TWI382841B - 用於抑制發炎之醫藥組合物 - Google Patents
用於抑制發炎之醫藥組合物 Download PDFInfo
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- TWI382841B TWI382841B TW099137186A TW99137186A TWI382841B TW I382841 B TWI382841 B TW I382841B TW 099137186 A TW099137186 A TW 099137186A TW 99137186 A TW99137186 A TW 99137186A TW I382841 B TWI382841 B TW I382841B
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- hyaluronic acid
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Description
本發明係關於一種用於抑制發炎之醫藥組合物，尤其關於可用於關節炎之醫藥組合物。
關節炎係一種常見之慢性疾病，其係因關節軟骨退化或結締組織發炎而造成關節疼痛，進而影響關節的正常活動。依據發生部位與原因，關節炎共可分為一百多種類型，最常見者係包括骨關節炎(退化性關節炎)、類風濕性關節炎、痛風性關節炎、細菌性關節炎、僵直性脊椎關節炎、及紅斑性狼瘡等。
針對關節炎之治療，一般係先於初期採取保守性、非手術性的療法，當初期治療未見成效時，才會採用外科手術的治療方式。初期治療包括藥物治療與注射劑治療，於藥物治療中，係使用類固醇與非類固醇之抗發炎藥物，其中，儘管類固醇藥物的止痛效果快且顯著，但會引起許多副作用，例如骨質疏鬆症、傷口不易癒合、上消化道出血，甚至會加重如高血壓或糖尿病等疾病之症狀，因此，目前大致上已停止使用類固醇藥物進行治療。至於非類固醇藥物，雖亦具良好的止痛效果，但若長期使用，則會產生如消化性潰瘍、下肢水腫及腎臟功能損傷等副作用，故於實際應用上亦多受限制。
玻尿酸(hyaluronic acid，又稱「透明質酸」或「醣醛酸」)注射劑已廣泛運用於骨關節炎之治療，其係將含有玻尿酸之注射液直接注射至關節中，以適度減緩發炎及病患之疼痛感。雖然玻尿酸的作用機制尚不清楚，但已知其可作為一種潤滑劑以幫助關節活動，同時達到改善關節功能的效果。然而，儘管玻尿酸可有效減輕疼痛，但其本身於進入人體後兩天至一周內反而會引起暫時性發炎反應，甚至造成慢性發炎(此可參見Leopold et al.,Increased frequency of acute local reaction to intra-articular hylan GF-20(Synvisc) in patients receiving more than one course of treatment.J Bone Joint Surg
,2002;84: 1619-23；Bernardeau et al.,Acute arthritis after intra-articular hyaluronate injection: onset of effusions without crystal.Ann Rheum Dis
,2001;60:518-20；以及Kroesen et al.,Induction of an acute attack of calcium pyrophosphate dihydrate arthritis by intra-articular injection of hylan G-F 20(Synvisc).Clin Rheumatol
,2000;19:147-9，彼等文獻全文併於此處以供參考)，因此，目前市面上之玻尿酸製劑產品的抗發炎效果仍未臻理想。
業經文獻揭露一種改進玻尿酸製劑之方法，其利用化學合成方式，將玻尿酸經由一多胜肽連結至具有抗發炎活性之胺基甲基葉酸(methotrexate，MTX)上以形成一共軛物(conjugate)，由此製得之產物具有改良之抗發炎效果(此可參見Homma et al.,Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment,Bioorganic and Medicinal Chemistry
,17(2009),4647-4656，該文獻全文併於此處以供參考)。惟，根據該文獻之教示，單純混合玻尿酸與胺基甲基葉酸所形成之混合物並無法達到改良效果，其使得合成該共軛物成為必要之手段。然而，製備該共軛物必須使用多胜肽原料且涉及繁複的合成步驟，此勢必增加玻尿酸製劑之製造成本，不僅於量產製程上造成困難，亦增加使用者的經濟負擔，故在臨床應用上多有侷限。因此，市面上仍須要一種製程簡便、且可有效改善玻尿酸之抗發炎活性的藥物或方法。
本發明即係針對上述需求所為之研究，本案發明人發現，藉由混合3-羥基-3-甲基戊二醯輔酶A(HMG-CoA)還原酶抑制劑與玻尿酸所製得之組合物，可抑制玻尿酸引起之暫時性發炎反應，進而改善玻尿酸抗發炎的效果。
本發明之一目的在於提供一種用於抑制發炎之醫藥組合物，其係包含：(a)玻尿酸、(b)一3-羥基-3-甲基戊二醯輔酶A(HMG-CoA)還原酶抑制劑、及(c)一醫藥可接受載劑。
本發明之另一目的在於提供一種抑制發炎之方法，其係包含使一患者施用一有效量之上述醫藥組合物。
本發明之詳細技術及較佳實施態樣，將描述於以下內容中，以供本發明所屬領域具通常知識者據以明瞭本發明之特徵。
於本文中(尤其後附申請專利範圍中)，除非另外說明，所使用之「一」、「該」及類似用語應理解為包含單數及複數形式。
如上述，於玻尿酸進入人體後兩天至一周內會引起暫時性發炎反應，甚至造成慢性發炎，而影響其抗發炎之效果；另一方面，業經文獻提出之製備玻尿酸與胺基甲基葉酸之共軛物的改良方法具有諸多限制。本發明藉由結合玻尿酸與3-羥基-3-甲基戊二醯輔酶A(HMG-CoA)還原酶抑制劑，可以簡易手段改進習知玻尿酸製劑之缺點。
因此，本發明提供一種用於抑制發炎之醫藥組合物，其係包含：(a)玻尿酸及(b)一3-羥基-3-甲基戊二醯輔酶A(HMG-CoA)還原酶抑制劑。
玻尿酸為細胞外基質之主要構成成分之一，廣佈於內皮組織、結締組織、表皮組織及神經組織中，且對於細胞之增生及遷移等生理活動至關重要，此外，由於玻尿酸為皮膚真皮層內重要之保濕成分，且具有優異之黏容性與伸縮性，是一種非常理想的填充物質，故常用於美容產品及整形手術中。玻尿酸係一不具硫元素之糖胺聚醣，其基本結構是由兩個雙糖單位D-葡萄糖醛酸及N-乙醯葡糖胺組成的大型多醣類，具如下式(I)之化學式：
適用於本發明醫藥組合物之玻尿酸並無特別限制，但較佳地，構成本發明醫藥組合物之成份(a)之玻尿酸，係具平均分子量約30萬至約600萬道爾頓(Dalton)，更佳為具平均分子量約50萬至約300萬道爾頓。
本發明醫藥組合物之成份(b)係一3-羥基-3-甲基戊二醯輔酶A(下文簡稱為「HMG-CoA」)還原酶抑制劑，係包含一類稱為「史坦酊(statins)」之用於降血脂的藥物，包含如下表1所示之化合物：
因此，適用為本發明醫藥組合物之成分(b)之HMG-CoA還原酶抑制劑，係可選自以下群組：阿托法史坦酊(Atorvastatin)、薛利伐史坦酊(Cerivastatin)、氟伐史坦酊(Fluvastatin)、樂瓦史坦酊(Lovastatin)、美伐史坦酊(Mevastatin)、匹他伐史坦酊(Pitavastatin)、普伐史坦酊(Pravastatin)、瑞舒伐史坦酊(Rosuvastatin)、辛維史坦酊(Simvastatin)、及其組合。較佳地，該成分(b)係為樂瓦史坦酊。如後附實施例所示，儘管單獨使用HMG-CoA還原酶抑制劑會惡化發炎反應，但出乎意料之外地，若合併使用HMG-CoA還原酶抑制劑與玻尿酸，則反而可以促進玻尿酸之抗發炎效果。
於本發明醫藥組合物中，成分(a)與(b)之含量配比並無特別限制，一般而言，以成分(a)與(b)之總重計，成分(a)之含量為約80重量%至約99.9重量%，且成分(b)之含量為約0.1重量%至約20重量%。較佳地，以成分(a)與(b)之總重計，成分(a)之含量為約85重量%至約99.5重量%，且成分(b)之含量為約0.5重量%至約15重量%。
本發明醫藥組合物可使用於獸醫與人類醫藥上，且可呈任何形式，並以任何合宜之方式施用。舉例言之，但不以此為限，該醫藥組合物可以口服、皮下、靜脈或關節內注射等投藥方式施用之。視使用形式及用途而定，可於本發明醫藥組合物中包含一成分(c)醫藥可接受載劑。
以製備適於口服投藥之藥劑形式為例，可於本發明醫藥組合物中含有不會不利影響玻尿酸及HMG-CoA還原酶抑制劑活性之醫藥可接受載劑，例如：溶劑、油性溶劑、稀釋劑、安定劑、吸收延遲劑、崩散劑、乳化劑、抗氧化劑、黏合劑、潤滑劑、吸濕劑等。舉例言之，溶劑可選自水及蔗糖溶液，稀釋劑可選自乳糖、澱粉及微晶纖維素，吸收延遲劑可選自幾丁聚醣及葡萄胺基聚醣，潤滑劑可選自碳酸鎂，油性溶劑可選自植物或動物油類，如橄欖油、葵花油及魚肝油等。可利用任何合宜之方法，將該組合物製成適於口服投藥的形式，例如：錠劑、膠囊劑、顆粒劑、散劑、流浸膏劑、溶液劑、糖漿劑、懸液劑、乳劑、及酊劑等等。
至於適於皮下、靜脈或關節內注射之藥劑形式，則可於本發明醫藥組合物中含有一或多種例如等張溶液、鹽類緩衝液(如磷酸鹽緩衝液或檸檬酸鹽緩衝液)、增溶劑、乳化劑、以及其他載劑等成分，以製成如靜脈輸注液、乳劑靜脈輸注液、乾粉注射劑、懸液注射劑、或乾粉懸液注射劑等。可能採用之溶劑例如：水、生理食鹽溶液、醇類(例如：乙二醇、丙醇、或甘油等)、糖溶液(例如：葡萄糖或甘露糖溶液)、或前述之組合。
本發明醫藥組合物可視需要另含有調味劑、調色劑、著色劑等添加劑，以提高所得藥劑服用時的口適感及視覺感受；另可添加合理用量之保存劑、防腐劑、抗菌劑(例如苯甲醇)、抗真菌劑等，以改善所得藥劑的儲存性。
視需要地，可於本發明醫藥組合物中併含一或多種其他活性成分，進一步加強本發明醫藥組合物之功效或增加製劑配方的運用靈活性與調配度。舉例言之，可於本發明醫藥組合物含有一或多種如下活性成分：類固醇抗發炎藥物、非類固醇抗發炎藥物、葡萄糖胺(glucosamine)、以及其他活性成分等，只要該其他活性成分對玻尿酸及HMG-CoA還原酶抑制劑之效益沒有不利的影響即可。
由於本發明醫藥組合物可抑制玻尿酸引起的暫時性發炎現象，並促進玻尿酸之抗發炎效果，故可用於抑制發炎，尤其可用於抑制關節炎，包括骨關節炎(退化性關節炎)、類風濕性關節炎、痛風性關節炎、細菌性關節炎、僵直性脊椎關節炎、及紅斑性狼瘡等，較佳係用於抑制骨關節炎及類風濕性關節炎。於一實施態樣中，係將本發明醫藥組合物製成注射劑之型式，以供用於關節注射之治療方法。
相較於習知玻尿酸製劑對於類風濕性關節炎無法達成顯著之治療效果，本發明醫藥組合物之一有利之處在於，本發明組合物可提供優異之抑制類風濕性關節炎的功效，因此，尤其可用於類風濕性關節炎之治療。此外，不同於已知玻尿酸與胺基甲基葉酸之組合，須透過多胜肽之繁複手段以形成共軛物方可提供所欲之抗發炎效果，於本發明醫藥組合物中，玻尿酸及HMG-CoA還原酶抑制劑僅需簡單混合即可，故另具有製程簡便、適於大規模量產之優點。
由於本發明醫藥組合物可改善習知玻尿酸製劑之缺點，故亦可應用於玻尿酸之任何已知用途，而不限於抗關節炎。舉例言之，可將本發明組合物運用於美容產品或整形外科，例如可將其添加於皮膚保養品或臉部的玻尿酸注射劑中。
本發明亦提供一種抑制發炎之方法，其係包含使一患者施用一有效量之本發明之醫藥組合物。於本發明之一實施態樣中，係以注射劑之型式，將本發明醫藥組合物注射至患者之關節中，以達成治療關節炎之效果。
可以一日一次、一日多次、或數日一次等不同投藥頻率施用本發明醫藥組合物，端視投予標的之需求而異。舉例言之，當使用於人體以治療類風濕性關節炎時，藥劑之用量，以成分(a)及(b)計，為每天約25毫克/公斤體重至約50毫克/公斤體重，其中，該單位『毫克/公斤體重』係指每公斤體重所須之投藥量。惟，對於急性病患(如痛風病患)而言，其用量可視實際需要而酌增至數倍或數十倍。
茲以下列具體實施態樣以進一步例示說明本發明。其中該些實施態樣僅提供作為說明，而非用以限制本發明之範疇。
於一預裝式玻尿酸注射針器(購自弘如洋公司)內，添加1毫升之等張溶液，其包含5至20毫克之玻尿酸(購自弘如洋公司，平均分子量為60至80萬道爾頓)及0.5至1.2毫克之HMG-CoA還原酶抑制劑(樂瓦史坦酊(lovastatin)，M2147，購自Sigma)作為主要成分，再添加5至20毫克之氯化鈉、硫酸氫鈉、雙氫硫酸鈉及注射用水作為賦型劑，以製得一玻尿酸關節注射液。
收集來自七個罹患有類風濕性關節炎之病患的纖維母細胞樣滑膜細胞(fibroblast-like synoviocytes，FLS)並進行培養。首先，將病患之關節滑膜(synovium)切成小碎片，再使其懸浮於一DMEM(Dulbecco modified eagle’s medium)培養基(含有1.5公克/公升碳酸氫鈉(S6297，Sigma-Aldrich，St Louis，密蘇里州，美國)、1%盤尼西林-鏈黴素-新黴素(P4083，Sigma-Aldrich)、以及10%胎牛血清(04-001-1A，Biological Industries，Grand Island，紐約州，美國)中，並於37℃、5%之二氧化碳的環境中培養3天。
以磷酸鹽緩衝液(PBS)洗去未附著之細胞，並更換培養基，再培養留下之附著的細胞達2周。重複上述程序3至6次，存留下的細胞即為纖維母細胞樣滑膜細胞，將其用於以下試驗。
於不含血清之培養基中培養實驗A製得之纖維母細胞樣滑膜細胞達24小時，使其生長至半滿(subconfluence)狀態後，再將其培養於含有10%胎牛血清之DMEM培養基中，並分成以下四組：1)保持細胞為未接受刺激及處理之狀態的控制組；2)單獨以玻尿酸(平均分子量為60至80萬道爾頓)處理細胞達24小時；3)單獨以HMG-CoA還原酶抑制劑(樂瓦史坦酊，M2147，Sigma)處理細胞達24小時；以及4)將100微克之玻尿酸(平均分子量為60至80萬道爾頓)及5微莫耳之HMG-CoA還原酶抑制劑(樂瓦史坦酊)混合於1毫升之溶液中，再以製得之混合物處理細胞達24小時。
接著，分別收集上述四組細胞並離心，再收集上清液，以進行以下試驗。
使用夾層結合蛋白質分析套組(sandwich binding protein assay kit或sandwich ELISA kits，購自eBioscience and R＆D公司)，並依據廠商之使用手冊利用標準曲線測定實驗B中所收集之上清液中，兩個與類風濕性關節炎相關之因子的濃度，以觀察其表現程度，藉此判斷細胞之發炎情形，該因子分別為腫瘤壞死因子-α(TNF-α，標準品購自88-7340，eBioscience)及介白素-8(IL-8，標準品購自DY208，R＆D systems，美國)。各樣本進行兩次試驗，並使用一酵素免疫吸附分析(ELISA)讀取器(Sunrise Remote，TECAN)進行測定。結果係如表2、表3、第1圖及第2圖所示。
表2、表3、第1圖及第2圖顯示來自類風濕性關節炎患者之關節細胞，會分泌大量的發炎介質TNF-α及IL-8，說明其發炎情況嚴重(如控制組所示)，但單獨以玻尿酸處理後可降低發炎現象。另一方面，若結合HMG-CoA還原酶抑制劑與玻尿酸，則可進一步加強玻尿酸抑制發炎的效果(如混合物組所示)。
因此，以上實施例說明，若結合HMG-CoA還原酶抑制劑與玻尿酸，比單獨以玻尿酸處理，更可以使發炎介質TNF-α及IL-8的濃度降低，換言之，結合HMG-CoA還原酶抑制劑與玻尿酸，比單獨以玻尿酸處理，更具抗發炎效果。此結果可以證明本發明醫藥組合物可加強玻尿酸抗發炎的效果，對於類風濕性關節炎具有更良好之抑制發炎效果；此外，也證明本發明之醫藥組合物可抑制玻尿酸所引起之暫時性發炎的現象。
上述實施例僅係用以例示說明本發明之原理及功效，而非用於限制本發明。任何熟於此項技藝之人士均可在不違背本發明之技術原理及精神的情況下，對上述實施例進行修改及變化。因此，本發明之權利保護範圍應如後附申請專利範圍所界定者。
第1圖所示為纖維母細胞樣滑膜細胞(fibroblast-like synoviocytes)中發炎介質腫瘤壞死因子-α(TNF-α)之表現量的統計直條圖；以及
第2圖所示為纖維母細胞樣滑膜細胞中發炎介質介白素-8(IL-8)之表現量的統計直條圖。
Claims (11)
- 一種用於抑制發炎之醫藥組合物，其係包含：(a)玻尿酸；(b)一3-羥基-3-甲基戊二醯輔酶A(HMG-CoA)還原酶抑制劑；及(c)一醫藥可接受載劑。
- 如請求項1之醫藥組合物，其中以成分(a)與(b)之總重計，成分(a)之含量為約80重量%至約99.9重量%，且成分(b)之含量為約0.1重量%至約20重量%。
- 如請求項2之醫藥組合物，其中以(a)與(b)之總重計，成分(a)之含量為約85重量%至約99.5重量%，且成分(b)之含量為約0.5%至約15%。
- 如請求項1之醫藥組合物，其中成分(a)之平均分子量為約30萬至約600萬道爾頓(Dalton)。
- 如請求項4之醫藥組合物，其中成分(a)之平均分子量為約50萬至約300萬道爾頓。
- 如請求項1之醫藥組合物，其中成分(b)係選自以下群組之HMG-CoA還原酶抑制劑：阿托法史坦酊(Atorvastatin)、薛利伐史坦酊(Cerivastatin)、氟伐史坦酊(Fluvastatin)、樂瓦史坦酊(Lovastatin)、美伐史坦酊(Mevastatin)、匹他伐史坦酊(Pitavastatin)、普伐史坦酊(Pravastatin)、瑞舒伐史坦酊(Rosuvastatin)、辛維史坦酊(Simvastatin)、及其組合。
- 如請求項6之醫藥組合物，其中成分(b)係樂瓦史坦酊。
- 如請求項1至7中任一項之醫藥組合物，其係用於抗關節炎。
- 如請求項8之醫藥組合物，其係用於抗骨關節炎、抗類風濕性關節炎或抗痛風性關節炎。
- 如請求項9之醫藥組合物，其係用於抗類風濕性關節炎。
- 如請求項1至7中任一項之醫藥組合物，其係呈供口服、皮下注射、靜脈注射或關節內注射投藥之形式。
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| JP2011069623A JP5513430B2 (ja) | 2010-10-29 | 2011-03-28 | 炎症を抑制するための薬剤組成物及び方法 |
| ES11181939.7T ES2501040T3 (es) | 2010-10-29 | 2011-09-20 | Composición para inhibir la inflamación que comprende ácido hialurónico y un inhibidor de la HMG-CoA reductasa |
| PT111819397T PT2446884E (pt) | 2010-10-29 | 2011-09-20 | Composição para inibição de inflamação compreendendo ácido hialurónico e um inibidor da hmg-coa-redutase |
| SI201130266T SI2446884T1 (sl) | 2010-10-29 | 2011-09-20 | Sestavek za inhibiranje vnetja, ki obsega hialuronsko kislino in HMG-CoA reduktazni inhibitor |
| EP11181939.7A EP2446884B1 (en) | 2010-10-29 | 2011-09-20 | Composition for inhibiting inflammation comprising hyaluronic acid and a hmg-coa reductase inhibitor |
| RSP20140489 RS53546B1 (en) | 2010-10-29 | 2011-09-20 | INFLAMMATION INHIBITING COMPOSITION CONSISTING OF Hyaluronic Acid And HMG-COA Reductase Inhibitor |
| PL11181939T PL2446884T3 (pl) | 2010-10-29 | 2011-09-20 | Kompozycja do hamowania zapalenia zawierająca kwas hialuronowy i inhibitor reduktazy HMG-CoA |
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| CN2011102875733A CN102462843A (zh) | 2010-10-29 | 2011-09-23 | 用于抑制发炎的医药组合物 |
| HK12107176.7A HK1166468A1 (zh) | 2010-10-29 | 2012-07-23 | 電解質材料調配物、由此形成之電解質材料聚合物及其用途 |
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| WO2017203529A1 (en) * | 2016-05-24 | 2017-11-30 | Bol Pharma Ltd. | Compositions comprising cannabidiol and hyaluronic acid for treating inflammatory joint diseases |
| WO2016201682A1 (zh) * | 2015-06-18 | 2016-12-22 | 高雄医学大学 | 一种医药组合物用于制备促进软骨细胞生成的药物的用途 |
| US10149868B2 (en) * | 2016-05-31 | 2018-12-11 | Tco Co., Ltd. | Use of Streptococcus thermophilis TCI633 in treating arthritis |
| FR3062797A1 (fr) * | 2017-02-10 | 2018-08-17 | Centre Hospitalier Et Universitaire De Clermont-Ferrand | Gelule a liberation gastro-intestinale destinee a etre utilisee dans une methode permettant de desensibiliser et/ou d'induire une tolerance chez un sujet allergique a l'arachide |
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| AU2004243513A1 (en) | 2003-05-30 | 2004-12-09 | Arc Pharmaceuticals, Inc. | Pharmaceutical compositions and methods relating to inhibiting fibrous adhesions using various agents |
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- 2011-09-20 PL PL11181939T patent/PL2446884T3/pl unknown
- 2011-09-20 SI SI201130266T patent/SI2446884T1/sl unknown
- 2011-09-20 DK DK11181939.7T patent/DK2446884T3/da active
- 2011-09-20 ES ES11181939.7T patent/ES2501040T3/es active Active
- 2011-09-20 EP EP11181939.7A patent/EP2446884B1/en active Active
- 2011-09-20 RS RSP20140489 patent/RS53546B1/en unknown
- 2011-09-20 PT PT111819397T patent/PT2446884E/pt unknown
- 2011-09-23 CN CN2011102875733A patent/CN102462843A/zh active Pending
-
2012
- 2012-07-23 HK HK12107176.7A patent/HK1166468A1/zh not_active IP Right Cessation
-
2014
- 2014-09-05 HR HRP20140842AT patent/HRP20140842T1/hr unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200410677A (en) * | 2002-08-22 | 2004-07-01 | Warner Lambert Co | Method of treating osteoarthritis |
| US20070003636A1 (en) * | 2003-01-22 | 2007-01-04 | Francois Mach | Statins (HMG-COA reductase inhibitors) as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent |
Non-Patent Citations (1)
| Title |
|---|
| Homma et al., Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment, Bioorganic and Medicinal Chemistry, 17, 4647-4656, 2009. * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5513430B2 (ja) | 2014-06-04 |
| JP2012097066A (ja) | 2012-05-24 |
| PL2446884T3 (pl) | 2014-12-31 |
| US20120108536A1 (en) | 2012-05-03 |
| HRP20140842T1 (hr) | 2015-03-13 |
| CN102462843A (zh) | 2012-05-23 |
| ES2501040T3 (es) | 2014-10-01 |
| EP2446884A1 (en) | 2012-05-02 |
| TW201216970A (en) | 2012-05-01 |
| SI2446884T1 (sl) | 2014-10-30 |
| DK2446884T3 (da) | 2014-09-08 |
| EP2446884B1 (en) | 2014-06-25 |
| US8691796B2 (en) | 2014-04-08 |
| HK1166468A1 (zh) | 2012-11-02 |
| RS53546B1 (en) | 2015-02-27 |
| PT2446884E (pt) | 2014-09-05 |
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