TW201414506A - 噴灑用凝膠型皮膚及/或黏膜附著型製劑及使用該製劑之投藥系統 - Google Patents
噴灑用凝膠型皮膚及/或黏膜附著型製劑及使用該製劑之投藥系統 Download PDFInfo
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Abstract
本發明係提供由在含有皮膚及/或黏膜附著劑之凝膠基劑中包含醫藥活性物質的凝膠製劑所組成的噴灑用凝膠型皮膚及/或黏膜附著型製劑,以及使用該製劑之投藥系統。
Description
本發明係有關將包含醫藥活性物質之凝膠型皮膚及/或黏膜附著製劑、以及包含醫藥活性物質之黏性凝膠型皮膚及/或黏膜附著製劑,使用凝膠型製劑用噴霧容器(上方排壓無氣式噴霧容器),而可任意設定噴霧容器之投藥方向來使用的投藥系統。特別是有關以噴鼻用而言,使用鼻用噴灑容器而可任意設定噴霧容器之投藥方向且將該製劑噴霧在鼻腔內,並且使凝膠基劑廣泛分布並滯留在鼻腔內的製劑以及使用該製劑之投藥系統。
以往藥物的投藥手段係廣泛利用將液劑裝入噴霧容器,在內腔及身體表面上之黏膜及皮膚噴霧的投藥方法。特別是鼻腔內投藥型製劑已被廣泛地利用。在此所用的藥物雖然只限於期待鼻炎治療等局部作用者,但近來以全身作用為目的之藥物的投藥路徑亦受到注目。期待能全身作用之美妥芬諾(Butorphanol)或舒馬普坦(sumatriptan)等低分子藥物,以及抑鈣素(calctonin)或去氨加壓素(Desmopressin)等胜肽性藥物的鼻腔內投藥型製劑係已在市面上販售,此外,還大量嘗試期待能改善吸收、速效性之藥物
的經鼻投藥應用。
對黏膜之噴霧投藥型製劑,特別是鼻腔內投藥型製劑的優點,可列舉(1)因快速吸收而能期待即效性,(2)能迴避因初次通過肝臟而引起的藥物分解,(3)能迴避在胃酸或消化道酶等消化道中的藥物分解,(4)藉由高之生物利用率(bioavaliability)而可使藥物用量降低,(5)與注射相比,為非侵襲性之投藥路徑,(6)本身能進行治療,(7)能使藥物直接到達血液循環或中樞神經系統等;另一方面,鼻腔內投藥型製劑的缺點,可列舉(1)能投藥於鼻腔的投藥量1次限定為25至200μL,(2)1kD以上之高分子量的化合物用此路徑投藥是有困難的,(3)會受到鼻腔的病理狀態而影響吸收,(4)鼻腔狀態具有個體差異,(5)黏液纖毛清除作用(mucociliary clearance)的異物排除系統會影響藥物吸收,(6)有鼻腔內酶屏障的存在,(7)因藥物而導致對鼻黏膜的刺激等。
鼻腔和口腔同為與外界接觸的最初部位,具有非常優異的異物去除能力與感染防禦能力。這些功能之異常活性化或因此而導致之破綻,係成為鼻炎、鼻子過敏等的原因。特別是花粉症已成為嚴重的社會問題。以治療這些鼻局部性疾病為目的,含有血管收縮劑、抗過敏劑、類固醇劑等的噴鼻藥已在市面上販售多數。
另一方面,含有分子量1000至3000之生理活性胜肽或水溶性胜肽的經鼻吸收型製劑係已販售於市面上。這些水溶性高分子藥物以經口投藥為無效,只有以注射劑投藥才是有效的投藥方法,但經鼻投藥可得到數%至十幾%左右的高之生物利用率。重要的原因是作為水溶性高分子藥物吸收路徑的鼻黏膜上皮
層之滲透性比消化道或其他黏膜之滲透性都要高出許多。如此一來,期待能全身作用之水溶性高分子藥物的經鼻吸收型製劑對於用來作為代替注射劑的非侵襲性投藥劑形式是非常有用的。
近年來,利用鼻黏膜上皮層之滲透性比其他部位黏膜之滲透性更好的特點,已設計及/或開發出像麻藥性鎮痛藥、偏頭痛藥等可期待緩和劇烈疼痛的經鼻吸收型製劑。如此含有中樞神經作用型藥物的經鼻吸收製劑,能期待比經口投藥劑有更快的藥理效果,而且由於可讓患者自己投藥,因此對提升患者的生活品質有顯著的貢獻。鼻腔有類似淋巴系統組織的NALT(鼻咽相關淋巴組織)的存在。目前已設計及/或開發出將利用鼻之免疫反應性高之特點的流行性感冒疫苗或白喉疫苗等作為對於會空氣傳染之病毒之疫苗投藥路徑的鼻腔內投藥型製劑。儘管對這類活用鼻腔解剖生理學特徵之鼻腔內投藥型製劑的開發寄予厚望,但為了設計及/或開發該等製劑,必須了解鼻黏膜與周圍組織的解剖生理學特徵來進行製劑設計。
在鼻腔內投藥型製劑中,由於從鼻腔的清除作用(clearance)為大,因此需要想盡各種辦法。已開發的製劑劑型係包含鼻腔軟膏型製劑、液滴(droplet)型製劑、噴灑型製劑、粉末型製劑等。這些製劑係以藉由提高在鼻腔內分散性並使活性藥物與鼻黏膜接觸之時間增加,或提高滯留性(附著性)並使活性藥物與鼻黏膜接觸之時間增加,而使活性藥物有效率地於鼻腔表現效果,並使其從鼻腔吸收為目的而進行設計及/或開發(專利文獻1)。
鼻腔軟膏型製劑通常因為用手指塗布所以不衛生,而且只用手指塗布無法到達鼻腔深部的黏膜,故要投與一定量的
活性藥物是有困難的。
液滴(droplet)型製劑雖然是過去最簡便的方法,但除了難以投予正確量之外,還會因黏液纖毛清除作用而快速地從鼻腔往咽頭側被去除。
噴灑型製劑因為藉由唧筒(pump)吸取藥液製劑,在鼻腔內噴霧成霧狀,所以比液滴(droplet)型製劑的分散性更好。
粉末(power)型製劑是在溶液中容易分解的藥物或是欲確保在鼻腔內之滯留性的情況下利用。然而,有時會有對鼻子投藥時的不舒服感或黏膜阻礙性,而在粒子系之均勻化等製劑設計上有困難。
在這些鼻腔內投藥型製劑中,最常使用的劑型是噴灑型製劑,因為其係簡便且使用感良好。噴灑型製劑也進行改善活性藥物與鼻黏膜之接觸面積、增長接觸時間(亦即滯留性),以及提升藥效、吸收性的各種嘗試。
一般的噴灑型製劑為了避免被鼻前庭捕捉或從鼻孔流失,普遍都奉勸在噴霧操作時用鼻子吸氣,但推測實際上鼻瓣(nasal valve)的彈性組織會進一步變窄,而大部分的製劑會從鼻子流到嘴巴,有被吞下之虞。
此處通常使用的液體噴灑裝置,多半使用藉由唧筒以管吸取內容藥液之液劑噴灑型製劑,通常以角度在約0至25°的範圍使用(參照第3圖)。為了必須讓用以將容器中設置之藥液吸取的管的前端與藥液接觸,故頭部前傾以噴霧容器之投藥角度接近0°的方式使用並投藥。然而,用此投藥方法,沒有黏度、沒有附著性的一般液劑或低黏度液劑會直接流向外鼻孔,另一方面,
在頭部後仰並使噴霧容器之投藥角度為約65至90°之方式使用時,在一般液劑噴灑型製劑中,藥液會碰撞至鼻腔內的鼻甲或鼻隔等壁上,因為沒有附著性所以流到下鼻道,大部分的製劑會流到嘴巴而被吞下。像這樣流到下鼻道,雖然可添加後述之附著性高分子作為製劑基劑,而得到某種程度之改善,但藉由使用附著性高分子,因噴霧製劑粒子的粒徑會變大、噴霧容器的噴射角度會變窄而無法廣泛地分散,且由於鼻腔內的粒徑彼此的碰撞而成為更大的粒子並碰撞至壁上,所以有相當多部分的製劑仍會流到嘴巴而被吞下。此外,使投藥角度增加來進行噴霧,雖然也能期待製劑廣泛分布於鼻甲,但是在使用一般噴灑型製劑時,用以吸取的管的前端係變得無法與藥液接觸,在頭部前傾後仰而調整投藥角度時會有一定的限制。
再者,由於上述液體噴灑裝置是吸入外部空氣的系統,因此不得不使用一定量的防腐劑等。
此外,用噴鼻裝置噴霧的製劑粒徑,也是欲改善藥物之清除作用(clearance)時應考慮的要素之一。換言之,人類的鼻腔大約有150至180cm2的面積,從外鼻孔到鼻咽的距離以直線測定也有12至14cm,為了保護鼻腔的下呼吸道,以最佳化的方式形成狹窄複雜的幾何學構造,鼻腔內之鼻瓣之狹窄間隙係相當於鼻腔之總空氣阻力之一半。此外,鼻瓣後部是由鼻甲分隔成狹縫狀的空間,經噴霧之製劑粒子在此處的速度會下降,與鼻黏膜接觸並分散。然而,在複雜彎曲的鼻腔內,經噴霧之製劑粒子會直接碰撞鼻腔內壁而被捕捉沈積。也就是說,使製劑噴射在鼻腔內時,粒徑5μm以上的製劑粒子幾乎被鼻腔所捕捉,然後,碰撞
到鼻腔內之鼻甲黏膜並被捕捉沈積的製劑粒子會藉由覆蓋在黏膜上之纖毛細胞的纖毛運動而傳送至後方,經過後鼻腔、咽,最後吞嚥或從口腔排出。對於因此纖毛與黏液而使作為異物之活性藥物被清除(黏液纖毛清除作用)的對策,是鼻腔內投藥型製劑在設計上非常重要的一點,作用於鼻黏膜之藥物之效果及/或吸收性係主要取決於鼻黏膜捕捉部位之藥物的滯留性(製劑附著性)與滲透性。於鼻腔內之有效捕捉部位投藥的藥物,主要是藉由黏液纖毛清除作用而往食道或呼吸道方向被去除、與透過鼻黏膜而往鼻黏膜細胞側的吸收方向被去除,以該等之併發反應而從投藥的捕捉部位消失。若從有效捕捉部位往食道、呼吸道方向的去除速度快時,吸收方向的清除作用就會降低,減少生物利用率。另一方面,經噴霧之製劑粒徑變小雖然也可將鼻腔內的到達部位改善為廣範圍,但因為到達肺部的危險性會提高,所以必須考量其均衡是熟習此項技術者已知的事實。因此,為了使往吸收方向的清除作用增大,重要的是以最佳的經噴霧之製劑粒徑、適當的噴射角度、均勻的密度噴霧,更進一步加強藥物的滯留性,亦即加強製劑的鼻黏膜附著性,以改善吸收,而且必須添加附著性高分子作為製劑基劑以獲得上述改善。
在噴鼻製劑之噴霧方面,理論上雖然可使用霧化器將噴霧製劑粒子控制在50μm以下,而得以一邊吸入噴霧一邊使用,並送達至該製劑之鼻瓣的後部,但若使用50μm以下的微粒,則一半以上在到達支氣管、肺部之前,會在鼻腔內被捕捉而使藥物流失,同時亦出現不良之副作用。而且,像霧化器這類的機器係價格昂貴,對於能夠使製劑以價廉、簡便的方式廣泛分布於整
個鼻腔內的粒徑而言,並不是有效的系統。
本案發明者已發明可改善噴灑型製劑之藥物在鼻腔內的滯留性,並適用於黏膜或皮膚之可噴霧的噴霧用凝膠基劑,進而提出適用於乃黏膜部位之鼻腔,並可作為展著性優異的鼻用噴灑型製劑使用的噴霧用凝膠基劑及在該基劑中混合活性藥物而成的噴霧用凝膠劑(專利文獻1)。
然而,即使調製用以提高滯留性的高黏度噴霧用凝膠劑,也會有因噴霧操作而導致黏度降低的習知問題。
再者,由於該噴霧用凝膠製劑具有高黏度,因此作為噴灑型製劑使用時,會附著在噴灑容器中的側壁,導致無法噴出容器外而使製劑殘留在容器內的殘留率比一般的液劑高,而且,因為內容製劑的液體不容易在噴灑容器內迅速地流動,故依據噴射角度有劇烈的變化等,會有難以保證一定量之穩定噴霧量的情形。另外,還有因粒度分布使噴霧製劑粒子難以到達鼻腔深處,以及無法調整噴射角度,難以均勻密度進行噴霧的缺點。
再者,在對皮膚噴霧而投藥之製劑方面,也存在著關於製劑之滯留性、噴霧容器之投藥角度等與上述噴鼻製劑類似的問題。
[專利文獻1]日本專利第2011069號
如上所述,雖然確認到若將藥液製成噴霧用凝膠基劑,對於改善對鼻腔、眼睛、耳朵、口腔、直腸、陰道、尿道等黏膜的噴霧投藥型製劑,特別是鼻用噴灑型製劑之藥液的滯留性會有一定的改善效果,但即使使用現有的噴鼻劑,因為其滯留性
故從容器噴霧時會伴隨如上所述之高殘留率或噴霧量不穩定的阻礙,此外還必須改善藥液本身因噴霧操作而導致之黏度降低。再者,由於現有的鼻用噴灑裝置係吸入外部空氣的系統,必須使用一定量的防腐劑等,所以在安全性或製造成本方面仍有改善的空間。
此外,對於複雜的鼻腔內部構造,為了使噴霧製劑廣泛分布於鼻甲,而認為能配合鼻腔內部構造而調整噴灑的投藥角度來投藥等方法係有效,但以往鼻用噴灑型製劑的投藥角度也有一定的限度,因此必須開發出以有效角度投藥而使噴霧製劑廣泛分布於鼻甲之投藥系統、以及可達到此目的之噴鼻製劑。
再者,對於手、指頭、腳、身體、胯股、頭皮、肛門周圍、性器周圍等皮膚的噴霧投藥型製劑,也有和上述噴鼻製劑類似的問題。
本案發明者鑑於上述狀況重複進行深入研究的結果,發現藉由將凝膠型皮膚及/或黏膜附著型製劑裝填入與一般噴鼻製劑等所用的噴霧容器不同的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)中,可任意設定噴霧容器之投藥方向的投藥系統,因而完成本發明。具體而言,藉由含有一定量的羧乙烯聚合物及/或結冷膠(gellan gum)作為皮膚及/或黏膜附著劑,而可調製出能達到上述目的的凝膠型皮膚及/或黏膜附著製劑。特別是發現藉由添加結冷膠,可顯著改善因為鼻涕等而使本製劑黏度降低的情形。
此外,發現從外部賦予剪切力給上述製劑,將有較高的黏度(例如10000mPa‧s至50000mPa‧s)之製劑之黏度予以
調整,使均勻噴霧變得可能,並且可完全抑制因噴霧操作而導致的黏度降低。而且,賦予黏度調節劑以及從外部來之剪切力以調整黏度時,令人驚奇地發現能以適合使用目的之方式來管理噴霧容器的噴射角度、噴射密度。換言之,發現施加剪切力來調整黏度的凝膠型黏膜附著製劑會使噴霧容器的噴射角度有變窄的傾向,而添加黏度調節劑及施加剪切力時,噴射角度會有變寬的傾向。只要利用這個原理,不管是否為相同的噴霧容器,都能以適合使用目的之方式來調整管理噴霧角度。再者,關於噴霧密度,由於發現在不施加剪切力只藉由黏度調節劑調整之凝膠型黏膜附著製劑中,雖然噴霧容器之噴霧有偏向外圍的傾向,但藉由施加剪切力即可使噴霧均勻,故只要利用這些要素,亦能以適合使用目的之方式來管理此噴霧之噴射密度。
此外,發現這些凝膠型皮膚及/或黏膜附著製劑具有黏性及/或附著性,且難以穩定的噴霧量進行噴霧,並且難以將容器內的製劑用完,但若使用凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器),則有穩定的噴霧量而且能大幅改善使用後的殘留率。
尤其是使用此製劑及系統之噴鼻製劑,將投藥姿勢(頭部角度)與噴灑容器設定為有效角度並對鼻腔噴霧時,可使製劑廣泛分布於鼻甲。
具體而言,本發明係提供由在含有皮膚及/或黏膜附著劑之凝膠基劑中包含醫藥活性物質的凝膠製劑所組成的噴灑用凝膠型皮膚及/或黏膜附著型製劑。
再者,本發明係提供適用的黏膜為鼻腔、眼睛、耳朵、口腔、直腸、陰道或尿道,或是適用的皮膚為手、指頭、腳、
身體、胯股、頭皮、肛門周圍或性器周圍之上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。特別是本發明係以噴鼻用而言,提供由在含有黏膜附著劑之凝膠基劑中包含醫藥活性物質的凝膠製劑所組成的鼻噴灑用凝膠型黏膜附著型製劑。
再者,本發明係提供含有羧乙烯聚合物及/或結冷膠作為皮膚及/或黏膜附著劑之上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。此外,本發明係提供在含有作為皮膚及/或黏膜附著劑之羧乙烯聚合物或結冷膠時,其重量%為0.1%至2.0%;在含有羧乙烯聚合物及結冷膠兩者時,兩者合計為0.2%至4.0%之上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。
再者,本發明係提供含有0.1重量%至2.0重量%之羧乙烯聚合物作為皮膚及/或黏膜附著劑,並從外部賦予剪切力來調整黏度的上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。調整過的黏度通常為50mPa‧s至5000mPa‧s,較佳為100mPa‧s至4000mPa‧s,更佳為500mPa‧s至3000mPa‧s,最佳為2000mPa‧s至2500mPa‧s。
另外,本發明係提供含有0.1重量%至2.0重量%之羧乙烯聚合物作為皮膚及/或黏膜附著劑,並賦予黏度調節劑以及從外部來之剪切力,將有較高的黏度(例如10000mPa‧s至50000mPa‧s)之製劑之黏度予以調整,以適合使用目的之方式來管理噴霧容器的噴射角度、噴射密度之上述鼻噴灑用凝膠型皮膚及/或黏膜附著型製劑。藉由從外部施加剪切力,而使噴射角度有變窄的傾向。此變窄的噴射角度係因為添加黏度調節劑而變寬,調整這2個要素即能以適合使用目的之方式來管理噴射角度。再
者,藉由從外部施加剪切力,會使只用黏度調節劑調整時偏向外圍的噴霧密度成為均勻噴霧。因此,藉由從外部來的剪切力能以適合使用目的之方式來管理噴射密度。
在此,黏度調節劑最好係從氯化鈉、氯化鉀及氯化鈣所成群組中選出。調整過的黏度通常為50mPa‧s至5000mPa‧s,較佳為100mPa‧s至4000mPa‧s,更佳為500mPa‧s至3000mPa‧s,最佳為2000mPa‧s至2500mPa‧s。
再者,本發明係提供含有從中性或鹼性之水溶性胺基酸中選出的羧乙烯聚合物增黏劑,該增黏劑相對於羧乙烯聚合物之重量比在1:0.5至1:3(較佳為1:1至1:2)的範圍之上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。此外,該羧乙烯聚合物的增黏劑較佳為精胺酸、離胺酸及/或烏胺酸。
再者,本發明係提供包含0.001至10重量%之醫藥活性物質的上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。
再者,本發明係提供醫藥活性物質為溶解狀態、懸浮狀態或乳化狀態之上述噴灑用凝膠型皮膚及/或黏膜附著型製劑。
本發明係提供特徵為將上述噴灑用凝膠型皮膚及/或黏膜附著型製劑裝填入凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)中,而可任意設定噴霧容器之投藥方向且噴霧在欲處理之患部,並能以所有角度來噴霧凝膠基劑之投藥系統。特別是提供特徵為將上述鼻噴灑用凝膠型黏膜附著型製劑裝填入凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)中,而可任意設定噴射角度且噴霧在鼻腔內,並且使凝膠基劑廣泛分布並滯留在鼻腔內的
投藥系統。
再者,本發明係提供凝膠製劑的黏度在50mPa‧s至5000mPa‧s(較佳為100mPa‧s至4000mPa‧s)的範圍,且藉由噴霧操作所得到之經噴霧之製劑粒子的黏度保持率為50%以上之上述投藥系統。
再者,本發明係提供含有藉由從外部來的剪切力將凝膠製劑的黏度調整為50mPa‧s至5000mPa‧s之範圍的凝膠製劑,且藉由噴霧操作所得到之經噴霧之製劑粒子的黏度保持率為90%以上之上述投藥系統。
再者,本發明係提供經噴霧之製劑粒子的平均粒徑在10μm至100μm(較佳為50μm至100μm)的範圍之上述投藥系統。
再者,本發明係提供含有藉由從外部來的剪切力(添加適當的黏度調節劑)而將凝膠製劑的黏度調整到50mPa‧s至5000mPa‧s之範圍的凝膠製劑,並使噴霧容器的噴射角度設在10°至70°的範圍,且使噴射密度成為均勻或集中於外圍,以適合使用目的之方式來管理調整之上述投藥系統。
再者,本發明係提供噴霧因使用至完全無法噴霧時,容器中的凝膠製劑殘留率為20%以下(較佳為15%以下,更佳為10%以下),且在設定量±10%以內之範圍的噴霧率為70%以上(較佳為80%以上)之上述投藥系統。
再者,本發明係提供噴霧容器的投藥角度為0°至360°之任一角度或角度範圍之上述投藥系統。此外,本發明係提供投藥角度為45°至180°之任一噴霧容器的投藥角度或角度範圍
之上述噴鼻用投藥系統。
再者,本發明係提供特徵為沒有調配防腐劑或保存劑或是其通常調配量減量至50%以下之上述投藥系統。
再者,本發明係提供在凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)的容器內裝填入能消除無效空間的環,並在滑動底蓋主體上具有5°至30°(較佳為15°至25°)的角度,而該環也具有相同角度之上述投藥系統。
第1圖係表示本發明所使用的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)。圖面之右半面表示可看到內部構造之剖面圖。
第2圖係表示第1圖所示之凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)剖面圖之重要部分的放大圖。惟,右半面表示在本發明之特徵的滑動底蓋主體上具有一定角度(本圖面係以20°作為一例)的容器,左半面則表示習知的上方排壓無氣式噴霧容器。
第3圖係表示將本發明之噴鼻製劑,以規定的角度插入人體之鼻甲(鼻道)並投藥的情形。以噴鼻製劑成垂直的狀態作為0°,表示出在25°、45°、65°、90°、135°及180°下投藥的7種態樣。
第4圖係表示在黏度為1000mPa‧s(噴射角度為0°)下的各噴霧容器之噴霧量的穩定性。
第5圖係表示在黏度為2000mPa‧s(噴射角度為0°)下的各噴霧容器之噴霧量的穩定性。
第6圖係表示在黏度為3600mPa‧s(噴射角度為0°)下的各噴霧容器之噴霧量的穩定性。
第7圖係表示在噴射角度為45°(黏度為2000mPa‧s)下的各噴霧容器之噴霧量的穩定性。
第8圖係表示在噴射角度為65°(黏度為2000mPa‧s)下的各噴霧容器之噴霧量的穩定性。
第9圖係表示在噴射角度為90°(黏度為2000mPa‧s)下的各噴霧容器之噴霧量的穩定性。
第10圖係表示實施例5(藉由氯化鈉0%及從外部來的剪切力將黏度調整為2500mPa‧s之製劑)的噴射密度分布圖。
第11圖係表示實施例6(藉由氯化鈉0.125%及從外部來的剪切力將黏度調整為2500mPa‧s之製劑)的噴射密度分布圖。
第12圖係表示實施例7(藉由氯化鈉0.25%及從外部來的剪切力將黏度調整為2500mPa‧s之製劑)的噴射密度分布圖。
第13圖係表示實施例8(藉由氯化鈉0.50%但沒有從外部來的剪切力而將黏度調整為2500mPa‧s之製劑)的噴射密度分布圖。
第14圖係表示實施例4至實施例10及比較例之人工鼻涕的黏度變化。
本發明中,凝膠基劑係指由作為黏膜附著劑之水溶性高分子化合物與水及/或醇類所組成的具有黏稠性的基劑。在凝膠基劑中,亦可復包含藥品中常用的防腐劑、保存劑、等滲劑、pH調整劑、著色劑等。
本發明中,作為皮膚及/或黏膜附著劑(附著性高分子)而使用的水溶性高分子化合物,可例示如阿拉伯樹膠、褐藻酸鈉、丙二醇褐藻酸酯、羧乙烯聚合物、羧甲基纖維素、鈉、三仙膠、
結冷膠、明膠、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯醇、甲基纖維素等。也可使用將複數種上述化合物組合之黏膜附著劑。此外,為了同時滿足具有皮膚及/或黏膜附著性、因噴灑操作而導致的製劑黏度變化小、可保持原本的高黏度而到達欲處理之患部(在噴鼻用時為鼻腔內)、與噴霧後之製劑的平均粒徑為十分微細的10μm至100μm(較佳為50μm至100μm),較佳為使用以羧乙烯聚合物或結冷膠或是同時以羧乙烯聚合物及結冷膠作為附著性高分子的凝膠基劑。也可使用本案發明者另外發明的「噴霧用凝膠基劑以及使用該基劑之凝膠劑」(專利文獻1)作為使用羧乙烯聚合物之基劑。
再者,也可調製一種基劑,其係從外部賦予剪切力以調整羧乙烯聚合物之黏度,或是賦予黏度調節劑與從外部來之剪切力以調整羧乙烯聚合物之黏度,而以適合使用目的之方式來管理噴霧容器的噴射角度、噴射密度。
關於本文中所進行之賦予剪切力的操作,可用熟習此項技術者所周知的方法進行,具體而言,賦予剪切力之裝置可使用高速旋轉型乳化裝置、膠體磨型乳化裝置、高壓乳化裝置、輥磨型乳化裝置、超音波式乳化裝置及膜式乳化裝置。尤其是以均質攪拌型、梳齒型及產生間歇噴流型的高速旋轉型乳化裝置為較佳。
本文中調整過的黏度通常為50mPa‧s至5000mPa‧s,較佳為100mPa‧s至4000mPa‧s,更佳為500mPa‧s至3000mPa‧s,最佳為2000mPa‧s至2500mPa‧s。
再者,本文中的噴射角度係指將從噴射口筆直噴射
出之製劑作為0°,而從此基準擴展的經噴射之凝膠製劑之角度。再者,噴射密度係指已噴射之凝膠製劑之展開區域中顯示均等程度的指標。具體而言,表示均等地噴霧、或偏向外圍等。另外,此噴射密度的評估係從噴射口朝板噴霧,以目視觀察附著於其上的凝膠製劑而判斷。
作為本發明之附著性高分子而使用的羧乙烯聚合物,是以丙烯酸作為主成分進行聚合所得到的親水性聚合物,通常可使用例如美國Noveon公司所市售的Carbopol(註冊商標)等。羧乙烯聚合物的使用濃度通常以約0.1至2.0重量%使用。結冷膠係由稱為Sphingomonas elodea之微生物在菌體外所產出的多糖類,廣泛地運用在各種食品等。特別適合使用的是低乙醯化型之結冷膠,商品名為Gelrite(註冊商標)等。結冷膠的使用濃度通常以約0.1至2.0重量%使用。在同時使用羧乙烯聚合物及結冷膠的情況下,與鼻涕(鼻黏液)接觸時,為了使其對於離子的感受性逆行,依據離子強度(離子濃度),將此基劑對鼻腔進行噴霧,最初黏度會降低,一旦基劑廣泛於鼻腔,之後藉由維持黏度(上升)而表現出長時間停留在鼻腔內的理想曲線。羧乙烯聚合物及結冷膠的合計使用濃度通常以0.2至4.0重量%使用,其調配比率可因應含有活性藥物之製劑與鼻涕(鼻黏液)接觸時的黏度變化而調整。
用以使羧乙烯聚合物增黏的增黏劑,係指藉由中和身為酸性物質的羧乙烯聚合物而使羧乙烯聚合物離子化並立體增大以使其增黏化的水溶性鹼物質,其具體例可列舉例如氫氧化鈉、氫氧化鉀等無機鹼;二異丙醇胺、三乙醇胺、三丙醇胺等胺類,精胺酸、離胺酸、鳥胺酸(ornithine)等胺基酸等有機鹼,較佳
而言為精胺酸、離胺酸、鳥胺酸。本文中包含胺基酸之增黏劑係通常相對於羧乙烯聚合物之重量比在1:0.5至1:3的範圍,較佳為1:1至1:2。這些水溶性鹼物質也可中和羧乙烯聚合物而調整到所要的pH範圍。增黏劑也可將複數種上述物質組合而使用。
在本發明中,溶解在凝膠基劑中的「醫藥活性物質」係指通常用於皮膚及/或黏膜部位之藥品,列舉例如經局部作用而治療發炎、過敏之藥物,經皮與經鼻等經黏膜吸收而期待可作用於全身之藥物,但不限於此。具體而言,本發明能投藥於皮膚及/或黏膜部位之醫藥活性物質的實例,可列舉硝酸萘甲唑啉(naphazoline nitrate)、鹽酸四氫唑啉(tetrahydrozoline hydrochloride)、鹽酸羥甲唑啉(oxymetazoline hydrochloride)、鹽酸曲馬唑啉(tramazoline hydrochloride)等局部血管收縮藥;氫皮質酮(hydrocortisone)、去氫皮質醇(prednisolone)、曲安奈德(triamcinolone acetonide)、磷酸地塞米松(dexamethasone phosphate)、氟尼縮鬆(flunisolide)、磷酸倍他米松(betamethasone phosphate)、丙酸倍氯米松鈉(beclomethasone dipropionate)、丙酸氟替卡松(fluticasone propionate)、呋喃甲酸莫美他松(mometasone furancarboxylate)、布地奈德(budesonide)、環索奈德(ciclesonide)等類固醇藥;阿斯匹靈(aspirin)、甲滅酸(mefenamic acid)、吡啶甲醇布洛芬(ibuprofen piconol)、舒洛芬(suprofen)、丁苯羥酸(bufexamac)、苄達酸(Bendazac)、烏芬那酯(Ufenamate)、雙氯芬酸鈉(diclofenac sodium)、吲哚美辛(indomethacin)、聯苯乙酸(Felbinac)、可多普洛非(ketoprofen)、氟比洛芬(flurbiprofen)、萘普生(naproxen)、普拉洛芬
(Pranoprofen)、洛索洛芬鈉(loxoprofen sodium)、胺普芬(Alminoprofen)、扎托洛芬(zaltoprofen)、吡羅昔康(piroxicam)、美洛昔康(Meloxicam)、氯諾昔康(Lornoxicam)、塞來昔布(celecoxib)、羅菲昔布(rofecoxib)等非類固醇系鎮痛消炎藥;苯海拉明(diphenhydramine)、富馬酸氯馬斯汀(clemastine fumarate)、鹽酸曲普利啶(triprolidine hydrochloride)、鹽酸異西噴地(isothipendyl hydrochloride)、酒石酸阿利馬(alimemazine tartrate)、馬來酸氯苯那敏(chlorpheniramine maleate)、鹽酸異丙(promethazine hydrochloride)等抗組織胺藥;色甘酸鈉(sodium cromoglycate)、曲尼司特(tranilast)、富馬酸酮替芬(ketotifen fumarate)、氨來呫諾(amlexanox)、鹽酸氮卓斯汀(azelastine hydrochloride)、奧沙米特(oxatomide)、鹽酸非索非那定(fexofenadine hydrochloride)、鹽酸依匹斯汀(epinastine hydrochloride)、依巴斯汀(Ebastine)、鹽酸西替利(cetirizine hydrochloride)、苯磺酸貝他斯汀(bepotastine besilate)、鹽酸奧洛他定(olopatadine hydrochloride)、氯雷他定(loratadine)、鹽酸奧扎格雷(ozagrel hydrochloride)、塞曲司特(seratrodast)、普崙司特水合物(Pranlukast hydrate)、札魯斯特(zafirlukast)、孟魯司特鈉(montelukast sodium)、甲磺司特(suplatast tosylate)等抗過敏藥;那氟沙星(nadifloxacin)、磷酸克林達黴素(clindamycin phosphate)、左氧氟沙星(levofloxacin)、鹽酸頭孢卡品酯水合物(cefcapene pivoxil hydrochloride hydrate)、克拉黴素(clarithromycin)、頭孢妥崙匹酯(Cefditoren pivoxil)、鹽酸萬古黴素(vancomycin hydrochloride(VCM))、美洛培南水合物(meropenem hydrate)、氟氧頭孢鈉(Flomoxef sodium)、鹽酸頭孢替安酯(Cefotiam hexetil hydrochloride)
等抗菌劑;無環鳥苷(acyclovir)、鹽酸伐昔洛韋(valacyclovir hydrochloride)、阿糖腺苷(vidarabine)等抗皰疹病毒藥;更昔洛韋(ganciclovir)、膦甲酸鈉水合物(foscarnet sodium hydrate)等抗細胞巨大病毒藥;磷酸奧斯他韋(oseltamivir phosphate)、扎那米韋水合物(Zanamivir hydrate)等抗流行性感冒病毒藥;兩性黴素B(amphotericin B)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、米卡芬淨鈉(micafungin sodium)、鹽酸特比萘芬(terbinafine hydrochloride)、鹽酸奈康唑(neticonazole hydrochloride)、拉諾康唑(Lanoconazole)、盧立康唑(luliconazole)、利拉萘酯(liranaftate)、鹽酸布替萘酚(butenafine hydrochloride)、鹽酸阿莫洛芬(amorolfine hydrochloride)等抗真菌藥;聚維酮碘(povidon iodine)、氯化苯二甲羥銨(benzalkonium chloride)、苄索氯銨(benzethonium chloride)、葡萄糖酸氯己定(chlorhexine gluconate)等消毒藥;環孢靈(cyclosporine)、他克莫司水合物(tacrolimus hydrate)等免疫抑制藥;他卡西醇(tacalcitol)、鈣泊三醇(calcipotriol)、阿法骨化醇(alfacalcidol)、骨化三醇(calcitriol)、馬沙骨化醇(maxacalcitol)等活性型維生素D3製劑;米諾地爾(Minoxidil)、卡普氯銨(carpronium chloride)等脫毛治療藥;氯羥基尿囊素鋁(aluminum chlorohydroxy allantoinate)、托可維A酸(tretinoin tocoferil)、布拉地辛鈉(bucladesine sodium)、前列地爾α-環糊精(Alprostadil Alfadex)、曲弗明(Trafermin)等皮膚潰瘍治療藥;氰鈷胺(cyanocobalamin)、甲鈷胺(Mecobalamin)等維生素B12製劑;維生素K1(phytonadione)、維生素K2(Menatetrenone)等維生素K製劑;ε-胺基已酸(epsilon-aminocaproic acid)、傳明酸(Tranexamic acid)等抗血纖維蛋
白溶酶藥;氯硝西泮(clonazepam)、卡馬西平(carbamazepine)、唑尼沙胺(zonisamide)等抗癲癇藥;三唑侖(triazolam)、伯替唑他(brotizolam)、酒石酸唑吡坦(zolpidem tartrate)、誇西泮(quazepam)、硝西泮(nitrazepam)、地西泮(diazepam)等催眠鎮靜藥;鹽酸帕羅西汀水合物(paroxetine hydrochloride hydrate)、依替唑侖(etizolam)、馬來酸氟伏沙明(Fluvoxamine maleate)、鹽酸米那普崙(milnacipran hydrochloride)、鹽酸丙咪(imipramine hydrochloride)等抗憂鬱藥;奧氮平(olanzapine)、利培酮(risperidone)、富馬酸奎硫平(quetiapine fumarate)等統合失調症治療藥;鹽酸多奈哌齊(donepezil hydrochloride)、尼麥角林(nicergoline)等癡呆症治療藥;阿樸嗎啡(apomorphine)、卡麥角林(cabergoline)、甲磺酸培高利特(pergolide mesylate)、甲磺酸溴隱亭(Bromocriptine mesylate)、鹽酸金剛烷胺(amantadine hydrochloride)、屈昔多巴(droxidopa)等巴金森症藥;依達拉奉(edaravone)等腦保護藥;嗎啡(morphine)、羥考酮(oxycodone)、吩坦尼(fentanyl)、鹽酸丁丙諾啡(buprenorphine hydrochloride)、酒石酸布托啡諾(butorphanol tartrate)等鎮痛藥;菸鹼(nicotine)等戒煙輔助藥;酒石酸麥角胺(ergotamine tartrate)、舒馬普坦(sumatriptan)、佐米曲坦(zolmitriptan)、氫溴酸依來曲普坦(eletriptan hydrobromide)、苯甲酸利扎曲普坦(rizatriptan benzoate)、那拉曲坦(Naratriptan)、夫羅曲坦(Frovatriptan)、阿莫曲坦(almotriptan)、阿維曲坦(avitriptan)等偏頭痛藥;雌二醇(estradiol)、雌三醇(estriol)、助孕酮(progesterone)、睪固酮(testosterone)等性類固醇激素藥;甲磺酸去鐵胺(deferoxamine mesylate)等金屬解毒藥;磷酸可待因(codeine phosphate)、鹽酸異丙基腎上腺素
(isoproterenol hydrochloride)等鎮咳去痰藥;鹽酸恩丹西酮(ondansetron hydrochloride)、鹽酸雷莫司瓊(ramosetron hydrochloride)、鹽酸托烷司瓊(tropisetron hydrochloride)、鹽酸格拉司瓊(granisetron hydrochloride)、甲氧氯普胺(metoclopramide)、多潘立酮(Domperidone)、枸櫞酸莫沙必利(mosapride citrate)等止吐藥;醋酸戈舍瑞林(goserelin acetate)、比卡魯胺(bicalutamide)、替加氟(tegafur)、太平洋紫杉醇(paclitaxel)、枸櫞酸他莫昔芬(tamoxifen citrate)、鹽酸吉西他濱(gemcitabine hydrochloride)、去氧氟尿苷(doxifluridine)、卡培他濱(capecitabine)、甲磺酸伊馬替尼(imatinib mesylate)、利妥昔單抗(rituximab)、吉非替尼(gefitinib)、曲妥珠單抗(trastuzumab)、太平洋紫杉醇(paclitaxel)、多烯紫衫醇水合物(docetaxel hydrate)等抗癌藥;坎地沙坦酯(candesartan cilexetil)、纈沙坦(valsartan)、洛沙坦鉀(losartan potassium)、替米沙坦(telmisartan)、奧美沙坦酯(olmesartan medoxomil)、苯磺酸氨氯地平(amlodipine besilate)、硝苯地平(nifedipine)、鹽酸貝尼地平(benidipine hydrochloride)、鹽酸尼卡地平(nicardipine hydrochloride)、尼伐地平(nilvadipine)、阿折地平(azelnidipine)、鹽酸馬尼地平(manidipine hydrochloride)、鹽酸地爾硫卓(diltiazem hydrochloride)、馬來酸依那普利(enalapril maleate)、鹽酸咪達普利(imidapril hydrochloride)、鹽酸替莫普利(temocapril hydrochloride)、培哚普利(perindopril erbumine)、卡維地洛(carvedilol)、富馬酸比索洛爾(bisoprolol fumarate)、鹽酸普萘洛爾(propranolol hydrochloride)、阿替洛爾(atenolol)等降血壓藥;鹽酸坦索羅辛(tamsulosin hydrochloride)、萘哌地爾(naftopidil)等排尿障礙治療藥;西咪替丁
(cimetidine)、鹽酸雷尼替丁(ranitidine hydrochloride)、法莫替丁(famotidine)、尼扎替丁(nizatidine)等抗潰瘍藥;鹽酸多巴胺(dopamine hydrochloride)、鹽酸多巴酚丁胺(dobutamine hydrochloride)等強心藥;氫溴酸菲諾特洛(fenoterol hydrobromide)、溴化異丙托品(ipratropium bromide)、溴化氧托平(oxitropium bromide)等支氣管擴張藥;馬吲哚(mazindol)、胜肽YY(peptide YY)等肥胖治療藥;甲基硫酸新斯的明(neostigmine methylsulfate)等自律神經作用藥;硝化甘油(nitroglycerin)、硝酸異山梨酯(isosorbide dinitrate)、尼可地爾(nicorandil)等狹心症用藥;鹽酸噻氯匹定(ticlopidine hydrochloride)、西洛他唑(cilostazol)、鹽酸沙格雷酯(sarpogrelate hydrochloride)、貝前列素鈉(beraprost sodium)等血小板凝集抑制藥;伏格列波糖(Voglibose)、阿卡波糖(Acarbose)、格列美脲(glimepiride)、那格列奈(nateglinide)、鹽酸二甲雙胍(metformin hydrochloride)、鹽酸吡格列酮(pioglitazone hydrochloride)、格列齊特(gliclazide)等糖尿病藥;普伐他汀鈉(pravastatin sodium)、辛伐他汀(simvastatin)、氟伐他丁鈉(fluvastatin sodium)、阿托伐他汀鈣水合物(atorvastatin calcium hydrate)、匹伐他汀鈣(pitavastatin calcium)、瑞舒伐他汀鈣(rosuvastatin calcium)、苯扎貝特(bezafibrate)等高血脂症治療藥;鹽酸吡西卡尼(pilsicainide hydrochloride)、鹽酸美西律(mexiletine hydrochloride)、磷酸雙異丙吡胺(disopyramide phosphate)等脈搏不整用藥;巴氯芬(baclofen)、吡拉西坦(piracetam)、鹽酸乙哌立松(eperisone hydrochloride)、鹽酸替扎尼定(tizanidine hydrochloride)等肌肉鬆弛藥;布西拉明(bucillamine)、甲氨喋呤(methotrexate)、因福利美(infliximab)、法呢酸潑尼松龍酯
(prednisolone farnesylate)、阿克他利(actarit)等抗風濕病藥;此外還有作為胜肽/蛋白質性藥物之LHRH(黃體生成激素釋放激素)類;生長激素釋放因子類;體抑素(somatostatin)衍生物類;升壓素(vasopressin)、醋酸去胺加壓素(desmopressin acetate)等腦下腺後葉激素;催產素(oxytocin)類;水蛭素(hirudin)衍生物類;腦啡(enkephalin)類;ACTH(促腎上腺皮質激素(adrenocorticotropic hormone))衍生物類;緩動素(bradykinin)衍生物類;胰島素(insulin)類;升糖素(glucagon)衍生物類;生長激素(growth hormone)類;生長激素釋放激素(growth hormone releasing hormone);黃體生成激素(luteinizing hormone)類;似胰島素生長因子(insulin-like growth factor);降鈣素基因相關胜肽(calcitonin gene related peptide)類;心房性利尿鈉胜肽(atrial natriuretic peptide)衍生物類;干擾素(interferon)類;介白素(interleukin)類;紅血球生成素(erythropoietin);顆粒球群落生長刺激因子(granulocyte colony formation-stimulating factor);巨噬細胞生長刺激因子;副甲狀腺素(parathormone)類;副甲狀腺素釋放釋素;泌乳素(prolactin);促甲狀腺素釋放激素(thyrotropin-releasing hormone);及血管收縮素(angiotensin)類等;降鈣素(calcitonin)類;醋酸亮丙瑞林(leuprorelin acetate)、醋酸布舍瑞林(buserelin acetate)、醋酸那法瑞林(nafarelin acetate)等Gn-RH(促性腺激素釋放激素)衍生物類;替索激酶(tisokinase)、阿替普酶(alteplase)、孟替普酶(monteplase)、帕米普酶(pamiteplase)、那沙普酶(nasaruplase)等血栓溶解藥;流行性感冒病毒HA疫苗(influenza HA vaccine)、肺炎球菌疫苗(pneumococcal vaccine)、B型肝炎重組減活疫苗(recombinant adsorbed hepatitis B vaccine)等疫苗
類。該醫藥活性物質的含量並沒有特別限制,但含有0.001至10重量%。再者,凝膠製劑中也可包含複數種該等醫藥活性成分。
在使用非水溶性活性之藥物時,雖然所得到本發明之製劑為白濁狀,但活性藥物並不會沈降,所以在通常之投藥方面沒有障礙。然而,當活性藥物若為溶解而會使受治療之患部(噴鼻用時的鼻黏膜)之吸收為良好時,較佳為使用溶解劑,或事先將活性藥物溶解在水溶性有機溶劑中進行製劑化。這些水溶性有機溶劑列舉有乙醇、異丙醇等低級醇,丙二醇、1,3-丁二醇、分子量300至500的聚乙二醇等二醇類。再者,可根據活性藥物的溶解性來使用各種界面活性劑作為溶解劑。
再者,也可添加適當的懸浮劑使活性藥物懸浮,這些懸浮劑可例示如蔗糖脂肪酸酯、硬脂酸聚烴氫基40、聚氧伸乙基氫化蓖麻油60、聚山梨酸酯80、單硬脂酸甘油酯、山梨醇酐單硬脂酸酯、山梨醇酐單棕櫚酸酯等各種界面活性劑等。
再者,亦可添加適當的乳化劑使該凝膠基劑乳化以調配活性藥物,也可使活性藥物本身乳化,而可使用各種界面活性劑作為這些乳化劑。
本發明所使用的用語「黏膜」係指覆蓋在上皮細胞且源自於外胚葉的上皮層,具體而言,可列舉如鼻腔、眼睛、耳朵、口腔、直腸、陰道、性器、尿道、肛門等。再者,本發明所使用的用語「皮膚」係指覆蓋在身體表面的層,具體而言,可列舉如手、指頭、腳、身體、胯股、頭皮、肛門周圍、性器周圍等的層。
本發明所使用的「皮膚及/或黏膜」就是「皮膚及黏
膜、皮膚或黏膜」的意思,例如亦表示可包含如肛門周圍或性器周圍等皮膚與黏膜共存而難以區別之患部的意思。
本發明所規定的黏度,例如可用日本藥局處方一般試驗法之黏度測定法所列舉的毛細管黏度計法、旋轉黏度計法等而測定。
本發明之凝膠製劑的黏度通常為50mPa‧s至5000mPa‧s,較佳為100mPa‧s至4000mPa‧s,更佳為500mPa‧s至3000mPa‧s,最佳為2000mPa‧s至2500mPa‧s。
本發明所規定的黏度保持率係指剛噴霧後之噴霧粒子黏度相對於噴霧前之凝膠製劑黏度的比率。
本發明中,藉由噴霧操作所得到之經噴霧之製劑粒子的黏度保持率較佳為50%以上。
本說明書所使用之經噴霧之製劑粒子的平均粒徑,可使用例如雷射光散射式之粒徑測定裝置來測定。
本文中的平均粒徑較佳為10μm至100μm的範圍,更佳為50μm至100μm的範圍。
本發明所規定的殘留率係指使用凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器),直到完全無法噴霧出鼻噴灑用凝膠型黏膜附著型製劑時,容器中剩餘凝膠製劑之量相對於使用前總量的比率。
本發明中,上述殘留率通常為20%以下,較佳為15%以下,更佳為10%以下。
本發明所規定的設定值係指上述噴鼻劑1次噴霧操作所噴霧的內容製劑之預定量的值或量的範圍。具體而言,例如
若設定1次噴霧操作約噴霧100mg的內容製劑,則100mg就是設定值。
本發明中,在上述設定值之±10%以內之範圍的噴霧率較佳為70%以上,更佳為80%以上。
可列舉氯化苯二甲羥銨、苄索氯銨等作為本發明所規定之防腐劑的具體實例,但不限於此。再者,可列舉對羥苯甲酸甲酯、對羥苯甲酸丙酯等對羥苯甲酸酯類作為保存劑。本文中的調配量通常係指例如藥品所容許的添加量,係通常只要是熟習此項技術者就能輕易從已容許之藥品的添加量與化合物的結構等來類推的值。
本發明所使用的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)係例示如附圖之第1圖所示的容器。此處,該噴霧容器係一種附有唧筒之無氣容器,其特徵為:藉由取下容器罩並壓下安裝在容器頭部之唧筒的環狀操作部,而將內容物從容器內吸引至唧筒吸引室且自噴射孔往外部噴出,同時具有被將空氣排出容器內之吸引作用所連動而往上滑動的滑動底蓋主體,在此滑動底蓋主體之周圍,形成有壓接在容器內周面且以密封狀態移動之環狀外周面。
如上述機構的噴霧容器,雖然沒有特別載明用途是作為噴鼻用,但已揭示作為附有唧筒的無氣容器(日本特開2003-212262)。然而,如本發明之凝膠製劑用(上方排壓無氣式)噴霧容器,必須排除可能會限制且不供以噴霧的無效空間,並可在填充製劑時順暢地置換容器內的空氣與製劑。特別是可預料本發明所使用的滯留性凝膠製劑之流動性不佳,用完時所殘餘凝膠製
劑的量會比一般的製劑多。於是,在本發明中,除了更加改良以往之無氣噴霧容器以外,如第2圖之右半面所示,發現藉由裝填用以除去無效空間的環,更進一步,使平坦的滑動底蓋主體具有一定之角度,而使容器內之氣體容易被吸引,並且以相同角度亦附上環,當使用完畢時,滑動底蓋主體與環會幾乎完全相合而幾乎完全去除無效空間,因此,使用完畢時之殘存量可變得非常少。然後,具有此等特徵之如第1圖及第2圖所例示之本專利案所使用之凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器),可確保作為通常醫藥品之噴霧量精度。若此滑動底蓋主體之一定角度為小,則充填製劑時在容器主體之肩部分會殘留空隙;若該角度為大,在滑動底蓋之裙擺部分會殘留空隙,皆為不佳。該角度係以5°至30°為佳,又以15°至25°為更佳。
再者,由於本專利案所使用的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)並非吸入外部空氣的系統,所以對於難以承受外部空氣之微生物污染的醫藥製劑也具有非常有用的特性,從不需含有多餘防腐劑、保存劑的安全性或製造成本方面來看,也是非常優良的經鼻投藥系統。
本發明中,噴霧容器的投藥角度可以0°至360°之任一角度或角度範圍而使用。例如在噴鼻用的情況下,可像附圖之第3圖,對於投藥姿勢(頭部角度)與噴灑容器的投藥角度進行各種變化來使用上述的噴灑型噴鼻製劑。換言之,從以往之噴鼻器也可噴霧的角度0°附近,到難以噴霧的45°至90°,再到不可能噴霧的180°都可噴霧。
在此,推測若使頭往後倒並藉由將容器投藥角度以
65°至180°來使用,而使鼻甲(鼻道)從平行方向變化為垂直方向,則最初可確實使藥劑分散並附著於鼻甲之前端部分。被鼻甲所捕捉沈積之製劑,係被順應重力之流動與覆蓋黏膜之纖毛細胞而運送到後方,使製劑廣泛地分散於鼻甲。
因此,投藥姿勢與噴灑容器的投藥角度可為0°至180°之任一角度,較佳為45°至180°,進一步更佳為65°至180°,最佳為135°附近之鼻甲(鼻道)為垂直方向,是使製劑廣泛分布於鼻甲最有利的角度。再者,投藥時的姿勢可為站立狀態、坐姿、仰臥姿、橫臥姿等任一者,本發明之噴鼻製劑可在任一投藥角度下使用。
接著,根據實施例及試驗例更詳細說明本發明,但本發明不限定於此。另外,在以下實施例及試驗例中,黏度係使用C形黏度計並於20℃下測定。
使用下述成分製成黏度等不同的9種凝膠型皮膚及/或黏膜附著製劑以供試驗。但是,特別從考慮不影響物理化學性質來看,具有藥理活性之醫藥活性物質是不溶解的。
在實施例1至3,以未施加剪切並添加相同量之氯化鈉作為黏度調節劑所調製的凝膠製劑,分別具有1000、2000、3000mPa‧s的黏度(實施例1至3中,沒有添加氯化鈉作為黏度調節劑時,其黏度在實施例1為31000mPa‧s,在實施例2為35000mPa‧s,在實施例3為36000mPa‧s)。
實施例4至7為施加剪切所調製的凝膠製劑,實施例6和7是復添加氯化鈉作為黏度調節劑及施加剪切者。將任一
者之黏度皆調整到2500mPa‧s(實施例4中,沒有施加剪切時,黏度為23000mPa‧s;實施例5至7中,沒有施加剪切時(實施例5),或是未添加氯化鈉作為黏度調節劑、也沒有施加剪切時(實施例6、實施例7)的黏度為34000mPa‧s)。
實施例8與實施例4至7為同樣的組成,是沒有施加剪切,只用黏度調節劑將黏度調整到2500mPa‧s的製劑(未添加氯化鈉作為黏度調節劑時,其黏度為34000mPa‧s)。
再者,製成不用黏度調節劑亦不藉由從外部來之剪切力進行黏度調整之黏度為2500mPa‧s的製劑,以此作為比較例,當作實施例4至8的對照。
使用裝有1次操作可噴霧約100mg之唧筒的以下噴霧容器作為試驗容器。
本發明容器:凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)(100mg唧筒,填充量5g)
對照容器①:將主體容器製成雙重構造並在內側具有擂鉢型之形狀,對於容器內殘量有所考慮的市售製品之噴霧容器(100mg唧筒,填充量5g)
對照容器②:泛用型噴霧容器(100mg唧筒,填充量5g)
關於容器內殘餘量、規定範圍內噴霧量及次數之試驗
在測定過空容器重量之本發明容器、對照容器①及對照容器②的3種噴霧容器中,分別正確裝填入約5.0g之實施例1至實施例8之製劑,如表1及表2所示,使投藥角度從0°變化到180°,每噴霧1次即從前後的質量差求出1次的噴霧量,直到內容物幾乎噴完為止,重複噴霧操作而進行測定,將本發明容器之測定結果示於表1,對照容器之測定結果示於表2。
以作為此時之容器內充填製劑的使用分布(%),藉由下式求出無法從唧筒噴霧時的容器內殘餘量(%)、表示相對於在作為容器噴霧量之規定設定量(100mg)之範圍內(±10%以內)經噴霧之噴霧量累計總量(5.0g)的比率的「100±10mg範圍內之量(%)」、以及表示在設定量之範圍外經噴霧之同樣比率的「100±10mg範圍外之量(%)」,各值亦示於表1和表2中。
容器內殘餘量(%)=容器內殘餘量(g)/最初填充量(g)×100 100±10mg範圍內之量(%)=100±10mg範圍內噴霧量累計(g)/最初
填充量(g)×100 100±10mg範圍外之量(%)=100±10mg範圍外噴霧量累計(g)/最初填充量(g)×100
此外,也表示100±10mg範圍內的可使用次數。
只要是使用本發明容器之本發明系統,就算是具有高黏度之製劑,亦與黏度無關且與噴射角度無關,容器內填充製劑的使用分布(%)幾乎示為一定值,容器內製劑殘餘量(%)則表示低的值(約7.1%),設定值之範圍內之量(%)亦表示高的值(約87.7%),相對地,對照容器①及對照容器②係如下述表2所示與黏度相依,黏度越高,容器內製劑殘餘量(%)越增加,且規定範圍內之量(%)越減少。
以下根據上述表1及表2的結果,分成投藥角度及製劑種類,將重新排列的結果示於表3至表8。
首先,將投藥角度設為0°,將使用各黏度製劑之各
噴霧容器的使用分布(%)整理在表3、表4及表5。可知使用本發明容器之本發明系統為非常優異。另外,針對各噴霧容器之黏度與噴霧量的穩定性,亦可從將表3至表5之結果分別作圖而成的第4圖、第5圖及第6圖得知本發明系統為優異。
再者,選擇實施例2與實施例7的製劑作為內容製劑,使噴射角度進行各種變化,將各噴霧容器的使用分布(%)整理在表6至表11。可知不論在任一個噴射角度,使用本發明容器之本發明系統的殘留率都很低,可非常穩定地噴霧。再者,也可從將表6至表8之結果分別作圖而成的第7圖至第9圖得知各噴霧容器之噴射角度與噴霧量的穩定性,明白只有本發明系統可在噴射角度65°及90°下使用。
平均粒徑之比較
使用雷射光散射式之粒徑測定裝置,測定本發明之凝膠型皮膚及/或黏膜附著製劑與其他皮膚及/或黏膜附著製劑之噴霧的平均粒徑,以進行比較(表12)。容器係全部使用相同的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)。發現本發明之凝
膠型皮膚及/或黏膜附著製劑即使在高黏度的情況下,也能表現出小粒徑,特別是作為鼻腔內投藥型製劑之理想的平均粒徑(50至100μm)。
噴霧黏度保持之比較
測定本發明之凝膠型皮膚及/或黏膜附著製劑與其他皮膚及/或黏膜附著製劑的噴霧在噴霧前與剛噴霧後的黏度變化,以進行比較(表13)。容器係全部使用相同的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)。發現只有本發明之凝膠型皮膚及/或黏膜附著製劑具有極高的黏度保持率。特別是在施加剪切力以調整黏度之製劑的實施例4至7中,噴射前後的黏度完全沒有變化,具有極高的黏度保持率。
噴霧之噴射角度與噴射密度的比較
測定上述所調製之黏度、調製方法不同的各凝膠型皮膚及/或黏膜附著製劑之噴霧的噴射角度與噴射密度,以進行比較(表14)。容器係全部使用相同的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)。
雖然噴射角度沒有受到黏度差異的影響(例如將實施例1至3加以比較),但在施加剪切力以調整黏度之凝膠型黏膜附著製劑的實施例4至7中,噴射角度有變窄的傾向,並且在這些實施例的製劑中,將添加氯化鈉作為黏度調節劑的實施例6及實施例7,與沒有添加氯化鈉之相同組成的實施例5相比,噴射角度有變寬的傾向。
再者,噴射密度也會受到施加剪切力的影響。換言之,可知未施加剪切力之實施例1至3及實施例8的製劑會偏向外圍而噴霧,但施加剪切力之實施例4至7的製劑會以噴射密度均勻的方式噴霧(參照第10至13圖)。
由此可知,本發明之凝膠型皮膚及/或黏膜附著製劑,係藉由黏度調節劑及從外部來的剪切力以調整凝膠製劑的黏度,而能以適合使用目的之方式來控制噴霧容器之噴射角度、噴射密度,例如在醫藥活性物質為離子性且呈溶解狀態時,只藉由與黏度調節劑扮演相同角色的從外部來之剪切力,即可調整噴霧容器之噴射角度與噴射密度,使其變得均勻。
因人工鼻涕而導致製劑之黏度變化的比較
使用下述成分,製成調配有結冷膠之凝膠型皮膚及/或黏膜附著製劑,與實施例4至實施例8及比較例的製劑一起供以因人工鼻涕(組成如下)而導致製劑之黏度變化的比較試驗。
人工鼻涕係將與人類鼻涕相同的離子調配成同樣濃
度的調製液,添加後使其均勻化,約5分鐘後測定黏度。(人工鼻涕之添加量係以相對於10g製劑所添加之量(g)來表示)
〔人工鼻涕之組成〕
上述人工鼻涕係根據佐分利保雄等人「因鼻涕而導致杉樹花粉的破裂」(日本公眾衛生誌 1992年 第39卷 第6號 第341至346頁)記載的組成所調製者。
將本發明之凝膠型黏膜附著製劑因人工鼻涕而導致製劑的黏度變化示於第14圖。容器係全部使用相同的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)。換言之,在不藉由黏度調節劑進行黏度調整亦不藉由從外部來的剪切力進行黏度調整的比較例中,由於添加人工鼻涕而導致黏度顯著降低,相對於此,進行上述任一項黏度調整的實施例4至10係大幅抑制了黏度降低。尤其應注意的是,可知調配有結冷膠的實施例9和10係比沒有調
配結冷膠的其他實施例更不容易因人工鼻涕添加量增加而使黏度變化受到影響。
對於微生物之穩定性的比較
以加熱滅菌過的0.2%結冷膠溶液作為內容製劑,將5g製劑裝填入EOG滅菌處理過的凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器)及對照容器②,噴霧2.5g直到內容製劑變成50%為止,以37℃的恆溫器,在室溫下保存並經時觀察,比較對於微生物的穩定性(表11)。本發明之凝膠製劑用噴霧容器比以往噴鼻用容器對於微生物顯示出更優異的穩定性。
利用糖精製劑之鼻腔內滯留性的比較
將在實施例2之製劑中添加具有甜味之糖精鈉使其濃度成為0.5%的製劑、與能以100mg噴霧0.5%糖精鈉水溶液的唧筒裝填而成噴鼻用凝膠製劑用噴霧容器(上方排壓無氣式噴霧容器),使用此噴霧容器以各種角度對受試者(3名:A、B、C)進行噴鼻投藥(兩鼻孔1次,合計200mg),投藥後經過一定的時間後,使頭部姿勢成為垂直,對投藥後受試者感覺到甜味的時間做各種測定,以進行比較(表12至表15)。不論在哪一種情況下,實施例2之凝膠型皮膚及/或黏膜附著製劑都比非凝膠型的一般水溶液需
要更長時間才能感覺到甜味,從此特點來看,顯示出凝膠型在鼻腔內的滯留性為非常高。
如上所述,本發明之噴灑用凝膠型皮膚及/或黏膜附著型製劑比以往的藥液改善了滯留性,此外,在容器方面,也使用上方排壓無氣式噴霧容器而不是以往已廣泛使用的以管吸取型之噴灑容器,使本發明之凝膠製劑亦可適於作為噴灑製劑。特別是就應用於噴鼻藥而言,在以往噴鼻製劑係難以實現之在45°以上進行噴鼻投藥,但依據本發明則使其變得可能。
此外,也改良了上方排壓無氣式噴霧容器之容器內的滑動底蓋主體,提案一種可使殘留率為低且噴霧量為穩定的噴
霧容器,而可製成安全而且在製造成本方面亦經濟的凝膠型皮膚及/或黏膜附著型噴鼻製劑°
因此,本發明之噴鼻用凝膠型皮膚及/或黏膜附著型製劑以及使用該製劑之投藥系統,從具有能改善以往鼻炎治療等之吸收或清除作用,且可根據使用時所需要的角度投藥,而且到最後都能以穩定的噴霧量幾乎用到完的優點來看,可成為更有效且有用的噴鼻製劑等。再者,在以全身作用作為目的之藥物的投藥路徑之鼻腔內投藥型製劑的開發方面,也得到非常有用的投藥系統。
Claims (22)
- 一種噴灑用凝膠型皮膚及/或黏膜附著型製劑,其係由在含有皮膚及/或黏膜附著劑之凝膠基劑中包含醫藥活性物質的凝膠製劑所組成,其含有羧乙烯聚合物、且適當地含有結冷膠作為皮膚及/或黏膜附著劑,且已從外部賦予剪切力而調整過黏度。
- 如申請專利範圍第1項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其中,適用的黏膜為鼻腔、眼睛、耳朵、口腔、直腸、陰道或尿道,適用的皮膚為手、指頭、腳、身體、胯股、頭皮、肛門周圍或性器周圍。
- 如申請專利範圍第1項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其中,適用的黏膜為鼻腔。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其含有0.1重量%至2.0重量%之羧乙烯聚合物或結冷膠作為皮膚及/或黏膜附著劑。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其含有合計為0.2重量%至4.0重量%之羧乙烯聚合物及結冷膠作為皮膚及/或黏膜附著劑。
- 如申請專利範圍第4項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,從外部賦予剪切力將黏度調整為50mPa‧s至5000mPa‧s。
- 如申請專利範圍第4項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,賦予黏度調節劑以及從外部來之剪切力將黏度調整為50mPa‧s至5000mPa‧s。
- 如申請專利範圍第7項之噴灑用凝膠型皮膚及/或黏膜附著型 製劑,其中,該黏度調節劑係從氯化鈉、氯化鉀及氯化鈣所成群組中選出。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其含有從中性或鹼性之水溶性胺基酸中選出的胺基酸作為羧乙烯聚合物之增黏劑,該增黏劑相對於羧乙烯聚合物之重量比在1:0.5至1:3的範圍。
- 如申請專利範圍第9項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其中,該增黏劑為精胺酸、離胺酸及/或鳥胺酸。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其係含有0.001至10重量%之醫藥活性物質的凝膠製劑。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其中,該醫藥活性物質為溶解狀態。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其中,該醫藥活性物質為懸浮狀態。
- 如申請專利範圍第1至3項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑,其中,該醫藥活性物質為乳化狀態。
- 一種投藥系統,其特徵為:將申請專利範圍第1至14項中任一項之噴灑用凝膠型皮膚及/或黏膜附著型製劑裝填入上方排壓無氣式噴霧容器中,任意設定噴霧容器之投藥方向噴在欲處理之患部,並能以所有角度來將凝膠基劑予以噴霧。
- 如申請專利範圍第15項之投藥系統,其中,該凝膠製劑的黏度係在50mPa‧s至5000mPa‧s的範圍,且所得到之經噴霧之製劑粒子的黏度保持率為50%以上。
- 如申請專利範圍第15項之投藥系統,其包含將黏度調整到50mPa‧s至5000mPa‧s之範圍的凝膠製劑,且藉由噴霧操作所得到之經噴霧之製劑粒子的黏度保持率為90%以上。
- 如申請專利範圍第15至17項中任一項之投藥系統,其中,該經噴霧之製劑粒子的平均粒徑係在10μm至100μm的範圍。
- 如申請專利範圍第15項之投藥系統,其包含將黏度調整到50mPa‧s至5000mPa‧s之範圍的凝膠製劑,且將噴霧容器的噴射角度設在10°至70°的範圍,並使噴射密度成為均勻或集中於外圍。
- 如申請專利範圍第15至17項中任一項之投藥系統,其中,噴霧因使用而變得完全無法噴霧時,容器中的凝膠製劑之殘留率為20%以下,在設定量±10%以內之範圍的噴霧率為70%以上。
- 如申請專利範圍第15至17項中任一項之投藥系統,其中,噴霧因使用至完全無法噴霧時,容器中的凝膠製劑之殘留率為15%以下,在設定量±10%以內之範圍的噴霧率為80%以上。
- 如申請專利範圍第15至17項中任一項之投藥系統,其中,噴霧容器的投藥角度為0°至360°之任一角度或角度範圍。
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