Enhancement Of Transdermal Drug Delivery Research Articles

Essential Oils Distilled from Colombian Aromatic Plants and Their Constituents as Penetration Enhancers for Transdermal Drug Delivery.

The study aimed to determine the enhanced effects of essential oils (EOs) and plant-derived molecules (PDMs) as penetration enhancers (PEs) for transdermal drug delivery (TDD) of caffeine. A 1% w/w solution of eight EOs and seven PDMs was included in the 1% caffeine carbopol hydrogel. Franz diffusion cell experiments were performed using mice with full-thickness skin. At various times over 24 h, 300 μL of the receptor were withdrawn and replaced with fresh medium. Caffeine was analyzed spectrophotometrically at 272 nm. The skin irritation effects of the hydrogels applied once a day for 21 days were investigated in mice. The steady-state flux (JSS) of the caffeine hydrogel was 30 ± 19.6 µg cm-2 h-1. An increase in caffeine JSS was induced by Lippia origanoides > Turnera diffusa > eugenol > carvacrol > limonene, with values of 150 ± 14.1, 130 ± 47.6, 101 ± 21.7, 90 ± 18.4, and 86 ± 21.0 µg cm-2 h-1, respectively. The Kp of caffeine was 2.8 ± 0.26 cm h-1, almost 2-4 times lower than that induced by Lippia origanoides > Turnera diffusa > limonene > eugenol > carvacrol, with Kp values of 11 ± 1.7, 8.8 ± 4.2, 6.8 ± 1.7, 6.3 ± 1.2, and 5.15 ± 1.0 cm h-1, respectively. No irritating effects were observed. Lippia origanoides, Turnera diffusa, eugenol, carvacrol, and limonene improved caffeine's skin permeation. These compounds may be as effective as the PE in TDD systems.

Oxymatrine-fatty acid deep eutectic solvents as novel penetration enhancers for transdermal drug delivery: Formation mechanism and enhancing effect

Transdermal delivery of drugs is commonly limited by low skin permeability. The aim of the study was to synthesize deep eutectic solvents (DESs) based on oxymatrine (OMT) and fatty acids with various alkyl chain lengths (LCFAs) as novel vehicles, to solubilize the water-insoluble drug and enhance percutaneous penetration. Quercetin (QUE) was selected as a model drug. Combining differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and molecular simulations demonstrated that the formation of DESs was mediated by charge-assisted hydrogen bonding. Physicochemical properties including stability, viscosity, and solubilization capacity were also studied. Subsequently, the effect of three stable DESs on drug release and skin permeability was evaluated. The results showed that QUE was solubilized well and presented a different sustained release behavior in DESs. Meanwhile, DESs enhanced the skin permeation of OMT and QUE, which was influenced by alkyl chain lengths of LCFAs, whereas DES consisting of lauric acid (LA) exhibited the highest enhancing effect. FTIR, DSC, and molecular docking further demonstrated consistency between micro molecular mechanism and macro penetration behavior. Additionally, HaCaT cells treated with DESs showed high cell viability, suggesting their good skin safety. Taken together, OMT-LCFA DESs would be a promising penetration enhancer for transdermal drug delivery, which also provides guidance for the design of new DESs.

A theoretical investigation on the synergetic effect of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary complex.

Using chemical penetration enhancers to improve the penetration effect is one kind of important strategies in transdermal drug delivery system. Azone is a widely used transdermal absorption enhancer for transdermal drug delivery. To shed light on the permeation-promoting mechanism of azone, we selected ternary systems formed by azacyclopentane-2-one and N-methylolacetamide (1: 2) and explored the synergetic effect of hydrogen-bonding interactions among them and their thermodynamic properties. The findings indicate that the synergetic effects can enhance the ability of azone to change the original conformation of ceramides and even break the original hydrogen bonds, which is more beneficial for azone to destroy the 3D network structure of ceramides. When azone interacts with ceramide, the order of action tends to interact with one molecule of ceramide first and then with another molecule of ceramide. The synergetic effects of hydrogen-bonding interactions in ternary systems were computed at the B3LYP/6-311 + + G** and MP2(full)/6-311 + + G** levels. Thermodynamic parameters for two ternary-complex routes were worked out at the B3LYP/aug-cc-pVDZ level. The shift of the electron density occurring simultaneously with trimer formation was analyzed at the MP2(full)/6-311 + + G** level. The above calculations were carried out using the Gaussian 03 program packages. Atoms in molecules (AIM) method and the AIMPAC program showed the topological charge density at the MP2(full)/6-311 + + G** level. The synergetic effects of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary systems were investigated using the B3LYP and MP2(full) methods.

Cell-Penetrating Peptides as Passive Permeation Enhancers for Transdermal Drug Delivery.

Cell-penetrating peptides have been widely used as a tool to gain access to cytosol for numerous applications. The review highlights the advances made in preclinical and clinical research using cell-penetrating peptides since their discovery in 1980s. Further, the emphasis is on summarizing the role of cell-penetrating peptides as permeation enhancers for transdermal and topical drug delivery applications. A summary table of preclinical studies utilizing various peptides in combination with different active ingredients and drug delivery systems is included. Lastly, we capture the challenges associated with the cell-penetrating peptides to translate the preclinical work to clinical applications.

Hydrogel‐Forming Microneedles: Current Advancements and Future Trends

Front Cover: Hydrogel-forming microneedles have been primarily utilized for the enhancement of transdermal drug delivery and extraction of interstitial fluid. Applications including treatments for skin cancer and wound healing have been reported. Current applications, hydrogel materials, and potential future directions have been reported in the review article by Joseph G. Turner, Leah R. White, Pedro Estrela, and Hannah S. Leese in the article 2000307. Image Credit: Joseph G. Turner.

A Review on Role of Essential Oil as Penetration Enhancer in Transdermal Drug Delivery System

The use of essential oils and their constituents as skin penetration enhancers for transdermal drug delivery, as well as the mode of action and potential toxicity. Essential oils and their toxic components have the ability to penetrate the skin and improve the penetration of various drugs from topical formulations into the lower skin layers by various modes of action. (1) disintegration of the highly organised intercellular lipid structure between corneocytes in the Stratum Corneum, (2) association with the intercellular domain of proteins, causing conformational change, and (3) Increase a drug's partitioning essential oils and their components are easily metabolised, do not persist in the body, and are quickly excreted after application to the skin, indicating that they can be used as healthy penetration enhancers. Essential oils and their constituents can be preferable to synthetics as healthy and effective permeation enhancers for promoting the percutaneous absorption of hydrophilic and lipophilic drugs from topical formulations into the lower skin layers. they have been used successfully as secure penetration enhancers. To address these issues, the Transdermal Drug Delivery System (TDDS) was developed, which would increase the clinical effectiveness and safety of medications by allowing for more accurate (i.e., location specific) positioning inside the body, minimising both the size and number of doses. Many medications are now taken orally, but they are not as successful as they can be. This article offers a description of the transdermal drug delivery mechanism and forms of transdermal patches, as well as the use of polymer as a Transdermal Drug Delivery System, preparation processes, and physicochemical assessment methods and the various forms of transdermal systems currently on the market, with an emphasis on recent developments in Transdermal Drug Delivery Systems, which may serve as a forum for prescription drug dosage form research and development for Transdermal Drug Delivery.

Comparison of Ionic Liquids and Chemical Permeation Enhancers for Transdermal Drug Delivery

AbstractTransdermal delivery offers a patient‐friendly method of drug administration. An ideal formulation for transdermal drug delivery should have high potency to enhance skin permeation and low tendency to induce skin irritation. Ionic liquids (ILs) and deep eutectic solvents (DESs) have recently been proposed to serve as an excellent platform to enable transdermal delivery of various therapeutics including proteins and siRNA. In spite of their success, general safety‐efficacy behavior of ILs/DESs is not reported. Using safety and efficacy as two design criteria, a Fourier transform infrared (FTIR) spectroscopy study is conducted to compare the performance of 31 ammonium‐based ILs/DESs and 44 conventional chemical permeation enhancer (CPE) molecules. FTIR analysis of skin stratum corneum exposed to ILs/DESs and CPEs is performed to extract features indicative of their safety and efficacy. ILs/DESs, as a class, outperformed conventional CPEs in terms of both potency and safety. Analysis of ILs/DESs and CPEs based on Hansen solubility parameters indicates that ILs/DESs possess solubility parameters close to those of skin, which may explain their superiority over CPEs. These studies support ILs/DESs as promising materials for novel drug delivery systems.

Unconventional Passive Enhancement of Transdermal Drug Delivery: toward a Mechanistic Understanding of Penetration Enhancers Releasing from Acrylic Pressure-Sensitive Adhesive of Patches.

Penetration enhancers (PEs) enhancing efficacy depends on two processes: PEs release from patches and action on skin. Compared with their action on skin, PEs release process was poorly understood. Therefore, the purpose of this study was to make a mechanistic understanding of PEs release from acrylic pressure-sensitive adhesive of patches and propose an unconventional enhancement of PEs efficacy. PEs efficacy was evaluated both in drug permeation study and drug pharmacokinetic study. Confocal Raman spectroscopy was employed to observe PEs release behavior by mapping PEs dynamic distribution in skin. The mechanism of PEs release behavior was provided from molecular interaction and rheology using FT-IR, molecular docking, molecular dynamic simulation and rheometer, separately. The release behavior of PEs themselves greatly restricted their efficacy. By using PEG 400, an improvement of oleic acid (OA) release behavior was achieved, and the efficacy of OA was significantly enhanced with enhancing ratio (ER) from 2.69 to 4.10 and AUClast from 1574 ± 87 to 2664 ± 249ng·h/mL, separately. The improvement of OA release behavior was primarily resulted from reduction of the interaction between OA and adhesive, which was caused by other small molecules with a strong ability in forming hydrogen bonds with adhesive. Also, the rigidity of adhesive was a factor in affecting PEs release behavior. An unconventional passive enhancement of transdermal drug delivery was achieved via improving PEs themselves releasing from acrylic pressure-sensitive adhesive. Graphical abstract Influence of PEs release behavior on drug permeation through skin and molecular mechanism.

Ceramide cross‐linking leads to pore formation: Potential mechanism behind CAP enhancement of transdermal drug delivery

AbstractIn recent years, cold atmospheric plasma (CAP) has been proposed as a novel method to enhance transdermal drug delivery, while avoiding tissue damage. However, the underlying mechanism for the increasing skin permeability upon CAP treatment is still undefined. We propose a mechanism in which CAP‐generated reactive species induce cross‐linking of skin lipids, leading to the generation of nanopores, thereby facilitating the permeation of drug molecules. Molecular dynamics simulations support this proposed mechanism. Furthermore, our results indicate that to achieve maximum enhancement of the permeability, the optimal treatment will depend on the exact lipid composition of the skin, as well as on the CAP source used.

Ionic Liquids as Potential and Synergistic Permeation Enhancers for Transdermal Drug Delivery.

Transdermal drug delivery systems (TDDS) show clear advantages over conventional routes of drug administration. Nonetheless, there are limitations to current TDDS which warrant further research to improve current TDD platforms. Spurred by the synthesis of novel biodegradable ionic liquids (ILs) and favorable cytotoxicity studies, ILs were shown to be a possible solution to overcome these challenges. Their favorable application in overcoming challenges ranging from synthesis, manufacture, and even therapeutic benefits were documented. In this review, said ILs are highlighted and their role in TDDS is reviewed in terms of (a) ILs as permeation enhancers (single agents or combined), (b) ILs in drug modification, and (c) ILs as active pharmaceutical ingredients. Furthermore, future combination of ILs with other chemical permeation enhancers (CPEs) is proposed and discussed.

Permeation-enhancing effects and mechanisms of O-acylterpineol on isosorbide dinitrate: mechanistic insights based on ATR-FTIR spectroscopy, molecular modeling, and CLSM images

The present study aimed to evaluate the penetration activity of O-acylterpineol derivatives both in vitro and in vivo, and to investigate the enhancing mechanism of O-acylterpineol derivatives which were synthesized by α-terpineol and fatty acid. The promoting activities on the isosorbide dinitrate patch were tested across full thickness rabbit skin both in vitro and in vivo. In order to elucidate the permeation mechanism, attenuated total reflection Fourier transform infrared spectroscopy, molecular modeling, and confocal laser scanning microscopy were introduced to investigate the regulation of enhancers in the skin permeability and biophysical properties. With in vitro cytotoxicity test and in vivo erythema model, the skin irritation of enhancers was also evaluated. Permeation studies showed 2-(4-methylcyclohex-3-en-l-yl) propan-2-yl tetradecanoate produced the obvious enhancement activity for ISDN both in vitro and in vivo from patches. These results were supported by ATR-FTIR, molecular modeling, and CLSM studies which revealed that O-acylterpineol could decrease the order of the alkyl chains in the skin lipids. Additionally, it was found that TER-C14 produced a relatively low skin irritation, compared with the TER which was assumed to be a safe compound. The present research suggested that some newly designed acylterpineol derivatives are shown to be suitable permeation enhancers for transdermal drug delivery, and the chain length of C14 seem to be safe and more favorable for the penetration of ISDN from DIA patches.

Enhancement of Transdermal Drug Delivery by Rotational Stimulation Device

Enhancement of Transdermal Drug Delivery by Rotational Stimulation Device

Cationic Moieties in Polystyrene Gels Swollen with d-Limonene Improved Transdermal Delivery System.

d-limonene, a terpene and natural compound, has been found to be an excellent penetration enhancer for transdermal drug delivery (TDD). It hence has been incorporated within various transdermal formulations. Herein, we report the application of polystyrene gel swollen with d-limonene and its derivatives for TDD. Poly(styrene-co-divinylbenzene) (PS gel), poly(styrene-co-divinylbenzene-co-4-vinylpyridine) (PS-4VP) gel and poly(styrene-co-divinylbenzene-co-(vinylbenzyl) trimethylammonium chloride) (PS-VBAC gel) were employed as chemical gels to improve the stability of the TDD substrates. The drug permeation properties from the PS gels swollen in limonene were examined, regarding the effect of its network density as well as their rheological properties. The lowest density of the network showed the highest steady flux of the permeation at 43.7 ± 0.3 μg/cm2. FT-IR spectra were confirmed for PS-4VP and PS-VBAC, bearing cationic moieties and they could control the release of ibuprofen by the electrostatic interaction at the interface of organogel and skin. The steady state flux of skin permeation got low values from 55.2 ± 0.8 to 11.6 ± 2.0 μg/cm2, when the cationic moieties were increased. Moreover, the chemical network of PS gel swollen in limonene showed high mechanical stability illustrated by elastic modulus (G’) of about 98 kPa for 10% cross-linked PS gel. The developed PS gels swollen in limonene show highly promising results, suggesting their possible application in TDD.

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery.

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum, the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section “Frontiers in Bioengineering and Biotechnology,” the advances in this field and the handful of examples of thermal technologies for local and systemic transdermal drug delivery will be discussed and put into perspective.

Implementation of Design of Experiments in Development and Optimization of Transfersomal Carrier system of Tacrolimus for the Dermal Management of Psoriasis in Albino Wistar Rat

The present study was aimed to deal with development and optimization of transfersomal system for enhancement of transdermal drug delivery of tacrolimus drug for the treatment of psoriasis. Transfersomes containing tacrolimus was prepared by rotary evaporation method using Box- Behnken design. The levels of the drug, phosphatidylcholine and sodium desoxycholate (independent variables) were varied to study the influence on particle size, % entrapment efficiency and flux. The results of pharmacokinetic and pharmacodynamic studies proved that transfersomes were significantly superior in terms of drug permeation across the rat skin, with mean residence time of 52.58 ± 3.62 min. This was further confirmed by confocal laser scanning microscopic study. Transfersomes showed better antipsoriatic activities, compared to liposomes by virtue of better permeation through Wistar albino rat skin. Finally, it was concluded that the transfersomes accentuates the transdermal flux of tacrolimus and could be used for the management of psoriasis.

Microneedles: A painless approach for enhancement of transdermal drug delivery

Microneedles: A painless approach for enhancement of transdermal drug delivery

機械的刺激による経皮吸収促進

機械的刺激による経皮吸収促進

伸展刺激による皮膚構造変化と薬剤浸透

伸展刺激による皮膚構造変化と薬剤浸透

Natural Terpenes as Penetration Enhancers for Transdermal Drug Delivery.

The greatest hindrance for transdermal drug delivery (TDD) is the barrier property of skin, especially the stratum corneum (SC). Various methodologies have been investigated and developed to enhance the penetration of drugs through the skin. Among them, the most popular approach is the application of penetration enhancers (PEs), including natural terpenes, a very safe and effective class of PEs. In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of their action, the factors affecting their penetration enhancement effect, as well as their possible skin toxicity were discussed. Terpenes abundant in nature have great potential in the development of PEs. Compared to synthetic PEs, natural terpenes have been proved to possess higher enhancement activity. Interaction with SC intercellular lipids is the main mechanism of action for terpenes. The key factor affecting the enhancement effect is the lipophilicity of both terpenes and drug molecules. In addition, a lot of terpenes have also been proved to be much less toxic compared to azone, the classic synthetic PE. In summary, terpenes may be preferred over the chemically synthesized compounds as safe and effective PEs to promote the percutaneous absorption of drugs.

Ionic liquids as potential enhancers for transdermal drug delivery

The aim of this study was to verify the effect of several cyclic onium based ionic liquids (ILs), including mono- and dicationic derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO), a dialkyl morpholinium salt and a Brønsted acidic IL, as enhancers of the in vitro transdermal permeation and skin retention of diltiazem through and into hairless rat skin. The drug was used as both the hydrochloride salt (DZHCl) and the free base (DZB) to highlight the relationship between the enhancement effect and the physico-chemical characteristics of the active agent. Permeation tests were carried out using Gummer-type diffusion cells and excised rat skin with a 0.005M aqueous solution of diltiazem hydrochloride or diltiazem free base with and without the addition of 1% w/w ionic liquids. At the end of the permeation experiments with diltiazem hydrochloride, a suitable extraction procedure allowed for the determination of the drug content retained in the skin. Depending on the ionic liquid structure, a significant enhancement in diltiazem hydrochloride levels in the receiving phase was observed, and the transdermal permeation of the diltiazem free base was markedly increased by treatment with all of the ionic liquids. N-dodecyldabco bromide was the best enhancer for both salified and free base drug forms, even though it showed a certain toxicity. On the other hand, N-methyl-N-decylmorpholinium bromide showed a good balance between enhancer activity and cytotoxicity.