本發明標的為用於局部施用於有需要個體的醫藥調配物，該調配物包含： i) 1至10 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， ii) 0至90 % w/w之至少一種溶劑， iii) 0至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有2.0至8.0之pH值，較佳4.0至5.0之pH， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月， 其中該溶劑係選自包括乙醇、異山梨醇二甲酯、異丙醇、Transcutol P、丙二醇、聚乙二醇、PEG 400、PEG 4000及Super RefinedTM
(SR) PEG 400之群。 在上文段落背景下，該醫藥組合物具有4.0至4.5之更佳pH值。 本發明標的亦為用於局部施用於有需要個體的醫藥調配物，該調配物包含： i 1至10 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， ii ＞ 0至90 % w/w之至少一種溶劑， iii ＞ 0至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有2.0至8.0之pH值，較佳4.0至5.0之pH，更佳4.0至4.5之pH值， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月， 其中該溶劑係選自包括乙醇、異山梨醇二甲酯、異丙醇、Transcutol P、丙二醇、聚乙二醇、PEG 400、PEG 4000及Super RefinedTM
PEG 400之群，及 其中該抗氧化劑係選自包括丁基化羥基甲苯(BHT)、丁基化羥基苯甲醚(BHA)、抗壞血酸、棕櫚酸抗壞血酯、生育酚、乙酸生育酚酯、沒食子酸丙酯、沒食子酸十二酯、沒食子酸辛酯、硫代硫酸鹽之群。 在本發明之另一態樣中，含於如上所述之醫藥組合物中的該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 在此處，且在整個文本中相同地，術語「＞ 0至90 %」或類似表述意指大於「0」且至多及包含90 %之值。 在此處，且在整個文本中相同地，術語「＞ 0至10 %」或類似表述意指大於「0」且至多及包含10 %之值。 在本發明之一實施例中，含於上述實施例之醫藥組合物中的活性醫藥成分N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月。 在本發明之一實施例中，含於上述實施例之醫藥組合物中的活性醫藥成分N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 在本發明之另一實施例中，當按照歐洲藥典(Ph. Eur.)及/或美國藥典(USP)之藥典方法進行測定時，含於上述實施例之醫藥組合物中的活性醫藥成分N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月。 在本發明之另一實施例中，當按照歐洲藥典(Ph. Eur.)及/或美國藥典(USP)之藥典方法進行測定時，含於上述實施例之醫藥組合物中的活性醫藥成分N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 在本申請案中，術語「調配物」係關於賦形劑與活性成分之混合物，且可根據特定程序(稱為「配方(formula)」)製備成乳膏、凝膠或軟膏之形式。調配物係製藥非常重要的一面，因為這些調配物對於確保藥物之活性部分係呈正確的濃度且以正確的動力學(非太快且非太慢)遞送至身體之指定部分而言係至關重要的。一個良好的例子為利用過飽和之藥物遞送系統。這些調配物亦需要具有可接受之稠度、良好儲存穩定性，且在物理及化學上均足夠穩定以便從其等所製造之地點運輸至患者。 在上文段落背景下，該「正確的動力學」係指正確的穿透動力學。 在本申請案之背景下，本文所用之術語「局部調配物」通常包括可施用至皮膚或黏膜之調配物。例如，局部調配物可用於賦予患者治療益處或賦予消費者美容益處。局部調配物可用於物質之局部及經皮投與。 本文所用之術語「局部投與」通常包括將物質(諸如治療活性劑)遞送至皮膚或身體之局部區域。 如本文所用，術語「個體」係指活著的人或非人生物體，較佳人類個體，其中該個體係健康的、表面上健康的、罹患疱疹病毒感染的，特別是由於單純疱疹病毒1 (HSV-1)及單純疱疹病毒(HSV-2)。 在本申請案之背景下，「呈溶解狀態」意指普瑞利維之固體形式在溶劑中形成溶液。 在上文段落背景下，「呈溶解狀態」意指普瑞利維之固體形式亦可在賦形劑基質中形成液體或半液體溶液。 在本申請案之背景下，溶劑為溶解溶質(化學上不同之液體、固體或氣體)產生溶液之物質。溶劑通常為液體，但亦可為固體或氣體。可溶於特定體積之溶劑中之溶質的量隨溫度而變化。溶劑係以最大量存在之溶液的組分。 此外，在上文段落背景下，溶劑為溶解溶質(化學上不同之液體、固體或氣體)產生液體或半液體溶液之物質。溶劑通常為液體，但亦可為半固體、固體或氣體。 在本申請案中，所實施之調配物包含至少一種溶劑，此意指可存在其它溶劑(第二、第三、第四溶劑等)作為輔助溶劑以增強所述主要溶劑之溶劑能力。 在本申請案之背景下，「抗氧化劑」係抑制其它分子氧化之分子，特定言之抗氧化劑阻斷氧化反應並防止氧自由基(例如過氧化物)之作用，已知該兩個過程損害多種天然物質之完整性及功能。抗氧化劑係適用於防止調配物產品中之成分的降解。 此外，在上文段落背景下，「抗氧化劑」係抑制其它分子氧化之分子，特定言之抗氧化劑阻斷氧化反應並防止氧自由基(例如過氧化物)之作用，已知該兩個過程損害多種氧化敏感物質(如醫藥活性成分或賦形劑)之完整性及功能。抗氧化劑係適用於防止調配物產品中之此等成分的降解。 在本發明之另一實施例中，該至少一種溶劑係選自包括聚乙二醇之群，較佳PEG 400，更佳Super Refined™ (SR) PEG 400。 在本發明之一實施例中，本發明醫藥調配物之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺係選自包括以下化合物之群： • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之甲磺酸鹽
，及 • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
。 在本發明之另一實施例中，該抗氧化劑係選自包括丁基化羥基甲苯(BHT)、丁基化羥基苯甲醚(BHA)、抗壞血酸、棕櫚酸抗壞血酯、生育酚、乙酸生育酚酯、沒食子酸丙酯、沒食子酸十二酯、沒食子酸辛酯、硫代硫酸鹽之群。 在本申請案之又一實施例中，該抗氧化劑為BHT。 在本申請案之另一實施例中，該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠之調配物。 在本申請案之另一實施例中，該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠及貼片之調配物。貼片
在上文段落背景下，根據本發明之普瑞利維活性醫藥成分亦可使用施用於生物體(例如，經疱疹病毒感染之人類，例如經HSV-1及/或HSV-2感染之人類)身體之部位上的貼片進行投與。更特定言之，本發明之此類貼片可例示性地包括皮膚黏著層、背襯層及釋藥襯膜；藉此，黏著層可包含根據本發明之普瑞利維活性醫藥成分，及/或溶解於低揮發性溶劑中之其它活性化合物及可溶於高揮發性溶劑中之聚合物黏合劑。普瑞利維活性醫藥成分可作為抗病毒劑以治療及/或預防有效量(例如，乾燥黏合層之0.1至10 % w/w，較佳約5 % w/w)溶於低揮發性溶劑來併入黏著層。 在一實施例中，本發明係關於用於局部施用之軟膏、乳膏或凝膠，其包含呈以上形式之任一者的活性醫藥成分。 局部製劑呈多種形式存在，諸如軟膏、凝膠、乳膏、洗劑、溶液、懸浮液、發泡體及洗髮精。最常用之局部製劑為半固體或半液體劑型，包括軟膏、乳膏、乳液、洗劑及凝膠。此等醫藥半固體製劑之共同特性為能夠在其等被洗掉或磨掉之前黏附至施用表面持續適當時段。其等通常充作局部施用藥物之媒劑，作為潤膚劑(emollient)或作為保護劑。 在本申請案之背景下，術語「軟膏」包含烴凝膠、微脂膠、吸收基質、W/O軟膏基質、混合乳劑或聚乙二醇作為基質。 如本文所用，乳膏包含O/W基質。 在上文兩個段落之背景下，術語「軟膏」包含烴凝膠、微脂膠、吸收基質、W/O軟膏基、混合乳劑或聚乙二醇作為主要載劑系統。 因此，乳膏可包含O/W基質作為主要載劑系統。 在本申請案之背景下，術語糊膏除了軟膏或乳膏基質之外亦包含大量粉狀成分，諸如(例如)氧化鋅、滑石粉、澱粉或二氧化鈦。 在上文段落背景下，術語糊膏除了軟膏或乳膏基質作為主要載劑系統之外亦包含大量粉狀成分，諸如(例如)氧化鋅、滑石粉、澱粉或二氧化鈦。 如本文所使用，術語「凝膠」包含諸如水、乙醇、異丙醇或丙二醇之溶劑，且係使用諸如纖維素醚、藻酸鹽、聚丙烯酸酯、膨潤土、明膠、黃蓍膠、聚乙烯吡咯啶酮或聚乙烯醇之凝膠形成劑來生產。亦可使用親脂性凝膠基質或微乳液。 在本申請案之背景下，粉末包含粉狀添加劑諸如澱粉、硬脂酸鹽、二氧化矽、黏土、碳酸鎂、滑石粉、纖維素、氧化鋅及(特定言之)乳糖。 可添加穩定劑、抗氧化劑、防腐劑、保濕劑、富脂劑、溶劑或賦形劑以改良所有製劑之穿透性及功效。 在上文段落背景下，可添加穩定劑、抗氧化劑、防腐劑、保濕劑、富脂劑、溶劑或賦形劑作為皮膚穿透增強劑，以改良所有本文所揭示之局部調配物的滲透性及功效。業經針對此類滲透增強活性劑對許多化合物進行評估，包括亞碸(諸如二甲基亞碸，DMSO)、氮酮(例如月桂氮卓酮)、吡咯啶酮(例如2-吡咯烷酮，2P)、醇及烷醇(乙醇或癸醇)、二醇(例如丙二醇，PG，局部施用劑型中之常見賦形劑)、界面活性劑(亦常見於劑型)及萜烯。 在本發明之一實施例中，醫藥調配物中之活性醫藥成分普瑞利維係選自1.1至10 % w/w，更佳1.1至5 % w/w之範圍。 在本發明之另一實施例中，在醫藥調配物中，該至少一種溶劑之濃度為0.1至90 % w/w，例如5至90 % w/w、10至90 % w/w、10至80 % w/w、20至80 w/w、25至80 % w/w、15至50 % w/w或30至45 % w/w。 在本發明之另一實施例中，在醫藥調配物中，第二溶劑之濃度為0.1至60 % w/w，更佳10至50 % w/w，最佳10至40 % w/w。 在本發明之另一實施例中，在醫藥調配物中，該抗氧化劑之濃度為0.01至10 % w/w，更佳0.025至5 % w/w，最佳0.05至2 % w/w。 出乎意料且意外地，在本發明之特定態樣中，本發明者發現，藉由使用BHT及Super RefinedTM
PEG 400調配本文所提供之普瑞利維抗病毒劑，該普瑞利維抗病毒劑係呈溶解形式存在於該調配物中。藉此，該溶解形式確保局部調配物將其普瑞利維抗病毒劑以醫藥上足夠之量遞送至各自標靶側，以有效地解決HSV-1及/或HSV-2病毒。 隨著提供呈溶解形式之普瑞利維抗病毒劑，可能會出現穩定性挑戰，因此出現使溶解藥物穩定並保持穩定之挑戰。在此背景下，本發明者驚奇地發現，添加BHT作為自由基形成劑顯著地使含於本文所提供之局部調配物中的普瑞利維抗病毒劑穩定。但是，在用於醫療用途之最終局部調配物中，該BHT顯著降低至低於藥品之BHT檢測閾值的量。 此外，藉由添加Super Refined PEGTM
400，本發明者出乎意料地發現，呈溶解形式之普瑞利維抗病毒劑可在25℃/60 % RH下在最終調配物中保持穩定24個月。在此處，由於使用PEG 400及Super Refined PEGTM
400而產生之過氧化物雜質係由經混合之BHT中和，BHT亦可作為該等過氧化物雜質之自由基清除劑。此自由基清除活性可能係本發明最終局部調配物中BHT顯著降低之原因。因此，本發明局部調配物之初始BHT量以某種方式在調配物中消耗並降低，由此其等不會超過如醫學局部調配物中各自釋放說明書中所記錄之釋放內容物的BHT規定閾值(進一步參見下文)。 在上文三個段落之背景下及在本發明背景下，應注意，由美國食品及藥物管理局(Food and Drug Administration，FDA)為用於市售局部調配物中之局部途徑的BHT所設定之IIG限度為至多0.1 % w/w；及基於如本文所揭示之當前臨床調配物中之BHT的數據，用於局部施用於有需要個體之最終局部調配物的固定最大值為0.1 % w/w。至此，該由FDA所設定之IIG限度可經由以下鏈接找到：https://www.accessdata.fda.gov/ scripts/cder/iig/getiigWEB.cfm。 在此背景下，應注意，BHT可在製造過程期間以超過該由FDA所規定之0.1 % w/w之限度的量添加至本發明局部調配物中。但是如上所述，BHT在調配物製劑至最終產物過程中消耗，並因此在本發明最終局部調配物中不超過該0.1 % w/w限度。 根據本發明之例示性最終產物之進一步的規格可自下文表格中導出概述：
a：報告水平：0.05% TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 因此，具體而言，本發明提供該等醫藥調配物用於局部施用，其中該等調配物包含如上所述之呈溶解形式的抗病毒劑、丁基化羥基甲苯(BHT)及Super RefinedTM
PEG 400。 在上文所述背景下，本發明者亦發現，本發明最終局部調配物之pH值對於保持本文所提供之調配物中的呈溶解形式之普瑞利維抗病毒劑的穩定性而言係決定性的。在本發明之特定態樣中，發現就穩定性及避免需要投與之個體的的皮膚刺激而言pH為4.0至4.5之本發明最終局部調配物係最佳的。軟膏調配物
本申請案之另一實施例係關於本發明醫藥調配物之軟膏調配物。 在本發明之特定實施例中，提供用於局部施用於有需要個體的醫藥調配物，該調配物為軟膏調配物，其包含： (i) 15至20 % w/w PEG 4000， (ii) 7.5至10 % w/w丙二醇， (iii) 1.1至5 % w/w活性醫藥成分普瑞利維， (iv) 0.05至2 % w/w丁基化羥基甲苯(BHT)， (v) 25至80 % w/w Super RefinedTM
PEG 400，及 (vi) 0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液， 其中該醫藥調配物具有4.0至5.0之pH值，較佳4.0至4.5之pH值。 在上文段落里，應注意，該pH值係指表觀pH。pH/ 表觀 pH/ 局部調配物
在本發明背景下，pH值係局部調配物之重要參數，尤其歸因於其對患者順應性、藥物穩定性及活性部分之皮膚滲透的影響。大多數習知局部調配物係基於水性系統，諸如凝膠、乳膏及洗劑，然而，對疏水性藥物而言亦可使用非水性系統，諸如油、軟膏。與水性調配物相比，非水性調配物之精確pH測量要復雜得多。 理論上，在測量水溶液的pH時，一部分水分子解離為H+
及OH-
離子，並因此可以在0至14之範圍內精確地獲得pH值。然而，0至14之pH值範圍可能不適用於非水性系統。 由於pH值係氫離子活度之量度，在具有非質子溶劑之溶液中氫離子的濃度將顯著降低或幾乎可以忽略不計。 在正常實驗室設置中所用之pH電極係使用水性緩衝液進行校準且非常良好地適合記錄水性系統之H+
離子濃度。此等pH電極之電化學可能不適合記錄非水性系統中之H+
離子濃度，歸因於極低之濃度。 Porras及Kenndler建議可使用水溶液校準非水性系統之pH量測，然而應將該pH值視為表觀pH。表觀pH提供系統之相對酸度/鹼度。 在量測非水性系統之表觀pH時可能會遇到若干實際困難。低H+
離子濃度可導致玻璃pH指示電極與測試樣品之間之電化學電位的不精確檢測，其可導致pH量測值波動、響應時間長及讀數不準確。 存在可導致此等影響之其他因素： • 大多數pH電極依靠玻璃球外側上之水合凝膠層來檢測H+
活性。歸因於非水性樣品中之低含水量的凝膠層脫水導致響應時間緩慢及量測結果不準確。 • 非水性系統可具有不良電導率，並因此會降低檢測H+
活性變化所需之電組件的效率。 • 用於校準pH計之水性緩衝液可能與非水性樣品不相容，因此無法直接轉譯結果。 本發明者驚奇地發現，作為活性物質之根據本發明之抗病毒有效普瑞利維藥劑係在4.0至5.0之pH，更佳4.0至4.5之pH，最佳約4.0之pH下更穩定。因此，本發明亦提供(例如)用於局部施用之特定軟膏調配物，其pH為4.0至5.0，更佳pH為4.0至4.5，最佳pH為約4.0，然而眾所周知此為歸因於水性組分之極低濃縮的表觀pH。 在此背景下，重要的是應注意，本發明者之穩定性分析揭示在4.0至5.0之範圍內的表觀pH值對普瑞利維活性醫藥成分之純度無任何影響。因此，表觀pH之量測偏移對本發明普瑞利維活性醫藥成分(例如，含於其軟膏調配物中)之分析及純度無影響。 在又一特定實施例中，本發明提供用於局部施用於有需要個體的醫藥調配物，該調配物為軟膏調配物，其包含： (i) 17.5 % w/w PEG 4000， (ii) 9.78 % w/w丙二醇， (iii) 5 % w/w普瑞利維游離鹼半水合物， (iv) 0.1 % w/w丁基化羥基甲苯(BHT)， (v) 55 %至67.62 % w/w Super RefinedTM
PEG 400，及 (vi) 0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液， 其中該醫藥調配物具有4.0至5.0之pH值，較佳4.0至4.5之pH值。 在上文段落里，應注意，該pH值係指表觀pH。 在上文段落及整個文本之背景下，應注意，表述「55 %至67.62 % w/w Super RefinedTM
PEG 400」意指，在本發明背景下，當前臨床軟膏調配物包含最初添加之55 % w/w Super RefinedTM
PEG 400，且此係藉由第二次添加Super RefinedTM
PEG 400填充至67.62 % w/w Super RefinedTM
PEG 400含於該臨床軟膏調配物之最終量。 在又一特定實施例中，本發明提供用於局部施用於有需要個體的醫藥調配物，該調配物為軟膏調配物，其包含： (i) 17.5 % w/w PEG 4000， (ii) 9.78 % w/w丙二醇， (iii) 5 % w/w普瑞利維游離鹼半水合物， (iv) 0.1 % w/w丁基化羥基甲苯(BHT)， (v) 55 % w/w Super RefinedTM
PEG 400，及 (vi) 第二次添加適量Super RefinedTM
PEG 400以構成67.62 % w/w之Super RefinedTM
PEG 400的最終濃度， (vii) 適量之作為pH調節劑之稀HCl或稀NaOH溶液，以達到4.0至5.0之pH值，較佳4.0至4.5之pH值， 其中該醫藥調配物具有4.0至5.0之pH值，較佳4.0至4.5之pH值。 在上文段落里，應注意，該pH值係指表觀pH。 在上文段落及整個文本之背景下，應注意，表述「55 % w/w Super RefinedTM
PEG」及「67.62 % w/w Super RefinedTM
PEG 400」意指，在本發明背景下，當前臨床軟膏調配物包含最初添加之55 % w/w Super RefinedTM
PEG 400，且此係藉由第二次添加Super RefinedTM
PEG 400填充至67.62 % w/w Super RefinedTM
PEG 400含於該臨床軟膏調配物之最終量。 在本發明之一實施例中，如前述實施例中任一項之醫藥調配物為進一步包含0.01至20 % w/w之至少一種pH調節劑的軟膏。 在本發明之另一實施例中，在軟膏醫藥調配物中，該至少一種溶劑之濃度為25至90 % w/w，更佳25至80 % w/w，最佳60至80 % w/w。 在本發明之一實施例中，在軟膏醫藥調配物中，第二溶劑之濃度為0.1至40 % w/w，更佳5至20 % w/w，最佳7.5至10 % w/w。 在本發明之又一實施例中，在軟膏醫藥調配物中，第三溶劑之濃度為0.1至30 % w/w，更佳5至30 % w/w，最佳15至20 % w/w。 在本發明之另一實施例中，在軟膏醫藥調配物中，該抗氧化劑之濃度為0.015至10 % w/w，更佳0.1至5 % w/w，最佳0.1至2 % w/w。 在本發明之又一實施例中，在軟膏醫藥調配物中，該pH調節劑之濃度為0.015至20 % w/w。 在本發明之另一實施例中，在軟膏醫藥調配物中，該pH調節劑之濃度為0.015至20 % w/w以獲得4.0至5.0之pH值。 在本發明之另一實施例中，在軟膏醫藥調配物中，該溶劑係選自包括以下物質之群：聚乙二醇、丙二醇、凡士林、液體石蠟、羊毛脂、礦物油、矽酮油、矽酮衍生物、短鏈脂肪酸甘油單酯、二酯及三酯、中鏈脂肪酸甘油單酯、二酯及三酯、長鏈飽和脂肪酸甘油單酯、二酯及三酯、長鏈不飽和脂肪酸甘油單酯、二酯及三酯、植物油、杏仁油、巴巴蘇油、黑醋栗籽油、琉璃苣油、芥花籽油、蓖麻油、椰子油、魚肝油、玉米油、棉籽油、月見草油、魚油、葡萄籽油、芥菜籽油、燕麥油、橄欖油、棕櫚仁油、棕櫚油、花生油、菜籽油、紅花油、芝麻油、鯊魚肝油、角鯊烷、大豆油、葵花油、核桃油、小麥胚芽油、氫化蓖麻油、氫化椰子油、氫化棉籽油、氫化棕櫚油、氫化大豆油、部分氫化大豆油、氫化植物油、脂肪酸酯、短鏈脂肪酸丙二醇單酯及二酯、中鏈脂肪酸丙二醇單酯及二酯、長鏈飽和脂肪酸丙二醇單酯及二酯、長鏈不飽和脂肪酸丙二醇單酯及二酯、脂肪醇、分支鏈脂肪醇、維生素E、乙酸維生素E酯、生育酚、乙酸生育酚酯、飽和脂肪酸、不飽和脂肪酸。 在本發明之另一實施例中，在軟膏醫藥調配物中，該pH調節劑係選自包括以下物質之群：緩衝液、酸性及鹼性溶液、有機酸(例如檸檬酸、乳酸)、無機酸(鹽酸、硫酸、磷酸)、鹼性試劑(氫氧化鈉、碳酸氫鈉)、葡甲胺。乳膏調配物
本申請案之另一實施例係關於本發明醫藥調配物之乳膏調配物。 在本發明之一實施例中，如前述實施例中任一項之醫藥調配物為進一步包含以下物質之乳膏調配物： (i) 0至5 % w/w防腐劑 (ii) 0至20 % w/w之至少一種界面活性劑 (iii) 1至40 % w/w油相/潤膚劑 (iv) 0至40 % w/w水。 在上文段落及本發明背景下，術語「防腐劑」表示用於藉由分別延緩活性物質及賦形劑之氧化及藉由減少微生物增殖來延長藥物之儲藏壽命的抗微生物物質/藥劑。此等物質之性質係歸因於通常對活細胞具有攻擊性且在人體內使用時會導致某些風險之某些化學基團。 在此背景下，「抗氧化劑」可起防腐劑作用，並因此係根據本發明之該防腐劑的子群。 在本發明之另一實施例中，如前述實施例中任一項之醫藥調配物為進一步包含以下物質之乳膏調配物： (i) ＞ 0至5 % w/w防腐劑 (ii) ＞ 0至20 % w/w之至少一種界面活性劑 (iii) ＞ 1至40 % w/w油相/潤膚劑 (iv) ＞ 0至40 % w/w水。 在本申請案之背景下，摻入防腐劑(抗微生物劑)以降低調配物在製備、儲存及使用期間之微生物污染的風險。 如本文所用，界面活性劑(surfactant)係界面活性藥劑(surface-active agent)之縮寫。界面活性劑係降低表面與液體之間或兩種或更多種不混溶物質之間之張力的任何成分。界面活性劑係同時具有親水性及親油性部分之化學品。此分子組成意指當置於油及水之溶液中時，其等具有降低表面張力之能力。因此，其等起乳化劑作用以形成油及水之穩定混合物。界面活性劑之一些實例為月桂基(lauryl/laureth)硫酸鈉或月桂基硫酸銨、甲椰油醯基牛磺酸鈉、月桂醯基或椰油醯基肌胺酸鈉、椰油醯胺丙基甜菜鹼、三乙醇胺(TEA)化合物、脫乙醇胺(DEA)化合物、單乙醇胺(MEA)化合物、聚乙二醇(PEG) 化合物、Quaternium-7、15、31、60等、月桂基或椰油醯基肌胺酸、油酸醯胺二鈉或磺酸琥珀酸二辛酯。 在本申請案之背景下，潤膚劑或保濕劑為化學試劑之複雜混合物，其等經特殊設計用於使皮膚之外層(表皮)更柔軟及更柔韌。其等藉由減少蒸發來增加皮膚之水合作用。天然存在之皮膚脂質及固醇以及人造或天然油、保濕劑、潤膚劑、潤滑劑等可為商業皮膚保濕劑組合物之一部分。 在本發明之另一實施例中，在乳膏醫藥調配物中，該至少一種溶劑之濃度為0.1至60 % w/w，更佳15至50 % w/w，最佳30至45 % w/w。 在本發明之另一實施例中，在乳膏醫藥調配物中，第二溶劑之濃度為0.1至40 % w/w，更佳5至30 % w/w，最佳10至20 % w/w。 在本發明之一實施例中，在乳膏醫藥調配物中，第三溶劑之濃度為0.1至20 % w/w，更佳2至20 % w/w，最佳3至7 % w/w。 在本發明之另一實施例中，在乳膏醫藥調配物中，該防腐劑之濃度為0.01至5 % w/w，更佳0.025至5 % w/w，最佳1至2 % w/w。 在本發明之一實施例中，在乳膏醫藥調配物中，該抗氧化劑之濃度為0.01至5 % w/w，更佳0.025至1 % w/w，最佳0.05至0.15 % w/w。 在本發明之另一實施例中，在乳膏醫藥調配物中，該界面活性劑之濃度為0.01至20 % w/w，更佳2至18 % w/w，最佳5至15 % w/w。 在本發明之又一實施例中，在乳膏醫藥調配物中，該油相/潤膚劑之濃度為1至20 % w/w，更佳2至15 % w/w，最佳4至10 % w/w。 在本發明之另一實施例中，在乳膏醫藥調配物中，第二界面活性劑之濃度為0.015至20 % w/w，更佳0.5至10 % w/w，最佳1至4 % w/w。 在本發明之又一實施例中，在乳膏醫藥調配物中，水之濃度為0.01至40 % w/w，更佳5至30 % w/w，最佳10至20 % w/w。 在本發明之另一實施例中，在乳膏醫藥調配物中，該防腐劑係選自包括以下物質之群：苯氧基乙醇、苄醇、對羥基苯甲酸酯類(例如對羥基苯甲酸甲酯、對羥基苯甲酸丁酯)及其鹽、苯甲酸及其鹽、四級銨(例如氯化苄二甲烴銨(benzalkonium chloride)、氯化本索寧(benzethonium chloride))、硼酸、氯己定、氯丁醇、甲酚及其衍生物、依地酸及其鹽、偏亞硫酸氫鹽、硫柳汞、亞硫酸鹽、山梨酸。 在本發明之另一實施例中，在乳膏醫藥調配物中，該穿透增強劑係選自包括以下物質之群：丙二醇、聚乙二醇、二甲基亞碸、癸基甲基亞碸、氮酮、N-甲基吡咯啶酮、待乙妥(diethyltoluamide)、乙醇、肉豆蔻酸異丙酯、棕櫚酸異丙酯、油酸及其酯、中等鏈長甘油三酯、異山梨醇二甲酯、2-辛基十二烷醇、分支鏈脂肪酸酯類、苄醇、脲、水楊酸酯類及界面活性劑。 在本發明之一實施例中，在乳膏醫藥調配物中，該界面活性劑係選自包括以下物質之群：烷基聚乙二醇醚、烷基聚乙二醇酯、乙氧基化之醇類、聚氧乙烯山梨糖醇酐脂肪酸酯、蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙二醇氫化蓖麻油、聚氧乙二醇蓖麻油、脂肪酸山梨醇酐酯、環氧乙烷及環氧丙烷之嵌段共聚物，諸如(例如)泊洛沙姆(poloxamer)，較佳泊洛沙姆188、泊洛沙姆407；泰洛沙泊(tyloxapol)；聚山梨醇酯；蔗糖烷基酯；蔗糖烷基醚；短鏈脂肪酸甘油單酯及二酯；中鏈脂肪酸甘油單酯及二酯；長鏈飽和脂肪酸甘油單酯及二酯；長鏈不飽和脂肪酸甘油單酯及二酯；短鏈脂肪酸丙二醇單酯；中鏈脂肪酸丙二醇單酯；長鏈飽和脂肪酸丙二醇單酯；長鏈不飽和脂肪酸丙二醇單酯；聚氧甘油酯；聚氧乙烯烷基酯；聚氧乙烯醚；聚乙二醇琥珀酸維生素E酯、烷基聚甘油酯；基於四級銨之界面活性劑、基於脂肪酸酯之陰離子界面活性劑。 在本發明之又一實施例中，在乳膏醫藥調配物中，其他潤膚劑/油相係選自包括以下物質之群：短鏈脂肪酸甘油單酯、二酯及三酯、中鏈脂肪酸甘油單酯、二酯及三酯、長鏈飽和脂肪酸甘油單酯、二酯及三酯、長鏈不飽和脂肪酸甘油單酯、二酯及三酯、植物油、杏仁油、巴巴蘇油、黑醋栗籽油、琉璃苣油、芥花籽油、蓖麻油、椰子油、魚肝油、玉米油、棉籽油、月見草油、魚油、葡萄籽油、芥菜籽油、燕麥油、橄欖油、棕櫚仁油、棕櫚油、花生油、菜籽油、紅花油、芝麻油、鯊魚肝油、角鯊烷、大豆油、葵花油、核桃油、小麥胚芽油、氫化蓖麻油、氫化椰子油、氫化棉籽油、氫化棕櫚油、氫化大豆油、部分氫化大豆油、氫化植物油、脂肪酸酯、短鏈脂肪酸丙二醇單酯及二酯、中鏈脂肪酸丙二醇單酯及二酯、長鏈飽和脂肪酸丙二醇單酯及二酯、長鏈不飽和脂肪酸丙二醇單酯及二酯、脂肪醇、分支鏈脂肪醇、矽酮油、矽酮衍生物、礦物油、液體石蠟、維生素E、乙酸維生素E酯、生育酚、乙酸生育酚酯、飽和脂肪酸、不飽和脂肪酸、磷脂。凝膠調配物
本申請案之另一實施例係關於本發明醫藥調配物之凝膠調配物。 在本發明之一實施例中，如前述實施例中任一項之醫藥調配物為進一步包含以下物質之凝膠調配物： (i) 0至30 % w/w穿透增強劑 (ii) 0至20 % w/w膠凝劑 (iii) 0至50 % w/w水 (iv) 0.01至20 % w/w之至少一種pH調節劑， (v) 視情況進一步包含約0至5 % w/w之量之防腐劑。 在上文段落背景下，該「穿透增強劑」為皮膚穿透增強劑。 在本發明之另一實施例中，如前述實施例中任一項之醫藥調配物為進一步包含以下物質之凝膠調配物： (i) ＞ 0至30 % w/w穿透增強劑 (ii) ＞ 0至20 % w/w膠凝劑 (iii) ＞ 0至50 % w/w水 (iv) 0.01至20 % w/w之至少一種pH調節劑， (v) 視情況進一步包含約0至5 % w/w之量之防腐劑。 在上文段落背景下，該「穿透增強劑」為皮膚穿透增強劑。 本文所用之術語「穿透增強劑」通常包括改良分子(諸如活性劑)轉運至皮膚中或通過皮膚之藥劑。在身體不同部位之皮膚中或皮膚下面可出現各種情況，導致需要靶向遞送化合物。「穿透增強劑」可用於幫助將活性劑直接遞送至皮膚或下層組織或通過全身分佈間接遞送至疾病部位。穿透增強劑可為純物質或可包含不同化學實體之混合物。 在上文段落背景下，所述亦應用於本發明「皮膚穿透增強劑」。 在本申請案之背景下，凝膠為黏度範圍廣泛之半固體果凍狀調配物。其等係由膠凝劑在溶解或分散於適當介質中時經歷高度交聯或締合來製成。此等膠凝劑賦予特定凝膠之各種不同黏度及性質。膠凝劑為(例如)纖維素衍生物、甲基纖維素(MC)、羧甲基纖維素(CMC)、羥丙基纖維素、卡波姆(Carbomer)、Carbopol®
910、Carbopol®
941、泊洛沙姆、Pluronic®
或土溫(Tween)。 在本發明之又一實施例中，在凝膠醫藥調配物中，該至少一種溶劑之濃度為1至90 % w/w，更佳10至80 % w/w，最佳30至70 % w/w。 在本發明之另一實施例中，在凝膠醫藥調配物中，第二溶劑之濃度為0.1至50 % w/w，更佳5至40 % w/w，最佳15至25 % w/w。 在本發明之又一實施例中，在凝膠醫藥調配物中，該穿透增強劑之濃度為0.1至30 % w/w，更佳5至25 % w/w，最佳10至20 % w/w。 在本發明之又一實施例中，在凝膠醫藥調配物中，該防腐劑之濃度為0.25至5 % w/w，更佳0.5至3 % w/w，最佳1至2 % w/w。 在本發明之另一實施例中，在凝膠醫藥調配物中，該抗氧化劑之濃度為0.01至5 % w/w，更佳0.025至3 % w/w，最佳0.05至2 % w/w。 在本發明之又一實施例中，在凝膠醫藥調配物中，該膠凝劑之濃度為0.01至20 % w/w，更佳0.1至10 % w/w，最佳0.5至5 % w/w。 在本發明之一實施例中，在凝膠醫藥調配物中，該膠凝劑卡波姆之濃度為0.25至5 % w/w，更佳0,5至3 % w/w，最佳1至2 % w/w。 在本發明之又一實施例中，在凝膠醫藥調配物中，水之濃度為0.1至50 % w/w。 在本發明之另一實施例中，在凝膠醫藥調配物中，該pH調節劑之濃度為0.015至20 % w/w。 在本發明之又一實施例中，在凝膠醫藥調配物中，該溶劑為PEG，較佳PEG 400，更佳SR PEG 400。 在本發明之另一實施例中，在凝膠醫藥調配物中，該膠凝劑係選自包括以下物質之群：卡波姆、泊洛沙姆、聚卡波非(polycarbophil)、聚維酮(povidone)、共聚維酮(copovidone)、PVA、乙烯基醚聚合物及共聚物、纖維素及纖維素衍生物、羥丙基纖維素、羥丙基甲基纖維素、乙基纖維素、瓜耳膠、殼聚糖、藻酸及其鹽、角叉菜膠、黃原膠、聚乙二醇、右旋糖、絲蛋白、明膠、瓊脂，較佳卡波姆。特定軟膏調配物
在本發明之又一實施例中，該醫藥調配物為軟膏，其包含0.1至90 % w/w SR PEG 400、0.1至30 % w/w丙二醇、0.1至40 % w/w PEG 4000、0.01至10 % w/w丁基化羥基甲苯及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，更佳10至80 % w/w SR PEG 400、5至20 % w/w丙二醇、5至30 % w/w PEG 4000、0.025至5 % w/w丁基化羥基甲苯及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，最佳25至80 % w/w SR PEG 400、7.5至10 % w/w丙二醇、15至20 % w/w PEG 4000、0.05至0.2 % w/w丁基化羥基甲苯及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液。 在本發明之另一實施例中，醫藥調配物為包含以下在表1中所揭示之範圍內之賦形劑的軟膏：表 1. 軟膏調配物 表 1a. 軟膏調配物 特定乳膏調配物
在本發明之另一實施例中，該醫藥調配物為乳膏，其進一步包含0.1至20 % w/w乙醇、0.1至60 % w/w PEG 400、0.1至40 % w/wTranscutol HP、0.01至5 % w/w苯氧基乙醇、0.01至5 % w/w丁基化氧基甲苯、0.01至10 % w/w Brij-72、0.01至20 % w/w鯨蠟硬脂醇、1至20 % w/w Crodamol GTCC、0.01至20 % w/w Brij-721、0至10 % w/w二甲基矽酮及0.01至40 % w/w水，較佳2至20 % w/w乙醇、15至50 % w/w PEG 400、5至30 % w/wTranscutol HP、0.025至5 % w/w苯氧基乙醇、0.025至1 % w/w丁基化氧基甲苯、0.5至7 % w/w Brij-72、3至15 % w/w鯨蠟硬脂醇、2至15 % w/w Crodamol GTCC、0.5至10 % w/w Brij-721、0.25至5 % w/w二甲基矽酮及5至30 % w/w水；最佳3至7 % w/w乙醇、30至45 % w/w PEG 400、10至20 % w/wTranscutol HP、1至2 % w/w苯氧基乙醇、0.05至15 % w/w丁基化氧基甲苯、1至3 % w/w Brij-72、5至10 % w/w鯨蠟硬脂醇、4至10 % w/w Crodamol GTCC、1至4 % w/w Brij-721、0.5至3 % w/w二甲基矽酮及10至20 % w/w水。 在本發明之另一實施例中，醫藥調配物為包含以下在表2中所揭示之範圍內之賦形劑的乳膏：表 2 ：乳膏調配物 表 2a ：乳膏調配物 特定凝膠調配物
在本發明之另一實施例中，該醫藥調配物為凝膠，其進一步包含1至90 % w/w SR PEG 400、0.1至50 % w/w丙二醇、0.1至30 % w/w異山梨醇二甲酯、0.25至5 % w/w苯氧基乙醇、0.01至5 % w/w丁基化羥基甲苯、0.25至5 % w/w卡波姆、0.1至50 % w/w水及0.0 1至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液(請補充)，更佳10至80 % w/w SR PEG 400、5至40 % w/w丙二醇、5至25 % w/w異山梨醇二甲酯、0.5至3 % w/w苯氧基乙醇、0.025至3 % w/w丁基化羥基甲苯、0.5至3 % w/w卡波姆、0.1至50 % w/w水及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，最佳30至70 % w/w SR PEG 400、15至25 % w/w丙二醇、10至20 % w/w異山梨醇二甲酯、1至2 % w/w苯氧基乙醇、0.05至2 % w/w丁基化羥基甲苯、1至2 % w/w卡波姆、0.1至50 % w/w水及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液。 在本發明之另一實施例中，醫藥調配物為包含以下在表3中所揭示之範圍內之賦形劑的凝膠：表 3 ：凝膠調配物 表 3a ：凝膠調配物
在本發明之又一實施例中，該醫藥調配物為軟膏，其包含67.72 % w/w SR PEG 400、9.78 % w/w丙二醇、17.5 % w/w PEG 4000及5 %活性醫藥成分普瑞利維，其中pH值為pH 4.0至5.0。 在本發明之又一實施例中，該醫藥調配物為軟膏，其包含67.62 % w/w SR PEG 400、9.78 % w/w丙二醇、17.5 % w/w PEG 4000、0.1 % BHT及5 %活性醫藥成分普瑞利維，其中pH值為pH 4.0至4.5。 在本發明之另一實施例中，該醫藥調配物為凝膠，其進一步包含39.1 % w/w SR PEG 400、9.59 % w/w乙醇、4.8 % w/w pH 4緩衝液、23.98 % w/wTranscutol HP、14.39 % w/w異山梨醇二甲酯、1.92 % w/w苄醇、1.25 % w/w羥丙基纖維素。 在本發明之一實施例中，所例示之醫藥調配物係用作藥劑。 在本發明之另一實施例中，該醫藥調配物係用於治療及/或預防疱疹病毒感染。 在本發明之一實施例中，該醫藥調配物係用於治療及/或預防疱疹病毒感染，其中該疱疹病毒係選自單純病毒目。 在本發明之另一實施例中，該醫藥調配物係用於治療及/或預防疱疹病毒感染，其中該單純病毒係選自單純疱疹病毒1 (HSV-1)及單純疱疹病毒2 (HSV-2)。 本發明之另一實施例中係關於治療及/或預防疱疹病毒感染之方法，其包括將局部醫藥調配物投與於有需要個體。游離鹼半水合物
在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以約5.0 % w/w之量存在。 在上文段落及整個文本之背景下，表述「5 % w/w普瑞利維抗病毒劑」或針對本文所揭示之普瑞利維活性醫藥成分之任一者的類似表述表示普瑞利維藥物係以確保最終存在5 % w/w之普瑞利維游離鹼作為活性部分之量添加至局部調配物。此意味著例示性地對於普瑞利維游離鹼半水合物而言，由於存在結晶水，其係以5.11 % w/w添加至局部調配物中，但是將最終導致僅有5 % w/w之游離鹼普瑞利維作為活性部分。此同樣應用於(例如)1.0 %至10 % w/w普瑞利維含於在本發明局部調配物中之情況。因此，基本上及在整個文本中，針對普瑞利維所給定之量係指作為活性部分之最終游離鹼含量；例如，在半水合物的情況下，不考慮存在於普瑞利維游離鹼半水化合物中之當前結晶水。應注意，此應用於整個文本中如本文所呈現。 在本發明之一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以5.0 % w/w之量存在，其中該醫藥組合物為軟膏。 在本發明之又一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以約1.0至約7.5 % w/w，較佳約5.0 % w/w之量存在，其中該醫藥組合物為軟膏，且其中該軟膏係每天投與1至10次、或每天2至10次、或每天3至8次、或每天3至7次、或每天4至6次、或每天5次。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以1.0至7.5 % w/w，較佳5.0 % w/w之量存在，其中該醫藥組合物為軟膏，且其中該軟膏係每天投與1至10次、或每天2至10次、或每天3至8次、或每天3至7次、或每天4至6次、或每天5次，且其中該軟膏係經投與歷時2至14天、3至10天、3至7天、4至5天、或歷時5天、或歷時4天。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以5.0% w/w之量存在，其中該醫藥組合物為軟膏，且其中該軟膏係每天投與5次，且其中該軟膏係經投與歷時4天。 在本發明之另一實施例中，在醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以足夠使接受使用該組合物處理之個體的表皮及真皮達到＞ 10 nM之濃度的量存在。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用作藥劑。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療及/或預防疱疹病毒感染。 在本發明之又一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療及/或預防疱疹病毒感染，其中該疱疹病毒係選自單純病毒目。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療及/或預防該疱疹病毒感染，其中該單純病毒係選自單純疱疹病毒1 (HSV-1)及單純疱疹病毒2 (HSV-2)。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
或其衍生物係用於局部醫藥調配物以治療及/或預防對其有需要之個體中之疱疹病毒感染。 在本發明之又一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
或其衍生物係用於局部醫藥調配物以治療對其有需要之個體中，其中該個體患有疱疹病毒感染或疑似患有疱疹病毒感染。 在本發明之一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於局部投與至其有需要之個體，其中該局部投與係用於面部施用、及/或施用至口腔、生殖器及/或眼睛。 在本發明之一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於局部投與至其有需要之個體，其中該局部投與係用於除了上述段落中明確給出者之外的任何其它身體部位。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於全身性投與於有需要個體，其中該個體疑似患有疱疹病毒感染或為患有疱疹病毒感染之個體。 在本發明之又一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療復發性唇疱疹。 在本發明之特定實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
較佳係提供用於治療復發性唇疱疹。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療選自以下患者之群的復發性唇疱疹：顯示唇疱疹前期階段跡象之患者、患有紅斑之患者、顯示唇丘疹之患者、患有唇囊泡之患者、患有唇部潰瘍及/或軟殼之患者、患有唇部硬殼之患者、患有殘留唇部紅斑之患者。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療生殖器疱疹。 在本發明之又一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療疱疹性角膜炎。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療疱疹性腦膜炎及/或腦炎。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療新生兒疱疹感染。 在本發明之另一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療在免疫功能正常及/或免疫功能不全之個體中的疱疹感染。 在本發明之又一實施例中，在該醫藥調配物中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係用於治療在免疫功能正常及/或免疫功能不全之個體中的疱疹感染，其中該免疫功能不全之個體係選自包括以下患者之群：器官移植接受者、患有另一種病毒或細菌感染(特定言之經HIV及/或另一種疱疹病毒感染)之個體、及對至少一種抗病毒活性劑抵抗之經單純疱疹病毒感染的個體。 在另一實施例中，本發明係關於治療及/或預防疱疹病毒感染之方法，其包括將N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
投與於有需要個體。 術語「預防(prophylaxis/prevention)」或與本發明相關之領域中的類似術語對於一般技術者而言顯然意味著抑制或減少感染復發或抑制或減少單純疱疹病毒亞型1或2感染之傳染。在本發明背景下，術語「預防」不意味著完全不存在來自患者之任何感染性病毒顆粒或受感染細胞，即使在最寬泛的合理解釋下。在本發明背景下，此定位係在與所揭示之標的相關之技術中係合理的。為了支持術語「預防」之此等定義，以下出版物以引用之方式併入本文中： Abdool Karim,S.S.等人(2015)。 Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection. N Engl. J Med 373, 530-539。 Andrei,G.等人(2011)。Topical tenofovir, a microbicide effective against HIV, inhibits herpes simplex virus-2 replication. Cell Host. Microbe 10, 379-389。 Corey, L.等人(2004)。Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N. Engl. J. Med. 350, 11-20。 Kleymann, G.等人(2002)。New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat. Med. 8, 392-398。 Mertz, G.J.等人(1985)。Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm. Dis. 12, 33-39。 Reitano, M.等人(1998)。Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J. Infect. Dis. 178, 603-610。 Schiffer, J.T.等人(1997)。Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J. Clin Invest 99, 1092-1097。 Wald, A.等人(2014)。Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl. J Med 370, 201-210。 Wald, A.等人(2000)。Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 342, 844-850。 Zhu, J.等人(2007)。Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595-603。 Gold, D.及Corey,L.，MINIREVIEW Acyclovir Prophylaxis for Herpes Simplex Virus Infection. Antimicrobial Agents and Chemotherapy, 1987年3月，第361至367頁。 Tyring, S.、Baker,D.、Snowden, W.，Valacyclovir for Herpes Simplex Virus Infection: Long-Term Safety and Sustained Efficacy after 20 Years’ Experience with Acyclovir. The Journal of Infectious Diseases 2002; 186(增刊1):S40–6。 此等文獻支持解旋酶-引子酶抑制作用與防止單純疱疹病毒感染之傳染之間的相關性，如此項技術中已經證實。此外，上述Kleymann，2002，在第396頁左欄底部教示，復發性疾病及無症狀病毒脫落幾乎被解旋酶-引子酶抑制劑完全抑制，此將減少人與人之間之傳染，即有效防止HSV之傳染。上述Corey，2004，中之揭示在第11頁底部及第17頁第一欄中教示，使用伐昔洛韋(valacyclovir)之一天一次抑制療法顯著降低異性HSV-2不一致伴侶之間之生殖器疱疹的傳染風險，即，防止其傳染。該研究藉由已顯示抑制生殖器黏膜表面上之2型HSV (HSV-2)脫落的藥物實現了此等結果。參見第11頁頂部。此外，已發現，在生殖器黏膜表面上亞臨床脫落之HSV的頻率及數量係傳染感染之主要來源。參見引用20至22，以所列舉之順序追溯至1997年、1998年及1997年。因此，減少在生殖器黏膜表面上亞臨床脫落之HSV的頻率及數量之方法係實現防止疱疹傳染的一種方式。 Karim，2015，在第530頁底部教示，基於其中之研究，顯示田諾弗(tenofovir)凝膠之性交前(pericoital)施用減少女性之HSV-2獲得，即防止獲得HSV。效果為減少51%。參見第534頁，第二欄。在追溯至2010年之同一組的早期研究(參見本文參考文獻引用6)中顯示，田諾弗之局部陰道-凝膠調配物的性交前施用減少了HIV獲得。雖然HIV係不同之病毒，但鑑於上述情況，一般技術者並非不可相信，一種藥物能夠防止獲得病毒感染。此外，在HSV之情況下，Karim明確證實了這一點。Gold及Corey在1987年3月支持熟知之阿昔洛維(即，病毒DNA聚合酶抑制劑)之有效預防。另外，Tyring等人在2002年支持前藥伐昔洛韋(即，病毒DNA聚合酶抑制劑)之療效。 熟習此項技術者知曉，在HSV-1及HSV-2感染之情況下，儘管病毒因感染而存在於體內，但並無症狀爆發，因為N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物有效地抑制病毒脫落及爆發，此「預防」或「抑制」HSV-1及HSV-2感染之所得症狀。在本發明預防=抑制之態樣的又一支持中，重申上述針對伐昔洛韋(即，Tyring等人2002)及阿昔洛維(即，Gold等人1987)之引用，其亦證明，公認HSV感染係在正常個體中無症狀，及預防/抑制療法在此技術中之意義。此外，有效HSV預防係在臨床上在人體試驗中得到證實。就此而言，來自ICAAC 2014之關於HSV-2生殖器疱疹適應症之海報係以引用之方式併入(前述Wald等人，2014)。最後，一般技術者知曉，類似於田諾弗，已知N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物作為解旋酶-引子酶抑制劑在HIV之情況下比田諾弗具有更高之抗病毒療效，且因此，對於熟習此項技術者，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺亦將預計具有更顯著之預防療效。就此而言，尤其相關的係上述Andrei等人及Kleymann等人之出版物。其中證實，當與N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物比較時，田諾弗之IC50
值係顯著更高。製備該游離鹼半水合物之方法
本發明之另一實施例係關於製備N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
之方法，其中該方法包括以下步驟： a) 將4-吡啶-2-基-苯基)-乙酸及胺基噻唑磺酸醯胺在N-甲基吡咯啶酮(NMP)中混合； b) 冷卻在步驟a)中所獲得之混合物； c) 將N-乙基-N'-(3-二甲基胺基丙基)-碳二醯亞胺鹽酸鹽(EDC x HCl)添加至步驟b)中所獲得之該混合物中； d) 攪拌步驟c)中所獲得之溶液並添加至純H2
O； e) 過濾在步驟d)中所獲得之溶液； f) 洗滌在步驟e)中所獲得之產物濾餅； g) 乾燥在步驟f)中所獲得之產物； h) 將H2
O添加至在步驟g)中所獲得之溶液; i) 攪拌在步驟h)中所獲得之懸浮液； j) 冷卻在步驟i)中所獲得之懸浮液； k) 攪拌在步驟j)中所獲得之懸浮液； l) 藉由過濾在步驟k)中所獲得之懸浮液來分離產物； m) 使用H2
O洗滌步驟l)中所獲得之產物； n) 乾燥在步驟m)中所獲得之產物。 在本發明之另一實施例中，包含N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
的醫藥組合物係可藉由如前述實施例中所述之方法獲得。 在本發明之一實施例中，醫藥組合物係可藉由調配藉由如前述實施例中所述之方法所獲得之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
與至少一種醫藥賦形劑獲得。 本發明之另一實施例係關於N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
的用途，其係在如前述實施例中所述之方法中可獲得作為藥劑。馬來酸鹽
本發明之另一實施例係關於包含游離鹼馬來酸鹽
之醫藥組合物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼馬來酸鹽係以約5.0 % w/w之量存在。 在上文段落及整個文本之背景下，表述「5 % w/w普瑞利維抗病毒劑」或針對本文所揭示之普瑞利維活性醫藥成分之任一者的類似表述表示普瑞利維藥物係以確保最終存在5 % w/w之普瑞利維游離鹼作為活性部分之量添加至局部調配物。此意味著例示性地對於普瑞利維馬來酸鹽而言，其係以可超過該5 % w/w之量添加至局部調配物中，但將最終導致僅有5 % w/w之游離鹼普瑞利維作為活性部分。此同樣應用於(例如)1.0 %至10 % w/w普瑞利維馬來酸鹽含於在本發明局部調配物中之情況。因此，基本上及在整個文本中，針對普瑞利維所給定之量係指作為活性部分之最終游離鹼含量。 本發明之另一較佳實施例係關於包含游離鹼馬來酸鹽
之醫藥組合物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼馬來酸鹽係以約1.0至約7.5 % w/w，特定言之約5.0% w/w之量存在。 本發明之另一實施例係關於N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之馬來酸鹽
，其中當該耐光性係藉由使用按照「歐洲藥典」及/或「美國藥典」之藥典方法進行測定時，該馬來酸鹽之特徵在於在經300 nm至800 nm範圍內之波長，及至少120萬勒克斯小時之曝光量，及至少200瓦小時/m²之曝光能量曝光至少29小時後之耐光性為至少殘餘70% N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼。 本發明之又一實施例係關於如前述實施例之馬來酸鹽
，其中當藉由使用按照「歐洲藥典」及/或「美國藥典」之藥典方法進行測定時，該馬來酸鹽之特徵進一步在於具有特徵XRPD波峰6.6、15.9、16.2、18.1、20.5、22.5、26.1及28.6 2θ。 本發明之另一實施例係關於如前述實施例之馬來酸鹽
，其中當藉由使用按照「歐洲藥典」及/或「美國藥典」之藥典方法進行測定時，該馬來酸鹽係物理化學穩定的，其特徵在於在室溫下及在3.5至7.0之pH下在水溶液中儲存兩週後，該馬來酸鹽之回收率為起始濃度之至少85%。 本發明之另一實施例係關於如前述實施例之馬來酸鹽
，其中當藉由使用按照「歐洲藥典」及/或「美國藥典」之藥典方法進行測定時，該馬來酸鹽之特徵在於在水中的溶解度為約0.48mg / mL。 本發明之又一實施例係關於包含游離鹼馬來酸鹽之醫藥組合物，其中當藉由使用按照「歐洲藥典」及/或「美國藥典」之藥典方法進行測定時，其中該馬來酸鹽
係以足夠使接受使用該組合物局部治療之方法的個體之表皮及真皮中的濃度≥ 10 nM之量存在。 本發明之另一實施例係關於包含游離鹼馬來酸鹽
之醫藥組合物，其用於治療及/或預防疱疹病毒感染。 本發明之另一實施例係關於製備如前述實施例中所定義之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之馬來酸鹽
的方法，該方法包括以下步驟： i) 提供混合裝置，較佳配有頂置攪拌之混合裝置， ii) 用460至490 g普瑞利維游離鹼填充步驟i)之該混合裝置， iii) 用3至5體積之水使步驟ii)之普瑞利維游離鹼懸浮， iv) 藉由合適加熱裝置將步驟iii)之懸浮液加熱至45至55℃， v) 在40至90分鐘之時間內添加225至240 g呈固體形式之馬來酸直至獲得最終溶液， vi) 使在步驟v)下所獲得之溶液冷卻至44至52℃ vii) 將用游離鹼普瑞利維之馬來酸鹽接種等份之步驟vi)溶液， viii) 在1.5至2.5小時時間段內，允許使步驟vii)之所得懸浮液冷卻至18至24℃， ix) 之後攪拌步驟viii)之懸浮液過夜， x) 過濾步驟ix)之懸浮液，以獲得所得濾餅， xi) 將在步驟x)下所獲得之固體濾餅轉移至混合裝置，較佳燒瓶中， xii) 將步驟xi)之混合裝置旋轉蒸發25-32小時，同時應用以下條件： a. 30至40℃之環境溫度， b. 15至25毫巴之壓力， 以獲得恆定質量， xiii) 之後進行均質化，較佳使用研缽及研杵進行均質化， xiv) 以獲得本發明普瑞利維之游離鹼之馬來酸鹽。 鑒於本發明描述，熟習此項技術者將明瞭本發明之各種態樣之其他修飾及替代實施例。因此，本發明描述應被理解為僅具說明性且其旨在教示熟習此項技術者實行本發明之一般方式。應明白文中所示且所述的本發明之形式應被視作實施例之實例。熟習此項技術者在知曉本發明描述內容之益處後將明白可用元件及材料替代彼等文中所述的元件及材料，可倒換部件及過程，且可獨立地使用本發明之某些特徵。在不脫離如以下實施例所述之本發明之精神及範圍的情況下，可對文中所述之元件進行改變。 在上文背景下，以下連續編號之實施例提供本發明之其他特定態樣： 1. 一種用於局部施用於有需要個體的醫藥調配物，該調配物包含： i.) 1至10 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， ii.) 0至90 % w/w之至少一種溶劑， iii.) 0至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有2.0至8.0之pH值，較佳4.0至5.0之pH， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月， 其中該溶劑係選自包括乙醇、異山梨醇二甲酯、異丙醇、Transcutol P、丙二醇、聚乙二醇、PEG 400、PEG 4000及Super RefinedTM (SR) PEG 400之群。 在與實施例1相鄰之實施例中，該醫藥調配物之pH值較佳為4.0至4.5。 在與實施例1相鄰之實施例中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 2. 如實施例1中所定義之用於局部施用於有需要個體的醫藥調配物，其中該至少一種溶劑係選自包括聚乙二醇之群，較佳PEG 400，更佳SR PEG 400。 3. 如實施例1中所定義之用於局部施用於有需要個體的醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺係選自包括以下化合物之群： • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之甲磺酸鹽
，及 • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
。 4. 如實施例1至3中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該抗氧化劑係選自包括丁基化羥基甲苯(BHT)、丁基化羥基苯甲醚(BHA)、抗壞血酸、棕櫚酸抗壞血酯、生育酚、乙酸生育酚酯、沒食子酸丙酯、沒食子酸十二酯、沒食子酸辛酯、硫代硫酸鹽之群。 5. 如實施例1至4中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其中該抗氧化劑為BHT。 6. 如實施例1至5中任一項之用於局部施用於有需要個體的醫藥調配物，該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠之調配物。 在與實施例6相鄰之實施例中，該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠及貼片之調配物。 7. 如實施例1至6中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中活性醫藥成分普瑞利維之濃度係選自1.1至10 % w/w，更佳1.1至5 % w/w之範圍。 8. 如實施例1至7中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該至少一種溶劑之濃度為0.1至90 % w/w，例如5至90 % w/w、10至90 % w/w、10至80 % w/w、20至80 w/w、25至80 % w/w、15至50 % w/w或30至45 % w/w。 9. 如實施例1至8中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中第二溶劑之濃度為0.1至60 % w/w，更佳10至50 % w/w，最佳10至40 % w/w。 10. 如實施例1至9中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該抗氧化劑之濃度為0.01至10 % w/w，更佳0.025至5 % w/w，最佳0.05至2 % w/w。 11. 如實施例1至10中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為進一步包含以下之軟膏： (i) 0.01至20 % w/w之至少一種pH調節劑。 12. 如實施例11所定義之用於局部施用於有需要個體的醫藥調配物，其中對於該軟膏調配物而言，該至少一種溶劑之濃度為25至90 % w/w，更佳25至80 % w/w，最佳60至80 % w/w。 13. 如實施例11至12中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於軟膏調配物而言，第二溶劑之濃度為0.1至40 % w/w，更佳5至20 % w/w，最佳7.5至10 % w/w。 14. 如實施例11至13中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於軟膏調配物而言，第三溶劑之濃度為0.1至30 % w/w，更佳5至-30 % w/w，最佳15至20 % w/w。 15. 如實施例11至14中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於軟膏調配物而言，該抗氧化劑之該濃度為0.015至10 % w/w，更佳0.1至5 % w/w，最佳0.1至2 % w/w。 16. 如實施例11至15中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於軟膏調配物而言，該pH調節劑之濃度為0.015至20 % w/w。 17. 如實施例11至16中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於軟膏調配物而言，該溶劑係選自包括以下物質之群：聚乙二醇、丙二醇、凡士林、液體石蠟、羊毛脂、礦物油、矽酮油、矽酮衍生物、短鏈脂肪酸甘油單酯、二酯及三酯、中鏈脂肪酸甘油單酯、二酯及三酯、長鏈飽和脂肪酸甘油單酯、二酯及三酯、長鏈不飽和脂肪酸甘油單酯、二酯及三酯、植物油、杏仁油、巴巴蘇油、黑醋栗籽油、琉璃苣油、芥花籽油、蓖麻油、椰子油、魚肝油、玉米油、棉籽油、月見草油、魚油、葡萄籽油、芥菜籽油、燕麥油、橄欖油、棕櫚仁油、棕櫚油、花生油、菜籽油、紅花油、芝麻油、鯊魚肝油、角鯊烷、大豆油、葵花油、核桃油、小麥胚芽油、氫化蓖麻油、氫化椰子油、氫化棉籽油、氫化棕櫚油、氫化大豆油、部分氫化大豆油、氫化植物油、脂肪酸酯、短鏈脂肪酸丙二醇單酯及二酯、中鏈脂肪酸丙二醇單酯及二酯、長鏈飽和脂肪酸丙二醇單酯及二酯、長鏈不飽和脂肪酸丙二醇單酯及二酯、脂肪醇、分支鏈脂肪醇、維生素E、乙酸維生素E酯、生育酚、乙酸生育酚酯、飽和脂肪酸、不飽和脂肪酸。 18. 如實施例1至17中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該pH調節劑係選自包括以下物質之群：緩衝液、酸性及鹼性溶液、有機酸(例如檸檬酸、乳酸)、無機酸(鹽酸、硫酸、磷酸)、鹼性試劑(氫氧化鈉、碳酸氫鈉)、葡甲胺。 在實施例18之背景下及在本發明之背景下，應注意，pH調節劑係在「表觀pH調節劑」之意義上進行使用。本發明局部調配物之所有給定pH值均係指表觀pH。 19. 如實施例1至10中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為進一步包含以下之乳膏： i. 0至5 % w/w之防腐劑 ii. 0至20 % w/w之至少一種界面活性劑 iii. 1至40 % w/w油相/潤膚劑 iv. 0至40 % w/w水。 20. 如實施例19所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，該至少一種溶劑之濃度為0.1至60 % w/w，更佳15至50 % w/w，最佳30至45 % w/w。 21. 如實施例19至20中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，第二溶劑之濃度為0.1至40 % w/w，更佳5至30 % w/w，最佳10至20 % w/w。 22. 如實施例19至21中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，第三溶劑之濃度為0.1至20 % w/w，更佳2至20 % w/w，最佳3至7 % w/w。 23. 如實施例19至22中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，該防腐劑之濃度為0.01至5 % w/w，更佳0.025至5 % w/w，最佳1至2 % w/w。 24. 如實施例19至23中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，該抗氧化劑之濃度為0.01至5 % w/w，更佳0.025至1 % w/w，最佳0.05至0.15 % w/w。 25. 如實施例19至24中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，該界面活性劑之濃度為0.01至20 % w/w，更佳2至18 % w/w，最佳5至15 % w/w。 26. 如實施例19至25中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，該油相/潤膚劑之濃度為1至20 % w/w，更佳2至15 % w/w，最佳4至10 % w/w。 27. 如實施例19至26中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，第二界面活性劑之濃度為0.015至20 % w/w，更佳0.5至10 % w/w，最佳1至4 % w/w。 28. 如實施例19至27中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於乳膏調配物而言，水之濃度為0.01至40 % w/w，更佳5至30 % w/w，最佳10至20 % w/w。 29. 如實施例1至28中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該防腐劑係選自包括以下物質之群：苯氧基乙醇、苄醇、對羥基苯甲酸酯類(例如對羥基苯甲酸甲酯、對羥基苯甲酸丁酯)及其鹽、苯甲酸及其鹽、四級銨(例如氯化苄二甲烴銨、氯化本索寧)、硼酸、氯己定、氯丁醇、甲酚及其衍生物、依地酸及其鹽、偏亞硫酸氫鹽、硫柳汞、亞硫酸鹽、山梨酸。 30. 如實施例1至29中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該穿透增強劑係選自包括以下物質之群：丙二醇、聚乙二醇、二甲基亞碸、癸基甲基亞碸、氮酮、N-甲基吡咯啶酮、待乙妥、乙醇、肉豆蔻酸異丙酯、棕櫚酸異丙酯、油酸及其酯、中等鏈長甘油三酯、異山梨醇二甲酯、2-辛基十二烷醇、分支鏈脂肪酸酯類、苄醇、脲、水楊酸酯類及界面活性劑。 在實施例30及整個文本之背景下，「穿透增強劑」為「皮膚穿透增強劑」。 31. 如實施例1至30中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該界面活性劑係選自包括以下物質之群：烷基聚乙二醇醚、烷基聚乙二醇酯、乙氧基化之醇類、聚氧乙烯山梨糖醇酐脂肪酸酯、蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙二醇氫化蓖麻油、聚氧乙二醇蓖麻油、脂肪酸山梨醇酐酯、環氧乙烷及環氧丙烷之嵌段共聚物，諸如(例如)泊洛沙姆，較佳泊洛沙姆188、泊洛沙姆407；泰洛沙泊；聚山梨醇酯；蔗糖烷基酯；蔗糖烷基醚；短鏈脂肪酸甘油單酯及二酯；中鏈脂肪酸甘油單酯及二酯；長鏈飽和脂肪酸甘油單酯及二酯；長鏈不飽和脂肪酸甘油單酯及二酯；短鏈脂肪酸丙二醇單酯；中鏈脂肪酸丙二醇單酯；長鏈飽和脂肪酸丙二醇單酯；長鏈不飽和脂肪酸丙二醇單酯；聚氧甘油酯；聚氧乙烯烷基酯；聚氧乙烯醚；聚乙二醇琥珀酸維生素E酯、烷基聚甘油酯；基於四級銨之界面活性劑、基於脂肪酸酯之陰離子界面活性劑。 32. 如實施例1至31中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該潤膚劑/油相係選自包括以下物質之群：短鏈脂肪酸甘油單酯、二酯及三酯、中鏈脂肪酸甘油單酯、二酯及三酯、長鏈飽和脂肪酸甘油單酯、二酯及三酯、長鏈不飽和脂肪酸甘油單酯、二酯及三酯、植物油、杏仁油、巴巴蘇油、黑醋栗籽油、琉璃苣油、芥花籽油、蓖麻油、椰子油、魚肝油、玉米油、棉籽油、月見草油、魚油、葡萄籽油、芥菜籽油、燕麥油、橄欖油、棕櫚仁油、棕櫚油、花生油、菜籽油、紅花油、芝麻油、鯊魚肝油、角鯊烷、大豆油、葵花油、核桃油、小麥胚芽油、氫化蓖麻油、氫化椰子油、氫化棉籽油、氫化棕櫚油、氫化大豆油、部分氫化大豆油、氫化植物油、脂肪酸酯、短鏈脂肪酸丙二醇單酯及二酯、中鏈脂肪酸丙二醇單酯及二酯、長鏈飽和脂肪酸丙二醇單酯及二酯、長鏈不飽和脂肪酸丙二醇單酯及二酯、脂肪醇、分支鏈脂肪醇、矽酮油、矽酮衍生物、礦物油、液體石蠟、維生素E、乙酸維生素E酯、生育酚、乙酸生育酚酯、飽和脂肪酸、不飽和脂肪酸、磷脂。 33. 如實施例1至10中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為進一步包含以下之凝膠： (i) 0至30 % w/w穿透增強劑 (ii) 0至20 % w/w之至少一種膠凝劑 (iii) 0至50 % w/w水 (iv) 0.01至20 % w/w之至少一種pH調節劑， (v) 視情況進一步包含約0至5 % w/w之量之防腐劑。 34. 如實施例33所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該至少一種溶劑之濃度為1至90 % w/w，更佳10至80 % w/w，最佳30至70 % w/w。 35. 如實施例33至34中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，第二溶劑之濃度為0.1至50 % w/w，更佳5至40 % w/w，最佳15至25 % w/w。 36. 如實施例33至35中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該穿透增強劑之濃度為0.1至30 % w/w，更佳5至25 % w/w，最佳10至20 % w/w。 37. 如實施例33至36中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該防腐劑之濃度為0.25至5 % w/w，更佳0.5至3 % w/w，最佳1至2 % w/w。 38. 如實施例33至37中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該抗氧化劑之濃度為0.01至5 % w/w，更佳0.025至3 % w/w，最佳0.05至2 % w/w。 39. 如實施例33至38中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該膠凝劑之濃度為0.01至20 % w/w，更佳0.1至10 % w/w，最佳0.5至5 % w/w。 40. 如實施例33至39中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該膠凝劑卡波姆之濃度為0.25至5 % w/w，更佳0.5至3 % w/w，最佳1至2 % w/w。 41. 如實施例33至40中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，水之濃度為0.1至50 % w/w。 42. 如實施例33至41中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該pH調節劑之濃度為0.015至20 % w/w。 43. 如實施例33至42中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中對於凝膠調配物而言，該溶劑為PEG，較佳PEG 400，更佳SR PEG 400。 44. 如實施例1至43中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該膠凝劑係選自包括以下物質之群：卡波姆、泊洛沙姆、聚卡波非、聚維酮、共聚維酮、PVA、乙烯基醚聚合物及共聚物、纖維素及纖維素衍生物、羥丙基纖維素、羥丙基甲基纖維素、乙基纖維素、瓜耳膠、殼聚糖、藻酸及其鹽、角叉菜膠、黃原膠、聚乙二醇、右旋糖、絲蛋白、明膠、瓊脂，較佳卡波姆。 45. 如實施例1至18中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為軟膏，其包含0.1至90 % w/w SR PEG 400、0.1至30 % w/w丙二醇、0.1至40 % w/w PEG 4000、0.01至10 % w/w丁基化羥基甲苯及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，更佳10至80 % w/w SR PEG 400、5至20 % w/w丙二醇、5至30 % w/w PEG 4000、0.025至5 % w/w丁基化羥基甲苯及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，最佳25至80 % w/w SR PEG 400、7.5至10 % w/w丙二醇、15至20 % w/w PEG 4000、0.05至0.2 % w/w丁基化羥基甲苯及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液。 46. 如實施例1至10及19至32中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為乳膏，其包含0.1至20 % w/w乙醇、0.1至60 % w/w PEG 400、0.1至40 % w/wTranscutol HP、0.01至5 % w/w苯氧基乙醇、0.01至5 % w/w丁基化氧基甲苯、0.01至10 % w/w Brij-72、0.01至20 % w/w鯨蠟硬脂醇、1至20 % w/w Crodamol GTCC、0.01至20 % w/w Brij-721、0至10 % w/w二甲基矽酮及0.01至40 % w/w水，較佳2至20 % w/w乙醇、15至50 % w/w PEG 400、5至30 % w/wTranscutol HP、0.025至5 % w/w苯氧基乙醇、0.025至1 % w/w丁基化氧基甲苯、0.5至7 % w/w Brij-72、3至15 % w/w鯨蠟硬脂醇、2至15 % w/w Crodamol GTCC、0.5至10 % w/w Brij-721、0.25至5 % w/w二甲基矽酮及5至30 % w/w水；最佳3至7 % w/w乙醇、30至45 % w/w PEG 400、10至20 % w/wTranscutol HP、1至2 % w/w苯氧基乙醇、0.05至15 % w/w丁基化氧基甲苯、1至3 % w/w Brij-72、5至10 % w/w鯨蠟硬脂醇、4至10 % w/w Crodamol GTCC、1至4 % w/w Brij-721、0.5至3 % w/w二甲基矽酮及10至20 % w/w水。 47. 如實施例1至10及33至44中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為凝膠，其包含1至90 % w/w SR PEG 400、0.1至50 % w/w丙二醇、0.1至30 % w/w異山梨醇二甲酯、0.25至5 % w/w苯氧基乙醇、0.01至5 % w/w丁基化羥基甲苯、0.25至5 % w/w卡波姆、0.1至50 % w/w水及0.0 1至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，更佳10至80 % w/w SR PEG 400、5至40 % w/w丙二醇、5至25 % w/w異山梨醇二甲酯、0.5至3 % w/w苯氧基乙醇、0.025至3 % w/w丁基化羥基甲苯、0.5至3 % w/w卡波姆、0.1至50 % w/w水及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液，最佳30至70 % w/w SR PEG 400、15至25 % w/w丙二醇、10至20 % w/w異山梨醇二甲酯、1至2 % w/w苯氧基乙醇、0.05至2 % w/w丁基化羥基甲苯、1至2 % w/w卡波姆、0.1至50 % w/w水及0.01至20 % w/w作為pH調節劑之稀HCl或稀NaOH溶液。 48. 如實施例1至47中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為軟膏，其包含67.72 % w/w SR PEG 400、9.78 % w/w丙二醇、17.5 % w/w PEG 4000及5 %活性醫藥成分普瑞利維，其中pH值為pH 4.0至5.0。 49. 如實施例1至48中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為凝膠，其包含39.1 % w/w SR PEG 400、9.59 % w/w乙醇、4.8 % w/w pH 4緩衝液、23.98 % w/wTranscutol HP、14.39 % w/w異山梨醇二甲酯、1.92 % w/w苄醇、1.25 % w/w羥丙基纖維素。 50. 如實施例1至49中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其用作藥劑。 51. 如實施例1至50中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其用於治療及/或預防疱疹病毒感染。 52. 如實施例1至51中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其用於治療及/或預防疱疹病毒感染，其中該疱疹病毒係選自單純病毒目。 53. 如實施例1至52中任一項中所定義之用於局部施用於有需要個體的醫藥調配物，其用於治療及/或預防如實施例51至52之疱疹病毒感染，其中該單純病毒係選自單純疱疹病毒1 (HSV-1)及單純疱疹病毒2 (HSV-2)。 54. 一種治療及/或預防疱疹病毒感染之方法，其包括將如實施例1至53中任一項所定義之局部醫藥調配物投與於有需要個體。 55. 如實施例1至54中任一項中所定義之局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以約5.0 % w/w之量存在。 56. 如實施例1至54中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以5.0 % w/w之量存在，其中該醫藥組合物為軟膏。 57. 如實施例1至56中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以約1.0至約7.5 % w/w，較佳約5.0 % w/w之量存在，其中該醫藥組合物為軟膏，且其中該軟膏係每天投與1至10次、或每天2至10次、或每天3至8次、或每天3至7次、或每天4至6次、或每天5次。 58. 如實施例1至57中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以1.0至7.5 % w/w，較佳5.0 % w/w之量存在，其中該醫藥組合物為軟膏，且其中該軟膏係每天投與1至10次、或每天2至10次、或每天3至8次、或每天3至7次、或每天4至6次、或每天5次，且其中該軟膏係經投與歷時2至14天、3至10天、3至7天、4至5天、或歷時5天、或歷時4天。 59. 如實施例1至58中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以5.0 % w/w之量存在，其中該醫藥組合物為軟膏，且其中該軟膏係每天投與5次，且其中該軟膏係經投與歷時4天。 60. 如實施例1至59中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
係以足夠使接受使用該組合物處理之個體的表皮及真皮達到＞ 10 nM之濃度的量存在。 61. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療及/或預防疱疹病毒感染。 62. 一種用於治療及/或預防疱疹病毒感染之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其中該疱疹病毒係選自單純病毒目。 63. 如實施例62之用於治療及/或預防疱疹病毒感染的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其中該單純病毒係選自單純疱疹病毒1 (HSV-1)及單純疱疹病毒2 (HSV-2)。 64. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
或其衍生物，其係用於局部醫藥調配物以治療及/或預防對其有需要之個體中之疱疹病毒感染。 65. 一種用於治療對其有需要之個體中之局部醫藥調配物的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
或其衍生物，其中該個體患有疱疹病毒感染或疑似患有疱疹病毒感染。 66. 一種用於局部投與於有需要個體的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其中該局部投與係用於面部施用、及/或施用至口腔、生殖器及/或眼睛。 67. 一種用於全身性投與於有需要個體的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其中該個體疑似患有疱疹病毒感染或為患有疱疹病毒感染之個體。 68. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療復發性唇疱疹。 69. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療選自以下患者之群的復發性唇疱疹：顯示唇疱疹前期階段跡象之患者、患有紅斑之患者、顯示唇丘疹之患者、患有唇囊泡之患者、患有唇部潰瘍及/或軟殼之患者、患有唇部硬殼之患者、患有殘留唇部紅斑之患者。 70. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療生殖器疱疹。 71. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療疱疹性角膜炎。 72. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療疱疹性腦膜炎及/或腦炎。 73. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療新生兒疱疹感染。 74. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其用於治療在免疫功能正常及/或免疫功能不全之個體中的疱疹感染。 75. 一種用於治療在免疫功能正常及/或免疫功能不全之個體中之疱疹感染的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
，其中該免疫功能不全之個體係選自包括以下患者之群：器官移植接受者、患有另一種病毒或細菌感染(特定言之經HIV及/或另一種疱疹病毒感染)之個體、及對至少一種抗病毒活性劑抵抗之經單純疱疹病毒感染的個體。 76. 一種治療及/或預防疱疹病毒感染之方法，其包括將N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
投與於有需要個體。 77. 一種製備N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
之方法，其中該方法包括以下步驟： a) 將4-吡啶-2-基-苯基)-乙酸及胺基噻唑磺酸醯胺在N-甲基吡咯啶酮(NMP)中混合； b) 冷卻在步驟a)中所獲得之化合物； c) 將N-乙基-N'-(3-二甲基胺基丙基)-碳二醯亞胺鹽酸鹽(EDC x HCl)添加至步驟b)中所獲得之該混合物中； d) 攪拌步驟c)中所獲得之溶液並添加至純H2
O； e) 過濾在步驟d)中所獲得之溶液； f) 洗滌在步驟e)中所獲得之產物濾餅； g) 乾燥在步驟f)中所獲得之產物； h) 將H2
O添加至在步驟g)中所獲得之溶液; i) 攪拌在步驟h)中所獲得之懸浮液； j) 冷卻在步驟i)中所獲得之懸浮液； k) 攪拌在步驟j)中所獲得之懸浮液； l) 藉由過濾在步驟k)中所獲得之懸浮液來分離產物； m)使用H2
O洗滌步驟l)中所獲得之產物； n) 乾燥在步驟m)中所獲得之產物； 78. 一種醫藥組合物，其包含在如實施例77之方法中可獲得的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
。 79. 一種醫藥組合物，其可藉由調配在如實施例77之方法中可獲得的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
與至少一種醫藥賦形劑獲得。 80. 一種在如實施例77之方法中可獲得的N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼半水合物
的用途，其用作藥劑。 81. 如實施例1至80中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼馬來酸鹽
係以約5.0 % w/w之量存在。 82. 如實施例1至81中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼馬來酸鹽
係以約1.0至約7.5 % w/w，特定言之約5.0% w/w之量存在。 83. 如實施例81至82之馬來酸鹽
，其中當耐光性係使用按照「歐洲藥典」及/或「美國藥典」之藥典方法測定時，該馬來酸鹽之特徵在於經300 nm至800 nm範圍內之波長，及至少120萬勒克斯(Lux)小時之曝光量，及至少200瓦小時/m²之曝光能量曝光至少29小時後耐光性為至少殘餘70% N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼。 84. 如前述實施例中任一項之馬來酸鹽
，其中當使用按照「歐洲藥典」及/或「美國藥典」之藥典方法測定時，該馬來酸鹽之特徵進一步在於具有特徵XRPD波峰在6.6、15.9、16.2、18.1、20.5、22.5、26.1及28.6 2θ。 85. 如前述實施例中任一項之馬來酸鹽
，其中當使用按照「歐洲藥典」及/或「美國藥典」之藥典方法測定時，該馬來酸鹽係物理化學穩定的，其特徵在於在室溫及在3.5至7.0之pH在水溶液中儲存兩週後，該馬來酸鹽之回收率為起始濃度之至少85%。 86. 如前述實施例中任一項之馬來酸鹽
，其中當使用按照「歐洲藥典」及/或「美國藥典」之藥典方法測定時，該馬來酸鹽之特徵在於在水中的溶解度為約0.48mg/mL。 87. 如前述實施例中任一項中所定義之用於局部施用於有需要個體的局部醫藥調配物， 其中當使用按照「歐洲藥典」及/或「美國藥典」之藥典方法測定時，其中該馬來酸鹽
係以足夠使接受該組合物局部治療之方法的個體之表皮及真皮中的濃度達到≥ 10 nM之量存在。 88. 一種N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼馬來酸鹽
，其用於治療及/或預防疱疹病毒感染。 89. 一種製備如實施例81至88中所定義之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之馬來酸鹽
的方法，該方法包括以下步驟： i) 提供混合裝置，較佳配有頂置攪拌之混合裝置， ii) 用460至490 g普瑞利維游離鹼填充步驟i)之該混合裝置， iii) 用3至5體積之水使步驟ii)之普瑞利維游離鹼懸浮， iv) 藉由合適加熱裝置將步驟iii)之懸浮液加熱至45至55℃， v) 在40至90分鐘之時間內添加225至240 g呈固體形式之馬來酸直至獲得最終溶液， vi) 使在步驟v)下所獲得之溶液冷卻至44至52℃ vii) 將用游離鹼普瑞利維之馬來酸鹽接種等份之步驟vi)溶液， viii) 在1.5至2.5小時時間段內，允許使步驟vii)之所得懸浮液冷卻至18至24℃， ix) 之後攪拌步驟viii)之懸浮液過夜， x) 過濾步驟ix)之懸浮液，以獲得所得濾餅， xi) 將在步驟x)下所獲得之固體濾餅轉移至混合裝置，較佳燒瓶中， xii) 將步驟xi)之混合裝置旋轉蒸發25-32小時，同時應用以下條件： a. 30至40℃之環境溫度， b. 15至25毫巴之壓力， 以獲得恆定質量， xiii) 之後進行均質化，較佳使用研缽及研杵進行均質化， xiv) 以獲得本發明普瑞利維之游離鹼之馬來酸鹽。 在本發明之上述背景下，本發明之其他特定態樣係由下文連續列舉之實施例提供： a. 一種用於局部施用於有需要個體的醫藥調配物，該調配物包含： 1至-10 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， 0至90 % w/w之至少一種溶劑， 0至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有2.0至8.0之pH值，較佳4.0至5.0之pH， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺係在25-60℃下呈溶解狀態或呈溶解形式穩定12個月， 其中該溶劑係選自包括乙醇、異山梨醇二甲酯、異丙醇、Transcutol P、聚乙二醇、PEG 400、PEG 4000及Super RefinedTM
(SR) PEG 400之群。 在與實施例a相鄰之實施例中，該醫藥調配物之pH值較佳為4.0至4.5。 在與實施例a相鄰之實施例中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 b. 如實施例a中所定義之醫藥調配物，其中該至少一種溶劑係選自包括聚乙二醇之群，較佳PEG 400，更佳SR PEG 400。 c. 如實施例a至b中所定義之醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺係選自包括以下化合物之群： N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之甲磺酸鹽
，及 N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
。 d. 如實施例a至c中任一項所定義之醫藥調配物，其中該抗氧化劑係選自包括丁基化羥基甲苯(BHT)、丁基化羥基苯甲醚(BHA)、抗壞血酸、棕櫚酸抗壞血酯、生育酚、乙酸生育酚酯、沒食子酸丙酯、沒食子酸十二酯、沒食子酸辛酯、硫代硫酸鹽之群。 e. 如實施例a至d之醫藥調配物，其中該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠之調配物。 f. 如實施例a至e中任一項所定義之醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之濃度係選自1.1至10 % w/w，更佳1.1至5 % w/w之範圍。 g. 如實施例a至f中任一項所定義之醫藥調配物，其中該至少一種溶劑之濃度為0.1至90 % w/w，例如5至90 % w/w、10至90 % w/w、10至80 % w/w、20至80 w/w、25至80 % w/w、15至50 % w/w或30至45 % w/w。 h. 如實施例a至g中任一項中所定義之醫藥調配物，其中該調配物為進一步包含以下之軟膏： 0.01至20 % w/w之至少一種pH調節劑。 i. 如實施例a至h中任一項中所定義之醫藥調配物，其中該調配物為進一步包含以下之乳膏： 0至5 % w/w防腐劑 0至20 % w/w之至少一種界面活性劑 1至40 % w/w油相/潤膚劑 0至40 % w/w水。 j. 如實施例a至i中任一項中所定義之醫藥調配物，其中該調配物為進一步包含以下之凝膠： 0至30 % w/w穿透增強劑 0至20 % w/w之至少一種膠凝劑 0至50 % w/w水 0.01至20 % w/w之至少一種pH調節劑。 k. 如實施例a至j中任一項中所定義之醫藥調配物，其用作藥劑。 l. 如實施例a至k中任一項中所定義之醫藥調配物，其用於治療及/或預防疱疹病毒感染。 m. 如實施例a至l中任一項中所定義之醫藥調配物，其用於治療及/或預防疱疹病毒感染，其中該疱疹病毒係選自單純病毒目。 n. 如實施例a至m中任一項中所定義之醫藥調配物，其用於治療及/或預防疱疹病毒感染，其中該單純病毒係選自單純疱疹病毒1 (HSV-1)及單純疱疹病毒2 (HSV-2)。 在本發明之上述背景下，本發明之其他特定態樣係由下文連續編號之實施例提供： I. 一種用於局部施用於有需要個體的醫藥調配物，該調配物包含： i. 1至10 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， ii. ＞ 0至90 % w/w之至少一種溶劑， iii. ＞ 0至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有2.0至8.0之pH值，較佳4.0至5.0之pH， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月， 其中該溶劑係選自包括乙醇、異山梨醇二甲酯、異丙醇、Transcutol P、丙二醇、聚乙二醇、PEG 400、PEG 4000及Super RefinedTM
PEG 400之群，及 其中該抗氧化劑係選自包括丁基化羥基甲苯(BHT)、丁基化羥基苯甲醚(BHA)、抗壞血酸、棕櫚酸抗壞血酯、生育酚、乙酸生育酚酯、沒食子酸丙酯、沒食子酸十二酯、沒食子酸辛酯、硫代硫酸鹽之群。 在與實施例I相鄰之實施例中，該醫藥調配物之pH值較佳為4.0至4.5。 在與實施例I相鄰之實施例中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 II. 如實施例I之用於局部施用於有需要個體的醫藥調配物，其中該調配物包含： i. 1至10 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， ii. 0.1至90 % w/w之至少一種溶劑， iii. 0.01至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有4.0至5.0之pH值， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月， 其中該溶劑需選自包括聚乙二醇、PEG 400、PEG 4000及Super RefinedTM
PEG 400之群，及 其中該抗氧化劑為丁基化羥基甲苯(BHT)。 在與實施例II相鄰之實施例中，該醫藥調配物之pH值較佳為4.0至4.5。 在與實施例II相鄰之實施例中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 III. 如實施例I至II中任一項之用於局部施用於有需要個體的醫藥調配物，該調配物包含： i. 1.1至5 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺， ii. 0.1至90 % w/w之至少一種溶劑， iii. 0.01至10 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有4.0至5.0之pH值， 其中N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定12個月， 其中該溶劑為Super RefinedTM
PEG 400，及 其中該抗氧化劑為丁基化羥基甲苯(BHT)。 在與實施例III相鄰之實施例中，該醫藥調配物之pH值較佳為4.0至4.5。 在與實施例III相鄰之實施例中，N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺呈溶解狀態或呈溶解形式在25℃/60 % RH下穩定至少24個月。 IV. 如前述實施例I至III中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺係選自包括以下化合物之群： • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之甲磺酸鹽
，及 • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
。 V. 如實施例I至IV中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中當藉由光散射方法、拉曼光譜及IR光譜以及在XRPD期間各自不存在固相來測定時，該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺或該 • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之甲磺酸鹽
，及 • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
。 係呈溶解狀態或呈溶解形式存在。 VI. 如前述實施例I至V中任一項所定義之用於局部施用於有需要個體的醫藥調配物，該調配物包含： i. 5 % w/w之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺，或該 • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼之甲磺酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
， ii. 25至80 % w/w之至少一種溶劑， iii. 0.05至2 % w/w之至少一種抗氧化劑， 其中該醫藥調配物具有4.0之pH值，及 其中該溶劑為SR PEG 400，及 其中該抗氧化劑為丁基化羥基甲苯(BHT)。 VII. 如實施例I至VI中任一項所定義之用於局部施用於有需要個體的醫藥調配物，其中該N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺係選自包括以下化合物之群： • 呈溶解狀態之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼半水合物
， • 呈溶解狀態之N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之馬來酸鹽
， • N-[5-(胺基-磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼
。 VIII. 如前述實施例I至VII中任一項之用於局部施用於有需要個體的醫藥調配物，該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠之調配物。 在與實施例VIII相鄰之實施例中，該調配物係選自包括以下調配物之群：用於乳膏、軟膏、凝膠、油膏、潤膚液、蠟調配物、唇膏、補劑、慕思、發泡體、薄膜、乳劑、糊膏、溶液、油狀物、微脂膠及貼片之調配物。 IX. 如實施例I至VIII中任一項之用於局部施用於有需要個體的醫藥調配物，其中該調配物為進一步包含以下之軟膏： (i) 0.01至20 % w/w之至少一種pH調節劑。 在與實施例IX相鄰之實施例中，該pH調節劑為表觀pH調節劑。 X. 如實施例IX中所定義之用於局部施用於有需要個體的醫藥調配物，其中該調配物為包含以下之軟膏： 17.5 % w/w PEG 4000， 9.78 % w/w丙二醇， 5 % w/w活性醫藥成分普瑞利維， 0.1 % w/w丁基化羥基甲苯(BHT)， 67.62 % w/w Super RefinedTM
PEG 400，及 其中該醫藥調配物具有4.0至5.0之pH值，較佳4.0至4.5之pH值。 XI. 如實施例XIII之用於局部施用於有需要個體的醫藥調配物，其中該調配物為進一步包含以下之乳膏： i. 0至5 % w/w防腐劑 ii. 0至20 % w/w之至少一種界面活性劑 iii. 1至40 % w/w油相/潤膚劑 iv. 0至40 % w/w水。 XII. 如實施例XIII之用於局部施用於有需要個體的醫藥調配物，其中該調配物為進一步包含以下之凝膠： i. 0至30 % w/w穿透增強劑 ii. 0至20 % w/w膠凝劑 iii. 0至50 % w/w水 iv. 0.01至20 % w/w之至少一種pH調節劑， v. 視情況進一步包含約0至5 % w/w之量之防腐劑。 在與實施例XII相鄰之實施例中，該調配物在(i)項下包含下0至30%皮膚穿透增強劑。 XIII. 如前述實施例I至XVII中任一項中所定義之醫藥調配物，其用作藥劑。 XIV. 如前述實施例I至XIII中任一項中所定義之醫藥調配物，其用於治療及/或預防疱疹病毒感染。 XV. 如前述實施例I至XIV中任一項中所定義之醫藥調配物，其用於治療及/或預防疱疹病毒感染，其中該疱疹病毒係選自單純病毒目。 XVI. 如前述實施例I至XV中任一項中所定義之醫藥調配物，其用於治療及/或預防疱疹病毒感染，其中該單純病毒係選自單純疱疹病毒1 (HSV-1)及單純疱疹病毒2 (HSV-2)。實例 實例 1 ：調配物開發
基於廣泛的預調配物研究分別使用N‑[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
及N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺甲磺酸鹽
兩者(後文亦稱為「普瑞利維游離鹼」及「普瑞利維甲磺酸鹽」)開發一種局部軟膏調配物。開發包括測定N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺之兩種形式在不同賦形劑中的溶解度及穩定性。此外，進行調配物體外皮膚滲透及皮膚刺激研究。根據短期穩定性的研究，挑選出領先調配物以便進一步進行量產研究。調配物之組成
5% w/w N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
軟膏為用於局部投與之白色至略帶顏色的不透明軟膏。每克活性成分N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
5% w/w軟膏含有溶解於Super RefinedTM
乙二醇400 (SR PEG 400)基質之51.1 mg N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
。下表4中提供以% (w/w)表示之定性及定量組成。表 4
a 對應於5.0%之普瑞利維(活性部分) 上表4描述根據本發明之臨床軟膏調配物之基本組成。 下表5中列出在製備成品中所用之賦形劑及其功能。所有賦形劑均係眾所周知且廣泛用於軟膏之製備。表 5
上表5描述臨床軟膏調配物中所用之組分的功能及等級。藉由 HPLC 之 N-[5-( 胺基磺醯基 )-4- 甲基 -1,3- 噻唑 -2- 基 ]-N- 甲基 -2-[4-(2- 吡啶基 )- 苯基 ]- 乙醯胺之鑑別、分析及其相關物質
為了鑑別，將樣品層析圖中普瑞利維波峰的滯留時間與參考層析圖中普瑞利維波峰的滯留時間進行比較，並將從樣品層析圖中普瑞利維波峰所提取的UV光譜與從參考標準層析圖中所提取的UV光譜進行比較。使用外標定量確定分析。報告等級設定為0.05%面積/面積。使用以下 HPLC 參數：
HPLC系統：配有DAD檢測器及數據處理軟體之HPLC 管柱：Phenomenex Luna C18, 5 μm, 250 x 3.0 mm；或相當物 保護柱：C18保護濾筒 樣品溫度：5 ± 2℃ 柱溫：45 ± 2℃ 注射體積：2 μL 流速：0.5 mL/min 運行時間：75.0 min 檢測波長：282 nm 移動相A：10 mM乙酸銨緩衝液pH 5.0 移動相B：乙腈 梯度：參見下表6。表 6
標準及樣品稀釋劑：0.1% v/v甲酸含於50:50 v/v 水:乙腈 注射空白：0.1% v/v甲酸含於50:50 v/v 水:乙腈 針洗液：60:40 v/v 甲醇:水 已知雜質：PP 乙酸：RRT約0.33 胺基噻唑磺醯胺：RRT約0.19 上表6藉由給定PHLC參數之方式描述用於如上所述之層析法的梯度。調配物開發
調配物開發旨在包含5%之N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺之局部調配物，其係以不低於10 nM至20 nM之N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
含於表皮及真皮中的目標濃度快速滲透皮膚(表皮)且僅極少全身性曝露，其易於擴散、吸收迅速，且其使用起來保濕、不油膩且美觀。本文所述之調配物係根據溶解度及相容性實驗、短期(光)穩定性研究、體外藥物釋放實驗、體外皮膚滲透及穿透實驗以及在迷你豬中尋找劑量範圍之研究及體外皮膚刺激研究之結果所挑選出的。溶解度研究
下表7顯示N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
之飽和溶解度與甲磺酸鹽
比較。N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
顯示比甲磺酸鹽顯著更高之溶解度。表 7 ：
N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
之飽和溶解度與甲磺酸鹽
比較。
BLOQ - 低於分析方法之LOQ。A
溶解度藉由肉眼觀察確定。溶劑系統
基於溶解度數據設計溶劑系統。下表8中顯示組成。表 8– 溶劑系統
(-)：不包含 N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
之溶解度係在該等溶劑系統中測定。顯然，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
顯示比甲磺酸鹽
顯著更高之溶解度，如表9中所示： 上表8描述針對臨床軟膏調配物進行測試之溶劑系統。表 9
上表9描述普瑞利維游離鹼及甲磺酸鹽在該等所用溶劑系統中之溶解度。短期穩定性：
N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
之短期穩定性測試係在個別賦形劑及溶劑系統中進行。當在40℃及50℃下，將化合物單獨在苄醇、丙二醇、Arlasolve DMI、10 % w/v Kleptose溶液及SS5 (丙二醇:緩衝液 pH 3.5)中進行兩周及四周短期穩定性測試時，觀察到與t=0值相比良好之游離鹼半水合物回收率(90至110%) (表10)。在單獨PEG及含有高百分比PEG 400之二元及溶劑系統中觀察到N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺半水合物游離鹼之低回收率(與t=0相比＜ 50 %)。觀察到與N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物之回收率良好對應的波峰純度數據。表 10 ：
在t = 0時及在所述時間點及溫度下儲存後所測定之普瑞利維游離鹼
在溶劑中的回收率及波峰純度。與t = 0值相比之回收率，n = 2，括號內說明範圍(分析方法)。波峰純度值，n= 1 (雜質方法)。
亦使甲磺酸鹽
接受含於所選賦形劑及溶劑系統中之短期穩定性研究。當在40℃及50℃下，將普瑞利維甲磺酸鹽單獨在苄醇、苯氧基乙醇、丙二醇、10 % w/v Kleptose溶液、水SS5、SS6及SS7中進行兩周及四周短期穩定性測試時，觀察到良好普瑞利維甲磺酸鹽回收率(與t=0相比在90至110%之間)與對應波峰純度數據(表8)。在苄醇、PEG 400、Transcutol P、甘油、50:50 pH 4緩衝液:PEG 400及SS1-4中觀察到普瑞利維甲磺酸鹽之不良穩定性(在t=4週，50℃下，波峰純度＜ 90%)；然而，當與普瑞利維游離鹼比較時，甲磺酸鹽似乎在個別賦形劑及溶劑系統兩者中均具有改良之穩定性。表 11 ：
在t = 0時及在所述時間點及溫度下儲存後所測定之普瑞利維甲磺酸鹽在溶劑中的回收率及波峰純度。與t = 0值相比之回收率，n = 2，括號內說明範圍(分析方法)。波峰純度值，n= 1 (雜質方法)。
在諸如SR PEG 400之額外賦形劑中對游離鹼及甲磺酸鹽
兩者進行進一步短期穩定性研究。結果指示，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物顯示與甲磺酸鹽相比之優異穩定性(參見下表12)。 表12 a (參見上表) – 在T0時及在所述時間點及溫度下儲存後普瑞利維游離鹼在溶劑中之回收率及波峰純度。與T0值相比之回收率，n = 2，括號內說明範圍(分析方法)，波峰純度值n=1 (雜質方法)。 表12 b (參見下表) – 在t=0時及在所述時間點及溫度下儲存後所測定之普瑞利維甲磺酸鹽在溶劑中的回收率及波峰純度。與t=0值相比之回收率，n=2，括號內說明範圍(分析方法)。波峰純度值，n=1 (雜質方法)。
表34.在t=0時及在所述時間點及溫度下儲存後所測定之普瑞利維甲磺酸鹽在溶劑中的回收率及波峰純度。與t=0值相比之回收率，n=2，括號內說明範圍(分析方法)。波峰純度值，n=1 (雜質方法)。
出於調配物優化目的，研究其他溶劑系統(組成顯示於下表13中)表 13
此等溶劑系統中之飽和溶解度係如下表14所示，作為開發乳劑之基礎。 表13描述在t=0時及在所述時間點及溫度下儲存後所測定之普瑞利維甲磺酸鹽在溶劑中的回收率及波峰純度。與t=0值相比之回收率，n=2，括號內說明範圍(分析方法)。波峰純度值，n=1 (雜質方法)。表 1 4
*n=2 表14描述普瑞利維鹼及鹽在用於開發局部凝膠之不同溶劑系統中的溶解度。 下表15顯示，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺之游離鹼及甲磺酸鹽
在用於軟膏調配物之溶劑系統中的溶解度。應注意，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
具有與甲磺酸鹽相比之極高溶解度，此係實現5%之載藥量的先決條件。表 15 s
提取值高於ULOQ，*n=2 表15描述普瑞利維鹼及鹽在用於開發局部軟膏之不同溶劑系統中的溶解度。選擇SSO1和SSO3作為用於開發分別含有5 % w/w及1% w/w之普瑞利維游離鹼及普瑞利維甲磺酸鹽之軟膏調配物的組分。 以下部分顯示在開發乳膏、凝膠及軟膏中所選之調配物。凝膠調配物 表 16– 含有普瑞利維游離鹼半水合物之凝膠調配物的組成。
(-)：不包含表 17– 含有普瑞利維甲磺酸鹽之凝膠調配物的組成。
(-)：不包含乳膏調配物 表 18– 含有普瑞利維游離鹼半水合物之乳膏調配物的組成。
(-)：不包含表 19– 含有普瑞利維甲磺酸鹽之乳膏調配物的組成。
(-)：不包含表 20 ：
在t = 1及8小時後在表皮及部分真皮中所觀察到之普瑞利維或阿昔洛維的濃度(μM)。每個值代表平均值 ± SEM (n= 4-6)。 基於軟膏之調配物 表 21– 含有普瑞利維游離鹼半水合物之軟膏調配物的組成。
(-)：不包含表 22– 含有普瑞利維甲磺酸鹽之軟膏調配物的組成。
(-)：不包含體外皮膚滲透研究
使用代表性調配物進行體外皮膚滲透研究： 在施用該等調配物後t=15分鐘、1小時及8小時時，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼
(μM)在表皮及真皮中之濃度範圍(基於平均量及一系列皮膚厚度)係在表23中呈現，其中所觀察到之濃度實質上比普瑞利維(10至20 nM)之目標濃度更高(1,000至1,000,000倍)且比阿昔洛維(2μM)之IC50更高。亦應注意，起效速度亦係重要的。表 23
-在施用該等調配物後t=15分鐘、1小時及8小時時，普瑞利維半水合物游離鹼
(μM)及甲磺酸鹽
在表皮及真皮中之濃度範圍(基於平均量及一系列皮膚厚度)。值代表基於皮膚厚度及回收平均量之範圍，n=5至6。 在微型豬中之 DRF 研究
以下調配物表24係用於在微型豬中之劑量範圍發現研究。表 24– 製備用於 DRF 微型豬研究之調配物之賦形劑的組成
(-)：不包含表 25– 用於 DRF 微型豬研究之調配物的批號、物理描述、分析及 pH
沉積於皮膚層中之N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
的量係第1天及第5天進行測定，且下表26顯示結果。表 26 ( 所回收之普瑞利維的量 (ng))
*部分15.4.2附錄4中提供總結在第6天及第7天之屍檢的額外表格。 表26顯示以[ng]表示之自皮膚層所回收之普瑞利維的量。 如下進行N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
自活檢樣本之角質層、表皮及真皮的回收。在第1天，觀察到自表皮之游離鹼半水合物之回收率的以下排序，其中無明顯統計學差異(p ＞ 0.05)：G7V3 ＞ O3v4 ＞ C3v3。在第5天及在屍檢之後，觀察到與第1天相同之自表皮之游離鹼半水合物之回收率的排序，然而，施用G7v3後之游離鹼半水合物的回收率係在統計學上(p ＜ 0.05)比來自其餘調配物之回收率更大。當考慮自部分真皮之游離鹼半水合物的回收率時，觀察到以下排序，其中在施用G7v3後之游離鹼的回收率係在統計學上(p ＜ 0.05)比在第1天時其餘調配物之回收率更大；比C3v3之第5天更大，且在屍檢時無統計學差異(p ＞ 0.05)： 第1天：G7V3 ＞ O3v4 ＞ C3v3。 第5天：G7V3 ＞ O3v4 ＞ C3v3 屍檢：G7V3 ＞ C3v3 ＞ O3v4。 一般而言，觀察到在角質層、表皮及真皮中所觀察到之N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
的濃度隨時間的增加而減少，此表明N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物隨時間被吸收至血液中。其他調配物開發
在體外皮膚滲透及穿透實驗之後，決定各自以達到5 %及1.5 % N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
及甲磺酸鹽
之目標濃度為目標繼續調配物開發，其中表觀pH值為約4。亦決定評估紫外線阻斷劑以開發光穩定調配物。下文列出所總結之大量防曬活性成分： •UVA 過濾劑：
二苯甲酮類(氧苯酮、磺異苯酮、二氧苯酮)、二苯甲醯基甲烷類(阿伏苯宗(avobenzone))、鄰胺基苯甲酸鹽類(Anthralates) (美拉地酯(meradimate))、樟腦類(依莰舒(ecamsule)) •UVB 過濾劑：
胺基苯甲酸酯類(對胺基苯甲酸、二甲胺基苯甲酸戊酯-O)、肉桂酸酯類(西諾沙酯(cinoxate)、桂皮酸鈉(octinoxate))、水楊酸酯類(水楊酸辛酯(octisalate)、胡莫柳酯(homosalate)、水楊酸三乙醇胺)、奧克立林(Octocrylene)、恩索利唑(Ensulizole) •無機過濾劑：
二氧化鈦、氧化鋅。 開發含有及不含桂水楊酸辛酯之調配物(每中調配物類型n = 2)。因此，開發結合水楊酸辛酯之溶劑系統以確定N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
或甲磺酸鹽
之飽和溶解度及確定是否各自5 %及1.5 % w/w之N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物及甲磺酸鹽之目標濃度係可能的。 表27顯示N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
及甲磺酸鹽
各自在水楊酸辛酯中的飽和溶解度。數值代表平均值，其中括號內為範圍，n=3。
N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物及甲磺酸鹽
在溶劑系統中之其他溶解度： 各自基於N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物及甲磺酸鹽
之初始溶解度數據，在N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物及甲磺酸鹽(各自為5 %及1.5 % w/w)之目標濃度下，開發其他溶劑系統試圖在表觀pH為4同時維持所得調配物之藥物熱力學活性劑及物理穩定性下使N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物及甲磺酸鹽各自之溶解度最大化。 表28顯示普瑞利維游離鹼
及甲磺酸鹽
在用於開發凝膠之基礎的溶劑系統中之飽和溶解度
表29顯示普瑞利維游離鹼
及甲磺酸鹽
在用於開發凝膠之基礎的溶劑系統中之飽和溶解度
(-)：不包含，ND：未測定 表30顯示普瑞利維游離鹼
及甲磺酸鹽
在用於開發乳膏之基礎的溶劑系統中之飽和溶解度
(-)：不包含，ND：未測定，* 剩餘量將為最終調配物之油相。 表31顯示普瑞利維游離鹼
及甲磺酸鹽
在用於開發軟膏之基礎的溶劑系統中之飽和溶解度
(-)：不包括，ND：未測定，* 剩餘量將為最終調配物之PEG4000。 表32顯示普瑞利維游離鹼
及甲磺酸鹽
在用於開發軟膏之基礎的溶劑系統中之飽和溶解度
(-)：不包含，ND：未測定，* 剩餘量將為最終調配物之PEG4000。凝膠調配物之開發
-表33顯示含有普瑞利維游離鹼
及甲磺酸鹽
之凝膠調配物的組成
(-)：不包含基於乳膏之調配物的開發
-表34顯示含有普瑞利維游離鹼
及甲磺酸鹽
之乳膏調配物的組成 表 35
(-)：不包含表 35 顯示
普瑞利維游離鹼及甲磺酸鹽之乳膏調配物的組成。基於軟膏之調配物的開發
-表36顯示含有普瑞利維游離鹼
及甲磺酸鹽
之軟膏調配物的組成
(-)：不包含基於凝膠、乳膏及軟膏之調配物的短期應力穩定性：
下表中總結，在25℃及40℃下儲存t=2及4週後，調配物中N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物
及甲磺酸鹽
各自之回收率及純度。當考慮含有N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物之調配物時，在40℃下至多t=4週之所有凝膠調配物中觀察到良好回收率(97至105%)。此係由N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物在G8、G8v3、G24及G24v3中之良好百分比純度(＞ 99%)所支持。在一些乳膏調配物中觀察到可變回收率，此可歸因於在40℃儲存時所觀察到之相分離以及藥物提取程序(其為通用方法)之低效率。然而，在除Cr03v5 (98.62%)外之所有調配物中觀察到N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼之良好百分比純度(＞ 99%)。在除O4v4 OCT外之所有軟膏調配物中觀察到N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物之良好回收率(在40℃下儲存t=4週後約87%)，然而觀察到N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物在所有軟膏調配物中之百分比純度＞ 99%。一般而言，觀察到含有N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺甲磺酸鹽之調配物相比含有游離鹼半水合物之調配物更不穩定。然而，在除G15 (81%)外之所有凝膠調配物中觀察到N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺甲磺酸鹽之良好回收率。此係由N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺甲磺酸鹽在此調配物中之百分比波峰純度(86%)所支持，然而在剩餘調配物中觀察到N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺甲磺酸鹽之百分比波峰純度自t=0減少。總而言之，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺游離鹼半水合物出人意料地比甲磺酸鹽更穩定。表 37
–在t=0時及在25℃及40℃下儲存t=2及4週後普瑞利維游離鹼
之回收率(呈理論濃度之百分比)，n=3*n=1，ND：未測定表 38
–在t=0時及在25℃及40℃下儲存t=2及4週後調配物中普瑞利維游離鹼
之百分比純度，n=1ND：未測定表 39
–在t=0時及在25℃及40℃下儲存t=2及4週後普瑞利維甲磺酸鹽
之回收率(呈理論濃度之百分比)，n=2至3*n=1，ND：未測定表 40
–在t=0時及在25℃及40℃下儲存t=2及4週後調配物中普瑞利維甲磺酸鹽
之百分比純度，n=1ND：未測定強制降解研究
調配物之強制降解數據顯示，N-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺可經由氧化易於降解。此外，在調配物開發期間觀察到標準PEG 400質量中之藥物物質的降解，參見下表41。因此，使用一種特殊之PEG 400等級(Super RefinedTM
PEG 400)並對包含抗氧化劑進行評估。基於所獲得之數據，作為抗氧化劑之丁基化羥基甲苯(BHT)係以0.1 % w/w之濃度包含於調配物中。所用濃度符合在相當產品中用作抗氧化劑之BHT的濃度(參見FDA之非活性成分數據庫(FDA's Inactive Ingredients Database))。藉由使用Super RefinedTM
PEG 400、抗氧化劑(BHT)及酸性pH值4.0至5.0之組合來限制普瑞利維之氧化降解。丙二醇係用作溶劑系統(軟膏基質)中之附加溶劑。在調配物開發期間所獲得之數據推測，低pH值可改良普瑞利維之穩定性並因此對酸化賦形劑之使用進行評估。產品製備期間之目標pH值係設定在4.0與5.0之間。若必要，使用氫氯酸及氫氧化鈉調節pH。用於藥品製備之賦形劑與藥物具有良好相容性，且短期調配物穩定性數據顯示可接受結果(參見下表42)。表 41
–在t=0時及在所述時間點及溫度下儲存後所測定之普瑞利維在不同溶劑中的回收率及純度(1% w/w溶液)。與t=0值相比之回收率，n=2，括號內說明範圍，純度值，n=1 表 42
–短期調配物穩定性研究 耐光性評估
將含有及不含UV阻斷劑水楊酸辛酯之調配物在ICH條件(120萬勒克斯小時及超過200瓦小時/m²)下曝露至UV光，並分別測定普瑞利維(游離鹼及甲磺酸鹽
)之回收率及純度，如下表中所總結。觀察到含有普瑞利維游離鹼之調配物具有良好百分比純度(＞ 99%)，且似乎沒有摻入水楊酸辛酯之主要優點。然而，含有普瑞利維甲磺酸鹽之調配物似乎對UV光不穩定(普瑞利維甲磺酸鹽之百分比純度範圍為74至99 %)，且當併入水楊酸辛酯時觀察到普瑞利維甲磺酸鹽之百分比純度巨大增加(例如，在Cr12及Cr12v2中分別為約74 %至98 %)。然而，當解釋此等結果時應小心，因為當在25℃無UV光下培育t=2及4週時，觀察到此等調配物表現相似。表43發現普瑞利維游離鹼相比甲磺酸鹽對光應力條件更穩定。表 43
–在t=0時及在ICH條件下曝露至UV光時調配物中普瑞利維游離鹼之回收率(呈理論濃度之百分比)及波峰純度。 表 44
–在t=0時及在ICH條件下曝露至UV光時調配物中普瑞利維甲磺酸鹽之回收率(呈理論濃度之百分比)及波峰純度。
調配物之體外皮膚滲透以選擇領先調配物： 已在先前研究期間建立用於評估所開發之調配物的體外皮膚滲透及穿透之實驗參數，因此沒有進行進一步可行性實驗作為此研究之一部分。測定在施用t=1及8小時後各種皮膚基質中之普瑞利維(及阿昔洛維)的濃度。選擇總共7種調配物用於體外皮膚滲透及穿透實驗，其等係基於來自短期化學穩定性實驗之最有希望的候選物進行選擇。當考慮在t=1小時時從表皮所回收之藥物量時，觀察到以下排序，然而在該等調配物中之任一者之間無顯著差異(p ＞ 0.05)： O1v3 ＞ G8v3 ＞ Zovirax (阿昔洛維) ＞ G15v1 ＞ G8 ＞ O2 ＞ G7v3。表 45
-在施用所有調配物1小時後，從角質層、部分真皮及接收液中回收之普瑞利維及阿昔洛維的量(ng)。數據表示平均值+
SEM (n=4至6)
表46-在施用所有調配物8小時後，從角質層、部分真皮及接收液中回收之普瑞利維及阿昔洛維的量(ng)。數據表示平均值+ SEM (n=4至6)
本發明目標為在表皮及部分真皮內具有10 - 20 nM之普瑞利維目標濃度。出乎意料地，表47證實，此等皮膚層內之普瑞利維濃度超出目標約3,500至257,500倍。表 47
表47顯示1小時及8小時後從表皮及部分真皮回收之普瑞利維及阿昔洛維的量。 基於在體外皮膚滲透及穿透測試期間所生成之數據及由體外藥物釋放數據、短期化學穩定性數據及體外皮膚刺激性研究所支持，選擇O1v3和G8v3作為領先及備用調配物候選物(規模擴大，GLP供應及ICH穩定)。體外藥物釋放實驗
測定普瑞利維自總共9種調配物之體外釋放，並與阿昔洛維自市售比較物Zovirax®
(阿昔洛維)之體外釋放進行比較。圖2總結整個數據組，而圖3僅關注所開發之調配物(為了清晰起見，移除Zovirax®
)。由於線性穩態藥物釋放出現在0與2小時之間，所以圖4顯示描繪在t=1小時時每單位面積所釋放之藥物量的另一圖。在t=1小時時，觀察到藥物從調配物中釋放之以下排序，其中普瑞利維自調配物O2之釋放在統計學上(p ＜ 0.05)比從除O1v3、G7v3及Zovirax®
(阿昔洛維)外之所有調配物之釋放更高：O2 ＞ O1v3 ＞ G7v3 ＞ Zovirax ＞ G8v3 ＞ O3v4 ＞ G15v1 ＞ G8 ＞ G24 ＞ CR12 針對藥物熱力學活性對每種調配物進行優化(普瑞利維係以約70至85%之飽和極限存在於調配物中)。此等數據表明，藥物釋放量係由普瑞利維在調配物中之濃度所驅動。一般而言，普瑞利維存在之更高濃度導致藥物釋放之更高濃度。 除了施用劑量之百分比外，藥物在t=1小時時所釋放之平均累積量的原始數據值亦在表48中給出，並觀察到以下排序：G15v1 ＞ O2 ＞ O1v3 ＞ Zovirax®
＞ G7v3 ＞ G8 ＞ G8v3 ＞ O3v4 ＞ G24 ＞ CR12。此排名使數據標準化且顯示，雖然與一系列其它調配物相比，G15v1釋放較少普瑞利維，但當與所有其他調配物相比時，其顯示在t=1小時時之藥物釋放之更高效率。雖然與體外藥物釋放同時進行體外皮膚滲透及穿透實驗，但是本文所生成之數據似乎支持選擇G15v1、O2、O1v3、G7v3、G8及G8v3進行評估。表 48 表 48 顯示
普瑞利維游離鹼局部調配物與Zovirax®
相比之IVRT曲線圖。局部用調配物之體外皮膚刺激性
除比較物(Zovirax®
唇疱疹乳膏(Cold Sore Cream)，5 % w/w阿昔洛維)外，此研究評估含有普瑞利維游離鹼
(PFB)及普瑞利維甲磺酸鹽
(PMS)之一系列凝膠、軟膏及乳膏調配物(9種活性劑及9種安慰劑調配物)的體外刺激潛能。此研究之總體目標是產生出體外刺激數據，併與正在進行之調配物穩定性、體外皮膚滲透/穿透及藥物釋放研究(252-1402-01及252-1402-02)以便輔助挑選出用於普瑞利維之領先候選調配物。此研究中所用之重構人類表皮(RHE)培養物(EpiDerm™)係正常人類細胞所衍生的三維器官型體外皮膚模型。此研究中所用之方法係基於MatTek詳細記錄之ET-50 (化學品降低活力(viability)至對照之50 %所需的曝露時間)分析，其允許定量量測測試物質之刺激性。在此研究期間，成功地評估了19種調配物在全面(full scale)體外皮膚刺激性研究中之刺激性潛力。可行性實驗顯示，觀察到所有開發之調配物(活性劑及安慰劑調配物)與MTT (用於光毒性研究之標準MTT測試)相互作用。另外研究顯示，BHA及BHT係導致MTT相互作用之賦形劑，因為彼等為所有測試調配物共同的。亦研究Zovirax®唇疱疹乳膏5 % w/w阿昔洛維且顯示其與MTT無相互作用。然後使用O10 (PFB)活性劑及安慰劑作為所選調配物進行小規模體外刺激性實驗，其顯示無刺激性(ET-50 ＞ 24小時)。該小規模實驗中包括冷凍(非活性)(non-viable) RHE組織對照，並顯示與MTT有一些相互作用(均＜ 6 %)。該等可行性實驗之結果導致用於全面體外皮膚刺激性實驗方案的優化。因此，冷凍(非活性)對照RHE組織僅併入t=6小時之時間點。此使得能夠進行背景扣除以解釋RHE組織中存在之任何殘餘調配物的任何MTT降低。全面體外皮膚刺激性實驗顯示，所測試調配物的範圍為從中度/輕度至無刺激，其中活性劑調配物之表現與各安慰劑調配物類似。表49列出所研究之各調配物之ET-50值的總結。在施用所開發之調配物及比較物後，RHE組織的細胞活力證實，該等調配物中之三者(G8 (PFB)、O2 (PFB)及Cr12 (PFB))在實驗期間(t=2、6及24 h)內對RHE組織之活力無顯著影響。因此，不可能計算出確切的ET-50值，並因此認為該等調配物無刺激性。相反地，G24 (PFB)顯示最大的刺激性潛力(ET-50 ＜ 6 h)。表現最低刺激性潛力之調配物(G8 (PFB)、O2 (PFB)及Cr12 (PFB))的表現與市售比較物Zovirax®
唇疱疹乳膏5 % w/w阿昔洛維類似。因此，該可行性研究顯示，所有所研究之調配物(活性劑及安慰劑兩者)均顯示輕度至強烈與MTT的相互作用。此保證進一步研究，其中評估BHA及BHT與MTT之相互作用，因為所有調配物含有BHA或BHT。觀察到對於BHA之輕度相互作用，且觀察到對於BHT之強烈相互作用，表明BHA和BHT導致所觀察到之相互作用。因為此等發現，將冷凍(非活性)RHE組織對照添加至小規模體外刺激性研究中，以解釋RHE組織表面上剩餘之任何殘餘調配物與MTT之間的相互作用。未發現Zovirax®
唇疱疹乳膏5 % w/w阿昔洛維(對照項目1)與MTT相互作用。 小規模體外刺激性研究表明，O10 (PFB)活性劑及安慰劑調配物係無刺激性(ET-50 ＞ 24 h)，且顯示所用時間點及MTT分析方法足夠用於全面實驗。此外，存在於所處理之RHE組織中的殘餘調配物顯示與MTT有一些相互作用，如由冷凍(非活性)對照RHE組織之活力(全部＜6 %)所證明。 全面體外刺激性研究顯示，所測試之調配物的範圍為從中等/輕度至無刺激。活性調配物之表現與所研究之各自安慰劑調配物類似。顯示最低刺激潛力之調配物為G8 (PFB)、O2 (PFB)及Cr12 (PFB)，因為此等調配物之表現與市售比較物Zovirax®
唇疱疹乳膏5 % w/w阿昔洛維(對照項目1)類似。最具刺激性之調配物為G24 (PFB) (ET-50 ＜ 6 h)。表 49
–所選調配物與Zovirax®
(對照項目1)之ET-50計算值 具有恢復期及毒代動力學之在微型豬中的 1 個月毒性研究
該研究評估當連續4周每天兩次地局部投與至微型豬時普瑞利維游離鹼
之毒性及毒代動力學曲線圖，並評估在2週恢復期間測試項目之副作用的可逆性。該研究中共使用38隻哥廷根(Göttingen)微型豬(19隻雄性及19隻雌性；Ellegaard Göttingen Minipigs A/S)。約總皮膚表面積1%、5%或10%之施用面積係藉由紋身在動物之背部進行標記。根據下文時間表對動物進行給藥(表50)。表 50
上表50顯示在微型豬中之1個月毒性研究的研究計劃。 評估以下準側：死亡率、臨床症狀、體重、食物消耗量、心電圖、眼科檢查、臨床病理學(包括血液學、血液化學及尿液分析)、全面屍檢(包括處理及未經處理之皮膚的宏觀觀察)、器官重量及組織病理學。在第1天及第28天之6個不同時間點收集用於毒代動力學評估之血液樣本。此外，檢查給藥部位對治療的反應，並對紅斑、水腫及其他皮膚反應進行評分。未見測試項目之相關變化。其中，每天兩次地局部投與5%普瑞利維O1v3游離鹼持續4周係良好耐受的。未觀察到與測試項目相關之皮膚反應或全身性毒性。關於 O1V3 調配物 ( 臨床調配物 ) 之進一步研究 - 耐光性測試
調配物之耐光性測試顯示，普瑞利維在根據ICH準則Q1B (提供不少於120萬勒克斯小時及不少於200瓦小時/平方米之總照明)直接曝露至UV光之後係穩定的。下表51中總結普瑞利維之回收率及雜質濃度： 表51-耐光性測試之結果
在上表51中，「t = 0」代表在光應力曝露之前的樣品。標準ICH條件係用於光應力研究。 雖然普瑞利維甲磺酸鹽係光敏性的，但是光穩定局部調配物可使用游離鹼而非使用光阻斷劑來開發。強制降解測試
進行普瑞利維游離鹼
之強制降解測試(以進一步評估特異性及確保HPLC方法係指示穩定性)，使其曝露至熱、光、氧化、酸及鹼(表52)。 表52-普瑞利維游離鹼之強制降解測試的結果
a pH調節至8用於鹼性水解體外藥物釋放測試
使用Franz滲濾池(圖5)測試普瑞利維自調配物之體外藥物釋放。在開發研究期間，確定含於磷酸鹽緩衝溶液(PBS)之2% w/v Brij 98作為用於藉由HPLC1從體外皮膚滲透實驗分析樣品之合適接收液。出於體外釋放測試之目的，使用相同接收液。表53中提供普瑞利維在2% w/v Brij 98含於PBS中之穩定性的數據。 表53-接收液中游離鹼半水化合物之穩定性，藉由HPLC定量。各數值代表與在t=0時獲得之值比較的平均回收率，其中括號內為範圍，n=3。
觀察到普瑞利維在2% w/v Brij 98含於PBS中之飽和溶解度為0.02% w/w。為了避免在體外藥物釋放測試期間超過漏槽條件，在每個時間點將接收液之全部內含物移除。藉由HPLC分析樣品。 下文圖6顯示調配物之體外釋放測試(IVRT)曲線圖。體外皮膚滲透及穿透測試
進行體外皮膚滲透及穿透測試以估計在施用本文所述調配物之後普瑞利維穿過並進入人類皮膚之滲透。圖7描繪在t = 1小時及t = 8小時時普瑞利維自角質層、表皮及真皮之回收率。製程
： 下文圖8顯示普瑞利維5%軟膏之方法流程圖表。 針對6 kg之批量大小，示例性地描述製程： 0.1 M鹽酸含於Super RefinedTM
PEG 400之製備。將1.75 g鹽酸，37%與198.25 g Super RefinedTM
PEG 400混合並攪拌直至獲得視覺上均勻之溶液。 0.1 M氫氧化鈉含於Super RefinedTM
PEG 400之製備。將0.40 g氫氧化鈉與112.55 g Super RefinedTM
PEG 400混合並攪拌直至獲得視覺上均勻之溶液。 PEG 4000相之製備。稱取1050.00 g PEG 4000至於標有PEG 4000 PHASE (PEG 4000相)之不鏽鋼容器中並將該容器置於約65℃之水浴中。加熱(目標溫度：約65℃)並攪拌直至觀察到明顯的熔化。最終調配物製備
： 稱取3948.60 g Super RefinedTM
PEG 400及6.00 g丁基化羥基甲苯至於標有FINAL FORMULATION (最終調配物)之不鏽鋼容器中。將該容器置於約40℃之水浴中並攪拌直至BHT完全溶解。隨後將該溶劑自水浴移除。將586.80 g丙二醇及306.60 g普瑞利維半水合物
添加至所獲得之溶液。在將該容器轉移至約65℃之水浴中後，加熱容器中之內含物直至普瑞利維半水合物溶解同時持續攪拌溶液。隨後添加102.00 g 0.1 M鹽酸溶液含於Super RefinedTM
PEG 400。加熱容器中之內含物直至達到約65℃之溫度，同時持續攪拌溶液。一旦兩個容器中之內含物均達到目標溫度，就將標有PEG 4000 PHASE之容器中的內含物轉移至標有FINAL FORMULATION之容器中。將標有FINAL FORMULATION之容器從約65℃之水浴中移除，將其置於約40℃之水浴中並攪拌直至容器中之內含物達到約40℃。隨後將容器轉移至約25℃之水浴中並繼續攪拌調配物直至觀察到灰白色黏性軟膏。量測調配物之pH值。若pH超出4.0至5.0之限制，則藉由逐滴添加0.1 M鹽酸含於Super RefinedTM
PEG 400 (用於降低pH)或0.1 M氫氧化鈉含於Super RefinedTM
PEG 400 (用於增加pH)來調節pH。在pH調節期間攪拌調配物。記錄最終pH值及所添加之溶液重量。計算獲得總共100%所需之Super RefinedTM
PEG 400的量。 添加計算量之Super RefinedTM
PEG 400，同時繼續攪拌。記錄所添加之Super RefinedTM
PEG 400之重量。當調配物達到環境溫度(15℃至25℃)，停止攪拌並將容器自水浴移除。[IPC散裝調配物-頂部+中部+底部]。若需放置過夜，則在容器上蓋上蓋子並用實驗室薄膜密封。散裝材料保持在受控環境溫度下直到填充。理想地，填充係在製備完成後第二天完成。對於1期試驗而言，使用100 ml琥珀色玻璃小瓶，而對於2期試驗而言，將軟膏填充至鋁管。 表54–製程中控制
上表54顯示在製備局部軟膏調配物中所用之製程中控制。用於分析藥品之規格
表55提供用於普瑞利維5 % w/w軟膏之質量控制規格。該等規格係初步規格，並將隨著更多批次數據之生成而進行檢視。 表55–質量控制規格
a：報告水平：0.05% TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 上表55顯示用於局部軟膏調配物之質量控制規格。外觀：目視判定外觀。
顯微外觀：使用具有400x放大率之光學顯微鏡評估調配物之顯微外觀。偏振光及非偏振光均用於檢查晶體材料之存在。 普瑞利維之識別、分析及相關物質(HPLC)：為了識別，將樣品層析圖中之普瑞利維波峰的滯留時間與參考層析圖中之普瑞利維波峰的滯留時間進行比較，並將從樣品層析圖中之普瑞利維波峰所提取的UV光譜與從參考標準層析圖中所提取的UV光譜進行比較。使用外標定量確定分析。報告等級設定為0.05 %面積/面積。BHT 之鑑定及定量 (HPLC)
使用外標定量確定BHT之分析。使用HPLC方法來估計BHT含量。 表觀pH：根據USP ＜791＞進行表觀pH之量測。 表觀黏度：使用布氏黏度計測定表觀黏度(Spindle E，helipath，0.6 rpm，25℃，2分鐘進行讀數)。微生物學品質
各自根據USP ＜61＞及＜62＞及歐洲藥典2.6.12及2.6.13進行微生物學品質之測試。 抗微生物有效性測試 根據USP ＜51＞進行抗微生物有效性測試。批量分析。
不同批次分析之結果係顯示於下表56中 表56–對用於臨床試驗之普瑞利維5% w/w軟膏的批量分析
表57-對用於臨床試驗之普瑞利維5 % w/w軟膏的批量分析
TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 a 報告水平：0.05% b Spindle E，helipath，0.6 rpm，25℃，2分鐘後進行讀數 上表57顯示在臨床試驗中所用之普瑞利維5 % w/w游離鹼半水合物的批量分析。 表58–普瑞利維5 % w/w軟膏之批量分析
上表58顯示5 % w/w普瑞利維游離鹼半水合物軟膏之批量分析。 表59–普瑞利維5 % w/w軟膏之批量分析
表60–普瑞利維5 % w/w軟膏之批量分析
TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 a 報告水平：0.05% b 使用個別相關物質之未舍入結果計算相關物質之總和 c 穩定性研究之初步分析結果 d Spmdle E，helipath，50 rpm，25℃ 注釋： 批次7264/001及7277/001含有4.89%普瑞利維(游離鹼)而非5%，歸因於藥物之半水合物形式(參見部分3.2.P.2,2,3，表1)。此係在II期臨床製備中進行修正，其中調節API濃度以使最終產物含有5%普瑞利維(游離鹼)，參見部分3.2.P.1。 用於測試GLP批次之HPLC方法(普瑞利維之識別、分析及相關物質)與用於測試GMP批次之HPLC方法部分不同。ICH 穩定性數據：在鋁管中之穩定性
在25℃/60 % RH及40℃/75 % RH下，對封裝於具有螺旋蓋(類型：花盆穿孔器蓋)之2 g可摺疊鋁管中的一個技術批次普瑞利維5 % w/w軟膏進行穩定性研究。 表61–在25℃/60 % RH下之穩定性 時間點(月)
a n=2 b 原始分析方法 c 先進分析方法 注釋：在t = 3個月後，使用略有不同之HPLC方法(稱為「原始分析方法」)來測試普瑞利維之識別、分析及相關物質，此後使用經修正之HPLC方法(參見部分3.2.P.5.2，稱為「先進分析方法」)。 表62–在40℃/75 % RH下之穩定性 時間點(月)
a 原始分析方法 b 先進分析方法 c n=2 注釋：在t = 3個月後，使用略有不同之HPLC方法(稱為「原始分析方法」)來測試普瑞利維之識別、分析及相關物質，此後使用經修正之HPLC方法(參見部分3.2.P.5.2，稱為「先進分析方法」)。 表63-使用中穩定性數據
TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 上表63顯示5 % w/w普瑞利維游離鹼半水合物之局部調配物的使用中穩定性數據。在玻璃瓶中之穩定性 ( 先前封裝 )
自一個技術批次及一個GMP批次所獲得之穩定性結果係在下文中詳細描述。兩個批次均含有4.89 %普瑞利維(游離鹼)而非5 %，歸因於藥物之半水合物形式
。此係在II期臨床製備中進行修正，其中調節API濃度以使最終產物含有5 %普瑞利維(游離鹼)。該等批次係封裝於帶螺旋蓋之100 mL琥珀色玻璃瓶中。技術批次之規格係與GMP批次之規格略有不同。除指示測試普瑞利維之識別、分析及相關物質外，且除測試表觀黏度(布氏黏度計，Spindle E，helipath，50 rpm，25℃)外，測試方法為彼等上文所列者。亦提供所獲得之使用中穩定性結果。 表64–在25℃/60 % RH下之穩定性 時間點(月)
表65
a 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 上表65顯示局部調配物之MQT測試的結果。 表66–在25℃/60 % RH下之穩定性時間點 ( 月 )
表67–在40℃/75 % RH下之穩定性時間點 ( 月 )
表68時間點 ( 月 )
a 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 表69時間點 ( 月 )
a 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 注釋：在t = 4個月後，使用略有不同之HPLC方法(稱為「原始分析方法」)來測試普瑞利維之識別、分析及相關物質，此後使用經修正之HPLC方法(參見部分3.2.P.5.2，稱為「先進分析方法」)。 表70-使用中穩定性數據時間點 ( 天 )
上表70顯示填充於管中之局部調配物之使用中穩定性數據。 表71–在40℃/75 % RH下之穩定性時間點 ( 月 )
a 報告水平：0.05% b 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 表72–在25℃/60 % RH下之穩定性時間點 ( 月 )
a 報告水平：0.05% b 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 表73–在40℃/75 % RH下之穩定性時間點 ( 月 )
a 報告水平：0.05% b 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 表74–在40℃/75 % RH下之穩定性時間點 ( 月 )
a 報告水平：0.05% b 至少測試穩定性研究之開始及結束 RRT:相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 表75–在40℃/75 % RH下之穩定性時間點 ( 月 )
a 報告水平：0.05% b 至少測試穩定性研究之開始及結束 c OOS：所分析之樣品提取物中三分之二導致BHT含量低於標稱之90.0%低接受限度(89.7%、91.6%、89.8%) RRT：相對滯留時間；TAMC：總需氧微生物數量；TYMC：總酵母及黴菌數量；CFU：菌落形成單位 實例2馬來酸鹽之溶解度
表76-馬來酸鹽在水中及相應調配物媒劑中之溶解度
表77-馬來酸鹽在局部調配物基質中之溶解度
(-)委託人未要求評估，*pH為8.42，**pH為2.65 * SS01代表用於當前臨床調配物之調配物基質馬來酸鹽之穩定性
如下表78中所示，相比PEG 400，馬來酸鹽在SR PEG 400中顯示更佳穩定性。 表78-在t=0時及在40℃及50℃下儲存t=2及4週後，普瑞利維馬來酸鹽在PEG400及SR PEG 400中之回收率(數據以平均值表示，其中括號內為範圍；n = 3)。 實例 3 ： 游離鹼、甲磺酸鹽及游離鹼半水合物在個別賦形劑中之比較溶解度
游離鹼半水合物顯示更高溶解度，其中游離鹼中之一批係與第二批相當。因此，針對游離鹼所獲得之所有數據可外推至游離鹼半水合物之溶解度。 表79：普瑞利維之兩種形式(批次BXR2KVE及M023862-CA15-033)在PEG 400及丙二醇中的飽和溶解度(% w/w)，平均值(範圍，n = 3)。
* 在252-1402-01期間進行測定。當前臨床調配物 O1v3 之耐光性測試
領先調配物(O1v3)在252-1402-01中之耐光性測試顯示普瑞利維游離鹼(批次BXR2KVE，測試項目1)對曝光穩定。對含普瑞利維半水合物之O1v3進行附加耐光性測試(M023862-CA15-033，測試項目2)以確認使用此形式之普瑞利維所製備的調配物在曝光後係穩定的。根據ICH指南Q1B將含有O1v3之經填充硼矽酸鹽小瓶的樣品曝露於光下，並分別在表80及表81中總結普瑞利維回收率及純度水平。數據表明，曝露至UV光後，調配物(O1v3)中之普瑞利維顯得穩定，因為普瑞利維之回收率及純度與t=0時相比幾乎沒有變化，此支持先前在252-1402-01中所做之觀察。平均純度水平之輕微差異可歸因於與分析方法之LOQ接近的相關物質。 表80：根據ICH指南Q1B，普瑞利維半水合物在t = 0時及在曝露至UV光後之平均回收率(%) (範圍，n = 3)。
在上表80中，「T=0」代表在光應力曝露條件之前的普瑞利維半水合物(%)調配物。 表81：根據ICH指南Q1B，普瑞利維半水合物在t = 0時及在曝露至UV光後之平均純度水平(% a/a) (範圍，n = 3)。
在上表81中，「T=0」代表在光應力曝露條件之前的普瑞利維半水合物(% a/a)調配物。普瑞利維游離鹼與甲磺酸鹽之間的溶解度差異
下表82顯示用於評估游離鹼及甲磺酸鹽之溶解度的溶劑系統組成：
(-)：不包含 表83-普瑞利維游離鹼、甲磺酸鹽在溶劑系統中之溶解度
* 請忽略利多卡因及氫皮質酮之數據 顯然，游離鹼在所用溶劑系統中顯示顯著更高之溶解度。游離鹼及甲磺酸鹽在個別賦形劑及溶劑系統中之短期穩定性
使溶解於個別賦形劑及溶劑系統中之游離鹼及甲磺酸鹽兩者在40℃及50℃下接受2週及4週。 在40℃及50℃下，游離鹼在不同溶劑系統中2及4週之穩定性。 表84-在t = 0時及在所述時間點及溫度下儲存後所測定之普瑞利維游離鹼
在溶劑中的回收率及波峰純度。與t=0值相比之回收率，n=2，括號內說明範圍(分析方法)。波峰純度值，n= 1 (雜質方法)。
表85中顯示在40℃及50℃下，馬來酸鹽鹼在不同溶劑系統中2及4週之穩定性：
游離鹼及甲磺酸鹽之溶解度在相似條件下之不同媒劑系統中可見顯著差異。游離鹼與甲磺酸鹽對比在光阻斷劑中之溶解度
如上表XX所示，與甲磺酸鹽相比，游離鹼在水楊酸辛酯(光阻斷劑)中顯示更高之溶解度。 表86-普瑞利維(游離鹼及甲磺酸鹽)在水楊酸辛酯中之飽和溶解度。數值代表平均值，其中括號內為範圍，n=3。 游離鹼及甲磺酸鹽在不同溶劑系統中之溶解度差異
評估游離鹼與甲磺酸鹽對比在用於開發軟膏調配物之不同溶劑系統中的溶解度。如下表87所示，與甲磺酸鹽相比，游離鹼在水楊酸辛酯(光阻斷劑)中顯示更高之溶解度。因此，只能開發含有普瑞利維游離鹼而不含其甲磺酸鹽之5 %軟膏調配物。 保持藥物呈溶解形式對藥物穿過皮膚之滲透速率具有顯著影響，並最終對局部施用時之效能有影響。 表87-普瑞利維游離鹼及甲磺酸鹽在用於開發軟膏之基礎的溶劑系統中之飽和溶解度。
(-)：不包含，ND：未測定，* 剩餘量將為最終調配物之PEG4000。本發明之含有普瑞利維游離鹼及甲磺酸鹽之調配物的短期穩定性數據
使含有普瑞利維游離鹼及甲磺酸鹽之調配物接受40℃及50℃持續4週。 當與甲磺酸鹽比較時，發現游離鹼係相對穩定。 表88–在t=0時及在25℃及40℃下儲存t=2及4週後調配物中普瑞利維游離鹼之百分比純度，n=1。ND：未測定 表89–在t=0時及在25℃及40℃下儲存t=2及4週後調配物中普瑞利維甲磺酸鹽之百分比純度，n=1。ND：未測定當前臨床調配物之長期穩定性數據
已生成含有游離鹼半水合物
之局部調配物O1V3的24個月穩定性數據，其中藥物係呈溶解形式(5%載藥量)且調配物在分析、純度、pH、黏度方面係穩定的。 下表顯示該局部調配物O1V3之90個月穩定性。 表90 - O1v3，在25℃/60 % RH及40℃/75 % RH下封裝於硼矽酸鹽小瓶中之5%穩定性測試結果 在存在及不存在光阻斷劑下，游離鹼及甲磺酸鹽調配物在光應力條件下之穩定性
根據ICH指南，使含有及不含光阻斷劑之普瑞利維游離鹼及甲磺酸鹽的局部調配物接受UV-應力條件。藉此，發現游離鹼在存在及不存在光阻斷劑兩種情況下均對光應力條件穩定。然而，在大多數情況下，普瑞利維甲磺酸鹽僅在存在光阻斷劑下穩定。 表91–在t=0時及在ICH條件下曝露至UV光時所測定之調配物中普瑞利維游離鹼的回收率(呈理論濃度之百分比)及波峰純度。
表92–在t=0時及在ICH條件下曝露至UV光時所測定之調配物中普瑞利維甲磺酸鹽的回收率(呈理論濃度之百分比)及波峰純度。 游離鹼及游離鹼半水合物在個別賦形劑中之比較溶解度
游離鹼半水合物顯示比游離鹼之兩個批次更高之溶解度。因此，針對游離鹼所獲得之所有數據可外推至游離鹼半水合物之溶解度。 下表93中顯示普瑞利維之兩種形式(游離鹼批次為BXR2KVE及普瑞利維游離鹼半水合物為M023862-CA15-033)在PEG 400及丙二醇中的飽和溶解度(% w/w)，平均值(範圍，n = 3)。表93 當前臨床調配物之耐光性測試
當前臨床調配物包含以下賦形劑及活性成分(單位% w/w)： –Super RefinedTM
PEG 400 55.00 –0.5 M NaOH/HCI 以達到pH為4至5 –Super RefinedTM
PEG 400 (第二次添加) 適量100 % –丙二醇 9.78 –BHT 0.10 –PEG 4000 17.50 –普瑞利維游離鹼半水合物 5.0 對上述含普瑞利維游離鹼半水合物之臨床調配物進行耐光性測試，以確認使用此形式之普瑞利維所製備的調配物在曝光後係穩定的。根據ICH指南Q1B將含有該臨床調配物之經填充硼矽酸鹽小瓶的樣品曝露於光下，並分別在表94及表95中總結普瑞利維游離鹼半水合物回收率及純度水平。數據表明，曝露至UV光後，該臨床調配物中之普瑞利維游離鹼半水合物顯得穩定，因為普瑞利維游離鹼半水合物之回收率及純度與t=0時相比幾乎沒有變化，此支持先前在252-1402-01中所做之觀察。平均純度水平之輕微差異可歸因於與分析方法之LOQ接近的相關物質。表 94
：根據ICH指南Q1B，普瑞利維游離鹼半水合物在t = 0時及在曝露至UV光後之平均回收率(%) (範圍，n = 3) 表 95
：根據ICH指南，普瑞利維游離鹼半水合物在t = 0時及在曝露至UV光後之平均純度水平(% a/a) (範圍，n = 3) 提供當前臨床調配物在 25 ℃ /60 % RH 下之 24 個月長期穩定性數據：
已生成含有以溶解形式存在之普瑞利維游離鹼半水合物作為活性醫藥成分之當前臨床調配物的24個月穩定性數據，其中作為活性部分之普瑞利維游離鹼具有5 % w/w之載藥當量，且發現各自局部調配物在分析、純度、pH及黏度方面係穩定的。此調配物係由表觀pH為4.0至4.5 (在製程期間進行調整)之Super RefinedTM
PEG 400組成。下表96顯示當前臨床調配物各自之24個月穩定性數據。 表96 a)-c)：提供含有5 % w/w普瑞利維游離鹼半水合物之當前臨床調配物在25℃/60 % RH下24個月之長期穩定性數據。 表96 a)：含有5 % w/w普瑞利維游離鹼半水合物之臨床調配物–在25℃/60 % RH及40℃/75 % RH下封裝於硼矽酸鹽小瓶中之穩定性測試結果(批號：BMR7264/001)。
表96 b)：含有5 % w/w普瑞利維游離鹼半水合物之臨床調配物，在25℃/60 % RH及40℃/75 % RH下封裝於硼矽酸鹽小瓶中之媒劑穩定性測試結果(批號：BMR7263/001)。
表96 c)：在25℃/60 % RH下持續24個月之長期穩定性數據的總結。 PEG 400 等級之影響：
使用PEG 400與Super RefinedTM
PEG 400對比在40℃及50℃下使呈溶解形式之普瑞利維接受4週應力條件。如下表97中所示，相比Super RefinedTM
PEG 400，當普瑞利維藥物係溶解於PEG 400中時，降解程度顯著更高。表 97 ：當使用 PEG 400 與 Super RefinedTM
PEG 400 對比進行調配時，普瑞利維游離鹼之回收率及波峰純度 媒劑之 pH 的影響：
使用PEG 400在調節及不調節pH至4.0下，在40℃及50℃下使呈溶解形式之普瑞利維接受4週應力條件。如下表98中所示，相比pH 4.0，當該普瑞利維藥物係溶解於PEG 400中而無任何pH調節時，降解程度顯著更高。因此可以說，當pH處於酸性範圍(即4.0至4.5)時，該呈溶解形式之普瑞利維藥物顯示更高穩定性。而從生理可接受性之角度來看，pH 4.0是最低之可接受pH。 表98-當針對不同表觀pH進行測試時，普瑞利維游離鹼之回收率及波峰純度
基於所獲得之此等數據可以說，氧化雜質(例如藉由PEG 400)之存在及中性pH對呈溶解形式之普瑞利維藥物之穩定性係不利的。因此，當接受長期穩定性研究時(在40℃/75 RH下6個月及在25℃/60 %下24個月)，在pH 4.0至4.5下，使用Super RefinedTM
PEG 400與BHT(作為抗氧化劑)組合之本發明局部調配物經證明係足夠穩定。當前臨床調配物之耐光性：
呈溶解形式之普瑞利維對光應力條件敏感，然而，令人驚訝且出人意料地，當前臨床調配物對光應力條件穩定。此等發現亦解釋Super RefinedTM
PEG 400、BHT及pH 4.0至4.5對穩定普瑞利維對抗光應力條件之作用。表 99- 當前臨床調配物之耐光性 PEG 400 與 Super RefinedTM
PEG 400 對比在本發明軟膏調配物中使用之影響
呈軟膏調配物之當前臨床調配物係使用標準PEG 400及Super RefinedTM
PEG 400同時使用相同方法及組成來製備。此等測試調配物係在40℃/75 % RH下儲存2個月。表 100- 使用 Super RefinedTM
PEG 400 及 BHT 在 pH 4.0 下之當前臨床調配物的穩定性數據 表 101- 使用標準 PEG 400 、 BHT 及 pH 4.0 之當前臨床調配物的穩定性數據
如上表100及101所示，使用標準PEG 400代替Super Refined PEGTM
400導致在儲存2個月後便增加雜質(儘管調配物含有BHT，pH為4.0)。因此，Super RefinedTM
PEG 400與BHT之組合及在pH 4.0下之作用對於穩定藥物及防止其發生任何氧化降解(當其係以溶解形式存在時)而言係相當重要的。無 pH 調節之影響：
呈軟膏調配物之當前臨床調配物係使用Super RefinedTM
PEG 400且無需任何pH調節劑使用相同方法及組成來製備。其係在40℃/75 %下儲存2個月。表 102- 使用 Super Refined PEGTM
400 、 BHT 及無 pH 調節之當前臨床調配物的穩定性數據
如上表102中所示，無pH調節導致普瑞利維之顯著降解(在40℃/ 75 RH下2個月內降解約24%)。因此，根據本發明，pH調節至4.0至4.5對於呈溶解狀態或溶解形式之普瑞利維的穩定係非常關鍵的。PEG 400 等級及無 pH 調節之影響
呈軟膏調配物之當前臨床調配物係使用標準PEG 400且無需任何pH調節使用相同方法及組成來製備。其係在40℃/75 % RH下儲存2個月。表 103- 使用標準 PEG 400 、 BHT 及無 pH 調節之當前臨床調配物的穩定性數據
如上所示，無pH調節及使用標準PEG 400導致普瑞利維之顯著降解(在40℃/75 %下2個月內降解約88.6 %)。因此，pH調節至4.0至4.5與Super Refined PEGTM
400之組合對於呈溶解狀態或溶解形式之普瑞利維的穩定係非常關鍵的。BHT 作為抗氧化劑之影響
呈軟膏調配物之當前調配物臨床調配物係使用Super RefinedTM
PEG 400、pH調節至4.0至4.5但無任何BHT使用相同方法及組成來製備。其係在40℃/75 RH下儲存2個月。表 104- 使用 Super RefinedTM
PEG 400 及 BHT ， pH 調節至 4.0 至 4.5 但無任何 BHT 之當前臨床調配物的穩定性數據
如上表104所示，將BHT自當前氯軟膏調配物移除導致在儲存2個月後便增加雜質(儘管調配物含有Super Refined PEGTM
400且pH為4.0)。因此，Super RefinedTM
PEG 400與BHT之組合及pH 4.0至4.5之作用對於穩定呈溶解狀態或溶解形式之藥物而言係相當重要的。The subject of the present invention is a pharmaceutical formulation for topical application to an individual in need, the formulation comprising: i) 1 to 10% w / w of N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide, ii) 0 to 90% w / w of at least one solvent, iii ) 0 to 10% w / w of at least one antioxidant, wherein the pharmaceutical formulation has a pH of 2.0 to 8.0, preferably a pH of 4.0 to 5.0, wherein N- [5- (amino-sulfonyl)- 4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is in a dissolved state or in a dissolved form at 25 ° C / 60 Stable at% RH for 12 months, where the solvent is selected from ethanol, dimethyl isosorbide, isopropanol, Transcutol P, propylene glycol, polyethylene glycol, PEG 400, PEG 4000 and Super RefinedTM
(SR) Group of PEG 400. In the context of the above paragraph, the pharmaceutical composition has a better pH value of 4.0 to 4.5. The subject of the present invention is also a pharmaceutical formulation for topical application to individuals in need, the formulation comprising: i 1 to 10% w / w of N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide, ii> 0 to 90% w / w of at least one solvent, iii > 0 to 10% w / w of at least one antioxidant, wherein the pharmaceutical formulation has a pH of 2.0 to 8.0, preferably a pH of 4.0 to 5.0, more preferably a pH of 4.0 to 4.5, where N- [5- (Amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is in a dissolved state Or in a dissolved form, it is stable for 12 months at 25 ° C / 60% RH, where the solvent is selected from ethanol, dimethyl isosorbide, isopropanol, Transcutol P, propylene glycol, polyethylene glycol, PEG 400, PEG 4000 and Super RefinedTM
The group of PEG 400, wherein the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopheryl acetate , Propyl gallate, dodecyl gallate, octyl gallate, thiosulfate group. In another aspect of the present invention, the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl contained in the pharmaceutical composition as described above ] -N-Methyl-2- [4- (2-pyridyl) phenyl] acetamide is stable in dissolved state or in dissolved form at 25 ° C / 60% RH for at least 24 months. Here, and throughout the text, the term "> 0 to 90%" or similar expression means a value greater than "0" and up to and including 90%. Here, and throughout the text, the term "> 0 to 10%" or similar expression means a value greater than "0" and up to and including 10%. In one embodiment of the present invention, the active pharmaceutical ingredient N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole-2-contained in the pharmaceutical composition of the above embodiment Yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is stable in a dissolved state or in a dissolved form at 25 ° C / 60% RH for 12 months. In one embodiment of the present invention, the active pharmaceutical ingredient N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole-2-contained in the pharmaceutical composition of the above embodiment Yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is stable in a dissolved state or in a dissolved form at 25 ° C / 60% RH for at least 24 months. In another embodiment of the present invention, when measured according to the Pharmacopoeia methods of the European Pharmacopoeia (Ph. Eur.) And / or the United States Pharmacopoeia (USP), the active pharmaceutical ingredient N contained in the pharmaceutical composition of the above embodiment -[5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide The amine is stable in a dissolved state or in a dissolved form at 25 ° C / 60% RH for 12 months. In another embodiment of the present invention, when measured according to the Pharmacopoeia methods of the European Pharmacopoeia (Ph. Eur.) And / or the United States Pharmacopoeia (USP), the active pharmaceutical ingredient N contained in the pharmaceutical composition of the above embodiment -[5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide The amine is stable in a dissolved state or in a dissolved form at 25 ° C / 60% RH for at least 24 months. In this application, the term "formulation" refers to a mixture of excipients and active ingredients, and can be prepared in the form of a cream, gel, or ointment according to a specific procedure (referred to as "formula"). The formulation is a very important aspect of pharmacy, because these formulations are crucial to ensure that the active part of the drug is in the correct concentration and delivered to the specified part of the body with the correct kinetics (not too fast and not too slow) important. A good example is the use of supersaturated drug delivery systems. These formulations also need to have an acceptable consistency, good storage stability, and be physically and chemically stable enough to be transported to patients from places where they are manufactured. In the context of the above paragraph, the "correct dynamics" refers to the correct penetration dynamics. In the context of this application, the term "topical formulation" as used herein generally includes formulations that can be applied to the skin or mucous membranes. For example, topical formulations can be used to confer therapeutic benefits on patients or confer cosmetic benefits on consumers. Topical formulations can be used for local and transdermal administration of substances. The term "topical administration" as used herein generally includes the delivery of a substance (such as a therapeutically active agent) to a local area of the skin or body. As used herein, the term "individual" refers to a living person or non-human being, preferably a human individual, in which the system is healthy, apparently healthy, suffering from herpes virus infection, especially due to herpes simplex virus 1 ( HSV-1) and herpes simplex virus (HSV-2). In the context of the present application, "in the dissolved state" means that the solid form of Previvir forms a solution in a solvent. In the context of the above paragraph, "in the dissolved state" means that the solid form of pregarib can also form a liquid or semi-liquid solution in the excipient matrix. In the context of this application, a solvent is a substance that dissolves a solute (a chemically different liquid, solid, or gas) to produce a solution. The solvent is usually liquid, but can also be solid or gas. The amount of solute soluble in a specific volume of solvent varies with temperature. The solvent is the component of the solution present in the largest amount. Furthermore, in the context of the above paragraph, a solvent is a substance that dissolves solutes (liquids, solids, or gases that are chemically different) to produce a liquid or semi-liquid solution. The solvent is usually liquid, but can also be semi-solid, solid or gas. In the present application, the formulated formulation contains at least one solvent, which means that other solvents (second, third, fourth, etc.) may be present as auxiliary solvents to enhance the solvent capacity of the main solvent. In the context of this application, "antioxidants" are molecules that inhibit the oxidation of other molecules. Specifically, antioxidants block the oxidation reaction and prevent the effects of oxygen free radicals (such as peroxides). These two processes are known to damage Integrity and function of various natural substances. Antioxidants are suitable for preventing the degradation of ingredients in formulated products. In addition, in the context of the above paragraph, "antioxidant" is a molecule that inhibits the oxidation of other molecules. Specifically, antioxidants block the oxidation reaction and prevent the role of oxygen free radicals (such as peroxides). These two processes are known Impair the integrity and function of various oxidation-sensitive substances (such as pharmaceutical active ingredients or excipients). Antioxidants are suitable to prevent the degradation of these ingredients in formulated products. In another embodiment of the present invention, the at least one solvent is selected from the group consisting of polyethylene glycol, preferably PEG 400, more preferably Super Refined ™ (SR) PEG 400. In one embodiment of the present invention, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl- 2- [4- (2-pyridyl) phenyl] acetamide is selected from the group consisting of: • N- [5- (amino-sulfonyl) -4-methyl-1,3- Thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideMaleate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] The free base of acetamideMesylate
, And • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base
. In another embodiment of the present invention, the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, acetic acid Group of tocopherol esters, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate. In yet another embodiment of the present application, the antioxidant is BHT. In another embodiment of the present application, the formulation is selected from the group consisting of the following formulations: creams, ointments, gels, ointments, lotions, wax formulations, lipsticks, tonics, Blend of mousse, foam, film, emulsion, paste, solution, oil, and microfat. In another embodiment of the present application, the formulation is selected from the group consisting of the following formulations: creams, ointments, gels, ointments, lotions, wax formulations, lipsticks, tonics, Formulated with mousse, foam, film, emulsion, paste, solution, oil, grease, and patch.Patch
In the context of the above paragraph, the active pharmaceutical ingredients of Pravivir according to the present invention can also be applied to organisms (eg, humans infected with herpes virus, such as humans infected with HSV-1 and / or HSV-2) The patch on the body part is administered. More specifically, the patch of the present invention can illustratively include a skin adhesive layer, a backing layer, and a drug release liner; thereby, the adhesive layer can include pregaribic active pharmaceutical ingredients according to the present invention, and / Or other active compounds dissolved in low volatility solvents and polymer binders soluble in high volatility solvents. The active medicinal ingredients of Prairil can be used as antiviral agents in a therapeutically and / or prophylactically effective amount (for example, 0.1 to 10% w / w of the dry adhesive layer, preferably about 5% w / w) in low volatility solvents To incorporate the adhesive layer. In one embodiment, the invention relates to an ointment, cream or gel for topical application, which contains the active pharmaceutical ingredient in any of the above forms. Topical formulations exist in many forms, such as ointments, gels, creams, lotions, solutions, suspensions, foams, and shampoos. The most commonly used topical formulations are semi-solid or semi-liquid dosage forms, including ointments, creams, lotions, lotions and gels. The common feature of these pharmaceutical semi-solid preparations is their ability to adhere to the application surface for an appropriate period of time before they are washed away or worn away. They are usually used as vehicles for topical application of drugs, as emollients or as protective agents. In the context of the present application, the term "ointment" includes hydrocarbon gel, microlipid, absorption base, W / O ointment base, mixed emulsion or polyethylene glycol as the base. As used herein, the cream contains an O / W matrix. In the context of the above two paragraphs, the term "ointment" includes hydrocarbon gel, microlipid, absorption matrix, W / O ointment base, mixed emulsion or polyethylene glycol as the main carrier system. Therefore, the cream may contain an O / W matrix as the main carrier system. In the context of the present application, the term paste contains a large amount of powdery ingredients in addition to an ointment or cream base, such as, for example, zinc oxide, talc, starch or titanium dioxide. In the context of the above paragraph, the term paste contains a large amount of powdered ingredients in addition to ointment or cream base as the main carrier system, such as, for example, zinc oxide, talc, starch or titanium dioxide. As used herein, the term "gel" includes solvents such as water, ethanol, isopropanol, or propylene glycol, and uses such as cellulose ethers, alginates, polyacrylates, bentonite, gelatin, tragacanth, polyethylene Produced as a gel former for pyrrolidone or polyvinyl alcohol. A lipophilic gel matrix or microemulsion can also be used. In the context of the present application, the powder contains powdered additives such as starch, stearate, silica, clay, magnesium carbonate, talc, cellulose, zinc oxide and (specifically) lactose. Stabilizers, antioxidants, preservatives, humectants, fat-rich agents, solvents or excipients can be added to improve the penetration and efficacy of all formulations. In the context of the above paragraphs, stabilizers, antioxidants, preservatives, humectants, fat-rich agents, solvents or excipients can be added as skin penetration enhancers to improve the permeability of all the topical formulations disclosed herein And efficacy. Many compounds have been evaluated for such penetration enhancing active agents, including sulfonamide (such as dimethyl sulfoxide, DMSO), azone (such as laurazine), pyrrolidone (such as 2-pyrrolidone, 2P), Alcohols and alkanols (ethanol or decanol), glycols (such as propylene glycol, PG, common excipients in topical dosage forms), surfactants (also commonly found in dosage forms), and terpenes. In one embodiment of the present invention, the active pharmaceutical ingredient Prapiric in the pharmaceutical formulation is selected from the range of 1.1 to 10% w / w, more preferably 1.1 to 5% w / w. In another embodiment of the present invention, in the pharmaceutical formulation, the concentration of the at least one solvent is 0.1 to 90% w / w, such as 5 to 90% w / w, 10 to 90% w / w, 10 to 80% w / w, 20 to 80 w / w, 25 to 80% w / w, 15 to 50% w / w, or 30 to 45% w / w. In another embodiment of the present invention, in the pharmaceutical formulation, the concentration of the second solvent is 0.1 to 60% w / w, more preferably 10 to 50% w / w, and most preferably 10 to 40% w / w. In another embodiment of the present invention, in the pharmaceutical formulation, the concentration of the antioxidant is 0.01 to 10% w / w, more preferably 0.025 to 5% w / w, and most preferably 0.05 to 2% w / w. Unexpectedly and unexpectedly, in a particular aspect of the invention, the inventors found that by using BHT and Super RefinedTM
PEG 400 formulates the Pravivir antiviral agent provided herein, which is present in the formulation in a dissolved form. By this, the dissolved form ensures that the local formulation delivers its pregaribic antiviral agent in a medically sufficient amount to the respective target side to effectively resolve the HSV-1 and / or HSV-2 virus. With the provision of pregaribic antiviral agents in dissolved form, stability challenges may arise, and therefore the challenge of stabilizing and maintaining the stability of dissolved drugs. Against this background, the inventors have surprisingly found that the addition of BHT as a free radical forming agent significantly stabilizes the Prairil antiviral agents contained in the topical formulations provided herein. However, in the final topical formulation for medical use, the BHT is significantly reduced to an amount below the BHT detection threshold of the drug. In addition, by adding Super Refined PEGTM
400. The inventors have unexpectedly found that Prelivir antiviral agents in dissolved form can remain stable in the final formulation for 24 months at 25 ° C / 60% RH. Here, due to the use of PEG 400 and Super Refined PEGTM
The peroxide impurities generated at 400 are neutralized by the mixed BHT, and BHT can also be used as a radical scavenger for these peroxide impurities. This free radical scavenging activity may be responsible for the significant reduction of BHT in the final topical formulation of the present invention. Therefore, the initial BHT amount of the local formulation of the present invention is consumed and reduced in the formulation in some way, so that it will not exceed the BHT prescribed threshold of the release content as recorded in the respective release instructions of the medical local formulation (See further below). In the context of the above three paragraphs and in the context of the present invention, it should be noted that the Food and Drug Administration (FDA) has set the BHT for the local route used in the marketed local formulations The IIG limit is at most 0.1% w / w; and based on the data of BHT in current clinical formulations as disclosed herein, the fixed maximum value for the final local formulation for local application to individuals in need is 0.1% w / w. At this point, the IIG limit set by the FDA can be found via the following link: https://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm. In this context, it should be noted that BHT may be added to the topical formulation of the present invention during the manufacturing process in an amount exceeding the limit of 0.1% w / w prescribed by the FDA. But as mentioned above, BHT is consumed from the formulation formulation to the final product, and therefore does not exceed this 0.1% w / w limit in the final topical formulation of the present invention. Further specifications of the exemplary final product according to the present invention can be derived from the following table:
a: Reporting level: 0.05% TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming units. Therefore, specifically, the present invention provides these pharmaceutical formulations for topical application, of which The formulation contains the antiviral agent, butylated hydroxytoluene (BHT) and Super Refined in dissolved form as described aboveTM
PEG 400. In the context of the foregoing, the inventors have also found that the pH of the final topical formulation of the present invention is essential for maintaining the stability of the prestigious antiviral agent in the form provided herein in dissolved form. Decisive. In a particular aspect of the present invention, it has been found that the final topical formulation of the present invention having a pH of 4.0 to 4.5 is optimal in terms of stability and avoidance of skin irritation of the individual to be administered.Ointment formulation
Another embodiment of the present application relates to the ointment formulation of the pharmaceutical formulation of the present invention. In a specific embodiment of the present invention, there is provided a pharmaceutical formulation for topical application to an individual in need, the formulation is an ointment formulation, which comprises: (i) 15 to 20% w / w PEG 4000, (ii) 7.5 to 10% w / w propylene glycol, (iii) 1.1 to 5% w / w active pharmaceutical ingredient pregarib, (iv) 0.05 to 2% w / w butylated hydroxytoluene (BHT), (v) 25 Up to 80% w / w Super RefinedTM
PEG 400, and (vi) 0.01 to 20% w / w dilute HCl or dilute NaOH solution as a pH adjusting agent, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5. In the above paragraph, it should be noted that the pH value refers to the apparent pH.pH / Apparent pH / Local formulation
In the context of the present invention, pH is an important parameter for local formulations, especially due to its effect on patient compliance, drug stability and skin penetration of the active part. Most conventional topical formulations are based on aqueous systems such as gels, creams and lotions, however, for hydrophobic drugs, non-aqueous systems such as oils and ointments can also be used. Compared to aqueous formulations, the precise pH measurement of non-aqueous formulations is much more complicated. In theory, when measuring the pH of an aqueous solution, a part of the water molecules dissociate into H+
And OH-
Ions, and therefore the pH can be accurately obtained in the range of 0 to 14. However, the pH range of 0 to 14 may not be suitable for non-aqueous systems. Since the pH value is a measure of the activity of hydrogen ions, the concentration of hydrogen ions in a solution with an aprotic solvent will be significantly reduced or almost negligible. The pH electrodes used in normal laboratory settings are calibrated using aqueous buffers and are very well suited for recording H in aqueous systems+
Ion concentration. Electrochemistry of these pH electrodes may not be suitable for recording H in non-aqueous systems+
The ion concentration is due to very low concentration. Porras and Kenndler suggest that aqueous solutions can be used to calibrate the pH measurement of non-aqueous systems, however, the pH should be regarded as the apparent pH. Apparent pH provides the relative acidity / alkalinity of the system. Several practical difficulties may be encountered when measuring the apparent pH of non-aqueous systems. Low H+
Ion concentration can lead to inaccurate detection of the electrochemical potential between the glass pH indicator electrode and the test sample, which can cause fluctuations in pH measurement values, long response times, and inaccurate readings. There are other factors that can cause these effects: • Most pH electrodes rely on a hydrated gel layer on the outside of the glass ball to detect H+
active. The dehydration of the gel layer due to the low water content in the non-aqueous sample leads to a slow response time and inaccurate measurement results. • Non-aqueous systems can have poor electrical conductivity and therefore reduce detection H+
The efficiency of electrical components required for activity changes. • The aqueous buffer used to calibrate the pH meter may not be compatible with non-aqueous samples, so the results cannot be directly translated. The present inventors have surprisingly found that the active antiviral pregavir agent as an active substance is more stable at a pH of 4.0 to 5.0, more preferably a pH of 4.0 to 4.5, and most preferably a pH of about 4.0. Therefore, the present invention also provides, for example, a specific ointment formulation for topical application, which has a pH of 4.0 to 5.0, more preferably a pH of 4.0 to 4.5, and an optimal pH of about 4.0, however, it is well known that this is due to the aqueous group Very low concentrated apparent pH. In this context, it is important to note that the stability analysis of the inventors revealed that the apparent pH value in the range of 4.0 to 5.0 has no effect on the purity of the active pharmaceutical ingredients of Pravivir. Therefore, the measurement deviation of the apparent pH has no effect on the analysis and purity of the active pharmaceutical ingredient (for example, contained in its ointment formulations) of Pravivir of the present invention. In yet another specific embodiment, the present invention provides a pharmaceutical formulation for topical application to an individual in need, the formulation is an ointment formulation, which comprises: (i) 17.5% w / w PEG 4000, (ii) 9.78 % w / w propylene glycol, (iii) 5% w / w Pravicarb free base hemihydrate, (iv) 0.1% w / w butylated hydroxytoluene (BHT), (v) 55% to 67.62% w / w Super RefinedTM
PEG 400, and (vi) 0.01 to 20% w / w dilute HCl or dilute NaOH solution as a pH adjusting agent, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5. In the above paragraph, it should be noted that the pH value refers to the apparent pH. In the context of the above paragraph and the entire text, it should be noted that the expression "55% to 67.62% w / w Super RefinedTM
"PEG 400" means that, in the context of the present invention, the current clinical ointment formulation contains 55% w / w Super Refined initially addedTM
PEG 400, and this is by adding Super Refined for the second timeTM
PEG 400 filled to 67.62% w / w Super RefinedTM
PEG 400 is included in the final amount of the clinical ointment formulation. In yet another specific embodiment, the present invention provides a pharmaceutical formulation for topical application to an individual in need, the formulation is an ointment formulation, which comprises: (i) 17.5% w / w PEG 4000, (ii) 9.78 % w / w propylene glycol, (iii) 5% w / w Pravicarb free base hemihydrate, (iv) 0.1% w / w butylated hydroxytoluene (BHT), (v) 55% w / w Super RefinedTM
PEG 400, and (vi) Add appropriate amount of Super Refined for the second timeTM
PEG 400 to constitute Super Refined of 67.62% w / wTM
The final concentration of PEG 400, (vii) an appropriate amount of dilute HCl or dilute NaOH solution as a pH adjuster to achieve a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5, wherein the pharmaceutical formulation has a value of 4.0 to 5.0 The pH value is preferably from 4.0 to 4.5. In the above paragraph, it should be noted that the pH value refers to the apparent pH. In the context of the above paragraph and the entire text, it should be noted that the expression "55% w / w Super RefinedTM
PEG '' and `` 67.62% w / w Super RefinedTM
"PEG 400" means that, in the context of the present invention, the current clinical ointment formulation contains 55% w / w Super Refined initially addedTM
PEG 400, and this is by adding Super Refined for the second timeTM
PEG 400 filled to 67.62% w / w Super RefinedTM
PEG 400 is included in the final amount of the clinical ointment formulation. In one embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is an ointment further comprising at least one pH adjusting agent in the range of 0.01 to 20% w / w. In another embodiment of the present invention, in the ointment pharmaceutical formulation, the concentration of the at least one solvent is 25 to 90% w / w, more preferably 25 to 80% w / w, most preferably 60 to 80% w / w. In one embodiment of the present invention, in the ointment pharmaceutical formulation, the concentration of the second solvent is 0.1 to 40% w / w, more preferably 5 to 20% w / w, and most preferably 7.5 to 10% w / w. In still another embodiment of the present invention, in the ointment pharmaceutical formulation, the concentration of the third solvent is 0.1 to 30% w / w, more preferably 5 to 30% w / w, and most preferably 15 to 20% w / w . In another embodiment of the present invention, in the ointment pharmaceutical formulation, the concentration of the antioxidant is 0.015 to 10% w / w, more preferably 0.1 to 5% w / w, most preferably 0.1 to 2% w / w . In still another embodiment of the present invention, in the ointment pharmaceutical formulation, the concentration of the pH adjusting agent is 0.015 to 20% w / w. In another embodiment of the present invention, in the ointment pharmaceutical formulation, the concentration of the pH adjusting agent is 0.015 to 20% w / w to obtain a pH value of 4.0 to 5.0. In another embodiment of the present invention, in the ointment pharmaceutical formulation, the solvent is selected from the group consisting of polyethylene glycol, propylene glycol, petrolatum, liquid paraffin, lanolin, mineral oil, silicone oil, Silicone derivatives, short chain fatty acid monoglycerides, diesters and triesters, medium chain fatty acid monoglycerides, diesters and triesters, long chain saturated fatty acid monoglycerides, diesters and triesters, long chain unsaturated fatty acids Monoglycerides, diesters and triesters, vegetable oils, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil , Fish oil, grape seed oil, mustard seed oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnuts Oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid esters, short-chain fatty acid propylene glycol monoesters and diesters, medium Fatty acid propylene glycol monoesters and diesters, long chain saturated fatty acid propylene glycol monoesters and diesters, long chain unsaturated fatty acid propylene glycol monoesters and diesters, fatty alcohols, branched chain fatty alcohols, vitamin E, vitamin E acetate, tocopherol, Tocopheryl acetate, saturated fatty acids, unsaturated fatty acids. In another embodiment of the present invention, in the ointment pharmaceutical formulation, the pH adjusting agent is selected from the group consisting of buffers, acidic and alkaline solutions, organic acids (eg citric acid, lactic acid), inorganic Acid (hydrochloric acid, sulfuric acid, phosphoric acid), alkaline reagents (sodium hydroxide, sodium bicarbonate), meglumine.Cream formulation
Another embodiment of the present application relates to a cream formulation of the pharmaceutical formulation of the present invention. In one embodiment of the present invention, the pharmaceutical formulation according to any of the preceding embodiments is a cream formulation further comprising: (i) 0 to 5% w / w preservative (ii) 0 to 20 % w / w of at least one surfactant (iii) 1 to 40% w / w oil phase / emollient (iv) 0 to 40% w / w water. In the paragraphs above and in the context of the present invention, the term "preservative" means an antimicrobial substance / agent used to extend the shelf life of a drug by delaying the oxidation of active substances and excipients, respectively, and by reducing the proliferation of microorganisms. The nature of these substances is attributed to certain chemical groups that are usually aggressive to living cells and which cause certain risks when used in the human body. In this context, "antioxidants" can act as preservatives, and therefore are a subgroup of the preservatives according to the invention. In another embodiment of the present invention, the pharmaceutical formulation according to any of the preceding embodiments is a cream formulation further comprising: (i)> 0 to 5% w / w preservative (ii)> 0 to 20% w / w of at least one surfactant (iii)> 1 to 40% w / w oil phase / emollient (iv)> 0 to 40% w / w water. In the context of this application, preservatives (antimicrobials) are incorporated to reduce the risk of microbial contamination of the formulation during preparation, storage, and use. As used herein, a surfactant is an abbreviation for surface-active agent. A surfactant is any component that reduces the tension between a surface and a liquid or between two or more immiscible substances. Surfactants are chemicals with both hydrophilic and lipophilic parts. This molecular composition means that when placed in a solution of oil and water, it has the ability to reduce surface tension. Therefore, they act as emulsifiers to form a stable mixture of oil and water. Some examples of surfactants are sodium lauryl (lauryl / laureth) sulfate or ammonium lauryl sulfate, sodium methylcocoyl taurine, sodium lauryl or coconut oil sarcosinate, coconut propylaminopropyl Betaine, triethanolamine (TEA) compound, deethanolamine (DEA) compound, monoethanolamine (MEA) compound, polyethylene glycol (PEG) compound, Quaternium-7, 15, 31, 60, etc., lauryl or coconut oil Acetyl sarcosinate, disodium oleamide or dioctyl succinate sulfonate. In the context of this application, emollients or humectants are complex mixtures of chemical agents, which are specially designed to make the outer layer of the skin (epidermis) softer and more flexible. They increase skin hydration by reducing evaporation. Naturally occurring skin lipids and sterols as well as artificial or natural oils, moisturizers, emollients, lubricants, etc. can be part of commercial skin moisturizer compositions. In another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the at least one solvent is 0.1 to 60% w / w, more preferably 15 to 50% w / w, and most preferably 30 to 45% w / w. In another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the second solvent is 0.1 to 40% w / w, more preferably 5 to 30% w / w, most preferably 10 to 20% w / w. In one embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the third solvent is 0.1 to 20% w / w, more preferably 2 to 20% w / w, most preferably 3 to 7% w / w . In another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the preservative is 0.01 to 5% w / w, more preferably 0.025 to 5% w / w, most preferably 1 to 2% w / w. In one embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the antioxidant is 0.01 to 5% w / w, more preferably 0.025 to 1% w / w, most preferably 0.05 to 0.15% w / w . In another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the surfactant is 0.01 to 20% w / w, more preferably 2 to 18% w / w, most preferably 5 to 15% w / w. In still another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the oil phase / emollient is 1 to 20% w / w, more preferably 2 to 15% w / w, most preferably 4 to 10% w / w. In another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of the second surfactant is 0.015 to 20% w / w, more preferably 0.5 to 10% w / w, most preferably 1 to 4% w / w. In still another embodiment of the present invention, in the cream pharmaceutical formulation, the concentration of water is 0.01 to 40% w / w, more preferably 5 to 30% w / w, and most preferably 10 to 20% w / w. In another embodiment of the present invention, in the cream pharmaceutical formulation, the preservative is selected from the group consisting of phenoxyethanol, benzyl alcohol, and parabens (eg, paraben) Methyl ester, butyl paraben) and its salts, benzoic acid and its salts, quaternary ammonium (e.g. benzalkonium chloride, benzethonium chloride), boric acid, Chlorhexidine, chlorobutanol, cresol and its derivatives, edetic acid and its salts, metabisulfite, thimerosal, sulfite, sorbic acid. In another embodiment of the present invention, in the cream pharmaceutical formulation, the penetration enhancer is selected from the group consisting of propylene glycol, polyethylene glycol, dimethyl sulfoxide, decyl methyl sulfoxide Ash, azone, N-methylpyrrolidone, diethyltoluamide, ethanol, isopropyl myristate, isopropyl palmitate, oleic acid and its esters, medium chain long triglycerides, isosorbide Dimethyl alcohol, 2-octyldodecanol, branched chain fatty acid esters, benzyl alcohol, urea, salicylates and surfactants. In one embodiment of the invention, in the cream pharmaceutical formulation, the surfactant is selected from the group consisting of alkyl polyglycol ether, alkyl polyglycol ester, ethoxylation Alcohols, polyoxyethylene sorbitan fatty acid esters, castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene glycol hydrogenated castor oil, polyoxyethylene glycol castor oil, fatty acid sorbitan esters, Block copolymers of ethylene oxide and propylene oxide, such as (for example) poloxamer (poloxamer), preferably poloxamer 188, poloxamer 407; tyloxapol (tyloxapol); polysorbate Alcohol esters; sucrose alkyl esters; sucrose alkyl ethers; short chain fatty acid mono and diglycerides; medium chain fatty acid mono and diglycerides; long chain saturated fatty acid mono and diglycerides; long chain unsaturated fatty acid glycerol Monoesters and diesters; short chain fatty acid propylene glycol monoester; medium chain fatty acid propylene glycol monoester; long chain saturated fatty acid propylene glycol monoester; long chain unsaturated fatty acid propylene glycol monoester; polyoxyglyceride; polyoxyethylene alkyl ester; poly Oxyethylene ether; polyethylene glycol tocopherol succinate, alkyl poly Glycerol ester; surfactant based on quaternary ammonium, anionic surfactant based on fatty acid ester. In yet another embodiment of the present invention, in cream pharmaceutical formulations, other emollient / oil phases are selected from the group consisting of short chain fatty acid monoglycerides, diesters and triesters, medium chain fatty acids Monoglycerides, diesters and triesters, long chain saturated fatty acid monoglycerides, diesters and triesters, long chain unsaturated fatty acid monoglycerides, diesters and triesters, vegetable oils, almond oil, babassu oil, black vinegar Chestnut oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, oat oil, olive oil, palm kernel oil , Palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil , Hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid ester, short chain fatty acid propylene glycol monoester and diester, medium chain fatty acid propylene glycol monoester and diester, long chain saturated fatty acid propylene glycol monoester and diester, long chain Do not Saturated fatty acid propylene glycol monoesters and diesters, fatty alcohols, branched chain fatty alcohols, silicone oils, silicone derivatives, mineral oils, liquid paraffin, vitamin E, vitamin E acetate, tocopherol, tocopheryl acetate, saturated fatty acids , Unsaturated fatty acids, phospholipids.Gel formulation
Another embodiment of the present application relates to the gel formulation of the pharmaceutical formulation of the present invention. In one embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is a gel formulation further comprising: (i) 0 to 30% w / w penetration enhancer (ii) 0 To 20% w / w gelling agent (iii) 0 to 50% w / w water (iv) at least one pH adjuster from 0.01 to 20% w / w, (v) optionally further containing about 0 to 5% w / w amount of preservatives. In the context of the above paragraph, the "penetration enhancer" is a skin penetration enhancer. In another embodiment of the present invention, the pharmaceutical formulation according to any of the preceding embodiments is a gel formulation further comprising: (i)> 0 to 30% w / w penetration enhancer (ii )> 0 to 20% w / w gelling agent (iii)> 0 to 50% w / w water (iv) 0.01 to 20% w / w of at least one pH adjusting agent, (v) optionally further containing about 0 Preservative in an amount of up to 5% w / w. In the context of the above paragraph, the "penetration enhancer" is a skin penetration enhancer. The term "penetration enhancer" as used herein generally includes agents that improve the transport of molecules (such as active agents) into or through the skin. Various conditions can occur in or under the skin in different parts of the body, leading to the need for targeted delivery of compounds. "Penetration enhancers" can be used to help deliver the active agent directly to the skin or underlying tissues or indirectly to the disease site through systemic distribution. The penetration enhancer may be a pure substance or may contain a mixture of different chemical entities. In the context of the above paragraph, the description also applies to the "skin penetration enhancer" of the present invention. In the context of this application, the gel is a semi-solid jelly formulation with a wide range of viscosities. They are made by gelling agents that undergo a high degree of crosslinking or association when dissolved or dispersed in a suitable medium. These gelling agents impart various viscosities and properties to a particular gel. The gelling agent is (for example) cellulose derivative, methyl cellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose, carbomer (Carbomer), Carbopol®
910, Carbopol®
941, Poloxamer, Pluronic®
Or soil temperature (Tween). In still another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the at least one solvent is 1 to 90% w / w, more preferably 10 to 80% w / w, and most preferably 30 to 70% w / w. In another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the second solvent is 0.1 to 50% w / w, more preferably 5 to 40% w / w, most preferably 15 to 25% w / w. In still another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the penetration enhancer is 0.1 to 30% w / w, more preferably 5 to 25% w / w, and most preferably 10 to 20% w / w. In yet another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the preservative is 0.25 to 5% w / w, more preferably 0.5 to 3% w / w, most preferably 1 to 2% w / w. In another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the antioxidant is 0.01 to 5% w / w, more preferably 0.025 to 3% w / w, most preferably 0.05 to 2% w / w. In yet another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the gelling agent is 0.01 to 20% w / w, more preferably 0.1 to 10% w / w, most preferably 0.5 to 5% w / w. In one embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the gelling agent carbomer is 0.25 to 5% w / w, more preferably 0,5 to 3% w / w, best 1 To 2% w / w. In yet another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of water is 0.1 to 50% w / w. In another embodiment of the present invention, in the gel pharmaceutical formulation, the concentration of the pH adjusting agent is 0.015 to 20% w / w. In yet another embodiment of the present invention, in the gel pharmaceutical formulation, the solvent is PEG, preferably PEG 400, more preferably SR PEG 400. In another embodiment of the present invention, in the gel pharmaceutical formulation, the gelling agent is selected from the group consisting of carbomer, poloxamer, polycarbophil, polydimensional Ketone (povidone), copovidone (copovidone), PVA, vinyl ether polymers and copolymers, cellulose and cellulose derivatives, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, Guar gum, chitosan, alginic acid and its salts, carrageenan, xanthan gum, polyethylene glycol, dextrose, silk protein, gelatin, agar, preferably carbomer.Specific ointment formulations
In yet another embodiment of the present invention, the pharmaceutical formulation is an ointment, which contains 0.1 to 90% w / w SR PEG 400, 0.1 to 30% w / w propylene glycol, 0.1 to 40% w / w PEG 4000, 0.01 To 10% w / w butylated hydroxytoluene and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjuster, more preferably 10 to 80% w / w SR PEG 400, 5 to 20% w / w Propylene glycol, 5 to 30% w / w PEG 4000, 0.025 to 5% w / w butylated hydroxytoluene and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as a pH adjuster, preferably 25 to 80 % w / w SR PEG 400, 7.5 to 10% w / w propylene glycol, 15 to 20% w / w PEG 4000, 0.05 to 0.2% w / w butylated hydroxytoluene and 0.01 to 20% w / w for pH adjustment Dilute HCl or dilute NaOH solution. In another embodiment of the present invention, the pharmaceutical formulation is an ointment containing the following excipients within the range disclosed in Table 1:table 1. Ointment formulation table 1a. Ointment formulation Specific cream formulations
In another embodiment of the present invention, the pharmaceutical formulation is a cream, which further comprises 0.1 to 20% w / w ethanol, 0.1 to 60% w / w PEG 400, 0.1 to 40% w / w Transcutol HP, 0.01 To 5% w / w phenoxyethanol, 0.01 to 5% w / w butylated oxytoluene, 0.01 to 10% w / w Brij-72, 0.01 to 20% w / w cetearyl alcohol, 1 To 20% w / w Crodamol GTCC, 0.01 to 20% w / w Brij-721, 0 to 10% w / w dimethyl silicone and 0.01 to 40% w / w water, preferably 2 to 20% w / w w ethanol, 15 to 50% w / w PEG 400, 5 to 30% w / w Transcutol HP, 0.025 to 5% w / w phenoxyethanol, 0.025 to 1% w / w butyloxytoluene, 0.5 to 7% w / w Brij-72, 3 to 15% w / w cetearyl alcohol, 2 to 15% w / w Crodamol GTCC, 0.5 to 10% w / w Brij-721, 0.25 to 5% w / w Dimethicone and 5 to 30% w / w water; optimal 3 to 7% w / w ethanol, 30 to 45% w / w PEG 400, 10 to 20% w / w Transcutol HP, 1 to 2% w / w phenoxyethanol, 0.05 to 15% w / w butylated oxytoluene, 1 to 3% w / w Brij-72, 5 to 10% w / w cetearyl alcohol, 4 to 10% w / w Crodamol GTCC, 1 to 4% w / w Brij-721, 0.5 to 3% w / w dimethyl silicone and 10 to 20% w / w water. In another embodiment of the present invention, the pharmaceutical formulation is a cream containing the following excipients within the range disclosed in Table 2:table 2 : Cream preparation table 2a : Cream preparation Specific gel formulations
In another embodiment of the present invention, the pharmaceutical formulation is a gel, which further comprises 1 to 90% w / w SR PEG 400, 0.1 to 50% w / w propylene glycol, 0.1 to 30% w / w isosorbide Dimethyl alcohol, 0.25 to 5% w / w phenoxyethanol, 0.01 to 5% w / w butylated hydroxytoluene, 0.25 to 5% w / w carbomer, 0.1 to 50% w / w water and 0.0 1 to 20% w / w dilute HCl or dilute NaOH solution as a pH adjuster (please add), preferably 10 to 80% w / w SR PEG 400, 5 to 40% w / w propylene glycol, 5 to 25% w / w dimethyl isosorbide, 0.5 to 3% w / w phenoxyethanol, 0.025 to 3% w / w butylated hydroxytoluene, 0.5 to 3% w / w carbomer, 0.1 to 50% w / w water and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjuster, best 30 to 70% w / w SR PEG 400, 15 to 25% w / w propylene glycol, 10 to 20% w / w dimethyl isosorbide, 1 to 2% w / w phenoxyethanol, 0.05 to 2% w / w butylated hydroxytoluene, 1 to 2% w / w carbomer, 0.1 to 50% w / w water and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjuster. In another embodiment of the present invention, the pharmaceutical formulation is a gel containing the following excipients within the range disclosed in Table 3:table 3 : Gel formulation table 3a : Gel formulation
In yet another embodiment of the present invention, the pharmaceutical formulation is an ointment, which contains 67.72% w / w SR PEG 400, 9.78% w / w propylene glycol, 17.5% w / w PEG 4000, and 5% active pharmaceutical ingredient Purui Levy, where the pH is pH 4.0 to 5.0. In yet another embodiment of the present invention, the pharmaceutical formulation is an ointment, which contains 67.62% w / w SR PEG 400, 9.78% w / w propylene glycol, 17.5% w / w PEG 4000, 0.1% BHT and 5% activity The medicinal ingredient Pregavir has a pH of 4.0 to 4.5. In another embodiment of the present invention, the pharmaceutical formulation is a gel, which further comprises 39.1% w / w SR PEG 400, 9.59% w / w ethanol, 4.8% w / w pH 4 buffer, 23.98% w / wTranscutol HP, 14.39% w / w dimethyl isosorbide, 1.92% w / w benzyl alcohol, 1.25% w / w hydroxypropyl cellulose. In one embodiment of the present invention, the exemplified pharmaceutical formulation is used as a medicine. In another embodiment of the present invention, the pharmaceutical formulation is used to treat and / or prevent herpes virus infection. In one embodiment of the present invention, the pharmaceutical formulation is used for the treatment and / or prevention of herpes virus infection, wherein the herpes virus is selected from the order of pure virus. In another embodiment of the present invention, the pharmaceutical formulation is used to treat and / or prevent herpes virus infection, wherein the simple virus is selected from herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV- 2). Another embodiment of the present invention relates to a method for treating and / or preventing herpes virus infection, which includes administering a local pharmaceutical formulation to an individual in need.Free base hemihydrate
In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of about 5.0% w / w. In the context of the above paragraph and the entire text, the expression "5% w / w Pravivir antiviral agent" or a similar expression for any of the Pralivi active pharmaceutical ingredients disclosed herein means Pralivi Vitamin drugs are added to the local formulations in an amount to ensure the final presence of 5% w / w of pregavir free base as the active part. This means that exemplarily for pregaribic free base hemihydrate, due to the presence of crystal water, it is added to the local formulation at 5.11% w / w, but will eventually result in only 5% w / w The free base pregarib is used as the active part. The same applies to, for example, 1.0% to 10% w / w Pralivi contained in the topical formulation of the present invention. Therefore, basically and throughout the text, the amount given for Previvix refers to the final free base content as the active part; for example, in the case of hemihydrate, the presence of Prelivi free base The current water of crystallization in hemihydrate compounds. It should be noted that this applies throughout the text as presented in this article. In one embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl -2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of 5.0% w / w, in which the pharmaceutical composition is an ointment. In still another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of about 1.0 to about 7.5% w / w, preferably about 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times per day, or 2 to 10 per day Times, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Is present in an amount of 1.0 to 7.5% w / w, preferably 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day, and wherein the ointment is administered for 2 to 14 days, 3 to 10 days, 3 to 7 days, 4 To 5 days, or 5 days, or 4 days. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 5 times a day, and wherein the ointment is administered for 4 days. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl -2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount sufficient to achieve a concentration of> 10 nM in the epidermis and dermis of individuals treated with the composition. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Used as a medicament. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat and / or prevent herpes virus infection. In still another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat and / or prevent herpes virus infection, wherein the herpes virus is selected from the order of pure virus. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat and / or prevent the herpes virus infection, wherein the simple virus is selected from herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Or derivatives thereof are used in topical pharmaceutical formulations to treat and / or prevent herpes virus infections in individuals in need thereof. In still another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Or a derivative thereof is used in a local pharmaceutical formulation to treat an individual in need thereof, wherein the individual has or is suspected of having a herpes virus infection. In one embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl -2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is for local administration to individuals in need thereof, where the local administration is for facial application, and / or application to the oral cavity, genitals, and / or eyes. In one embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl -2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is for local administration to individuals in need thereof, where the local administration is for any body part other than those explicitly given in the above paragraph. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used for systemic administration to individuals in need, where the individual is suspected of having herpes virus infection or is an individual with herpes virus infection. In still another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat recurrent cold sores. In a specific embodiment of the invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl -2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is preferably provided for the treatment of recurrent cold sores. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat recurrent cold sores selected from the group of patients: patients showing signs of early stage of cold sores, patients with erythema, patients showing lip papules, patients with labial vesicles, lip ulcers And / or patients with soft shells, patients with hard shells on the lips, patients with residual erythema on the lips. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat genital herpes. In still another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat herpes keratitis. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat herpes meningitis and / or encephalitis. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat neonatal herpes infections. In another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat herpes infections in individuals with normal immune function and / or immune insufficiency. In still another embodiment of the present invention, in the pharmaceutical formulation, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is used to treat herpes infections in individuals with normal immune function and / or immune insufficiency, wherein the system with immune insufficiency is selected from the group consisting of patients with organ transplant recipients, suffering from another viral or bacterial infection (Specifically infected with HIV and / or another herpes virus), and individuals infected with herpes simplex virus that are resistant to at least one antiviral active agent. In another embodiment, the present invention relates to a method for treating and / or preventing herpes virus infection, which includes combining N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole- 2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Give to individuals in need. The term "prophylaxis / prevention" or a similar term in the field related to the present invention obviously means to the ordinary skilled person to inhibit or reduce the recurrence of infection or to suppress or reduce the infection of herpes simplex virus subtype 1 or 2 infection. In the context of the present invention, the term "prevention" does not mean that there are no infectious viral particles or infected cells from the patient at all, even under the broadest reasonable interpretation. In the context of the present invention, this positioning is reasonable in the technology related to the disclosed subject matter. To support these definitions of the term "prevention", the following publications are incorporated herein by reference: Abdool Karim, S.S. et al. (2015). Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection. N Engl. J Med 373, 530-539. Andrei, G. et al. (2011). Topical tenofovir, a microbicide effective against HIV, inhibits herpes simplex virus-2 replication. Cell Host. Microbe 10, 379-389. Corey, L. et al. (2004). Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N. Engl. J. Med. 350, 11-20. Kleymann, G. et al. (2002). New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat. Med. 8, 392-398. Mertz, G.J. et al. (1985). Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm. Dis. 12, 33-39. Reitano, M. et al. (1998). Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J. Infect. Dis. 178, 603-610. Schiffer, J.T. et al. (1997). Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J. Clin Invest 99, 1092-1097. Wald, A. et al. (2014). Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl. J Med 370, 201-210. Wald, A. et al. (2000). Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 342, 844-850. Zhu, J. et al. (2007). Virus-specific CD8 + T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595-603. Gold, D. and Corey, L., MINIREVIEW Acyclovir Prophylaxis for Herpes Simplex Virus Infection. Antimicrobial Agents and Chemotherapy, March 1987, pages 361 to 367. Tyring, S., Baker, D., Snowden, W., Valacyclovir for Herpes Simplex Virus Infection: Long-Term Safety and Sustained Efficacy after 20 Years' Experience with Acyclovir. The Journal of Infectious Diseases 2002; 186 (Supplement 1): S40–6. These documents support the correlation between helicase-primerase inhibition and prevention of infection with herpes simplex virus infection, as has been confirmed in such a technique. In addition, the above Kleymann, 2002, at the bottom of the left column of page 396 teaches that recurrent disease and asymptomatic virus shedding are almost completely inhibited by helicase-primerase inhibitors, which will reduce human-to-human infection, that is, effective Prevent infection of HSV. The above disclosure of Corey, 2004, teaches at the bottom of page 11 and the first column of page 17, that one-day use of valacyclovir (valacyclovir) once-inhibition therapy significantly reduces genital herpes between heterosexual HSV-2 inconsistent partners The risk of infection, that is, to prevent its transmission. The study achieved these results with drugs that have been shown to inhibit the shedding of type 2 HSV (HSV-2) on the surface of the genital mucosa. See top on page 11. In addition, it has been found that the frequency and quantity of subclinical HSV shed on the surface of the genital mucosa is the main source of infectious infections. See references 20 to 22, dating back to 1997, 1998 and 1997 in the order listed. Therefore, a method of reducing the frequency and number of subclinical HSVs that fall off on the surface of the genital mucosa is a way to prevent herpes infection. Karim, 2015, teaches at the bottom of page 530 that, based on research therein, it is shown that preofoviral administration of tenofovir gel reduces the acquisition of HSV-2 in women, that is, prevents the acquisition of HSV. The effect is a 51% reduction. See page 534, second column. In an earlier study of the same group dating back to 2010 (see reference 6 in this article), it was shown that the pre-sexual application of Tiannov ’s topical vaginal-gel formulation reduced HIV acquisition. Although HIV is a different virus, in view of the above, it is not unbelievable for the average skilled person that a drug can prevent the acquisition of viral infections. In addition, in the case of HSV, Karim clearly confirmed this. Gold and Corey supported the effective prevention of the well-known acyclovir (ie, viral DNA polymerase inhibitor) in March 1987. In addition, Tyring et al. Supported the efficacy of the prodrug valacyclovir (ie, viral DNA polymerase inhibitor) in 2002. Those skilled in the art know that in the case of HSV-1 and HSV-2 infection, although the virus is present in the body due to the infection, there is no symptom outbreak, because N- [5- (amino-sulfonyl)- 4-Methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide free base hemihydrate effectively inhibits virus shedding and outbreak , "Prevent" or "inhibit" the symptoms of HSV-1 and HSV-2 infection. In yet another support for the prevention = inhibition aspect of the present invention, reiterating the above references to valacyclovir (ie, Tyring et al. 2002) and acyclovir (ie, Gold et al. 1987), which also proves It is recognized that HSV infection is asymptomatic in normal individuals, and the significance of prevention / suppression therapy in this technique. In addition, effective HSV prevention has been clinically confirmed in human trials. In this regard, the poster from ICAAC 2014 on the indications for HSV-2 genital herpes is incorporated by reference (Wald et al., 2014). Finally, the general artisan knows that, similar to Tenofo, it is known that N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl- 2- [4- (2-pyridyl) phenyl] acetamide free base hemihydrate as a helicase-primerase inhibitor has a higher antiviral efficacy than Tian Nuofu in the case of HIV, and therefore For those skilled in the art, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2 -Pyridyl) phenyl] acetamide will also be expected to have a more significant preventive effect. In this regard, particularly relevant are the publications of the aforementioned Andrei et al. And Kleymann et al. Which confirmed that when N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl ) Phenyl] acetamide free base hemihydrate when compared, Tian Nuofu IC50
The value is significantly higher.Method for preparing the free base hemihydrate
Another embodiment of the present invention relates to the preparation of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl) acetamideFree base hemihydrate
Method, wherein the method includes the following steps: a) mixing 4-pyridin-2-yl-phenyl) -acetic acid and amide thiazole sulfonamide in N-methylpyrrolidone (NMP); b) Cool the mixture obtained in step a); c) Add N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC x HCl) to the step b) in the mixture obtained in d); d) stir the solution obtained in step c) and add to pure H2
O; e) filtering the solution obtained in step d); f) washing the product cake obtained in step e); g) drying the product obtained in step f); h) applying H2
O added to the solution obtained in step g); i) stirring the suspension obtained in step h); j) cooling the suspension obtained in step i); k) stirring in step j) The suspension obtained; l) the product is isolated by filtering the suspension obtained in step k); m) using H2
O washing the product obtained in step l); n) drying the product obtained in step m). In another embodiment of the present invention, it contains N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4 -(2-pyridyl) phenyl] acetamideFree base hemihydrate
The pharmaceutical composition of can be obtained by the method as described in the foregoing examples. In one embodiment of the present invention, the pharmaceutical composition can be prepared by formulating N- [5- (amino-sulfonyl) -4-methyl- obtained by the method as described in the foregoing embodiment 1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Obtained with at least one pharmaceutical excipient. Another embodiment of the present invention relates to N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- ( 2-pyridyl) phenyl] acetamideFree base hemihydrate
Is used as a medicament in the method as described in the previous examples.Maleate
Another embodiment of the invention relates to inclusionFree base maleate
Pharmaceutical composition, wherein the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- The free base maleate of pyridyl) phenyl] acetamide is present in an amount of about 5.0% w / w. In the context of the above paragraph and the entire text, the expression "5% w / w Pravivir antiviral agent" or a similar expression for any of the Pralivi active pharmaceutical ingredients disclosed herein means Pralivi Vitamin drugs are added to the local formulations in an amount to ensure the final presence of 5% w / w of pregavir free base as the active part. This means that exemplarily for preliminium maleate, it is added to the local formulation in an amount that can exceed the 5% w / w, but will eventually result in only 5% w / w The free base pregavir is used as the active part. The same applies, for example, when 1.0% to 10% w / w Pravivir maleate is contained in the topical formulation of the present invention. Therefore, basically and throughout the text, the amount given for Previvi refers to the final free base content as the active part. Another preferred embodiment of the invention relates toFree base maleate
Pharmaceutical composition, wherein the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- The free base maleate of pyridyl) phenyl] acetamide is present in an amount of about 1.0 to about 7.5% w / w, specifically about 5.0% w / w. Another embodiment of the present invention relates to N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- ( 2-pyridyl) phenyl] free base of acetamideMaleate
, Where when the light resistance is determined by using the Pharmacopoeia method according to the "European Pharmacopoeia" and / or "United States Pharmacopoeia", the maleate is characterized by a wavelength in the range of 300 nm to 800 nm, and Exposure of at least 1.2 million lux hours, and exposure energy of at least 200 watt hours / m². Light resistance after exposure for at least 29 hours is at least 70% residual N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide free base. Another embodiment of the present invention relates to theMaleate
, Where the maleate is further characterized by characteristic XRPD peaks 6.6, 15.9, 16.2, 18.1, 20.5, 22.5, when measured by using the Pharmacopoeia method according to "European Pharmacopoeia" and / or "U.S. Pharmacopoeia" 26.1 and 28.6 2θ. Another embodiment of the present invention relates toMaleate
, Where the maleate is physicochemically stable when measured by using the Pharmacopoeia method according to the "European Pharmacopoeia" and / or "U.S. Pharmacopoeia", characterized by a temperature of 3.5 to 7.0 at room temperature After being stored in an aqueous solution for two weeks, the recovery rate of the maleate is at least 85% of the initial concentration. Another embodiment of the present invention relates toMaleate
Wherein, when measured by using the Pharmacopoeia method according to the "European Pharmacopoeia" and / or "American Pharmacopoeia", the maleate is characterized by a solubility in water of about 0.48 mg / mL. Yet another embodiment of the present invention relates to a pharmaceutical composition containing a free base maleate salt, wherein when measured by using a pharmacopoeial method according to "European Pharmacopoeia" and / or "U.S. Pharmacopoeia", wherein theMaleate
It is present in an amount sufficient for the concentration of ≥ 10 nM in the epidermis and dermis of individuals receiving the method of topical treatment with the composition. Another embodiment of the invention relates to the inclusion of free baseMaleate
The pharmaceutical composition is used for treating and / or preventing herpes virus infection. Another embodiment of the present invention relates to the preparation of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- as defined in the foregoing embodiment The free base of methyl-2- [4- (2-pyridyl) phenyl] acetamideMaleate
The method includes the following steps: i) providing a mixing device, preferably equipped with an overhead stirring mixing device, ii) filling the mixing device of step i) with 460 to 490 g of Pravivir free base, iii) Suspend the prerivative free base of step ii) with 3 to 5 volumes of water, iv) heat the suspension of step iii) to 45 to 55 ° C with a suitable heating device, v) for a time of 40 to 90 minutes Add 225 to 240 g of maleic acid in solid form until a final solution is obtained, vi) Cool the solution obtained under step v) to 44 to 52 ° C vii) Use the free base of prednisyl maleic acid Salt inoculate an aliquot of the step vi) solution, viii) allow the resulting suspension of step vii) to cool to 18 to 24 ° C for a period of 1.5 to 2.5 hours, ix) then stir the suspension of step viii) overnight, x ) Filter the suspension in step ix) to obtain the resulting filter cake, xi) transfer the solid filter cake obtained in step x) to a mixing device, preferably a flask, xii) rotate the mixing device in step xi) 25-32 hours, while applying the following conditions: a. 30 to 40 ℃ Ambient temperature, b. 15 to 25 mbar pressure to obtain a constant mass, xiii) homogenization afterwards, preferably using a mortar and pestle to homogenize, xiv) to obtain the free of pregarib of the present invention Alkaline maleate. In view of the description of the present invention, those skilled in the art will understand other modifications and alternative embodiments of the various aspects of the present invention. Therefore, the description of the present invention should be understood as illustrative only and it is intended to teach those skilled in the art to implement the present invention in a general manner. It should be understood that the form of the invention shown and described herein should be considered as an example of an embodiment. Those skilled in the art, after knowing the benefits of the description of the present invention, will understand that elements and materials described in these articles can be replaced by elements and materials, parts and processes can be reversed, and certain features of the invention can be used independently. Changes may be made to the elements described herein without departing from the spirit and scope of the invention as described in the following embodiments. In the context of the above, the following consecutively numbered examples provide other specific aspects of the invention: 1. A pharmaceutical formulation for topical application to an individual in need, the formulation comprising: i.) 1 to 10% w / w of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] acetamide, ii.) 0 to 90% w / w of at least one solvent, iii.) 0 to 10% w / w of at least one antioxidant, wherein the pharmaceutical formulation has a pH of 2.0 to 8.0, The pH is preferably 4.0 to 5.0, wherein N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- ( 2-pyridyl) phenyl] acetamide in a dissolved state or in a dissolved form is stable at 25 ° C / 60% RH for 12 months, wherein the solvent is selected from ethanol, dimethyl isosorbide, isopropanol , Transcutol P, propylene glycol, polyethylene glycol, PEG 400, PEG 4000 and Super RefinedTM (SR) PEG 400 group. In an example adjacent to Example 1, the pH value of the pharmaceutical formulation is preferably 4.0 to 4.5. In an example adjacent to Example 1, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) phenyl] acetamide is stable in dissolved state or in dissolved form at 25 ° C / 60% RH for at least 24 months. 2. A pharmaceutical formulation for topical application to an individual in need as defined in Example 1, wherein the at least one solvent is selected from the group comprising polyethylene glycol, preferably PEG 400, more preferably SR PEG 400. 3. A pharmaceutical formulation for topical application to an individual in need as defined in Example 1, wherein the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole- 2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is selected from the group consisting of: • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideMaleate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] The free base of acetamideMesylate
, And • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base
. 4. A pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 1 to 3, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT) and butylated hydroxybenzene Methyl ether (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopheryl acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate . 5. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 4, wherein the antioxidant is BHT. 6. The pharmaceutical formulation for topical application to an individual in need as in any one of Examples 1 to 5, the formulation is selected from the group consisting of the following formulations: for creams, ointments, gels, oils Ointments, lotions, wax formulations, lipsticks, tonics, mousses, foams, films, emulsions, pastes, solutions, oils, and microlipid formulations. In an embodiment adjacent to embodiment 6, the formulation is selected from the group consisting of the following formulations: used in creams, ointments, gels, ointments, lotions, wax formulations, lipsticks, tonics , Mousse, foam, film, emulsion, paste, solution, oil, fat glue and patch formulations. 7. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 6, wherein the concentration of the active pharmaceutical ingredient Prelivi is selected from 1.1 to 10% w / w, more The range of 1.1 to 5% w / w is better. 8. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 1 to 7, wherein the concentration of the at least one solvent is 0.1 to 90% w / w, for example 5 to 90% w / w, 10 to 90% w / w, 10 to 80% w / w, 20 to 80 w / w, 25 to 80% w / w, 15 to 50% w / w, or 30 to 45% w / w. 9. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 8, wherein the concentration of the second solvent is 0.1 to 60% w / w, more preferably 10 to 50% w / w, preferably 10 to 40% w / w. 10. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 9, wherein the concentration of the antioxidant is 0.01 to 10% w / w, more preferably 0.025 to 5% w / w, preferably 0.05 to 2% w / w. 11. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 10, wherein the formulation is an ointment further comprising: (i) 0.01 to 20% w / w At least one pH adjusting agent. 12. A pharmaceutical formulation for topical application to an individual in need as defined in Example 11, wherein for the ointment formulation, the concentration of the at least one solvent is 25 to 90% w / w, more preferably 25 to 80% w / w, preferably 60 to 80% w / w. 13. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 11 to 12, wherein for the ointment formulation, the concentration of the second solvent is 0.1 to 40% w / w, Better 5 to 20% w / w, best 7.5 to 10% w / w. 14. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 11 to 13, wherein for the ointment formulation, the concentration of the third solvent is 0.1 to 30% w / w, More preferably, it is 5 to -30% w / w, and most preferably 15 to 20% w / w. 15. A pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 11 to 14, wherein for an ointment formulation, the concentration of the antioxidant is 0.015 to 10% w / w , More preferably 0.1 to 5% w / w, most preferably 0.1 to 2% w / w. 16. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 11 to 15, wherein the concentration of the pH adjusting agent is 0.015 to 20% w / w for ointment formulation . 17. A pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 11 to 16, wherein for ointment formulations, the solvent is selected from the group consisting of polyethylene dichloride Alcohol, propylene glycol, petrolatum, liquid paraffin, lanolin, mineral oil, silicone oil, silicone derivatives, short chain fatty acid monoglycerides, diesters and triesters, medium chain fatty acid monoglycerides, diesters and triesters, Long chain saturated fatty acid monoglycerides, diesters and triesters, long chain unsaturated fatty acid monoglycerides, diesters and triesters, vegetable oils, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola Seed oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, Safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogen Vegetable oil, fatty acid ester, short chain fatty acid propylene glycol monoester and diester, medium chain fatty acid propylene glycol monoester and diester, long chain saturated fatty acid propylene glycol monoester and diester, long chain unsaturated fatty acid propylene glycol monoester and diester, Fatty alcohols, branched chain fatty alcohols, vitamin E, vitamin E acetate, tocopherol, tocopheryl acetate, saturated fatty acids, unsaturated fatty acids. 18. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 17, wherein the pH adjusting agent is selected from the group consisting of buffers, acidic and alkaline solutions , Organic acids (such as citric acid, lactic acid), inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid), alkaline reagents (sodium hydroxide, sodium bicarbonate), meglumine. In the context of Example 18 and in the context of the present invention, it should be noted that the pH adjusting agent is used in the sense of "apparent pH adjusting agent". All given pH values of the topical formulations of the present invention refer to apparent pH. 19. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 10, wherein the formulation is a cream further comprising: i. 0 to 5% w / w The preservative ii. 0 to 20% w / w of at least one surfactant iii. 1 to 40% w / w oil phase / emollient iv. 0 to 40% w / w water. 20. A pharmaceutical formulation for topical application to an individual in need as defined in Example 19, wherein for cream formulations, the concentration of the at least one solvent is 0.1 to 60% w / w, more preferably 15 to 50% w / w, preferably 30 to 45% w / w. 21. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 19 to 20, wherein for the cream formulation, the concentration of the second solvent is 0.1 to 40% w / w , Better 5 to 30% w / w, best 10 to 20% w / w. 22. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 19 to 21, wherein for the cream formulation, the concentration of the third solvent is 0.1 to 20% w / w , Better 2 to 20% w / w, best 3 to 7% w / w. 23. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 19 to 22, wherein for cream formulations, the concentration of the preservative is 0.01 to 5% w / w , Better 0.025 to 5% w / w, best 1 to 2% w / w. 24. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 19 to 23, wherein for a cream formulation, the concentration of the antioxidant is 0.01 to 5% w / w , Better 0.025 to 1% w / w, best 0.05 to 0.15% w / w. 25. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 19 to 24, wherein for the cream formulation, the concentration of the surfactant is 0.01 to 20% w / w, better 2 to 18% w / w, best 5 to 15% w / w. 26. A pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 19 to 25, wherein for cream formulations, the concentration of the oil phase / emollient is 1 to 20 % w / w, better 2 to 15% w / w, best 4 to 10% w / w. 27. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 19 to 26, wherein for cream formulations, the concentration of the second surfactant is 0.015 to 20% w / w, better 0.5 to 10% w / w, best 1 to 4% w / w. 28. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 19 to 27, wherein for the cream formulation, the concentration of water is 0.01 to 40% w / w, more Best 5 to 30% w / w, best 10 to 20% w / w. 29. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 28, wherein the preservative is selected from the group consisting of phenoxyethanol, benzyl alcohol, Parabens (such as methylparaben, butylparaben) and their salts, benzoic acid and its salts, quaternary ammonium (such as benzalkonium chloride, bensonin chloride) , Boric acid, chlorhexidine, chlorobutanol, cresol and its derivatives, edetic acid and its salts, metabisulfite, thimerosal, sulfite, sorbic acid. 30. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 1 to 29, wherein the penetration enhancer is selected from the group consisting of propylene glycol, polyethylene glycol, Dimethyl sulfoxide, decylmethyl sulfoxide, azone, N-methylpyrrolidone, diethyl ethyl, ethanol, isopropyl myristate, isopropyl palmitate, oleic acid and its esters, medium Chain-length triglycerides, dimethyl isosorbide, 2-octyldodecanol, branched-chain fatty acid esters, benzyl alcohol, urea, salicylates and surfactants. In the context of Example 30 and the entire text, "penetration enhancer" is "skin penetration enhancer". 31. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 1 to 30, wherein the surfactant is selected from the group consisting of alkyl polyglycol ether, Alkyl polyethylene glycol esters, ethoxylated alcohols, polyoxyethylene sorbitan fatty acid esters, castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene glycol hydrogenated castor oil, polyoxygen Block copolymers of ethylene glycol castor oil, fatty acid sorbitan esters, ethylene oxide and propylene oxide, such as (for example) poloxamer, preferably poloxamer 188, poloxamer 407; Thai Losapol; Polysorbate; Sucrose alkyl esters; Sucrose alkyl ethers; Short chain fatty acid mono and diglycerides; Medium chain fatty acid mono and diglycerides; Long chain saturated fatty acid mono and diglycerides; Long chain unsaturated fatty acid monoglyceride and diester; short chain fatty acid propylene glycol monoester; medium chain fatty acid propylene glycol monoester; long chain saturated fatty acid propylene glycol monoester; long chain unsaturated fatty acid propylene glycol monoester; polyoxyglyceride; polyoxygen Ethylene alkyl ester; polyoxyethylene ether; polyethylene glycol amber Vitamin E esters, alkyl polyglycerol esters; of quaternary ammonium-based surfactant, the fatty acid ester-based anionic surfactant. 32. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 31, wherein the emollient / oil phase is selected from the group consisting of: short-chain fatty acid monoglyceride Esters, diesters and triesters, medium chain fatty acid monoglycerides, diesters and triesters, long chain saturated fatty acid monoglycerides, diesters and triesters, long chain unsaturated fatty acid monoglycerides, diesters and triesters, Vegetable oil, almond oil, babassu oil, black currant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed Oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, Hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid ester, short chain fatty acid propylene glycol monoester and diester, medium chain fatty acid propylene glycol monoester and diester, long chain Saturated fat Propylene glycol monoesters and diesters of fatty acids, long chain unsaturated fatty acid propylene glycol monoesters and diesters, fatty alcohols, branched chain fatty alcohols, silicone oils, silicone derivatives, mineral oils, liquid paraffin, vitamin E, vitamin E acetate Ester, tocopherol, tocopheryl acetate, saturated fatty acids, unsaturated fatty acids, phospholipids. 33. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 10, wherein the formulation is a gel further comprising: (i) 0 to 30% w / w penetration enhancer (ii) 0 to 20% w / w at least one gelling agent (iii) 0 to 50% w / w water (iv) 0.01 to 20% w / w at least one pH adjuster, ( v) If necessary, further contain preservatives in an amount of about 0 to 5% w / w. 34. The pharmaceutical formulation for topical application to an individual in need as defined in Example 33, wherein for the gel formulation, the concentration of the at least one solvent is 1 to 90% w / w, more preferably 10 to 80% w / w, preferably 30 to 70% w / w. 35. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 33 to 34, wherein for the gel formulation, the concentration of the second solvent is 0.1 to 50% w / w , Better 5 to 40% w / w, best 15 to 25% w / w. 36. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 33 to 35, wherein for the gel formulation, the concentration of the penetration enhancer is 0.1 to 30% w / w, better 5 to 25% w / w, best 10 to 20% w / w. 37. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 33 to 36, wherein for gel formulations, the concentration of the preservative is 0.25 to 5% w / w , Better 0.5 to 3% w / w, best 1 to 2% w / w. 38. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 33 to 37, wherein for the gel formulation, the concentration of the antioxidant is 0.01 to 5% w / w , Better 0.025 to 3% w / w, best 0.05 to 2% w / w. 39. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 33 to 38, wherein for the gel formulation, the concentration of the gelling agent is 0.01 to 20% w / w, more preferably 0.1 to 10% w / w, most preferably 0.5 to 5% w / w. 40. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 33 to 39, wherein for the gel formulation, the concentration of the gelling agent carbomer is 0.25 to 5 % w / w, better 0.5 to 3% w / w, best 1 to 2% w / w. 41. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 33 to 40, wherein for the gel formulation, the concentration of water is 0.1 to 50% w / w. 42. The pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 33 to 41, wherein for the gel formulation, the concentration of the pH adjusting agent is 0.015 to 20% w / w. 43. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 33 to 42, wherein for the gel formulation, the solvent is PEG, preferably PEG 400, and more preferably SR PEG 400. 44. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 43, wherein the gelling agent is selected from the group consisting of carbomer, poloxamer , Polycarbophil, povidone, copovidone, PVA, vinyl ether polymers and copolymers, cellulose and cellulose derivatives, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl fiber Vegetarian, guar gum, chitosan, alginic acid and its salts, carrageenan, xanthan gum, polyethylene glycol, dextrose, silk protein, gelatin, agar, preferably carbomer. 45. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 18, wherein the formulation is an ointment, which contains 0.1 to 90% w / w SR PEG 400, 0.1 to 30% w / w propylene glycol, 0.1 to 40% w / w PEG 4000, 0.01 to 10% w / w butylated hydroxytoluene and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjuster, more 10 to 80% w / w SR PEG 400, 5 to 20% w / w propylene glycol, 5 to 30% w / w PEG 4000, 0.025 to 5% w / w butylated hydroxytoluene and 0.01 to 20% w / w w Dilute HCl or dilute NaOH solution as pH adjuster, best 25 to 80% w / w SR PEG 400, 7.5 to 10% w / w propylene glycol, 15 to 20% w / w PEG 4000, 0.05 to 0.2% w / w butylated hydroxytoluene and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjuster. 46. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 10 and 19 to 32, wherein the formulation is a cream, which contains 0.1 to 20% w / w ethanol , 0.1 to 60% w / w PEG 400, 0.1 to 40% w / w Transcutol HP, 0.01 to 5% w / w phenoxyethanol, 0.01 to 5% w / w butylated oxytoluene, 0.01 to 10% w / w Brij-72, 0.01 to 20% w / w cetearyl alcohol, 1 to 20% w / w Crodamol GTCC, 0.01 to 20% w / w Brij-721, 0 to 10% w / w dimethyl Based silicone and 0.01 to 40% w / w water, preferably 2 to 20% w / w ethanol, 15 to 50% w / w PEG 400, 5 to 30% w / w Transcutol HP, 0.025 to 5% w / w Phenoxyethanol, 0.025 to 1% w / w butylated oxytoluene, 0.5 to 7% w / w Brij-72, 3 to 15% w / w cetearyl alcohol, 2 to 15% w / w Crodamol GTCC, 0.5 to 10% w / w Brij-721, 0.25 to 5% w / w dimethyl silicone and 5 to 30% w / w water; optimal 3 to 7% w / w ethanol, 30 to 45 % w / w PEG 400, 10 to 20% w / w Transcutol HP, 1 to 2% w / w phenoxyethanol, 0.05 to 15% w / w butylated oxytoluene, 1 to 3% w / w Brij -72, 5 to 10% w / w cetearyl alcohol, 4 to 10% w / w Crodamol G TCC, 1 to 4% w / w Brij-721, 0.5 to 3% w / w dimethyl silicone and 10 to 20% w / w water. 47. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 10 and 33 to 44, wherein the formulation is a gel, which contains 1 to 90% w / w SR PEG 400, 0.1 to 50% w / w propylene glycol, 0.1 to 30% w / w dimethyl isosorbide, 0.25 to 5% w / w phenoxyethanol, 0.01 to 5% w / w butylated hydroxytoluene , 0.25 to 5% w / w carbomer, 0.1 to 50% w / w water and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjuster, more preferably 10 to 80% w / w SR PEG 400, 5 to 40% w / w propylene glycol, 5 to 25% w / w dimethyl isosorbide, 0.5 to 3% w / w phenoxyethanol, 0.025 to 3% w / w butylated hydroxyl Toluene, 0.5 to 3% w / w carbomer, 0.1 to 50% w / w water and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjusters, optimal 30 to 70% w / w SR PEG 400, 15 to 25% w / w propylene glycol, 10 to 20% w / w dimethyl isosorbide, 1 to 2% w / w phenoxyethanol, 0.05 to 2% w / w butylated hydroxyl Toluene, 1 to 2% w / w carbomer, 0.1 to 50% w / w water, and 0.01 to 20% w / w dilute HCl or dilute NaOH solution as pH adjusters. 48. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 47, wherein the formulation is an ointment, which contains 67.72% w / w SR PEG 400, 9.78% w / w Propylene glycol, 17.5% w / w PEG 4000, and 5% active pharmaceutical ingredient pregaribil, of which pH is pH 4.0 to 5.0. 49. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 48, wherein the formulation is a gel, which contains 39.1% w / w SR PEG 400, 9.59% w / w ethanol, 4.8% w / w pH 4 buffer, 23.98% w / w Transcutol HP, 14.39% w / w dimethyl isosorbide, 1.92% w / w benzyl alcohol, 1.25% w / w hydroxypropyl fiber Prime. 50. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 49, which is used as a medicament. 51. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 50, which is used to treat and / or prevent herpes virus infection. 52. A pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 1 to 51, which is used to treat and / or prevent herpes virus infection, wherein the herpes virus is selected from simple viruses Mesh. 53. The pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 52, which is used to treat and / or prevent the herpes virus infection as in Examples 51 to 52, wherein the The simplex virus is selected from herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). 54. A method of treating and / or preventing herpes virus infection, which comprises administering a local pharmaceutical formulation as defined in any one of Examples 1 to 53 to an individual in need. 55. The topical pharmaceutical formulation as defined in any one of embodiments 1 to 54, wherein the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole-2- Group] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of about 5.0% w / w. 56. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 54, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of 5.0% w / w, in which the pharmaceutical composition is an ointment. 57. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 56, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Is present in an amount of about 1.0 to about 7.5% w / w, preferably about 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times per day, or 2 to 10 per day Times, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day. 58. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 57, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Is present in an amount of 1.0 to 7.5% w / w, preferably 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day, and wherein the ointment is administered for 2 to 14 days, 3 to 10 days, 3 to 7 days, 4 To 5 days, or 5 days, or 4 days. 59. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 58, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 5 times a day, and wherein the ointment is administered for 4 days. 60. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments 1 to 59, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
It is present in an amount sufficient to achieve a concentration of> 10 nM in the epidermis and dermis of individuals treated with the composition. 61. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat and / or prevent herpes virus infections. 62. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 for treating and / or preventing herpes virus infection -[4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, Wherein the herpes virus is selected from the order of pure viruses. 63. N- [5- (Amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- for treating and / or preventing herpes virus infection as in Example 62 Methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, Wherein the simple virus is selected from herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). 64. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
Or derivatives thereof, which are used in topical pharmaceutical formulations to treat and / or prevent herpes virus infections in individuals in need thereof. 65. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N for the treatment of topical pharmaceutical formulations in individuals in need thereof -Methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Or a derivative thereof, wherein the individual has or is suspected of having herpes virus infection. 66. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2-for local administration to individuals in need [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, Wherein the topical administration is for facial application, and / or application to the oral cavity, genitals, and / or eyes. 67. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 for systemic administration to individuals in need -[4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, Where the individual is suspected of having herpes virus infection or an individual suffering from herpes virus infection. 68. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat recurrent cold sores. 69. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat recurrent cold sores selected from the group of patients: patients showing signs of early stage cold sores, patients with erythema, patients showing lip papules, patients with labial vesicles, patients with lips Patients with ulcers and / or soft shells, patients with lip hard shells, patients with residual erythema on the lips. 70. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat genital herpes. 71. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat herpes keratitis. 72. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat herpes meningitis and / or encephalitis. 73. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat neonatal herpes infections. 74. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base hemihydrate
, Which is used to treat herpes infections in individuals with normal immune function and / or immune insufficiency. 75. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole-2-used for the treatment of herpes infection in individuals with normal immune function and / or immune insufficiency Group] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, Where the system of immune insufficiency is selected from the group consisting of: an organ transplant recipient, an individual with another virus or bacterial infection (specifically infected with HIV and / or another herpes virus), and Individuals infected with herpes simplex virus are resistant to at least one antiviral active agent. 76. A method for treating and / or preventing herpes virus infections, which comprises combining N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl Yl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Give to individuals in need. 77. A preparation of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) Phenyl] acetamideFree base hemihydrate
Method, wherein the method includes the following steps: a) mixing 4-pyridin-2-yl-phenyl) -acetic acid and amide thiazole sulfonamide in N-methylpyrrolidone (NMP); b) Cool the compound obtained in step a); c) Add N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC x HCl) to the step b) in the mixture obtained in d); d) stir the solution obtained in step c) and add to pure H2
O; e) filtering the solution obtained in step d); f) washing the product cake obtained in step e); g) drying the product obtained in step f); h) applying H2
O added to the solution obtained in step g); i) stirring the suspension obtained in step h); j) cooling the suspension obtained in step i); k) stirring in step j) The suspension obtained; l) the product is isolated by filtering the suspension obtained in step k); m) using H2
O washing the product obtained in step l); n) drying the product obtained in step m); 78. A pharmaceutical composition comprising N- [5- (5 ( Amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
. 79. A pharmaceutical composition, which can be prepared by formulating N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazole-2- available in the method of Example 77 Group] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Obtained with at least one pharmaceutical excipient. 80. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 available in the method of Example 77 -[4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
Its use as a medicament. 81. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 80, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base maleate
It is present in an amount of about 5.0% w / w. 82. A local pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples 1 to 81, wherein the N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base maleate
It is present in an amount of about 1.0 to about 7.5% w / w, specifically about 5.0% w / w. 83. As in Examples 81 to 82Maleate
, Where the light resistance is measured using the Pharmacopoeia method according to the "European Pharmacopoeia" and / or "United States Pharmacopoeia", the maleate is characterized by a wavelength in the range of 300 nm to 800 nm, and at least 1.2 million lux ( Lux) hours of exposure, and at least 200 watt hours / m² of exposure energy. After at least 29 hours of exposure, the light resistance is at least 70% residual N- [5- (amino-sulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide free base. 84. As in any of the preceding embodimentsMaleate
, Where the maleate is further characterized by characteristic XRPD peaks at 6.6, 15.9, 16.2, 18.1, 20.5, 22.5, 26.1 and when measured according to the Pharmacopoeia methods of the "European Pharmacopoeia" and / or the "United States Pharmacopoeia" 28.6 2θ. 85. As in any of the preceding embodimentsMaleate
, Where the maleate is physicochemically stable when measured according to the "European Pharmacopoeia" and / or "U.S. Pharmacopoeia" pharmacopoeia method, characterized by being stored in an aqueous solution at room temperature and at a pH of 3.5 to 7.0 After two weeks, the recovery rate of the maleate was at least 85% of the initial concentration. 86. As in any of the preceding embodimentsMaleate
Wherein, when measured according to the Pharmacopoeia method of the "European Pharmacopoeia" and / or "United States Pharmacopoeia", the maleate is characterized by a solubility in water of about 0.48 mg / mL. 87. A topical pharmaceutical formulation for topical application to an individual in need as defined in any of the preceding embodiments, wherein when measured according to the pharmacopoeial methods of the "European Pharmacopoeia" and / or "United States Pharmacopoeia", wherein TheMaleate
It is present in an amount sufficient to achieve a concentration of ≥ 10 nM in the epidermis and dermis of individuals receiving the method of topical treatment of the composition. 88. An N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base maleate
, Which is used to treat and / or prevent herpes virus infections. 89. Preparation of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 as defined in Examples 81 to 88 -[4- (2-pyridyl) phenyl] acetamide free baseMaleate
The method includes the following steps: i) providing a mixing device, preferably equipped with an overhead stirring mixing device, ii) filling the mixing device of step i) with 460 to 490 g of Pravivir free base, iii) Suspend the prerivative free base of step ii) with 3 to 5 volumes of water, iv) heat the suspension of step iii) to 45 to 55 ° C with a suitable heating device, v) for a time of 40 to 90 minutes Add 225 to 240 g of maleic acid in solid form until a final solution is obtained, vi) Cool the solution obtained under step v) to 44 to 52 ° C vii) Use the free base of prednisyl maleic acid Salt inoculate an aliquot of the step vi) solution, viii) allow the resulting suspension of step vii) to cool to 18 to 24 ° C for a period of 1.5 to 2.5 hours, ix) then stir the suspension of step viii) overnight, x ) Filter the suspension in step ix) to obtain the resulting filter cake, xi) transfer the solid filter cake obtained in step x) to a mixing device, preferably a flask, xii) rotate the mixing device in step xi) 25-32 hours, while applying the following conditions: a. 30 to 40 Ambient temperature, b. 15 to 25 mbar pressure to obtain a constant mass, xiii) homogenization afterwards, preferably using a mortar and pestle to homogenize, xiv) to obtain the free of pregarib of the present invention Alkaline maleate. Under the above background of the present invention, other specific aspects of the present invention are provided by the following continuously listed examples: a. A pharmaceutical formulation for topical application to an individual in need, the formulation comprising: 1 to -10 % w / w of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl ) Phenyl] acetamide, at least one solvent of 0 to 90% w / w, at least one antioxidant of 0 to 10% w / w, wherein the pharmaceutical formulation has a pH of 2.0 to 8.0, preferably 4.0 to PH of 5.0, where N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl ) Phenyl] acetamide series is stable in a dissolved state or in a dissolved form at 25-60 ℃ for 12 months, wherein the solvent system is selected from ethanol, dimethyl isosorbide, isopropanol, Transcutol P, poly Ethylene glycol, PEG 400, PEG 4000 and Super RefinedTM
(SR) Group of PEG 400. In an example adjacent to Example a, the pH value of the pharmaceutical formulation is preferably 4.0 to 4.5. In an example adjacent to Example a, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) phenyl] acetamide is stable in dissolved state or in dissolved form at 25 ° C / 60% RH for at least 24 months. b. The pharmaceutical formulation as defined in embodiment a, wherein the at least one solvent is selected from the group comprising polyethylene glycol, preferably PEG 400, more preferably SR PEG 400. c. The pharmaceutical formulation as defined in Examples a to b, wherein the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- Methyl-2- [4- (2-pyridyl) phenyl] acetamide is selected from the group consisting of: N- [5- (amino-sulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] AcetamideMaleate
, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] The free base of acetamideMesylate
, And N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideFree base
. d. The pharmaceutical formulation as defined in any one of embodiments a to c, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, palm Ascorbic acid esters, tocopherol, tocopheryl acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate group. e. The pharmaceutical formulation of embodiments a to d, wherein the formulation is selected from the group consisting of the following formulations: for creams, ointments, gels, ointments, lotions, wax formulations, lipsticks Preparation of tonic, mousse, foam, film, emulsion, paste, solution, oil, lipid. f. The pharmaceutical formulation as defined in any one of embodiments a to e, wherein the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] The concentration of -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is selected from the range of 1.1 to 10% w / w, more preferably 1.1 to 5% w / w. g. The pharmaceutical formulation as defined in any one of embodiments a to f, wherein the concentration of the at least one solvent is 0.1 to 90% w / w, for example 5 to 90% w / w, 10 to 90% w / w, 10 to 80% w / w, 20 to 80 w / w, 25 to 80% w / w, 15 to 50% w / w, or 30 to 45% w / w. h. The pharmaceutical formulation as defined in any one of embodiments a to g, wherein the formulation is an ointment further comprising: 0.01 to 20% w / w of at least one pH adjusting agent. i. The pharmaceutical formulation as defined in any one of embodiments a to h, wherein the formulation is a cream further comprising: 0 to 5% w / w preservative at least 0 to 20% w / w A surfactant 1 to 40% w / w oil phase / emollient 0 to 40% w / w water. j. The pharmaceutical formulation as defined in any one of embodiments a to i, wherein the formulation is a gel further comprising: 0 to 30% w / w penetration enhancer 0 to 20% w / w At least one gelling agent 0 to 50% w / w water 0.01 to 20% w / w at least one pH adjusting agent. k. The pharmaceutical formulation as defined in any one of embodiments a to j, which is used as a medicament. l. The pharmaceutical formulation as defined in any one of embodiments a to k, which is used for the treatment and / or prevention of herpes virus infection. m. The pharmaceutical formulation as defined in any one of embodiments a to 1 for use in the treatment and / or prevention of herpes virus infection, wherein the herpes virus is selected from the order of pure viruses. n. The pharmaceutical formulation as defined in any one of embodiments a to m for use in the treatment and / or prevention of herpes virus infection, wherein the simple virus is selected from herpes simplex virus 1 (HSV-1) and simple Herpes virus 2 (HSV-2). Under the above background of the present invention, other specific aspects of the present invention are provided by the following consecutively numbered examples: I. A pharmaceutical formulation for local application to an individual in need, the formulation comprising: i. 1 to 10% w / w of N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridine Radical) phenyl] acetamide, ii. At least one solvent> 0 to 90% w / w, iii. At least one antioxidant> 0 to 10% w / w, wherein the pharmaceutical formulation has a value of 2.0 to 8.0 pH value, preferably a pH of 4.0 to 5.0, wherein N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) phenyl] acetamide is stable in a dissolved state or in a dissolved form at 25 ° C / 60% RH for 12 months, wherein the solvent is selected from ethanol, dimethyl isosorbide, Isopropyl alcohol, Transcutol P, propylene glycol, polyethylene glycol, PEG 400, PEG 4000 and Super RefinedTM
The group of PEG 400, wherein the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopheryl acetate , Propyl gallate, dodecyl gallate, octyl gallate, thiosulfate group. In an example adjacent to Example I, the pH value of the pharmaceutical formulation is preferably 4.0 to 4.5. In an example adjacent to Example I, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) phenyl] acetamide is stable in dissolved state or in dissolved form at 25 ° C / 60% RH for at least 24 months. II. The pharmaceutical formulation for topical application to an individual in need as in Example I, wherein the formulation contains: i. 1 to 10% w / w of N- [5- (amino-sulfonyl)- 4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide, ii. At least 0.1 to 90% w / w A solvent, iii. 0.01 to 10% w / w of at least one antioxidant, wherein the pharmaceutical formulation has a pH of 4.0 to 5.0, where N- [5- (amino-sulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is stable in a dissolved state or in a dissolved form at 25 ° C / 60% RH 12 months, where the solvent needs to be selected from polyethylene glycol, PEG 400, PEG 4000 and Super RefinedTM
Group of PEG 400, and wherein the antioxidant is butylated hydroxytoluene (BHT). In an example adjacent to Example II, the pH value of the pharmaceutical formulation is preferably 4.0 to 4.5. In an example adjacent to Example II, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) phenyl] acetamide is stable in dissolved state or in dissolved form at 25 ° C / 60% RH for at least 24 months. III. A pharmaceutical formulation for topical application to an individual in need as in any one of embodiments I to II, the formulation comprising: i. 1.1 to 5% w / w of N- [5- (amino- Sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide, ii. 0.1 to 90% w / w at least one solvent, iii. 0.01 to 10% w / w at least one antioxidant, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, where N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is in a dissolved state or in a dissolved form at 25 ° C / Stable for 12 months at 60% RH, where the solvent is Super RefinedTM
PEG 400, and wherein the antioxidant is butylated hydroxytoluene (BHT). In an example adjacent to Example III, the pH value of the pharmaceutical formulation is preferably 4.0 to 4.5. In an example adjacent to Example III, N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) phenyl] acetamide is stable in dissolved state or in dissolved form at 25 ° C / 60% RH for at least 24 months. IV. A pharmaceutical formulation for topical application to an individual in need as defined in any one of the foregoing embodiments I to III, wherein the N- [5- (amino-sulfonyl) -4-methyl- 1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is selected from the group consisting of: • N- [5- (amine -Sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideMaleate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] The free base of acetamideMesylate
, And • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base
. V. A pharmaceutical formulation for topical application to an individual in need as defined in any one of Examples I to IV, where there are no solids during the XRPD by light scattering method, Raman spectroscopy and IR spectroscopy When measured by phase, the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridine Group) phenyl] acetamide or the N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4 -(2-pyridyl) phenyl] acetamideFree base hemihydrate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideMaleate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] The free base of acetamideMesylate
, And • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) benzene Base] of acetamideFree base
. The system exists in a dissolved state or in a dissolved form. VI. A pharmaceutical formulation for topical application to an individual in need as defined in any one of the foregoing embodiments I to V, the formulation comprising: i. 5% w / w of N- [5- (amino group -Sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide, or the N- [5- (Amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideMaleate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] The free base of acetamideMesylate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideFree base
, Ii. 25 to 80% w / w of at least one solvent, iii. 0.05 to 2% w / w of at least one antioxidant, wherein the pharmaceutical formulation has a pH of 4.0, and the solvent is SR PEG 400, And the antioxidant is butylated hydroxytoluene (BHT). VII. A pharmaceutical formulation for topical application to an individual in need as defined in any one of embodiments I to VI, wherein the N- [5- (amino-sulfonyl) -4-methyl-1 , 3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamide is selected from the group consisting of: • N- [5 in dissolved state -(Amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl] acetamideFree base hemihydrate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridine) in a dissolved state Radical) phenyl] acetamideMaleate
, • N- [5- (amino-sulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) phenyl ] AcetylamideFree base
. VIII. The pharmaceutical formulation for topical application to an individual in need as in any of the foregoing embodiments I to VII, the formulation is selected from the group consisting of the following formulations: for creams, ointments, gels, Ointments, lotions, wax formulations, lipsticks, tonics, mousses, foams, films, emulsions, pastes, solutions, oils, and microlipid formulations In an embodiment adjacent to embodiment VIII, the formulation is selected from the group consisting of the following formulations: for creams, ointments, gels, ointments, lotions, wax formulations, lipsticks, tonics , Mousse, foam, film, emulsion, paste, solution, oil, fat glue and patch formulations. IX. The pharmaceutical formulation for topical application to an individual in need as in any one of embodiments I to VIII, wherein the formulation is an ointment further comprising: (i) at least one of 0.01 to 20% w / w pH regulator. In an example adjacent to Example IX, the pH adjuster is an apparent pH adjuster. X. A pharmaceutical formulation for topical application to an individual in need as defined in Example IX, wherein the formulation is an ointment containing: 17.5% w / w PEG 4000, 9.78% w / w propylene glycol, 5% w / w active pharmaceutical ingredient Pregavir, 0.1% w / w butylated hydroxytoluene (BHT), 67.62% w / w Super RefinedTM
PEG 400, and wherein the pharmaceutical formulation has a pH of 4.0 to 5.0, preferably a pH of 4.0 to 4.5. XI. A pharmaceutical formulation for topical application to an individual in need as in Example XIII, wherein the formulation is a cream further comprising: i. 0 to 5% w / w preservative ii. 0 to 20% w / w of at least one surfactant iii. 1 to 40% w / w oil phase / emollient iv. 0 to 40% w / w water. XII. A pharmaceutical formulation for topical application to an individual in need as in Example XIII, wherein the formulation is a gel further comprising: i. 0 to 30% w / w penetration enhancer ii. 0 to 20 % w / w gelling agent iii. 0 to 50% w / w water iv. 0.01 to 20% w / w of at least one pH adjusting agent, v. optionally further comprising an amount of about 0 to 5% w / w preservative. In an example adjacent to Example XII, the formulation contains under 0 to 30% skin penetration enhancer under item (i). XIII. The pharmaceutical formulation as defined in any one of the foregoing embodiments I to XVII, which is used as a medicament. XIV. The pharmaceutical formulation as defined in any one of the foregoing embodiments I to XIII for use in the treatment and / or prevention of herpes virus infection. XV. The pharmaceutical formulation as defined in any one of the foregoing embodiments I to XIV, which is used for the treatment and / or prevention of herpes virus infection, wherein the herpes virus is selected from the order of pure viruses. XVI. The pharmaceutical formulation as defined in any one of the foregoing embodiments I to XV for use in the treatment and / or prevention of herpes virus infection, wherein the simple virus is selected from herpes simplex virus 1 (HSV-1) and Herpes simplex virus 2 (HSV-2).Examples Examples 1 : Development of formulations
Based on extensive pre-formulation studies using N‑ [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2 -Pyridyl) -phenyl] -acetamideFree base hemihydrate
And N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl] -AcetamideMesylate
Both (hereinafter also referred to as "pregarib free base" and "pregarib mesylate") developed a topical ointment formulation. Development includes determination of N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Base]-The solubility and stability of the two forms of acetamide in different excipients. In addition, conduct research on skin penetration and skin irritation outside the blended object. Based on short-term stability studies, leading formulations were selected for further mass production studies.Composition of the formulation
5% w / w N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -Phenyl] -acetamideFree base hemihydrate
Ointment is an opaque ointment that is locally applied to white to slightly colored. Per gram of active ingredient N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl)- Phenyl] -acetamideFree base hemihydrate
5% w / w ointment contains dissolved in Super RefinedTM
51.1 mg of N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [in ethylene glycol 400 (SR PEG 400) matrix 4- (2-pyridyl) -phenyl] -acetamideFree base hemihydrate
. The qualitative and quantitative composition in% (w / w) is provided in Table 4 below.table 4
a Corresponding to 5.0% pregarib (active fraction) Table 4 above describes the basic composition of the clinical ointment formulation according to the invention. Table 5 below lists the excipients and their functions used in the preparation of finished products. All excipients are well known and widely used in the preparation of ointments.table 5
Table 5 above describes the functions and grades of the components used in clinical ointment formulations.By HPLC Of N- [5- ( Sulfamoyl ) -4- methyl -1,3- Thiazole -2- base ] -N- methyl -2- [4- (2- Pyridyl )- Phenyl ]- Identification, analysis and related substances of acetamide
For identification, compare the retention time of the Prelivi peak in the sample chromatogram with the retention time of the Prelivi peak in the reference chromatogram, and extract the The UV spectrum is compared with the UV spectrum extracted from the reference standard chromatogram. Quantitative determination analysis using external standards. The reporting level is set at 0.05% area / area.Use the following HPLC parameter:
HPLC system: HPLC column with DAD detector and data processing software: Phenomenex Luna C18, 5 μm, 250 x 3.0 mm; or equivalent protection column: C18 protection filter cartridge Sample temperature: 5 ± 2 ℃ Column temperature: 45 ± 2 ° C Injection volume: 2 μL Flow rate: 0.5 mL / min Running time: 75.0 min Detection wavelength: 282 nm Mobile phase A: 10 mM ammonium acetate buffer pH 5.0 Mobile phase B: Acetonitrile gradient: see Table 6 below.table 6
Standard and sample diluent: 0.1% v / v formic acid in 50:50 v / v water: acetonitrile injection blank: 0.1% v / v formic acid in 50:50 v / v water: acetonitrile needle wash solution: 60:40 v / v Methanol: water Known impurities: PP Acetic acid: RRT about 0.33 Aminothiazole sulfonamide: RRT about 0.19 The above table 6 describes the gradient used for the chromatographic method described above by giving PHLC parameters.Formulation development
The formulation was developed to contain 5% N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2 -Pyridinyl) -phenyl] -acetamide local formulation, which is N- [5- (aminosulfamoyl) -4-methyl-1,3 not less than 10 nM to 20 nM -Thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl] -acetamideFree base hemihydrate
The target concentration contained in the epidermis and dermis quickly penetrates the skin (epidermis) and there is very little systemic exposure, it is easy to spread and absorb quickly, and it is moisturizing, non-greasy and beautiful to use. The formulations described herein are based on solubility and compatibility experiments, short-term (light) stability studies, in vitro drug release experiments, in vitro skin penetration and penetration experiments, studies to find the dose range in minipigs and in vitro skin irritation studies Selected by the results.Solubility study
Table 7 below shows N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl)- Phenyl] -acetamideFree base hemihydrate
The saturation solubility andMesylate
Compare. N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl]- AcetamideFree base hemihydrate
Shows significantly higher solubility than mesylate.table 7 :
N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl]- AcetamideFree base hemihydrate
The saturation solubility andMesylate
Compare.
BLOQ-LOQ lower than the analytical method.A
The solubility is determined by visual inspection.Solvent system
Design a solvent system based on solubility data. The composition is shown in Table 8 below.table 8- Solvent system
(-): Does not contain N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl ) -Phenyl] -acetamideFree base hemihydrate
The solubility is measured in these solvent systems. Obviously, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl ] -AcetamideFree base hemihydrate
Display ratioMesylate
Significantly higher solubility, as shown in Table 9: Table 8 above describes the solvent system tested for clinical ointment formulations.table 9
Table 9 above describes the solubility of Pravivir free base and mesylate in these solvent systems used.Short-term stability:
N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl]- AcetamideFree base hemihydrate
The short-term stability test is carried out in individual excipients and solvent systems. When the compound is separately tested in benzyl alcohol, propylene glycol, Arlasolve DMI, 10% w / v Kleptose solution and SS5 (propylene glycol: buffer pH 3.5) at 40 ° C and 50 ° C for two weeks and four weeks, A good free base hemihydrate recovery rate (90 to 110%) compared to the t = 0 value was observed (Table 10). N- [5- (Aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl was observed in PEG alone and binary and solvent systems containing a high percentage of PEG 400 Low recovery of yl-2- [4- (2-pyridyl) -phenyl] -acetamide hemihydrate free base (<50% compared to t = 0). Observed with N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Base]-Acetamide free base hemihydrate recovery rate corresponds to the peak purity data.table 10 :
Measured at t = 0 and after storage at said time point and temperaturePrevivi free base
Recovery rate and peak purity in solvent. The recovery rate compared with the t = 0 value, n = 2, the range (analysis method) is indicated in parentheses. Peak purity value, n = 1 (impurity method).
Also makeMesylate
Accept short-term stability studies contained in selected excipients and solvent systems. When at 40 ° C and 50 ° C, pregaribic mesylate is used in benzyl alcohol, phenoxyethanol, propylene glycol, 10% w / v Kleptose solution, water SS5, SS6 and SS7 for two weeks During the short-term stability test, a good prelimin mesylate recovery rate (between 90 and 110% compared to t = 0) and corresponding peak purity data were observed (Table 8). Poor stability of preliminium mesylate was observed in benzyl alcohol, PEG 400, Transcutol P, glycerin, 50:50 pH 4 buffer: PEG 400, and SS1-4 (at t = 4 weeks, 50 ° C Under, peak purity <90%); however, when compared to pregarib free base, the mesylate appears to have improved stability in both individual excipients and solvent systems.table 11 :
The recovery rate and peak purity of Previvi mesylate in the solvent measured at t = 0 and after storage at the time point and temperature. The recovery rate compared with the t = 0 value, n = 2, the range (analysis method) is indicated in parentheses. Peak purity value, n = 1 (impurity method).
In additional excipients such as SR PEG 400Free base and mesylate
Both conducted further short-term stability studies. The results indicated that N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Group] -acetamide free base hemihydrate shows excellent stability compared to the mesylate salt (see Table 12 below). Table 12 a (see table above)-the recovery rate and peak purity of Previvi free base in the solvent at T0 and after storage at said time point and temperature. The recovery rate compared with the T0 value, n = 2, the range in parentheses (analysis method), the peak purity value n = 1 (impurity method). Table 12 b (see the table below) – the recovery rate and peak purity of previribe mesylate in the solvent measured at t = 0 and after storage at the stated time point and temperature. The recovery rate compared with the t = 0 value, n = 2, the range in parentheses (analysis method). Peak purity value, n = 1 (impurity method).
Table 34. Recovery rate and peak purity of pregarib mesylate in the solvent measured at t = 0 and after storage at the time point and temperature. The recovery rate compared with the t = 0 value, n = 2, the range in parentheses (analysis method). Peak purity value, n = 1 (impurity method).
For the purpose of formulation optimization, study other solvent systems (composition is shown in Table 13 below)table 13
The saturation solubility in these solvent systems is shown in Table 14 below, as a basis for developing emulsions. Table 13 describes the recovery rate and peak purity of pregarib mesylate in the solvent measured at t = 0 and after storage at the time point and temperature. The recovery rate compared with the t = 0 value, n = 2, the range in parentheses (analysis method). Peak purity value, n = 1 (impurity method).table 1 4
* n = 2 Table 14 describes the solubility of previribine and salts in different solvent systems used to develop topical gels. Table 15 below shows that N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -Phenyl] -acetamideFree base and mesylate
Solubility in the solvent system used in ointment formulations. It should be noted that N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Base] -acetamideFree base hemihydrate
It has extremely high solubility compared to mesylate, which is a prerequisite for achieving a drug loading of 5%.table 15 s
The extraction value is higher than ULOQ, * n = 2 Table 15 describes the solubility of Pravivir base and salts in different solvent systems used to develop topical ointments. SSO1 and SSO3 were selected as the components for the development of ointment formulations containing 5% w / w and 1% w / w of Prelivi free base and Prelivi mesylate. The following section shows the formulations selected in the development of creams, gels and ointments.Gel formulation table 16– Composition of gel formulations containing Pravivir free base hemihydrate.
(-): Not includedtable 17– The composition of gel formulations containing preliminium mesylate.
(-): Not includedCream formulation table 18– Composition of cream formulations containing pregaribic free base hemihydrate.
(-): Not includedtable 19– The composition of cream formulations containing Prapirox mesylate
(-): Not includedtable 20 :
The concentration (μM) of pregavir or acyclovir observed in the epidermis and part of the dermis after t = 1 and 8 hours. Each value represents the mean ± SEM (n = 4-6). Ointment-based formulations table twenty one- Composition of ointment formulations containing pregarib free base hemihydrate
(-): Not includedtable twenty two- The composition of ointment formulations containing Pravicarb mesylate.
(-): Not includedIn vitro skin penetration studies
In vitro skin penetration studies using representative formulations: At t = 15 minutes, 1 hour, and 8 hours after application of these formulations, N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl] -acetamideFree base
(μM) The concentration range in epidermis and dermis (based on the average amount and a series of skin thicknesses) is presented in Table 23, where the observed concentration is substantially higher than the target concentration of pregaribly (10 to 20 nM) Higher (1,000 to 1,000,000 times) and higher IC50 than acyclovir (2 μM). It should also be noted that the speed of effect is also important.table twenty three
-At t = 15 minutes, 1 hour and 8 hours after the application of these formulations,Hemihydrate free base
(μM) andMesylate
Concentration range in epidermis and dermis (based on average amount and a range of skin thickness). Values represent the range based on skin thickness and average recovery, n = 5 to 6. Among the miniature pigs DRF the study
The following formulation Table 24 is used for the dose range discovery study in miniature pigs.table twenty four- Preparation for DRF Composition of excipients for the formulation of miniature pigs
(-): Not includedtable 25– For DRF Batch number, physical description, analysis and analysis of formulations for mini-pig research pH
N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) deposited in the skin layer ) -Phenyl] -acetamideFree base hemihydrate
The amount is measured on Day 1 and Day 5, and Table 26 below shows the results.table 26 ( The amount of Previvi recovered (ng))
* Section 15.4.2 Appendix 4 provides additional tables summarizing the autopsies on Days 6 and 7. Table 26 shows the amount of pregavir recovered from the skin layer expressed in [ng]. Carry out as follows N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl ] -AcetamideFree base hemihydrate
Recovery of cuticle, epidermis and dermis from biopsy samples. On the first day, the following ranking of the recovery rate of free base hemihydrate from the epidermis was observed, with no significant statistical difference (p> 0.05): G7V3> O3v4> C3v3. On day 5 and after the autopsy, the same ranking of the recovery rate of free base hemihydrate from the epidermis as on day 1 was observed, however, the recovery rate of free base hemihydrate after G7v3 administration was statistically (p <0.05) is greater than the recovery from the remaining formulations. When considering the recovery rate of free base hemihydrate from part of the dermis, the following ranking was observed, in which the recovery rate of the free base after the administration of G7v3 was statistically (p <0.05) compared to the rest on the first day The recovery rate of the material is greater; it is greater than the fifth day of C3v3, and there is no statistical difference at the time of autopsy (p> 0.05): Day 1: G7V3> O3v4> C3v3. Day 5: G7V3> O3v4> C3v3 Autopsy: G7V3> C3v3> O3v4. In general, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl was observed in the stratum corneum, epidermis and dermis Yl-2- [4- (2-pyridyl) -phenyl] -acetamideFree base hemihydrate
The concentration decreases with time, indicating that N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-Pyridyl) -phenyl] -acetamide free base hemihydrate is absorbed into the blood over time.Development of other formulations
After in vitro skin penetration and penetration experiments, it was decided to achieve 5% and 1.5% N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- Methyl-2- [4- (2-pyridyl) -phenyl] -acetamideFree base hemihydrate
andMesylate
The target concentration is the target for continued formulation development, where the apparent pH is about 4. It was also decided to evaluate UV blockers to develop light-stable formulations. The following lists a large number of sunscreen active ingredients summarized: •UVA Filter agent:
Benzophenones (oxybenzone, sulfisophenone, dioxybenzone), benzophenones (avobenzone), anthralates (American Meradimate), camphor (ecamsule) •UVB Filter agent:
Aminobenzoates (p-aminobenzoic acid, dimethylaminobenzoate pentyl-O), cinnamates (cinoxate, octinoxate), salicylates Classes (octisalate, homosalate, triethanolamine salicylate), octocrylene, ensulizole •Inorganic filter:
Titanium dioxide, zinc oxide. Development of formulations with and without octyl cinnamate (each formulation type n = 2). Therefore, a solvent system combined with octyl salicylate was developed to determine N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ 4- (2-pyridyl) -phenyl] -acetamideFree base hemihydrate
orMesylate
Saturated solubility and determine whether 5% and 1.5% w / w of N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl- The target concentrations of 2- [4- (2-pyridyl) -phenyl] -acetamide free base hemihydrate and mesylate are possible. Table 27 shows N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Base] -acetamideFree base hemihydrate
andMesylate
The saturated solubility of each in octyl salicylate. The value represents the average value, where the brackets are the range, n = 3.
N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl]- AcetamideFree base hemihydrate and methanesulfonate
Other solubility in solvent system: each based on N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- ( 2-pyridyl) -phenyl] -acetamideFree base hemihydrate and methanesulfonate
The initial solubility data of N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl ) -Phenyl] -acetamide free base hemihydrate and methanesulfonate (5% and 1.5% w / w each), developing other solvent systems in an attempt to maintain the result at an apparent pH of 4 The pharmaceutical thermodynamic active agent of the formulation and the physical stability make N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [ The solubility of 4- (2-pyridyl) -phenyl] -acetamide free base hemihydrate and mesylate is maximized. Table 28 showsPrevivi free base
andMesylate
Saturated solubility in the solvent system used to develop the gel
Table 29 showsPrevivi free base
andMesylate
Saturated solubility in the solvent system used to develop the gel
(-): Not included, ND: Not determined Table 30 showsPrevivi free base
andMesylate
Saturated solubility in the solvent system used to develop creams
(-): Not included, ND: Not determined, * The remaining amount will be the oil phase of the final formulation. Table 31 showsPrevivi free base
andMesylate
Saturated solubility in the solvent system used to develop ointments
(-): Not included, ND: Not determined, * The remaining amount will be PEG4000 of the final formulation. Table 32 showsPrevivi free base
andMesylate
Saturated solubility in the solvent system used to develop ointments
(-): Not included, ND: Not determined, * The remaining amount will be PEG4000 of the final formulation.Development of gel formulations
-Table 33 showsPrevivi free base
andMesylate
The composition of the gel formulation
(-): Not includedDevelopment of cream-based formulations
-Table 34 showsPrevivi free base
andMesylate
The composition of the cream formulation table 35
(-): Not includedtable 35 display
The composition of Prelivi free base and mesylate cream formulations.Development of formulations based on ointment
-Table 36 showsPrevivi free base
andMesylate
The composition of the ointment formulation
(-): Not includedShort-term stress stability of formulations based on gels, creams and ointments:
It is summarized in the table below that after storage at 25 ° C and 40 ° C for t = 2 and 4 weeks, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazole-2- Yl] -N-methyl-2- [4- (2-pyridyl) -phenyl] -acetamideFree base hemihydrate
andMesylate
Respective recovery and purity. When considering containing N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene In the formulation of acetyl] -acetamide free base hemihydrate, a good recovery rate (97 to 105%) was observed in all gel formulations at 40 ° C up to t = 4 weeks. This system consists of N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Base] -acetamide free base hemihydrate is supported by good percentage purity (> 99%) in G8, G8v3, G24 and G24v3. Variable recovery rates were observed in some cream formulations, which can be attributed to the phase separation observed during storage at 40 ° C and the low efficiency of the drug extraction procedure, which is a general method. However, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl was observed in all formulations except Cr03v5 (98.62%) Good percentage purity of -2- [4- (2-pyridyl) -phenyl] -acetamide free base (> 99%). N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [was observed in all ointment formulations except O4v4 OCT 4- (2-pyridyl) -phenyl] -acetamide free base hemihydrate has good recovery rate (about 87% after storage t = 4 weeks at 40 ° C), however, N- [5- ( Sulfamoyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl] -acetamide free base half The percentage purity of hydrates in all ointment formulations is> 99%. In general, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridine Group) -phenyl] -acetamide mesylate formulations are more unstable than formulations containing free base hemihydrate. However, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- was observed in all gel formulations except G15 (81%) Good recovery of methyl-2- [4- (2-pyridyl) -phenyl] -acetamide mesylate. This system consists of N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -benzene Base] -acetamide mesylate in this formulation is supported by the percentage peak purity (86%), however, N- [5- (aminosulfonamide) -4-methyl was observed in the remaining formulation Yl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl] -acetamide mesylate percentage peak purity decreases from t = 0 . All in all, N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridyl) -phenyl ] -Acetylamine free base hemihydrate is surprisingly more stable than mesylate.table 37
– Store at t = 0 and store at 25 ℃ and 40 ℃ for t = 2 and 4 weeksPrevivi free base
Recovery rate (percentage of theoretical concentration), n = 3* n = 1, ND: not determinedtable 38
– At t = 0 and at 25 ° C and 40 ° C after storage for t = 2 and 4 weeksPrevivi free base
Percent purity, n = 1ND: Not determinedtable 39
– Store at t = 0 and store at 25 ℃ and 40 ℃ for t = 2 and 4 weeksPrevivimethanesulfonate
Recovery rate (as a percentage of theoretical concentration), n = 2 to 3* n = 1, ND: not determinedtable 40
– At t = 0 and at 25 ° C and 40 ° C after storage for t = 2 and 4 weeksPrevivimethanesulfonate
Percent purity, n = 1ND: Not determinedForced degradation research
The data on the forced degradation of the formulation showed that N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- Pyridyl) -phenyl] -acetamide can be easily degraded via oxidation. In addition, degradation of the drug substance in standard PEG 400 quality was observed during formulation development, see Table 41 below. Therefore, a special PEG 400 grade (Super Refined) is usedTM
PEG 400) and evaluated for the inclusion of antioxidants. Based on the data obtained, butylated hydroxytoluene (BHT) as an antioxidant was included in the formulation at a concentration of 0.1% w / w. The concentration used corresponds to the concentration of BHT used as an antioxidant in equivalent products (see FDA's Inactive Ingredients Database). By using Super RefinedTM
The combination of PEG 400, antioxidants (BHT) and acidic pH value 4.0 to 5.0 limits the oxidative degradation of Previvi. Propylene glycol is used as an additional solvent in the solvent system (ointment base). The data obtained during formulation development speculate that a low pH value may improve the stability of Pravivir and therefore evaluate the use of acidifying excipients. The target pH value during product preparation is set between 4.0 and 5.0. If necessary, adjust the pH using hydrochloric acid and sodium hydroxide. The excipients used in the preparation of pharmaceuticals have good compatibility with drugs, and the short-term formulation stability data shows acceptable results (see Table 42 below).table 41
– The recovery rate and purity (1% w / w solution) of Previvi in different solvents measured at t = 0 and after storage at the time point and temperature. Recovery rate compared with t = 0 value, n = 2, the range in parentheses, purity value, n = 1 table 42
– Short-term formulation stability studies Lightfastness evaluation
The formulations with and without the UV blocker octyl salicylate were exposed to UV light under ICH conditions (1.2 million lux hours and more than 200 watt hours / m²), and the determination of Previvi (Free base and mesylate
) Recovery rate and purity are summarized in the following table. It was observed that formulations containing pregaribic free base had a good percentage purity (> 99%) and did not seem to have the main advantage of incorporating octyl salicylate. However, formulations containing preliminol mesylate appeared to be unstable to UV light (the percent purity of prelimin mesylate ranged from 74 to 99%), and was observed when octyl salicylate was incorporated The percentage purity of pregaribic mesylate has increased dramatically (eg, about 74% to 98% in Cr12 and Cr12v2, respectively). However, care should be taken when interpreting these results, as these formulations were observed to behave similarly when incubated at 25 ° C without UV light for t = 2 and 4 weeks. Table 43 found that pregaribic free base is more stable to light stress conditions than mesylate.table 43
– The recovery rate (as a percentage of the theoretical concentration) and peak purity of pregaribic free base in the formulation at t = 0 and when exposed to UV light under ICH conditions. table 44
– The recovery rate (as a percentage of the theoretical concentration) and peak purity of pregaribe mesylate in the formulation at t = 0 and when exposed to UV light under ICH conditions.
In vitro skin penetration of formulations to select leading formulations: The experimental parameters used to evaluate the in vitro skin penetration and penetration of the developed formulations have been established during previous studies, so no further feasibility experiments were conducted as part of this study. The concentration of pregavir (and acyclovir) in various skin matrices was measured after t = 1 and 8 hours after application. A total of 7 formulations were selected for in vitro skin penetration and penetration experiments, which were selected based on the most promising candidates from short-term chemical stability experiments. When considering the amount of drug recovered from the epidermis at t = 1 hour, the following rankings were observed, however, there was no significant difference between any of these formulations (p> 0.05): O1v3> G8v3> Zovirax ( Acyclovir)> G15v1> G8> O2> G7v3.table 45
-After 1 hour of application of all formulations, the amount (ng) of pregavir and acyclovir recovered from the stratum corneum, part of the dermis and the receiving fluid. Data represents average+
SEM (n = 4 to 6)
Table 46-The amount (ng) of pregavir and acyclovir recovered from the stratum corneum, part of the dermis and the receiving fluid after 8 hours of application of all formulations. Data represents mean + SEM (n = 4 to 6)
The objective of the present invention is to have a target concentration of 10-20 nM of pregavir in the epidermis and part of the dermis. Unexpectedly, Table 47 confirms that the pregavir concentration in these skin layers exceeds the target by approximately 3,500 to 257,500 times.table 47
Table 47 shows the amount of pregavir and acyclovir recovered from the epidermis and part of the dermis after 1 hour and 8 hours. Based on data generated during in vitro skin penetration and penetration testing and supported by in vitro drug release data, short-term chemical stability data and in vitro skin irritation studies, O1v3 and G8v3 were selected as leading and alternate formulation candidates , GLP supply and ICH stability).In vitro drug release experiment
Determination of in vitro release of Pravivi from a total of 9 formulations and comparison with acyclovir from commercially available Zovirax®
(Acyclovir) Comparison of in vitro release. Figure 2 summarizes the entire data set, while Figure 3 focuses only on the formulations developed (for clarity, remove Zovirax®
). Since linear steady-state drug release occurs between 0 and 2 hours, Figure 4 shows another graph depicting the amount of drug released per unit area at t = 1 hour. At t = 1 hour, the following ranking of drug release from the formulation was observed, where the release of Prelivi's self-formulation O2 was statistically (p <0.05) better than that of O1v3, G7v3, and Zovirax®
The release of all formulations except (Acyclovir) is higher: O2 ＞ O1v3 ＞ G7v3 ＞ Zovirax ＞ G8v3 ＞ O3v4 ＞ G15v1 ＞ G8 ＞ G24 ＞ CR12 Each formulation is optimized for the thermodynamic activity of the drug (Purapril It is maintained in the formulation with a saturation limit of about 70 to 85%). These data indicate that the amount of drug released is driven by the concentration of pregavir in the formulation. Generally speaking, the higher concentration of pregavir results in a higher concentration of drug release. In addition to the percentage of the administered dose, the raw data value of the average cumulative amount released by the drug at t = 1 hour is also given in Table 48, and the following ranking is observed: G15v1> O2> O1v3> Zovirax®
＞ G7v3 ＞ G8 ＞ G8v3 ＞ O3v4 ＞ G24 ＞ CR12. This ranking standardizes the data and shows that although G15v1 releases less pregavir than a series of other formulations, it shows the drug release at t = 1 hour when compared to all other formulations. Higher efficiency. Although in vitro skin penetration and penetration experiments were conducted in conjunction with in vitro drug release, the data generated in this article seem to support the selection of G15v1, O2, O1v3, G7v3, G8 and G8v3 for evaluation.table 48 table 48 display
Previvi free base local preparation and Zovirax®
In contrast, the IVRT curve.In vitro skin irritation of topical formulations
In addition to the comparison (Zovirax®
Cold sore cream (Cold Sore Cream), 5% w / w acyclovir), this study evaluatedPrevivi free base
(PFB) andPrevivimethanesulfonate
(PMS) One series of gel, ointment and cream formulations (9 active agents and 9 placebo formulations) in vitro stimulation potential. The overall goal of this study is to generate in vitro stimulation data and to work with ongoing formulation stability, in vitro skin penetration / penetration, and drug release studies (252-1402-01 and 252-1402-02) to assist in selection Leading candidate formulations in Previvi. The reconstructed human epidermal (RHE) culture (EpiDerm ™) used in this study is a three-dimensional organ type in vitro skin model derived from normal human cells. The method used in this study was based on MatTek's detailed ET-50 (exposure time required for chemicals to reduce viability to 50% of control) analysis, which allows quantitative measurement of the irritancy of the test substance. During this study, the irritant potential of 19 formulations in a full scale in vitro skin irritation study was successfully evaluated. Feasibility experiments show that all developed formulations (active agent and placebo formulations) are observed to interact with MTT (standard MTT test for phototoxicity studies). In addition, studies have shown that BHA and BHT are excipients that cause MTT interactions because they are common to all test formulations. Zovirax® cold sore cream 5% w / w acyclovir was also studied and showed no interaction with MTT. A small-scale in vitro irritation experiment was then conducted using O10 (PFB) active agent and placebo as selected formulations, which showed no irritation (ET-50> 24 hours). This small-scale experiment included frozen (non-viable) (non-viable) RHE tissue controls and showed some interaction with MTT (both <6%). The results of these feasibility experiments led to the optimization of a comprehensive in vitro skin irritation experiment protocol. Therefore, frozen (inactive) control RHE tissue was only incorporated at the time point of t = 6 hours. This enables background subtraction to account for any MTT reduction of any residual formulation present in the RHE tissue. A comprehensive in vitro skin irritation experiment showed that the formulations tested ranged from moderate / mild to no irritation, with the active agent formulations performing similarly to the placebo formulations. Table 49 lists a summary of the ET-50 values for each formulation studied. After administration of the developed formulation and comparator, the cell viability of RHE tissue confirmed that three of these formulations (G8 (PFB), O2 (PFB), and Cr12 (PFB)) during the experiment (t = 2 , 6 and 24 h) had no significant effect on the vitality of RHE organization. Therefore, it is impossible to calculate the exact ET-50 value, and therefore the formulations are considered non-irritating. Conversely, G24 (PFB) showed the greatest stimulatory potential (ET-50 <6 h). The performance of the formulations with the lowest irritant potential (G8 (PFB), O2 (PFB) and Cr12 (PFB)) is comparable to the commercially available Zovirax®
Cold sore cream 5% w / w acyclovir is similar. Therefore, this feasibility study showed that all the formulations studied (both active and placebo) showed mild to strong interaction with MTT. This warrants further research, which evaluates the interaction of BHA and BHT with MTT, as all formulations contain BHA or BHT. A slight interaction with BHA was observed, and a strong interaction with BHT was observed, indicating that BHA and BHT caused the observed interaction. Because of these findings, a frozen (inactive) RHE tissue control was added to a small-scale in vitro stimulation study to explain the interaction between any residual formulation remaining on the surface of the RHE tissue and MTT. No Zovirax found®
Cold sore cream 5% w / w acyclovir (control item 1) interacts with MTT. Small-scale in-vitro irritancy studies indicate that the O10 (PFB) active agent and placebo formulations are non-irritating (ET-50> 24 h), and show that the time points and MTT analysis methods used are sufficient for comprehensive experiments. In addition, the residual formulation present in the treated RHE tissue showed some interaction with MTT, as demonstrated by the viability of frozen (inactive) control RHE tissue (all <6%). A comprehensive in vitro irritation study showed that the formulations tested ranged from moderate / mild to no irritation. The performance of the active formulations is similar to the respective placebo formulations studied. The formulations showing the lowest stimulation potential are G8 (PFB), O2 (PFB), and Cr12 (PFB), because the performance of these formulations is comparable to the commercially available Zovirax®
Cold sore cream 5% w / w acyclovir (control item 1) is similar. The most irritating formulation is G24 (PFB) (ET-50 <6 h).table 49
– The selected formulation and Zovirax®
(Control Item 1) ET-50 calculated value With recovery period and toxicokinetics in miniature pigs 1 Monthly toxicity study
The study assessed when locally administered to miniature pigs twice a day for 4 consecutive weeksPrevivi free base
Toxicity and toxicokinetic curves, and to evaluate the reversibility of the side effects of the test items during the 2-week recovery period. A total of 38 Göttingen miniature pigs (19 males and 19 females; Ellegaard Göttingen Minipigs A / S) were used in the study. Approximately 1%, 5% or 10% of the total skin surface area is applied to the animal's back by tattooing. Animals were dosed according to the schedule below (Table 50).table 50
Table 50 above shows the research plan for the 1-month toxicity study in miniature pigs. Assess the following criteria: mortality, clinical symptoms, weight, food consumption, electrocardiogram, eye examination, clinical pathology (including hematology, blood chemistry, and urine analysis), full autopsy (including treatment and untreated skin Macroscopic observation), organ weight and histopathology. Blood samples for toxicokinetic evaluation were collected at 6 different time points on day 1 and day 28. In addition, check the response of the administration site to treatment, and score erythema, edema and other skin reactions. No relevant changes in the test project. Among them, the local administration of 5% previviol O1v3 free base twice a day for 4 weeks was well tolerated. No skin reactions or systemic toxicity related to the test items were observed.on O1V3 Formulation ( Clinical formulations ) Further research - Lightfastness test
The lightfastness test of the formulations shows that PuraLevi is stable after direct exposure to UV light in accordance with ICH guidelines Q1B (providing total lighting of not less than 1.2 million lux hours and not less than 200 watt hours / square meter). The following table 51 summarizes the recovery rate and impurity concentration of pregarib: Table 51-Results of light resistance test
In the above Table 51, "t = 0" represents the sample before light stress exposure. Standard ICH conditions are used for light stress studies. Although Prapirate mesylate is light-sensitive, light-stable topical formulations can be developed using free bases instead of using light blockers.Forced degradation test
get onPrevivi free base
The forced degradation test (to further assess specificity and ensure the stability of the HPLC method indicates stability), expose it to heat, light, oxidation, acid and alkali (Table 52). Table 52-Results of the forced degradation test of pregaribic free base
a pH adjusted to 8 for alkaline hydrolysisIn vitro drug release test
Franz diafiltration cells (Figure 5) were used to test the in vitro drug release of Pralivi self-formulation. During the development study, 2% w / v Brij 98 contained in phosphate buffer solution (PBS) was determined as a suitable receiving solution for the analysis of samples from in vitro skin penetration experiments by HPLC1. For the purpose of in vitro release testing, the same receiving solution is used. Table 53 provides data on the stability of pregarib at 2% w / v Brij 98 in PBS. Table 53-Stability of free base hemihydrate in receiver fluid, quantified by HPLC. Each value represents the average recovery rate compared with the value obtained at t = 0, where the brackets are the range and n = 3.
It was observed that the saturation solubility of Prelivi in 2% w / v Brij 98 in PBS was 0.02% w / w. To avoid exceeding the sink condition during the in vitro drug release test, the entire contents of the receiving fluid were removed at each time point. The samples were analyzed by HPLC. Figure 6 below shows a graph of the in vitro release test (IVRT) of the formulation.In vitro skin penetration and penetration testing
An in vitro skin penetration and penetration test was conducted to estimate the penetration of Previvi through and into human skin after application of the formulations described herein. Fig. 7 depicts the recovery rate of pregarib from the stratum corneum, epidermis and dermis at t = 1 hour and t = 8 hours.Process
： Figure 8 below shows the flow chart of the method of 5% ointment of Previvi. For a batch size of 6 kg, the process is described by way of example: 0.1 M hydrochloric acid is contained in Super RefinedTM
Preparation of PEG 400. Combine 1.75 g hydrochloric acid, 37% with 198.25 g Super RefinedTM
The PEG 400 was mixed and stirred until a visually homogeneous solution was obtained. 0.1 M sodium hydroxide contained in Super RefinedTM
Preparation of PEG 400. Combine 0.40 g sodium hydroxide with 112.55 g Super RefinedTM
The PEG 400 was mixed and stirred until a visually homogeneous solution was obtained. Preparation of PEG 4000 phase. Weigh 1050.00 g of PEG 4000 into a stainless steel container labeled PEG 4000 PHASE (PEG 4000 phase) and place the container in a water bath at approximately 65 ° C. Heat (target temperature: about 65 ° C) and stir until significant melting is observed.Final formulation preparation
: Weigh 3948.60 g Super RefinedTM
PEG 400 and 6.00 g butylated hydroxytoluene in a stainless steel container marked FINAL FORMULATION (final formulation). Place the vessel in a water bath at approximately 40 ° C and stir until the BHT is completely dissolved. The solvent is subsequently removed from the water bath. Will 586.80 g propylene glycol and 306.60 gPrevivi Hemihydrate
Add to the obtained solution. After transferring the container to a water bath of about 65 ° C, the contents of the container were heated until the prestigious hemihydrate dissolved while continuing to stir the solution. Then add 102.00 g 0.1 M hydrochloric acid solution contained in Super RefinedTM
PEG 400. The contents of the container are heated until reaching a temperature of about 65 ° C while continuously stirring the solution. Once the contents in both containers have reached the target temperature, transfer the contents of the container labeled PEG 4000 PHASE to the container labeled FINAL FORMULATION. Remove the container labeled FINAL FORMULATION from a water bath at approximately 65 ° C, place it in a water bath at approximately 40 ° C and stir until the contents of the container reach approximately 40 ° C. The container was then transferred to a water bath at approximately 25 ° C and the formulation continued to be stirred until an off-white sticky ointment was observed. Measure the pH of the formulation. If the pH exceeds the limit of 4.0 to 5.0, add 0.1 M hydrochloric acid drop by drop to Super RefinedTM
PEG 400 (for lowering pH) or 0.1 M sodium hydroxide contained in Super RefinedTM
PEG 400 (for increasing pH) to adjust the pH. The formulation was stirred during pH adjustment. Record the final pH and the weight of the added solution. Calculate the Super Refined required to get a total of 100%TM
The amount of PEG 400. Add calculation amount of Super RefinedTM
PEG 400 while continuing to stir. Record the added Super RefinedTM
The weight of PEG 400. When the formulation reached ambient temperature (15 ° C to 25 ° C), the stirring was stopped and the container was removed from the water bath. [IPC bulk formulation-top + middle + bottom]. If it needs to be left overnight, put a lid on the container and seal with a laboratory film. The bulk material is kept at a controlled ambient temperature until filling. Ideally, the filling system is completed the day after the preparation is completed. For the Phase 1 trial, a 100 ml amber glass vial was used, and for the Phase 2 trial, the ointment was filled into aluminum tubes. Table 54-In Process Control
Table 54 above shows the control in the process used in the preparation of topical ointment formulations.Used to analyze the specifications of drugs
Table 55 provides the quality control specifications for Prelivi's 5% w / w ointment. These specifications are preliminary specifications and will be reviewed as more batches of data are generated. Table 55 – Quality Control Specifications
a: Reporting level: 0.05% TAMC: total aerobic microorganisms; TYMC: total yeasts and molds; CFU: colony forming units The above table 55 shows the quality control specifications for local ointment formulations.Appearance: visually judge the appearance.
Microscopic appearance: The optical appearance of the formulation was evaluated using an optical microscope with 400x magnification. Both polarized and unpolarized light are used to check the presence of crystalline materials. Prelivi's Identification, Analysis and Related Substances (HPLC): For identification, compare the retention time of the Prelivi peak in the sample chromatogram with the retention time of the Prelivi peak in the reference chromatogram , And compare the UV spectrum extracted from the Prelivi peak of the sample chromatogram with the UV spectrum extracted from the reference standard chromatogram. Quantitative determination analysis using external standards. The reporting level is set at 0.05% area / area.BHT Identification and quantification (HPLC)
An external standard was used to quantitatively determine the analysis of BHT. The HPLC method was used to estimate the BHT content. Apparent pH: The apparent pH was measured according to USP <791>. Apparent viscosity: Apparent viscosity was measured using a Brookfield viscometer (Spindle E, helipath, 0.6 rpm, 25 ° C, 2 minutes for reading).Microbiological quality
Microbiological quality tests were conducted in accordance with USP <61> and <62> and European Pharmacopoeia 2.6.12 and 2.6.13, respectively. Antimicrobial effectiveness test Antimicrobial effectiveness test was conducted according to USP <51>.Batch analysis.
The results of the different batch analyses are shown in Table 56 below Table 56 – Batch analysis of Pralivi 5% ointment for clinical trials
Table 57-Batch analysis of Prelivi 5% ointment for clinical trials
TAMC: number of total aerobic microorganisms; TYMC: number of total yeasts and molds; CFU: colony forming unit a Reporting level: 0.05% b Spindle E, helipath, 0.6 rpm, 25 ° C, 2 minutes after reading. Table 57 shows clinical Batch analysis of Prelivi 5% free base hemihydrate used in the experiment. Table 58 – Bulk analysis of Prelivi's 5% w / w ointment
Table 58 above shows the batch analysis of 5% w / w pregavir free base hemihydrate ointment. Table 59 – Bulk analysis of Prelivi 5% w / w ointment
Table 60 – Bulk analysis of Prelivi 5% w / w ointment
TAMC: number of total aerobic microorganisms; TYMC: number of total yeasts and molds; CFU: colony forming unit a Reporting level: 0.05% b Calculate the sum of related substances using unrounded results of individual related substances d Spmdle E, helipath, 50 rpm, 25 ° C Note: Batches 7264/001 and 7277/001 contain 4.89% pregavir (free base) instead of 5%, due to the hemihydrate form of the drug (see section 3.2.P.2,2,3, Table 1). This system was revised in the phase II clinical preparation, in which the API concentration was adjusted so that the final product contained 5% pregavir (free base), see section 3.2.P.1. The HPLC method used to test GLP batches (Purelivi's identification, analysis and related substances) is partly different from the HPLC method used to test GMP batches.ICH Stability data: stability in aluminum tubes
At 25 ° C / 60% RH and 40 ° C / 75% RH, a technical batch of Previvi 5% packaged in a 2 g foldable aluminum tube with screw cap (type: flower pot perforator cover) w / w ointment for stability studies. Table 61-Stability at 25 ° C / 60% RH Time point (month)
an = 2 b Original analysis method c Advanced analysis method Note: After t = 3 months, a slightly different HPLC method (called "original analysis method") is used to test the identification, analysis and related substances of Previvi After that, the modified HPLC method is used (see section 3.2.P.5.2, called "Advanced Analysis Method"). Table 62-Stability at 40 ° C / 75% RH Time point (month)
a Original analysis method b Advanced analysis method cn = 2 Note: After t = 3 months, a slightly different HPLC method (called "original analysis method") was used to test the identification, analysis, and related substances of Previvi After that, the modified HPLC method is used (see section 3.2.P.5.2, called "Advanced Analysis Method"). Table 63-Stability data in use
TAMC: number of total aerobic microorganisms; TYMC: number of total yeasts and molds; CFU: colony forming units. Table 63 above shows the in-use stability data for local formulations of 5% w / w pregarib free base hemihydrate.Stability in glass bottles ( Previous package )
The stability results obtained from one technical batch and one GMP batch are described in detail below. Both batches contain 4.89% pregavir (free base) instead of 5%, due to the drug ’sHemihydrate form
. This system was revised during the phase II clinical preparation, in which the API concentration was adjusted so that the final product contained 5% pregavil (free base). These batches are packaged in screw-capped 100 mL amber glass bottles. The technical batch specifications are slightly different from the GMP batch specifications. Except for indicating the identification, analysis and related substances of pregarib, and in addition to testing the apparent viscosity (Brinell viscometer, Spindle E, helipath, 50 rpm, 25 ° C), the test methods are listed above By. The stability in use results obtained are also provided. Table 64-Stability at 25 ° C / 60% RH Time point (month)
Table 65
a At least test the beginning and end of the stability study. RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming units. Table 65 above shows the results of the MQT test for local formulations. Table 66 – Stability at 25 ° C / 60% RHPoint in time ( month )
Table 67 – Stability at 40 ° C / 75% RHPoint in time ( month )
Table 68Point in time ( month )
a At least test the beginning and end of the stability study RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming units Table 69Point in time ( month )
a At least test the beginning and end of the stability study RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming unit Note: after t = 4 months, use slightly Different HPLC methods (referred to as "original analysis methods") to test the identification, analysis and related substances of Previvi, and thereafter use modified HPLC methods (see section 3.2.P.5.2, called "advanced analysis methods" ). Table 70-Stability data in usePoint in time ( day )
Table 70 above shows the in-use stability data of the local formulations filled in the tubes. Table 71 – Stability at 40 ° C / 75% RHPoint in time ( month )
a Reporting level: 0.05% b At least test the beginning and end of the stability study RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming unit table 72 – at 25 ° C / Stability at 60% RHPoint in time ( month )
a Reporting level: 0.05% b At least test the beginning and end of the stability study RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming unit table 73 – at 40 ° C / Stability at 75% RHPoint in time ( month )
a Reporting level: 0.05% b At least test the beginning and end of the stability study RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming unit table 74 – at 40 ° C / Stability at 75% RHPoint in time ( month )
a Reporting level: 0.05% b At least test the beginning and end of the stability study RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming unit table 75–at 40 ° C / Stability at 75% RHPoint in time ( month )
a Reporting level: 0.05% b At least the beginning and end of the stability study c OOS: Two-thirds of the sample extracts analyzed resulted in BHT levels below the nominal 90.0% low acceptance limit (89.7%, 91.6%, 89.8%) RRT: relative residence time; TAMC: total aerobic microorganisms; TYMC: total yeast and molds; CFU: colony forming unit example 2Maleate solubility
Table 76-Solubility of maleate in water and corresponding formulation vehicles
Table 77-Solubility of maleate in topical formulation matrix
(-) The client has not requested an evaluation, * pH is 8.42, ** pH is 2.65 * SS01 represents the formulation matrix used in the current clinical formulationStability of maleate
As shown in Table 78 below, the maleate shows better stability in SR PEG 400 than PEG 400. Table 78-The recovery rate of Pravivir maleate in PEG400 and SR PEG 400 at t = 0 and after storage at 40 ° C and 50 ° C for t = 2 and 4 weeks (data are expressed as average, The brackets are the range; n = 3). Examples 3 : Comparative solubility of free base, mesylate and free base hemihydrate in individual excipients
The free base hemihydrate shows higher solubility, where one batch of free base is comparable to the second batch. Therefore, all data obtained for the free base can be extrapolated to the solubility of the free base hemihydrate. Table 79: Saturated solubility (% w / w), average value (range, n = 3) of two forms of Pravicarb (batch BXR2KVE and M023862-CA15-033) in PEG 400 and propylene glycol.
* Measured during 252-1402-01.Current clinical formulations O1v3 Light resistance test
The lightfastness test of the leading formulation (O1v3) in 252-1402-01 showed that Prelivi free base (batch BXR2KVE, test item 1) was stable to exposure. An additional light fastness test (M023862-CA15-033, test item 2) was carried out on O1v3 containing Prasulvi hemihydrate to confirm that the formulation prepared using Prasulvivir in this form was stable after exposure. The samples of filled borosilicate vials containing O1v3 were exposed to light in accordance with ICH guidelines Q1B, and the recovery and purity levels of previrib were summarized in Table 80 and Table 81, respectively. The data shows that after exposure to UV light, Prelivi in the formulation (O1v3) appears to be stable because the recovery and purity of Prelivi has little change compared to when t = 0. This support was previously at 252- The observations made in 1402-01. The slight difference in average purity level can be attributed to related substances that are close to the LOQ of the analytical method. Table 80: According to ICH guideline Q1B, the average recovery (%) of pregaribir hemihydrate at t = 0 and after exposure to UV light (range, n = 3).
In the above Table 80, "T = 0" represents premixed hemihydrate (%) formulations before light stress exposure conditions. Table 81: According to ICH guideline Q1B, the average purity level (% a / a) of pregaribir hemihydrate at t = 0 and after exposure to UV light (range, n = 3).
In the above Table 81, "T = 0" represents the formulation of Previvir Hemihydrate (% a / a) before light stress exposure conditions.Difference in solubility between pregaribic free base and mesylate
Table 82 below shows the composition of the solvent system used to evaluate the solubility of free base and mesylate:
(-): Not included Table 83-Solubility of Prelivi free base and mesylate in the solvent system
* Please ignore the data of lidocaine and hydrocorticosterone. Obviously, the free base shows significantly higher solubility in the solvent system used.Short-term stability of free base and mesylate in individual excipients and solvent systems
Both the free base and the mesylate dissolved in the individual excipients and solvent system were subjected to 2 and 4 weeks at 40 ° C and 50 ° C. The stability of the free base in different solvent systems at 40 ° C and 50 ° C for 2 and 4 weeks. Table 84-Measured at t = 0 and after storage at the time point and temperaturePrevivi free base
Recovery rate and peak purity in solvent. The recovery rate compared with the t = 0 value, n = 2, the range in parentheses (analysis method). Peak purity value, n = 1 (impurity method).
Table 85 shows the stability of maleate base in different solvent systems at 40 ° C and 50 ° C for 2 and 4 weeks:
The solubility of the free base and the mesylate salt can be seen to be significantly different in different vehicle systems under similar conditions.Solubility of free base and mesylate in photoblockers
As shown in Table XX above, the free base shows higher solubility in octyl salicylate (photoblocker) compared to mesylate. Table 86-Saturated solubility of previrib (free base and mesylate) in octyl salicylate. The value represents the average value, where the brackets are the range, n = 3. Differences in solubility of free base and mesylate in different solvent systems
Evaluate the solubility of free base versus mesylate in different solvent systems used to develop ointment formulations. As shown in Table 87 below, the free base shows higher solubility in octyl salicylate (photoblocker) compared to mesylate. Therefore, only 5% ointment formulations containing pregaribic free base without its mesylate salt can be developed. Keeping the drug in a dissolved form has a significant effect on the rate of penetration of the drug through the skin, and ultimately on the efficacy when applied topically. Table 87-Saturated solubility of Previvi free base and mesylate in the solvent system used to develop the ointment.
(-): Not included, ND: Not determined, * The remaining amount will be PEG4000 of the final formulation.Short-term stability data of the formulation of the present invention containing Pravivir free base and mesylate
The formulation containing pregaribic free base and mesylate was subjected to 40 ° C and 50 ° C for 4 weeks. When compared to mesylate, the free base system was found to be relatively stable. Table 88-Percent Purity of Free Base in the formulation at t = 0 and after storage at 25 ° C and 40 ° C for t = 2 and 4 weeks, n = 1.ND: Not determined Table 89-Percent purity of pregarib mesylate in the formulation at t = 0 and after storage at 25 ° C and 40 ° C for t = 2 and 4 weeks, n = 1.ND: Not determinedLong-term stability data of current clinical formulations
Generated containsFree base hemihydrate
The 24-month stability data of the local formulation O1V3, where the drug is in dissolved form (5% drug loading) and the formulation is stable in terms of analysis, purity, pH, viscosity. The following table shows the 90-month stability of the topical formulation O1V3. Table 90-O1v3, 5% stability test results packaged in borosilicate vials at 25 ° C / 60% RH and 40 ° C / 75% RH Stability of free base and mesylate formulations under light stress in the presence and absence of light blockers
According to the ICH guidelines, topical formulations of Pravivir free base and mesylate with and without photoblockers are subjected to UV-stress conditions. From this, it was found that the free base is stable to light stress conditions in the presence and absence of a light blocker. However, in most cases, pregaribic mesylate is only stable in the presence of a light blocker. Table 91-The recovery rate (as a percentage of the theoretical concentration) and peak purity of pregaribic free base in the formulation measured at t = 0 and when exposed to UV light under ICH conditions.
Table 92-The recovery rate (as a percentage of the theoretical concentration) and peak purity of pregarib mesylate in the formulation measured at t = 0 and when exposed to UV light under ICH conditions. Comparative solubility of free base and free base hemihydrate in individual excipients
The free base hemihydrate showed a higher solubility than the two batches of free base. Therefore, all data obtained for the free base can be extrapolated to the solubility of the free base hemihydrate. The following table 93 shows the saturated solubility (% w /) of the two forms of Pravicarb (free base batch is BXR2KVE and Pravivi free base hemihydrate is M023862-CA15-033) in PEG 400 and propylene glycol w), average (range, n = 3).Table 93 Lightfastness testing of current clinical formulations
Current clinical formulations include the following excipients and active ingredients (unit% w / w): – Super RefinedTM
PEG 400 55.00 –0.5 M NaOH / HCI to achieve a pH of 4 to 5 –Super RefinedTM
PEG 400 (second addition) Appropriate amount of 100% – Propylene glycol 9.78 – BHT 0.10 – PEG 4000 17.50 – Prelivi free base hemihydrate 5.0 Lightfastness to the above clinical formulation containing prelivi free base hemihydrate Performance test to confirm that the formulations prepared using this form of pregavir are stable after exposure. The samples of filled borosilicate vials containing this clinical formulation were exposed to light in accordance with ICH guidelines Q1B, and the recovery and purity levels of pregavir free base hemihydrate were summarized in Table 94 and Table 95, respectively. The data shows that after exposure to UV light, the prelivi free base hemihydrate in this clinical formulation appears to be stable because the recovery rate and purity of prelivi free base hemihydrate is almost the same as when t = 0 No change, this supports the observations made previously in 252-1402-01. The slight difference in average purity level can be attributed to related substances that are close to the LOQ of the analytical method.table 94
： According to ICH Guide Q1B, the average recovery rate of Prelivi free base hemihydrate at t = 0 and after exposure to UV light (%) (range, n = 3) table 95
: According to ICH guidelines, the average purity level (% a / a) of pregaribic free base hemihydrate at t = 0 and after exposure to UV light (range, n = 3) Provide current clinical formulations at 25 ℃ / 60% RH Under twenty four Monthly long-term stability data:
The 24-month stability data of the current clinical formulation containing pregarib free base hemihydrate in dissolved form as active pharmaceutical ingredient has been generated, in which pregavir free base as active part has 5% w / The drug loading equivalent of w, and it is found that the respective local formulations are stable in terms of analysis, purity, pH and viscosity. This formulation is from Super Refined with an apparent pH of 4.0 to 4.5 (adjusted during the process)TM
PEG 400 composition. Table 96 below shows the 24-month stability data for each of the current clinical formulations. Table 96 a) -c): Provides long-term stability data of the current clinical formulations containing 5% w / w pregavir free base hemihydrate at 25 ° C / 60% RH for 24 months. Table 96 a): Clinical formulations containing 5% w / w pregaribic free base hemihydrate – stable in borosilicate vials at 25 ° C / 60% RH and 40 ° C / 75% RH Sex test results (batch number: BMR7264 / 001).
Table 96 b): Medicinal formulations containing 5% w / w pregaribic free base hemihydrate, medium packaged in borosilicate vials at 25 ° C / 60% RH and 40 ° C / 75% RH Agent stability test results (batch number: BMR7263 / 001).
Table 96 c): Summary of long-term stability data at 25 ° C / 60% RH for 24 months. PEG 400 Effect of level:
Use PEG 400 with Super RefinedTM
PEG 400 versus 4 weeks of stress conditions at 40 ° C and 50 ° C in the form of presolivi® in dissolved form. As shown in Table 97 below, compared to Super RefinedTM
PEG 400, when the Prelivi drug system is dissolved in PEG 400, the degree of degradation is significantly higher.table 97 : When used PEG 400 versus Super Refined TM PEG 400 Compared with the preparation, the recovery rate and peak purity of Previvi free base The medium pH Impact:
Using pre-treated PEG 400 with and without adjusting the pH to 4.0, Pravivir in dissolved form was subjected to 4-week stress conditions at 40 ° C and 50 ° C. As shown in Table 98 below, compared to pH 4.0, when the pregavir drug system was dissolved in PEG 400 without any pH adjustment, the degree of degradation was significantly higher. Therefore, it can be said that when the pH is in the acidic range (ie, 4.0 to 4.5), the pregavir drug in a dissolved form shows higher stability. From the perspective of physiological acceptability, pH 4.0 is the lowest acceptable pH. Table 98-Purelivi free base recovery and peak purity when tested for different apparent pH
Based on the data obtained, it can be said that the presence of oxidized impurities (eg, by PEG 400) and neutral pH are detrimental to the stability of the prerelease drug in dissolved form. Therefore, when receiving long-term stability studies (6 months at 40 ° C / 75 RH and 24 months at 25 ° C / 60%), use Super Refined at pH 4.0 to 4.5TM
The topical formulation of the present invention in combination of PEG 400 and BHT (as an antioxidant) proved to be sufficiently stable.Lightfastness of current clinical formulations:
Prelivix in dissolved form is sensitive to light stress conditions, however, surprisingly and unexpectedly, current clinical formulations are stable to light stress conditions. These findings also explain Super RefinedTM
PEG 400, BHT, and pH 4.0 to 4.5 stabilize the effect of Prairivavir against light stress conditions.table 99- Lightfastness of current clinical formulations PEG 400 versus Super Refined TM PEG 400 Compare the effect of using in the ointment formulation of the present invention
The current clinical formulations of ointment formulations use standard PEG 400 and Super RefinedTM
PEG 400 was prepared using the same method and composition. These test formulations were stored at 40 ° C / 75% RH for 2 months.table 100- use Super Refined TM PEG 400 and BHT in pH 4.0 The stability data of current clinical formulations table 101- Use standard PEG 400 , BHT and pH 4.0 Stability data of current clinical formulations
As shown in Tables 100 and 101 above, use standard PEG 400 instead of Super Refined PEGTM
400 results in increased impurities after 2 months of storage (although the formulation contains BHT and the pH is 4.0). Therefore, Super RefinedTM
The combination of PEG 400 and BHT and its effect at pH 4.0 are very important for stabilizing the drug and preventing it from undergoing any oxidative degradation (when it is present in dissolved form).no pH The effect of regulation:
The current clinical formulations in the form of ointment formulations use Super RefinedTM
PEG 400 is prepared using the same method and composition without any pH adjusting agent. It is stored at 40 ° C / 75% for 2 months.table 102- use Super Refined PEG TM 400 , BHT And none pH Stability data of current clinical formulations adjusted
As shown in Table 102 above, the absence of pH adjustment resulted in significant degradation of Previvi (about 24% degradation within 2 months at 40 ° C / 75 RH). Therefore, according to the present invention, the adjustment of the pH to 4.0 to 4.5 is very critical for the stability of pregavir in the dissolved state or dissolved form.PEG 400 Level and none pH Moderating effects
The current clinical formulations as ointment formulations are prepared using standard PEG 400 and without the need for any pH adjustment using the same method and composition. It is stored at 40 ° C / 75% RH for 2 months.table 103- Use standard PEG 400 , BHT And none pH Stability data of current clinical formulations adjusted
As shown above, the absence of pH adjustment and the use of standard PEG 400 resulted in significant degradation of pregaribil (degradation of approximately 88.6% within 2 months at 40 ° C / 75%). Therefore, the pH is adjusted to 4.0 to 4.5 with Super Refined PEGTM
The combination of 400 is very critical for the stability of pregavir in the dissolved state or dissolved form.BHT Effect as an antioxidant
The current formulations of ointment formulations in clinical formulations use Super RefinedTM
PEG 400, pH adjusted to 4.0 to 4.5 but without any BHT was prepared using the same method and composition. It is stored at 40 ° C / 75 RH for 2 months.table 104- use Super Refined TM PEG 400 and BHT , pH Adjust to 4.0 to 4.5 But nothing BHT Stability data of current clinical formulations
As shown in Table 104 above, the removal of BHT from the current chlorine ointment formulation resulted in increased impurities after 2 months of storage (although the formulation contained Super Refined PEGTM
400 and pH 4.0). Therefore, Super RefinedTM
The combination of PEG 400 and BHT and the effect of pH 4.0 to 4.5 are very important for stabilizing the drug in a dissolved state or dissolved form.