200302103 (υ 玖、發明說明 【發明所屬之技術領域】 引言 本發明關於用於預防性治療原蟲病，尤其是利什曼病 之用於口服投藥的醫藥組成物其包含烷基磷酸膽鹼類，尤 其是十六院基憐酸膽驗（米泰富辛（miltefosine)，或磷 酸1，卜二甲基N-六氫吡啶-4-基十八烷酯（米利富辛（ perifosine)，D-2 1 266 )，還關於在預防性治療原蟲病， 尤其是利什曼病中，用於口服投予比醫藥組成物的劑量時 間表，及包含此醫藥組成物、抗嘔吐劑及/或抗腹瀉劑之 組合物。 【先前技術】 利什曼病係一代表多種熱帶疾病的名稱，其係由利什 曼原蟲屬之鞭毛蟲所引起，並由多種吸血昆蟲傳染。利什 曼病可表現在內臟（黑熱病）、黏膜皮膚（鼻咽黏膜利什 曼病）、或皮膚（皮膚利什曼病或瀰漫性皮膚利什曼病） 。其潛伏期爲從數週至數個月。在未治療之黑熱病及鼻咽 黏膜利什曼病的病例中尤其具有相當高之死亡率。 在治療利什曼病之標準治療中所使用的已知試劑，也 就是：五價銻化合物（如：銻醯葡糖酸鈉）和芳族聯脒類 必須經由非膠胃道之注射來投予，由於其具高毒性，因此 這不僅會導致嚴重的副作用，另外，亦會面臨感染的風險 -5- (2) (2)200302103 在艾伯，等於1991年提出之專利申請案DE-A 4 1 32344 號和EP-A 534445號中，第一次說明烷基磷酸膽鹼類，尤 其是十六烷基磷酸膽鹼（米泰富辛）適合用來經口服和局 部治療利什曼病。 另有許多其它作者說明以一類新藥，烷基磷酸膽鹼來 治療利什曼病，此類新藥具有相當卓越的抗原蟲活性。因 此’在赫，等之”米泰富辛，一種用於治療印度內臟性 利什曼病的口服試劑”新英格蘭醫學期刊（1 999)，341 ( 24)，1 97 5 - 1 800中報導一個對120位患者進行之口服試劑的 硏究，此硏究係在各患者身上每天使用50和150毫克之米 泰富辛，共數星期。S.山德，等之"以米泰富辛經口服治 療內臟性利什曼病，’，Ann.Trop. Med. Parasitol. ( 1999)， 93(6)， 5 8 9-5 97中係觀察在引導試驗中每日口服從100 至2 00毫克之米泰富辛可治療內臟性利什曼病。雖然米泰 富辛可以具高於200 °C之定義熔點的乾燥型結晶小九型 式取得，但由於其非常吸濕，因此很難處理。當攝取水分 子時，最多可使重量增加3 0重量％，並使熔點降低，且使 結晶結塊並成團。含水之米泰富辛的可處理性並不適合讓 其被進一步製成固體醫藥組成物，如：錠劑、膠囊或藥囊 。尤其是，含水之米泰富辛的可流動性並不適當。然而， 令人滿意之可流動性爲大規模製造醫藥組成物時所不可缺 少的必要條件之一。 另外’無水米泰富辛顯示出相當大之產生靜電的傾向 ，尤其是當其係在乾燥狀態被攪動時。帶靜電荷之米泰富 -6- (3) (3)200302103 辛的可流動性亦使其不適合進一步製成固體醫藥組成物。 再者’靜電荷總是牽涉到很多安全上的顧慮，因爲其將伴 隨著爆炸’以及對敏感之電子成分造成損害的風險。 爲了能在製造含米泰富辛之固態醫藥組成物時，圓滿 解決上述問題’艾伯，等人提出可經由將在溶液中之含有 1份重二氧化矽與1份重米泰富辛的懸浮液蒸發至乾燥，而 將米泰富辛鋪放在二氧化矽顆粒的表面。事實上，依艾伯 等人提出之方法所取得的固體分散物之可流動性足夠用來 鲁 塡入膠囊中，至少可適用於實驗室中之規模。然而，艾伯 等人所說明之方法係以同時使用高度揮發性和非可燃性（ 由於該靜電荷）溶劑爲基礎。在所有習知技術之實際應用 中，能符合這些要求的溶劑僅有二氯甲烷和氯仿。然而， 鹵化之烴類，尤其是氯仿，係被歸類爲具毒性及致癌性之 化合物。另外，鹵化之烴類會在脂肪組織中堆積，且僅會 慢慢地被破壞。 專利案WO 99/3 72 89已說明藉由將下列群體以物理方 ® 式混合來解決上述問題的可能性：烷基磷酸膽鹼類（尤其 是十六烷基磷酸膽鹼），至少一種流動控制劑及/或選自 如下群體之潤滑劑：細粒二氧化矽、滑石粉 '硬脂酸鎂及 其混合物，和至少一種選自如下群體之充塡劑：乳糖 '微 晶型纖維素及其混合物。 根據W 0 9 9 / 3 7 2 8 9，藉由簡單之物理混合院基磷酸膽 鹼，尤其是米泰富辛，流動-控制劑及/或潤滑劑，和至少 一種充塡劑可取得具有足夠之可流動性以進一步處理成’ (4) (4)200302103 如：膠囊、錠劑或藥囊的固態醫藥混合物。 根據此WO刊物，該固態醫藥組成物可用來充塡膠囊 (宜爲硬膠囊），或壓成錠劑或起泡錠劑’或包裹在藥囊 中以作爲可飮用的摻和物或起泡摻和物。 每一劑量單位中所含有之米泰富辛係在10至800毫克 之範圍內，宜爲從10至500毫克’而以從50至250毫克更佳 ，最佳之含量爲在50至150毫克之範圍內。 米泰富辛之製備方法係詳細說明於德國專利申請案 ® DE-A 4132344中之關於十六烷基磷酸膽鹼的實例中。其中 用於製備和純化米泰富辛之方法係說明於’如：德國專利 申請案DE-A 2752125、 DE-A 3641379、 DE-A 3641491、 DE-A 4013632 和 DE-A 3641377 中。 【發明內容】 發明之說明 令人驚訝且意外的，根據本申請案的一種觀點，已發 ® 現烷基磷酸贍鹼，尤其是十六烷基磷酸膽鹼（米泰富辛） 、和磷酸1，1-二甲基N-六氫吡啶-4-基十八烷酯（米利富辛 ，D-2 1 266 )適合用來預防性治療原蟲病，尤其是利什曼 病。烷基磷酸膽鹼類，尤其是十六烷基磷酸膽鹼和磷酸 1，1-二甲基N-六氫吡啶_4_基十八烷酯在預防原蟲病，尤其 是利什曼病方面的製藥用途並未說明於習知技術之通訊中 ，也無法從其中得知。 根據本發明的一種觀點，提供一種經由口服投予醫藥 -8- (5) (5)200302103 組成物，以用來預防性治療人體中之利什曼病的劑量時間 表。 在一種較佳之實施例中，下列劑量時間表適合用來經 由口服投藥，以預防性地治療人體中之利什曼病。 每日總劑量：1 〇 - 2 5 0毫克米泰富辛活性成分，以2 〇 _ 150毫克較佳，尤其以30-100毫克更佳； 每曰之單一或複數劑量：每日總劑量爲-5〇毫克活 性成分時，宜以單一每日劑量之型式來投予； ^ 每日5 0 - 2 5 0毫克活性成分（以5 0 - 1 5 0毫克活性成分較 佳）之劑量係以每日複數劑量之型式，經口服投予，宜爲 每日二次劑量（每日總劑量爲1 〇 〇毫克活性成分），或每 日二次劑量（每日總劑量爲1 5 0毫克活性成分）。關於患 者之順應性’通常係將分成4 - 5個劑量之每日劑量視爲上 限。然而，爲了達到預防之目的，亦可將試劑分割成除了 每日1 - 5次之劑量外的其它型式來投予。 在一較佳之實施例中，每一天係投予相同分量之複數 · 劑量（如：1〇〇毫克活性成分/天=2 X 5〇毫克活性成分/天 ’或者，i5〇毫克活性成分/天=3 x 5〇毫克活性成分/天） 〇 預防法亦可以先投予一起始劑量，再接著投予維持劑 量的方式來進行，如：先投予1 00毫克或更多之活性成分 作爲起始劑量，再投予，如：3〇毫克活性成分作爲維持劑 量。 預防法之使用期間：2週至6個月，宜用於有感染風險 -9 - (6) (6)200302103 的期間。 根據本發明之另一觀點係提供一用於預防性治療非人 類之哺乳動物體內的利什曼病之劑量時間表，此預防性治 療法係經由口服投予本發明之醫藥組成物。 本方法也可能治療所有哺乳動物。使用劑量時間表可 預防性治療所有可能型式之利什曼病’尤其是碩大利什曼 原蟲和嬰兒利什曼原蟲根據劑量時間表，在口服投藥的情 況中，用於預防性治療之總每日劑量係在每公斤動物體重 · 使用0.5 - 1 5毫克米泰富辛或米利富辛活性成分（毫克活性 成分/公斤）的範圍內。在一較佳之實施例中，預防法係 先投予一在3 -1 5 (宜爲5 - 1 0 )毫克活性成分/公斤之範圍內 的起始總單一劑量（飽和劑量），然後持續投予一在1 -1 〇 (宜爲3 - 5 )毫克活性成分/公斤之範圍內的總每日劑量（ 維持劑量）。預防治療的期間係在2週至6個月，宜用於感 染風險的期間。 根據另一觀點，本發明提供一種醫藥組成物與抗嘔吐 鲁 劑及/或抗腹瀉劑的組合物，以供利什曼病之預防性治療 中之口服投藥用。 在本發明之一種較佳實施例中，本發明之醫藥組成物 係與抗嘔吐劑及/或抗腹瀉劑一起投藥。其可同時投給或 連續投給。抗嘔吐劑及抗腹瀉劑可彼此獨立地投給。抗嘔 吐劑及/或抗腹瀉劑可存在於所描述之醫藥組成物中或存 在於其獨立之製藥配方中。 合適之抗嘔吐劑的實例有：5-HT3受體拮抗劑，經取 -10- (7) (7)200302103 代之苯甲醯胺、皮質類固醇、抗組織胺、吩噻汀（ phenothiatine)型之精神安定劑、丁醯苯型之精神安定劑 、苯並二氮雜罩類和大麻類。較佳之抗嘔吐劑爲，尤其是 鄰茴香醯胺、哌雙咪酮和乂利來普（a 1 i z a p r i d e )。特別 合適之抗腹瀉劑爲鸦片樣類’如：優腹寧（loperamide)。 固態之口服醫藥組成物較適合用於利什曼病之預防性 治療中。其它由原蟲類引起之疾病的實例有：瘧疾、剛比 亞錐蟲病、弓蟲症、梨漿蟲病 '阿米巴性痢疾和蘭伯氏鞭 毛蟲病。 【實施方式】 示範性實施例 下列實施例係用來更詳細地說明本發明。 可使用之固態口服製藥配方的實施例。 實施例1 :硬膠囊（含量：1 0毫克米泰富辛） 鲁 將100克十六烷基磷酸膽鹼，808.50克乳糖，448.50 克微晶型纖維素，26克滑石粉及13克微粒型二氧化矽通過 一網孔寬度爲〇 . 8毫米的篩，然後將其在一合適之混合器 中均化30分鐘。加入4克硬脂酸鎂（0.8毫米網篩），並將 成分再摻和5分鐘。將由此所得之混合物利用適合用來裝 塡此混合物的膠囊裝塡機，以已知方式，把每份爲1 40毫 克之混合物塡入50毫克重之硬膠囊內。以此方式所得之各 膠囊（總重量：190毫克）含有10毫克之十六烷基磷酸膽鹼 -11 - (8) (8)200302103 在充塡混合物中之十六烷基磷酸膽鹼：流動控制劑/ 表面活性劑：充塡劑的比例爲1: 〇·4: 12.4(份數以重量計 實施例2:硬膠囊（含量：1〇〇毫克米泰富辛） 藉實施例1中所描述之方法將下列群體摻和在一起： 1 000毫克十六烷基磷酸膽鹼、5 84克乳糖、345克微晶型纖 維素、5 0克滑石粉、1 5克微粒型二氧化矽和6克硬脂酸鎂 〇 將以此方法所得之充塡混合物，利用適合用來裝塡此 混合物的膠囊裝塡機，以已知方式，把每份爲200毫克之 混合物塡入一 76毫克重之硬膠囊中。 以此方式所得之各膠囊（總重量27 6毫克）含有100毫 克之十六烷基磷酸膽鹼。在充塡混合物中之十六烷基磷酸 膽鹼：流動控制劑：充塡劑之比例爲1: 0.07: 0.9 (份數以 重量計）。 實施例3:硬膠囊（含量：100毫克米泰富辛） 藉實施例1中所描述之方法將下列群體摻和在一起： 1 000毫克十六烷基磷酸膽鹼、5 84克乳糖、345克微晶型纖 維素、50克滑石粉、15克微粒型二氧化矽和6克硬脂酸鎂 〇 將以此方法所得之充塡混合物，利用適合用來裝塡此 -12- 200302103 Ο) 混合物的膠囊裝塡機，以已知方式，把每份爲200毫克之 混合物塡入一 7 6毫克重之硬膠囊中。 以此方式所得之各膠囊（總重量276毫克）含有100毫 克之十六烷基磷酸膽鹼。在充塡混合物中之十六烷基磷酸 膽鹼：流動控制劑：充塡劑之比例爲1: 0.07: 0.9 (份數以 重量計）。 實施例4:錠劑（含量：250毫克十六烷基磷酸膽鹼） 將5 0克十六烷基磷酸膽鹼，24.25克微晶型纖維素和 22.00克無水磷酸二鈣過篩，並摻和在一起。將3.75克硬脂 酸鎂過篩並加入混合物中。然後，將混合物再混合一次。 將以此方式所得到之混合物壓成各重500毫克之錠劑。這 些錠劑各含有250毫克十六烷基磷酸膽鹼。 在錠劑中，十六烷基磷酸膽鹼：流動控制劑/表面活 性劑：充塡劑之比例爲1: 0.07: 0.925 (份數以重量計）。 實施例5:錠劑（含量：30毫克十六烷基磷酸膽鹼） 將23克十六烷基磷酸膽鹼，23克微晶型纖維素和52克 經噴霧乾燥之乳糖過篩，並摻和在一起。將1克膠狀二氧 化矽和1克硬脂酸鎂加入混合物中。然後，將混合物再混 合一次。將以此方式所得到之混合物壓成各重130.5毫克 之錠劑。這些錠劑各含有30毫克十六烷基磷酸膽鹼。 在錠劑中，十六烷基磷酸膽鹼：流動控制劑/表面活 性劑：充塡劑之比例爲1: 0.0 8 7 : 0.3 1 (份數以重量計）。 (10) (10)200302103 實施例6 :起泡錠劑和起泡摻和物（十六院基磷酸膽驗含 量：250毫克） 將1 700克粒狀碳酸氫鈉在100 °C烤箱中加熱60分鐘 。在冷卻至室溫後，將已轉化之碳酸氫鹽與1 60克粒狀單 鹼性磷酸鈣、1 030克粒狀無水檸檬酸、100克滑石粉和50 克硬脂酸鎂混合在一起。將300克十六烷基磷酸膽鹼加入 以此方式所得到之混合物中，再接著摻和1 0分鐘。 鲁 將由此所得之起泡摻和物壓成各重27 8毫克之錠劑。 各起泡錠劑中含有250毫克十六烷基磷酸膽鹼。 在錠劑中，十六烷基磷酸膽鹼：流動控制劑/表面活 性劑：充塡劑之比例爲1: 0 · 5 0 : 0 · 5 3 (份數以重量計）。 一種替代之可行方法爲將每份2 7 8毫克之起泡摻和物 塡入小藥囊內，以製成一種起泡摻和物。 實施例7 :起泡錠劑和起泡摻和物（5 0毫克十六院基憐酸 ® 膽鹼） 將1 6 0 0克粒狀碳酸氫鈉在1 0 0 °C烤箱中加熱6 0分鐘 。在冷卻至室溫後，將已轉化之碳酸氫鹽與1 5 〇克粒狀單 鹼性磷酸15、9 0 0克粒狀無水棒檬酸、8 〇克滑石粉和3 〇克 硬脂酸鎂混合在一起。將200克十六烷基磷酸膽鹼加入以 此方式所得到之混合物中，再接著摻和丨〇分鐘。 將由此所得之起泡ί爹和物壓成各重7 4 〇毫克之錠劑。 各起泡錠劑中含有50毫克十六烷基磷酸膽驗。 -14- (11) (11)200302103 在錠劑中，十六烷基磷酸膽鹼：流動控制劑/表面活 性劑：充塡劑之比例爲1:0.55: 0.7 5 (份數以重量計）。 一種替代之可行方法爲將每份740毫克之起泡摻和物 塡入小藥囊內，以製成一種起泡摻和物。 實施例8:可飮用之摻和物（小藥囊）（含量：50毫克十六 烷基磷酸膽鹼） 將5克十六烷基磷酸膽鹼，308克乳糖，280克微晶型 · 纖維素，5克糖精和2克膠狀二氧化矽摻和在一起。將混合 物塡入小藥囊內。這些小藥囊各重6克，並含有50毫克十 六院基磷酸膽驗。 在混合物中之十六烷基磷酸膽鹼：流動控制劑/表面 活性劑：充塡劑之比例爲1: 〇·4: Π7·5(份數以重量計） 實施例9:可飲用之摻和物（小藥囊）（含量：50毫克十六 鲁 院基碟酸膽驗） 將20克十六烷基磷酸膽鹼，306克乳糖，403克微晶型 纖維素，5克糖精和6克膠狀二氧化矽摻和在一起。將混合 物塡入小藥囊內。這些小藥囊各重7·4克’並含有200晕·克 十六院基磷酸膽驗。 在混合物中之十六院基磷酸膽鹼：流動控制劑/表面 活性劑：充塡劑之比例爲1: 0.3 : 3 5.5 (份數以重量計）° 這些實施例亦可含有米利富辛以取代活性成分米泰富 -15- 200302103200302103 (υ 玖, description of the invention [Technical field to which the invention belongs] Introduction The present invention relates to a pharmaceutical composition for the prophylactic treatment of protozoan diseases, particularly Leishmaniasis, for oral administration, which contains alkyl phosphate choline , Especially the 16-base biliary acid test (miltefosine), or 1,2-dimethyl N-hexahydropyridin-4-yloctadecyl phosphate (perifosine, D- 2 1 266), and also about the dosage schedule for the oral administration of specific pharmaceutical compositions in the prophylactic treatment of protozoan diseases, especially Leishmaniasis, and the inclusion of such pharmaceutical compositions, antiemetic agents and / or Anti-diarrheal agent composition. [Prior art] Leishmaniasis is a name representing a variety of tropical diseases. It is caused by flagellans of the genus Leishmania and is transmitted by many blood-sucking insects. Leishmaniasis can Shows viscera (black fever), mucosal skin (nasopharyngeal mucosal leishmaniasis), or skin (cutaneous leishmaniasis or diffuse cutaneous leishmaniasis). Its incubation period is from weeks to months. In untreated Black fever and nasopharyngeal mucosa Leishman In particular, there is a relatively high mortality rate. Known agents used in the standard treatment of Leishmaniasis, namely: pentavalent antimony compounds (such as: antimony / sodium gluconate) and aromatic hydrazone Classes must be administered by non-gluing gastrointestinal injection. Due to their high toxicity, this not only causes serious side effects, but also faces the risk of infection. -5- (2) (2) 200302103 It is equivalent to the patent applications DE-A 4 1 32344 and EP-A 534445 filed in 1991, which for the first time show that alkylcholine phosphates, especially cetyl phosphate choline (mitefuxin) are suitable for use. It has been used orally and topically to treat Leishmaniasis. Many other authors have stated that a new class of drugs, alkylcholine phosphate, is used to treat Leishmaniasis. Such new drugs have quite excellent antiprotozoal activity. "Metafuxin, an oral agent for the treatment of visceral leishmaniasis in India" The New England Journal of Medicine (1 999), 341 (24), 1 97 5-1 800 reported a study of 120 patients Study of oral agents, this study is in each patient Subjects used 50 and 150 milligrams of metformin daily for several weeks. S. Sander, et al. &Quot; Metafuxine orally treated visceral leishmaniasis, ', Ann.Trop. Med. Parasitol. (1999), 93 (6), 5 8 9-5 97. Observation in the guided trials of oral methafuxin from 100 to 200 mg per day can treat visceral leishmaniasis. Dry-type small crystals with a defined melting point above 200 ° C were obtained, but because they are very hygroscopic, it is difficult to handle. When ingesting water molecules, it can increase the weight by up to 30% by weight and lower the melting point. And the crystals are agglomerated and agglomerated. The processability of hydrated mitofuxin is not suitable for further processing into solid pharmaceutical compositions, such as lozenges, capsules, or sachets. In particular, the flowability of the water-containing Mitexine is not appropriate. However, satisfactory flowability is one of the necessary conditions for large-scale manufacturing of pharmaceutical compositions. In addition, 'anhydrometer Metuxin shows a considerable tendency to generate static electricity, especially when it is agitated in a dry state. The flowability of Mitafur-6- (3) (3) 200302103 with its electrostatic charge also makes it unsuitable for further manufacture into solid pharmaceutical compositions. Furthermore, the electrostatic charge always involves many safety concerns, because it will be accompanied by the risk of explosion and damage to sensitive electronic components. In order to satisfactorily solve the above problems in the manufacture of medicoflavin-containing solid pharmaceutical compositions, Albert, et al. Proposed that a suspension containing 1 part by weight of silicon dioxide and 1 part by weight of metaifuxin in a solution Evaporate to dryness and spread metafuxine on the surface of the silica particles. In fact, the flowability of the solid dispersion obtained by the method proposed by Alber et al. Is sufficient to be used in capsules, at least on a laboratory scale. However, the method described by Abb et al. Is based on the use of both highly volatile and non-flammable (due to this electrostatic charge) solvents. In practical applications of all known techniques, the only solvents that meet these requirements are dichloromethane and chloroform. However, halogenated hydrocarbons, especially chloroform, are classified as toxic and carcinogenic compounds. In addition, halogenated hydrocarbons accumulate in adipose tissue and are only slowly destroyed. Patent case WO 99/3 72 89 has demonstrated the possibility of solving the above problems by physically mixing the following groups: alkylcholine phosphates (especially cetylcholine phosphate), at least one kind of flow Control agents and / or lubricants selected from the group consisting of fine-grained silica, talc 'magnesium stearate and mixtures thereof, and at least one filler selected from the group consisting of lactose' microcrystalline cellulose and Its mixture. According to W 0 9 9/3 7 2 8 9, by simple physical mixing of choline phosphate choline, especially mifeprixine, flow-controlling agent and / or lubricant, and at least one filler can be obtained with sufficient The fluidity can be further processed into '(4) (4) 200302103 such as: solid pharmaceutical mixture of capsule, lozenge or sachet. According to this WO publication, the solid pharmaceutical composition can be used to fill capsules (preferably hard capsules), or compressed into lozenges or blistering lozenges' or wrapped in sachets for use as admixtures or capsules. Blended admixture. The mitofuxin contained in each dosage unit is in the range of 10 to 800 mg, preferably from 10 to 500 mg ', and more preferably from 50 to 250 mg. The most preferred content is 50 to 150 mg. Within range. The method for the preparation of metformin is described in detail in the German patent application ® DE-A 4132344 for an example of cetyl phosphate choline. Among them, the method for preparing and purifying metafuxin is described in, for example, German patent applications DE-A 2752125, DE-A 3641379, DE-A 3641491, DE-A 4013632, and DE-A 3641377. [Summary of the Invention] The description of the invention is surprising and unexpected. According to one point of view of this application, it has been discovered that alkylphosphonium base, especially cetyl phosphate choline (metafuxin), and phosphate 1 1,1-dimethyl N-hexahydropyridin-4-yl octadecyl ester (Millifusin, D-2 1 266) is suitable for the prophylactic treatment of protozoan diseases, especially Leishmaniasis. Alkyl phosphate choline, especially cetyl phosphate choline and 1,1-dimethyl N-hexahydropyridine_4-octadecyl phosphate in the prevention of protozoal diseases, especially Leishmaniasis The pharmaceutical use of this aspect is not described in the communication of known technology, nor can it be learned from it. According to an aspect of the present invention, there is provided a dosage schedule for orally administering a pharmaceutical composition to prevent (5) (5) 200302103 for the preventive treatment of Leishmaniasis in a human body. In a preferred embodiment, the following dosage schedule is suitable for the prophylactic treatment of Leishmaniasis in humans by oral administration. Total daily dose: 10-250 mg of mitexine active ingredient, preferably 20-150 mg, especially 30-100 mg; single or multiple doses per day: the total daily dose is- For 50 mg of active ingredient, it should be administered in a single daily dose; ^ 50-250 mg of active ingredient per day (preferably 50-150 mg of active ingredient) per day Multiple daily doses are administered orally, preferably as a second daily dose (total daily dose of 100 mg of active ingredient), or a second daily dose (total daily dose of 150 mg of active ingredient) ). With regard to patient compliance, 'a daily dose divided into 4-5 doses is usually considered the upper limit. However, for the purpose of prevention, the agent can also be divided into dosages other than 1 to 5 times a day for administration. In a preferred embodiment, each day is administered in the same amount of multiple doses (eg: 100 mg of active ingredient / day = 2 x 50 mg of active ingredient / day 'or i50 mg of active ingredient / day) = 3 x 50 mg of active ingredient / day). ○ The preventive method can also be performed by first administering a starting dose and then a maintenance dose. For example, firstly administer 100 mg or more of the active ingredient as a starting point. The initial dose is re-administered, such as 30 mg of active ingredient as a maintenance dose. The period of use of the preventive method: 2 weeks to 6 months, suitable for periods with a risk of infection -9-(6) (6) 200302103. According to another aspect of the present invention, there is provided a dosage schedule for the prophylactic treatment of Leishmaniasis in non-human mammals, and the prophylactic treatment is administered orally to the pharmaceutical composition of the present invention. This method may also treat all mammals. Dosage schedules preventively treat all possible forms of Leishmaniasis, especially Leishmania gigas and Leishmania infantis, according to the dose schedule, for preventive treatment in the case of oral administration The total daily dose is in the range of 0.5-15 mg of mitexine or milifoxine active ingredient (mg active ingredient / kg) per kilogram of animal body weight. In a preferred embodiment, the preventive method first administers a starting total single dose (saturated dose) in the range of 3 to 15 (preferably 5 to 10) mg of active ingredient / kg, and then continuously A total daily dose (maintenance dose) in the range of 1-10 (preferably 3-5) mg of active ingredient / kg is administered. The period of preventive treatment is 2 weeks to 6 months, and it is suitable for the period of risk of infection. According to another aspect, the present invention provides a composition of a medicinal composition and an anti-vomiting agent and / or an anti-diarrhea agent for oral administration in the prophylactic treatment of Leishmaniasis. In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention is administered together with an anti-emetic agent and / or an anti-diarrheal agent. It can be administered simultaneously or continuously. The antiemetic and antidiarrheal agents can be administered independently of each other. Antiemetic and / or antidiarrheal agents may be present in the described pharmaceutical composition or in their separate pharmaceutical formulation. Examples of suitable anti-emetic agents are: 5-HT3 receptor antagonists, which are replaced by -10- (7) (7) 200302103 by benzamidine, corticosteroids, antihistamines, phenothiatine Neuroleptics, butadiene-type neuroleptics, benzodiazepines and cannabis. Preferred antiemetic agents are, in particular, o-anisidine, piperidimone, and ililipide (a 1 i z a p r i d e). Particularly suitable anti-diarrheal agents are opioids such as: loperamide. Solid oral pharmaceutical compositions are more suitable for the prophylactic treatment of Leishmaniasis. Examples of other diseases caused by protozoa are: malaria, trypanosomiasis, toxoplasmosis, trichomoniasis, amoebic dysentery and Lambert flagellosis. [Embodiments] Exemplary Examples The following examples are used to explain the present invention in more detail. Examples of solid oral pharmaceutical formulations that can be used. Example 1: Hard capsule (content: 10 mg of metafuxin) Lu Jiang 100 g of cetyl phosphate choline, 808.50 g of lactose, 448.50 g of microcrystalline cellulose, 26 g of talc powder and 13 g of particulate type II The silicon oxide was passed through a sieve with a mesh width of 0.8 mm and then homogenized in a suitable mixer for 30 minutes. Add 4 grams of magnesium stearate (0.8 mm mesh sieve) and blend the ingredients for another 5 minutes. The thus-obtained mixture was poured into 50 mg hard capsules in a known manner using a capsule filling machine suitable for containing the mixture in a known manner. Each capsule obtained in this way (total weight: 190 mg) contains 10 mg of cetyl phosphate choline-11-(8) (8) 200302103 Cetyl phosphate choline in a filling mixture: flowing The ratio of control agent / surfactant: filling agent is 1: 〇 · 4: 12.4 (parts by weight Example 2: hard capsule (content: 100 mg metformin) as described in Example 1 The following groups were blended together: 1,000 mg of cetyl phosphate choline, 5 84 g of lactose, 345 g of microcrystalline cellulose, 50 g of talc, 15 g of particulate silica, and 6 G of magnesium stearate. The filling mixture obtained in this way is poured into a 76 mg weight mixture in a known manner using a capsule filling machine suitable for containing this mixture. In hard capsules. Each capsule obtained in this way (total weight 276 mg) contains 100 mg of cetyl phosphate choline. Cetyl phosphate choline in a filling mixture: flow control agent: filling The ratio of the agent is 1: 0.07: 0.9 (parts by weight). Example 3: Hard capsule (content 100 mg metformin) The following groups were blended together by the method described in Example 1: 1,000 mg of cetyl phosphate choline, 5 84 g of lactose, 345 g of microcrystalline cellulose, 50 g of talc Powder, 15 g of particulate silicon dioxide and 6 g of magnesium stearate. The filling mixture obtained in this way is used in a capsule filling machine suitable for containing this mixture of -12-200302103 0). By pouring 200 mg of each mixture into a 76 mg hard capsule. Each capsule (total weight 276 mg) obtained in this way contained 100 mg of cetyl phosphate choline. The ratio of hexadecyl phosphate choline: flow control agent: filling agent in the filling mixture is 1: 0.07: 0.9 (parts by weight). Example 4: Lozenges (content: 250 mg of cetyl phosphate choline) 50 g of cetyl phosphate choline, 24.25 g of microcrystalline cellulose and 22.00 g of anhydrous dicalcium phosphate were sieved and mixed And together. Sieve 3.75 g of magnesium stearate and add to the mixture. Then, the mixture was mixed again. The mixture obtained in this way was compressed into tablets of 500 mg each. Each of these lozenges contains 250 mg of cetyl phosphate choline. In the lozenge, the ratio of cetyl phosphate choline: flow control agent / surfactant: tincture is 1: 0.07: 0.925 (parts by weight). Example 5: Lozenges (content: 30 mg cetyl phosphate choline) 23 g of cetyl phosphate choline, 23 g of microcrystalline cellulose and 52 g of spray-dried lactose were sieved and mixed And together. 1 g of colloidal silica and 1 g of magnesium stearate were added to the mixture. Then, the mixture was mixed again. The mixture obtained in this way was compressed into tablets of 130.5 mg each. These lozenges each contain 30 mg of cetyl phosphate choline. In the lozenge, the ratio of cetyl phosphate choline: flow control agent / surfactant: tincture is 1: 0.0 8 7: 0.3 1 (parts by weight). (10) (10) 200302103 Example 6: Foaming lozenge and foaming admixture (hexadecyl-based bile phosphate content: 250 mg) 1 700 g of granular sodium bicarbonate was heated in a 100 ° C oven 60 minutes. After cooling to room temperature, the converted bicarbonate was mixed with 160 grams of granular monobasic calcium phosphate, 1,030 grams of granular anhydrous citric acid, 100 grams of talc, and 50 grams of magnesium stearate. 300 grams of hexadecyl phosphate choline was added to the mixture obtained in this manner, followed by blending for 10 minutes. Lu compressed the resulting foaming blend into 278 mg tablets each. Each foaming lozenge contains 250 mg of cetyl phosphate choline. In the lozenge, the ratio of hexadecyl phosphate choline: flow control agent / surfactant: tincture is 1: 0 · 5 0: 0 · 5 3 (parts by weight). An alternative method is to pour 278 mg of the foaming blend into a sachet to make a foaming blend. Example 7: Foaming lozenge and foaming admixture (50 mg of cetyl-hosinol® choline) 1 600 g of granular sodium bicarbonate were heated in an oven at 100 ° C for 60 ° minute. After cooling to room temperature, the converted bicarbonate was mixed with 150 g of granular monobasic phosphoric acid 15, 900 g of granular anhydrous citric acid, 800 g of talc, and 30 g of stearic acid. Magnesium is mixed together. 200 grams of cetyl phosphate choline was added to the mixture obtained in this manner, followed by blending for 10 minutes. The resulting foamed mixture was compressed into tablets of 740 mg each. Each foaming lozenge contains 50 mg of hexadecyl phosphate. -14- (11) (11) 200302103 In the tablet, the ratio of cetylcholine phosphate: flow control agent / surfactant: tincture is 1: 0.55: 0.7 5 (parts by weight) . An alternative method is to pour 740 mg of the blistering admixture into a sachet to make a blistering admixture. Example 8: A ready-to-use admixture (small sachet) (content: 50 mg of cetyl phosphate choline) 5 g of cetyl phosphate choline, 308 g of lactose, 280 g of microcrystalline form · Cellulose, 5 grams of saccharin and 2 grams of colloidal silica are blended together. The mixture is poured into a sachet. Each of these sachets weighs 6 grams and contains 50 mg of Hexaphyllyl Phosphate Test. The ratio of hexadecyl phosphate choline in the mixture: flow control agent / surfactant: filling agent is 1: 0.4. Π 7. 5 (parts by weight). Example 9: Drinkable blend Japanese medicine (small sachet) (content: 50 mg of Shiliu Lujiji acid bile test) 20 grams of cetyl phosphate choline, 306 grams of lactose, 403 grams of microcrystalline cellulose, 5 grams of saccharin and 6 Grams of colloidal silica are blended together. The mixture is poured into a sachet. These sachets each weighed 7.4 grams and contained 200 halograms. The ratio of hexadecyl choline phosphate: flow control agent / surfactant: filling agent in the mixture is 1: 0.3: 3 5.5 (parts by weight) ° These examples may also contain milifoxine to Substitute the active ingredient Mitaifu-15- 200302103