A (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)-dispersed sustained-release tablet for imperialine to simultaneously prolong the drug release and improve the oral bioavailability.
Imperialine, extracted from Bulbus Fritillariae Cirrhosae, is an efficient antitussive and expectorant medicine. However, its short half-life and stomach degradation limited imperialine from further clinical use. The current study was conducted to develop a sustained-release tablet for imperialine both to prolong absorption time and to improve the oral bioavailability of the drug. The tablets were prepared by a direct compression method formulated on optimized solid dispersion (SD) for imperialine based on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) with imperialine/Soluplus(®) ratio of 1:8 (w/w). In order to obtain the optimized formulation, factors that affected the drug release were investigated by in vitro dissolution studies in the media of pH1.2, 5.8, 7.0 and 7.4. Powder X-ray diffraction and scanning electron microscope confirmed that the imperialine in SD was amorphous instead of crystalline, and still stayed amorphous even after the direct compression. And besides, pharmacokinetic study in Beagle dogs was performed to inspect the in vivo sustained release. Plasma concentration-time curves and pharmacokinetic parameters were gained. As a result, the Cmax of imperialine was one-fold reduced and Tmax was two-fold prolonged, and the mean AUC0-24 was expressed as 89.581±21.243μgh/L, which showed that the oral bioavailability of imperialine was 2.46-fold improved. Moreover, the in vitro-in vivo correlation was recommended to carry out, demonstrating the percentages of drug release in vitro were well-correlated with the absorptive fraction in vivo with the correlation coefficients above 0.9900. By mathematically modeling and moment imaging of the drug release, Peppas equation was selected as the most fitted model for the sustained-release tablets with the diffusional coefficient in the range of 0.59-0.62, indicating the release of imperialine from the sustained-release tablets was an anomalous process involving polymer swelling, drug diffusion and matrix erosion.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
Qing
Q
Lin
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
Yu
Y
Fu
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
Jia
J
Li
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
Mengke
M
Qu
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
Li
L
Deng
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: gongtaoy@126.com.
Tao
T
Gong
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: zrzzl@vip.sina.com.
Zhirong
Z
Zhang
D000284:Administration, Oral; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D002595:Cevanes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004285:Dogs; D005260:Female; D008297:Male; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011145:Polyvinyls / Q000627:therapeutic use*; D013607:Tablets
D000996:Antitussive Agents; D002595:Cevanes; D003692:Delayed-Action Preparations; D011145:Polyvinyls; D013607:Tablets; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols; C047331:peiminine
Acetonitrile (PubMed CID: 6342); Carbamazepine (PubMed CID: 2554); Carboxymethyl cellulose sodium (PubMed CID: 6328154); Dimethylsulfoxide (PubMed CID: 679); Formic acid (PubMed CID: 284); Fumaric acid (PubMed CID: 444972); Hydrochloric acid (PubMed CID: 313); Imperialine; Imperialine (PubChem CID: 442977); In vitro dissolution; In vitro–in vivo correlation; Magnesium stearate (PubMed CID: 11177); Pharmacokinetics; Release mechanism; Soluplus®; Sustained-release tablet; Tartaric acid (PubMed CID: 875)