TW202214247A - 陰道凝膠 - Google Patents
陰道凝膠 Download PDFInfo
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- TW202214247A TW202214247A TW110116778A TW110116778A TW202214247A TW 202214247 A TW202214247 A TW 202214247A TW 110116778 A TW110116778 A TW 110116778A TW 110116778 A TW110116778 A TW 110116778A TW 202214247 A TW202214247 A TW 202214247A
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- Prior art keywords
- metronidazole
- composition
- terconazole
- gel
- present
- Prior art date
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- 239000000029 vaginal gel Substances 0.000 title description 4
- 229940044950 vaginal gel Drugs 0.000 title description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229960000282 metronidazole Drugs 0.000 claims abstract description 66
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 claims abstract description 49
- 229960000580 terconazole Drugs 0.000 claims abstract description 49
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
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- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
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- KGVBVOYQIKFIGA-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound CN(C)C.CN(C)C KGVBVOYQIKFIGA-UHFFFAOYSA-N 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本發明係關於一種具有凝膠樣稠度之組合物,其包含甲硝唑(metronidazole)、特康唑(terconazole)、生理上可接受之增稠劑及水。該組合物可用於治療細菌性陰道炎以及外陰陰道念珠菌病。
Description
本發明係關於針對細菌性陰道感染之組合物及治療。
細菌性陰道炎(BV)係育齡婦女最常見的陰道病症之一。BV之特徵係陰道菌群(vaginal flora)之變化,藉此陰道乳酸桿菌(Lactobacilli)之正常菌群下降且取而代之的是兼性且厭氧之細菌(諸如陰道加特納菌(
Gardnerella vaginalis)、奇異菌屬(
Atopobium)、普雷沃菌屬(
Prevotella)、擬桿菌(
Bacteriodes)、消化鏈球菌屬(
Peptostreptococcus)及動彎桿菌(
Mobiluncus)物種)之過度生長。
BV與增加量之具有惡臭、魚腥味之陰道排出物(discharge)之相關。陰道pH自正常範圍(pH 3-4)升高至大於約pH 4.5之值。異味及升高之pH係由陰道中高含量之胺,最顯著的是三甲胺三甲胺引起。當pH升高時,例如,隨著添加KOH或與精液相互作用,此等胺揮發。
通常,若存在以下四個臨床標準(稱為安塞爾(Amsel)標準)中之三者或更多者,則作出BV之臨床診斷:(1)異常排出物;(2) pH值大於或等於約4.5;(3) 在添加10% KOH至排出物後「魚腥味」胺惡臭;(4)基於陰道流體濕抹片(wet mount)之顯微鏡檢查,存在大於或等於約20%之陰道上皮細胞之量的上皮線索細胞(其中該細胞邊界經細菌遮掩)。
通常用具有針對厭氧生物之活性之抗細菌劑(例如甲硝唑(metronidazole)或克林達黴素(clindamycin))治療BV。甲硝唑係常用且可以口服錠劑、及陰道霜劑及凝膠兩種形式使用。通常以陰道劑型為較佳,因為其限制全身暴露於藥物,同時提供高局部抗細菌劑濃度。例如,用於治療BV之典型口服甲硝唑劑量為500毫克,每天兩次持續7天,而甲硝唑0.75%陰道凝膠一般以每天一次含有37.5毫克甲硝唑之5公克凝膠的劑量使用五天。投與單次劑量之含有37.5毫克甲硝唑之甲硝唑0.75%凝膠後之藥物動力學特性顯示血液含量(Cmax 237 ng/ml及AUC 4,977 ng*hr/ml)遠低於標準口服500毫克錠劑後之血液含量(Cmax 12,785 ng/ml及AUC 133,395 ng*hr/ml)。
外陰陰道念珠菌病(Vulvovaginal candidiasis;VVC),亦稱為酵母陰道炎,是特徵係酵母過度生長之另一常見陰道感染。VVC之主要症狀係陰道及/或外陰之瘙癢、灼痛及刺激。相關徵兆包括紅斑、水腫及表皮脫落(excoriation)。在大多數病例中,白色念珠菌(
Candida albicans)係病因性病原體。念珠菌生物可經培養或基於陰道流體之濕抹片檢查見到。
通常用具有針對念珠菌物種之活性之唑類抗真菌劑治療VVC。劑型包括口服三唑(諸如氟康唑(fluconazole))及含有唑類(諸如咪康唑(miconazole)、克黴唑(clotrimazole)及特康唑(terconazole))之陰道霜劑或栓劑。
在一些情況下,女性患者同時罹患BV及外陰陰道念珠菌病(VVC)。微生物學研究已指示,多達15%的經歷陰道感染之婦女共同感染BV生物體以及酵母(諸如念珠菌)。在此種情況下,成功的治療需要使用超過一種藥物,治療BV之抗細菌劑及治療VVC之抗真菌劑。通常此種治療由口服劑型(諸如口服甲硝唑)及陰道劑型(諸如咪康唑霜劑)組成。
對於用於治療陰道感染之局部作用之抗細菌及抗真菌藥物,藥物自調配物釋放之程度及時序係重要的。尤其是在考慮容易跨陰道黏膜吸收之藥物(諸如甲硝唑)時,藥物動力學特性在一定程度上反映藥物自調配物釋放之程度及時序。
例如,用於治療BV之兩種市售水基陰道凝膠顯示相似藥物動力學特性,即使其每劑包含不同量之藥物。含有65 mg甲硝唑/劑之1.3%甲硝唑陰道凝膠產生血液含量(Cmax 239 ng/ml及AUC 5,434 ng*hr/ml),其幾乎與包含37.5 mg/劑之0.75%甲硝唑凝膠相同。(Cmax 237 ng/ml及AUC 4,977 ng*hr/ml)。
本發明提供用於治療BV以及VCC之甲硝唑及特康唑之獨特凝膠調配物。出人意料地,當抗真菌劑特康唑與抗細菌劑甲硝唑一起調配時,此種組合展現當與單獨抗細菌調配物相比時增強之抗細菌生物利用度。此種增強之生物利用度亦已顯示當與單獨抗細菌劑相比時有利於治療同時患有BV及VVC的婦女之BV。
一種用於治療細菌性陰道炎(BV)且提供增強之甲硝唑生物利用度之治療組合物(諸如陰道凝膠)除甲硝唑外還包含特康唑、生理上可接受之增稠劑及緩衝體系,該緩衝體系為組合物提供在約3.75至約4.25之範圍內之經緩衝pH值。甲硝唑與特康唑之相應莫耳比較佳在約3至約4之範圍內,更佳係約3.5。
定義
術語「緩衝體系」或「緩衝液」如本文中及隨附申請專利範圍中所用係指當溶解於水中時使所得溶液穩定抗添加酸或鹼時pH大改變之一或多種溶劑試劑。用於本發明之目的之較佳緩衝體系係檸檬酸-檸檬酸鈉體系。
術語「單位劑量」或「單位劑型」如本文中及隨附申請專利範圍中所用係指適於投與人類女性個體之本發明組合物之物理離散單位。各單位含有經計算以產生所需治療效應之預定量之甲硝唑及特康唑。意欲投與任何給定患者之單位劑型由以下決定並取決於以下:(1)意欲達成的特定治療效應(2)及活性劑自所利用之特定組合物之釋放速率。
術語「陰道」如本文中及隨附申請專利範圍中所用一般包含陰道區域,包括外陰及子宮頸。
經陰道內引入以用於治療細菌性陰道炎(BV)之治療組合物之量可廣泛變化,端視患者之年齡及身體狀態、病痛程度、投與頻率及類似因素而定。
本發明治療組合物中之活性成分為甲硝唑(1-(2-羥乙基)-2-甲基-5-硝基咪唑;M.W. 171.156 g/mol)及特康唑順式-1-[對-[[2-(2,4-二氯苯基)-2-(1
H-1,2,4-三唑-1-基甲基)-1,3-二氧雜環戊烷-4-基]甲氧基]苯基]-4-異丙基哌嗪;M.W. 532.462 g/mol)。術語「甲硝唑」及「特康唑」如本文中及隨附申請專利範圍中所用亦包括其在如本文所述使用時展現治療活性之類似物及衍生物。
甲硝唑及特康唑均係市售化合物。
適宜生理上可接受之增稠劑係纖維素衍生物,諸如羥丙基甲基纖維素、羥乙基纖維素、羧甲基纖維素鈉、以及與聚丙烯酸聚合物交聯且以名稱CARBOPOL 934、CARBOPOL 940、CARBOPOL 950及類似者購自Lubrizol Corporation(Cleveland Ohio)之聚丙烯酸聚合物。
本發明組合物亦可含有可選防腐劑、螯合劑、共溶劑、黏度穩定劑及類似者。
適宜防腐劑係對羥基苯甲酸之低碳數烷基酯(例如對羥基苯甲酸甲酯、對羥基苯甲酸丙酯及類似者)、苯甲酸鈉、乙二胺四乙酸(EDTA)及類似者。
適宜共溶劑係二元醇及多元醇,諸如丙二醇、甘油、山梨糖醇、1,2,6-己三醇及類似者。
適宜黏度穩定劑係甲硫胺酸及類似者。在實施本發明之凝膠樣組合物中,甲硝唑及特康唑以在約3至約4之範圍內,較佳約3.5之相應莫耳比存在。
存在於組合物中之甲硝唑之濃度為基於組合物之重量計至少約0.5重量百分比,較佳在約0.75重量百分比至約1重量百分比之範圍內,且更佳係約0.9重量百分比。
存在於組合物中之特康唑之濃度為基於組合物之重量計至少約0.4重量百分比,較佳在約0.6重量百分比至約1.2重量百分比之範圍內,更佳係約0.8重量百分比。
包含在單位劑量中之甲硝唑之量一般為至少約20毫克但不超過約100毫克。凝膠媒劑中甲硝唑之較佳單位劑量在約20至約60毫克之範圍內,更佳係約45毫克。
包含在單位劑量中之特康唑之量一般為至少約16毫克但不超過約80毫克。凝膠媒劑中特康唑之較佳單位劑量在約16至約50毫克之範圍內,更佳係約40毫克。
製備具有顯示於下表1中之組成之實驗組合物以測定來自單一實體凝膠以及來自組合凝膠之甲硝唑以及特康唑之生物利用度。此等實驗凝膠亦用於治療患有混合型(相伴) BV及VVC的婦女。表1中之所示百分比係重量百分比。
表 1. 實驗組合物
甲硝唑 + 特康唑凝膠 (T1) | 僅甲硝唑凝膠 (T2) | 僅特康唑凝膠 (T3) | |
活性成分 | |||
甲硝唑 | 0.9% | 0.9% | 0 |
特康唑 | 0.8% | 0 | 0.8% |
非活性成分 | |||
Hypromellose,2208,USP | 2.5% | 2.5% | 2.5% |
丙二醇,USP | 3% | 3% | 3% |
l-甲硫胺酸,USP | 0.18% | 0.18% | 0.18% |
對羥基苯甲酸甲酯,NF | 0.08% | 0.08% | 0.08% |
對羥基苯甲酸丙酯,NF | 0.02% | 0.02% | 0.02% |
EDTA | 0.05% | 0.05% | 0.05% |
檸檬酸,USP | 0.43% | 0.43% | 0.43% |
檸檬酸鈉,USP | 補充適量至pH 4.0 | 補充適量至pH 4.0 | 補充適量至pH 4.0 |
純化水,USP | 補充適量至100% | 補充適量至100% | 補充適量至100% |
使用顯示於上表1中之製劑在健康女性志願者中進行單劑量交叉生物利用度研究。將五公克的各製劑填充至陰道施用器中且投與各個體。各施用器對應於45毫克甲硝唑、或40毫克特康唑、或45毫克甲硝唑及40毫克特康唑。二十四(24)名個體入選本研究,其中二十一(21)名完成本研究。在藥物投與前至少12小時直至此後的24小時安置個體。此後,個體在36小時、48小時及72小時時對研究設施進行報告。根據隨機化時間表,用此等凝膠中之各者處理個體。
在各研究期中在劑量投與前(0小時)的90分鐘內及給藥後在劑量投與後一小時開始的前十二小時以每小時時間間隔及此後在14小時、16小時、24小時、36小時、48小時、及72小時時自個體獲得血漿樣品。
進行三個獨立研究期。除了在由於月經在研究期II與研究期III之間的三個實例中之外,在研究期之間維持七天之清除期。在該等三個實例中,清除期為14天。
甲硝唑 + 特康唑凝膠(T1)及僅甲硝唑凝膠(T2)之所觀測到的平均甲硝唑血漿濃度與時間之線性圖顯示於圖1中。清楚地指示在特康唑存在下甲硝唑之生物利用度提高。
圖2係甲硝唑 + 特康唑凝膠(T1)及僅特康唑凝膠(T3)之所觀測到的平均特康唑血漿濃度與時間之線性圖且顯示甲硝唑之存在不會提高特康唑之生物利用度。
下表2及3呈現所觀測到的藥物動力學參數。
表 2. 甲硝唑生物利用度
參數 ( 單位 ) | 平均值 ± SD( 未轉換之數據 ) | |
甲硝唑 + 特康唑凝膠 (T1) | 僅甲硝唑凝膠 (T2) | |
(N = 23) | (N = 22) | |
C max(ng/mL) | 597.4 ± 167.5 | 348.3 ± 154.3 |
AUC 0 至 t(hr. ng/mL) | 9286.8 ± 2562.8 | 7371.7 ± 2031.1 |
AUC 0 至 ∞(hr. ng/mL) | 9396.2 ± 2593.4 | 7463.8 ± 2027.9 |
以上數據顯示,對於甲硝唑 + 特康唑凝膠,甲硝唑之最大血漿濃度(C
max)以及曲線下面積(AUC)大得多(對於所有參數,p<0.001)。藉由連同特康唑一起調配,顯著提高甲硝唑生物利用度。
表 3. 特康唑生物利用度
參數 ( 單位 ) | 平均值 ± SD ( 未轉換之數據 ) | |
甲硝唑 + 特康唑凝膠 (T1) | 僅特康唑凝膠 (T3) | |
(N = 23) | (N = 23) | |
C max(ng/mL) | 18.7 ± 18.4 | 22.1 ± 20.3 |
AUC 0 至 t(h. ng/mL) | 285.9 ± 158.5 | 307.0± 180.7 |
AUC 0 至 ∞(h. ng/mL) | 320.3 ± 156.3 | 320.6 ± 183.2 |
表3中之數據顯示,甲硝唑之存在不會顯著影響特康唑之生物利用度。
實施本發明之組合物用於治癒患有混合型(相伴) BV及VVC的婦女之細菌性陰道炎(BV)感染亦比單獨甲硝唑更有效。
將此等相同三種實驗調配物在滿足確立BV及VVC二者之診斷所需的所有臨床及實驗室標準的婦女中進行測試。婦女連續3天在睡前給予裝滿凝膠之五公克施用器。在第7至14天,對其評估BV及VVC二者之臨床治癒。
BV治癒定義為異常排出物消退,針對胺之KOH臭味測試為陰性,及基於陰道流體濕抹片之檢查存在20%或更多線索細胞為陰性。在同時患有BV及VVC的此等婦女中,預期甲硝唑 + 特康唑組合將治癒與單獨特康唑相比顯著更多的BV且提供與單獨甲硝唑相似的BV之治癒率。然而,此等婦女之BV治癒率在使用甲硝唑 + 特康唑組合凝膠的婦女中與使用僅甲硝唑凝膠的婦女相比出人意料地高,如下表4中可見。
表 4. BV 治癒率
混合型感染之 BV 臨床治癒 | 甲硝唑 + 特康唑凝膠 (T1) | 僅甲硝唑凝膠 (T2) | 僅特康唑凝膠 (T3) |
個體數 | 82 | 84 | 83 |
BV臨床治癒 | 54 (65.9%) | 46 (54.8%) | 38 (45.8%) |
95%信賴區間 | (55.0%、76.7%) | (43.5%、66.0%) | (34.5%、57.1%) |
差異:組合凝膠減去單實體凝膠 | 11.1% | 20.1% | |
p值(連續性校正之卡方) | 0.193 | 0.015 |
VVC治癒定義為歸因於VVC之所有症狀及徵兆之消退。在同時患有BV及VVC的此等婦女中,預期甲硝唑 + 特康唑組合將治癒與單獨甲硝唑相比顯著更多的VVC且提供與單獨特康唑相似的VVC之治癒率。此等預期係正確的,如下表5中可見:
表 5. VVC 治癒率
混合型感染之 VVC 臨床治癒 | 甲硝唑 + 特康唑凝膠 (T1) | 僅甲硝唑凝膠 (T2) | 僅特康唑凝膠 (T3) |
個體數 | 82 | 84 | 83 |
VVC臨床治癒 | 53 (64.6%) | 37 (44.0%) | 52 (62.7%) |
95%信賴區間 | (53.7%、75.6%) | (32.8%、55.3%) | (51.6%、73.7%) |
差異:組合凝膠減去單實體凝膠 | 20.6% | 2.0% | |
p值(連續性校正之卡方) | 0.012 | 0.918 |
在圖式中,
圖1係顯示於凝膠樣載劑中單獨甲硝唑及與特康唑之組合之生物利用度之圖;及
圖2係顯示在相同凝膠樣載劑中單獨特康唑及與甲硝唑之組合之生物利用度之圖。
Claims (7)
- 一種組合物,其具有凝膠樣稠度且包含甲硝唑(metronidazole)、特康唑(terconazole)、生理上可接受之增稠劑及水; 其中存在於該組合物中之特康唑之量係足以提高甲硝唑之生物利用度。
- 一種組合物,其具有凝膠樣稠度且包含甲硝唑、特康唑、生理上可接受之增稠劑及水; 其中甲硝唑係以基於該組合物之重量計至少0.5重量百分比之濃度存在,特康唑係以基於該組合物之重量計至少0.4重量百分比之濃度存在,及該甲硝唑係連同緩衝體系一起存在,該緩衝體系向該組合物提供在約3.75至約4.25之範圍內的緩衝pH值。
- 如請求項2之組合物,其中甲硝唑及特康唑分別以在約3:1至約4:1之範圍內的莫耳比存在。
- 如請求項1之組合物,其中甲硝唑及特康唑分別以約3.5:1之莫耳比存在。
- 如請求項2之組合物,其中存在於該組合物中之甲硝唑之量係在基於該組合物之重量計約0.75重量百分比至約1重量百分比之範圍內及存在於該組合物中之特康唑之量係在基於該組合物之重量計約0.6重量百分比至約1.2重量百分比之範圍內。
- 如請求項2之組合物,其中甲硝唑濃度為約0.9重量百分比,特康唑濃度為約0.8重量百分比,該生理上可接受之增稠劑為羥丙基甲基纖維素,及該緩衝體系包含檸檬酸及檸檬酸鈉。
- 一種如請求項1至6中任一項之組合物於製造用於治療人類患者之細菌性陰道炎的藥物中之用途。
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Application Number | Priority Date | Filing Date | Title |
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US16/904,678 US11529346B2 (en) | 2020-06-18 | 2020-06-18 | Vaginal gel |
US16/904,678 | 2020-06-18 |
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TW202214247A true TW202214247A (zh) | 2022-04-16 |
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US4837378A (en) * | 1986-01-15 | 1989-06-06 | Curatek Pharmaceuticals, Inc. | Topical metronidazole formulations and therapeutic uses thereof |
US5536743A (en) | 1988-01-15 | 1996-07-16 | Curatek Pharmaceuticals Limited Partnership | Intravaginal treatment of vaginal infections with buffered metronidazole compositions |
FR2777783A1 (fr) | 1998-04-24 | 1999-10-29 | Innothera Lab Sa | Association pharmaceutique d'imidazoles pour le traitement local des vulvo-vaginites infectieuses et des vaginoses |
US20030130225A1 (en) * | 2001-10-16 | 2003-07-10 | Nawaz Ahmad | Novel methods of treating local fungal and bacterial infections |
US6899890B2 (en) * | 2002-03-20 | 2005-05-31 | Kv Pharmaceutical Company | Bioadhesive drug delivery system |
MXPA05004578A (es) * | 2002-10-31 | 2005-07-26 | Umd Inc | Composicion terapeutica para el suministro de drogas a y a traves de epitelios de proteccion. |
US6913759B2 (en) * | 2003-03-11 | 2005-07-05 | Curatek Pharmaceuticals Holding, Inc. | Gel composition and method for treatment of vaginal infections |
GB0405406D0 (en) * | 2004-03-10 | 2004-04-21 | Edko Pazarlama Tanitim Ltd Sti | Anti-vaginitis compositions |
US20060093675A1 (en) * | 2004-10-29 | 2006-05-04 | Mathew Ebmeier | Intravaginal treatment of vaginal infections with metronidazole compositions |
US10398692B2 (en) | 2006-09-12 | 2019-09-03 | Curatek Pharmaceuticals Holding, Inc. | Terconazole composition and method |
CN103536592B (zh) * | 2013-10-11 | 2015-04-08 | 哈尔滨欧替药业有限公司 | 甲硝唑呋喃唑酮阴道膨胀栓及其制备方法和检测方法 |
ITRM20130690A1 (it) * | 2013-12-17 | 2015-06-18 | Over S R L | Composizioni per il trattamento topico delle infezioni da gardnerella vaginalis |
EP3388063A1 (en) * | 2017-04-14 | 2018-10-17 | Adamed sp. z o.o. | Treatment of a bacterial vaginal infection |
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IL299066A (en) | 2023-02-01 |
CA3182553A1 (en) | 2021-12-23 |
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CN115955967A (zh) | 2023-04-11 |
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AU2021292945A1 (en) | 2023-02-16 |
EP4167964A1 (en) | 2023-04-26 |
WO2021257179A1 (en) | 2021-12-23 |
US20210393619A1 (en) | 2021-12-23 |
JP2023531443A (ja) | 2023-07-24 |
US11529346B2 (en) | 2022-12-20 |
AR122687A1 (es) | 2022-09-28 |
CO2023000415A2 (es) | 2023-01-26 |
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