200940061 六、發明說明： 【發明所屬之技術領域】 本發明係關於波生坦（bosentan)與紫杉醇之組合用於同 時、分開或經一段時期治療卵巢癌之治療用途。 【先前技術】 卵巢癌係女性最常見癌症之一。卵巢癌最常見的併發症 、係、腹水形成。目前’尚不能滿意的治療_巢癌或其併發症 (例如腹水形成）。 波生坦係Tracleer®之活性成份。其係雙重内皮素受體拮 抗劑化合物（即，對内皮素ETa與ETb受體二者皆具親和性 之化合物），其具有下式200940061 VI. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to the therapeutic use of bosentan in combination with paclitaxel for the simultaneous, separate or prolonged treatment of ovarian cancer. [Prior Art] One of the most common cancers in women with ovarian cancer. The most common complications, system, and ascites of ovarian cancer. Currently, 'unsatisfactory treatment _ nest cancer or its complications (such as ascites formation). The active ingredient of Bosentan Tracleer®. It is a dual endothelin receptor antagonist compound (i.e., a compound having affinity for both endothelin Eta and ETb receptor) having the following formula
❹ 波生坦及其製備已特別闡述於歐洲專利第〇 526 708號或 美國專利第5,292,740號中》 紫杉醇（在美國以商標Taxol®出售之藥劑的活性成份）係 自太平洋紫杉（Pacific yew tree，roucMj 6revz/o//a)之針葉及 樹皮提取的抗微管劑。目前’該化合物在歐盟及美國已批 准尤其用於治療晚期卵巢癌。 文獻中已建議將内皮素受體A (ETAR)拮抗劑與紫杉醇之 組合用於治療卵巢癌。 舉例而言，L. Rosano 等人63，2447- 138209.doc 200940061 2453)教不選擇性ETAR拮抗劑ΑΒΤ-627(阿曲生坦 (atrasentan))與紫杉醇組合產生加性抗腫瘤、細胞凋亡及 抗血管生成效應。 此外 ’ L· Rosano 等人（M〇/ Cimcer 77ier.(2007)，6(7)， 2003-2011)揭示ZD4054(特異性etaR拮抗劑）在活體外及活 體内在人類卵巢癌中抑制腫瘤生長且增強紫杉醇活性。 另一方面 ’ L. Rosano 等人（Mo/· Carwcer 77zer.(2006)， 5(4)，833-842)亦表明BQ788(選擇性内皮素受體B (ETBR)拮 抗劑）與ETAR拮抗劑相反，在活體外不能有效抑制卵巢腫 瘤細胞之細胞黏附。 【發明内容】 本申請者現已發現，波生坦當與紫杉醇組合時在卵巢癌 活體内模型中產生極高作用。此外’在同一活體内模型 中，本申請者發現使用波生坦與紫杉醇之組合可防止腹水 形成。因此，波生坦與紫杉醇組合可用於製備治療卵巢癌 及/或預防或治療與卵巢癌有關之腹水形成的藥劑’且適 於治療卵巢癌及/或預防或治療與卵巢癌有關之腹水形 成。 因此，本發明首先係關於一種產物’其含有波生坦或該 化合物之醫藥上可接受之鹽或水合物與紫杉醇或其醫藥上 可接受之鹽的組合，且本發明亦係關於該產物同時、分開 或經一段時期治療卵巢癌之治療用途。 【實施方式】 以下段落提供本專利申請案中所用各種術語之定義，且 138209.doc 200940061 除非另有清晰陳述之定義提供更廣或更窄之定義，否則， 帛欲在整個說明書及申請專利範圍中統一應用。 術語「醫藥上可接受之鹽」係指無毒、無機或有機酸 及/或鹼加成鹽。可參照"Salt selecti〇n f〇r basic drugs"， 如PAam. (1986)，33, 201-217。 ’ . 在本文中術語「水合物」係指藉助將水分子納入晶體結 構中而得到的產物。在;皮生坦水合物之情形中波生坦單 ❹t合物較佳。 - 在提及治療㈣時，「同時地」或「同時的」在本發明 申清案中意指所關注治療用途包括藉由相同途徑同時投與 兩種或更多種活性成份。 在提及治療用途時，「分開地」或「分開的」在本發明 申請案中意指所關注治療用途包括藉由至少兩種不同途 徑，在大約相同時間投與兩種或更多種活性成份。 「經一段時期」之治療投與在本發明申請案中意指在不 ❹㈣間投與兩種或更多種活性成份，且尤其指根據其投藥 法’在完成其中一種活性成份全部投與之後才開始投與另 一種或其他活性成份。以此方式，可投與—種活性成份並 持續數月，之後才投與另一種或其他活性成份。在此情況 下，不會出現同時投與。「經一段時期」之治療投與亦涵 蓋該等成份不依相同週期給予之情形（例如其中一種成份 係每天給予一次且另一種係每週給予一次）。 「腹水形成之預防」或「肋腹水形成」在本發明申請 案中意指依照本發明實施適宜預防治療後，可避免腹水形 138209.doc 200940061 成或減少該形成’或者，消除或減少已形成之腹水。 「腹水形成之治療」或「治療腹水形成」在本發明申請 案中意指依照本發明實施適宜治療之後，可消除或減少存 於患者中之腹水。 在本發明較佳實施例中，含有波生坦或該化合物之醫藥 上了接受之鹽或水合物與紫杉醇或其醫藥上可接受之鹽之 組合的產物可用於同時、分開或經一段時期預防或治療患 有卵巢癌之患者腹水形成的治療用途。 根據本發明之一種變體，波生坦或其醫藥上可接受之鹽 或水合物意欲藉由靜脈内或腹膜内途徑投與。 根據本發明之另一種變體，波生坦或其醫藥上可接受之 鹽或水合物意欲藉由經口途徑投與。 紫杉醇或其醫藥上可接受之鹽較佳藉由靜脈㈣腹膜内 途徑投與。 〜儘管本發明產物之確切投與劑量必須由治療醫生來確 一預。十 〇〇5_30 mg(且較佳 0.1-10 mg 且更佳 〇.5_5 mg) :生坦/kg患者體重/天之劑量與〇 m〇叫(且較佳W _ 醇/kg患者體重/天之劑量組合將適宜。 本發明㈣關於醫藥組合物，其含有作為活性成份的 =化合物之醫藥上可接受之鹽或水合物與紫杉醇 、可接受之鹽的組合以及至少—種無毒賦形劑。 液體形合物可呈適於靜脈内或腹膜内投與 合物之醫藥之;合物可含有波生坦或該' 接又之鹽或水合物及紫杉醇或其醫藥上1 138209.doc 200940061 . 接受之鹽，該醫藥組合物呈存於聚氧乙烯化蓖麻油（例如 Cremophor® EL)與乙醇之混合物中之溶液形式（該混合物含 有例如40-60體積％存於乙醇中之聚氧乙烯化蓖麻油）。 或者，波生坦或其醫藥上可接受之鹽或該化合物之水合 物可調配成錠劑（例如市售Tracleer®)，而紫杉醇可調配成 存於聚氧乙稀化蓖麻油（例如Cremophor® EL)與乙醇之混合 物中之溶液。 醫藥組合物之製備可以任何熟習此項技術者熟悉之方式 (參見例如 Remington, TTze awe? ’ 第 21 版（2005)，第 5 部分"Pharmaceutical Manufacturing" [由Lippincott Williams & Wilkins出版])藉由將所述化合物 或其醫藥上可接受之鹽或水合物、視情況與其他有治療價 值之物質組合連同適宜無毒惰性治療相容固體或液體載劑 材料及若需要常用醫藥佐劑製成蓋侖製劑投與形式來實 施。 φ 本發明進一步係關於波生坦或該化合物之醫藥上可接受 之鹽或水合物與紫杉醇或其醫藥上可接受之鹽之組合用於 製造意欲治療卵巢癌之醫藥之用途。其亦係關於波生坦或 該化合物之醫藥上可接受之鹽或水合物與紫杉醇或其醫藥 上可接受之鹽之組合用於製造意欲預防或治療患有卵巢癌 之患者腹水形成之醫藥的用途。 本發明進一步係關於治療患有卵巢癌之患者之方法，其 藉由向該患者投與波生坦或該化合物之醫藥上可接受之鹽 或水合物與紫杉醇或其醫藥上可接受之鹽的組合來達成。 138209.doc 200940061 其亦係關於預防或治療患有卵巢癌之患者腹水形成之方 法’其藉由向該患者投與波生坦或該化合物之醫藥上可接 受之鹽或水合物與紫杉醇或其醫藥上可接受之鹽的組合來 達成。 此外，針對本發明產物所示之偏好經適當變通後當然亦 適用於本發明之醫藥組合物及應用。 本發明具體實施例闡述於以下部分中，其用來更詳細闡 釋本發明而並非以任何方式限制本發明範圍。 本發明產物之藥理性質 在小鼠中人類SKOV3ipl臚瘤生長抑制分析 實聆方法： 媒劑溶液 由適量甲基纖維素於適量水中授拌4小時，來製備 0.5%(以重量計）甲基纖維素水溶液。該溶液可提前至多3 天製備。在實驗當天，將0.05%(以體積計）吐溫8〇(Tween 80)溶解於預先獲得之甲基纖維素溶液中，獲得媒劑溶 液。 實驗程序 用1〇6個SKOV3ipl細胞i.p,注射43隻小鼠。10天後，評估 三隻小鼠之腫瘤重量且使用以下藥劑投與小鼠來進行治 療：波生坦於媒劑溶液中形成之懸浮液（1〇隻小鼠）、以於 磷酸鹽緩衝鹽水（PBS)中稀釋1:6之紫杉醇用於Lp.注射（1〇 隻小鼠）、波生坦於媒劑溶液中形成之懸浮液及以於ΡΒ8中 稀釋1:6之紫杉醇用於i.p.注射（1〇隻小鼠）、或僅媒劑溶液 138209.doc 200940061 。 (1 〇隻小鼠）’投與劑量、頻率及途徑係如下： ❖紫杉醇：5 mg/kg(125 於200 μι PBS中之紫杉醇/小 鼠），每週一次，i.p.途徑； ❖波生坦：300 mg/kg(以至高25 mg/mL之濃度存於媒劑溶 液中之懸浮液），每天一次，經口途徑β 治療一，個月後，測定每隻小鼠之腫瘤發生率及重量。同 時’亦測定腹水發生率及體積。 結果： ❿ 一 關於腫瘤發生率及重量獲得以下結果： 治療组 Λ 重(g) 平均值土 S.D. 朦瘤發生率 腫瘤重董(g) 中值(範面） Ρ 對照 23.1 ±2.5 8/10 1.1 (0-1.8^ 紫杉醇 23.6 ± 1.9 9/9 0.4(0.1-0.5) 0 01 Bos 23.0 ±2.1 9/10 1.1 (0A.9) 0.9 紫杉醇+ Bos 23.4 ±3.2 4/10 〇(〇-!.η 0.004 S.D.= 標準偏差 Bos= 波生坦 ® 關於腹水發生率及禮積獲得以下結果： 治療組 Λ重⑻ 平均值士 S.D. 腹水發生率 趿水(mL) 中值(範ffi) Ρ 對照 23.1 ±2.5 8/10 0.4 (Ό-0.9、 紫杉醇 23.6 ±1.9 4/9 0.1 (Ό-0 0 005 Bos 23.0 ±2.1 5/10 0 1 fO-1 Q、 0 9 紫杉醇+ Bos 23.4 ±3.2 0/10 0 0.002 S.D.= 標準偏差 Bos= 波生土曰 可以看出，波生坦與紫杉醇組合相對於僅用紫杉醇進行 138209.doc -9- 200940061 治療顯著提高響應： -10只小鼠中的6只經組合治療後不再有腫瘤，而紫杉醇 治療組中之所有小鼠皆仍有腫瘤； -組合治療組中之平均腫瘤重量接近為零，但在僅用波生 坦治療之小鼠中’平均腫瘤重量與對照組相同且在僅用 東杉醇治療之小鼠中，平均腫瘤重量仍為對照組小鼠之 平均腫瘤重量的約1 /3 ;且 -經組合治療之小鼠不再發生腹水，即便1〇只中的4只仍 有腫瘤，而僅經紫杉醇治療之小鼠中9只中的4只發生腹 水且僅經波生坦治療之小鼠中10只中的5只發生腹水。 138209.doc 10·❹ Bosentan and its preparation have been specifically described in European Patent No. 526 708 or U.S. Patent No. 5,292,740. Paclitaxel (active ingredient of the agent sold under the trademark Taxol® in the United States) is from the Pacific yew tree. , roucMj 6revz/o//a) anti-microtubule agent for needle and bark extraction. Currently, the compound has been approved in the European Union and the United States, especially for the treatment of advanced ovarian cancer. The combination of an endothelin receptor A (ETAR) antagonist and paclitaxel has been suggested in the literature for the treatment of ovarian cancer. For example, L. Rosano et al. 63, 2447-138209.doc 200940061 2453) teaches the selective ETAR antagonist ΑΒΤ-627 (atrasentan) in combination with paclitaxel to produce additive anti-tumor, apoptosis And anti-angiogenic effects. Furthermore, 'L. Rosano et al. (M〇/Cimcer 77ier. (2007), 6(7), 2003-2011) revealed that ZD4054 (specific etaR antagonist) inhibits tumor growth in human ovarian cancer in vitro and in vivo and Enhances paclitaxel activity. On the other hand, 'L. Rosano et al. (Mo/· Carwcer 77zer. (2006), 5(4), 833-842) also showed that BQ788 (selective endothelin receptor B (ETBR) antagonist) and ETAR antagonists In contrast, cell adhesion of ovarian tumor cells is not effectively inhibited in vitro. SUMMARY OF THE INVENTION The Applicant has now found that the combination of bosentan and paclitaxel produces a very high effect in an in vivo model of ovarian cancer. Furthermore, in the same in vivo model, the Applicant has found that the combination of bosentan and paclitaxel prevents the formation of ascites. Therefore, bosentan in combination with paclitaxel can be used for the preparation of an agent for treating ovarian cancer and/or preventing or treating the formation of ascites associated with ovarian cancer' and is suitable for treating ovarian cancer and/or preventing or treating ascites formation associated with ovarian cancer. Accordingly, the present invention relates first to a product comprising a combination of bosentan or a pharmaceutically acceptable salt or hydrate of the compound with paclitaxel or a pharmaceutically acceptable salt thereof, and the present invention also relates to the product simultaneously Therapeutic use of ovarian cancer, either separately or over a period of time. [Embodiment] The following paragraphs provide definitions of various terms used in the present patent application, and 138209.doc 200940061 provides a broader or narrower definition unless otherwise clearly stated, otherwise, the entire specification and patent application scope are intended. Unified application. The term "pharmaceutically acceptable salt" means a non-toxic, inorganic or organic acid and/or base addition salt. See "Salt selecti〇n f〇r basic drugs", as in PAam. (1986), 33, 201-217. The term "hydrate" as used herein refers to a product obtained by incorporating water molecules into a crystal structure. In the case of picentan hydrate, bosentan mono quinone is preferred. - When referring to treatment (4), "simultaneously" or "simultaneously" in the context of the present invention means that the therapeutic use of interest comprises the simultaneous administration of two or more active ingredients by the same route. When referring to a therapeutic use, "separately" or "separate" in the present application means that the therapeutic use of interest comprises administering two or more active ingredients at about the same time by at least two different routes. . The treatment of "through a period of time" in the present application means that two or more active ingredients are administered between (4), and in particular, after the administration of one of the active ingredients is completed according to its administration method. Start with another or other active ingredient. In this way, the active ingredient can be administered for several months before the other or other active ingredient is administered. In this case, there will be no simultaneous contributions. The treatment of "through a period of time" also covers situations in which the ingredients are not administered in the same cycle (for example, one of the ingredients is given once a day and the other is given once a week). "Prevention of ascites formation" or "facial ascites formation" in the present application means that the formation of the ascites 138209.doc 200940061 can be avoided or reduced, or eliminated or reduced, after the appropriate preventive treatment is carried out in accordance with the present invention. ascites. "Treatment of ascites formation" or "treatment of ascites formation" in the present application means that ascites can be eliminated or reduced in a patient after appropriate treatment in accordance with the present invention. In a preferred embodiment of the invention, the product comprising bosentan or a pharmaceutically acceptable salt or hydrate of the compound in combination with paclitaxel or a pharmaceutically acceptable salt thereof, can be used for simultaneous, separate or prolonged prevention. Or therapeutic use to treat ascites formation in patients with ovarian cancer. According to a variant of the invention, bosentan or a pharmaceutically acceptable salt or hydrate thereof is intended to be administered by intravenous or intraperitoneal route. According to another variant of the invention, bosentan or a pharmaceutically acceptable salt or hydrate thereof is intended to be administered by the oral route. Paclitaxel or a pharmaceutically acceptable salt thereof is preferably administered by the intravenous (iv) intraperitoneal route. ~ Although the exact dosage of the product of the invention must be determined by the treating physician. Shiyan 5_30 mg (and preferably 0.1-10 mg and more preferably 5.5_5 mg): the dose of body weight/day of Shengtan/kg patient and 〇m ( (and preferably W _ alcohol / kg patient weight / day The dosage combination will be suitable. The present invention (4) relates to a pharmaceutical composition comprising as an active ingredient a pharmaceutically acceptable salt or hydrate of a compound in combination with paclitaxel, an acceptable salt, and at least one non-toxic excipient. The liquid form may be in a form suitable for intravenous or intraperitoneal administration; the compound may contain bosentan or the salt or hydrate of the salt and paclitaxel or its medicinal application 1 138209.doc 200940061 . The salt to be received, the pharmaceutical composition being in the form of a solution in a mixture of polyoxyethylated castor oil (e.g., Cremophor® EL) and ethanol (the mixture containing, for example, 40-60% by volume of polyoxyethylenene in ethanol) Castor oil. Alternatively, bosentan or a pharmaceutically acceptable salt thereof or a hydrate of the compound may be formulated into a tablet (for example, commercially available Tracleer®), and paclitaxel may be formulated as a polyoxyethylene castor oil. (eg Cremophor® EL) in a mixture with ethanol The pharmaceutical compositions can be prepared in any manner familiar to those skilled in the art (see, for example, Remington, TTze awe? '21st Edition (2005), Section 5 "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins] By combining the compound or a pharmaceutically acceptable salt or hydrate thereof, optionally with other therapeutically valuable substances, together with a suitable non-toxic inert therapeutically compatible solid or liquid carrier material and, if desired, a conventional pharmaceutical adjuvant. The invention is further carried out in the form of administration of the galenical formulation. φ The invention further relates to the combination of bosentan or a pharmaceutically acceptable salt or hydrate of the compound with paclitaxel or a pharmaceutically acceptable salt thereof for the manufacture of an ovary intended for treatment The use of a pharmaceutical for cancer, which is also a combination of bosentan or a pharmaceutically acceptable salt or hydrate of the compound with paclitaxel or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of ovarian cancer. Use of a medicament for the formation of ascites in a patient. The invention further relates to a method of treating a patient suffering from ovarian cancer by The patient is administered bosentan or a pharmaceutically acceptable salt or hydrate of the compound in combination with paclitaxel or a pharmaceutically acceptable salt thereof. 138209.doc 200940061 It is also for the prevention or treatment of ovarian cancer A method of forming ascites in a patient's by administering to the patient a combination of bosentan or a pharmaceutically acceptable salt or hydrate of the compound with paclitaxel or a pharmaceutically acceptable salt thereof. The preferences shown by the inventive products are of course also applicable to the pharmaceutical compositions and applications of the present invention. The specific embodiments of the present invention are set forth in the following section, which is intended to illustrate the invention in detail and not to limit the scope of the invention. Pharmacological properties of the product of the invention in human SKOV3ipl tumor growth inhibition assay in vivo: The vehicle solution is mixed with an appropriate amount of methylcellulose in an appropriate amount of water for 4 hours to prepare 0.5% by weight of methyl fiber Aqueous solution. This solution can be prepared up to 3 days in advance. On the day of the experiment, 0.05% by volume of Tween 80 was dissolved in a previously obtained methylcellulose solution to obtain a vehicle solution. Experimental procedure 43 mice were injected with 1 〇 6 SKOV3ipl cells i.p. After 10 days, the tumor weight of the three mice was evaluated and the mice were administered with the following agents for treatment: a suspension of bosentan in a vehicle solution (1 mouse), phosphate buffered saline 1:6 of paclitaxel diluted in PBS for Lp. injection (1 mouse), suspension of bosentan in vehicle solution and paclitaxel diluted 1:6 in ΡΒ8 for ip injection (1 mouse), or vehicle only solution 138209.doc 200940061. (1 〇 mice) The dose, frequency and route of administration were as follows: Paclitaxel: 5 mg/kg (125 paclitaxel/mouse in 200 μl PBS) once a week, ip route; ❖波生坦: 300 mg / kg (up to a concentration of 25 mg / mL of the suspension in the vehicle solution), once a day, oral treatment of β one, after a month, determine the tumor incidence and weight of each mouse . At the same time, the incidence and volume of ascites were also measured. Results: ❿ The following results were obtained for tumor incidence and weight: Treatment group Λ Weight (g) Mean soil SD 朦 tumor incidence Tumor weight Dong (g) Median (norm) Ρ Control 23.1 ± 2.5 8/10 1.1 (0-1.8^ Paclitaxel 23.6 ± 1.9 9/9 0.4(0.1-0.5) 0 01 Bos 23.0 ±2.1 9/10 1.1 (0A.9) 0.9 Paclitaxel + Bos 23.4 ±3.2 4/10 〇(〇-!.η 0.004 SD=standard deviation Bos= Bosentan® The following results were obtained for ascites incidence and labor accumulation: Treatment group weight (8) Mean SD SD Ascites incidence rate (mL) Median (fan ffi) 对照 Control 23.1 ± 2.5 8/10 0.4 (Ό-0.9, paclitaxel 23.6 ±1.9 4/9 0.1 (Ό-0 0 005 Bos 23.0 ±2.1 5/10 0 1 fO-1 Q, 0 9 paclitaxel + Bos 23.4 ±3.2 0/10 0 0.002 SD = standard deviation Bos = Bosen soil can be seen, bosentan and paclitaxel combination significantly improved response compared to paclitaxel only 138209.doc -9- 200940061 treatment: 6 out of 10 mice were treated with combination There were no more tumors afterwards, and all mice in the paclitaxel-treated group still had tumors; - the average tumor weight in the combination treatment group was close to zero, but In the mice treated with bosentan alone, the average tumor weight was the same as that of the control group, and in the mice treated with only docetaxel, the average tumor weight was still about 1/3 of the average tumor weight of the control mice; And - the ascites no longer occurred in the mice treated with the combination, even though 4 of the 1 仍有 had tumors, and only 4 out of 9 of the paclitaxel-treated mice developed ascites and were treated only with bosentan. Ascites occurred in 5 out of 10 mice. 138209.doc 10·