Carrier For Transdermal Drug Delivery Research Articles

Recent Advances in Development of Vesicular Carrier for Transdermal Drug Delivery: A Review

Transdermal drug delivery has gained significant attention as a non-invasive and convenient method for administering drugs. However, the stratum corneum, the outermost layer of the skin, poses a significant barrier to drug permeation. To overcome this challenge, vesicular carriers have emerged as promising systems for enhancing drug delivery through the skin. This review highlights recent advances in the development of vesicular carriers for transdermal drug delivery. Liposomes, niosomes, transfersomes, ethosomes, and solid lipid nanoparticles are among the commonly used vesicular carriers. These carriers offer advantages such as improved drug solubility, prolonged drug release, and enhanced drug stability. Additionally, they can encapsulate a wide range of drugs, including hydrophilic and lipophilic compounds. Various strategies have been employed to optimize vesicular carriers for transdermal drug delivery. These include modifying the vesicle composition, size, and surface charge to enhance skin penetration. The incorporation of penetration enhancers, such as surfactants, has also been explored to improve drug permeation across the skin. Furthermore, advancements in nanotechnology have led to the development of novel vesicular carriers, such as nanostructured lipid carriers and elastic liposomes. These carriers offer improved drug loading capacity, sustained release profiles, and enhanced skin penetration. Moreover, the use of vesicular carriers has shown promise in delivering a wide range of therapeutic agents, including small molecules, peptides, proteins, and genetic material. The ability to encapsulate and deliver these diverse drug entities opens new possibilities for transdermal drug delivery in various therapeutic areas.

Transfersomes as a Surfactant-based Ultradeformable Liposome

In the modern era, there are numerous ways for drug delivery. The change in time has led to the progress of drug delivery systems gaining significant development. Even though most of the drugs are administered orally i.e., in conventional dosage form it has its limitations too like poor patient compliance, metabolism in the liver's first passage, poor absorption, and fluctuations in plasma level.Because our skin is indeed the largest organ, transdermal medication administration has received increased attention in recent years. Many lipids nanovesicles like Liposomes, Niosome, Ethosome, and Transfersomes have been developed as a carrier for transdermal drug delivery. But out of them, Transfersomes are the ones which are of great interest as they show better permeation among all as most of the other carriers cannot pass through the stratum corneum. The method of transdermal medication administration has been used to provide controlled and targeted action and can act as topical and dermal preparation. This review provides basic information about Transfersomes, their mechanism of action, applications, and comparison with other lipid nanocarriers.

Curcumin-laden amphiphilic chitosan microemulsion with enhanced transdermal delivery, skin compatibility and anti-arthritic activity

Transdermal administration can avoid the first-pass effect of liver, improve the bioavailability of drugs and the adaptability of patients. However, there are still many problems, such as low load efficiency, short drug half-life, unfavorable transdermal efficiency, poor skin compatibility, which hinder the development of transdermal administration. In order to solve the above problems, amphiphilic chitosan microemulsion (AC-ME) is developed by using chitosan with hydrophilic carboxyl groups and hydrophobic long alkane chains as surfactant. AC-ME is efficient for drug loading and transdermal delivery, which is demonstrated by extremely high drug loading, improved drug stability and excellent transdermal efficiency. Specifically, the loading amount of curcumin (Cur) can reach up to 3.41 ± 0.13 mg/mL, an increase of approximately 30,000 times compared to its water solution. The light stability of Cur is improved from 43% to 75%. The transdermal process and skin retention of Cur exhibit 1.76-fold and 5.29-fold increase, respectively. Moreover, AC-ME is skin-compatible and does not damage skin structure. Finally, AC-ME can improve the therapeutic effect of Cur and exhibit superb anti-inflammatory effect in the rheumatoid arthritis (RA) model of mice. In a word, AC-ME would be a promising drug carrier for transdermal drug delivery.

<p>Poly(Acrylic Acid)-Modified MoS<sub>2</sub> Nanoparticle-Based Transdermal Delivery of Atenolol</p>

IntroductionHypertension is a major health problem worldwide and is typically treated using oral drugs. However, the frequency of oral administration may result in poor patient compliance, and reduced bioavailability owing to the first-pass effect can also prove problematic.MethodsIn this study, we developed a new transdermal-drug-delivery system (TDDS) for the treatment of hypertension using atenolol (ATE) based on poly(acrylic acid) (PAA)-decorated three-dimensional (3D) flower-like MoS2 nanoparticles (PAA-MoS2 NPs) that respond to NIR laser irradiation. The PAA-modified MoS2 NPs were synthesized and characterized using attenuated total reflection Fourier-transform infrared spectroscopy, X-ray diffraction measurements, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, and the sedimentation equilibrium method. The drug-loading efficiency and photothermal conversion effect were also explored.ResultsThe results showed that the colloidally stable PAA-MoS2 NPs exhibited a high drug-loading capacity of 54.99% and high photothermal conversion ability. Further, the capacity of the PAA-MoS2 NPs for controlled release was explored using in vitro drug-release and skin-penetration studies. The drug-release percentage was 44.72 ± 1.04%, and skin penetration was enhanced by a factor of 1.85 in the laser-stimulated group. Sustained and controlled release by the developed TDDS were observed with laser stimulation. Moreover, in vivo erythema index analysis verified that the PAA-MoS2 NPs did not cause skin irritation.DiscussionOur findings demonstrate that PAA-MoS2 NPs can be used as a new carrier for transdermal drug delivery for the first time.

Preparation and Characterization of PVA-Co-PE Drug-Loaded Nanofiber Membrane by Electrospinning Technology.

A new transdermal drug delivery system of nanofiber membrane with good biocompatibility and high drug loading was developed by electrospinning technology in this study. Using vinyl alcohol-co-ethylene (PVA-co-PE) polymer as a spinning matrix and non-steroidal anti-inflammatory drug (NSAID) sulindac (SUL) as a model drug, the SUL@PVA-co-PE nanofiber membrane was prepared and characterized systematically. The morphology, molecular vibrational transitions, thermogravimetric attributes, and in vitro drug release and transdermal characteristics of drug-loaded nanofiber membranes were analyzed. The results indicated that the surface of PVA-co-PE nanofibers was uniform and smooth with the diameter ranged from 461 to 696nm. Notably in vitro simulation experiments demonstrated that SUL@PVA-co-PE nanofiber membrane could provide a continuous drug release to reach the effective concentration of the drug, and exhibited significantly higher cumulative drug permeability compared to commercially available patches, Taken together, PVA-co-PE nanofiber membranes exhibited the characteristics of high drug loading and stability, and represented the potential to be utilized as a new transdermal drug delivery carrier with pronounced development prospect.

Cubosomes: A Novel Carrier for Transdermal Drug Delivery

Cubosomes are square and rounded particles with internal cubic lattice. Cubosomes are thermodynamically stable and consist of honeycombed (cavernous) structures separating two internal aqueous channels and a large interfacial area. Cubosomes are nanoparticles which are self assembled liquid crystalline particles of certain surfactants with proper ratio of water with microstructure that provides unique properties of practical interest. Bicontinuous cubic liquid crystalline phase is optically clear and very viscous material has the unique structure at nanometer scale. The word bicontinuous refers to the division of the two continuous but non-intersecting aqueous regions by lipid bilayer that is twisted into space filling structure. Hydrating a surfactant or polar lipid that forms cubic phase and then dispersing a solid like phase into smaller particles usually forms a cubosomes. Self-assembled cubosomes as active drug delivery systems are receiving more and more attention and interest after the first discovery and nomination. They exhibit different internal cubic structure and composition with different drug-loading modalities. It has high internal surface area and cubic crystalline structures, relatively simple preparation method, biodegradability of lipids, the ability of encapsulating hydrophobic, hydrophilic and amphiphilic substances, targeting and controlled release of bioactive agents. Cubosomes are having wide range of applications in various fields and they can be characterized by various evaluation parameters. So, Cubosomes are gaining more attention in pharmaceutical field.
 Keywords: Cubosomes, Liquid crystal, drug-loading, hydrophilic, hydrophobic, amphiphilic.

Outer membrane vesicles derived from E. coli as novel vehicles for transdermal and tumor targeting delivery.

Transdermal drug delivery is favored in clinical therapy because of its ability to overcome the shortcomings of the first pass elimination of the liver caused by traditional oral administration and the irreversibility of the injection. However, skin stratum corneum (SC) forms a big barrier that precludes most of the biomacromolecules. Herein, we propose the engineering of transformed Escherichia coli (E. coli) derived outer membrane vesicles, detoxified by lysozymes (named TEVs) as the carrier for transdermal drug delivery. TEVs were derived from transgenic E. coli and then modified by an integrin alpha(v)beta(3) (αvβ3) targeting peptide and co-loaded with indocyanine green (ICG) (P-TEVs-G). TEVs were shown to have excellence in penetrating through intact SC without any additional enhancement, followed by targeting of melanoma cells. TEVs are promising nanoplatforms for transdermal and tumor targeting drug delivery with high efficacy and biosafety, possessing great potential in the treatment of superficial tumors.

Framework nucleic acids as programmable carrier for transdermal drug delivery

DNA nanostructures are promising drug carriers with their intrinsic biocompatibility, uniformity and versatility. However, rapid serum disintegration leads to low bioavailability at targeted sites following systemic administration, hindering their biomedical applications. Here we demonstrate transdermal delivery of framework nucleic acids (FNAs) through topical applications. By designing FNAs with distinct shapes and sizes, we interrogate their penetration on mice and human skin explant. Skin histology reveals size-dependent penetration, with FNAs ≤75 nm effectively reaching dermis layer. 17 nm-tetrahedral FNAs show greatest penetration to 350 µm from skin periphery. Importantly, structural integrity is maintained during the skin penetration. Employing a mouse melanoma model, topical application of doxorubicin-loaded FNAs accommodates ≥2-fold improvement in drug accumulation and tumor inhibition relative to topically-applied free doxorubicin, or doxorubicin loaded in liposomes and polymeric nanoparticles. Programmable penetration with minimal systemic biodistribution underlines FNA potential as localized transdermal drug delivery carriers.

Eprinomectin nanoemulgel for transdermal delivery against endoparasites and ectoparasites: preparation, in vitro and in vivo evaluation

Nanoemulgels are composed of O/W nanoemulsion and hydrogels and are considered as ideal carriers for the transdermal drug delivery because these have high affinity to load hydrophobic drugs. The stable formulation of eprinomectin (EPR) is very challenging because of it is high hydrophobic nature. In this work, we have prepared EPR loaded nanoemulgel for the treatment of endo- and ectoparasites. The surface morphology of optimized formulations was characterized by scanning electron microscopy. Additionally, skin permeability and irritation tests were conducted for in vitro safety and in vivo skin retention and pearmeation test of EPR nanoemulgel were conducted for efficacy study. Obtained results indicated that the optimized formulation had good shear-thinning behavior, bioadhesiveness properties, and are nanosized droplets with porous internal structure, which are required for topical application. Furthermore, this formulation has showed good skin permeability in comparison to suspension and has no skin irritating property. Overall, the obtained results proved that nanoemulgel is a promising carrier for transdermal drug delivery and EPR nanoemulgel is a promising formulation for the treatment of endo- and ectoparasites.

Graphene Based Poly(Vinyl Alcohol) Nanocomposites Prepared by In Situ Green Reduction of Graphene Oxide by Ascorbic Acid: Influence of Graphene Content and Glycerol Plasticizer on Properties.

The enhanced properties of polymer nanocomposites as compared with pure polymers are only achieved in the presence of well-dispersed nanofillers and strong interfacial adhesion. In this study, we report the preparation of nanocomposite films based on poly(vinyl alcohol) (PVA) filled with well dispersed graphene sheets (GS) by in situ reduction of graphene oxide (GO) dispersed in PVA solution using ascorbic acid (L-AA) as environmentally friendly reductant. The combined effect of GS content and glycerol as plasticizer on the structure, thermal, mechanical, water absorption, and water barrier properties of PVA/GS nanocomposite films is studied for the first time. Higher glass transition temperature, lower crystallinity, melting, and crystallization temperature, higher mechanical properties, and remarkable improvement in the thermal stability compared to neat PVA are obtained as a result of strong interfacial interactions between GS and PVA by hydrogen bonding. PVA/GS composite film prepared by ex situ process is more brittle than its in situ prepared counterpart. The presence of GS improves the water barrier and water resistance properties of nanocomposite films by decreasing water vapor permeability and water absorption of PVA. This work demonstrates that the tailoring of PVA/GS nanocomposite properties is enabled by controlling GS and glycerol content. The new developed materials, particularly those containing plasticizer, could be potential carriers for transdermal drug delivery.

Ethosome: a novel vesicular carrier for transdermal drug delivery

Delivery across skin is striking due to its easy convenience. However, drug delivery across skin is still a confront in biomedical sciences. Over the past few decades, various successful narrative devices and techniques have emerged to optimize drug delivery across skin whose barricading behaviour constricts entry of most of the therapeutic agents. Ethosomes are non-invasive delivery transporter that enables drugs to reach the deep skin layers and/or the systemic circulation. Although ethosomal systems are theoretically sophisticated, they are characterized by simplicity in their preparation, efficacy and safety. A combination that can highly inflate their application. Ethosomes are soft, malleable vesicles adapted for enhanced delivery of active agents. This article reviews work carried out method of preparation, application and characterization of ethosomal systems. Because of their exceptional structure, ethosomes are able to encapsulate and deliver through the skin highly lipophilic molecules such as testosterone, cannabinoids and minoxidil as well as cationic drugs such as trihexyphenidil and propranolol. Results obtained in a double-blind two-armed randomized clinical study showed that treatment with the ethosomal acyclovir formulation appreciably improved all the evaluated parameters. In further work, the ethosomal expertise was broadened to introduce agents into cultured cells and microorganisms. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal transporter opens numerous confronts and prospects for the research and future development of novel improved therapies.
 Keywords: Ethosomes, Skin layers, Characterization

Hyaluronic acid-containing ethosomes as a potential carrier for transdermal drug delivery.

A hyaluronic acid-containing ethosomes (HA-ES) as the transdermal drug delivery system was prepared in this work, and rhodamine B (RB) was used as a model drug to be encapsulated. The obtained HA-ES-RB was then characterized by the surface morphology, entrapment efficiency, drug loading and the stability. Results showed that the prepared HA-ES-RB was spherical and showed good dispersion as well as the stability, with a particle size of below 100 nm. The skin permeation experiments were carried out in vitro with the Franz diffusion cells and the rat dorsal skins were used. It was found that the penetration effect of HA-ES-RB was much better than that of ES-RB. The fluorescence microscopy image showed that HA-ES-RB penetrated into the deepest dermis. The excellent transdermic drug delivery effect of HA-ES-RB maybe attributed from its smaller size, hydration of hyaluronic acid as well as greater potential targeting to skin and skin appendages of liposomal carriers. Moreover, the HA-ES delivery system showed non-cytotoxicity to normal cells, indicating a good biocompatibility. This work provded a hyaluronic acid-containing ethosomes which can offer a quick, high efficient, safe and self-administered transdermal drug delivery system.

An Optimized and Feasible Preparation Technique for the Industrial Production of Hydrogel Patches.

For hydrogel patches, the laboratory tests could not fully reveal the existing problems of full scale of industrial production, and there are few studies about the preparation technique for the industrial manufacturing process of hydrogel patches. So, the purpose of this work was to elucidate the effects of mainly technological operation and its parameters on the performance of hydrogel patches at the industrial-scale production. The results revealed the following: (1) the aqueous phase was obtained by polyvinylpyrrolidone (PVP) along with tartaric acid dissolved in purified water, then feeding this into a vacuum mixer as a whole in one batch, thus extended the crosslinking reaction time of hydrogel paste (matrix) and allowed the operation of coating/cutting-off to be carried out easily, and there was no permeation of backing layer; (2) the gel strength of the hydrogel patches increased with the increase of working temperature, however, once the temperature exceeded 35±2°C, the hydrogel paste would lose water severely and the resultant physical crosslinking structure which has lower gel/cohesive strength would easily bring gelatinization/residues during application; (3) the relative humidity (RH) of the standing-workshop was dynamically controlled (namely at 35±2°C, keeping the RH at 55±5% for 4days, then 65±5% for 2days), which would make patches with satisfactory characteristics such as better flexibility, higher adhesive force, smooth flat matrix surface, and without gelatinization/residues and warped edge during the using process; (4) the aging of the packaged hydrogel patches was very sensitive to storage temperature, higher temperature, higher gel strength and lower adhesiveness. The storage temperature of 10±2°C could effectively prevent matrix aging and adhesion losing, which would also facilitate the expiration date of patches extended obviously. In conclusion, this work provides an optimized and feasible preparation technique for the industrial production of the hydrogel patches and establishes the hydrogel patches as a novel carrier for transdermal drug delivery.

Formulation and characterization of acetate based ionic liquid in oil microemulsion as a carrier for acyclovir and methotrexate

Ionic Liquid (ILs) in oil microemulsions (IL/O MEs) have emerged as a potential carrier for transdermal drug delivery, particularly for sparingly soluble drug molecules, such as acyclovir and methotrexate. However, less attention was paid in the selection of non-toxic and biodegradable ILs. In this paper, we report new IL/O MEs with ammonium acetate ILs, which can dissolve acyclovir and methotrexate significantly. Microemulsions were composed of a mixture of nonionic surfactants, polyoxyethylene sorbitan monooleate (Tween-80), and sorbitan laurate (Span-20)/ILs/oil isopropyl myristate (IPM). Three ILs called 1-ethyl-3-methylimidazolium acetate ([EMIM][OAc]), triethylammonium acetate ([TEA][OAc]) and diethylammonium acetate ([DEA][OAc]) were selected due to their non-toxic property. Based on the pseudo-ternary diagrams constructed, it was evident that Span-20 played the key role as a surfactant while Tween-80 acted as the co-surfactant, showing optimal dissolution of the ILs into the system prepared with a ratio of 1:3 (Tween 80:Span20). This binary mixture also depicted the lowest viscosity, which is favorable as a carrier agent in drug delivery. The incorporation of various ILs into microemulsions resulted in a particle size ranging from 11 to 39.7 nm at diverse drug loading capacity. The formulation with IL [TEA][OAc] and IL [DEA][OAc] displayed substantial drug carrying capacity and stability compared to the commercially available IL [EMIM][OAc] loaded system.

Fabrication and Characterization of Sildenafil Citrate Loaded Transfersomes as a Carrier for Transdermal Drug Delivery

Fabrication and Characterization of Sildenafil Citrate Loaded Transfersomes as a Carrier for Transdermal Drug Delivery

Tocopheryl phosphate mixture (TPM) as a novel lipid-based transdermal drug delivery carrier: formulation and evaluation.

Transdermal drug delivery is a useful route of administration that avoids first-pass metabolism and more invasive delivery options. However, many drugs require enhancers to enable sufficient drug absorption to reach therapeutic effect. Alpha-tocopheryl phosphate (TP) and di-alpha-tocopheryl phosphate (T2P) are two phosphorylated forms of vitamin E which form tocopheryl phosphate mixture (TPM) when combined, and have been proposed to enhance the dermal and transdermal delivery of actives of interest. Here, we report the physicochemical characteristics and morphological properties of TPM formulations, including particle size, deformability and morphology, and its ability to facilitate the transport of carnosine, vitamin D3, CoEnzyme Q10 and caffeine into, and across, the skin. Results demonstrate that TPM self-assembles to form vesicular structures in hydroethanolic solutions ranging in mean size from 101 to 162nM depending on the amount of TPM and ethanol present in the formulation. The ratio of TP to T2P in TPM formulations altered vesicle size and elasticity, with vesicles high in TP found to be more deformable than those rich in T2P. TPM produced a significant (p<0.05) 2.4-3.4-fold increase in the absorption of carnosine, vitamin D3, CoEnzyme Q10 and caffeine into, or through, the skin. The TPM delivery platform was able to deliver a diverse range of actives with differing size and solubility profiles and therefore has significant potential to expand the number and types of drugs available for topical application and transdermal delivery.

Transdermal delivery from liposomal formulations – Evolution of the technology over the last three decades

Strong barrier properties of stratum corneum often limits the efficiency of drug delivery through skin. Several strategies were tried to improve permeation of drug through skin for local as well as systemic drug delivery. Incorporation of the drug within flexible liposomal vesicles has been one of the popular and well-studied approaches for delivering drug to deeper layers of the skin or even systemic circulation. Flexible/deformable/elastic liposomal systems such as invasomes, Transfersomes®, ethosomes, niosomes, etc. have demonstrated encouraging results in delivering small molecules and large proteins to the skin. It is necessary to recognize the promising concepts and analyze their potential, since a clear understanding of the drawbacks and advantages of these approaches will lead towards future development. In the current review we have attempted to give an overview of different liposomal drug carriers for transdermal drug delivery and their efficiency as drug delivery system through different in vivo and in vitro studies. Also, an overview of the studies which investigated the interactions between skin and vesicles, which have lead us to our current understanding of the skin penetration mechanisms of liposomal formulations is presented.

Ethosomes: Novel noninvasive carrier for Transdermal Drug Delivery

Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Although ethosomal systems are conceptually sophisticated, they are characterized by simplicity in their preparation, safety, and efficacy a combination that can highly expand their application. Ethosomes are soft, malleable vesicles tailored for enhanced delivery of active agents. This article reviews various aspect of ethosomes including their preparation, characterization, potential advantages and their applications in drug delivery. Because of their unique structure, ethosomes are able to encapsulate and deliver through the skin highly lipophilic molecules such as cannabinoids, testosterone, and minoxidil, as well as cationic drugs such as propranolol, trihexyphenidil, Cyclosporine A, insulin, Salbutamol etc. Ethosomes provides a number of important benefits including improving the drug's efficacy, enhancing patient compliance and comfort and reducing the total cost of treatment. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal carrier opens numerous challenges and opportunities for the research and future development of novel improved therapies.

On the correlation between the structure of lyotropic carriers and the delivery profiles of two common NSAIDs

Two non-steroidal anti-inflammatory drugs (NSAIDs), sodium diclofenac (Na-DFC) and celecoxib (CLXB) were solubilized within cubic and lamellar mesophases as carriers for transdermal drug delivery. SD-NMR, SAXS, ATR-FTIR, and EPR measurements were performed to examine the systems’ characteristics and the interactions between the drugs and their hosting mesophases. The amphiphilic drug Na-DFC was found to incorporate at the interfaces of the cubic and lamellar mesophases and thus to act as a cosurfactant and a “structure stabilizer”. It increased the order degree and the interactions between the GMO molecules and led the systems toward denser packing. CLXB exhibits an opposite effect on the mesophases. Its solubilization within both systems is accompanied with significant channel swelling and decrease in the order degree. The hydrophobic, rigid and bulky CLXB behaves as a “structure breaker”, incorporated between the GMO tails, disturbing the mesophase packing and enhancing the repulsion at the tails region, limiting their close binding. Release experiments from Franz cells revealed that Na-DFC release is dependent on the quantity of water within the hosting mesophase as the water-rich formulation exhibits 1.5-fold enhancement in the release of the drug, compared to the lamellar phase. In contrast, CLXB release was not influenced by the water quantity, hinting that the release mechanisms of the drugs are different while Na-DFC diffuses from the water channels to the external phase, CLXB diffusion occurs through the continuous lipophilic region. The difference in the solubilization sites and interactions of each drug with the mesophases affect their release profiles and determine the preferred formulations for each drug's delivery vehicle.

Skin permeation of d-limonene-based nanoemulsions as a transdermal carrier prepared by ultrasonic emulsification

Nanoemulsions can be used for transporting pharmaceutical phytochemicals in skin-care products because of their stability and rapid permeation properties. However, droplet size may be a critical factor aiding permeation through skin and transdermal delivery efficiency. We prepared d-limonene nanoemulsions with various droplet sizes by ultrasonic emulsification using mixed surfactants of sorbitane trioleate and polyoxyethylene (20) oleyl ether under different hydrophilic–lipophilic balance (HLB) values. Droplet size decreased with increasing HLB value. With HLB 12, the droplet size was 23nm, and the encapsulated ratio peaked at 92.3%. Transmission electron microscopy revealed spherical droplets and the gray parts were d-limonene precipitation incorporated in spherical droplets of the emulsion system. Franz diffusion cell was used to evaluate the permeation of d-limonene nanoemulsion through rat abdominal skin; the permeation rate depended on droplet size. The emulsion with the lowest droplet size (54nm) achieved the maximum permeation rate. The concentration of d-limonene in the skin was 40.11μL/cm2 at the end of 360min. Histopathology revealed no distinct voids or empty spaces in the epidermal region of permeated rat skin, so the d-limonene nanoemulsion may be a safe carrier for transdermal drug delivery.