanoparticles purchased from Sigma-Aldrich, USA were used as silica nanoparticles.
본 발명은 텔로머라제 활성화 물질을 포함하는 나노 리포좀 혹은 나노 버블 혹은 메조포러스 실리카 나노입자 결합체를 포함하는 탈모의 개선 또는 치료용 조성물을 제공할 수 있다.The present invention can provide a composition for improving or treating hair loss containing a nanoliposome or nanobubble or mesoporous silica nanoparticle conjugate containing a telomerase activating material.
본 발명은 TA-65 또는 GPC 등, 식물 추출물의 성분 또는 화합물로서 텔로머라제를 활성화하는 물질이 봉입된 나노리포좀 또는 메조다공성 나노실리카 입자 또는 동 물질과 결합된 나노 버블 및 이를 함유하는 탈모 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to nanoliposomes or mesoporous nanosilica particles encapsulated with a substance that activates telomerase as a component or compound of a plant extract, such as TA-65 or GPC, or nanobubbles combined with the same substance, and hair loss improvement or It relates to a therapeutic composition.
텔로머라제 활성화 물질을 표준 화장수에 용해한 용액을 노화동물에 도포한 결과 탈모 개선 및 발모 효과가 없었다. 이 결과는 그동안 텔로머라제 활성화 물질의 탈모 개선 효과를 보고한 논문 및 특허가 없었던 이유를 설명해주는 것이다. When a solution of a telomerase activating substance dissolved in standard lotion was applied to aging animals, there was no hair loss improvement or hair growth effect. This result explains why there have been no papers or patents reporting the hair loss improvement effect of telomerase activating substances.
그러나 텔로머라제의 활성화는 노화된 모공의 재생 및 모공줄기세포의 활성화을 유도한다. 이는 유전자조작 마우스를 이용한 실험에서 증명된 바 있다. 상세하게는 텔로머라제 유전자를 마우스가 노화로 인하여 모공이 노화되고, 발모가 중단된 후에 인위적인 방법으로 텔로머라제 동물에 발현하면 모공줄기세포의 재성장, 모공의 재성장, 발모가 재개된다는 것이다. However, activation of telomerase induces regeneration of aged pores and activation of pore stem cells. This has been proven in experiments using genetically modified mice. In detail, if the telomerase gene is expressed in an animal using an artificial method after the pores of the mouse have aged and hair growth has stopped due to aging, the regrowth of pore stem cells, the regrowth of pores, and the hair growth will resume.
그러나 텔로머라제 활성화 물질이 모공 줄기세포의 재성장과 발모를 유도한다는 보고가 없는 것은 텔로머라제 활성화 물질을 두피에 도포하는 것으로는 이들 물질이 모공 속으로 들어가서 텔로머라제를 활성화시키지 못하며 따라서 모공의 재생을 유도하여 발모 재개의 효능을 발휘하지 못하는 것으로 생각할 수 있다. However, there are no reports that telomerase activating substances induce the regrowth of pore stem cells and hair growth because applying telomerase activating substances to the scalp does not allow these substances to enter the pores and activate telomerase, thus preventing the pores from activating. It may be thought that it is not effective in inducing regeneration and resuming hair growth.
따라서 약물 전달체를 활용하여 텔로머라제 활성화 물질의 모공 내부로의 전달 효율을 높이는 것이 중요하다. 본 발명의 나노 버블, 나노리포좀, 다공성 실리카 나노입자 등을 이용할 경우, 텔로머라제 활성화 물질이 탈모의 개선 및 치료용 약물 로서의 효능이 있다는 것을 보여준다. 노화로 인한 모공의 노화 및 발모의 중단으로 인한 탈모의 치료를 매우 효과적으로 수행할 수 있다.Therefore, it is important to use a drug carrier to increase the delivery efficiency of the telomerase activating substance into the pores. When using the nanobubbles, nanoliposomes, porous silica nanoparticles, etc. of the present invention, it is shown that the telomerase activating material is effective as a drug for improving and treating hair loss. It can be very effective in treating hair loss caused by aging of pores and cessation of hair growth due to aging.
나노리포좀, 다공성 실리카 나노입자, 나노 버블 등은 약물 전달수단으로 주목받아왔지만 텔로머라제 활성화 물질을 노화된 모공에 전달하는 목적으로 사용된 적은 없다. Nanoliposomes, porous silica nanoparticles, nanobubbles, etc. have received attention as drug delivery vehicles, but have never been used for the purpose of delivering telomerase activating substances to aged pores.
본 발명에서 텔로머라제 활성화 물질을 포함하는 나노 버블, 나노 리포좀, 메조다공성 실리카 나노입자는 각각 정도의 차이는 있으나 일정한 발모 및 모공 재성장 효능이 나타냈다. 따라서 약물과 전달체의 혼합물은 조성의 차이에 의하여 정도의 차이는 있으나 이들 조성물이 탈모 개선 및 치료제로서의 효능이 있다는 것을 나타낸다. In the present invention, nanobubbles, nanoliposomes, and mesoporous silica nanoparticles containing a telomerase activating material each showed certain hair growth and pore regrowth effects, although there were differences in degree. Therefore, the mixture of drug and carrier shows that these compositions are effective in improving hair loss and as a treatment, although there are differences in degree due to differences in composition.
도 1은 표준 화장수와 이에 TA-65(100ng/ml) 혹은 GPC(100ng/ml)을 함유한 용액을 20개월령 C57/BL6 마우스의 털을 제모하고 그후 4주간 다시 털이 나지 않는 것을 확인한 후 피부에 8주간 도포하고, 8주 후에 발모 상태를 확인한 것이다. 마우스는 20개월령으로 제한되지 않는다. 다만 제모 후 다시 털이 나지 않은 노화된 마우스를 선별하여 실험에 사용하였다.
도 2는 3차 증류수에 나노 버블을 발생시킨 용액(A), TA-65(B) 혹은 GPC(C)을 함유한 3차 증류수에 나노 버블을 발생시킨 용액을 20개월령 C57/BL6 마우스의 털을 제모하고 그후 4주간 다시 털이 나지 않는 것을 확인한 후 피부에 8주간(주 3회) 도포하고, 8주 후에 발모 상태를 확인한 것이다.
도 3는 나노리포좀(A), TA-65(B) 혹은 GPC(C)을 포집한 나노리포좀 용액을 20개월령 C57/BL6 마우스의 털을 제모하고 그후 4주간 다시 털이 나지 않는 것을 확인한 후 피부에 8주간(주 5회) 도포하고, 8주 후에 발모 상태를 확인한 것이다.
도 4는 나노 실리카 입자(A), TA-65(B) 혹은 GPC(C)을 포집한 용액을 20개월령 C57/BL6 마우스의 털을 제모하고 그후 4주간 다시 털이 나지 않는 것을 확인한 후 피부에 8주간(주 5회) 도포하고, 8주 후에 발모 상태를 확인한 것이다.
도 5는 도2, 도3, 도4에 사용한 마우스의 피부를 바이옵시한 후 H&E 염색을 행한 후 현미경(배율은 40배)로 촬영한 후, 모공의 분포와 상태를 보여주는 것이다. 모공의 종류는 도 5C에서 비활성 모공(검은색 화살표), 활성 모공으로서 1차모공(붉은색 화살표)과 2차모공(황색 화살표)를 표시하였다. 나노 버블을 발생시킨 용액(A), 나노 버블-TA-65(B) 혹은 나노 버블-GPC(C), 나노리포좀(D), 나노리포좀-TA-65(E), 나노리포좀-GPC(F), 나노 실리카 입자(G), 나노-실리카-TA-65(H), 나노실리카-GPC(I).
도 6은 텔로머라제 활성화 물질에 의한 활성 모공의 증가를 보여준다. H&E 염색한 피부조직에서 1제곱밀리미터를 단위면적으로 비활성모공을 제외한 활성모공(1차 모공+2차모공) 수의 분포도이다.
도 7은 도2, 도3, 도4에서처럼 GPC을 함유한 나노 버블 용액, 나노리포좀, 혹은 나노실리카 용액을 도포한 마우스의 피부를 바이옵시한 후 파라핀으로 고형화한 조직을 측면으로 절단한 후, H&E 염색을 행하여 모공의 깊이를 관찰한 것이다.
도 8은 텔로머라제 활성화 물질 GPC에 의한 모공의 깊이를 보여준다. 20제곱밀리미터를 단위면적으로 모공의 깊이를 측정하였다. 나노 버블과 나노실리카에 포함된 GPC 용액을 도포한 피부에서 비슷한 모공의 깊이를 보여주는 반면, 나노리포좀의 경우 나노 버블과 나노실리카의 약 50% 정도이며, 표준화장수의 경우 활성 모공이 거의 관찰되지 않아서 통계치를 낼 수 없었다.Figure 1 shows a standard lotion and a solution containing TA-65 (100ng/ml) or GPC (100ng/ml) removed from the hair of a 20-month-old C57/BL6 mouse and then applied to the skin after confirming that hair did not grow back for 4 weeks. It was applied for 8 weeks, and hair growth was checked after 8 weeks. Mice are not limited to 20 months of age. However, aged mice that did not grow hair again after hair removal were selected and used in the experiment.
Figure 2 shows a solution generating nanobubbles in tertiary distilled water (A), a solution generating nanobubbles in tertiary distilled water containing TA-65 (B) or GPC (C), on the hair of a 20-month-old C57/BL6 mouse. After removing the hair and confirming that hair did not grow again for 4 weeks, it was applied to the skin for 8 weeks (3 times a week) and the condition of hair growth was checked after 8 weeks.
Figure 3 shows a nanoliposome solution containing nanoliposomes (A), TA-65 (B), or GPC (C) after removing hair from a 20-month-old C57/BL6 mouse and confirming that hair does not grow again for 4 weeks. It was applied for 8 weeks (5 times a week), and hair growth was checked after 8 weeks.
Figure 4 shows a solution containing nano-silica particles (A), TA-65 (B), or GPC (C) removed from the hair of a 20-month-old C57/BL6 mouse, and then applied to the skin after confirming that hair did not grow again for 4 weeks. It was applied weekly (5 times a week), and hair growth was checked after 8 weeks.
Figure 5 shows the distribution and condition of pores after biopsy of the skin of the mouse used in Figures 2, 3, and 4, followed by H&E staining and photographing with a microscope (magnification: 40x). In Figure 5C, the types of pores are indicated as inactive pores (black arrows), and as active pores, primary pores (red arrows) and secondary pores (yellow arrows) are indicated. Solution generating nanobubbles (A), nanobubble-TA-65(B) or nanobubble-GPC(C), nanoliposome (D), nanoliposome-TA-65(E), nanoliposome-GPC(F) ), nano-silica particles (G), nano-silica-TA-65 (H), nano-silica-GPC (I).
Figure 6 shows the increase in active pores by telomerase activating substances. This is a distribution chart of the number of active pores (primary pores + secondary pores) excluding inactive pores per unit area of 1 square millimeter in H&E-stained skin tissue.
Figure 7 shows biopsy of the skin of a mouse to which a nanobubble solution, nanoliposome, or nanosilica solution containing GPC was applied as shown in Figures 2, 3, and 4, and then the tissue solidified with paraffin was cut laterally. H&E staining was performed to observe the depth of the pores.
Figure 8 shows the depth of pores by the telomerase activating substance GPC. The depth of pores was measured with a unit area of 20 square millimeters. While the skin applied with the GPC solution contained in nanobubbles and nanosilica shows similar pore depths, in the case of nanoliposomes it is about 50% of that of nanobubbles and nanosilica, and in the case of standard longevity, almost no active pores are observed. Statistics could not be produced.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
이하, 본 발명의 바람직한 실시예 및 비교예를 통해 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail through preferred examples and comparative examples.
[비교예 1][Comparative Example 1]
TA-65(100ng/ml)을 각각 표준적인 로션 화장수(99.5% Ethanol, 1% Carbomer solution, Reverse Osmosis water, 1,2-Hexanediol)에 100mg/L 농도로 용해한 용액을 제조하였다.A solution was prepared by dissolving TA-65 (100ng/ml) in standard lotion water (99.5% Ethanol, 1% Carbomer solution, Reverse Osmosis water, 1,2-Hexanediol) at a concentration of 100mg/L.
[비교예 2][Comparative Example 2]
GPC(100ng/ml)을 각각 표준적인 로션 화장수(99.5% Ethanol, 1% Carbomer solution, Reverse Osmosis water, 1,2-Hexanediol)에 100mg/L 농도로 용해한 용액을 제조하였다.A solution was prepared by dissolving GPC (100ng/ml) in standard lotion water (99.5% Ethanol, 1% Carbomer solution, Reverse Osmosis water, 1,2-Hexanediol) at a concentration of 100mg/L.
[실험예 1][Experimental Example 1] 표준 화장수에 용해된 TA-65 및 GPC의 발모 효능 Hair growth efficacy of TA-65 and GPC dissolved in standard lotion
*모공의 노화로 인해서 더이상 발모가 일어나지 않는 동물을 준비하기 위해서 먼저 C57/BL6 마우스가 약 20개월령에 도달했을 때 제모를 한다(20개월 마우스로 제한하지 않는다). 제모 후 4주간 발모가 일어나지 않는 마우스를 선택하는데 이는 모공이 노화되어 완전 휴지기(털의 생성이 중단된 상태)에 들어간 것으로 간주하는 것이다.*To prepare animals in which hair growth no longer occurs due to aging of the pores, hair is first removed when C57/BL6 mice reach approximately 20 months of age (not limited to 20-month-old mice). Mice that do not grow hair for 4 weeks after hair removal are selected, which means that their pores have aged and are considered to have entered a complete telogen phase (a state in which hair production has stopped).
비교예 1 및 2의 용액을 각각 제모 후 4주간 발모가 관찰되지 않는 노화 동물의 제모된 피부에 8주간 주 5회 도포한 후 8주 후부터 16주까지 발모의 상태를 관찰하였다. 도 1을 참조하면, (A)는 표준 화장수를 도포한 것이고, (B)는 비교예 1의 용액을 도포한 것이며, (C)는 비교예 2의 용액을 도포한 것으로서, 표준적인 화장수에 용해된 TA-65 및 GPC은 노화 동물의 발모를 유발하지 못했다.The solutions of Comparative Examples 1 and 2 were applied 5 times a week for 8 weeks to the depilated skin of an aging animal in which hair growth was not observed for 4 weeks after hair removal, and the state of hair growth was observed from 8 weeks to 16 weeks. Referring to Figure 1, (A) is an application of a standard lotion, (B) is an application of the solution of Comparative Example 1, and (C) is an application of the solution of Comparative Example 2, which is dissolved in a standard lotion. TA-65 and GPC failed to induce hair growth in aging animals.
아래 실시예 1을 통해 나노 버블에 의한 TA-65 및 GPC의 발모 효능을 확인하였다.The hair growth efficacy of TA-65 and GPC by nanobubbles was confirmed through Example 1 below.
- TA-65가 포집된 나노 버블 용액 생성- Creation of nano bubble solution containing TA-65
TA-65을 3차 증류수에 100mg/L의 농도로 용해한 후, 동 용액을 나노 버블 하우징에 주입하고 20분간 약 200와트의 전기를 가하는 방법으로 TA-65가 포집된 나노 버블이 생성된 용액을 마련하였다.After dissolving TA-65 in tertiary distilled water at a concentration of 100 mg/L, the solution was injected into the nanobubble housing and applied about 200 watts of electricity for 20 minutes to create a solution in which nanobubbles containing TA-65 were generated. prepared.
- GPC가 포집된 나노 버블 생성- Creation of nano bubbles containing GPC
GPC를 3차 증류수에 100mg/L의 농도로 용해한 후, 동 용액을 나노 버블 하우징에 주입하고 20분간 약 200와트의 전기를 가하는 방법으로 GPC가 포집된 나노 버블이 생성된 용액을 마련하였다.After dissolving GPC in tertiary distilled water at a concentration of 100 mg/L, the solution was injected into the nanobubble housing and applied about 200 watts of electricity for 20 minutes to prepare a solution in which nanobubbles containing GPC were generated.
그리고 대조군으로서, TA-65 및 GPC를 모두 포함하지 않는 3차 증류수로 나노 버블이 생성된 용액을 마련하였다.As a control, a solution in which nanobubbles were generated was prepared with triple distilled water containing neither TA-65 nor GPC.
[실험예 2][Experimental Example 2]
1. 나노 버블이 생성된 용액에 대한 실험1. Experiment on solutions in which nanobubbles were generated
도 2의 (A)와 같이 3차 증류수에 나노 버블이 생성된 용액을 도포한 마우스는 16주 후에도 피부에 특별한 병변이 생기지 않았다. 그리고 나노 버블이 생성된 용액을 제모 후 4주간 발모가 관찰되지 않는 노화 동물의 탈모된 피부에 8주간 주 5회 도포한 후, 8주 후에 발모의 상태를 관찰하였으나, 총 16주 후에도 재 발모가 나타나지 않았다.As shown in Figure 2 (A), mice to which a solution containing nanobubbles was applied to triple distilled water did not develop any special lesions on the skin even after 16 weeks. Then, the solution in which nano bubbles were generated was applied to the depilated skin of an aging animal in which hair growth was not observed for 4 weeks after hair removal, 5 times a week for 8 weeks, and the state of hair growth was observed after 8 weeks, but re-growth was observed even after a total of 16 weeks. didn't show up
동물의 피부의 모공의 상태를 확인하기 위하여 C57/BL6 마우스를 4mm 크기의 등 아래 쪽 피부 생검을 취하였다. 피부 생검을 10% 포르말린 용액에 담근 상태로 16시간 보존한 후 포매제로 파라핀을 이용하여 생검을 고형화 하였다. 박절용 칼을 이용하여 조직의 수평으로 절편을 만든 후에 크실렌을 이용하여 파라핀을 제거한 후, Hematoxylin-Eosin(H&E) 염색액으로 염색하여 모공의 형태(퇴화된 모공, 일차 모공, 2차모공)와 수를 관찰하였다. 또한 조직을 수평 절편과 동시에 수직 절편을 만들어서 모공의 깊이(길이)를 관찰하였다. H&E 염색에서도 이상 징후는 발견되지 않았으나, 모공의 증가가 거의 발견되지 않았고, 퇴화된 것으로 보이는 모공의 관찰되었다.(도 5의 A)To check the condition of the animal's skin pores, a 4 mm-sized skin biopsy was taken from the lower back of a C57/BL6 mouse. The skin biopsy was preserved in a 10% formalin solution for 16 hours and then solidified using paraffin as an embedding agent. After making a horizontal section of the tissue using a cutting knife, paraffin was removed using xylene, and then stained with Hematoxylin-Eosin (H&E) staining solution to determine the shape of the pores (degenerated pores, primary pores, secondary pores). The number was observed. In addition, the tissue was simultaneously sliced horizontally and vertically sliced to observe the depth (length) of the pores. No abnormal signs were found in H&E staining, but almost no increase in pores was found, and pores that appeared to have degenerated were observed (Figure 5A).
2. 실시예 1, 2의 용액에 대한 실험2. Experiments on the solutions of Examples 1 and 2
TA-65를 포함하는 실시예 1의 나노 버블 용액 및 GPC를 포함하는 실시예 2의 나노 버블 용액 8주간의 도포를 통해서 16주 후에는 제모한 피부 영역의 거의 대부분에서 발모가 진행되었다(도 2의 B, C).Through application of the nanobubble solution of Example 1 containing TA-65 and the nanobubble solution of Example 2 containing GPC for 8 weeks, hair growth progressed in most of the removed skin area after 16 weeks (Figure 2 B, C).
따라서 이들 마우스의 피부 생검을 취하여 모공을 관찰하였으며(도 5의 B, C), 도 5의 (A)에 비해서 모공의 수가 대폭적으로 증가하였다. 그러나 도 5의 (B)에 비하여 도 5의 (C)의 모공이 더 크고 밀집된 형태를 보여준다.Therefore, skin biopsies were taken from these mice and the pores were observed (Figure 5B, C), and the number of pores was significantly increased compared to Figure 5(A). However, compared to Figure 5 (B), the pores in Figure 5 (C) are larger and more dense.
- TA-65가 포집된 나노 리포좀 용액 생성- Creation of nano liposome solution containing TA-65
본 발명에 사용된 양이온성 리포좀의 구성은 다음과 같다; dimyristoylphosphatidylcholine,N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate, and cholesterol (50:10:40 mol%). The composition of the cationic liposome used in the present invention is as follows; dimyristoylphosphatidylcholine,N-(2,3-dioleoyloxy-1-propyl)trimethylammonium methyl sulfate, and cholesterol (50:10:40 mol%).
- 리포좀 제작 방법은 다음과 같다.- The liposome production method is as follows.
먼저 지질을 chloroform/methanol(3:1) 용액에서 녹인 후 증발기에서 진공 상태로 건조한다.First, the lipids are dissolved in a chloroform/methanol (3:1) solution and then dried in a vacuum in an evaporator.
10mM N-[2-hydroxyethyl]piperazine-N0-[2-ethanesulphonic acid] + 150mM NaCl(pH=7.5, 약물 용해 후 sodium hydroxide로 재조정)용액에 TA-65를 100mM의 농도로 용해한 약물 용액을 마련한다.Prepare a drug solution by dissolving TA-65 at a concentration of 100mM in 10mM N-[2-hydroxyethyl]piperazine-N0-[2-ethanesulphonic acid] + 150mM NaCl (pH=7.5, readjusted with sodium hydroxide after dissolving the drug). .
Lipid 고형물은 60℃에서 2ml의 약물 용액에 넣어 지질의 농도가 50mM이 되도록 용액을 만든 다음, 세번 얼린 후 녹이는 과정을 반복한 후. 400nm의 pore를 가진 polycarbonate filters를 통하여 압출시켜 TA-65가 포집된 나노 리포좀 용액을 만든다.Lipid solids are added to 2 ml of drug solution at 60°C to create a solution with a lipid concentration of 50mM, and then the freezing and thawing process is repeated three times. A nano liposome solution containing TA-65 is created by extruding it through polycarbonate filters with pores of 400 nm.
- GPC가 포집된 나노 리포좀 용액 생성- Creation of nano liposome solution containing GPC
위 실시예 1에서 TA-65가 포집된 나노 리포좀 용액 생성 과정 중 TA-65 대신 GPC를 사용한 것을 제외하고 동일한 방법으로 GPC가 포집된 나노 리포좀 용액을 만들었다.A nano-liposome solution containing GPC was prepared in the same manner as in Example 1 above, except that GPC was used instead of TA-65 during the production process of the nano-liposome solution containing TA-65.
그리고 대조군으로서, TA-65 및 GPC를 모두 포함하지 않는 나노 리포좀 용액을 마련하였다.And as a control, a nano liposome solution containing neither TA-65 nor GPC was prepared.
나노 리포좀에 포집된 TA-65 또는 GPC의 발모 효능을 확인하기 위해 아래 실험예 3을 진행하였다.Experimental Example 3 below was conducted to confirm the hair growth efficacy of TA-65 or GPC captured in nanoliposomes.
[실험예 3][Experimental Example 3]
1. 나노 리포좀이 생성된 용액에 대한 실험1. Experiment on the solution in which nano liposomes were generated
나노 리포좀이 포함된 용액은 16주 후에도 피부에 특별한 병변이 생기지 않았고(도 3의 A), H&E염색에서도 이상 징후는 발견되지 않았으나 모공이 거의 발견되지 않았으며, 퇴화된 것으로 보이는 모공이 관찰되었다(도 5의 D).The solution containing nano-liposomes did not cause any special lesions on the skin even after 16 weeks (Figure 3A), and no abnormalities were found in H&E staining, but almost no pores were found, and pores that appeared to have degenerated were observed ( Figure 5D).
또한 제모 후 4주간 발모의 현상이 나타나지 않은 마우스를 선별했는데, 이들은 그로부터 16주 후에도 재발모가 나타나지 않았다(도 3의 A).In addition, mice that did not show hair growth for 4 weeks after hair removal were selected, and they did not show regrowth even 16 weeks later (Figure 3A).
2. 실시예 3, 4의 TA-65 또는 GPC을 포집한 나노 리포좀을 함유한 용액을 제모 후 4주간 발모가 관찰되지 않는 노화 동물의 탈모된 피부에 8주간 주 5회 도포한 후, 8주 후에 발모의 상태를 관찰하였다.2. A solution containing nano-liposomes encapsulating TA-65 or GPC of Examples 3 and 4 was applied to the depilated skin of an aging animal in which hair growth was not observed for 4 weeks after hair removal, 5 times a week for 8 weeks, and then treated for 8 weeks. Afterwards, the state of hair growth was observed.
그러나 실시예 3, 4의 TA-65 또는 GPC을 60mg/L의 농도로 포함하는 나노 리포좀 용액은 8주간의 도포를 통해서 16주 후에는 제모한 피부 영역의 거의 대부분에서 발모가 진행되었다(도 3의 B, C). 따라서 이들 마우스의 피부 생검을 취하여 모공을 관찰하였는데(도 5의 E, F), 도 5의 (D)에 비해서 모공의 수가 대폭적으로 증가하였다. 그러나 도 5의 (E)에 비하여 도 5의 (F)의 모공이 더 크고 밀집되어 있었다.However, the nano-liposome solution containing TA-65 or GPC of Examples 3 and 4 at a concentration of 60 mg/L showed hair growth in most of the removed skin area after 16 weeks through application for 8 weeks (Figure 3 B, C). Therefore, skin biopsies were taken from these mice and the pores were observed (FIG. 5E, F), and the number of pores was significantly increased compared to FIG. 5(D). However, compared to Figure 5 (E), the pores in Figure 5 (F) were larger and more dense.
TA-65를 상기의 MCM-41과 48시간 일정한 속도의 교반으로 반응시켜서 TA-65가 포집된 실리카 나노입자 용액 (300mg/L, TA-65 60mg/L + MCM-41 240mg/L)를 마련하였다.TA-65 was reacted with the MCM-41 above with constant stirring for 48 hours to prepare a silica nanoparticle solution containing TA-65 (300mg/L, TA-65 60mg/L + MCM-41 240mg/L). did.
GPC를 상기의 MCM-41과 48시간 일정한 속도의 교반으로 반응시켜서 GPC가 포집된 실리카 나노입자 용액 (300mg/L, GPC 60mg/L + MCM-41 240mg/L)를 마련하였다.GPC was reacted with the MCM-41 above with constant stirring for 48 hours to prepare a silica nanoparticle solution containing GPC (300 mg/L, GPC 60 mg/L + MCM-41 240 mg/L).
그리고 대조군으로서, TA-65 및 GPC를 모두 포함하지 않는 나노 실리카 용액을 마련하였다.And as a control, a nano silica solution containing neither TA-65 nor GPC was prepared.
나노 실리카에 포집된 TA-65 또는 GPC의 발모 효능을 확인하기 위해 아래 실험예 4를 진행하였다.Experimental Example 4 below was conducted to confirm the hair growth efficacy of TA-65 or GPC captured in nano-silica.
[실험예 4][Experimental Example 4]
1. 메조다공성 실리카 나노입자가 포함된 용액을 도포한 마우스는 16주 후에도 피부에 특별한 병변이 생기지 않았고(도 4의 A), H&E염색에서도 이상 징후는 발견되지 않았으나 모공이 거의 발견되지 않았으며, 퇴화된 것으로 보이는 모공이 관찰 되었다(도 5의 G). 또한 제모 후 4주간 발모의 현상이 나타나지 않은 마우스를 선별했는데, 이들은 그로부터 16주 후에도 재발모가 나타나지 않았다(도 4의 A).1. Mice to which a solution containing mesoporous silica nanoparticles was applied did not develop any special lesions on the skin even after 16 weeks (Figure 4A), and no abnormal signs were found in H&E staining, but almost no pores were found. Pores that appeared to have degenerated were observed (Figure 5G). In addition, mice that did not show hair growth for 4 weeks after hair removal were selected, and they did not show regrowth even 16 weeks later (A in Figure 4).
2. 그러나 실시예 5, 6의 TA-65 또는 GPC을 60mg/L의 농도로 포함하는 용액에 나노리포좀 용액은 8주간의 도포를 통해서 16주 후에는 제모한 피부 영역의 거의 대부분에서 발모가 진행되었다(도 4의 B, C). 따라서 이들 마우스의 피부 생검을 취하여 모공을 관찰하였으며(도 5의 H, I), 도 5의 (G)에 비해서 모공의 수가 대폭적으로 증가하였나, 도 5의 (H)에 비하여 도 5의 (I)의 모공이 더 크고 밀집되어 있었다.2. However, the nanoliposome solution containing TA-65 or GPC of Examples 5 and 6 at a concentration of 60 mg/L was applied for 8 weeks, and hair growth progressed in most of the removed skin area after 16 weeks. (Figure 4B, C). Therefore, skin biopsies were taken from these mice and the pores were observed (FIG. 5H, I). Did the number of pores significantly increase compared to Figure 5(G)? Figure 5(I) compared to Figure 5(H) )'s pores were larger and more dense.
한편, 도 6은 텔로머라제 활성화 물질에 의한 활성 모공의 증가를 나타내는 것으로서, H&E 염색한 피부조직에서 1제곱밀리미터를 단위면적으로 비활성모공을 제외한 활성모공(1차 모공 + 2차 모공) 수의 분포도이다. 도 5의 (C)에 불활성모공, 1차모공, 2차모공으로서 대표적인 모공을 각각 검은색 화살표, 은색 화살표, 노란색 화살표로 표시하였으며, 화장수에 용해된 텔로머라제 활성화물질(TA-65과 GPC)을 도포한 노화동물 피부에서는 활성모공을 발견하기 어려웠다.Meanwhile, Figure 6 shows the increase in active pores due to telomerase activating substances, showing the number of active pores (primary pores + secondary pores) excluding inactive pores in a unit area of 1 square millimeter in H&E-stained skin tissue. It is a distribution chart. In Figure 5 (C), representative pores such as inactive pores, primary pores, and secondary pores are indicated by black arrows, silver arrows, and yellow arrows, respectively, and telomerase activating substance (TA-65) dissolved in lotion. It was difficult to find active pores on the skin of aging animals to which GPC and GPC had been applied.
그러나 나노 버블, 나노 리포좀, 다공성 실리카 나노입자에 결합 혹은 포집된 텔로머라제 활성화 물질을 도포한 경우에는 동물 피부의 활성모공의 분명한 수적 증가를 보여준다.However, when telomerase activating substances bound or captured in nanobubbles, nanoliposomes, or porous silica nanoparticles are applied, a clear increase in the number of active pores in animal skin is shown.
도 7은 도 2, 도 3, 도 4에서처럼 GPC을 함유한 나노버블 용액(B), 나노리포좀(C), 혹은 나노실리카(C) 용액을 도포한 마우스의 피부를 바이옵시한 후 파라핀으로 고형화한 조직을 측면으로 절단한 후, H&E 염색을 행하여 모공의 깊이를 관찰한 것이고, 도 8은 텔로머라제 활성화 물질 GPC에 의한 모공의 깊이를 20제곱밀리미터를 단위면적으로 측정하였다. 도 7, 8에서 확인할 수 있듯이, 화장수(A) 대비 GPC을 함유한 나노버블 용액(B), 나노리포좀(C), 혹은 나노실리카(D) 용액의 모공의 깊이가 크다는 것을 확인할 수 있었다. GPC을 함유한 나노 리포좀 용액(C)은 GPC을 함유한 나노버블 용액(B)과, 나노실리카(D) 용액의 약 50% 정도의 모공 깊이를 보여주었고, 표준 화장수의 경우 활성 모공이 거의 관찰되지 않아서 통계치를 낼 수 없었다.Figure 7 is a biopsy of the skin of a mouse coated with a nanobubble solution (B), nanoliposome (C), or nanosilica (C) solution containing GPC as shown in Figures 2, 3, and 4, and then solidified with paraffin. After cutting one tissue from the side, H&E staining was performed to observe the depth of the pores, and Figure 8 shows the depth of the pores using the telomerase activating substance GPC, measured at a unit area of 20 square millimeters. As can be seen in Figures 7 and 8, it was confirmed that the pore depth of the nanobubble solution (B), nanoliposome (C), or nanosilica (D) solution containing GPC was greater than that of the lotion (A). The nano liposome solution containing GPC (C) showed a pore depth of about 50% of that of the nano bubble solution containing GPC (B) and the nano silica (D) solution, and in the case of standard lotion, almost no active pores were observed. Because it didn't work, statistics couldn't be produced.
앞서 살펴본 실시예에서는 TA-65와 GPC를 각각 60 ~ 100 mg/L의 농도로 나노버블, 나노리포좀, 나노실리카 용액을 조성한 실시예들을 제시하였으나, 이에 한정되는 것은 아니며, 바람직하게는 0.2mg/L ~ 2g/L 농도를 사용할 수 있다.In the previous examples, nanobubbles, nanoliposomes, and nanosilica solutions were presented with TA-65 and GPC at concentrations of 60 to 100 mg/L, but the concentration is not limited to this, and preferably 0.2 mg/L. Concentrations from L to 2g/L can be used.
이상에서 설명된 본 발명은 예시적인 것에 불과하며, 본 발명이 속한 기술분야의 통상의 지식을 가진 자라면 이로부터 다양한 변형 및 균등한 타 실시예가 가능하다는 점을 잘 알 수 있을 것이다. 그러므로 본 발명은 상기의 상세한 설명에서 언급되는 형태로만 한정되는 것은 아님을 잘 이해할 수 있을 것이다. 따라서 본 발명의 진정한 기술적 보호 범위는 첨부된 특허청구범위의 기술적 사상에 의해 정해져야 할 것이다. 또한, 본 발명은 첨부된 청구범위에 의해 정의되는 본 발명의 정신과 그 범위 내에 있는 모든 변형물과 균등물 및 대체물을 포함하는 것으로 이해되어야 한다.The present invention described above is merely illustrative, and those skilled in the art will appreciate that various modifications and other equivalent embodiments are possible therefrom. Therefore, it will be understood that the present invention is not limited to the forms mentioned in the detailed description above. Therefore, the true scope of technical protection of the present invention should be determined by the technical spirit of the attached patent claims. In addition, the present invention should be understood to include all modifications, equivalents and substitutes within the spirit and scope of the present invention as defined by the appended claims.
Claims (1)
나노 입자;를 포함하되,
상기 나노 입자는 나노 실리카이며,
상기 텔로머라제 활성화제는 구아니디노펜틸페닐아이소옥사졸카복사마이드(Guanidinopentylphenylisoxazolecarboxamide)이고,
상기 구아니디노펜틸페닐아이소옥사졸카복사마이드(Guanidinopentylphenylisoxazolecarboxamide)가 상기 나노 실리카에 봉입 내지 포집된 결합체 구조인 것을 특징으로 하는 탈모 예방, 개선 또는 치료용 조성물.telomerase activator; and
Nanoparticles; including,
The nanoparticles are nano silica,
The telomerase activator is guanidinopentylphenylisoxazolecarboxamide,
A composition for preventing, improving or treating hair loss, characterized in that the guanidinopentylphenylisoxazolecarboxamide is a conjugate structure in which the guanidinopentylphenylisoxazolecarboxamide is encapsulated or trapped in the nano-silica.
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