title: Tanshinone IIA - loaded pellets developed for angina chronotherapy: Deconvolution-based formulation design and optimization, pharmacokinetic and pharmacodynamic evaluation.
abstract: This paper put forward a deconvolution-based method for designing and optimizing tanshinone IIA sustained-release pellets (TA-SRPs) with improved efficacy in the treatment of variant angina. TA-SRPs were prepared by coating TA ternary solid dispersion immediate-release pellets (TA-tSD-IRPs) with the blends of polyvinyl acetate (PVAc) and polyvinyl alcohol-polyethylene glycol (PVA-PEG) using fluidized bed technology. The plasma concentration-time curve of TA-tSD-IRPs following oral administration as a weight function was investigated in New Zealand white rabbits. The predicted/expected plasma concentration-time curve of TA-SRPs as a response function was simulated according to the circadian rhythm of variant angina during 24h based on chronotherapy theory. The desired drug release profile of TA-SRPs was obtained via the point-area deconvolution procedure using the weight function and response function, and used for formulation optimization of TA-SRPs. The coating formulation of TA-SRPs was optimized as 70:30 (w/w) PVAc/PVA-PEG with 5% (w/w) coating weight due to in vitro drug release profile of these TA-SRPs was similar to the desired release profile (similarity factor f2=64.90). Pharmacokinetic studies of these optimized TA-SRPs validated that their actual plasma concentration-time curve possessed a basically consistent trend with the predicted plasma concentration-time curve and the absolute percent errors (%PE) of concentrations in 8-12h were less than 10%. Pharmacodynamic studies further demonstrated that these TA-SRPs had stable and improved efficacy with almost simultaneous drug concentration-efficacy. In conclusion, deconvolution could be employed in the development of TA-SRPs for angina chronotherapy with simultaneous drug efficacy and reduced design blindness and complexity.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Yan
authors.affiliation: Department of Pharmacy, Xuzhou Medical College, Xuzhou, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Zheng-Hua
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, PR China. Electronic address: zwllz@163.com.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, PR China. Electronic address: liujianpingljp@hotmail.com.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Liu
mesh_terms: D045784:Abietanes / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000787:Angina Pectoris / Q000097:blood / Q000188:drug therapy*; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D055870:Drug Chronotherapy; D005079:Excipients / Q000737:chemistry; D008297:Male; D008954:Models, Biological; D009569:Nitric Oxide / Q000097:blood; D011092:Polyethylene Glycols / Q000737:chemistry; D011142:Polyvinyl Alcohol / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D011817:Rabbits; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D045784:Abietanes; D002317:Cardiovascular Agents; D003692:Delayed-Action Preparations; D005079:Excipients; D011145:Polyvinyls; C021751:tanshinone; D009569:Nitric Oxide; C013215:polyvinyl acetate; D011092:Polyethylene Glycols; D011142:Polyvinyl Alcohol
keywords: 1,2-propylene glycol (PubChem CID: 1030); Angina chronotherapy; Deconvolution-based design; Ethyl acetate (PubChem CID: 8857); Methanol (PubChem CID: 887); Nitric oxide (PubChem CID: 145068); Nitrogen (PubChem CID: 947); Pellets; Pharmacodynamics; Pharmacokinetics; Poloxamer 188 (PubChem CID: 24751); Polyvinylpyrrolidone (PubChem CID: 6917); Sodium dodecyl sulfate (PubChem CID: 3423265); Talc (PubChem CID: 16211421); Tanshinone IIA; Tanshinone IIA (PubChem CID: 164676)