TW200927118A - Treatment of vasomotor symptoms - Google Patents
Treatment of vasomotor symptoms Download PDFInfo
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- TW200927118A TW200927118A TW097134893A TW97134893A TW200927118A TW 200927118 A TW200927118 A TW 200927118A TW 097134893 A TW097134893 A TW 097134893A TW 97134893 A TW97134893 A TW 97134893A TW 200927118 A TW200927118 A TW 200927118A
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- acid
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- vascular
- motility
- menopause
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- 239000002700 tablet coating Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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Description
200927118 九、發明說明： 【發明所屬之技術領域】 本發明係有m療與更钱㈣之血管運動徵候之 方法’其包括投與治療有效量之_色林（flibanserin)。 【發明内容】 化合物1-[2-(4-(3-三氟甲基-苯基）痕嘻小基）乙基]_2,3_ 二氫-1H-苯並口米唾-2-綱（氟班色林（fHbanserin))以鹽酸鹽形
式揭露於歐洲專利申請案EP_A_526434並具有以下化學結 構：
氟班色林對5-HT1A和5-HT2_受體顯示親合力。因此， $治療例如沮喪、精神***症和憂慮之各種疾病上為頗具 前景的治療劑。
經歷絕經之婦女常感受許多歸因於卵巢衰竭導致*** 喪失引起之各種症狀。婦女更年期定義為月經停止。更年 期時間為事後才知道的，在閉經後十二個月得以確定。大 夕數婦女在40歲和5 5歲之間經歷更年期。過渡更年期之特 徵在於：帛熱、頭疼、夜盜汗、萎縮性***炎、頻繁尿道 感染、手腳發冷、健忘和注意力分散。過渡更年期之情緒 表現包括焦躁、沮喪、煩躁不安、情緒不$、憂鬱和減少 性衝動。當女性經歷更年期時，因身體變化造成之不良症 狀繁多至無法詳述。 133147.doc 200927118 一些症狀如外陰和***萎縮可明顯地歸因於***不 足，然而，潮熱很可能為位於 、 -mr Ά 、 勝則申樞神經系統體 :":二.、、。。潮熱（又名”血管運動熱潮紅"或"熱 在近絕經和絕經後婦女中很常見。潮熱期間，周圍 血液膨脹導致臉紅和皮膚變暖。 又适步症狀比如心率增 1口、夜盜汗、頭疼、眩暈、重量增加、疲勞和失眠可能盘 2有關。潮熱可以出現於月經停止之前，並可能是更年 期接近之主要癥兆。在近更年期期間，約75%的婦女有潮 熱。在此類大多數婦女中，症狀將持續約1年。大約三分 之一絕經後婦女M H然更年期以後，症狀持續達刀5 年，20。/。或更多的婦女潮熱持續達叫。手術引起之更年 期在第一年期間因此發生潮熱之可能性為90%，較之與非 手術更年期有關之潮熱’與手術有關之潮熱常常為更急劇 且嚴重，並持續更久。 美國人口調查統計局估計當前有49,〇〇〇,〇〇〇位美國婦女 年齡超過50歲。因此，在美國，現今超過32,〇〇〇,〇〇〇位婦 女也許出現潮熱，6,000,000位也許已報告有嚴重的症狀。 來自嚴重抑鬱症病人研究之試驗結果現已顯示氟班色林 可能適用於治療血管運動徵候（如潮熱、夜盜汗、情緒不 定和煩躁不安）。 因此’本發明係有關一種用於治療血管運動徵候之方 法’其包括投與治療有效量之氟班色林，視需要呈游離驗 形式、其藥理學可接受酸加成鹽及/或視需要呈其水合物 及/或溶劑化物形式。 133147.doc 200927118 另一態樣中’本發明係有關—種用㈣療與過渡更年期 有關之血管運動徵候之方法，其包括投與治療有效量之氟 班色林’視需要呈游離驗形式、其藥理學可接受酸加成鹽 及/或視需要呈其水合物及/或溶劑化物形式。 【實施方式】 血管運動徵候之原因不僅僅為自然發生之更年期，而且 可能因手術（例如子宮切除和雙側印巢切除）引起之更年期 或使用藥物（例如使用選擇性***受體㈣劑、 似物和芳香環轉化酶抑制劑），4因㈣和化療劑引起， 本發明係有關—種治療或防止與醫源性更年期㈣之血管 ㈣徵候之方法’其包括投與治療有效量之敗班色林視 需要呈游離驗形式，其藥理學可接受酸加成鹽及/或視需 要呈其水合物及/或溶劑化物形式。 本發明另-個實施例中係有關—種治療潮熱、夜盜汗、 Ο 情緒不定和煩躁不安之方法’其包括投與治療有效量之氟 班色林’視需要呈游離驗形式’其藥理學可接受酸加成鹽 及/或視需要呈其水合物及/或溶劑化物形式。 本發明另-態樣係有關-種以氟班色林治療與男性自然 或醫源性性腺機能減退有關之中度至重度血管運動徵候I 之用途。 本發明另-態樣係有關使用氟班色林治療H朝 性腺機能減退之男性較佳）及因治療而喪失雄教素或接典 閹割之男性。 、落文 本發明之另-個實施例係有關以氟班色林，視需要至游 133147.doc 200927118 離鹼形式、其藥理學可接受酸加成鹽及/或視需要呈其水 合物及/或溶劑化物形式於製備治療上述任何病症之藥劑 上之用途。 如上所述’氟班色林可呈游離驗形式、視需要呈其藥理 學可接受酸加成鹽及/或視需要呈其水合物及/或溶劑化物 形式使用’適基酸加成鹽包括例如：選自下列之酸類：丁 二酸、氫溴酸、乙酸、反丁烯二酸、馬來酸、，續酸、乳 ❹ 酸、磷酸、鹽酸、硫酸、酒石酸和擰檬酸。可同時使用上 述酸加成鹽之混合物。上述酸加成鹽中，以鹽酸鹽和氫溴 酸鹽較佳，尤指鹽酸鹽。如果使用之氟班色林為游離鹼形 • 式，其以W〇 03/014079揭露之氟班色林多晶型A形式較 佳。 視需要呈游離鹼形式、其藥理學可接受酸加成鹽及/或 視需要呈其水合物及/或溶劑化物形式之氟班色林可以呈 固體、液體或者喷霧狀態併入傳統藥物製劑中。組合物可 ❹ 》例如：適合經口、經直腸、非經腸式投藥或經鼻吸入之 形式：較佳形式包括例如：膠囊、藥片、包衣藥片、安 瓶、栓劑和鼻喷入劑。 活性成分可併入常用於醫藥組合物之賦形劑或載體中， ' 例如：滑石、***膠、乳糖、明膠、硬脂酸鎂、玉米澱 粉、水性或非水性媒劑、聚乙稀η比略燒綱、半合成脂肪酸 之甘匕油醋、氣化节烧錄、填酸納、乙二胺四醋酸、聚山裂 酸賴。該組合物宜調配成劑量單也形式，每一劑量單位 提供單1量之活性成分。每日之適用劑量範圍介於 133147.doc
200927118 至 mg之間；丨於1.0至300 mg之間較佳，介於2至200 邮之間更佳。每1量單位宜包含0.01至100 mg之間，介 於0.1至50 mg之間較佳。 獲得適田藥片之方式為例如··混合活性物質與已知賦形 齊J例如.惰性稀釋劑，如：碳酸約、碌酸妈或乳糖，崩 解齊丨如.玉米幾粉或藻酸，粘合劑，如：殿粉或明膠， 潤π劑如.硬脂酸鎂或滑石及/或用於延遲釋放之製 劑’如.缓甲基纖維素、苯二甲酸醋酸纖維素或聚醋酸乙 烯酯。藥片也可能包含若干層。 製備包衣藥片之方式可使用常用於包覆藥片之物質， 如：可力酮或蟲谬、***樹膠、滑石、二氧化欽或糖， 包覆類似藥片製法所生產之核芯。為延遲釋放或防止不相 容性’核怒也可由許多層組成。同樣地’此藥片包衣亦可 由若干層組成，以延遲釋放，可使用如上所述用於藥片之 賦形劑。 根據本發明包含活性物質或其組合之糖漿或酿劑可以另 外包含增甜劑，如：糖精、環績酸鹽（eyei_te)、甘油或 糖’及風味增強劑，例如：香料，如：香草精或橙萃取 物。其也可包含懸浮佐劑或增拥劑，如：羧甲基纖維素 鈉’潤濕、劑，"°，例如：脂肪醇與環氧乙烷之縮合產物， 或防腐劑，如：對羥基苯甲酸鹽。 注射溶液按慣例製備， 苯甲酸鹽或穩定劑，如： 移入注射小瓶或安瓶中。 例如：添加防腐劑，如 乙二胺四醋酸之鹼金屬 :對羥基 鹽，並轉 133147.doc 200927118 包含一種或多種活性物質 買次活性物質組合之膠囊之 可以例如：混合活性物質與 法 頁兴m性載體，如：乳糖或 醇，並填充至膠囊中。 &山梨糖 之載體，如 適當栓劑製法可例如：混合為此目的提供 中性脂肪或聚乙二醇或其衍生物。 下列不例說明本發明，但不限制其範圍： 示例 臨床試驗 在經確診為嚴重抑鬱症病人之12個II期臨床研究中，由 超過1500名介於18至65歲之間的男性與女性受試者接受介 於2至i 00 mg之間（1天2次（η」.））之一種或多種劑量之氣班 色林。初步分析這些受試者安全資料顯示：相較於安慰劑 (1.25%)或選擇性5-羥色胺再吸收抑制劑（21%)，氟班色林 與實際上沒有出現AE所指示之潮熱/臉紅有關。（見表丨）。 治療 安慰劑 氟班色林 (mg) 羅西汀 (Paroxetine) (mg) 洛克汀 (Fluoxetine) (mg) 20 bid 50 bid 100 bid 20 qd 50 qd 100 qd 2 bid 20 20 N 718 225 521 154 63 64 63 120 275 145 臉紅 5 2 0 0 1 0 0 1 2 2 潮熱 4 2 1 0 0 0 0 1 3 2 表1 :
表1顯示：接受安慰劑之718人中有9人（1.25%)、接受帕 羅西汀（Paroxetine)之275人中有5人（1.8 %)或接受費洛克汀 (Fluoxetine )之145人中有4人（2.75 %)出現臉紅或潮熱。形 133147.doc •11· 200927118 成鮮明對比的是：接受日劑量5G至細mg氟班色林之8〇2 患者中僅1人出現臉紅。 此類資料顯示，氟班色林可用於治療更年期婦女如潮熱 之血管運動徵候。 醫藥調配物示例 ❹ A) 藥片 每藥片 氟班色林鹽酸鹽 100 mg 乳糖 240 mg 玉米澱粉 340 mg 聚乙烯°比略炫嗣 45 mg 硬脂酸鎂 」5 mg 740 mg 混合磨得很細的活性物質、乳糖和一些玉米澱粉。混合 物過篩，使用含於水中之聚乙烯吡咯烷酮潤濕、揉搓、濕 法粒化和乾燥。顆粒、剩餘玉米澱粉和硬脂酸鎂過篩並混 合"壓縮混合物，產生適當形狀和大小之藥片 0 B) 藥片 每一藥片 氟班色林鹽酸鹽 80 mg 玉米澱粉 190 mg 乳糖 55 mg 微晶纖維素 35 mg 聚乙稀D比洛燒酮 15 mg 羧曱基澱粉鈉 23 mg 硬脂酸鎂 2 mg 400 mg 133147.doc •12- 200927118 ❹ 混口磨得很細的活性物質、—些玉米㈣、乳糖、微晶 纖維素和聚乙稀鱗’混合物過筛並與剩餘玉米搬粉 和水共同形成㈣’經乾燥和過篩。添加並混續基曱基 殿粉鈉和硬脂酸鎂’壓縮混合物形成適當大小之藥片。) 包衣藥片 每一包衣藥片 氣班色林鹽酸鹽 玉米澱粉 乳糖 5 mg 41.5 mg 聚乙烯β比略院_ 硬脂酸鎂 30 mg 3 mg 0.5 mg 80 mg ❹ 活性物質、玉米澱粉、乳糖和聚乙烯吡咯烷酮均勻混合 並用水潤濕。潮濕物質通過1毫米網目的篩子，在大約45 C乾燥，然後顆粒再通過相同的篩網。與硬脂酸鎂混合 後，於藥片製造器中壓縮成6毫米直徑之凸面藥片核芯。 依已知方式使用基本上由糖和滑石組成之包覆層包覆所製 造之藥片核芯。使用蠟磨光製成之藥片。 每一膠囊 150 mg 268.5 mg __1.5 mg D) 膠囊 氟班色林鹽酸鹽 玉米澱粉 硬脂酸鎂 420 mg 此物質和玉米澱粉混合，並用水潤濕。過篩和乾燥潮濕 物質。乾燥顆粒過篩並與硬脂酸鎂混合。完成之混合物填 133147.doc •13- 200927118 充至1號硬膠囊中。 E) 安瓿溶液 150 mg 氟班色林鹽酸鹽 氯化納 注射用水 50 mg 5 ml ❹
50 mg 1650 mg 取此活性物質依其原有pH或視需要在ρΗ5·5至6.5之間溶 於水並添加氣化鈉使其呈等張性。過濾獲得之溶液，以去 除致熱原，並於無菌條件下轉移濾液至安瓿，然後消毒並 融合雄、封安瓶。 F) 栓劑 氟班色林鹽酸鹽 固體脂肪 1700 mg :硬脂肪。在下’均質分散研磨的活性物質。A 卻至38C並倒入微冷的栓劑模型中。 飞 在本發明之一個特別佳實施例 々讲命* ^ 从特定膜衣藥片之彤 式投與氟班色林。此類較佳調 ^ μ au奶不例如 列膜衣藥片可依相關技藝已知 、 斤 03/097058)。 法製造（參考 G)膜衣藥片
133147.doc
•14- 200927118 HPMC(曱基纖維素(Methocel)E5) 1.250 羧曱基纖維素鈉 2.500 硬脂酸鎂 0.625 包衣 成分 mg/藥片 HPMC(甲基纖維素E5) 1.440 聚乙二醇6000 0.420 二氧化鈦 0.600 滑石 0.514 氧化鐵紅 0.026 膜衣藥片總重_ 128.000 ® Η)膜衣藥片 核芯 成分 mg/藥片 氟班色林 50.000 乳糖單水化物 143.440 微晶纖維素 47.810 HPMC(例如 Pharmacoat 606) 2.500 羧甲基纖維素鈉 5.000 硬脂酸鎂 1.250 包衣 成分 mg/藥片 HPMC(例如 Pharmacoat 606) 2.400 聚乙二醇6000 0.700 二氧化鈦 1.000 滑石 0.857 氧化鐵紅 0.043 膜衣藥片總重 255.000 I)膜衣藥片 核芯 成分 mg/藥片 氟班色林 100.000 乳糖單水化物 171.080 133147.doc -15- 200927118 微晶纖維素 57.020 HPMC(例如甲基纖維素E5) 3.400 羧曱基纖維素鈉 6.800 硬脂酸鎂 1.700 包衣
成分 mg/藥片 HPMC(例如甲基纖維素E5) 3.360 聚乙二醇6000 0.980 二氧化鈦 1.400 滑石 1.200 氧化鐵紅 0.060 膜衣藥片總重 347.000 J)膜衣藥片 核芯 成分 mg/藥片 HPMC(曱基纖維素E5) 1.440 聚乙二醇6000 0.420 二氧化鈦 0.600 滑石 0.514 氧化鐵紅 0.026 成分 mg/藥片 氟班色林 2.000 二鹼價磷酸鈣，無水型 61.010 微晶纖維素 61.010 HPMC(甲基纖維素E5) 1.950 羧曱基纖維素鈉 2.600 膠體二氧化矽 0.650 硬脂酸鎂 0.780 膜衣藥片總重_ 133.000 K)膜衣藥片 核芯 133147.doc •16- 200927118 成分 mg/藥片 氟班色林 100.000 二鹼價磷酸鈣，無水型 69.750 微晶纖維素 69.750 HPHPMC(例如甲基纖維素E5) 2.750 羧甲基纖維素鈉 5.000 膠體二氧化矽 1.250 硬脂酸鎂 1.500 包衣 成分 mg/藥片 HPMC(例如甲基纖維素E5) 2.400 聚乙二醇6000 0.700 二氧化鈦 1.043 滑石 0.857 膜衣藥片總重 255.000 L)膜衣藥片 核芯 成分 mg/藥片 氟班色林 20.000 乳糖單水化物 130.000 微晶纖維素 43.100 羥基丙基纖維素(例如Klucel LF) 1.900 澱粉羥基乙酸鈉 4.000 硬脂酸鎂 1.000 成分 mg/藥片 HPMC(例如甲基纖維素E5) 2.400 聚乙二醇6000 0.700 二氧化鈦 1.043 滑石 0.857 膜衣藥片總重 205.000 包衣 133147.doc
Claims (1)
- 200927118 十、申請專利範圍： =班色林（fiibanserin)於製備治療▲管運動徵候 劑之用途，該氣班色林視需要呈游離驗、其藥理學可接 =加成鹽之形式’及/或視需要呈其水合物 化物之形式β ^ 2. Τ請求項i之用途，其特徵在於該血管運動徵候係與更 年期有關之灰管運動徵候。❹ 青求項1之用途，其特徵在於該血管運動徵候係與手 術所引起更年期有關之血管運動徵候。 求項1之用途，其特徵在於該血管運動徵候係與醫 源性更年期有關之血管運動徵候。 5.如1項_之料，其特徵在於該也管運動徵候係與 使用藥物、轄射或化療劑有關之血管運動徵候。 用求項1之用途，其特徵在於該血管運動徵候係選自 由潮熱、夜盜汗、情緒不定和煩躁不安所組成之群中。 7. 如印求項丨之用途，其特徵在於該血管運動徵候係選自 與男性自然或醫源性性腺機能減退有關之中度至重度血 官運動徵候所組成之群中。 8. 如咐求項7之用途，其特徵在於該血管運動徵候係與使 用藥物、轄射或化療劑有關之血管運動徵候。 9. 如叫求項7或8之用途，其特徵在於該血管運動徵候是男 性潮熱。 ' 1〇’如*青求項1至4及6至8中任一項之用途，其特徵在於該氟 班色林之形式為醫藥可接受的酸加成鹽，其係選自由選 133147.doc 200927118 自下列之酸類所形成鹽類中：丁二·酸、氫漠酸、乙酸、 反丁烯二酸、馬來酸、甲磺酸、乳酸、磷酸、鹽酸硫 酸、酒石酸、檸檬酸及其混合物。 11. 如請求項1至4及6至8中任一項之用途，其特徵在於該氟 班色林之形式為氟班色林多晶型A。 12. 如請求項丨至4及6至8中任一項之用途，其特徵在於該藥 劑之使用劑量範圍係介於每曰〇1至4〇〇叫敦班色林之133147.doc 200927118 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：lxHCl133147.doc
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-
2008
- 2008-09-10 CL CL2008002693A patent/CL2008002693A1/es unknown
- 2008-09-10 PE PE2008001580A patent/PE20091188A1/es not_active Application Discontinuation
- 2008-09-10 UY UY31335A patent/UY31335A1/es not_active Application Discontinuation
- 2008-09-11 WO PCT/EP2008/062011 patent/WO2009034111A1/en active Application Filing
- 2008-09-11 NZ NZ584183A patent/NZ584183A/en not_active IP Right Cessation
- 2008-09-11 CN CN2008801069327A patent/CN101801380B/zh not_active Expired - Fee Related
- 2008-09-11 ES ES08803978.9T patent/ES2444707T3/es active Active
- 2008-09-11 MX MX2010002032A patent/MX2010002032A/es not_active Application Discontinuation
- 2008-09-11 AU AU2008297104A patent/AU2008297104A1/en not_active Abandoned
- 2008-09-11 KR KR1020107005191A patent/KR20100059848A/ko not_active Application Discontinuation
- 2008-09-11 EP EP08803978.9A patent/EP2200614B1/en active Active
- 2008-09-11 US US12/675,231 patent/US20110136825A1/en not_active Abandoned
- 2008-09-11 JP JP2010524478A patent/JP2010539130A/ja active Pending
- 2008-09-11 AR ARP080103952A patent/AR068416A1/es unknown
- 2008-09-11 BR BRPI0816791A patent/BRPI0816791A2/pt not_active IP Right Cessation
- 2008-09-11 EA EA201000433A patent/EA201000433A1/ru unknown
- 2008-09-11 CA CA2699414A patent/CA2699414C/en not_active Expired - Fee Related
- 2008-09-11 TW TW097134893A patent/TW200927118A/zh unknown
-
2010
- 2010-01-19 ZA ZA201000384A patent/ZA201000384B/xx unknown
- 2010-03-11 TN TNP2010000108A patent/TN2010000108A1/fr unknown
- 2010-03-12 CO CO10029659A patent/CO6260073A2/es not_active Application Discontinuation
- 2010-04-08 MA MA32746A patent/MA31757B1/fr unknown
-
2013
- 2013-03-20 US US13/847,683 patent/US20140005203A1/en not_active Abandoned
-
2014
- 2014-12-26 US US14/583,275 patent/US10166230B2/en active Active
-
2017
- 2017-08-25 US US15/686,665 patent/US9949969B2/en not_active Expired - Fee Related
-
2018
- 2018-11-26 US US16/200,004 patent/US10596170B2/en not_active Expired - Fee Related
-
2020
- 2020-03-05 US US16/810,273 patent/US20200253962A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20180071283A1 (en) | 2018-03-15 |
| US20140005203A1 (en) | 2014-01-02 |
| MA31757B1 (fr) | 2010-10-01 |
| UY31335A1 (es) | 2009-04-30 |
| US20190091219A1 (en) | 2019-03-28 |
| CN101801380A (zh) | 2010-08-11 |
| US10596170B2 (en) | 2020-03-24 |
| US20110136825A1 (en) | 2011-06-09 |
| EP2200614B1 (en) | 2013-11-27 |
| WO2009034111A1 (en) | 2009-03-19 |
| CO6260073A2 (es) | 2011-03-22 |
| US10166230B2 (en) | 2019-01-01 |
| EP2200614A1 (en) | 2010-06-30 |
| PE20091188A1 (es) | 2009-08-31 |
| CN101801380B (zh) | 2013-05-08 |
| MX2010002032A (es) | 2010-03-15 |
| US9949969B2 (en) | 2018-04-24 |
| CL2008002693A1 (es) | 2009-10-16 |
| AR068416A1 (es) | 2009-11-18 |
| CA2699414C (en) | 2016-04-05 |
| AU2008297104A1 (en) | 2009-03-19 |
| NZ584183A (en) | 2012-05-25 |
| CA2699414A1 (en) | 2009-03-19 |
| KR20100059848A (ko) | 2010-06-04 |
| US20150250783A1 (en) | 2015-09-10 |
| ZA201000384B (en) | 2010-09-29 |
| ES2444707T3 (es) | 2014-02-26 |
| BRPI0816791A2 (pt) | 2019-09-24 |
| JP2010539130A (ja) | 2010-12-16 |
| EA201000433A1 (ru) | 2010-10-29 |
| TN2010000108A1 (fr) | 2011-09-26 |
| US20200253962A1 (en) | 2020-08-13 |
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