KR20210117534A - Composition for preventing or treating gout - Google Patents
Composition for preventing or treating gout Download PDFInfo
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- KR20210117534A KR20210117534A KR1020200033849A KR20200033849A KR20210117534A KR 20210117534 A KR20210117534 A KR 20210117534A KR 1020200033849 A KR1020200033849 A KR 1020200033849A KR 20200033849 A KR20200033849 A KR 20200033849A KR 20210117534 A KR20210117534 A KR 20210117534A
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- composition
- coenzyme
- gout
- acid
- preventing
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
Description
본 발명은 코엔자임 Q10 가용화 조성물의 통풍 치료 용도에 관한 것이다. The present invention relates to the use of a coenzyme Q10 solubilizing composition for the treatment of gout.
통풍(gout)은 혈액 중에 요산이 높은 상태로 지속되어 형성되는 요산의 결정체가 몸 밖으로 배출되지 못하고 여러 조직에 쌓여 다양한 증상을 유발하는 대사성 질환이다. 혈중 요산이 증가하는 경우는 과도한 요산의 생산과 신장을 통한 배설 과정의 이상 때문에 제대로 배출되지 못함에 따라 나타날 수 있다. 혈중 요산치가 높다고 해서 바로 통풍이 발병하는 것은 아니고, 혈중 요산의 과포화로 인하여 관절과 기타 조직의 monosoudium urate(MUS) 결정의 침착으로 초래되는 염증성 관절염의 형태이다. 높은 요산치에 의해 요산 결정체가 쉽게 형성되어 여러 조직에 침착된 상태가 10~20년간 지속되면 유발인자에 의해 통풍을 일으키게 된다. 이는 주로 40~50대 남성에게서 흔하지만 식생활 변화 및 환경변화에 따라 발병연령이 점점 낮아지고 있으며, 여성은 폐경기 이후 혹은 장기이식 수술 후 면역억제제를 장기 복용하거나 이뇨제의 장기 복용으로 신기능이 저하된 여성에게서 발병할 가능성이 높다. 또한 통풍과 동반되는 염증은 활성화된 면역세포에 의해 일어나는 일련의 면역반응으로 염증반응이 일어나면 여러가지 염증인자들이 만들어져 염증이 발생된다. 이들이 통증의 감수성을 높이는 것으로 알려져 있다.Gout is a metabolic disease in which uric acid crystals formed when uric acid remains high in the blood cannot be discharged out of the body and accumulate in various tissues, causing various symptoms. An increase in uric acid in the blood may occur as a result of excessive uric acid production and abnormal excretion through the kidneys due to abnormalities in excretion. A high blood uric acid level does not immediately cause gout, but it is a form of inflammatory arthritis caused by deposition of monosoudium urate (MUS) crystals in joints and other tissues due to hypersaturation of blood uric acid. When uric acid crystals are easily formed by high uric acid levels and deposited in various tissues for 10 to 20 years, gout is caused by triggers. It is common in men in their 40s and 50s, but the age of onset is getting lower due to changes in diet and environment. is more likely to develop from Inflammation accompanying gout is a series of immune responses caused by activated immune cells. They are known to increase the sensitivity to pain.
이와 같은 통풍의 원인을 살펴보면, 우리 몸을 구성하고 있는 대부분의 세포는 핵을 가지고 있는데, 이는 유전 정보를 담고 있는 핵산으로 이루어져 있다. 핵산은 퓨린이나 피리미딘으로 구성되어 있고, 세포 수명이 다하면 파괴되어 핵 속의 퓨린체가 분해되어 요산이 대량 만들어지고 요산나트륨의 결정이 조직에 침착함으로써 염증을 일으키는 질병으로 고요산혈증, 통풍성 신질환, 통풍성 신결석증 등을 일으킨다.Looking at the causes of gout, most cells that make up our body have a nucleus, which consists of nucleic acids containing genetic information. Nucleic acids are composed of purines or pyrimidines, and when the cell life is over, they are destroyed and the purine bodies in the nucleus are decomposed to produce a large amount of uric acid, and sodium urate crystals are deposited in the tissues to cause inflammation. cause kidney stones, etc.
현재 이와 같은 통풍 치료로 콜히신(colchicine), 비스테로이드 항염제 또는 스테로이드를 주로 사용하고 있으나, 현대 의학적으로 통풍을 근본적으로 치료하는 약은 개발되어 있지 않다. 다만, 항고요산제로 요산생성억제제인 알로퓨리놀(allopurinor)과 요산 신장배설 촉진제인 프로베네시드(probenecid) 등이 있으나, 알로퓨리놀의 경우 피부발진, 위장장애, 골수억제, 가려움증, 근육통과 같은 심각한 부작용을 나타내므로, 인체에 안전하고 부작용을 감소시키면서 통풍을 예방 또는 치료할 수 있는 치료제의 개발이 요구되어 지고 있다. 또한, 국내등록특허공보 제10-0492470호(통풍 치료 및 예방용 조성물), 국내등록특허공보 제10-1346281호(29가지 약재 추출물을 유효성분으로 함유하는 통풍 예방, 개선 또는 치료용 조성물) 및 국내공개특허공보 제10-2013-0130580호(혼합 약재 추출물을 유효성분으로 포함하는 통풍 예방 또는 치료용 조성물 및 그 제조방법)에 대한 기술이 공개되었으나, 조성물을 제조함에 있어 사용되는 약재의 종류가 많아 비경제적인 문제점이 있거나, 약재의 종류가 적거나 함량이 적어 통풍 진통 완화 및 항염 작용에 대한 효과가 미미한 한계가 있다.Currently, colchicine, non-steroidal anti-inflammatory drugs, or steroids are mainly used for the treatment of gout, but a drug that fundamentally treats gout in modern medical science has not been developed. However, there are allopurinol, a uric acid production inhibitor, and probenecid, a uric acid kidney excretion promoter. Therefore, there is a demand for the development of a therapeutic agent that is safe for the human body and can prevent or treat gout while reducing side effects. In addition, Korean Patent Publication No. 10-0492470 (composition for treatment and prevention of gout), Korean Patent Publication No. 10-1346281 (composition for prevention, improvement or treatment of gout containing 29 medicinal extracts as active ingredients) and Although the technology for Korean Patent Publication No. 10-2013-0130580 (a composition for preventing or treating gout containing a mixed medicinal extract as an active ingredient and a method for manufacturing the same) has been disclosed, the type of drug used in preparing the composition is There are many uneconomical problems, or there are few kinds or small amounts of drugs, so there is a slight limit to the effect on gout pain relief and anti-inflammatory action.
본 발명의 목적은 통풍의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of gout.
아울러, 본 발명의 목적은 통풍의 예방 또는 개선용 식품 조성물을 제공하는 것이다.In addition, it is an object of the present invention to provide a food composition for preventing or improving gout.
상기 과제를 해결하기 위하여, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 통풍의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating gout comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
아울러, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 통풍의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving gout comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
본 발명에 따르면, 코엔자임 Q10이 마이셀에 봉입된 CoQ10 마이셀은 요산염으로 유발된 통풍 동물모델에서 공기 주머니로의 염증세포 및 호중구 세포의 침윤을 억제하며, 피하 염증 침윤을 억제하는 효과가 있으므로, 이를 통증의 예방 또는 치료 용도로 유용하게 이용할 수 있다.According to the present invention, CoQ10 micelles in which coenzyme Q10 is encapsulated in micelles inhibit the infiltration of inflammatory cells and neutrophils into the air sac in an animal model of urate-induced gout, and have an effect of inhibiting subcutaneous inflammatory infiltration. It can be usefully used for the prevention or treatment of pain.
도 1은 고압 균질 유화기를 이용한 CoQ10 가용화 조성물 제조 방법을 나타낸 모식도이다:
a: 마이셀의 제조방법; 및
b: CoQ10 마이셀의 제조방법.
도 2는 CoQ10을 농도별로 HPLC 분석하여 정량 곡선을 작성한 결과이다.
도 3은 고압 균질 유화기를 이용하여 제조된 CoQ10 가용화 조성물의 입자분포도를 분석한 결과이다.
도 4는 고압 균질 유화기를 이용하여 제조된 CoQ10 가용화 조성물의 표면전하를 분석한 결과이다.
도 5는 통풍 동물모델의 공기 주머니 내 침윤된 전체 염증세포를 확인한 도이다:
Vehicle: 무처리 대조군 (정상대조군);
MSU+micelle: 대조군 마이셀을 투여한 요산염(monosodium urate monohydrate) 유도 통풍 동물모델군 (통풍유도군);
MSU+CoQ10 micelle: 본 발명의 CoQ10 가용화 조성물(CoQ10 마이셀)을 투여한 통풍 동물모델군 (통풍치료군); 및
MSU+Colchicine: 콜히친 투여한 통풍 동물모델군 (양성대조군).
도 6은 통풍 동물모델의 공기 주머니 내 침윤된 호중구 세포를 확인한 도이다:
Vehicle: 무처리 대조군 (정상대조군);
MSU+micelle: 대조군 마이셀을 투여한 요산염(monosodium urate monohydrate) 유도 통풍 동물모델군 (통풍유도군);
MSU+CoQ10 micelle: 본 발명의 CoQ10 가용화 조성물(CoQ10 마이셀)을 투여한 통풍 동물모델군 (통풍치료군); 및
MSU+Colchicine: 콜히친 투여한 통풍 동물모델군 (양성대조군).
도 7은 통풍 동물모델의 공기 주머니의 피하 염증 침윤을 확인한 도이다:
Vehicle: 무처리 대조군 (정상대조군);
MSU+micelle: 대조군 마이셀을 투여한 요산염(monosodium urate monohydrate) 유도 통풍 동물모델군 (통풍유도군);
MSU+CoQ10 micelle: 본 발명의 CoQ10 가용화 조성물(CoQ10 마이셀)을 투여한 통풍 동물모델군 (통풍치료군); 및
MSU+Colchicine: 콜히친 투여한 통풍 동물모델군 (양성대조군).1 is a schematic diagram showing a method for preparing a CoQ10 solubilizing composition using a high-pressure homogeneous emulsifier:
a: a method for preparing micelles; and
b: Method for producing CoQ10 micelles.
2 is a result of preparing a quantitative curve by HPLC analysis of CoQ10 for each concentration.
3 is a result of analyzing the particle distribution of the CoQ10 solubilizing composition prepared using a high-pressure homogeneous emulsifier.
4 is a result of analyzing the surface charge of the CoQ10 solubilizing composition prepared using a high-pressure homogeneous emulsifier.
5 is a view confirming the total inflammatory cells infiltrated in the air sac of the gout animal model:
Vehicle: untreated control group (normal control group);
MSU+micelle: urate (monosodium urate monohydrate)-induced gout animal model group (gout induction group) administered with control micelles;
MSU+CoQ10 micelle: Gout animal model group (gout treatment group) administered with the CoQ10 solubilizing composition (CoQ10 micelles) of the present invention; and
MSU+Colchicine: Colchicine-administered gout animal model group (positive control group).
Figure 6 is a view confirming the infiltrating neutrophil cells in the air sac of the gout animal model:
Vehicle: untreated control group (normal control group);
MSU+micelle: urate (monosodium urate monohydrate)-induced gout animal model group (gout induction group) administered with control micelles;
MSU+CoQ10 micelle: Gout animal model group (gout treatment group) administered with the CoQ10 solubilizing composition (CoQ10 micelles) of the present invention; and
MSU+Colchicine: Colchicine-administered gout animal model group (positive control group).
7 is a view confirming the subcutaneous inflammatory infiltration of the air sac in the gout animal model:
Vehicle: untreated control group (normal control group);
MSU+micelle: urate (monosodium urate monohydrate)-induced gout animal model group (gout induction group) administered with control micelles;
MSU+CoQ10 micelle: Gout animal model group (gout treatment group) administered with the CoQ10 solubilizing composition (CoQ10 micelles) of the present invention; and
MSU+Colchicine: Colchicine-administered gout animal model group (positive control group).
이하, 첨부된 도면을 참조하여 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다. Hereinafter, the present invention will be described in detail as an embodiment of the present invention with reference to the accompanying drawings. However, the following embodiments are presented as examples of the present invention, and when it is determined that detailed descriptions of well-known techniques or configurations known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted, and , the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the scope of equivalents interpreted therefrom and the description of the claims to be described later.
또한, 본 명세서에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서, 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, the terms used in this specification are terms used to properly express the preferred embodiment of the present invention, which may vary according to the intention of a user or operator, or customs in the field to which the present invention belongs. Accordingly, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 도입된다.All technical terms used in the present invention, unless otherwise defined, have the meaning as commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. The contents of all publications herein incorporated by reference are incorporated herein by reference.
일 측면에서, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 통풍의 예방 또는 치료용 약학적 조성물에 관한 것이다.In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating gout comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
일 구현예에서, 마이셀은 글리시리진산 또는 글리시리진산의 염, 및 EPA 또는 DHA를 포함할 수 있다.In one embodiment, the micelles may comprise glycyrrhizic acid or a salt of glycyrrhizic acid, and EPA or DHA.
일 구현예에서, 글리시리진산 또는 글리시리진산의 염, EPA 또는 DHA, 및 코엔자임 Q10의 혼합 비율은 중량기준으로 0.1 내지 5:0.1 내지 5:0.1 내지 5의 범위로 혼합될 수 있다.In one embodiment, the mixing ratio of glycyrrhizic acid or a salt of glycyrrhizic acid, EPA or DHA, and coenzyme Q10 may be in the range of 0.1 to 5:0.1 to 5:0.1 to 5 by weight.
일 구현예에서, 코엔자임 Q10 가용화 조성물에 봉입되는 코엔자임 Q10의 함량이 조성물 총 중량에 대하여 1∼50 중량%일 수 있다.In one embodiment, the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition may be 1 to 50 wt% based on the total weight of the composition.
일 구현예에서, 코엔자임 Q10은 코엔자임 Q10 가용화 조성물 수용액에 0.05∼3 mg/mL의 농도로 포함될 수 있다.In one embodiment, coenzyme Q10 may be included in an aqueous solution of coenzyme Q10 solubilizing composition at a concentration of 0.05 to 3 mg/mL.
일 구현예에서, 본 발명의 약학적 조성물 총 100 중량부에 대하여, 코엔자임 Q10 가용화 조성물이 0.01 내지 90 중량부로 함유될 수 있다.In one embodiment, based on 100 parts by weight of the total pharmaceutical composition of the present invention, the coenzyme Q10 solubilizing composition may be contained in an amount of 0.01 to 90 parts by weight.
일 구현예에서, 코엔자임 Q10 가용화 조성물은 10∼200 nm의 입자크기를 가질 수 있다.In one embodiment, the coenzyme Q10 solubilizing composition may have a particle size of 10-200 nm.
일 구현예에서, 통풍은 요산염(monosodium urate monohydrate; MSU)결정에 의해 유발될 수 있다.In one embodiment, gout may be induced by monosodium urate monohydrate (MSU) crystals.
일 구현예에서, 코엔자임 Q10 가용화 조성물은 요산염(MSU) 결정에 의한 공기 주머니(air-pouch)로의 면역 세포의 침윤을 저해할 수 있다.In one embodiment, the coenzyme Q10 solubilizing composition can inhibit the infiltration of immune cells into the air-pouch by urate (MSU) crystals.
본 발명에 따른 상기 글리시리진산은 이의 염, 바람직하게는 약학적으로 허용 가능한 염의 형태로 사용될 수 있다. 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다. 본 발명에 따른 커큐민 화합물은 천연으로부터 분리되거나 당업계에 공지된 화학적 합성법으로 제조된 것을 사용할 수 있다.The glycyrrhizic acid according to the present invention may be used in the form of a salt thereof, preferably a pharmaceutically acceptable salt. The salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid. The organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid. In addition, the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. The curcumin compound according to the present invention may be isolated from nature or prepared by a chemical synthesis method known in the art.
본 발명의 약학적 조성물에는 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 면역성을 증가시킬 수 있다.The pharmaceutical composition of the present invention may further include an adjuvant. The adjuvant may be used without limitation as long as it is known in the art, and for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
본 발명의 용어, "치료"란, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미하며, 본 발명에서 사용된 상기 치료란 용어는 치료하는 행위를 말한다. As used herein, the term "treatment" means, unless otherwise stated, the disease or condition to which the term applies, or one or more symptoms of the disease or disorder, which reverses, ameliorates, inhibits the progression, or It means to prevent, and the term treatment as used in the present invention refers to the act of treating.
따라서 포유동물에 있어서 통풍의 치료 또는 치료요법은 하기의 하나 이상을 포함할 수 있다:Thus, treatment or therapy for gout in a mammal may include one or more of the following:
(1) 통풍의 성장을 저해함, 즉, 그 발달을 저지시킴;(1) inhibiting the growth of gout, ie, arresting its development;
(2) 통풍의 확산을 예방함, 즉, 전이를 예방함; (2) preventing the spread of gout, ie, preventing metastasis;
(3) 통풍을 경감시킴; (3) alleviating gout;
(4) 통풍의 재발을 예방함; 및 (4) prevent recurrence of gout; and
(5) 통풍의 증상을 완화함(palliating) (5) alleviating the symptoms of gout (palliating)
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term "mammal" refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
만약, 수혜동물이 조성물의 투여에 견딜 수 있거나, 조성물의 그 동물에의 투여가 적합한 경우라면, 조성물은 "약학적으로 또는 생리학적으로 허용가능함"을 나타낸다. 투여된 양이 생리학적으로 중요한 경우에는 상기 제제는 "치료학적으로 유효량"으로 투여되었다고 말할 수 있다. 상기 제제의 존재가 수혜 환자의 생리학적으로 검출가능한 변화를 초래한 경우라면 상기 제제는 생리학적으로 의미가 있다.A composition is indicated to be "pharmaceutically or physiologically acceptable" if the recipient animal can tolerate administration of the composition, or if administration of the composition to that animal is suitable. When the amount administered is physiologically important, the agent can be said to have been administered in a "therapeutically effective amount". An agent is physiologically meaningful if the presence of the agent results in a physiologically detectable change in the recipient patient.
본 발명의 조성물의 치료적으로 유효한 양은 여러 요소, 예를 들면 투여방법, 목적부위, 환자의 상태 등에 따라 달라질 수 있다. 따라서, 인체에 사용 시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다. 동물실험을 통해 결정한 유효량으로부터 인간에 사용되는 양을 추정하는 것도 가능하다. 유효한 양의 결정시 고려할 이러한 사항은, 예를 들면 Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.(2001), Pergamon Press; 및 E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack Publishing Co.에 기술되어있다.The therapeutically effective amount of the composition of the present invention may vary depending on several factors, for example, the administration method, the target site, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined as an appropriate amount in consideration of both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. These considerations in determining effective amounts are found, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's Health status, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other factors well known in the medical field can be determined according to The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 조성물은 또한 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 약학적으로 허용 가능한 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack Publishing Company, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The compositions of the present invention may also include carriers, diluents, excipients or combinations of two or more commonly used in biological agents. The pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc. Compounds described in , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used, and if necessary, other antioxidants, buffers, bacteriostats, etc. Conventional additives may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to formulate into injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets. Furthermore, it can be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
본 발명의 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. have.
본 발명에서 사용되는 용어, "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. As used herein, the term “pharmaceutically acceptable” refers to exhibiting non-toxic properties to cells or humans exposed to the composition.
본 발명의 약학적 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive includes starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate. , lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, sucrose, dextrose, sorbitol and talc and the like can be used. The pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. As used herein, the term "administration" means providing a predetermined substance to a patient by any suitable method, and parenteral administration (eg, intravenous, subcutaneous, intraperitoneal or topical administration according to a desired method) ) or oral administration, and the dosage varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
본 발명의 조성물은 목적하는 방법에 따라 비경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 적용)하거나 경구 투여할 수 있으며, 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학적 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학적 조성물에 0.01 ㎍/ml ~ 50 mg/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 50 mg/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) or orally, depending on the desired method, and the dosage may vary depending on the subject's age, weight, sex, physical condition, etc. is selected taking into account. It is self-evident that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 μg/ml to 50 mg/ml. If the concentration is less than 0.01 μg/ml, pharmaceutical activity may not appear, and if it exceeds 50 mg/ml, it may be toxic to the human body.
본 발명의 약학적 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화될 수 있다. 경구 투여용 제형으로는 예를 들면 정제, 환제, 경질, 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제 (예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제 (예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 추가로 포함할 수 있다. 또한, 상기 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다. 또한, 비경구 투여용 제형의 대표적인 것은 주사용 제제이며, 주사용 제제의 용매로서 물, 링거액, 등장성 생리식염수 또는 현탁액을 들 수 있다. 상기 주사용 제제의 멸균 고정 오일은 용매 또는 현탁 매질로서 사용할 수 있으며 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있다. 또한, 상기 주사용 제제는 올레산과 같은 지방산을 사용할 수 있다. The pharmaceutical composition of the present invention may be formulated in various oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg, silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). In addition, the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid. or disintegrants such as sodium salts thereof or effervescent mixtures and/or absorbents, coloring, flavoring and sweetening agents. The formulation may be prepared by conventional mixing, granulating or coating methods. In addition, representative formulations for parenteral administration are injection formulations, and water, Ringer's solution, isotonic physiological saline, or suspension can be exemplified as a solvent for the injection formulation. The sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose. In addition, the injection preparation may use a fatty acid such as oleic acid.
본 발명에서, 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 통풍의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any action that suppresses or delays the occurrence, spread, and recurrence of gout by administration of the pharmaceutical composition according to the present invention.
일 측면에서, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 통풍의 예방 또는 개선용 식품 조성물에 관한 것이다.In one aspect, the present invention relates to a food composition for preventing or improving gout comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
일 구현예에서, 마이셀은 글리시리진산 또는 글리시리진산의 염, 및 EPA 또는 DHA를 포함할 수 있다.In one embodiment, the micelles may comprise glycyrrhizic acid or a salt of glycyrrhizic acid, and EPA or DHA.
일 구현예에서, 글리시리진산 또는 글리시리진산의 염, EPA 또는 DHA, 및 코엔자임 Q10의 혼합 비율은 중량기준으로 0.1 내지 5:0.1 내지 5:0.1 내지 5의 범위로 혼합될 수 있다.In one embodiment, the mixing ratio of glycyrrhizic acid or a salt of glycyrrhizic acid, EPA or DHA, and coenzyme Q10 may be in the range of 0.1 to 5:0.1 to 5:0.1 to 5 by weight.
일 구현예에서, 코엔자임 Q10 가용화 조성물에 봉입되는 코엔자임 Q10의 함량이 조성물 총 중량에 대하여 1∼50 중량%일 수 있다.In one embodiment, the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition may be 1 to 50 wt% based on the total weight of the composition.
일 구현예에서, 코엔자임 Q10은 코엔자임 Q10 가용화 조성물 수용액에 0.05∼3 mg/mL의 농도로 포함될 수 있다.In one embodiment, coenzyme Q10 may be included in an aqueous solution of coenzyme Q10 solubilizing composition at a concentration of 0.05 to 3 mg/mL.
일 구현예에서, 코엔자임 Q10 가용화 조성물은 10∼200 nm의 입자크기를 가질 수 있다.In one embodiment, the coenzyme Q10 solubilizing composition may have a particle size of 10-200 nm.
본 발명의 조성물을 식품 조성물로 사용하는 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상의 방법에 따라 적절하게 사용할 수 있다. 상기 조성물은 유효성분 이외에 식품학적으로 허용가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When the composition of the present invention is used as a food composition, the composition may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method. In addition to the active ingredient, the composition may contain a food additive that is pharmaceutically acceptable, and the mixing amount of the active ingredient may be suitably determined according to the purpose of use (prevention, health or therapeutic treatment).
본 발명에서 사용되는 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term "food supplement additive" used in the present invention refers to a component that can be added to food as an auxiliary, and is added to the manufacture of health functional food of each formulation, and those skilled in the art can appropriately select and use it. Examples of food supplement additives include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners , pH adjuster, stabilizer, preservative, glycerin, alcohol, carbonation agent used in carbonated beverages, etc., but the above examples are not limited to the type of food supplement additive of the present invention.
본 발명의 식품 조성물에는 건강기능식품이 포함될 수 있다. 본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 통풍 치료제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The food composition of the present invention may include a health functional food. The term "health functional food" as used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful in the human body. Here, the term 'functionality' refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be prepared by a method commonly used in the ordinary technical field, and at the time of the preparation, it can be prepared by adding raw materials and components commonly added in the conventional technical field. In addition, if the formulation of the health functional food is also recognized as a health functional food, it can be prepared without limitation. The composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability, and the present invention health functional food can be taken as a supplement to enhance the effect of gout treatment.
또한, 본 발명의 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 추출물 또는 이의 분획물을 활성성분으로 포함하는 조성물은 당업자의 선택에 따라 건강기능식품에 함유될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 추출물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.In addition, there is no limitation on the type of health food in which the composition of the present invention can be used. In addition, the composition comprising the extract of the present invention or a fraction thereof as an active ingredient can be prepared by mixing known additives with other suitable auxiliary ingredients that may be contained in health functional foods according to the selection of those skilled in the art. Examples of foods that can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and There are vitamin complexes and the like, and it can be prepared by adding the extract according to the present invention as a main component to juice, tea, jelly, juice, and the like.
본 발명의 조성물은 천연 재료를 원료로 하므로 약학적 조성물 또는 식품 조성물로 사용할 경우에도 일반적인 합성 화합물에 비하여 부작용이 덜할 수 있으므로, 안전하게 약학적 조성물 및 건강기능식품에 포함되어 유용하게 사용될 수 있다.Since the composition of the present invention is made from natural materials, side effects may be less than that of general synthetic compounds even when used as a pharmaceutical composition or a food composition, so it can be safely included in pharmaceutical compositions and health functional foods to be usefully used.
일 측면에서, 본 발명은 본 발명의 조성물을 하나 이상의 단위 투여 형태로 포함하는 키트에 관한 것이다.In one aspect, the invention relates to a kit comprising a composition of the invention in one or more unit dosage forms.
일 구현예에서, 본 발명에서 기술되는 투여 형태는 투여 형태의 사용에 대한 설명서와 함께 블리스터 팩으로서 또는 병에 포장될 수 있다. 예를 들어, 설명서는 패키지 삽입물로서 제공되거나 블리스터 팩, 병에 부착된 표지물 상 또는 블리스터 팩 또는 병이 사람 피험자에게 제공되었던 이차적인 포장재 상에 직접적으로 제공될 수 있다. 설명서는, 예를 들어, 투약 횟수, 음식과 함께 또는 음식 없이 투여되는 투여 형태의 투여, 투여 형태를 구성하는 활성 성분 및 투여 형태를 포함할 수 있다.In one embodiment, the dosage forms described herein may be packaged in a bottle or as a blister pack with instructions for use of the dosage form. For example, instructions may be provided as a package insert or may be provided directly on a blister pack, label affixed to the bottle, or on a secondary packaging material from which the blister pack or bottle was provided to a human subject. Instructions may include, for example, the number of doses, the administration of the dosage form to be administered with or without food, the active ingredient constituting the dosage form, and the dosage form.
하기의 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나 하기 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐 이에 의해 본 발명이 한정되는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are only for specifying the contents of the present invention, and the present invention is not limited thereto.
실시예 1. CoQ10 가용화 조성물 제조Example 1. Preparation of CoQ10 Solubilizing Composition
1-1. 고압 균질 유화기를 이용한 CoQ10 가용화 조성물 제조1-1. Preparation of CoQ10 Solubilizing Composition Using High Pressure Homogeneous Emulsifier
CoQ10(코엔자임 Q10)이 고농도로 함유된 CoQ10 가용화 조성물을 제조하기 위하여, 하기 표 1의 조건으로 도 1에 기재된 제조 방법을 수행하였다. 보다 구체적으로, 반응기에 증류수(Distilled water)를 주입한 후, 마이셀 형성을 위한 글리시리진산 이칼륨염(Dipotassium glycyrrhizinate), 아이코사펜타에노익산(EPA), 난용성 약물인 CoQ10을 하기 표 1에 기재된 함량으로 첨가하여 고르게 분산되도록 교반하였다. 반응기에서 원활한 마이셀 생성을 위해 60 내지 70 ℃로 중탕된 상태로 각 원료가 포함된 상태에서 10,000 rpm으로 10분간 교반하였다. 상기 반응액을 APV사의 APV-2000 유동층 혼합기(microfluidizer, SPX Flow, UK)를 이용하여 1200 bar의 고압에서 1 시간 동안 마이셀 형성을 위한 CoQ10의 봉입을 수행하였으며, 0.45 ㎛ 시린지 필터를 이용하여 마이셀을 확보하였다. 이 때, 과포화 상태의 조성물의 경우, 유동층 혼합기를 이용한 조성물 가용화 수행 후 수용액상에서 봉입되지 않은 CoQ10은 0.45 ㎛ 시린지 필터를 이용하여 제거하였다. In order to prepare a CoQ10 solubilized composition containing CoQ10 (Coenzyme Q10) at a high concentration, the preparation method described in FIG. 1 was performed under the conditions shown in Table 1 below. More specifically, after injecting distilled water into the reactor, glycyrrhizinate dipotassium salt (Dipotassium glycyrrhizinate) for micell formation, eicosapentaenoic acid (EPA), and CoQ10, a poorly soluble drug, are shown in Table 1 below. It was added in the indicated amount and stirred to evenly disperse. In order to generate micelles smoothly in the reactor, the mixture was stirred at 10,000 rpm for 10 minutes while each raw material was included in a bath at 60 to 70 °C. The reaction solution was encapsulated with CoQ10 for micelle formation for 1 hour at a high pressure of 1200 bar using APV-2000 fluid bed mixer (microfluidizer, SPX Flow, UK) of APV, and micelles were removed using a 0.45 μm syringe filter. secured. At this time, in the case of the composition in the supersaturated state, CoQ10 not encapsulated in the aqueous phase after solubilization of the composition using a fluidized bed mixer was removed using a 0.45 μm syringe filter.
1-2. CoQ10 가용화 조성물의 입도 분석 1-2. Particle size analysis of CoQ10 solubilizing composition
상기에서 제조한 수용성 코엔자임 Q1의 마이셀 입자크기를 나타내는 입도분석 결과 (Zetasizer Nano ZS9, Malvern Instrument, Ltd., UK), 도 2에 나타낸 바와 같이, CoQ10 가용화 조성물은 80 nm 내외로 균일한 입자 크기가 나타남을 확인하였다.As shown in the particle size analysis results (Zetasizer Nano ZS9, Malvern Instrument, Ltd., UK) showing the micellar particle size of the water-soluble coenzyme Q1 prepared above, FIG. 2 , the CoQ10 solubilization composition had a uniform particle size around 80 nm. Appearance was confirmed.
1-3. CoQ10 가용화 조성물의 CoQ10 함유량 분석 1-3. Analysis of CoQ10 content of CoQ10 solubilizing composition
상기 실시예와 같이 CoQ10 : 아이코사펜타에노익산 : 글리시리진산 (1 g : 1 mL : 1 g)을 1 리터의 증류수를 이용하여 제조된 CoQ10 가용화 조성물 2.4 g/L을 이용하여 CoQ10의 정량을 HPLC로 분석하였다. HPLC 조건은 하기 표 2와 같으며, 하기 조건을 통해 검출한 CoQ10의 HPLC 상에서의 시간대는 6.9분에 피크나 나타나는 것을 확인하였으며, 이를 도 3에 도시하였다.As in the above example, CoQ10: eicosapentaenoic acid: glycyrrhizinic acid (1 g: 1 mL: 1 g) CoQ10 solubilization composition 2.4 g / L prepared using 1 liter of distilled water Quantification of CoQ10 Analyzed by HPLC. HPLC conditions are as shown in Table 2 below, and it was confirmed that a peak appeared at 6.9 minutes on HPLC of CoQ10 detected through the following conditions, which is shown in FIG. 3 .
Flow rate 1 mL/min
Injection sample 10 μL
UV detection at 220, 254 and 280 nm
CoQ10 분석 조건 (메탄올 : 이소프로판올 = 40:60, 등용매용리)
EPA 및 glycyrrhizinate 분석 조건 (0.1% TFA를 포함하는 물과 아세토니트릴의 농도구배용리)C18 column, 5 μ4.6 mm x 250 mm (Waters, Xbridge)
UV detection at 220, 254 and 280 nm
CoQ10 analysis conditions (methanol: isopropanol = 40:60, isocratic elution)
EPA and glycyrrhizinate assay conditions (gradient elution of water with 0.1% TFA and acetonitrile)
이 때, 상기 조건은 CoQ10:EPA:글리시리진산 (0.1 내지 5:0.1 내지 5:0.1 내지 5)을 이용한 가용화 조성물 제작 중 최적의 조건을 표기한 것일 뿐, 그 혼합 범위는 변경될 수 있다. 그 결과, 도 4에 나타낸 바와 같이, CoQ10의 정량곡선을 통해, 유동층 혼합기를 이용한 CoQ10 가용화 조성물의 CoQ10의 가용화 정도를 하기 수학식 1을 통해 확인하였다. At this time, the above conditions are only indicating the optimum conditions during the preparation of the solubilization composition using CoQ10:EPA:glycyrrhizic acid (0.1 to 5:0.1 to 5:0.1 to 5), and the mixing range may be changed. As a result, as shown in FIG. 4 , the degree of solubilization of CoQ10 in the CoQ10 solubilization composition using a fluidized bed mixer was confirmed through
x = CoQ10 농도; 및 x = CoQ10 concentration; and
y = micelle 1 mg을 MeOH에 용해한 후 측정한 HPLC 상에서의 흡광 intensity.y = Absorption intensity on HPLC measured after dissolving 1 mg of micelles in MeOH.
그 결과, 상기 표 1에 나타낸 바와 같이, 난용성 물질인 CoQ10이 함유된 생체 친화적 마이셀 입자를 수득하였으며, 수율 100%의 CoQ10 가용화 조성물 (CoQ10 마이셀, CoQ10 micelle)을 제조하고, 봉입효율을 확인하였다.As a result, as shown in Table 1, biocompatible micellar particles containing CoQ10, a poorly soluble material, were obtained, and a CoQ10 solubilization composition (CoQ10 micelles, CoQ10 micelles) with a yield of 100% was prepared, and the encapsulation efficiency was confirmed. .
실시예 2. CoQ10 가용화 조성물의 통풍 치료 효과Example 2. Gout treatment effect of CoQ10 solubilizing composition
2-1. 통풍 동물모델에서 CoQ10 마이셀의 염증세포 침윤 억제 효과2-1. Inhibitory effect of CoQ10 micelles on inflammatory cell infiltration in gout animal model
호중구와 같은 대식세포 및 섬유아세포를 포함하고 있는 윤활막과 같은 막을 따라 이용가능한 공간에 공기 주머니를 발생시킨 후 공기 주머니 안에 MSU 결정을 현탁시킨 PBS 1 ml을 국소 주입하여 발생시킨 통풍 동물모델을 제작하고, 통풍에 대한 CoQ10 마이셀의 효과를 확인하기 위해, C57BL/6 마우스에 요산염(monosodium urate monohydrate, MSU) 결정을 피하 주사하기 17일 전부터 마이셀 및 CoQ10 마이셀을 각각 경구 투여하고, 시험 개시 6일 및 3일 전에 피하에 멸균된 공기 3cc씩 주사하였다. 그 후, 시험 개시일에 MSU를 3mg/1ml/mouse의 용량으로 피하주사하여 통풍 동물 모델인 공기 주머니(air-pouch) 모델을 제작하였다. 양성대조물질인 콜히친(Colchicine)은 MSU를 주입하기 2시간 전에 1mg/kg의 용량으로 공기 주머니 안으로 피하주사하였다. MSU 결정 주입 6시간 후 생쥐를 안락사시키고, 공기 주머니(air-pouch)내 액체를 5mM EDTA가 포함된 PBS 2ml로 세척하여 수집한 뒤 12,000rpm으로 2분간 원심분리하여 분석한 결과, 통풍 유도군에서 공기 주머니 내로 침윤된 염증세포가 증가하였으며, CoQ10 마이셀을 투여한 군은 콜히친을 투여한 양성 대조군의 수준으로 염증 세포 침윤이 감소하였다 (도 5).After generating air pockets in the available space along the membrane-like synovial membrane containing macrophages such as neutrophils and fibroblasts, local injection of 1 ml of PBS in which MSU crystals are suspended in the air pockets was used to produce a gout animal model. , In order to confirm the effect of CoQ10 micelles on gout, micelles and CoQ10 micelles were orally administered 17 days before subcutaneous injection of monosodium urate monohydrate (MSU) crystals into C57BL/6 mice. 3 cc of sterile air was injected subcutaneously 3 days before. Then, on the test start day, MSU was injected subcutaneously at a dose of 3 mg/1ml/mouse to prepare an air-pouch model, which is a gout animal model. Colchicine, a positive control, was subcutaneously injected into the air bag at a dose of 1 mg/
2-2. 통풍 동물모델에서 CoQ10 마이셀의 호중구 세포 침윤 억제 효과2-2. Inhibitory effect of CoQ10 micelles on neutrophil cell infiltration in gout animal model
상기 통풍 동물모델에서 수집한 공기 주머니(air-pouch) 세척액을 유세포 분석을 통해 공기 주머니 내로 침윤한 전체 염증 세포들 중에서 IL-1β 생성의 주된 원인인 CD11b+Ly-6G+ (호중구)세포의 침윤 정도를 확인하였다.The degree of infiltration of CD11b+Ly-6G+ (neutrophil) cells, which is the main cause of IL-1β production, among all inflammatory cells infiltrating the air-pouch wash solution collected from the gout animal model into the air pockets through flow cytometry. was confirmed.
그 결과, 통풍 동물모델에서 공기 주머니로 침윤한 호중구세포가 정상 대조군 마우스에 비해 현저히 증가하였으나, CoQ10 마이셀을 투여한 군에서는 현저히 감소하는 것으로 나타났다 (도 6). 특히, CoQ10 마이셀은 5mg/kg/day의 용량으로 경구 투여한 경우 기존 치료제로 상용중인 콜히친을 1mg/kg/day의 용량으로 피하 투여하는 것과 유사한 수준으로 통풍 염증 부위로의 호중구 세포 침윤을 억제하는 것으로 나타났다.As a result, in the gout animal model, the number of neutrophils infiltrating into the air sac significantly increased compared to the normal control mice, but it was significantly decreased in the group administered with CoQ10 micelles ( FIG. 6 ). In particular, when CoQ10 micelles are orally administered at a dose of 5 mg/kg/day, it is similar to subcutaneous administration of colchicine, which is commercially available as a conventional treatment, at a dose of 1 mg/kg/day, which inhibits neutrophil cell infiltration into the gout inflammatory site. appeared to be
2-3. 통풍 동물모델에서 CoQ10 마이셀의 염증 침윤 억제 효과2-3. Inhibitory effect of CoQ10 micelles on inflammatory infiltration in gout animal models
상기 통풍 동물모델에서 수집한 공기 주머니의 조직학적 분석을 위해, 공기 주머니의 시상 절편(sagittal section)을 4% 파라포름알데하이드로 고정한 후 헤모톡실린&에오신(H&E)로 염색하고 염증침윤 정도를 분석하였다.For histological analysis of the air sacs collected in the gout animal model, the sagittal section of the air sac was fixed with 4% paraformaldehyde, stained with hemotoxylin & eosin (H&E), and the degree of inflammatory infiltration was analyzed. did.
그 결과, 정상 대조군 대비 통풍 동물 모델 파우치 피하 내 염증침윤이 증가하는 것으로 나타났으며, 이는 CoQ10 마이셀의 투여에 의해 감소하는 것으로 나타났다 (도 7).As a result, it was found that the inflammatory infiltration in the pouch subcutaneously in the gout animal model increased compared to the normal control group, which was decreased by the administration of CoQ10 micelles ( FIG. 7 ).
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