Apomorphine經固體脂質奈米顆粒化之口服輸送系統研究

Development of the solid lipid nanoparticle formulation of apomorphine for oral delivery

高耀仁(Yao-Jen Kao)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/藥學研究所/碩士(2008年)

https://doi.org/10.6832/KMU.2008.00077

摘要

Apomorphine為D1和D2多巴胺受體類似劑，皮下注射Apomorphine能大幅降低巴金森氏症之難治性的陣發性停電（on-off phenomenon）。因胃腸道首渡效應的影響，其口服生體可用率差（1.7％），因此藉由surface-modified lipid nanoparticles來提高口服生體可用率，減少口服給藥之藥量進而降低其副作用，且延長藥物在血漿中之作用時間。Solid lipid nanoparticles（SLN）處方是由PEG（X EO）monostearate（X＝2、4、10、25、40、45、55）和 glyceryl monostearate作為油相中的界面活性劑，Vitamin C 作為抗氧化劑。處方評估是利用平均粒徑、包埋率、模擬胃腸液中的安定性。在模擬胃腸液中最安定的處方為代碼PEG-55+VitC，將其製成SLN，以靜脈注射投予，觀察大鼠體內血液中藥物動力學情形以及腦部組織分佈。以Apomorphine-SLN（PEG-55+VitC-15和GMS+VitC-15）和Apomorphine-Solution（Solution+VitC-15）口服投予於大鼠後，以AUC0-8（ng•hr /mL）評估，Apomorphine-SLN大於Apomorphine-Solution（264.51 ng•hr /mL和238.61 ng•hr /mL＞20.04 ng•hr /mL），可增加藥物的半衰期，延長藥物的代謝，使得Apomorphine能在血漿中有較高的濃度。且在第2小時之後的血中濃度呈現平穩趨勢。Apomorphine因PEG-55+VitC有SLN劑型修飾，能穿透血腦障壁有較多的藥量抵達腦中紋狀體，以致能夠影響紋狀體dopamine receptor的功能；亦可說明同劑量之PEG-55+VitC-15和Solution+VitC-15以口服投予於巴金森氏症鼠，以對側旋轉反應評估（平均轉圈次數為114.50次＞20.00次；平均轉圈時間為107.50分＞31.25分；平均轉圈速率1.08次/分＞0.62次/分），得知PEG-55+VitC-15表示較佳的藥效。

關鍵字

阿朴嗎啡 ； 口服藥物輸送 ； 固體脂質奈米顆粒 ； PEG monostearate包覆奈米粒子

並列摘要

Apomorphine was a potent D1 and D2 dopamine receptor agonist, which is effective in the treatment of Parkinsonism. Upon oral administration, the drug is rapidly degraded in the gastrointestinal tract and subjected to a high first-pass effect, resulting in an oral bioavailability of 1.7%. By developing surface-modified lipid nanoparticles intended to encapsulate apomorphine within their structure, then increase an oral bioavailability, decrease an oral dose and decrease the side effect, and extend the period of apomorphine in blood. The formulation of solid lipid nanoparticles（SLN）prepared with PEG（X EO）monostearate（X＝2、4、10、25、40、45、55）and glyceryl monostearate as surfactant at lipid phase and vitamin C as antioxidant. The formulation was evaluated by measuring the mean particle size, entrapment efficiency of apomorphine, in vitro stability in simulated gastrointestinal fluids. The most stable of the SLN in gastrointestinal fluids was PEG-55+VitC, and then was intravenously administrated into the rat. The pharmacokinetics and distribution of Apomorphine-SLN（PEG-55+VitC）in brain tissue were evaluated in rat. Using oral administration for rat with Apomorphine-SLN（PEG-55+VitC-15 and GMS+VitC-15）and Apomorphine-Solution（Solution+VitC-15）. The AUC0-8 of Apomorphine-SLN was higher than Apomorphine-Solution（264.51 ng•hr /mL, 238.61 ng•hr/mL＞20.04 ng•hr/mL）. Higher concentration of Apomorphine-SLN（PEG-55+VitC）was found in the striatum of the rat. It proved that using oral administration for Parkinsonism rat. The mean contralateral rotation counts of PEG-55+VitC-15 was higher than Solution+VitC-15 at duration time（114.50 counts＞20.00 counts）.

並列關鍵字

Apomorphine ； Oral drug delivery ； Solid lipid nanoparticles ； PEG monostearate coated nanoparticles

參考文獻

Almeida A.J., Souto E., Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Deliv Rev, 59: 478-490. 2007.

Cavalli R., Caputo O., Gasco M.R., Preparation and characterization of solid lipid nanospheres containing paclitaxel. Eur J Pharm Sci, 10: 305-309. 2000.

Clarke C.E., Neuroprotection and pharmacotherapy for motor symptoms in Parkinson disease. Lancet Neurol, 3: 466-474. 2004.

Desai M.P., Labhasetwar V., Amidon G.L., Levy R.J., Gastrointestinal uptake of biodegradable microparticles: effect of particle size. Pharm Res, 13: 1838-1845. 1996.

Doxastakis G., Sherman P., The interaction of sodium caseinate with monoglyceride and diglyceride at the oil-water interface and its effect on interfacial rheological properties. Colloid Polym Sci, 264: 254-259. 1996.