Mechanistic insights of the controlled release capacity of polar functional group in transdermal drug delivery system: the relationship of hydrogen bonding strength and controlled release capacity.

BACKGROUND: Hydrogen bonding interaction was considered to play a critical role in controlling drug release from transdermal patch. However, the quantitative evaluation of hydrogen bonding strength between drug and polar functional group was rarely reported, and the relationship between hydrogen bonding strength and controlled release capacity of pressure sensitive adhesive (PSA) was not well understood. The present study shed light on this relationship. METHODS: Acrylate PSAs with amide group were synthesized by a free radical-initiated solution polymerization. Six drugs, i.e., etodolac, ketoprofen, gemfibrozil, zolmitriptan, propranolol and lidocaine, were selected as model drugs. In vitro drug release and skin permeation experiments and in vivo pharmacokinetic experiment were performed. Partial correlation analysis, fourier-transform infrared spectroscopy and molecular simulation were conducted to provide molecular details of drug-PSA interactions. Mechanical test, rheology study, and modulated differential scanning calorimetry study were performed to scrutinize the free volume and molecular mobility of PSAs. RESULTS: Release rate of all six drugs from amide PSAs decreased with the increase of amide group concentrations; however, only zolmitriptan and propranolol showed decreased skin permeation rate. It was found that drug release was controlled by amide group through hydrogen bonding, and controlled release extent was positively correlated with hydrogen bonding strength. CONCLUSION: From these results, we concluded that drugs with strong hydrogen bond forming ability and high skin permeation were suitable to use amide PSAs to regulate their release rate from patch.

The Improved Cargo Loading and Physical Stability of Ibuprofen Orodispersible Film: Molecular Mechanism of Ion-Pair Complexes on Drug-Polymer Miscibility.

High drug cargo loading in polymer and physical stability was essential for the development of orodispersible films (ODFs) because of the small amount of excipients used in a thin film. The present study aimed to investigate the mechanism of ion-pair strategy in improving drug cargo loading and physical stability of drug in ODFs. The results showed that the ion pair, especially ibuprofen-ethanolamine, improved the drug solubility in polymer up to 60% (w/w) and physical stability by 30% than the pure ibuprofen film. In addition, drug dissolution rate was increased over 2 times. The high drug cargo loading, physical stability and drug dissolution rate was derived from the improved the drug-polymer miscibility introduced by the formation of ion-pair complex. Investigations from the standpoint of physicochemical properties, intermolecular interaction, and polymer mobility indicated the modulation mechanism of ion-pair complexes in the ODFs at molecular level. The amino group and -OH of counter ion exhibited strong hydrogen bond forming ability, which increased the bilateral interaction with both drug and polymer, delayed the onset temperature of sublimation and decreased the polymer mobility. Therefore, ion-pair technology is a promising strategy for high drug loading ODFs in improving the drug-excipient miscibility and stability.

Development of a w/o emulsion using ionic liquid strategy for transdermal delivery of anti - aging component α - lipoic acid: Mechanism of different ionic liquids on skin retention and efficacy evaluation.

Skin aging affects personal image and health. α - lipoic acid (ALA), with excellent free radical scavenging capacity, was used in this research to prepare W/O emulsion. Considering the instability of ALA, ionic liquid strategy was adopted to heighten the solubility of ALA for dissolving in water phase. The mechanism of different ionic liquids (ILs) on skin retention of ALA was investigated by in vitro skin permeation experiment, emulsion quality characterization, rheological test, ATR - FTIR and molecular simulation. The results showed that ionic liquid strategy had a positive influence on the solubilization of ALA. Different ILs were different in skin retention and regulated by skin layers rather than drug release, in which ALA - triethanolamine (ALA - TEOA) presented the best affinity with both stratum corneum (SC) and viable epidermis and dermis (VED), while ALA - N - (2 - Hydroxyethyl) piperidine (ALA - HEPP) as well as ALA - N - (2 - hydroxyethyl) pyrrolidine (ALA - HEPR) showed affinity with either SC or VED respectively. Finally, the emulsion presented brilliant anti - aging efficacy. This study provided a new method of emulsion research and had great significance for the development of topical formulations.

Investigation on the effect of deep eutectic formation on drug-polymer miscibility and skin permeability of rotigotine drug-in-adhesive patch.

The aim of present study was to develop a rotigotine (ROT) transdermal patch by converting ROT to a form of deep eutectic 'liquid co-crystal'. Formulation factors including the type of ROT-organic acid deep eutectics, pressure sensitive adhesives (PSAs), drug-loading and patch thickness were investigated by in vitro skin permeation study and the optimized patch was evaluated by pharmacokinetics study. It was particularly concerned about the drug-polymer miscibility and skin permeability of ROT-lactic acid deep eutectics (ROT-LA). FTIR study, thermal analysis and molecular modeling were conducted to investigate the drug-PSA interaction. Multiple linear regression was performed to investigate the mechanism of the promoted skin permeability. The results showed that strong interaction was observed between ROT-LA and hydroxyl PSA, which inhibited the formation of ROT crystals. Skin permeability of ROT-organic acids deep eutectics were improved by the variations of apparent partition coefficient and glass transition temperature. AUC0-t and Cmax of optimized patch were 1290.6 ± 102.7 h ng/mL and 60.7 ± 12.0 ng/mL, respectively, which had no significant difference with commercial product. In conclusion, a reduced administration area (75%) and low risk of crystallization were introduced by the ROT deep eutectics, which demonstrated the feasibility of improving drug-polymer miscibility and skin permeability of transdermal drug.

Dicarboxylic acid as a linker to improve the content of amorphous drug in drug-in-polymer film: Effects of molecular mobility, electrical conductivity and intermolecular interactions.

Amorphous solid dispersion (ASD) is a well-established approach to improve the dissolution rate of the drugs with low water solubility. However, the application of the ASD was hindered by the low drug content and high risk of re-crystallization of drugs. The purpose of this research was to develop an ASD film with high content of amorphous olanzapine (OLN) for oral delivery. To overcome the high crystallization tendency of OLN in polyvinyl alcohol (PVA) films, three dicarboxylic acids (succinic acid (Suc), fumaric acid (Fum) and malic acid (Mal)) were introduced in the drug-in-polymer system as linkers between the drug and the polymer. The influence of the linkers on the re-crystallization of OLN in PVA films was evaluated by polarized light microscopy (PLM) and x-ray diffraction (XRD). Then, the possible mechanisms of crystallization inhibition were discussed based on the results of dielectric spectroscopy (DES), differential scanning calorimetry (DSC), attenuated total reflectance Fourier transform infrared (ATR-FTIR), Raman spectroscopy and molecular modeling. Finally, the effect of the linkers on the in vitro dissolution of the OLN-in-PVA films was studied in simulant saliva, and the in vivo performance of the optimal formulation was evaluated in rats. The results showed that OLN-in-PVA film have lower molecular mobility, lower electrical conductivity and stronger intermolecular interactions with the existence of Mal, which led to a better crystallization inhibition of OLN in PVA films. The re-crystallization of OLN in PVA films decreased the dissolution rate of OLN in simulant saliva. The in vivo performance of the optimal formulation was similar with that of OLN solution in rats. This study introduced a novel strategy to reduce the risk of drug re-crystallization in ASD, and also provided a deeper insight into the mechanisms of crystallization inhibition in ASD. The results will improve the judicious selection of excipients in pharmaceutical formulations.

Investigation of Effect of Isopropyl Palmitate on Drug Release from Transdermal Patch and Molecular Dynamics Study.

Chemical penetration enhancers are widely used in transdermal drug delivery system. However, few studies have focused on changes of concentration in chemical penetration enhancers. In this study, the effect of concentrations of enhancers on drug release and its mechanism were investigated. Zolmitriptan (ZOL) was used as a model drug and isopropyl palmitate (IPP) was used as a model enhancer to investigate drug release behaviors in pressure-sensitive adhesives (PSAs). The IPP concentrations were 2, 5, 10, 12, and 15%. Drug release percents increased by 4.8, 11.5, 16, 15.1, and 14.8%, respectively. Interestingly, the linear relationship between concentrations of IPP and release percents was improved in the 0-10% and remained unchanged in the 10-15%. Moreover, thermal and rheology studies were performed to investigate changes of the fluidity of PSAs. FT-IR and molecular dynamics simulation were conducted to confirm the interaction strength among ZOL, IPP, and PSAs. The results elucidated that IPP increased fluidity of PSAs and vied for drug from PSAs. As a result, the interaction among three components played a major role in changing release behaviors of ZOL, but the increased fluidity only worked in the concentration of less than 10%.

A donepezil/cyclodextrin complexation orodispersible film: Effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption.

The aim of this study was to develop a palatable donepezil (DP) orodispersible film (ODF) to facilitate the swallowing process and investigate the effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption. Complexation of DP with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was applied to mask the bitter taste then the prepared complexes were incorporated into ODF using solvent casting method. The taste-masking efficiency was evaluated by e-tongue; meanwhile the pharmacokinetic behavior of DP/HP-ß-CD ODF was investigated by in vivo study. Results showed the optimized film was more palatable than donepezil hydrochloride (DH) film and was bioequivalent with DH. The molecular mechanism was revealed by phase solubility study, Fourier-transform infrared spectrometer (FT-IR), Differential scanning calorimeter (DSC), X-ray diffraction (XRD) and molecular modeling. Taste-masking was attributed to the formation of DP/HP-ß-CD which was due to moderate interaction between DP and HP-ß-CD. The stability of DP/HP-ß-CD was decreased because of the acid environment in stomach, which facilitated the absorption of DP. These results extended our understanding about the application of cyclodextrin complexation and provided guidance for the design of ODF especially for drugs with disgusting taste.

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.

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 ±â€¯63 ng/mL) and longer MRT (19.9 ±â€¯3.4 h) compared to BSP patch (Cmax,BSP = 450 ±â€¯28 ng/mL, MRTBSP = 7.9 ±â€¯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.

Impact of Pore Size and Surface Chemistry of Porous Silicon Particles and Structure of Phospholipids on Their Interactions.

By exploiting its porous structure and high loading capacity, porous silicon (PSi) is a promising biomaterial to fabricate protocells and biomimetic reactors. Here, we have evaluated the impact of physicochemical properties of PSi particles [thermally oxidized PSi, TOPSi; annealed TOPSi, AnnTOPSi; (3-aminopropyl) triethoxysilane functionalized thermally carbonized PSi, APTES-TCPSi; and thermally hydrocarbonized PSi, THCPSi] on their surface interactions with different phospholipids. All of the four phospholipids were similarly adsorbed by the surface of PSi particles, except for TOPSi. Among four PSi particles, TOPSi with hydrophilic surface and smaller pore size showed the weakest adsorption toward phosphatidylcholines. By increasing the pore size from roughly 12.5 to 18.0 nm (TOPSi vs AnnTOPSi), the quantity of phosphatidylcholines adsorbed by TOPSi was enhanced to the same level of hydrophilic APTES-TCPSi and hydrophobic THCPSi. The 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) exhibited the highest release ratio of phospholipids from all four PSi particles, and phosphatidylserine (DPPS) showed the lowest release ratio of phospholipids from PSi particles, except for TOPSi, which adsorbed less phospholipids due to the small pore size. There is consistency in the release extent of phospholipids from PSi particles and the isosteric heat of adsorption. Overall, our study demonstrates the importance of pore size and surface chemistry of PSi particles as well as the structure of phospholipids on their interactions. The obtained information can be employed to guide the selection of PSi particles and phospholipids to fabricate highly ordered structures, for example, protocells, or biomimetic reactors.

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.

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.

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

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.

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.

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 ±â€¯747.8 h ∗ ng/mL and 127.8 ±â€¯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.

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.

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.

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

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 ±â€¯0.3% and 50.0 ±â€¯2.0% respectively, while from AAOH, the release percent of ZOL and ETO were 61.4 ±â€¯1.2% and 81.0 ±â€¯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.

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.

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.

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 (P'o/w) in the hydrophobic vehicle caprylic/capric triglyceride, (log kp=-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 1H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes.

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

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 OH 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.

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.