KR20240078598A - Composition for inhibiting intestinal bacterial translocation comprising sustained release formulation for drug delivery system as effective component - Google Patents
Composition for inhibiting intestinal bacterial translocation comprising sustained release formulation for drug delivery system as effective component Download PDFInfo
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- KR20240078598A KR20240078598A KR1020230163257A KR20230163257A KR20240078598A KR 20240078598 A KR20240078598 A KR 20240078598A KR 1020230163257 A KR1020230163257 A KR 1020230163257A KR 20230163257 A KR20230163257 A KR 20230163257A KR 20240078598 A KR20240078598 A KR 20240078598A
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- drug delivery
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- bacterial translocation
- intestinal bacterial
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Abstract
본 발명은 서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 조성물에 관한 것으로, 본 발명의 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체(HME-DDS)는 인공 위장관 환경에서 안토시아닌을 안정적으로 방출하고, 병원성 세균에 대한 항균 효과 및 프로바이오틱스 균주의 증식 유도 효과가 우수하므로, 장내 세균 전위 억제용 건강기능식품 조성물, 장내 세균 전위 억제용 사료 첨가제로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a composition for inhibiting intestinal bacterial translocation containing a sustained-release drug delivery system as an active ingredient, and includes mulberries of the present invention; and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; a sustained-release drug delivery system (HME-DDS) obtained by heat melt extrusion molding of anthocyanins in an artificial gastrointestinal environment. Since it stably releases and has an excellent antibacterial effect against pathogenic bacteria and an effect of inducing the growth of probiotic strains, it is expected to be useful as a health functional food composition for inhibiting intestinal bacterial translocation and a feed additive for inhibiting intestinal bacterial translocation.
Description
본 발명은 서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting intestinal bacterial translocation containing a sustained-release drug delivery system as an active ingredient.
장(intestine)은 소화계를 이루는 주요 장기 중 하나로 소장과 대장으로 구분되며, 소장은 길이가 6~7m로 소화기관 중에서 가장 길며 다양한 소화효소를 분비하고 활발한 장운동을 통해 영양소 및 약리활성물질의 대부분이 흡수되는 곳이다. 또한, 장은 외부로부터 유입된 물질들이 접촉하는 주요 장소로, 장의 표면을 이루고 있는 점막에서는 음식물, 병원균 등 외부로부터 유입된 물질과 장내 미생물의 상호작용이 이루어지며, 다양한 외부 자극으로부터 우리 몸을 보호해주는 중요한 역할을 담당한다. 장내 생체방어는 1차적으로 장관의 구조적 특성과 고유한 운동성에 의해 가능한데, 이때 관여하는 것이 장내 미생물, 점막 장벽, 장운동이다. 2차적으로는 세포성, 체액성 면역에 의한 방어기전이 작용하게 된다. 장 점막에 서식하는 장내 미생물은 체내 방어 기전에서 매우 중요한 역할을 한다. 상재균(commensal bacteria)의 경우 병원균(pathogen)의 성장을 저해하는 항균 물질을 분비할 수 있고, 장 점막 결합부위에 대해 경쟁함으로써 병원균이 장내 점막을 투과하여 상피세포로 이동하는 '장내 세균 전위(intestinal bacterial translocation)'를 차단하는 장벽 역할을 한다. 그러나, 장 점막이 손상되거나 기능적 이상이 있을 경우 병원균이 장 점막을 투과하여 림프(lymph)를 통해 체내로 유입되어 면역 시스템이 무너지고 염증반응이 유도되어, 궁극적으로 염증성 장질환 또는 전신질환이 유발될 수 있다. The intestine is one of the major organs that make up the digestive system and is divided into the small and large intestines. The small intestine is the longest of the digestive organs at 6 to 7 meters in length. It secretes various digestive enzymes and absorbs most of the nutrients and pharmacologically active substances through active intestinal movements. This is where it is absorbed. In addition, the intestine is a major place where substances introduced from the outside come into contact. The mucous membrane that forms the surface of the intestine is where interactions between substances introduced from the outside, such as food and pathogens, and intestinal microorganisms occur, and protects the body from various external stimuli. plays an important role. Intestinal biodefense is primarily possible due to the structural characteristics and inherent motility of the intestinal tract, and what is involved are intestinal microorganisms, mucosal barrier, and intestinal motility. Secondarily, defense mechanisms based on cellular and humoral immunity come into play. Intestinal microorganisms that live in the intestinal mucosa play a very important role in the body's defense mechanism. In the case of commensal bacteria, they can secrete antibacterial substances that inhibit the growth of pathogens, and by competing for the intestinal mucosa binding site, pathogens penetrate the intestinal mucosa and move to epithelial cells (intestinal bacterial translocation). It acts as a barrier to block intestinal bacterial translocation. However, when the intestinal mucosa is damaged or has a functional abnormality, pathogens penetrate the intestinal mucosa and enter the body through lymph, causing the immune system to collapse and inducing an inflammatory response, ultimately causing inflammatory bowel disease or systemic disease. It can be.
장내 세균 전위는 장 상피세포의 투과성(permeability)에 의존적이기 때문에 세포 사이에 존재하는 밀착연접(tight junction)이 장내 자극이나 손상으로 인해 느슨해지면 유해한 분자(병원균, 독소, 항원 등)들이 장 상피에 과량 투과되고, 비정상적인 전해질 및 수분 이동, 조직 염증 등을 일으킬 수 있다. 이렇게 밀착연접이 느슨해져 장의 투과성이 증가된 상태를 장누수증후군(leaky gut syndrome)이라 부른다. 결국, 밀착연접의 파손과 장누수증후군의 발생으로 인한 장 점막 장벽 손상과 장 내로 도입된 병원균으로 인한 과도한 만성적 염증반응은 각종 염증성 잘질환을 유발하게된다. Since intestinal bacterial translocation is dependent on the permeability of intestinal epithelial cells, when the tight junctions between cells become loose due to intestinal stimulation or damage, harmful molecules (pathogens, toxins, antigens, etc.) enter the intestinal epithelium. Excessive permeation may cause abnormal electrolyte and moisture movement and tissue inflammation. This condition in which tight junctions become loose and intestinal permeability increases is called leaky gut syndrome. Ultimately, damage to the intestinal mucosa barrier due to destruction of tight junctions and the occurrence of leaky gut syndrome and excessive chronic inflammatory response due to pathogens introduced into the intestine cause various inflammatory diseases.
또한, 비피도박테리아 또는 락토바실러스와 같은 프로바이오틱스(probiotics) 균주들은 장 상피세포나 점막세포에 대해서 병원균들과 접착 경쟁을 함으로써 병원균의 침입을 막기도 하지만 병원균의 활성을 저해할 수 있는 물질을 생산함으로써 병원균을 감소시키는 역할을 한다고 알려져 있다. 따라서, 장내 미생물을 통해서 건강을 유지하기 위해서는 유익균을 증가시키고, 유해균을 감소시킬 수 있는 소재의 개발이 필요하며 위장관의 소화 흡수 경로에 있어 각 부위에 유익균과 유해균의 미생물 균총의 종류와 농도가 다르므로 위장관 각 위치에서 병원균에 대한 항균 효과와 유익균에 대한 증식 효과가 효과적으로 작용할 수 있는 소재의 개발이 필요하다. In addition, probiotic strains such as Bifidobacteria or Lactobacillus prevent the invasion of pathogens by competing for adhesion with pathogens to intestinal epithelial cells or mucosal cells, but also produce substances that can inhibit the activity of pathogens. It is known to play a role in reducing pathogens. Therefore, in order to maintain health through intestinal microorganisms, it is necessary to develop materials that can increase beneficial bacteria and reduce harmful bacteria. In the digestive and absorption pathways of the gastrointestinal tract, the types and concentrations of beneficial and harmful microbial flora are different in each part. Therefore, it is necessary to develop materials that can effectively exert an antibacterial effect on pathogens and a proliferative effect on beneficial bacteria in each location of the gastrointestinal tract.
한편, 오디(Morus alba L., mulberry)는 아시아, 아프리카, 아메리카, 유럽 및 인도를 포함한 많은 지역에서 널리 재배되고 있는 열매로, 신경 안정, 시력 개선, 기억력 개선, 항노화작용, 항고지혈증, 항산화작용, 항당뇨, 항염증 등 여러 생리적 기능을 가지고 있다고 보고된 바 있으며, 안토시아닌(anthocyanin)을 포함한 폴리페놀 화합물이 풍부하게 존재한다고 알려져 있다. 오디의 총 안토시아닌 함량은 과실 생체 중에 0.79% 내외로 존재하며, 안토시아닌의 종류 중에서 C3G 및 C3R이 거의 대부분을 차지한다고 알려져 있다. 안토시아닌은 항산화 활성과 더불어 항염 활성, 항비만 활성, 항종양 활성, 항당뇨 활성 등을 가지고 있으나, 사람 또는 동물이 직접 섭취하였을 경우 생체이용률(bioavailability)이 매우 낮은 것으로 보고되고 있다. 따라서, 매우 불안정한 안토시아닌을 위해 보다 안정적이고 효율적인 전달 시스템을 개발하는 것이 중요하다.Meanwhile, mulberry ( Morus alba L., mulberry) is a fruit widely cultivated in many regions including Asia, Africa, America, Europe, and India. It has nervous stability, improved vision, improved memory, anti-aging effects, anti-hyperlipidemia, and antioxidant properties. It has been reported to have various physiological functions such as anti-inflammatory, anti-diabetic, and anti-inflammatory, and is known to be rich in polyphenol compounds, including anthocyanin. The total anthocyanin content of mulberries is approximately 0.79% in the living fruit, and it is known that C3G and C3R account for most of the types of anthocyanins. Anthocyanins have antioxidant activity as well as anti-inflammatory activity, anti-obesity activity, anti-tumor activity, and anti-diabetic activity, but their bioavailability is reported to be very low when consumed directly by humans or animals. Therefore, it is important to develop more stable and efficient delivery systems for highly unstable anthocyanins.
한편, 열용융압출(hot melt extrusion, HME) 공정은 생리활성물질 및 약물을 제어된 조건하에서 혼합함으로써 균일한 형태 및 밀도를 가지는 물질을 제조할 수 있으며, 결정형(crystalline) 구조를 파괴하여 비정형질(amorphous) 또는 부분적 비정형질(partially amorphous)로 변환시킬 수 있는 고체분산체의 물리적 특성을 변화시킴으로써 생체 내에서의 반감기를 조절하고, 활성물질의 용해성 및 생체이용률을 향상시킬 수 있다고 보고되고 있다. 또한, HME 공정은 생리활성물질과 중합체(polymer)를 함께 압출 성형함으로써 수용성을 증대시킬 수 있도록 입자의 크기를 감소시킬 뿐 아니라, 중합체 매트릭스 안으로 생리활성물질을 분산시킬 수 있는 새로운 가공기술로 각광받고 있다.Meanwhile, the hot melt extrusion (HME) process can produce materials with uniform shape and density by mixing bioactive substances and drugs under controlled conditions, and destroys the crystalline structure to create amorphous form. It has been reported that the half-life in vivo can be adjusted and the solubility and bioavailability of the active substance can be improved by changing the physical properties of the solid dispersion that can be converted into an amorphous or partially amorphous form. In addition, the HME process is attracting attention as a new processing technology that not only reduces particle size to increase water solubility by extruding bioactive substances and polymers together, but also disperses bioactive substances into the polymer matrix. there is.
한국등록특허 제1224004호에는 '단백질, 폴리펩타이드 또는 펩타이드 약물전달용 고분자 및 그 제조방법, 및 단백질, 폴리펩타이드 또는 펩타이드 약물의 서방형 조성물 및 그 제조 방법'이 개시되어 있고, 한국등록특허 제1926024호에는 '서방형 약물전달체로서 히드록시아파타이트-칼슘설페이트 마이크로스피어'가 개시되어 있으나, 본 발명의 '서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 조성물'에 대해서는 기재된 바가 없다.Korean Patent No. 1224004 discloses 'polymers for protein, polypeptide or peptide drug delivery and methods for producing the same, and sustained-release compositions for protein, polypeptide or peptide drugs and methods for producing the same', and Korean Patent No. 1926024 The issue discloses 'Hydroxyapatite-calcium sulfate microspheres as a sustained-release drug delivery system', but there is no description of the 'composition for inhibiting intestinal bacterial translocation containing a sustained-release drug delivery vehicle as an active ingredient' of the present invention.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명자는 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형하여 서방형 약물전달체(HME-DDS)를 제조하였고, 상기 HME-DDS는 인공 위장관 환경에서 오디의 안토시아닌을 안정적으로 방출하고, 병원성 세균에 대한 항균 효과 및 프로바이오틱스 균주의 증식 유도 효과가 우수한 것을 확인함으로써, 본 발명을 완성하였다.The present invention was derived in response to the above-mentioned needs, and the present inventor has developed mulberries; and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; a sustained-release drug delivery system (HME-DDS) was prepared by heat melt extrusion molding, and the HME -DDS stably releases anthocyanins from mulberries in an artificial gastrointestinal tract environment and has excellent antibacterial effects against pathogenic bacteria and an excellent effect of inducing the proliferation of probiotic strains, thereby completing the present invention.
상기 과제를 해결하기 위해, 본 발명은 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 건강기능식품 조성물을 제공한다.In order to solve the above problem, the present invention includes mulberry; and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; for inhibiting intestinal bacterial translocation, comprising as an active ingredient a sustained-release drug delivery system obtained by heat melt extrusion molding. Provides a health functional food composition.
또한, 본 발명은 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 사료 첨가제를 제공한다.In addition, the present invention relates to mulberries; and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; for inhibiting intestinal bacterial translocation, comprising as an active ingredient a sustained-release drug delivery system obtained by heat melt extrusion molding. Provides feed additives.
또한, 본 발명은 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체를 제공한다.In addition, the present invention relates to mulberries; and a carrier composed of ascorbyl palmitate, mannitol, alginate, and poloxamer. A sustained-release drug delivery system is provided by heat melt extrusion molding.
본 발명의 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체(HME-DDS)는 인공 위장관 환경에서 안토시아닌을 안정적으로 방출하고, 병원성 세균에 대한 항균 효과 및 프로바이오틱스 균주의 증식 유도 효과가 우수하므로, 장내 세균 전위 억제용 건강기능식품 조성물, 장내 세균 전위 억제용 사료 첨가제로 유용하게 사용될 수 있을 것으로 기대된다.Mulberries of the present invention; and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; a sustained-release drug delivery system (HME-DDS) obtained by heat melt extrusion molding of anthocyanins in an artificial gastrointestinal environment. Since it stably releases and has an excellent antibacterial effect against pathogenic bacteria and an effect of inducing the growth of probiotic strains, it is expected to be useful as a health functional food composition for inhibiting intestinal bacterial translocation and a feed additive for inhibiting intestinal bacterial translocation.
도 1은 본 발명의 서방형 약물전달체(HME-DDS)를 제조하는 방법을 나타낸 모식도로, 오디(mulberry), 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)를 열용융압출성형한 후, 건조하고 분말화하는 과정을 나타낸 것이다.
도 2는 인공 위장관 환경에서 안토시아닌(C3G 및 C3R) 방출 특성을 확인한 결과로, A는 열용융압출하지 않은 오디 분말(MUL)의 결과이고, B 및 C는 HME-DDS와 구성성분의 조성비가 다른 비교군(HME-MUL1 및 HME-MUL2)의 결과이며, D는 HME-DDS의 결과이다.
도 3은 프로바이오틱스 균주 첨가에 따른 안토시아닌(C3G 및 C3R) 방출 특성을 확인한 결과로, A는 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 균주의 첨가에 따른 결과이고, B는 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus) 균주의 첨가에 따른 결과이다. MUL은 열용융압출하지 않은 오디 분말을 처리한 비교군이다.
도 4는 대장균(Escherichia coli), 황색포도상구균(Staphylococcus aureus) 및 엔테로코커스 패칼리스(Enterococcus faecalis)에 대한 항균 활성을 확인한 결과로, A는 페이퍼 디스크 주변에 형성된 생육저해환(clear zone)을 확인한 사진이고, B는 생육저해환의 직경(mm)을 비교한 결과이다. 도 4B 내 서로 다른 문자 a~c는 서로 유의미한 차이가 있다는 것을 의미하며, p<0.05이다.
도 5는 대장균(Escherichia coli), 황색포도상구균(Staphylococcus aureus) 및 엔테로코커스 패칼리스(Enterococcus faecalis)에 대한 항균 활성을 확인한 결과로, A는 열용융압출하지 않은 오디 분말(MUL)을 처리하였을 때의 각 병원균의 OD600값을 측정한 결과이고, B는 HME-DDS를 처리하였을 때의 각 병원균의 OD600값을 측정한 결과이다.
도 6은 프로바이오틱스 균주의 증식 유도 활성을 확인한 결과로, A는 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 및 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus)와 HME-DDS를 공동 배양한 후, 각 균주의 콜로니를 확인한 사진이고, B는 콜로니 수를 비교한 결과이다. CON은 각 균주를 단독 배양한 대조군이고, MUL은 열용융압출하지 않은 오디 분말을 처리한 비교군이다. 도 6B 내 내 서로 다른 문자 a~c는 서로 유의미한 차이가 있다는 것을 의미하며, p<0.05이다.
도 7은 프로바이오틱스 균주 배양 배지의 pH 변화를 측정한 결과로, A는 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 균주의 결과이고, B는 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus) 균주의 결과이다. control은 아무것도 처리하지 않은 대조군이고, MUL은 열용융압출하지 않은 오디 분말을 처리한 비교군이며, C3G-C3R은 안토시아닌을 처리한 비교군이다.Figure 1 is a schematic diagram showing a method of manufacturing the sustained-release drug delivery system (HME-DDS) of the present invention, using mulberry, ascorbyl palmitate, mannitol, alginate, and poloxamer. This shows the process of thermal melt extrusion of (poloxamer), followed by drying and powdering.
Figure 2 shows the results of confirming the release characteristics of anthocyanins (C3G and C3R) in an artificial gastrointestinal environment. A is the result of mulberry powder (MUL) without heat melt extrusion, and B and C are HME-DDS and the composition ratio of the components are different. These are the results of the comparison group (HME-MUL1 and HME-MUL2), and D is the result of HME-DDS.
Figure 3 shows the addition of probiotic strains. As a result of confirming the anthocyanin (C3G and C3R) release characteristics, A is the result of the addition of the Lacticaseibacillus rhamnosus strain, and B is the result of the addition of the Pediococcus pentosaceus strain. This is the result. MUL is a comparison group treated with mulberry powder that was not heat-melted and extruded.
Figure 4 shows the results of confirming antibacterial activity against Escherichia coli , Staphylococcus aureus , and Enterococcus faecalis . A shows a growth inhibition ring (clear zone) formed around the paper disk. This is a photo, and B is the result of comparing the diameter (mm) of growth inhibition rings. Different letters a to c in Figure 4B mean that there is a significant difference from each other, p<0.05.
Figure 5 shows the results of confirming the antibacterial activity against Escherichia coli , Staphylococcus aureus , and Enterococcus faecalis , where A is when mulberry powder (MUL) that was not heat melt extruded was treated. B is the result of measuring the OD 600 value of each pathogen, and B is the result of measuring the OD 600 value of each pathogen when treated with HME-DDS.
Figure 6 shows the results of confirming the proliferation inducing activity of probiotic strains. A is co-cultured with Lacticaseibacillus rhamnosus and Pediococcus pentosaceus and HME-DDS, and then each strain This is a photo confirming the colonies, and B is the result of comparing the number of colonies. CON is a control group in which each strain was cultured alone, and MUL is a comparison group treated with mulberry powder that was not heat-melted and extruded. Different letters a to c in Figure 6B mean that there is a significant difference from each other, p < 0.05.
Figure 7 shows the results of measuring the pH change of the probiotic strain culture medium, where A is the result of the Lacticaseibacillus rhamnosus strain, and B is the result of the Pediococcus pentosaceus strain. . control is a control group that was not treated with anything, MUL is a comparison group treated with mulberry powder that was not heat-melted and extruded, and C3G-C3R is a comparison group treated with anthocyanin.
본 발명의 목적을 달성하기 위하여, 본 발명은 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 건강기능식품 조성물을 제공한다. In order to achieve the object of the present invention, the present invention is mulberry (mulberry); and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; for inhibiting intestinal bacterial translocation, comprising as an active ingredient a sustained-release drug delivery system obtained by heat melt extrusion molding. Provides a health functional food composition.
본 명세서에 사용된 용어 "장내 세균 전위(intestinal bacterial translocation)"는 장내 세균이 장 점막층을 투과하여 상피세포로 이동하여 체내 염증 반응을 유도하게 되는 것을 말한다.The term “intestinal bacterial translocation” used herein refers to the condition in which intestinal bacteria penetrate the intestinal mucosa layer and move to epithelial cells, thereby inducing an inflammatory response in the body.
본 발명의 장내 세균 전위 억제용 건강기능식품 조성물에 있어서, 상기 서방형 약물전달체는 바람직하게는In the health functional food composition for inhibiting intestinal bacterial translocation of the present invention, the sustained-release drug delivery system is preferably
(1) 40~60중량%의 오디(mulberry), 2~8중량%의 아스코빌 팔미테이트(ascorbyl palmitate), 30~40중량%의 만니톨(mannitol), 2~8중량%의 알지네이트(alginate) 및 2~8중량%의 폴록사머(poloxamer)를 열용융압출기에 투입한 후, 압출하여 압출물을 제조하는 단계; 및(1) 40-60% by weight of mulberry, 2-8% by weight of ascorbyl palmitate, 30-40% by weight of mannitol, 2-8% by weight of alginate and adding 2 to 8% by weight of poloxamer into a heat melt extruder and extruding it to produce an extrudate; and
(2) 상기 단계 (1)에서 제조한 압출물을 건조하여 분말화하는 단계;를 포함하는 서방형 약물전달체의 제조방법으로 제조된 것일 수 있으며,(2) drying the extrudate prepared in step (1) and powdering it; it may be manufactured by a method for producing a sustained-release drug delivery system,
더 바람직하게는more preferably
(1) 50중량%의 오디(mulberry), 5중량%의 아스코빌 팔미테이트(ascorbyl palmitate), 35중량%의 만니톨(mannitol), 5중량%의 알지네이트(alginate) 및 5중량%의 폴록사머(poloxamer)를 열용융압출기에 투입한 후, 압출하여 압출물을 제조하는 단계; 및(1) 50% by weight of mulberry, 5% by weight of ascorbyl palmitate, 35% by weight of mannitol, 5% by weight of alginate and 5% by weight of poloxamer ( poloxamer) into a heat melt extruder and then extruding to produce an extrudate; and
(2) 상기 단계 (1)에서 제조한 압출물을 건조하여 분말화하는 단계;를 포함하는 서방형 약물전달체의 제조방법으로 제조된 것일 수 있으나, 이에 제한되지 않는다.(2) drying the extrudate prepared in step (1) and powdering it; it may be manufactured by a method for manufacturing a sustained-release drug delivery system, but is not limited thereto.
본 발명의 장내 세균 전위 억제용 건강기능식품 조성물에 있어서, 상기 열용융압출기는 생리활성물질 및 약물을 제어된 조건하에서 혼합함으로써 균일한 형태 및 밀도를 가지는 열용융압출법(hot melt extrusion, HME)을 적용한 기기이다. In the health functional food composition for inhibiting intestinal bacterial translocation of the present invention, the hot melt extruder uses a hot melt extrusion (HME) method to achieve a uniform shape and density by mixing the bioactive material and the drug under controlled conditions. This is a device that has been applied.
본 발명의 일 구현 예에 따른 장내 세균 전위 억제용 건강기능식품 조성물에 있어서, 상기 폴록사머는 폴록사머 188일 수 있으나, 이에 제한되지 않는다.In the health functional food composition for inhibiting intestinal bacterial translocation according to one embodiment of the present invention, the poloxamer may be poloxamer 188, but is not limited thereto.
본 명세서에 사용된 용어 "서방형(sustained release)"은 약물의 방출 또는 용출 기전을 조절하여 복용 이후 체내에서 장시간 약물이 방출되는 것으로, 약물이 체내에서 천천히 흡수되도록 하여 약효가 오래가는 것이 특징이며, 본 발명의 "서방형 약물"은 오디의 안토시아닌일 수 있으며, 본 발명의 "서방형 약물전달체"는 소장에서의 안토시아닌 방출량을 증가시킴으로써, 안토시아닌을 안정적으로 지속 방출할 수 있는 것일 수 있으나, 이에 제한되지 않느다.The term "sustained release" used in this specification refers to the release of a drug in the body for a long period of time after administration by controlling the release or dissolution mechanism of the drug, and is characterized by long-lasting drug effects by allowing the drug to be absorbed slowly in the body. , the “sustained-release drug” of the present invention may be anthocyanin from mulberry, and the “sustained-release drug delivery vehicle” of the present invention may be capable of stably and continuously releasing anthocyanin by increasing the amount of anthocyanin released in the small intestine. It's not limited.
또한, 본 발명의 장내 세균 전위 억제용 건강기능식품 조성물에 있어서, 상기 장내 세균은 대장균(Escherichia coli), 황색포도상구균(Staphylococcus aureus) 및 엔테로코커스 패칼리스(Enterococcus faecalis) 중에서 선택된 하나 이상일 수 있으나, 이에 제한되지 않는다.In addition, in the health functional food composition for inhibiting intestinal bacterial translocation of the present invention, the intestinal bacteria may be one or more selected from Escherichia coli, Staphylococcus aureus , and Enterococcus faecalis , It is not limited to this.
또한, 본 발명의 장내 세균 전위 억제용 건강기능식품 조성물에 있어서, 상기 서방형 약물전달체는 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 및 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus) 중에서 선택된 하나 이상의 프로바이오틱스를 증식시키는 것일 수 있으나, 이에 제한되지 않으며, 상기 프로바이오틱스를 증식시키면 장내 유익균 균총을 유지함으로써 장건강을 유도할 수 있는 것이 특징이다.In addition, in the health functional food composition for inhibiting intestinal bacterial translocation of the present invention, the sustained-release drug carrier is one or more probiotics selected from Lacticaseibacillus rhamnosus and Pediococcus pentosaceus. It may be, but is not limited to, the probiotics, and the characteristic feature is that the proliferation of the probiotics can induce intestinal health by maintaining the beneficial bacterial flora in the intestines.
상기 건강기능식품 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽 및 음료 중에서 선택된 어느 하나의 제형으로 제조되는 것이 바람직하지만 이에 한정하는 것은 아니다. 본 발명의 건강기능식품 조성물은 서방형 약물전달체를 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 혼합하여 제조될 수 있고, 통상적인 방법에 따라 적절하게 제조될 수 있다. 상기 서방형 약물전달체를 첨가할 수 있는 식품의 예로는 캐러멜, 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 수프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 중에서 선택된 어느 하나의 형태일 수 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다. 즉, 상기 식품의 종류에는 특별한 제한은 없다. 상기 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 및 천연 풍미제, 착색제 및 증진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 또한, 천연 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 상기의 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 본 발명의 건강기능식품 조성물은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있으며, 상기 천연 탄수화물은 포도당, 과당과 같은 단당류, 말토스, 슈크로스와 같은 이당류, 덱스트린, 사이클로 덱스트린과 같은 다당류, 자일리톨, 소르비톨, 에리트리톨 등의 당 알코올이다. 상기 천연 탄수화물의 비율은 크게 중요하지 않지만, 본 발명의 조성물 100g에 대하여, 0.01~0.04g인 것이 바람직하고, 더욱 바람직하게는 0.02~0.03g을 포함하는 것이지만 이에 한정하지 않는다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.The health functional food composition is preferably manufactured in a formulation selected from powder, granule, pill, tablet, capsule, candy, syrup, and beverage, but is not limited thereto. The health functional food composition of the present invention can be prepared by adding the sustained-release drug carrier as is or by mixing it with other foods or food ingredients, and can be manufactured appropriately according to conventional methods. Examples of foods to which the sustained-release drug carrier can be added include caramel, meat, sausages, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, and beverages. , it may be in any form selected from tea, drinks, alcoholic beverages, and vitamin complexes, and includes all health functional foods in the conventional sense. In other words, there are no particular restrictions on the type of food. The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, and protective colloidal thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Additionally, it may contain pulp for the production of natural fruit juice and vegetable drinks. The above components can be used independently or in combination. In addition, the health functional food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, and the natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, dextrins, and cyclosaccharides. These are polysaccharides such as dextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The ratio of the natural carbohydrate is not very important, but is preferably 0.01 to 0.04 g, more preferably 0.02 to 0.03 g, per 100 g of the composition of the present invention, but is not limited thereto. As sweeteners, natural sweeteners such as thaumatin and stevia extract, and synthetic sweeteners such as saccharin and aspartame can be used.
본 발명은 또한, 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체를 유효성분으로 포함하는 장내 세균 전위 억제용 사료 첨가제를 제공한다.The present invention also relates to mulberries; and a carrier consisting of ascorbyl palmitate, mannitol, alginate, and poloxamer; for inhibiting intestinal bacterial translocation, comprising as an active ingredient a sustained-release drug delivery system obtained by heat melt extrusion molding. Provides feed additives.
본 발명의 사료 첨가제는 사료관리법상의 보조사료에 해당한다. 본 발명에서 용어 '사료'는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미할 수 있다. 상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act. In the present invention, the term 'feed' may mean any natural or artificial diet, meal, etc., or a component of the meal, for or suitable for eating, ingestion, and digestion by animals. The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant feeds such as grains, roots and fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, cucurbits or grain by-products; Examples include animal feeds such as proteins, inorganic substances, fats and oils, minerals, fats and oils, single-cell proteins, zooplanktons or food. These may be used alone or in combination of two or more types.
본 발명은 또한, 오디(mulberry); 및 아스코빌 팔미테이트(ascorbyl palmitate), 만니톨(mannitol), 알지네이트(alginate) 및 폴록사머(poloxamer)로 이루어진 캐리어;를 열용융압출성형한 서방형 약물전달체를 제공한다.The present invention also relates to mulberries; and a carrier composed of ascorbyl palmitate, mannitol, alginate, and poloxamer. A sustained-release drug delivery system is provided by heat melt extrusion molding.
이하, 제조예 및 실시예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 제조예 및 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다.Hereinafter, the present invention will be described in more detail using manufacturing examples and examples. These manufacturing examples and examples are only for illustrating the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.
제조예 1. 서방형 약물전달체(HME-DDS)의 제조Preparation Example 1. Preparation of sustained-release drug delivery system (HME-DDS)
오디(mulberry), 아스코빌 팔미테이트(ascorbyl palmitate, esfood, Korea ), 만니톨(mannitol, Daejung chemical, Korea), 알지네이트(alginate, esfood, Korea) 및 폴록사머 188(poloxamer 188, Thermofisher, USA)을 50:5:35:5:5 중량비로 준비하여 열용융압출기(STS25-28ED, Hankook E.M Ltd., Korea)에 투입한 후, 분말 1kg 기준 증류수 250g을 첨가하였다. 배럴을 총 6구간으로 다르게 제조하여, 1구간: 50℃, 2구간: 60℃, 3,4 구간: 65℃, 5,6 구간: 70℃로 온도를 맞춘 후, 압출 속도 180rpm, 압출 출구 직경 0.2cm, 압출 압력은 12~18 bar의 조건으로 압출하여 압출물을 제조하였고, 열풍건조기(KED-132A, Kiturami, Korea)를 사용하여 50℃에서 76시간 동안 건조한 후, 분말화하여 서방형 약물전달체(HME-DDS)를 제조하였다(도 1). Mulberry, ascorbyl palmitate (esfood, Korea), mannitol (Daejung chemical, Korea), alginate (esfood, Korea), and poloxamer 188 (poloxamer 188, Thermofisher, USA) :5:35:5:5 weight ratio was prepared and put into a heat melt extruder (STS25-28ED, Hankook E.M Ltd., Korea), and then 250g of distilled water was added based on 1kg of powder. The barrel was manufactured differently in a total of 6 sections, and the temperature was adjusted to section 1: 50℃, section 2: 60°C, section 3 and 4: 65°C, and section 5 and 6: 70°C, with an extrusion speed of 180 rpm and an extrusion outlet diameter. The extrudate was manufactured by extrusion under the conditions of 0.2cm and extrusion pressure of 12~18 bar, dried at 50℃ for 76 hours using a hot air dryer (KED-132A, Kiturami, Korea), and then powdered to produce sustained-release drug. The delivery vehicle (HME-DDS) was prepared (Figure 1).
한편, 열용융압출성형하지 않은 오디 분말(MUL) 및 본 발명의 HME-DDS의 구성성분의 비율을 조절하고, 분리유청단백질(whey protein isolate) 및 레시틴(lecithin)을 추가로 첨가하여 동일한 방법으로 압출성형한 HME-MUL1, HME-MUL2를 비교군으로 이용하였다(표 1).Meanwhile, the ratio of the components of mulberry powder (MUL) and the HME-DDS of the present invention without heat melt extrusion was adjusted, and whey protein isolate and lecithin were additionally added in the same manner. Extruded HME-MUL1 and HME-MUL2 were used as comparison groups (Table 1).
실시예 1. 오디의 안토시아닌 방출 특성 확인Example 1. Confirmation of anthocyanin release characteristics of mulberries
1-1. 인공 위장관 환경에서 오디의 안토시아닌 방출 특성 확인1-1. Determination of anthocyanin release characteristics of mulberry in artificial gastrointestinal environment
본 발명의 서방형 약물전달체(HME-DDS)의 약물 방출 특성을 확인하기 위하여 인공 위액 및 인공 소장액 환경에서 오디의 안토시아닌(anthocyanin) 방출량을 측정하였다. 구체적으로는, 상기 제조예 1의 HME-DDS, HME-MUL1, HME-MUL2 또는 MUL 분말 0.2g을 물 5㎖에 각각 녹여 투석백(Spectra/Por Cellulose Ester Membrane MWCO: 25 kDa, Spectrum Labs, USA) 안에 넣어 준비하였다. 1% Tween 80(pH 7.4) 및 펩신(pepsin)을 비커에 채워 인공 위액 환경을 조성한 후, 상기 준비한 투석백을 비커에 넣고 실온의 진탕조에서 100rpm으로 교반하며 정해진 시간 간격(0.5, 1 및 2시간)에 2㎖의 용액을 샘플링하고, 동일한 부피의 새 용액을 첨가하였다. 2시간 후, PBS 1M, 0.02% Tween 80, 판크레아틴(pancreatin)을 새로운 비커에 채워 인공 소장액 환경을 조성한 후, 상기 투석백을 비커로 그대로 옮겨 실험을 계속 진행하였다. 실온의 진탕조에서 100rpm으로 교반하며 정해진 시간 간격(4, 8, 12 및 24시간)에 2㎖의 용액을 샘플링하고, 동일한 부피의 새 용액을 첨가하였다. 샘플링한 각 용액은 0.45μm 시린지 필터로 여과하고, 하기 표 2의 조건으로 HPLC 분석을 통해 C3G(cyanidin-3-glucoside) 및 C3R(cyanidin-3-rutinoside) 함량을 측정하였다. 데이터 분석은 Agilent ChemStation for LC 3D Systems(Agilent Technologies, Germany)을 이용하여 수행하였고, 표준물질은 C3G(kuromanin chloride≥95.0%, Sigma. USA) 및 C3R(keracynin chloride≥98.0%, Sigma. USA)로 검량선을 작성하였다. To confirm the drug release characteristics of the sustained-release drug delivery system (HME-DDS) of the present invention, the anthocyanin release amount of mulberries was measured in artificial gastric fluid and artificial small intestine fluid environments. Specifically, 0.2 g of HME-DDS, HME-MUL1, HME-MUL2 or MUL powder of Preparation Example 1 was dissolved in 5 ml of water and placed in a dialysis bag (Spectra/Por Cellulose Ester Membrane MWCO: 25 kDa, Spectrum Labs, USA). ) was prepared by placing it inside. After creating an artificial gastric fluid environment by filling the beaker with 1% Tween 80 (pH 7.4) and pepsin, the prepared dialysis bag was placed in the beaker, stirred at 100 rpm in a shaking bath at room temperature, and stirred at set time intervals (0.5, 1, and 2). 2 mL of solution was sampled and an equal volume of new solution was added. After 2 hours, a new beaker was filled with 1M PBS, 0.02% Tween 80, and pancreatin to create an artificial small intestine fluid environment, and then the dialysis bag was transferred to the beaker and the experiment was continued. While stirring at 100 rpm in a shaking bath at room temperature, 2 mL of solution was sampled at designated time intervals (4, 8, 12, and 24 hours), and an equal volume of new solution was added. Each sampled solution was filtered through a 0.45 μm syringe filter, and the contents of C3G (cyanidin-3-glucoside) and C3R (cyanidin-3-rutinoside) were measured through HPLC analysis under the conditions shown in Table 2 below. Data analysis was performed using Agilent ChemStation for LC 3D Systems (Agilent Technologies, Germany), and standard materials were C3G (kuromanin chloride≥95.0%, Sigma. USA) and C3R (keracynin chloride≥98.0%, Sigma. USA). A calibration curve was prepared.
그 결과, 인공 위장관 환경에서 24시간 동안 반응시켰을 때, 대조군(MUL)의 안토시아닌은 약 16% 방출된 반면, HME-DDS의 안토시아닌은 약 80% 방출된 것을 확인하였다. 또한, 인공 위액 환경에서는(0~2시간) 비교군(HME-MUL1, HME-MUL2)과 HME-DDS의 안토시아닌은 유사한 양으로 방출되었지만, 인공 소장액 환경에서는(2~24시간) 비교군(HME-MUL1, HME-MUL2)보다 HME-DDS의 안토시아닌이 더 많이 방출되는 것을 확인하였다(도 2).As a result, when reacted in an artificial gastrointestinal environment for 24 hours, it was confirmed that about 16% of anthocyanins in the control group (MUL) were released, while about 80% of anthocyanins in HME-DDS were released. In addition, in the artificial gastric fluid environment (0 to 2 hours), anthocyanins from the comparison group (HME-MUL1, HME-MUL2) and HME-DDS were released in similar amounts, but in the artificial small intestine fluid environment (2 to 24 hours), the comparison group ( It was confirmed that more anthocyanins were released from HME-DDS than from HME-MUL1 and HME-MUL2 (Figure 2).
상기 결과를 통해, 본 발명의 HME-DDS는 폴리머로 이루어진 매트릭스에 의해 오디의 생리활성물질인 안토시아닌이 안정적으로 보호되고 있으며, 소장에서도 지속적으로 방출되어 효율적인 체내 흡수가 가능함을 알 수 있었다.Through the above results, it was confirmed that in the HME-DDS of the present invention, anthocyanin, a bioactive substance of mulberry, is stably protected by a polymer matrix, and is continuously released in the small intestine, enabling efficient absorption into the body.
1-2. 프로바이오틱스 균주 첨가에 따른 오디의 안토시아닌 방출 특성 확인1-2. Confirmation of anthocyanin release characteristics of mulberry according to addition of probiotic strains
안토시아닌은 장내 미생물 균총 중 유산균과 같은 프로바이오틱스 균주의 대사에 의해 페놀산과 유기산으로 변환된다고 알려져 있다. 이에, 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 또는 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus) 균주의 첨가에 따른 본 발명의 HME-DDS의 안토시아닌 방출 특성을 확인하고자 하였다. It is known that anthocyanins are converted into phenolic acids and organic acids through the metabolism of probiotic strains such as lactic acid bacteria among the intestinal microbial flora. Accordingly, we sought to confirm the anthocyanin release characteristics of the HME-DDS of the present invention according to the addition of Lacticaseibacillus rhamnosus or Pediococcus pentosaceus strains.
구체적으로, MRS 배지 100㎖에 107 CFU/㎖의 락티카제이바실러스 람노서스(L. rhamnosus) 또는 페디오코쿠스 펜토사세우스(P. pentosaceus)를 각각 접종한 후, 본 발명의 HME-DDS를 첨가하고 37℃에서 배양하면서 4시간 간격으로 3㎖의 배지를 채취한 후, 동일한 부피의 새 배지를 첨가하며 24시간 동안 배양하였다. 이후, 0, 4, 8, 12, 16, 20 및 24시간째에 채취한 각 배지를 0.45㎛ 실린지 필터로 여과한 후, 상기 실시예 1-1에 기재한 방법으로 안토시아닌(C3G 및 C3R)의 함량을 측정하였다.Specifically, after inoculating 10 7 CFU/ml of Lactica J Bacillus rhamnosus ( L. rhamnosus ) or Pediococcus pentosaceus ( P. pentosaceus ) in 100 ml of MRS medium, HME-DDS of the present invention was added and incubated at 37°C, collecting 3 ml of medium at 4-hour intervals, then adding the same volume of new medium and culturing for 24 hours. Thereafter, each medium collected at 0, 4, 8, 12, 16, 20, and 24 hours was filtered through a 0.45㎛ syringe filter, and then anthocyanins (C3G and C3R) were filtered by the method described in Example 1-1 above. The content was measured.
그 결과, 락티카제이바실러스 람노서스(L. rhamnosus) 또는 페디오코쿠스 펜토사세우스(P. pentosaceus) 균주를 첨가하였을 때, 대조군(MUL)의 안토시아닌 방출량은 배양이 진행됨에 따라 급격히 감소한 반면, HME-DDS의 안토시아닌 방출량은 배양이 진행되어도 약 2㎍/㎖로 유지되는 것을 확인하였다(도 3).As a result, when Lactica J Bacillus rhamnosus ( L. rhamnosus ) or Pediococcus pentosaceus ( P. pentosaceus ) strains were added, the anthocyanin release amount of the control group (MUL) decreased rapidly as the culture progressed. It was confirmed that the anthocyanin release amount of HME-DDS was maintained at about 2 μg/ml even as culture progressed (Figure 3).
상기 결과를 통해, 본 발명의 HME-DDS는 폴리머로 이루어진 매트릭스에 의해 오디의 생리활성물질인 안토시아닌이 안정적으로 보호되고 있으며, 장내 미생물 대사에 의해 방출된 안토시아닌이 페놀산과 유기산으로 변환되어 그 함량이 일부 감소하기는 하지만 HME-DDS 제제의 서방형 특성에 의해 천천히 지속적으로 방출되어 배양 시간이 경과하여도 배지 내에 안토시아닌 함량이 일정 수준으로 유지되는 것을 알 수 있었다. Based on the above results, in the HME-DDS of the present invention, anthocyanin, a bioactive substance of mulberry, is stably protected by a polymer matrix, and anthocyanin released by intestinal microbial metabolism is converted into phenolic acid and organic acid, thereby increasing its content. Although there was some decrease, it was slowly and continuously released due to the sustained-release characteristics of the HME-DDS preparation, and it was found that the anthocyanin content in the medium was maintained at a certain level even over culture time.
실시예 2. 항균 활성 평가Example 2. Evaluation of antibacterial activity
안토시아닌은 병원균의 성장을 억제하는 항균 효과가 있다는 것이 알려져 있으며, 이러한 항균 효과는 안토시아닌 및 그들의 대사체 물질들이 체내로 감염된 병원균의 세포 투과성을 증대시켜 세포 내 기질의 구조적 안정성을 파괴함과 동시에 세포의 형태학적 손상을 유발하여 나타나는 것으로 알려져 있다.It is known that anthocyanins have an antibacterial effect that inhibits the growth of pathogens. This antibacterial effect is caused by anthocyanins and their metabolites increasing the cell permeability of pathogens infected into the body, destroying the structural stability of the intracellular matrix and simultaneously destroying the cell's It is known to cause morphological damage.
이에, 본 발명의 HME-DDS에 의한 안토시아닌의 항균 활성을 평가하였다. 상기 제조예 1의 각 분말 1g을 50㎖의 물에 넣고 상온(25℃)에서 30분간 초음파를 처리하고(120V, 60Hz, UCP-20, JeioTech, Korea), 다시 30분간 500rpm에서 교반한 후, 필터 페이퍼(No.6, Whatman International Ltd., England)로 여과하고, 감압농축(Eyela Co., Ltd., Japan)하였다. 이후, 최종 농도가 2mg/㎖이 되도록 조정한 시료 100㎕를 직경 10mm의 원형 페이퍼 디스크에 점적 처리하여 준비하였다. 열용융압출하지 않은 오디 분말(MUL)을 대조군으로 이용하였고, 최종 농도가 1X107 CFU/100㎕가 되도록 조정한 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 및 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus)의 배양액을 각각 비교군으로 이용하였다. Accordingly, the antibacterial activity of anthocyanin by HME-DDS of the present invention was evaluated. 1 g of each powder of Preparation Example 1 was placed in 50 ml of water, treated with ultrasonic waves (120 V, 60 Hz, UCP-20, JeioTech, Korea) for 30 minutes at room temperature (25°C), and stirred at 500 rpm for another 30 minutes, It was filtered through filter paper (No. 6, Whatman International Ltd., England) and concentrated under reduced pressure (Eyela Co., Ltd., Japan). Afterwards, 100 μl of the sample adjusted to a final concentration of 2 mg/ml was prepared by dropping it on a circular paper disk with a diameter of 10 mm. Mulberry powder (MUL) without heat melt extrusion was used as a control, and Lacticaseibacillus rhamnosus and Pediococcus pentosaceus were adjusted to a final concentration of 1X10 7 CFU/100㎕. )'s culture medium was used as a comparison group.
에스케리키아 콜라이(Escherichia coli), 스타필로코커스 아우레우스(Staphylococcus aureus) 또는 엔테로코커스 패칼리스(Enterococcus faecalis)를 배양한 후, 최종 농도가 1X106 CFU/100㎕가 되도록 각각 준비하여 페트리디쉬에 고르게 도말하고, 상기 준비한 각 페이퍼 디스크를 올리고 37℃에서 24시간 배양한 후 각 페이퍼 디스크 주변에 형성된 생육저해환(clear zone)의 직경(mm)을 측정하여 항균 활성을 평가하였다. After culturing Escherichia coli , Staphylococcus aureus, or Enterococcus faecalis , prepare the final concentration to be 1 After smearing evenly, each paper disk prepared above was placed and cultured at 37°C for 24 hours, and the antibacterial activity was evaluated by measuring the diameter (mm) of the clear zone formed around each paper disk.
그 결과, 본 발명의 HME-DDS의 E. coli에 대한 생육저해환의 크기는 18.1±0.2mm이고, S. aureus에 대한 생육저해환의 크기는 21.9±2.2mm이며, E. faecalis에 대한 생육저해환의 크기는 18.5±0.2mm인 것을 확인하였고, 이는 대조군 및 비교군보다 우수한 항균 활성임을 확인하였다(도 4).As a result, the size of the growth inhibition ring for E. coli of the HME-DDS of the present invention is 18.1 ± 0.2 mm, the size of the growth inhibition ring for S. aureus is 21.9 ± 2.2 mm, and the size of the growth inhibition ring for E. faecalis is 18.1 ± 0.2 mm. The size was confirmed to be 18.5 ± 0.2 mm, which confirmed that it had superior antibacterial activity than the control and comparison groups (Figure 4).
또한, 에스케리키아 콜라이(Escherichia coli), 스타필로코커스 아우레우스(Staphylococcus aureus) 및 엔테로코커스 패칼리스(Enterococcus faecalis) 1X106 CFU/㎖을 BHI(Brain Heart Infusion) 액체 배지에 접종한 후, 본 발명의 HME-DDS(1mg/㎖ 또는 2mg/㎖) 또는 열용융압출하지 않은 오디 분말(MUL, 1~6mg/㎖)을 첨가하고, 37℃에서 24시간 동안 배양하며 4, 8, 12, 16, 20 또는 24시간 째에 OD600값을 측정하였다. 병원균을 접종한 후, 아무것도 첨가하지 않은 군을 대조군으로 이용하였다. In addition, after inoculating Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis at 1 Add HME-DDS (1 mg/ml or 2 mg/ml) of the invention or mulberry powder (MUL, 1 to 6 mg/ml) without heat melt extrusion, and culture at 37°C for 24 hours, 4, 8, 12, 16. , OD 600 values were measured at 20 or 24 hours. After inoculation with pathogens, a group to which nothing was added was used as a control group.
그 결과, 본 발명의 HME-DDS는 저농도의 처리에도, E. coli, S. aureus 또는 E. faecalis에 대한 성장 억제 효과가 우수한 것을 확인하였다(도 5).As a result, it was confirmed that the HME-DDS of the present invention had an excellent growth inhibition effect on E. coli , S. aureus or E. faecalis even when treated at low concentrations (FIG. 5).
상기 결과를 바탕으로, 본 발명의 HME-DDS는 지속적이고 안정적인 안토시아닌 방출에 의해 병원균에 항균 효과가 오디 원물 대비 우수한 것을 알 수 있었다.Based on the above results, it was found that the HME-DDS of the present invention has an excellent antibacterial effect on pathogens compared to the raw mulberry material due to the continuous and stable release of anthocyanins.
실시예 3. 프로바이오틱스 균주 증식 유도 활성 평가Example 3. Evaluation of probiotic strain proliferation inducing activity
안토시아닌은 장내 미생물 균총 중 유산균과 같은 프로바이오틱스 균주의 세포 성장을 촉진한다고 알려져 있다. Anthocyanins are known to promote cell growth of probiotic strains such as lactic acid bacteria among the intestinal microbial flora.
3-1. 프로바이오틱스 균주 증식능 측정3-1. Measurement of probiotic strain proliferation ability
본 발명의 HME-DDS에 의한 프로바이오틱스 균주의 증식 유도 활성을 평가하기 위하여, 상기 제조예 1의 각 분말 1g을 50㎖의 물에 넣고 상온(25℃)에서 30분간 초음파를 처리하고(120V, 60Hz, UCP-20, JeioTech, Korea), 다시 30분간 500rpm에서 교반한 후, 여과지(No.6, Whatman International Ltd., England)로 여과하고, 감압농축(Eyela Co., Ltd., Japan)하였다. 이후, 최종 농도가 2mg/㎖이 되도록 조정한 시료 50㎕를 준비하였다. 프로바이오틱스 균주로 알려진 락티카제이바실러스 람노서스(Lacticaseibacillus rhamnosus) 및 페디오코쿠스 펜토사세우스(Pediococcus pentosaceus)를 각각 배양하여 최종 농도가 1X107 CFU/100㎕가 되도록 조정한 배양액 50㎕와 상기 준비한 시료 50㎕를 혼합하여 MRS 한천 배지에 도말하고 37℃에서 24시간 동안 공동 배양한 후, 형성된 프로바이로틱스 균주의 콜로니 수를 측정하였다. 시료를 혼합하지 않고 프로바이오틱스 균주만 단독 배양하여 대조군(CON)으로 사용하였다.In order to evaluate the proliferation inducing activity of probiotic strains by HME-DDS of the present invention, 1 g of each powder of Preparation Example 1 was placed in 50 ml of water and ultrasonicated for 30 minutes at room temperature (25°C) (120 V, 60 Hz). , UCP-20, JeioTech, Korea), stirred again at 500 rpm for 30 minutes, filtered through filter paper (No. 6, Whatman International Ltd., England), and concentrated under reduced pressure (Eyela Co., Ltd., Japan). Afterwards, 50 μl of sample adjusted to a final concentration of 2 mg/ml was prepared. Lacticaseibacillus rhamnosus and Pediococcus pentosaceus , known as probiotic strains, were each cultured and 50 ㎕ of culture medium adjusted to a final concentration of 1X10 7 CFU/100 ㎕ and the sample prepared above 50㎕ was mixed, spread on MRS agar medium, and co-cultured at 37°C for 24 hours, and then the number of colonies of the formed probiotic strain was measured. The probiotic strains were cultured alone without mixing the samples and used as a control (CON).
그 결과, 본 발명의 HME-DDS와 공동 배양한 L. rhamnosus의 콜로니 수는 L. rhamnosus 단독 배양한 대조군(CON)보다 약 4배 이상 증가하였고, 오디 원물만 분말화한 대조군(MUL)보다 약 2배 이상 증가하는 것을 확인하였다. 또한, 본 발명의 HME-DDS와 공동 배양한 P. pentosaceus의 콜로니 수는 P. pentosaceus 단독 배양한 대조군(CON)보다 약 3.5배 이상 증가하였고, 오디 원물만 분말화한 대조군(MUL)보다 약 1.5배 이상 증가하는 것을 확인하였다(도 6).As a result, the number of colonies of L. rhamnosus co-cultured with the HME-DDS of the present invention increased by about 4 times more than the control group (CON) cultured alone with L. rhamnosus , and about 4 times more than the control group (MUL) in which only raw mulberry powder was powdered. It was confirmed that it increased more than 2-fold. In addition, the number of colonies of P. pentosaceus co-cultured with the HME-DDS of the present invention increased by about 3.5 times more than the control group (CON) in which P. pentosaceus was cultured alone, and about 1.5 times more than the control group (MUL) in which only raw mulberry powder was powdered. It was confirmed that it increased by more than twofold (Figure 6).
상기 결과를 바탕으로, 본 발명의 HME-DDS는 지속적이고 안정적인 안토시아닌 방출에 의해 프로바이오틱스 균주의 증식을 효과적으로 유도함으로써 장내 유익균 균총을 유지하는데 도움을 줄 수 있음을 알 수 있었다. Based on the above results, it was found that the HME-DDS of the present invention can help maintain the beneficial intestinal flora by effectively inducing the proliferation of probiotic strains through continuous and stable anthocyanin release.
3-2. 프로바이오틱스 균주 배양 배지의 pH 변화 측정3-2. Measurement of pH change in probiotic strain culture medium
본 발명의 HME-DDS 제제의 적용이 장내 미생물의 생육 촉진과 기질로서 공급되는 안토시아닌의 전환 반응에 의한 페놀산 및 유기산과 같은 항균 인자의 합성 증가를 확인하고자 하였다.The purpose of this study was to confirm that the application of the HME-DDS preparation of the present invention promotes the growth of intestinal microorganisms and increases the synthesis of antibacterial factors such as phenolic acids and organic acids through the conversion reaction of anthocyanins supplied as substrates.
구체적으로, MRS 배지 100㎖에 107 CFU/㎖의 락티카제이바실러스 람노서스(L. rhamnosus) 또는 페디오코쿠스 펜토사세우스(P. pentosaceus) 균주 배양액 1㎖를 접종한 후, 본 발명의 HME-DDS 또는 MUL을 최종 농도가 2mg/㎖이 되도록 첨가하고 37℃에서 24시간 동안 배양하면서 pH 미터기를 이용하여 균주 배양액의 pH를 4시간마다 측정하였다. 본 발명의 HME-DDS 첨가에 따른 pH의 변화가 오디의 안토시아닌에 의한 것인지 여부를 확인하기 위하여 본 발명의 HME-DDS 처리량에 포함되어질 것으로 예측되는 60mg의 C3G 및 39mg의 C3R 처리군을 비교군으로 이용하였다. Specifically, after inoculating 1 ml of 10 7 CFU/ml Lactica J Bacillus rhamnosus ( L. rhamnosus ) or Pediococcus pentosaceus ( P. pentosaceus ) strain culture in 100 ml of MRS medium, HME-DDS or MUL was added to a final concentration of 2 mg/ml and incubated at 37°C for 24 hours, and the pH of the strain culture was measured every 4 hours using a pH meter. In order to confirm whether the change in pH due to the addition of HME-DDS of the present invention was caused by anthocyanin of mulberry, 60 mg of C3G and 39 mg of C3R treatment group, which are expected to be included in the HME-DDS treatment amount of the present invention, were used as a comparison group. used.
그 결과, 본 발명의 HME-DDS의 첨가에 의해 람노서스(L. rhamnosus) 또는 페디오코쿠스 펜토사세우스(P. pentosaceus) 균주의 대수생장기가 시작되는 16시간이 경과하면서부터 대조군(MUL) 또는 비교군(C3G-C3R) 대비 낮은 pH 값을 나타내는 것을 확인하였다(도 7). As a result, after 16 hours when the logarithmic growth period of the L. rhamnosus or P. pentosaceus strain begins due to the addition of the HME-DDS of the present invention, the control group (MUL) Alternatively, it was confirmed that the pH value was lower than that of the comparison group (C3G-C3R) (Figure 7).
상기 결과를 바탕으로, 본 발명의 HME-DDS는 지속적이고 안정적인 안토시아닌 방출에 의해 기질로서 공급되는 안토시아닌의 전환 반응에 의해 프로바이오틱스 균주의 페놀산 및 유기산의 대사 활성이 증가시킬 수 있음을 알 수 있었다. Based on the above results, it was found that the HME-DDS of the present invention can increase the metabolic activity of phenolic acids and organic acids of probiotic strains through a conversion reaction of anthocyanins supplied as substrates through continuous and stable anthocyanin release.
Claims (7)
(1) 40~60중량%의 오디(mulberry), 2~8중량%의 아스코빌 팔미테이트(ascorbyl palmitate), 30~40중량%의 만니톨(mannitol), 2~8중량%의 알지네이트(alginate) 및 2~8중량%의 폴록사머(poloxamer)를 열용융압출기에 투입한 후, 압출하여 압출물을 제조하는 단계; 및
(2) 상기 단계 (1)에서 제조한 압출물을 건조하여 분말화하는 단계;를 포함하는 서방형 약물전달체의 제조방법으로 제조된 것임을 특징으로 하는 장내 세균 전위 억제용 건강기능식품 조성물.The method of claim 1, wherein the sustained-release drug delivery system is
(1) 40-60% by weight of mulberry, 2-8% by weight of ascorbyl palmitate, 30-40% by weight of mannitol, 2-8% by weight of alginate and adding 2 to 8% by weight of poloxamer into a heat melt extruder and extruding it to produce an extrudate; and
(2) A health functional food composition for inhibiting intestinal bacterial translocation, characterized in that it is manufactured by a method for producing a sustained-release drug delivery system comprising the step of drying and powdering the extrudate prepared in step (1).
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