TW201304789A - Use of Taiwanese green propolis for slowing the progression of the disease of a patient - Google Patents
Use of Taiwanese green propolis for slowing the progression of the disease of a patient Download PDFInfo
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本發明係關於含有台灣綠蜂膠萃取物減緩患者病情發展之用途。The present invention relates to the use of Taiwan green propolis extract to slow the progression of a patient's condition.
癌症是一種重大且惡性之疾病。隨著衛生條件改善，及人類壽命之延長，與科學診斷儀器之進步，癌症被診斷之病患數逐年增加。癌症病患除了手術以外，最常使用的治療方式是化學治療，化療藥物會使癌細胞停止生長或受到破壞，因此達到治療癌症的效果。化療藥物依照藥物的作用方式可分為：烷基化劑、抗代謝劑、位置異構酶抑制劑及微管抑制劑等。目前常用的抗癌藥物有脂質體阿黴素(liposomal doxorubicin)、托泊替康(topotecan；商品名Hycamtin)及太平洋紫杉醇(paclitaxel；商品名Taxol)等藥物。Cancer is a major and malignant disease. With the improvement of sanitary conditions, the extension of human life, and the advancement of scientific diagnostic instruments, the number of patients diagnosed with cancer has increased year by year. In addition to surgery, the most common treatment for cancer patients is chemotherapy. Chemotherapy drugs can stop cancer cells from dying or being destroyed, thus achieving cancer treatment. Chemotherapy drugs can be classified according to the mode of action of the drugs: alkylating agents, antimetabolites, position isomerase inhibitors, and microtubule inhibitors. Currently commonly used anticancer drugs are liposomal doxorubicin, topotecan (trade name Hycamtin) and paclitaxel (trade name Taxol).
傳統之抗癌化療藥物效果有限，及引發顯著之副作用，造成病患生活品質下降，且病人之存活率提升有限。因此，許多新一代的抗癌標靶藥物被研發上市，這些抗癌標靶藥物具有顯著抗癌活性；同時擁有較低之副作用，但整體而言，其對病患壽命之延長仍難令人滿意。這些抗癌標靶藥物依作用機制不同可分為：血管新生抑制劑、酪氨酸激酶抑制劑、分化誘導劑及免疫治療劑等(Nygren P et al. J Intern Med. 2003;253(1): 46-75.)。The traditional anti-cancer chemotherapy drugs have limited effects and cause significant side effects, resulting in a decline in the quality of life of patients and a limited increase in the survival rate of patients. Therefore, many new generations of anti-cancer target drugs have been developed and marketed. These anti-cancer target drugs have significant anti-cancer activity; at the same time, they have lower side effects, but overall, their life extension is still difficult. satisfaction. These anti-cancer target drugs can be divided into: angiogenesis inhibitors, tyrosine kinase inhibitors, differentiation inducers and immunotherapeutics according to different mechanisms of action (Nygren P et al . J Intern Med. 2003; 253(1) : 46-75.).
血管新生抑制劑(angiogenesis inhibitor)已有許多藥物上市，如貝伐單抗(bevacizumab；商品名Avastin)是人類單株抗體(Willett CG et al. Nat Med. 2004;10(2):145-7.)；另一個是沙利多邁(thalidomide)，是一種鎮靜劑，也是一種血管新生抑制劑(Bosch ME et al. J Pharm Biomed Anal. 2008;46(1):9-17.)。另一類為基質金屬蛋白水解酶(matrix metalloproteinase)抑制劑，如巴馬司他(Batimastat)及馬立馬司他(Marimastat)等藥物(Gialeli C et al. FEBS J. 2011;278(1):16-27.)。血管新生抑制劑主要是抑制腫瘤血管的生成，抑制腫瘤取得許多營養物質及移除廢棄物。腫瘤的成長若無血液養份源源不斷之供應，將無法成長。因此，抑制腫瘤血管之新生，將可有效抑制腫瘤生長，而達到抗癌之目的。Many drugs have been marketed for angiogenesis inhibitors, such as bevacizumab (trade name Avastin), which is a human monoclonal antibody (Willett CG et al . Nat Med. 2004; 10(2): 145-7 .); The other is thalidomide, a sedative and an angiogenesis inhibitor (Bosch ME et al . J Pharm Biomed Anal. 2008;46(1):9-17.). The other type is matrix metalloproteinase inhibitors, such as Bamastat and Marimastat (Gialeli C et al . FEBS J. 2011;278(1):16 -27.). Angiogenesis inhibitors mainly inhibit the formation of tumor blood vessels, inhibit tumors from obtaining many nutrients and remove waste. If the tumor grows without a steady supply of blood nutrients, it will not grow. Therefore, inhibiting the neovascularization of tumors will effectively inhibit tumor growth and achieve anti-cancer purposes.
酪氨酸激酶抑制劑(tyrosine kinase inhibitor)(Soria JC et al. Ann Oncol. 2011.)已有超過10個藥物上市，包括吉非替尼(Gefitinib)、阿西替尼(Axitinib)、伯舒替尼(Bosutinib)、達沙替尼(Dasatinib)、厄洛替尼(Erlotinib)、凡德他尼(Vandetanib)、曲妥珠單抗(Trastuzumab；商品名Herceptin)、拉帕替尼(Lapatinib；商品名Xeloda)及伊馬替尼(Imatinib；商品名Gleevec)等藥物。這類藥物主要是抑制訊號傳遞，抑制癌細胞增生，而達到抗癌目標。格列衛(Gleevec)是這類藥物最先上市的，藥價相當昂貴。而這類藥物中最著名的，如EGF(Epidermal growth factor)家族接受器HER2/neu表現之乳癌，可以使用赫賽汀(Herceptin)來治療(Soria JC et al. Ann Oncol. 2011.)。目前研究也發現，此類藥物適合與其它機制之抗癌藥物合併使用，增加治療成效。More than 10 drugs have been marketed for tyrosine kinase inhibitors (Soria JC et al. Ann Oncol. 2011.), including Gefitinib, Axitinib, and Boshu Bosutinib, Dasatinib, Erlotinib, Vandetanib, Trastuzumab (trade name Herceptin), Lapatinib (Lapatinib; Trade name Xeloda) and imatinib (Imatinib; trade name Gleevec) and other drugs. These drugs mainly inhibit signal transmission, inhibit cancer cell proliferation, and achieve anti-cancer goals. Gleevec is the first to market for these drugs, and the price is quite expensive. The most famous of these drugs, such as the EGF (Epidermal Growth Factor) family receptor HER2/neu breast cancer, can be treated with Herceptin (Soria JC et al. Ann Oncol. 2011.). The current study also found that these drugs are suitable for use in combination with other mechanisms of anticancer drugs to increase treatment effectiveness.
分化誘導劑(differentiation inducer)包含二類。一類是全反式視黃酸(all trans retinoic acid,ATRA)主要用於血癌(Tsukada N et al. Intern Med. 1996;35(1):10-4.)。另一類是epigenetic調控劑，主要有DMT(DNA Methyltransferase)抑制劑及HDAC(Histone deacetylase)抑制劑二種(Lyko F et al. J Natl Cancer Inst. 2005;97(20):1498-506. and okmanovic M et al. Mol Cancer Res. 2007;5(10):981-9.)。DMT目前已有藥物上市包括有：氮胞嘧啶核苷(azacytidine；商品名Vidaza)及decitabine(商品名Dacogen)主要用於治療骨髓增生不良症候群(myelodysplastic syndrome；MDS)(Stresemann C et al. Int J Cancer. 2008;123(1):8-13.)。而HDAC抑制劑目前已有二個藥物上市，分別是羥胺酸(SAHA；商品名Zolinza)及伊斯托達(Istodax)被應用於治療皮膚T細胞淋巴癌(cutaneous T cell lymphoma；CTCL)(Duvic M et al. Blood. 2007;109(1):31-9.)。這類藥物可以調節癌細胞失控的表觀遺傳(epigenetic)作用；進而抑制癌細胞增生，促進癌細胞分化，或是誘導細胞自我凋亡而達到抗癌目的。Differentiation inducers contain two classes. One type is all trans retinoic acid (ATRA), which is mainly used for blood cancer (Tsukada N et al. Intern Med. 1996; 35(1): 10-4.). The other is epigenetic modulators, mainly DMT (DNA Methyltransferase) inhibitors and HDAC (Histone deacetylase) inhibitors (Lyko F et al. J Natl Cancer Inst. 2005; 97 (20): 1498-506. and okmanovic M et al. Mol Cancer Res. 2007; 5(10): 981-9.). DMT currently has drug listings including: azacytidine (trade name Vidaza) and decitabine (trade name Dacogen) for the treatment of myelodysplastic syndrome (MDS) (Stresemann C et al. Int J) Cancer. 2008;123(1):8-13.). HDAC inhibitors are currently available in two drugs, namely hydroxyglycolic acid (SAHA; trade name Zolinza) and Istodox (Istodax) for the treatment of cutaneous T cell lymphoma (CTCL) (Duvic). M et al . Blood. 2007;109(1):31-9.). These drugs can regulate the epigenetic effects of cancer cells out of control; thereby inhibiting cancer cell proliferation, promoting cancer cell differentiation, or inducing cell self-apoptosis for anti-cancer purposes.
免疫治療劑(immunotherapy)目前已上市藥物為攝護腺癌疫苗(Provenge)，主要是藉由病人自己的免疫力，用於攝護腺癌前期之治療(Small EJ et al. J Clin Oncol. 2000;18(23):3894-903.)。攝護腺癌是美國男性癌症排名第二位，在2009年，新診斷之病患數為192,000人；死亡人數為27,000人。Immunotherapy The currently marketed drug is the Provenge vaccine, which is mainly used for the treatment of precancerous prostate cancer by the patient's own immunity (Small EJ et al . J Clin Oncol. 2000). ;18(23):3894-903.). Prostate cancer ranks second in the United States for male cancer. In 2009, the number of newly diagnosed patients was 192,000; the death toll was 27,000.
以上四大類抗癌標靶藥物，雖然有顯著療效且有較低之副作用，然而，癌症病患之存活率仍無法大幅提高。因此，對於癌症治療而言，亟需開發更有效或是更低副作用的療法，以期增強抗癌功效並有效延長病患壽命，提升癌症病人之生活品質。Although the above four major anti-cancer target drugs have significant effects and have low side effects, the survival rate of cancer patients cannot be greatly improved. Therefore, for cancer treatment, it is urgent to develop a therapy with more effective or lower side effects, in order to enhance the anti-cancer effect and effectively prolong the life of the patient and improve the quality of life of cancer patients.
本發明意外地發現台灣綠蜂膠萃取物(Taiwanese green propolis)或蜂膠素(Propolins)可用以減緩患者病情發展，特定而言，其可用以增進癌症病人生活品質。The present inventors have unexpectedly discovered that Taiwanese green propolis extract or Propolins can be used to slow the progression of a patient's condition, in particular, it can be used to improve the quality of life of cancer patients.
因此，在一方面，本發明提供一種台灣綠蜂膠萃取物用以製備減緩患者病情發展的營養補充劑之用途。Accordingly, in one aspect, the present invention provides a use of a Taiwan green propolis extract for the preparation of a nutritional supplement that slows the progression of a patient's condition.
另一方面，本發明提供一種台灣綠蜂膠萃取物用以製備增進患有癌症之個體生活品質的營養補充劑之用途。In another aspect, the present invention provides a use of a Taiwan green propolis extract for the preparation of a nutritional supplement that enhances the quality of life of an individual suffering from cancer.
另一方面，本發明提供一種用以增進患有癌症之個體生活品質之營養補充劑，其係包含台灣綠蜂膠萃取物或蜂膠素，其可與一或多種抗癌藥物或成分合併使用，且本發明之營養補充劑係可增進該一或多種抗癌藥物或成分之抗癌功效。在一具體實施例中，其包含2.5-25wt%之台灣綠蜂膠萃取物。In another aspect, the present invention provides a nutritional supplement for enhancing the quality of life of an individual suffering from cancer, which comprises a Taiwan green propolis extract or propolis, which can be used in combination with one or more anticancer drugs or ingredients, and The nutritional supplement of the present invention enhances the anticancer effect of the one or more anticancer drugs or ingredients. In a specific embodiment, it comprises from 2.5 to 25 wt% of the Taiwan green propolis extract.
在本發明之一具體實施例中，該營養補充劑可與一或多種抗癌藥物或成分合併使用，因而提高該一或多種抗癌藥物或成分抑制腫瘤生長之功效。In a particular embodiment of the invention, the nutritional supplement can be used in combination with one or more anti-cancer drugs or ingredients, thereby enhancing the efficacy of the one or more anti-cancer drugs or ingredients to inhibit tumor growth.
在本發明之又一具體實施例中，本發明之營養補充劑可與一或多種抗癌藥物或成分合併使用，因而延長患有癌症之個體壽命。In yet another embodiment of the invention, the nutritional supplement of the present invention can be used in combination with one or more anti-cancer drugs or ingredients, thereby extending the lifespan of an individual suffering from cancer.
另一方面，本發明提供一種具增進抗癌功效並可提升患有癌症之個體壽命之組合物，其包含本發明台灣綠蜂膠萃取物或蜂膠素之營養補充劑、蜂王乳及黃耆萃取物。經本發明驗證，本發明台灣綠蜂膠萃取物之營養補充劑、蜂王乳及黃耆萃取物之組合物，對於抑制腫瘤生長具有無法預期之增進功效，同時可縮小腫瘤之大小以及延長癌症患者之壽命。In another aspect, the present invention provides a composition having an anti-cancer effect and enhancing the lifespan of an individual suffering from cancer, comprising the Taiwan green propolis extract or propolis nutritional supplement, royal jelly and astragalus extract . The invention proves that the combination of the nutritional supplement of the green propolis extract of the invention, the royal jelly and the extract of the astragalus extract has unpredictable improvement effect on inhibiting tumor growth, and can reduce the size of the tumor and prolong the life of the cancer patient. .
另一方面，本發明提供一種調節免疫功能之藥物，其係包含台灣綠蜂膠萃取物或蜂膠素。In another aspect, the present invention provides a medicament for modulating an immune function comprising a Taiwan green propolis extract or propolis.
本發明之各個具體實例的細節說明如後。本發明之其他特徵將會經由以下各個具體實例中的詳細說明及申請專利範圍而清楚呈現。Detailed descriptions of various specific examples of the invention are given below. Other features of the present invention will be apparent from the following detailed description and claims.
無須進一步的闡述，咸相信本發明所屬技術領域中具有通常知識者基於前述說明即可利用本發明至最廣的程度。因此，可以理解以下的說明僅僅是作為例示說明之用，而非以任何方式限制其餘的揭露內容。Without further elaboration, it is believed that those of ordinary skill in the art of Therefore, it is to be understood that the following description is for illustrative purposes only and is not intended to limit the disclosure.
除非另有指明，所有在此處使用的技術性和科學性術語具有如同本發明所屬技藝中之通常技術者一般所瞭解的意義。All technical and scientific terms used herein have the meaning as commonly understood by one of ordinary skill in the art to which the invention pertains, unless otherwise indicated.
本文所使用的「一」乙詞，如未特別指明，係指至少一個(一個或一個以上)之數量。The term "a" as used herein, unless otherwise specified, refers to the quantity of at least one (one or more).
本文所使用的「萃取物」乙詞係指使用一溶劑萃取原料而得之產物，其中該溶劑包括但不限於水或乙醇。As used herein, the term "extract" refers to a product obtained by extracting a starting material with a solvent, including but not limited to water or ethanol.
本文所使用的「營養補充劑」乙詞係指日常飲食之外補充品，其形式包括但不限於膠囊、錠劑、丸劑、懸浮液、顆粒、食品或飲品。As used herein, the term "nutritional supplement" refers to supplements other than daily diets, including but not limited to capsules, lozenges, pills, suspensions, granules, foods or beverages.
本文所使用的「癌症」乙詞係指任何異常之細胞或組織生長，例如，腫瘤，不論為惡性、前惡性或非惡性，其特徵在於不受控制的細胞增殖。本文所使用的「癌症」乙詞包括但不限於肺癌、結腸癌、乳癌、攝護腺癌、肝癌、胰臟癌及口腔癌。As used herein, the term "cancer" refers to the growth of any abnormal cell or tissue, for example, a tumor, whether malignant, pre-malignant or non-malignant, characterized by uncontrolled cell proliferation. As used herein, the term "cancer" includes, but is not limited to, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, and oral cancer.
本文所使用的「個體」乙詞係指動物或人類。As used herein, the term "individual" refers to an animal or a human.
在本發明中，「台灣綠蜂膠(Taiwanese green propolis)」乙辭係指盛產期為5-8月、產於台灣的翠綠色蜂膠，含有豐富的蜂膠素(propolins)。In the present invention, "Taiwanese green propolis" refers to emerald green propolis which is produced in Taiwan from May to August and is rich in proolins.
本發明的台灣綠蜂膠萃取物主要可含有蜂膠素(propolins)。The Taiwan green propolis extract of the present invention may mainly contain proolins.
本文所使用的「蜂膠素(propolins)」乙詞係指具有以下通式(式1)之化合物及其水合物。The term "propolins" as used herein refers to a compound having the following formula (Formula 1) and a hydrate thereof.
其中R1、R3及R6為OH、OCH3、OCH2CH3或H；R2為H、Wherein R 1 , R 3 and R 6 are OH, OCH 3 , OCH 2 CH 3 or H; R 2 is H,
R4為H、R 4 is H,
R5為OH、H、；R7為H、。R 5 is OH, H, ; R7 is H, .
本發明所使用的「蜂膠素」乙詞包括但不限於下列化合物及其水合物：The term "propolis" as used in the present invention includes but is not limited to the following compounds and hydrates thereof:
本文所使用的「水合物」乙詞又稱水化物，是指含有水的化合物，其中水可以是配位與其他部分相連，或以共價鍵相结合，化合物與水分子藉氫鍵结合形成结晶。本發明中，水合物係指一分子水在支鏈的尾端形成一個含有三級醇的化合物，例如蜂膠素A(propolin A)、蜂膠素B(propolin B)、蜂膠素E(propolin E)等。As used herein, the term "hydrate" is also referred to as hydrate, and refers to a compound containing water in which water may be coordinated to other moieties or combined by covalent bonds, and the compound and water molecules are bonded by hydrogen bonding. crystallization. In the present invention, hydrate refers to a molecule of water forming a compound containing a tertiary alcohol at the tail end of the branch, such as propolin A, propolin B, and propolin E. Wait.
在本發明中，「抗癌藥物或成分」乙辭係指具有抑制癌細胞生長或增生之功效的藥物或有效成分，包括任何此技術領域中已知的抗癌藥物或具有抗癌功效的成分、物質、天然物、萃取物、組合物、中草藥單方或複方或蛋白質等。例如，其可選自由蜂王乳、黃耆萃取物、脂質體阿黴素、太平洋紫杉醇、托泊替康(topotecan)、癌思停(Avastin)、巴馬司他(Batimastat)、馬立馬司他(Marimastat)、吉非替尼(Gefitinib)、阿西替尼(Axitinib)、伯舒替尼(Bosutinib)、達沙替尼(Dasatinib)、厄洛替尼(Erlotinib)、凡德他尼(Vandetanib)、赫賽汀(Herceptin)、希羅達(Xeloda)、格列衛(Gleevec)、維達扎(Vidaza)、達珂(Dacogen)、伏立諾他(vorinostat;Zolinza)、伊斯托達(Istodax)、攝護腺癌疫苗(Provenge)、硼替佐米(Bortezomib)、紓癌特(Sutent)、伊沙匹隆(Ixabepione)、雙羥蒽醌(mitoxantrone)、多西紫杉醇(Docetaxel)、伊達比星(idarubicin)、道紅鏈絲菌素(daunorubicin)、***糖基胞嘧啶(cytarabine)、二氯二胺鉑(cisplatin)、阿黴素(doxorubicin)、內皮抑制素(endostatin)、角鯊胺(squalamine)、腫瘤抑制素(tumstatin)、阿他美坦(atamestane)、法倔唑(fadrozole)、來曲唑(letrozole)、羅谷亞胺(rogletimide)、伏氯唑(vorozole)、環磷醯胺(cyclophosphamide)、苯達莫司汀(bendamustine)、氮芥子氣(nitrogen mustard)、依弗醯胺(ifosfamide)、替莫唑胺(temozolomide;temodar)、伊妥普賽(etoposide)、伊立替康(irinotecan)、喜樹鹼(camptothecin)、長春花鹼(vinblastine)、胺基甲基葉酸(methotrexate)、抗***(tamoxifen)、伏立諾他(vorinostat)其組合所組成之群。In the present invention, the term "anticancer drug or component" refers to a drug or an active ingredient having an effect of inhibiting the growth or proliferation of cancer cells, and includes any anticancer drug or anticancer agent known in the art. , substances, natural substances, extracts, compositions, Chinese herbal medicines unilateral or compound or protein. For example, it can be selected from royal jelly, scutellaria extract, liposomal doxorubicin, paclitaxel, topotecan, Avastin, Batimastat, Marimastat. (Marimastat), Gefitinib, Axitinib, Bosutinib, Dasatinib, Erlotinib, Vandetanib ), Herceptin, Xeloda, Gleevec, Vidaza, Dacogen, vorinostat (Zolinza), Istodda (Istodax), Provenge, Bortezomib, Sutent, Ixabepione, mitoxantrone, Docetaxel, Idarubicin, daunorubicin, cytarabine, cisplatin, doxorubicin, endostatin, horn Squalamine, tumstatin, atamestane, fadrozole, letrozole, roque Aromatic (rogletimide), vorozole, cyclophosphamide, bendamustine, nitrogen mustard, ifosfamide, temozolomide (temodar) , etoposide, irinotecan, camptothecin, vinblastine, methotrexate, tamoxifen, vorinostat (vorinostat) A group of its combinations.
在本發明中，「減緩患者病情發展」乙辭係指使患有一疾病之個體其疾病發展進程減緩。In the present invention, the phrase "mitigating the progression of a patient's condition" refers to slowing down the progression of the disease in an individual suffering from a disease.
在本發明中，「增進癌症病人生活品質」乙辭係指癌症治療過程之痛苦或副作用之降低及免疫力之增進，而使病人之生活可近於常人。In the present invention, the phrase "improving the quality of life of a cancer patient" refers to a decrease in the pain or side effects of the cancer treatment process and an increase in immunity, so that the life of the patient can be close to that of an ordinary person.
根據本發明，包含台灣綠蜂膠萃取物或蜂膠素之營養補充劑係可調節免疫功能並減緩患者病情發展。According to the present invention, a nutritional supplement comprising Taiwan green propolis extract or propolis can modulate immune function and slow the progression of the patient's condition.
在本發明之一具體實施例中，本發明之營養補充劑係可調節特異性免疫能力。In a particular embodiment of the invention, the nutritional supplement of the invention modulates specific immunity.
在另一具體實施例中，本發明之營養補充劑係可調節非特異性免疫能力。In another embodiment, the nutritional supplement of the present invention modulates non-specific immunity.
根據本發明，單獨投與包含台灣綠蜂膠萃取物或蜂膠素之營養補充劑，並無顯著之抗癌功效。但當與抗癌藥物或成分合併使用，可增進該抗癌藥物或成分之抗癌功效；具體而言，本發明營養補充劑與抗癌藥物或成分合併使用時可提高該抗癌藥物或成分抑制腫瘤生長之功效，以及可延長患有癌症之個體壽命。藉由此增進效果，可降低抗癌藥物之使用劑量或縮短療程，進而減輕藥物副作用帶來之不適。因此，本發明提供一種台灣綠蜂膠萃取物用以製備增進患有癌症之個體生活品質營養補充劑之用途。在一較佳具體實施例中，該台灣綠蜂膠萃取物係包含一或多種蜂膠素。According to the present invention, a nutritional supplement containing Taiwan green propolis extract or propolis is administered alone without significant anticancer effect. However, when used in combination with an anticancer drug or a component, the anticancer effect of the anticancer drug or component can be enhanced; in particular, the nutritional supplement of the present invention can be used in combination with an anticancer drug or component to enhance the anticancer drug or component. It inhibits the growth of tumors and prolongs the lifespan of individuals with cancer. By increasing the effect, the dosage of the anticancer drug can be reduced or the course of treatment can be shortened, thereby reducing the discomfort caused by side effects of the drug. Accordingly, the present invention provides a use of a Taiwan green propolis extract for the preparation of a nutritional supplement that enhances the quality of life of an individual suffering from cancer. In a preferred embodiment, the Taiwan green propolis extract comprises one or more propolis.
本發明亦提供一種用以增進患有癌症之個體生活品質之營養補充劑，係包含台灣綠蜂膠萃取物或蜂膠素且其係可與一或多種抗癌藥物或成分合併使用，且本發明之營養補充劑係可增進該一或多種抗癌藥物或成分之抗癌功效。The present invention also provides a nutritional supplement for promoting the quality of life of an individual suffering from cancer, comprising a Taiwan green propolis extract or propolis and which can be used in combination with one or more anticancer drugs or ingredients, and the invention A nutritional supplement can enhance the anti-cancer efficacy of the one or more anti-cancer drugs or ingredients.
在本發明之一具體實施例中，該台灣綠蜂膠萃取物係包含一或多種蜂膠素。In a specific embodiment of the invention, the Taiwan green propolis extract comprises one or more propolis.
在本發明之一具體實施例中，該營養補充劑係包含2.5-25wt%之台灣綠蜂膠萃取物。In a particular embodiment of the invention, the nutritional supplement comprises from 2.5 to 25% by weight of the Taiwan green propolis extract.
在本發明之一具體實施例中，該營養補充劑係包含2.5-25wt%之蜂膠素。In a particular embodiment of the invention, the nutritional supplement comprises from 2.5 to 25% by weight of propolis.
在本發明之一具體實施例中，該營養補充劑可進一步包含一生理上可接受之載劑。In a particular embodiment of the invention, the nutritional supplement may further comprise a physiologically acceptable carrier.
在本發明之一具體實施例中，該營養補充劑係為口服形式。In a particular embodiment of the invention, the nutritional supplement is in oral form.
另一方面，本發明提供一種用以增進患有癌症之個體生活品質之抗癌藥物組合，其包含本發明台灣綠蜂膠萃取物或蜂膠素之營養補充劑，以及一或多種抗癌藥物或成分。In another aspect, the present invention provides an anticancer drug combination for enhancing the quality of life of an individual suffering from cancer, comprising the Taiwan green propolis extract or a propolis nutritional supplement, and one or more anticancer drugs or ingredients .
本發明進一步提供一種具增進抗癌功效且可提升患有癌症之個體壽命之組合物，其包含台灣綠蜂膠萃取物或蜂膠素之營養補充劑，蜂王乳及黃耆萃取物。The present invention further provides a composition having an anti-cancer effect and which can enhance the lifespan of an individual suffering from cancer, which comprises a Taiwan green propolis extract or a propolis vitamin supplement, a royal jelly and an astragalus extract.
在本發明之一具體實施例中，該組合物中台灣綠蜂膠萃取物，蜂王乳及黃耆萃取物三者之重量比可為10-30wt%之台灣綠蜂膠萃取物或蜂膠素、40-75wt%之蜂王乳及10-25wt%之黃耆萃取物，較佳為1-10：3-30：1-10，更佳為1.5：7：1.5。In a specific embodiment of the present invention, the weight ratio of Taiwan green propolis extract, royal jelly and astragalus extract in the composition may be 10-30% by weight of Taiwan green propolis extract or propolis, 40- 75 wt% of royal jelly and 10-25 wt% of xanthine extract, preferably 1-10:3-30:1-10, more preferably 1.5:7:1.5.
在本發明之一具體實施例中，該組合物係可增進患有癌症之個體的免疫力。In a particular embodiment of the invention, the composition enhances the immunity of an individual having cancer.
另一方面，本發明提供一種調節免疫功能之藥物，其係包含台灣綠蜂膠萃取物或蜂膠素。In another aspect, the present invention provides a medicament for modulating an immune function comprising a Taiwan green propolis extract or propolis.
在本發明之一具體實施例中，該藥物係可調節特異性免疫能力。In a specific embodiment of the invention, the drug system modulates specific immunity.
在另一具體實施例中，該藥物係可調節非特異性免疫能力。In another specific embodiment, the drug system modulates non-specific immunity.
以下實例僅作為說明，而非作為本發明之限制。The following examples are illustrative only and not intended to be limiting of the invention.
蜂王乳之製備Preparation of royal jelly
新鮮蜂王乳約4.0公斤係於2009年10月份採集自台灣花蓮之蜂場。其中2公斤經冷凍乾燥，約取得700公克蜂王乳粉。放置於-20℃冰箱待進一步使用。另2公斤蜂王乳，加5公斤純水充份混合，再使用離心機4000 rpm，10分鐘在4℃。離心後之上清液加入蛋白水解酶(protease A)(2 mg/mL)，在溫度約50℃，轉速150 rpm震盪培養箱作用約2小時進行蜂王乳蛋白水解。之後，以90℃高溫將protease A之活性去除，再進行減壓濃縮。將原來離心之沉澱物與濃縮液混合，再進行冷凍乾燥得到約640公克水解蜂王乳粉。放置於-20℃冰箱直到進一步使用。About 4.0 kilograms of fresh royal jelly was collected in the bee house of Hualien, Taiwan in October 2009. 2 kg of the lyophilized, about 700 grams of royal jelly powder. Place in a refrigerator at -20 ° C for further use. Another 2 kg of royal jelly, add 5 kg of pure water to mix thoroughly, then use a centrifuge 4000 rpm, 10 minutes at 4 ° C. After centrifugation, the supernatant was added with protease A (2 mg/mL), and the protein was hydrolyzed by shaking the incubator at a temperature of about 50 ° C and shaking at 150 rpm for about 2 hours. Thereafter, the activity of the protease A was removed at a high temperature of 90 ° C, and concentrated under reduced pressure. The originally centrifuged precipitate was mixed with the concentrate, and then freeze-dried to obtain about 640 g of hydrolyzed royal jelly powder. Place in a -20 ° C freezer until further use.
台灣綠蜂膠萃取物之製備Preparation of Taiwan Green Propolis Extract
台灣綠蜂膠約2公斤係於2009年7月份採集自台灣花蓮之蜂場。將台灣綠蜂膠脫蠟，再使用95%酒精進行萃取約3個星期。萃取液進行過濾，去除雜質，經減壓濃縮取得台灣綠蜂膠萃取物約1.5公斤。放置於-20℃冰箱直到進一步使用。萃取物經HPLC分析確認活性化合物之含量。About 2 kilograms of Taiwan green propolis was collected from the bee farm of Hualien, Taiwan in July 2009. The Taiwan green propolis is dewaxed and extracted with 95% alcohol for about 3 weeks. The extract was filtered to remove impurities, and concentrated under reduced pressure to obtain about 1.5 kg of Taiwan green propolis extract. Place in a -20 ° C freezer until further use. The extract was analyzed by HPLC to confirm the content of the active compound.
黃耆萃取物之製備Preparation of Astragalus membranaceus extract
黃耆約1公斤係於2010年1月份購買自台北市某中藥房。進行黃耆之萃取，使用30%酒精進行浸泡約3天，萃取液進行過濾，去除殘渣，過濾液使用減壓濃縮機進行濃縮，取得黃耆萃取物約300公克。放置於-20℃冰箱直到進一步使用。測定黃耆萃取物多醣體之總含量。Approximately 1 kilogram of Astragalus was purchased from a Chinese pharmacy in Taipei City in January 2010. The extract of Astragalus membranaceus was subjected to soaking for 30 days using 30% alcohol, and the extract was filtered to remove the residue, and the filtrate was concentrated using a vacuum condenser to obtain about 300 g of the extract of Astragalus membranaceus. Place in a -20 ° C freezer until further use. The total content of the polysaccharide of the astragalus extract was determined.
台灣綠蜂膠萃取物之特異性免疫調節功效試驗Specific immunomodulatory efficacy test of Taiwan green propolis extract
受試動物為8週齡BALB/c雄性小鼠，購自樂斯科生物科技股份有限公司。進行連續強迫管餵試驗物質8週後，犧牲小鼠，採取檢體進行分析。在第4及6週以卵白蛋白(OVA)加上全佛朗氏佐劑(Complete Freund’s Adjuvant)混合注入腹腔內進行誘發。受試小鼠共分為4組，分別為滅菌水的正常控制組(NC)、管餵試驗物質(台灣綠蜂膠萃取物)分為3組：15 mg/kg的低劑量組(TAL)、45 mg/kg的中劑量組(TAM)、90mg/kg的高劑量組(TAH)，每組試驗動物隻數為10隻。在試驗前及試驗期間第4、5、6及7週以眼窩採血方式，第8週以犧牲方式，收集血液樣本。在試驗結束後實驗動物以CO2麻醉，剪開腹部採集脾臟並稱重；將脾臟以細胞培養液製成單一細胞懸浮液並置於冰上，待使用於細胞激素分析、脾臟細胞及表面標記分析、血液中OVA-IgG、IgM、IgG1b及IgG2a抗體含量分析。如下進行細胞激素分析。脾臟細胞懸浮液定量後取5×105細胞/孔，分別置入24孔平底細胞培養盤中，加入細胞培養液、細胞裂殖素ConA及OVA，於CO2細胞培養箱中培養48小時。收集細胞激素檢體，將每一個well中的細胞培養液取出轉入新的1.5 ml微量離心管，離心(1200 rpm，4℃，10分鐘)後取上清液，以ELISA Cytokine assay kit(購自eBioscience Cat. No. 88-7024(介白素-2，IL-2)，88-7044(介白素-4,IL-4)，88-7121(腫瘤壞死因子，TNF-α)，88-7314(干擾素γ，IFN-γ)，88-7334(顆粒狀細胞-巨噬細胞群落刺激因子(granulocyte-macrophage colony stimulating factor)GM-CSF))測定脾臟細胞細胞激素分泌情形。血液中OVA IgG、IgM、IgG1b及IgG2a抗體含量測量如下。實驗動物經由眼窩採血(約80~100 μl)所得的血液樣本，經離心(3600 rpm，10分鐘)後取血清保存於-80℃冰箱等待測定。測定方法以ELISA方式測定血清中含有的OVA抗體濃度。ELISA單位(E.U.)=(樣本OD值-控制組OD值)/(血清OD值-控制組OD值)(OD：Optical Density)。如下進行脾臟細胞及表面標記分析。脾臟單一細胞懸浮液利用螢光異硫氰酸鹽(FITC)、藻紅蛋白(PE)及PE-Cry5螢光染色單株抗體(購自eBioscience)計算細胞表面抗原的比例及數目。淋巴細胞定量後取相同細胞數(5×105)經過螢光染色、清洗及固定後利用流式細胞儀進行分析。數據以實驗結果之平均值(Mean)±標準差(Standard deviation S.D.)來表示。The test animals were 8-week-old BALB/c male mice purchased from Lesco Biotech Co., Ltd. After 8 weeks of continuous forced tube feeding of the test substance, the mice were sacrificed and the samples were taken for analysis. In the 4th and 6th weeks, ovalbumin (OVA) plus Complete Freund's Adjuvant was injected into the peritoneal cavity for induction. The test mice were divided into 4 groups, the normal control group (NC) for sterilized water and the tube test substance (Taiwan green propolis extract) were divided into 3 groups: 15 mg/kg low dose group (TAL), The middle dose group (TAM) of 45 mg/kg and the high dose group (TAH) of 90 mg/kg had only 10 animals in each group. Blood samples were collected by eye socket at 4, 5, 6 and 7 weeks before and during the test, and sacrificed at 8 weeks. At the end of the experiment, the animals were anesthetized with CO 2 , the abdomen was cut open and the spleen was harvested and weighed; the spleen was made into a single cell suspension in cell culture medium and placed on ice, and used for cytokine analysis, spleen cells and surface marker analysis. Analysis of OVA-IgG, IgM, IgG1b and IgG2a antibody content in blood. Cytokine analysis was performed as follows. After spleen cell suspension was quantified, 5×10 5 cells/well were taken and placed in a 24-well flat-bottom cell culture tray, and cell culture medium, cytosine ConA and OVA were added, and cultured in a CO 2 cell incubator for 48 hours. Collect cytokine samples, transfer the cell culture solution from each well to a new 1.5 ml microcentrifuge tube, centrifuge (1200 rpm, 4 ° C, 10 minutes) and take the supernatant to the ELISA Cytokine assay kit. From eBioscience Cat. No. 88-7024 (Interleukin-2, IL-2), 88-7044 (Interleukin-4, IL-4), 88-7121 (Tumor Necrosis Factor, TNF-α), 88 -7314 (interferon gamma, IFN-γ), 88-7334 (granulocyte-macrophage colony stimulating factor GM-CSF)) The cytokine secretion of spleen cells was determined. The contents of OVA IgG, IgM, IgG1b and IgG2a antibodies in the blood were measured as follows. The blood samples obtained by blood sampling (about 80-100 μl) from the experimental animals were centrifuged (3600 rpm, 10 minutes), and the serum was stored in a -80 ° C refrigerator for measurement. Assay method The concentration of OVA antibody contained in the serum was measured by ELISA. ELISA unit (EU) = (sample OD value - control group OD value) / (serum OD value - control group OD value) (OD: Optical Density). Spleen cells and surface marker analysis were performed as follows. Spleen single cell suspension The proportion and number of cell surface antigens were calculated using fluorescent isothiocyanate (FITC), phycoerythrin (PE), and PE-Cry5 fluorescently stained monoclonal antibody (purchased from eBioscience). After the lymphocytes were quantified, the same number of cells (5 × 10 5 ) were stained, washed, and fixed, and then analyzed by flow cytometry. Data are expressed as the mean (Mean) ± standard deviation SD of the experimental results.
台灣綠蜂膠萃取物之非特異性免疫調節功效試驗Non-specific immunomodulatory efficacy test of Taiwan green propolis extract
受試動物為8週齡BALB/c雄性小鼠，購自樂斯科生物科技股份有限公司。以連續強迫管餵試驗物質6週方式，於試驗結束後犧牲小鼠，採取檢體進行免疫功能評估分析。受試動物共分為4組，分別為管餵滅菌水的正常控制組(NC)、試驗物質(台灣綠蜂膠萃取物)低劑量組(15 mg/kg,TAL)、中劑量組(45 mg/kg,TAM)及高劑量組(90 mg/kg,TAH)，每組試驗動物隻數為10隻。在試驗前及第3週以眼窩採血方式，試驗結束以犧牲方式，收集血液樣本。在試驗結束後以CO2麻醉，剪開腹部收集脾臟細胞，待進行細胞激素分析、血液中抗體含量分析及自然殺手細胞活性分析。如下進行細胞激素分析。脾臟細胞懸浮液定量後取5×105細胞/孔，分別置入24孔平底細胞培養盤中，加入細胞培養液、細胞裂殖素Con A及LPS，於CO2細胞培養箱中培養48小時。將各孔中的細胞培養液取出轉入新的1.5 ml微量離心管，離心(250×g，於4℃離心10分鐘)。取出上清液，利用細胞激素之上清液，以ELISA Cytokine assay kit(購自eBioscience Cat. No. 88-7024(介白素-2，IL-2)，88-7044(介白素-4,IL-4)，88-7121(腫瘤壞死因子，TNF-α)，88-7314(干擾素γ，IFN-γ)，88-7334(顆粒狀細胞-巨噬細胞群落刺激因子(granulocyte-macrophage colony stimulating factor)GM-CSF))測定脾臟細胞細胞激素分泌情形。分析血液中抗體含量如下。實驗動物經由眼窩或是犧性採血所得的血液樣本，離心(250×g，10分鐘)，取其血清，以Mouse IgM、IgE及IgG ELISA定量套組(購自Bethy Cat. No.E90-101,E90-115,E90-131)方式測定血清中抗體濃度。如下進行自然殺手細胞活性分析。取自脾臟之細胞(含自然殺手細胞)，以YAC-1細胞株為自然殺手細胞的標的細胞，依一定的自然殺手細胞：標的細胞比例(6.25：1、12.5：1)混合，作用約4小時，測試殺手細胞毒殺標的細胞之能力。首先將YAC-1細胞定量並利用市售PKH67套組(購自Sigma Cat No. PKH67-GL)染色標定，使YAC-1細胞表面具有FICT螢光，再加入已定量的脾臟細胞依照一定比例作用，放入37℃ CO2培養箱培養4小時。待作用時間到達後加入50 μl之PI溶液作用10分鐘，利用流式細胞儀進行分析。數據以實驗結果之平均值(Mean)±標準差(Standard deviation S.D.)來表示。The test animals were 8-week-old BALB/c male mice purchased from Lesco Biotech Co., Ltd. The test substance was fed continuously for 6 weeks, and the mice were sacrificed after the end of the test, and the samples were taken for evaluation of immune function. The test animals were divided into 4 groups, which were the normal control group (NC), the test substance (Taiwan green propolis extract), the low dose group (15 mg/kg, TAL) and the middle dose group (45 mg). /kg, TAM) and high dose group (90 mg/kg, TAH), the number of animals in each group was only 10. Blood samples were collected at the end of the trial and at the end of the trial at the end of the trial. After the end of the experiment, the rats were anesthetized with CO 2 , and the spleen cells were collected by cutting the abdomen, and the cytokine analysis, the antibody content in the blood, and the natural killer cell activity analysis were performed. Cytokine analysis was performed as follows. The spleen cell suspension was quantified and taken 5×10 5 cells/well, placed in a 24-well flat-bottomed cell culture dish, and added to the cell culture medium, cytosin Con A and LPS, and cultured in a CO 2 cell incubator for 48 hours. . The cell culture solution in each well was taken out and transferred to a new 1.5 ml microcentrifuge tube, centrifuged (250 x g, and centrifuged at 4 ° C for 10 minutes). The supernatant was taken out, and the cytokine supernatant was used to obtain an ELISA Cytokine assay kit (purchased from eBioscience Cat. No. 88-7024 (Interleukin-2, IL-2), 88-7044 (Interleukin-4). , IL-4), 88-7121 (tumor necrosis factor, TNF-α), 88-7314 (interferon gamma, IFN-γ), 88-7334 (granulocyte-macrophage community stimulating factor (granulocyte-macrophage) Colony stimulating factor) GM-CSF)) Determination of cytokine secretion in spleen cells. The amount of antibody in the blood was analyzed as follows. The experimental animals were centrifuged (250 × g, 10 minutes) through a blood sample obtained from eye sockets or sacrificed blood samples, and serum was taken for use in Mouse IgM, IgE and IgG ELISA quantitative kits (purchased from Bethy Cat. No. E90-101). , E90-115, E90-131) method to determine the concentration of antibodies in serum. Natural killer cell activity assays were performed as follows. Cells from the spleen (including natural killer cells), YAC-1 cell line as the target cell of natural killer cells, according to a certain number of natural killer cells: the target cell mix (6.25: 1, 12.5: 1), the effect of about 4 Hours, test the ability of killer cytotoxic cells. YAC-1 cells were first quantified and stained with a commercially available PKH67 kit (purchased from Sigma Cat No. PKH67-GL) to have FICT fluorescence on the surface of YAC-1 cells, and a certain proportion of spleen cells were added according to a certain proportion. It was placed in a 37 ° C CO 2 incubator for 4 hours. After the time of action was reached, 50 μl of the PI solution was added for 10 minutes, and analysis was performed by flow cytometry. Data are expressed as the mean (Mean) ± standard deviation SD of the experimental results.
EF(epigenetic formula)配方之混合Mix of EF (epigenetic formula) formula
將台灣綠蜂膠之萃取物使用95%酒精回溶，取得所需之量。再將黃耆萃取物以30%酒精回溶，取得所需之量。將此二者混合並加入助溶劑，再經減壓濃縮去除酒精。此混合物再加入純水、甜味劑及所需量之蜂王乳粉或水解蜂王乳粉而得到本發明之配方。EF-1配方中台灣綠蜂膠萃取物、蜂王乳粉及黃耆萃取物之組成(重量)比例為1.5：3：1.2，EF-1配方中含有約26wt%之台灣綠蜂膠萃取物；EF-2配方中台灣綠蜂膠萃取物、蜂王乳粉及黃耆萃取物之組成(重量)比例為1.5：6：1.2，EF-2配方中含有約17wt%之台灣綠蜂膠萃取物The extract of Taiwan green propolis is reconstituted with 95% alcohol to obtain the required amount. The Astragalus membranaceus extract is then reconstituted with 30% alcohol to obtain the desired amount. The two were mixed and a co-solvent was added, followed by concentration under reduced pressure to remove alcohol. This mixture is further added with pure water, a sweetener, and a desired amount of royal jelly powder or hydrolyzed royal jelly powder to obtain a formulation of the present invention. The composition (weight) ratio of Taiwan green propolis extract, queen bee powder and astragalus extract in EF-1 formula is 1.5:3:1.2, and EF-1 formula contains about 26wt% of Taiwan green propolis extract; EF- The composition (weight) ratio of Taiwan green propolis extract, queen bee milk powder and astragalus extract in formula 2 is 1.5:6:1.2, and EF-2 formula contains about 17wt% of Taiwan green propolis extract.
EF-2配方與化療藥合併使用抑制腫瘤生長EF-2 formula combined with chemotherapeutic drugs to inhibit tumor growth
雄性4週齡之BALB/c裸鼠共32隻係購自台灣國家動物中心。裸鼠飼養二週之後將人類乳癌細胞株MDA-MB-231(5×106細胞/隻)種於裸鼠背部(1.6×108乳癌細胞係分散於3,840 μL L15/10% FBS並混合960 μL Matrigel)。約3週後(裸鼠之腫瘤大小約100 mm3)進行分組。將所有裸鼠隨機分成四組。(1)控制組(僅載劑)；(2)試驗組投予EF-2配方(載劑、水解蜂王乳、台灣綠蜂膠萃取物及黃耆萃取物)放於水瓶中，讓裸鼠自然飲用；(3)試驗組投予化療藥物-太平洋紫杉醇(10 mg/kg)，腹腔注射給藥，每兩天一次連續六週；(4)EF-2配方與化療藥合併使用。預估裸鼠一天約飲用3.5毫升的水，可依此換算每日人體服用劑量(60公斤成人)約為水解蜂王乳粉2000毫克，台灣綠蜂膠萃取物約500毫克，黃耆萃取物約400毫克。每三天重新配製一次直到試驗結束。每週進行裸鼠體重及腫瘤大小測量。A total of 32 BALB/c nude mice of 4 weeks old males were purchased from the National Animal Center of Taiwan. Two weeks after the nude mice were fed, the human breast cancer cell line MDA-MB-231 (5×10 6 cells/only) was seeded on the back of nude mice (1.6×10 8 breast cancer cell lines were dispersed in 3,840 μL L15/10% FBS and mixed 960). μL Matrigel). Grouping was performed after about 3 weeks (the tumor size of nude mice was about 100 mm 3 ). All nude mice were randomly divided into four groups. (1) Control group (carrier only); (2) The test group was given EF-2 formula (carrier, hydrolyzed royal jelly, Taiwan green propolis extract and astragalus extract) in a water bottle, allowing nude mice to naturally (3) The experimental group was administered chemotherapy drug paclitaxel (10 mg/kg), administered intraperitoneally, once every two days for six weeks; (4) EF-2 formula was combined with chemotherapy drugs. It is estimated that nude mice will drink about 3.5 ml of water a day. According to this, the daily dose of human body (60 kg adult) is about 2000 mg of hydrolyzed royal jelly powder, about 500 mg of Taiwan green propolis extract, and about 400 of astragalus extract. Mg. Reconstitute every three days until the end of the experiment. Nude mouse body weight and tumor size measurements were performed weekly.
EF-1配方乳癌動物試驗EF-1 formula breast cancer animal test
雄性4週齡之BALB/c裸鼠共26隻係購自台灣國家動物中心。裸鼠飼養二週之後將人類乳癌細胞株MDA-MB-231(5×106細胞/隻)種於裸鼠背部(1.3×108乳癌細胞係分散於3.2 mL L15/10% FBS並混合0.8 mL Matrigel)。3週後(腫瘤大小約150 mm3)進行分組。僅含載劑(例如，水、助溶劑及甜味劑)之控制組飲水，及含載劑及EF-1配方(其係含蜂王乳粉、台灣綠蜂膠萃取物及黃耆萃取物)之試驗組飲水，分別供控制組及試驗組裸鼠自然飲用。預估裸鼠一天約飲用3.5毫升的水，可依此換算每日人體服用劑量(60公斤成人)約為蜂王乳粉1000毫克，台灣綠蜂膠萃取物約500毫克，黃耆萃取物約400毫克。飲水每三天重新配製一次直到試驗結束(約180天)。每週進行裸鼠體重及腫瘤大小測量。A total of 26 male BALB/c nude mice of 4 weeks old were purchased from the National Animal Center of Taiwan. Two weeks after the nude mice were housed, human breast cancer cell line MDA-MB-231 (5×10 6 cells/only) was seeded on the back of nude mice (1.3×10 8 breast cancer cell lines were dispersed in 3.2 mL L15/10% FBS and mixed 0.8 mL Matrigel). Grouping was performed 3 weeks later (tumor size approximately 150 mm 3 ). Control group drinking water containing only carrier (eg water, co-solvent and sweetener), and carrier and EF-1 formula (which contains royal jelly powder, Taiwan green propolis extract and astragalus extract) The experimental group drank water and was used for natural drinking in the control group and the experimental group. It is estimated that nude mice will drink about 3.5 ml of water a day. According to this, the daily dose of human body (60 kg adult) is about 1000 mg of queen bee powder, about 500 mg of Taiwan green propolis extract, and about 400 mg of astragalus extract. . Drinking water is reconstituted every three days until the end of the trial (about 180 days). Nude mouse body weight and tumor size measurements were performed weekly.
EF-2配方肝癌動物試驗EF-2 formula liver cancer animal test
雄性4週齡之BALB/c裸鼠共12隻係購自台灣國家動物中心。裸鼠飼養二週之後將人類肝癌細胞株HepG2(1.0×107細胞/隻)種於裸鼠背部(1.2×108肝癌細胞係分散於1440μL DMEM/10% FBS並混合360μL Matrigel)。約4週後(腫瘤大小約105 mm3)進行隨機分組。(1)控制組飲水僅含載劑；(2)含EF-2配方(以水解蜂王乳調配)之試驗組飲水；及(3)含EF-2配方(以無水解蜂王乳調配)之試驗組飲水，分別供控制組及試驗組裸鼠自然飲用。預估裸鼠一天約飲用3.5毫升的水，可依此換算每日人體服用劑量(60公斤成人)約為蜂王乳粉2000毫克，台灣綠蜂膠萃取物約500毫克，黃耆萃取物約400毫克。飲水每三天重新配製一次直到試驗結束(約42天)。每週進行裸鼠體重及腫瘤大小測量。A total of 12 male BALB/c nude mice of 4 weeks old were purchased from the National Animal Center of Taiwan. Two weeks after the nude mice were housed, human hepatoma cell line HepG2 (1.0 × 10 7 cells/cell) was seeded on the back of nude mice (1.2 × 10 8 liver cancer cell lines were dispersed in 1440 μL DMEM/10% FBS and mixed with 360 μL Matrigel). Randomization was performed approximately 4 weeks later (tumor size approximately 105 mm 3 ). (1) The drinking water in the control group contains only the carrier; (2) the drinking water of the test group containing the EF-2 formula (mixed with hydrolyzed royal jelly); and (3) the test containing the EF-2 formula (mixed with the unhydrolyzed royal jelly) The group of drinking water was used for natural drinking in the control group and the experimental group. It is estimated that nude mice will drink about 3.5 ml of water a day. According to this, the daily dose of human body (60 kg adult) is about 2000 mg of queen bee powder, about 500 mg of Taiwan green propolis extract, and about 400 mg of astragalus extract. . Drinking water is reconstituted every three days until the end of the trial (about 42 days). Nude mouse body weight and tumor size measurements were performed weekly.
EF-2配方大腸癌動物試驗EF-2 formula colorectal cancer animal test
雄性4週齡之BALB/c裸鼠共16隻係購自台灣國家動物中心。裸鼠飼養二週之後將人類大腸癌細胞株HT29(5×106細胞/隻)種於裸鼠背部(8×107大腸癌細胞係分散於1,920μL RPMI/10% FBS並混合480μL Matrigel)。約1.5週後(腫瘤大小約120 mm3)進行隨機分組。(1)控制組飲水僅含載劑；(2)含EF-2配方之試驗組飲水，分別供控制組及試驗組裸鼠自然飲用。預估裸鼠一天約飲用3.5毫升的水，可依此換算每日人體服用劑量(60公斤成人)約為蜂王乳粉2000毫克，台灣綠蜂膠萃取物約500毫克，黃耆萃取物約400毫克。飲水每三天重新配製一次直到試驗結束。每週進行裸鼠體重及腫瘤大小測量。A total of 16 BALB/c nude mice of 4 weeks old males were purchased from the National Animal Center of Taiwan. Two weeks after the nude mice were housed, human colorectal cancer cell line HT29 (5×10 6 cells/only) was seeded on the back of nude mice (8×10 7 colorectal cancer cell lines were dispersed in 1,920 μL RPMI/10% FBS and mixed with 480 μL Matrigel). . Randomization was performed approximately 1.5 weeks later (tumor size approximately 120 mm 3 ). (1) The drinking water of the control group only contains the carrier; (2) The drinking water of the test group containing the EF-2 formula is used for natural drinking in the control group and the experimental group. It is estimated that nude mice will drink about 3.5 ml of water a day. According to this, the daily dose of human body (60 kg adult) is about 2000 mg of queen bee powder, about 500 mg of Taiwan green propolis extract, and about 400 mg of astragalus extract. . Drinking water is reconstituted every three days until the end of the trial. Nude mouse body weight and tumor size measurements were performed weekly.
EF-2配方和台灣綠蜂膠萃取物、黃耆抽出物、水解蜂王乳蛋EF-2 formula and Taiwan green propolis extract, astragalus extract, hydrolyzed queen bee 白抑制腫瘤生長的活性比較Comparison of the activity of white inhibiting tumor growth
雄性4週大之BALB/c裸鼠共40隻係購自台灣國家動物中心。裸鼠飼養二週之後將人類乳癌細胞株MDA-MB-231(5×106 cells/隻)種於裸鼠背部(2×108乳癌細胞係分散於4,800μL L15/10% FBS並混合1,200 μL Matrigel)。約2週後裸鼠之腫瘤大小約100 mm3開始進行分組。將所有裸鼠隨機分成五組。(1)控制組(僅載劑)；(2)投予台灣綠蜂膠萃取物之試驗組；(3)投予黃耆萃取物之試驗組；(4)投予水解蜂王乳蛋白之試驗組；(5)含EF-2配方之試驗組。預估裸鼠一天約飲用3.5毫升的水，可依此換算每日人體服用劑量(60公斤成人)約為蜂王乳粉2000毫克，台灣綠蜂膠萃取物約500毫克，黃耆萃取物約400毫克。(2)、(3)、(4)組中成份的含量相當於EF2配方單獨成份之用量。飲水每三天重新配製一次直到試驗結束。每週進行裸鼠體重及腫瘤大小測量。A total of 40 male BALB/c nude mice of 4 weeks old were purchased from the National Animal Center of Taiwan. Two weeks after the nude mice were housed, human breast cancer cell line MDA-MB-231 (5×10 6 cells/only) was planted on the back of nude mice (2×10 8 breast cancer cell lines were dispersed in 4,800 μL L15/10% FBS and mixed 1,200). μL Matrigel). After about 2 weeks, the tumor size of nude mice was about 100 mm 3 and grouping began. All nude mice were randomly divided into five groups. (1) Control group (carrier only); (2) Test group for injection of Taiwan green propolis extract; (3) Test group for administration of Astragalus membranaceus extract; (4) Test group for administration of hydrolyzed royal milk protein (5) Test group containing EF-2 formulation. It is estimated that nude mice will drink about 3.5 ml of water a day. According to this, the daily dose of human body (60 kg adult) is about 2000 mg of queen bee powder, about 500 mg of Taiwan green propolis extract, and about 400 mg of astragalus extract. . The content of the components in groups (2), (3), and (4) is equivalent to the amount of the individual components of the EF2 formulation. Drinking water is reconstituted every three days until the end of the trial. Nude mouse body weight and tumor size measurements were performed weekly.
生物統計organism count
台灣綠蜂膠萃取物之特異性及非特異性免疫調節功效採用SPSS電腦統計套裝軟體，各試驗組之數據先依單因子變異數分析(One-way analysis of variance,ANOVA)進行檢定，再以鄧肯(Duncan)試驗比較各組間是否具差異性。若p值小於0.05則表示兩試驗組之間具有統計上顯著差異。The specific and non-specific immunomodulatory effects of Taiwan green propolis extracts were determined using the SPSS computer statistical software package. The data of each test group was first determined by One-way analysis of variance (ANOVA) and then Duncan. The (Duncan) trial compared differences between groups. A p value of less than 0.05 indicates a statistically significant difference between the two test groups.
其他動物試驗數據係以student t-test進行控制組與試驗組之統計，p值小於0.05即有統計差異。Other animal test data were calculated by the student t- test with the control group and the test group. There was a statistical difference when the p value was less than 0.05.
「*」表示相較控制組具統計上之顯著差異(p<0.05)，「**」表示相較控制組具統計上之顯著差異(p<0.01)，「***」表示相較控制組具統計上之顯著差異(p<0.001)。"*" indicates statistically significant difference ( p < 0.05) compared to the control group, "**" indicates statistically significant difference ( p <0.01) compared to the control group, and "***" indicates comparison control Statistically significant differences were observed ( p < 0.001).
實例1：EF-2配方增進化療藥物之腫瘤生長抑制效果Example 1: EF-2 Formulation Improves Tumor Growth Inhibition Effect of Chemotherapeutic Drugs
圖1顯示EF-2配方與化療藥物合併使用之效果。單獨投予化療藥物太平洋紫杉醇或EF-2配方與化療藥物合併使用的組別腫瘤生長速度均受到顯著地抑制，在第4週測量時相較控制組分別有32%及40%的抑制；而從第4-6週的數據顯示出EF-2配方與化療藥物合併使用較單獨投予化療藥物太平洋紫杉醇增進9~13%之抑制效果。此結果顯示，化療藥物搭配EF-2配方對於抑制腫瘤生長優於單獨使用化療藥物。Figure 1 shows the effect of combining EF-2 formulation with a chemotherapeutic drug. The tumor growth rate of the combination of the chemotherapy drug paclitaxel or the EF-2 formula and the chemotherapy drug was significantly inhibited, and the measurement at the 4th week was 32% and 40% inhibition compared with the control group, respectively; Data from weeks 4-6 showed that the combination of EF-2 formulation and chemotherapy drugs increased the inhibitory effect by 9-13% compared with the chemotherapy drug paclitaxel alone. This result shows that chemotherapy drugs combined with EF-2 formula is superior to chemotherapy alone in inhibiting tumor growth.
實例2：台灣綠蜂膠萃取物之特異性免疫調節功效Example 2: Specific immunomodulatory efficacy of Taiwan green propolis extract
在誘發免疫細胞之細胞激素分泌的試驗中，結果顯示台灣綠蜂膠萃取物可增加免疫細胞在Con A刺激下的IL-2、TFN-α及IFN-γ分泌量，並降低IL-4分泌量(參見表1)。在使用卵白蛋白(OVA)進行免疫的小鼠中，台灣綠蜂膠萃取物可促進血清中特異性抗體OVA-IgG、OVA-IgG2a及OVA-IgM的生成(參見表2)，且台灣綠蜂膠萃取物可促進T細胞CD4表現百分比，並在活化態表現上也具有明顯增加情形(參見表3)。In the test of cytokine secretion induced by immune cells, the results showed that Taiwan green propolis extract can increase the secretion of IL-2, TFN-α and IFN-γ in immune cells stimulated by Con A, and reduce the secretion of IL-4. (See Table 1). In mice immunized with ovalbumin (OVA), Taiwan green propolis extract promoted the production of specific antibodies OVA-IgG, OVA-IgG2a and OVA-IgM in serum (see Table 2), and Taiwan green propolis extract The substance can promote the percentage of CD4 expression in T cells and also has a significant increase in the activation state (see Table 3).
以平均值±標準差來表示；n=10；不同的上標(a,b,c)表示具顯著差異(p<0.05)。Expressed as mean ± standard deviation; n = 10; different superscripts (a, b, c) indicate significant differences ( p < 0.05).
以平均值±標準差來表示；n=10；不同的上標(a,b,c)表示具顯著差異(p<0.05)。Expressed as mean ± standard deviation; n = 10; different superscripts (a, b, c) indicate significant differences ( p < 0.05).
以平均值±標準差來表示；n=10；不同的上標(a,b,c)表示具顯著差異(p<0.05)。Expressed as mean ± standard deviation; n = 10; different superscripts (a, b, c) indicate significant differences ( p < 0.05).
實例3：台灣綠蜂膠萃取物之非特異性免疫調節功效Example 3: Non-specific immunomodulatory efficacy of Taiwan green propolis extract
在此試驗中，結果顯示台灣綠蜂膠萃取物可增加免疫細胞在Con A刺激下的IL-2、IFN-γ及分泌量，並調節TFN-α及IL-4分泌量(參見表4)，並可促進自然殺手細胞的活性(參見表5)，同時提升血清抗體IgM含量(參見表6)。因此，台灣綠蜂膠萃取物具有調節免疫功能中非特異性免疫能力之功效。In this experiment, the results showed that Taiwan green propolis extract can increase the IL-2, IFN-γ and secretion of immune cells under Con A stimulation, and regulate the secretion of TFN-α and IL-4 (see Table 4). It also promotes the activity of natural killer cells (see Table 5) while increasing serum antibody IgM content (see Table 6). Therefore, Taiwan green propolis extract has the effect of regulating non-specific immunity in immune function.
以平均值±標準差來表示；n=10；不同的上標(a,b,c)表示具顯著差異(p<0.05)。Expressed as mean ± standard deviation; n = 10; different superscripts (a, b, c) indicate significant differences ( p < 0.05).
以平均值±標準差來表示；n=10；不同的上標(a,b,c)表示具顯著差異(p<0.05)。Expressed as mean ± standard deviation; n = 10; different superscripts (a, b, c) indicate significant differences ( p < 0.05).
以平均值±標準差來表示；n=10；不同的上標(a,b,c)表示具顯著差異(p<0.05)。Expressed as mean ± standard deviation; n = 10; different superscripts (a, b, c) indicate significant differences ( p < 0.05).
實例4：EF-1配方無毒性並可抑制乳癌腫瘤生長Example 4: EF-1 formulation is non-toxic and inhibits breast cancer tumor growth
乳癌裸鼠投予EF-1配方32天後開始進行腫瘤大小之測量，結果顯示服用EF-1配方組裸鼠腫瘤生長較緩慢約有20%的抑制(參見圖2及圖3)。當配方投予至74天，控制組之裸鼠已大量死亡12隻剩下一隻存活，然而EF-1配方組僅2隻死亡，仍有10隻老鼠存活。從研究結果可以得知EF-1配方可有效抑制腫瘤生長。裸鼠投予EF-1配方53天後體重略低於控制組，然而，裸鼠體重皆維持在約22.5公克。其後直至試驗結束EF-1配方組體重仍持續成長。此顯示本配方並無毒性，而在投予配方前期可能是適口性問題造成體重微幅下降(參見圖4)。Breast cancer nude mice began to measure tumor size 32 days after administration of EF-1 formulation, and the results showed that tumor growth in nude mice in the EF-1 formulation group was about 20% slower (see Figures 2 and 3). When the formula was administered for 74 days, the control group of nude mice had died in a large number of 12 and only one survived. However, only 2 of the EF-1 formula group died and 10 mice survived. It can be seen from the results that EF-1 formula can effectively inhibit tumor growth. Nude mice were slightly lower in weight than the control group after 53 days of administration of the EF-1 formulation, however, the body weight of the nude mice was maintained at approximately 22.5 grams. The body weight of the EF-1 formula group continued to grow until the end of the trial. This shows that the formula is not toxic, and may be a palatability problem in the early stage of administration of the formulation, resulting in a slight decrease in body weight (see Figure 4).
實例5：EF-1配方延長乳癌裸鼠之壽命Example 5: EF-1 Formulation Extends Life of Breast Cancer in Nude Mice
投予EF-1配方可強化乳癌裸鼠之免疫力，並延長乳癌裸鼠之壽命(參見圖5)。控制組裸鼠集中在50-65天大量死亡，然而，EF-1配方組之死亡集中在65-160天；直至180天試驗結束，仍有3隻EF-1配方組裸鼠存活。經統計控制組約存活60天，EF-1配方組則約為116天。由此結果可得知，EF-1配方無明顯毒性，不止抑制腫瘤生長更可大幅延長乳癌裸鼠之壽命。Administration of the EF-1 formulation potentiates the immunity of breast cancer nude mice and prolongs the lifespan of breast cancer nude mice (see Figure 5). The control group of nude mice concentrated on 50-65 days of massive death, however, the death of the EF-1 formula group was concentrated in 65-160 days; until the end of the 180-day trial, there were still 3 EF-1 formula group nude mice survived. The statistical control group survived for approximately 60 days, and the EF-1 formulation group was approximately 116 days. From this result, it can be known that the EF-1 formulation has no obvious toxicity, and not only inhibiting tumor growth, but also significantly prolonging the life span of breast cancer nude mice.
實例6：EF-2配方無毒性並可抑制肝癌腫瘤生長Example 6: EF-2 formulation is non-toxic and inhibits tumor growth of liver cancer
進一步我們使用人類肝癌細胞株進行EF-2配方試驗。EF-2配方與EF-1配方主要之不同在於蜂王乳粉之量為EF-1配方之2倍，其餘組成不變。結果顯示，不管是以水解或未水解蜂王乳調配之EF-2配方皆有效抑制腫瘤生長(參見圖6及7)。這個結果與EF-1配方類似但EF-2配方似乎比EF-1配方更有效。EF-2配方類似EF-1配方，並無明顯毒性，裸鼠之體重無顯著下降(參見圖8)。Further, we used human liver cancer cell lines for the EF-2 formulation test. The main difference between the EF-2 formula and the EF-1 formula is that the amount of the queen milk powder is twice that of the EF-1 formula, and the rest of the composition is unchanged. The results showed that the EF-2 formulation formulated with either hydrolyzed or unhydrolyzed royal jelly inhibited tumor growth (see Figures 6 and 7). This result is similar to the EF-1 formulation but the EF-2 formulation appears to be more effective than the EF-1 formulation. The EF-2 formulation was similar to the EF-1 formulation and was not significantly toxic, with no significant decrease in body weight in nude mice (see Figure 8).
實例7：EF-2配方可抑制大腸癌腫瘤生長Example 7: EF-2 Formulation Can Inhibit Colorectal Cancer Growth
使用人類大腸癌細胞株(HT-29 cells)進行EF-2配方試驗。結果顯示，服用EF-2配方組裸鼠腫瘤生長較緩慢，在第2週開始約有22%的抑制，觀察到第四週EF-2配方組裸鼠腫瘤生長皆較控制組緩慢(參見圖9)。體重無明顯下降(參見圖10)。結果顯示，EF-2配方可有效抑制腫瘤生長且無明顯毒性，裸鼠之體重無顯著下降。EF-2 formulation tests were performed using human colorectal cancer cell lines (HT-29 cells). The results showed that the nude mice in the EF-2 formula group had slower tumor growth and about 22% inhibition at the second week. It was observed that the tumor growth of the EF-2 formula group was slower than that of the control group in the fourth week (see figure). 9). There was no significant decrease in body weight (see Figure 10). The results showed that the EF-2 formula was effective in inhibiting tumor growth without significant toxicity, and the body weight of nude mice did not decrease significantly.
實例8：比較台灣綠蜂膠萃取物、黃耆萃取物、水解蜂王乳蛋白及EF-2配方之抑制腫癌生長的活性Example 8: Comparison of Taiwan green propolis extract, astragalus extract, hydrolyzed royal milk protein and EF-2 formula to inhibit the growth of tumor growth
試驗是否單獨的台灣綠蜂膠萃取物、黃耆萃取物、或水解蜂王乳蛋白可以有效抑制腫瘤生長。將裸鼠殖入人類乳癌細胞(MDA-MB-231 cells)，待腫瘤成長至100 mm3進行分組，並投予試驗物質。我們發現，單獨投予相當於人體服用劑量500毫克之台灣綠蜂膠萃取物效果不佳；單獨投予相當於人體服用劑量400毫克之黃耆萃取物效果亦不佳；而單獨投予相當於人體服用劑量2,000毫克水解蜂王乳蛋白效果亦不佳，如圖11所示。然而，EF-2配方(台灣綠蜂膠萃取物+黃耆萃取物+水解蜂王乳蛋白)在投予4-5週，抑制腫瘤效果即達到25%(參見圖11)且裸鼠體重無明顯下降(參見圖12)。由此結果可得知，EF-2配方具有顯著抑制腫瘤生長活性，單獨投予任一配方組成之效果不佳。It is tested whether the individual Taiwan green propolis extract, astragalus extract, or hydrolyzed royal milk protein can effectively inhibit tumor growth. Nude mice were colonized into human breast cancer cells (MDA-MB-231 cells), and the tumors were grown to 100 mm 3 for grouping and the test substances were administered. We found that it was not effective to administer a single dose of 500 mg of Taiwan green propolis extract alone. The effect of administering a dose of 400 mg of Astragalus membranaceus alone was not good. The effect of taking 2,000 mg of hydrolyzed royal jelly protein was also poor, as shown in Figure 11. However, the EF-2 formula (Taiwan Green Propolis Extract + Astragalus Extract + Hydrolyzed Royal Milk Protein) was administered for 4-5 weeks, and the tumor suppressing effect reached 25% (see Figure 11) and the body weight of nude mice did not decrease significantly. (See Figure 12). From the results, it was found that the EF-2 formulation has a remarkable inhibitory effect on tumor growth, and the effect of administering any of the formulations alone is not good.
圖1顯示EF-2配方與化療藥物合併使用之效果。「*」表示相較控制組具統計上之顯著差異(p<0.05)，「**」表示相較控制組具統計上之顯著差異(p<0.01)，「***」表示相較控制組具統計上之顯著差異(p<0.001)。Figure 1 shows the effect of combining EF-2 formulation with a chemotherapeutic drug. "*" indicates statistically significant difference ( p < 0.05) compared to the control group, "**" indicates statistically significant difference ( p <0.01) compared to the control group, and "***" indicates comparison control Statistically significant differences were observed ( p < 0.001).
圖2為乳癌裸鼠投予EF-1配方32天之比較圖。Figure 2 is a comparison of breast cancer nude mice administered EF-1 formulation for 32 days.
圖3顯示乳癌裸鼠服用EF-1配方抑制腫瘤生長。Figure 3 shows that breast cancer nude mice take EF-1 formulation to inhibit tumor growth.
圖4顯示投予EF-1配方之裸鼠體重之變化情形。「★」：試驗進行至102天時，控制組老鼠已全部死亡。Figure 4 shows the change in body weight of nude mice administered with the EF-1 formula. "★": When the test was carried out until 102 days, all mice in the control group had died.
圖5顯示EF配方可以顯著延長裸鼠之壽命Figure 5 shows that EF formula can significantly extend the life of nude mice
圖6顯示投予六週後EF-2配方與控制組之肝癌腫瘤抑制生長比較。Figure 6 shows a comparison of tumor growth inhibition of liver cancer between the EF-2 formulation and the control group after six weeks of administration.
圖7顯示EF-2配方是否將蜂王乳水解皆有效抑制肝癌腫瘤生長之結果。「*」表示相較控制組具統計上之顯著差異(p<0.05)，「**」表示相較控制組具統計上之顯著差異(p<0.01)，「***」表示相較控制組具統計上之顯著差異(p<0.001)。Figure 7 shows whether the EF-2 formulation is effective in inhibiting the growth of liver cancer tumors by hydrolyzing the royal jelly. "*" indicates statistically significant difference ( p < 0.05) compared to the control group, "**" indicates statistically significant difference ( p <0.01) compared to the control group, and "***" indicates comparison control Statistically significant differences were observed ( p < 0.001).
圖8顯示控制組與EF-2配方組經過6個星期投予EF-2配方組不會讓肝癌裸鼠體重下降。Figure 8 shows that the control group and the EF-2 formulation group did not allow weight loss in liver cancer nude mice after 6 weeks of administration to the EF-2 formulation group.
圖9顯示EF-2配方可抑制大腸癌腫瘤生長。Figure 9 shows that the EF-2 formulation inhibits colorectal cancer tumor growth.
圖10顯示控制組與EF-2配方組經過4個星期投予EF-2配方組不會讓大腸癌裸鼠體重下降。Figure 10 shows that the control group and the EF-2 formulation group did not allow colorectal cancer to lose weight in nude mice after 4 weeks of administration to the EF-2 formulation group.
圖11顯示單獨投予台灣綠蜂膠、黃耆萃取物或水解蜂王乳及投予EF-2配方評估抑制腫瘤生長活性之結果。Figure 11 shows the results of evaluating the inhibition of tumor growth activity by administering Taiwan green propolis, astragalus extract or hydrolyzed royal jelly alone and administering the EF-2 formulation.
圖12比較單獨投予台灣綠蜂膠、黃耆萃取物或水解蜂王乳及投予EF-2配方對裸鼠體重之影響。Figure 12 compares the effects of Taiwanese green propolis, astragalus extract or hydrolyzed royal jelly and EF-2 formulation on the body weight of nude mice.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW100136539A TWI494113B (en) | 2011-07-22 | 2011-10-07 | Use of taiwanese green propolis for slowing the progression of the disease of a patient |
| CN201210114649.7A CN102885854B (en) | 2011-07-22 | 2012-04-18 | Use of Taiwan green propolis extract for slowing down the progression of a patient's condition |
| JP2012115853A JP6038486B2 (en) | 2011-07-22 | 2012-05-21 | Drugs and nutritional supplements containing Taiwan Green Propolis Extract |
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| Application Number | Priority Date | Filing Date | Title |
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| TW100126089 | 2011-07-22 | ||
| TW100136539A TWI494113B (en) | 2011-07-22 | 2011-10-07 | Use of taiwanese green propolis for slowing the progression of the disease of a patient |
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| Publication Number | Publication Date |
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| TW201304789A true TW201304789A (en) | 2013-02-01 |
| TWI494113B TWI494113B (en) | 2015-08-01 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2783684A1 (en) | 2013-03-29 | 2014-10-01 | NatureWise Biotech & Medicals Corporation | Prenylflavanone compounds for modulating diabetes |
| TWI793922B (en) * | 2021-12-14 | 2023-02-21 | 彥臣生技藥品股份有限公司 | Composition for enhancing cognitive abilities and use thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829246A (en) * | 2010-01-18 | 2010-09-15 | 郑延明 | Transdermal infusion paste preparation for enhancing immunity and preparation method thereof |
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2011
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2783684A1 (en) | 2013-03-29 | 2014-10-01 | NatureWise Biotech & Medicals Corporation | Prenylflavanone compounds for modulating diabetes |
| TWI793922B (en) * | 2021-12-14 | 2023-02-21 | 彥臣生技藥品股份有限公司 | Composition for enhancing cognitive abilities and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TWI494113B (en) | 2015-08-01 |
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