KR102000473B1 - Composition comprising bee venom for prevention or treating avian influenza - Google Patents
Composition comprising bee venom for prevention or treating avian influenza Download PDFInfo
- Publication number
- KR102000473B1 KR102000473B1 KR1020170119574A KR20170119574A KR102000473B1 KR 102000473 B1 KR102000473 B1 KR 102000473B1 KR 1020170119574 A KR1020170119574 A KR 1020170119574A KR 20170119574 A KR20170119574 A KR 20170119574A KR 102000473 B1 KR102000473 B1 KR 102000473B1
- Authority
- KR
- South Korea
- Prior art keywords
- bee venom
- avian influenza
- composition
- bees
- preventing
- Prior art date
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Abstract
본 발명은 봉독을 함유하는 조성물에 관한 것으로서, 상기 봉독이 포함된 조성물은 H9N2 바이러스의 활성을 억제하는 효과가 우수하여 조류 인플루엔자를 예방 또는 치료할 수 있는 약학 조성물, 식품 조성물, 동물약품, 사료 첨가제 조성물 등으로 용이하게 사용될 수 있다. The present invention relates to a composition containing bee venom, wherein the bee venom-containing composition is excellent in the effect of inhibiting the activity of H9N2 virus, so that a pharmaceutical composition, a food composition, an animal medicine, and a feed additive composition capable of preventing or treating avian influenza And the like.
Description
본 발명은 봉독을 유효성분으로 포함하는 조류 인플루엔자의 예방 또는 치료용 조성물에 관한 것으로서, 자세하게는 H9N2 바이러스의 활성을 억제시키는 효과가 있는 서양종꿀벌의 정제봉독을 함유하는 조류 인플루엔자의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for preventing or treating avian influenza comprising bee venom as an active ingredient, and more particularly, to a composition for preventing or treating avian influenza, which contains purified bee venom of bees of the Western species having an effect of inhibiting the activity of H9N2 virus .
인플루엔자 바이러스는 '오르소믹소'과에 속하는 RNA 바이러스(Orthomyxovirus)로서 A, B, C형으로 분류된다. A형은 사람에게 주로 감염이 확인되며 B, C형에 비하여 돼지, 기타 포유류 및 다양한 야생조류에서 감염이 확인되고 있는 바이러스이다. 최근, 전 세계적으로 문제가 되고 있는 조류 인플루엔자(Avian influenza), 돼지 인플루엔자(Swine influenza) 및 신종플루(Novel flu) 등은 모두 A형 바이러스에 속한다.Influenza viruses are classified as A, B, and C as Orthomyxoviruses belonging to Orthomyxia. Type A is a virus that has been confirmed to be infected in pigs, other mammals, and various wild birds compared to B and C types, which are mainly infected to humans. Recently, Avian influenza, Swine influenza and Novel flu, all of which are a problem in the world, all belong to type A virus.
인플루엔자 바이러스의 표면에는 헤마글루티닌(hemagglutinin, HA)과 뉴라미니데이즈(neuraminidase, NA)라는 두 가지 단백질이 존재하는데, HA는 16종이 있고 NA는 9종이 있으므로 16×9=144 종류의 인플루엔자 바이러스가 발생할 수 있다. 조류에서의 인플루엔자 감염은 주로 H5형이나 H7형 및 H9형에 관련되며, 3종류의 헤마글루티닌(H1, H2, H3)과 2가지 형태의 뉴라미니데이즈(N1과 N2)만이 인간에서 인플루엔자 감염을 일으키므로 원칙적으로 인간은 조류 인플루엔자에 감염되지 않았다. 그러나 최근에는 조류의 인플루엔자 바이러스가 유전자 재조합 과정을 거치지 않고 직접 사람에게 전파된 예도 발생하고 있다.There are two proteins on the surface of influenza virus: hemagglutinin (HA) and neuraminidase (NA). There are 16 species of HA and 9 species of NA. Therefore, 16 × 9 = 144 influenza viruses May occur. Influenza infections in birds are mainly associated with H5, H7 and H9 types, and only three types of hemagglutinin (H1, H2, H3) and two forms of neuraminidase (N1 and N2) In principle, humans are not infected with avian influenza because they cause infections. Recently, however, there have been instances where avian influenza viruses have been transmitted directly to humans without undergoing genetic recombination.
조류 인플루엔자는 닭과 오리, 칠면조 등 가금류를 접촉하는 것 이외에도 야생조류와 우리나라에 온 철새들을 통해서 빠르게 전파된다. 조류 인플루엔자 바이러스는 조류 인플루엔자가 발생한 동남아로부터 주기적으로 유입되어 전파되며 특히 봄철 황사를 통해 중국으로부터도 전염이 가능하다. 세계적으로 문제가 되고 있는 동물의 바이러스 질환인 조류 인플루엔자는 국내에서 1996년 이후 발생해 매년 직접적인 피해가 발생하고 있으며, 아시아를 비롯한 여러 국가에서도 조류 인플루엔자의 발생으로 양계산업의 경제적 손실이 막대한 실정이다. In addition to contact with poultry such as chickens, ducks and turkeys, avian influenza is spread rapidly through wild birds and migratory birds in Korea. The avian influenza virus is transmitted periodically from Southeast Asia where avian influenza occurs, and it is possible to spread it from China through spring dust, especially in the spring. The avian influenza virus, a viral disease of animals worldwide, has been suffering direct damage every year since 1996, and the economic loss of the poultry industry has been widespread in many countries, including Asia, due to the outbreak of avian influenza.
바이러스의 감염 및 증식과정을 살펴보면 바이러스는 세포에 감염 후 세포내에서 새로운 바이러스를 만들고 다른 세포로 전파되기 위하여 세포 외부에 존재하는 시알릭산(siliac acid)을 바이러스가 만든 뉴라미니데이즈를 이용하여 절단하는 것이 필요하다. 조류 인플루엔자의 치료제로서 가장 잘 알려져 있는 것은 타미플루인데, 타미플루와 같은 치료약에 대해서도 내성이 있는 바이러스가 보고되어 있어 신규 치료제에 대한 개발이 시급하다. 내성 조류 인플루엔자 바이러스는 보통 타미플루가 결합하는 타미플루의 수용체 단백질의 아미노산을 변화시키는 3개의 유전적 변이(Arg292Lys, Asn274Ser, His294Tyr)를 통해 발생하는 것으로 알려져 있다. 3개의 유전적 변이 중 타미플루 내성 조류 인플루엔자 바이러스의 변종으로 가장 많이 발현하는 294의 His가 Tyr으로 변화한 바이러스의 경우는 타미플루의 소수성 잔기(hydrophobic residue)가 타미플루 수용체에 결합하지 못하게 변이된 경우이다. 따라서 이러한 바이러스의 등장은 인간이 새로운 바이러스 치료제를 지속적으로 개발하여야 하는 당위성을 제공한다.The infection and proliferation process of viruses reveals that the virus infects cells and makes new viruses inside the cells. In order to propagate to other cells, siliac acid existing outside the cells is cleaved with virus-generated neurominidase It is necessary. One of the best known treatments for avian influenza is Tamiflu, which is reported to be resistant to treatments such as Tamiflu, and development of new treatments is urgent. Resistant avian influenza viruses are known to occur through three genetic mutations (Arg292Lys, Asn274Ser, His294Tyr) that alter the amino acid of the receptor protein of the Tamiflu binding to the common Tamiflu. Among the three genetic mutations, Tamiflu-resistant avian influenza virus, 294 His, which is most frequently expressed as a variant of the influenza virus, has been converted to Tyr in cases where the hydrophobic residue of Tamiflu mutated to prevent binding to the Tamiflu receptor. Therefore, the emergence of these viruses provides the necessity for humans to continuously develop new viral therapeutic agents.
일반적으로 새로운 성분의 약제를 개발하기 위해 기존 약제를 실험적으로 변형시키는 것보다는 전통 의학에서 사용되고 있는 천연물 약제들로부터 새로운 활성성분을 찾는 것이 여러가지 면에서 장점이 많다. 특히 이러한 활성 성분들은 오랫동안 사용되어 왔기 때문에 약물들에 의한 독성 염려가 적다. 이러한 사실은 타미플루도 출발물질은 중국의 토착식물인 '스타아니스' 열매를 주원료로 개발한 것에서 확인할 수 있다. Rather than experimentally transforming existing medicines to develop new medicines in general, finding new active ingredients from natural medicines used in traditional medicine has many advantages. Particularly, these active ingredients have been used for a long time and thus they are less toxic to the drugs. This fact can be seen from the fact that Tamiflu was also developed as a main ingredient of star anise, an indigenous plant of China.
꿀벌의 종류는 일반적으로 서양종꿀벌(Apis mellifera), 동양종꿀벌(Apis cerana), 인도최대종(Apis dorsata), 인도최소종(Apis florea) 등 4개의 종이 알려져 있다. 이 중 현재 우리나라에는 서양종꿀벌과 동양종 꿀벌이 서식하고 있다. 특히 동양종꿀벌은 고려시대부터 사육되기 시작하였으며, 민간과 한방에서 봉침요법으로 사용되어져 왔다. 그러나 서양종꿀벌은 이탈리안 계통 일벌로서 조선시대 고종황제시기에 독일인 선교사에 의해 1892년경에 우리나라에 도입되어 사육되고 있다. 봉독은 벌의 독낭에 들어있는 것으로, 약 40여 가지의 물질로 이루어져 있으며 기원전부터 인체의 질병치료에 이용되어 왔다. 봉독은 벌의 종류에 따라 그 성분에 차이를 보이며, 동일한 벌이라도 일령에 따라 성분의 차이가 발생한다. 현재 봉독 성분에 따른 작용과 기전, 봉독의 과민성과 독성, 면역요법 및 관절염, 단순포진, 다발성 경화증, 종양 등의 질병 치료 등에 대한 연구가 보고되고 있으며 특히 항균작용과 세포 손상개선효과를 갖고 있는 것으로 알려져 있다.There are four species of bees: Apis mellifera , Apis cerana , Apis dorsata , Apis florea , and so on. At present, there are western and oriental bees in Korea. Especially, oriental bees have been reared since the Goryeo Dynasty, and have been used as a needle therapy in the private sector and in the oriental medicine. However, the western varieties of bees were introduced into Korea in 1892 by German missionaries during the Emperor Gojong period of Joseon Dynasty. Bee venom is contained in the bee venom of the bee, which is composed of about 40 substances and has been used for the treatment of diseases of the human body since BC. The bee venom shows differences in its components depending on the bees, and even in the same bee, there is a difference in composition depending on the age. Currently, studies on the action and mechanism of bee venom component, sensitivity and toxicity of bee venom, immunotherapy and treatment of diseases such as arthritis, herpes simplex, multiple sclerosis and tumor have been reported. Especially, It is known.
본 발명자들은 이러한 정제봉독이 갖는 다양한 생리활성을 연구하던 중, 상기 정제봉독이 조류 인플루엔자의 활성을 억제하는 효과가 있음을 확인하여 본 발명을 완성할 수 있었다. The present inventors have studied various physiological activities of the tablet bee venom, and confirmed that the tablet bee venom has the effect of inhibiting the avian influenza activity, thus completing the present invention.
본 발명의 목적은 봉독을 유효성분으로 포함하는 조류 인플루엔자의 예방 또는 치료용 조성물을 제공하는 데에 있다. It is an object of the present invention to provide a composition for preventing or treating avian influenza comprising bee venom as an active ingredient.
본 발명은 봉독을 유효성분으로 포함하는 조류 인플루엔자의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for preventing or treating avian influenza comprising bee venom as an active ingredient.
상기 봉독은 서양종꿀벌(Apis mellifera L.) 일벌의 독낭에서 분리한 정제봉독일 수 있다. 이 때, 상기 일벌은 15일령 이상의 일벌인 것이 바람직하다. The bee venom can be a purified rod isolated from a bee venom of the bees ( Apis mellifera L.). At this time, it is preferable that the worker bees are at least 15 days old.
또한 봉독을 유효성분으로 포함하는 조류 인플루엔자의 예방 또는 개선용 건강기능식품에 관한 것이다. The present invention also relates to a health functional food for preventing or ameliorating avian influenza comprising bee venom as an active ingredient.
상기 건강기능식품은 각종 드링크제, 육류, 소세지, 빵, 캔디류, 스넥류, 면류, 아이스크림, 유제품, 스프, 이온음료, 음료수, 알코올 음료, 껌, 차 및 비타민 복합제에서 선택되는 것을 특징으로 한다. The health functional food is characterized in that it is selected from various drinks, meat, sausage, bread, candy, snack, noodle, ice cream, dairy product, soup, ionic drink, beverage, alcoholic beverage, gum, tea and vitamin complex.
또한 액상의 제형을 갖는 건강기능식품 내의 봉독 농도는 0.5~10 ㎎/㎖인 것이 좋다. 바람직하게는 0.5~5.0 ㎎/㎖인 것이 좋다. 더 바람직하게는 0.5~1.5 ㎎/㎖인 것이 좋다. 가장 바람직하게는 1.0 ㎎/㎖인 것이 가장 좋다. The bee venom concentration in the health functional food having a liquid formulation is preferably 0.5 to 10 mg / ml. And preferably 0.5 to 5.0 mg / ml. More preferably 0.5 to 1.5 mg / ml. Most preferably 1.0 mg / ml.
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 봉독은 정제봉독으로서, 채집하는 과정은 통상의 양잠농가에서 사용하는 방법을 사용할 수 있다. 특히, 봉독 외의 이물질인 당류와 휘발성물질을 제거하여 얻은 정제봉독인 것으로서, 자세하게는 상기 정제봉독은 서양종꿀벌의 15일령 이상 일벌의 독낭에서 봉독채집장치를 이용하여 분리한 봉독에서 봉독 외의 이물질인 당류와 휘발성물질을 제거하여 얻은 것일 수 있다. The bee venom of the present invention is a tablet bee venom, and the collecting process may be a method used in a conventional silkworm farm. Specifically, the tablet bee venom obtained by removing saccharides and volatile substances, which are foreign substances other than bee venom, is described in detail. In detail, the purified bee venom is a bee venom which is separated from bee venom by bee venom collection apparatus in beeswax of more than 15 days old, And volatile substances.
본 발명은 또한 상기 서양종꿀벌(Apis mellifera) 일벌의 독낭에서 분리한 봉독을 유효성분으로 포함하는 조류 인플루엔자의 예방 또는 치료용 약학 조성물을 제공한다. 상기 봉독은 본 발명의 약학 조성물에 0.001~99.9 중량%로 하여 첨가될 수 있다. The present invention also provides a pharmaceutical composition for the prevention or treatment of avian influenza comprising bee venom isolated from a bee venom of the bees of the Western species ( Apis mellifera ). The bee venom may be added to the pharmaceutical composition of the present invention in an amount of 0.001 to 99.9% by weight.
본 발명의 약학 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 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 본 발명의 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 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 단순희석제인 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, 폴리에틸렌글리콜, 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 pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method. Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is 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 or 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 use 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 발명의 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 투여받을 대상이 갖고 있는 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex and weight of the subject to be treated, the specific disease or condition to be treated, the severity of the disease or pathological condition, the route of administration and the judgment of the prescriber. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
본 발명의 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. 본 발명의 조성물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있다. The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. Since the composition of the present invention has little toxicity and side effects, it can be safely used for prolonged use for preventive purposes.
한편, 이상과 같은 약학 조성물에 대한 특징은 조류 인플루엔자의 예방 또는 치료용 동물약품에 적용될 때에도 동일하게 적용된다. On the other hand, the above-mentioned characteristics of the pharmaceutical composition apply equally to animal medicine for the prevention or treatment of avian influenza.
본 발명의 조성물은 동물 사료 첨가제로서 적용될 수 있는데, 동물 사료 100 중량부를 기준으로 0.001~10 중량부로 첨가될 수 있다. The composition of the present invention may be applied as an animal feed additive, and may be added in an amount of 0.001 to 10 parts by weight based on 100 parts by weight of animal feed.
또한, 본 발명은 상기 봉독 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 조류 인플루엔자의 예방 또는 개선용 건강기능식품을 제공한다. 이 때, 봉독은 본 발명의 건강기능식품에 0.001~100 중량%로 하여 첨가될 수 있다. 본 발명의 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 봉독을 첨가할 수 있는 식품으로는, 예를 들어, 각종 드링크제, 육류, 소세지, 빵, 캔디류, 스넥류, 면류, 아이스크림, 유제품, 스프, 이온음료, 음료수, 알코올 음료, 껌, 차 및 비타민 복합제 등이 있다. The present invention also provides a health functional food for preventing or ameliorating avian influenza comprising the bee venom and food acceptable food additive additives. At this time, bee venom can be added to the health functional food of the present invention in an amount of 0.001 to 100% by weight. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquids. Examples of foods to which the bee venom of the present invention can be added include various drinks, meat, sausage, bread, Snacks, noodles, ice cream, dairy products, soups, ionic drinks, beverages, alcoholic beverages, gums, tea and vitamin complexes.
본 발명은 봉독을 함유하는 조성물에 관한 것으로서, 상기 봉독이 포함된 조성물은 H9N2 바이러스의 활성을 억제하는 효과가 우수하여 조류 인플루엔자를 예방 또는 치료할 수 있는 약학 조성물, 식품 조성물, 동물약품, 사료 첨가제 조성물 등으로 용이하게 사용될 수 있다. 대한민국 등록특허 제10-1553109호와 대한민국 등록특허 제10-1596344호에 봉독이 자궁경부암이나 뉴캐슬병 등의 원인이 되는 바이러스의 억제 효과가 있음이 개시되어 있지만, 아직까지 봉독의 조류 인플루엔자에 대한 항바이러스 효과는 개시된 바 없다. The present invention relates to a composition containing bee venom, wherein the bee venom-containing composition is excellent in the effect of inhibiting the activity of H9N2 virus, so that a pharmaceutical composition, a food composition, an animal medicine, and a feed additive composition capable of preventing or treating avian influenza And the like. Korean Patent No. 10-1553109 and Korean Patent No. 10-1596344 disclose that bee venom has an inhibitory effect on viruses causing cervical cancer and Newcastle disease. However, The effect has not been disclosed.
도 1은 봉독채집장치를 이용하여 봉독을 채집하는 과정을 나타내는 사진이다.
도 2는 꿀벌의 일령별로 독낭을 액체크로마토그래피 분석하여 봉독 성분의 분포를 확인한 크로마토그램 결과이다.
도 3은 꿀벌의 일령에 따른 독낭을 액체크로마토그래피 분석하여 독낭 내의 봉독 함량을 나타낸 그래프이다.
도 4는 15일령 이상된 일벌에서 채집한 정제봉독봉독의 정제 전(도 4의 좌측) 및 정제 후(도 4의 우측) 사진(도 4의 상단)과 이를 전자현미경으로 관찰한 사진(도 4의 하단)을 나타낸다.
도 5는 초고성능액체크로마토그래피(UPLC)를 이용하여 정제봉독 내에 봉독의 표준물질인 아파민, 포스포리파아제 A2, 아돌라핀, 히알루니다아제 및 멜리틴이 존제하는지 확인한 결과를 나타내는 크로마토그램이다.
도 6은 정제봉독의 항바이러스 효과를 EID50(Egg Infectious Dose)로 산출하여 나타낸 결과값의 그래프이다(1~3차 평균 log EID50/㎖).
도 7은 정제봉독의 항바이러스 효과를 EID50(Egg Infectious Dose)로 산출하여 나타낸 결과값을 대조군과 대비하여 나타낸 그래프이다(1~3차 평균 log EID50/㎖reduction).1 is a photograph showing a process of collecting bee venom using a bee venom collecting device.
FIG. 2 is a chromatogram showing the distribution of the bee venom components by liquid chromatography analysis of the capsular bag by the ages of bees.
FIG. 3 is a graph showing the bee venom contents in the viscus by liquid chromatography analysis of the viscus according to the age of bees.
Fig. 4 is a photograph (left side of Fig. 4) (left side of Fig. 4) and a photograph (right side of Fig. 4) of the tablet bean poison beet collected from a 15- .
FIG. 5 is a chromatogram showing the results of confirming whether the bean sprouts used as the bee venom reference agents, afalmine, phospholipase A2, adolapine, hyaluronidase and melittin are present in purified bee venom using ultra high performance liquid chromatography (UPLC).
FIG. 6 is a graph showing the antiviral effect of tablet bee venom as calculated by EID 50 (Egg Infectious Dose) (1st to 3rd average log EID 50 / ml).
FIG. 7 is a graph showing the antiviral effect of tablet bee venom as calculated by EID 50 (Egg Infectious Dose) in comparison with the control group (1st to 3rd average log EID 50 / ml).
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나, 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지도록, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다. Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.
<실시예 1. 정제봉독의 제조>≪ Example 1: Preparation of tablet bee venom &
서양종꿀벌(Apis meliffera L.)을 봉독채집장치를 이용하여 봉독을 채집하되, 성충이 된 시간이 1시간 이내인 일벌, 3~8일령인 일벌, 9~14일령인 일벌, 15일령 이상된 일벌에서 각각 봉독을 별도로 채집하였고, 봉독의 간이정제방법을 통해 당류와 휘발성물질을 제거함으로써 순수한 수용성을 갖는 정제 봉독 건조물을 제조하였다. 도 1에는 이와 같은 봉독채집장치를 이용한 봉독 채집과정이 개시되어 있다. Collecting bee venom from bee venom using bee venom collecting device of western bees ( Apis meliffera L.), bees with an adult time of less than 1 hour, worker bees of 3 to 8 days, worker bees of 9 to 14 days, Respectively, and purified bee venom dried beverages with pure water solubility were prepared by removing saccharides and volatile substances through a simple purification method of bee venom. FIG. 1 shows a bee venom collecting process using such a bee venom collecting device.
한편, 각 일령별 꿀벌의 독낭 내의 봉독 함량을 확인한 바, 도 2 및 도 3에 개시된 것처럼, 15일령 이상된 일벌의 독낭에서 순수한 봉독의 함유량이 가장 높았이다. 따라서 본 발명에서는 15일령 이상된 일벌에서 채집된 정제봉독을 실험에 사용하기로 하였다. 이렇게 얻은 정제봉독 분말은 2~8℃에서 빛이 차단되도록 알루미늄 호일로 포장하여 보관하였다. On the other hand, when the bee venom contents of the bee venom of each day were checked, as shown in Fig. 2 and Fig. 3, the pure bee poison content was the highest in the tourniquet of the bees of more than 15 days old. Therefore, in the present invention, tablet bee venom collected from worker bees over 15 days of age will be used for the experiment. Tablet bee powder thus obtained was packed with aluminum foil so that the light was blocked at 2 ~ 8 ° C.
<실시예 2. 정제봉독의 성분 확인을 위한 초고성능액체크로마토그래피 분석>≪ Example 2: Ultra high performance liquid chromatography analysis for confirming the components of tablet bee venom &
15일령 이상된 일벌에서 채집한 정제봉독 40 ㎎을 3차 증류수 10 ㎖에 녹여 PTFE 0.2 μm필터로 여과하였고, 아파민, 멜리틴, 포스포리파아제 A2, 아돌라핀, 히알루니다아제 표준품을 동일하게 3차 증류수에 녹여 2 ㎎/㎖로 만들어 시험봉독과 동일한 필터를 사용하여 여과하여 준비하였다. 봉독 성분 분석은 초고성능액체크로마토그래피(UPLC)하여 확인하였으며, 분석기기는 Waters 회사의 I class 모델을 사용하였고, Advanced materials technology사의 Halo peptide ES-C18(입자크기: 2.7 μm, 내경: 4.6mm, 길이: 10 cm) 컬럼을 장착하였다. 이동상으로는, A용액: 20 mM 트리플루오르아세트산(TFA)의 아세토나이트릴(MeCN) 용액과, B용액: 20 mM 트리플루오르아세트산(TFA)의 수용액을 혼합한 혼합용액을 이용하였다. 상기 혼합용액은 이동시간이 3분 미만일 때는 A용액이 10 부피% 이상 31 부피% 미만, 이동시간이 3분 이상에서 5분 미만일 때는 A용액이 31 부피% 이상 40 부피% 미만, 이동시간이 5분 이상에서 10분 이하일 때는 A용액이 40 부피% 이상에서 45 부피% 이하가 되도록 B용액과 혼합하여 사용하였다. 이동상의 흐름속도는 1.5 ㎖/min이고, 시료 주입량은 4 ㎕이며 자외부 흡광광도계 파장은 220 nm로 설정하였으며 분석시 컬럼의 온도는 50℃로 조절하였다. 검출한계는 ICH 가이드라인(International Conference on Harmonisation guideline)에 따라 산출하였다. 상기 조건은 다시 하기 표 1에 자세하게 나타내었다. 40 mg of purified bee venom collected from 15-day old or older bees was dissolved in 10 ml of distilled water and filtered through a 0.2 μm PTFE filter. The standard of apamin, melittin, phospholipase A2, adalapine and hyaluronidase Dissolved in tea distilled water to make 2 mg / ml and prepared by filtration using the same filter as the test bee venom. Analysis of the bee venom components was carried out by ultra high performance liquid chromatography (UPLC). Analytical instruments were the I class model of Waters Company and Halo peptide ES-C18 (particle size: 2.7 μm, inner diameter: 4.6 mm, Length: 10 cm). As the mobile phase, a solution A: a mixed solution obtained by mixing an acetonitrile (MeCN) solution of 20 mM trifluoroacetic acid (TFA) and an aqueous solution of B solution: 20 mM trifluoroacetic acid (TFA) was used. When the migration time is less than 3 minutes, the solution A is less than 31% by volume and when the migration time is less than 3 minutes and less than 5 minutes, the solution A is less than 40% by volume and the migration time is 5 Min and less than 10 minutes, the solution A was mixed with the solution B so that the volume ratio of the solution A was not less than 40 vol.% And not more than 45 vol.%. The flow rate of the mobile phase was 1.5 ml / min, the injection amount of the sample was 4 μl, and the wavelength of the ultraviolet absorptiometer was set at 220 nm. The temperature of the column was adjusted to 50 ° C during the analysis. The detection limits were calculated according to the ICH guidelines (International Conference on Harmonization Guideline). The above conditions are shown in detail in Table 1 below.
(A) 0-3 min:10-31부피%/ 3-5 min:31-40부피%/ 5-10 min:40-45부피% (A) 20 mM TFA / MeCN, (B) 20 mM TFA / H 2 O
(A) 0-3 min: 10-31 vol% / 3-5 min: 31-40 vol% / 5-10 min: 40-45 vol%
이렇게 분석한 정제봉독 수용액의 분석결과는 표준품 용액과의 피크 비교를 통해 도 5에 나타내었으며, 상기 정제봉독 수용액 내의 아파민, 멜리틴, 포스포리파아제 A2, 아돌라핀, 히알루니다아제 함량은 하기 표 2에 나타내었다. The analytical results of the thus-analyzed aqueous solutions of purified bee venom were shown in FIG. 5 through comparison of peaks with standard solutions, and the content of ampholytic, melittin, phospholipase A2, adolapine and hyaluronidase Respectively.
<실시예 3. 시료의 준비>≪ Example 3: Preparation of sample &
실시예 3-1. 종란 및 계혈(Chicken blood)의 준비Example 3-1. Preparation of Blood and Chicken Blood
7일령 SPF 종란(Chicken embryo)을 구입(경기도 화성, 성민축산)하여 실험 전까지 부화기(38℃)내 보관하고, 9일째 생존상태의 것만 바이러스 배양용으로 사용하였다(실험 도중 죽은 종란은 냉장보관 또는 접종 자체가 원인이 된 것이며, 검란용 라이트를 사용하여 생존상태를 확인함). 10%(v/v) 닭 날개에서 채취한 Chicken blood는 PBS(Phosphate Buffer Solution, Gibco, USA)를 이용하여 0.5%(v/v) 용액이 되도록 희석하였다(희석된 용액은 1주일 동안 사용가능함).7 days old SPF chick embryo was purchased (Seongmin Livestock, Gyeonggi-do, Hwaseong, Gyeonggi-do) and kept in the incubator (38 ℃) until the experiment. Only the virus surviving on the 9th day was used for virus culture It is caused by the inoculation itself, and the survival status is confirmed by using a lighter light). Chicken blood from 10% (v / v) chicken wings was diluted to 0.5% (v / v) solution with PBS (Phosphate Buffer Solution, Gibco, USA) ).
실시예 3-2. 인플루엔자 바이러스의 준비Example 3-2. Preparation of influenza virus
실험에 사용한 조류 인플루엔자 바이러스는 저병원성 조류 인플루엔자 바이러스인 A/chicken/Korea/MS96/96(H9N2)을 사용하였다(건국대학교 분양). 이것을 9일령 종란의 요막강 내의 요막액(allantoic fluid)에 0.2ml씩 접종(5개, 1㎖ syringe)하고, 38℃에서 2일간 배양하였다(배양 도중 죽은 종란은 폐기함). 2일간의 배양 후, 11일령이 된 종란의 온도를 4℃로 낮춘 후 요막액을 수집하여 3,000rpm에서 5분간 원심분리하고 상층액만을 채취하였다. 채취된 상층액을 1.1㎖ 씩 분주 후 사용 전까지 40℃에 보관하였다. 실험직전에는 -40℃ 보관 중인 바이러스 배양액을 상온에서 녹인 후, PBS(Phosphate Buffer Solution, Gibco, USA)를 이용하여 10-1 ~ 10-8 EID50/㎖으로 10배씩 연속 희석 후 사용하였다. A / chicken / Korea / MS96 / 96 (H9N2) was used as an avian influenza virus (Avian influenza virus). This was inoculated (5 ml, 1 ml syringe) to allantoic fluid in the umbilical membrane of 9-day-old cattle and incubated for 2 days at 38 ° C (discard dead cells during culture). After 2 days of incubation, the temperature of the 11-day-old bovine pox was lowered to 4 ° C, and the supernatant was collected and centrifuged at 3,000 rpm for 5 minutes, and only supernatant was collected. 1.1 ml of the supernatant was dispensed and stored at 40 ° C until use. Immediately before the experiment was used after being dissolved in -40 ℃ storage viral culture medium at room temperature, PBS (Phosphate Buffer Solution, Gibco , USA) to 10 -1 ~ 10 -8 EID 50 / ㎖ to 10-fold dilution after continuous use.
실시예 3-3. 정제봉독 수용액의 준비Example 3-3. Preparation of purified beaked aqueous solution
실시예 1에서 얻은 정제봉독 분말을 2차 증류수(D.W) 50ml를 이용해 녹인 후 3,000rpm 10min 원심분리 후 0.2um syringe filter(Coring, German)를 이용하여 불순물을 제거한 후, 실험 직전에 2차 증류수(D.W; Distilled water)를 이용하여 농도별로 희석하여 수용액 상태로 제조하였다(봉독 농도 : 32, 16, 8, 4, 2, 1㎍/㎖). The purified beexotic powder obtained in Example 1 was dissolved in 50 ml of distilled water (DW), centrifuged at 3,000 rpm for 10 min, and then impurities were removed using a 0.2 μm syringe filter (Coring, German) DW (distilled water), and the solution was diluted with water to prepare an aqueous solution (bee venom concentration: 32, 16, 8, 4, 2, 1 μg / ml).
<실시예 4. 항바이러스 활성 억제 효과 확인> ≪ Example 4: Confirmation of antiviral activity inhibitory effect >
각 희석배수별 바이러스(10-1 ~ 10-8 EID50/㎖) 500㎕와 농도별 봉독 500㎕씩을 혼합하여 시료를 준비하였다. 음성 대조군(negative control)은 희석배수별 바이러스 500㎕와 PBS 500㎕를 혼합하였고, 양성 대조군(positive control)은 조류 인플루엔자 감소효력이 증명된 소독제(유효성분 : 이염화이소시아뉼산나트륨[NaDCC 0.01%])와 바이러스 혼합하여 사용하였다. 모든 실험은 [농림축산검역본부 고시 제2016-29호, '16.3.9.]의 소독제 효력시험지침에 따라 표준조건 하에서 진행하였다. ※ 소독제는 제조회사의 권장희석배수에 맞추어 희석 후 사용함. 500 μl of each virus (10 -1 to 10 -8 EID 50 / ml) was mixed with 500 μl of bee venom at each concentration to prepare samples. The positive control was a disinfectant (effective ingredient: sodium dodecylisocyanate sodium [NaDCC 0.01%]), which was proved to be effective in reducing avian influenza. ) And viruses. All experiments were carried out under standard conditions according to the disinfectant efficacy test guidelines of [Ministry of Agriculture, Forestry and Livestock Quarantine Administration Notice 2016-29, '16 .3.9.]. ※ The disinfectant is used after diluting to the dilution ratio recommended by the manufacturer.
각 시료를 주사기(1㎖, Korea Vaccine, Korea)를 이용하여 0.1㎖씩 9일령 종란의 요막강 내 요막액에 접종하였다. Each sample was inoculated into the urokinate urokinase solution of the 9-day-old bovine using 0.1 ml of syringe (1 ml, Korea Vaccine, Korea).
접종된 종란은 1회 실험당 240 eggs[바이러스 희석배수(8set) × 봉독 희석배수(6set) × 접종 종란(5set)]를 사용하였고, 대조군 그룹(control group)에 30 eggs를 사용하였고, 본 실험조건을 3번 반복하여, 총 810 eggs(270 eggs × 3)를 사용하였다. 접종된 종란은 38℃ 배양기 내에서 48시간 보관하였고, 도중에 죽은 종란(냉장보관사 또는 접종사 원인)은 폐기하였다.Inoculated birds were used in a total of 240 eggs (8 sets of virus dilution × 6 sets of inoculation × 5 sets of inoculated eggs) per experiment and 30 eggs were used in the control group. The condition was repeated 3 times and a total of 810 eggs (270 eggs x 3) was used. The inoculated bovine embryos were stored for 48 hours in a 38 ° C incubator and the dead bovine (refrigerated or inoculated) died.
이렇게 48시간 보관 된 종란 내에서 요막액을 1㎖ 씩 회수하여 micro haemagglutination(HA) test를 수행하였다. In this way, microalgaemogglutination (HA) test was performed by collecting 1 ml of urogenous solution in a stock maintained for 48 hours.
이를 위해 96well U-type cell culture plate(SPL, Korea)에 각 종란에서 얻은 요막액 50㎕와 0.5% chicken blood 50㎕를 반응하게 하여 35~40분 후 응집 유무 관찰을 통해 감염 여부 확인하였다. 응집이 일어난 것은 적혈구가 well 전체에 골고루 퍼져있고 응집이 일어나지 않은 것은 혈구가 가운데로 모여 단추 모양 (⊙)을 이루고 있다. 최종 결과 판정은 plate를 45° 기울여서 흐르는 것을 기준으로 판정한다. 응집결과는 EID50(Egg Infectious Dose)로 산출하여 나타내었고, Reed and Muench mathematical technique를 이용하여 계산하였으며, 산출된 EID50 값은 log10 변환 후 표시하였다. For this, 50 μl of urothelial fluid and 50 μl of 0.5% chicken blood were incubated in a 96-well U-type cell culture plate (SPL, Korea) for 35-40 min. The coagulation occurred when the red blood cells spread evenly throughout the well and the coagulation did not occur because the blood cells gathered in the middle and formed a button shape (⊙). The final result determination is based on a 45 ° tilt of the plate. The aggregation results were calculated using EID 50 (Egg Infectious Dose), calculated using the Reed and Muench mathematical technique, and the calculated EID 50 values were expressed after log 10 transformation.
이에 대한 실험결과의 평균값을 하기의 표 3에 나타내었고 이를 도 6에 그래프로서 표시하였다. 표 3과 도 6의 기준값은 log EID50/㎖이다. The average value of the experimental results is shown in Table 3 below and is shown in FIG. 6 as a graph. The reference values in Table 3 and FIG. 6 are log EID 50 / ml.
표 4는 표 3의 값을 음성대조군(N.C)에 대한 값으로 환산하여 나타낸 것으로 이에 대한 값도 역시 도 7에 그래프로서 표시하였다. 표 4와 도 7의 기준값은 log EID50/㎖ reduction이다. Table 4 shows the values of Table 3 in terms of values for the negative control (NC) values, which are also shown graphically in FIG. The reference values in Table 4 and Figure 7 are log EID 50 / ml reduction.
표 3과 도 6, 표 4와 도 7의 결과를 참고하여, 봉독이 농도 의존적으로 조류 인플루엔자의 활성을 현저하게 억제함을 알 수 있다. Referring to the results of Table 3, FIG. 6, Table 4 and FIG. 7, it can be seen that bee venom significantly inhibited the avian influenza activity in a concentration-dependent manner.
<제제예 1. 약학적 제제>≪ Formulation Example 1 >
제제예 1-1. 정제의 제조Formulation Example 1-1. Manufacture of tablets
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독 200g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다. 200 g of purified bee venom collected from the bees of the western species of bees aged 15 days or more in Example 1 of the present invention were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
제제예 1-2. 주사액제의 제조Formulation Example 1-2. Injection preparation
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.1 g of tablets of bee venom, 0.6 g of sodium chloride and 0.1 g of ascorbic acid, which were collected from bees of a western species of bees aged 15 days or more in Example 1 of the present invention, were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20 DEG C for 30 minutes.
<제제예 2. 식품 제조><Formulation Example 2: Food Preparation>
제제예 2-1. 조리용 양념의 제조Formulation Example 2-1. Manufacture of cooking seasonings
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독을 조리용 양념에 1 중량%로 첨가하여 건강 증진용 조리용 양념을 제조하였다.Tablet bean poison taken from a bee of a Western species of bees aged 15 days or more in Example 1 of the present invention was added to the cooking seasoning at 1 wt% to prepare a cooking sauce for health promotion.
제제예 2-2. 밀가루 식품의 제조Formulation Example 2-2. Manufacture of flour food products
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독을 밀가루에 0.1 중량%로 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.The bee venom collected from the bees of the western species of bees aged 15 days or more in Example 1 of the present invention was added to flour at 0.1 wt% and bread, cake, cookies, crackers and noodles were prepared using the mixture to prepare health promotion foods .
제제예 2-3. 스프 및 육즙(gravies)의 제조Preparation Example 2-3. Manufacture of soups and gravies
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독을 스프 및 육즙에 0.1 중량%로 첨가하여 건강 증진용 수프 및 육즙을 제조하였다.The health enhancing soup and the juice were prepared by adding 0.1% by weight of purified beacon collected from the bees of the western species of bees aged 15 days or more in Example 1 of the present invention to the soup and the juice.
제제예 2-4. 유제품(dairy products)의 제조Formulation Example 2-4. Manufacture of dairy products
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독을 우유에 0.1 중량%로 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.The bee venom collected from the bees of the western species of bees aged 15 days or more in Example 1 of the present invention was added to milk at 0.1 wt%, and various dairy products such as butter and ice cream were prepared using the milk.
제제예 2-5. 야채주스 제조Formulation Example 2-5. Vegetable juice manufacturing
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독 0.5g을 토마토주스 또는 당근주스 1,000㎖에 가하여 건강 증진용 야채주스를 제조하였다.The vegetable juice for health promotion was prepared by adding 0.5 g of tablets bee venom collected from the bees of the western species of bees aged 15 days or more in Example 1 of the present invention to 1,000 ml of tomato juice or carrot juice.
제제예 2-6. 과일주스 제조Formulation Example 2-6. Manufacture of fruit juice
본 발명의 실시예 1의 15일령 이상의 서양종꿀벌의 일벌에서 채취한 정제봉독 0.1g을 사과주스 또는 포도주스 1,000㎖에 가하여 건강 증진용 과일주스를 제조하였다.Health enhancing fruit juice was prepared by adding 0.1 g of purified bee venom collected from a worker bees of a Western species of bees aged 15 days or more in Example 1 of the present invention to apple juice or grape juice 1,000 ml.
Claims (7)
봉독은 서양종꿀벌(Apis mellifera L.) 일벌의 독낭에서 분리한 정제봉독인 것을 특징으로 하는 H9N2형 조류 인플루엔자의 예방 또는 치료용 조성물.The method according to claim 1,
A composition for preventing or treating H9N2 avian influenza characterized in that bee venom is a purified bee venom isolated from a bee venom of a western bees ( Apis mellifera L.).
상기 일벌은 15일령 이상의 일벌인 것을 특징으로 하는 H9N2형 조류 인플루엔자의 예방 또는 치료용 조성물.3. The method of claim 2,
The composition for preventing or treating H9N2 avian influenza characterized in that said worker bees are at least 15 days old.
상기 건강기능식품은 각종 드링크제, 육류, 소세지, 빵, 캔디류, 스넥류, 면류, 아이스크림, 유제품, 스프, 이온음료, 음료수, 알코올 음료, 껌, 차 및 비타민 복합제에서 선택되는 것을 특징으로 하는 H9N2형 조류 인플루엔자의 예방 또는 개선용 건강기능식품. 5. The method of claim 4,
The health functional food is selected from a variety of drinks, meats, sausages, breads, candies, snacks, noodles, ice cream, dairy products, soups, ionic drinks, beverages, alcoholic beverages, gums, tea and vitamin complexes. Health functional food for prevention or improvement of influenza.
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