Transdermal Permeation Research Articles

Formulation and permeability evaluation of Aloe vera gel containing Acyclovir

Background (including purposes): Acyclovir (ACV) is a widely-used drug in the prevention and specific treatment of diseases caused by Herpes virus. However, due to its limited solubility and poor permeability, its therapeutic effectiveness is not high. Therefore, improving the transdermal permeability of ACV is necessary to increase the therapeutic effect of the drug for topical administration. Materials and methods: The study investigated the effect of the concentration of gelling agent, and the concentration of Aloe vera (A.vera) on the physico-chemical properties, especially the in vitro and ex vivo permeability by using Franz diffusion cells. Results: The formulation with 5% (w/w) of ACV, 4.5% (w/w) of A.vera, 5% (w/w) of glycerin and 2% (w/w) of HPMC K100M had the physico-chemical properties suitable for topical administration and the best permeability enhancement as compared to other formulations with different concentrations of A.vera, and a commercial cream formulation containing 5% (w/w) of ACV. Conclusion: A.vera in the gel form was successful prepared and applied to increase the permeability of ACV. This A.vera gel has the potential to develop the formulations for transdermal administration Key words: Acyclovir, Aloe vera, permeability enhancement

Development and Assessment of Phytophospholipid Nanovesicular Systems for Treatment of Diabetic Neuropathy

Pharmacognosy Research,2022,14,4,360-368.DOI:10.5530/pres.14.4.54Published:October 2022Type:Original ArticleAuthors:Gaurav Tiwari, Deepa Yadav, Bhuwanendra Singh, Abhitendra Kumar, Pranay Wal, and Ruchi Tiwari Author(s) affiliations:Gaurav Tiwari1, Deepa Yadav2, Bhuwanendra Singh3, Abhitendra Kumar1, Pranay Wal1, Ruchi Tiwari1,* 1Pranveer Singh Institute of Technology (Pharmacy), Kalpi Road, Kanpur, INDIA. 2Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, INDIA. 3Department of Pharmacognosy, SD College of Pharmacy and Vocational Studies, Muzaffarnagar, Uttar Pradesh, INDIA. Abstract:Background: Diabetic neuropathy (DN) is the most prevalent and problematic consequence of diabetes mellitus, with the highest rates of morbidity and death, as well as a significant financial burden on diabetes treatment. Aside from commercially available formulations, substantial research on herbal-based natural therapies to treat hyperglycemia and related consequences is underway. Objectives: The major aim of the study was to use an ethosomal gel to improve transdermal penetration of Curcuma longa and Boswellia serrata and to overcome the challenges of low transdermal drug delivery permeability. Materials and Methods: Curcuma longa and Boswellia serrata loaded ethosomes were made using a cold process with various amounts of ethanol and soya lecithin, and were improved based on entrapment efficiency, vesicular size, and ex-vivo investigations. Results: The optimized ethosomal formulation was then put into a gel and evaluated. Ex-vivo tests were conducted with Curcuma longa and Boswellia serrata ethosomal gels, which were compared to plain gel. The ethosomal system produced vesicles with sizes ranging from 1 to 100 nm, a spherical, smooth surface, and a maximum entrapment efficiency of Ne9. A modified ethosomal system (Ne9) was introduced into the gel and studied further. Conclusion: According to the findings, the ethosomal gel has a lot of potential for transdermal Curcuma longa and Boswellia serrata administration. Keywords:Boswellia serrata, Curcuma longa, Drying studies, Ethosomal gel, Ethosomes, Ex-vivo studiesView:PDF (1.55 MB)

Validation and testing of a new artificial biomimetic barrier for estimation of transdermal drug absorption

Human skin remains the most reliable model for studying the transdermal permeation of active compounds. Due to the limited source, porcine skin has been used extensively for performing penetration tests. Performing penetration studies by using human and animal skin, however, would also involve a series of ethical issues and restrictions. For these reasons, new biomimetic artificial barriers are being developed as possible alternatives for transdermal testing. If appropriately optimized, such products can be cost-effective, easily standardized across laboratories, precisely controlled in specific experimental conditions, or even present additional properties compared to the human and animal skin models such as negligible variability between replicates. In this current work we use the skin mimicking barrier (SMB) for drug permeability tests. The aim was to evaluate the suitability of the new barrier for studying the percutaneous absorption of the lipophilic extract of the plant Zingiber officinale Roscoe in vitro and compare its permeability ability with the artificial membrane Permeapad® and porcine skin. Our results showed that the permeability values obtained through the SMB are comparable are comparable to those obtained by using the porcine skin, suggesting that the new barrier may be an acceptable in vitro model for conducting percutaneous penetration experiments.

Erbium:YAG fractional laser ablation improves cutaneous delivery of pentoxifylline from different topical dosage forms

Topical application of pentoxifylline (PTX) would enable targeted treatment of radiation-induced skin fibrosis. However, PTX is hydrophilic with limited partitioning into the stratum corneum. The objective of this study was to investigate whether use of Erbium:YAG fractional laser ablation and different topical dosage forms (solution, hydrogel and patch) could be used to improve PTX cutaneous delivery as opposed to transdermal permeation. Initial results confirmed that fractional laser ablation significantly increased PTX delivery from each dosage form compared to passive controls. Delivery efficiencies of ∼ 30% were achieved with each dosage form but a large proportion of PTX permeated across the skin; thus, fluences were decreased to create shallower micropores, their depth being linearly dependent on fluence. The hydrogel was selected as the optimal formulation and PTX delivery efficiencies were further increased (44%-67%) by reducing the amount of hydrogel applied (better mimicking conditions of use). As this resulted in PTX depletion in the formulation, a loss of dependence of delivery on laser fluence was observed. These findings suggest that fractional laser ablation at moderate fluences enables an effective and targeted cutaneous delivery of PTX from a hydrogel formulation, which can be easily produced without the need for complex equipment.

Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties.

The purpose of the present study was to explore the feasibility of transdermal delivery of metformin, a commonly used oral antidiabetic drug, by ionic liquid (IL) technology. Metformin hydrochloride (MetHCl) was first transformed into three kinds of ILs with different counterions. The physicochemical properties of the obtained ILs were characterized in depth. The simulation of stable configuration and calculation of interaction energies were conducted based on density functional theory (DFT). Skin-PAMPA was used to evaluate the intrinsic transdermal permeation properties. The cytotoxicity assay of these ILs was conducted using HaCaT cells to evaluate the toxicity to skin. These metformin ILs were then formulated into transdermal patch, and the transdermal potential was further evaluated using in vitro dissolution test and skin permeation assay. Finally, the pharmacokinetic profiles of these metformin IL-containing patches were determined. Among all the three Met ILs, metformin dihexyl sulfosuccinate (MetDH) with proper overall physiochemical and biological properties demonstrated the highest relative bioavailability. Metformin docusate (MetD) with the highest lipophilicity and intrinsic transdermal permeability exhibited the most significant sustained release profile in vivo. Both MetDH and MetD were the promising candidates for further clinical investigations. Overall, the properties of ILs were closely related to the structures of counterion. IL technology provided the opportunities to finely tune the solid-state and biological properties of Metformin and facilitated the successful delivery by transdermal route.

Conjugation of iontophoresis and minimally invasive techniques to improve transdermal drug delivery

Iontophoresis is an active drug delivery technique that has been demonstrated to significantly enhance the transdermal permeability of numerous active pharmaceutical ingredients (APIs), especially with hydrophilic drugs and large molecules. However, the technique poses limitations in delivering medications reaching therapeutic concentrations of high-dose drugs, proteins, and nanoparticles. Conjugation of iontophoresis with minimally invasive delivery techniques for further improving transdermal absorption is a potential approach to those limitations. Succonjugation possesses great potential to widen the application range of topical dosage forms to various APIs and drug carrier systems. This article aimed to review the fundamental as well as results of studies applying the approach of combining iontophoresis with minimally invasive drug delivery techniques, namely electroporation, chemical enhancers, low-frequency ultrasound, microneedle arrays, and magnetophoresis.

Transdermal delivery of celecoxib and α-linolenic acid from microemulsion-incorporated dissolving microneedles for enhanced osteoarthritis therapy

Dissolving microneedles, the promising vehicles for transdermal delivery, are incapable of directly loading hydrophobic components that limit the application of transdermal drug delivery. Microemulsion holds great potential in the solubilisation of water-insoluble drugs but is limited by the high epidermal retention. In this study, we fabricated microemulsion-incorporated dissolving microneedles co-loading celecoxib and α-linolenic acid (Cel-MEs@MNs) for enhancing osteoarthritis (OA) therapy via synergistic anti-inflammation and potent transdermal delivery. Cel-MEs@MNs composed of celecoxib & α-linolenic acid-coloaded microemulsion (Cel-MEs) and hyaluronic acid-based microneedles (MNs) can be completely dissolved in 90 s with a particle size of ∼30 nm. Each microneedle array with a hardness exceeding 30 N contained 57.9 ± 2.5 μg of celecoxib and 442.5 ± 24.2 μg of α-linolenic acid. The 8 h-cumulative transdermal of celecoxib from Cel-MEs@MNs was 89.2 ± 5.1 μg celecoxib/cm2, which is 2.98-fold higher than that from Cel-MEs. Combinational celecoxib and α-linolenic acid with a weight ratio of 1/5 can synergistically induce M1-like macrophage to M2 repolarization, reduce M1-like macrophages-resulted chondrocytes apoptosis, and lower serum prostaglandin E-2 (PGE-2). Notably, Cel-MEs@MNs amplified such collaborated anti-inflammatory effects. More importantly, in the treatment of OA-bearing rat models, Cel-MEs@MNs with a half-dose of celecoxib and α-linolenic acid significantly shrunk the paw swelling, reduced inflammatory cytokines, and improved cartilage damage compared with the oral administration of celecoxib and α-linolenic acid, as well as transdermal administration of Cel-MEs. Such an integrational strategy of microemulsion-incorporated dissolving MNs offers the feasibility of combinational celecoxib and α-linolenic acid in transdermal permeation and boosted OA therapy.

Central Composite Design (CCD) for the Optimisation of Ethosomal Gel Formulation of Punica granatum Extract: In Vitro and In Vivo Evaluations.

This research manuscript’s objective was to develop the Punica granatum extract ethosome gel. The use of nanotechnology can improve transdermal drug delivery permeation of its major bioactive compound β-sitosterol. The optimised and developed formulations were further studied in vitro and in vivo. The assessment of the anti-inflammatory activity of the gel was performed in Albino rats. Methanolic extract was prepared and developed into an ethosome suspension and an ethosome gel. To optimise the formulation’s response in terms of particle size (nm) and entrapment efficiency (%), the central composite design (CCD) was used in 22 levels. The effects of factors such as lecithin (%) and ethanol (mL) in nine formulations were observed. Characterisation of ethosome gel was performed and the results showed the particle size (516.4 nm) and mean zeta potential (−45.4 mV). Evaluations of the gel formulation were performed. The results were good in terms of pH (7.1), viscosity (32,158 cps), spreadability (31.55 g cm/s), and no grittiness. In an in vitro study, the percentages of β-sitosterol release of ethosome gel (91.83%), suspension (82.74%), and extracts (68.15%) at 279 nm were recorded. The effects of the formulated gel on formalin-induced oedema in Albino rats showed good results in terms of anti-inflammatory activity. The comparative anti-inflammatory activity of Punica granatum extract and gel showed that the gel action was good for their topical application.

Linoleic Acid-Based Transferosomes for Topical Ocular Delivery of Cyclosporine A.

Delivering high-molecular-weight hydrophobic peptides, such as cyclosporine A, across the corneal epithelium remains a challenge that is complicated by other physio-anatomical ocular structures that limit the ocular bioavailability of such peptides. Transferosomes have previously been used to improve transdermal permeability, and have the potential for improving the ocular corneal permeability of applicable drugs. In this study, transferosomes for the potential ocular delivery of cyclosporine A were investigated. Linoleic acid was evaluated for its effect on the stability of the transferosomes and was substituted for a portion of the cholesterol in the vesicles. Additionally, Span® 80 and Tween® 80 were evaluated for their effect on transferosome flexibility and toxicity to ocular cells as edge activators. Attenuated Total Reflectance–Fourier Transform Infrared spectroscopy (ATF-FTIR), differential scanning calorimetry (DSC), and dynamic light scattering (DLS) were used to evaluate the physicochemical parameters of the blank and the cyclosporine A-loaded transferosomes. Cyclosporine A release and corneal permeability were studied in vitro and in a New Zealand albino rabbit corneal model, respectively. The linoleic acid contributed to improved stability and the nano-size of the transferosomes. The Tween®-based formulation was preferred on the basis of a more favorable toxicity profile, as the difference in their corneal permeability was not significant. There was an initial burst release of cyclosporine A in the first 24 h that plateaued over one week. The Tween®-based formulation had a flux of 0.78 µg/cm2/h. The prepared transferosomes demonstrated biocompatibility in the ocular cell line, adequately encapsulated cyclosporine A, ensured the corneal permeability of the enclosed drug, and were stable over the period of investigation of 4 months at −20 °C.

Percutaneous absorption and exposure risk assessment of organophosphate esters in children’s toys

The percutaneous penetration and exposure risk of organophosphate esters (OPEs) from children’s toys remains largely unknown. Percutaneous penetration of OPEs was evaluated by EPISkin™ model. Chlorinated OPEs (Cl-OPEs) and alkyl OPEs, except tris(2-ethylhexyl) phosphate, exhibited a fast absorption rate and good dermal penetration ability with cumulative absorptions of 57.6–127 % of dosed OPEs. Cumulative absorptions of OPEs through skin cells were inversely associated with their molecular weight and log octanol-water partition coefficient. Additionally, a quantitative structure-activity relationship model indicated that topological charge and steric features of OPEs were closely related to the transdermal permeability of these chemicals. With the clarification of the factors affecting the transdermal penetration of OPEs, the level and exposure risk of OPEs in actual toys were studied. The summation of 18 OPE concentrations in 199 toy samples collected from China ranged from 6.82 to 228,254 ng/g, of which Cl-OPEs presented the highest concentration. Concentrations of OPEs in toys exhibited clear type differences. Daily exposure to OPEs via dermal, hand-to-mouth contact, and mouthing was evaluated, and dermal contact was a significant route for children’s exposure to OPEs. Hazard quotients for noncarcinogenic risk assessment were below 1, indicating that the health risk of OPEs via toys was relatively low.

Preparation and evaluation of dissolving microneedle loaded with azelaic acid for acne vulgaris therapy

Anti-acne microneedle technology is an emerging approach to acne vulgaris and acne scars therapy. Currently, solid microneedle is the most common one in clinical practices. Nevertheless, it needs to be operated by professionals. Additionally, there is a potential risk of needle breakage, leading to a biohazard inside the skin. This study prepared and evaluated a dissolving microneedle (DMN) containing azelaic acid (AZA), providing a novel self-administered and rapid-onset pathway for acne patients. The AZA-loaded DMN can be inserted into the skin under the loaded force of 5 N. We examined the safety, transdermal release, stability, antibacterial activity, and pharmacokinetic studies of AZA-DMN to provide reference and guarantee for clinical trials. Besides, to evaluate the efficacy of DMN containing AZA, a randomized and controlled pilot study was conducted on adult acne patients. The results indicated that AZA-DMN had good skin compatibility and formulation stability. Furthermore, there was no significant difference in AZA concentrations in rats’ plasma before and after administration, revealing that AZA-DMN mainly worked on local skin. Compared to the control groups, more remarkable inflammation subsidence appeared in the AZA-DMN group. Meanwhile, it was shown that the delivery of AZA using DMN significantly shortened the therapy cycle compared with commercially available AZA cream. In summary, our studies confirmed that AZA-loaded DMN provided a promising treatment strategy for acne patients due to the enhanced transdermal permeability of AZA and its noticeable antibacterial effect on Propionibacterium acnes and Staphylococcus epidermidis.

Enhancement of transdermal permeation of cannabinoids and their pharmacodynamic evaluation in rats

The objective of the present study was to enhance the transdermal permeation of cannabinoids: cannabidiol (CBD), cannabigerol (CBG) and tetrahydrocannabivarin (THCV) using chemical permeation enhancer approach and evaluate them for their anti-inflammatory effect in vivo in a paw edema model in rats. Cannabinoids gel formulations were developed using FDA approved inactive ingredients: lactic acid (LA), polyethylene glycol-400 (PEG-400), N-methyl-2 pyrrolidone (NMP), dimethyl sulfoxide (DMSO). In vitro skin permeation testing (IVPT) showed flux of ∼ 13.25 μg/cm2/h for CBD, ∼9.38 μg/cm2/h for CBG and ∼ 51.74 μg/cm2/h for THCV. Additionally, IVPT study showed cumulative drug permeation of 610.96 ± 88.92 μg/cm2, 432.09 ± 35.59 μg/cm2 and 2384.44 ± 42.22 μg/cm2 from CBD, CBG and THCV gel formulations respectively. Further, effect of excipients on cannabinoid permeation showed that, formulation containing lactic acid, NMP and DMSO showed significantly (p < 0.0001) enhanced flux of cannabinoids as compared to formulation without LA, NMP and DMSO. In vivo studies showed that paw edema was significantly (p < 0.0001) reduced in the groups containing CBD, CBG, THCV as compared to control and placebo formulation. In conclusion, flux of CBD, CBG and THCV was significantly enhanced using chemical permeation enhancers approach which helped in reducing rat paw edema.

Ozonated Olive Oil: Enhanced Cutaneous Delivery via Niosomal Nanovesicles for Melanoma Treatment.

Ozonated olive oil (OL) combines the therapeutic effects of both ozone and olive oil. However, it suffers from limited water solubility and poor transdermal permeation, which hinder its application in melanoma treatment. Nanocarrier host molecules, such as niosomes, were used to improve the water solubility, transdermal permeation, and anticancer effect of hydrophobic compounds. This study aims to design and optimize a niosomal vesicular nanoplatform loaded with OL (OL/NSs) to improve OL’s skin permeation and anti-melanoma effect. In this regard, OL was prepared and characterized by evaluating its chemical properties (acid, peroxide, and iodine values) and fatty acid composition using gas chromatography. Then, OL/NSs were developed using the thin film hydration method employing cholesterol, Span 60, and Tween 60 at five different molar ratios. The optimized niosomes had an average diameter of 125.34 ± 13.29 nm, a surface charge of −11.34 ± 4.71 mV, and a spherical shape. They could entrap 87.30 ± 4.95% of the OL. OL/NSs showed a 75% sustained oil release over 24 h. The skin permeation percentage of OL/NSs was 36.78 ± 3.31 and 53.44 ± 6.41% at 12 and 24 h, respectively, three times higher than that of the free OL (11.50 ± 1.3 and 17.24 ± 2.06%, at 12 and 24 h, respectively). Additionally, the anticancer activity of the developed niosmal formulation, when tested on human melanoma cells (A375), was double that of the free OL; the IC50 of the OL/NSs was 8.63 ± 2.8 μg/mL, and that of the free OL was 17.4 ± 3.7 μg/mL. In conclusion, the encapsulation of ozonated olive oil in niosomes enhanced its water solubility, skin permeation, and anticancer activity and thus may represent potent natural chemotherapy in treating melanoma.

Clove Oil Endorsed Transdermal Flux of Dronedarone Hydrochloride Loaded Bilosomal Nanogel: Factorial Design, In vitro Evaluation and Ex vivo Permeation

The goal of this study was to develop a bilosomal gel formulation to enhance transdermal permeability of dronedarone hyrdrochloride (DRN) which suffers from poor oral absorption and limited bioavailability. To overcome this obstacle, bilosomes were successfully prepared using 23 full-factorial design. Span®40, cholesterol, sodium deoxycholate (bile salt), clove oil (permeability enhancer), and either Tween® 60 or Tween® 80 (edge activator) were used in bilosome preparation by ethanol injection method. In this design, independent variables were X1, edge activator type; X2, edge activator amount (mg); and X3, permeability enhancer concentration (% w/v). Optimal formula (B2) of the highest desirability of (0.776) demonstrated minimum vesicle size (VS) of 312.4 ± 24.42 nm, maximum absolute value of zeta potential (ZP) − 36.17 ± 2.57 mV, maximum entrapment efficiency (EE %) of 80.95 ± 3.01%, maximum deformability Index (DI) of 8.24 ± 1.26 g and maximum drug flux after 12 h (J12) of 21.23 ± 1.54 µg/cm2 h upon ex vivo permeation study. After 12 h, 70.29 ± 6.46% of DRN was released from B2. TEM identification of B2 showed spherical shaped nanosized vesicles which were physically stable for 3 months at different temperatures. B2 was incorporated into carboxymethylcellulose gel base for easiness of dermal application. B2 gel demonstrated good physical properties, non-Newtonian psuedoplastic flow, and enhanced release (57.0 ± 8.68% of DRN compared to only 13.3 ± 1.2% released from drug suspension after 12 h) and enhanced skin permeation.Graphical abstract

How physical techniques improve the transdermal permeation of therapeutics: A review.

Background:Transdermal delivery is very important in pharmaceutics. However, the barrier function of the stratum corneum hinders drugs absorption. How to improve transdermal delivery efficiency is a hot topic. The key advantages of physical technologies are their wide application for the delivery of previously nonappropriate transdermal drugs, such as proteins, peptides, and hydrophilic drugs. Based on the improved permeation of drugs delivered via multiple physical techniques, many more diseases may be treated, and transdermal vaccinations become possible. However, their wider application depends on the related convenient and portable devices. Combined products comprising medicine and devices represent future commercial directions of artificial intelligence and 3D printing.Methods:A comprehensive search about transdermal delivery assisted by physical techniques has been carried out on Web of Science, EMBASE database, PubMed, Wanfang Database, China National Knowledge Infrastructure, and Cochrane Library. The search identified and retrieved the study describing multiple physical technologies to promote transdermal penetration.Results:Physical technologies, including microneedles, lasers, iontophoresis, sonophoresis, electroporation, magnetophoresis, and microwaves, are summarized and compared. The characteristics, mechanism, advantages and disadvantages of physical techniques are clarified. The individual or combined applicable examples of physical techniques to improve transdermal delivery are summarized.Conclusion:This review will provide more useful guidance for efficient transdermal delivery. More therapeutic agents by transdermal routes become possible with the assistance of various physical techniques.

Efficient transdermal delivery of functional protein cargoes by a hydrophobic peptide MTD 1067

The skin has a protective barrier against the external environment, making the transdermal delivery of active macromolecules very difficult. Cell-penetrating peptides (CPPs) have been accepted as useful delivery tools owing to their high transduction efficiency and low cytotoxicity. In this study, we evaluated the hydrophobic peptide, macromolecule transduction domain 1067 (MTD 1067) as a CPP for the transdermal delivery of protein cargoes of various sizes, including growth hormone-releasing hexapeptide-6 (GHRP-6), a truncated form of insulin-like growth factor-I (des(1-3)IGF-I), and platelet-derived growth factor BB (PDGF-BB). The MTD 1067-conjugated GHRP-6 (MTD-GHRP-6) was chemically synthesized, whereas the MTD 1067-conjugated des(1-3)IGF-I and PDGF-BB proteins (MTD-des(1-3)IGF-I and MTD-PDGF-BB) were generated as recombinant proteins. All the MTD 1067-conjugated cargoes exhibited biological activities identical or improved when compared to those of the original cargoes. The analysis of confocal microscopy images showed that MTD-GHRP-6, MTD-des(1-3)IGF-I, and MTD-PDGF-BB were detected at 4.4-, 18.8-, and 32.9-times higher levels in the dermis, respectively, compared to the control group without MTD. Furthermore, the MTD 1067-conjugated cargoes did not show cytotoxicity. Altogether, our data demonstrate the potential of MTD 1067 conjugation in developing functional macromolecules for cosmetics and drugs with enhanced transdermal permeability.

Supramolecular Hydrogels Consisting of Nanofibers Increase the Bioavailability of Curcuminoids in Inflammatory Skin Diseases

The low bioavailability of curcuminoids (CCMoids) limits their use in the treatment of inflammatory skin diseases. Our work shows that this constraint can be overcome upon their incorporation into supramolecular hydrogels assembled from a gemini-imidazolium amphiphilic gelator. Three structural CCMoid analogues were used to prepare supramolecular hydrogels, and it was observed that the concentration of both the gelator and CCMoid and the proportion of solvents influence the self-assembly process. Moreover, the mechanical properties of the nanostructured gels were studied to find the optimum gels, which were then further characterized microscopically, and their ability to release the CCMoid was evaluated. The physicochemical properties of the CCMoids play a fundamental role in the interaction with the gelator, influencing not only the gelation but also the morphology at the microscopic level, the mechanical properties, and the biopharmaceutical behavior such as the amount of CCMoid released from the gels. The nanostructured supramolecular hydrogels, which contain the CCMoids at much lower concentrations (μg/mL) in comparison to other products, promote the penetration of the CCMoids within the skin, but not their transdermal permeation, thus preventing any possible systemic effects and representing a safer option for topical administration. As a result, the CCMoid-containing hydrogels can effectively reduce skin inflammation in vivo, proving that these supramolecular systems are excellent alternatives in the treatment of inflammatory skin diseases.

Optimizing and Evaluating the Transdermal Permeation of Hydrocortisone Transfersomes Formulation Based on Digital Analysis of the In Vitro Drug Release and Ex Vivo Studies.

Transfersomes can be used to enhance transdermal drug delivery due to their flexibility and ability to incorporate various molecules. For example, hydrocortisone (HC), a corticosteroid, is taken by different routes and serves as immunosuppressive, anticancer, and antiallergenic; however, it is poorly absorbed by the skin. Therefore, the current study suggested HC-loaded transfersomes as an alternative route of administration for reaching deeper skin layers or systemic circulation, to reduce the side effects of HC and improve its bioavailability. HC transfersomes were prepared by the thin-film hydration method and characterized for their vesicular size, zeta potential, drug entrapment efficiency, elasticity, FTIR spectroscopy, in vitro drug release, ex vivo permeation, and irritancy in rabbits. The optimized formulation, F15 (containing HC 20 mg, egg phosphatidylcholine (EPC) 400 mg, and 75 mg of Span 80), was chosen because it showed the highest (p< 0.05) EE% (60.4±0.80) and optimized sustained in vitro drug release (Q8 = 87.9±0.6%). Extensive analysis of the drug release data from all formulas was performed using the DDSolver software which quantitatively confirmed the successful formulation. The Weibull equation was the best model to fit the release data compared to others, and the release mechanism was Fickian diffusion. The simulated pharmacokinetic parameters showed that F15 had the highest AUC, MDT, and DE. Furthermore, F15 significantly enhanced HC permeation by 12-folds compared to the control through the excised rat's skin. The skin irritancy test has proven F15 safety and skin compatibility.

Fabrication of Ethosomes Containing Tocopherol Acetate to Enhance Transdermal Permeation: In Vitro and Ex Vivo Characterizations.

Background: Tocopherol acetate (TA) is known as a skin moisturizing and photoprotective agent. One major drawback with tocopherol and its derivatives remains its limited stability. Aim: To develop highly stable TA-containing ethosomal gel (TAEG) as an advanced dosage form. Methods: A cold method technique was used to produce the ethosomes. An in vitro evaluation of viscosity, conductivity, and pH stability was carried out for three months. An in vitro physical characterization of the nanoparticles (NPs) that included particle size (PS), zeta potential (ZP), transmission electron microscopy (TEM), and Fourier-transform infrared (FTIR) spectroscopy analysis was then performed. Organoleptic evaluation, thermostability at 8 °C, 25 °C, 40 °C and 40 °C ± 75% RH, pH, conductivity, viscosity, and spreadability measurements were also performed in vitro for three months. An ex vivo permeation study was performed in phosphate-buffered solution (1× PBS; pH 5.5 or pH 7.4) at 37 ± 0.2 °C by using rat abdominal skin and the Franz diffusion cell method. The data of three independent experiments were expressed as mean ± SD. A two-way ANOVA was applied to compare data on TAEG versus TA control gel (TACG). Results: PS of the ethosomes was in the range of 144–289 nm. A total of nine formulations were developed. Optimized TAEG formulation (TA-5) was selected based on the highest entrapment efficiency (EE) of 99.71%, while the stability, the PS, and the uniformity-based polydispersity index (PDI) were also among the best. TA-5 exhibited smooth spherical ethosomal NPs with PS of 200.6 nm, ZP value of −18.6 V, and PDI of 0.465. Stability data obtained for TA-5 in terms of rheology, conductivity, and pH presented no significant change (p > 0.05) during the entire study duration. Rheological studies indicated that TA-5 followed a non-Newtonian behavior of shear thinning system. The ex vivo drug permeation was 44.55 ± 0.01% in TA-5 and the drug retention in skin was 51.20%, which was significantly higher than TACG as observed after 24 h permeation study (p < 0.05). Conclusions: The newly developed TAEG formulation appears promising to enhance the effectivity of TA and its topical application.

Beneath the Skin: A Review of Current Trends and Future Prospects of Transdermal Drug Delivery Systems.

The ideal drug delivery system has a bioavailability comparable to parenteral dosage forms but is as convenient and easy to use for the patient as oral solid dosage forms. In recent years, there has been increased interest in transdermal drug delivery (TDD) as a non-invasive delivery approach that is generally regarded as being easy to administer to more vulnerable age groups, such as paediatric and geriatric patients, while avoiding certain bioavailability concerns that arise from oral drug delivery due to poor absorbability and metabolism concerns. However, despite its many merits, TDD remains restricted to a select few drugs. The physiology of the skin poses a barrier against the feasible delivery of many drugs, limiting its applicability to only those drugs that possess physicochemical properties allowing them to be successfully delivered transdermally. Several techniques have been developed to enhance the transdermal permeability of drugs. Both chemical (e.g., thermal and mechanical) and passive (vesicle, nanoparticle, nanoemulsion, solid dispersion, and nanocrystal) techniques have been investigated to enhance the permeability of drug substances across the skin. Furthermore, hybrid approaches combining chemical penetration enhancement technologies with physical technologies are being intensively researched to improve the skin permeation of drug substances. This review aims to summarize recent trends in TDD approaches and discuss the merits and drawbacks of the various chemical, physical, and hybrid approaches currently being investigated for improving drug permeability across the skin.