PROCESS BIOCHEMISTRY
·
2019
·
IF 2.883
Panliang Zhang,Wanru Wang,Guilin Dai,Shichuan Wang,Weifeng Xu,Kewen Tang
Symmetric and asymmetric separations of bisoprolol (BS) enantiomers were performed by fractional extraction with iso-butyl-L-tartrate (LT) as chiral extractant. The extraction process is complicated involving multiple chemical equilibrium, and the fractional extraction efficiency is strongly influenced by pH, boric acid (BA) and LT concentration, number of transfer units (NTU), feeding position, and phase ratios. An interfacial reaction phase equilibrium model was established and verified by experiment. A multistage model was further developed to model the extraction process to achieve the optimal operational parameters. Under the optimized parameters, S-bisoprolol (S-BS) was obtained by symmetric and asymmetric separations of racemic BS in a cascade of 10 centrifugal contactor separators (CCSs). The ee of S-BS in organic phase obtained by symmetric and asymmetric separations are 0.753 and 0.942, respectively. The relative errors of 3.12% and 4.24% show experiment is in good agreement with predictions. The required number of stage is greatly reduced to obtain high enantiomeric excess (ee) of S-BS by asymmetric separation.
研究领域:
药学
·
化学工程
✓ 已验证
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Yu Pang,Wenxuan Jia,Liuyang Wang,Yang Zhang,Kaihua Gong,Liang Fang
This study aims to develop a sustained release patch for bisoprolol (BSP) to address the issue of blood pressure fluctuations caused by traditional dosing methods, ensuring continuous drug release and efficient utilization. Long-chain saturated fatty acids (C6–C12) were chosen as counterions to precisely control BSP’s permeation rate in the patch formulation, and the ion-pairing strategy’s mechanism in drug delivery was thoroughly investigated. Molecular docking results revealed significant differences in the adsorption capacities of different ion pairs in the stratum corneum (SC) and epidermis, directly influencing their residence times and thereby regulating BSP’s passive diffusion rate. Particularly, the BSP-C10 ion pair successfully reduced BSP’s permeation rate to one-third of its baseline. To enhance drug delivery efficiency and reduce costs, chemical permeation enhancers (CPEs) are typically added to sustained release patches. In contrast to traditional static analyses based on cumulative permeation, this study utilized ATR-FTIR dynamic detection of isopropyl myristate (IPM) as a preferred enhancer, studying its disruptive effects on the skin barrier during drug delivery. The study observed that during drug delivery, the interaction between IPM and skin lipids follows a U-shaped trend: initially increasing, then decreasing, with the peak occurring at 10 h. Similarly, the drug delivery rate displays a comparable pattern. The addition of IPM as CPE increased the patch utilization rate from 39.8 ± 4.31 to 79.8 ± 7.27%. This strategy aims to rapidly reduce blood pressure in the initial phase with subsequent weakening of IPM disruption, allowing the ion-pairing strategy to dominate drug delivery control and maintain stable long-term therapeutic effects. Pharmacokinetic studies demonstrated that the newly developed BSP sustained release patch maintains stable blood drug concentrations, reduces burst release effects, increases bioavailability to 84.679%, doubles MRT0–t, halves Cmax, and significantly reduces the occurrence of blood pressure fluctuations.
研究领域:
药剂学
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药物递送系统
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2017
·
IF 3.649
Hanqing Zhao,Chao Liu,Peng Quan,Xiaocao Wan,Meiyue Shen,Liang Fang
Though ion-pair strategy has been widely used in transdermal drug delivery system , knowledge about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes is still limited. In the present study, a homologous series of fatty acids were chosen to form model ion-pair complexes with bisoprolol (BSP) to rule out the influence of functional groups on polar surface area, stability and other physicochemical properties of ion-pair complexes. The ion-pair complexes were characterized by FTIR , thermal analysis, and 1 H NMR. The skin permeability of BSP as well as its ion-pair complexes was investigated by in vitro skin permeation experiments then visualized by CLSM . The skin permeability coefficient ( k p ) of BSP ion-pair complex was negatively related to its n -octanol/water apparent partition coefficient ( P’ o/w ) in the hydrophobic vehicle caprylic/capric triglyceride , (log k p = −1.657 − 1.229 log P’ o/w ), suggesting that the instability of ion-pair complexes due to their dissociation in the viable epidermis (VED) played an important role in controlling the skin permeability of BSP, which was further proved by 1 H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes.
研究领域:
药剂学
·
皮肤科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2018
·
IF 7.877
Hanqing Zhao,Chao Liu,Degong Yang,Xiaocao Wan,Rui Shang,Peng Quan,Liang Fang
Though ion-pair strategy has been employed as an effective and promising method for controlling transdermal delivery of drugs, investigations into the underlying mechanisms involved in the controlled release process of ion-pairs are still limited. In the present study, a brand-new controlled release system combining acrylic pressure sensitive adhesive containing carboxyl group (carboxylic PSA) with ion-pair strategy was developed, and the molecular mechanism of ion-pair releasing from carboxylic PSA was systemically elucidated. Bisoprolol (BSP) and bisoprolol-lauric acid ion-pair (BSP-C 12 ) were chosen as model drugs. Carboxylic PSA was designed and synthesized. Effect of ion-pair on controlling BSP release from carboxylic PSA was evaluated by in vitro drug release study, in vitro skin permeation study and pharmacokinetic study. Molecular mobility of PSA, along with the strength of drug-PSA interaction was evaluated by thermal analysis and dielectric spectroscopy . Molecular details of drug-PSA interaction were identified by FTIR , XPS and Raman. Roles of drug-PSA interaction in the controlled release process were clarified by molecular modeling. Results showed that BSP-C 12 patch demonstrated a controlled release drug plasma profile, with lower C max (193 ± 63 ng/mL) and longer MRT (19.9 ± 3.4 h) compared to BSP patch ( C max,BSP = 450 ± 28 ng/mL, MRT BSP = 7.9 ± 0.9 h). Besides, there was no significant difference between the AUC of BSP-C 12 and BSP patch. It turned out that instead of PSA molecular mobility, molecular interaction between ion-pair and PSA played a dominant role in the controlled release process of BSP: as illustrated by FTIR , Raman and molecular docking, the ionic interaction between BSP-C 12 and PSA determined the amount of BSP released, namely the thermodynamic process; while the doubly ionic hydrogen bond between BSP-C 12 and PSA-COO – controlled the release rate, which was the kinetic process. In conclusion, it was found that the doubly ionic hydrogen bond formed between carboxylic PSA and ion-pair controlled the release profile of BSP, which broadened our understanding about the molecular mechanisms involved in ion-pair controlled release transdermal patches and contributed to the design of controlled release TDDS .
研究领域:
药学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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