JP6742123B2 - Cancer cell migration inhibitor - Google Patents
Cancer cell migration inhibitor Download PDFInfo
- Publication number
- JP6742123B2 JP6742123B2 JP2016065921A JP2016065921A JP6742123B2 JP 6742123 B2 JP6742123 B2 JP 6742123B2 JP 2016065921 A JP2016065921 A JP 2016065921A JP 2016065921 A JP2016065921 A JP 2016065921A JP 6742123 B2 JP6742123 B2 JP 6742123B2
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- Prior art keywords
- cell migration
- cancer
- cancer cell
- extract
- green tea
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Description
本発明は、癌細胞遊走抑制剤および当該癌細胞遊走抑制剤を用いる癌細胞遊走または癌転移の抑制方法に関する。 The present invention relates to a cancer cell migration inhibitor and a method for suppressing cancer cell migration or cancer metastasis using the cancer cell migration inhibitor.
現在、癌は死亡原因の上位であり、また、年々患者数は増加傾向にある。その中で、癌細胞増殖抑制効果を有する天然物由来の抽出物が見出され、従来の抗癌剤と比べ、安全性が高いことから、副作用の少ない細胞増殖抑制剤およびこれらの成分を含有する抗腫瘍剤(抗癌剤、制癌剤とも呼ばれる)、さらには癌の予防用の健康食品を提供することが期待されている。 Currently, cancer is the leading cause of death, and the number of patients is increasing year by year. Among them, an extract derived from a natural product having a cancer cell growth inhibitory effect has been found, and since it is highly safe as compared with conventional anticancer agents, a cell growth inhibitor with few side effects and an anti-cancer agent containing these components. It is expected to provide a tumor drug (also called an anti-cancer drug or an anti-cancer drug) and a health food for preventing cancer.
また、イヌなどのペットにおいても、近年、家族の一員であるとみなす傾向にあり、2001年の調査では、全体の64%の人が「ペットも家族の一員である」と考え、ライフスタイルが人間に近いものとなっている。その一方で、ペットの平均寿命が延びたことに伴い、腫瘍性疾患が増加している。特にイヌやネコでは、高齢での癌による死亡率が高く、犬種・猫種によっては癌の発症率がヒトよりも高い場合もある。癌の治療法は、人間と同様、外科手術、化学療法、薬物療法、放射線療法、免疫療法などがある。しかし、ペットは、人間と同様、癌にかかっていても初期段階では症状に現れることが少なく、かなり進行してようやく食欲不振やリンパ腫の腫れなどの症状が現れることが多い。また、たとえ癌を外科手術などにより除去したとしても、癌転移の可能性は否定できないため、抗癌剤の投与や定期検査を行う必要がある。しかし、人間のように重要性を認識できないため、抗癌剤の投与や定期検査自体がペットにとってはかなりの負担となるため、飼い主にとってもストレスになる。 In addition, pets such as dogs tend to be considered to be a member of the family in recent years, and a 2001 survey found that 64% of all people thought that "pets are also members of the family" It is close to humans. On the other hand, neoplastic diseases are increasing as the average life span of pets is extended. In particular, dogs and cats have a high mortality rate due to cancer in old age, and depending on the breed of dog or cat, the incidence of cancer may be higher than that of humans. Similar to humans, cancer treatment methods include surgery, chemotherapy, drug therapy, radiation therapy, and immunotherapy. However, like humans, pets rarely show symptoms in the early stages even if they have cancer, and in many cases, pets often show symptoms such as anorexia and swelling of lymphoma at last. Further, even if the cancer is removed by surgery or the like, the possibility of cancer metastasis cannot be ruled out, so it is necessary to administer an anticancer drug or perform regular examinations. However, since it is not possible to recognize the importance like human beings, the administration of anti-cancer agents and the periodic inspection itself impose a considerable burden on pets, which also causes stress to the owner.
このため、癌治療後の転移を抑制できる薬剤が求められている。例えば、特許文献1には、MAST205(セリンスレオニンキナーゼ)に対するRNA干渉作用を有する短鎖二重鎖オリゴヌクレオチドを有効成分として含む癌細胞の遊走阻害剤が報告されている。 Therefore, there is a need for a drug that can suppress metastasis after cancer treatment. For example, Patent Document 1 reports a cancer cell migration inhibitor containing, as an active ingredient, a short double-stranded oligonucleotide having an RNA interference action on MAST205 (serine threonine kinase).
特許文献1に記載の癌細胞の遊走阻害剤は核酸分子である。しかしながら、核酸分子は、近年、その安全性への不安から、一般的に使用されるまでに至らず、むしろ食品に「組換体不使用」などが表示され、その使用が控えられる傾向にある。 The cancer cell migration inhibitor described in Patent Document 1 is a nucleic acid molecule. However, in recent years, nucleic acid molecules have not been generally used due to concerns about their safety, and rather, “non-recombinant” is displayed in foods, and their use tends to be refrained.
本発明は、上記事情をかんがみてなされたものであり、従来公知の癌細胞の遊走阻害剤に代替できかつ安全性の高い癌細胞遊走抑制剤および当該癌細胞遊走抑制剤を用いる癌細胞遊走または癌転移の抑制方法を提供することを目的とする。 The present invention has been made in view of the above circumstances, and a highly safe and highly safe cancer cell migration inhibitor that can substitute for a conventionally known cancer cell migration inhibitor and cancer cell migration using the cancer cell migration inhibitor or It is an object to provide a method for suppressing cancer metastasis.
本発明者らは、上記課題を解決すべく、従来安全性が認められている様々な植物の抽出物を用いて癌細胞遊走抑制効果について鋭意研究を行った。その結果、ローズマリー抽出物と緑茶抽出物とを特定の混合比で併用することによって、癌細胞遊走抑制効果を有意に向上できることを見出し、本発明を完成させた。 In order to solve the above-mentioned problems, the inventors of the present invention have conducted intensive studies on the cancer cell migration inhibitory effect using extracts of various plants which have been conventionally recognized as safe. As a result, they have found that the combined use of a rosemary extract and a green tea extract at a specific mixing ratio can significantly improve the cancer cell migration inhibitory effect, and completed the present invention.
すなわち、上記目的は、緑茶抽出物およびローズマリー抽出物を10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で含む、癌細胞遊走抑制剤によって達成できる。 That is, the above-mentioned object can be achieved by a cancer cell migration inhibitor containing a green tea extract and a rosemary extract in a weight ratio of 10:1 to 1:10 (mixing weight ratio of green tea extract:rosemary extract). ..
また、上記目的は、緑茶抽出物およびローズマリー抽出物を10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で投与することを有する、癌細胞遊走の抑制方法によっても達成できる。 Further, the above-mentioned object comprises administering the green tea extract and the rosemary extract in a weight ratio of 10:1 to 1:10 (mixing weight ratio of the green tea extract:rosemary extract), which is used for the migration of cancer cells. It can also be achieved by a suppression method.
本発明によれば、従来公知の癌細胞の遊走阻害剤に代替できかつ安全性の高い癌細胞遊走抑制剤(癌細胞遊走または癌転移の抑制のための組成物)が提供される。 According to the present invention, there is provided a highly safe cancer cell migration inhibitor (composition for suppressing cancer cell migration or cancer metastasis), which can substitute for a conventionally known cancer cell migration inhibitor and is highly safe.
以下、本発明の実施の形態を説明する。なお、本発明は、以下の実施の形態のみには限定されない。本明細書において、範囲を示す「X〜Y」は、XおよびYを含み、「X以上Y以下」を意味する。また、特記しない限り、操作および物性等の測定は室温(20〜25℃)/相対湿度40〜50%RHの条件で行う。 Embodiments of the present invention will be described below. The present invention is not limited to the following embodiments. In the present specification, “X to Y” indicating a range includes X and Y, and means “X or more and Y or less”. Unless otherwise specified, operations and measurements of physical properties are performed at room temperature (20 to 25° C.)/relative humidity of 40 to 50% RH.
(癌細胞遊走抑制剤および癌細胞遊走の抑制方法)
本発明の癌細胞遊走抑制剤は、緑茶抽出物およびローズマリー抽出物を10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で含む。
(Cancer cell migration inhibitor and method for suppressing cancer cell migration)
The cancer cell migration inhibitor of the present invention contains a green tea extract and a rosemary extract in a weight ratio of 10:1 to 1:10 (mixed green tea extract:rosemary extract weight ratio).
また、本発明の癌細胞遊走の抑制方法は、10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で緑茶抽出物およびローズマリー抽出物を、癌細胞遊走を抑制する必要のある患者に投与することを有する。 In addition, the method for suppressing migration of cancer cells of the present invention uses a green tea extract and a rosemary extract as cancer cells at a weight ratio of 10:1 to 1:10 (green tea extract:rosemary extract mixed weight ratio). Administering to a patient in need of inhibiting migration.
本発明者らは、先の出願(PCT/JP2015/085680)にて、ローズマリー抽出物と緑茶抽出物とを特定の混合比で含む組成物が癌細胞増殖において顕著な抑制効果を示すことを見出した。本発明者らは、この組成物についてさらに鋭意研究を行った結果、当該組成物が癌細胞の遊走を相乗的に抑制または阻害できることを見出した。なお、先の出願(PCT/JP2015/085680)では、上記特定の組成の組成物が癌細胞の増殖抑制に有意な効果を示すことを見出したことに基づくものである。これに対して、本発明では、癌細胞の遊走を抑制または阻害(以下、単に「抑制・阻害」とも称する)することを見出したことに基づくものである。ここで、「細胞の遊走」または「細胞遊走」とは、細胞がその運動能により元の位置から別の位置へと動くことを意味する。これに対して、「細胞の増殖」または「細胞増殖」とは、細胞がその場所で細胞数を増加することを意味する。このため、「細胞の遊走」または「細胞遊走」と、「細胞の増殖」または「細胞増殖」と、は、意味が全く異なり、その発生メカニズムも有意に異なる。ゆえに、特定の組成を有する本発明の組成物が癌細胞遊走を抑制できるという本発明に係る技術思想は、上記と同様の組成の組成物が癌細胞増殖を抑制できるという先の出願に係る技術思想とは異なるものであり、先の出願において、本発明と同様の混合比でローズマリー抽出物と緑茶抽出物との混合物が癌細胞増殖に対して抑制効果を奏したからといって、癌細胞遊走に対しても抑制効果を奏するとは限らない。 In the previous application (PCT/JP2015/085680), the inventors of the present invention have shown that a composition containing a rosemary extract and a green tea extract in a specific mixing ratio exhibits a remarkable inhibitory effect on cancer cell growth. I found it. As a result of further intensive studies on this composition, the present inventors have found that the composition can synergistically suppress or inhibit the migration of cancer cells. In addition, it is based on the finding in the previous application (PCT/JP2015/085680) that the composition of the above-mentioned specific composition exhibits a significant effect in suppressing the growth of cancer cells. On the other hand, the present invention is based on the finding that it suppresses or inhibits the migration of cancer cells (hereinafter, also simply referred to as “suppression/inhibition”). Here, “cell migration” or “cell migration” means that cells move from their original position to another position due to their motility. By contrast, "proliferation of cells" or "cell proliferation" means that the cells increase their number in situ. Therefore, “cell migration” or “cell migration” and “cell growth” or “cell growth” have completely different meanings, and their development mechanisms are significantly different. Therefore, the technical idea according to the present invention that the composition of the present invention having a specific composition can suppress the migration of cancer cells is the technology according to the previous application that the composition having the same composition as the above can suppress the growth of cancer cells. It is different from the idea, and in the previous application, even if the mixture of the rosemary extract and the green tea extract had the inhibitory effect on the cancer cell growth in the same mixing ratio as the present invention, It does not always have an inhibitory effect on cell migration.
上述したように、本発明の癌細胞遊走抑制剤は、癌細胞の遊走を抑制・阻害できる。ここで、癌細胞の遊走は、癌細胞が能動的に移動する現象であり、癌治療の大きな障害となっている癌転移でも生じる現象である。このため、本発明の癌細胞遊走抑制剤は、癌細胞が発生した場所(原発巣)から遊走(移動)して、遠隔部位に再び癌または腫瘍を形成する現象(転移)をも抑制・阻害できると考えられる。したがって、本発明の癌細胞遊走抑制剤は、癌治療(癌切除手術)後の癌転移の抑制または予防にも効果が期待される。このため、本発明は、緑茶抽出物およびローズマリー抽出物を10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で含む癌転移の抑制または予防剤(以下、「癌転移抑制/予防剤」とも称する)を包含する。また、本発明は、10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で緑茶抽出物およびローズマリー抽出物を、癌転移を抑制または予防する必要のある患者に投与することを有する癌転移の抑制または予防方法をも包含する。 As described above, the cancer cell migration inhibitor of the present invention can suppress or inhibit the migration of cancer cells. Here, the migration of cancer cells is a phenomenon in which cancer cells actively move and also occurs in cancer metastasis, which is a major obstacle to cancer treatment. Therefore, the cancer cell migration inhibitor of the present invention also suppresses/inhibits the phenomenon (metastasis) of migrating (migrating) from a place where a cancer cell has occurred (primary focus) and forming a cancer or tumor again at a remote site. It is thought to be possible. Therefore, the cancer cell migration inhibitor of the present invention is also expected to be effective in suppressing or preventing cancer metastasis after cancer treatment (cancer resection surgery). Therefore, the present invention provides an agent for suppressing or preventing cancer metastasis, which comprises a green tea extract and a rosemary extract in a weight ratio of 10:1 to 1:10 (mixing weight ratio of green tea extract: rosemary extract) ( Hereinafter, the term "cancer metastasis inhibitor/preventive agent" is also included. In addition, the present invention requires the use of a green tea extract and a rosemary extract at a weight ratio of 10:1 to 1:10 (mixing weight ratio of green tea extract:rosemary extract) to suppress or prevent cancer metastasis. It also includes a method for suppressing or preventing cancer metastasis, which comprises administering to a patient.
また、本発明の癌細胞遊走抑制剤で使用される緑茶抽出物およびローズマリー抽出物は双方とも、抗酸化剤や香辛料及び機能性を有する抽出物として食品に使用され、日常的に摂取しているものであり、安全性が認められている。このため、本発明の癌細胞遊走抑制剤は、癌細胞遊走を抑制することを目的として、または癌治療(癌切除手術)後の癌転移を抑制または予防することを目的として、健康食品などとして、またはペットフードに混ぜて、日常的に摂取することも可能である。 Further, both the green tea extract and the rosemary extract used in the cancer cell migration inhibitor of the present invention are used in foods as antioxidants, spices and extracts having functionality, and are taken daily. It is present and safety is recognized. Therefore, the cancer cell migration inhibitor of the present invention is used as a health food or the like for the purpose of suppressing cancer cell migration, or for suppressing or preventing cancer metastasis after cancer treatment (cancer resection surgery). Or, it can be mixed with pet food and taken daily.
すなわち、本発明によれば、従来公知の癌細胞遊走抑制に代替しうる、安全な癌細胞遊走抑制剤(癌転移の抑制・予防剤)が提供される。 That is, according to the present invention, there is provided a safe cancer cell migration inhibitor (suppressant/prevention agent for cancer metastasis) that can substitute for the conventionally known suppression of cancer cell migration.
本明細書において、「癌細胞の遊走」または「癌細胞遊走」とは、癌細胞がその運動能により癌細胞が発生した場所(原発巣)から別の位置へと動くことを意味する。細胞遊走の種類としては、細胞がケモカインなどの走化性因子の濃度勾配によって遊走するケモタキシス(Chemotaxis、走化性)、細胞が細胞接着サイトもしくは、細胞外マトリックスに結合した走化性因子の濃度勾配に従って遊走するハプトタキシス(Haptotaxis、走触性)、細胞が創傷の間を渡って遊走する創傷治癒(Wound Healing)、および細胞が細胞外マトリックス(ECM)分解やタンパク質分解を介して、ECMを通って近接する組織へ移動する細胞浸潤(Invasion)がある。このため、癌細胞遊走抑制効果は、公知の方法、例えば、ラッフル膜の形成阻害、創傷治癒アッセイを用いて、または市販の細胞遊走測定システムを用いて評価できる。本明細書では、癌細胞遊走抑制効果を創傷治癒アッセイを用いて評価する。 In the present specification, “cancer cell migration” or “cancer cell migration” means that a cancer cell moves from a place where the cancer cell has occurred (primary focus) to another position due to its motility. Types of cell migration include chemotaxis (Chemotaxis), in which cells migrate according to the concentration gradient of chemokine and other chemotactic factors, and the concentration of chemotactic factors in which cells bind to cell adhesion sites or extracellular matrix. Haptotaxis, which migrates according to the gradient, Wound Healing, in which cells migrate between wounds, and cells pass through the ECM through extracellular matrix (ECM) degradation and proteolysis. Cell invasion (Invasion) that migrates to adjacent tissues. Therefore, the cancer cell migration inhibitory effect can be evaluated using a known method, for example, inhibition of formation of a raffle membrane, a wound healing assay, or a commercially available cell migration measurement system. Here, the cancer cell migration inhibitory effect is evaluated using a wound healing assay.
本発明の癌細胞遊走抑制剤は、緑茶抽出物およびローズマリー抽出物を10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で含む。緑茶抽出物およびローズマリー抽出物の混合比が上記範囲を外れると、緑茶抽出物単独またはローズマリー抽出物単独に比して、癌細胞遊走抑制効果の有意な差が認められない。ここで、癌細胞遊走抑制効果のより顕著な相乗効果の達成の観点から、癌細胞遊走抑制剤は、緑茶抽出物およびローズマリー抽出物を、好ましくは5:1〜1:5、より好ましくは4:1〜1:4の重量比、さらにより好ましくは3:1〜1:3の重量比、さらに好ましくは2:1〜1:2の重量比、特に好ましくはおおよそ1:1(実質的に等量)(緑茶抽出物:ローズマリー抽出物の混合重量比)で含む。上記混合重量比では、緑茶抽出物とローズマリー抽出物との併用による癌細胞遊走抑制効果が特に相乗的に達成できる。 The cancer cell migration inhibitor of the present invention contains a green tea extract and a rosemary extract in a weight ratio of 10:1 to 1:10 (mixed green tea extract:rosemary extract weight ratio). When the mixing ratio of the green tea extract and the rosemary extract is out of the above range, no significant difference in the cancer cell migration inhibitory effect is observed as compared with the green tea extract alone or the rosemary extract alone. Here, from the viewpoint of achieving a more remarkable synergistic effect of the cancer cell migration inhibitory effect, the cancer cell migration inhibitor is a green tea extract and a rosemary extract, preferably 5:1 to 1:5, more preferably 4:1 to 1:4 weight ratio, even more preferably 3:1 to 1:3 weight ratio, even more preferably 2:1 to 1:2 weight ratio, particularly preferably about 1:1 (substantially The same amount) (mixed weight ratio of green tea extract: rosemary extract). With the above mixing weight ratio, the effect of suppressing the migration of cancer cells by the combined use of the green tea extract and the rosemary extract can be particularly synergistically achieved.
ここで、癌細胞遊走抑制剤の治療対象(癌細胞遊走または癌転移を抑制する必要のある患者)は、特に制限されないが、哺乳動物や鳥類、好ましくは癌に罹患した哺乳動物や鳥類である。ここで、哺乳動物は、ヒト、サル、ゴリラ、チンパンジー、オランウータン等の霊長類、ならびにマウス、ラット、ハムスター、モルモット、ウサギ、イヌ、ネコ、ブタ、ウシ、ウマ、ヒツジ、ラクダ、ヤギなどの非ヒト哺乳動物双方を包含する。鳥類としては、ニワトリ、ウズラ、ハトなどが挙げられる。これらのうち、好ましくは、ヒト、ハムスター、モルモット、ウサギ、イヌ、ネコ、ブタであり、より好ましくは、ヒト及びイヌ、ネコ、ウサギ等のペット動物である。すなわち、本発明の好ましい形態によると、本発明の癌細胞遊走抑制剤は、ヒトまたはイヌ、ネコ、ウサギからなる群より選択される少なくとも一種のペット動物に経口的に使用される。本発明のより好ましい形態によると、本発明の癌細胞遊走抑制剤は、ヒト、イヌ、またはネコに経口的に使用される。本発明の特に好ましい形態によると、本発明の癌細胞遊走抑制剤は、イヌまたはネコに経口的に使用される。 Here, the target to be treated with the cancer cell migration inhibitor (patient in need of suppressing cancer cell migration or cancer metastasis) is not particularly limited, but is a mammal or a bird, preferably a mammal suffering from cancer or a bird. .. Here, mammals include primates such as humans, monkeys, gorillas, chimpanzees, orangutans, and non-human animals such as mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, pigs, cows, horses, sheep, camels, and goats. Includes both human mammals. Examples of birds include chickens, quails, pigeons, and the like. Of these, humans, hamsters, guinea pigs, rabbits, dogs, cats, and pigs are preferable, and humans and pet animals such as dogs, cats, and rabbits are more preferable. That is, according to a preferred embodiment of the present invention, the cancer cell migration inhibitor of the present invention is orally used for humans or at least one pet animal selected from the group consisting of dogs, cats, and rabbits. According to a more preferred form of the present invention, the cancer cell migration inhibitor of the present invention is orally used in humans, dogs or cats. According to a particularly preferred embodiment of the present invention, the cancer cell migration inhibitor of the present invention is orally used in dogs or cats.
本発明の癌細胞遊走抑制剤は、癌細胞遊走を抑制・阻害するため、癌治療の大きな障害となっている癌転移に対しても抑制・阻害効果が期待される。すなわち、本発明の癌細胞遊走抑制剤は、癌転移の抑制および/または予防(本明細書では、単に「癌転移の抑制/予防」とも称する)にも効果があると考えられる。このため、本発明の癌細胞遊走抑制剤は、癌転移の抑制/予防剤としても有用である。本明細書において、「癌の転移」とは、癌が原発巣から分離して、別の組織や臓器に移動し、そこで増殖することを意味する。また、「癌転移の抑制」または「癌転移抑制」とは、癌細胞が発生した場所(原発巣)から移動(遊走)して、遠隔部位に再び腫瘍を形成する現象(転移)を抑制することを意味する。また、「癌転移の予防」または「癌転移予防」とは、癌や腫瘍の転移を防止若しくは遅延させる、または癌や腫瘍の転移の危険性を低下させることを意味する。ゆえに、本明細書において、「癌転移抑制/予防剤」とは、癌治療(例えば、癌摘出手術)後に上記癌転移の抑制/予防効果を示す薬剤を意味する。 Since the cancer cell migration inhibitor of the present invention suppresses/inhibits cancer cell migration, it is expected to have an inhibitory/inhibitory effect also on cancer metastasis, which is a major obstacle to cancer treatment. That is, it is considered that the cancer cell migration inhibitor of the present invention is also effective in inhibiting and/or preventing cancer metastasis (herein, also simply referred to as “inhibition/prevention of cancer metastasis”). Therefore, the cancer cell migration inhibitor of the present invention is also useful as an agent for inhibiting/preventing cancer metastasis. As used herein, the term “metastasis of cancer” means that cancer is separated from the primary focus, migrates to another tissue or organ, and grows there. In addition, “suppression of cancer metastasis” or “suppression of cancer metastasis” refers to suppression of a phenomenon (metastasis) in which a cancer cell migrates (migrates) from the place where it originates (primary nest) and forms a tumor again at a remote site. Means that. Further, “prevention of cancer metastasis” or “prevention of cancer metastasis” means preventing or delaying the metastasis of cancer or tumor, or reducing the risk of metastasis of cancer or tumor. Therefore, in the present specification, the “cancer metastasis suppressive/preventive agent” means a drug exhibiting the suppressive/preventive effect of the above-mentioned cancer metastasis after cancer treatment (for example, surgery for removing cancer).
上述したように、癌細胞遊走抑制剤で使用される緑茶抽出物およびローズマリー抽出物は双方とも、抗酸化剤や香辛料及び機能性を有する抽出物として食品に使用され、日常的に摂取しているものであり、安全性が認められている。このため、本発明の癌細胞遊走抑制剤は、癌細胞遊走の抑制を目的として、または癌転移の予防もしくは抑制を目的として、健康食品などとして、またはペットフードに混ぜて、日常的に摂取することも可能である。すなわち、本発明の好ましい形態によると、本発明の癌細胞遊走抑制剤は、ヒト用健康食品またはペットフード組成物である。 As described above, both the green tea extract and the rosemary extract used in the cancer cell migration inhibitor are used in foods as antioxidants, spices, and functional extracts, and can be taken daily. It is present and safety is recognized. Therefore, the cancer cell migration inhibitor of the present invention is ingested on a daily basis for the purpose of suppressing cancer cell migration, or for the purpose of preventing or suppressing cancer metastasis, as a health food, or mixed with pet food. It is also possible. That is, according to a preferred embodiment of the present invention, the cancer cell migration inhibitor of the present invention is a human health food or pet food composition.
ここで、(癌転移の抑制/予防のための)癌細胞遊走抑制剤の対象となる癌の種類は、特に限定されない。例えば、神経系の癌(例えば、脳腫瘍、頚癌);消化器系の癌(例えば、口腔癌、咽頭癌、食道癌、胃癌、肝癌、胆嚢癌、胆道癌、脾臓癌、大腸癌、小腸癌、十二指腸癌、結腸癌、結腸腺癌、直腸癌、膵臓癌、肝臓癌);筋骨格系の癌(例えば、肉腫、骨肉種、骨髄腫);泌尿器系の癌(例えば、膀胱癌、腎癌);生殖器系の癌(例えば、乳癌、子宮癌、卵巣癌、精巣癌、前立腺癌);呼吸器系の癌(例えば、肺癌);造血器系の癌(例えば、急性または慢性骨髄性白血病、急性前骨髄性白血病、急性または慢性リンパ性白血病等の白血病、悪性リンパ腫(リンパ肉腫)、血管肉腫、多発性骨髄腫、骨髄異形成症候群、原発性骨髄線維症、血管外膜細胞腫);甲状腺癌、副甲状腺癌、舌癌、悪性黒色腫(メラノーマ)、肥満細胞腫、皮膚組織球腫、脂肪腫、毛包腫瘍、皮膚乳頭腫、皮脂腺腫、基底細胞癌などが挙げられる。これらのうち、本発明の癌細胞遊走抑制剤は、造血器系の癌、消化器系の癌、生殖器系の癌、悪性黒色腫(メラノーマ)、肥満細胞腫、基底細胞癌に対してより高い効果を有する。すなわち、本発明の好ましい形態によると、本発明の癌細胞遊走抑制剤は、造血器系の癌、消化器系の癌、生殖器系の癌、悪性黒色腫(メラノーマ)、肥満細胞腫および基底細胞癌からなる群より選択される少なくとも一種の疾患の転移の抑制および/または予防に使用される。本発明のより好ましい形態によると、本発明の癌細胞遊走抑制剤は、造血器系の癌または消化器系の癌の転移の抑制および/または予防に使用される。本発明の特に好ましい形態によると、本発明の癌細胞遊走抑制剤は、消化器系の癌の転移の抑制および/または予防に使用される。 Here, the type of cancer targeted by the cancer cell migration inhibitor (for suppressing/preventing cancer metastasis) is not particularly limited. For example, cancer of nervous system (eg, brain tumor, cervical cancer); cancer of digestive system (eg, oral cancer, pharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, spleen cancer, colon cancer, small intestine cancer) , Duodenal cancer, colon cancer, colon adenocarcinoma, rectal cancer, pancreatic cancer, liver cancer); musculoskeletal cancer (eg, sarcoma, osteosarcoma, myeloma); urinary system cancer (eg, bladder cancer, renal cancer) ); genital cancer (eg, breast cancer, uterine cancer, ovarian cancer, testicular cancer, prostate cancer); respiratory cancer (eg lung cancer); hematopoietic cancer (eg acute or chronic myelogenous leukemia, Acute promyelocytic leukemia, leukemias such as acute or chronic lymphocytic leukemia, malignant lymphoma (lymphosarcoma), angiosarcoma, multiple myeloma, myelodysplastic syndrome, primary myelofibrosis, adventitial cell tumor); thyroid Cancer, parathyroid cancer, tongue cancer, malignant melanoma, mastocytoma, cutaneous histiocytoma, lipoma, hair follicle tumor, cutaneous papilloma, sebaceous adenoma, basal cell carcinoma and the like can be mentioned. Among these, the cancer cell migration inhibitor of the present invention is higher for hematopoietic cancer, digestive cancer, reproductive cancer, malignant melanoma (melanoma), mastocytoma, basal cell cancer Have an effect. That is, according to a preferred embodiment of the present invention, the cancer cell migration inhibitor of the present invention comprises hematopoietic cancer, digestive cancer, reproductive cancer, malignant melanoma (melanoma), mastocytoma and basal cell. It is used for suppressing and/or preventing metastasis of at least one disease selected from the group consisting of cancer. According to a more preferred embodiment of the present invention, the cancer cell migration inhibitor of the present invention is used for inhibiting and/or preventing metastasis of hematopoietic cancer or digestive cancer. According to a particularly preferred embodiment of the present invention, the cancer cell migration inhibitor of the present invention is used for suppressing and/or preventing metastasis of cancer of the digestive system.
(緑茶抽出物)
本発明の癌細胞遊走抑制剤の有効成分である緑茶抽出物は、チャノキ(Camellia sinensis)(全体または一部)を適当な溶媒を用い抽出することによって、得られる。ここで、抽出の対象となるチャノキの部分は、特に制限されず、植物体全体、葉、茎、芽、花(ガク、花弁、めしべ、おしべ等を含む)、木質部、木皮部(樹皮)、果実(花托(果肉)、子房、果皮(内果皮、中果皮、外果皮)等を含む)、種子等の地上部;根、根茎、塊茎等の地下部などの植物体の一部などを包含する。上記植物の部分は、単独で抽出に供せられてもあるいは2種以上の混合物の形態で抽出に供せられてもよい。これらのうち、癌細胞遊走抑制/防止効果、安全性などを考慮すると、チャノキの葉(茶葉)を原料として使用することが好ましい。または、チャノキの葉(茶葉)を発酵を防止するために加熱処理したものを抽出に使用してもよい。具体的には、抽出の対象となるチャノキの部分は、チャノキの生葉(茶葉)を蒸して揉み潰し、茶葉の型を整えつつ乾燥する(蒸熱⇒冷却⇒葉打ち⇒粗揉⇒揉捻⇒中揉⇒精捻⇒乾燥⇒篩分と切断⇒木茎分離)ことによって作製される。なお、本明細書では、抽出の対象となるチャノキの部分を、単に「緑茶原料」とも称する。
(Green tea extract)
The green tea extract, which is an active ingredient of the cancer cell migration inhibitor of the present invention, can be obtained by extracting Camellia sinensis (all or part) using a suitable solvent. Here, the part of tea tree to be extracted is not particularly limited, and the whole plant body, leaves, stems, buds, flowers (including gaku, petals, pistil, stamen, etc.), wood part, bark part (bark), Fruits (including husks (flesh), ovary, pericarp (inner skin, mesocarp, outer skin) etc.), above-ground parts such as seeds; parts of plant bodies such as roots, rhizomes and underground parts such as tubers Include. The plant part may be subjected to extraction alone or in the form of a mixture of two or more kinds. Among these, considering the effect of suppressing/preventing migration of cancer cells, safety and the like, it is preferable to use tea leaves as a raw material. Alternatively, tea leaves (tea leaves) that have been heat-treated to prevent fermentation may be used for extraction. Specifically, the part of the tea tree that is the target of extraction is steamed and mashed raw leaves (tea leaves) of tea tree, and dried while adjusting the shape of the tea leaves (steaming ⇒ cooling ⇒ leafing ⇒ rough massage ⇒ massage ⇒ middle massage) ⇒Refining ⇒drying ⇒sieving and cutting ⇒separation of tree stems). In addition, in the present specification, a portion of the tea tree that is the target of extraction is also simply referred to as “green tea raw material”.
また、緑茶原料は、そのままの形態で抽出に供されてもよいが、抽出に供される前に、予め乾燥および/または粉砕されてもよい。これにより、緑茶原料から所望の有効成分をより効率よく抽出できる。 The green tea raw material may be subjected to extraction as it is, but may be dried and/or pulverized in advance before being subjected to extraction. Thereby, the desired active ingredient can be more efficiently extracted from the green tea raw material.
ここで、緑茶原料を予め乾燥する際の、乾燥条件は、特に制限されない。粉砕されやすさなどを考慮すると、乾燥温度は、好ましくは20〜90℃であり、より好ましくは25〜80℃である。また、乾燥時間は、好ましくは24〜120時間であり、より好ましくは48〜96時間である。または、緑茶原料を、凍結乾燥粉末化法、高圧法、超高圧法等の方法によって、乾燥してもよい。このうち、高圧法は、例えば、100〜150℃で2〜10時間(例えば、120℃で4時間)の高圧加熱処理することにより、緑茶原料中の細胞を加圧破砕する方法である。 Here, the drying conditions for previously drying the green tea raw material are not particularly limited. Considering the crushability and the like, the drying temperature is preferably 20 to 90°C, more preferably 25 to 80°C. The drying time is preferably 24 to 120 hours, more preferably 48 to 96 hours. Alternatively, the green tea raw material may be dried by a freeze-drying powdering method, a high-pressure method, an ultra-high-pressure method, or the like. Among them, the high-pressure method is a method in which cells in the green tea raw material are pressure-crushed by performing high-pressure heat treatment at 100 to 150° C. for 2 to 10 hours (for example, 120° C. for 4 hours).
また、緑茶原料を予め粉砕する際の、粉砕条件もまた、特に制限されない。抽出効率などを考慮すると、0.1〜10mm程度の大きさ、より好ましくは0.5〜5mm程度の大きさにまで、所定の植物の部分(緑茶原料)を粉砕できることが好ましい。粉砕方法としては、裁断機、スライサー、カッター、ピーラー、ジョークラッシャー、ジェットミル、ブレンダーなどで細断する方法などが挙げられる。 In addition, the crushing conditions for crushing the green tea raw material in advance are also not particularly limited. Considering extraction efficiency and the like, it is preferable that a predetermined plant part (green tea raw material) can be pulverized to a size of about 0.1 to 10 mm, more preferably about 0.5 to 5 mm. Examples of the crushing method include a method of shredding with a cutter, a slicer, a cutter, a peeler, a jaw crusher, a jet mill, a blender, and the like.
次に、必要であれば予め乾燥および/または粉砕した緑茶原料を、適当な溶媒を用いて抽出する。ここで使用できる溶媒は、緑茶原料から有効成分を抽出できるものであれば特に制限されず、使用される植物や植物の部分に応じて適宜選択される。具体的には、水(水道水、工業用水、蒸留水、逆浸透膜水、濾過水、滅菌水、精製水等を含む);メタノール、エタノール、1−プロパノール、2−プロパノール、1−ブタノール、2−ブタノール、プロピレングリコール、1,3−ブチレングリコール等のアルコール;酢酸メチル、酢酸エチル等のエステル;アセトン等のケトン;エチルエーテル、ホルムアルデヒド、ジメチルスルホキシドなどが挙げられる。上記溶媒は、単独で使用されてもあるいは2種以上の混合溶媒の形態で使用されてもよい。これらのうち、抽出効率、安全性などを考慮すると、水、エタノールまたは水とエタノールとの混合液が抽出溶媒として好ましい。すなわち、本発明の好ましい形態では、抽出物は、前記緑茶原料の、水、エタノールまたは水とエタノールとの混合液による抽出物である。 Next, if necessary, the previously dried and/or ground green tea raw material is extracted with a suitable solvent. The solvent that can be used here is not particularly limited as long as it can extract the active ingredient from the green tea raw material, and is appropriately selected depending on the plant or plant part to be used. Specifically, water (including tap water, industrial water, distilled water, reverse osmosis membrane water, filtered water, sterile water, purified water, etc.); methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, Examples include alcohols such as 2-butanol, propylene glycol and 1,3-butylene glycol; esters such as methyl acetate and ethyl acetate; ketones such as acetone; ethyl ether, formaldehyde, dimethyl sulfoxide and the like. The above solvents may be used alone or in the form of a mixed solvent of two or more kinds. Of these, water, ethanol, or a mixed solution of water and ethanol is preferable as the extraction solvent in consideration of extraction efficiency and safety. That is, in a preferred embodiment of the present invention, the extract is an extract of the green tea raw material with water, ethanol or a mixed liquid of water and ethanol.
また、抽出は、1回のみ行われてもあるいは2回以上行われてもよい。後者の場合、各抽出工程は、いずれの溶媒を使用してもよく、また、各工程における抽出条件は同一であってもあるいは異なってもよい。水、熱水、エタノールまたは水とエタノールとの混合液による抽出を少なくとも2回行うことが好ましく、水または熱水による抽出後、エタノールまたは水とエタノールとの混合液による抽出を行うことがより好ましく、熱水による抽出後、エタノールによる抽出を行うことが特に好ましい。当該方法により有効成分(活性成分である茶ポリフェノール)の純度をさらに向上できる。 Moreover, the extraction may be performed only once, or may be performed twice or more. In the latter case, any solvent may be used in each extraction step, and the extraction conditions in each step may be the same or different. Extraction with water, hot water, ethanol or a mixed solution of water and ethanol is preferably performed at least twice, and more preferably extraction with water or a mixed solution of water and ethanol is performed after extraction with water or hot water. It is particularly preferable to carry out extraction with ethanol after extraction with hot water. By this method, the purity of the active ingredient (tea polyphenol which is the active ingredient) can be further improved.
なお、必要であれば、緑茶原料を酸性またはアルカリ性条件下で抽出してもよい、即ち、酸性またはアルカリ性の溶媒を使用してもよい。ここで、酸性溶媒を調製する際に使用できる酸としては、特に制限されないが、塩酸、硫酸、硝酸、リン酸等の無機酸、酢酸、クエン酸、シュウ酸、コハク酸、ギ酸、プロピオン酸等の有機酸などが挙げられる。また、アルカリ性溶媒を調製する際に使用できるアルカリとしては、特に制限されないが、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウムなどが挙げられる。緑茶原料を酸性またはアルカリ性条件下で抽出する際の溶媒のpHは、使用される植物及び植物の部分の種類、抽出条件などを考慮して、適宜選択される。また、酸性溶媒またはアルカリ性溶媒を使用した場合には、抽出後に、抽出液を中性(pH=7±1程度)になるように中和することが好ましい。 If necessary, the green tea raw material may be extracted under acidic or alkaline conditions, that is, an acidic or alkaline solvent may be used. Here, the acid that can be used when preparing the acidic solvent is not particularly limited, but inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, succinic acid, formic acid, propionic acid, etc. Examples of organic acids include The alkali that can be used when preparing the alkaline solvent is not particularly limited, and examples thereof include potassium hydroxide, sodium hydroxide and sodium carbonate. The pH of the solvent used when extracting the green tea raw material under acidic or alkaline conditions is appropriately selected in consideration of the types of plants and plant parts to be used, extraction conditions, and the like. When an acidic solvent or an alkaline solvent is used, it is preferable to neutralize the extract after the extraction so that the extract becomes neutral (pH=about 7±1).
溶媒の添加量は、緑茶原料から有効成分を抽出できるものであれば特に制限されない。具体的には、溶媒を、緑茶原料10gに対して、10〜1000mlの量、より好ましくは50〜500mlの量を添加することが好ましい。 The amount of the solvent added is not particularly limited as long as the active ingredient can be extracted from the green tea raw material. Specifically, it is preferable to add the solvent in an amount of 10 to 1000 ml, more preferably 50 to 500 ml, based on 10 g of the green tea raw material.
また、抽出条件もまた、緑茶原料から有効成分を抽出できるものであれば特に制限されない。具体的には、抽出温度は、好ましくは25〜100℃、より好ましくは40〜100℃である。また、抽出時間は、好ましくは30分〜6時間、より好ましくは1〜4時間である。このような条件であれば、緑茶原料から有効成分を効率よく抽出できる。 The extraction conditions are also not particularly limited as long as the active ingredient can be extracted from the green tea raw material. Specifically, the extraction temperature is preferably 25 to 100°C, more preferably 40 to 100°C. The extraction time is preferably 30 minutes to 6 hours, more preferably 1 to 4 hours. Under such conditions, the active ingredient can be efficiently extracted from the green tea raw material.
上記抽出工程後は、緑茶原料及び溶媒の混合液から、固形物(緑茶原料残渣)を除去して、抽出液を分離する。ここで、分離方法としては、特に制限されないが、濾過、遠心分離などが挙げられる。さらに、この抽出液は、そのまま使用してもよいが、必要であれば、希釈液による希釈形態、濃縮によるエキス、ペースト若しくは固体形態、凍結による凍結物形態、凍結乾燥による乾燥粉末物形態など、様々な形態(抽出物)に変換してもよい。ここで、変換方法は、単独で適用してもあるいは2種以上を組み合わせて適用してもよい。好ましくは、抽出液を適当な濃度になるまで濃縮(例えば、減圧濃縮)し、得られた濃縮物を凍結した後、凍結乾燥する方法や抽出液を微細な霧状にし、これを熱風中に噴出させ、瞬間的に粉状の乾燥物を得る方法が好ましく使用される。 After the extraction step, the solid matter (green tea raw material residue) is removed from the mixed solution of the green tea raw material and the solvent to separate the extract. Here, the separation method is not particularly limited, but examples thereof include filtration and centrifugation. Furthermore, this extract may be used as it is, but if necessary, it may be diluted with a diluent, extract by concentration, paste or solid form, frozen product form by freezing, dry powder product form by freeze-drying, etc. It may be converted into various forms (extracts). Here, the conversion method may be applied alone or in combination of two or more kinds. Preferably, the extract is concentrated to an appropriate concentration (for example, concentrated under reduced pressure), the obtained concentrate is frozen, and then freeze-dried, or the extract is made into a fine mist, which is then placed in hot air. A method of jetting and instantaneously obtaining a powdery dried product is preferably used.
また、抽出液または抽出物はさらに精製してもよい。ここで、精製方法としては、特に制限されず、公知の精製方法が使用できる。具体的には、塩化セチルピリジニウムなどの4級アンモニウム塩を添加して沈殿物を得、この沈殿物を適当な溶媒(例えば、水、アルコール)で洗浄する方法、陰イオン交換クロマトグラフィー、陽イオン交換クロマトグラフィー、ホスホセルロースクロマトグラフィー、疎水性反応(疎水性相互作用)によるクロマトグラフィー、アフィニティークロマトグラフィー、ヒドロキシアパタイトクロマトグラフィーやレクチンクロマトグラフィーなどを用いたクロマトグラフィーを用いる方法、再結晶法などが挙げられる。 The extract or extract may be further purified. Here, the purification method is not particularly limited, and a known purification method can be used. Specifically, a method in which a quaternary ammonium salt such as cetylpyridinium chloride is added to obtain a precipitate, and the precipitate is washed with a suitable solvent (eg, water or alcohol), anion exchange chromatography, cation Exchange chromatography, phosphocellulose chromatography, chromatography by hydrophobic reaction (hydrophobic interaction), affinity chromatography, chromatography using hydroxyapatite chromatography and lectin chromatography, recrystallization method, etc. To be
なお、ペット動物(例えば、イヌ)にカフェインを与えると、頻脈、震え・痙攣、不整脈、過度な興奮、下痢などの症状を引き起こすことがある。このため、本発明の癌細胞遊走抑制剤をペットフード(例えば、イヌ用)に使用する場合には、癌細胞遊走抑制剤は、カフェインを可能な限り含まないことが好ましい。具体的には、緑茶抽出物中のカフェインの含有量は、好ましくは5重量%以下、より好ましくは2.5重量%以下、さらにより好ましくは1重量%以下、特に好ましくは0.5重量%以下(下限:0重量%)である。このため、上述したようにして緑茶原料から抽出する前後にカフェインを低減または除去してもよい。ここで、カフェインの低減または除去方法は特に制限されず、公知の方法が同様にしてあるいは適宜修飾して使用できる。具体的には、特開2014−140351号公報、特開2013−209428号公報、特開2008−212024号公報などの公知の方法が挙げられる。 When caffeine is given to pet animals (eg, dogs), symptoms such as tachycardia, tremors/convulsions, arrhythmia, excessive excitement, and diarrhea may occur. Therefore, when the cancer cell migration inhibitor of the present invention is used in pet food (for example, for dogs), it is preferable that the cancer cell migration inhibitor does not contain caffeine as much as possible. Specifically, the content of caffeine in the green tea extract is preferably 5% by weight or less, more preferably 2.5% by weight or less, even more preferably 1% by weight or less, particularly preferably 0.5% by weight. % Or less (lower limit: 0% by weight). Therefore, caffeine may be reduced or removed before and after extraction from the green tea raw material as described above. Here, the method for reducing or removing caffeine is not particularly limited, and known methods can be used in the same manner or modified appropriately. Specifically, known methods such as JP-A-2014-140351, JP-A-2013-209428 and JP-A-2008-212024 can be mentioned.
または、緑茶抽出物は、市販品であってもよい。市販品としては、緑茶エキス末(松浦薬業株式会社製)、サンフード(登録商標)末、サンフード(登録商標)100、サンフード(登録商標)CD、サンフード(登録商標)水性、サンフード(登録商標)油性等のサンフード(登録商標)シリーズ(いずれも三菱化学フーズ株式会社製)、緑茶抽出物MF(丸善製薬株式会社製)、サンフェノン(登録商標)30S−OP、サンフェノン(登録商標)30LB−OP、サンフェノン(登録商標)EGCG−OP、サンフェノン(登録商標)BG−3、サンフェノン(登録商標)90LB−OP、サンフェノン(登録商標)90S、サンフェノン(登録商標)90MB−OP、サンフェノン(登録商標)CF−T−OP、サンフェノン(登録商標)NB−60、等のサンフェノン(登録商標)シリーズ(いずれも太陽化学株式会社製)、ポリフェノンG、ポリフェノン70A等のポリフェノン(登録商標)シリーズ、サンカテキン水性F、サンカテキン油性E、GTA−MNK−1(いずれも三井農林株式会社製)、茶抽出物−40、茶抽出物−70、茶抽出物(脱カフェイン品)(いずれもタマ生化学株式会社製)などが挙げられる。 Alternatively, the green tea extract may be a commercial product. Commercially available products include green tea extract powder (Matsuura Pharmaceutical Co., Ltd.), sun hood (registered trademark) powder, sun hood (registered trademark) 100, sun hood (registered trademark) CD, sun hood (registered trademark) aqueous solution, sun Sun Food (registered trademark) series such as Food (registered trademark) oil (all manufactured by Mitsubishi Kagaku Foods Co., Ltd.), green tea extract MF (manufactured by Maruzen Pharmaceutical Co., Ltd.), Sunphenon (registered trademark) 30S-OP, Sunphenon (registered trademark) Trademark) 30LB-OP, Sanphenon (registered trademark) EGCG-OP, Sanphenon (registered trademark) BG-3, Sanphenon (registered trademark) 90LB-OP, Sanphenon (registered trademark) 90S, Sunphenon (registered trademark) 90MB-OP, Sanphenon (Registered trademark) CF-T-OP, Sanphenon (registered trademark) NB-60, etc., Sanphenon (registered trademark) series (all manufactured by Taiyo Kagaku Co., Ltd.), polyphenon G, polyphenone (registered trademark) series such as 70A. , Sancatechin Aqueous F, Sancatechin Oil E, GTA-MNK-1 (all manufactured by Mitsui Norin Co., Ltd.), Tea Extract-40, Tea Extract-70, Tea Extract (decaffeinated) (all Tama Seikagaku Co., Ltd.) and the like.
上記緑茶抽出物は、単独で使用されてもあるいは2種以上の混合物の形態で使用されてもよい。 The green tea extract may be used alone or in the form of a mixture of two or more kinds.
(ローズマリー抽出物)
本発明の癌細胞遊走抑制剤の有効成分であるローズマリー抽出物は、ローズマリー(Rosmarinus officinalis L.)(全体または一部)を適当な溶媒を用い抽出することによって、得られる。ここで、抽出の対象となるローズマリーの部分は、特に制限されず、植物体全体、葉、茎、芽、花(ガク、花弁、めしべ、おしべ等を含む)、木質部、木皮部(樹皮)、果実(花托(果肉)、子房、果皮(内果皮、中果皮、外果皮)等を含む)、種子等の地上部;根、根茎、塊茎等の地下部などの植物体の一部などを包含する。上記植物の部分は、単独で抽出に供せられてもあるいは2種以上の混合物の形態で抽出に供せられてもよい。これらのうち、癌細胞遊走抑制/防止効果、安全性などを考慮すると、ローズマリーの葉を原料として使用することが好ましい。なお、本明細書では、抽出の対象となるローズマリーの部分を、単に「ローズマリー原料」とも称する。
(Rosemary extract)
The rosemary extract, which is an active ingredient of the cancer cell migration inhibitor of the present invention, can be obtained by extracting rosemary (Rosmarinus officinalis L.) (all or part) with an appropriate solvent. Here, the portion of the rosemary to be extracted is not particularly limited, and the whole plant body, leaves, stems, buds, flowers (including rattle, petals, pistil, stamen, etc.), wood part, bark part (bark) , Fruits (including husks (flesh), ovary, pericarp (inner skin, mesocarp, outer pericarp), etc.), above-ground parts such as seeds; parts of plant bodies such as roots, rhizomes, underground parts such as tubers, etc. Includes. The plant part may be subjected to extraction alone or in the form of a mixture of two or more kinds. Of these, rosemary leaves are preferably used as a raw material in consideration of the effect of suppressing/preventing cancer cell migration, safety, and the like. In addition, in this specification, the part of the rosemary to be extracted is also simply referred to as “rosemary raw material”.
また、ローズマリー原料は、そのままの形態で抽出に供されてもよいが、抽出に供される前に、予め乾燥および/または粉砕されてもよい。これにより、ローズマリー原料から所望の有効成分をより効率よく抽出できる。 The rosemary raw material may be subjected to extraction as it is, but may be dried and/or pulverized in advance before being subjected to extraction. Thereby, the desired active ingredient can be more efficiently extracted from the rosemary raw material.
ここで、ローズマリー原料を予め乾燥する際の、乾燥条件は、特に制限されない。粉砕されやすさなどを考慮すると、乾燥温度は、好ましくは20〜90℃であり、より好ましくは25〜80℃である。また、乾燥時間は、好ましくは24〜120時間であり、より好ましくは48〜96時間である。または、ローズマリー原料を、凍結乾燥粉末化法、高圧法、超高圧法等の方法によって、乾燥してもよい。このうち、高圧法は、例えば、100〜150℃で2〜10時間(例えば、120℃で4時間)の高圧加熱処理することにより、ローズマリー原料中の細胞を加圧破砕する方法である。 Here, the drying conditions for drying the rosemary raw material in advance are not particularly limited. Considering the crushability and the like, the drying temperature is preferably 20 to 90°C, more preferably 25 to 80°C. The drying time is preferably 24 to 120 hours, more preferably 48 to 96 hours. Alternatively, the rosemary raw material may be dried by a freeze-drying powdering method, a high-pressure method, an ultra-high-pressure method, or the like. Among these, the high-pressure method is a method in which cells in the rosemary raw material are pressure-crushed by high-pressure heat treatment at 100 to 150° C. for 2 to 10 hours (for example, 120° C. for 4 hours).
また、ローズマリー原料を予め粉砕する際の、粉砕条件もまた、特に制限されない。抽出効率などを考慮すると、0.1〜10mm程度の大きさ、より好ましくは0.5〜5mm程度の大きさにまで、所定の植物の部分(ローズマリー原料)を粉砕できることが好ましい。粉砕方法としては、裁断機、スライサー、カッター、ピーラー、ジョークラッシャー、ジェットミル、ブレンダーなどで細断する方法などが挙げられる。 Further, the crushing conditions for crushing the rosemary raw material in advance are also not particularly limited. Considering extraction efficiency and the like, it is preferable that a predetermined plant part (rosemary raw material) can be pulverized to a size of about 0.1 to 10 mm, more preferably about 0.5 to 5 mm. Examples of the crushing method include a method of shredding with a cutter, a slicer, a cutter, a peeler, a jaw crusher, a jet mill, a blender, and the like.
次に、必要であれば予め乾燥および/または粉砕したローズマリー原料を、適当な溶媒を用いて抽出する。ここで使用できる溶媒は、ローズマリー原料から有効成分を抽出できるものであれば特に制限されず、使用される植物や植物の部分に応じて適宜選択される。具体的には、水(水道水、工業用水、蒸留水、逆浸透膜水、濾過水、滅菌水、精製水等を含む);メタノール、エタノール、1−プロパノール、2−プロパノール、1−ブタノール、2−ブタノール、プロピレングリコール、1,3−ブチレングリコール等のアルコール;酢酸メチル、酢酸エチル等のエステル;アセトン等のケトン;エチルエーテル、ホルムアルデヒド、ジメチルスルホキシドなどが挙げられる。上記溶媒は、単独で使用されてもあるいは2種以上の混合溶媒の形態で使用されてもよい。これらのうち、抽出効率、安全性などを考慮すると、水、エタノールまたは水とエタノールとの混合液が抽出溶媒として好ましい。脂溶性画分に癌細胞遊走抑制成分がより多量に含まれている。このため、癌細胞遊走抑制効果をより向上できるとの観点から、エタノールまたは水とエタノールとの混合液でローズマリー原料から抽出することがより好ましい。すなわち、本発明の好ましい形態では、抽出物は、前記ローズマリー原料の、エタノールまたは水とエタノールとの混合液による抽出物である。 Then, if necessary, the rosemary raw material which has been dried and/or ground in advance is extracted with a suitable solvent. The solvent that can be used here is not particularly limited as long as it can extract the active ingredient from the rosemary raw material, and is appropriately selected depending on the plant or plant part to be used. Specifically, water (including tap water, industrial water, distilled water, reverse osmosis membrane water, filtered water, sterile water, purified water, etc.); methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, Examples include alcohols such as 2-butanol, propylene glycol and 1,3-butylene glycol; esters such as methyl acetate and ethyl acetate; ketones such as acetone; ethyl ether, formaldehyde, dimethyl sulfoxide and the like. The above solvents may be used alone or in the form of a mixed solvent of two or more kinds. Of these, water, ethanol, or a mixed solution of water and ethanol is preferable as the extraction solvent in consideration of extraction efficiency and safety. The lipophilic fraction contains a larger amount of the cancer cell migration inhibitory component. Therefore, from the viewpoint that the cancer cell migration inhibitory effect can be further improved, it is more preferable to extract from the rosemary raw material with ethanol or a mixed solution of water and ethanol. That is, in a preferred embodiment of the present invention, the extract is an extract of the rosemary raw material obtained by using ethanol or a mixed liquid of water and ethanol.
なお、必要であれば、ローズマリー原料を酸性またはアルカリ性条件下で抽出してもよい、即ち、酸性またはアルカリ性の溶媒を使用してもよい。ここで、酸性溶媒を調製する際に使用できる酸としては、特に制限されないが、塩酸、硫酸、硝酸、リン酸等の無機酸、酢酸、クエン酸、シュウ酸、コハク酸、ギ酸、プロピオン酸等の有機酸などが挙げられる。また、アルカリ性溶媒を調製する際に使用できるアルカリとしては、特に制限されないが、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウムなどが挙げられる。ローズマリー原料を酸性またはアルカリ性条件下で抽出する際の溶媒のpHは、使用される植物及び植物の部分の種類、抽出条件などを考慮して、適宜選択される。また、酸性溶媒またはアルカリ性溶媒を使用した場合には、抽出後に、抽出液を中性(pH=7±1程度)になるように中和することが好ましい。 If necessary, the rosemary raw material may be extracted under acidic or alkaline conditions, that is, an acidic or alkaline solvent may be used. Here, the acid that can be used when preparing the acidic solvent is not particularly limited, but inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, succinic acid, formic acid, propionic acid, etc. Examples of organic acids include The alkali that can be used when preparing the alkaline solvent is not particularly limited, and examples thereof include potassium hydroxide, sodium hydroxide and sodium carbonate. The pH of the solvent when extracting the rosemary raw material under acidic or alkaline conditions is appropriately selected in consideration of the type of plant and plant part to be used, extraction conditions, and the like. When an acidic solvent or an alkaline solvent is used, it is preferable to neutralize the extract after the extraction so that the extract becomes neutral (pH=about 7±1).
溶媒の添加量は、ローズマリー原料から有効成分を抽出できるものであれば特に制限されない。具体的には、溶媒を、ローズマリー原料10gに対して、10〜1000mlの量、より好ましくは50〜500mlの量を添加することが好ましい。 The amount of the solvent added is not particularly limited as long as the active ingredient can be extracted from the rosemary raw material. Specifically, it is preferable to add the solvent in an amount of 10 to 1000 ml, more preferably 50 to 500 ml, based on 10 g of the rosemary raw material.
また、抽出条件もまた、ローズマリー原料から有効成分を抽出できるものであれば特に制限されない。具体的には、抽出温度は、好ましくは25〜100℃、より好ましくは40〜100℃である。また、抽出時間は、好ましくは30分〜6時間、より好ましくは1〜4時間である。このような条件であれば、ローズマリー原料から有効成分を効率よく抽出できる。 The extraction conditions are also not particularly limited as long as the active ingredient can be extracted from the rosemary raw material. Specifically, the extraction temperature is preferably 25 to 100°C, more preferably 40 to 100°C. The extraction time is preferably 30 minutes to 6 hours, more preferably 1 to 4 hours. Under such conditions, the active ingredient can be efficiently extracted from the rosemary raw material.
上記抽出工程後は、ローズマリー原料及び溶媒の混合液から、固形物(ローズマリー原料残渣)を除去して、抽出液を分離する。ここで、分離方法としては、特に制限されないが、濾過、遠心分離などが挙げられる。さらに、この抽出液は、そのまま使用してもよいが、必要であれば、希釈液による希釈形態、濃縮によるエキス、ペースト若しくは固体形態、凍結による凍結物形態、凍結乾燥による乾燥粉末物形態など、様々な形態(抽出物)に変換してもよい。ここで、変換方法は、単独で適用してもあるいは2種以上を組み合わせて適用してもよい。好ましくは、抽出液を適当な濃度になるまで濃縮(例えば、減圧濃縮)し、得られた濃縮物を凍結した後、凍結乾燥する方法や抽出液を微細な霧状にし、これを熱風中に噴出させ、瞬間的に粉状の乾燥物を得る方法が好ましく使用される。 After the extraction step, the solid matter (residue of the rosemary raw material) is removed from the mixed solution of the rosemary raw material and the solvent, and the extract is separated. Here, the separation method is not particularly limited, but examples thereof include filtration and centrifugation. Furthermore, this extract may be used as it is, but if necessary, it may be diluted with a diluent, extract by concentration, paste or solid form, frozen product form by freezing, dry powder product form by freeze-drying, etc. It may be converted into various forms (extracts). Here, the conversion method may be applied alone or in combination of two or more kinds. Preferably, the extract is concentrated to an appropriate concentration (for example, concentrated under reduced pressure), the obtained concentrate is frozen, and then freeze-dried, or the extract is made into a fine mist, which is then placed in hot air. A method of jetting and instantaneously obtaining a powdery dried product is preferably used.
また、抽出液または抽出物はさらに精製してもよい。ここで、精製方法としては、特に制限されず、公知の精製方法が使用できる。具体的には、塩化セチルピリジニウムなどの4級アンモニウム塩を添加して沈殿物を得、この沈殿物を適当な溶媒(例えば、水、アルコール)で洗浄する方法、陰イオン交換クロマトグラフィー、陽イオン交換クロマトグラフィー、ホスホセルロースクロマトグラフィー、疎水性反応(疎水性相互作用)によるクロマトグラフィー、アフィニティークロマトグラフィー、ヒドロキシアパタイトクロマトグラフィーやレクチンクロマトグラフィーなどを用いたクロマトグラフィーを用いる方法、再結晶法などが挙げられる。 The extract or extract may be further purified. Here, the purification method is not particularly limited, and a known purification method can be used. Specifically, a method in which a quaternary ammonium salt such as cetylpyridinium chloride is added to obtain a precipitate, and the precipitate is washed with a suitable solvent (eg, water or alcohol), anion exchange chromatography, cation Exchange chromatography, phosphocellulose chromatography, chromatography by hydrophobic reaction (hydrophobic interaction), affinity chromatography, chromatography using hydroxyapatite chromatography and lectin chromatography, recrystallization method, etc. To be
または、ローズマリー抽出物は、市販品であってもよい。市販品としては、ローズマリー抽出液(松浦薬業株式会社製)、ローズマリーエキスMF(丸善製薬株式会社製)、RMキーパーMP、RMキーパーSF、RMキーパーOS、RMキーパーOSE等のRMキーパーシリーズ(いずれも三菱化学フーズ株式会社製)、RM−21A、RM−21S、RM−21Aベース、RM−21Bベース等のRM−21シリーズ(いずれも三菱化学フーズ株式会社製)、モルッカ(ローズマリー抽出物、アサマ化成株式会社製)などが挙げられる。 Alternatively, the rosemary extract may be a commercial product. Commercially available RM keeper series such as rosemary extract (Matsuura Yakugyo Co., Ltd.), rosemary extract MF (Maruzen Pharmaceutical Co., Ltd.), RM keeper MP, RM keeper SF, RM keeper OS, RM keeper OSE (All manufactured by Mitsubishi Chemical Foods Co., Ltd.), RM-21 series such as RM-21A, RM-21S, RM-21A base, and RM-21B base (all manufactured by Mitsubishi Chemical Foods Co., Ltd.), Molka (rosemary extraction) Products, manufactured by Asama Kasei Co., Ltd.) and the like.
上記ローズマリー抽出物は、単独で使用されてもあるいは2種以上の混合物の形態で使用されてもよい。 The rosemary extract may be used alone or in the form of a mixture of two or more kinds.
(癌細胞遊走抑制剤の用途)
本発明の癌細胞遊走抑制剤は、医療用途(癌転移の抑制または予防目的)で使用されてもまたは健康食品として使用されてもよく、本発明の癌細胞遊走抑制剤を有効成分として含む以外は、従来と同様の剤形で使用できる。すなわち、本発明の癌細胞遊走抑制剤は、賦形剤などの製薬上許容できる添加剤と混合して非経口投与、経口投与または外部投与に適した、医薬品、医薬部外品、食品組成物の形態で使用することができる。
(Use of cancer cell migration inhibitor)
The cancer cell migration inhibitor of the present invention may be used for medical purposes (for the purpose of suppressing or preventing cancer metastasis) or may be used as a health food, except that it contains the cancer cell migration inhibitor of the present invention as an active ingredient. Can be used in a conventional dosage form. That is, the cancer cell migration inhibitor of the present invention is mixed with a pharmaceutically acceptable additive such as an excipient, and is suitable for parenteral administration, oral administration or external administration, pharmaceuticals, quasi drugs and food compositions. Can be used in the form of
ここで、本発明の癌細胞遊走抑制剤を食品組成物の形態で使用する場合には、癌細胞遊走抑制剤を、油脂製品、乳化製品、清涼飲料等の食品、さらにはペットフードや健康食品として添加・使用することができる。ここで、「食品組成物」とは、人間等の哺乳動物(ペットを含む)による摂取を意図した組成物を意味する。例えば、ペットフード組成物は、ペットによる摂取を意図した食品組成物である。食品組成物は、当技術分野において広く知られている。ペットフード組成物は、栄養的にバランスがとれていてもまたとれていなくてもよく、サプリメント(例えば、エサ)の他に、毎日の食事に適した栄養的にバランスがとれた組成物であってもよい。ここで、「栄養的にバランスのとれた」とは、本発明の組成物が、ペット栄養学分野において適切な量及び割合で、生命を維持するために必要な既知の栄養素を有することを意味する。 Here, when the cancer cell migration inhibitor of the present invention is used in the form of a food composition, the cancer cell migration inhibitor is a fat or oil product, an emulsified product, a food such as a soft drink, and further a pet food or a health food. Can be added and used as. Here, the "food composition" means a composition intended to be ingested by mammals (including pets) such as humans. For example, a pet food composition is a food composition intended for ingestion by pets. Food compositions are widely known in the art. A pet food composition may or may not be nutritionally balanced and, in addition to supplements (eg, food), is a nutritionally balanced composition suitable for daily eating. May be. Here, "nutritionally balanced" means that the composition of the present invention has known amounts of nutrients necessary for sustaining life in an appropriate amount and ratio in the field of pet nutrition. To do.
特に本発明の癌細胞遊走抑制剤をヒトへの健康食品(ヒト用健康食品)及びペットフードに添加・使用する場合の、癌細胞遊走抑制剤の添加量(含有量)は、特に制限されないが、健康食品及びペットフード(固形分換算)に対して、好ましくは0.01〜30重量%、より好ましくは0.05〜20重量%程度になるような量である。または、本発明の癌細胞遊走抑制剤を、1日に合計重量として、好ましくは0.1〜1000mg/kg 体重、より好ましくは1〜500mg/kg 体重程度投与されるような量である。このような量であれば、十分な癌の予防効果を達成できる。また、上記したような量であれば、ペットの嗜好を阻害することがなく、ペットは与えられたペットフード全量を摂取する。 In particular, when the cancer cell migration inhibitor of the present invention is added to and used in human health foods (human health foods) and pet foods, the addition amount (content) of the cancer cell migration inhibitor is not particularly limited. The amount is preferably 0.01 to 30% by weight, more preferably about 0.05 to 20% by weight, based on the health food and pet food (solid content conversion). Alternatively, the cancer cell migration inhibitor of the present invention is administered in an amount of preferably 0.1 to 1000 mg/kg body weight, more preferably 1 to 500 mg/kg body weight as a total weight per day. With such an amount, a sufficient cancer preventive effect can be achieved. In addition, if the amount is as described above, the pet takes the total amount of the given pet food without inhibiting the preference of the pet.
上述したように、ペット動物(例えば、イヌ)にカフェインを与えると、頻脈、震え・痙攣、不整脈、過度な興奮、下痢などの症状を引き起こすことがある。このため、本発明の癌細胞遊走抑制剤をペットフード(例えば、イヌ用)に使用する場合には、癌細胞遊走抑制剤は、カフェインを可能な限り含まないことが好ましい。具体的には、癌細胞遊走抑制剤中のカフェインの含有量は、好ましくは10重量%以下、より好ましくは5重量%以下、さらにより好ましくは2重量%以下、特に好ましくは1重量%以下(下限:0重量%)である。 As described above, when caffeine is given to pet animals (for example, dogs), symptoms such as tachycardia, tremors/convulsions, arrhythmia, excessive agitation, and diarrhea may be caused. Therefore, when the cancer cell migration inhibitor of the present invention is used in pet food (for example, for dogs), it is preferable that the cancer cell migration inhibitor does not contain caffeine as much as possible. Specifically, the content of caffeine in the cancer cell migration inhibitor is preferably 10% by weight or less, more preferably 5% by weight or less, even more preferably 2% by weight or less, particularly preferably 1% by weight or less. (Lower limit: 0% by weight).
ペットフードは、本発明の癌細胞遊走抑制剤を含む以外は従来と同様の成分を含む。例えば、ペットフードは、本発明の癌細胞遊走抑制剤に加えて、
単糖類、オリゴ糖、多糖類、食物繊維、デンプン類(例えば、ワキシーコーンデンプン、コーンデンプン、小麦デンプン、米デンプン、糯米デンプン、馬鈴薯デンプン、甘露デンプン、タピオカデンプン、サゴデンプン、これらに化学的処理を施したものや化学修飾した加工デンプン)や穀物類(例えば、とうもろこし、大麦、小麦、ライ麦、ソルガム、米、ひえ、あわ、アマラサンサス、キヌア)等の炭水化物源;牛、豚、羊、うさぎ、カンガルー等の畜肉や獣肉、その副生成物及び加工品、鶏、七面鳥、うずら等の鳥肉、その副生成物及び家屋品、魚、白身魚等の魚肉、その副生成物及び加工品、ミートミール、ミートボーン、チキンミール、ポータリーミール、フィッシュミール等の上記原料のレタリング等の、動物性タンパク質源;大豆タンパク質、小麦タンパク質、小麦グルテン、コーングルテン等の、植物性のタンパク質源;α−シトステロール、β−シトステロール、スチグマステロール、カンペステロール、α−シトスタノール、β−シトスタノール、スチグマスタノール、カンペスタノール、シクロアルテノール等のフリー体、これらの脂肪酸エステル、フェルラ酸エステル、桂皮酸エステル等のエステル体等の植物ステロール;米ぬか、ふすま等のぬか類、大豆粕等の粕類、野菜エキス等の野菜、ビタミンA、B1、B2、D、E、ナイアシン、パントテン酸、カロチン等のビタミン類などが挙げられる。上記に加えて、一般的にペットフードに使用されるゲル化剤、保型剤、pH調整剤、調味料、防腐剤、栄養補強剤等の他の添加剤を含有してもよい。上記他の添加剤に加えてまたは上記他の添加剤に代えて、ブチルヒドロキシアニソール(BHA)、ジブチルヒドロキシトルエン(BHT)、エトキシキン、tert−ブチルヒドロキノン(TBHQ)、プロピルガレートなどの抗酸化剤を併用することも可能である。上記した各成分の添加量(含有量)は特に制限されず、従来と同様の量が適用できる。
The pet food contains the same components as conventional except that it contains the cancer cell migration inhibitor of the present invention. For example, pet food, in addition to the cancer cell migration inhibitor of the present invention,
Monosaccharides, oligosaccharides, polysaccharides, dietary fibers, starches (for example, waxy corn starch, corn starch, wheat starch, rice starch, starch starch, potato starch, honey starch, tapioca starch, sago starch, chemically treated to these. Carbohydrate sources such as processed and chemically modified starch) and cereals (eg corn, barley, wheat, rye, sorghum, rice, loin, fluff, amarasanthus, quinoa); cattle, pigs, sheep, rabbits, kangaroos Meat and beef, etc., by-products and processed products thereof, chicken meat such as chicken, turkey, quail, etc., by-products and house products, fish meat such as fish and white fish, by-products and processed products, meat meal , Protein source such as soybean protein, wheat protein, wheat gluten, corn gluten, etc.; α-sitosterol; animal protein source such as lettering of the above raw materials such as meat bone, chicken meal, porridge meal, fish meal and the like; , Β-sitosterol, stigmasterol, campesterol, α-sitostanol, β-sitostanol, stigmasteranol, campestanol, cycloartenol, etc., free form thereof, fatty acid ester, ferulic acid ester, cinnamic acid ester, etc. Sterols such as ester form; rice bran, bran such as bran, meal such as soybean meal, vegetables such as vegetable extract, vitamins A, B1, B2, D, E, niacin, pantothenic acid, vitamins such as carotene And so on. In addition to the above, other additives generally used in pet foods such as gelling agents, shape-retaining agents, pH adjusters, seasonings, preservatives and nutritional supplements may be contained. In addition to or instead of the above-mentioned other additives, antioxidants such as butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), ethoxyquin, tert-butylhydroquinone (TBHQ), propyl gallate, etc. It is also possible to use together. The addition amount (content) of each component described above is not particularly limited, and the same amount as the conventional amount can be applied.
ペットフードは、従来公知の方法によって製造される。例えば、本発明の癌細胞遊走抑制剤および前記した必要成分を混合し、所望の形態にすることにより製造できる。一例としては、本発明の癌細胞遊走抑制剤、穀物、肉ミール並びに鉄及び銅等のミネラル成分とともに、必要であればクエン酸またはクエン酸塩を混合し、十分混合したあとに、水や水蒸気で加水しながらエクストルーダーによって押出成型をする。その後に、好ましくは水分を10%以下になるまで熱風乾燥させて、ペットフードを製造する。なお、ペットフードが二重結合を二つ以上存在する脂肪酸を有する油脂を含む場合には、熱風乾燥させた後、コーティングするのが望ましい。 The pet food is manufactured by a conventionally known method. For example, it can be produced by mixing the cancer cell migration inhibitor of the present invention and the above-mentioned necessary components to obtain a desired form. As an example, together with the cancer cell migration inhibitor of the present invention, grains, meat meal and mineral components such as iron and copper, if necessary, citric acid or citrate is mixed, and after sufficient mixing, water or steam. Extrude with an extruder while adding water. Then, it is preferably dried with hot air until the water content is 10% or less, to produce a pet food. When the pet food contains an oil or fat having a fatty acid having two or more double bonds, it is desirable that the pet food be dried with hot air and then coated.
ペットフードとしては、ドライタイプ、ウェットタイプ、セミモイストタイプ、ジャーキータイプ、ビスケットタイプ、ガムタイプ、粒状、粉状、スープ状等いずれの形態であってもよいが、ドライタイプであることが保存の簡便性から好ましい。ドライタイプのペットフードとしては、キブル形状、平板形状、骨形状などが挙げられる。ペットの噛み易さや扱いやすい形状を得るなどの観点からは、嵩密度が100kg/m3以上、好ましくは300kg/m3以上であり、そして900kg/m3以下、好ましくは700kg/m3以下であり、または、100〜900kg/m3、特に300〜700kg/m3であることが好ましい。また、ペットフードは、袋詰め、箱詰め、パック詰め、缶詰、レトルトパウチされた形態で提供され得る。 The pet food may be in any form such as dry type, wet type, semi-moist type, jerky type, biscuit type, gum type, granular, powdery, soup type, etc., but the dry type is convenient for storage. It is preferable in terms of sex. Examples of dry pet foods include kibble shapes, flat plate shapes, and bone shapes. From the standpoint of obtaining a chewable and easy-to-handle shape for pets, the bulk density is 100 kg/m 3 or more, preferably 300 kg/m 3 or more, and 900 kg/m 3 or less, preferably 700 kg/m 3 or less. Yes, or 100 to 900 kg/m 3 , and particularly 300 to 700 kg/m 3 . Also, the pet food may be provided in bagged, boxed, packed, canned, retort pouched forms.
また、本発明の癌細胞遊走抑制剤を医療用途で癌転移の抑制/予防剤として使用することもできる。すなわち、本発明は、10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で緑茶抽出物およびローズマリー抽出物を癌細胞遊走を抑制する必要のある患者に投与することを有する、癌細胞遊走の抑制方法をも提供する。また、本発明は、10:1〜1:10の重量比(緑茶抽出物:ローズマリー抽出物の混合重量比)で緑茶抽出物およびローズマリー抽出物を、癌摘出後の癌転移を抑制または予防する必要のある患者に投与することを有する、癌摘出後の癌転移の抑制または予防方法をも提供する。ここで、緑茶抽出物およびローズマリー抽出物は、これらの有効成分を双方とも含む一剤の形態で投与されても、またはこれらの有効成分を別々に含む二剤の形態で同時に投与されてもよい。これらの有効成分による相乗効果の向上や投与しやすさを考慮すると、緑茶抽出物およびローズマリー抽出物双方とも含む一剤の形態で投与することが好ましい。 Further, the cancer cell migration inhibitor of the present invention can be used as a suppressant/preventive agent for cancer metastasis in medical applications. That is, the present invention provides a patient who needs to suppress cancer cell migration with a green tea extract and a rosemary extract at a weight ratio of 10:1 to 1:10 (green tea extract:rosemary extract mixed weight ratio). There is also provided a method of suppressing cancer cell migration, which comprises administering to the. In addition, the present invention suppresses cancer metastasis after excision of a green tea extract and a rosemary extract at a weight ratio of 10:1 to 1:10 (mixing weight ratio of green tea extract:rosemary extract) or Also provided is a method for suppressing or preventing cancer metastasis after cancer removal, which comprises administering to a patient in need of prevention. Here, the green tea extract and the rosemary extract may be administered in the form of a single agent containing both of these active ingredients, or may be administered simultaneously in the form of a dual agent containing these active ingredients separately. Good. Considering the synergistic effect of these active ingredients and the ease of administration, it is preferable to administer them in the form of a single agent containing both the green tea extract and the rosemary extract.
本形態では、癌細胞遊走抑制剤を経口剤、外用剤、注射剤、吸入剤、点鼻・点眼剤等に添加することができ、これらの使用方法に応じて、錠剤、液剤、注射剤、軟膏、クリーム、ローション、エアゾール剤、座剤等の所望の剤型にすることができる。また、必要に応じて賦形剤、基剤、乳化剤、安定剤、溶解助剤、矯味剤、保存剤、芳香剤、着色剤、コーティング剤などを適宜配合することができる。医薬部外品・化粧品としては、化粧水、乳液、クリーム等に添加することができ、必要に応じて油分、保湿剤、紫外線吸収剤、水溶性高分子、酸化防止剤、界面活性剤、金属イオン封鎖剤、抗菌防腐剤等が配合できる。 In this embodiment, the cancer cell migration inhibitor can be added to oral agents, external preparations, injections, inhalants, nasal drops/eye drops, etc., and tablets, solutions, injections, The desired dosage form can be an ointment, cream, lotion, aerosol, suppository, and the like. Further, if necessary, an excipient, a base, an emulsifier, a stabilizer, a solubilizing agent, a corrigent, a preservative, an aromatic, a coloring agent, a coating agent and the like can be appropriately mixed. As quasi-drugs/cosmetics, it can be added to lotions, emulsions, creams, etc., and if necessary, oils, moisturizers, UV absorbers, water-soluble polymers, antioxidants, surfactants, metals. Ion blocking agents, antibacterial preservatives, etc. can be added.
本発明の癌細胞遊走抑制剤を医薬品として利用する場合の投与量は、投与経路;患者の病気の性質;患者のサイズ、体重、表面積、年齢および性別;投与される他の薬剤;ならびに主治医の判断などによって異なる。適当な投与量(緑茶抽出物及びローズマリー抽出物の合計量(乾燥重量換算))は、1日当たり、1〜500mg/kg 体重である。様々な利用できる癌細胞遊走抑制剤および様々な投与経路の異なる有効性を考慮すると、必要な投与量は広範に変化しうると予想される。これらの投与量レベルの変動は、当該分野において既知の最適に関する標準的な経験上の手順を用いて調節できる。特に経口によるデリバリーでは、適当なデリバリーベヒクル(例えば、ポリマーミクロ粒子または移植可能な装置)への癌細胞遊走抑制剤のカプセル化により、デリバリー効率が上がる。また、上記投与量は、1日1回または複数回に分けてもよい。または、場合によっては、より低い頻度(例えば、週もしくは月単位)で投与されてよい。加えて、同一患者であっても、患者の症状や重篤度に応じて、投与量は変化しうる。 When the cancer cell migration inhibitor of the present invention is used as a drug, the dose is as follows: route of administration; patient's illness; patient size, weight, surface area, age and sex; other drugs administered; It depends on the judgment. A suitable dose (total amount of green tea extract and rosemary extract (dry weight conversion)) is 1 to 500 mg/kg body weight per day. Given the variety of available cancer cell migration inhibitors and the different efficacies of different routes of administration, it is expected that the required dosage can vary widely. Variations in these dosage levels can be adjusted using standard empirical procedures for optimality known in the art. Particularly for oral delivery, encapsulation of the cancer cell migration inhibitor in a suitable delivery vehicle (eg, polymer microparticles or implantable device) enhances delivery efficiency. In addition, the dose may be divided into one or more times a day. Alternatively, in some cases, it may be administered less frequently (eg, weekly or monthly). In addition, even in the same patient, the dose may vary depending on the patient's symptoms and severity.
医薬品(癌細胞遊走抑制剤、癌転移の抑制/予防剤)に使用する場合、治療上有効な量の癌細胞遊走抑制剤が、1つまたは複数の薬学的に許容できる担体(添加剤)および/または希釈剤とともに処方される。すなわち、本発明の癌細胞遊走抑制剤はさらに製薬上許容できる添加剤(例えば、賦形剤、担体など)を含む薬剤組成物の形態でも提供されうる。当該形態の本発明の癌細胞遊走抑制剤は、以下で詳細に説明するように、固体または液体での投与のために具体的に処方することができる。経口投与として、例えば、水薬(水溶液もしくは非水溶液または懸濁液)、錠剤、巨丸剤、粉末薬、顆粒剤、舌に塗布するためのペーストを例示することができる。非経口投与としては、例えば、滅菌溶液もしくは懸濁液として例えば皮下、筋内もしくは静脈内注射のための製剤、あるいは、局所用として、例えば皮膚に応用されるクリーム、軟膏またはスプレーとして、または、膣内または直腸内に、例えば膣座薬、クリームまたは発泡剤として製剤化することができる。 When used as a drug (cancer cell migration inhibitor, cancer metastasis suppressor/preventive agent), a therapeutically effective amount of a cancer cell migration inhibitor is contained in one or more pharmaceutically acceptable carriers (additives) and And/or is formulated with a diluent. That is, the cancer cell migration inhibitor of the present invention may be provided in the form of a pharmaceutical composition further containing a pharmaceutically acceptable additive (eg, excipient, carrier, etc.). The cancer cell migration inhibitor of the present invention in this form can be specifically formulated for administration in solid or liquid form, as described in detail below. Examples of oral administration include drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, and pastes for application to the tongue. For parenteral administration, for example, as a sterile solution or suspension, for example, for subcutaneous, intramuscular or intravenous injection, or for topical application, for example, as a cream, ointment or spray applied to the skin, or It can be formulated vaginally or rectally, for example as a vaginal suppository, cream or effervescent.
本明細書において、「治療上有効な量」とは、本明細書で使用される場合、いずれの医療にも適用可能な妥当な便益/リスク比で、何らかの所望の抑制効果を生じるために有効な作用物質または癌細胞遊走抑制剤の量を意味する。例えば、本発明の癌細胞遊走抑制剤の投与量は、対象疾患、投与対象、投与ルートなどにより差異はあるが、癌転移の抑制/予防目的で本発明の癌細胞遊走抑制剤を経口投与する場合、用量は対象となる者の体重等の条件によって容易に変動しうるため、当業者によって適宜選択されうる。また、最終的には、主治医が患者の症状や重篤度などを考慮して、適宜選択する。 As used herein, "therapeutically effective amount", as used herein, is an effective benefit/risk ratio applicable to any medical treatment and is effective to produce any desired inhibitory effect. Amount of a different agent or cancer cell migration inhibitor. For example, although the dose of the cancer cell migration inhibitor of the present invention varies depending on the target disease, administration subject, administration route, etc., the cancer cell migration inhibitor of the present invention is orally administered for the purpose of suppressing/preventing cancer metastasis. In this case, the dose can be easily changed depending on the conditions such as the body weight of the target person, and thus can be appropriately selected by those skilled in the art. In the end, the attending physician will make an appropriate selection in consideration of the patient's symptoms and severity.
本明細書において、「製薬上許容できる」とは、正しい医学的判断の範囲内で、妥当な便益/リスク比に見合って、過剰な毒性、刺激、アレルギー反応等の問題や合併症なしに、治療対象(ヒト、哺乳動物など)の組織に接触しての使用に好適な、化合物、材料、組成物、および/または投薬形態を指すために使用される。 In the present specification, "pharmaceutically acceptable" means, within the scope of correct medical judgment, in proportion to a reasonable benefit/risk ratio, without problems such as excessive toxicity, irritation, allergic reaction or complication, Used to refer to a compound, material, composition, and/or dosage form suitable for use in contact with the tissue of the subject to be treated (human, mammal, etc.).
製薬上許容できる担体とは、体の一器官または一部から体の別の器官または一部へ本発明の癌細胞遊走抑制剤を運搬または輸送することに関与する液体または固体の充填剤、希釈剤、補形薬、溶剤またはカプセル化材料のような、製薬上許容できる材料、組成物または賦形剤を意味する。各担体は、剤形の他の成分と適合し、患者に有害でないという意味で「許容できる」ものでなければならない。製薬上許容できる担体としては、以下に制限されないが、ラクトース、グルコースおよびスクロースのような糖;トウモロコシデンプンおよびバレイショデンプンのようなデンプン;カルボキシメチルセルロースナトリウム、エチルセルロースおよび酢酸セルロースのようなセルロースおよびその誘導体;粉末トラガカント;麦芽;ゼラチン;タルク;ココアバターおよび座薬ワックスのような補形薬;落花生油、綿実油、ベニバナ油、ゴマ油、オリーブ油、トウモロコシ油およびダイズ油のような油;プロピレングリコールのようなグリコール;グリセリン、ソルビトール、マンニトールおよびポリエチレングリコールのようなポリオール;オレイン酸エチルおよびラウリン酸エチルのようなエステル;寒天;水酸化マグネシウムおよび水酸化アルミニウムのような緩衝剤;アルギン酸;パイロジェンフリー水;等張食塩液;リンガー溶液;エチルアルコール;リン酸緩衝溶液;ならびに薬物処方で使用される他の非毒性の適合物質が挙げられる。いくつかの実施形態では、薬物製剤は非発熱性である。すなわち、患者の体温を上昇させないものが望ましい。その他、ラウリル硫酸ナトリウムおよびステアリン酸マグネシウムのような湿潤剤、乳化剤および潤滑剤、ならびに着色剤、放出剤、被覆剤、甘味料、香味剤および香料、保存料および酸化防止剤が本発明の癌細胞遊走抑制剤(癌転移の抑制/予防剤)中に含まれてもよい。 The pharmaceutically acceptable carrier means a liquid or solid filler or diluent that is involved in carrying or transporting the cancer cell migration inhibitor of the present invention from one organ or part of the body to another organ or part of the body. By pharmaceutically acceptable material, composition or excipient, such as an agent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the dosage form and not injurious to the patient. Pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; celluloses such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate and its derivatives; Powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; Polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline. Ringer's solution; ethyl alcohol; phosphate buffered solutions; as well as other non-toxic compatible substances used in drug formulation. In some embodiments, the drug formulation is non-pyrogenic. That is, it is desirable that the body temperature of the patient is not increased. In addition, the wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, and coloring agents, releasing agents, coating agents, sweeteners, flavoring agents and flavoring agents, preservatives and antioxidants are cancer cells of the present invention. It may be included in a migration inhibitor (suppressor/preventer of cancer metastasis).
製薬上許容できる酸化防止剤としては、以下に制限されないが、アスコルビン酸、塩酸システイン、硫酸水素ナトリウム、二亜硫酸ナトリウム、亜硫酸ナトリウム等のような水溶性酸化防止剤;パルミチン酸アスコルビル、ブチルヒドロキシアニソール(BHA)、ブチルヒドロキシトルエン(BHT)、レシチン、没食子酸プロピル、α−トコフェロール等のような油溶性酸化防止剤;ならびにクエン酸、エチレンジアミン四酢酸(EDTA)、ソルビトール、酒石酸、リン酸等のような金属キレート剤が挙げられる。 Pharmaceutically acceptable antioxidants include, but are not limited to, water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, etc.; ascorbyl palmitate, butylhydroxyanisole ( BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and other oil-soluble antioxidants; as well as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. A metal chelating agent is mentioned.
本発明の癌細胞遊走抑制剤は、経口、経鼻、局所(口内および舌下を含む)、直腸、膣および/または非経口投与に等の様々な剤形で使用できる。剤形は、単位投薬形態で都合よく差し出されてもよく、薬学分野で周知のいかなる方法によって調製されてもよい。担体材料と組み合わせて単一投薬形態を作製することができる活性成分の量は、治療されるホスト、特定の投与方式に応じて変わるであろう。担体材料と組み合わせて単一投薬形態を作製することができる活性成分の量は一般に、治療効果を生じる化合物の量であるが、一般に、活性成分(緑茶抽出物及びローズマリー抽出物)の量は、癌細胞遊走抑制剤に対して、約0.1〜約99重量%であり、好ましくは約1〜約70重量%であり、より好ましくは約5〜約50重量%である。 The cancer cell migration inhibitor of the present invention can be used in various dosage forms such as oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The dosage form may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect, but generally the amount of active ingredient (green tea extract and rosemary extract) will be The amount is about 0.1 to about 99% by weight, preferably about 1 to about 70% by weight, more preferably about 5 to about 50% by weight, based on the cancer cell migration inhibitor.
これらの剤形または組成物を調製する方法は、本発明の癌細胞遊走抑制剤を担体と、随意に1つまたは複数の副成分と結びつけるステップを含む。一般に、剤形は本発明の1つまたは複数の作用物質を液体担体、もしくは微粉化した固体担体、またはその両方と均一かつ緊密に結びつけ、必要であれば製品を成形することによって調製される。 The methods of preparing these dosage forms or compositions include the step of bringing into association the cancer cell migration inhibitor of the invention with the carrier and, optionally, one or more accessory ingredients. In general, dosage forms are prepared by uniformly and intimately bringing into association the agent or agents of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
例えば、経口投与に好適な本発明の剤形は、カプセル、サシェ(sachet)、丸薬、錠剤、ロゼンジ(味付けされた主薬、通常はスクロースおよびアラビアゴムまたはトラガカント、を用いる)、粉末、顆粒の形態でもよく、または水性もしくは非水性液体中の溶液もしくは懸濁液として、または水中油もしくは油中水液体乳剤として、またはエリキシルもしくはシロップとして、または香錠(ゼラチンおよびグリセリン、またはスクロースおよびアラビアゴムのような不活性基剤を用いる)および/または含嗽剤等としてでもよく、それぞれ活性成分として所定量の本発明の化合物を含む。本発明の作用物質は、巨丸剤、舐剤、またはペーストとして投与されてもよい。 For example, dosage forms of the invention suitable for oral administration are in the form of capsules, sachets, pills, tablets, lozenges (using seasoned bases, usually sucrose and acacia or tragacanth), powders, granules. Or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or pastilles (such as gelatin and glycerin, or sucrose and acacia). It may be used as an inert base) and/or a gargle and the like, each containing a predetermined amount of the compound of the present invention as an active ingredient. The agents of the present invention may be administered as a bolus, electuary or paste.
経口投与のための本発明の固体投薬形態(カプセル、錠剤、丸薬、糖衣錠、粉末薬、顆粒剤等)では、活性成分(緑茶抽出物及びローズマリー抽出物)は、クエン酸ナトリウムまたはリン酸二カルシウムのような1つまたは複数の製薬上許容できる担体、および/または以下のもののいずれかと混合される:デンプン、ラクトース、スクロース、グルコース、マンニトール、および/またはケイ酸のような充填剤または増量剤;例えばカルボキシメチルセルロース、アルギン酸塩、ゼラチン、ポリビニルピロリドン、スクロースおよび/またはアラビアゴムのような粘結剤;グリセロールのような保湿剤;寒天、炭酸カルシウム、バレイショまたはタピオカデンプン、アルギン酸、ある特定のケイ酸塩、および炭酸ナトリウムのような崩壊剤;パラフィンのような溶解遅延剤;4級アンモニウム化合物のような吸収促進剤;セチルアルコールおよびモノステアリン酸グリセロールのような湿潤剤;カオリンおよびベントナイト粘土のような吸収剤;タルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、固体ポリエチレングリコール、ラウリル硫酸ナトリウム、およびそれらの混合物のような潤滑剤;ならびに着色剤。カプセル、錠剤および丸薬の場合、癌細胞遊走抑制剤は緩衝剤を含んでもよい。同様の種類の固体組成物が、ラクトースまたは乳糖のような補形薬と、高分子量ポリエチレングリコール等とを用いたソフトおよびハード充填ゼラチンカプセル内の充填剤としても使用可能である。 In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredients (green tea extract and rosemary extract) are sodium citrate or diphosphate diphosphate. Mixed with one or more pharmaceutically acceptable carriers such as calcium, and/or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid. Binding agents such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; moisturizers such as glycerol; agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids. Salts and disintegrants such as sodium carbonate; dissolution retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; such as kaolin and bentonite clay. Absorbents; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the cancer cell migration inhibitor may comprise a buffer. Solid compositions of the same type can also be used as fillers in soft and hard filled gelatin capsules with excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.
また、錠剤は、圧縮または成形によって、随意に1つまたは複数の副成分とともに、作製されうる。圧縮された錠剤は、粘結剤(例えば、ゼラチンもしくはヒドロキシプロピルメチルセルロース)、潤滑剤、不活性希釈剤、保存料、崩壊剤(例えば、グリコール酸ナトリウムデンプンもしくは架橋型カルボキシメチルセルロースナトリウム)、表面活性剤または分散剤を用いて調製されうる。成形タブレットは、不活性液体希釈剤で湿潤化された粉末化合物の混合物を好適な機械で成形することによって作製されうる。 Also, tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets include binders (eg gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate or crosslinked carboxymethylcellulose sodium), surface active agents. Alternatively, it may be prepared using a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
糖衣錠、カプセル、丸薬および顆粒剤のような、本発明の癌細胞遊走抑制剤の錠剤等の固体投薬形態は、随意に、刻み目を付けられ、または薬物調剤分野において周知の腸溶性被膜等の被膜および殻を用いて調製されてもよい。それらは、例えば、所望の放出プロフィールを提供するための種々の比率でのヒドロキシプロピルメチルセルロース、他のポリマーマトリックス、リポソームおよび/またはミクロスフェアを用いて、内部の活性成分の徐放性または制御された放出を提供するように調剤されてもよい。それらは、例えば、細菌保持フィルターを通す濾過によって、または使用直前に滅菌水等の滅菌注射可能媒質に溶解することができる滅菌固体組成物の形態で滅菌剤を組み込むことによって、滅菌してもよい。これらの組成物は、随意に乳白剤を含んでもよく、胃腸管のある特定の部分のみで、またはそこで優先的に、随意に遅延したやり方で、1つまたは複数の活性成分を放出する組成であってもよい。使用可能な埋込み組成物の例として、ポリマー物質およびワックスがある。活性成分は、適当であれば1つまたは複数の上記の補形薬とともに、マイクロカプセル化された形態であってもよい。 Solid dosage forms, such as tablets of the cancer cell migration inhibitor of the invention, such as sugar-coated tablets, capsules, pills and granules, are optionally scored or coated, such as enteric-coated coatings well known in the pharmaceutical dispensing art. And shells may be used. They have been used, for example, with hydroxypropylmethylcellulose, other polymeric matrices, liposomes and/or microspheres in various ratios to provide the desired release profile, to provide a sustained or controlled release of the active ingredient inside. It may be formulated to provide release. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilant in the form of a sterile solid composition which can be dissolved in sterile injectable medium such as sterile water immediately before use. .. These compositions may optionally contain an opacifying agent, only in certain parts of the gastrointestinal tract or preferentially there, optionally in a delayed manner, in a composition that releases one or more active ingredients. It may be. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
本発明の癌細胞遊走抑制剤の経口投与のための液体投薬形態としては、製薬上許容できる乳剤、マイクロエマルジョン、溶液、懸濁液、シロップおよびエリキシルがある。液体投薬形態は、活性成分に加えて、例えば水や他の溶媒のような当技術分野で一般に使用される不活性希釈剤、エチルアルコール、イソプロピルアルコール、炭酸エチル、酢酸エチル、ベンジルアルコール、安息香酸ベンジル、プロピレングリコール、1,3−ブタジエングリコール、油(特に、綿実油、落花生油、トウモロコシ油、胚油、オリーブ油、ヒマシ油およびゴマ油)、グリセロール、テトラヒドロフリルアルコール、ポリエチレングリコールおよびソルビタンの脂肪酸エステルのような可溶化剤および乳化剤、およびそれらの混合物を含んでもよい。また、不活性希釈剤の他に、経口組成物は、湿潤剤、乳化剤および懸濁剤、甘味料、香味剤、着色剤、香料および保存剤のような補助薬を含んでもよい。懸濁液は、活性化合物に加えて、例えば、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およびソルビタンエステル、微結晶セルロース、メタ水酸化アルミニウム、ベントナイト、寒天およびトラガカント、ならびにそれらの混合物のような懸濁剤を含んでもよい。 Liquid dosage forms for oral administration of the cancer cell migration inhibitors of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, inert diluents commonly used in the art, such as water and other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid. Like benzyl, propylene glycol, 1,3-butadiene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan. Solubilizers and emulsifiers, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, flavoring agents and preservatives. The suspension may contain, in addition to the active compound, a suspension such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. A turbidity agent may be included.
直腸または膣投与のための本発明の癌細胞遊走抑制剤の剤形は、座薬として提示されうる。この座薬は、例えば、ココアバター、ポリエチレングリコール、座薬ワックスまたはサリチル酸塩を含む1つまたは複数の好適な非刺激性補形薬または担体と、本発明の1つまたは複数の作用物質を混合することによって調製することが可能であり、室温で固体であるが、体温では液体であるため、直腸または膣腔で融解し、活性化合物を放出することになる。膣投与に好適な剤形はまた、当技術分野で適当であることが知られているような担体を含むペッサリー、タンポン、クリーム、ゲル、ペースト、発泡またはスプレー剤形も含む。 The dosage form of the cancer cell migration inhibitor of the invention for rectal or vaginal administration may be presented as a suppository. This suppository is prepared by admixing one or more agents of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates. , Which is a solid at room temperature, but is a liquid at body temperature, will melt in the rectal or vaginal cavity and release the active compound. Dosage forms suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, effervescent or spray formulations containing such carriers as are known in the art to be appropriate.
本発明の1つもしくは複数の癌細胞遊走抑制剤の局所的または経皮的投与の投薬形態は、粉末、スプレー、軟膏、ペースト、クリーム、ローション、ゲル、溶液、パッチおよび吸入薬を含む。活性成分(緑茶抽出物及びローズマリー抽出物)は、製薬上許容できる基材と、および必要であれば保存料、緩衝液、または推進剤と、滅菌条件下で混合してもよい。軟膏、ペースト、クリームおよびゲルは、活性成分(緑茶抽出物及びローズマリー抽出物)に加えて、動物脂または植物脂、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、シリコーン、ベントナイト、ケイ酸、タルクおよび酸化亜鉛、またはそれらの混合物のような補形薬を含んでもよい。 Dosage forms for topical or transdermal administration of one or more cancer cell migration inhibitors of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredients (green tea extract and rosemary extract) may be mixed under sterile conditions with a pharmaceutically acceptable base material and with any preservatives, buffers or propellants which may be required. Ointments, pastes, creams and gels, in addition to the active ingredients (green tea extract and rosemary extract), animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites. , Silicic acid, talc and zinc oxide, or mixtures thereof.
粉末およびスプレーは、活性成分(緑茶抽出物及びローズマリー抽出物)に加えて、ラクトース、タルク、ケイ酸、水酸化アルミニウム、ケイ酸カルシウムおよびポリアミド粉末、またはこれらの物質の混合物のような補形薬を含んでもよい。スプレーは、塩化フッ化炭化水素や、ブタンおよびプロパンのような揮発性非置換炭化水素のような通例の高圧ガスをさらに含んでもよい。 Powders and sprays contain, in addition to the active ingredients (green tea extract and rosemary extract), complementary forms such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. You may include a medicine. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
経皮的パッチは、本発明の癌細胞遊走抑制剤を、体に制御して配送するという更なる利点を有する。このような投薬形態は、適当な媒質に本発明の癌細胞遊走抑制剤を溶解または分散させることによってなされうる。吸収増進剤を用いて、皮膚を横切る本発明の癌細胞遊走抑制剤を含有する物質のフラックスを上昇させることも可能である。このようなフラックスの速さは、速さ制御膜を設けるか、またはポリマーマトリックスもしくはゲル中に化合物を分散させるかのいずれかによって制御することができる。 Transdermal patches have the added advantage of providing controlled delivery of a cancer cell migration inhibitor of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the cancer cell migration inhibitor of the present invention in a suitable medium. Absorption enhancers can also be used to increase the flux of a substance that contains the cancer cell migration inhibitor of the present invention across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
非経口投与に好適な本発明の癌細胞遊走抑制剤は、当該組成物とともに、1つまたは複数の製薬上許容できる滅菌等張水溶液または非水溶液、分散剤、懸濁液もしくは乳剤、または使用直前に滅菌注射可能溶液または分散剤中で戻すことが可能な滅菌粉末を含み、これは酸化防止剤、緩衝剤、静菌剤、調剤を目的レシピエントの血液と等張にする溶質、または懸濁剤もしくは濃縮剤を含みうる。 The cancer cell migration inhibitor of the present invention suitable for parenteral administration comprises one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or immediately before use, together with the composition. Include sterile powders that can be reconstituted in sterile injectable solutions or dispersions, which include antioxidants, buffers, bacteriostats, solutes or suspensions that make the preparation isotonic with the blood of the intended recipient. Agents or concentrates may be included.
本発明の癌細胞遊走抑制剤で使用可能な好適な水性および非水性担体の例としては、水、エタノール、ポリオール(例えば、グリセロール、プロピレングリコール、ポリエチレングリコール等)、およびそれらの好適な混合物、オリーブ油のような植物油、ならびにオレイン酸エチルのような注射可能有機エステルがある。固有の流動性は、例えば、レシチンのような被覆材料の使用によって、分散剤の場合には必要な粒子サイズの維持によって、および界面活性剤の使用によって、維持することができる。 Examples of suitable aqueous and non-aqueous carriers that can be used in the cancer cell migration inhibitor of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, olive oil. There are vegetable oils such as, as well as injectable organic esters such as ethyl oleate. The inherent fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
本発明の癌細胞遊走抑制剤は、保存料、湿潤剤、乳化剤および分散剤のような補助薬を含んでもよい。微生物の活動の防止は、例えば、パラベン、クロロブタノール、ソルビン酸フェノール等の種々の抗菌剤および抗真菌剤の含有によって確保しうる。糖、塩化ナトリウム等の等張剤を組成物に含めると望ましいかもしれない。さらに、注射可能薬物形態の持続性吸収が、モノステアリン酸アルミニウムおよびゼラチンのような吸収を遅延させる作用物質の含有により引き起こされうる。 The cancer cell migration inhibitor of the present invention may include auxiliary agents such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial activity can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol sorbate and the like. It may be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, sustained absorption of the injectable drug form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
また、本発明の癌細胞遊走抑制剤は、食品(食品組成物)としても利用することができる。この際、本発明の癌細胞遊走抑制剤をそのまま用いてもよく、液状、ゲル状あるいは固形状の食品、例えばジュース、清涼飲料、茶、スープ、豆乳、サラダ油、ドレッシング、ヨーグルト、ゼリー、プリン、ふりかけ、育児用粉乳、ケーキミックス、粉末状または液状の乳製品、パン、クッキー等に添加したり、必要に応じてデキストリン、乳糖、澱粉等の賦形剤や香料、色素等とともにペレット、錠剤、顆粒等に加工したり、またゼラチン等で被覆してカプセルに成形加工して健康食品や栄養補助食品等として利用できる。これらの食品類あるいは食用組成物における本発明の癌細胞遊走抑制剤の配合量は、当該食品や組成物の種類や状態等により一律に規定しがたいが、食品の全重量に対して、0.01〜90重量%、より好ましくは0.1〜80重量%である。このような配合量であれば、風味を損なうことなく、癌細胞遊走抑制剤による効能を十分発揮できる。また、食品を容易に調製できる。 The cancer cell migration inhibitor of the present invention can also be used as a food (food composition). At this time, the cancer cell migration inhibitor of the present invention may be used as it is, liquid, gel-like or solid food, such as juice, soft drink, tea, soup, soy milk, salad oil, dressing, yogurt, jelly, pudding, Sprinkle, powdered baby milk, cake mix, powdered or liquid dairy products, bread, added to cookies, etc., if necessary, excipients and flavors such as dextrin, lactose, starch, and pellets, tablets, etc. It can be used as a health food, a dietary supplement, etc. by processing it into granules or the like, or by coating it with gelatin etc. to form a capsule. The blending amount of the cancer cell migration inhibitor of the present invention in these foods or edible compositions is difficult to uniformly define depending on the type and state of the food or composition, but is 0 relative to the total weight of the food. 0.01 to 90% by weight, more preferably 0.1 to 80% by weight. With such a blending amount, the effect of the cancer cell migration inhibitor can be sufficiently exerted without impairing the flavor. Also, the food can be easily prepared.
さらに、本発明の癌細胞遊走抑制剤は、化粧品(化粧料組成物)としても利用することができる。この際、化粧品(化粧用組成物)の形態としては、ローション、乳液、クリーム、パウダーなどが挙げられるが、特にこれらに限定はされない。本発明の癌細胞遊走抑制剤を含有するこのような化粧品(化粧料組成物)は、当業者に公知の手法を用いて製造されうる。本発明の癌細胞遊走抑制剤を化粧品(化粧料組成物)として用いられる場合の形態としては、ローション、乳液、クリーム、パウダーなどが挙げられるが、特にこれらに限定はされない。本発明の癌細胞遊走抑制剤を含有するこのような化粧料組成物は、当業者に公知の手法を用いて製造されうる。 Furthermore, the cancer cell migration inhibitor of the present invention can be used as a cosmetic (cosmetic composition). At this time, examples of the form of the cosmetic (cosmetic composition) include lotions, emulsions, creams, and powders, but are not particularly limited thereto. Such a cosmetic product (cosmetic composition) containing the cancer cell migration inhibitor of the present invention can be produced using a method known to those skilled in the art. When the cancer cell migration inhibitor of the present invention is used as a cosmetic (cosmetic composition), the form includes, but is not particularly limited to, lotion, emulsion, cream, powder and the like. Such a cosmetic composition containing the cancer cell migration inhibitor of the present invention can be produced using a method known to those skilled in the art.
本発明の効果を、以下の実施例および比較例を用いて説明する。ただし、本発明の技術的範囲が以下の実施例のみに制限されるわけではない。なお、下記実施例において、特記しない限り、操作は室温(25℃)で行われた。また、特記しない限り、「%」および「部」は、それぞれ、「重量%」および「重量部」を意味する。 The effects of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, the operations were performed at room temperature (25°C) unless otherwise specified. Further, unless otherwise specified, “%” and “part” mean “wt %” and “part by weight”, respectively.
実施例1および比較例1〜3:大腸癌細胞に対する細胞遊走抑制の評価
本発明の癌細胞遊走抑制剤による大腸癌細胞遊走抑制効果を、下記創傷治癒アッセイによって評価した。
Example 1 and Comparative Examples 1 to 3: Evaluation of Cell Migration Inhibition on Colorectal Cancer Cells The effect of the cancer cell migration inhibitor of the present invention on colon cancer cell migration inhibition was evaluated by the following wound healing assay.
(サンプル調製)
ローズマリー抽出物(三菱化学フーズ株式会社製、RM−21Bベース)および緑茶抽出物(三井農林株式会社製、ポリフェノン(登録商標)70A、カフェイン含有量:0.5重量%以下)を、ローズマリー抽出物と緑茶抽出物との重量比(ローズマリー抽出物:緑茶抽出物の混合重量比)が1:1(実施例1:サンプル1)となるようにジメチルスルホキシド(DMSO)で調製した(ローズマリー抽出物および緑茶抽出物の混合物の濃度(合計濃度):40mg/ml)。また、比較対象として、ローズマリー抽出物(比較例1:サンプル2)および緑茶抽出物(比較例2:サンプル3)をそれぞれ、DMSOで40mg/mlに調製した。
(Sample preparation)
Rosemary extract (Mitsubishi Chemical Foods Co., Ltd., RM-21B base) and green tea extract (Mitsui Norin Co., Ltd., Polyphenon (registered trademark) 70A, caffeine content: 0.5 wt% or less), rose It was prepared with dimethyl sulfoxide (DMSO) so that the weight ratio of the mary extract and the green tea extract (the mixing weight ratio of the rosemary extract:green tea extract) was 1:1 (Example 1: Sample 1). Concentration (total concentration) of the mixture of rosemary extract and green tea extract: 40 mg/ml). In addition, as comparison targets, a rosemary extract (Comparative Example 1: Sample 2) and a green tea extract (Comparative Example 2: Sample 3) were each prepared in DMSO at 40 mg/ml.
(創傷治癒アッセイ)
ヒト結腸腺癌由来DLD−1細胞を、10(v/v)%FBS含有RPMI1640培地を用いて、5体積%CO2雰囲気下で37℃で培養した。この培養細胞を、6ウェルプレートに1ウェルあたり5×104個になるように2ml播種した。5体積%CO2雰囲気下で37℃で72時間、DLD−1細胞を培養した後、マイクロピペット用のチップを用いて細胞を一定の間隔(幅:約240mm)で掻き取った(下記図1の左側の写真参照)。培地を新しい10(v/v)%FBS含有RPMI1640培地に交換し、上記で調製された各サンプル1〜3を、最終濃度が40μg/mlとなるように、培地に2μl添加した。コントロールには、溶媒(DMSO)のみを2μl添加した。各サンプルまたはDMSOを添加した直後(0時間後)および上記添加後5体積%CO2雰囲気下で37℃で10時間培養した後のDLD−1細胞の様子を写真に収め、細胞の遊走能について評価を行った。各写真からランダムに4ヶ所選び、細胞が遊走した面積を画像処理ソフトGNU Image Manipulation Programを用いて計測し、その平均値および標準偏差を計算した。結果を図1および図2に示す。なお、図1中、図1(a)はローズマリー抽出物及び緑茶抽出物の1:1混合物(サンプル1)を、図1(b)はローズマリー抽出物(サンプル2)を、図1(c)は緑茶抽出物(サンプル3)を、および図1(d)はコントロール(DMSOのみ)を、それぞれ、示す。また、図2において、各値は、コントロールの遊走面積を100%としたときの各サンプルを添加したDLD−1細胞の遊走面積を平均値±標準偏差(n=4)として表したものである。図2中、「*」は、ローズマリー抽出物単独及び緑茶抽出物単独と比較した場合、特に有意差がある(p<0.01である)ことを示す。
(Wound healing assay)
Human colon adenocarcinoma-derived DLD-1 cells were cultured in RPMI1640 medium containing 10 (v/v)% FBS at 37° C. in a 5 vol% CO 2 atmosphere. 2 ml of this cultured cell was seeded on a 6-well plate so that 5×10 4 cells were formed per well. After culturing the DLD-1 cells at 37° C. for 72 hours in a 5 vol% CO 2 atmosphere, the cells were scraped off at regular intervals (width: about 240 mm) using a micropipette tip (FIG. 1 below). See the photo on the left). The medium was replaced with a fresh RPMI1640 medium containing 10 (v/v)% FBS, and 2 μl of each of Samples 1 to 3 prepared above was added to the medium so that the final concentration was 40 μg/ml. As a control, only 2 μl of the solvent (DMSO) was added. Immediately after the addition of each sample or DMSO (after 0 hour) and after the above addition and after culturing at 37° C. for 10 hours in a 5% CO 2 atmosphere, the appearance of DLD-1 cells is photographed, and the cell migration ability is shown. An evaluation was made. Four areas were randomly selected from each photograph, and the area where cells migrated was measured using image processing software GNU Image Manipulation Program, and the average value and standard deviation thereof were calculated. The results are shown in FIGS. 1 and 2. In FIG. 1, FIG. 1(a) shows a 1:1 mixture of rosemary extract and green tea extract (sample 1), FIG. 1(b) shows a rosemary extract (sample 2), and FIG. c) shows the green tea extract (Sample 3), and FIG. 1(d) shows the control (DMSO only). In addition, in FIG. 2, each value represents the migration area of DLD-1 cells to which each sample was added, where the migration area of the control was 100%, as an average value±standard deviation (n=4). .. In FIG. 2, “*” indicates that there is a particularly significant difference (p<0.01) when compared with the rosemary extract alone and the green tea extract alone.
図1および図2から明らかなように、サンプル1(実施例1;ローズマリー抽出物及び緑茶抽出物の1:1混合物;図1(a)、図2左から2番目)は、サンプル2(比較例1;ローズマリー抽出物単独;図1(b)、図2左から3番目)およびサンプル3(比較例2;緑茶抽出物単独;図1(c)、図2左から4番目)、およびコントロール(無添加;図1(d)、図2左から1番目)に比して、大腸癌細胞の遊走抑制効果が有意に高いことが分かる。なた、図1および図2から、本発明の癌細胞遊走抑制剤を用いることによって、癌細胞遊走抑制効果を、ローズマリー抽出物単独および緑茶抽出物単独に比して、相乗的に向上できると考察される。 As is clear from FIGS. 1 and 2, sample 1 (Example 1; 1:1 mixture of rosemary extract and green tea extract; FIG. 1(a), second from the left in FIG. 2) was sample 2 ( Comparative Example 1; rosemary extract alone; FIG. 1(b), FIG. 2 left third) and sample 3 (Comparative Example 2: green tea extract alone; FIG. 1(c), FIG. 2 left fourth), It can be seen that the colon cancer cell migration inhibitory effect is significantly higher than that of the control (no addition; FIG. 1(d), the first from the left in FIG. 2). From FIGS. 1 and 2, by using the cancer cell migration inhibitor of the present invention, the cancer cell migration inhibitory effect can be synergistically improved as compared with the rosemary extract alone and the green tea extract alone. Is considered.
上記結果から、本発明の癌細胞遊走抑制剤は、結腸癌等の消化器系の癌転移の抑制/予防に使用できると考察される。また、本発明の癌細胞遊走抑制剤を構成する緑茶抽出物およびローズマリー抽出物は双方とも酸化防止剤、香辛料、機能性を有する抽出物として食品に使用されており、安全性が認められている。このため、本発明の組成物を含む食品やペットフードは、結腸癌等の消化器系の癌転移の抑制/予防用健康食品としても有用であると期待される。 From the above results, it is considered that the cancer cell migration inhibitor of the present invention can be used for inhibiting/preventing cancer metastasis of digestive system such as colon cancer. Further, both the green tea extract and the rosemary extract that constitute the cancer cell migration inhibitor of the present invention are used in foods as antioxidants, spices, and functional extracts, and are recognized as safe. There is. Therefore, the food or pet food containing the composition of the present invention is expected to be useful as a health food for suppressing/preventing cancer metastasis of digestive system such as colon cancer.
なお、本実施例では、ヒト細胞について癌細胞増殖抑制効果を評価したが、イヌ、ネコなどのペット動物に対しても同様の結果が得られると推測される。 In this example, the cancer cell growth inhibitory effect on human cells was evaluated, but it is speculated that similar results can be obtained on pet animals such as dogs and cats.
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