JP2013060455A - Composition using bee venom as active ingredient - Google Patents
Composition using bee venom as active ingredient Download PDFInfo
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- JP2013060455A JP2013060455A JP2012261417A JP2012261417A JP2013060455A JP 2013060455 A JP2013060455 A JP 2013060455A JP 2012261417 A JP2012261417 A JP 2012261417A JP 2012261417 A JP2012261417 A JP 2012261417A JP 2013060455 A JP2013060455 A JP 2013060455A
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- Prior art keywords
- bee venom
- composition
- skin
- growth factor
- active ingredient
- Prior art date
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Abstract
Description
本発明は、ハチ毒を有効成分とする組成物に関する。 The present invention relates to a composition containing bee venom as an active ingredient.
皮膚の外傷や火傷後の正常な創傷治癒過程は、止血段階、炎症段階、増殖段階及び創傷収縮段階を経るが、各段階で正常な均衡が起こらない場合、創傷治癒が遅くなったり、創傷治癒後に傷跡が残ったりしてしまう。創傷治癒の各過程には、炎症細胞、角質細胞及び線維芽細胞などから分泌される様々な種類の成長因子又はサイトカインが作用して、創傷治癒に関与する。即ち、創傷治癒過程では、創傷部位の炎症細胞が分泌する媒介体の信号によりマクロファージが創傷部位に集まり、サイトカインなどを分泌すると、創傷部位で線維芽細胞などの移動と増殖を進行させながら、損傷された創傷部位の真皮層が基質を形成して、創傷部位が治癒される。反面、２次感染などにより炎症細胞などの異常増殖がある創傷には、ＴＮＦ−α及びインターロイキン−８など様々な種類の炎症誘導性サイトカインなどが分泌されながら、角質層形成細胞などの増殖速度を低下させ、瘢痕形成のおそれが生じる。従って、瘢痕の矯正は、皮膚再生と合せて非常に重要な問題である。このような瘢痕の矯正又は大きさを減少させるための努力は継続的に行われており、特に、免疫学、結合組織の生化学及び細胞の成長因子などに対する理解及び発達と共に、最近相当な研究が進められているが、皮膚再生において瘢痕をなくす方法は未だ見つかっていない。 The normal wound healing process after skin trauma or burn goes through the hemostasis stage, inflammation stage, proliferation stage and wound contraction stage, but if normal balance does not occur in each stage, wound healing slows down or wound healing Scars will remain afterwards. In each process of wound healing, various types of growth factors or cytokines secreted from inflammatory cells, keratinocytes, fibroblasts and the like act to participate in wound healing. That is, in the wound healing process, macrophages gather at the wound site due to signals from mediators secreted by inflammatory cells at the wound site and secrete cytokines, etc., while the migration and proliferation of fibroblasts and the like progress at the wound site. The dermal layer of the wound site forms a matrix and the wound site is healed. On the other hand, wounds with abnormal growth of inflammatory cells due to secondary infection, etc. are secreted with various types of inflammation-inducing cytokines such as TNF-α and interleukin-8, and the growth rate of stratum corneum forming cells and the like. Lowers the risk of scar formation. Therefore, the correction of scars is a very important issue along with skin regeneration. Efforts to correct or reduce the size of such scars are continually undertaken, especially recently with considerable understanding and development in immunology, connective tissue biochemistry and cell growth factors, etc. However, a method for eliminating scars in skin regeneration has not yet been found.
更に、皮膚火傷は、重度の浮腫を誘発して、血管の透過性増加により血管内の静水圧が低下して虚血性損傷を引き起こすだけでなく、火傷した皮膚組織は部分層火傷及び全層火傷の場合、植皮術を施行しなければならないという困難も伴う。皮膚の火傷には、熱により細胞が破壊され、組織が壊死した熱損傷による全身的な熱液力学的、代謝的、栄養学的及び免疫学的な観点で措置が必要であるため、様々な合成医薬品及び天然材料を成分とする治療剤が使用される。火傷が重度の場合は、無菌バセリンガーゼで傷を覆い、２次感染を防ぐためにペニシリン及びサルファ剤などを用いる抗生剤療法を長期間適用するのが一般的であるが、回復後にも外形上及び機能上、重度の後遺症が残るのが問題である。 In addition, skin burns not only induce severe edema and increase the permeability of the blood vessels to reduce the hydrostatic pressure in the blood vessels and cause ischemic damage, but the burned skin tissue can cause partial and full-thickness burns. In this case, there is also the difficulty of having to perform skin grafting. Various types of skin burns require treatment from the viewpoint of systemic thermohydraulic, metabolic, nutritional and immunological aspects due to thermal damage caused by thermal destruction of cells and tissue necrosis. Therapeutic agents composed of synthetic pharmaceuticals and natural materials are used. If the burn is severe, it is common to cover the wound with sterile vaseline gauze and apply antibiotic therapy using penicillin and sulfa drugs for a long time to prevent secondary infection. The problem is that severe sequelae remain.
更に、創傷若しくは火傷治療又は手術後の創傷感染は、最も多い合併症であり、回復期間を遅延させるだけでなく、死亡率が高い敗血症などの重度の合併症を招き、個人や国家間で莫大な経済的人的損失をもたらす。最も良い対策は予防であり、治療前後に無菌操作をし、免疫能力を増加させたり、抗生剤を投与したりすることである。しかし、最近、抗生剤の過信による既存抗生剤の乱用によって抗生剤の耐性菌が出現するため、未だに皮膚の創傷、火傷及び手術後の合併症の多い原因として細菌感染が占めている。 In addition, wound or burn treatment or wound infection after surgery is the most common complication, not only delaying the recovery period, but also causing severe complications such as high mortality sepsis, which is enormous among individuals and nations Cause significant economic and human loss. The best countermeasure is prevention, which involves aseptic manipulation before and after treatment to increase immunity and administer antibiotics. However, recently, due to overuse of existing antibiotics due to overconfidence of antibiotics, antibiotic-resistant bacteria have emerged, and bacterial infections still account for many causes of skin wounds, burns and post-operative complications.
マヌカハニーを含有する創傷治療用ドレッシングの場合、皮膚細胞の再生効果が非常に優れてはいるものの、瘢痕形成を減少させることができる効能は持っていない。また、蜂蜜の特性上、粘つきがあるため、患部に着用する時に不快感を与えることとなる。何よりも創傷による粘液が発生すると、酸度により蜂蜜の薬効が減少し、また、軟膏及びドレッシングなどの医薬品を製造する際に、ガンマ線及び高圧滅菌過程以降の薬効に対する安定性が確保されないという問題がある。 In the case of a dressing for wound treatment containing manuka honey, although the regeneration effect of skin cells is very excellent, it does not have the effect of reducing scar formation. In addition, because of the stickiness due to the characteristics of honey, it causes discomfort when worn on the affected area. Above all, when mucus is generated by a wound, the medicinal effect of honey decreases due to acidity, and when manufacturing pharmaceutical products such as ointments and dressings, there is a problem that stability against medicinal effects after gamma radiation and autoclaving is not ensured. .
一般に国内産（韓国）のミツバチ（Apis mellifera）のハチ毒は、電気衝撃法を利用したハチ毒採集装置を利用してミツバチの被害なく、純粋なハチ毒のみを多量に採取し、異物を除去した後、凍結乾燥して錠剤のハチ毒を得ることができる。このようにして得られたハチ毒は、多様な成分が複合的に構成されており、二重ペプチドが抗炎症と抗菌作用、強力な鎮痛作用及び免疫増強などの役割を担う。ハチ毒は、グラム陰性菌及び陽性菌に対
して抗菌作用を見せるが、特に、グラム陽性菌に対して抗菌作用がより強いことが知られている。ハチ毒に対する大部分の薬理作用は全体の毒成分及び単一主要成分群の活性に起因する。このようなハチ毒の成分及び効能は次のように知られている。
In general, bee venom from domestic (Korea) bees (Apis mellifera), using bee venom collection equipment using the electric shock method, collects a large amount of pure bee venom without damage, and removes foreign matter. After that, it can be freeze-dried to obtain a bee venom of a tablet. The bee venom thus obtained is composed of various components in a complex manner, and the double peptide plays a role such as anti-inflammatory and antibacterial action, strong analgesic action and immune enhancement. Bee venom shows antibacterial activity against gram-negative and positive bacteria, but is particularly known to have stronger antibacterial activity against gram-positive bacteria. Most pharmacological actions against bee venom result from the activity of the entire toxic component and a single major component group. The components and efficacy of such bee venom are known as follows.
第１に免疫系疾患の治療であり、大部分の免疫性疾患の治療にハチ毒は効果を見せ、これは、ハチ毒が哺乳動物の免疫系を刺激して疾病と成功裏に戦うことができるようにする。ハチ毒の主なる２種類の免疫作用は、有機体の生体系を刺激し、生体の防御力を増加させる。 The first is the treatment of immune system diseases, and bee venoms are effective in the treatment of most immune diseases, as they can successfully fight the disease by stimulating the immune system of mammals. It can be so. The two main types of immune effects of bee venom stimulate the organism's biological system and increase the defenses of the organism.
第２に抗炎症作用であり、ハチ毒の主成分が炎症抑制に非常に有効に作用する。特に、関節炎において、メリチンとアパミンとを注入した場合、著しく浮腫が抑制される。タンパク酵素抑制剤及びアドラピン処理の場合も、浮腫が１５〜４０％抑制される。 Secondly, it has an anti-inflammatory effect, and the main component of bee venom is very effective in suppressing inflammation. In particular, in arthritis, when melittin and apamin are injected, edema is remarkably suppressed. Also in the case of a protein enzyme inhibitor and an adrapine treatment, edema is suppressed by 15 to 40%.
第３に神経毒効果である。蜂に刺されると痛みと炎症を誘発し、この誘発物質は、哺乳動物においては回避反応、即ち、鎮痛剤を開発するのに効果的に使用される。特に、ハチ毒の中のアパミンが鎮痛作用を有しており、各種神経痛、関節炎及びリウマチ性関節炎、痛風並びに筋肉痛などに鎮痛作用が強く、治療効果も高い。 Third is the neurotoxic effect. When stung by a bee, it induces pain and inflammation, and this inducer is effectively used in mammals to develop an avoidance response, ie, an analgesic. In particular, apamin in bee venom has an analgesic action, has a strong analgesic action on various neuralgias, arthritis and rheumatoid arthritis, gout and muscle pain, and has a high therapeutic effect.
第４に溶血作用であり、ハチ毒の作用のうち最も優れた作用の一つが溶血作用である。メリチン及びホスホリパーゼなどの作用により、打撲症及び内出血などの溢血を吸収及び排泄させ、組織に新しい血液と酸素及び栄養とを供給して治療と溶血とを行う。 The fourth is hemolysis, and one of the most excellent effects of bee venom is hemolysis. The action of melittin and phospholipase absorbs and excrets extravasation such as bruises and internal bleeding, and supplies tissue with new blood, oxygen, and nutrients for treatment and hemolysis.
第５に血管拡張作用であり、ヒスタミン性物質の作用により、毛細血管、小動脈、小静脈、特に内臓血管を拡張させるのに効果が大きい。従って、冷え性、凍傷及び筋肉痛などの疾患を治療する。 Fifth, it is a vasodilatory effect, and is highly effective in dilating capillaries, small arteries, venules, especially visceral blood vessels, by the action of histamine substances. Accordingly, diseases such as coldness, frostbite and muscle pain are treated.
第６に血圧降下作用であり、ヒスタミン性物質の作用により、血圧を下げる強力な作用をする。特に、２億５千万分の１の濃度でも血圧降下作用があり、本態性高血圧などの治療に卓越な効果がある。 Sixth, it is a blood pressure lowering action, and has a powerful action to lower blood pressure by the action of histamine substances. In particular, even at a concentration of 1/250 million, it has a blood pressure lowering effect, and has an excellent effect on treatment of essential hypertension and the like.
第７に自律神経調節作用である。人体はストレスを受け続けると、交感神経及び副交感神経の自律神経の乱調が起こり、これが多くの病気の原因となる。この自律神経を正常化するのに必要な物資であるカテコールアミンとアセチルコリンとがハチ毒の中に含有されており、この物質は脳細胞伝達物質であるため、心身症、更年期障害及びストレス性疾患の治療に効果的である。 Seventh, it is an autonomic nerve regulating action. When the human body continues to be stressed, sympathetic and parasympathetic autonomic turbulence occurs, which causes many diseases. Since catecholamine and acetylcholine, which are materials necessary for normalizing this autonomic nerve, are contained in bee venom and this substance is a brain cell transmitter, psychosomatic disorders, climacteric disorders and stress-related diseases It is effective for treatment.
第８に抗菌作用であり、抗細菌及び抗真菌作用が非常に優れており、ウイルス性腫瘍などにも効果的である。特に、歯周炎、扁桃腺炎、麦粒腫及び化膿性疾患に対して治療効果が高い。 Eighth, it is an antibacterial action, has an excellent antibacterial and antifungal action, and is effective for viral tumors and the like. Particularly effective for periodontitis, tonsillitis, stye, and purulent disease.
本発明の発明者は、上記の作用の他にハチ毒の優れた皮膚再生に関わる表皮成長因子（ＥＧＦ）と血管内皮成長因子（ＶＥＧＦ）の発現促進能を見出して、これを有効成分とする新しい組成物を開発することで、本発明を完成するに至った。従って、本発明の目的は、皮膚細胞増殖の成長因子である表皮成長因子（ＥＧＦ）と血管内皮成長因子（ＶＥＧＦ）との発現を促進する組成物を得ること、及びその組成物を皮膚細胞の再生等に応用することにある。 The inventor of the present invention has found the ability to promote the expression of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) related to the excellent skin regeneration of bee venom in addition to the above action, and uses this as an active ingredient. By developing new compositions, the present invention has been completed. Accordingly, an object of the present invention is to obtain a composition that promotes the expression of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which are growth factors for skin cell proliferation, and to apply the composition to skin cells. It is to be applied to reproduction.
本発明は、０．０１μｇ／ｍＬ以上１μｇ／ｍＬ以下のハチ毒を有効成分として含み、適用された細胞内の表皮成長因子（ＥＧＦ）及び血管内皮成長因子（ＶＥＧＦ）の発現を促進するための組成物をその特徴とする。 The present invention includes bee venom of 0.01 μg / mL or more and 1 μg / mL or less as an active ingredient, and promotes the expression of applied intracellular epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). The composition is characterized.
本発明に係る組成物によると、皮膚細胞増殖の成長因子である表皮成長因子（ＥＧＦ）と血管内皮成長因子（ＶＥＧＦ）との発現を促進できて、皮膚細胞の促進等を可能とする。 According to the composition of the present invention, the expression of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which are growth factors for skin cell proliferation, can be promoted, and skin cells can be promoted.
従って、本発明の組成物は、重度の火傷と各種皮膚創傷又は各種皮膚疾患及び外傷とにより苦痛を受ける患者の治療だけでなく、ハチ毒の高付加価値用途の開発による養蜂農家の所得増大に寄与するだろう。 Therefore, the composition of the present invention not only treats patients suffering from severe burns and various skin wounds or various skin diseases and traumas, but also increases the income of beekeepers by developing high-value-added uses of bee venom. Will contribute.
本発明は、ハチ毒を有効成分とする組成物に関する。 The present invention relates to a composition containing bee venom as an active ingredient.
以下、前記組成物の成分について更に説明する。 Hereinafter, the components of the composition will be further described.
本発明の組成物は、抗炎症作用、神経毒作用、溶血作用、血管拡張作用、血圧降下作用及び自律神経調節作用などが優れており、免疫系疾患治療効果があると知られているハチ毒を有効成分として含む。 The composition of the present invention is superior in anti-inflammatory action, neurotoxic action, hemolysis action, vasodilator action, blood pressure lowering action, autonomic nerve regulating action, etc., and bee venom known to have an immune system disease treatment effect As an active ingredient.
本発明の組成物は、患部への塗布及び前記ハチ毒の吸収を助けるために、ゲルマトリクスのような生吸収性材料である微粒子又は繊維を更に含むことで、治療の効率性を増大させることができる。このようなゲルマトリクスとしては、ゲル化が可能な通常の材料が全て使用可能であり、そのうちアルギン酸塩及びヒアルロン酸などが最も好ましい。 The composition of the present invention further increases the efficiency of treatment by further including fine particles or fibers, which are bioabsorbable materials such as a gel matrix, to aid application to the affected area and absorption of the bee venom. Can do. As such a gel matrix, all ordinary materials capable of gelation can be used, and of these, alginates and hyaluronic acid are most preferred.
本発明の組成物は、皮膚外用剤形態で投与され、具体的に、ペースト、クリーム、ゲル、パウダー、スプレー、溶液、乳濁液及び懸濁液などの液剤、軟膏剤、ドレッシング剤及びパッチ剤などの剤形で投与可能である。 The composition of the present invention is administered in the form of an external preparation for skin, specifically, liquids such as pastes, creams, gels, powders, sprays, solutions, emulsions and suspensions, ointments, dressings and patches. It can be administered in a dosage form.
剤形がペースト、クリーム又はゲルである場合は、担体成分として動物性油、植物性油、ワックス、パラフィン、デンプン、トラガカント、セルロース誘導体、ポリエチレングリコール、シリコン、ベントナイト、シリカ、タルク又は酸化亜鉛などが利用できる。剤形がパウダー又はスプレーである場合は、担体成分としてラクトース、タルク、シリカ、アルミニウムヒドロキシド、カルシウムシリケート又はポリアミドパウダーが利用できる。特にスプレーである場合は、追加的にクロロフルオロヒドロカーボン、プロパン／ブタン又はジメチルエーテルのような推進剤を含むことができる。剤形が溶液又は乳濁液である場合は、担体成分として溶媒、溶解化剤又は乳濁化剤が利用されて、例えば、水、エタノール、イソプロパノール、エチルカーボネート、エチルアセテート、ベンジルアルコール、ベンジルベンゾエート、プロピレングリコール、１，３−ブチルグリコールオイル、グリセロール脂肪族エステル、ポリエチレングリコール又はソルビタンの脂肪酸エステルがある。剤形が懸濁液である場合は、担体成分として水、エタノール又はプロピレングリコールのような液状の希釈剤、エトキシル化イソステアリルアルコール、ポリオキシエチレンソルビトールエステル及びポリオキシエチレンソルビタンエステルのような懸濁剤、微小結晶性セルロース、アルミニウムメタヒドロキシド、ベントナイト、寒天又はトラガカントなどが利用できる。このような剤形は、充填剤、抗凝集剤、潤滑剤、湿潤剤、香料、乳化剤及び防腐剤などを追加的に含むことができる。 When the dosage form is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycol, silicon, bentonite, silica, talc or zinc oxide are used as carrier components. Available. When the dosage form is powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder can be used as a carrier component. Especially in the case of a spray, it can additionally contain a propellant such as chlorofluorohydrocarbon, propane / butane or dimethyl ether. When the dosage form is a solution or an emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component. For example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , Propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan. When the dosage form is a suspension, the carrier component is a liquid diluent such as water, ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester. Agents, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth can be used. Such dosage forms can additionally contain fillers, anti-agglomerating agents, lubricants, wetting agents, perfumes, emulsifiers and preservatives and the like.
本発明の組成物の適合した投与量は、製剤化方法、投与方式、投与時間、投与経路並びに患者の年齢、体重、性別、症状、食餌、排泄速度及び反応感応性のような要因により多様に処方され得る。本発明の薬剤学的組成物の投与量は、好ましくは１日当り０．１ｍｇ／ｋｇ（体重）〜１ｍｇ／ｋｇ（体重）である。 The suitable dosage of the composition of the present invention varies according to the formulation method, mode of administration, administration time, administration route and factors such as patient age, weight, sex, symptoms, diet, excretion rate and response sensitivity. Can be prescribed. The dosage of the pharmaceutical composition of the present invention is preferably 0.1 mg / kg (body weight) to 1 mg / kg (body weight) per day.
本発明によるハチ毒は、皮膚細胞増殖の成長因子である表皮成長因子（ＥＧＦ）と血管内皮成長因子（ＶＥＧＦ）との発現促進効果に優れているため、創傷又は火傷による皮膚細胞の再生を早くすることができる。 The bee venom according to the present invention has an excellent effect of promoting the expression of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which are growth factors for skin cell proliferation. can do.
本発明による組成物は、光老化誘発主要因子であるマトリクス・メタロプロテアーゼ（ＭＭＰ）−１及びＭＭＰ−３の発現を抑制することで、しわ及び老化防止に優れ、コラーゲンの合成と皮膚細胞増殖の成長因子であるＥＧＦとＶＥＧＦとの発現を促進することで、優れた品質の化粧品を製造することができる。 The composition according to the present invention suppresses the expression of matrix metalloprotease (MMP) -1 and MMP-3, which are the main factors for inducing photoaging, and is excellent in preventing wrinkles and aging. By promoting the expression of EGF and VEGF, which are growth factors, it is possible to produce an excellent quality cosmetic.
一方、本発明はハチ毒を有効成分として含むしわ改善又は紫外線遮断用化粧量を含む。前記ハチ毒は、化粧品分野で通常的に使用される基剤、補助剤及び添加剤を使用して液体又は固体形態に製造できる。液体又は固体形態の化粧品としては例えば、化粧水、クリーム剤、ローション剤及び入浴剤などの形態を含むことができるが、これに限定されない。化粧品分野で通常的に使用される基剤、補助剤及び添加剤は特別に限定せず、例えば、水、アルコール、プロピレングリコール、ステアリン酸、グリセロール、セチルアルコール及び流動パラフィンなどを含むことができる。 On the other hand, the present invention includes a wrinkle improving or UV blocking cosmetic amount containing bee venom as an active ingredient. The bee venom can be produced in liquid or solid form using bases, adjuvants and additives commonly used in the cosmetic field. Examples of liquid or solid form cosmetics include, but are not limited to, forms such as lotions, creams, lotions, and baths. Bases, adjuvants, and additives that are commonly used in the cosmetic field are not particularly limited, and may include, for example, water, alcohol, propylene glycol, stearic acid, glycerol, cetyl alcohol, and liquid paraffin.
以下、本発明を実施例を通じて更に詳しく説明する。しかし、本発明の権利範囲がこれら実施例により限定されるわけではなく、また、全ての資料はＳＡＳ(SAS enterprise guide 3.0)のDuncan’s t-testを利用して分散分析を実施した。 Hereinafter, the present invention will be described in more detail through examples. However, the scope of rights of the present invention is not limited by these examples, and all materials were subjected to analysis of variance using Duncan's t-test of SAS (SAS enterprise guide 3.0).
製造例１：ハチ毒の製造
国内産（韓国）のミツバチ（Apis mellifera）を電気衝撃法を利用したハチ毒採集装置（CHUNGJIN TECH、韓国）を利用して、ミツバチの被害なく純粋なハチ毒のみを多量に採
取して、異物を除去した後、凍結乾燥して精製ハチ毒を得た。精製されたハチ毒は、液体クロマトグラフィ（AKTA explorer、アマシャムファルマシアバイオテック、米国）を使
用して、ハチ毒標準品であるシグマ産ミツバチ毒、メリチン、アパミン及びホスホリパーゼと比較して確認した。本発明で製造されたハチ毒（Ｂ）は市販のハチ毒（Ａ）と比較すると、ハチ毒の主要成分であるメリチン（Ｍ）、アパミン（Ａ）及びホスホリパーゼＡ２（ＰＡ２）の成分がほぼ同一であることを図１を通して確認することができた。
Production Example 1: Manufacture of bee venom A domestic bee (Apis mellifera) bee poison collecting device (CHUNGJIN TECH, Korea) using the electric shock method, pure bee venom without damage to bees A large amount was collected to remove foreign substances, and then lyophilized to obtain a purified bee venom. Purified bee venom was confirmed using liquid chromatography (AKTA explorer, Amersham Pharmacia Biotech, USA) compared to the bee venom standards sigma honey bee venom, melittin, apamin and phospholipase. Compared with the commercially available bee venom (A), the bee venom produced in the present invention has almost the same components of melittin (M), apamin (A) and phospholipase A2 (PA2), which are the main components of bee venom. It was confirmed through FIG.
製造例２：ドレッシング剤の製造
前記製造例１で得られたハチ毒０．１ｇとアルギン酸塩１ｇとを均一に混合し、蒸留水５ｍＬを入れてよく混ぜた後、６０℃の温度のホットプレート上で透明になるまでよく混ぜ、ガラス板に移してガラス棒を利用して薄く広げた。このとき、ハチ毒とアルギン酸塩及び水の比率は治療しようとする適用部位と状態とによって調節が可能であり、ドレッシングの大きさ、厚さ及び空隙などはどのような形態にでも製造可能である。また、アルギン酸塩の代わりに、ヒアルロン酸などのような通常のゲルマトリクス材料を使用できる。このように製造されたドレッシング剤は図２の通りである。
Production Example 2: Production of dressing agent 0.1 g of bee venom obtained in Production Example 1 and 1 g of alginate are uniformly mixed, and 5 mL of distilled water is added and mixed well, followed by a hot plate at a temperature of 60 ° C. The mixture was mixed well until it became transparent, transferred to a glass plate and spread thinly using a glass rod. At this time, the ratio of bee venom, alginate and water can be adjusted according to the application site and condition to be treated, and the size, thickness and voids of the dressing can be manufactured in any form. . Further, instead of alginate, a normal gel matrix material such as hyaluronic acid can be used. The dressing thus produced is as shown in FIG.
製造例３：軟膏剤の製造
前記ハチ毒を有効成分として利用して次のような組成で軟膏剤を製造した。
（組成）
ハチ毒１．０重量部、蜜ろう１０重量部、ポリソルベート６０ ５．０重量部、ＰＥＧ
６０硬化ヒマシ油２．０重量部、セスキオレイン酸ソルビタン０．５重量部、バセリン５．０重量部、流動パラフィン１０．０重量部。
Production Example 3 Production of Ointment An ointment was produced with the following composition using the bee venom as an active ingredient.
(composition)
1.0 part by weight of bee venom, 10 parts by weight of beeswax, 5.0 parts by weight of polysorbate 60, PEG
60 hardened castor oil 2.0 parts by weight, sorbitan sesquioleate 0.5 parts by weight, 5.0 parts by weight of vaseline, 10.0 parts by weight of liquid paraffin.
製造例４：パッチ剤の製造
前記ハチ毒を有効成分として利用して次のような組成でパッチ剤を製造した。
（組成）
ハチ毒１．２重量部、ヘキシレングリコール２０．０重量部、ジエキルアミン０．７重量部、ポリアクリル酸１．０重量部、亜硫酸ナトリウム０．１重量部、ポリオキシエチレンラウリルエーテル１．０重量部、ポリヒドロキシエチレンセチルステアリルエーテル１．０重量部、粘性のパラフィンオイル２．５重量部、カプリル酸エステル／カプリン酸エステル２．５重量部、ポリエチレングリコール４００ ３．０重量部、脱イオン水１００重
量部。
Production Example 4: Production of Patch Agent A patch agent was produced with the following composition using the bee venom as an active ingredient.
(composition)
1.2 parts by weight of bee venom, 20.0 parts by weight of hexylene glycol, 0.7 parts by weight of dialkylamine, 1.0 part by weight of polyacrylic acid, 0.1 part by weight of sodium sulfite, 1.0 part by weight of polyoxyethylene lauryl ether Parts, polyhydroxyethylene cetyl stearyl ether 1.0 parts by weight, viscous paraffin oil 2.5 parts by weight, caprylic acid ester / capric acid ester 2.5 parts by weight, polyethylene glycol 400 3.0 parts by weight, deionized water 100 Parts by weight.
製造例５：化粧品の製造
前記ハチ毒を有効成分として利用して次のような組成でエッセンスを製造した。
（組成）
有効成分１ｍｇ、グリセリン３．０ｍｇ、ＥＤＴＡ０．０５ｍｇ、ベンゾフェノン−９
０．０４ｍｇ、カルボキシビニルポリマー０．２ｍｇ、トリエタノールアミン０．１８ｍｇ、オクチルドデセス−２５ ０．６ｍｇ、グリセリルモノステアレート１．０ｍｇ、防
腐剤０．０１ｍｇ、香料０．０１ｍｇ、精製水適量。
Production Example 5 Production of Cosmetics Essence was produced with the following composition using the bee venom as an active ingredient.
(composition)
Active ingredient 1 mg, glycerin 3.0 mg, EDTA 0.05 mg, benzophenone-9
0.04 mg, carboxyvinyl polymer 0.2 mg, triethanolamine 0.18 mg, octyldodeces-25 0.6 mg, glyceryl monostearate 1.0 mg, preservative 0.01 mg, fragrance 0.01 mg, purified water appropriate amount.
実施例１：皮膚創傷モデルでの再生率及び成長因子の発現量試験
細胞培養１００ｍｍディッシュに１次培養皮膚細胞であるＨＤＦ（Human Dermal Fibroblast）細胞が８０％増殖したとき、滅菌された爪楊枝を利用して１０ｍｍの幅で細胞に
傷をつけ、ハチ毒を０．０１μｇ／ｍＬ〜１０μｇ／ｍＬ注入した後、細胞の再生を確認した。
Example 1: Regeneration rate and growth factor expression test in skin wound model When sterilized toothpick is used when HDF (Human Dermal Fibroblast) cells, which are primary cultured skin cells, are grown to 80% in a cell culture 100 mm dish Then, cells were injured with a width of 10 mm, and bee venom was injected at 0.01 μg / mL to 10 μg / mL, and then cell regeneration was confirmed.
このとき、細胞の増殖を測定する方法は特別に限定しないが、ＭＴＴ（メチルチアゾール−２−イル−２，５−ジフェニルテトラゾリウムブロミド）分析方法とディフ・クイック染色（Diff quic stain）を利用して細胞染色をした後、顕微鏡で確認した。また、コ
ラーゲン合成量についてコラーゲン分析キットを用いて分析し、そして細胞増殖に関与する成長因子である表皮成長因子（ＥＧＦ）と血管内皮成長因子（ＶＥＧＦ）との発現量について酵素結合免疫吸収分析法（ＥＬＩＳＡ）キットを用いて分析し、その結果は図３〜図６の通りである。
At this time, the method for measuring the proliferation of cells is not particularly limited, but using MTT (methylthiazol-2-yl-2,5-diphenyltetrazolium bromide) analysis method and Diff quic stain. After cell staining, it was confirmed with a microscope. In addition, the amount of collagen synthesis is analyzed using a collagen analysis kit, and the expression levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which are growth factors involved in cell proliferation, are enzyme-linked immunosorbent assay. (ELISA) It analyzed using the kit and the result is as FIG.
観察の結果、０．０１μｇ／ｍＬ〜１μｇ／ｍＬのハチ毒を含む組成物で処理した場合、細胞再生が促進され、コラーゲンの精製量が増加したことが分かる。更に、皮膚細胞成長因子であるＥＧＦとＶＥＧＦ生成量が各々２倍以上増加したことを確認することができた。一方、細胞の形態的な形においても正常的に成長した。 As a result of observation, it was found that when treated with a composition containing 0.01 μg / mL to 1 μg / mL bee venom, cell regeneration was promoted and the amount of purified collagen was increased. Furthermore, it was confirmed that the production amounts of EGF and VEGF, which are skin cell growth factors, each increased by 2 times or more. On the other hand, it grew normally in the morphological form of the cells.
実施例２：皮膚火傷モデルでの再生率試験
１次培養皮膚細胞であるＨＤＦに紫外線を照射して皮膚火傷を誘導した。具体的に、皮膚火傷としわの生成の原因であるＵＶＡ（３２０ｎｍ〜３８０ｎｍ）（６３０ｍＬ／ｃｍ２）を使用して、細胞培養１００ｍｍディッシュにＨＤＦ細胞が８０％増殖したときに３０分間照射した。その後、新しい培地と共にハチ毒０．０１μｇ／ｍＬ〜１０μｇ／ｍＬを注入し、細胞再生率、コラーゲン合成量並びに光老化誘発主要因子であるＭＭＰ−１及びＭＭＰ−３の発現量を確認し、その結果は図７〜図９の通りであった。このとき、細胞増殖効果の測定は実施例１と同じように実施した。
Example 2: Regeneration rate test in a skin burn model Skin burns were induced by irradiating HDF, which is a primary cultured skin cell, with ultraviolet rays. Specifically, UVA (320 nm to 380 nm) (630 mL / cm 2 ), which is the cause of skin burns and wrinkles, was used for 30 minutes when HDF cells grew to 80% in a cell culture 100 mm dish. Thereafter, 0.01 μg / mL to 10 μg / mL of bee venom was injected together with a new medium, and the cell regeneration rate, the amount of collagen synthesis, and the expression levels of MMP-1 and MMP-3, which are the main factors causing photoaging, were confirmed. The results were as shown in FIGS. At this time, the cell proliferation effect was measured in the same manner as in Example 1.
観察の結果、ＵＶＡとＵＶＢとにより損傷された皮膚細胞の細胞再生率及びコラーゲンの生成量においてハチ毒の効果が優れていることが分かった。紫外線ＵＶＢにより損傷された皮膚細胞に前記組成物を処理してＭＭＰ−１とＭＭＰ−３との発現抑制されたことを確認した。これにより、紫外線ＵＶＡ及びＵＶＢの照射による細胞損傷にハチ毒が大きな効果があることが分かった。更に、細胞再生とコラーゲンの合成とが促進され、特にＵＶＢによる光老化促進酵素であるＭＭＰ−１とＭＭＰ−３との生成を大きく抑制することで、しわ及び老化防止に効果があるだろうと予想される。また、形態学的にも非常に早く正常細胞に成長したことを図１０の通り確認できた。 As a result of observation, it was found that the effect of bee venom was excellent in the cell regeneration rate of skin cells damaged by UVA and UVB and the amount of collagen produced. It was confirmed that the expression of MMP-1 and MMP-3 was suppressed by treating the skin cells damaged by ultraviolet rays UVB with the composition. Thus, it was found that bee venom has a great effect on cell damage caused by irradiation with ultraviolet rays UVA and UVB. Furthermore, cell regeneration and collagen synthesis are promoted, and it is expected that wrinkles and aging will be effectively prevented, especially by greatly suppressing the production of MMP-1 and MMP-3 which are photoaging promoting enzymes by UVB. Is done. In addition, it was confirmed as shown in FIG. 10 that morphologically very rapidly grown into normal cells.
実施例３：創傷又は火傷後の２次感染細菌に対する抗菌効果
創傷、火傷及び手術後の治療期間中に容易に感染される代表的な病原菌である黄色ブドウ球菌（Staphylococcus aureus）、緑膿菌（Pseudomonas aeruginosa）、大腸菌（Escherichia coli）、コアグラーゼブドウ球菌（Coagulase staphylococci）及び大腸菌（Coliform bacilli）に対する抗菌効果を観察するために、ハチ毒の最小発育阻止濃度（ＭＩＣ）を検定し、その結果は下記［表１］に示した。
Example 3: Antibacterial effect against secondary infectious bacteria after wounds or burns Staphylococcus aureus, Pseudomonas aeruginosa, a representative pathogen that is easily infected during wounds, burns and post-surgical treatment periods In order to observe the antibacterial effect against Pseudomonas aeruginosa, Escherichia coli, Coagulase staphylococci and Coliform bacilli, the minimum inhibitory concentration (MIC) of bee venom was assayed. It showed in [Table 1].
観察の結果、ハチ毒を含有する組成物の抗菌効果が確認された。但し、上記のＥＧＦ及びＶＥＧＦの発現促進を可能とするハチ毒の濃度範囲である０．０１μｇ／ｍｌ以上１μｇ／ｍｌ以下では、黄色ブドウ球菌（Staphylococcus aureus）及び大腸菌（Escherichia coli）に対して抗菌効果を示すことができる。 As a result of the observation, the antibacterial effect of the composition containing bee venom was confirmed. However, antibacterial activity against Staphylococcus aureus and Escherichia coli at a concentration range of 0.01 μg / ml to 1 μg / ml, which is a concentration range of bee venom that enables the above-described expression promotion of EGF and VEGF. The effect can be shown.
実施例４：温度、酸度及びガンマ線照射による安定性試験
温度による安定性実験
ゲルマトリクスや賦形剤として使用される材料の特性上、加温が必要な場合、温度によるハチ毒の成分及び効果に対する安定性が必要であるため、ハチ毒を５０℃〜１００℃で１時間〜１２時間放置した後、黄色ブドウ球菌成分の変化及び効果を観察し、その結果は下記［表２］の通りである。
Example 4: Stability test by temperature, acidity and gamma irradiation Stability experiment by temperature When the heating is necessary due to the characteristics of the material used as a gel matrix or an excipient, it is effective for the components and effects of bee venom depending on the temperature. Since stability is necessary, the bee venom was allowed to stand at 50 ° C. to 100 ° C. for 1 to 12 hours, and then the changes and effects of the Staphylococcus aureus components were observed. The results are as shown in [Table 2] below. .
観察の結果、１００℃でその成分が変化せず、黄色ブドウ球菌に対する抗菌効果に影響を与えなかった。 As a result of observation, the components did not change at 100 ° C. and did not affect the antibacterial effect against S. aureus.
酸度による安定性実験
重度の創傷及び火傷治療時に発生する粘液などによる酸度変化により、ハチ毒の成分及び薬理効果にどのような影響を及ぼすかを確認するために、ハチ毒の酸度がｐＨ２、５及び９であるときの成分の変化と効果を確認した。
Stability experiment by acidity In order to confirm how the acidity change caused by mucus generated during the treatment of severe wounds and burns affects the components and pharmacological effects of bee venom, the acidity of bee venom is adjusted to pH 2, 5 And the change and effect of the component when it was 9 were confirmed.
観察の結果、本発明の組成物は、酸度の影響を受けないことが分かった。 As a result of observation, it was found that the composition of the present invention was not affected by the acidity.
ガンマ線照射による安定性実験
医薬品として使用される全ての素材は滅菌過程を経る。従って、０ｋＧｙ、３ｋＧｙ及
び５ｋＧｙのガンマ線を照射した後、黄色ブドウ球菌の成分変化及び効果を観察し、その結果は下記［表４］の通りである。
Stability experiments with gamma irradiation All materials used as pharmaceuticals undergo a sterilization process. Therefore, after irradiating 0 kGy, 3 kGy, and 5 kGy of gamma rays, component changes and effects of Staphylococcus aureus were observed, and the results are as shown in [Table 4] below.
観察結果、５ｋＧｙで抗菌力が多少減少したが、本発明の組成物は、ガンマ線の影響を大きく受けないことが分かった。 As a result of the observation, although the antibacterial activity decreased somewhat at 5 kGy, it was found that the composition of the present invention was not greatly affected by gamma rays.
以上の処理を行ったハチ毒を液体クロマトグラフィにより分析した結果のグラフを図１１に示す。 The graph of the result of having analyzed the bee venom which performed the above process by liquid chromatography is shown in FIG.
実施例５：ハチ毒の毒性試験
ハチ毒に対する毒性を調べるために、ハチ毒０．５ｍｇ／ｋｇ〜５ｍｇ／ｋｇを２４匹のネズミに腹腔内投与して、行動観察を２４時間した後、生存可否を確認した。その結果、ハチ毒２ｍｇ／ｋｇ〜３ｍｇ／ｋｇを投与したネズミ６匹のうち３匹が生存し、残りの３匹は犠牲になったことが分かった。反面、１ｍｇ／ｋｇ未満の容量を投与したネズミの場合は全て生存し、行動観察上、薬物を投与しなかったネズミと比較して統計学上有意性のある差は見せなかった。以上の結果を考慮したとき、ネズミにおいて約半数が生存するハチ毒の毒性容量は、２．５ｍｇ／ｋｇと判断される。
Example 5: Toxicity test of bee venom In order to investigate the toxicity to bee venom, 0.5 mg / kg to 5 mg / kg of bee venom was intraperitoneally administered to 24 mice, followed by behavior observation for 24 hours, and then survival. Confirmed availability. As a result, it was found that 3 out of 6 mice administered with 2 mg / kg to 3 mg / kg of bee venom survived and the remaining 3 were sacrificed. On the other hand, all the mice administered with a dose of less than 1 mg / kg survived, and the behavioral observation showed no statistically significant difference compared to the mice that did not receive the drug. Considering the above results, the toxic capacity of bee venom in which about half of the rats survive is determined to be 2.5 mg / kg.
実施例６：ハチ毒の皮膚刺激測定試験
本発明のハチ毒の皮膚刺激程度は、次の方法を使用して測定した。ハチ毒０．０１μｇ／ｍＬ〜２０μｇ／ｍＬを含有するパッチ剤を製造し、ネズミ２０匹に、１匹当り擦過皮膚２ヶ所と非擦過皮膚２ヶ所として、そのうちの擦過皮膚１ヶ所と非擦過皮膚１ヶ所とに各々パッチ剤１個ずつを１回塗布し、もう１方を無処置対照区として処置を行わなかった。その後、それぞれの部分を基剤で覆い、非刺激性テープでしっかり固定して２４時間適用させた。適用終了後には、ぬるま湯を利用して塗布部を軽く洗浄した。試験物質適用終了後、適用のパッチを除去して２４時間及び７２時間後に紅斑と浮腫形成などの刺激性の可否を観察した。皮膚反応の評価は医薬品などの毒性試験基準を利用して評価し、結果に対する刺激性の程度判定は下記［表５］に示したように、一般的に多く利用されるドレイズ（Draiz）法のＰＩＩ（１次刺激性指数）の算出方法に伴った。
Example 6: Skin irritation measurement test of bee venom The degree of skin irritation of bee venom of the present invention was measured using the following method. A patch containing 0.01 μg / mL to 20 μg / mL of bee venom was produced. In 20 mice, there were 2 scratched skins and 2 non-scratched skins per animal, 1 of which was scratched and 1 non-scratched skin. One patch was applied to each site once, and the other was not treated as an untreated control. Thereafter, each part was covered with a base, firmly fixed with non-irritating tape, and applied for 24 hours. After the application was completed, the application part was lightly washed using lukewarm water. After application of the test substance, the applied patch was removed, and irritability such as erythema and edema formation was observed 24 hours and 72 hours later. Skin reaction is evaluated using toxicity test standards such as pharmaceuticals, and the degree of irritation to the results is determined by the commonly used Draiz method as shown in [Table 5] below. Accompanying the calculation method of PII (primary irritancy index).
動物の皮膚に組成物を２４時間付着して紅班と浮腫を評価して、ＰＩＩ値で皮膚刺激の程度を数値化して、その値が０の場合を無刺激、２以下の場合を低刺激、２〜５の場合を中刺激、５以上の場合を高刺激と評価して、２以下の値を有する組成物のみが経皮投与用
組成物として選択され得る。
The composition is applied to the skin of an animal for 24 hours to evaluate erythema and edema, and the degree of skin irritation is quantified by the PII value. In the case of 2-5, medium irritation is evaluated, and the case of 5 or more is evaluated as high irritation.
観察の結果、ハチ毒を０．０１μｇ／ｍＬ〜２０μｇ／ｍＬ投与したネズミ１０匹のＰＩＩ平均値は２．１であり、ハチ毒を０．０１μｇ／ｍＬ〜１０μｇ／ｍＬ投与したネズミ１０匹の平均ＰＩＩの平均値は約０．４であり、１０μｇ／ｍＬ未満含有する場合、皮膚に刺激がないと判断される。 As a result of the observation, the PII average value of 10 mice administered with 0.01 μg / mL to 20 μg / mL of bee venom was 2.1, and that of 10 mice administered with 0.01 μg / mL to 10 μg / mL of bee venom. The average value of average PII is about 0.4, and when it contains less than 10 μg / mL, it is judged that the skin is not irritated.
以上に説明したように、本発明のハチ毒を有効成分として含む組成物は、ＥＧＦ及びＶＥＧＦの発現促進効果に優れるので細胞再生効果に優れ、皮膚疾患等の患者の治療に効果的であると期待される。 As described above, the composition containing the bee venom of the present invention as an active ingredient is excellent in the expression promoting effect of EGF and VEGF, and thus has an excellent cell regeneration effect and is effective in treating patients with skin diseases and the like. Be expected.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020090028544A KR101099550B1 (en) | 2009-04-02 | 2009-04-02 | Composition of comprising bee-venoms for treating wounds or burns |
| KR10-2009-0028544 | 2009-04-02 |
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| JP2009218986A Division JP2010241786A (en) | 2009-04-02 | 2009-09-24 | Composition for treating wound and burn with bee venom as effective ingredient |
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| JP2009218986A Pending JP2010241786A (en) | 2009-04-02 | 2009-09-24 | Composition for treating wound and burn with bee venom as effective ingredient |
| JP2012261417A Pending JP2013060455A (en) | 2009-04-02 | 2012-11-29 | Composition using bee venom as active ingredient |
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| KR101382404B1 (en) * | 2012-01-04 | 2014-04-14 | 대한민국 | Massive purification method of bee venom |
| KR101425018B1 (en) * | 2012-11-26 | 2014-08-01 | (주)비센 | Cosmetic composition for anti-aging comprising lipid soluble fraction of bee venom and method for manufacturing the same |
| CN103006530B (en) * | 2012-12-20 | 2014-10-29 | 中国科学院南海海洋研究所 | Bee venom compound with sun-proof effect |
| CN106163617A (en) * | 2013-08-23 | 2016-11-23 | D·米切尔 | The compositions comprising queen bee venom for skin |
| KR101876176B1 (en) * | 2016-02-17 | 2018-07-09 | 가톨릭관동대학교산학협력단 | Transdermal patch containg bee venom extracts |
| KR102085570B1 (en) * | 2017-08-14 | 2020-03-06 | 한국 한의학 연구원 | Composition for preventing or treating gouty arthritis comprising apamin as effective component |
| CN109674772B (en) * | 2019-02-28 | 2023-04-11 | 大理大学 | Wasp needle patch and preparation method thereof |
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| JP2010241786A (en) | 2010-10-28 |
| GB0916573D0 (en) | 2009-10-28 |
| KR101099550B1 (en) | 2011-12-28 |
| GB2469154A (en) | 2010-10-06 |
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