JP5190637B2 - Foods and beverages and pharmaceuticals such as health foods - Google Patents
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Description
本発明は特定のコラーゲン（これを含む生体成分）より成る健康食品等の飲食物及び医薬品に関する。更に本発明はタイプＩＶコラーゲンより及び又はその分画やペプタイドより成るもしくはこれらを認識する抗体より成る抗癌剤に関する。
更に骨由来コラーゲン（これを含む生体成分）及び又はタイプＩコラーゲン及び又はタイプＩＩＩコラーゲン（これらを含む生体成分）より成る骨粗鬆症予防及び改善治療剤又は健康食品等の飲食物に関する。The present invention relates to foods and drinks such as health foods and pharmaceuticals comprising specific collagen (a biological component containing the same). Furthermore, the present invention relates to an anticancer agent comprising type IV collagen and / or an antibody comprising or recognizing a fraction or peptide thereof.
Furthermore, the present invention relates to a food and drink such as osteoporosis prevention and amelioration therapeutic agent or health food comprising bone-derived collagen (a biological component containing this) and / or type I collagen and / or type III collagen (a biological component containing these).
「医食同源」とは病気を治すこと（薬物療法）も食事をするのも命を養い健康を保つためで、その本質は同じであるということである。この考えに立てば、日常摂取している飲食物には病気予防や治療の本質物質が存在する事になる。それ故、日常飲食している物から、有効成分を見出だして濃縮や精製し、日常的に疾患を予防し抑制することが健康食品や医薬品として望ましいと発明者は考える。飲食物として摂取する時には、人体成分に近い構成物のものが望ましく、例えば動物成分が、特に望ましいと考える。
しかし実際には、関節疾患患者に、関節成分のコンドロイチン硫酸やタイプＩＩコラーゲン（特に断らない限りコラーゲンとゼラチンは同義に用いる）を直接摂取するか又はこれらを主に含む生体成分や抽出スープとして摂取しているのみであり、治療改善に有効量が摂取されているか不明である。
又、従来の癌治療、特に固形癌の治療は、化学療法やホルモン療法などの全身的な方法と、手術や放射線療法などの局所療法が行われている。しかし、癌は治らないという諦観から、いずれも延命などの緩やかな治療を目指すようにようになっている。実際、転移し易い癌、例えば肝細胞癌は、脈管内に浸潤する傾向が強く、特に門脈へ浸潤する傾向が強く、治療に苦慮している。この場合、局所的な治療（肝臓動脈塞栓術、経皮的エタノール注入療法・マイクロ波凝固療法・ラジオ波焼灼療法）では、対処困難である。又、化学療法は、いずれの薬剤の単独投与でも有効率が１０％程度と低く、副作用も強く、有効な治療方法とは言えない。“Medical food companion” means to cure the disease (pharmacotherapy) and to eat to feed and maintain health, and the essence is the same. Based on this idea, there are essential substances for disease prevention and treatment in food and drink taken daily. Therefore, the inventor believes that it is desirable for health foods and pharmaceuticals to discover and concentrate and purify active ingredients from things that are eaten and consumed daily, and to prevent and control diseases on a daily basis. When ingesting as a food or drink, it is desirable that the composition is close to the human body component, for example, an animal component is particularly desirable.
However, in practice, patients with joint diseases take joint components chondroitin sulfate and type II collagen (collagen and gelatin are used synonymously unless otherwise specified) or take them as a biological component or extract soup mainly containing these. However, it is unclear whether an effective dose is being taken to improve treatment.
In addition, conventional cancer treatments, particularly solid cancer treatments, include systemic methods such as chemotherapy and hormone therapy, and local therapies such as surgery and radiation therapy. However, from the view that cancer will not be cured, all have come to aim for gradual treatment such as prolonging life. In fact, cancers that easily metastasize, such as hepatocellular carcinoma, have a strong tendency to infiltrate into the vasculature, and in particular, have a strong tendency to infiltrate the portal vein, and are difficult to treat. In this case, local treatment (liver artery embolization, percutaneous ethanol injection therapy, microwave coagulation therapy, radiofrequency ablation therapy) is difficult to cope with. Chemotherapy is not an effective treatment method because the effective rate is as low as about 10% even with single administration of any drug and the side effects are strong.
本発明の目的は前記「医食同源」の考えに応え、食品中より、動物由来の有効物質、特に特定のコラーゲンを用いて健康食品等の飲食物及び医薬品として提供することにある。
更に本発明の目的は、新しいバイオ利用の抗癌剤で特に増殖性や転移性の強い癌を抑制する抗癌剤の開発にある。
又、近年多く見られる骨粗鬆症では、骨由来物や生体由来の有効物質の投与が望まれるが、実際の治療や予防には、カルシュウムや骨粉が適用されそれ以外ではビタミンＫ、Ｄ群が適用されているにすぎず、めぼしい生体由来の有効成分がない。この現状を打破すべく発明者は鋭意研究し、特定のコラーゲンを特定量用いて解決することを見出だした。
一方、癌細胞は活動が活発になると基底膜を破壊して拡大するが、有効な生体由来の薬剤はなかった。又、従来、癌疾患の治療剤は、長期投与では副作用が強いという欠点があった。長期の治療で副作用がなく安心して投与できる癌疾患の治療薬が望まれていた。本発明は有効物質として基底膜の主成分であるタイプＩＶコラーゲン及びその抗体を利用して、癌の転移と増殖を抑制することにある。The object of the present invention is to respond to the above-mentioned idea of “medicine and food consortium” and provide foods and drinks such as health foods and pharmaceuticals using animal-derived active substances, particularly specific collagen, from foods.
A further object of the present invention is to develop a new bio-based anticancer agent that suppresses particularly proliferative and metastatic cancers.
In osteoporosis, which is often seen in recent years, administration of bone-derived substances and active substances derived from living bodies is desired. However, for actual treatment and prevention, calcium and bone meal are applied, and otherwise vitamins K and D are applied. However, there is no active ingredient derived from a remarkable living body. In order to overcome this situation, the inventors have intensively researched and found that a specific amount of specific collagen is used to solve the problem.
On the other hand, when cancer cells become active, the basement membrane is destroyed and expands, but there is no effective biological agent. Conventionally, therapeutic agents for cancer diseases have the drawback of having strong side effects when administered for a long time. There has been a demand for a therapeutic agent for cancer diseases that can be safely administered with no side effects in long-term treatment. The present invention is to suppress the metastasis and growth of cancer by using type IV collagen, which is a main component of the basement membrane, and its antibody as an effective substance.
本発明は、生体各部の中心的成分の特定のコラーゲンを抽出し、これを健康食品等の飲食物及び医薬品とすることに関する。更に、本発明はタイプＩＶコラーゲン及び又はその分画やペプタイド自身より成る加えてこれらを認識する抗体より成る抗癌剤に関する。
抗癌剤とするコラーゲンの種類は、各タイプの混合でも単独でも良いが単独では特にタイプＩＶコラーゲンが望ましい。抗癌剤とするコラーゲンの用いる部分はコラーゲン全体でも良く、又その部分を構成する分画やペプタイドでも良く、又、これらの混合物でも良い。通常、タイプＩＶコラーゲンは、ＮＣ１（Ｃ末端非螺旋部）、中央三本鎖螺旋部（内部に乱れ有り）、７Ｓ（Ｎ末端三本鎖螺旋部）の三領域に分けられ、更に、それぞれが、アルファ１から６まで分画されるが、抗癌剤とする時これらを単独又は組み合わせて使用して良く、望ましくは三本鎖螺旋部（中央及び又はＮ末端、以下三本鎖）を、更に望ましくは三本鎖のアルファ１及び又はアルファ２であり、そのペプタイドである。タイプＩＶコラーゲンの三本鎖は、由来臓器（胎盤、腎糸球体、眼レンズカプセル、各種組織基底膜）、抽出条件及び精製条件で得られる分子量は異なるが、いずれでも良く、特に望ましくは、電気泳動した時、約１８０Ｋから約１６０Ｋに属するものや約３０Ｋよりも、約５０Ｋから約１００Ｋに属するものである。The present invention relates to extracting specific collagen, which is a central component of each part of a living body, and using it as food and drink such as health foods and pharmaceuticals. Furthermore, the present invention relates to an anticancer agent comprising type IV collagen and / or a fraction thereof or a peptide itself and an antibody recognizing these.
The type of collagen used as the anticancer agent may be a mixture of each type or a single type, but type IV collagen is particularly desirable when used alone. The part of the collagen used as the anticancer agent may be the whole collagen, the fraction or peptide constituting the part, or a mixture thereof. Normally, type IV collagen is divided into three regions: NC1 (C-terminal non-helical part), central triple-stranded helical part (with internal disorder), and 7S (N-terminal triple-stranded helical part). These are fractionated from alpha 1 to 6, but may be used alone or in combination when used as an anticancer agent, preferably a triple-stranded helix (central and / or N-terminal, hereinafter triple-stranded) is more desirable. Is a triple stranded alpha 1 and / or alpha 2 peptide. The type IV collagen triple chain has different molecular weights depending on the organ of origin (placenta, kidney glomerulus, ophthalmic lens capsule, various tissue basement membranes), extraction conditions and purification conditions. When it migrates, it belongs to about 50K to about 100K rather than about 180K to about 160K or about 30K.
コラーゲンは生体内に存在し、各種の型があり、安全な成分である。
コラーゲンは、体蛋白の約３０％を占めるので、健常者は、日常の食事で動物蛋白源としてコラーゲンを常時取り込んでいる。例えば、動物を生食（例えば生卵、ステーキレア、馬刺、魚類の刺身、鮭頭軟骨の酢の物）し、又動物を加熱調理し、干物を食べ、抽出（例えば軟骨を含むスープ類）して食することで生体内に取り込んでいる。コラーゲンは、菓子類（通称グミ）や健康食品としても広く利用され、安全に経口摂取できる。又、コラーゲンは、動物細胞の培養時に、足場として安全に細胞を増殖するのに用いられている。更に、変性コラーゲン（ゼラチン）が、ワクチン、内服薬や注射薬に、賦形剤、安定剤等として添加されている。Collagen exists in the living body, has various types, and is a safe component.
Since collagen accounts for about 30% of body protein, healthy people always take collagen as a source of animal protein in their daily diet. For example, animals are eaten raw (eg, raw eggs, steak rares, horse sashimi, fish sashimi, vinegar of bun cartilage), animals are cooked, dried, extracted (eg, soup containing cartilage) Is taken into the living body. Collagen is widely used as confectionery (commonly known as gummy) and health food, and can be safely taken orally. Collagen is used to safely proliferate cells as a scaffold during animal cell culture. Further, denatured collagen (gelatin) is added as an excipient, a stabilizer and the like to vaccines, internal medicines and injections.
本発明者は、長年の研究の結果、正常で組織特有なコラーゲンを含む結合組織の強化は、その組織の疾患の進展を抑制することを見出だした。更にその強化の為には、正常で組織特有なコラーゲンの投与が良いとすることを見出だした。As a result of many years of research, the present inventor has found that the strengthening of connective tissue containing normal and tissue-specific collagen suppresses the progression of disease in the tissue. Furthermore, it has been found that administration of normal and tissue-specific collagen is good for strengthening.
コラーゲンは、手に入りやすい組織のもの、例えば、真皮由来のタイプＩ、ＩＩＩコラーゲンや、胎盤由来のタイプＩＶコラーゲンでも良いが、治療対象組織に含まれる型のコラーゲンと同一型が好ましく、最も好ましいのは改善や治療対象もしくは強化対象の組織由来のものであるがこれに限定されない。Collagen may be easily obtained tissue, for example, type I or III collagen derived from the dermis or type IV collagen derived from placenta, but the same type as the type of collagen contained in the tissue to be treated is preferred and most preferred Is derived from a tissue to be improved or treated or strengthened, but is not limited thereto.
コラーゲンは通常テロペプチドを含んでいるもの及びこれを除去したものが知られており、本発明においては両者のものを単独、もしくは混合して使用可能であるが、抗原性の面からテロペプチドを除去したものの方が好ましい。
更に本発明に於いてコラーゲンは、変性、修飾、低分子化したものでも、ペプタイド合成機で製したものでもこれらを組み合わせたものでも良い。つまり変性させてゼラチンにしても良く、サクシニル化などの修飾をしたものでも、低分子化したものでも良い。Collagen is usually known to contain telopeptides and those from which telopeptides have been removed. In the present invention, both can be used alone or in combination. The removed one is preferred.
Furthermore, in the present invention, the collagen may be denatured, modified, reduced in molecular weight, produced by a peptide synthesizer, or a combination thereof. That is, it may be modified to gelatin, which may be modified by succinylation or the like, or may have a low molecular weight.
本発明に於いてコラーゲンの由来は哺乳類、鳥類、魚類、甲殻類、爬虫類、昆虫類、菌類等、例えば、ヒト、サル、牛、豚、鯨、ラット、マウス、馬、家兎、山羊、ニワトリ、魚、カニ、えび、カエル、蚕、昆虫、大腸菌等のいづれの生物でもよく、これらを混合して用いてもよい。In the present invention, collagen is derived from mammals, birds, fish, crustaceans, reptiles, insects, fungi, etc., such as humans, monkeys, cows, pigs, whales, rats, mice, horses, rabbits, goats, chickens , Fish, crabs, shrimps, frogs, frogs, insects, Escherichia coli, etc., or a mixture of these.
コラーゲンの製法は、生体抽出、組織・細胞培養、遺伝子工学的製法等すでに知られている方法（「細胞外マトリックス研究法」コラーゲン技術研修会刊行）、又、ペプタイド合成機で製してのいずれでも良い。
コラーゲンを生体から製するには、一般的には塩酸や酢酸等の酸抽出とペプシン等の酵素抽出があり、両者を組合わせても良い。更にＤＥＡＥカラムクロマトグラフィーや分画分子量の透析で、微量ならＨＰＬＣで精製しても良い。
１）胎盤よりタイプＩＶコラーゲンを製する一例を示す。
以下、できる限り４Ｃで行う。ヒト胎盤を細裁断し洗浄（精製水−蛋白分解酵素阻害剤含有０．０５Ｍトリス緩衝液ｐＨ７．５−精製水）−凍乾し粉砕−ペプシン含有０．５Ｍ酢酸（酢酸のみでも良い）で可溶化し遠心で上清を採取（沈殿は再可溶化、約５回繰り返す）−終濃度０．７Ｍ塩化ナトリウムを添加−遠心で上清を採取−終濃度１．２Ｍ塩化ナトリウム添加−遠心で沈殿採取−１Ｍ塩化ナトリウム含有０．０５Ｍトリス緩衝液ｐＨ７．５に溶解透析−４．５Ｍ塩化ナトリウムを添加−遠心で沈殿採取−１．０Ｍ塩化ナトリウム含有０．０５Ｍトリス緩衝液ｐＨ７．５に溶解透析−遠心で上清採取−４．５Ｍ塩化ナトリウム添加−沈殿（タイプＩＶコラーゲン）−カラムクロマトグラフィーで精製。
なお公開特許公報（昭和６２−５３９２７）にも製する例がある。
２）胎盤よりタイプＩ及びＩＩＩコラーゲンを製する一例を示す。
以下、できる限り４Ｃで行う。ヒト胎盤を細裁断−洗浄（蛋白分解酵素阻害剤含有ＰＢＳ）と遠心で沈殿を採取（この操作を約６回繰り返す）−凍乾し粉砕−ペプシン含有０．５Ｍ酢酸（酢酸のみでも良い）で可溶化し遠心で上清を採取（沈殿は再可溶化、約５回繰り返す）−終濃度２Ｍ塩化ナトリウムを添加−遠心で沈殿を採取−０．０５Ｍ酢酸に溶解−遠心で上清採取−終濃度１Ｍ塩化ナトリウムを添加−遠心で沈殿を採取−０．０５Ｍ酢酸に溶解−透析し遠心分離−上清（タイプＩ）、沈殿（タイプＩＩＩ）−更に透析し精製。
なお、真皮よりタイプＩ及びＩＩＩコラーゲンを製する時、例えば、ウシ胎児、子ウシの真皮を用いる時は、皮膚の除毛、脂肪の除去を充分に行う。脱脂には、ジエチルエーテルとエタノールの混合液（１：１）を用いる。Collagen can be produced by known methods such as biological extraction, tissue / cell culture, genetic engineering, etc. ("extracellular matrix research method" published by Collagen Technology Workshop), or by using a peptide synthesizer. But it ’s okay.
In order to produce collagen from a living body, generally, there are acid extraction such as hydrochloric acid and acetic acid and enzyme extraction such as pepsin, and both may be combined. Further, it may be purified by DEAE column chromatography or dialysis of the molecular weight cut off, and if it is trace amount, it may be purified by HPLC.
1) An example of producing type IV collagen from the placenta is shown.
Hereinafter, it is performed at 4C as much as possible. Human placenta is shredded and washed (purified water-0.05M Tris buffer pH 7.5 containing purified protease inhibitor-purified water)-freeze-dried and pulverized-0.5ps acetic acid containing pepsin (only acetic acid may be used) Solubilize and collect supernatant by centrifugation (precipitate resolubilized, repeat approximately 5 times)-Add final concentration 0.7M sodium chloride-Collect supernatant by centrifugation-Add final concentration 1.2M sodium chloride-Precipitate by centrifugation Sampling-Dissolving dialysis in 0.05 M Tris buffer pH 7.5 containing 1 M sodium chloride-Adding 4.5 M sodium chloride-Precipitation by centrifugation-Dissolving dialysis in 0.05 M Tris buffer pH 7.5 containing 1.0 M sodium chloride -Supernatant collection by centrifugation-Addition of 4.5 M sodium chloride-Precipitation (type IV collagen)-Purification by column chromatography.
There is also an example manufactured in the published patent publication (Showa 62-53927).
2) An example of producing type I and III collagen from the placenta is shown.
Hereinafter, it is performed at 4C as much as possible. Human placenta is shredded-washed (protease inhibitor-containing PBS) and centrifuged (this operation is repeated about 6 times)-freeze-dried and ground-pepsin-containing 0.5 M acetic acid (only acetic acid may be used) Solubilize and collect supernatant by centrifugation (precipitate is resolubilized, repeat approximately 5 times)-Add final concentration 2M sodium chloride-Collect precipitate by centrifugation-Dissolve in 0.05M acetic acid-Collect supernatant by centrifugation-Finish Add 1M sodium chloride concentration-Collect the precipitate by centrifugation-Dissolve in 0.05M acetic acid-Dialyze and centrifuge-Supernatant (type I), precipitate (type III)-Further dialyze and purify.
In addition, when making type I and III collagen from the dermis, for example, when using bovine fetus or calf dermis, the skin is sufficiently removed and the fat is removed. For degreasing, a mixture of diethyl ether and ethanol (1: 1) is used.
更に抗癌剤として使用する場合は、本発明に於けるコラーゲンのみでなく、これに対する抗体を用いることも可能である。抗体を用いる場合は、ポリクローナルよりもモノクローナルが望ましく、より望ましくは、ヒト型モノクローナル抗体である。
マウスやラットのモノクローナル抗体をヒトに投与した時、長期では中和抗体ができ効果が弱まるが、ヒト型ではこのような事が起きにくい。抗体としてのイムノグロブリンは、ＩｇＧ１やＧ２ａなどのＩｇＧやＩｇＭ及び他の型でも，各型混合したものでも良く、更に小さくしたもの、例えばＨ鎖、Ｌ鎖、Ｆｃ、Ｆａｂ、Ｆ（ａｂ´）２、その他などでも抗原と反応性を持つ限り良い。Furthermore, when used as an anticancer agent, it is possible to use not only the collagen in the present invention but also an antibody against it. When an antibody is used, monoclonal is preferable to polyclonal, and more preferably a human monoclonal antibody.
When mouse or rat monoclonal antibodies are administered to humans, neutralizing antibodies are produced over a long period of time, and the effect is weakened. Immunoglobulin as an antibody may be IgG, IgM such as IgG1 or G2a, and other types, or may be a mixture of each type, and further reduced, for example, H chain, L chain, Fc, Fab, F (ab ′) 2. Others are good as long as they have reactivity with the antigen.
本発明として使用する健康食品等の飲食物とは、いわゆる健康食品のみならず、特定保健用食品、医薬部外品、一般飲食物等、任意の食品形態を含む。The foods and drinks such as health foods used in the present invention include not only so-called health foods but also arbitrary food forms such as foods for specified health use, quasi drugs, and general foods and drinks.
本発明のコラーゲンとしての１日量は通常、健康食品等の飲食物としては、０．１ｇ以上であればよく、好ましい範囲として１ｇ〜１００ｇ、特に好ましい範囲として５〜１０ｇをあげることができる。
骨粗鬆症薬としての本発明のコラーゲンは、１日１〜３０ｇが良く、好ましくは１日５〜１５ｇが良い。
抗癌剤としての本発明のコラーゲン量は、１日０．００１ｍｇ以上３０ｇ以下で、好ましくは１日０．０１ｍｇ〜１０ｇで、抗体量としては１日０．００１ｍｇ以上３０ｇ以下で、好ましくは１日０．０１ｍｇ〜１０ｇである。数値は目安であり、疾患の重傷度、服用者の状態により増減されるべきで、これに限定されない。The daily dose of the collagen of the present invention is usually 0.1 g or more for foods and drinks such as health foods, and a preferred range is 1 to 100 g, and a particularly preferred range is 5 to 10 g.
The collagen of the present invention as an osteoporosis drug is 1 to 30 g per day, preferably 5 to 15 g per day.
The amount of the collagen of the present invention as an anticancer agent is 0.001 mg to 30 g per day, preferably 0.01 mg to 10 g per day, and the amount of antibody is 0.001 mg to 30 g per day, preferably 0 per day. 0.01 mg to 10 g. The numerical value is a guideline and should be increased or decreased depending on the severity of the disease and the condition of the user, and is not limited to this.
本発明の投与方法は、経口投与、注射、生体内留置等、通常、医療現場や食品として利用されている方法なら特に限定されない。投与時期は、食後、食間、就寝前のいずれでも、又これらを組み合わせても良く、１日の投与回数も特に限定しない。
例えば、抗癌剤としてタイプＩＶコラーゲンを用い、転移性肝癌に局所的な治療を行う時である。タイプＩＶコラーゲン０．０１ｍｇ〜１ｇを単独又はこれを含む微粒子を肝臓動脈へカテーテルから注入し血管造影で確認しながら塞栓を形成させることで、抗癌剤の転移と増殖を抑制する。The administration method of the present invention is not particularly limited as long as it is a method that is usually used as a medical site or food, such as oral administration, injection, and in vivo placement. Administration time may be any after meals, between meals, before going to bed, or a combination thereof, and the number of administrations per day is not particularly limited.
For example, when type IV collagen is used as an anticancer agent to locally treat metastatic liver cancer. By injecting 0.01 mg to 1 g of type IV collagen alone or microparticles containing this into a liver artery from a catheter and forming an embolus while confirming by angiography, metastasis and proliferation of the anticancer agent are suppressed.
本発明の摂取（投与）形態は、末、錠、液、カプセル等既存の健康食品や医薬品の形態で良い。内服の形態の時の賦形剤には、内服の形態に必要とし通常用いられるものが適応できる。例えば、増量剤としては澱粉、乳糖などである。必要に応じ、香味料、甘味料、着色料、賦形剤などを添加しても良い。The intake (administration) form of the present invention may be in the form of existing health foods and pharmaceuticals such as powders, tablets, liquids and capsules. As excipients in the form of internal use, those which are usually used and required for the form of internal use can be applied. For example, the bulking agent is starch, lactose, or the like. A flavoring agent, a sweetening agent, a coloring agent, an excipient and the like may be added as necessary.
更に既存医薬品の様に注射剤にしても、内服剤にしても、外用剤としても、局所投与形態にしても良い。
又主剤はコラーゲン単独や抗体単独でも、他の薬物と混合して内服薬、注射剤にしても良い。他の薬物は特に限定されず、通常医薬品として使用可能な薬物、例えば消化剤、整腸剤、抗潰瘍剤、抗生物質、ホルモン、酵素、ステロイド、内分泌系用薬、循環器系剤、抗リウマチ剤、抗炎症剤、鎮痛剤、解熱剤、抗アレルギー剤、抗腫瘍剤、更にはインターフェロン、インターロイキン、腫瘍壊死因子等のペプチド等をあげることができる。Furthermore, it may be an injection, an internal preparation, an external preparation, or a local administration form like existing pharmaceuticals.
The main agent may be collagen alone or antibody alone, or may be mixed with other drugs to be used as an internal medicine or injection. Other drugs are not particularly limited, drugs that can be usually used as pharmaceuticals, such as digestive agents, intestinal regulating agents, anti-ulcer agents, antibiotics, hormones, enzymes, steroids, endocrine agents, cardiovascular agents, anti-rheumatic agents, Examples include anti-inflammatory agents, analgesics, antipyretic agents, antiallergic agents, antitumor agents, and peptides such as interferons, interleukins, and tumor necrosis factors.
本発明の健康食品等の飲食物や内服薬、注射剤等の医薬品に於いて溶液として用いる時、溶液は、滅菌精製水、水溶性溶剤（例えば、グリセリン）、油性溶剤（例えば、精製オリーブ油）等を単独又は組み合わせて使用することができる。又、本発明の健康食品等の飲食物や内服薬、注射剤等の医薬品に於いては、添加剤として等張化剤、緩衝剤、溶解補助剤、界面活性剤、安定化剤、防腐剤、油脂類、水溶性高分子、局所麻酔剤等を添加してもよい。その等張化剤としては塩化ナトリウム等の無機塩を、緩衝剤としてはリン酸等の無機酸、及びクエン酸の有機酸を、界面活性剤としてはゼラチン、ポリソルベート８０、油脂類としては植物油等を、水溶性高分子としてはカルボキシメチルセルロースナトリウム等をあげることができる。
更に、本発明の健康食品等の飲食物、内服溶液剤、注射剤において、このように製された溶液、もしくは懸濁液に等張化剤、緩衝剤以外の前記添加物を、溶解もしくは懸濁させてもよい。
このように製された溶液、もしくは懸濁液をミリポアフィルター等を用いて無菌化し、次いで瓶、バイアルもしくは、アンプルに充てんさせることにより本発明の健康食品液、内服液、注射剤を製することができる。又本発明の液においては製された瓶、バイアルもしくはアンプルを凍結乾燥し、用時溶解液とすることも可能である。When used as a solution in foods and drinks such as the health food of the present invention, pharmaceuticals such as internal medicine, injections, etc., the solution is sterilized purified water, a water-soluble solvent (for example, glycerin), an oily solvent (for example, purified olive oil), etc. Can be used alone or in combination. In addition, in pharmaceutical products such as health foods and other foods and oral medicines and injections of the present invention, as additives, isotonic agents, buffers, solubilizers, surfactants, stabilizers, preservatives, Oils and fats, water-soluble polymers, local anesthetics and the like may be added. The isotonic agent is an inorganic salt such as sodium chloride, the buffer is an inorganic acid such as phosphoric acid, and the citric acid is an organic acid, the surfactant is gelatin, polysorbate 80, the fats and oils are vegetable oils, etc. Examples of the water-soluble polymer include sodium carboxymethyl cellulose.
Furthermore, in the foods and drinks such as health foods, the oral solution, and the injection of the present invention, the additives other than the isotonic agent and buffer are dissolved or suspended in the solution or suspension thus prepared. It may be clouded.
The solution or suspension thus prepared is sterilized using a Millipore filter, etc., and then filled into a bottle, vial or ampoule to produce the health food liquid, oral liquid, or injection of the present invention. Can do. In the liquid of the present invention, the bottle, vial or ampoule produced can be freeze-dried to obtain a solution for use.
医食同源の発想から、日常の飲食物から、特に動物成分から、必要な有効成分を得て、これを健康食品あるいは医薬品の形態とし、生体内で効率良く摂取可能とし、疾病の予防及び治療に提供するものである。又、その抗体についても同様である。特にコラーゲンは２か月以上の長期に渡って使用しても自他覚の副作用を認めない安全な健康食品等の飲食物及び薬剤である。
以下、本発明を更に実施例で説明するが本発明はこれらにより限定されるものではない。From the idea of the same source of medical foods, the necessary active ingredients are obtained from daily foods and drinks, especially from animal ingredients, and are made into health foods or pharmaceutical forms that can be efficiently ingested in vivo to prevent disease and It is provided for treatment. The same applies to the antibody. Collagen in particular is a safe food and drink such as health foods and drugs that do not show any side effects of self-intention even when used for a long period of 2 months or longer.
Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited thereto.
基底膜の主要成分であるタイプＩＶコラーゲンのＮＣ１（ウシ由来、ここでは腎臓由来を使用）、タイプＩＶコラーゲン（ヒト由来、ここでは胎盤由来でペプシン処理を使用、以下３本鎖）及び抗体（ウサギ由来、ここでは抗ＮＣ１抗血清）の抗癌作用につき検討した。
癌細胞（ＨＥＰＧ２）の培養液にＮＣ１、３本鎖及びその抗血清を加えて比較した。
結果は、３本鎖が最も癌細胞の増殖を抑制した。抗血清（ウサギ由来）も抑制効果があった。ＮＣ１（ウシ由来）も濃度を上げると抑制した。
＊培養条件 ＢＭＥＭ＋１０％ＦＢＳ、５％ＣＯ２濃度、３７ＣType IV collagen NC1 (bovine origin, here using kidney origin), type IV collagen (human origin, here placenta origin, using pepsin treatment, the following three chains) and antibodies (rabbit), which are the main components of the basement membrane Origin, here anti-NC1 antiserum) was examined for anticancer action.
NC1, triple chain and its antiserum were added to a culture of cancer cells (HEPG2) for comparison.
As a result, the triple chain most inhibited the growth of cancer cells. Antiserum (from rabbits) also had a suppressive effect. NC1 (derived from bovine) was also suppressed by increasing the concentration.
細胞「Ｂ１６ マウスメラノーマ（黒色腫）」を用い、「実施例１−１」に準じて培養実験をした。Ｔｙｐｅ Ｉ ｃｏｌｌａｇｅｎ（ヒト胎盤由来、以下の実験も同様）。
細胞「ＦＢＪＬＬ マウスＯｓｔｅｏｃａｒｃｕｎｏｍａ」を用い、「実施例１−１」に準じて培養実験をした。
細胞「ＯＶＣＡＲ４ ヒトＯｖａｒｉａｎ ｃａｎｃｅｒ ｃｅｌｌ」を用い、「実施例１−１」に準じて培養実験をした。
細胞「ＨＴ１０８０ ヒトＦｉｂｒｏｓａｒｃｏｍａ」を用い、「実施例１−１」に準じて培養実験をした。
細胞「ヒト Ｈｕｍａｎ ｇａｓｔｒｉｃ ｃａｒｃｉｎｏｍａ」を用い、「実施例１−１」に準じて培養実験をした。
安全性
コラーゲンの健常者への影響について確認した。健常者ボランテア２名が、豚骨由来コラーゲン（タイプＩコラーゲン８０％以上 コラーゲン技術研修会）約１０％を含有する市販スポーツドリンク（大塚製薬）液を暖め、１日２回食後に約１００ｍｌ（コラーゲン含量約１０ｇ）を１か月服用したが、使用中、使用直後も更に服薬休止１か月後も特段の自覚変化は見られなかった。Safety The effect of collagen on healthy subjects was confirmed. Two healthy volunteers warmed a commercial sports drink (Otsuka Pharmaceutical) solution containing about 10% of pork bone collagen (type I collagen 80% or more, collagen technology workshop), about 100 ml (collagen after twice a day) The content of about 10 g) was taken for 1 month, but no noticeable change was observed during use, immediately after use or even 1 month after taking the drug.
有効性
毎日の散歩を１時間以上行う骨粗鬆症患者３名が充分な同意の上で豚骨由来コラーゲン（タイプＩコラーゲン８０％以上 コラーゲン技術研修会）を市販スポーツドリンク（大塚製薬）液に暖めて溶解し内服した。内服量は、１日３回食後にコラーゲン各５ｇに相当する。
その結果、１名は最短１か月より骨密度が３％上昇し、２ヵ月後には８％の上昇であった。他の２名は変化が見られなかった。Effectiveness Three patients with osteoporosis who take daily walks for more than 1 hour, with sufficient consent, warm and dissolve pork bone-derived collagen (type I collagen 80% or more collagen technology workshop) in a commercial sports drink (Otsuka Pharmaceutical) I took it. The amount of internal use corresponds to 5 g of collagen after eating three times a day.
As a result, one person had a 3% increase in bone density since the shortest month, and an increase of 8% after 2 months. The other two did not change.
有効性
骨折経験のある骨粗鬆症患者（７０才、女子）が事前の充分な同意の上で、豚真皮由来コラーゲン（タイプＩ及びタイプＩＩＩコラーゲン コラーゲン技術研修会）を毎日１回就寝前に、約１０ｇをオレンジジュース４０ｍｌ（ビタミンＣ約１０ｍｇ相当含有）に懸濁させて４０日間内服した。その結果、骨密度が５％上昇した（ＤＥＸＡ法による測定誤差は２％以内）。About 10 g of porcine dermis-derived collagen (type I and type III collagen collagen technical workshop) once a day before going to bed with the prior consent of an osteoporotic patient (70 years old, female) who has experienced an effective fracture. Was suspended in 40 ml of orange juice (containing about 10 mg of vitamin C) and taken for 40 days. As a result, the bone density increased by 5% (measurement error by DEXA method is within 2%).
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