Chemical Penetration Enhancers Research Articles

In Vitro Skin Permeation of Idebenone from Lipid Nanoparticles Containing Chemical Penetration Enhancers.

Lipid nanoparticles (LNPs) have been proposed as carriers for drug skin delivery and targeting. As LNPs effectiveness could be increased by the addition of chemical penetration enhancers (PE), in this work, the feasibility of incorporating PE into LNPs to improve idebenone (IDE) targeting to the skin was investigated. LNPs loading IDE 0.7% w/w were prepared using hydrophilic (propylene glycol, PG, 10% w/w or N-methylpyrrolidone, NMP, 10% w/w) and/or lipophilic PE (oleic acid, OA, 1% w/w; isopropyl myristate, IPM, 3.5% w/w; a mixture of 0.5% w/w OA and 2.5% w/w IPM). All LNPs showed small sizes (<60 nm), low polydispersity index and good stability. According to the obtained results, IDE release from LNPs was not the rate-limiting step in IDE skin penetration. No IDE permeation was observed through excised pigskin from all LNPs, while the greatest increase of IDE penetration into the different skin layers was obtained using the mixture OA/IPM. The antioxidant activity of IDE-loaded LNPs, determined by the oxygen radical absorbance capacity assay, was greater than that of free IDE. These results suggest that the use of suitable PE as LNPs components could be regarded as a promising strategy to improve drug targeting to the skin.

Effect of Chemical Penetration Enhancer-Adhesive Interaction on Drug Release from Transdermal Patch: Mechanism Study Based on FT-IR Spectroscopy, 13C NMR Spectroscopy, and Molecular Simulation.

Chemical penetration enhancers (CPEs) are commonly added into transdermal patches to impart improved skin permeation of drug. However, significant unexplained variability in drug release kinetics in transdermal patches is possible as a result of the addition of CPEs; investigations into the underlying mechanisms are still limited. In the present study, a diverse set of CPEs was employed to draw broad conclusions. Solubility parameters of CPEs and acrylate pressure-sensitive adhesive were calculated by molecular dynamics simulation and Fedors group contribution method to evaluate drug-adhesive miscibility. CPE-adhesive interaction was characterized by FT-IR study, 13C NMR spectroscopy, and molecular docking simulation. Results showed that release enhancement ratio (ERR) of CPEs for zolmitriptan was rank ordered as isopropyl myristate > azone > Plurol Oleique® CC497 > Span® 80 > N-methylpyrrolidone > Transcutol® P. It was found that solubility parameter difference (Δδ) between CPE and adhesive was negatively related with ERR. It was proved that hydrogen bonding between CPE and adhesive would increase drug release rate, but only if the CPE showed good miscibility with adhesive. CPE like isopropyl myristate, which had good miscibility with adhesive, could decrease drug-adhesive interaction leading to the release of drug from adhesive.

Abstract P-2: Multiscale Molecular Dynamics Simulations of the Skin Membranes as a Tool for the Interpretation of the Transmission Electron Microscopy Images

Background: Human skin can inhibit chemical penetration which limits the clinical applications of transdermal drug delivery. The stratum corneum (SC) is the primary barrier and organized in lamellar membranes containing the lipids of ceramides (CER), free fatty acids (FFA), and cholesterol (CHOL). One of the most widely used ways to overcome the SC is the addition of chemical penetration enhancers (CPEs) to active ingredients. There are various methods, which have been employed to explore the mechanisms by which CPEs with drugs can change the morphology of SC including transmission electron microscopy. Here, we propose to use multiscale coarse-grained (CG) molecular dynamics (MD) simulations for the interpretation of the images of the SC from the electron microscopy experiments. Methods: We utilized the MARTINI force field for the CG simulations. We employed the mixed-lipid bilayer model of SC consisting of CER, CHOL, and FFA in a 1:1:1 molar ratio assembled with CHARMM-GUI web-service. The systems of the SC model membrane and various enhancers were simulated in the NPT ensemble with the polarizable water model and the reaction field approach for the long-range electrostatics with the usage of Gromacs 2019.4 software. Results: The membrane model was validated with standard characteristics: thickness, diffusion of the lipids, order parameters, and density profiles. After, we have added CPEs and active ingredients to the systems: menthol and osthole as control simulations, ethanol with linoleic acid and lidocaine as test simulations. We have observed the membrane desegregation in the case of menthol and osthole formulations similar to the published results while the permeation of lidocaine with ethanol and linoleic acid did not cause the disruption of the membranes but increased its fluidity and permeability properties. Conclusion: The method of multiscale coarse-grained molecular dynamics simulations can be utilized for the prediction and interpretation of morphology change of SC in addition to various substances.

Comparative efficacy evaluation of different penetration enhancement strategies for dermal delivery of poorly soluble drugs – A case with sertaconazole nitrate

The aim of this study was to compare the efficacy of different approaches for enhancement of dermal availability of the highly lipophilic antifungal model drug – sertaconazole nitrate (SN). For this purpose, a physical penetration enhancer – dissolving microneedles (MNs) was fabricated by filling moulds with liquid formulation based on polyvinylpyrrolidone and loaded with SN. Dissolving MNs were characterised regarding their morphological and mechanical characteristics. A penetration enhancement efficacy of MNs was evaluated in vitro using porcine ear skin in parallel with the efficacy of formerly developed chemical penetration enhancer – biocompatible microemulsion (ME) formulation. Moreover, an ability of solid silicon MNs to significantly improve delivery of SN from ME into the skin has also been investigated. The obtained results showed that dissolving MNs had satisfying morphological properties and mechanical strength. This type of MNs provided comparable drug deposition in the skin as ME formulation, but also revealed an indication of percutaneous absorption of a portion of the administered drug dose. However, the penetration/permeation study results were largely influenced by experimental setup and dosing regimen. Although solid silicon MNs assisted SN dermal delivery led to increase of drug cutaneous retention (1.9-fold) under infinite dosing regimen, the synergistic action of solid MNs and ME applied under finite dosing was more pronounced in comparison with the application either of physical (dissolving MNs) or chemical enhancer (ME) alone. Namely, SN amount accumulated into the skin increased up to 4.67 and 4.37 folds in comparison with ME and dissolving MNs alone, respectively, while reaching a significant decrease in drug permeation through the skin compared to the use of dissolving MNs. Application of ME per se was the only approach that provided selective in vitro dermal drug delivery without SN permeation across the skin. However, despite both types of the used MNs lead to SN permeation in vitro, the ratio between the drug amount deposited in the skin and SN content permeated was significantly higher for the combined approach (12.05) than for dissolving MNs (2.10). Therefore, a combination of solid silicon MNs and biocompatible ME favoured more pronouncedly SN skin accumulation, which is preferable in the treatment of skin fungal infections.

Ex-vivo confocal Raman microspectroscopy of porcine skin with 633/785-NM laser excitation and optical clearing with glycerol/water/DMSO solution

Confocal Raman microspectroscopy (CRM) with 633- and 785-nm excitation wavelengths combined with optical clearing (OC) technique was used for ex-vivo study of porcine skin in the Raman fingerprint region. The optical clearing has been performed on the skin samples by applying a mixture of glycerol and distilled water and a mixture of glycerol, distilled water and chemical penetration enhancer dimethyl sulfoxide (DMSO) during 30[Formula: see text]min and 60[Formula: see text]min of treatment. It was shown that the combined use of the optical clearing technique and CRM at 633[Formula: see text]nm allowed one to preserve the high probing depth, signal-to-noise ratio and spectral resolution simultaneously. Comparing the effect of different optical clearing agents on porcine skin showed that an optical clearing agent containing chemical penetration enhancer provides higher optical clearing efficiency. Also, an increase in treatment time allows to improve the optical clearing efficiency of both optical clearing agents. As a result of optical clearing, the detection of the amide-III spectral region indicating well-distinguishable structural differences between the type-I and type-IV collagens has been improved.

Synergistic Effect of Chemical Penetration Enhancers on Lidocaine Permeability Revealed by Coarse-Grained Molecular Dynamics Simulations.

The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs—linoleic acid (LA) and ethanol—through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid. In our simulations, we probed the effects of individual CPEs as well as their combination on various properties of the SC membrane and the lidocaine penetration across it. We demonstrated that the addition of both CPEs decreases the membrane thickness and the order parameters of the DPCE hydrocarbon chains. Moreover, LA also enhances diffusion of the SC membrane components, especially cholesterol. The estimated potential of mean force (PMF) profiles for the lidocaine translocation across SC in the presence/absence of two individual CPEs and their combination demonstrated that while ethanol lowers the free energy barrier for lidocaine to enter SC, LA decreases the depth of the free energy minima for lidocaine inside SC. These two effects supposedly result in synergistic penetration enhancement of drugs. Altogether, the present simulations provide a detailed molecular picture of CPEs’ action and their synergistic effect on the penetration of small molecular weight therapeutics that can be beneficial for the design of novel drug and cosmetics formulations.

CPE-DB: An Open Database of Chemical Penetration Enhancers.

The cutaneous delivery route currently accounts for almost 10% of all administered drugs and it is becoming more common. Chemical penetration enhancers (CPEs) increase the transport of drugs across skin layers by different mechanisms that depend on the chemical nature of the penetration enhancers. In our work, we created a chemical penetration enhancer database (CPE-DB) that is, to the best of our knowledge, the first CPE database. We collected information about known enhancers and their derivatives in a single database, and classified and characterized their molecular diversity in terms of scaffold content, key chemical moieties, molecular descriptors, etc. CPE-DB can be used for virtual screening and similarity search to identify new potent and safe enhancers, building quantitative structure–activity relationship (QSAR) and quantitative structure–property relationship (QSPR) models, and other machine-learning (ML) applications for the prediction of biological activity.

Transdermal Delivery Systems for Biomolecules.

PurposeThe present review article focuses on highlighting the main technologies used as tools that improve the delivery of transdermal biomolecules, addressing them from the point of view of research in the development of transdermal systems that use physical and chemical permeation enhancers and nanocarrier systems or a combination of them.ResultsTransdermal drug delivery systems have increased in importance since the late 1970s when their use was approved by the Food and Drug Administration (FDA). They appeared to be an alternative resource for the administration of many potent drugs. The first transdermal drug delivery system used for biomolecules was for the treatment of hormonal disorders. Biomolecules have been used primarily in many treatments for cancer and diabetes, vaccines, hormonal disorders, and contraception.ConclusionsThe latest technologies that have used such transdermal biomolecule transporters include electrical methods (physical penetration enhancers), some chemical penetration enhancers and nanocarriers. All of them allow the maintenance of the physical and chemical properties of the main proteins and peptides through these clinical treatments, allowing their efficient storage, transport, and release and ensuring the achievement of their target and better results in the treatment of many diseases.Graphical abstract

Topical anesthetic and pain relief using penetration enhancer and transcriptional transactivator peptide multi-decorated nanostructured lipid carriers

Many strategies have been developed to overcome the stratum corneum (SC) barrier, including functionalized nanostructures. Chemical penetration enhancers (CPEs) and cell-penetrating peptides (CPP) were applied to decorate nanostructured lipid carriers (NLC) for topical anesthetic and pain relief. A novel pyrenebutyrate (PB-PEG-DSPE) compound was synthesized by the amide action of the carboxylic acid group of PB with the amido groups of DSPE-PEG. PB-PEG-DSPE has a hydrophobic group, hydrophilic group, and lipid group. The lipid group can be inserted into NLC to form PB functional NLC. In order to improve the penetrability, TAT and PB multi-decorated NLC were designed for the delivery of lidocaine hydrochloride (LID) (TAT/PB LID NLC). The therapeutic effects of NLC in terms of in vitro skin penetration and in vivo in animal models were further studied. The size of TAT/PB LID NLC tested by DLS was 153.6 ± 4.3 nm. However, the size of undecorated LID NLC was 115.3 ± 3.6 nm. The PDI values of NLC vary from 0.13 ± 0.01 to 0.16 ± 0.03. Zeta potentials of NLC were negative, between −20.7 and −29.3 mV. TAT/PB LID NLC (851.2 ± 25.3 µg/cm2) showed remarkably better percutaneous penetration ability than PB LID NLC (610.7 ± 22.1 µg/cm2), TAT LID NLC (551.9 ± 21.8 µg/cm2) (p < .05) and non-modified LID NLC (428.2 ± 21.4 µg/cm2). TAT/PB LID NLC exhibited the most prominent anesthetic effect than single ligand decorated or undecorated LID NLC in vivo. The resulting TAT/PB LID NLC exhibited good skin penetration and anesthetic efficiency, which could be applied as a promising anesthesia system.

Skin Penetration Enhancement Strategies Used in the Development of Melanoma Topical Treatments.

Malignant melanoma is an aggressive form of skin cancer for which there is currently no reliable therapy and is considered one of the leading health issues in the USA. At present, surgery is the most effective and acceptable treatment; however, surgical excision can be impractical in certain circumstances. Topical skin delivery of drugs using topical formulations is a potential alternative approach which can have many advantages aside from being a non-invasive delivery route. Nevertheless, the presence of the stratum corneum (SC) limits the penetration of drugs through the skin, lowering their treatment efficacy and raising concerns among physicians and patients as to their effectiveness. Currently, research groups are trying to circumvent the SC barrier by using skin penetration enhancement (SPE) strategies. The SPE strategies investigated include chemical skin penetration enhancers (CPEs), physical skin penetration enhancers (PPEs), nanocarrier systems, and a combination of SPE strategies (cream). Of these, PPEs and cream are the most advanced approaches in terms of preclinical and clinicalstudies, respectively.

Correction to: Enhanced Follicular Delivery of Finasteride to Human Scalp Skin Using Heat and Chemical Penetration Enhancers.

The article Enhanced Follicular Delivery of Finasteride to Human Scalp Skin Using Heat and Chemical Penetration Enhancers, written by Farah, Brown, and McAuley was originally published electronically on the publisher's internet portal on 31 May, 2020 without open access.

Formulation and Evaluation of Transdermal Gel of Ibuprofen: Use of Penetration Enhancer and Microneedle

The objective of the current study was to develop Ibuprofen (IBP) gel using different polymers individually and in combination and then to select best gel formulation based on various in-vitro evaluation parameters such as bioadhesive strength, gel strength, spreadability, viscosity and drug release study. The selected gel formulation was found to be composed of 1% (w/w) each of hydroxypropyl methylcellulose (HPMC K100M) and sodium carboxy methylcellulose (NaCMC). Two techniques such as chemical method using 1,8-cineole as chemical penetration enhancer (CPE) and physical technique using microneedle were employed to improve IBP permeation across the abdominal skin of rat. Out of the two techniques, the later technique showed higher (2.865-fold) permeation enhancement compared to control. Furthermore, a synergistic effect was also observed when both the techniques were used simultaneously with 3.307-fold increase in permeation enhancement. In-vivo anti-inflammatory study on rats induced with carrageenan paw oedema and analgesic activity investigation by tail flick method in rat model exhibited sustained effect up to 8 h compared to orally treated group. The stability study at room and accelerated conditions for three months did not show any sign of instability. Thus, the developed IBP gel is stable and have potential to illicit both anti-inflammatory and analgesic effect when administered transdermally.

Potential of Sonophoresis as a Skin Penetration Technique in the Treatment of Rheumatoid Arthritis with Transdermal Patch.

Rheumatoid arthritis, a chronic disorder, limits the use of chemical penetration enhancers for a prolonged period of time. Moreover, systemic routes of administration of the first-line drug, methotrexate, have shown undesirable systemic as well as local side effects. The objective of this research was to overcome the limitations associated with treatment of rheumatoid arthritis by utilizing three physical transdermal penetration enhancement techniques namely cold-laser, electroporation, and sonophoresis to deliver methotrexate. Methotrexate patch was prepared using solvent casting method and the ex-vivo release of methotrexate in combination with three physical penetration enhancers (sonophoresis, electroporation, and cold laser) were studied. The best technique was employed in pre-clinical testing in arthritic and control groups of male Wistar rats excluding remaining two techniques. The comparative ex-vivo studies showed that the penetration enhancement of methotrexate is maximum by sonophoresis followed by electroporation and cold laser (sonophoresis > electroporation > cold laser). In pharmacodynamic studies, the reduction in diameter of injected and non-injected paw on day 5 and day 21 for group 4 (ultrasound pre-treated group) was higher as compared to group 3 (group receiving only methotrexate patch). The motility score and the reduction in pain were significantly improved for group 4 than group 3 on both day 5 and day 21 (P˂0.05) which confirmed the faster recovery of animals of group 4 due to penetration enhancement of methotrexate patch by ultrasound treatment. From the results, it can be concluded that sonophoresis along with methotrexate patch has shown a significant effect in the treatment of rheumatoid arthritis.

Chemical Penetration Enhancers Increase Hydrogen Peroxide Uptake in C. elegans for In Vivo Fast Photochemical Oxidation of Proteins.

Fast photochemical oxidation of proteins (FPOP) is a hydroxyl radical protein footprinting method that covalently labels solvent-accessible amino acids by photolysis of hydrogen peroxide. Recently, we expanded the use of FPOP for in vivo (IV-FPOP) covalent labeling in C. elegans. In initial IV-FPOP studies, 545 proteins were oxidatively modified in all body systems within the worm. Here, with the use of chemical penetration enhancers (CPEs), we increased the number of modified proteins as well as the number of modifications per protein to gain more structural information. CPEs aid in the delivery of hydrogen peroxide inside C. elegans by disturbing the highly ordered lipid bilayer of the worm cuticle without affecting worm viability. IV-FPOP experiments performed using the CPE azone showed an increase in oxidatively modified proteins and peptides. This increase correlated with greater hydrogen peroxide uptake by C. elegans quantified using a chemical fluorophore demonstrating the efficacy of using CPEs with IV-FPOP. Mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD019290.

Enhanced Follicular Delivery of Finasteride to Human Scalp Skin Using Heat and Chemical Penetration Enhancers

PurposeThe aim of this work was to evaluate whether improved topical delivery of finasteride, focussed to the hair follicles of human scalp skin could be achieved with application of short durations of heat and use of specific chemical penetration enhancers.MethodsFranz cell experiments with human scalp skin were performed with a range of chemical penetration enhancers at 32°C and 45°C to simulate normal and heated conditions. Selected chemical penetration enhancers were taken forward for finite dose Franz cell studies which examined the effect of heat produced by a prototype external heating system that supplied either 20 or 30 min of additional heat over both a 24 h and a 1 h time period.ResultsShort durations of externally applied heat significantly increased finasteride penetration into human scalp skin after 24 h. Analysis of drug distribution in the skin after 1 h and 24 h indicated that both heat and chemical penetration enhancer selection influenced drug delivery to the hair follicles.ConclusionThe use of short durations of heat in combination with specific chemical penetration enhancers was able to increase the delivery of finasteride to human scalp skin and provide focussed drug delivery to the hair follicles.

Correlations Between Skin Barrier Integrity and Delivery of Hydrophilic Molecules in the Presence of Penetration Enhancers.

We investigated the potential correlations between skin barrier integrity and hydrophilic drugs distribution in skin in the presence of different types of penetration enhancers (PEs) and their combinations. We measured skin conductivity to evaluate skin barrier integrity before and after the topical application of different chemical PEs, physical PE, peptide PE and their combinations in vitro. We also investigated their effect on the skin distribution profiles of two hydrophilic model drugs, Fluorescein sodium (376Da) and Fluorescein isothiocyanate-dextrans 10 (10 KDa). The physical PE significantly increased the skin conductivity compared to all other PEs, while the peptide PE had no effect on it. The drug deposition in different skin layers was not only dependent on PE applied but also its own molecular weight. We further found two excellent correlations: one (R2= 0.9388) between skin barrier integrity and total skin absorption of FNa and another one(R2= 0.9212) between skin barrier integrity and the deposition of FNa in dermis and receptor in presence of chemical or physical PEs and their combinations. The total skin absorption or the deposition in dermis and receptor of small hydrophilic drug in the presence of chemical and physical PEs and their combinations show a good correlation with skin barrier integrity. However, such correlations hold true neither for large hydrophilic drug nor for peptide PE. All good relationships found in this work will allow screening suitable PEs or combinations by measuring the skin conductivity induced by corresponding PEs. Graphical Abstract The total skin absorption of small hydrophilic drug shows a good correlation with skin barrier integrity in the presence of chemical and physical penetration enhancers and their combinations. However, such a correlation hold true neither for large hydrophilic drug nor for peptide penetration enhancer.

Transdermal Drug Delivery for Hair Regrowth.

Today, about 50% of men and 15-30% of women suffer from hair loss as well as the associated psychological impact. Drug therapy, especially through topical administration, is the main treatment strategy for stimulating hair regrowth. However, challenges exist due to the skin barrier that hinders drug penetration. To this end, many efforts have been made to enhance drug penetration efficiency. This review focuses on the advancement of the transdermal drug delivery strategies for hair loss therapy reported in the last five years, especially those via nanoformulations for topical administration and microneedles for transdermal delivery. In addition, physical or chemical penetration enhancers are also introduced, which are often applied with the drug delivery systems to achieve a synergy effect.

The Effect of Various Penetration Enhancers on the Octyl Methoxycinnamate Permeability: Mechanisms of Action Study

Octyl methoxycinnamate is one of the ingredients in sunscreen products. The main aim of this study was to investigate the effect of different enhancers of in vitro skin permeability of Octyl methoxycinnamate. Octyl methoxycinnamate permeability parameters were evaluated through the whole skin of the rat with and without chemical enhancers including eucalyptus oil, urea, menthol and olive oil by Franz cell diffusion. The effects of enhancers on skin structure were also studied using DSC and FT-IR techniques. The skin prevented the permeability of Octyl methoxycinnamate so that after 24 hours less than 3% of the substance passed through the skin. The results of this study showed that by increasing the time, it is possible to increase the skin permeation and the highest rate of skin absorption were corresponded to olive oil (ERflux=63.074), eucalyptus oil (ERflux=48.78) and menthol (ERflux=33.5), respectively while the least amount of skin absorption was related to urea (ERflux=29.53). Chemical penetration enhancers are substances that interfere with the complex structure of the skin and protein lipids. Two endothermic transitions were obtained at about 67 (Tm1) and 112 ° C (Tm2) in thermogram of the hydrated whole rat skin. Tm1 and Tm2 seems to be due to the melting of the lipids and the irreversible intracellular keratin or melting of the lipid-protein (keratin) complex, respectively. The amount of Tm1, ΔH1 and ΔH2 were decreased by all penetration enhancers compared to the hydrated skin. The FT-IR results suggested the mechanism of increasing absorption effect by lipid fluidization and lipid extraction. All of penetration enhancers used in this study significantly increased the skin permeability of Octyl methoxycinnamate.

Recent Advances in the Transdermal Delivery of Protein Therapeutics with a Combinatorial System of Chemical Adjuvants and Physical Penetration Enhancements

AbstractSince the development of protein‐based therapeutics, research has been underway to deliver protein therapeutics into the systemic circulation and target sites have been actively conducted. Most protein‐based therapeutics require parenteral administration, due to their intrinsic vulnerability and susceptibility to enzyme‐mediated degradation. Among the routes of administration, the transdermal delivery system has been regarded as a promising technique to deliver protein therapeutics, offering the advantages of painless administration, ease of termination, and avoidance of first‐pass metabolism. However, unlike small molecular drugs, protein therapeutics have limited skin penetration, due to their macromolecular and hydrophilic properties. Both cheimcal adjuvants (CAs)‐treatment methods and physical penetration enhancer methods (PPEs) have been utilized to increase skin permeability for protein therapeutics. The CAs, which include chemical penetration enhancers and nanocarriers, permit the protein therapeutics to transport easily into the skin, by modifying the stratum corneum (SC) or fabricating their stable formulation. The PPEs, including iontophoresis, electroporation, and ultrasound, can improve the skin permeability of the therapeutic agent through disrupting the SC. In this review, the techniques of both chemical and physical enhancement methods are introduced and an overview of the latest approaches to the transdermal delivery of protein therapeutics is provided.

Novel skin permeation enhancers based on amino acid ester ionic liquid: Design and permeation mechanism

This study developed novel ionic liquids (ILs) based on amino acids. We first screened 15 methyl amino acid ester hydrochlorides ([AAC1]Cl) for their skin permeation enhancements using 5-Fluorouracil (5-Fu) and Hydrocortisone (HC) as model drugs. Glycine methyl ester hydrochloride ([GlyC1]Cl), L-proline methyl ester hydrochloride ([L-ProC1]Cl), and L-leucine methyl ester hydrochloride ([L-LeuC1]Cl) were selected, and their ester sites were modified with different carbon chains (C8 and C12). The resulting ILs showed improved permeation to the two drugs. TEWL and CLSM assays revealed the moderation effects of the modified ILs on skin barrier function, whereas L-proline dodecyl ester hydrochloride ([ProC12]Cl) and L-leucine dodecyl ester hydrochloride ([L-LeuC12]Cl) exhibited the strongest activities. Permeation mechanisms were further investigated by ATR-FTIR, solid-NMR, SEM, and TEM analyses. The results suggested that [L-ProC12]Cl and [L-LeuC12]Cl combined the advantages of amino acid esters and IL solvent and could interact with the intercellular lipid domain by the multi-functions of lipid fluidization and lipid extraction, which were observed in a dosage- and time-dependent manner. Additionally, pathological examination suggested that the amino acid ester-based ILs (AAE-ILs) had good biocompatibility. In conclusion, this study has generated novel chemical penetration enhancers (CPEs) based on AAE-ILs and may be potentially utilized in drug transdermal delivery systems (TDDSs).