目的 制備鹽酸右美托咪定舌下片并評價其關(guān)鍵質(zhì)量。方法 選擇粉末直壓法、泡騰法、升華法制備鹽酸右美托咪定舌下片，通過休止角、卡爾系數(shù)評價中間體顆粒性能；以脆碎度、含量及含量均勻度、溶出度、崩解時限、潤濕時間和吸水比等片劑關(guān)鍵質(zhì)量屬性以及離體口腔黏膜穩(wěn)態(tài)滲透速率評價處方及工藝的合理性；比較鹽酸右美托咪定舌下片與市售注射液在比格犬體內(nèi)的藥動學(xué)差異。結(jié)果 中間體混合粉末具有良好的流動性能；樣品脆碎度、含量及含量均勻度均良好；采用升華法制備的樣品釋放最快，在同種工藝條件下，當處方中交聯(lián)羧甲基纖維素鈉與羧甲基淀粉鈉比例為1∶3時，樣品的釋放速率最快；各處方均能在5 min內(nèi)完全崩解，采用升華法制備的樣品崩解最快，泡騰法次之；各處方樣品完全潤濕所需的時間與其完全崩解所消耗的時間呈正比，各樣品吸水比無明顯差異；采用升華法制備的樣品體外穩(wěn)態(tài)滲透速率較大，當處方中交聯(lián)羧甲基纖維素鈉與羧甲基淀粉鈉比例為1∶3時，穩(wěn)態(tài)滲透速率最大；舌下給藥后比格犬體內(nèi)t_max、C_max、AUC_0-t分別為（48.0±12.6）min、（5.6±0.5）ng·mL⁻¹、（8.7±0.9）ng·min·mL⁻¹，與iv給藥相比，鹽酸右美托咪定舌下片的生物利用度為85.29%，C_max降低約15%，但tmax明顯延長。結(jié)論 采用升華法制備的鹽酸右美托咪定舌下片處方和制備工藝合理，質(zhì)量可控，體外穩(wěn)態(tài)滲透速率最好，絕對生物利用度為85.29%，與注射液生物不等效，可以通過改變規(guī)格來解決。

Objective To prepare dexmedetomidine hydrochloride sublingual tablets and to evaluate its key quality. Methods Dexmedetomidine hydrochloride sublingual tablets was prepared by powder direct pressing method, effervescence method and sublimation method. The particle properties of the intermediate were evaluated by Angle of rerest and Karl coefficient. The rationality of prescription and process was evaluated by the key quality attributes of tablets, such as friability, content and content uniformity, dissolution, disintegrating time, wetting time and water absorption ratio, as well as the steady penetration rate of oral mucosa in vitro. The pharmacokinetic differences between sublingual tablets and injection of dexmedetomidine hydrochloride were compared in beagle dogs. Results The intermediate mixed powder had good flow performance. The friability, content and content uniformity of the samples were all good. The release rate of the sample prepared by sublimation method was the fastest. Under the same conditions, the release rate of the sample was the fastest when the ratio of sodium carboxymethyl cellulose and sodium carboxymethyl starch in the prescription was 1∶ 3. All the formulas could completely disintegrate within 5 min. The samples prepared by sublimation method had the fastest disintegration, followed by bubbling method. The time required for complete wetting of each prescription sample was proportional to the time consumed for complete disintegration, and there was no significant difference in water absorption ratio of each sample. The steady-state osmosis rate of the sample prepared by sublimation method was higher than that of the sample prepared by sublimation method. The steady-state osmosis rate was the highest when the ratio of sodium carboxymethyl cellulose and sodium carboxymethyl starch in the prescription was 1∶3. After sublingual administration, tmax, C_max and AUC_0-t in beagle dogs were (48.0±12.6) min, (5.6±0.5) ng·mL⁻¹ and (8.7±0.9) ng·min·mL⁻¹, respectively. Compared with iv administration, the bioavailability of dexmedetomidine hydrochloride sublingual tablet was 85.29%. C_max decreased by about 15%, but t_max increased significantly. Conclusion Dexmedetomidine hydrochloride sublingual tablet prepared by sublimation method has reasonable prescription and preparation process, controllable quality, best steady-state infiltration rate in vitro and absolute bioavailability of 85.29%, which is not equivalent to injection, and can be solved by changing specifications.

R944.4