TW201808266A - 微小奈米化藥劑及其利用 - Google Patents
微小奈米化藥劑及其利用 Download PDFInfo
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Abstract
本發明的目的在於提供一種新穎的藥劑,其具有比以往的藥劑更高的治療效果。本發明藉由提供一種微小奈米化藥劑,來解決上述問題,該微小奈米化藥劑的分散於溶劑中的有效成分的平均粒徑為1~20nm。
Description
本發明有關一種微小奈米化藥劑、該藥劑作為微小血管血流減少劑的用途、使用該藥劑而實行的腫瘤及/或炎症性疾病的治療方法等,該微小奈米化藥劑的分散於溶劑中的有效成分的平均粒徑為1~20nm。
癌細胞和癌組織的間質細胞,能夠分泌血管內皮生長因子(VEGF)等血管生成因子(angiogenic factor),而在組織內形成新的血管網,該血管網是從已存在的血管系統分枝出來。此新的血管網被認為能夠供給癌組織成長所需要的營養,或成為轉移時的路徑。因此,阻礙腫瘤血管生成或將血管栓塞以免營養從這些腫瘤血管供給至癌組織之治療法受到注目,且已實行用以使小血管栓塞的藥劑的開發。 然而,腫瘤血管,如前所述,是形成細密的血管網,因此難以僅選擇性地將腫瘤血管栓塞,而多數的情況是採取下述方法:將已分枝有腫瘤血管之原本的血管栓塞,藉此阻止營養傳遞。然而,此方法需要使正常的血管栓塞,因此擔心對於正常組織造成的影響。
近年來,將藥劑送達至組織的特定部分的方法受到注目。利用血管造影等來特定出腫瘤部位,並對用以供給營養至該腫瘤部位的動脈注入微導管(microcatheter),然後從該處投予抗癌劑等藥劑,此方法被稱為超選擇性動脈注射法,能夠以高濃度將藥劑選擇性地送達至特定部位,被認為相較於全身性化學治療法,副作用較少且效果較高。
以這樣的方式使用插入於血管的醫療來進行治療的血管內治療,為低侵入性且能夠獲得較高效果而受到注目,但現狀是對於以腫瘤血管為主之各種微小血管的治療法在臨床上未充分實用化。
近年來,已開發一種方法,其應用超選擇性動脈注射法,對於腫瘤血管或其支持血管投予栓塞劑等,來將血管栓塞。例如,專利文獻1記載一種微球體(microsphere)血管栓塞劑,其含有抗癌劑也就是太平洋紫杉醇(paclitaxel)。專利文獻1亦記載,該製劑的目的之一在於將腫瘤血管中流動的血流物理性地栓塞,因此製劑的粒徑在乾燥狀態下為100~350μm。 [先前技術文獻] (專利文獻)
專利文獻1:日本特表2008-513381號公報
[發明所欲解決的問題] 本發明的目的在於提供一種新穎的藥劑,其對於細胞具有特別高的滲透效果。 [解決問題的技術手段]
本發明人在對於使用局部性地送達抗癌劑之超選擇性動脈注射法而實行的血管內治療進行研究的過程中,發現如果將分散於生理食鹽水中的吉西他濱(gemcitabine)鹽酸鹽(健澤(Gemzar))與甘草酸銨混合,則成為具有約60~120nm左右的平均粒徑的藥劑,所述藥劑能夠發揮減少腫瘤血管的高血流量、使腫瘤血管的密度下降的功效,並且本發明人認為此功效可能起因於:因抗癌劑的粒徑較小,以致該藥劑能夠穿透腫瘤血管的血管壁而能夠輕易到達腫瘤組織。基於所述見解,在進一步繼續研究用於癌症的血管內療法的製劑的過程中,發現藉由進一步縮小藥劑的粒徑,能夠使製劑送達至腫瘤細胞內,甚至進一步能夠送達至腫瘤細胞的核內,其結果,例如當作為微小血管血流減少劑來使用時,能夠發揮使腫瘤血管密度更下降等較高的治療效果,從而完成本發明。
亦即,本發明有關下述所揭露的技術: (1) 一種微小奈米化藥劑,其分散於溶劑中的有效成分的平均粒徑為1~20nm。 (2) 如(1)所述之微小奈米化藥劑,其中,分散於溶劑中的有效成分的粒度分佈為1~20nm。 (3) 如(1)或(2)所述之微小奈米化藥劑,其中,微小奈米化是藉由照射放射線來進行。 (4)如(1)~(3)所述之微小奈米化藥劑,其中,有效成分為抗癌劑。 (5)如(1)~(4)所述之微小奈米化藥劑,其中,該微小奈米化藥劑為腫瘤血管血流減少劑或炎症血管血流減少劑。 (6)如(5)所述之微小奈米化藥劑,其中,有效成分包含免疫檢查點抑制劑(immune checkpoint inhibitor)。 (7) 一種使藥劑微小奈米化的方法,其包含下述步驟:對前述藥劑照射100~200μSv/h的放射線10分鐘~60分鐘。 (8) 如(7)所述之方法,其中,放射線是以瀝青鈾礦石(uraninite)作為放射線源。 (9) 如(7)或(8)所述之方法,其中,藥劑是奈米化後的抗癌劑。 (10) 如(9)所述之方法,其中,奈米化後的抗癌劑包含吉西他濱鹽酸鹽與甘草酸之混合物。 [發明的功效]
根據本發明,能夠提供一種新穎的藥劑,其對於細胞的滲透力高。與以往的製劑相比,本案發明的藥劑的粒徑極端小,因而能夠通過細胞膜,甚至亦能夠通過核膜,因此成為一種藥劑,該藥劑對於細胞能夠發揮特別高的功效。所述藥劑,尤其當作為以減少腫瘤血管或炎症血管中流動的血流為目的之藥劑來使用時,能夠特別適當地發揮功效。
在具有微小血管的疾病、尤其是腫瘤部位中,由於過於發達的微小血管導致血管網複雜化,其結果,由於大量血液流動,導致血流鬱積,因而疾病部位成為低氧狀態。然而,藉由利用本發明的藥劑來選擇性地使微小血管中流動的血流減少,能夠消除血流鬱積,而改善微小血管周圍的低氧狀態。如果改善低氧狀態,則能夠破壞癌幹細胞的利基(niche),藉此抑制癌細胞增生,結果便能夠處置癌症。儘管是已發生癌症的器官,所述機轉仍能夠發揮功效,因此能夠確立一種處置方法,該處置方法對於所有癌症皆同樣有效。
以下詳細地說明本發明。 <1>本發明的微小奈米化藥劑 本發明提供一種微小奈米化藥劑,其分散於溶劑中的有效成分的平均粒徑為約1~20nm。 在本發明中,「藥劑」,意指能夠顯示特定的藥理學上的效果之有效成分(化合物)本身,但亦有時意指包含該有效成分之製劑(組成物)。 在本發明中,「微小奈米化藥劑」,意指一種藥劑,其具有顯示比以往的藥劑更高的細胞膜穿透性的程度的小粒徑,雖然不限定於此,但例如是具有小於40nm的粒徑的藥劑。微小奈米化藥劑,可藉由單獨地分散於溶劑中或藉由與其他成分組合並分散於溶劑中,來成為小粒徑,亦可在分散於溶劑中後施加縮小粒徑的處理。作為縮小粒徑的方法,能夠使用例如下述在該技術領域中通常使用的方法:振動、稀釋、攪拌等。
在本發明中,「微小血管」,意指在特定疾病部位中構成新生的微小血管網的血管。與通常的血管相比,作為微小血管的特徵,可列舉:較無秩序、過於密集,且具有較多動靜脈短路,血管壁的滲透性較高。作為微小血管的例子,雖然不限定於此,但可列舉例如:腫瘤血管、炎症血管、缺血的周圍血管、長期持續疼痛的部位的血管等。在本發明的一態樣中,微小血管較佳是腫瘤血管和炎症血管,更佳是腫瘤血管。
在本發明中,「腫瘤血管」,典型地意指一種從已存在的血管分枝出來且新生的血管,其可見於腫瘤組織中,且構成無秩序、過於密集、而且具有許多動靜脈短路之血管網。腫瘤血管,主要是藉由腫瘤細胞或腫瘤組織內的間質細胞所分泌的血管內皮生長因子(VEGF)等血管生成因子來形成,但其結構不穩定,且具有高穿透性。此血管,不僅對腫瘤細胞供給氧或營養,亦涉及血行性轉移(hematogenous metastasis)。 在本發明中,「炎症血管」,意指一種新生血管,其由炎症性細胞激素所誘發,該炎症性細胞激素是由炎症部位所產生,可典型地列舉例如:在風濕病(rheumatism)中於滑膜新生且構成血管網的血管等。
在本發明中,「長期持續疼痛的部位的血管」,意指在主訴為持續3個月以上的慢性疼痛且被診斷為變形性骨關節炎(osteoarthrosis deformans)、肌腱變性(tendinosis)、筋膜炎等的病態中,於觀察到疼痛的部位的筋膜(fascia)、肌腱、脂肪組織等處新生的血管。這些血管,不會顯示像腫瘤血管或炎症血管那樣明顯的血管密度異常,但如果仔細觀察,則伴隨早期的靜脈描繪,能夠確認血管密度增加。
在本發明中,「微小血管血流減少劑」,意指一種藥劑,其當被導入至微小血管時,具有使該微小血管的血流量減少的功效。在本發明的一態樣中,血流量的減少,能夠藉由將微小血管栓塞來產生。在另一態樣中,血流量的減少,能夠藉由破壞微小血管來產生。因此,微小血管血流減少劑,雖然不限定於此,但可包含例如:血管的栓塞物質、能夠阻礙血管生成的物質、能夠從血管漏出而減少血流的物質等。微小血管血流減少劑,可與其他藥劑合併使用,雖然不限定於此,但可與例如抗癌劑、消炎劑等合併使用。
本發明,是根據下述新的見解:將分散於溶劑中的抗癌劑等藥劑的粒徑設為特定的尺寸,雖然不限定於此,但例如設為小於40nm,藉此能夠顯示比以往的有效成分更高的藥效。因此,與含有同樣的有效成分之以往的藥劑相比,能夠以低用量來使用本發明的微小奈米化藥劑。 本發明的微小奈米化藥劑顯示較高藥效的理由並不清楚。雖然不受限於理論,但推測為例如下述理由:由於粒徑變小,導致與細胞表面受器的相配性提升等。
在本發明的一態樣中,微小奈米化藥劑的分散於溶劑中的有效成分的平均粒徑為1~20nm。在一較佳態樣中,微小奈米化藥劑的分散於溶劑中的有效成分的粒度分佈為1~20nm。本說明書中所用的「平均粒徑」,意指分散於溶劑中的全部粒子的粒徑的平均值;「粒度分佈」,意指分散於溶劑中的全部粒子的粒徑的分佈範圍。在本發明的一更佳態樣中,平均粒徑或粒度分佈為1~10nm。在一進一步較佳態樣中,平均粒徑或粒度分佈為2~6nm。
如上所述,本發明的微小奈米化藥劑,可藉由使其分散於溶劑中來成為小粒徑,亦可在分散於溶劑中後施加縮小粒徑的處理。作為使粒徑微小奈米化的處理,可使用下述在該技術領域中通常使用的方法:振動、稀釋、攪拌等,在一較佳態樣中,作為微小奈米化的方法,亦可列舉使用放射線的激效(hormesis)效果的方法等,該方法是藉由照射放射線來進行。可藉由例如下述方式來達成小粒度分佈:在已加入欲進行微小奈米化的藥劑之容器附近,設置能夠放射100~200μSv/h左右的γ射線的瀝青鈾礦,並放置10~30分鐘左右。
與粒度分佈較大的藥劑相比,本發明的微小奈米化藥劑,具有易於被細胞攝入的性質,因此能夠適合用於各種用途的醫藥製劑。作為能夠作為醫藥製劑來使用的有效成分,雖然不限定於此,但可列舉例如:抗癌劑、消炎劑、抗體製劑、雙磷酸鹽劑等。在一較佳態樣中,有效成分為抗癌劑。如上所述,與通常的藥劑相比,本發明的微小奈米化藥劑,即便低用量亦能夠發揮功效,因此在基於全身性投予的用途上亦能夠減輕副作用等。
在本發明的一態樣中,本發明的微小奈米化藥劑,能夠作為微小血管血流減少劑來使用。在微小血管中,血管壁的穿透性常是亢進的,因此能夠特別適合使用本發明的微小奈米化藥劑。作為能夠應用本態樣的微小血管血流減少劑的微小血管,雖然不限定於此,但可列舉例如腫瘤血管、炎症血管等。特佳是腫瘤血管。
當將本發明的微小奈米化藥劑作為腫瘤血管血流減少劑來使用時,作為其有效成分,可列舉例如抗癌劑、免疫檢查點抑制劑等。 作為用於腫瘤血管血流減少劑的抗癌劑,可較佳地列舉奈米化後的抗癌劑等。在本說明書中,「奈米化」,是指藉由單獨地分散於溶劑中或藉由與其他成分組合並分散於溶劑中,或者藉由在分散於溶劑中後施加縮小粒徑的處理,來製成具有約60~120nm左右的粒度分佈的藥劑。作為奈米化後的抗癌劑的例子,在沒有限定的情況下,除了吉西他濱鹽酸鹽(健澤)與甘草酸銨之混合物(G-G乳化液)以外,還可列舉:阿黴素(adriamycin)、益樂鉑(oxaliplatin)、博來黴素(bleomycin)等其他抗癌劑與G-G乳化液之混合物等。
在本發明的一特佳態樣中,可列舉微小奈米化後的抗癌劑,該微小奈米化後的抗癌劑是使用激效效果,來使G-G乳化液等奈米化後的抗癌劑微小奈米化而得。可藉由下述方式來製成2~6nm左右的粒度分佈:在具有60~120nm左右的粒度分佈的奈米化後的抗癌劑的附近,設置能夠放射150μSv/h左右的γ射線的瀝青鈾礦,並放置10~30分鐘左右。
用於腫瘤血管血流減少劑的免疫檢查點抑制劑,可以是在該技術領域中作為免疫檢查點抑制劑而已知的任意藥劑,雖然不限定於此,但可列舉例如:抗CTLA-4抗體、抗PD-1抗體、抗PD-L1抗體、抗TIM-3抗體、抗LAG-3抗體、抗B7-H3抗體、抗B7-H4抗體、抗BTLA抗體、抗VISTA抗體、及抗TIGIT抗體等。在本發明的一態樣中,免疫檢查點抑制劑,較佳是抗CTLA-4抗體、抗PD-1抗體及抗PD-L1抗體,更佳是抗CTLA-4抗體和抗PD-1抗體。作為抗CTLA-4抗體,可典型地列舉伊匹單抗(ipilimumab);作為抗PD-1抗體,可典型地列舉納武單抗(nivolumab)和派姆單抗(pembrolizumab);作為抗PD-L1抗體,可典型地列舉阿特朱單抗(atezolizumab)和MSB0010718C(阿維單抗(avelumab))。
在本發明中,「腫瘤(tumor)」,包含良性腫瘤和惡性腫瘤(癌症、惡性贅生物(malignant neoplasm))。癌症(cancer),包含造血器官的腫瘤、上皮性的惡性腫瘤(癌症,carcinoma)與非上皮性的惡性腫瘤(肉瘤,sarcoma)。本發明的藥劑能夠特別發揮治療效果的是具有腫瘤血管的癌症,典型地是實體癌(solid cancer)。通常當將免疫檢查點抑制劑用於處置癌症時,能夠處置的癌症,限於所對應的免疫檢查點蛋白質有涉及免疫逃避(immune evasion)的癌症。然而,當使用免疫檢查點抑制劑來作為腫瘤血管血流減少劑時,能夠處置的癌症並無特別限定。因此,例如,即便在使用抗CTLA-4抗體來作為本發明的微小血管血流減少劑的情況下,處置對象的癌症不一定必須表現CTLA-4。
本發明人發現,藉由將免疫檢查點抑制劑與其他免疫檢查點抑制劑或貝伐單抗(bevacizumab)等抗體藥劑加以組合來製備腫瘤血管血流減少劑,能夠達成約10~15nm左右的粒度分佈。因此,本發明的另一較佳態樣,包含以免疫檢查點抑制劑作為有效成分之微小血管血流減少劑,更佳是包含腫瘤血管血流減少劑。
本發明的微小奈米化藥劑,是分散於溶劑中,因此,典型地是液劑、注射劑等能夠注入的形態。作為能夠用於本發明的微小奈米化藥劑的溶劑,可列舉在該技術領域中通常作為注射劑的溶劑或稀釋劑來使用的溶劑等,雖然不限定於此,但可典型地列舉水、生理食鹽水等。
<2>本發明的使藥劑微小奈米化的方法 如上所述,本發明始於下述新發現:藉由使藥劑微小奈米化,與以往的藥劑相比,能夠以低用量來發揮所希望的功效。因此,在一方面,本發明有關使藥劑微小奈米化的方法。
在本發明的微小奈米化方法中,特別適合使用的是利用了放射線的激效效果的方法。激效效果,是指「一般在高濃度或大量使用的情況下為有害之物質,當低濃度或微量使用時卻能夠帶來有益的效果」的現象,在放射線中亦能觀察到此效果。作為能夠放射顯示激效效果的放射線之放射線來源,可列舉例如瀝青鈾礦等,在本發明的微小奈米化方法中亦能夠適合使用瀝青鈾礦。
本發明的微小奈米化方法,典型地是藉由下述方式實施:在欲進行微小奈米化的藥劑附近,照射約100~200μSv/h左右的放射線10~60分鐘左右。所照射的放射線的劑量,較佳是約100~150μSv/h左右,更佳是約150μSv/h。照射的時間,較佳是10~30分鐘。
如上所述,當使用本發明的微小奈米化藥劑來作為微小血管血流減少劑時,能夠期待特別高的效果。因此,在本發明的一較佳態樣中,被微小奈米化的藥劑,是奈米化後的抗癌劑。作為奈米化後的抗癌劑,雖然不限定於此,但可典型地列舉:吉西他濱鹽酸鹽與甘草酸之混合物(G-G乳化液)、或G-G乳化液與其他抗癌劑之混合物等。
<3>本發明的實體腫瘤處置方法 如上所述,本發明的微小奈米化藥劑,能夠使各種疾病中的微小血管的血流減少,作為其結果,能夠減少微小血管的密度。因此,本發明的微小奈米化藥劑,能夠適合用於微小血管的血流減少方法、及被認為過度形成微小血管的疾病或症狀的處置方法。亦即,在一方面,本發明包括:使用本發明的微小奈米化藥劑而實行的微小血管的血流減少方法、及被認為過度形成微小血管的疾病或症狀的處置方法。作為能夠利用本發明的微小血管血流減少方法進行處置的疾病或症狀,可列舉:實體腫瘤、風濕病、主訴為持續3個月以上的慢性疼痛的變形性骨關節炎、肌腱變性、筋膜炎、椎管狹窄症( spinal stenosis)或被認為是慢性疼痛症候群的各種疼痛等。 本發明的微小奈米化藥劑,能夠適合用來作為一種腫瘤血管血流減少劑,其當投予至腫瘤血管時,能夠使該腫瘤血管的血流減少,藉此改善低氧狀態,且使腫瘤血管密度下降。因此,本發明的微小奈米化藥劑,能夠用於下述方法:藉由改善實體腫瘤周圍的微環境(利基),來處置實體腫瘤。亦即,在一較佳方面,本發明有關一種實體腫瘤的處置方法,其是藉由使腫瘤血管的血流減少來進行。
本發明的實體腫瘤的處置方法,一般而言,能夠使用被稱為「血管內治療」的手法來加以實施,且包含下述步驟:將本發明的微小奈米化藥劑導入欲減少血流的微小血管網中。只要將本發明的微小奈米化藥劑導入微小血管即可,因此可以是全身性投予,亦可以是局部性投予。在本發明中,「血管內治療」一詞,除非另有記載,否則是指一種治療法,其藉由對於微小血管投予能夠使血流減少的藥劑,來處置疾病。因此,作為血管內治療的一態樣,能夠適合使用本發明的微小血管血流減少方法、及包含實體腫瘤且被認為過度形成微小血管之疾病或症狀的處置方法。
在本發明的一較佳態樣中,微小奈米化藥劑,是局部性投予至對象的微小血管中。作為局部性投予的方法,可典型地列舉動脈注射法,其中,較佳是下述方法:將導管導入至目的血管附近為止,並直接投予藥劑。在本發明的方法中,目的血管是微小血管,因此為了將導管導入至更靠近目的血管附近為止,導管較佳是使用微導管。使用微導管而實行的對微小血管進行局部性投予的方法,在該技術領域中為公知技術,雖然不限定於此,但可列舉例如超選擇性動脈注射法等。所投予的微小奈米化藥劑的用量,是隨著藥劑的有效成分的種類而不同,但只要是本發明所屬技術領域中具有通常知識者,即能夠計算適當的量。
如上所述,本發明的實體腫瘤處置方法,是藉由下述方式來處置固體腫瘤:使將營養送達至固體腫瘤的腫瘤血管的血流減少,來使腫瘤血管密度下降,因此,若是具有腫瘤血管之實體腫瘤,則任何腫瘤皆能夠處置。因此,作為能夠處置的腫瘤,並不限定於此,可列舉例如:頭頸癌、食道癌、肺癌、乳癌、胃癌、肝癌、膽管癌、胰臟癌、大腸癌、腎癌、膀胱癌、攝護腺癌、睪丸癌、卵巢癌、子宮頸癌、子宮內膜癌、惡性淋巴瘤、肉瘤等。
又,如上所述,本發明的實體腫瘤的處置方法,是藉由下述方式來發揮治療效果:使腫瘤血管的血流減少,藉此使腫瘤血管密度下降。此處,已知腫瘤血管不僅是將營養送達至腫瘤,亦扮演作為血中循環腫瘤細胞(CTC)的出入口的角色。本發明的方法,藉由使腫瘤血管密度下降且使腫瘤血管消失,能夠堵塞此出入口,其結果,CTC的量下降。藉此,能夠防止腫瘤轉移。因此,實體腫瘤,可以是原發性的實體腫瘤,亦可以是轉移後的實體腫瘤。根據本發明的方法,藉由處置原發部位的腫瘤,而能夠處置轉移處的腫瘤。相反地,藉由處置轉移處的腫瘤,亦能夠處置原發部位的腫瘤。 [實施例]
參照以下的例子來更詳細地說明本發明,但這些例子是表示本發明的特定的具體例,本發明不限定於這些例子。
<例1.微小奈米化抗癌劑> (1) 奈米化後的抗癌劑的粒度分佈的測量 將200mg健澤(從日本禮來股份有限公司取得)、80mg甘草酸單銨(從米諾發源製藥股份有限公司(MINOPHAGEN PHARMACEUTICAL CO., LTD)取得)、及5mg亞伯杉(Abraxane,從大鵬藥品工業股份有限公司取得)混合,來製備乳化液。又,以相同方式進行,來製備添加有下述成分來取代亞伯杉而成之乳化液:10mg阿黴素、10mg剋癌易(taxotere)、50mg益樂鉑、50mg益樂鉑+4mg絲裂黴素(mitomycin)、50mg益樂鉑+4mg絲裂黴素+10mg阿黴素、或15mg博來黴素。
粒度分佈,是使用LS粒度分佈測定裝置LS13 320(貝克曼庫爾特公司製造)來測量。 結果如表1所示。
[表1]
如表1所示,雖然隨著所混合的製劑而有些許差異,但製備了成為約60~120nm的粒度分佈的藥劑。
(2) 微小奈米化後的抗癌劑的粒度分佈的測量 在已加入奈米化抗癌劑(在上述(1)中,於添加有50mg益樂鉑+4mg絲裂黴素+250mg5-氟尿嘧啶來取代5mg亞伯杉而成之混合物(cocktail)中,添加25mg亞伯杉、10μg馬沙骨化醇(maxacalcitol)、0.35mg硼替佐米(bortezomib)、2mg普潘奈(propranolol)、36NU神經妥樂平(neurotropin )、25mg依那西普(etanercept)、3200U凝血酶調節素(thrombomodulin),並進行製劑化而成)之容器附近,設置能夠放射約150μSv/h的γ射線的瀝青鈾礦,並放置30分鐘後,測量粒度分佈。粒度分佈的測量,是使用DelsaMax Pro(貝克曼庫爾特公司製造)來實行。結果如第1圖所示。存在於約60nm附近的峰,因照射放射線而被微小奈米化,遷移至約4nm附近。
<例2.微小奈米化免疫檢查點抑制治療製劑> 將20mg納武單抗、10mg派姆單抗及50mg貝伐單抗分散於100ml生理食鹽水中,來製備微小奈米化免疫檢查點治療(CBT)製劑A。又,將20mg納武單抗、10mg派姆單抗及2mg伊匹單抗分散於100ml生理食鹽水中,來製備微小奈米化CBT製劑B。利用DelsaMax Pro(貝克曼庫爾特公司製造),並使用表2的條件來測定粒度分佈。結果如第1圖所示。
[表2] 儀器
儀器參數:測量
第1圖中的A表示微小奈米化CBT製劑A的測定結果,第1圖中的B表示微小奈米化CBT製劑B的測定結果。微小奈米化CBT製劑A在約13nm的粒徑處顯示峰,微小奈米化CBT製劑B在約12.6nm的粒徑處顯示峰。 [產業上之可利用性]
根據本發明,能夠製備一種藥劑,其具有數nm~十數nm級的粒度分佈,藉由將所述藥劑投予至腫瘤血管,能夠帶來比以往的藥劑更優異的藥物動力學(pharmacokinetics)的變化,尤其當作為腫瘤血管的血流減少劑來使用時,能夠帶來腫瘤的血流動力學(hemodynamics)的變化。又,根據本發明亦可知,藉由將具有微小奈米化後的粒徑之免疫檢查點抑制劑作為包含腫瘤血管之微小血管的血流減少劑來使用,若與以往的血管內治療相比,能夠以較長的治療間隔來進行處置,從而能夠對於改善晚期癌症患者的生活品質有很大的貢獻。進一步,在本發明的投予中,是以局部性投予為主,因此與以往的投予方法相比,能夠以少量來發揮功效,因此當使用高價的免疫檢查點抑制劑時亦能夠減輕經濟上的負擔。
無
第1圖是表示藉由照射放射線來使奈米化抗癌劑微小奈米化而得之製劑的粒度分佈測量結果的圖。上方的圖表是表示粒子的粒度分佈的圖表,下方的表是峰的數據。在照射放射線前已存在於Peak2的位置(60nm附近)的峰,因照射放射線而遷移至Peak1的位置(4nm附近)。 第2圖是表示微小化奈米免疫檢查點抑制劑的粒徑測量結果的圖表。A表示微小奈米化CBT製劑A的粒度分佈測量結果,B表示微小奈米化CBT製劑B的粒度分佈測量結果。
國內寄存資訊 (請依寄存機構、日期、號碼順序註記) 無
國外寄存資訊 (請依寄存國家、機構、日期、號碼順序註記) 無
Claims (10)
- 一種微小奈米化藥劑,其分散於溶劑中的有效成分的平均粒徑為1~20nm。
- 如請求項1所述之微小奈米化藥劑,其中,分散於溶劑中的有效成分的粒度分佈為1~20nm。
- 如請求項1或2所述之微小奈米化藥劑,其中,微小奈米化是藉由照射放射線來進行。
- 如請求項1~3中任一項所述之微小奈米化藥劑,其中,有效成分為抗癌劑。
- 如請求項1~4中任一項所述之微小奈米化藥劑,其中,該微小奈米化藥劑為腫瘤血管血流減少劑或炎症血管血流減少劑。
- 如請求項5所述之微小奈米化藥劑,其中,有效成分包含免疫檢查點抑制劑。
- 一種使藥劑微小奈米化的方法,其包含下述步驟:對前述藥劑照射100~200μSv/h的放射線10分鐘~60分鐘。
- 如請求項7所述之方法,其中,放射線是以瀝青鈾礦石作為放射線源。
- 如請求項7或8所述之方法,其中,藥劑是奈米化後的抗癌劑。
- 如請求項9所述之方法,其中,奈米化後的抗癌劑包含吉西他濱鹽酸鹽與甘草酸之混合物。
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