Apomorphine利用感溫水性凝膠之輸藥系統研究

controlled apomorphine delivery system based on thermosensitive biodegradable hydrogel

陳怡秀(Yi-Xiu Chen)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/藥學研究所/碩士(2005年)

摘要

巴金森氏症是一運動緩慢、全身僵硬之慢性進行性神經退化的疾病。目前治療巴金森氏症之藥仍是levodopa最有效，但在使用超過五年後，常開始產生陣發性運動不良(motor fluctuation)，甚至最後有陣發性停電(on-off phenomenon)之現象。Apomorphine為一超短效之多巴胺增強劑，最近研究得知皮下注射Apomorphine能大幅降低巴金森氏症之難治性的陣發性停電
現象，且較不易造成運動不能之副作用。經由皮下注射的藥動分析得知R-apomorphine能快速且完全由皮下組織吸收，雖快速吸收與快速產生臨床療效有關，但因apomorphine半衰期短，故為維持其療效，則須多次少量的
皮下注射，而極大影響到病人之順從性。此缺點擬用原位成膠(In-situ gel formation)輸送系統來改善，本實驗製備15-18%(w/v)Pluronic F127 聚合物溶液作為apomorphine之輸送載體，藉助載體會使液體變成凝膠相轉移，來達到藥物控制釋出效果。經粘度測試之流變性狀發現17% Pluronic F127在非生理狀態(25℃)成流動狀態，而在生理狀態(37℃)成凝膠態，表示其可作為Apomorphine之控釋材質。
在體外釋出方面，探討給藥端pH之改變、Pluronic濃度及添加粘度增強
劑等對apomorphine體外釋出影響。結果顯示，apomorphine在17％
PluronicF127、17% PluronicF127/ 1% Sodium Alginate(pH6)凝膠劑型,其釋出速率分別0.07及0.045mg/cm2/hr；而不含polymer的apomorphine其釋出速
率0.89 mg/cm2/hr。
另以腹腔皮下注射投予劑量1 mg/kg含17% PluronicF127/ 1% Sodium Alginate(pH6)之apomorphine水溶液至體重為200∼260克之Wistar大白鼠體內，經時收集血液檢品並以Ether作為藥品之萃取溶媒，以Electrochemical detector（ECD）作為藥品之檢出器，以HPLC分析血中藥物濃度，藉此探討含polymer之apomorphine水溶液在皮下釋出後被吸收的情形。結果顯
示，在第15分鐘血中濃度最高，為9.27 ng/mL，而後血中濃度逐漸下降，直到第4小時後血中濃度近趨平穩，其值約為1.5 ng/mL。由此，含17% PluronicF127/ 1% Sodium Alginate(pH6)之凝膠劑型，可讓apomorphine在體內緩慢釋出，以延長藥物作用時間。

關鍵字

皮下控釋 ； 慢性進行性神經退化 ； 陣發性停電 ； 原位成膠 ； 多巴胺增強劑 ； 利用感溫水性凝膠 ； 巴金森氏症

並列摘要

Parkinson disease was a chronically progressive neurodegenerative disorder characterized by bradykinesia and generalized rigidity.The
Antiparkinson agent such as levodopa has good response initially,
but after more than 5 years used,the symptoms of paroxysmal motor
fluctuation.Apomorphine was a shorting-acting dopamine agonist,
It was reported that subcutaneous injection will reduce the intractable off-state phenomenon. Unfortunately,as a result of the short duration of therapeutic effect,high injection frequencies（up to 10-12 times a day）can improved by in-situ gel formation delivery system.The study
was to formulate a subcutaneous controlled delivery of apomorphine
using 15-18%(w/v)Pluronic F127 as a polymeric carrier. Pluronic F127 was a thermoreversible gelation and observed significant sol-gel phase transition from non-physiological to physiological condition.
The rheological results of 17% Pluronic F127 showed a significant enhancement in gel strength in the physiological condition and free flowing at non-physiological condition.The in-vitro release profiles of apomorphine from effect of Pluronic formulation and pH of donor cell profiles were obtained.The apomorphine release profiles showed that in-vitro release of apomorphine from 17% Pluronic F127 and 17% Pluronic F127/1% Sodium Alginate（pH=6）gel formulations, the flux were 0.07 and 0.045 mg/cm2/hr,respectively;but, the flux of apomorphine without any polymer was 0.89 mg/cm2/hr.In-vivo release was investigated by determining plasma apomorphine concentrations after the subcutaneous polymeric delivery system into the abdominal cavity of Wistar rats.In the study,apomorphine was administered by subcutaneous into Wistar rats weighted 200 to 260 g.
The blood samples were extracted with ether and analyzed by HPLC method.Based on our results,after the peak,the plasma levels slowly
decreased until the fourth hour,remained at a plasma level of 1ng/ml

並列關鍵字

In-situ gel.pluronic F127 ； alginate ； low critical solution temperature ； apomorphine ； sol-gel transition temperature

參考文獻

陸、參 考 文 獻

AHFS Drug Information. 89

Bianchi, G., Landi, M., 1985. Determination of apomorphine in rat plasma and brain by high-performance liquid chromatography with electrochemical detection. J. Chromatogr, 338: 230-235

Burkman, A.M., Notari, R.E., Van, T.W., 1974. Structural effects in drug

distribution:Comparative pharmacokinetics of apomorphine analogues. J. Pharm. Pharmacol, 26: 493-507