TW201444561A - Therapeutic composition for treating cancers - Google Patents

Therapeutic composition for treating cancers Download PDF

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TW201444561A
TW201444561A TW102118742A TW102118742A TW201444561A TW 201444561 A TW201444561 A TW 201444561A TW 102118742 A TW102118742 A TW 102118742A TW 102118742 A TW102118742 A TW 102118742A TW 201444561 A TW201444561 A TW 201444561A
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cancer
composition
pharmaceutical composition
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cell
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TW102118742A
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TWI469784B (en
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Shwu-Bin Lin
Cheng-Po Huang
Teng-Hai Chen
Kuang-Dee Chen
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Double Crane Biotechnology Co Ltd
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Abstract

Disclosed herein is a composition that includes a novel combination of triterpenoids for the treatment or prophylaxis of a cancer. The mixture of triterpenoids includes at least ganoderic acid S (GAS), ganoderic acid T (GAT), ganoderic acid Me (GAMe), ganoderic acid R (GAR), and ganodermic acid S (GMAS). The composition is suitable for the treatment or prophylaxis of colon cancer, hepatic cancer, breast cancer, lung cancer or leukemia.

Description

可治療癌症之藥學組合物 Pharmaceutical composition for treating cancer

本揭示內容是有關於一種藥學性組合物,其包含一新穎的三萜化合物的組合,可用來治療癌症,包括具有抗藥性的癌症。 The present disclosure is directed to a pharmaceutical composition comprising a novel combination of triterpenoids useful in the treatment of cancer, including cancers that are resistant.

長久以來,在東南亞地區,食用性真菌都被當作營養補充品或健康食品來使用,其中又以靈芝(Ganoderma lucidum)為大宗,且因其具有醫療效果也被當作藥材使用超過千年之久。自靈芝中分離出來的活性成分大致包括靈芝三萜類(triterpenoids)、多醣體(polysaccharides)、核苷(nucleic acids)、多肽類(polypeptides)、和植物固醇類(phytosterols)等等。在這些活性成分中,又以靈芝三萜類最重要,因其具有藥學活性,包括抑制膽固醇合成、抗癌、抗高血壓等等。靈芝三萜類包含各式靈芝酸(ganoderic acids,GAs)、赤靈酸(ganodermic acids,GMAs)、靈芝醇(ganoderic alcohol)、靈芝酮(ganoderic ketone)、靈芝醛(ganoderic aldehyde)等化合物。在靈芝酸的相關研究中發現,靈芝酸具有可殺死癌細胞的細胞毒性和抑制其擴增的效果。舉例來說,已知靈芝酸D(ganoderic acid D,GAD)可防止人類子宮頸 癌細胞(即,Hela細胞)增生(Yue et al.,Mol Cell Proteomics(2008)7:949-961);靈芝酸A和H(ganoderic acids A and H;簡稱GAA及GAH)可抑制乳癌細胞生長或防止其侵犯其他組織(Jiang et al.,Int J Mol Med(2008)21:577-584);靈芝酸X(ganoderic acid X,GAX)可抑制拓樸酶活性並能誘使肝癌細胞進入細胞凋亡程序(Li et al.,Life Sci.(2005)77,252-265);靈芝酸M除了可有效地抑制癌細胞生長外,還可抑制肺癌細胞的遷移(Wang et al.,Int Immunopharmacol(2007)7:864-870),GMAS則已知可誘發血小板聚集(Wang et al.,Biochim.Biophys.Acta.(1989)986,151-160)、抑制血小板功能(Wang et al.,Biochem.J.(1991)277(Pt 1),189-197)和抑制由血栓素A2(Su et al.,Biochem.Pharmacol.(1999)58,587-595;Su et al.,Biochim.Biophys.Acta.(1999b)1437,223-234)或***素E1(Su et al.,Thromb.Res.(1999c)99,135-145)在血小板中所誘發的細胞反應。 For a long time, in Southeast Asia, edible fungi have been used as nutritional supplements or health foods, among which Ganoderma lucidum is a large-scale, and because of its medical effects, it has been used as a medicinal material for more than a thousand years. . The active ingredients isolated from Ganoderma lucidum generally include triterpenoids, polysaccharides, nucleic acids, polypeptides, and phytosterols. Among these active ingredients, Ganoderma lucidum triterpenoids are most important because of their pharmaceutically active activities, including inhibition of cholesterol synthesis, anticancer, antihypertensive and the like. Ganoderma lucidum triterpenoids include various compounds such as ganoderic acids (GAs), ganodermic acids (GMAs), ganoderic alcohols, ganoderic ketones, and ganoderic aldehydes. In a related study of ganoderic acid, it was found that ganoderic acid has the effect of killing cytotoxicity of cancer cells and inhibiting the amplification thereof. For example, ganoderic acid D (GAD) is known to prevent proliferation of human cervical cancer cells (ie, Hela cells) (Yue et al., Mol Cell Proteomics (2008) 7: 949-961); Acids A and H (GAA and GAH) can inhibit the growth of breast cancer cells or prevent them from invading other tissues (Jiang et al., Int J Mol Med (2008) 21: 577-584); Ganoderma acid X (ganoderic acid X, GAX) inhibits topographic enzyme activity and induces hepatoma cells to enter the apoptotic program (Li et al., Life Sci. (2005) 77, 252-265); Ganoderma lucidum M can effectively inhibit cancer In addition to cell growth, it also inhibits the migration of lung cancer cells (Wang et al., Int Immunopharmacol (2007) 7: 864-870), which is known to induce platelet aggregation (Wang et al., Biochim. Biophys. Acta. 1989) 986, 151-160), inhibition of platelet function (Wang et al., Biochem. J. (1991) 277 (Pt 1), 189-197) and inhibition by thromboxane A2 (Su et al., Biochem. Pharmacol. 1999) 58, 587-595; Su et al., Biochim. Biophys. Acta. (1999b) 1437, 223-234) or prostaglandin E1 (Su et al., Thromb. Res. (1999c) 99, 135-145) in platelets Induced cellular response

本案發明人意外地發現,一種新穎的三萜化合物之組合,具有可抑制特定種類的癌細胞的功效,包括具抗藥性和的癌細胞,使其不致增生,因此,可做為治療或預防癌症之藥物或其佐劑。 The inventors of the present invention have unexpectedly discovered that a novel combination of triterpenoids has the effect of inhibiting specific types of cancer cells, including cancer cells which are resistant and resistant, so that they are not proliferative and, therefore, can be used for treating or preventing cancer. a drug or an adjuvant thereof.

本揭示內容至少部分係基於發現一種新穎的三萜化合物之組合,其具有可延緩或抑制癌細胞生長的特性而來,該些三萜化合物係分別自靈芝(Ganoderma lucidum)之子實體或菌絲體中單離或純化而來。上述發現暗示本揭示內容中的新穎的三萜化合物組合可作為能治 療或預防癌症,包括對藥物具有抗性的癌症,之藥物或佐劑。 The present disclosure is based, at least in part, on the discovery of a novel combination of triterpenoids having properties that retard or inhibit the growth of cancer cells, which are derived from fruiting bodies or mycelia of Ganoderma lucidum , respectively. In the process of isolation or purification. The above findings suggest that the novel triterpenoid combination in the present disclosure can be used as a cancer, drug or adjuvant that can treat or prevent cancer, including drugs.

因此,本揭示內容之第一目的是關於一種可治療或預防癌症的藥學組合物。此藥學組合物包含一藥學有效量之三萜化合物,其至少包含靈芝酸S(ganoderic acid S,GAS)、靈芝酸T(ganoderic acid T, GAT)、靈芝酸Me(ganoderic acid Me,GAMe)、靈芝酸R(ganoderic acid R,GAR)和赤靈酸S(ganodermic acid S,GMAS);及其藥學上可接受的載體。 Accordingly, a first object of the present disclosure is directed to a pharmaceutical composition that treats or prevents cancer. The pharmaceutical composition comprises a pharmaceutically effective amount of a triterpenoid compound comprising at least ganoderic acid S (GAS), ganoderic acid T (GAT), ganoderic acid Me (GAMe), Ganoderic acid R (GAR) and ganodermic acid S (GMAS); and a pharmaceutically acceptable carrier thereof.

依據一較佳實施方式,所述GMAS、GAMe和GAR、GAT、與GAS之量分別約為總三萜化合物含量的0.5-20%、0.5-20%、20-75%及10-30%(重量比)。適合以所述藥學組合物進行治療或預防之癌症可以是直腸癌、肝癌、乳癌、肺癌或血癌。在一實例中,該癌症為肺癌。在另一實例中,該癌症為對吉非替尼(gefitinib)發展出抗藥性的肺癌。 According to a preferred embodiment, the amounts of GMAS, GAMe and GAR, GAT, and GAS are about 0.5-20%, 0.5-20%, 20-75%, and 10-30%, respectively, of the total triterpenoid content. weight ratio). A cancer suitable for treatment or prevention with the pharmaceutical composition may be rectal cancer, liver cancer, breast cancer, lung cancer or blood cancer. In one example, the cancer is lung cancer. In another example, the cancer is a lung cancer that develops resistance to gefitinib.

若以醫藥品或藥學組合物總重量為基準,本發明的新穎三萜化合物組合約占該藥學組合物總重量的0.1%至99%(重量%)。在某些實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的1%。在特定實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的5%。在其他實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的10%。在另外實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的25%。 The novel triterpenoid combination of the present invention comprises from about 0.1% to about 99% by weight based on the total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical or pharmaceutical composition. In certain embodiments, the total amount of the triterpenoid compound of the present invention is at least about 1% by weight based on the total weight of the pharmaceutical composition. In a particular embodiment, the total amount of the triterpenoid compound of the present invention is at least about 5% by weight based on the total weight of the pharmaceutical composition. In other embodiments, the total amount of the triterpenoid compound of the present invention is at least about 10% by weight based on the total weight of the pharmaceutical composition. In other embodiments, the total amount of the triterpenoid compound of the invention is at least about 25% by weight of the total weight of the pharmaceutical composition.

在某些實施方式中,本發明所述醫藥品或藥 學組合物更可做為諸如外科手術、放射線治療或化學治療之類的其他主要癌症治療方式外的另一種輔助性治療,以改善該癌症治療效果。 In certain embodiments, the medicament or medicament of the invention The composition can be used as another auxiliary treatment in addition to other major cancer treatment methods such as surgery, radiation therapy or chemotherapy to improve the therapeutic effect of the cancer.

本揭示內容之第二目的是提供一種治療癌症的方法。所揭示方法包括對需要治療的個體施用一治療有效量之三萜化合物,其包含GMAS、GAMe和GAR、GAT、與GAS。適合以本發明方法進行治療的癌症可以是直腸癌、肝癌、乳癌、肺癌或血癌。在一實例中,上述的癌症為肺癌。在一較佳實施方式中,該癌症是對吉非替尼具有抗藥性的肺癌。該個體可以是哺乳動物,較佳是人類。 A second object of the present disclosure is to provide a method of treating cancer. The disclosed method comprises administering to a subject in need of treatment a therapeutically effective amount of a triterpenoid compound comprising GMAS, GAMe and GAR, GAT, and GAS. A cancer suitable for treatment by the method of the invention may be rectal cancer, liver cancer, breast cancer, lung cancer or blood cancer. In one example, the cancer described above is lung cancer. In a preferred embodiment, the cancer is lung cancer that is resistant to gefitinib. The individual can be a mammal, preferably a human.

在某些實施方式中,本發明所述方法更包括在對該個體施用本發明藥學組合物之前、同時或之後,額外對該個體施加外科手術、放射線治療或化學治療之類的其他主要癌症治療手段,以改善對該個體之癌症治療效果。 In certain embodiments, the methods of the invention further comprise additionally administering to the individual, prior to, concurrently with, or after the administration of the pharmaceutical composition of the invention, additional primary cancer treatments such as surgery, radiation therapy, or chemotherapy. Means to improve the therapeutic effect of cancer on the individual.

透過以下的詳細說明與附隨之申請專利範圍將可更了解本揭示內容的這些及其他特徵。需知以上的概述及以下的詳細說明僅為例示,用來闡述本揭示內容,而非用以限制本揭示內容之範疇。 These and other features of the present disclosure will be more apparent from the following detailed description and appended claims. The above summary and the following detailed description are merely illustrative, and are not intended to limit the scope of the disclosure.

為了使本揭示內容的敘述更加詳盡與完備,下文針對了本發明的實施態樣與具體實施例提出了說明性的描述;但這並非實施或運用本發明具體實施例的唯 一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而,亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。 In order to make the description of the present disclosure more detailed and complete, the following description of the embodiments of the present invention and the specific embodiments of the present invention a form. The features of various specific embodiments, as well as the method steps and sequences thereof, are constructed and manipulated in the embodiments. However, other specific embodiments may be utilized to achieve the same or equivalent function and sequence of steps.

以下為本說明書中所用特定名詞的說明:在本文中,「治療(treatment or treating)」一詞包括可導致欲求之藥學和/或生理效果的防止性(即,預防性)、治癒性或緩和性處置。該效果較佳是指醫療上可部分或完全治癒或防止癌細胞的生長。此外,「治療」一詞在此係指基於可部分或完全減輕、延遲發生、抑制進程、減輕嚴重性、和/或減少一種特定疾病、異常和/或醫療狀況之一或多個病徵出現機率之目的,而對受測個體(或患者),尤指具有一種醫療狀況、一種該醫療狀況之症狀、一種因該醫療狀況而引起的疾病或病症、或是一種會使朝向該醫療狀況發展的先期狀況的個體,施用或施加本揭示內容的化合物。可對尚未出現特定疾病、異常和/或醫療狀況之明顯病徵的個體,和/或僅對該特定疾病、異常和/或醫療狀況產生早期病徵的個體進行治療以期降低產生該特定疾病、異常和/或醫療狀況相關之病理的風險。在本文中,所述病徵、疾病、異常和/或醫療狀況可以是原位癌或轉移性癌。若能減少一或多個病徵或臨床指標即代表該治療是「有效」的。 In the following, the term "treatment or treating" includes the prevention (ie, prophylactic), curative or palliative effects that may lead to a desired pharmaceutical and/or physiological effect. Sexual disposal. Preferably, the effect refers to medically partially or completely curing or preventing the growth of cancer cells. In addition, the term "treatment" is used herein to mean the occurrence of one or more symptoms based on partial or complete mitigation, delayed onset, inhibition of progression, reduction in severity, and/or reduction in a particular disease, disorder, and/or medical condition. For the purpose of the test subject (or patient), especially having a medical condition, a symptom of the medical condition, a disease or condition caused by the medical condition, or a condition that would lead to the development of the medical condition. An individual of the prior condition, administering or applying a compound of the present disclosure. An individual who has not developed a significant condition for a particular disease, disorder, and/or medical condition, and/or an individual who has an early onset of the particular disease, abnormality, and/or medical condition may be treated to reduce the occurrence of the particular disease, abnormality, and / or the risk of pathology associated with medical conditions. Herein, the condition, disease, abnormality, and/or medical condition may be carcinoma in situ or metastatic cancer. Reducing one or more signs or clinical indicators means that the treatment is "effective."

「預防(prophylaxis)」在此是指對一種未來事件的防制手段。基於本文中預防癌細胞或因手術或診斷程序進而潛藏地增加了該些癌細胞轉移的文意,因此, 可於實施該手術或診斷程序之前、同時或之後,實施本文所述的預防性處置手段。 "Prophylaxis" here refers to a means of preventing a future event. Based on the prevention of cancer cells in this article or the potential for the transfer of cancer cells due to surgery or diagnostic procedures, therefore, The prophylactic treatment means described herein can be performed prior to, concurrently with, or subsequent to the practice of the procedure or diagnostic procedure.

「一有效量(an effective amount)」一詞意將對於治療癌症的目的,此一用量在經過適當的給藥期間後,能夠達到減少癌細胞數目的欲求效果。 The term "an effective amount" is intended to achieve the desired effect of reducing the number of cancer cells after a suitable administration period for the purpose of treating cancer.

「化合物(compound)」、「組合物(composition)」、「藥劑(agent)」或「醫藥品(medicine or medicament)」等詞在此可交替使用,且都是指當施用於一個體(人類或動物)時,能夠透過局部和/或全身性作用而誘發所亟求的藥學和/或生理反應的一種化合物或組合物。 The words "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to when applied to a body (human Or an animal, a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

「施用(administered、administering或、administration)」一詞在此係指直接施用所述的化合物或組合物,或施用活性化合物的前驅藥(prodrug)、衍生物(derivative)、或類似物(analog)等,而可於施用個體體內形成該活性化合物之一相當用量者。 The term "administered, administered" or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound. Alternatively, a substantial amount of the active compound can be formed in the subject to be administered.

本文中交替使用「個體(subject)」或「患者(patient)」等詞,其係指可接受所述化合物和/或方法治療的動物(包括人類)。「個體」或「患者」在此涵蓋了雄性與雌性兩種性別,除非另有具體說明。因此「個體」或「患者」包含任何哺乳類動物,包括,但不限於,人類、非人類的靈長類,如哺乳動物、狗、貓、馬、羊、豬、牛等,其可因利用所述化合物進行治療而獲益。適合接受本發明化合物和/或方法治療的動物較佳為人類。一般來說,「患者」一詞及「個體」一詞在本文中可彼此交替使 用。 The words "subject" or "patient" are used interchangeably herein to mean an animal (including a human) that is treatable by the compounds and/or methods. "Individual" or "patient" is used herein to encompass both male and female genders unless otherwise specified. Therefore, "individual" or "patient" includes any mammal, including, but not limited to, human, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cattle, etc. The compounds benefit from treatment. Animals suitable for treatment with the compounds and/or methods of the invention are preferably human. In general, the words "patient" and "individual" are used interchangeably in this paper. use.

雖然用以界定本發明較廣範圍的數值範圍與參數皆是約略的數值,此處已盡可能精確地呈現具體實施例中的相關數值。然而,任何數值本質上不可避免地含有因個別測試方法所致的標準偏差。在此處,「約」通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是,「約」一詞代表實際數值落在平均值的可接受標準誤差之內,視本發明所屬技術領域中具有通常知識者的考量而定。除了實驗例之外,或除非另有明確的說明,當可理解此處所用的所有範圍、數量、數值與百分比(例如用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他相似者)均經過「約」的修飾。因此,除非另有相反的說明,本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值,且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。 Although numerical ranges and parameters are used to define a broad range of values for the present invention, the relevant values in the specific embodiments have been presented as precisely as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the average, depending on the considerations of those of ordinary skill in the art to which the invention pertains. Except for the experimental examples, or unless otherwise explicitly stated, all ranges, quantities, values, and percentages used herein are understood (eg, to describe the amount of material used, the length of time, the temperature, the operating conditions, the quantity ratio, and the like. Are all modified by "about". Therefore, unless otherwise indicated to the contrary, the numerical parameters disclosed in the specification and the appended claims are intended to be At a minimum, these numerical parameters should be understood as the number of significant digits indicated and the values obtained by applying the general carry method.

除非本說明書另有定義,此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。此外,在不和上下文衝突的情形下,本說明書所用的單數名詞涵蓋該名詞的複數型;而所用的複數名詞時亦涵蓋該名詞的單數型。 The scientific and technical terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention pertains, unless otherwise defined herein. In addition, the singular noun used in this specification covers the plural of the noun in the case of no conflict with the context; the plural noun of the noun is also included in the plural noun used.

本揭示內容至少有一部分是基於單離自靈芝子實體或菌絲體之三萜化合物的新穎組合,具有可對抗癌細胞(包括具抗藥性的癌細胞)增生之特性,而發展出來的。因此,此三萜化合物的新穎組合是潛在可用來治療 或預防癌症的藥劑或可作為癌症藥物之佐劑。 At least a portion of the present disclosure has been developed based on novel combinations of triterpenoids that are isolated from the body or mycelium of Ganoderma lucidum, and which have the property of combating the proliferation of cancer cells, including drug-resistant cancer cells. Therefore, this novel combination of triterpenoid compounds is potentially useful for treatment Or an agent for preventing cancer or an adjuvant for cancer drugs.

因此,本揭示內容之第一態樣提供一種可治療或預防癌症的藥學組合物。此藥學組合物包含一藥學有效量之三萜化合物,其至少包含靈芝酸S(ganoderic acid S,GAS)、靈芝酸T(ganoderic acid T,GAT)、靈芝酸Me(ganoderic acid Me,GAMe)、靈芝酸R(ganoderic acid R,GAR)和赤靈酸S(ganodermic acid S,GMAS);及其藥學上可接受的載體。 Accordingly, a first aspect of the present disclosure provides a pharmaceutical composition that treats or prevents cancer. The pharmaceutical composition comprises a pharmaceutically effective amount of a triterpenoid compound comprising at least ganoderic acid S (GAS), ganoderic acid T (GAT), ganoderic acid Me (GAMe), Ganoderic acid R (GAR) and ganodermic acid S (GMAS); and a pharmaceutically acceptable carrier thereof.

本揭示內容之三萜化合物是由靈芝屬菌類中分離而來,並可透過習知的純化方法由赤芝(Ganoderma lucidum)的子實體或菌絲體中分離而得,例如GAS、GAT和GAMe和GAR可利用Xu等人(App.Microbiol Biotechnol(2010)DOI 10.1007/s00253-010-2576-5)所揭示的方法進行分離或純化;GMAS則可依據Hirotani等人(Phytochemistry(1987),26(10),2797-2803)所揭示的方法進行分離純化,或是依據2013年1月11日授予給陳等人的台灣專利號I381844中所述方法,利用取自培養靈芝用的廢棄太空包中的靈芝菌絲體做為原料來進行分離。無論原料來自靈芝子實體或是菌絲體,所用的分離純化方法一般都包括以溶劑(較佳是醇類溶液),在高於室溫的溫度下進行萃取,接著將萃取物進行管柱層析,其包括但不限於高效率液態層析(HPLC)和逆相液態層析(Reverse Phase Liquid Chromatograpy)等,以及濃縮、乾燥等步驟,直到獲得該靈芝活性化合物的乾燥粉末為止。 The triterpenoids of the present disclosure are isolated from Ganoderma genus and can be isolated from fruit bodies or mycelia of Ganoderma lucidum by conventional purification methods, such as GAS, GAT and GAMe. GAR can be isolated or purified using the method disclosed by Xu et al. (App. Microbiol Biotechnol (2010) DOI 10.1007/s00253-010-2576-5); GMAS can be based on Hirotani et al. (Phytochemistry (1987), 26 (10). ), 2797-2803), which is isolated and purified, or in accordance with the method described in Taiwan Patent No. I381844, issued to Chen et al. on January 11, 2013, in an abandoned space bag for culturing Ganoderma lucidum. Ganoderma lucidum mycelium is used as a raw material for separation. Regardless of whether the raw material is from a Ganoderma lucidum fruit body or a mycelium, the separation and purification method generally involves extracting at a temperature higher than room temperature with a solvent (preferably an alcohol solution), and then performing the column layer on the extract. The analysis includes, but is not limited to, high-efficiency liquid chromatography (HPLC) and reverse phase liquid chromatography (Reverse Phase Liquid Chromatograpy), and the like, and steps of concentration, drying, and the like until a dry powder of the active compound of the ganoderma lucidum is obtained.

在某些較佳實施方式中,所述GMAS的量約為總三萜化合物含量的0.5-20%(重量%),例如約0.5、1、 1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、19.5或20%(重量%),此係以組合物中所含三萜化合物的總量當作100%計算而得。在一實例中,該GMAS的量約為組合物中三萜化合物總量的1.5%。在另一實例中,該GMAS的量約為組合物中三萜化合物總量的2%。在又一實例中,該GMAS的量約為組合物中三萜化合物總量的8%。 In certain preferred embodiments, the amount of GMAS is from about 0.5% to about 20% by weight of the total triterpene compound, for example about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14. 14.5, 15.5, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20% (% by weight), which is calculated as 100% of the total amount of triterpenoids contained in the composition. And got it. In one example, the amount of GMAS is about 1.5% of the total amount of triterpenoids in the composition. In another example, the amount of GMAS is about 2% of the total amount of triterpenoids in the composition. In yet another example, the amount of GMAS is about 8% of the total amount of triterpenoids in the composition.

所述GAMe與GAR的量約為總三萜化合物含量的0.5-20%(重量%),例如約0.5、1、1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、19.5或20%(重量%),此係以組合物中所含三萜化合物的總量當作100%計算而得。在一實例中,該GAMe與GAR的量約為組合物中三萜化合物總量的4.5%。在另一實例中,該GAMe與GAR的量約為組合物中三萜化合物總量的6.5%。在又一實例中,該GAMe與GAR的量約為組合物中三萜化合物總量的15%。 The amount of the GAMe and GAR is about 0.5-20% by weight of the total triterpenoid content, for example, about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19. 19.5% or 20% by weight, which is calculated as 100% of the total amount of the triterpenoid compound contained in the composition. In one example, the amount of GAMe and GAR is about 4.5% of the total amount of triterpenoids in the composition. In another example, the amount of GAMe and GAR is about 6.5% of the total amount of triterpenoids in the composition. In yet another example, the amount of GAMe and GAR is about 15% of the total amount of triterpenoids in the composition.

所述GAT的量約為總三萜化合物含量的20-75%(重量%),例如約20、22、25、27、30、32、35、37、40、42、45、47、50、52、55、57、60、62、65、67、70、72或75%(重量%),此係以組合物中所含三萜化合物的總量當作100%計算而得。在一實例中,該GAT的 量約為組合物中三萜化合物總量的65%。在另一實例中,該GAT的量約為組合物中三萜化合物總量的70%。在又一實例中,該GAT的量約為組合物中三萜化合物總量的73%。 The amount of the GAT is about 20-75% by weight of the total triterpenoid content, for example about 20, 22, 25, 27, 30, 32, 35, 37, 40, 42, 45, 47, 50, 52, 55, 57, 60, 62, 65, 67, 70, 72 or 75% by weight, calculated as the total amount of the triterpenoid compound contained in the composition as 100%. In an example, the GAT The amount is about 65% of the total amount of the triterpenoid compound in the composition. In another example, the amount of GAT is about 70% of the total amount of triterpenoids in the composition. In yet another example, the amount of GAT is about 73% of the total amount of triterpenoids in the composition.

所述GAS的量約為總三萜化合物含量的10-30%(重量%),例如約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30%(重量%),此係以組合物中所含三萜化合物的總量當作100%計算而得。在一實例中,該GAS的量約為組合物中三萜化合物總量的17%。在另一實例中,該GAS的量約為組合物中三萜化合物總量的18%。在又一實例中,該GAS的量約為組合物中三萜化合物總量的20%。 The amount of the GAS is about 10-30% by weight of the total triterpenoid content, for example about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30% (% by weight), which is calculated as 100% of the total amount of the triterpenoid compound contained in the composition. In one example, the amount of GAS is about 17% of the total amount of triterpenoids in the composition. In another example, the amount of GAS is about 18% of the total amount of triterpenoids in the composition. In yet another example, the amount of GAS is about 20% of the total amount of triterpenoids in the composition.

若以醫藥品或藥學組合物總重量為基準,本發明的新穎三萜化合物組合(即,GMAS、GAMe和GAR、GAT、與GAS之組合)約占該藥學組合物總重量的0.1%至99%(重量%)。在某些實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的1%。在特定實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的5%。在其他實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的10%。在另外實施方式中,本發明三萜化合物的總量至少約為該藥學組合物總重量的25%。 The novel triterpenoid combination of the invention (ie, a combination of GMAS, GAMe and GAR, GAT, and GAS) comprises from about 0.1% to about 99% by weight based on the total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical or pharmaceutical composition. %(weight%). In certain embodiments, the total amount of the triterpenoid compound of the present invention is at least about 1% by weight based on the total weight of the pharmaceutical composition. In a particular embodiment, the total amount of the triterpenoid compound of the present invention is at least about 5% by weight based on the total weight of the pharmaceutical composition. In other embodiments, the total amount of the triterpenoid compound of the present invention is at least about 10% by weight based on the total weight of the pharmaceutical composition. In other embodiments, the total amount of the triterpenoid compound of the invention is at least about 25% by weight of the total weight of the pharmaceutical composition.

適合以本發明所揭示之藥學組合物進行治療的癌症包括,但不限於,直腸癌、肝癌、乳癌、肺癌或血癌。較佳是,以本發明所揭示之藥學組合物來治療具 有抗藥性的癌症,例如對吉非替尼具有抗藥性的肺癌。 Cancers suitable for treatment with the pharmaceutical compositions disclosed herein include, but are not limited to, rectal cancer, liver cancer, breast cancer, lung cancer, or blood cancer. Preferably, the pharmaceutical composition disclosed in the present invention is used to treat the device. Drug-resistant cancers, such as lung cancer that is resistant to gefitinib.

在本文中,抗藥性(drug-resistance)是指癌的一種特定狀態,尤指已對單一藥物發展出抗性的癌的狀態。舉例來說,已發展出抗藥性的癌包括對長春花生物鹼(vinca alkaloids)(如,長春鹼(vinblastine)、長春新鹼(vincristine)及長春瑞賓(vinorelvine))具有抗性;對蒽環黴素(anthracyclines)(如,阿黴素(doxorubicin)、唐黴素(daunorubicin)、艾達黴素(idarubicin))具有抗性;對微管穩定藥物-泰素(paclitaxel)具有抗性;和對以酪胺酸激酶(tyrosine kinase,TK)活性做為標的之藥物(如,達沙替尼(dasatinib)、尼羅替尼(nilotinib)、伊馬替尼(imatinib)、吉非替尼(gefitinib))具有抗性。在一較佳實施方式中,適合以本發明藥學組合物進行治療的癌是肺癌,其係已對一種FDA核可藥物-吉非替尼,發展出抗藥性的肺癌。 In this context, drug-resistance refers to a specific state of cancer, especially the state of cancer that has developed resistance to a single drug. For example, cancers that have developed resistance include resistance to vinca alkaloids (eg, vinblastine, vincristine, and vinorelvine); Anthracyclines (eg, doxorubicin, daunorubicin, and idarubicin) are resistant; resistant to the microtubule-stable drug, paclitaxel; And drugs that target tyrosine kinase (TK) activity (eg, dasatinib, nilotinib, imatinib, gefitinib) Gefitinib)) is resistant. In a preferred embodiment, a cancer suitable for treatment with a pharmaceutical composition of the invention is lung cancer, which has developed drug-resistant lung cancer against an FDA-approved drug, gefitinib.

在某些實施方式中,可將本發明所揭示的藥物或藥學組合物做為諸如外科手術、放射線治療或化學治療之類的其他主要癌症治療方式外的另一種輔助性治療藥物,以改善該癌症的治療效果。 In certain embodiments, the pharmaceutical or pharmaceutical compositions disclosed herein can be used as an additional adjunctive therapeutic other than other major cancer treatment modalities such as surgery, radiation therapy, or chemotherapy to improve the The therapeutic effect of cancer.

可根據眾所接受的藥學製程來製備上述藥物或藥學組合物,如Remington’s Pharmaceutical Sciences(17th edition,ed.Alfonoso R.Gennaro,Mack Publishing Company,Easton,Pa(1985))一書中所揭示的製程。藥學上可接受的賦型劑係指可和藥學製劑中其他成分相容且與生物體相容者。 The above pharmaceuticals or pharmaceutical compositions can be prepared according to well-accepted pharmaceutical processes such as those disclosed in Remington's Pharmaceutical Sciences (17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa (1985)). . A pharmaceutically acceptable excipient is meant to be compatible with the other ingredients of the pharmaceutical formulation and compatible with the organism.

依據本發明所揭示的實施方式,可經由任何 適當的給藥途徑來施用本發明所揭示的藥物或藥學組合物,例如經過口腔服用的膠囊、懸浮液或藥錠,或是以不經過腸胃道方式來施用。不經過腸胃道的施用方式包括諸如肌肉注射、靜脈血管注射、皮下注射或腹腔內注射等系統性施用方式。或是,也可透過穿皮膜方式施用,如局部皮膚塗抹或是吸入性(如,支氣管內、鼻腔內、口腔內或鼻滴劑等);或是直腸內方式施用。施用時可單獨給藥或併同習知藥學可接受輔劑一起給藥。在較佳實施方式中,可經由口服方式(如,透過食物)將本發明化合物投予個體。 According to the disclosed embodiments of the present invention, The medicament or pharmaceutical composition disclosed herein, such as a capsule, suspension or syrup for oral administration, is administered by a suitable route of administration or is administered without gastrointestinal route. The mode of administration without gastrointestinal route includes systemic administration such as intramuscular injection, intravenous injection, subcutaneous injection or intraperitoneal injection. Alternatively, it can be applied by means of a transdermal membrane, such as topical skin application or inhalation (eg, intrabronchial, intranasal, intraoral or nasal drops, etc.); or intrarectal administration. Administration may be carried out alone or in combination with conventional pharmaceutically acceptable adjuvants. In a preferred embodiment, the compounds of the invention can be administered to an individual via oral means (e.g., through food).

若以口服方式施用,可將本發明三萜化合物的新穎組合配方成為內含各種輔劑(如,微晶纖維素、碳酸鈣、磷酸二鈣及甘胺酸);各種崩解劑(如澱粉、藻酸及特定矽酸鹽);以及顆粒黏合劑(如,聚乙烯吡咯烷酮、蔗糖、明膠及相思樹膠(acacia))的藥錠。除此外,還可包含諸如硬脂酸鎂、十二烷基硫酸鈉及滑石等的潤滑劑。與此相關的較佳材料包括乳糖或牛奶中的糖以及高分子量聚乙二醇。上述的固態劑型也可非必要地包括塗層或殼,例如腸衣塗層,以及用來改善任一藥物活性成分釋放速率的塗層。這類塗層的實例已為此領域中人士所熟知。在一實例中,所述藥學組合物是被配方成為藥錠。在另一實例中,所述藥學組合物是被配方成為充填在軟或硬明膠膠囊內或是封裝在生物可分解之藥包內的顆粒。當使用方式是口服用懸浮液和/或特效藥液(elixirs)時,可組合活性成分與各種甜味劑或風味劑、著色劑或染料一起 配方,需要時還可加入乳化劑和/或懸浮劑,以及諸如水、酒精、丙二醇、甘油等稀釋劑。在某些實施方式中,本發明藥學組合物是被配方成為適合口服的液體劑型。此類液體配方可更包括用來維持pH值的緩衝液。也可將此液體配方充填在軟膠囊內。此液體劑型可為一種溶液,懸浮液,乳化液,微乳化液,沉澱或是可攜帶本發明化合物、其之藥學上可接受的衍生物、異構物、代謝物、鹽類或溶合物之任何液體介質。此液體可被設計成能改善本發明化合物其之藥學上可接受鹽類之溶解度,以便形成一種含有藥物的乳化液或分散液。當使用這種劑型時,是將活性化合物與至少一種藥學上可接受的輔藥(包括,但不限於,上述輔藥)一起混合後形成。 If administered orally, the novel combination of the triterpenoids of the present invention can be formulated to contain various adjuvants (eg, microcrystalline cellulose, calcium carbonate, dicalcium phosphate, and glycine); various disintegrants (such as starch) , alginic acid and specific citrate); and granule binders (eg, polyvinylpyrrolidone, sucrose, gelatin, and acacia). In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may also be included. Preferred materials associated therewith include sugars in lactose or milk as well as high molecular weight polyethylene glycols. The above solid dosage forms may also optionally include a coating or shell, such as a casing coating, and a coating to improve the rate of release of any of the pharmaceutically active ingredients. Examples of such coatings are well known to those skilled in the art. In one example, the pharmaceutical composition is formulated as a tablet. In another example, the pharmaceutical composition is a granule formulated to be filled in a soft or hard gelatin capsule or encapsulated in a biodegradable kit. When used in the form of oral suspensions and / or special effects (elixirs), the active ingredients may be combined with various sweeteners or flavors, colorants or dyes. The formulation may, if desired, be added with an emulsifier and/or a suspending agent, and a diluent such as water, alcohol, propylene glycol or glycerin. In certain embodiments, the pharmaceutical compositions of the invention are formulated as liquid dosage forms suitable for oral administration. Such liquid formulations may further include a buffer to maintain the pH. This liquid formulation can also be filled in a soft capsule. The liquid dosage form can be a solution, suspension, emulsion, microemulsion, precipitate or can carry a compound of the invention, a pharmaceutically acceptable derivative, isomer, metabolite, salt or solvate thereof Any liquid medium. The liquid can be designed to improve the solubility of the pharmaceutically acceptable salts of the compounds of the invention to form a drug-containing emulsion or dispersion. When such a dosage form is employed, it is formed by mixing the active compound with at least one pharmaceutically acceptable adjuvant, including, but not limited to, the above-described adjuvants.

若以腸胃外(parenterally)方式施用,可將本發明三萜化合物的新穎組合配方成為液態的藥學組合物,其可為能以靜脈內注射、肌肉內注射、皮下注射或腹膜內注射等方式施用的無菌溶液或懸浮液。可用來製造上述無菌注射溶液或懸浮液的稀釋劑包括,但不限於,1,3-丁二醇、甘露醇、水、林格氏溶液、等張性氯化鈉溶液。也可使用脂肪酸(如,油酸)及其之甘油酯衍生物,或是天然藥學可接受的油(如,橄欖油或菜籽油)來製造可供注射用的溶液或懸浮液。這類油性溶液或懸浮液中也可包含用來稀釋的醇類或羧甲基纖維素或類似的分散劑。也可使用其他常用的界面活性劑(如,Tweens或Spans系列)或乳化劑,或藥學領域製造配方時常用來增強生物可利用性的藥劑。 If administered in a parenterally manner, the novel combination of the triterpenoids of the present invention can be formulated into a liquid pharmaceutical composition which can be administered by intravenous, intramuscular, subcutaneous or intraperitoneal injection. Sterile solution or suspension. Diluents which can be used in the manufacture of such sterile injectable solutions or suspensions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer's solution, isotonic sodium chloride solution. Fatty acids (e.g., oleic acid) and their glyceride derivatives, or natural pharmaceutically acceptable oils (e.g., olive oil or rapeseed oil) can also be used to make solutions or suspensions for injectable use. Alcohols or carboxymethylcellulose or similar dispersing agents for dilution may also be included in such oily solutions or suspensions. Other commonly used surfactants (e.g., Tweens or Spans series) or emulsifiers, or agents commonly used in the pharmaceutical arts to enhance bioavailability can be used.

亦可將本發明之上述醫藥品或藥學組合物製成多種適用於局部皮膚表面施用的劑型。在此種實施方式中,可採用多種已知、適於皮膚表面使用的惰性載體來製造適合的劑型。這類劑型包括溶液、乳液、乳霜、凝膠、軟膏、噴劑、皮膚貼布等。典型的惰性載體可以是,例如水、乙醇、聚乙烯吡咯烷酮、聚丙二醇、礦物油、硬脂酸醇、和可產生凝膠的物質。以上所揭示的載體或劑型都是此領域中習知技藝人士所熟知的,適合劑型的選擇與本發明藥學組合物的功效兩者間並不具有必然的相關性。 The above pharmaceutical or pharmaceutical compositions of the present invention may also be formulated into a variety of dosage forms suitable for topical application to the skin surface. In such embodiments, a variety of known inert carriers suitable for use on the skin surface can be employed to make a suitable dosage form. Such dosage forms include solutions, lotions, creams, gels, ointments, sprays, dermal patches, and the like. Typical inert carriers can be, for example, water, ethanol, polyvinylpyrrolidone, polypropylene glycol, mineral oil, stearic alcohol, and gel-forming materials. The carriers or dosage forms disclosed above are well known to those skilled in the art, and there is no necessary correlation between the choice of suitable dosage form and the efficacy of the pharmaceutical compositions of the present invention.

亦可將本發明上述醫藥品或藥學組合物製成多種適用於黏膜給藥(mucosal application)的劑型,如經頰(buccal)和/或舌下(sublingual)藥物劑型單元,以遞送藥物穿過口腔黏膜。可使用多種生物可降解且藥學可接受的高分子輔劑,此種輔劑可使得藥學組合物具有可接受的吸附效果以及所欲的藥物釋放模式,且可和經頰和/或舌下藥物劑型單元中所含的欲施用活性成分或其他成分相容。一般來說,上述的高分子輔劑包含親水性聚合物,其可黏附至口腔黏膜的濕潤表面。高分子輔劑的實施例包括但不限於丙烯酸聚合物與共聚物(acrylic acid polymers and copolymers);水解聚乙烯醇(hydrolyzed polyvinylalcohol);聚乙烯氧化物(polyethylene oxides);聚丙烯酸酯(polyacrylates);乙烯聚合物與共聚物(vinyl polymers and copolymers);聚乙烯吡咯啶;葡萄糖(dextran);瓜膠(guar gum); 果膠(pectins);澱粉;及纖維素聚合物(cellulosic polymers)。 The above pharmaceuticals or pharmaceutical compositions of the present invention may also be formulated into a variety of dosage forms suitable for mucosal applications, such as buccal and/or sublingual pharmaceutical dosage units, for delivery of drugs through Oral mucosa. A wide variety of biodegradable and pharmaceutically acceptable polymeric adjuvants can be used which provide the pharmaceutical compositions with acceptable adsorption and desired drug release patterns, as well as buccal and/or sublingual drugs. The active ingredient or other ingredients to be administered in the dosage unit are compatible. In general, the above polymeric adjuvants comprise a hydrophilic polymer that adheres to the wetted surface of the oral mucosa. Examples of polymeric adjuvants include, but are not limited to, acrylic acid polymers and copolymers; hydrolyzed polyvinyl alcohol; polyethylene oxides; polyacrylates; Vinyl polymers and copolymers; polyvinylpyrrolidine; dextran; guar gum; Pectins; starch; and cellulosic polymers.

當可理解,本發明三萜化合物組合的劑量會因個體而異,這不僅是因為所用的特定化合物或組合物、給藥途徑、化合物(單獨或連同一或多種藥物)於患者體內所引發之所欲反應等因素之不同,還可能受到其他因素影響,例如:欲治療症狀的疾病狀態或嚴重程度;患者的年齡、性別或體重、患者的健康狀況;以及欲治療的病理狀態的嚴重程度、患者於同時進行的其他醫療或特殊飲食內容;以及本領域通常知識者可想到的其他因素;而負責照料的醫療人員最終可基於這些因素而判斷出適當的劑量。可調整給藥劑量與形式以提供較佳的治療反應。治療有效量同時也是指化合物或組合物所致的毒性或有害的效果不及於其所帶來的治療利益。在較佳的情形中,本發明三萜化合物之組合於投藥時,應採用適當的劑量並持續一段時間,以減少出現症狀的次數和/或嚴重程度。 It will be understood that the dosage of the triterpenoid combination of the present invention will vary from individual to individual, not only because of the particular compound or composition employed, the route of administration, the compound (either alone or in combination with one or more drugs) The factors such as the desired response may also be affected by other factors, such as the state or severity of the condition to be treated; the age, sex or weight of the patient, the health of the patient; and the severity of the pathological condition to be treated, Other medical or special dietary content that the patient performs at the same time; and other factors conceivable by those of ordinary skill in the art; and the medical personnel responsible for care may ultimately determine the appropriate dosage based on these factors. The dosage and form of administration can be adjusted to provide a preferred therapeutic response. A therapeutically effective amount also refers to a toxic or detrimental effect of a compound or composition that is less than the therapeutic benefit it brings. In a preferred embodiment, the combination of the triterpenoids of the present invention, when administered, should be administered in an appropriate dosage for a period of time to reduce the number and/or severity of symptoms.

依此,本揭示內容還提供一種可治療一患者之癌症的方法。所揭示方法包括對該患者施用一有效量的上述本發明藥學組合物,且該藥學組合物可經由抑制癌細胞生長和/或複製而能有效地治療該患者之癌症。可以任何能夠有效傳送此藥學組合物至適合的生體作用位置的途徑(如,口服、鼻用、肺、穿皮膜等方式,或是諸如直腸栓劑、皮下、靜脈注射、肌肉注射、眼科溶液或軟膏之類的方式)來將該藥學組合物施用至一哺乳動物個 體上,較佳是人類身上。此外,本發明藥學組合物也可與其他活性成分同時一起施用。 Accordingly, the present disclosure also provides a method of treating cancer in a patient. The disclosed method comprises administering to the patient an effective amount of a pharmaceutical composition of the invention described above, and the pharmaceutical composition is effective to treat cancer in the patient by inhibiting growth and/or replication of cancer cells. Any means capable of efficiently delivering the pharmaceutical composition to a suitable location of action (eg, oral, nasal, pulmonary, percutaneous, or the like, or such as rectal suppository, subcutaneous, intravenous, intramuscular, ophthalmic solution or Ointment or the like) to apply the pharmaceutical composition to a mammal Physically, it is better for humans. Furthermore, the pharmaceutical compositions of the invention may also be administered concurrently with other active ingredients.

適合以本發明方法進行治療的癌症包括直腸癌、肝癌、乳癌或肺癌。較佳是以本發明化合物來治療具有抗藥性的癌,包括對吉非替尼具有抗藥性的癌症。 Cancers suitable for treatment by the methods of the invention include rectal cancer, liver cancer, breast cancer or lung cancer. Preferably, the compounds of the invention are used to treat cancers that are resistant, including cancers that are resistant to gefitinib.

當本發明藥學組合物被施用至一個體身上時,所施用的有效用量約為1-100毫克/公斤個體體重間。每天可施用至該個體身上之藥學組合物的用量約為10、20、30、40、50、60、70、80、90或100毫克/公斤體重;較佳是約30-70毫克/公斤體重,例如約30、40、50、60、70毫克/公斤體重;更佳是約50毫克/公斤體重。這些劑量可以單次施用或是分成多次在一天內施用。 When the pharmaceutical composition of the present invention is applied to a body, the effective amount to be administered is from about 1 to 100 mg/kg of the individual body weight. The pharmaceutical composition to be administered to the individual per day is used in an amount of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg/kg body weight; preferably about 30-70 mg/kg body weight. For example, about 30, 40, 50, 60, 70 mg/kg body weight; more preferably about 50 mg/kg body weight. These doses can be administered in a single administration or divided into multiple administrations within one day.

在某些實施方式中,本發明所述方法更包括在對該個體施用本發明藥學組合物之前、同時或之後,額外對該個體施加外科手術、放射線治療或化學治療之類的其他主要癌症治療手段,以改善對該個體之癌症治療效果。 In certain embodiments, the methods of the invention further comprise additionally administering to the individual, prior to, concurrently with, or after the administration of the pharmaceutical composition of the invention, additional primary cancer treatments such as surgery, radiation therapy, or chemotherapy. Means to improve the therapeutic effect of cancer on the individual.

以下實施例是用來闡明本揭示內容特定態樣,並幫助習知技藝者了解並實施本揭示內容。但本揭示內容範疇並不限於這些實施例中。 The following examples are presented to illustrate certain aspects of the present disclosure and to assist those skilled in the art to understand and practice the present disclosure. However, the scope of the disclosure is not limited to these embodiments.

實施例Example

材料與方法Materials and Methods

細胞培育 Cell culture

本研究係使用人類乳癌細胞株MDA-MB-231、人類肝臟細胞癌株HepG2(human hepatocarcinoma cell line HepG2)、人類肺腺癌(lung adenocarcinoma)細胞株A549,人類直腸癌細胞株HCT116、人類非小型肺癌細胞株PC-9、對吉非替尼具有抗性的人類非小型肺癌細胞株PC-9(PC9-IR)、人類非小型肺癌細胞株H1650、人類骨髓性白血球細胞株K652、人類前骨髓性白血球細胞株HL-60,以及小鼠肺癌細胞株(Lewis lung carcinoma LLC)。 This study used human breast cancer cell line MDA-MB-231, human liver cell carcinoma strain HepG2 (human hepatocarcinoma cell) Line HepG2), human lung adenocarcinoma cell line A549, human rectal cancer cell line HCT116, human non-small lung cancer cell line PC-9, human non-small lung cancer cell line PC-resistant to gefitinib 9 (PC9-IR), human non-small lung cancer cell line H1650, human myeloid leukocyte cell line K652, human promyelocytic leukocyte cell line HL-60, and mouse lung carcinoma cell line (Lewis lung carcinoma LLC).

將MDA-MB-231、HepG2、HCT116,以及LLC細胞分別培育在經Dulbecco氏改良過之Eagle氏培養基(Dulbecco's modified Eagle's medium,DMEM)中,PC9,PC9-IR、H1650、K562,以及HL-60培育在RPMI培養基中,並在培養基中都添加10%胎牛血清(fetal calf serum,FCS)、100單位/ml之盤尼西林、100 ng/ml之鏈黴素(Invitrogen,Carlsbad,CA)、2mM L-穀氨酸和非必要胺基酸及丙酮酸鈉,並維持在37℃的潮溼環境下(5% CO2及95%空氣)。平時將細胞培養於10公分培養盤內,當細胞長到八分滿時進行繼代培養。繼代培養方式係先吸去舊的培養液後,以3毫升的磷酸緩衝液(PBS)清洗培養細胞一次,接著,在37℃下以1毫升之胰蛋白酶/EDTA(0.05%/0.025%)溶液處理細胞5分鐘,使細胞脫離培養盤成懸浮狀態;接著,在懸浮細胞中加入2毫升新鮮的培養液,以中和胰蛋白酶的活性。然後,將細胞打散使平均分布於細胞懸浮液中,留下適當比例的細胞數後,加入新培養液補至適當體積並混勻後,放入37℃培養箱內培養。 MDA-MB-231, HepG2, HCT116, and LLC cells were separately cultured in Dulbecco's modified Eagle's medium (DMEM), PC9, PC9-IR, H1650, K562, and HL-60. Incubate in RPMI medium and add 10% fetal calf serum (FCS), 100 units/ml penicillin, 100 ng/ml streptomycin (Invitrogen, Carlsbad, CA), 2 mM L - Glutamate and non-essential amino acids and sodium pyruvate, and maintained at 37 ° C in a humid environment (5% CO 2 and 95% air). Cells are usually cultured in a 10 cm culture dish and subcultured as the cells grow to eight minutes. The subculture method was to first aspirate the old culture medium, and then wash the culture cells once with 3 ml of phosphate buffer (PBS), followed by 1 ml of trypsin/EDTA (0.05%/0.025%) at 37 °C. The cells were treated with the solution for 5 minutes, and the cells were detached from the culture plate to be in a suspended state; then, 2 ml of fresh culture solution was added to the suspension cells to neutralize the activity of trypsin. Then, the cells were dispersed to be evenly distributed in the cell suspension, and after a proper ratio of the number of cells was left, the new culture solution was added to an appropriate volume and mixed, and then cultured in a 37 ° C incubator.

細胞活性分析 Cell viability analysis

取約3,000個細胞,將之接種在平底96孔盤 中,以培養液補充每一培養孔內的培養液,使體積達180 L,接著將培養盤放入37℃之培養箱培養過夜。次日加入含不同濃度的三萜化合物組合、吉非替尼或是伊馬替尼,於上述培養液。各培養孔內最終體積為200 μL,每個濃度進行三重覆,放入37℃培養箱培養,於48小時後測定細胞活性。 Take about 3,000 cells and inoculate them in a flat 96-well plate. In the medium, the culture solution in each culture well was replenished to a volume of 180 L, and then the culture plate was placed in an incubator at 37 ° C overnight. On the next day, a combination of triterpenoids containing different concentrations, gefitinib or imatinib was added to the above culture solution. The final volume in each well was 200 μL, each concentration was triple-coated, placed in a 37 ° C incubator, and cell viability was measured after 48 hours.

酸性磷酸酶活性(Acid phosphatase,ACP)分析Acid phosphatase (ACP) analysis

活細胞中有大量ACP可將其受質磷酸對硝基苯酯(p-nitrophenyl phosphate,p-NPP)轉換成對-硝基苯酚(p-nitrophenol,p-NP),p-NP在405 nm波長下有最大吸光值,故可藉測定吸光值可定量出細胞中ACP活性,進而推算出細胞的活性。測定細胞活性時,先吸去培養液,以200 μL PBS清洗一次,加入100 μl的分析用緩衝液(內含10 mM p-NPP、0.1 M醋酸鈉、0.1% Triton X-100,且pH約為5.5),於37℃反應30-40分鐘後加入10 μl的氫氧化鈉(0.1 N)終止反應,以SpectraMax M5 Microplate Reader(Molecular Devices,Sunnyvale,CA,USA)於波長405 nm測定吸光值為細胞活性,以未處理藥物組的細胞活性為1,計算出不同條件處理下的細胞活性比。 A large number of living cells can be subject to quality ACP p-nitrophenyl phosphate (p -nitrophenyl phosphate, p -NPP) translate into - nitrophenol (p -nitrophenol, p -NP), p -NP at 405 nm The maximum absorbance at the wavelength, so the absorbance value can be used to quantify the ACP activity in the cell, and then calculate the activity of the cell. To measure cell viability, first aspirate the culture solution, wash once with 200 μL PBS, and add 100 μl of assay buffer (containing 10 mM p- NPP, 0.1 M sodium acetate, 0.1% Triton X-100, and pH approx. 5.5), after reacting at 37 ° C for 30-40 minutes, 10 μl of sodium hydroxide (0.1 N) was added to terminate the reaction, and the absorbance was measured at a wavelength of 405 nm using a SpectraMax M5 Microplate Reader (Molecular Devices, Sunnyvale, CA, USA). Cell viability, and the cell activity ratio of the untreated drug group was 1, and the cell activity ratio under different conditions was calculated.

誘發原位癌及活體內治療Induced carcinoma in situ and in vivo treatment

本試驗使用6週齡之C57BL/6及NOD/SCID雄鼠,飼養在無病原菌的環境下,室溫維持於22±3℃,相對濕度保持於50±20%,日夜週期維持12/12小時,並可自由取用飲水及食物。動物飼料使用實驗鼠飼料 5001(Laboratory Rodent Diet 5001)(購自PMI® Nutrition International,Inc.,MO,USA)。動物飲水則使用煮沸過之自來水。所有動物實驗操作,皆遵循中華實驗動物學會出版之「實驗動物管理與使用指南」之規範。 This test used 6-week-old C57BL/6 and NOD/SCID male rats, kept in a pathogen-free environment, maintained at 22±3°C at room temperature, maintained at 50±20% relative humidity, and maintained 12/12 hours in day and night. Drinking water and food are freely available. Animal feed was used with experimental rodent diet 5001 (purchased from PMI ® Nutrition International, Inc., MO, USA). For drinking water, boiled tap water is used. All animal experiments were carried out in accordance with the "Guidelines for the Management and Use of Laboratory Animals" published by the Chinese Society of Laboratory Animals.

試驗前一天,將動物依體重分組,分組後確認各組間體重無統計上顯著差異,然後,將動物右後大腿外側剃毛。試驗開始當天,注射腫瘤細胞於剃毛處皮下,將A549人類肺癌細胞或HCT116人類直腸癌細胞(0.1 mL生理食鹽水內含1×107個細胞)注射至NOD/SCID小鼠,或將LLC小鼠肺癌細胞(0.1 mL生理食鹽水內含1×106個細胞)注射至C57BL/6小鼠。注射3天後,再開始投予本發明藥學組合物,投藥當日定為投藥試驗第1天。所有投藥溶液均當日配製。投藥時,以餵食針對試驗動物灌食投藥用懸浮液;每日灌食兩次,兩次間隔至少三小時。C57BL/6小鼠第22天完成試驗,NOD/SCID小鼠第35天完成實驗,實驗完成後將腫瘤取下,秤量腫瘤重量並且計算本發明藥學組合物抑制腫瘤生長的比例。 One day before the experiment, the animals were grouped according to their body weight. After grouping, it was confirmed that there was no statistically significant difference in body weight between the groups, and then the outside of the right thigh was shaved. On the day of the test, the injected tumor cells were subcutaneously injected into the shaved area, and A549 human lung cancer cells or HCT116 human rectal cancer cells (1 × 10 7 cells in 0.1 mL of physiological saline) were injected into NOD/SCID mice, or LLC. Mouse lung cancer cells (1 × 10 6 cells in 0.1 mL of physiological saline) were injected into C57BL/6 mice. Three days after the injection, the pharmaceutical composition of the present invention was administered again, and the day of administration was designated as the first day of the administration test. All dosing solutions were prepared on the same day. At the time of administration, the test animals were fed with a drug-administered suspension by feeding; twice daily, at least three hours apart. The C57BL/6 mice completed the experiment on the 22nd day, and the NOD/SCID mice completed the experiment on the 35th day. After the completion of the experiment, the tumor was removed, the tumor weight was weighed, and the proportion of the pharmaceutical composition of the present invention inhibiting tumor growth was calculated.

實施例1 抑制活體外之癌細胞活性Example 1 Inhibition of cancer cell activity in vitro

1.1藥學組合物1.1 pharmaceutical composition

本揭示內容中特定可預防及/或治療癌症的藥學組合物係透過將各活性成分依據下表所示配方混合成一均勻混合物後而製得,該些活性成分係可依據本發明揭示內容中所載明的方法,自靈芝子實體或菌絲體中分離或純化而得。 The pharmaceutical compositions of the present disclosure that specifically prevent and/or treat cancer are prepared by mixing the active ingredients into a homogeneous mixture according to the formulation shown in the following table, which may be in accordance with the present disclosure. The method specified is isolated or purified from the fruit body or mycelium of Ganoderma lucidum.

表1 本揭示內容之藥學組合物配方 Table 1 Formulation of the pharmaceutical composition of the present disclosure

1.2實施例1.1之組合物1可抑制各式癌細胞活性1.2 Composition 1 of Example 1.1 inhibits the activity of various cancer cells

分別依上述方式,透過測定ACP活性來評估實施例1.1所揭示之藥學組合物1抑制各種癌細胞株活性的功效,包括直腸癌、肝癌、乳癌、肺癌及血癌,結果示於表2中。 The efficacy of the pharmaceutical composition 1 disclosed in Example 1.1 for inhibiting the activity of various cancer cell lines, including rectal cancer, liver cancer, breast cancer, lung cancer, and blood cancer, was evaluated by measuring ACP activity in the above manner, and the results are shown in Table 2.

如表2所示,實施例1.1所揭示之組合物1可抑制包括乳癌細胞株MDA-MB-231、肝癌細胞株HepG2、直腸癌細胞株HCT-116、肺癌細胞株A549、血癌細胞株K562或HL-60等癌細胞的活性,且以血癌細胞株對治療的感受性最強,乳癌細胞株則最不敏感。 As shown in Table 2, the composition 1 disclosed in Example 1.1 can inhibit the cancer cell line MDA-MB-231, the liver cancer cell line HepG2, the rectal cancer cell line HCT-116, the lung cancer cell line A549, the blood cancer cell line K562 or The activity of cancer cells such as HL-60 is the most sensitive to treatment by blood cancer cell lines, and the least sensitive to breast cancer cell lines.

1.3實施例1.1之組合物2可抑制各式癌細胞活性1.3 Composition 2 of Example 1.1 inhibits the activity of various cancer cells

同樣,利用ACP活性當作細胞活性指標來驗證本揭示內容藥學性組合物2對直腸癌與肺癌細胞株的效果。結果示於表3。 Similarly, the effect of the pharmaceutical composition 2 of the present disclosure on rectal cancer and lung cancer cell lines was examined using ACP activity as an indicator of cell activity. The results are shown in Table 3.

總結表2與表3的結果,就抑制癌細胞活性而言,本發明組合物2的功效至少約為組合物1的3倍,因組合物2中所包含的GMAS量為約為組合物1中GMAS量的4倍,故推測組合物2較強的功效(即,抑制癌細胞活性)應來自GMAS的貢獻。 Summarizing the results of Table 2 and Table 3, the efficacy of Composition 2 of the present invention is at least about 3 times that of Composition 1 in terms of inhibiting the activity of cancer cells, since the amount of GMAS contained in Composition 2 is about Composition 1 The amount of GMAS is 4 times, so it is speculated that the stronger efficacy of Composition 2 (ie, inhibition of cancer cell activity) should be derived from the contribution of GMAS.

1.4實施例1.1之組合物1可抑制對吉非替尼具有抗性之肺癌細胞活性1.4 Composition 1 of Example 1.1 inhibits lung cancer cell activity resistant to gefitinib

依據實施例1.1所述方式,測試組合物1在已對吉非替尼發展出抗藥性之肺癌細胞株PC9-IR上的效果。組合物1或吉非替尼抑制細胞株之50%活性的濃度,以及兩細胞株對藥物的細胞抗性比(resistant ratio,RR)總結於下表4中。細胞抗性比乃是一種用以決定細胞株對一測試藥物之感受性的方式,透過將某一特定藥物對不同細胞株的IC50濃度相除,即可獲得RR值,用以表示一細胞株,相對於另一細胞株而言,對該測試藥物的敏感程度。 The effect of the test composition 1 on the lung cancer cell line PC9-IR which had developed resistance to gefitinib was carried out in the manner described in Example 1.1. The concentration of composition 1 or gefitinib inhibiting 50% activity of the cell line, and the cell resistance ratio (RR) of the two cell lines to the drug are summarized in Table 4 below. The cell resistance ratio is a way to determine the susceptibility of a cell strain to a test drug. By dividing the IC 50 concentration of a particular drug against a different cell strain, an RR value can be obtained to represent a cell strain. Sensitivity to the test drug relative to another cell strain.

無論是PC-9或PC9-IR細胞,在以吉非替尼處理72小時後,其細胞活性均明顯下降,其50%細胞活性受到抑制的濃度分別為0.0371 μM與10.6 μM。類似的,組合物1同樣可抑制PC-9或PC9-IR細胞的細胞活性,且其可抑制50%細胞活性的濃度均約在35 μg/mL左右(分別為35.7與34.6 μg/mL)。但是如果分別比較兩細胞株對組合物1和吉非替尼的細胞抗性比(resistant ratio),就可明顯看出吉非替尼對不具抗藥性的PC-9細胞株較有效。 相反的,兩株肺癌細胞株對組合物1的細胞抗性比則大略相同,表示無論癌細胞是否具有抗藥性,組合物1毒殺有或無抗藥性之肺癌細胞的能力並無差異。 Both PC-9 or PC9-IR cells showed a significant decrease in cell viability after 72 hours of treatment with gefitinib, and their 50% inhibition of cell viability was 0.0371 μM and 10.6 μM, respectively. Similarly, Composition 1 also inhibited the cell viability of PC-9 or PC9-IR cells, and its concentration which inhibited 50% of cell activity was about 35 μg/mL (35.7 and 34.6 μg/mL, respectively). However, if the cell resistance ratios of composition 1 and gefitinib were compared between the two cell lines, respectively, it was apparent that gefitinib was more effective against the non-resistant PC-9 cell line. In contrast, the cell resistance ratio of the two lung cancer cell lines to the composition 1 was almost the same, indicating that there was no difference in the ability of the composition 1 to kill lung cancer cells with or without drug resistance regardless of whether the cancer cells were resistant or not.

1.5實施例1.1之組合物1可抑制血癌細胞活性1.5 Composition 1 of Example 1.1 inhibits blood cell cancer activity

依據實施例1.1所述方式,測試組合物1在血癌細胞株HL-60或K562上的效果。組合物1或伊馬替尼抑制細胞株50%活性的濃度,以及兩細胞株對藥物的細胞抗性比(resistant ratio,RR)總結於下表5中。 The effect of composition 1 on blood cancer cell line HL-60 or K562 was tested in the manner described in Example 1.1. The concentration of composition 1 or imatinib to inhibit 50% activity of the cell line, and the cell resistance ratio (RR) of the two cell lines to the drug are summarized in Table 5 below.

無論是HL-60或K562細胞,在以伊馬替尼處理72小時後,其細胞活性均明顯下降,其50%細胞活性受到抑制的濃度分別為35 μM與0.4 μM。類似的,組合物1同樣可抑制HL-60或K562細胞的細胞活性,且其可抑制50%細胞活性的濃度分別為25.8與30.7 μg/mL。但是如果分別比較兩細胞株對組合物1和伊馬替尼的細胞抗性比,就可明顯看出伊馬替尼對HL-60細胞株較有效。相反的,兩株血癌細胞株對組合物1的細胞抗性比則大略相同,表示組合物1毒殺兩血癌細胞的能力並無差異。 Both HL-60 and K562 cells showed a significant decrease in cell viability after treatment with imatinib for 72 hours, and their 50% inhibition of cell viability was 35 μM and 0.4 μM, respectively. Similarly, Composition 1 also inhibited the cellular activity of HL-60 or K562 cells, and its concentration which inhibited 50% of cellular activity was 25.8 and 30.7 μg/mL, respectively. However, if the cell resistance ratio of the two cell lines to composition 1 and imatinib was compared, it was apparent that imatinib was more effective against the HL-60 cell line. In contrast, the cell resistance ratio of the two blood cancer cell lines to Composition 1 was almost the same, indicating that there was no difference in the ability of Composition 1 to poison both blood cancer cells.

實施例2 活體內抑制癌細胞生長的效果Example 2 Effect of inhibiting cancer cell growth in vivo

2.1實施例1.1所揭示之組合物可抑制活體內癌細胞的生長2.1 The composition disclosed in Example 1.1 inhibits the growth of cancer cells in vivo

以「材料與方法」段落中所揭示方式誘發試驗動物產生腫瘤(如,肺癌與直腸癌),然後再施用本發明藥學組合物(即,實施例1.1所揭示之組合物),以測試本發明藥學組合物於活體內抑制腫瘤生長的功效。結果示於下表6。 The test animals are induced to produce tumors (e.g., lung cancer and rectal cancer) in the manner disclosed in the "Materials and Methods" section, and then the pharmaceutical composition of the present invention (i.e., the composition disclosed in Example 1.1) is administered to test the present invention. The efficacy of a pharmaceutical composition for inhibiting tumor growth in vivo. The results are shown in Table 6 below.

如表6所示,實施例1.1所揭示的兩種組合物配方(組合物1及3)均可有效地抑制活體內癌的生長,約80%的肺癌生長可被組合物1抑制,約50%的直腸癌生長則可被組合物3所抑制。 As shown in Table 6, the two composition formulations disclosed in Example 1.1 (Compositions 1 and 3) were effective in inhibiting the growth of cancer in vivo, and about 80% of lung cancer growth was inhibited by Composition 1, about 50. % of rectal cancer growth can be inhibited by composition 3.

2.2三萜化合物抑制肺癌生長的效果2.2 Triterpenoids inhibit the growth of lung cancer

本實施方式探討組合物中總活性三萜化合物的含量對抑制腫瘤生長的效果。本試驗使用實施例1.1之組合物3的配方來進行測試,於不改變配方內各成份間(靈芝酸和/或赤靈酸)相對比例的情況下,提高組合物中總三萜化合物的含量。結果總結於表7中。 This embodiment investigates the effect of the total active triterpenoid compound content in the composition on inhibiting tumor growth. This test was carried out using the formulation of Composition 3 of Example 1.1 to increase the total triterpenoid content of the composition without changing the relative proportions of the components (Ganoderma lucidum and/or erythritol) in the formulation. . The results are summarized in Table 7.

此結果與本發明其他實施例中所觀察到的現象一致,亦即,本發明藥學組合物中具有治療功效的成分乃是三萜類化合物。相較於安慰劑,其僅含少量三萜 類化合物且僅能於活體內產生些許抑制癌生長的效果,本發明組合物3可達成至少抑制約50-65%的癌的生長。 This result is consistent with the phenomenon observed in other embodiments of the present invention, that is, the therapeutically effective ingredient in the pharmaceutical composition of the present invention is a triterpenoid. Compared to placebo, it contains only a small amount of triterpenoids The compound of the present invention can produce at least about 50-65% of the growth of cancer by inhibiting the growth of the cancer only in vivo.

此外,因組合物3所含GMAS的量小於2%,因此,縱使提高組合物中總三萜類化合物含量,但並未觀察到等比例之抑制癌生長的效果。 Further, since the amount of GMAS contained in the composition 3 was less than 2%, even if the content of the total triterpenoids in the composition was increased, an effect of inhibiting the growth of cancer in an equal ratio was not observed.

綜上所述,本發明結果顯示本揭示內容具有新穎三萜化合物之組合的藥學組合物是潛在可用來治療癌症的藥物,特別是具抗藥性之癌症的治療藥物。 In summary, the results of the present invention show that the pharmaceutical compositions of the present disclosure having a combination of novel triterpenoid compounds are potential therapeutic agents for the treatment of cancer, particularly cancers resistant to cancer.

當可理解上述實施方式與實施例僅為例示,且熟習此技藝者可對齊進行各種修飾。上文提出之說明書、實施例與資料的目的在於使本說明書的結構完備,並作為實作本發明之例示。雖然本揭示內容已以實施方式揭露如上,然其並非用以限定本揭示內容,任何熟習此技藝者,在不脫離本揭示內容之精神和範圍內,當可作各種之更動與潤飾,因此本揭示內容之保護範圍當視後附之申請專利範圍所界定者為準。 It will be understood that the above-described embodiments and examples are merely illustrative, and that those skilled in the art can align various modifications. The description, examples, and materials set forth above are intended to be illustrative of the present invention and are illustrative of the invention. The present disclosure has been disclosed in the above embodiments, but it is not intended to limit the disclosure, and any person skilled in the art can make various changes and refinements without departing from the spirit and scope of the disclosure. The scope of protection of the disclosure is subject to the definition of the scope of the patent application.

Claims (7)

一種用於治療癌症的藥學組合物,包含一藥學有效量之三萜化合物,其至少包含靈芝酸S(ganoderic acid S,GAS)、靈芝酸T(ganoderic acid T, GAT)、靈芝酸Me(ganoderic acid Me,GAMe)、靈芝酸R(ganoderic acid R,GAR)和赤靈酸S(ganodermic acid S,GMAS);及其藥學上可接受的載體。 A pharmaceutical composition for treating cancer comprising a pharmaceutically effective amount of a triterpenoid compound comprising at least ganoderic acid S (GAS), ganoderic acid T (GAT), and ganoderic acid (ganoderic) Acid Me, GAMe), ganoderic acid R (GAR) and ganodermic acid S (GMAS); and a pharmaceutically acceptable carrier thereof. 如請求項1所述的藥學組合物,其中GMAS的量約為該組合物中三萜化合物總量的0.5-20%(重量%)。 The pharmaceutical composition according to claim 1, wherein the amount of GMAS is from about 0.5% to about 20% by weight based on the total amount of the triterpenoid compound in the composition. 如請求項1所述的藥學組合物,其中GAMe與GAR的量約為該組合物中三萜化合物總量的0.5-20%(重量%)。 The pharmaceutical composition according to claim 1, wherein the amount of GAMe and GAR is from about 0.5% to about 20% by weight based on the total amount of the triterpenoid compound in the composition. 如請求項1所述的藥學組合物,其中GAT的量約為該組合物中三萜化合物總量的20-70%(重量%)。 The pharmaceutical composition according to claim 1, wherein the amount of GAT is from about 20% to about 70% by weight based on the total amount of the triterpenoid compound in the composition. 如請求項1所述的藥學組合物,其中GAS的量約為該組合物中三萜化合物總量的10-30%(重量%)。 The pharmaceutical composition according to claim 1, wherein the amount of GAS is about 10-30% by weight based on the total amount of the triterpenoid compound in the composition. 如請求項1所述的藥學組合物,其中該癌症可以是肝癌、直腸癌、肺癌、乳癌或血癌。 The pharmaceutical composition according to claim 1, wherein the cancer may be liver cancer, rectal cancer, lung cancer, breast cancer or blood cancer. 如請求項6所述的藥學組合物,其中該肺癌對吉非替尼(gefitinib)具有抗藥性。 The pharmaceutical composition according to claim 6, wherein the lung cancer is resistant to gefitinib.
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TWI728551B (en) * 2019-11-13 2021-05-21 三華生物科技股份有限公司 Use of pharmaceutical composition for treating of a cancer associated with the activation of galectin-1
CN114053285A (en) * 2021-09-07 2022-02-18 中国医学科学院药用植物研究所 Application of ganoderic acid X in treating tumor

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TWI728551B (en) * 2019-11-13 2021-05-21 三華生物科技股份有限公司 Use of pharmaceutical composition for treating of a cancer associated with the activation of galectin-1
CN114053285A (en) * 2021-09-07 2022-02-18 中国医学科学院药用植物研究所 Application of ganoderic acid X in treating tumor

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