Xiaocao Wan

Mechanistic insights of the enhancement effect of sorbitan monooleate on olanzapine transdermal patch both in release and percutaneous absorption processes

Abstract In this paper, based on the optimized formulation of olanzapine (OLN) transdermal patch, the role of sorbitan monooleate (SP) in OLN release and percutaneous absorption processes was probed in vitro and in vivo. Rheological test, DSC, FT‐IR and molecular modeling were conducted to elucidate the effect of SP on the release process of OLN from transdermal patch. Additionally, the action of SP on the percutaneous absorption process was probed using tape stripping transdermal experiment, confocal laser scanning microscopy (CLSM), ATR‐FTIR and molecular docking. The results showed that the hydrogen bonding interaction between OLN and pressure sensitive adhesive (PSA) was weakened by SP, which resulted in a decrease in the cohesive interaction between polymer chains and an increase in the formation of free volume of PSA, thus, the release of OLN from patch was promoted. Meanwhile, the O—H groups of SP interacted with the polar head groups of the ceramides, which increased the fluidity of the skin lipids, thereby improved the ability of OLN percutaneous absorption. In summary, this study demonstrated that not only the release but also the percutaneous absorption processes were promoted by SP. This study provided comprehensive molecular level understanding on the effect of penetration enhancer on transdermal patch and strategies for rationally selection of chemical enhancer for transdermal drug delivery systems. Graphical abstract Figure. No Caption available.

Mechanism study on ion-pair complexes controlling skin permeability: Effect of ion-pair dissociation in the viable epidermis on transdermal permeation of bisoprolol

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 1H 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 (kp) of BSP ion-pair complex was negatively related to its n-octanol/water apparent partition coefficient (Po/w) in the hydrophobic vehicle caprylic/capric triglyceride, (log kp=-1.657-1.229 log Po/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 1H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes.

Investigate the control release effect of ion-pair in the development of escitalopram transdermal patch using FT-IR spectroscopy, molecular modeling and thermal analysis

The aim of this study was to develop a controlled release drug-in-adhesive patch containing escitalopram (ESP) using ion-pair technique. Special attention was paid on the mechanism of how counter ion controlled the release of ESP. Five organic acids were chosen as the counter ions. Formulation factors including adhesive matrix, drug loading and permeation enhancers were investigated through in vitro experiments using rat skin and the optimized patch was evaluated using in vivo pharmacokinetic study. Drug-counter ion-PSA interactions were characterized by FT-IR, molecular modeling and DSC at molecular level. The optimized patch prepared with ESP-BA showed zero-order skin permeation profile and a satisfied permeation amount of three days (1059±104.9μg/cm2) in vitro, which also showed a steady-state drug plasma concentration lasting 36h in vivo and the Cmax was significantly controlled compared with the control group. The controlled release of ESP was attributed to the interactions among ESP-counter ion-PSA by hydrogen bonding, and counter ion enhanced the interaction between ESP and PSA molecule, which acted as a bridge between them. In conclusion, a controlled release ESP transdermal patch was developed and a novel insight of ion-pair controlled release was proposed at molecular level.

The role of carboxyl group of pressure sensitive adhesive in controlled release of propranolol in transdermal patch: Quantitative determination of ionic interaction and molecular mechanism characterization

Abstract Acrylic pressure sensitive adhesives (PSAs) are widely used in transdermal drug delivery system (TDDS). However, there was little research about the quantitative relationship between drug release and drug‐PSAs interaction. In this study, five acrylic PSAs with different molar fraction of carboxyl group were designed and synthesized. Propranolol (PRO) was used as model drug to evaluate release profiles in the PSAs in vitro and in vivo. The drug release percent in the PSAs were 81.66, 78.22, 51.66, 21.81 and 11.73%, and their release behaviors were decreased with carboxyl group content of PSAs. Furthermore, it was found that quantity of carboxyl group of PSAs was equal to residual drug by the quantitative determination. In addition, the ionic interaction between PRO and PSAs was confirmed by FT‐IR and MDSC results qualitatively. Using the FT‐IR, MDSC, Flory‐Huggins interaction parameters and molecular dynamic simulation, interaction strength between drug and PSAs was determined quantitatively, which demonstrated that the drug release amount decreased linearly with interaction strength. Based on above results, we proposed that the PRO was possibly binding to the carboxyl group of PSAs one‐by‐one, which provided references for the accurate design of TDDS. Graphical abstract Figure. No caption available.

Molecular mechanism of ion-pair releasing from acrylic pressure sensitive adhesive containing carboxyl group: Roles of doubly ionic hydrogen bond in the controlled release process of bisoprolol ion-pair

&NA; 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‐C12) 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‐C12 patch demonstrated a controlled release drug plasma profile, with lower Cmax (193 ± 63 ng/mL) and longer MRT (19.9 ± 3.4 h) compared to BSP patch (Cmax,BSP = 450 ± 28 ng/mL, MRTBSP = 7.9 ± 0.9 h). Besides, there was no significant difference between the AUC of BSP‐C12 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‐C12 and PSA determined the amount of BSP released, namely the thermodynamic process; while the doubly ionic hydrogen bond between BSP‐C12 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.

Investigating the role of ion-pair strategy in regulating nicotine release from patch: Mechanistic insights based on intermolecular interaction and mobility of pressure sensitive adhesive.

ABSTRACT The aim of this study was to prepare a drug‐in‐adhesive patch of nicotine (NIC) and use ion‐pair strategy to regulate drug delivery rate. Moreover, the mechanism of how ion‐pair strategy regulated drug release was elucidated at molecular level. Formulation factors including pressure sensitive adhesives (PSAs), drug loading and counter ions (C4, C6, C8, C10, and C12) were screened. In vitro release experiment and in vitro transdermal experiment were conducted to determine the rate‐limiting step in drug delivery process. FT‐IR and molecular modeling were used to characterize the interaction between drug and PSA. Thermal analysis and rheology study were conducted to investigate the mobility variation of PSA. The optimized patch prepared with NIC‐C8 had the transdermal profile fairly close to that of the commercial product (p>0.05). The release rate constants (k) of NIC, NIC‐C4 and NIC‐C10 were 21.1, 14.4 and 32.4, respectively. Different release rates of NIC ion‐pair complexes were attributed to the dual effect of ion‐pair strategy on drug release. On one hand, ion‐pair strategy enhanced the interaction between drug and PSA, which inhibited drug release. On the other hand, using ion‐pair strategy improved the mobility of PSA, which facilitated drug release. Drug release behavior was determined by combined effect of two aspects above. These conclusions provided a new idea for us to regulate drug release behavior from patch.

Investigation of the enhancement effect of the natural transdermal permeation enhancers from Ledum palustre L. var. angustum N. Busch: Mechanistic insight based on interaction among drug, enhancers and skin

ABSTRACT It has been reported that natural transdermal permeation enhancers (TPEs) are superior in safety compared with synthetic TPEs. The essential oil (EO) of Ledum palustre L. var. angustum N. Busch had a strong enhancement effect on drug skin permeation based on previous studies. However, their enhancement mechanisms and safety were still unclear. The composition of the EO was determined using GC–MS. By using donepezil (DNP) as a model drug, the enhancement effect of the constituents of the EO and the EO were evaluated by in vitro skin permeation test. Confocal laser scanning microscopy (CLSM), attenuated total reflection‐Fourier transform infrared spectroscopy (ATR‐FTIR) and molecular docking were used to investigate the interaction among drug, enhancers and skin. Skin retention amount, apparent partition coefficient (K′) and molecular simulation were used to reflect the effect of the enhancers on drug partition into skin. The skin irritation potential was evaluated using in vivo skin erythema analysis. The results showed that the main constituents of the EO were sabinene (SA), 4‐terpineol (TE), p‐cymene (CY) and cuminaldehyde (CU). CU was the main active constituent of the EO, which facilitated skin permeation of DNP. CU improved the skin permeation of DNP by increasing the mobility of the stratum corneum (SC) intercellular lipids, decreasing the interaction between DNP and the SC intercellular lipids, and improving the partition of DNP into the SC layer. Besides the superior enhancement effect, CU also showed a lower skin irritation potential compared with the EO. This work gave us some enlightenment that the effectiveness and safety of the natural transdermal permeation enhancers could be improved by understanding their composition and the enhancement mechanisms.

Mechanistic insights of the controlled release properties of amide adhesive and hydroxyl adhesive

ABSTRACT Although interactions between drugs and acrylate pressure sensitive adhesives (PSAs) containing amide groups were reported in the previous studies, detailed studies elucidating their mechanism of action are still lacking. In the present study, an amide PSA (AACONH2) and a hydroxyl PSA (AAOH, as the control) were synthesized, and their molecular mechanism of controlled drug release was described. Using zolmitriptan (ZOL) and etodolac (ETO) as model drugs, in vitro drug release and skin permeation experiments were performed. Intermolecular interactions between drugs and PSAs were determined by Flory‐Huggins model, FT‐IR spectroscopic analysis and molecular modeling. In addition, PSA mobility was evaluated using differential scanning calorimetry and rheology study. Release percent of ZOL and ETO from AACONH2 were 43.9±0.3% and 50.0±2.0% respectively, while from AAOH, the release percent of ZOL and ETO were 61.4±1.2% and 81.0±1.2% separately. As a consequence of controlled drug release, skin permeation of both drugs was significantly controlled by AACONH2. It was demonstrated that AACONH2 markedly interacted with drugs, especially with ETO, through hydrogen bonding and weak intermolecular forces (e.g. dipole‐dipole and van der waals). PSA mobility of AACONH2 was significantly increased due to drug‐PSA interactions. In conclusion, AACONH2 had stronger controlled release properties compared with AAOH, which was mainly caused by the stronger interactions between amide groups and drugs. The amide PSA synthesized in the present study was a potential sustained‐release excipient for transdermal drug delivery system.

Investigation of molecular mobility of pressure-sensitive-adhesive in oxybutynin patch in vitro and in vivo: Effect of sorbitan monooleate on drug release and patch mechanical property

&NA; The aim of present study was to develop an oxybutynin (OXY) transdermal patch with good permeation behavior and mechanical property. Special attention was paid to the effect of chemical enhancer on the molecular mobility of pressure sensitive adhesive (PSA) at molecular level. PSAs and permeation enhancers were investigated through in vitro experiment using rat skin. The optimized formulation was evaluated through pharmacokinetic study using rat. In addition, the molecular mechanism of sorbitan monooleate (Span® 80) in the improvement of PSA molecular mobility was investigated using FT‐IR, molecular dynamics simulation, DSC and rheological study. As a result, the optimized formulation using amide PSA demonstrated good adhesion property. And the AUC0‐t and Cmax of optimized patch were 6435.8 ± 747.8 h * ng/mL and 127.8 ± 18.0 ng/mL, respectively, which had no significant difference with commercial product. Furthermore, the improvement of the PSA mobility by Span® 80 rather than the decrease of interaction between drug and PSA was the main factor that enhanced the release of OXY from patch. In conclusion, a drug‐in‐adhesive OXY patch was developed, and the effect of PSA molecular mobility increase on the enhancement of drug skin permeation was proposed at molecular level. Graphical abstract Figure. No caption available.

Development of a daphnetin transdermal patch using chemical enhancer strategy: insights of the enhancement effect of Transcutol P and the assessment of pharmacodynamics

Abstract Objective: The aim of this study was to develop a drug-in-adhesive patch for transdermal delivery of daphnetin (DA), which is a coumarin derivative in Girald Daphne, and to investigate the role of Transcutol P (TP) in the release and percutaneous permeation processes of DA. Methods: Backing films, permeation enhancers and enhancer content in the transdermal patch were investigated through in vitro experiments using rat skin. Anti-inflammatory and analgesic effects of the optimized formulation were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. In addition, the enhancement effect of TP was investigated using differential scanning calorimetry (DSC), FTIR, and molecular dynamic simulation. Results: The optimal formulation, composed of DURO-TAK® 87-2852, CoTranTM 9680, 1% DA, and 10% TP showed anti-inflammatory and analgesic effects. It was found that TP only promoted the release process of DA from its transdermal patch. Furthermore, the decrease of interaction between drug and pressure sensitive adhesive (PSA) as well as the improvement of PSA mobility due to TP addition were the main factors that enhanced the release of DA from patch. Conclusions: This study successfully used TP to develop a DA patch with good anti-inflammatory and analgesic effects, proving that TP promotes the release of DA by reducing the interaction between DA and PSA and increasing the mobility of PSA.