The effect of skin diffusion kinetics of isopropyl ester permeation enhancers on drug permeation: Role of lateral spread and penetration characteristics.

The purpose of present work was to study the effects of permeation enhancers' two kinetic behaviors of simultaneous lateral diffusion and vertical penetration in the skin on its enhancing effect. The skin diffusion kinetics of isopropyl ester permeation enhancers were characterized by the innovative concentric tape peeling study and Raman imaging, which were quantitatively assessed through innovative parameters, namely, lateral-to-vertical penetration amount (CL-V) and lateral-to-vertical penetration distance (DL-V). The enhancement effect of permeation enhancers on drug flurbiprofen (FLU) was assessed by in vitro skin permeation tests, which were confirmed by transdermal water loss and skin resistance study. The relationship between kinetic parameters of permeation enhancers and permeation parameters of FLU was carried out by correlation analysis. The molecular mechanisms of effect of skin diffusion kinetics of permeation enhancers on drug permeation were characterized by molecular docking, modulated-temperature differential scanning calorimetry (MTDSC), Raman spectra, solid-state NMR and molecular dynamic simulation. The results indicated skin diffusion kinetics of short-chain (C8-C12) isopropyl ester permeation enhancers were governed by vertical penetration, while long-chain (C14-C18) ones were characterized by lateral spread. Quadratic correlation between CL-V and enhancement ratio of permeation-retention ratio of FLU (ERQ/R) (R2 = 0.95), DL-V and enhancement ratio of permeation area (ERA) of FLU (R2 = 0.98) indicating that varied skin diffusion kinetics of permeation enhancers directly influenced the barrier function of stratum corneum (SC) and further enhancing drug permeation. In terms of molecular mechanism, long-chain isopropyl ester enhancers had good miscibility with SC, leading to their high CL-V and DL-V, and causing strong interaction strength with SC and resulting in weaker skin barrier function for drug permeation. In summary, in comparison to short-chain isopropyl ester enhancers that relied on penetration, long-chain ones that depended on lateral spread exhibited greater enhancement efficacy, which guided the application of enhancers in transdermal formulations.

Rhamnose-PEG-induced supramolecular helices: Addressing challenges of drug solubility and release efficiency in transdermal patch.

Transdermal drug delivery systems (TDDS) demand both high drug loading capacity and efficient delivery. In order to improve both simultaneously, this study aims to develop a novel rhamnose-induced pressure-sensitive adhesive (HPR) by dispersing the drug in the supramolecular helical structure. Ten model drugs, categorized as acidic and basic compounds, were chosen to understand the characteristics of the HPR and its inner mechanism. Notably, it enhanced drug loading by 1.41 to 5 times over commercially available pressure-sensitive adhesives Duro-Tak@ 87-4098 and Duro-Tak@ 87-2287, in addition to increasing drug release efficiency by a factor of about 5. Pharmacokinetic evaluation demonstrated that the HPR group had >4-fold (Tulobuterol TUL) and 3-fold (Diclofenac DIC) more area under the blood drug concentration curve (AUC) than the commercial TUL and DIC patches in the absence of added excipients and a significantly prolonged mean residence time (MRT) of >4-fold (TUL) and 3-fold (DIC), demonstrating the potential for highly efficacious and prolonged dosing. Furthermore, its safety and mechanical properties meet the requisite standards. Mechanistic inquiries unveiled that both acidic and basic drugs establish hydrogen bonds with HPR and become encapsulated within supramolecular helical structures. The supramolecular helical structures, significantly elevated both the enthalpy of the drug-HPR and entropy of the drugs release, thereby substantially enhancing drug delivery efficiency. In summary, HPR enabled a significant simultaneous enhancement of drug loading and drug delivery, which, together with its unique spatial structure, would contribute to the development of TDDS. In addition, the establishment of rhamnose-induced supramolecular helical structures would provide innovative pathways for different drug delivery systems.

Evaluation of Dose-Response Relationship of Permeation Enhancer Isopropyl Myristate Release on Drug Release: Release Enhancement Efficiency and Molecular Mechanism.

The objective of this study is to investigate the dose-response relationship between various concentrations of permeation enhancers (PEs) and their ability to enhance drug release from a polymer matrix, utilizing an innovative parameter known as release enhancement efficiency (K). Additionally, the molecular mechanism underlying dynamic enhancement was also examined. Isopropyl myristate (IPM) was used as model enhancer and zolmitriptan (ZOL) was used as model drug to investigate dose-effect relationship in pressure sensitive adhesives (PSA). The release behavior of the PEs was determined by LC-MS/MS and verified by confocal laser scanning microscopy (CLSM). The enhancing effect of the PE on ZOL release was evaluated through in vitro release experiments and further validated by pharmacokinetics study. And the molecular mechanism was characterized with thermal analysis (DSC), Fourier transform infrared spectroscopy (FT-IR) and molecular dynamics simulation. K was 0.156, 0.286 and 0.279 at 3%, 6% and 9% IPM concentrations, indicating that the enhancement efficiency reached the maximum when the 6% IPM was applied. According to the mechanism research results, the fluidity of PSA increased linearly with the increase of IPM concentrations, but the interaction between IPM and ZOL reached its strongest point at 6%. In summary, the increase of K value (from 0 to 6% IPM content) was caused by the synergy of increased mobility of PSA and interaction (dipole-dipole and hydrogen-bond) among three components, and when the above two actions were in antagonistic, K no longer increased (6-9% IPM content).

Development of mabuterol transdermal patch: Molecular mechanism study of ion-pair improving patch stability.

This paper aimed to prepare a Mabuterol (MAB) patch for treating asthma by ion-pair strategy to overcome the drug's thermal instability and elucidate the molecular mechanisms of the stabilization effect. The formulation factor, including counter-ion and pressure-sensitive adhesive (PSA), was optimized by the stability and in vitro skin permeation studies. The molecular mechanism of ion-pair stability was characterized using TGA, Raman, FT-IR, NMR, XPS, and molecular modeling. The optimized patch comprised MAB-Lactic acid (MAB-LA) and hydroxyl adhesive (AAOH) as the matrix, with Q = 126.47 ± 9.75 µg/cm2 and Fabs = 75.27%. The increased TGA (213.11 °C), disproportionation energy (ΔG = 97.44 KJ), and ion-pair lifetime (Tlife = 2.21 × 103) indicated that the counter-ion improved MAB stability through strong ionic and hydrogen bonds with LA. The remaining drug content in the MAB-LA patch was 15% higher than that of the pure MAB patch after storage for 12 months at room temperature, which was visualized by Raman imaging. The interaction between MAB-LA and AAOH PSA via hydrogen bond decreased the diffusion rate and increased the drug stability further. This study successfully developed the MAB patch, which provided a reference for applying ion-pairing strategies to improve the stability of transdermal patches.

Formulation Development and Molecular Mechanism Characterization of Long-Acting Patches of Asenapine for Efficient Delivery by Combining API-ILs Strategy and Controlled-Release Polymers.

The objective of our study, which combined API-ILs strategy and controlled-release polymers, was to prepare a 72 h long-acting drug-in-adhesive patch for optimum delivery of asenapine (ASE). Special attention was paid to the permeation promotion mechanism and the controlled release behavior of ASE-ILs in pressure sensitive adhesives (PSA). Formulation factors were investigated by ex vivo transdermal experiments. The optimized patch was evaluated by pharmacokinetics study and skin irritation test. The obtained formulation was as follows, 15% w/w ASE-MA (about 1136 µg/cm2 ASE, 413 µg/cm2 MA), AACONH2 (Amide adhesive) as the matrix, 80 µm thickness, backing film of CoTran™ 9733. The optimized patch displayed satisfactory ex vivo and in vivo performance with Q 72 h of 620 ± 44 µg/cm2 and Fabs of 62.4%, which utilization rate (54.6%) was significantly higher than the control group (38.3%). By using the classical shake flask method, 13C NMR, DSC, and FTIR, the physicochemical properties and structure of ILs were characterized. log Do/w, ATR-FTIR, Raman, and molecular dynamics simulation results confirmed that ASE-MA (MA: 3-Methoxypropionic acid) had appropriate lipophilicity, and affected lipid fluidity as well as the conformation of keratin to improve the skin permeation. The FTIR, MDSC, rheology, and molecular docking results revealed that hydrogen bond (H-bond), were formed between ASE-MA and PSA, and the drug increased the molecular mobility of polymer chains. In summary, the 72 h long-acting patch of ASE was successfully prepared and it supplied a reference for the design of long-acting patches with ASE.

A skin pharmacokinetics study of permeation enhancers: The root cause of dynamic enhancement effect on in vivo drug permeation.

Skin pharmacokinetics (SPK) of permeation enhancers can answer the question of why enhancement effects different at the kinetic level. Herein, SPK of permeation enhancers were classified into two categories, namely, lateral elimination (elimination to surrounding stratum corneum (SC)) and longitudinal elimination (elimination to deep epidermal (EP)). They were evaluated with a specific parameter for permeation enhancers, diffusion ratio (DRSC-EP), according to results of tissue-distribution test, molecular dynamic (MD) simulation, and confocal laser scanning microscopy (CLSM). The linear relationship between ke-enahcer and Δ Cmax-drug (R2 = 0.92), MRTenhancer and Δ Tmax-drug (R2 = 0.97), AUCt-enhancer and Δ AUCt-drug (R2 = 0.90) suggesting that SPK of permeation enhancers precisely controlled dynamic process of drug permeation in vivo. The molecular mechanisms of the dynamic effect of SPK process on drug transdermal behaviors were characterized by modulated-temperature differential scanning calorimetry (MTDSC), dielectric spectroscopy, small-angle X-ray scattering (SAXS), solid-state NMR. Permeation enhancers with high molecular weight (M.W.) and high polar surface area (P.S.A.) had good compatibility and strong interaction strength with SC, leading their lateral-elimination behavior, causing their low DRSC-EP and resulting in low ke-enhancer, long MRTenhancer, and large AUCt-enhancer. Consequently, skin barrier can be rapidly opened fast and to a great extent. In summary, compared with SPK of permeation enhancers with longitudinal elimination, SPK of permeation enhancers with lateral elimination can enable more sustainable and greater drug permeation. The information about SPK of permeation enhancers offered a criterion to estimate its permeation-enhancement effect on the drug and its subsequent application in transdermal formulations.

High drug-loading and controlled-release hydroxyphenyl-polyacrylate adhesive for transdermal patch.

Long-acting transdermal drug delivery system (TDDS) requires high drug-loading and drug controlled-release. To simultaneously improve drug-polymer miscibility and realize drug controlled-release, this work aimed to develop a new pressure sensitive adhesive modified with hydroxyphenyl (HP-PSA) by introducing doubly ionic H-bond into drug-PSA interaction. Eight model drugs divided into R3N, R2NH and no N type were chosen to understand the characteristics of the HP-PSA and inner mechanism. The results showed that the doubly ionic H-bond between R3N and R2NH type drugs and HP-PSA, differing from the ionic bond and neutral H-bond, was a reversible and relatively strong interaction. It could significantly enhance their drug-loading by 1.5 to 7 times and control drug release rate to its 1/5 to 1/2 without altering its total release properties, outperforming the commercial Duro-Tak® 87-2510 and Duro-Tak® 87-2852 adhesives. According to the pharmacokinetics results, the high drug-loading patches based on HP-PSA achieved a sustainable plasma drug concentration avoiding burst release, and over 2 times area under concentration-time curve (AUC) as well as 6 times mean residence time (MRT) revealed its potential to realize long-acting drug delivery. Additionally, its safety and mechanical features were satisfied. The mechanism study showed that the repulsion of the ionic drugs in HP-PSA increased drug-loading, and the relatively strong interaction could also control drug release. The incomplete H-bond transfer determined its reversibility, thus making the drug release percentage up to that of non-functional PSA. In conclusion, the high drug-loading efficiency and drug controlled-release capacity of HP-PSA, as well as its unique interaction, would contribute to the development of TDDS. Moreover, the construction of the doubly ionic H-bond would provide further inspiration for various drug delivery systems in the non-polar environment.

Combination of ion-pair strategy and chemical enhancers for design of dexmedetomidine long-acting patches: Dual action mechanism induced longer controlled release and better delivery efficiency.

The purpose of this study was to prepare a dexmedetomidine (Dex) 72 h long-acting patch by the combined use of ion-pair strategy and chemical enhancers (CEs), and to investigate molecular mechanisms of drug-loading enhancement and controlled release. The formulation of patch was optimized by single-factor investigation and Box-Behnken design. The pharmacokinetics, analgesic pharmacodynamics and irritation of the formulation were evaluated, respectively. Moreover, the effects of ion-pairs and CEs on the patch were characterized by DSC, rheology study, FTIR, and molecular docking, and the effects on the skin were evaluated by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR), Raman study, and molecular dynamics, respectively. The optimized formulation was 17.00 % (w/w) Dex-NA (Naphthoic acid), 7.20 % Polyglyceryl-3 dioleate (POCC), 25-AAOH as pressure sensitive adhesives (PSA) and 66.50 µm in thickness. Compared with the control group (Cmax = 62.02 ± 16.55 ng/mL, MRT0-t = 26.74 ± 1.27 h), the pharmacokinetics behavior of the optimization group was more stable and durable (Cmax = 31.22 ± 13.26 ng/mL, MRT0-t = 33.62 ± 1.62 h). Besides, it also showed good analgesic effect and no obvious irritation. The results indicated that Dex-NA both increased the drug-PSA interactions and inhibited the penetration of the drug into the skin. POCC increased the molecular mobility of the PSA and disrupted skin lipids thereby improving the drug penetration rate. In summary, the Dex long-acting patch was developed, which provided a reference for the combined application of ion-pair strategy and CEs in other long-acting transdermal delivery.

Efficacy and safety of permeation enhancers: A kinetic evaluation approach and molecular mechanism study in the skin.

This study sought to provide approach for evaluating and predicting the efficacy and safety of permeation enhancers on the basis of their kinetic distribution behavior in the skin dictated by physicochemical properties. Herein, the efficacy-safety regularity of eight permeation enhancers were studied with ex vivo skin permeation study, small-angle X-ray scattering, MTT assay, H&E staining, and in vivo skin erythema analysis, classifying into the following three categories: high enhancement-low irritation, medium enhancement-high irritation, and low enhancement-low irritation. These three modes were positively correlated with the distribution amount of permeation enhancers in the skin layers and verified by the in vitro tape-stripping study. The kinetic parameter, effective-safety index (IES), was proposed to describe the regularity of enhancement effect tendency and irritation risk, and the relationship between IES and physicochemical properties of permeation enhancers was analyzed with multiple regression analysis. According to the results of modulated temperature differential scanning calorimetry and dielectric spectrum, permeation enhancers with high lipophilicity and low polarity had IES > 1, suggesting high enhancement effect and low irritation due to their higher affinity with the stratum corneum (SC) than with epidermis (EP). Permeation enhancers with medium lipophilicity and medium polarity exhibited 0 < IES ≤ 1, showing medium enhancement effect and high irritation, as determined by their comparable affinity with the SC and epidermis (EP). However, permeation enhancers with low lipophilicity and high polarity had IES â†’ 0, demonstrating low enhancement effect and irritation, as indicated by their poor affinity with the SC. In summary, different physicochemical properties of permeation enhancers influenced their affinities with skin layers, resulting in their different enhancement effect and irritation potential. This study will provide a theoretical basis and criteria for evaluating and predicting the safety and efficacy of permeation enhancers, which will enable a more rational selection of permeation enhancers in the optimization of transdermal patches.

A Systematic Quantitative Evaluation of Permeation Enhancement Window: Transdermal Permeation Enhancing Dynamics Establishment and Molecular Mechanisms Characterization of Permeation Enhancer.

At present, transdermal permeation enhancing dynamics studies on permeation enhancers are still limited. In this study, these dynamics were established based on the content of enhancer Plurol Oleique CC in skin (CPOCC) and the increment of drug permeation amount (ΔQ). A new concept deemed "permeation enhancement window" (ΔCPOCC), comprised of a threshold dose (Cthr), maximal dose (Cmax) and permeation enhancement efficiency (Eff) was used to evaluate the enhancement effect of POCC for different drugs. According to results of FT-IR, ATR-FTIR and DSC analyses, the higher CPOCC of patches containing acidic drugs vs. basic drugs resulted from their stronger interaction with pressure-sensitive adhesives, leading to more free POCC and a greater disturbing effect on stratum corneum (SC) lipids. Below Cthr, a longer lag phase for acidic drugs resulted from more POCC required to compete with ceramide. When CPOCC exceeded Cmax by about 400 µg/g, plateau phases for all drugs were reached due to the upper limit of SC lipid fluidity, as confirmed by SAXS and Raman imaging. In summary, the differences in the permeation enhancement window for the test drugs resulted from the varied interaction strengths among POCC, drugs and adhesives, as well as changeable SC lipid fluidity.

Effect of the combination of permeation enhancer and ion-pairs strategies on transdermal delivery of tofacitinib.

The aim of the present study was to develop a tofacitinib (TOF) transdermal patch by the combination of ion-pairs and chemical permeation enhancer strategies. And a theory of controlled release of chemical permeation enhancers by counterion was proposed on the basis of in vitro skin permeation and skin retention study. Through the in vitro skin permeation study, the formulation factors such as counterion, pressure sensitive adhesive (PSA), drug loading and patch thickness were investigated, and the optimized patch (6.5% LA-TOF, 15% POCC and thickness = 50 µm) was evaluated by the pharmacokinetic study. The AUC0-t of the optimized patch was 529.89 ± 45 h ng/mL. Special attention has been paid to the molecular mechanism of the effects of counterion concentration on the release and permeation enhancement effect of penetration enhancer. FTIR study, 13C NMR, XPS and molecular modeling were conducted to investigate the molecular interaction between POCC and LA. Raman Imaging and ATR-FTIR were used to explore the POCC content in the skin and the interference degree to lipid. The results revealed that a strong hydrogen bond appeared between LA and the hydroxyl group of POCC, which inhibited the release of POCC, thus reducing the lipid disturbance and permeation enhancement effect of POCC. In conclusion, this TOF patch was successfully developed. The effect of counterion on permeation enhancers was clarified at molecular level, and these results provided references for the development of TOF patch.

Sustainable and efficient skin absorption behaviour of transdermal drug: The effect of the release kinetics of permeation enhancer.

At present, how the release kinetics of permeation enhancers affected their enhancement efficacy on drug skin absorption and its molecular mechanisms remained unclear. Herein, the release kinetics of permeation enhancer (Plurol Oleique CC (POCC)) which involved release percent (PR), release duration (RD) and release kinetic constant (k) and its enhancement efficacy on drug skin absorption were investigated with in vitro skin retention study and in vitro skin permeation study, respectively. POCC released from the acidic-drug loading patches followed with the Higuchi release model and had short RD (8-16 h), resulting in its unsustainable enhancement efficiency for acidic drugs. However, POCC released from the basic-drug loading patches followed with zero-order model with long RD (12-24 h), inducing a sustainable and efficient enhancement efficiency for basic drugs. The lower variance of an innovative parameter permeation enhancement coefficient (CPE) represented the relatively sustainable and effective enhancement effect and was listed as followed: 0.20 (Zaltoprofen (ZPF)), 0.31 (Diclofenac (DCF)), 0.27 (Indomethacin (IMC)), 0.07 (Azasetron (AST)), 0.11 (Oxybutynin (OBN)) and 0.06 (Donepezil (DNP)). According to the results of FT-IR, MTDSC, 13C NMR spectra, molecular dynamics simulation, SAXS and Raman imaging, the Higuchi release model was caused by strong interaction between the acid drugs and pressure sensitive adhesive (PSA). This strong interaction induced faster diffusion speed of POCC from acidic-drug loading patches and make the swell degree of long periodicity phase (LPP) of stratum corneum (SC) lipids reached plateau early. The zero-order release model was because the weak interaction between basic drugs and PSA making most of POCC was still bound to PSA, which in turn lead to LPP swelled at a slow but sustainable process. In conclusion, zero-order release kinetic of POCC lead to sustainable and efficient penetration enhancement efficiency on basic drug, while the Higuchi release kinetic showed opposite effect for acidic drugs. A deep understanding of release kinetics of enhancer and its enhancement efficiency may drive the ideal selection of permeation enhancers and rational optimization of transdermal patches.

Mechanism insight on drug skin delivery from polyurethane hydrogels: Roles of molecular mobility and intermolecular interaction.

Though polyurethane (PU) hydrogel had great potential in topical drug delivery system, drug skin delivery behavior from hydrogel and the underlying molecular mechanism were still unclear. In this study, PU and Carbomer (CP as control) hydrogels were prepared with lidocaine (LID) and ofloxacin (OFX) as model drugs. In vitro skin permeation and tissue distribution study were conducted to evaluate the drug delivery behaviors. The underlying molecular mechanisms were characterized by drug release with octanol as release medium, rheological study, ATR-FTIR, NMR, and molecular simulation. The results showed that the skin permeation amount of LID-PU (45.50 ± 7.12 µg) was lower than LID-CP (45.50 ± 7.12 µg). And the LID diffusion coefficient of PU (26.21 µg/h0.5) was also lower than CP (31.30 µg/h0.5), which attributed to H-bonding between LID (-CONH) and PU (-NHCOO). However, the OFX-PU showed a higher skin permeation amount (10.06 ± 1.29 µg) than OFX-CP (5.28 ± 1.39 µg). And the OFX-PU also showed a higher diffusion coefficient (30.0 µg/h0.5) than OFX-CP (21.37 µg/h0.5), which was caused by increased mobility of hydrogel when interaction action site was C-O-C in PU. In conclusion, drug skin delivery behavior from PU hydrogel was controlled by molecular mobility and intermolecular interaction, which clarified the influence of the functional group of PU hydrogel on drug skin delivery behavior and broadened our understanding of PU hydrogel application in topical drug delivery system.

Development of Tizanidine Drug-in-Adhesive Patch: Molecular Mechanism of Permeation Enhancer on Regulating Miscibility and Drug Release by Affecting the Status of Ion-Pair in Polymer Matrix.

The objective of this work was to develop a drug-in-adhesive (DIA) patch of TIZ by employing ion-pair and permeation enhancer to increase drug-polymer miscibility and drug release. Special attention was paid on the regulation effect of permeation enhancer on ion-pair status in pressure sensitive adhesives (PSA). Formulation factors including TIZ-fatty acids ion-pair, drug loading and permeation enhancer were investigated by ex-vivo transdermal experiments. Optimized patch was evaluated by pharmacokinetics study. The better polarity similarity and strong hydrogen bonding interactions between TIZ-caproic acid ion-pair (TIZ-C6) and PSA was confirmed by polarity determination, FT-IR, TOPEM of MDSC and theoretical calculation, which determined enhanced miscibility of ion-pair and PSA. The permeation enhancer affected status of ion-pair in PSA by regulating polarity similarity and interaction between ion-pair and PSA, resulting in increased drug-PSA miscibility and drug release, which was characterized by FT-IR, polarity determination, thermal analysis and molecular dynamics simulation. The optimized patch showed high drug-polymer miscibility and drug skin permeability with AUC0-t of 14641.12 ± 854.45 h ng/mL and Cmax of 834.55 ± 155.68 ng/mL, which was significantly higher than the control group. In conclusion, DIA patch of TIZ was prepared and it supplied a reference for design of DIA patches with TIZ.

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%.