比格犬與人體胃腸道的生理學(xué)差異及其對口服緩控釋制劑體內(nèi)評(píng)價(jià)的影響

1、科技信息比格犬是口服固體制劑體內(nèi)評(píng)價(jià)最常用的實(shí)驗(yàn)動(dòng)物。然而,比格犬與人體胃腸道的生理學(xué)差異可能對制劑的釋放和吸收行為造成不同影響,因此,有必要對其差異和對制劑體內(nèi)行為的影響進(jìn)行比較研究。本文主要就比格犬與人體胃腸液pH值、胃排空時(shí)間、小腸轉(zhuǎn)運(yùn)時(shí)間和胃腸道攪拌強(qiáng)度和對制劑破壞力的差異作一綜述。1.胃腸液pH值1.1胃液pH值禁食狀態(tài)下,比格犬胃液pH值約為1.51,人體胃液pH值約為1.6 2。進(jìn)食后,比格犬胃液pH值約為2.11,沒有表現(xiàn)出較大波動(dòng)。相反,進(jìn)食后,人體胃液pH值約為5.02。1.2小腸液pH值比格犬與人體小腸液pH值較接近,均約為6.2-7.51,2。由于大腸表面積小,內(nèi)容物粘

2、稠,水分含量低,會(huì)阻礙大多數(shù)藥物的釋放和吸收,因而不做討論。由于藥物大多為弱酸或弱堿,并且緩控釋制劑中的阻滯材料也經(jīng)常表現(xiàn)出pH依賴性,故探討比格犬與人體胃腸液pH值的差異具有重要意義。2.胃腸道轉(zhuǎn)運(yùn)時(shí)間2.1胃排空時(shí)間禁食狀態(tài)下,比格犬與人體胃排空時(shí)間接近,且均小于1h2,3。進(jìn)食后,比格犬與人體胃排空時(shí)間均顯著延長,且比格犬更明顯。溶液劑和多單元制劑(如小丸的胃滯留時(shí)間不受是否進(jìn)食的影響,均會(huì)迅速由胃排入小腸4。單單元制劑(如片劑受進(jìn)食狀態(tài)的影響明顯:禁食狀態(tài)下迅速胃排空;進(jìn)食后,胃排空顯著延遲4。2.2小腸轉(zhuǎn)運(yùn)時(shí)間小腸是藥物吸收的主要部位,其轉(zhuǎn)運(yùn)時(shí)間的長短對于緩控釋制劑生物利用度的高低具

3、有重要影響。比格犬小腸轉(zhuǎn)運(yùn)時(shí)間約為2-3h,人體小腸轉(zhuǎn)運(yùn)時(shí)間約為4h5,6。人體小腸轉(zhuǎn)運(yùn)時(shí)間明顯長于比格犬,因此以比格犬評(píng)價(jià)緩控釋制劑的生物利用度,如果藥物在結(jié)腸內(nèi)不釋放或不被吸收的話,測得的生物利用度往往低于人體試驗(yàn)結(jié)果,導(dǎo)致不必要的處方改進(jìn)。同時(shí),小腸轉(zhuǎn)運(yùn)時(shí)間不受是否進(jìn)食的影響,也與劑型無關(guān),即溶液劑、顆粒劑和片劑具有相似的小腸轉(zhuǎn)運(yùn)時(shí)間。人們通常以為小腸轉(zhuǎn)運(yùn)時(shí)間為8h,這種觀點(diǎn)現(xiàn)在看來是錯(cuò)誤的?，F(xiàn)在出現(xiàn)了一批12h或24h緩慢釋藥的制劑,如果藥物在結(jié)腸內(nèi)不釋放或不被吸收的話,這類制劑的療效是值得懷疑的。因?yàn)檫@種制劑在經(jīng)過4h的小腸轉(zhuǎn)運(yùn)后會(huì)將大多數(shù)藥物帶到結(jié)腸,而在那里藥物卻不能釋放或不被吸

4、收。因此對大多數(shù)藥物的緩控釋制劑來說,在實(shí)現(xiàn)藥物的逐步釋放的同時(shí)也要保證在進(jìn)入結(jié)腸前完全釋放。了解胃排空時(shí)間和小腸轉(zhuǎn)運(yùn)時(shí)間的規(guī)律對緩控釋制劑的設(shè)計(jì)是很有意義的。某些緩控釋片可以在飯后服用延長其胃滯留時(shí)間,也可以做成胃漂浮制劑或生物粘附制劑延長其胃滯留時(shí)間。這樣制劑可以滯留在胃部較長時(shí)間逐漸釋放藥物,溶出的藥物則隨胃液進(jìn)入小腸而被吸收,從而同時(shí)實(shí)現(xiàn)緩慢釋放與完全吸收。3.胃腸道的物理作用力胃腸液的pH值和胃腸轉(zhuǎn)運(yùn)時(shí)間對緩控釋制劑體內(nèi)行為的影響經(jīng)常受到人們的關(guān)注,然而胃腸道的物理作用力卻經(jīng)常為人忽略。胃腸道的物理作用力有兩部分組成,攪拌強(qiáng)度和機(jī)械破壞力。人體胃腸道內(nèi)的攪拌強(qiáng)度約相當(dāng)于體外溶出試驗(yàn)中

5、的漿法10rpm,比格犬胃腸道內(nèi)的攪拌強(qiáng)度約相當(dāng)于體外溶出試驗(yàn)中的漿法100rpm7。通常體外溶出試驗(yàn)采用的轉(zhuǎn)數(shù)為50-100rpm,遠(yuǎn)高于人體內(nèi)的實(shí)際情況。禁食狀態(tài)下,人體胃部的機(jī)械破壞力約為1.5N,進(jìn)食后約為1.9N。比格犬胃部的機(jī)械破壞力約為3.2N,且不受是否進(jìn)食的影響8。由于比格犬胃腸道的攪拌強(qiáng)度和機(jī)械破壞力均強(qiáng)于人體,所以緩控釋制劑在比格犬體內(nèi)的釋藥速度要快于人體?？傮w來說,不溶蝕的制劑(如膜控型緩控釋制劑由于在胃腸道內(nèi)其完整性不易被破壞,其體內(nèi)釋藥速度低于體外溶出測定的釋藥速度9,10,11,12;相反,易溶蝕的制劑(如溶蝕骨架緩控釋制劑由于其完整性易被胃腸道破壞,其體內(nèi)釋藥速

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