JP2017178813A - Cancer cell proliferation inhibiting composition - Google Patents
Cancer cell proliferation inhibiting composition Download PDFInfo
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- JP2017178813A JP2017178813A JP2016065913A JP2016065913A JP2017178813A JP 2017178813 A JP2017178813 A JP 2017178813A JP 2016065913 A JP2016065913 A JP 2016065913A JP 2016065913 A JP2016065913 A JP 2016065913A JP 2017178813 A JP2017178813 A JP 2017178813A
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- cancer
- cancer cell
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- cell growth
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Abstract
Description
本発明は、癌細胞増殖抑制組成物および癌細胞増殖の抑制方法に関する。 The present invention relates to a cancer cell proliferation inhibiting composition and a method for inhibiting cancer cell proliferation.
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 safer than conventional anticancer agents, it contains a cell growth inhibitor with few side effects and an anti-cancer agent containing these components. It is expected to provide tumor agents (also called anticancer agents and anticancer agents), and health foods 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。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。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。これらの方法は早期治療であれば有効であるが、上述したようにかなり進行した段階ではなかなか有効な治療とはいえない。また、上記方法はいずれもペットにかなり負担がかかるため、ペットにとっても、また、飼い主にとってもつらい思いをする。 In recent years, pets such as dogs tend to be regarded as members of the family, and in the 2001 survey, 64% of the total population thought that “pets are also part of the family” and the lifestyle was It is close to humans. On the other hand, with increasing life expectancy of pets, neoplastic diseases are increasing. Especially in dogs and cats, the death rate due to cancer is high in elderly people, and the incidence of cancer may be higher than that in humans depending on the breed of dog and cat. However, pets, like humans, rarely show symptoms at an early stage even when they have cancer, and often progress only to symptoms such as loss of appetite and swelling of lymphoma. Cancer treatment methods, like humans, include surgery, chemotherapy, drug therapy, radiation therapy, and immunotherapy. Although these methods are effective if they are early treatments, they cannot be said to be effective treatments at the stage of considerable progress as described above. In addition, all of the above methods put a considerable burden on the pet, which makes it difficult for the pet and the owner.
このため、癌細胞増殖抑制に有効な薬剤を癌患者(ヒト、ペット)に投与して、癌を治療もしくは癌症状を緩和する、または予めこのような物質を含む食品やペットフードを摂取して、癌を予防することが求められている。例えば、特許文献1では、ハタケシメジ抽出物が抗癌剤による白血球数、特に好中球数、の減少を有意に抑制することを見出し、抗癌剤による化学療法によって引き起こされる副作用を軽減するのにハタケシメジ抽出物を使用できることが開示されている。 For this reason, drugs effective for cancer cell growth inhibition are administered to cancer patients (humans, pets) to treat cancer or alleviate cancer symptoms, or ingest food or pet food containing such substances in advance. There is a need to prevent cancer. For example, Patent Document 1 has found that Hatake shimeji mushroom extract significantly suppresses the decrease in the number of white blood cells, particularly the number of neutrophils, caused by an anticancer drug, and the use of Hatake shimeji mushroom extract to reduce the side effects caused by chemotherapy with an anticancer drug. It is disclosed that it can be used.
本発明は、従来公知の抗腫瘍剤に代替しうる安全性の高い癌細胞増殖抑制組成物(癌の予防・治療のための組成物)および当該組成物を用いる癌細胞増殖の抑制方法を提供することを目的とする。 The present invention provides a highly safe cancer cell growth inhibitory composition (a composition for preventing or treating cancer) that can replace a conventionally known antitumor agent, and a method for suppressing cancer cell growth using the composition. The purpose is to do.
本発明者らは、上記課題を解決すべく、鋭意研究を行った。その結果、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、上記抽出物中で特に癌細胞増殖を抑制するのに有効である成分の組み合わせを発見し、本発明を完成させた。 In order to solve the above-mentioned problems, the present inventors have intensively studied. As a result, in the previous application (PCT / JP2015 / 085680), it was found that a composition containing a rosemary extract and a green tea extract in a specific mixing ratio has a remarkable inhibitory effect on cancer cell proliferation. As a result of further intensive studies on the composition, the present inventors have discovered a combination of components that are particularly effective in suppressing cancer cell growth in the extract, and completed the present invention.
すなわち、上記目的は、カルノシン酸およびカルノソールの少なくとも一方、ならびにエピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方を含む、癌細胞増殖抑制組成物によって達成できる。 That is, the above object can be achieved by a cancer cell growth inhibitory composition comprising at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.
また、上記目的は、カルノシン酸およびカルノソールの少なくとも一方、ならびにエピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方を、癌細胞増殖を抑制する必要のある患者に投与することを有する、癌細胞増殖の抑制方法によっても達成できる。 In addition, the object is to suppress cancer cell proliferation, comprising administering at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate to a patient in need of inhibiting cancer cell proliferation. It can also be achieved by the method.
本発明によれば、従来公知の癌細胞増殖抑制(癌の予防・治療剤)に代替しうる、安全な癌細胞増殖抑制組成物(癌の予防・治療のための組成物)が提供される。 ADVANTAGE OF THE INVENTION According to this invention, the safe cancer cell growth inhibitory composition (composition for the prevention and treatment of cancer) which can replace a conventionally well-known cancer cell growth suppression (cancer prevention and treatment agent) is provided. .
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%の条件で行う。 Embodiments of the present invention will be described below. In addition, this invention is not limited only to the following embodiment. In this specification, “X to Y” indicating a range includes X and Y, and means “X or more and Y or less”. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.
(癌細胞増殖抑制組成物および癌細胞増殖の抑制方法)
本発明の一態様によると、カルノシン酸およびカルノソールの少なくとも一方、ならびにエピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方を含む、癌細胞増殖抑制組成物が提供される。
(Cancer cell proliferation inhibiting composition and cancer cell proliferation inhibiting method)
According to one aspect of the present invention, there is provided a cancer cell growth inhibitory composition comprising at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.
また、本発明の他の態様によると、カルノシン酸およびカルノソールの少なくとも一方、ならびにエピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方を、癌細胞増殖を抑制する必要のある患者に投与することを有する、癌細胞増殖の抑制方法が提供される。 According to another aspect of the present invention, the method includes administering at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate to a patient in need of suppressing cancer cell growth. Methods for inhibiting cancer cell growth are provided.
本明細書では、「カルノシン酸およびカルノソールの少なくとも一方(カルノシン酸および/またはカルノソール)」を、「成分A」とも称する。同様にして、「エピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方(エピガロカテキンガレートおよび/またはエピカテキンガレート)」を、「成分B」とも称する。また、本明細書では、「エピガロカテキンガレート」を単に「EGCG」と、および「エピカテキンガレート」を単に「ECG」とも称する。 In the present specification, “at least one of carnosic acid and carnosol (carnosic acid and / or carnosol)” is also referred to as “component A”. Similarly, “at least one of epigallocatechin gallate and epicatechin gallate (epigallocatechin gallate and / or epicatechin gallate)” is also referred to as “component B”. In the present specification, “epigallocatechin gallate” is also simply referred to as “EGCG”, and “epicatechin gallate” is also simply referred to as “ECG”.
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、それぞれを単独で使用する場合に比して、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。その結果、ローズマリー抽出物中のカルノシン酸またはカルノソールと、緑茶抽出物中のエピガロカテキンガレート(EGCG)またはエピカテキンガレート(ECG)との組み合わせが特に癌細胞増殖を抑制するのに有効な組み合わせであることを見出した。なお、上記カルノシン酸、カルノソール、エピガロカテキンガレート及びエピカテキンガレートは、単独で抗癌作用があることは知られている。しかし、本発明者らは、カルノシン酸および/またはカルノソールと、エピガロカテキンガレートおよび/またはエピカテキンガレートと、を組み合わせることによって、各成分を単独で使用する場合に比して、癌細胞増殖抑制効果が相乗的に向上できることを見出した。上記癌細胞増殖抑制効果は、特に成分Aを、成分B 1モルに対して、0.1モル以上15モル以下の割合で併用する際に、顕著に達成できる。 In the previous application (PCT / JP2015 / 085680), the inventors of the present invention compared to a case where a composition containing a rosemary extract and a green tea extract in a specific mixing ratio is used alone. The present inventors have found that a remarkable inhibitory effect on cancer cell proliferation is exhibited. The inventors have further studied this composition. As a result, a combination of carnosic acid or carnosol in rosemary extract and epigallocatechin gallate (EGCG) or epicatechin gallate (ECG) in green tea extract is particularly effective in suppressing cancer cell growth I found out. The carnosic acid, carnosol, epigallocatechin gallate and epicatechin gallate are known to have an anticancer effect alone. However, the present inventors combined carnosic acid and / or carnosol with epigallocatechin gallate and / or epicatechin gallate to suppress cancer cell growth compared to when each component was used alone. It has been found that the effect can be synergistically improved. The above-mentioned cancer cell growth inhibitory effect can be significantly achieved particularly when component A is used in combination at a ratio of 0.1 mol or more and 15 mol or less with respect to 1 mol of component B.
また、これらの成分は食品に抗酸化剤として使用されてもおり、安全性が認められている。このため、本発明の癌細胞増殖抑制組成物は、癌を発症した後の治療目的に加えて、癌の予防を目的として、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。 Moreover, these components are used as an antioxidant in foods, and safety is recognized. For this reason, the cancer cell growth inhibitory composition of the present invention is ingested daily for the purpose of preventing cancer, in addition to the purpose of treatment after onset of cancer, as a health food, etc. or mixed with pet food. It is also possible.
加えて、本発明の組成物は、様々な物質の混合物である抽出物の形態ではなく、特定の物質である成分A及びBを含む。このため、組成物は、カフェインなど、ペット動物(例えば、イヌ)に与えると副作用(例えば、頻脈、震え・痙攣)を誘発する物質を含まない。ゆえに、本発明の組成物は、ペットフードを摂取した際の副作用を抑えることができるため、ペットフードに好適に添加できる。 In addition, the composition of the present invention includes components A and B, which are specific substances, rather than in the form of an extract that is a mixture of various substances. For this reason, the composition does not contain substances that induce side effects (eg, tachycardia, tremors / convulsions) when given to pet animals (eg, dogs), such as caffeine. Therefore, the composition of the present invention can be suitably added to pet food because it can suppress side effects when taking pet food.
ここで、癌細胞増殖抑制組成物の治療対象(癌細胞増殖を抑制する必要のある被検者)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、本発明の癌細胞増殖抑制組成物は、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、本発明の癌細胞増殖抑制組成物は、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、本発明の癌細胞増殖抑制組成物は、イヌまたはネコに経口的に使用される。 Here, the treatment target of the cancer cell growth inhibitory composition (subject who needs to suppress cancer cell growth) is not particularly limited, but is a mammal or a bird, preferably a mammal or a bird suffering from cancer. . Here, mammals include primates such as humans, monkeys, gorillas, chimpanzees, orangutans, and non-humans 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 and pigeons. Of these, humans, hamsters, guinea pigs, rabbits, dogs, cats and pigs are preferred, and humans and pet animals such as dogs, cats and rabbits are more preferred. That is, according to a preferred embodiment of the present invention, the cancer cell growth-suppressing composition of the present invention is used orally for at least one pet animal selected from the group consisting of humans, dogs, cats, and rabbits. According to a more preferred form of the invention, the cancer cell growth inhibitory composition of the invention is used orally for humans, dogs or cats. According to a particularly preferred form of the invention, the cancer cell growth inhibitory composition of the invention is used orally in dogs or cats.
本発明の癌細胞増殖抑制組成物は、癌の治療および/または予防(本明細書では、単に「癌の治療/予防」とも称する)に効果がある。このため、本発明の癌細胞増殖抑制組成物は、癌治療/予防剤としても有用である。本明細書において、「癌の治療/予防」とは、癌に罹患した患者の癌の進行を抑制すること、癌や腫瘍を消失させること、癌や腫瘍の増大を抑制すること、癌の発症を予防すること、および癌の再発を予防することの少なくとも一つを満足することを意味する。ここで、「予防」とは、癌や腫瘍の発症を防止若しくは遅延させる、または癌や腫瘍の発症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、「癌治療/予防剤」とは、癌の治療に用いた際に上記癌の治療/予防効果を示す薬剤を意味する。 The cancer cell proliferation-suppressing composition of the present invention is effective for the treatment and / or prevention of cancer (herein, simply referred to as “cancer treatment / prevention”). For this reason, the cancer cell proliferation inhibitory composition of the present invention is also useful as an agent for treating / preventing cancer. In the present specification, “treatment / prevention of cancer” refers to suppressing the progression of cancer in a patient suffering from cancer, eliminating cancer or tumor, suppressing the growth of cancer or tumor, and onset of cancer. It means satisfying at least one of prevention of cancer and prevention of cancer recurrence. Here, “prevention” means preventing or delaying the onset of cancer or tumor, or reducing the risk of onset of cancer or tumor. Therefore, in the present specification, the “cancer treatment / prevention agent” means a drug exhibiting the above-mentioned cancer treatment / prevention effect when used in the treatment of cancer.
上述したように、成分A(カルノシン酸、カルノソール)および成分B(エピガロカテキンガレート、エピカテキンガレート)は、それぞれ、ローズマリーおよび緑茶から抽出されうる成分であり、抗酸化剤として食品に使用され、安全性が認められている。このため、本発明の癌細胞増殖抑制組成物は、癌の予防を目的として、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、本発明の癌細胞増殖抑制組成物は、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, component A (carnosic acid, carnosol) and component B (epigallocatechin gallate, epicatechin gallate) are components that can be extracted from rosemary and green tea, respectively, and are used as an antioxidant in foods. , Safety is recognized. For this reason, the cancer cell proliferation inhibitory composition of the present invention can be taken on a daily basis for the purpose of preventing cancer, for example, as a health food or mixed with pet food. That is, according to a preferred embodiment of the present invention, the cancer cell growth inhibitory composition of the present invention is a human health food or pet food composition.
ここで、(癌治療/予防のための)癌細胞増殖抑制組成物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、本発明の癌細胞増殖抑制組成物は、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、本発明の癌細胞増殖抑制組成物は、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予防および/または治療に使用される。本発明のより好ましい形態によると、本発明の癌細胞増殖抑制組成物は、造血器系の癌または消化器系の癌の予防および/または治療に使用される。本発明の特に好ましい形態によると、本発明の癌細胞増殖抑制組成物は、消化器系の癌の予防および/または治療に使用される。 Here, the type of cancer that is the subject of the cancer cell proliferation inhibitory composition (for cancer treatment / prevention) is not particularly limited. For example, cancer of the nervous system (eg, brain tumor, cervical cancer); cancer of the digestive system (eg, oral cancer, pharyngeal cancer, esophageal cancer, stomach 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 cancer (eg bladder cancer, renal cancer) ); Reproductive cancer (eg, breast cancer, uterine cancer, ovarian cancer, testicular cancer, prostate cancer); Respiratory cancer (eg, lung cancer); Hematopoietic cancer (eg, acute or chronic myeloid leukemia, Acute promyelocytic leukemia, leukemia such as acute or chronic lymphocytic leukemia, malignant lymphoma (lymphosarcoma), angiosarcoma, multiple myeloma, myelodysplastic syndrome, primary myelofibrosis, epivascular cell tumor); thyroid Cancer, parathyroid cancer, tongue cancer, malignant melanoma, mastocytoma, skin tissue Tumor, lipoma, follicular tumor, cutaneous papillomas, sebaceous adenoma, such as basal cell cancer. Among these, the cancer cell proliferation suppressing composition of the present invention is more effective against hematopoietic cancer, digestive cancer, genital cancer, malignant melanoma, mastocytoma, and basal cell carcinoma. Has a high effect. That is, according to a preferred embodiment of the present invention, the composition for inhibiting cancer cell proliferation of the present invention comprises hematopoietic cancer, digestive cancer, genital cancer, melanoma, mastocytoma and basal tumor. It is used for the prevention and / or treatment of at least one disease selected from the group consisting of cell carcinomas. According to a more preferred embodiment of the present invention, the cancer cell growth inhibitory composition of the present invention is used for the prevention and / or treatment of hematopoietic or digestive cancer. According to a particularly preferred form of the present invention, the cancer cell growth inhibitory composition of the present invention is used for the prevention and / or treatment of cancer of the digestive system.
(成分A)
本発明の癌細胞増殖抑制組成物は、カルノシン酸およびカルノソールの少なくとも一方(成分A)を含む。
(Component A)
The cancer cell growth inhibitory composition of the present invention contains at least one of carnosic acid and carnosol (component A).
ここで、カルノシン酸は、下記構造を有する天然のベンゼンジオールアビエタンのジテルペンであり、ローズマリー(Rosmarinus officinalis)の乾燥葉に含まれている。カルノシン酸は、抗酸化物質であり、食品の防腐剤や酸化防止剤として使用されており、安全性が認められている。 Here, carnosic acid is a natural benzenediol abietane diterpene having the following structure, and is contained in dried leaves of rosemary (Rosmarinus officinalis). Carnosic acid is an antioxidant and is used as a food preservative and antioxidant and has been recognized as safe.
また、カルノソールは、下記構造を有する天然のポリフェノールであり、ローズマリー(Rosmarinus officinalis)に含まれている。カルノソールは、カルノシン酸と同様抗酸化作用を示し、また、生体防御機構を活性化させる作用や解毒作用などがあることが知られている。カルノソールもまた、食品の防腐剤や酸化防止剤として使用されており、安全性が認められている。 Carnosol is a natural polyphenol having the following structure, and is contained in rosemary (Rosmarinus officinalis). It is known that carnosol exhibits an antioxidant action like carnosic acid, and has an action of activating a biological defense mechanism, a detoxification action, and the like. Carnosol is also used as a food preservative and antioxidant and has been recognized as safe.
カルノシン酸およびカルノソールは、市販品を使用しても、または、ローズマリー等の天然物から抽出・精製してもよい。 Carnosic acid and carnosol may be a commercially available product, or may be extracted and purified from natural products such as rosemary.
また、本発明の癌細胞増殖抑制組成物は、カルノシン酸およびカルノソールの少なくとも一方を含むものであればよいが、カルノシン酸およびカルノソール双方を含むことが好ましい。当該形態によると、癌細胞増殖抑制組成物は、癌細胞増殖抑制に関する成分Bとの相乗効果をより顕著に発揮できる。すなわち、本発明の好ましい形態によると、癌細胞増殖抑制組成物は、カルノシン酸、カルノソールならびにエピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方を含む。上記本発明の好ましい形態は、癌細胞増殖抑制組成物が、(i)カルノシン酸、カルノソールおよびエピガロカテキンガレートの3成分を有効成分として含む形態;(ii)カルノシン酸、カルノソールおよびエピカテキンガレートの3成分を有効成分として含む形態;または(iii)カルノシン酸、カルノソール、エピガロカテキンガレートおよびエピカテキンガレートの4成分を有効成分として含む形態を包含する。 Moreover, although the cancer cell growth inhibitory composition of this invention should just contain at least one of carnosic acid and carnosol, it is preferable that both carnosic acid and carnosol are included. According to the said form, the cancer cell growth inhibitory composition can exhibit a synergistic effect with the component B regarding cancer cell growth suppression more notably. That is, according to a preferred embodiment of the present invention, the cancer cell growth inhibitory composition comprises carnosic acid, carnosol, and at least one of epigallocatechin gallate and epicatechin gallate. The preferred form of the present invention is that the cancer cell growth-suppressing composition comprises (i) three components of carnosic acid, carnosol and epigallocatechin gallate as active ingredients; (ii) carnosic acid, carnosol and epicatechin gallate A form containing three components as active ingredients; or (iii) a form containing four ingredients of carnosic acid, carnosol, epigallocatechin gallate and epicatechin gallate as active ingredients.
(成分B)
本発明の癌細胞増殖抑制組成物は、成分Aに加えて、エピガロカテキンガレート(EGCG)およびエピカテキンガレート(ECG)の少なくとも一方(成分B)を含む。
(Component B)
The cancer cell growth inhibitory composition of the present invention contains at least one of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) (component B) in addition to component A.
ここで、エピガロカテキンガレート(EGCG)は、エピガロカテキンと没食子酸のエステルであり、下記構造を有するカテキンである。このエピガロカテキンガレートは緑茶に含まれ、抗酸化作用や抗菌性を有することが知られている。 Here, epigallocatechin gallate (EGCG) is an ester of epigallocatechin and gallic acid, and is a catechin having the following structure. This epigallocatechin gallate is contained in green tea and is known to have antioxidant and antibacterial properties.
また、エピカテキンガレート(ECG)は, 下記構造を有するカテキンである。このエピカテキンガレートは緑茶に含まれ、抗酸化作用や抗菌性を有することが知られている。 Epicatechin gallate (ECG) is a catechin having the following structure. This epicatechin gallate is contained in green tea and is known to have antioxidant and antibacterial properties.
エピガロカテキンガレート(EGCG)およびエピカテキンガレート(ECG)は、市販品を使用しても、または、緑茶等の天然物から抽出・精製してもよい。 Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) may be commercially available or may be extracted and purified from natural products such as green tea.
本発明の癌細胞増殖抑制組成物は、エピガロカテキンガレート(EGCG)およびエピカテキンガレート(ECG)の少なくとも一方を含むものであればよいが、エピガロカテキンガレート(EGCG)またはエピカテキンガレート(ECG)を含むことが好ましい。当該形態によると、癌細胞増殖抑制組成物は、癌細胞増殖抑制に関する成分Aとの相乗効果をより顕著に発揮できる。すなわち、本発明の特に好ましい形態によると、癌細胞増殖抑制組成物は、(i)カルノシン酸、カルノソールおよびエピガロカテキンガレートの3成分を有効成分として含む;または(ii)カルノシン酸、カルノソールおよびエピカテキンガレートの3成分を有効成分として含む。 The cancer cell growth inhibitory composition of the present invention only needs to contain at least one of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), but epigallocatechin gallate (EGCG) or epicatechin gallate (ECG). ) Is preferably included. According to the said form, the cancer cell growth suppression composition can exhibit a synergistic effect with the component A regarding cancer cell growth suppression more notably. That is, according to a particularly preferred form of the present invention, the cancer cell growth inhibitory composition comprises (i) three components of carnosic acid, carnosol and epigallocatechin gallate as active ingredients; or (ii) carnosic acid, carnosol and epi Contains three components of catechin gallate as an active ingredient.
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。一方、本発明の組成物は、緑茶抽出物の形態ではなく、特定の成分AおよびBを含むものである。このため、本発明の組成物は(カフェインを意図的に添加しない限り)カフェインを実質的に含まないので、ペット動物(例えば、イヌ)が本発明の組成物を含むペットフードを摂取しても、上記したような症状を発症することがない。ゆえに、本発明の組成物はペットフードに好適に添加できる。 When caffeine is given to a pet animal (for example, a dog), symptoms such as tachycardia, tremors / convulsions, arrhythmia, excessive excitement, and diarrhea may occur. On the other hand, the composition of the present invention contains specific components A and B, not in the form of a green tea extract. For this reason, since the composition of the present invention is substantially free of caffeine (unless caffeine is intentionally added), a pet animal (eg, a dog) ingests a pet food containing the composition of the present invention. However, the above symptoms do not develop. Therefore, the composition of the present invention can be suitably added to pet food.
上述したように、本発明の癌細胞増殖抑制組成物は、成分Aとしてカルノシン酸および/またはカルノソール、ならびに成分Bとしてエピガロカテキンガレートおよび/またはエピカテキンガレートを有効成分として含む。ここで、成分Aと成分Bとの混合比は特に制限されない。例えば、成分Aが、成分B 1モルに対して、0.1モル以上15モル以下、より好ましくは0.25モル以上5モル以下、さらに好ましくは0.5モル以上2.5モルの割合で存在することが好ましい。このような範囲であれば、成分Aと成分Bとのより優れた相乗効果が達成できる。また、成分Aと成分Bとのさらなる優れた相乗効果を考慮すると、成分Aの方が成分Bより多いことが好ましい。具体的には、組成物において、成分Aが、成分B 1モルに対して、1モルを超えて5モル以下、1.1モル以上4.5モル以下、1.2モル以上4モル以下、1.3モル以上3.5モル以下、1.4モル以上3モル以下、1.5モル以上2.8モル以下、1.7モル以上2.7モル以下、1.9モル以上2.5モル以下の割合の順で存在することが好ましい。なお、成分Aがカルノシン酸およびカルノソールの混合物である場合には、上記成分Aの含有量は、カルノシン酸およびカルノソールの合計量(モル)である。同様にして、成分Bがエピガロカテキンガレートおよびエピカテキンガレートの混合物である場合には、上記成分Bの含有量は、エピガロカテキンガレートおよびエピカテキンガレートの合計量(モル)である。 As described above, the cancer cell growth inhibitory composition of the present invention contains carnosic acid and / or carnosol as component A, and epigallocatechin gallate and / or epicatechin gallate as component B as active ingredients. Here, the mixing ratio of component A and component B is not particularly limited. For example, the component A is in a ratio of 0.1 mol to 15 mol, more preferably 0.25 mol to 5 mol, and still more preferably 0.5 mol to 2.5 mol with respect to 1 mol of the component B. Preferably it is present. If it is such a range, the more excellent synergistic effect of the component A and the component B can be achieved. In consideration of a further excellent synergistic effect between component A and component B, it is preferable that component A is more than component B. Specifically, in the composition, the component A is more than 1 mol to 5 mol, 1.1 mol to 4.5 mol, 1.2 mol to 4 mol, relative to 1 mol of the component B, 1.3 to 3.5 mol, 1.4 to 3 mol, 1.5 to 2.8 mol, 1.7 to 2.7 mol, 1.9 to 2.5 It is preferable that they are present in the order of a molar ratio. When component A is a mixture of carnosic acid and carnosol, the content of component A is the total amount (mole) of carnosic acid and carnosol. Similarly, when component B is a mixture of epigallocatechin gallate and epicatechin gallate, the content of component B is the total amount (mol) of epigallocatechin gallate and epicatechin gallate.
(癌細胞増殖抑制組成物の用途)
本発明の癌細胞増殖抑制組成物は、医療用途(治療または予防目的)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、本発明の癌細胞増殖抑制組成物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、本発明の癌細胞増殖抑制組成物は、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 growth inhibitory composition)
The cancer cell growth inhibitory composition of the present invention may be used for medical purposes (therapeutic or preventive purposes) or as a health food, except that it contains the cancer cell proliferation inhibitory composition of the present invention as an active ingredient. , And can be used in the same dosage form as before. That is, the cancer cell growth inhibitory composition of the present invention is mixed with a pharmaceutically acceptable additive such as an excipient, and is suitable for parenteral, oral or external administration. It can be used in the form of a thing.
ここで、本発明の癌細胞増殖抑制組成物を食品組成物の形態で使用する場合には、癌細胞増殖抑制組成物を、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 proliferation inhibitory composition of the present invention is used in the form of a food composition, the cancer cell proliferation inhibitory composition can be used as a food such as an oil product, an emulsified product, a soft drink, It can be added and used as a health food. Here, the “food composition” means a composition intended for consumption by mammals (including pets) such as humans. For example, a pet food composition is a food composition intended for consumption by a pet. 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), it is a nutritionally balanced composition suitable for a daily diet. May be. Here, “nutritionally balanced” means that the composition of the present invention has known nutrients necessary to maintain life in an appropriate amount and proportion in the pet nutrition field. To do.
特に本発明の癌細胞増殖抑制組成物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、癌細胞増殖抑制組成物の添加量(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、本発明の癌細胞増殖抑制組成物を、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。 Especially when the cancer cell proliferation inhibitory composition of the present invention is added to and used in human health food (health food for humans) and pet food, the amount (content) of the cancer cell proliferation inhibitory composition is particularly limited. Although not, the amount is preferably 0.01 to 30% by weight, more preferably about 0.05 to 20% by weight with respect to health food and pet food (in terms of solid content). Alternatively, the amount is such that the cancer cell growth inhibitory composition of the present invention is administered at a total weight of 0.1 to 1000 mg / kg body weight, more preferably about 1 to 500 mg / kg body 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 will not disturb the pet's taste and the pet will consume the entire amount of the given pet food.
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、本発明の組成物をペットフード(例えば、イヌ用)に使用する場合には、組成物は、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、癌細胞増殖抑制組成物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 a pet animal (for example, a dog), symptoms such as tachycardia, tremors / convulsions, arrhythmia, excessive excitement, and diarrhea may occur. For this reason, when using the composition of this invention for pet food (for example, for dogs), it is preferable that a composition does not contain caffeine as much as possible. Specifically, the content of caffeine in the cancer cell growth inhibitory composition is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 2% by weight or less, and particularly preferably 1% by weight. The following (lower limit: 0% by weight).
ペットフードは、本発明の癌細胞増殖抑制組成物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、本発明の癌細胞増殖抑制組成物に加えて、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 in the prior art except that it contains the cancer cell growth inhibitory composition of the present invention. For example, the pet food is a monosaccharide, oligosaccharide, polysaccharide, dietary fiber, starch (for example, waxy corn starch, corn starch, wheat starch, rice starch, glutinous rice, in addition to the cancer cell growth inhibitory composition of the present invention. Starch, potato starch, honeydew starch, tapioca starch, sago starch, chemically treated or chemically modified starch) and cereals (eg, corn, barley, wheat, rye, sorghum, rice, mushroom, awa Carbohydrate sources such as cattle, pigs, sheep, rabbits, kangaroos, by-products and processed products, chicken, turkey, quail, etc. , Fish, white fish, etc., by-products and processed products, meat meal, meat bones, chicken meal, porter meal, fish Animal protein sources such as lettering such as schmir; vegetable protein sources such as soy protein, wheat protein, wheat gluten, corn gluten; α-sitosterol, β-sitosterol, stigmasterol, campesterol, α-sit Plant sterols such as free forms such as stanol, β-sitostanol, stigmasteranol, campestanol, and cycloartenol, and esters such as these fatty acid esters, ferulic acid esters, and cinnamic acid esters; bran such as rice bran and bran And soy bean paste, vegetables such as vegetable extract, vitamins A, B1, B2, D, E, niacin, pantothenic acid, carotene and other vitamins. In addition to the above, other additives such as a gelling agent, a shape-retaining agent, a pH adjuster, a seasoning, an antiseptic, and a nutrient reinforcing agent that are generally used in pet foods may be contained. In addition to or in place of the other additives, an antioxidant such as butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), ethoxyquin, tert-butylhydroquinone (TBHQ), propyl gallate, etc. It can also be used in combination. The addition amount (content) of each component described above is not particularly limited, and the same amount as conventional 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、本発明の癌細胞増殖抑制組成物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、本発明の癌細胞増殖抑制組成物、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。 Pet food is manufactured by a conventionally well-known method. For example, it can be produced by mixing the cancer cell growth inhibitory composition of the present invention and the above-mentioned necessary components into a desired form. As an example, citric acid or citrate is mixed with the cancer cell growth inhibitory composition of the present invention, cereal, meat meal, and mineral components such as iron and copper, if necessary, and after mixing, Extrude with an extruder while watering with steam. Thereafter, it is preferably dried with hot air until the water content becomes 10% or less, to produce a pet food. In addition, when pet food contains the fats and oils which have the fatty acid which has two or more double bonds, it is desirable to coat after drying with hot air.
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, biscuits type, gum type, granular, powdery, soup, etc. It is preferable from the property. Examples of dry-type pet foods include kibble shapes, flat plate shapes, and bone shapes. From the standpoint of obtaining pets that are easy to chew and handle, 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. Or 100 to 900 kg / m 3 , particularly 300 to 700 kg / m 3 is preferable. In addition, the pet food can be provided in the form of bagging, boxing, packing, canning, and retort pouch.
また、本発明の癌細胞増殖抑制組成物を医療用途(治療または予防目的)で癌治療/予防剤として使用することもできる。すなわち、本発明は、カルノシン酸およびカルノソールの少なくとも一方、ならびにエピガロカテキンガレートおよびエピカテキンガレートの少なくとも一方を、癌細胞増殖を抑制する必要のある被検者(疾患を患っている患者を含む)に投与することを有する、癌細胞増殖の抑制方法をも提供する。ここで、成分A(カルノシン酸および/またはカルノソール)、および成分B(エピガロカテキンガレートおよび/またはエピカテキンガレート)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、成分AおよびB双方とも含む一剤の形態で投与することが好ましい。 Moreover, the cancer cell proliferation inhibiting composition of the present invention can also be used as a cancer treatment / prevention agent for medical use (for treatment or prevention). That is, the present invention relates to a subject (including a patient suffering from a disease) who needs to suppress cancer cell growth using at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate. The present invention also provides a method for inhibiting cancer cell proliferation, which comprises administering to a cell. Here, component A (carnosic acid and / or carnosol) and component B (epigallocatechin gallate and / or epicatechin gallate) may be administered in the form of one agent containing both of these active ingredients, or These active ingredients may be administered simultaneously in the form of two agents separately. Considering the improvement of synergistic effect by these active ingredients and the ease of administration, it is preferable to administer in the form of one agent containing both components A and B.
本形態では、癌細胞増殖抑制組成物を経口剤、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。なお、上述したように、成分A及びBは、抗酸化作用を有するため、酸化防止剤は必ずしも添加する必要はないが、より長期間貯蔵することを目的する場合など、必要に応じて添加してもよい。 In this embodiment, the cancer cell growth inhibitory composition can be added to oral preparations, external preparations, injections, inhalants, nasal drops, eye drops, etc., and tablets, liquids, injections can be used depending on their usage. , Ointments, creams, lotions, aerosols, suppositories and the like. Moreover, an excipient | filler, a base, an emulsifier, a stabilizer, a solubilizing agent, a corrigent, a preservative, a fragrance | flavor, a coloring agent, a coating agent, etc. can be suitably mix | blended as needed. For quasi-drugs and cosmetics, it can be added to lotions, emulsions, creams, etc., if necessary, oil, moisturizer, UV absorber, water-soluble polymer, antioxidant, surfactant, metal An ion sequestering agent, an antibacterial preservative and the like can be blended. As described above, since the components A and B have an antioxidant action, it is not always necessary to add an antioxidant, but they may be added as needed for the purpose of storing for a longer period of time. May be.
本発明の癌細胞増殖抑制組成物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(成分Aおよび成分Bの合計量)は、1日当たり、1〜500mg/kg 体重である。様々な利用できる組成物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)への組成物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 growth inhibitory composition of the present invention is used as a pharmaceutical, the dosage is determined by the route of administration; the nature of the patient's disease; the patient's size, weight, surface area, age and sex; other drugs to be administered; It depends on the judgment. A suitable dose (total amount of component A and component B) is 1 to 500 mg / kg body weight per day. Given the different available compositions and the different effectiveness of the different routes of administration, it is expected that the required dosage can vary widely. These dosage level variations can be adjusted using standard empirical procedures for optimality known in the art. In particular for oral delivery, encapsulation of the composition in a suitable delivery vehicle (eg, polymer microparticles or implantable devices) increases delivery efficiency. The dose may be divided once or multiple times a day. Or, 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(癌治療/予防剤)に使用する場合、治療上有効な量の癌細胞増殖抑制組成物が、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、本発明の癌細胞増殖抑制組成物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増殖抑制組成物は、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。 For use in pharmaceuticals (cancer treatment / prevention agents), a therapeutically effective amount of a cancer cell growth inhibitory composition is formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The That is, the cancer cell growth inhibitory composition of the present invention can be provided in the form of a pharmaceutical composition further containing a pharmaceutically acceptable additive (eg, excipient, carrier, etc.). The cancer cell proliferation inhibiting composition of the present invention in this form can be specifically formulated for administration in solid or liquid as will be described in detail below. As oral administration, for example, liquid medicine (aqueous solution or non-aqueous solution or suspension), tablet, bolus, powder medicine, granule, paste for application to the tongue can be exemplified. For parenteral administration, for example, as a sterile solution or suspension, for example, a formulation for subcutaneous, intramuscular or intravenous injection, or as a topical, for example as a cream, ointment or spray applied to the skin, or It can be formulated in the vagina or rectum, for example, as a vaginal suppository, cream or foam.
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、何らかの所望の治療効果を生じるために有効な作用物質または組成物の量を意味する。例えば、本発明の癌細胞増殖抑制組成物の投与量は、対象疾患、投与対象、投与ルートなどにより差異はあるが、癌の治療/予防目的で本発明の癌細胞増殖抑制組成物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 effective to produce any desired therapeutic effect at a reasonable benefit / risk ratio applicable to any medical treatment. Means the amount of the active agent or composition. For example, although the dose of the cancer cell growth inhibitory composition of the present invention varies depending on the target disease, administration subject, administration route, etc., the cancer cell growth inhibitory composition of the present invention is orally administered for the purpose of cancer treatment / prevention. In this case, the dose can be easily selected by those skilled in the art because it can easily vary depending on conditions such as the weight of the subject. 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。 As used herein, “pharmaceutically acceptable” means that within a reasonable medical judgment, commensurate with a reasonable benefit / risk ratio, without problems or complications such as excessive toxicity, irritation, and allergic reaction, Used to refer to compounds, materials, compositions, and / or dosage forms suitable for use in contact with tissue of a 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増殖抑制組成物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増殖抑制組成物(癌治療/予防剤)中に含まれてもよい。 A pharmaceutically acceptable carrier is a liquid or solid filler involved in transporting or transporting the cancer cell growth-inhibiting composition of the present invention from one organ or part of the body to another organ or part of the body, By a pharmaceutically acceptable material, composition or excipient, such as a diluent, 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; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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; magnesium hydroxide and water Buffers such as aluminum; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other adaptations non-toxic substance which is used in the drug formulation and the like. In some embodiments, the drug formulation is non-pyrogenic. That is, the thing which does not raise a patient's body temperature is desirable. In addition, wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants are cancer cells of the present invention. It may be contained in a growth inhibitory composition (cancer treatment / prevention agent).
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 and the like; ascorbyl palmitate, butylhydroxyanisole ( Oil-soluble antioxidants such as BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like A metal chelating agent is mentioned.
本発明の癌細胞増殖抑制組成物は、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、活性成分の量(成分Aおよび成分Bの合計量)は、癌細胞増殖抑制組成物に対して、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 growth inhibitory composition 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 be conveniently presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can 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 that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect, but generally the amount of active ingredient (the total amount of component A and component B) is And about 0.1 to about 99% by weight, preferably about 1 to about 70% by weight, and more preferably about 5 to about 50% by weight, based on the cancer cell growth inhibitory composition.
これらの剤形または組成物を調製する方法は、本発明の癌細胞増殖抑制組成物を担体と、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整形することによって調製される。 Methods for preparing these dosage forms or compositions comprise the step of combining the cancer cell growth inhibitory composition of the present invention with a carrier and optionally one or more accessory ingredients. In general, dosage forms are prepared by uniformly and intimately bringing into association one or more agents of the present invention with liquid carriers or finely divided solid carriers or both and, 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、カシェ(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, cachets, pills, tablets, lozenges (with seasoned active ingredients, usually sucrose and gum arabic or tragacanth), powders, granules Or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or pastilles (such as gelatin and glycerin, or sucrose and gum arabic) And / or a gargle and the like, each containing a predetermined amount of the compound of the present invention as an active ingredient. The agent 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(成分Aおよび成分B)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、癌細胞増殖抑制組成物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 solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredients (component A and component B) are as sodium citrate or dicalcium phosphate. One or more pharmaceutically acceptable carriers and / or mixed with any of the following: a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; Binders such as methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; humectants such as glycerol; agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and Disintegrants such as sodium carbonate; paraffinic Such absorption retardants as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; talc, calcium stearate, magnesium stearate, solid polyethylene Lubricants such as glycols, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the cancer cell growth inhibitory composition may include a buffer. Similar types of solid compositions 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。 A tablet may also be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be binders (eg, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium glycolate starch or crosslinked sodium carboxymethylcellulose), surfactants Alternatively, it can be prepared using a dispersant. Molded tablets can 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、本発明の癌細胞増殖抑制組成物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 growth-inhibiting composition of the present invention, such as sugar-coated tablets, capsules, pills and granules, are optionally nicked or such as enteric coatings well known in the pharmaceutical dispensing arts. It may be prepared using a coating and shell. They are controlled or controlled release of the internal active ingredient using, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile. 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 that can be dissolved in a sterile injectable medium such as sterile water immediately before use. . These compositions may optionally contain opacifiers, in compositions that release one or more active ingredients only in certain parts of the gastrointestinal tract or preferentially there, optionally in a delayed manner. There may be. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient may be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
本発明の癌細胞増殖抑制組成物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 growth inhibitory composition 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 fatty acids esters of benzyl, propylene glycol, 1,3-butadiene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan Solubilizers and emulsifiers, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents. Suspensions may be suspended in addition to the active compound, 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増殖抑制組成物の剤形は、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 growth inhibitory composition of the present invention for rectal or vaginal administration may be presented as a suppository. This suppository comprises mixing one or more agents of the present invention with one or more suitable nonirritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates. Which is solid at room temperature but liquid at body temperature, it will melt in the rectum or vaginal cavity and release the active compound. Dosage forms suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray dosage forms containing carriers as known to be suitable in the art.
本発明の1つもしくは複数の癌細胞増殖抑制組成物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(成分Aおよび成分B)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(成分Aおよび成分B)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 growth inhibitory compositions of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredients (component A and component B) may be mixed under sterile conditions with a pharmaceutically acceptable base material and, if necessary, preservatives, buffers, or propellants. Ointments, pastes, creams and gels contain, in addition to the active ingredients (component A and component B), animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids And excipients such as talc and zinc oxide, or mixtures thereof.
粉末およびスプレーは、活性成分(成分Aおよび成分B)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 ingredient (component A and component B), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. But you can. The spray may further comprise customary high pressure gases such as chlorofluorinated hydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
経皮的パッチは、本発明の癌細胞増殖抑制組成物を、体に制御してデリバリー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増殖抑制組成物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増殖抑制組成物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 additional advantage of delivering the cancer cell growth inhibitory composition of the present invention to the body in a controlled manner. Such a dosage form can be obtained by dissolving or dispersing the cancer cell growth inhibitory composition of the present invention in an appropriate medium. It is also possible to increase the flux of the substance containing the cancer cell proliferation inhibiting composition of the present invention across the skin using an absorption enhancer. The speed of such flux can be controlled by either providing a speed control 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増殖抑制組成物は、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 growth inhibitory composition of the present invention suitable for parenteral administration is used with one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or uses with the composition. Includes sterile powders that can be reconstituted in sterile injectable solutions or dispersions immediately before, for example, solutes or suspensions that make the antioxidants, buffers, bacteriostats, preparations isotonic with the blood of the intended recipient. Can include turbidity or thickening agents.
本発明の癌細胞増殖抑制組成物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 growth inhibitory composition of the present invention include water, ethanol, polyol (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof. There are vegetable oils such as olive oil, and 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 dispersants and by the use of surfactants.
本発明の癌細胞増殖抑制組成物は、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 growth inhibitory composition of the present invention may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol and phenol sorbate. It may be desirable to include isotonic agents such as sugars, sodium chloride in the composition. In addition, prolonged absorption of the injectable drug form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
また、本発明の癌細胞増殖抑制組成物は、食品(食品組成物)としても利用することができる。この際、本発明の癌細胞増殖抑制組成物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増殖抑制組成物の配合量は、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、癌細胞増殖抑制組成物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。 Moreover, the cancer cell proliferation inhibitory composition of this invention can be utilized also as a foodstuff (foodstuff composition). At this time, the cancer cell proliferation inhibiting composition of the present invention may be used as it is, and it may be used as a liquid, gel or solid food such as juice, soft drink, tea, soup, soy milk, salad oil, dressing, yogurt, jelly, pudding. , Sprinkles, infant formula, cake mix, powdered or liquid dairy products, bread, cookies, etc., pellets, tablets with excipients such as dextrin, lactose, starch, flavorings, pigments, etc. It can be processed into granules, etc., or coated with gelatin and molded into capsules for use as health foods or dietary supplements. The amount of the cancer cell proliferation-suppressing composition of the present invention in these foods or edible compositions is difficult to define uniformly depending on the type or state of the food or composition, but with respect to the total weight of the food, 0.01 to 90% by weight, more preferably 0.1 to 80% by weight. If it is such a compounding quantity, the effect by the cancer cell proliferation inhibitory composition can fully be exhibited, without impairing flavor. Moreover, food can be easily prepared.
さらに、本発明の癌細胞増殖抑制組成物は、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。本発明の癌細胞増殖抑制組成物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。本発明の癌細胞増殖抑制組成物を化粧品(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。本発明の癌細胞増殖抑制組成物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 growth inhibitory composition of the present invention can also be used as a cosmetic (cosmetic composition). In this case, the form of the cosmetic (cosmetic composition) includes lotion, milky lotion, cream, powder and the like, but is not particularly limited thereto. Such a cosmetic (cosmetic composition) containing the cancer cell growth-inhibiting composition of the present invention can be produced using techniques known to those skilled in the art. Examples of the form in which the cancer cell growth inhibitory composition of the present invention is used as a cosmetic (cosmetic composition) include lotions, emulsions, creams, powders and the like, but are not particularly limited thereto. Such a cosmetic composition containing the cancer cell proliferation-inhibiting composition of the present invention can be produced using techniques 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 only to the following examples. In the following examples, the operation was performed at room temperature (25 ° C.) unless otherwise specified. Unless otherwise specified, “%” and “part” mean “% by weight” and “part by weight”, respectively.
実施例1〜2および比較例1〜5:大腸癌細胞に対する細胞増殖抑制効果の評価
(サンプルの調製)
カルノシン酸(和光純薬工業社製)、カルノソール(和光純薬工業社製)、エピガロカテキンガレート(EGCG)(シグマアルドリッチ社製)およびエピカテキンガレート(ECG)(和光純薬工業社製)を、それぞれ、ジメチルスルホキシド(DMSO)に、6.7mM濃度となるように添加して、6.7mM カルノシン酸溶液(サンプル3)、6.7mM カルノソール溶液(サンプル4)、6.7mM EGCG溶液(サンプル5)および6.7mM ECG溶液(サンプル6)を調製した。また、このようにして調製した溶液を用いて、カルノシン酸、カルノソール及びEGCGを1:1:1の混合比(モル比)で含む溶液(合計濃度:20mM、サンプル1)、カルノシン酸、カルノソール及びECGを1:1:1の混合比(モル比)で含む溶液(合計濃度:20mM、サンプル2)を調製した。
Examples 1-2 and Comparative Examples 1-5: Evaluation of cell growth inhibitory effect on colon cancer cells (Sample preparation)
Carnosic acid (manufactured by Wako Pure Chemical Industries), carnosol (manufactured by Wako Pure Chemical Industries), epigallocatechin gallate (EGCG) (manufactured by Sigma Aldrich) and epicatechin gallate (ECG) (manufactured by Wako Pure Chemical Industries) The 6.7 mM carnosic acid solution (sample 3), the 6.7 mM carnosol solution (sample 4), and the 6.7 mM EGCG solution (sample) were respectively added to dimethyl sulfoxide (DMSO) to a concentration of 6.7 mM. 5) and 6.7 mM ECG solution (sample 6) were prepared. Further, using the solution thus prepared, a solution (total concentration: 20 mM, sample 1) containing carnosic acid, carnosol and EGCG at a 1: 1: 1 mixing ratio (molar ratio), carnosic acid, carnosol and A solution (total concentration: 20 mM, sample 2) containing ECG at a mixing ratio (molar ratio) of 1: 1: 1 was prepared.
(癌細胞増殖抑制効果の評価)
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、12ウェルプレートに1ウェルあたり1×104個になるように1ml播種した。5体積%CO2雰囲気下で37℃で24時間、DLD−1細胞を培養した後、上記サンプル1〜6を、最終濃度が6.7μM(サンプル3(比較例1)、サンプル4(比較例2)、サンプル5(比較例3)、サンプル6(比較例4))または20μM(サンプル1(実施例1)、サンプル2(実施例2))となるように、それぞれ、培地に1μl添加した。また、コントロールには、溶媒のDMSOのみを1μl添加した(サンプル7、比較例5)。
(Evaluation of cancer cell growth inhibitory effect)
Human colon adenocarcinoma-derived DLD-1 cells were cultured at 37 ° C. in a 5% by volume CO 2 atmosphere using 10 (v / v)% FBS-containing RPMI1640 medium. 1 ml of this cultured cell was seeded on a 12-well plate so that the number of cells was 1 × 10 4 per well. After culturing DLD-1 cells for 24 hours at 37 ° C. in an atmosphere of 5% by volume CO 2 , the above-mentioned samples 1 to 6 were subjected to final concentrations of 6.7 μM (sample 3 (comparative example 1), sample 4 (comparative example) 2), sample 5 (Comparative Example 3), sample 6 (Comparative Example 4)) or 20 μM (Sample 1 (Example 1), Sample 2 (Example 2)) was added to each medium in an amount of 1 μl. . In addition, 1 μl of only DMSO as a solvent was added as a control (Sample 7, Comparative Example 5).
各サンプルまたはDMSOを添加してから48時間、DLD−1細胞を、5体積%CO2雰囲気下で37℃で培養した。所定時間培養後、生存細胞数をトリパンブルー染色法により測定し、下記に示す式(1)により各サンプルの細胞増殖抑制率(%)を算出した。結果を下記表1及び図1に示す。なお、下記式(1)において、「各サンプルの生存細胞数」は各サンプルを添加・培養した際のDLD−1細胞の生存細胞数を示し、「コントロールの生存細胞数」は、DMSOを添加・培養した際のDLD−1細胞の生存細胞数を示す。 Forty-eight hours after adding each sample or DMSO, DLD-1 cells were cultured at 37 ° C. in a 5% by volume CO 2 atmosphere. After culturing for a predetermined time, the number of viable cells was measured by trypan blue staining, and the cell growth inhibition rate (%) of each sample was calculated by the following formula (1). The results are shown in Table 1 below and FIG. In the following formula (1), “the number of viable cells of each sample” indicates the number of viable cells of DLD-1 cells when each sample is added and cultured, and “the number of viable cells of control” is added with DMSO. -The number of viable cells of DLD-1 cells when cultured is shown.
上記表1及び図1から明らかなように、実施例1〜2の組成物は、各成分単独(カルノシン酸(比較例1)、カルノソール(比較例2)、EGCG(比較例3)およびECG(比較例4))ならびに無添加(比較例5)に比して、癌細胞増殖抑制率が有意に高いことが分かる。また、実施例1〜2の組成物によると、各成分単独での癌細胞増殖抑制率の合計より有意に高い癌細胞増殖抑制率が達成できることが分かる。当該結果から、本発明の組成物を用いることによって、癌細胞増殖抑制効果を相乗的に向上できると考察される。 As apparent from Table 1 and FIG. 1, the compositions of Examples 1 and 2 were prepared using each component alone (carnosic acid (Comparative Example 1), carnosol (Comparative Example 2), EGCG (Comparative Example 3) and ECG ( It can be seen that the inhibition rate of cancer cell proliferation is significantly higher as compared with Comparative Example 4)) and without addition (Comparative Example 5). Moreover, according to the composition of Examples 1-2, it turns out that the cancer cell proliferation suppression rate significantly higher than the sum total of the cancer cell proliferation suppression rate by each component single can be achieved. From the results, it is considered that the cancer cell proliferation inhibitory effect can be synergistically improved by using the composition of the present invention.
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 proliferation inhibitory effect was evaluated for human cells, but it is presumed that similar results can be obtained for pet animals such as dogs and cats.
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