KR101481709B1 - Composition for preventing or treating erectile dysfunction comprising Sac-1004 compound - Google Patents
Composition for preventing or treating erectile dysfunction comprising Sac-1004 compound Download PDFInfo
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- KR101481709B1 KR101481709B1 KR20140000755A KR20140000755A KR101481709B1 KR 101481709 B1 KR101481709 B1 KR 101481709B1 KR 20140000755 A KR20140000755 A KR 20140000755A KR 20140000755 A KR20140000755 A KR 20140000755A KR 101481709 B1 KR101481709 B1 KR 101481709B1
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- erectile dysfunction
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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Abstract
Description
본 발명은 Sac-1004 복합체를 유효성분으로 포함하는 발기부전 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating erectile dysfunction comprising Sac-1004 complex as an active ingredient.
발기부전은 남성 성기능 장애의 일종으로서, 남성의 성기가 발기되지 않거나 발기 상태가 지속되지 않아 성행위를 할 수 없는 현상이다. 발기부전의 원인은 크게 심인성 원인과 기질성 원인으로 구별된다. 심인성 발기부전은 심리적, 정신적 영향에 의한 교감신경의 과다한 작용으로 인한 노르아드레날린(noradrenaline)의 과도한 분비, 음경해면체 평활근 긴장도 증가, 신경 전달물질의 분비 억제 등에 기인한다. 또한, 기질성 발기 부전은 그 원인에 따라, 신경인성, 혈관성, 및 내분비성 발기부전으로 분류된다. 상기 혈관성 발기부전은 고지질혈증, 당뇨, 고혈압, 흡연, 전신 심혈관질환 등으로 인해서 음경 혈관내피세포가 손상되어 혈관내피세포에서 일산화질소(nitric oxide: NO) 등의 이완성 물질의 분비가 원활하지 않아 생기는 장애이다.Erectile dysfunction is a type of male sexual dysfunction that can not be done because male penis is not erect or erect state is not maintained. The causes of erectile dysfunction are largely classified into psychogenic causes and substrate causes. Cardiogenic erectile dysfunction is caused by excessive secretion of noradrenaline due to excessive action of sympathetic nerves due to psychological and psychological influences, increased smooth muscle tension of the penis cavernosum, and suppression of neurotransmitter secretion. In addition, organic erectile dysfunction is classified as neurogenic, vascular, and endocrine erectile dysfunction, depending on its cause. The vascular erectile dysfunction is caused by damage to penile vascular endothelial cells due to hyperlipidemia, diabetes, hypertension, smoking, systemic cardiovascular disease, etc., and the secretion of nitric oxide (NO) It is a disorder that occurs.
최근 발기부전에 관한 연구는 기질성 원인에 더 비중을 두고 있고, 그의 치료로서 주로 비아그라(viagra, 성분명: 실데나필)를 포함한 경구용 PDE-5(phosphodiesterase-5) 저해제가 전세계적으로 사용되고 있다. 이러한 경구용 약물은 음경해면체에 특이적으로 분포하는 PDE-5의 저해에 의한 cGMP의 농도를 증가시킴으로써 음경해면체 내 혈류를 증대시켜 발기를 유도하여 발기부전의 치료효과가 있는 것으로 알려져 있다. 그러나 비아그라와 같은 PDE-5 저해제 계열의 약물들은 두통, 안면홍조, 소화불량, 및 심장마비 등 여러 가지 부작용을 가지고 있다고 보고되고 있을 뿐만 아니라, 분자적 수준에서 일시적인 단백질 발현 및 관련 인자들을 조절하는 것으로 근본적인 치료라 할 수 없다. 더욱이 당뇨에 의한 발기부전의 경우, 이와 같은 치료 효과가 잘 나타나지 않을 뿐만 아니라, 설령 효과가 있다 해도 그 효능이 장기간 지속되지 못한다는 단점이 있다.Recently, studies on erectile dysfunction have focused more on the underlying causes, and oral PDE-5 (phosphodiesterase-5) inhibitors, including Viagra (sildenafil), have been used worldwide for its treatment. These oral drugs are known to increase the concentration of cGMP due to the inhibition of PDE-5, which is specifically distributed in the corpus cavernosum, thereby enhancing blood flow in the corpus cavernosum, thereby inducing erection and treating erectile dysfunction. However, PDE-5 inhibitors such as Viagra have been reported to have several side effects such as headache, flushing, dyspepsia, and cardiac arrest, as well as to modulate transient protein expression and related factors at the molecular level It is not a fundamental treatment. Furthermore, in the case of erectile dysfunction caused by diabetes, such a therapeutic effect is not shown well, and even if it is effective, its efficacy can not be sustained for a long time.
따라서, 발기부전 음경 내의 비정상화된 혈관 구조를 근본적으로 치료하고, 그 효능도 장시간 지속되는 발기부전 치료제의 필요성이 요구되고 있는 실정이다.Therefore, there is a need for a therapeutic agent for erectile dysfunction which fundamentally treats the abnormal normalized blood vessel structure in the erectile dysfunction penis, and the effect is also prolonged for a long time.
한편, Sac-1004 복합체는 콜레스테롤 pseudo-sugar 유도체(pseudo-sugar derivative of cholesterol)로서, 최근 연구에서 인간제대정맥 내피세포 이음부물질(endothelial cell-cell junctions)을 안정화시킴으로써 내피세포 과투과성(endothelial hyperpermeability)을 억제시키는 것으로 보고되었다(Majarjan S et al., Biochem Biophys Res Commun., 435, pp420-7, 2013). 그러나, 현재까지 Sac-1004 복합체의 발기부전 예방 또는 치료 효과에 대해서는 알려진 바 없으며, 이에 대한 연구도 전무한 상태이다. The Sac-1004 complex is a pseudo-sugar derivative of cholesterol. In recent studies, endothelial cell-cell junctions have been stabilized in the human umbilical vein endothelial cell-cell junctions to produce endothelial hyperpermeability ) (Majarjan S et al., Biochem Biophys Res Commun., 435, pp420-7, 2013). However, the effect of preventing or treating erectile dysfunction of the Sac-1004 complex has not been known, and there have been no studies on this.
이에 본 발명자들은 새로운 발기부전 예방 또는 치료용 조성물을 개발하기 위해 연구를 수행한 결과, Sac-1004 복합체가 정상 세포의 생존에 영향을 미치지 않으면서도, 음경해면체내피세포, 평활근세포 및 혈관주위세포 특이적인 단백질의 수준을 증가시켜 음경 발기조직의 재생을 유도하고, 음경해면체의 내압을 증가시킴으로써, 우수한 발기부전 개선 효과가 있음을 확인하고, 본 발명을 완성하였다. Accordingly, the present inventors have conducted studies to develop a composition for preventing or treating erectile dysfunction. As a result, the present inventors have found that Sac-1004 complex does not affect survival of normal cells, but also enhances penile endoplasmic reticulum endothelial cells, smooth muscle cells, The present invention has been accomplished by confirming that the erectile dysfunction improves by increasing the level of the protein and inducing the regeneration of the penile erectile tissue and increasing the internal pressure of the corpus cavernosum.
본 발명의 목적은 Sac-1004 복합체를 유효성분으로 포함하는 발기부전 예방 또는 치료용 조성물을 제공하는 것이다. It is an object of the present invention to provide a composition for preventing or treating erectile dysfunction which comprises Sac-1004 complex as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 Sac-1004 복합체를 유효성분으로 포함하는 발기부전 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating erectile dysfunction comprising Sac-1004 complex as an active ingredient.
또한 본 발명은 Sac-1004 복합체를 유효성분으로 포함하는 발기부전 예방 또는 개선용 의약외품 조성물을 제공한다. The present invention also provides a quasi-drug composition for preventing or improving erectile dysfunction, which comprises Sac-1004 complex as an active ingredient.
또한 본 발명은 Sac-1004 복합체를 유효성분으로 포함하는 발기부전 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or improving erectile dysfunction, which comprises Sac-1004 complex as an active ingredient.
본 발명에 따른 Sac-1004 복합체는 정상 세포의 생존에 영향을 미치지 않으면서도, 음경해면체내피세포, 평활근세포 및 혈관주위세포 특이적인 단백질의 수준을 증가시켜 음경 발기조직의 재생을 유도하고, 음경해면체의 내압을 증가시킴으로써, 우수한 발기부전 개선 효과가 있어, 발기부전의 예방 또는 치료에 유용하게 이용될 수 있다.The Sac-1004 complex according to the present invention induces regeneration of penile erectile tissues by increasing levels of specific proteins of penile cavernosal endothelial cells, smooth muscle cells and perivascular cells without affecting survival of normal cells, It is possible to improve the erectile dysfunction by effectively increasing the internal pressure of the erectile dysfunction.
도 1은 발기부전 동물 모델에서 본 발명의 Sac-1004 복합체 투여에 의한 음경신경 전기자극에 따른 음경해면체 내압(발기력) 측정 결과를 나타낸 도이다.
도 2는 발기부전 동물 모델의 음경 조직에서 본 발명의 Sac-1004 복합체 투여에 의한 혈관내피세포 특이적 단백질인 PECAM-1 및 혈관평활근세포 특이적 단백질인 SM α-액틴의 발현 정도를 공초점 현미경으로 분석한 결과를 나타낸 도이다.
도 3은 발기부전 동물 모델의 음경 조직에서 본 발명의 Sac-1004 복합체 투여에 의한 eNOS 및 p-eNOS의 발현 정도를 공초점 현미경(도3A~3C)과 웨스턴 블랏(도3D)을 통해 분석한 결과를 나타낸 도이다. .
도 4는 발기부전 동물 모델의 음경 조직에서 본 발명의 Sac-1004 복합체 투여에 의한 Ox-LDL의 생성 정도를 공초점 현미경으로 분석한 결과를 나타낸 도이다.
도 5는 발기부전 동물 모델의 음경 조직에서 본 발명의 Sac-1004 복합체 투여에 의한 혈관주위세포의 발현 정도를 비교하기 위해, NG2와 PDGFR-β에 대한 면역조직화학염색 후 공초점 현미경으로 분석한 결과를 나타낸 도이다.
도 6은 발기부전 동물 모델의 음경 조직에서 본 발명의 Sac-1004 복합체 투여에 의한 혈관내피세포 연접 단백질의 발현양상을 비교하기 위해, claudin-5, occludin, VE-cadherin에 대한 면역조직화학염색 후 공초점 현미경으로 분석한 결과를 나타낸 도이다.
도 7은 발기부전 동물 모델의 음경 조직에서 본 발명의 Sac-1004 복합체 투여에 의한 혈관내피세포 연접 단백질의 발현 정도를 웨스턴 블랏을 통해 분석한 결과를 나타낸 도이다.
도 8은 마우스 음경 조직을 일차배양 하여 수득한 해면체내피세포에 본 발명의 Sac-1004 복합체를 처리하여, 관형성 정도에 미치는 영향을 분석한 결과를 나타낸 도이다.
도 9는 마우스 음경 조직을 일차배양 하여 수득한 해면체내피세포에 본 발명의 Sac-1004 복합체를 처리하여, 세포 독성에 미치는 영향을 분석한 결과를 나타낸 도이다.Brief Description of the Drawings Fig. 1 is a graph showing measurement results of intracoronary sponge pressure (erectile force) according to penile nerve electrical stimulation by the Sac-1004 complex administration of the present invention in an erectile dysfunctional animal model.
FIG. 2 shows the expression levels of PECAM-1, a vascular endothelial cell-specific protein and SM a-actin, a vascular smooth muscle cell specific protein, by Sac-1004 complex administration of the present invention in a penile tissue of an erectile dysfunction animal model, As shown in FIG.
Figure 3 shows the expression levels of eNOS and p-eNOS by the Sac-1004 complex administration of the present invention in penile tissues of erectile dysfunctional animal models through confocal microscopy (Figures 3A-3C) and Western blot (Figure 3D) Fig. .
FIG. 4 is a graph showing the results of analysis of the degree of production of Ox-LDL by Sac-1004 complex administration of the present invention in a penile tissue of an erectile dysfunction animal model by confocal microscopy.
FIG. 5 shows immunohistochemical staining for NG2 and PDGFR-β in a penile tissue of an erectile dysfunctional animal model to compare the degree of peripheral vascular cell expression by administration of the Sac-1004 complex of the present invention, followed by confocal microscopy Fig.
FIG. 6 shows the results of immunohistochemical staining for claudin-5, occludin, and VE-cadherin to compare the expression pattern of vascular endothelial cell-associated protein by the Sac-1004 complex administration of the present invention in the penile tissues of the erectile dysfunctional animal model And the result of analysis by confocal microscope.
FIG. 7 is a graph showing the results of western blot analysis of the expression level of vascular endothelial cell-associated protein by administration of Sac-1004 complex of the present invention in penile tissues of an erectile dysfunctional animal model.
Fig. 8 is a graph showing the results of analyzing the effect of treating the Sac-1004 complex of the present invention on the degree of tube formation to the cavernosal endothelial cells obtained by primary culture of mouse penile tissue.
FIG. 9 is a graph showing the results of analyzing the effect of treating the Sac-1004 complex of the present invention on the cytotoxicity to the caustic endothelial cells obtained by primary culture of mouse penile tissue.
본 발명은 화학식 1로 표시되는 Sac-1004 복합체를 유효성분으로 포함하는 발기부전 예방 또는 치료용 조성물을 제공한다. The present invention provides a composition for preventing or treating erectile dysfunction, comprising the Sac-1004 complex represented by the general formula (1) as an active ingredient.
상기 조성물은 약학적 조성물, 의약외품 조성물 또는 식품 조성물을 포함한다. The composition comprises a pharmaceutical composition, a quasi-drug composition or a food composition.
상기 Sac-1004 복합체는 일반적인 방법으로 구입하거나, 종래 공지된 방법에 따라 합성하여 수득할 수 있다.
The Sac-1004 complex may be obtained by a general method or may be synthesized according to a conventionally known method.
본 발명에서 용어, "발기부전"은 성생활에 충분한 발기가 되지 않거나 유지되지 않은 상태를 의미하며, 일반적으로 이러한 상태가 3개월 이상 지속되었을 경우 발기부전으로 정의한다.The term "erectile dysfunction" in the present invention means a state in which erectile function is not sufficiently maintained or maintained in the sex life, and erectile dysfunction is generally defined as a state in which such state lasts for 3 months or more.
상기 발기부전은 음경 해면체내피세포 및 평활근세포의 기능 저하 또는 손상에 의하여 야기될 수 있다. 이러한 음경내피세포 및 평활근세포의 기능 저하 또는 손상은 고지질혈증(고콜레스테롤증 발기부전 포함), 당뇨병, 고혈압, 음경신경손상 및 이들의 조합으로부터 선택된 것으로부터 야기될 수 있으나, 이에 제한되지 않는다.The erectile dysfunction may be caused by a decrease or impairment of penile endothelial cells and smooth muscle cells. Such degradation or impairment of penile endothelial cells and smooth muscle cells may result from, but is not limited to, selected from hyperlipidemia (including hypercholesterolemia deficiency), diabetes, hypertension, penile nerve damage and combinations thereof.
본 발명에서 용어, "예방"은 본 발명의 Sac-1004 복합체를 유효성분으로 포함하는 조성물을 이용하여 발기부전 증상을 차단하거나, 발기부전 증상의 억제 또는 지연시키는 모든 행위를 말한다.The term "preventive " in the present invention refers to any action that inhibits erectile dysfunction or inhibits or delays erectile dysfunction using a composition comprising the Sac-1004 complex of the present invention as an active ingredient.
본 발명에서 용어, "치료"는 본 발명의 Sac-1004 복합체를 유효성분으로 포함하는 조성물을 이용하여 발기부전 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.The term "treatment" in the present invention refers to any action that improves or improves the symptoms of erectile dysfunction by using a composition comprising the Sac-1004 complex of the present invention as an active ingredient.
본 발명에서 용어, "해면체"는 포유류의 음경이나 음핵의 주체를 이루는 발기조직으로, 주위가 탄성섬유를 함유하는 두껍고 튼튼한 결합조직의 막으로 쌓여있으며, 이 막이 내부로 들어가 있어 해면상의 작은 방을 이루고 있다. 남성의 음경 내부에는 좌우에 2개의 음경 해면체와 그 아래쪽에 1개의 요도 해면체가 있고, 여성에게는 음경 해면체와 비슷한 구조를 가진 음핵 해면체와 요도 해면체가 있다. 해면체에 정맥혈이 가득차게 되면 음경이 발기하게 된다. 음경 해면체 평활근과 음경 혈관은 평상시 아드레날린성 교감 신경에 의해 수축 상태에 있으며, 이완에 의한 발기 반응 후, 아드레날린성 교감 신경계의 자극에 의해 다시 수축 상태로 되돌아온다. 이렇듯 발기조직은 평상시 수축 상태를 유지하지만, 성적 각성시 뇌 중추에서 보내는 신호와 신경계의 자극, 체 내 및 발기조직 내의 여러 신경 전달 물질 및 호르몬 등에 의해 발기조직이 이완되고, 발기가 시작되며, 발기가 유지된다. 이러한 발기반응이 끝난 후, 다시 발기조직은 수축 상태를 유지하게 된다.In the present invention, the term "corpuscle" is an erectile tissue constituting the main body of the mammalian penis or clitoris. The corpuscle is piled up with a membrane of a thick and durable connective tissue containing elastic fibers. . Within the male penis, there are two penile cavernosomes on the left and right, and one urethral cavernosum on the lower side. There are clitoral cavernosomes and urethral cavernosomes with similar structures to the penis cavernosum in women. When the cavernosum is full of venous blood, the penis becomes erect. The penile cavernosal smooth muscle and penile blood vessels are usually contracted by adrenergic sympathetic nerves, and after erectile response due to relaxation, they return to contracted state by stimulation of the adrenergic sympathetic nervous system. Although erectile tissues maintain normal contraction state, erectile tissues are relaxed by the stimulation of the nervous system, various neurotransmitters and hormones in the body and erectile tissues, and erection is started. Is maintained. After this erection reaction is completed, the erectile tissue is maintained in a contracted state.
본 발명에 따른 Sac-1004 복합체는 정상 세포의 생존에 영향을 미치지 않으면서도, 음경해면체내피세포, 평활근세포 및 혈관주위세포 특이적인 단백질의 수준을 증가시켜 음경 발기조직의 재생을 유도하고, 음경해면체의 내압을 증가시킴으로써, 우수한 발기부전 개선 효과를 가지고 있다. The Sac-1004 complex according to the present invention induces regeneration of penile erectile tissues by increasing levels of specific proteins of penile cavernosal endothelial cells, smooth muscle cells and perivascular cells without affecting survival of normal cells, Thereby improving the erectile dysfunction.
상기한 바와 같이, 본 발명에 따른 Sac-1004 복합체는 발기부전의 예방, 개선 및 치료 효과가 우수하므로, 발기부전의 예방 또는 치료에 유용한 의약품, 의약외품 또는 건강기능식품으로 사용될 수 있다.
As described above, the Sac-1004 complex according to the present invention is excellent in prevention, improvement, and therapeutic effect of erectile dysfunction, and thus can be used as a medicament, quasi-drug, or health functional food useful for prevention or treatment of erectile dysfunction.
본 발명의 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 또한 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 당해 기술 분야에 알려진 적합한 제제는 문헌 (Remington's Pharmaceutical Science, 최근, Mack Publishing Company, Easton PA)에 개시되어 있는 것을 사용하는 것이 바람직하다. 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 상기 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. The compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions. In addition, it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, oral preparations such as syrups and aerosols, external preparations, suppositories and sterilized injection solutions according to a conventional method. Suitable formulations known in the art are preferably those as disclosed in Remington ' s Pharmaceutical Science, recently, Mack Publishing Company, Easton PA. Examples of carriers, excipients and diluents which may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When the composition is formulated, it is prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명에서 용어, "투여"는 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.The term "administering" as used herein means providing the subject invention with a composition of the invention in any suitable manner.
본 발명의 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 조성물의 투여는 하루에 한번 투여할 수도 있고, 수 회 나누어 투여할 수도 있다. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. The composition may be administered once a day, or divided into several doses.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention may be administered to a subject in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
본 발명의 조성물은 Sac-1004 복합체와 함께 발기부전의 예방 또는 치료 효과를 갖는 공지의 유효성분을 1종 이상 더 함유할 수 있다. The composition of the present invention may contain one or more known active ingredients having the effect of preventing or treating erectile dysfunction together with Sac-1004 complex.
본 발명의 조성물은 발기부전의 예방 및 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.
The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers for prevention and treatment of erectile dysfunction.
본 발명의 조성물은 발기부전의 예방 또는 개선을 목적으로 의약외품 조성물에 첨가될 수 있다. The composition of the present invention may be added to a quasi-drug composition for the purpose of preventing or improving erectile dysfunction.
본 발명의 조성물을 외약외품 조성물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 의약외품 또는 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.
When the composition of the present invention is used as an external composition for an external medicine, the composition may be added as it is or may be used together with other quasi-drugs or quasi-drugs, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment).
본 발명의 조성물은 발기부전의 예방 또는 개선을 목적으로 건강기능식품에 첨가될 수 있다. The composition of the present invention may be added to a health functional food for the purpose of preventing or improving erectile dysfunction.
본 발명에서 용어, "건강기능식품"이란 질병의 예방 및 개선, 생체방어, 면역, 병후의 회복, 노화 억제 등 생체조절기능을 가지는 식품을 말하는 것으로, 장기적으로 복용하였을 때 인체에 무해하여야 한다.The term "health functional food" in the present invention refers to a food having a biological control function such as prevention and improvement of disease, bio-defense, immunity, recovery after disease and aging inhibition.
본 발명의 조성물을 식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 사용 목적 (예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 15중량 % 이하, 바람직하게는 10 중량 % 이하의 양으로 첨가된다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When the composition of the present invention is used as a food additive, the composition can be added as it is or can be used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, the composition of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material, in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include dairy products including meats, sausages, breads, chocolates, candies, snacks, confectionery, pizza, ramen noodles, gums, ice cream, soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.
본 발명의 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 포함할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토오스, 수크로오스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ml 당 일반적으로 약 0.01 내지 10 g, 바람직하게는 약 0.01 내지 0.1 g 이다.The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. The natural carbohydrates may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharine and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 10 g, preferably about 0.01 to 0.1 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 포함할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 포함할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100중량부 당 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, A carbonating agent used in a carbonated beverage, and the like. In addition, the composition of the present invention may comprise flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
이하 본 발명의 이해를 돕기 위하여 바람직한 실험예를 제시한다. 그러나 하기의 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실험예에 의해 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred examples of the present invention will be described in order to facilitate understanding of the present invention. However, the following experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the experimental examples.
실험예 1. 발기부전 동물모델에서 Sac-1004 복합체의 발기부전 치료 효과 검증 Experimental Example 1. Efficacy of erectile dysfunction treatment of Sac-1004 complex in an erectile dysfunctional animal model
1-1. 발기부전 동물모델의 디자인1-1. Design of erectile dysfunctional animal models
생후 2개월 된 수컷 마우스(C57BL/6J)를 이용하였으며, 총 6 개의 군으로 나누어 실험을 진행하였다 (N = 6/군; 1군- 정상 마우스; 2군- 정상 마우스 + 스트렙토조토신(streptozotocin)을 이용한 당뇨 유도[50 mg/kg 농도로 5일 연속으로 복강 내 투여 후 8주째 된 마우스] + PBS(phosphate-buffered solution)[20 μL]를 투여한 마우스(대조군); 3군- 정상 마우스 + 스트렙토조토신을 이용한 당뇨 유도[50 mg/kg 농도로 5일 연속으로 복강 내 투여 후 8주째 된 마우스] + Sac1004 복합체를 2번 주사[day -3, 0; 1 μg/20 μL]한 마우스; 4군- 정상 마우스 + 스트렙토조토신을 이용한 당뇨 유도[50 mg/kg 농도로 5일 연속으로 복강 내 투여 후 8주째 된 마우스] + Sac1004 복합체를 2번 주사[day -3, 0; 2 μg/20 μL]한 마우스; 5군- 정상 마우스 + 스트렙토조토신을 이용한 당뇨 유도[50 mg/kg 농도로 5일 연속으로 복강 내 투여 후 8주째 된 마우스] + Sac1004 복합체를 2번 주사[day -3, 0; 5 μg/20 μL]한 마우스; 6군- 정상 마우스 + 스트렙토조토신을 이용한 당뇨 유도[50 mg/kg 농도로 5일 연속으로 복강 내 투여 후 8주째 된 마우스] + Sac1004 복합체를 2번 주사[day -3, 0; 10 μg/20 μL]한 마우스;). 상기 각 군의 마우스에 케타민(Ketamine, 100 mg/kg)과 자일라진(xylazine, 5 mg/kg)을 근육 주사하여 마취한 후, Sac-1004 복합체를 음경해면체 내에 주사한 뒤 1주 후에 하기와 같은 실험을 수행하였다.
The mice were divided into 6 groups (N = 6 / group, group 1 - normal mouse, group 2 - normal mouse + streptozotocin) Mice (control group) receiving diabetic induction [8-week-old mouse after intraperitoneal injection for 5 consecutive days at a concentration of 50 mg / kg] + PBS (phosphate-buffered solution) Mice injected with streptozotocin twice a day [day -3,0; 1 μg / 20 μl] of diabetes induction [8-week-old mouse after intraperitoneal administration for 5 consecutive days at a concentration of 50 mg / Diabetes induction with normal mouse + streptozotocin [mice at 8 weeks after intraperitoneal administration for 5 consecutive days at a concentration of 50 mg / kg] + Sac1004 complex twice [day -3,0; 2 μg / 20 μL ] Mice; group 5-normal mice + streptozotocin-induced diabetes induction [intraperitoneal injection for 5 consecutive days at a concentration of 50 mg / kg Mice were injected twice with a dose of 50 mg / kg [
1-2. 발기력 측정1-2. Erection power measurement
상기 실험예 1-1의 동물모델에 음경해면체 신경자극 후 발기력을 측정하기 위하여, 하기와 같은 실험을 수행하였다. 먼저, 각 마우스의 하복부에서 좌측 표피부분을 개복하고, 전립선의 후외측에 위치한 음경해면체신경(음경신경)이 잘 보이도록 준비하였다. 음경신경의 전기자극을 위해서 백금전극을 음경신경에 위치시킨 후, 5 볼트, 12 헤르츠의 강도로 약 1분 동안 전기자극을 가하였다. 전기자극을 가하게 되면, 음경은 발기를 하게 된다. 이때 발기 시 음경내부의 압력(음경해면체 내압)을 음경해면체에 삽입된 카테터를 통해 컴퓨터와 연결되어 있는 압력 전달기(바이오스팩 시스템, 미국)를 이용하여 측정하였다. 그 결과를 도 1에 나타내었다.In order to measure the erectile potency of the animal model of Experimental Example 1-1 after stimulation of the penile cavernosal nerve, the following experiment was conducted. First, the left part of the epidermis was opened in the lower abdomen of each mouse, and the penile cavernosal nerve (penile nerve) located on the posterior lateral side of the prostate was prepared. For electrical stimulation of the penis nerve, a platinum electrode was placed on the penis nerve, and electrical stimulation was applied for about 1 minute at a strength of 5 volts and 12 hertz. When an electrical stimulus is applied, the penis becomes erect. The pressure inside the penis during erection was measured using a pressure transducer (BioSpec System, USA) connected to the computer via a catheter inserted into the penis corpus cavernosum. The results are shown in Fig.
도 1에 나타낸 바와 같이, 각 마우스의 ICP(Intracavernous Pressure: 음경해면체 내압), 최고 음경해면체 내압(Maximal ICP)/평균 수축기 혈압(MSBP, Mean Systolic Blood Pressure) 및 균 수축기 혈압 음경해면체내압 곡선의 면적(Total ICP [area under the curve])/평균 수축기 혈압(MSBP)을 측정한 결과, Sac-1004 복합체를 투여한 군에서 대조군에 비해 현저하게 발기력이 상승함을 확인하였다. As shown in Fig. 1, ICP (Intracavalary Pressure), Maximal ICP / Mean Systolic Blood Pressure (MSBP), and Myocystic Blood Pressure (Total ICP [area under the curve]) / mean systolic blood pressure (MSBP), the erectile power of the Sac-1004 complex-treated group was significantly higher than that of the control group.
이하에서는 Sac-1004 복합체를 5 μg/20 μㅣ의 농도로 투여한 군의 조직을 이용하여 실험하였다.
Hereinafter, the tissue of the group administered with the Sac-1004 complex at a concentration of 5 μg / 20 μl was used.
1-3. PECAM-1 및 SM α-액틴의 발현 분석1-3. Expression analysis of PECAM-1 and SM a-actin
음경은 해면체조직으로 이루어져있고, 해면체 조직은 수 많은 해면체 동양구조(cavernous sinusoid)와 혈관들로 구성되어있다. 상기 해면체 동양구조는 단층의 세포로서 혈액과 직접 접촉하는 내피세포와 상기 내포세포의 안 쪽에 위치한 여러 개 세포층의 평활근세포로 이루어져 있다. 해면체내피세포와 평활근세포는 해면체동양구조 내의 혈액의 증가/감소, 음경발기를 담당하며, 음경 해면체의 비정상적인 구조나 기능은 발기부전을 초래한다.The penis consists of cavernosal tissue, and cavernous tissue is composed of numerous cavernous sinusoids and blood vessels. The cavernosal oriental structure is a monolayer cell composed of endothelial cells in direct contact with blood and smooth muscle cells of several cell layers located in the innermost cell. The cavernosal endothelial cells and smooth muscle cells are responsible for the increase / decrease of the blood in the cavernosal tissue, penile erection, and the abnormal structure or function of the cavernosal canal causes erectile dysfunction.
이에 상기 실험예 1-1의 동물모델의 음경 발기조직 내 혈관의 구조적 변화를 확인하기 위하여, 혈관내피세포에 특이적 단백질인 PECAM-1(platelet/endothelial cell adhesion molucule-1)의 발현 및 평활근세포에 특이적 단백질인 SM α-액틴(smooth muscle α- actin)의 발현을 측정하였다. In order to confirm structural changes of the blood vessels in the erectile tissues of the animal model of Experimental Example 1-1, expression of PECAM-1 (platelet / endothelial cell adhesion molucule-1), which is a specific protein in vascular endothelial cells, The expression of SM a-actin, a specific protein, was measured.
보다 구체적으로, 각 마우스로부터 음경 조직을 분리한 후, 이를 4% 파라포름알데히드에서 4℃, 24 시간 동안 고정하였다. 상기 조직을 동결용 포매제를 이용하여 고정시킨 후, 동결 절편기에서 7㎛ 두께로 잘라 음경조직 절편을 준비하였다. 다음으로, 준비된 음경조직 절편을 슬라이드 상에 올리고, PECAM-1 및 SM α-액틴의 발현 분석을 위해 준비된 슬라이드 상의 조직을 4% 파라포름알데히드에서 약 5분간 고정시켰다. 고정된 음경조직 절편을 세척 버퍼(2% FBS + 0.1% Sodium Azide in PBS)로 3회 세척한 후, 비특이적 단백질 차단 버퍼(5% BSA in PBS)로 1시간 동안 블락킹하였다. 1차 항체(항-PECAM-1 햄스터 항체 및 FITC-표지된 항-smooth muscle α-actin 항체, 1:50)와 4℃에서 16시간 동안 반응시킨 후, 남아 있는 항체를 제거하기 위해서 세척 버퍼로 3회 세척한 다음, 2차 항체(TRITC-표지된 항-햄스터 항체, 1:100)와 상온에서 2시간 동안 반응시켰다. 반응이 끝난 후, 남아있는 항체를 제거하기 위해 세척 버퍼로 다시 3회 세척한 후 공초점 현미경으로 발현 정도를 분석하였다. 그 결과를 도 2에 나타내었다. More specifically, penile tissues were separated from each mouse and fixed in 4% paraformaldehyde at 4 DEG C for 24 hours. The above tissues were fixed using a frozen foraging agent, and then cut into a thickness of 7 mu m in a frozen section to prepare a penile tissue section. Next, prepared penile tissue sections were placed on a slide, and the tissue on the slide prepared for the expression analysis of PECAM-1 and SM [alpha] -actin was fixed in 4% paraformaldehyde for about 5 minutes. Fixed penis tissue sections were washed three times with wash buffer (2% FBS + 0.1% Sodium Azide in PBS) and blocked with non-specific protein blocking buffer (5% BSA in PBS) for 1 hour. After reacting at 4 ° C for 16 hours with primary antibody (anti-PECAM-1 hamster antibody and FITC-labeled anti-smooth muscle α-actin antibody, 1:50) Washed three times and then reacted with a secondary antibody (TRITC-labeled anti-hamster antibody, 1: 100) at room temperature for 2 hours. After the reaction was completed, the cells were washed three times with a washing buffer to remove remaining antibodies, and the degree of expression was analyzed using a confocal microscope. The results are shown in Fig.
도 2A에 나타낸 바와 같이, 정상 마우스(Control)에 비해 대조군은 해면체내피세포의 수가 현저하게 감소하였으며, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 혈관 혈관내피세포 특이적 단백질인 PECAM-1과 평활근세포 특이적 단백질인 SM α-액틴의 발현이 증가함을 확인하였다. As shown in FIG. 2A, the number of cancellous endothelial cells was significantly decreased in the control group as compared to the control of normal mice. In the group to which the Sac-1004 complex of the present invention was administered, the group of blood vessel endothelial cell- -1 and smooth muscle cell specific protein SM a-actin.
또한, 도 2B 및 도 2C에 나타낸 바와 같이, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 음경해면체 면적 중에 해면체내피세포 발현 양 및 평활근세포의 발현 양이 유의하게 증가함을 확인하였다. As shown in FIG. 2B and FIG. 2C, it was confirmed that the group administered with the Sac-1004 complex of the present invention significantly increased the expression of the cavernosal endothelial cells and the smooth muscle cells in the corpus cavernosum area compared with the control group .
이상의 실험 결과를 통하여, 본 발명의 Sac-1004 복합체에 의해 당뇨에 의하여 감소된 해면체내피세포와 평활근세포의 재생이 유도되고, 그로 인해 발기력이 회복됨을 확인하였다.
From the above experimental results, it was confirmed that regeneration of cavernosal endothelial cells and smooth muscle cells reduced by diabetes was induced by the Sac-1004 complex of the present invention, thereby restoring erectile power.
1-4. 인산화된 내피성산화질소생성효소 (phosphorylated endothelial nitric oxide synthaes, P-eNOS)의 발현 분석1-4. Expression analysis of phosphorylated endothelial nitric oxide synthase (P-eNOS)
음경 해면체내피세포에서 생성되는 내피성 산화질소생성효소(endothelial nitric oxide synthase: eNOS)는 해면체의 이완 및 이로 인한 음경 발기에 중요한 역할을 하는 일산화질소(NO)를 생성하는 주된 효소이다. 해면체 내피세포의 비정상적인 구조나 기능은 내피성 산화질소생성효소의 활동성 저하를 통해 발기부전을 초래한다.Endothelial nitric oxide synthase (eNOS), which is produced in the corpus cavernosum endothelial cells, is the main enzyme that produces nitric oxide (NO), which plays an important role in cancellous relaxation and penile erection. Abnormal structures and functions of cavernosal endothelial cells cause erectile dysfunction through decreased activity of endothelial nitric oxide synthase.
이에 1차 항체로 항-eNOS 레빗 항체 또는 항-P-eNOS 레빗 항체를 이용하고, 2차 항체로 FITC-표지된 항-레빗 항체를 이용하는 것을 제외하고는, 상기 실험예 1-3과 동일한 방법으로 상기 실험예 1-1의 동물모델의 음경 발기조직 내 eNOS 및 P-eNOS의 발현을 측정하였다. 또한, 음경 조직으로부터 단백질을 분리한 후, 종래 공지된 방법에 따라 웨스턴 블랏을 수행하였다. 그 결과를 도 3에 나타내었다. In the same manner as in Experimental Example 1-3, except that anti-eNOS levitic antibody or anti-P-eNOS levitic antibody was used as a primary antibody and FITC-labeled anti-levitic antibody was used as a secondary antibody , The expression of eNOS and P-eNOS in the erectile tissue of the animal model of Experimental Example 1-1 was measured. In addition, proteins were separated from penile tissues and then subjected to Western blotting according to a conventionally known method. The results are shown in Fig.
도 3A 내지 도 3C에 나타낸 바와 같이, 공초점 현미경으로 관찰한 결과, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 음경 조직 내 eNOS 및 P-eNOS의 발현이 현저하게 증가함을 확인하였다. As shown in FIGS. 3A to 3C, when observed with a confocal microscope, it was found that the group to which the Sac-1004 complex of the present invention was administered showed a marked increase in the expression of eNOS and P-eNOS in the penile tissue as compared with the control group Respectively.
또한, 도 3D에 나타낸 바와 같이, 웨스턴 블랏을 수행한 결과, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 음경 조직 내 eNOS 및 P-eNOS의 발현이 현저하게 증가함을 확인하였다.
As shown in FIG. 3D, Western blotting showed that the group treated with the Sac-1004 complex of the present invention significantly increased the expression of eNOS and P-eNOS in penile tissues compared to the control group.
1-5. 산화된 저밀도 지단백질 (Oxidized-low density lipoprotein, Ox-LDL)의 발현 분석1-5. Expression analysis of oxidized low-density lipoprotein (Ox-LDL)
저밀도 지단백질(LDL)은 체내에서 콜레스테롤을 말초로 운반하는 역할을 한다. 체내에 LDL이 쌓이게 되면 죽상경맥동화 등 혈관성 질환을 일으킬 수 있다. 특히 LDL이 산화효소에 의해 Ox-LDL(oxidized LDL)로 전환되면 염증 반응 및 섬유화 등을 유발할 수 있다.Low-density lipoprotein (LDL) plays a role in transporting cholesterol to the periphery in the body. The accumulation of LDL in the body can cause vascular diseases such as atherosclerosis. In particular, the conversion of LDL to Ox-LDL (oxidized LDL) by oxidizing enzymes can lead to inflammatory reactions and fibrosis.
이에 1차 항체로 항-PECAM-1 햄스터 항체 및 항-Ox-LDL 레빗 항체를 이용하고, 2차 항체로 TRITC-표지된 항-햄스터 항체 및 FITC-표지된 항-레빗 항체를 이용하는 것을 제외하고는, 상기 실험예 1-3과 동일한 방법으로 상기 실험예 1-1의 동물모델의 음경 발기조직 내 Ox-LDL의 생성 여부를 측정하였다. 그 결과를 도 4에 나타내었다. Except that anti-PECAM-1 hamster antibody and anti-Ox-LDL levitic antibody were used as primary antibodies and TRITC-labeled anti-hamster antibody and FITC-labeled anti-rabbit antibody were used as secondary antibodies Produced Ox-LDL in the erectile tissues of the animal model of Experimental Example 1-1 in the same manner as in Experimental Example 1-3. The results are shown in Fig.
도 4에 나타낸 바와 같이, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 음경조직 내에서 발현되는 Ox-LDL 의 양이 현저하게 감소함을 확인하였다.
As shown in FIG. 4, the group administered with the Sac-1004 complex of the present invention showed a marked decrease in the amount of Ox-LDL expressed in the penile tissues compared to the control group.
1-6. NG2 및 PDGFR-β의 발현 분석1-6. Expression of NG2 and PDGFR-β
혈관 신생이란 이미 존재하는 혈관으로부터 미세혈관이 생성되는 것을 의미한다. 혈관 신생의 마지막 단계인, 내피세포ㅡ혈관주위세포의 구조가 형성되어, 새로운 혈관이 성숙되고 안정화되는 단계에서 혈관내피세포로부터 분비되는 NG2와 PDGFR(platelet-derived growth factor receptor)-β가 혈관주위세포의 모집과 차별화에 기여하는 것으로 알려져 있다. Angiogenesis refers to the production of microvessels from already existing blood vessels. In the stage of endothelial cell-periovascular cell formation, which is the final stage of angiogenesis, NG2 and PDGFR (platelet-derived growth factor receptor) -β secreted from endothelial cells at the stage where new blood vessels mature and stabilize It is known to contribute to cell recruitment and differentiation.
이에 1차 항체로 항-PECAM-1 햄스터 항체, 항-NG2 레빗 항체 및 항-PDGFR-β 렛드 항체를 이용하고, 2차 항체로 TRITC-표지된 항-햄스터 항체 및 FITC-표지된 항-레빗 항체를 이용하는 것을 제외하고는, 상기 실험예 1-3과 동일한 방법으로 상기 실험예 1-1의 동물모델의 음경 발기조직 내 NG2 및 PDGFR- β의 발현을 측정하였다. 그 결과를 도 5에 나타내었다.Anti-PECAM-1 hamster antibody, anti-NG2 levitic antibody and anti-PDGFR-βred antibody were used as primary antibodies, and TRITC-labeled anti-hamster antibody and FITC-labeled anti- The expression of NG2 and PDGFR-? In the erectile dysfunction tissue of the animal model of Experimental Example 1-1 was measured in the same manner as in Experimental Example 1-3, except that the antibody was used. The results are shown in Fig.
도 5에 나타낸 바와 같이, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 음경조직 내에서 발현되는 NG2 및 PDGFR-β의 양이 현저하게 증가함을 확인하였다. 이를 통해 본 발명의 Sac-1004 복합체를 투여한 군은 혈관주위세포의 양이 증가하여, 발기력이 회복됨을 확인하였다.
As shown in FIG. 5, it was confirmed that the group administered with the Sac-1004 complex of the present invention significantly increased the amounts of NG2 and PDGFR-β expressed in the penile tissues compared to the control group. As a result, it was confirmed that the group administered with the Sac-1004 complex of the present invention increased the amount of pericytes and the erectile power was restored.
1-7. 혈관내피세포 연접 단백질 (junction protein)의 발현 분석1-7. Analysis of vascular endothelial cell junction protein expression
세포간 밀착연접 기능은 격벽(barrier)기능이라 하여 상피세포나 내피세포의 시트를 구성하는 세포 사이로 물질이 누출하는 것을 방지하는 기능이며, 울타리기능이라 하여 세포막의 지질에서 끈모양 울타리를 둘러 세포막을 구획하는 기능을 의미한다. The intercellular adhesion function is barrier function and prevents leakage of substances between the cells constituting the sheets of epithelial cells or endothelial cells. It is a fence function, It means the function to divide.
이에 1차 항체로 항-Claudin-5 레빗 항체, 항-Occludin 레빗 항체 및 항-VE-cadherin(vascular endothelial-cadherin) 레빗 항체를 이용하고, 2차 항체로 TRITC-표지된 항-햄스터 항체 및 FITC-표지된 항-렛드 항체를 이용하는 것을 제외하고는, 상기 실험예 1-3과 동일한 방법으로 상기 실험예 1-1의 동물모델의 음경 발기조직 내 혈관내피세포 연접 단백질의 발현을 측정하였다. 또한, 음경 조직으로부터 단백질을 분리한 후, 종래 공지된 방법에 따라 웨스턴 블랏을 수행하였다(1차 항체로 항-ZO-1(zonula occludens) 레빗 항체, 항-Occludin 레빗 항체, 항-Claudin-5 레빗 항체를 이용함). 그 결과를 각각 도 6 및 도 7에 나타내었다.In this study, anti-cladin-5 Levitol antibody, anti-Occludin levit antibody and anti-VE-cadherin (vascular endothelial-cadherin) Levit antibody were used as the primary antibodies and TRITC-labeled anti-hamster antibody and FITC The expression of vascular endothelial cell-associated protein in the erectile dysfunction tissue of the animal model of Experimental Example 1-1 was measured in the same manner as in Experimental Example 1-3, except that the labeled anti-read antibody was used. In addition, proteins were separated from the penile tissues and then subjected to Western blotting according to a conventionally known method (primary antibodies were zonula occludens levitt antibody, anti-Occludin levitic antibody, anti-Claudin-5 Using levitra antibody). The results are shown in Figs. 6 and 7, respectively.
도 6 및 도 7에 나타낸 바와 같이, 본 발명의 Sac-1004 복합체를 투여한 군은 대조군에 비해 음경조직 내에서 발현되는 연접 단백질의 양이 현저하게 증가함을 확인하였다.
As shown in FIG. 6 and FIG. 7, it was confirmed that the group to which the Sac-1004 complex of the present invention was administered showed a significantly increased amount of connexin protein expressed in the penile tissue as compared with the control group.
실험예 2. 음경해면체에서 분리된 해면체내피세포에서 Sac-1004 복합체가 관형성능(tube formation)에 미치는 영향 분석 Experimental Example 2. Effect of Sac-1004 complex on tubule formation in cavernous endothelial cells isolated from penile corpus cavernosum
관형성 (tube formation) 단계는 혈관신생 과정 중 이동, 증식한 내피세포들이 분열을 계속하여 속이 빈 튜브 모양으로 성장하여 최종 혈관으로 분화하고 여기에 혈액이 들어가 혈관 생성이 완성되는 단계이다. In the tube formation stage, the endothelial cells that migrate and proliferate during the angiogenesis process continue to divide and grow into a hollow tube shape and differentiate into a final blood vessel, into which blood enters and blood vessel formation is completed.
음경해면체에서 분리된 해면체내피세포에서 Sac-1004 복합체가 관형성능(tube formation)에 미치는 영향을 분석하기 위하여, 관 형성 어쎄이 (tube formation assay)를 수행하였다. To investigate the effect of Sac-1004 complex on tube formation in cavernous endothelial cells isolated from penile corpus cavernosum, tube formation assays were performed.
먼저, 음경해면체에서 해면체내피세포를 분리하기 위하여, 음경 조직을 배양 디쉬에 놓고, 50 ng/ml의 VEGF 또는 bFGF 등 혈관내피세포 성장과 관련된 단백질이 포함된 마트리겔(50㎕)로 도포한 다음, 실온 또는 배양기(culture incubator)에서 약 10분 동안 유지시켜 마트리겔이 굳게 하였다. 마트리겔 층이 모두 잠기도록 배지를 첨가한 후, 1 내지 2주 동안 37℃, 5% CO2 조건으로 배양기에서 배양하였다. 배지는 2 내지 3일 간격으로 교환하였다. 1-2주 후에 마트리겔 내에 스프라우팅(sprouting)된 해면체내피세포를 확인하고 조직이 포함된 마트리겔을 1.5 ml 튜브로 옮겼다. 1.5 ml 튜브를 얼음 속에서 약 10분 동안 배양하여 마트리겔을 녹인 후, 조직을 제거하고 1.5 ml 튜브 안에 있는 혈관내피세포에 100 ㎕ 트립신-EDTA(Sigma-Aldrich, MO, USA)를 첨가한 다음, 파이펫 또는 핀셋(또는 칼)을 사용하여 조직 밖으로 방출된 세포를 분리하였다. 단일 세포로 된 조직-특이적 해면체내피세포를 60 mm 디쉬로 옮긴 다음 배지를 첨가하여 분석을 수행할만한 개체수가 될 때까지 37℃, 5% CO2 배양기에서 배양하였다. 상기 과정을 통하여 분리한 해면체내피세포를 혈청이 없는 배지에서 24시간 동안 처리한 후(serum starvation), 정상 포도당 배지 처리군 (Normal glucose), 고포도당 배지 및 PBS 처리군 (High glucose+PBS, 대조군) , 고포도당 배지 및 Sac-1004 복합체 처리군 (High glucose+Sac-1004)으로 각각 나누어 37℃, 5% CO2 배양기에서 배양하였다. 그 결과를 도 8에 나타내었다. First, in order to separate cavernosal endothelial cells from the corpus cavernosum, penile tissues were placed on a culture dish and coated with Matrigel (50 μl) containing proteins associated with vascular endothelial cell growth such as 50 ng / ml of VEGF or bFGF , Held at room temperature or in a culture incubator for about 10 minutes to solidify the matrigel. The medium was added so that all the matrigel layers were immersed, and then cultured in an incubator at 37 ° C and 5% CO 2 for 1 to 2 weeks. The medium was changed every 2 to 3 days. After 1-2 weeks, the spongy endothelial cells sprouting in the matrigel were identified and the tissue-containing matrigel was transferred to a 1.5 ml tube. The 1.5 ml tube was incubated in ice for about 10 minutes to dissolve the matrigel, the tissue was removed, and 100 μl trypsin-EDTA (Sigma-Aldrich, MO, USA) was added to the vascular endothelial cells in a 1.5 ml tube , A pipette or tweezers (or knife) was used to separate the cells that were released outside the tissue. Single-cell tissue-specific cancellous endothelial cells were transferred to a 60-mm dish, and then cultured in a 5% CO 2 incubator at 37 ° C until the population of the cells was analyzed by adding the medium. The spongy endothelial cells isolated by the above procedure were treated with serum-free medium for 24 hours (normal starvation) and then treated with normal glucose medium, high glucose medium and PBS-treated group (High glucose + PBS, ), High glucose medium and Sac-1004 complex treated group (High glucose + Sac-1004), and cultured in a 5% CO 2 incubator at 37 ° C. The results are shown in Fig.
도 8에 나타낸 바와 같이, 본 발명의 Sac-1004 복합체를 처리한 군은 대조군에 비해 튜브 형성이 현저하게 증가함을 확인하였다.
As shown in FIG. 8, it was confirmed that the group treated with the Sac-1004 complex of the present invention significantly increased the tube formation as compared with the control group.
실험예 3. 정상세포에서 Sac-1004 복합체의 세포 독성 분석 Experimental Example 3. Cytotoxicity analysis of Sac-1004 complex in normal cells
정상세포에서 Sac-1004 복합체의 세포 독성을 분석하기 위하여, 종래 공지된 방법에 따라 MTT(3-(4,5-dimethylthizol-2-yl)-2,5-diphenyl-tetrazolium bromide) 어세이를 수행하였다. 보다 구체적으로, 음경 조직을 일차배양 하여 얻은 세포에 PBS 또는 Sac-1004 복합체를 농도 별로(0.1μg, 1μg, 5μg, 10μg) 처리하였다. 24시간 동안 배지를 제거하고 MTT 시약을 첨가하였다. 이를 다시 4시간 동안 배양한 후 MTT 시약을 제거하고, DMSO를 첨가하였다. 15~20분간 흔들어준 후, ELISA 리더기를 사용하여 540nm 파장에서 흡광도를 측정하였다. 그 결과를 도 9에 나타내었다. To analyze the cytotoxicity of Sac-1004 complex in normal cells, MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide) assay was performed according to a conventionally known method Respectively. More specifically, PBS or Sac-1004 complex was treated with concentrations (0.1 μg, 1 μg, 5 μg, and 10 μg) to cells obtained by primary culture of penile tissue. The medium was removed for 24 hours and MTT reagent was added. After 4 hours of incubation, the MTT reagent was removed and DMSO was added. After shaking for 15 to 20 minutes, the absorbance was measured at 540 nm wavelength using an ELISA reader. The results are shown in Fig.
도 9에 나타낸 바와 같이, 본 발명에 따른 Sac-1004 복합체는 이상의 실험에 이용된 저농도에서 정상적인 음경해면체내피세포의 생존에 영향을 주지 않음을 확인하였다.
As shown in FIG. 9, the Sac-1004 complex according to the present invention did not affect the survival of normal corpus cavernosum endothelial cells at the low concentration used in the above experiments.
이상의 실험 결과를 통하여, 본 발명에 따른 Sac-1004 복합체는 정상 세포의 생존에 영향을 미치지 않으면서도, 음경해면체내피세포, 평활근세포 및 혈관주위세포 특이적인 단백질의 수준을 증가시켜 음경 발기조직의 재생을 유도하고, 음경해면체의 내압을 증가시킴으로써, 우수한 발기부전 개선 효과가 있어, 발기부전의 예방 또는 치료에 유용하게 이용될 수 있음을 확인하였다.
Through the above experimental results, the Sac-1004 complex according to the present invention increased the levels of specific proteins of the penile cavernosal endothelial cells, smooth muscle cells and perivascular cells without affecting survival of normal cells, And by increasing the internal pressure of the corpus cavernosum, it is possible to improve the erectile dysfunction, and thus it can be effectively used for preventing or treating erectile dysfunction.
이하 본 발명에 따른 약학적 조성물 및 식품 조성물의 제제예를 설명하나, 본 발명을 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Hereinafter, examples of pharmaceutical compositions and food compositions according to the present invention will be described, but the present invention is not to be construed as limiting the present invention .
제제예 1. 약학적 조성물의 제조Formulation Example 1. Preparation of a pharmaceutical composition
1. 산제의 제조 1. Manufacturing of powder
Sac-1004 복합체 20 mgSac-1004 complex 20 mg
유당 100 mgLactose 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above components are mixed and filled in airtight bags to prepare powders.
2. 정제의 제조2. Preparation of tablets
Sac-1004 복합체 10 mgSac-1004 complex 10 mg
옥수수전분 100 mgCorn starch 100 mg
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
3. 캡슐제의 제조3. Preparation of capsules
Sac-1004 복합체 10 mgSac-1004 complex 10 mg
결정성 셀룰로오스 3 mgCrystalline cellulose 3 mg
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
4. 주사제의 제조4. Preparation of injections
Sac-1004 복합체 10 mgSac-1004 complex 10 mg
만니톨 180 mg180 mg mannitol
주사용 멸균 증류수 2974 mgSterile sterilized water for injection 2974 mg
Na2HPO42H2O 26 mgNa 2 HPO 4 2H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2 ml) 상기의 성분 함량으로 제조한다.
(2 ml) per 1 ampoule in accordance with the usual injection preparation method.
5. 액제의 제조5. Manufacture of liquids
Sac-1004 복합체 20 mg Sac-1004 complex 20 mg
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ml로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.
Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.
제제예 2. 식품 조성물의 제조Formulation Example 2. Preparation of Food Composition
1. 건강식품의 제조1. Manufacture of health food
Sac-1004 복합체 100 mgSac-1004 complex 100 mg
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 g 70 g of vitamin A acetate
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 B1 0.13 mgVitamin B1 0.13 mg
비타민 B2 0.15 mg0.15 mg of vitamin B2
비타민 B6 0.5 mgVitamin B6 0.5 mg
비타민 B12 0.2 g 0.2 g of vitamin B12
비타민 C 10 mg
비오틴 10 g Biotin 10 g
니코틴산아미드 1.7 mgNicotinic acid amide 1.7 mg
엽산 50 g Folate 50 g
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75 mg1.75 mg of ferrous sulfate
산화아연 0.82 mg0.82 mg of zinc oxide
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mgPotassium monophosphate 15 mg
제2인산칼슘 55 mgSecondary calcium phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mgCalcium carbonate 100 mg
염화마그네슘 24.8 mg
Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.
Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
2. 건강음료의 제조2. Manufacture of health drinks
Sac-1004 복합체 100 mgSac-1004 complex 100 mg
비타민 C 15 gVitamin C 15 g
비타민 E(분말) 100 gVitamin E (powder) 100 g
젖산철 19.75 g19.75 g of ferrous lactate
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinic acid amide 3.5 g
비타민 A 0.2 gVitamin A 0.2 g
비타민 B1 0.25 gVitamin B1 0.25 g
비타민 B2 0.3gVitamin B2 0.3g
물 정량
Water quantification
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The solution thus prepared was filtered and sterilized in a sterilized 2 L container, It is used in the production of the health beverage composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
Claims (5)
[화학식 1]
A pharmaceutical composition for preventing or treating erectile dysfunction, comprising the Sac-1004 complex represented by the formula (1) as an active ingredient.
[Chemical Formula 1]
[화학식 1]
A composition for preventing or improving erectile dysfunction comprising Sac-1004 complex represented by formula (1) as an active ingredient.
[Chemical Formula 1]
[화학식 1]
A quasi-drug composition for preventing or improving erectile dysfunction, comprising the Sac-1004 complex represented by the formula (1) as an active ingredient.
[Chemical Formula 1]
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102223276B1 (en) * | 2020-05-04 | 2021-03-05 | 주식회사 큐라클 | New crystalline form of vascular leak blocker compound |
WO2021118003A1 (en) * | 2019-12-13 | 2021-06-17 | 주식회사 큐라클 | High-yield preparation method for novel vascular leakage blocker |
CN113906041A (en) * | 2020-05-04 | 2022-01-07 | 库拉科有限公司 | Novel crystalline forms of vascular leakage retardant compounds |
RU2809162C2 (en) * | 2020-05-04 | 2023-12-07 | Кьюракл Ко., Лтд. | New crystal form of vascular permeability blocker compound |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003030887A1 (en) | 2001-10-09 | 2003-04-17 | Herturn, L.L.C. | Composition and method for improving sexual desire and erectile function |
KR20110047170A (en) * | 2009-10-29 | 2011-05-06 | 연세대학교 산학협력단 | New Leak Blockers |
KR101275224B1 (en) | 2010-10-20 | 2013-06-14 | 인하대학교 산학협력단 | Compositions for preventing or treating erectile dysfunction comprising adipose tissue-derived stromal vascular fraction as an active ingredient |
-
2014
- 2014-01-03 KR KR20140000755A patent/KR101481709B1/en active IP Right Grant
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003030887A1 (en) | 2001-10-09 | 2003-04-17 | Herturn, L.L.C. | Composition and method for improving sexual desire and erectile function |
KR20110047170A (en) * | 2009-10-29 | 2011-05-06 | 연세대학교 산학협력단 | New Leak Blockers |
KR101275224B1 (en) | 2010-10-20 | 2013-06-14 | 인하대학교 산학협력단 | Compositions for preventing or treating erectile dysfunction comprising adipose tissue-derived stromal vascular fraction as an active ingredient |
Non-Patent Citations (1)
Title |
---|
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 435, 420-427 (2013.05.09) * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021118003A1 (en) * | 2019-12-13 | 2021-06-17 | 주식회사 큐라클 | High-yield preparation method for novel vascular leakage blocker |
US11453698B2 (en) | 2019-12-13 | 2022-09-27 | Curacle Co., Ltd. | Preparation method of vascular leakage blockers with a high yield |
KR102223276B1 (en) * | 2020-05-04 | 2021-03-05 | 주식회사 큐라클 | New crystalline form of vascular leak blocker compound |
WO2021225233A1 (en) * | 2020-05-04 | 2021-11-11 | 주식회사 큐라클 | Novel crystalline form of vascular leakage blocker compound |
CN113906041A (en) * | 2020-05-04 | 2022-01-07 | 库拉科有限公司 | Novel crystalline forms of vascular leakage retardant compounds |
JP2022525582A (en) * | 2020-05-04 | 2022-05-18 | キュラクル カンパニー リミテッド | New crystalline form of vascular leak blocker compound |
JP7220931B2 (en) | 2020-05-04 | 2023-02-13 | キュラクル カンパニー リミテッド | A novel crystalline form of a vascular leak blocker compound |
RU2809162C2 (en) * | 2020-05-04 | 2023-12-07 | Кьюракл Ко., Лтд. | New crystal form of vascular permeability blocker compound |
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