201113023 六、發明說明： 【發明所屬之技術領域】 本發明關於一種將含支鏈胺基酸而成的核酸類似物之 活性增強劑、支鏈胺基酸與核酸類似物組合而成的病毒性 肝炎之預防或治療劑'病毒性肝炎用醫藥等。 【先前技術】 B型肝炎病毒（以下亦記載爲「HBV」）屬於肝炎病 毒科（hepadnavirus)正肝病毒屬（〇rthohepadnavirus) ’爲引起B型肝炎的病毒，主要藉由血液媒介、母子（垂 直）、性行爲（水平）感染。其持續感染缺乏自覺症狀， 然而會引起慢性肝炎’接下來肝臟的纖維化徐緩進行，以 至於肝硬化，甚至會有發生肝癌的情形。另一方面，在感 染B型肝炎病毒的情況，理論上難以完全驅除該病毒，而 採用抗病毒療法使病毒減少，對於維持肝功能同時抑制肝 硬化或肝臟衰竭的發生，阻止肝癌的發生而言是非常重要 的。 拉美夫定係被開發作爲HBV治療藥的抗病毒劑有效 成分，而爲具有核苷樣構造的核酸類似物製劑的代表性成 分。拉美夫定已知最初對AIDS病毒表現出抗病毒作用， 然而對HBV也表現出增殖抑制效果。拉美夫定對HBV的 作用機制，是經過三磷酸衍生物磷酸化的拉美夫定在細胞 內阻礙了 HBV的反轉錄酵素而被收編在病毒的DNA鏈中 ，進而使其伸長停止（參照非專利文獻1)。以拉美夫定 -5- 201113023 爲首的核酸類似物，能夠以口服劑的形式使用，副作用也 很少，此外還具有與干擾素同等甚至以上的抗病毒活性》 然而，在中止投予該等核酸類似物製劑的情祝下，會 有病毒再增生機率高這樣的問題。爲了避免中止投予後的 再度增生，有必要半永久性地投予核酸類似物，然而即使 長期投予，其效果在早期階段即達到頂點，另外，因爲長 期投予而產生耐性病毒，或醫療成本增加等多項缺點。再 者，對年輕人長期投予，會有對生殖系統造成影響的顧慮 。另外，在B型TF炎帶原者中，隨著時間自然經過觀察到 肝炎的活動性降低的頻率很高，因此特別是對年輕人而言 ，早期投予且長期投予核酸類似物，也有可能變成過度醫 療。從這樣的觀點看來，與其他藥物的併用療法，正被廣 泛硏究作爲無藥物（drug free)且長期緩解爲目標的治療 策略（參照非專利文獻2)。 干擾素（以下記載爲「IFN」），係透過直接的抗病 毒作用與宿主免疫的賦活化這兩個機制而發揮效果的藥物 。干擾素有發熱 '頭痛、關節痛等多種副作用，醫療費用 昂貴（參照非專利文獻3 )，然而也會以優勢性且長期地 持續發生血清轉化現象或病毒DNA的沉默化（參照非專 利文獻4)，而爲以長期緩解爲目標的有力選擇。然而 PEG干擾素與核酸類似物的組合雖然有防止耐性病毒產生 的效果，但是有文獻提示其治療成效與單獨使用干擾素的 情況沒有差異（參照非專利文獻5〜7 )。因此，除了 IFN 以外，還需要有能夠與核酸類似物倂用，且提升治療成效 -6 - 201113023 的藥物。 已有文獻報告出，在將支鏈胺基酸適用於IFN療法的 情況下，血中濃度會降低（參照非專利文獻8)。另外， 還有文獻報告出支鏈胺基酸具有使IFN效果增強的作用， 或減輕IFN副作用的作用（參照專利文獻1 )。然而，支 鏈胺基酸具有增強核酸類似物所具有抗病毒作用的機能， 至目前爲止尙未解明。 [先前技術文獻] [專利文獻] [專利文獻1]國際公開W02007/01 3677號小冊子 [非專利文獻] [非專利文獻1]佐田通夫著，B型肝炎的拉美夫定療 法、臨床與藥物治療，1999年6月號 [非專利文獻2]南祐仁等，以B型慢性肝炎持續沉 默化爲目標之抗病毒療法評估：干擾素單獨療法、拉美夫 定·千擾素倂用療法、消化器官科，42 ( 4 ) : 41 1-416， 2006 [非專利文獻3 ]飯野四郎編著，慢性肝炎最新的治 療（中外醫學社）pl54(2001年） [非專利文獻 4] Van Nunen AB，et al.，Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B : relation to type of therapy and pretreatment serum hepatitis B virus D N A and alanine 201113023 aminotransferase. Gut 2003 ； 52 ; p p . 4 2 0 [非專利文獻 5] Marcellin P, et al.，Peginterferon al fa-2 a alone, 1 am i vu d i n e alone, and the two in combination i n patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med.，2004 ; 351 : pp.1206 [非專利文獻 6] Janssen H L, et al.，Pegylated interferon a 1 f a - 2 b alone or incombination with lamivudine for HBeAg-positive chronic hepatitis B ； a randomized trial. Lancet 2005 ； 3 65 ; p p . 1 2 3 [非專利文獻 7] Lau GK，et al·，Peginterfer on Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N. Engl. J. Med., 2005 ； 3 52 ； p p . 2 6 8 2 [非專利文獻8]各務等，犬山硏討會論文集（ Inuyama Symposium) 2 4 session 3，p.142-146 ( 2003 年 ) 【發明內容】 [發明所欲解決之課題] 本發明所欲解決之課題爲提供一種核酸類似物製劑之 活性增強劑等。 [用於解決課題之方法] 本發明人爲了解決上述課題反覆潛心硏究的結果，發 -8 - 201113023 現選自異白胺酸、白胺酸及纈胺酸之至少一種支鏈胺基酸 會使核酸類似物製劑之活性增強，而完成了本發明。 亦即，本發明如以下所述。 [1 ] 一種具有抗病毒活性的核酸類似物之活性增強劑 ’其特徵爲：含選自異白胺酸、白胺酸及纈胺酸之至少— 種支鏈胺基酸或其鹽； [2]如第[1 ]項所記載之劑，其係對於具有抗病毒活 性的核酸類似物之投予對象而言爲適用的； [3 ]如第[1 ]或[2 ]項所記載之劑，其係在具有抗病毒 活性的核酸類似物之投予前使用； [4] 如第Π]〜[3]項中任一項所記載之劑，其中具有 抗病毒活性的核酸類似物係拉美夫定、克拉夫定、恩替卡 韋或阿德福韋； [5] —種病毒性肝炎之預防或治療劑，係將選自異白 胺酸、白胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、與 具有抗病毒活性的核酸類似物組合而成； [6 ]如第[5 ]項所記載之劑’其中具有抗病毒活性的 核酸類似物係拉美夫定、克拉夫定、恩替卡韋或阿德福韋 t [7 ]如第[5 ]或[6 ]項所記載之劑，其中病毒性肝炎係 B型病毒性肝炎； [8] 一種病毒性肝炎用醫藥，係將選自異白胺酸、白 胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、與具有抗病 毒活性的核酸類似物組合而成； -9 _ 201113023 [9] 如第[8]項所記載之醫藥，其中具有抗病毒活性 的核酸類似物係拉美夫定、克拉夫定、恩替卡韋或阿德福 韋； [10] 如第[8]或[9]項所記載之醫藥，其中病毒性肝炎 係B型病毒性肝炎； [1 1 ] 一種肝儲備功能改善劑，係將選自異白胺酸、 白胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、與具有抗 病毒活性的核酸類似物組合而成； [1 2] —種耐性病毒出現抑制劑，係將選自異白胺酸 、白胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、與具有 抗病毒活性的核酸類似物組合而成； [1 3 ] —種使具有抗病毒活性的核酸類似物之活性增 強之方法，其特徵爲：使用有效量之選自異白胺酸、白胺 酸及纈胺酸之至少一種支鏈胺基酸或其鹽； [14] 一種使具有抗病毒活性的核酸類似物之活性增 強之方法，係包含以下之步驟而成： (1 )將具有抗病毒活性的核酸類似物投予至對象之 步驟； (2)將有效量之選自異白胺酸、白胺酸及纈胺酸之 至少一種支鏈胺基酸或其鹽投予至對象之步驟； [15] 如[14]項所記載之方法，其中步驟（2)比步驟 (1 )先進行； [16] 如[13]〜[15]項之任一項所記載之方法，其中具 有抗病毒活性的核酸類似物係拉美夫定、克拉夫定、恩替 -10- 201113023 卡韋或阿德福韋； [17] —種商業用包裝，係含有：選自異白胺酸、白 胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、及記載了該 支鏈胺基酸或其鹽可使用或應使用於使具有抗病毒活性的 核酸類似物之活性增強，而且記載了該支鏈胺基酸或其鹽 相關說明之記載物； [18] —種預防或治療病毒性肝炎之方法，其特徵爲 :使用選自異白胺酸、白胺酸及纈胺酸之至少一種支鏈胺 基酸或其鹽與具有抗病毒活性的核酸類似物； [19] 一種改善肝儲備功能之方法，其特徵爲：使用 選自異白胺酸、白胺酸及纈胺酸之至少一種支鏈胺基酸或 其鹽與具有抗病毒活性的核酸類似物； [2 0] —種抑制耐性病毒出現之方法，其特徵爲：使 用選自異白胺酸'白胺酸及纈胺酸之至少一種支鏈胺基酸 或其鹽與具有抗病毒活性的核酸類似物。 [發明之效果] 依據本發明，藉由持續投予，可使到達底限的核酸類 似物製劑之活性進一步增強。藉此，相較於單獨使用核酸 類似物製劑的情況，肝儲備功能更爲改善，因此以肝癌爲 首的肝病變治療法的選擇範圍變得更廣，以此觀點看來本 發明爲有效的。 另外，藉由本發明，可得到比以往所存在的核酸類似 物更強效的病毒性肝炎之預防或治療劑、病毒性肝炎治療 -11 - 201113023 用醫藥等。 進一步而言，藉由本發明，可長期安定地 似物製劑之病毒增殖抑制效果。另外，B型肝 患者會有急性惡化、急劇暴發的顧慮，而在發 酸類似物製劑的情況中，預後不良的情形很多 發明特別是在前述急劇暴發前之預防投予中能 不良。另外，在化學療法、免疫療法、移植療 劑或免疫抑制劑時，會有B肝炎病毒急劇增殖 在各療法施行前預·•防投予核酸類—似物製劑時， 有效的。 【實施方式】 本發明之「具有抗病毒活性的核酸類似物 劑（以下記載爲本發明之活性增強劑）」之中 (支鏈胺基酸）的異白胺酸、白胺酸及纈胺酸 用L-型、D-型、DL-型之任一者，而宜爲L-i 更佳爲L-型》 異白胺酸、白胺酸及纈胺酸，不僅分別可 還可採用鹽之形態。鹽之形態亦可列舉酸加成 鹽等，只要是化學上可容許的鹽，可採用任一 由本發明以醫療目的使用的觀點看來，係以選 、白胺酸及纈胺酸作爲醫藥品所容許的鹽爲佳 就分別加成至異白胺酸、白胺酸及纈胺酸 所容許的鹽而言，可列舉例如與酸所形成之鹽 維持核酸類 炎病毒陽性 病後投予核 ，此時，本 夠改善預後 法使用抗癌 的情況，而 本發明亦爲 之活性增強 ，有效成分 ，分別可使 .、DL-型， 爲游離體， 鹽或鹼加成 種形態，而 擇異白胺酸 〇 ，作爲醫藥 ，以及與鹼 -12- 201113023 所形成之鹽。就形成鹽的酸而言，可列舉例如氯化氫 溴酸、硫酸'磷酸等無機酸，或醋酸、乳酸、檸檬酸 石酸、馬來酸、富馬酸或硫酸單甲酯等有機酸。另外 等支鏈胺基酸亦可與鹼形成鹽，就如此的鹼之例子而 可列舉例如鈉、鉀等金屬之氫氧化物，或鈣等金屬之 化物、氨等無機鹼、乙烯二胺、丙烯二胺、乙醇胺、 基乙醇胺、二烷基乙醇胺、二乙醇胺、三乙醇胺等有 〇 就本發明之活性增強劑中使活性增強的「具有抗 活性的核酸類似物」而言，除了已知爲核酸類似物製 效成分之物質以外，只要是具有類似於核酸（核苷） 造，而且具有抗病毒活性的物質，則並未特別受到限 就如此的核酸類似物而言，可列舉例如嘌呤環或嘧啶 具有核酸（核苷）類似構造，而且產生與天然的核苷 競爭性的分子間交互作用，最終而言阻礙病毒的構成 質生合成的物質。如此的物質具體而言，可列舉拉美 (胞嘧啶類似物質）、克拉夫定（嘧啶類似物質）、 卡韋（去氧鳥苷類似物質）、阿德福韋（腺嘌呤類似 )、喜必福（胞嘧啶類似物質）、泰諾福韋（腺嘌呤 物質）、恩曲他濱（胞嘧啶類似物質）等。其中，核 似物宜爲拉美夫定、克拉夫定、恩替卡韋、阿德福韋 佳爲拉美夫定、恩替卡韋、阿德福韋。 另外，在B型慢性肝炎之治療之中，在未滿3 5 患者中，以無藥物（drug free)爲目標，基本上藉由201113023 VI. Description of the Invention: [Technical Field] The present invention relates to a virus which combines an activity enhancer of a nucleic acid analog containing a branched amino acid, a branched amino acid and a nucleic acid analog Hepatitis prevention or treatment agent 'viral hepatitis medicine, etc. [Prior Art] Hepatitis B virus (hereinafter also referred to as "HBV") belongs to the Hepadnavirus family of hepatic viruses (〇rthohepadnavirus), which is a virus that causes hepatitis B, mainly by blood media, mother and child (vertical ), sexual behavior (level) infection. Its persistent infection lacks self-conscious symptoms, but it can cause chronic hepatitis. Then the fibrosis of the liver is slowed down, so that cirrhosis may occur, and even liver cancer may occur. On the other hand, in the case of infection with hepatitis B virus, it is theoretically difficult to completely repel the virus, and antiviral therapy is used to reduce the virus, in order to maintain liver function while inhibiting the occurrence of liver cirrhosis or liver failure, and preventing the occurrence of liver cancer. is very important. Lamivudine is developed as an active ingredient of an antiviral agent for a therapeutic drug of HBV, and is a representative component of a nucleic acid analog preparation having a nucleoside-like structure. Lamivudine is known to initially exhibit an antiviral effect on the AIDS virus, but also exhibits a proliferation inhibitory effect on HBV. The mechanism of action of lamivudine on HBV is that the lamivudine phosphorylated by the triphosphate derivative hinders the reverse transcriptase of HBV and is incorporated into the DNA strand of the virus, thereby causing its elongation to stop (see Non-patent) Document 1). A nucleic acid analog such as Lamebine-5-201113023, which can be used in the form of an oral preparation, has few side effects, and has an antiviral activity equal to or higher than that of interferon. However, in suspending such administration In the case of a nucleic acid analog preparation, there is a problem that the probability of re-proliferation of the virus is high. In order to avoid re-expansion after discontinuation of administration, it is necessary to semi-permanently administer nucleic acid analogs. However, even if administered for a long period of time, the effect is at the apex of the early stage. In addition, resistant viruses are produced due to long-term administration, or medical costs are increased. A number of shortcomings. Furthermore, long-term investment in young people has concerns about the reproductive system. In addition, in the B-type TF inflammation zone, the frequency of activity reduction of hepatitis is naturally observed over time, so especially for young people, early administration and long-term administration of nucleic acid analogs are also available. May become over-medical. From such a point of view, the combination therapy with other drugs is being widely studied as a treatment strategy aimed at drug free and long-term remission (see Non-Patent Document 2). Interferon (hereinafter referred to as "IFN") is a drug that exerts its effects through direct antiviral action and activation of host immunity. Interferon has a variety of side effects such as headache, joint pain, and the like, and the medical expenses are expensive (see Non-Patent Document 3). However, the seroconversion phenomenon or the silencing of viral DNA may continue to occur for a long-term advantage (see Non-Patent Document 4). ), and a powerful choice for long-term relief. However, although the combination of PEG interferon and a nucleic acid analog has an effect of preventing the production of a resistant virus, there is a literature suggesting that the therapeutic effect is not different from the case of using interferon alone (see Non-Patent Documents 5 to 7). Therefore, in addition to IFN, there is a need for a drug that can be used with a nucleic acid analog and that enhances the therapeutic effect -6 - 201113023. It has been reported in the literature that when a branched amino acid is used for IFN therapy, the blood concentration is lowered (see Non-Patent Document 8). Further, it has been reported in the literature that branched-chain amino acids have an effect of enhancing the effect of IFN or attenuating the side effects of IFN (see Patent Document 1). However, the branched amino acid has a function of enhancing the antiviral action of the nucleic acid analog, and has not been clarified until now. [Prior Art Document] [Patent Document 1] [Patent Document 1] International Publication WO2007/01 3677 Booklet [Non-Patent Document] [Non-Patent Document 1] Sato Tatsuo, Rametudine Therapy, Clinical and Medical Treatment of Hepatitis B , June 1999 [Non-Patent Document 2] Nan Youren et al. Evaluation of antiviral therapy targeting persistent silence of type B chronic hepatitis: interferon alone, lamivudine, interferon therapy, digestive organs Section, 42 (4): 41 1-416, 2006 [Non-Patent Document 3] Edited by Iino Noro, the latest treatment of chronic hepatitis (Chinese and Foreign Medicine) pl54 (2001) [Non-Patent Document 4] Van Nunen AB, et al Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B : relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine 201113023 aminotransferase. Gut 2003 ; 52 ; pp . 4 2 0 [Non-Patent Document 5] Marcellin P, Et al., Peginterferon al fa-2 a alone, 1 am i vu dine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis BN Engl J. Med., 2004; 351: pp.1206 [Non-Patent Document 6] Janssen HL, et al., Pegylated interferon a 1 fa - 2 b alone or incombination with lamivudine for HBeAg-positive chronic hepatitis B ; a randomized trial Lancet 2005 ; 3 65 ; pp . 1 2 3 [Non-Patent Document 7] Lau GK, et al·, Peginterfer on Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis BN Engl. J. Med., 2005; 3 52 ; pp . 2 6 8 2 [Non-Patent Document 8] Various services, etc., Inuyama Symposium 2 4 session 3, p. 142-146 (2003) [Summary of the Invention] [Invention Problem to be Solved The problem to be solved by the present invention is to provide an activity enhancer or the like for a nucleic acid analog preparation. [Means for Solving the Problem] In order to solve the above problems, the present inventors have succeeded in researching the results, and the present invention is selected from the group consisting of at least one branched amino acid of isoleucine, leucine and valine. The activity of the nucleic acid analog preparation is enhanced, and the present invention has been completed. That is, the present invention is as follows. [1] An activity enhancer of a nucleic acid analog having antiviral activity, characterized by comprising at least one branched chain amino acid selected from the group consisting of isoleucine, leucine and valine, or a salt thereof; 2] The agent according to the item [1], which is suitable for administration to a nucleic acid analog having antiviral activity; [3] as described in the item [1] or [2] The agent described in any one of the above-mentioned items, wherein the nucleic acid analog having antiviral activity is used in the preparation of the nucleic acid analog having the antiviral activity; Lamivudine, clafidine, entecavir or adefovir; [5] a prophylactic or therapeutic agent for viral hepatitis, which is selected from at least one branch of isoleucine, leucine and valine An amino acid or a salt thereof, which is combined with a nucleic acid analog having antiviral activity; [6] The agent according to the item [5] wherein the nucleic acid analog having antiviral activity is lamivudine or claffle Ding, entecavir or adefovir [7] as described in Item [5] or [6], wherein viral hepatitis is type B viral [8] A medicine for viral hepatitis, which is a combination of at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine, or a salt thereof, and a nucleic acid analog having antiviral activity -9 _ 201113023 [9] The pharmaceutical according to the item [8], wherein the nucleic acid analog having antiviral activity is lamivudine, clafidine, entecavir or adefovir; The medicine described in the item [8] or [9], wherein the viral hepatitis is a type B viral hepatitis; [1 1 ] a liver reserve function improving agent selected from the group consisting of isoleucine, leucine and guanidine At least one branched amino acid of aminic acid or a salt thereof, combined with a nucleic acid analog having antiviral activity; [1 2] an inhibitor of the emergence of a resistant virus, which is selected from the group consisting of isoleucine and amine a method for combining at least one branched amino acid of acid and proline with a salt thereof and a nucleic acid analog having antiviral activity; [13] a method for enhancing activity of a nucleic acid analog having antiviral activity , characterized by: using an effective amount of at least one selected from the group consisting of isoleucine, leucine and proline A branched amino acid or a salt thereof; [14] A method for enhancing the activity of a nucleic acid analog having antiviral activity, comprising the steps of: (1) administering a nucleic acid analog having antiviral activity a step of administering to a subject; (2) a step of administering an effective amount of at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine to a subject thereof; [15] as in [ And the method of any one of [13] to [15], wherein the nucleic acid having antiviral activity is similar to the method described in the item (1). System of lamivudine, clafidine, entefa-10-201113023 kawei or adefovir; [17] a commercial package containing: selected from the group consisting of isoleucine, leucine and lysine At least one branched amino acid or a salt thereof, and the branched amino acid or a salt thereof can be used or used to enhance the activity of a nucleic acid analog having antiviral activity, and the branched amine is described A description of a base acid or a salt thereof; [18] A method for preventing or treating viral hepatitis, characterized by : using at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine, or a salt thereof, and a nucleic acid analog having antiviral activity; [19] a method for improving liver reserve function, characterized by Is: using at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine or a salt thereof and a nucleic acid analog having antiviral activity; [20] a method for inhibiting the appearance of a resistant virus It is characterized in that at least one branched amino acid selected from the group consisting of isoleucin acid and valine acid or a salt thereof and a nucleic acid analog having antiviral activity are used. [Effects of the Invention] According to the present invention, the activity of the nucleic acid analog preparation reaching the bottom limit can be further enhanced by continuous administration. Thereby, the liver reserve function is further improved as compared with the case of using the nucleic acid analog preparation alone, and thus the selection range of liver disease treatment methods including liver cancer becomes wider, and the present invention is effective from the viewpoint of the viewpoint. . Further, according to the present invention, it is possible to obtain a prophylactic or therapeutic agent for viral hepatitis which is more potent than the conventional nucleic acid analog, and a medical treatment for viral hepatitis -11 - 201113023. Further, according to the present invention, the virus growth inhibiting effect of the locus preparation can be stabilized for a long period of time. In addition, patients with type B liver may have acute exacerbations and sharp outbreaks, and in the case of acid analog preparations, many cases of poor prognosis are particularly poor in preventive administration prior to the aforementioned acute outbreak. In addition, in the case of chemotherapy, immunotherapy, transplantation therapy, or immunosuppressive agent, there is a rapid proliferation of hepatitis B virus. It is effective when pre-treatment is performed to prevent the administration of nucleic acid-like preparations. [Embodiment] In the "nucleic acid analog agent having antiviral activity (hereinafter referred to as an activity enhancer of the present invention)" of the present invention (isolated amino acid), leucine, leucine and guanamine The acid is used in any of L-type, D-form, and DL-form, and Li is preferably L-form. Isoleucine, leucine, and valine acid, not only salt but also salt form. The form of the salt may also be an acid addition salt or the like, and any chemically acceptable salt may be used as a pharmaceutical product from the viewpoint of the use of the present invention for medical purposes, and leucine and valine acid. The permissible salts are preferably added to the salts permitted by the isoleucine, leucine, and valine acid, and for example, the nucleus is administered after the nucleic acid-positive disease is maintained by the salt formed with the acid. At this time, it is sufficient to improve the prognosis method to use anti-cancer, and the present invention is also active, and the active ingredients can be respectively made into a form of DL-type, which is a free form, a salt or a base. Bismuth citrate, as a medicine, and a salt formed with base-12-201113023. The acid forming the salt may, for example, be an inorganic acid such as hydrogen chloride bromic acid or sulfuric acid 'phosphoric acid, or an organic acid such as acetic acid, lactic acid, citrate, maleic acid, fumaric acid or monomethyl sulfate. Further, the branched-chain amino acid may form a salt with a base. Examples of such a base include hydroxides of metals such as sodium and potassium, metal compounds such as calcium, inorganic bases such as ammonia, and ethylene diamine. A propylene diamine, an ethanolamine, a basal ethanolamine, a dialkylethanolamine, a diethanolamine, a triethanolamine, etc., in addition to the known "energy-resistant nucleic acid analog" which enhances activity in the activity enhancer of the present invention, In addition to the substance of the nucleic acid analog production component, as long as it is a substance similar to a nucleic acid (nucleoside) and has antiviral activity, the nucleic acid analog is not particularly limited, and examples thereof include an anthracene ring. Or a pyrimidine has a nucleic acid (nucleoside)-like structure and produces an intermolecular interaction that competes with a natural nucleoside, and ultimately a substance that constitutes a qualitative synthesis of the virus. Specific examples of such a substance include Latin America (cytosine-like substance), clafidine (pyrimidine-like substance), calvedic (deoxyguanosine-like substance), adefovir (adenine-like substance), and Xibifu. (cytosine-like substance), tenofovir (adenine), emtricitabine (cytosine-like substance), and the like. Among them, the nuclear substance should be lamivudine, clafidine, entecavir, adefovir, lamivudine, entecavir, adefovir. In addition, among the treatments for type B chronic hepatitis, among the less than 35 patients, the drug free is targeted, basically by
、氫 、酒 ，該 碳氧 單烷 機驗 病毒 劑有 的構 定。 環等 分子 蛋白 夫定 恩替 物質 類似 酸類 ，較 歲的 IFNHydrogen, wine, and the composition of the oxycarbol monoacid test agent. Circulating molecular protein Fuding Entin Substance Similar to acid , older IFN
S -13- 201113023 進行治療，而在35歲以上之患者中，以HBV DNA持續 陰性化爲目標，初次投予的核酸類似物製劑特別是以恩替 卡韋爲佳。另一方面，對於拉美夫定及恩替卡韋耐性株出 現的患者而言，係以合倂投予拉美夫定與阿德福韋爲佳。 本發明之活性增強劑，係基於發現選自異白胺酸、白 胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽會使具有抗病 毒活性的核酸類似物之活性增強而完成。因此本發明亦提 供一種使具有抗病毒活性的核酸類似物之活性增強之方法 ，其特徵爲：使用有效量之選自異白胺酸、白胺酸及纈胺 酸之至少一種支鏈胺基酸或其鹽。此處「有效量」是指後 述本發明之核酸類似物之活性增強劑中之支鏈胺基酸投予 量° 本發明之活性增強劑，只要含有選自異白胺酸、白胺 酸及纈胺酸之至少一種或該等鹽作爲支鏈胺基酸即可，例 如亦可只有異白胺酸，而以異白胺酸、白胺酸、纈胺酸全 部皆包含爲佳。 只要是業界人士，即能夠、因應於投予對象的狀態而 適當地調整如此的支鏈胺基酸之含有比（重量比），而在 例如異白胺酸、白胺酸、纈胺酸全部皆包含的情況，異白 胺酸、白胺酸、纈胺酸之重量比係以1 : 1〜3 : 〇. 5〜2.0 爲更佳。此外，異白胺酸、白胺酸、纈胺酸之重量比係以 1: 1_5〜2.5: 0.8〜1.5爲特佳，最佳重量比爲 1:2:1.2 〇 本發明之活性增強劑亦可進一步含有製劑用擔體。就 -14- 201113023 所使用的製劑用擔體而言，有例如乳糖、葡萄糖、D-甘露 醇、澱粉 '結晶纖維素、碳酸鈣、高嶺土、明膠 '羥丙基 纖維素、羥丙基甲基纖維素、聚乙烯基吡咯烷酮、乙醇、 羧甲基纖維素 '羧甲基纖維素鈣鹽、硬脂酸鎂、滑石、乙 醯基纖維素、白糖、氧化鈦 '安息香酸、對羥安息香酸酯 、脫氫醋酸鈉、阿拉伯膠、黃耆膠、甲基纖維素、蛋黃、 界面活性劑、單糖漿、檸檬酸、蒸餾水、甘油、丙二醇、 聚乙二醇、磷酸一氫鈉、磷酸二氫鈉、磷酸鈉、氯化鈉、 酚、硫柳汞、亞硫酸氫鈉等，該等機能爲業界人士所周知 。該等擔體因應於製劑的形態，以摻合於本發明之活性增 強劑的形式使用。只要是業界人士，即能夠適當地調整該 等製劑用擔體的含量。 只要是業界人士，即能夠考慮投予對象的疾病或對象 的年齡、性別、體重等而適當地調整本發明之活性增強劑 中支鏈胺基酸之摻合量。 本發明之活性增強劑亦可進一步因應於用途而含有支 鏈胺基酸以外的成分，例如胺基酸、糖類、脂肪、微量元 素等成分。 例如在倂發肝性腦病變的HBV陽性患者的情況中， 除了含有支鏈胺基酸（異白胺酸、白胺酸、纈胺酸之重量 比爲1: 0.9〜1.5: 0.7〜1.1)，還可含有支鏈胺基酸以外 的成分，例如離胺酸等胺基酸，或可含有糊精等糖類；米 油、大豆油等脂肪；或維生素類 '鈣 '鈉、鉀等礦質成分 ;鋅、鐵等微量元素。 -15- 201113023 前述倂發肝性腦病變的HBV陽性患者用之活性增強 劑，係以每次含3〜6g的方式摻合支鏈胺基酸，一天投予 3次爲佳。 具體的例子有：含有L-異白胺酸i.9225g、L-白胺酸 2.03 7g、L-離胺酸鹽酸鹽 0.2425g、L-蘇胺酸 0.133g、L-纈胺酸1.602g、L-精胺酸鹽酸鹽〇.3 02g、L-鹽酸組胺酸 0.1875g、L-色胺酸 73.5mg 的「Aminoleban (註冊商標） EN」，或含有L-異白胺酸l,730mg、L-白胺酸2，122mg、 L·離胺酸鹽酸鹽974mg、L-甲硫胺酸117mg、L-苯丙胺酸 117mg、L-蘇胺酸 43 6mg、L-色胺酸 56mg、L-纈胺酸 l，615mg、L-組胺酸 3 06mg、L-精胺酸 l，647mg、L-精胺酸 鹽酸鹽l〇8mg、L-丙胺酸97 8mg、甘胺酸43 0mg、L-脯胺 酸522mg、L-絲胺酸257mg的「HEPAN ED (註冊商標） 」等。 在本發明中「核酸類似物之活性增強」，是指直接增 強核酸類似物治療之中核酸類似物所具有的抗病毒作用。 另外，在其中亦包含使病毒減少的結果所得到的：血 中HBV RNA量之減少、血清蛋白素値之改善、ALT/AST 値之改善、治療時間之縮短、核酸類似物投予量之減少、 核酸類似物治療患者治療效率之顯著改善等。 HBV陽性患者之中，在對倂發惡性腫瘤的患者施行 化學療法的情況，由於病毒的急劇增殖、再活化，而會有 重症、猛暴性肝炎發病的顧慮。投予化學療法劑時，會直 接助長病毒基因的複製，因此可預防性地投予本發明之活 -16" 201113023 性增強劑。另外，藉由使核酸類似物活性增強，具體而言 在一定期間之化學療法之後藉由長期間投予本發明之活性 增強劑，在使HBV-DNA (可藉由PCR法或TMA法監測 的）持續陰性化方面也具有效果。 此處「核酸類似物治療」，是指藉由具有抗病毒活性 的核酸類似物，而發揮抗病毒作用，就結果而言，藉由抑 制病毒的增殖或使病毒減少等而治療病毒性疾病。 藉由核酸類似物治療，在例如病毒性疾病爲病毒性肝 炎的情況，不僅藉由抑制肝炎病毒的增殖或藉由使肝炎病 毒減少而治療病毒性肝炎，進一步而言，在起因於病毒性 肝炎的肝硬化及肝癌方面，對殘存的病毒也會表現出抗病 毒活性，而能夠遲延由病毒性肝炎演變爲肝硬化及肝癌。 因此，本發明之「具有抗病毒活性的核酸類似物之活 性增強劑」不僅可使用於例如病毒性肝炎，還可使用於預 防起因於病毒性肝炎的肝硬化及肝癌，或抑制其演變等用 途。 另外，假如是在由病毒性肝炎演變成肝硬化及肝癌的 情況，對肝癌治療法的選擇，會受到背景的肝病變的肝儲 備功能所限制，因此，重點爲盡可能使肝臟機能恢復而使 其後治療方法選擇範圍變廣。因此本發明之活性增強劑可 與核酸類似物合併，而作爲肝儲備功能之改善劑使用。 「核酸類似物治療」不僅包含使用單一核酸類似物進 行治療的情況，亦包含倂用多數核酸類似物進行治療的情 況’或倂用核酸類似物與其以外的藥劑進行治療的情況。 -17- 201113023 就如此的倂用的例子而言，可列舉例如核酸類似物與國際 公開W02007/0 1 3677號小冊子所記載之IFN作用物質的 組合，或相異核酸類似物彼此的組合。 本發明之活性增強劑，可適用於有核酸類似物投予經 歴的對象。若中止投予核酸類似物，則肝炎病毒增殖的機 率很高，另外，核酸類似物製劑本身的效果也到達了某一 定値的底限（參照例如「臨床與藥物醫療」1999年6月 號’ 5 63頁的圖6 )。在如此的情況下，藉由持續投予核 酸類似物，再加上採用本發明之活性增強劑，能夠使到達 底限的核酸類似物製劑效果進一步增強。 或者，對於將要投予核酸類似物製劑的對象，在投予 核酸類似物之前先投予本發明之活性增強劑，藉此亦能夠 使之後所投予的核酸類似物製劑的效果進一步增強。特別 是在單獨投予核酸類似物製劑的情況，其效果會到達某一 定値的底限，而藉由先投予本發明之活性增強劑，效果到 達底限會受到抑制，而能夠使核酸類似物製劑的效果增強 。此時，希望在投予核酸類似物之後，亦持續投予本發明 之活性增強劑8 關於本發明之活性增強劑開始投予的時期，只要是業 界人士，即能夠適當地選擇得到希望的核酸類似物製劑效 果所需要的適當時期。例如在對於投予對象以每天12g投 予本發明之活性增強劑1年，其後亦相同地投予本發明之 活性增強劑，同時投予核酸類似物製劑例如恩替卡韋水合 物的情況一天投予〇 · 5 m g (以恩替卡韋而計）。 -18- 201113023 就此處的對象而言’並未特別受到限定，能夠以所有 的哺乳動物當作投予對象，而宜爲人類。 本發明之活性增強劑，能夠與上述核酸類似物製劑一 起投予’以作爲醫藥品。該醫藥品相較於過往以核酸類似 物製劑爲有效成分的醫藥品，具有更強的核酸類似物治療 效果。 另外，本發明之活性增強劑’不僅能以上述劑或醫藥 品的投予形態’還能夠以各種形態，例如機能性食品或健 康食品（包含飮料）、特定保健用食品的形式供應。 本發明之活性增強劑，可藉由在食品或飲料之原料添 加支鏈胺基酸而製造’而能夠口服攝取。以機能性食品或 健康食品、特定保健用食品的形式投予本發明之活性增強 劑的情況，該食品本身除了添加支鏈胺基酸以外，調製方 式與通常的飮食品組成物相同。 就如此的飲食品組成物之形態而言，可例示清涼飲料 、碳酸飮料、營養飲料、果汁飲料、乳酸菌飮料等飲料（ 包含該等飮料的濃縮原液及調整用粉末）；冰淇淋、果汁 牛奶凍、刨冰等冰菓；糖、口香糖、糖果、泡泡糖、巧克 力、糖錠、零食點心、餅乾、果凍、果醬、鮮奶油'烘焙 點心等點心類；加工乳、乳飲料、發酵乳、奶油等乳製品 ;麵包；經腸營養食品'流食、育兒用牛乳、運動飲料； 其他機能性食品等。就飲食品的形狀而言，可例示錠、顆 粒狀的補給品等。因此，關於一天膳食量及所攝取的卡路 里之控制，並沒有斟酌與本發明之活性增強劑攝取的關係 -19- £ 201113023 以及其他食品的攝取量而進行控制的必要。另外，預先製 備成飮食品組成物之形態，則可正確地掌握活性增強劑的 攝取量。 只要是業界人士，即能夠考慮投予對象所患的疾病或 對象的年齡、性別、體重等適當地調整該等食品中所含支 鏈胺基酸之量。 就如此的食品之例子而言，可列舉含異白胺酸、白胺 酸、纈胺酸之重量比爲1:2:1之支鏈胺基酸3.2g作爲 活性增強劑，進一步含維生素類與鋅等微量元素，每次服 用量爲4g的顆粒狀食品。另外還可只摻合異白胺酸〇.5〜 3g作爲支鏈胺基酸而調製流食等營養組成物。 另外，本發明還提供一種方法，係基於以下之步驟 (1) 將具有抗病毒活性的核酸類似物投予至對象之 步驟； (2) 將有效量之選自異白胺酸、白胺酸及纈胺酸之 至少一種支鏈胺基酸或其鹽投予至對象之步驟； 而能夠增強具有抗病毒活性的核酸類似物之活性。 此時，希望在持續進行步驟（1)的狀態下進行步驟 (2)。在步驟（1)中，即使持續投予該核酸類似物，其 效果也已經達到頂點，因此在持續進行步驟（1 )的狀態 下進行步驟（2)，藉此使在步驟（1)所投予的該核酸類 似物之活性進一步增強，而能夠更有效地使病毒（例如肝 炎病毒）減少。 或者希望在持續進行上述步驟（2)的狀態下進行步 -20- 201113023 驟（η 。在只進行步驟（1)的情況中，即使持續投予該 核酸類似物，其效果也已經達到頂點，因此先進行步驟（ 2)，在持續進行此步驟的狀態下進行步驟（1)，藉此使 步驟（1 )所投予的該核酸類似物之活性進一步增強，能 夠更有效地使病毒（例如肝炎病毒）減少。 附帶一提，在使已經開始的藉由核酸類似物進行的治 療暫時中斷的情況下，一時減少的病毒再度增生的可能性 很高，因此有必要長期持續投予核酸類似物。然而投予對 象會由於長期持續的投予而經常受到投予核酸類似物導致 副作用的困擾（例如紅血球減少、白血球減少、血小板減 少、抑鬱、意識障礙、再生不良性貧血、呼吸困難、不整 脈、網膜症、發熱、倦怠感、頭痛、食慾不振、毛髮脫落 、關節痛等）。然而藉由採用本·發明之活性增強劑，能夠 以比其單獨使用的情況更少的量得到核酸類似物的同等效 果，因此就結果而言，可使製劑全體中的核酸類似物其本 身的相對投予量減少。所以，在本發明之活性增強劑倂用 核酸類似物的情況，亦可作爲核酸類似物的副作用緩和劑 使用。 進一步而言，藉著採用本發明之活性增強劑，可長期 投予核酸類似物，因此，抵抗性病毒出現的可能性變低。 因此，亦可將本發明之活性增強劑與核酸類似物倂用，以 作爲抵抗性病毒出現之抑制劑使用。 就本發明之核酸類似物治療對象的肝炎病毒而言，可 列舉所有周知的肝炎病毒爲對象，而其中以Β型肝炎病毒 -21 - 201113023 爲佳。 如之前所述，本發明之活性增強劑含有選自異白胺酸 、白胺酸及纈胺酸之至少一種支鏈胺基酸，而基於發現該 等支鏈胺基酸會使核酸類似物之活性增強而完成本發明之 活性增強劑。亦即，將選自異白胺酸、白胺酸及纈胺酸之 至少一種支鏈胺基酸與具有抗病毒活性的核酸類似物加以 組合而成之物，可作爲病毒性肝炎之預防或治療劑使用， 其與單獨的核酸類似物相比，對於病毒性肝炎具有更強的 活性。因此本發明亦提供一種病毒性肝炎之預-防或治療劑 (以下記載爲「本發明之預防或治療劑」），係將選自異 白胺酸 '白胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、 與具有抗病毒活性的核酸類似物組合而成。 本發明之預防或治療劑，只要含有異白胺酸、白胺酸 、纈胺酸中任一種以上的支鏈胺基酸即可，亦可只有例如 異白胺酸，而以異白胺酸、白胺酸、纈胺酸全部皆包含爲 佳。 只要是業界人士，即能夠因應於投予對象的狀態而適 當地調整如此的支鏈胺基酸的含量比（重量比），而異白 胺酸、白胺酸、纈胺酸之重量比係以1 : 1〜3 : 0.5〜2.0 爲更佳。此外，異白胺酸、白胺酸、纈胺酸之重量比爲1 :1.5〜2·5: 〇·8〜1.5爲特佳，最佳重量比爲1:2:1.2 〇 本發明之預防或治療劑亦可進一步含有本發明之活性 增強劑所記載一般的製劑用擔體。只要是業界人士，即能 -22- 201113023 夠適當地調整該等製劑用擔體的含量。 就本發明之預防或治療劑的對象肝炎病毒而言，並未 特別受到限定，可列舉所有周知的肝炎病毒爲對象，而其 中以B型肝炎病毒爲佳。藉著採用本發明之預防或治療劑 ，可預防或者治療起因於該等肝炎病毒的病毒性肝炎。 本發明之預防或治療劑，除了上述支鏈胺基酸及具有 抗病毒活性的核酸類似物以外，亦可含有周知的抗病毒成 分。就如此的抗病毒成分而言，可列舉例如IFN。只要是 業界人士，即能夠適當地調整該抗病毒成分的含量。 本發明之預防或治療劑可藉由使具有抗病毒活性的核 酸類似物之活性增強，抑制病毒性肝炎。具體而言，本發 明之預防或治療劑，可抑制肝炎病毒的增殖，另外，可使 肝炎病毒減少。因此本發明之預防或治療劑亦可與藥理學 所容許的擔體混合，而以病毒性肝炎用醫藥組成物（例如 注射劑、錠劑、顆粒劑、細粒劑、藥粉、膠囊劑、乳膏劑 、栓劑等）的形式利用。該醫藥或醫藥組成物可藉著口服 或非口服（例如局部、直腸、靜脈投予等）的方式投予， 而以藉由口服方式投予爲佳。 就所使用的藥理學容許的擔體而言，有例如乳糖、葡 萄糖、D·甘露醇、澱粉、結晶纖維素、碳酸鈣、高嶺土、 明膠、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯基吡咯 烷酮、乙醇、羧甲基纖維素、羧甲基纖維素鈣鹽、硬脂酸 鎂、滑石、乙醯基纖維素 '白糖、氧化鈦、安息香酸、對 羥安息香酸酯、脫氫醋酸鈉、阿拉伯膠、黃耆膠、甲基纖 -23- 201113023 維素、蛋黃、界面活性劑、單糖漿、檸檬酸、蒸餾水、甘 油、丙二醇、聚乙二醇、磷酸一氫鈉、磷酸二氫鈉、磷酸 鈉、氯化鈉、酚、硫柳汞、亞硫酸氫鈉等’而該等機能已 爲所業界人士周知。該等擔體係因應於製劑的形態，以摻 合於本發明之醫藥或醫藥組成物的形式使用。只要是業界 人士，即能夠適當地調整該等擔體的含量。 在本發明之活性增強劑、副作用緩和劑、預防或治療 劑、醫藥及醫藥組成物等（以下將該等總括記載爲「本發 明之劑、醫藥及醫藥組成物」）之中，支鏈胺基酸之投予 量（攝取量），隨著患者的病態、年齡、投予方法等而有 所不同，而通常每人每天爲異白胺酸0.5〜30.0g'白胺酸 1.0〜60.0g、纈胺酸0.5〜30.Og。一般成人的情況，宜爲 每人每天爲異白胺酸2.0〜l〇.〇g、白胺酸3.0〜20.0g、纈 胺酸2.0〜lO.Og、較佳爲異白胺酸2.5〜3.5g、白胺酸5.0 〜7.〇g、纈胺酸3.0〜4.0g。在上述本發明之劑、醫藥及 醫藥組成物之中，異白胺酸、白胺酸、纈胺酸全部皆包含 的情況，成人每天的投予量爲3種支鏈胺基酸的合計量通 常以2.0〜50.0g左右爲佳，因應必要將其分成1〜6次投 予（宜爲1〜3次）。 相對於此，核酸類似物的投予量，隨著投予的核酸類 似物種類、患者的病態、年齡、投予方法等各種條件而有 所不同，而成人1天的量通常爲O.Olmg〜100mg左右， 宜爲0.1 mg〜10Omg左右。特別是在腎機能障礙患者（進 行血液透析的患者等）的情況有必要減少其投予量，成人 -24- 201113023 1天的量爲〇.〇lmg〜1〇mg左右。 例如B型肝炎病毒陽性之患者群中，沒有罹患肝癌的 肝硬化患者之中’一天—次在空腹時投予恩替卡韋水合物 0.5mg (以恩替卡韋而計）（而且3種支鏈胺基酸全部皆 包含的胺基酸製劑（以支鏈胺基酸量而計一次3〜4g) — 天分別投予3次）爲佳。 在本發明之劑、醫藥及醫藥組成物之中，支鏈胺基酸 及核酸類似物可分別製成各個製劑，以相同或相異投予形 態投予，或可將支鏈胺基酸與核酸類似物，以包含於相同 製劑中的摻合劑形式進行投予。在支鏈胺基酸與核酸類似 物爲各個不同製劑的情況，或在摻合於相同製劑中的情況 ，上述本發明之劑、醫藥及醫藥組成物中每次投予的支鏈 胺基酸之摻合量通常定爲〇·5〜50.0g左右，宜爲1.0〜 20-〇g左右、較佳爲2.0〜6.0g左右。另外，每次投予的 核酸類似物之摻合量，依照各個藥劑而設定。 例如B型肝炎病毒陽性之患者群中，沒有罹患肝癌的 肝硬化患者之中，一天一次在空腹時投予恩替卡韋水合物 〇.5mg (以恩替卡韋而，計）的情況，3種支鏈胺基酸全部 包含的胺基酸製劑每次投予的支鏈胺基酸量爲3〜4g (宜 將其一天投予三次）。 在上述本發明之劑、醫藥及醫藥組成物之中，將支鏈 胺基酸與本發明之核酸類似物的各個製劑合倂投予的情況 ，就該合倂投予的順序而言，並未受到特別限定，而只要 是業界人士，即能夠依照能得到適當核酸類似物投予效果 -25- 201113023 的投予劑形、投予方法等而選擇適當的順序與時間差。 就投予順序與時間差的例子而言，可列舉例如在先投 予支鏈胺基酸的情況，投予支鏈胺基酸之後，5分鐘〜2 年以內投予核酸類似物的方法。另一方面，還可列舉在先 投予核酸類似物的情況，投予核酸類似物之後，在例如5 分鐘〜2年以內投予支鏈胺基酸的方法。 在先投予支鏈胺基酸的情況，希望爲在核酸類似物開 始投予之後，持續投予支鏈胺基酸。另一方面，在先投予 核酸類似物的情況，希望依照各個製劑附加文件所記載的 配方持續投予核酸類似物，另外，希望在支鏈胺基酸開始 投予之後，持續核酸類似物之投予。 在針對本發明之劑、醫藥及醫藥組成物中有效成分的 支鏈胺基酸算出其投予量（攝取量）時，本發明之目的； 疾病之預防、治療等目的所使用的藥劑等有效成分而言， 係以前述的方式決定每次投予的摻合量的範圍，因此關於 與本發明相異之目的，例如因爲通常的飮食生活的需要， 或治療其他疾病之目的而攝取或投予的支鏈胺基酸，並沒 有必要使其包含於前述摻合量。例如，沒有必要將通常的 飲食生活一天所攝取的支鏈胺基酸之量由前述本發明中之 有效成分一天的投予量扣除計算。 另外，本發明提供一種商業用包裝，係含有：選自異 白胺酸、白胺酸及纈胺酸之至少一種支鏈胺基酸或其鹽、 及記載了該支鏈胺基酸或其鹽可使用或應使用於使具有抗 病毒活性的核酸類似物之活性增強，而且記載了該支鏈胺 -26- 201113023 基酸或其鹽相關說明之記載物。 [實施例] 接下來，藉由實施例對本發明作進一步詳細地敘述。 另外，以下的實施例，係針對本發明的一例具體地說明， 而本發明不受其所限定。 實施例1 :核酸類似物製劑與本發明之活性增強劑的倂用 效果（1 ) (方法） 對於儘管進行充足的膳食攝取，仍呈現低蛋白素血症 的非代償性肝硬化患者而且B型肝炎病毒陽性之患者，以 1次1包、1天3次，在餐後口服投予異白胺酸、白胺酸 、纈胺酸之重量比爲1: 2: 1.2(異白胺酸：0.952g、白 胺酸：1.904g、纈胺酸：1.144g )的支鏈胺基酸製劑 Livact (註冊商標）顆粒（味之素股份有限公司），並逐 曰測定血清蛋白素値、AST及ALT値的變化。關於其結 果，按照抗病毒化學療法劑的拉美夫定（製品名：Zefix (註冊商標）錠、製造販賣之公司：GlaxoSmithKline股 份有限公司）處方經歴的有無分成2群進行解析。將前述 兩群患者背景揭示於表1。S -13- 201113023 is treated, and in patients over 35 years of age, with the goal of persistent negative HBV DNA, the first dose of nucleic acid analogs is preferably entecavir. On the other hand, for patients with ramivudine and entecavir resistant strains, it is preferred to administer lamivudine and adefovir. The activity enhancer of the present invention is based on the discovery that at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine or a salt thereof enhances the activity of the nucleic acid analog having antiviral activity. . The invention therefore also provides a method of enhancing the activity of a nucleic acid analog having antiviral activity, characterized by the use of an effective amount of at least one branched amine group selected from the group consisting of isoleucine, leucine and valine. Acid or its salt. Here, the "effective amount" means the amount of the branched amino acid to be administered in the activity enhancer of the nucleic acid analog of the present invention, and the activity enhancer of the present invention, as long as it contains a selected from the group consisting of isoleucine and leucine At least one of the proline acids or the salts may be used as the branched amino acid. For example, it may be only isoleucine, and all of the isoleucine, leucine and valine may be contained. As long as it is a person in the industry, it is possible to appropriately adjust the content ratio (weight ratio) of such a branched amino acid in accordance with the state of the target to be administered, and for example, all of methionine, leucine, and lysine. In the case of inclusion, the weight ratio of isoleucine, leucine, and valine is preferably 1: 1 to 3: 〇. 5 to 2.0. In addition, the weight ratio of isoleucine, leucine, and valine is particularly preferably 1:1_5~2.5: 0.8~1.5, and the optimum weight ratio is 1:2:1.2. The activity enhancer of the present invention is also Further, a carrier for preparation may be further contained. For the formulation carrier used in the period of-14-201113023, there are, for example, lactose, glucose, D-mannitol, starch 'crystalline cellulose, calcium carbonate, kaolin, gelatin 'hydroxypropyl cellulose, hydroxypropyl methyl group Cellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose 'carboxymethylcellulose calcium salt, magnesium stearate, talc, acetamyl cellulose, white sugar, titanium oxide 'benzoin acid, hydroxybenzoic acid ester , sodium dehydroacetate, gum arabic, tragacanth, methyl cellulose, egg yolk, surfactant, monosaccharide syrup, citric acid, distilled water, glycerin, propylene glycol, polyethylene glycol, sodium monohydrogen phosphate, sodium dihydrogen phosphate , sodium phosphate, sodium chloride, phenol, thimerosal, sodium hydrogen sulfite, etc., are well known in the industry. These supports are used in the form of an active reinforcing agent to be blended in the present invention in accordance with the form of the preparation. As long as it is an industrial person, the content of the preparation carrier can be appropriately adjusted. As long as it is an industrial person, the blending amount of the branched chain amino acid in the activity enhancer of the present invention can be appropriately adjusted in consideration of the disease, the age, the sex, the body weight, and the like of the subject to be administered. The activity enhancer of the present invention may further contain a component other than a branched amino acid, such as an amino acid, a saccharide, a fat, or a trace element, depending on the use. For example, in the case of HBV-positive patients with hepatic encephalopathy, in addition to the content of branched amino acids (isoleucine, leucine, and valine acid: 1: 0.9 to 1.5: 0.7 to 1.1) Further, it may contain a component other than a branched amino acid, for example, an amino acid such as an amine acid, or may contain a sugar such as dextrin; a fat such as rice oil or soybean oil; or a mineral component such as a vitamin 'sodium' or potassium. ; trace elements such as zinc and iron. -15- 201113023 The above-mentioned activity enhancer for HBV-positive patients with hepatic encephalopathy is preferably mixed with branched-chain amino acid in a manner of 3 to 6 g each time, preferably 3 times a day. Specific examples include: L. isoleucine i. 9225 g, L-leucine 2.03 7 g, L-isoamine hydrochloride 0.2425 g, L-threonine 0.133 g, L-valine acid 1.602 g , L-spermine hydrochloride 〇.3 02g, L-histidine hydrochloride 0.1875g, L-tryptophan 73.5mg of "Aminoleban (registered trademark) EN", or contain L-isoleucine l, 730 mg, L-leucine 2,122 mg, L·isoamine hydrochloride 974 mg, L-methionine 117 mg, L-phenylalanine 117 mg, L-threonate 43 6 mg, L-tryptophan 56 mg, L-proline acid 1,615 mg, L-histidine 3 06 mg, L-arginine 1,647 mg, L-spermine hydrochloride l 8 mg, L-alanine 97 8 mg, glycine 43 0 mg "HEPAN ED (registered trademark)" of 522 mg of L-proline and 257 mg of L-serine. In the present invention, "enhanced activity of a nucleic acid analog" means directly enhancing the antiviral action of a nucleic acid analog in the treatment of a nucleic acid analog. In addition, it also includes the results of reducing the virus: a decrease in the amount of HBV RNA in the blood, an improvement in serum albumin oxime, an improvement in ALT/AST 値, a shortened treatment time, and a decrease in the amount of nucleic acid analog administered. , nucleic acid analogs to treat patients with significant improvements in treatment efficiency, and the like. Among HBV-positive patients, in the case of chemotherapy for patients with malignant tumors, there is a concern about the onset of severe and violent hepatitis due to rapid proliferation and reactivation of the virus. When a chemotherapeutic agent is administered, the replication of the viral gene is directly promoted, so that the present invention can be administered prophylactically -16 " 201113023 sexual enhancer. In addition, by increasing the activity of the nucleic acid analog, in particular by administering the activity enhancer of the present invention for a long period of time after chemotherapy for a certain period of time, the HBV-DNA (which can be monitored by PCR or TMA) ) It also has an effect on continuous negatives. Here, "nucleic acid analog treatment" means that an antiviral action is exerted by a nucleic acid analog having antiviral activity, and as a result, a viral disease is treated by inhibiting proliferation of a virus or reducing a virus. By treating with a nucleic acid analog, for example, in the case where the viral disease is viral hepatitis, viral hepatitis is treated not only by inhibiting the proliferation of hepatitis virus or by reducing the hepatitis virus, but further, due to viral hepatitis. In terms of cirrhosis and liver cancer, it also exhibits antiviral activity against residual viruses, and can delay the progression from viral hepatitis to cirrhosis and liver cancer. Therefore, the "environment enhancer for nucleic acid analog having antiviral activity" of the present invention can be used not only for, for example, viral hepatitis, but also for preventing liver cirrhosis and liver cancer caused by viral hepatitis, or inhibiting the evolution thereof. . In addition, if it is changed from viral hepatitis to cirrhosis and liver cancer, the choice of liver cancer treatment will be limited by the liver reserve function of the background liver disease. Therefore, the focus is on recovering liver function as much as possible. Subsequent treatment options have become wider. Therefore, the activity enhancer of the present invention can be combined with a nucleic acid analog and used as an agent for improving liver reserve function. The "nucleic acid analog treatment" includes not only the case of treatment with a single nucleic acid analog, but also the case of treatment with a plurality of nucleic acid analogs or treatment with a nucleic acid analog and other agents. -17- 201113023 As an example of such an application, for example, a combination of a nucleic acid analog and an IFN-acting substance described in the pamphlet of International Publication WO2007/0 1 3677, or a combination of different nucleic acid analogs can be cited. The activity enhancer of the present invention is applicable to a subject having a nucleic acid analog administered to a wart. If the administration of the nucleic acid analog is suspended, the probability of proliferation of the hepatitis virus is high, and the effect of the nucleic acid analog preparation itself reaches a certain threshold (see, for example, "Clinical and Pharmaceutical Health" June 1999 issue" 5 Figure 6 on page 63). In such a case, by continuously administering the nucleic acid analog, in combination with the activity enhancer of the present invention, the effect of the nucleic acid analog preparation reaching the limit can be further enhanced. Alternatively, for a subject to be administered a nucleic acid analog preparation, the activity enhancer of the present invention is administered prior to administration of the nucleic acid analog, whereby the effect of the nucleic acid analog preparation to be administered later can be further enhanced. In particular, in the case of administering a nucleic acid analog preparation alone, the effect may reach a certain threshold, and by first administering the activity enhancer of the present invention, the effect reaches the bottom limit and the nucleic acid is similar. The effect of the preparation is enhanced. At this time, it is desirable to continue to administer the activity enhancer 8 of the present invention after administration of the nucleic acid analog. With regard to the period in which the activity enhancer of the present invention is administered, as long as it is an industrial person, the desired nucleic acid can be appropriately selected. The appropriate period of time required for the effect of the analog formulation. For example, the activity enhancer of the present invention is administered to the subject for administration for 12 years per day for 12 years, and thereafter the activity enhancer of the present invention is administered in the same manner, and the administration of the nucleic acid analog preparation such as entecavir hydrate is administered one day. 〇· 5 mg (based on entecavir). -18- 201113023 The subject here is not particularly limited and can be used as a target for all mammals, but should be human. The activity enhancer of the present invention can be administered as a pharmaceutical together with the above-mentioned nucleic acid analog preparation. This pharmaceutical product has a stronger therapeutic effect on nucleic acid analogs than a pharmaceutical product which has been used as an active ingredient in a nucleic acid analog preparation. Further, the activity enhancer of the present invention can be supplied not only in the form of administration of the above-mentioned agent or pharmaceutical product but also in various forms such as a functional food or a health food (including a dip) or a specific health food. The activity enhancer of the present invention can be produced orally by adding a branched amino acid to a raw material of a food or beverage. In the case where the activity enhancer of the present invention is administered in the form of a functional food or a health food or a specific health food, the food itself is prepared in the same manner as the usual mash food composition except for the addition of the branched amino acid. For the form of the food and beverage composition, a beverage such as a refreshing beverage, a carbonated beverage, a nutritional beverage, a fruit juice beverage, or a lactic acid bacteria beverage (a concentrated stock solution containing the same and a powder for conditioning); ice cream, sherbet, and Ice fruit such as shaved ice; sugar, chewing gum, candy, bubble gum, chocolate, sugar ingots, snacks, biscuits, jellies, jams, whipped cream, baking snacks, etc.; processed dairy products, milk drinks, fermented milk, cream and other dairy products; Bread; enteral nutrition food 'flow food, milk for child care, sports drinks; other functional foods. The shape of the food or drink may, for example, be an ingot or a granular supply. Therefore, the control of the daily meal amount and the calorie intake is not necessary to control the relationship with the intake of the activity enhancer of the present invention -19- £201113023 and the intake of other foods. Further, by preparing the form of the mash composition in advance, the amount of the activity enhancer can be accurately grasped. As long as it is an industrial person, it is possible to appropriately adjust the amount of branched amino acids contained in the foods in consideration of the disease, the age, sex, body weight, and the like of the subject. As an example of such a food, 3.2 g of a branched amino acid having a weight ratio of isoleucine, leucine, and valine acid of 1:2:1 is used as an activity enhancer, and further contains a vitamin. With a trace element such as zinc, the amount of granular food is 4g per dose. Further, it is also possible to mix only 5 to 3 g of isoleucinate as a branched amino acid to prepare a nutrient composition such as a liquid food. Further, the present invention provides a method of administering a nucleic acid analog having antiviral activity to a subject based on the following step (1); (2) an effective amount selected from the group consisting of isoleucine and leucine And the step of administering at least one branched amino acid of proline to the subject thereof; and enhancing the activity of the nucleic acid analog having antiviral activity. At this time, it is desirable to carry out the step (2) while the step (1) is continued. In the step (1), even if the nucleic acid analog is continuously administered, the effect has reached the apex, so the step (2) is carried out while the step (1) is continued, whereby the step (1) is administered. The activity of the nucleic acid analog is further enhanced to more effectively reduce the virus (e.g., hepatitis virus). Alternatively, it is desirable to carry out step -20-201113023 (η in the state in which the above step (2) is continued. In the case where only step (1) is carried out, even if the nucleic acid analog is continuously administered, the effect has reached a peak. Therefore, the step (2) is carried out first, and the step (1) is carried out while the step is continued, whereby the activity of the nucleic acid analog administered in the step (1) is further enhanced, and the virus can be more effectively made (for example). In addition, in the case of temporarily interrupting the treatment of the already started nucleic acid analog, the possibility of re-proliferation of the virus is high, and it is necessary to continue to administer the nucleic acid analog for a long period of time. However, the subject is often plagued by side effects caused by the administration of nucleic acid analogs due to long-term continuous administration (eg, red blood cell reduction, leukopenia, thrombocytopenia, depression, disturbance of consciousness, dysplastic anemia, difficulty breathing, incomplete veins, Omental disease, fever, burnout, headache, loss of appetite, hair loss, joint pain, etc.) The activity enhancer of the present invention can obtain the same effect as the nucleic acid analog in a smaller amount than in the case of using it alone, and as a result, the relative dose of the nucleic acid analog itself in the entire preparation can be reduced. Therefore, in the case of using the nucleic acid analog of the activity enhancer of the present invention, it can also be used as a side effect mitigating agent for the nucleic acid analog. Further, by using the activity enhancer of the present invention, the nucleic acid analog can be administered for a long period of time. Therefore, the possibility of the emergence of a resistant virus becomes low. Therefore, the activity enhancer of the present invention can also be used as a suppressor of the presence of a nucleic acid analog as an inhibitor of the emergence of a resistant virus. The hepatitis virus of the subject may be exemplified by all known hepatitis viruses, and among them, hepatitis A virus-21 - 201113023 is preferred. As described above, the activity enhancer of the present invention contains a substance selected from the group consisting of isoleucine, At least one branched amino acid of leucine and valine, based on the discovery that the branched amino acids enhance the activity of the nucleic acid analog An activity enhancer of the present invention, that is, a combination of at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine and a nucleic acid analog having antiviral activity, As a prophylactic or therapeutic agent for viral hepatitis, it is more active against viral hepatitis than a nucleic acid analog alone. Therefore, the present invention also provides a pre-anti- or anti-therapeutic agent for viral hepatitis (described below) The "prophylactic or therapeutic agent of the present invention" is a combination of at least one branched amino acid selected from the group consisting of isoleucin acid and valine and a salt thereof, and a nucleic acid analog having antiviral activity. The prophylactic or therapeutic agent of the present invention may contain any branched or branched amino acid of at least one of isoleucine, leucine and valine, and may be, for example, iso-amino acid. All of leucine, leucine and valine are preferred. As long as it is an industrial person, it is possible to appropriately adjust the content ratio (weight ratio) of such branched amino acids in accordance with the state of the target, and the weight ratio of isoleucine, leucine, and valine Take 1: 1~3: 0.5~2.0 for better. In addition, the weight ratio of isoleucine, leucine and valine is 1:1.5~2·5: 〇·8~1.5 is particularly good, and the optimum weight ratio is 1:2:1.2 〇Prevention of the present invention The therapeutic agent may further contain a general formulation carrier described in the activity enhancer of the present invention. As long as it is a person in the industry, it is possible to adjust the content of the carrier for these preparations appropriately -22-201113023. The hepatitis virus which is a prophylactic or therapeutic agent of the present invention is not particularly limited, and all known hepatitis viruses are exemplified, and hepatitis B virus is preferred. By using the prophylactic or therapeutic agent of the present invention, viral hepatitis caused by such hepatitis viruses can be prevented or treated. The prophylactic or therapeutic agent of the present invention may contain a well-known antiviral component in addition to the above-mentioned branched amino acid and a nucleic acid analog having antiviral activity. As such an antiviral component, for example, IFN can be mentioned. As long as it is an industry person, the content of the antiviral component can be appropriately adjusted. The prophylactic or therapeutic agent of the present invention can inhibit viral hepatitis by enhancing the activity of a nucleic acid analog having antiviral activity. Specifically, the prophylactic or therapeutic agent of the present invention can inhibit the proliferation of hepatitis virus and can reduce the hepatitis virus. Therefore, the prophylactic or therapeutic agent of the present invention may be mixed with a pharmacologically acceptable carrier, and a pharmaceutical composition for viral hepatitis (for example, an injection, a granule, a granule, a fine granule, a powder, a capsule, or a cream) , the use of the form of suppositories, etc.). The pharmaceutical or pharmaceutical composition can be administered orally or parenterally (e.g., topically, rectally, intravenously, etc.), preferably by oral administration. As the pharmacologically acceptable carrier to be used, there are, for example, lactose, glucose, D. mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose. , polyvinylpyrrolidone, ethanol, carboxymethyl cellulose, carboxymethyl cellulose calcium salt, magnesium stearate, talc, ethyl ketone cellulose 'white sugar, titanium oxide, benzoic acid, hydroxybenzoic acid ester, off Sodium hydroacetate, gum arabic, tragacanth, methyl fiber-23- 201113023 Vitamin, egg yolk, surfactant, monosaccharide syrup, citric acid, distilled water, glycerin, propylene glycol, polyethylene glycol, sodium monohydrogen phosphate, phosphoric acid Such functions as sodium dihydrogen, sodium phosphate, sodium chloride, phenol, thimerosal, sodium hydrogen sulfite, etc. have been known to those skilled in the art. These systems are used in the form of a pharmaceutical or pharmaceutical composition of the present invention depending on the form of the preparation. As long as it is an industrial person, the contents of the supports can be appropriately adjusted. In the case of the activity enhancer, the side effect mitigator, the prophylactic or therapeutic agent, the pharmaceutical and the pharmaceutical composition of the present invention (hereinafter referred to as "the agent, the pharmaceutical and the pharmaceutical composition of the present invention"), the branched amine The amount of base acid to be administered (intake amount) varies depending on the morbidity, age, administration method, etc. of the patient, and is usually 0.5 to 30.0 g of leucine 0.5 to 60.0 g per person per day. , valine acid 0.5~30.Og. In the case of an adult, it is preferably 2.0 to 1 〇g of leucine, 3.8 to 20.0 g of leucine, 2.0 to 10 g of valine, preferably 2.5 to 3.5 of isoleucine per person per day. g, leucine 5.0 to 7. 〇g, valine acid 3.0 to 4.0 g. In the above-mentioned agent, pharmaceutical, and pharmaceutical composition of the present invention, all of the isoleucine, leucine, and lysine are contained, and the daily dose of the adult is the total amount of the three branched amino acids. Usually, it is preferably about 2.0 to 50.0 g, and it is divided into 1 to 6 times (preferably 1 to 3 times) as necessary. In contrast, the administration amount of the nucleic acid analog varies depending on various types of the nucleic acid analog to be administered, the pathology of the patient, the age, the administration method, and the like, and the amount of the adult one day is usually O.Oml. ~100mg or so, preferably about 0.1 mg~10Omg. Especially in patients with renal dysfunction (patients undergoing hemodialysis, etc.), it is necessary to reduce the amount of administration. The amount of adult -24-201113023 for one day is about 〇.1mg~1〇mg. For example, among patients with hepatitis B virus-positive disease, among patients with cirrhosis who do not have liver cancer, one day-time, on the fasting, 0.5 mg of entecavir hydrate (based on entecavir) (and all three branched-chain amino acids) It is preferred that all of the amino acid preparations (3 to 4 g in terms of the amount of branched amino acid) are administered three times a day. In the agent, the pharmaceutical and the pharmaceutical composition of the present invention, the branched amino acid and the nucleic acid analog may be separately prepared into individual preparations, administered in the same or different administration form, or the branched amino acid may be Nucleic acid analogs are administered as a blending agent contained in the same formulation. In the case where the branched amino acid and the nucleic acid analog are each a different preparation, or in the case of being blended in the same preparation, the branched amino acid administered per time in the above-mentioned agent, pharmaceutical and pharmaceutical composition of the present invention The blending amount is usually about 〜5 to 50.0 g, preferably about 1.0 to 20-〇g, preferably about 2.0 to 6.0 g. Further, the amount of the nucleic acid analog administered per administration is set in accordance with each agent. For example, among patients with hepatitis B virus-positive disease, among patients with liver cirrhosis who do not have liver cancer, once a day, entecavir hydrate 〇. 5 mg (in entecavir) is administered on an empty stomach, and three kinds of branched amino groups are used. The amount of branched amino acid administered per time for the acid-containing acid preparation contained in the acid is 3 to 4 g (it is preferable to administer it three times a day). In the above-mentioned agent, pharmaceutical, and pharmaceutical composition of the present invention, a case where a branched amino acid is combined with each of the preparations of the nucleic acid analog of the present invention, in terms of the order in which the combination is administered, It is not particularly limited, and as long as it is an industrial person, an appropriate order and time difference can be selected in accordance with an administration form, a administration method, and the like which can obtain an appropriate nucleic acid analog administration effect-25-201113023. Examples of the administration sequence and the time difference include a method of administering a nucleic acid analog within 5 minutes to 2 years after administration of a branched amino acid, for example, when a branched amino acid is administered first. On the other hand, a method of administering a branched-chain amino acid, for example, within 5 minutes to 2 years after administration of the nucleic acid analog, in the case where the nucleic acid analog is administered first, may be mentioned. In the case where a branched amino acid is administered first, it is desirable to continuously administer a branched amino acid after the start of administration of the nucleic acid analog. On the other hand, in the case of first administering a nucleic acid analog, it is desirable to continuously administer the nucleic acid analog according to the formulation described in the attached file of each preparation, and further, it is desirable to continue the nucleic acid analog after the start of administration of the branched amino acid. Cast. When the dosage (intake amount) of the branched-chain amino acid of the active ingredient of the agent, the pharmaceutical, and the pharmaceutical composition of the present invention is calculated, the object of the present invention is effective, and the agent used for the purpose of prevention, treatment, and the like of the disease is effective. In terms of ingredients, the range of blending amount per administration is determined in the manner described above, and thus for purposes different from the present invention, for example, for the purpose of normal foraging life, or for the purpose of treating other diseases, or The branched chain amino acid to be administered is not necessarily included in the aforementioned blending amount. For example, it is not necessary to calculate the amount of branched-chain amino acid taken in a day of normal eating life from the amount of administration of the active ingredient in the present invention for one day. Further, the present invention provides a commercial package comprising: at least one branched amino acid selected from the group consisting of isoleucine, leucine and valine, or a salt thereof, and the branched amino acid or The salt may be used or used to enhance the activity of the nucleic acid analog having antiviral activity, and the description of the branched chain amine-26-201113023 base acid or its salt is described. [Examples] Next, the present invention will be described in further detail by way of examples. Further, the following examples are specifically described with reference to an example of the present invention, and the present invention is not limited thereto. Example 1: The effect of the nucleic acid analog preparation and the activity enhancer of the present invention (1) (Method) For patients with non-compensated cirrhosis who exhibit hypoproteinemia despite adequate dietary intake and type B Hepatitis virus-positive patients were given 1 packet, 3 times a day, and the ratio of isoleucine, leucine, and valine was orally administered after meal: 1: 2: 1.2 (isoleucine: 0.952g, leucine: 1.904g, proline: 1.144g) branched-chain amino acid preparation Livact (registered trademark) granules (Ajinomoto Co., Ltd.), and sputum determination of serum albumin 値, AST and Changes in ALT値. Regarding the results, the prescription of the antiviral chemotherapeutic agent of the lamivudine (product name: Zefix (registered trademark) ingot, manufacturing and selling company: GlaxoSmithKline Co., Ltd.) was divided into two groups for analysis. The background of the above two groups of patients is disclosed in Table 1.
S -27- 201113023 [表i] 表1 : B型肝炎病毒陽性之非代償性肝硬化患者背景 投予Livact顆粒的患者 投予Livact顆粒的患者 (無拉美夫定處方的經歴） (有拉美夫定處方的經歴） 188例(平均士SD) 3ό例(平均士SD) 年齡 60±10 56+9 性別(男性/女性） 130/58 22/14 血清蛋白素(g/dL) 3.1 ±0.4 3.2±0.4 血小板數(xlO4/" L) 9.4±7.3 7.5±41 AST(IU/L) 62±37 92±93 ALT(IU/L) 47±28 75±66 圖1表示，關於表1所揭示的兩患者群的血清蛋白素 値’以開始投予Li vact顆粒前之値爲基準，將經過6、12 、1 8、24個月後的變化量（各個經過後之値一投予開始 前之値）描點作圖。圖2表示AST之變化量。圖3表示 將ALT之變化量描點作圖。 (結果） 在B型肝炎病毒陽性之非代償性肝硬化患者之中， 藉由持續投予Li vact顆粒，特別是在2年長期投予的期 間，AST、ALT兩測定値皆沒有觀察到增加的傾向，判斷 並未導致病毒的再活化、肝硬化之重症化，而可維持安定 的狀態。另外，藉由投予拉美夫定錠，積極謀求抑制B型 肝炎病毒增殖的情況，若倂用Li vact顆粒，則能夠在長 期間維持AST、ALT的降低效果，血清蛋白素値亦每經過 半年觀察到有上昇的傾向。 -28 - 201113023 實施例2 :核酸類似物製劑與本發明之活性增強劑的倂用 效果（2 ) 針對投予Livact顆粒及/或作爲抗病毒劑投予選自拉 美夫定（「Zefix (註冊商標）」GlaxoSmithKline公司） 、恩替卡韋水合物（「Baraclude (註冊商標）」Bristol-Myers 公司） 及阿德 福韋酯 （ Adefovir pivoxil ， 「S -27- 201113023 [Table i] Table 1: Patients with hepatitis B virus-positive non-compensatory cirrhosis Background Patients who were administered Livact granules to patients with Livact granules (menstrual without Rammed formula) (with Ramie) 184 cases of prescription (average SD) 3 cases (mean SD) Age 60±10 56+9 Sex (male/female) 130/58 22/14 Serum albumin (g/dL) 3.1 ±0.4 3.2 ±0.4 Platelet count (xlO4/" L) 9.4±7.3 7.5±41 AST(IU/L) 62±37 92±93 ALT(IU/L) 47±28 75±66 Figure 1 shows the results disclosed in Table 1. The serum albumin 値 of the two patient groups is based on the sputum before the start of administration of Li vact granules, and the amount of change after 6, 12, 18, and 24 months will be administered before each start. Then) draw a picture. Figure 2 shows the amount of change in AST. Figure 3 shows the plot of the amount of change in ALT. (Results) In patients with non-compensated cirrhosis positive for hepatitis B virus, no increase was observed in both AST and ALT measurements by continuous administration of Li vact particles, especially during the long-term administration period of 2 years. The tendency to judge does not lead to reactivation of the virus and severe cirrhosis, but maintains a stable state. In addition, by administering Lamebine ingots, it is possible to actively suppress the proliferation of hepatitis B virus. If Li vact particles are used, the effect of reducing AST and ALT can be maintained for a long period of time. A tendency to rise was observed. -28 - 201113023 Example 2: The effect of the nucleic acid analog preparation and the activity enhancer of the present invention (2) The administration of Livact granules and/or as an antiviral agent is selected from the group consisting of lamivudine ("Zefix (registered trademark) )" GlaxoSmithKline), entecavir hydrate ("Baraclude (registered trademark)" Bristol-Myers) and adefovir pivoxil ("
Hepsera (註冊商標）」GlaxoSmithKline公司）的核酸類 似物製劑3個月〜12個月的B型肝硬化患者2 0名，藉由 核酸增幅檢查測定血清中之B型肝炎病毒量。 另外，前述20名患者爲肝硬化患者並且肝癌並未發 病。 核酸增幅檢查係因應於患者的病毒量，而藉由PCR 法與 TMA法之任一者進行（測定範圍：2.6〜7.6 log.copies/mL ( PCR 法）、3.7 - 8.7 L G E/m L ( TM A 法）） 。LGE，係意指 Logarithm genome equivalent，實際上意 義與log.copies相同。 算出相對於各患者的倂用前測定値（對於A群（圖4 中的橫紋長條）而言，係在藥劑投予前）的變化量’針對 Livact顆粒之合倂投予對B型肝炎病毒之減少所造成的影 響進行解析。將結果揭示於圖4。在圖4之中，A群係將 由開始單獨投予核酸類似物製劑之後第3、6、1 2個月的 HBV DNA値’減去在開始投予相同製劑之前的相同値所 得到的差値表示於縱軸（n=ll) °B群（圖4中的黑色 -29 - 201113023 長條）係表示以投予Livact顆粒一年之後所測定的HBV DNA値爲基準値，其後持續核酸類似物製劑的合倂投予 時，由病毒量減去基準値的差値（n=3)。（：群（圖4中 的白色長條）係與B群相反地，表示投予核酸類似物製劑 1年之後，合倂投予Livact顆粒的情況之差値。 (患者群） A群：單獨投予核酸類似物製劑的患者群（η=ΐι) B群：投予Livact顆粒1年之後，持續投予Livact 顆粒，同時開始投予核酸類似物製劑，持續合倂投予相同 製劑一年的患者群（n=3)、（：群：單獨投予核酸類似物 製劑1年之後，持續投予相同製劑，同時開始投予Livact 顆粒，持續合倂投予Livact顆粒1年的患者群（n=6) 〇 如圖4所示般，在單獨投予核酸類似物製劑的情況， 投予同製劑3個月病毒量即降低，而即使持續投予1年其 效果也沒有顯著增加。另一方面，在投予Livact顆粒1 年的患者中’在投予核酸類似物製劑的B群的情況，與核 酸類似物製劑單獨投予相比，認爲病毒量有容易降低的傾 向，另外，若合倂投予期間變爲1年，則觀察到其降低量 維持一定或甚至病毒量更爲降低的傾向。若觀察C群則發 現，在核酸類似物的病毒減低效果出現之後，即使倂用 Livact顆粒也並未觀察到病毒量大幅減低的效果，而持續 -30- 201113023 投予Livact顆粒1年，則與倂用3個月的時間點相比 觀察到病毒量有降低的傾向。 [產業上之可利用性] 依據本發明’藉由持續投予，可使到達底限的核酸類 似物製劑之活性進一步增強。藉此，相較於單獨使用核酸 類似物製劑的情況，肝儲備功能更爲改善，因此以肝癌爲 首的肝病變治療法的選擇範圍變得更廣，以此觀點看來本 發明爲有效的。 另外’藉由本發明，可得到比以往存在的核酸類似物 更強效的病毒性肝炎之預防或治療劑、病毒性肝炎治療用 醫藥等。 進一步而言，藉由本發明，可長期間安定地維持核酸 類似物製劑之病毒增殖抑制效果。另外，B型肝炎病毒陽 性患者會有急性惡化、急劇暴發的顧慮，而在發病後投予 核酸類似物製劑的情況中，預後不良的情形很多，此時， 本發明特別是在前述急劇暴發前之預防投予中能夠改善預 後不良。另外，在化學療法、免疫療法、移植療法時，若 使用抗癌劑或免疫抑制劑，則會有B肝炎病毒急劇增殖的 情況，而在各療法施行前預防投予核酸類似物製劑時，本 發明亦爲有效的。 6P3 本申請係以在日本申請的日本特願20 09-150296 (申 請日：2009年6月24日）及日本特願2010-040423 (申 日：2010年2月25日）爲基礎，該等內容全部被包含 £ -31 - 201113023 在本說明書中。 【圖式簡單說明】 圖1係表示Livact顆粒開始投予之後血清蛋白素値 的變化量。白點表示沒有拉美夫定處方經歴之群，黑點表 示有拉美夫定處方經歴之群。 圖2係表示Livact顆粒開始投予之後AST値的變化 量。白點表示沒有拉美夫定處方經歴之群，黑點表示有拉 美夫定處方經歴之群。 圖3係表示Livact顆粒開始投予之後ALT値的變化 量。白點表示沒有拉美夫定處方經歴之群，黑點表示有拉 美夫定處方經歴之群。 圖4係表示Livact顆粒與核酸類似物製劑合倂投予 的情況之血清中之B型肝炎病毒DNA量減低效果之圖。 縱軸表示與開始（倂用）投予Livact顆粒與核酸類似物 製劑時相比，各倂用期間的B型肝炎病毒DNA量減少量 之對數値。橫軸表示由開始（倂用）投予之後所經過的時 間。在圖4中，橫紋長條表示單獨投予核酸類似物製劑（ A群），黑色長條表示在投予Livact顆粒1年之後，合倂 投予核酸類似物製劑（B群），白色長條表示在投予核酸 類似物製劑一年之後，合倂投予Livact顆粒（C群）。 -32-Hepsera (registered trademark) "GlaxoSmithKline") The nucleic acid analog preparations were used for 20 patients with type B cirrhosis from 3 months to 12 months, and the amount of hepatitis B virus in the serum was measured by nucleic acid amplification test. In addition, the aforementioned 20 patients were patients with cirrhosis and liver cancer did not develop. The nucleic acid amplification test is performed by either the PCR method or the TMA method depending on the amount of virus in the patient (measurement range: 2.6 to 7.6 log.copies/mL (PCR method), 3.7 - 8.7 LGE/m L (TM) Method A)). LGE, which means Logarithm genome equivalent, is actually the same as log.copies. Calculate the amount of change before use for each patient (for Group A (horizontal strips in Figure 4), before the administration of the drug) - the combination of the Livact particles is administered to the type B. The impact of the reduction in hepatitis virus is analyzed. The results are disclosed in Figure 4. In Fig. 4, group A will subtract the same amount of HBV DNA 値' at 3, 6, and 12 months after the start of administration of the nucleic acid analog preparation alone, the same sputum before starting the same preparation. It is expressed on the vertical axis (n=ll) °B group (black -29 - 201113023 strip in Fig. 4), which is based on the HBV DNA 测定 measured after one year of administration of Livact granules, and thereafter the nucleic acid is similar. When the combined preparation of the preparation was administered, the difference of the standard 値 was subtracted from the amount of the virus (n=3). (: group (white strip in Fig. 4) is the opposite of group B, indicating the difference in the case of administration of Livact particles after administration of the nucleic acid analog preparation for one year. (Patient group) Group A: alone Patient group (n=ΐι) administered to the nucleic acid analog preparation Group B: After administration of Livact particles for 1 year, the Livact particles were continuously administered, and the nucleic acid analog preparation was started to be administered, and the same preparation was continuously administered for one year. Patient group (n=3), (: group: 1 year after the administration of the nucleic acid analog preparation alone, the same preparation was continuously administered, and the Livact granules were started at the same time, and the patient group who continued to administer Livact granules for 1 year (n =6) As shown in Fig. 4, in the case where the nucleic acid analog preparation was administered alone, the amount of virus was decreased in the same formulation for 3 months, and the effect was not significantly increased even after continuous administration for 1 year. In the case of the B group administered with the nucleic acid analog preparation in the case of the patient who has administered the Livact particles for one year, the amount of the virus tends to be lowered as compared with the case where the nucleic acid analog preparation is administered alone, and if When the period of the joint investment became 1 year, it was observed. The low amount maintains a certain or even a tendency to reduce the amount of virus. If the group C is observed, it is found that after the virus reduction effect of the nucleic acid analog occurs, even if the Livact particle is used, no significant reduction in the amount of the virus is observed. Continuing -30-201113023 When Livact granules were administered for 1 year, a tendency to reduce the amount of virus was observed compared with the time point of sputum use for 3 months. [Industrial Applicability] According to the present invention 'by continuous administration The activity of the nucleic acid analog preparation reaching the bottom limit can be further enhanced. Thereby, the liver reserve function is improved compared with the case of using the nucleic acid analog preparation alone, so the choice of liver disease treatment method including liver cancer is selected. The present invention is effective in view of the above. Further, by the present invention, a prophylactic or therapeutic agent for viral hepatitis which is more potent than a conventional nucleic acid analog, and a therapeutic for viral hepatitis can be obtained. Further, according to the present invention, the virus growth inhibitory effect of the nucleic acid analog preparation can be stably maintained for a long period of time. In addition, the hepatitis B virus is positive. There is a concern of acute exacerbation and rapid outbreak, and in the case of administering a nucleic acid analog preparation after the onset, there are many cases in which the prognosis is poor. In this case, the present invention can be improved particularly in the prophylactic administration before the aforementioned acute outbreak. In addition, in the case of chemotherapy, immunotherapy, and transplantation therapy, if an anticancer agent or an immunosuppressive agent is used, there is a case where the hepatitis B virus rapidly proliferates, and the nucleic acid analog preparation is prevented from being administered before each therapy is administered. The present invention is also effective. 6P3 This application is based on Japanese Patent Application No. 20 09-150296 (Application Date: June 24, 2009) and Japan Special Purpose 2010-040423 (Application Date: 2010 2) Based on the 25th of the month, all of these contents are included in £–31 - 201113023 in this specification. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the amount of change in serum albumin oxime after the administration of Livact particles is started. The white dots indicate that there is no group of Latin American formulas, and the black spots indicate that there is a group of Latin American formulas. Figure 2 is a graph showing the amount of change in AST値 after Livact particles were started to be administered. White dots indicate that there is no group of Latin American formulas, and black spots indicate that there is a group of Latin American formulas. Figure 3 is a graph showing the amount of change in ALT値 after Livact particles were started to be administered. White dots indicate that there is no group of Latin American formulas, and black spots indicate that there is a group of Latin American formulas. Fig. 4 is a graph showing the effect of reducing the amount of hepatitis B virus DNA in the serum of a case where Livact particles and a nucleic acid analog are administered in combination. The vertical axis indicates the logarithm of the amount of reduction in the amount of hepatitis B virus DNA during each administration period as compared with the case where the Livact particles and the nucleic acid analog preparation were administered at the beginning. The horizontal axis indicates the time elapsed after the start (administration). In Fig. 4, the horizontal strip indicates that the nucleic acid analog preparation (Group A) was administered alone, and the black strip indicates that the nucleic acid analog preparation (Group B) was administered after the administration of the Livact particles for one year, and the white length was long. The bars indicate that one year after the administration of the nucleic acid analog preparation, the combined administration of Livact particles (Group C). -32-