Fullerene nanoemulsions were formulated in palm kernel oil esters stabilized by low amount of mixed nonionic surfactants. Pseudoternary phase diagrams were established in the colloidal system of PKOEs/Tween 80 : Span 80/water incorporated with fullerene as antioxidant. Preformulation was subjected to combination of high and low energy emulsification methods and the physicochemical characteristics of fullerene nanoemulsions were analyzed using electroacoustic spectrometer. Oil-in-water (O/W) nanoemulsions with particle sizes in the range of 70-160 nm were formed. The rheological characteristics of colloidal systems exhibited shear thinning behavior which fitted well into the power law model. The effect of xanthan gum (0.2-1.0%, w/w) and beeswax (1-3%, w/w) in the estimation of thermodynamics was further studied. From the energetic parameters calculated for the viscous flow, a moderate energy barrier for transport process was observed. Thermodynamic study showed that the enthalpy was positive in all xanthan gum and beeswax concentrations indicating that the formation of nanoemulsions could be endothermic in nature. Fullerene nanoemulsions with 0.6% or higher xanthan gum content were found to be stable against creaming and flocculation when exposed to extreme environmental conditions.
Studies were conducted to assess the percutaneous absorption of the triacyglycerols (TAGs), tocols and carotenoids present in crude and refined palm oil. In vitro experiments using upright Franz diffusion cells were employed to investigate the permeability of these compounds across full thickness human skin and into the receptor solution. Cetrimide, a cationic surfactant was chosen to be used as a solubilising agent in the receptor phase with an optimum concentration of 3.0 mg/mL and was able to provide sink conditions throughout the permeation. TAGs, tocols and carotenoids all permeated human skin from crude palm oil (CPO), whereas only TAGs permeated when refined palm oil (RPO) was used. Of the TAGs, oleic acid-containing TAGs was preferentially absorbed despite palmitic acid being the most prevalent fatty acid (FA) in TAGs. Tocols in the form of α-T3 showed the highest permeation followed by γ-T3, α-T and the lowest permeation was observed for δ-T3. Carotenoids (α-carotene and β-carotene) also showed an appreciable amount of permeation from CPO.
Drug delivery through the skin improves solubility, bioavailability, and unwanted systemic side effects of the drug. The selection of a suitable carrier is a challenging process. The conventional lipid vesicles have some limitations. They deliver the drug in the stratum corneum and have poor colloidal stability. Here comes the need for ultra-deformable lipid vesicles to provide the drug beyond the stratum corneum. Transethosomes are novel ultra-deformable vesicles that can deliver drugs into deeper tissues. The composition of transethosomes includes phospholipid, ethanol and surfactants. Each ingredient has a pivotal role in the properties of the carrier. This review covers the design, preparation method, characterisation, and characteristics of the novel vesicle. Also, we cover the impact of surfactants on vesicular properties and the skin permeation behaviour of novel vesicles.
To assess dermal absorption of nicotine from tobacco leaves in relation to Green Tobacco Sickness (GTS), urinary cotinine concentrations were measured in 80 male tobacco-growing farmers and in 40 healthy males (controls) who did not handle wet tobacco leaves in Kelantan, Malaysia. Among non-smokers, urinary cotinine levels in farmers were significantly higher than those of controls; farmers with urinary cotinine of 50 ng/ml/m2 or above showed eye symptoms more frequently than those below this level (p<0.05). Farmers who did not wear protective equipment had subjective symptoms more frequently than those who used the equipment (p<0.05); some of these symptoms were seen more frequently in organophosphate (Tamaron) users than in non-users. As tobacco farmers evidence a risk of nicotine poisoning from tobacco leaves, assessment including GTS together with effects of pesticides will be necessary.
Virgin coconut oil (VCO) is the finest grade of coconut oil, rich in phenolic content, antioxidant activity and contains medium chain triglycerides (MCTs). In this work formulation, characterisation and penetration of VCO-solid lipid particles (VCO-SLP) have been studied. VCO-SLP were prepared using ultrasonication of molten stearic acid and VCO in an aqueous solution. The electron microscopy imaging revealed that VCO-SLP were solid and spherical in shape. Ultrasonication was performed at several power intensities which resulted in particle sizes of VCO-SLP ranged from 0.608 ± 0.002 µm to 44.265 ± 1.870 µm. The particle size was directly proportional to the applied power intensity of ultrasonication. The zeta potential values of the particles were from -43.2 ± 0.28 mV to -47.5 ± 0.42 mV showing good stability. The cumulative permeation for the smallest sized VCO-SLP (0.608 µm) was 3.83 ± 0.01 µg/cm(2) whereas for larger carriers it was reduced (3.59 ± 0.02 µg/cm(2)). It is concluded that SLP have the potential to be exploited as a micro/nano scale cosmeceutical carrying vehicle for improved dermal delivery of VCO.
This study sets out to investigate the in vitro permeation of ketoprofen from the formulated nanoemulsions through excised rat skin. In vitro permeation of ketoprofen nanoemulsion through rat skin was evaluated in Franz diffusion cells and compared with marketed product (Fastum gel). Limonene which has been reported to be a good enhancer for ketoprofen was selected. Moreover the effects of limonene which was added to the nanoemulsion formulations at levels of 1%, 2%, 3% and on rat skin permeation of ketoprofen were also evaluated. The selected optimized formulation was further studied for skin irritation. Utilization of limonene as a penetration enhancer increased the permeation of ketoprofen from the formulated nanoemulsion with increasing concentrations of limonene. The results obtained showed that nanoemulsion with 3% limonene produced similar and comparable skin permeation of ketoprofen with marketed formulation and the skin irritation study on rats showed the optimized formulation prepared was safe.
During recent years, there has been growing interest in the use of nanoemulsion as a drug-carrier system for topical delivery. A nanoemulsion is a transparent mixture of oil, surfactant and water with a very low viscosity, usually the product of its high water content. The present study investigated the modification of nanoemulsions with different hydrocolloid gums, to enhanced drug delivery of ibuprofen. The in vitro characterization of the initial and modified nanoemulsions was also studied.
Previous studies have shown that hydroxytyrosol (HT) can be a potential alternative therapeutic agent for the treatment of rheumatoid arthritis (RA). However, HT is extensively metabolized following oral administration, which leads to formulating HT in a topical vehicle to prolong drug action as well as to provide a localized effect. Hidrox-6 is a freeze-dried powder derived from fresh olives and contains a high amount of HT (∼3%) and other polyphenols. Alginate bilayer films containing 5% and 10% Hidrox-6 were formulated. The films were characterized with respect to their physical, morphology, rheological properties; drug content uniformity; and in vitro drug release. Acute dermal irritancy tests and a skin sensitization study were carried out in rats. An efficacy study of the bilayer films for RA was conducted using Freund's adjuvant-induced polyarthritis rats. Animal data showed that the bilayer film formulations did not cause skin irritancy. The efficacy in vivo results showed that the Hidrox-6 bilayer films lowered the arthritic scores, paw and ankle circumference, serum IL-6 level and cumulative histological scores compared with those measured for controls. The topical Hidrox-6 bilayer films improve synovitis and inflammatory symptoms in RA and can be a potential alternative to oral RA therapy.
Inhaled/oral insulin have been investigated as an alternative to injectable insulin, but are met with unsatisfactory outcomes. Transdermal administration bears several advantages unmet by inhalation/oral delivery, but macromolecular drugs permeation is poor. This study explored microwave to elicit transdermal insulin permeation, and compared against conventional permeation enhancers (fatty acids) in vitro/in vivo. The transdermal insulin permeation was promoted by microwave (2450 MHz/1 mW) > oleic acid (monounsaturated) ~ linoleic acid (double unsaturated bonds). The linolenic acid (triple unsaturated bonds) or combination of microwave/fatty acid reduced skin insulin permeation. Transdermal insulin permeation enhancement was attributed to epidermal lipid bilayer fluidization (CH) and corneocyte shrinkage due to keratin condensation (OH/NH, CO), which had aqueous pore enlarged to facilitate insulin transport. Its reduction by linolenic acid, a molecularly larger and rigid fatty acid with higher surface tension, was due to reduced fatty acid permeation into epidermis and minimal skin microstructural changes. The oleic acid, despite favoured skin microstructural changes, did not provide a remarkably high insulin permeation due to it embedded in skin as hydrophobic shield to insulin transport. Microwave penetrates skin volumetrically with no chemical residue retention. It alone promoted insulin absorption and sustained blood glucose level reduction in vivo.
The Nanoemulgel drug delivery system is a formulation related intervention to improve the systemic delivery and therapeutic profile of lipophilic drugs. Nanoemulgel is an amalgamated formulation of two different systems in which nanoemulsion containing drug is incorporated into a gel base. The fusion of the two systems makes this formulation advantageous in several ways. Lipophilic drugs can be easily incorporated and the skin permeability of the incorporated drugs can be enhanced in several folds due to the finely distributed droplets of nanoemulsion phase. As a result, the pharmacokinetic and pharmacodynamic profiles of the lipophilic drugs are improved significantly. An increasing trend in topical nanoemulgel use in recent years has been noticed because of the better acceptability of the preparation to the patients due to their noninvasive delivery, avoidance of gastrointestinal side effects, easier applicability and good therapeutic and safety profile. Despite of having few limitations, nanoemulgel formulation can be considered as a potential and promising candidates for topical delivery of lipophilic drugs in the future. The aim of this review is to evaluate and report the current potential and future scope of nanoemulgel formulation for becoming an effective delivery system for poorly water soluble drugs. In this review, we have summarized and discussed the outcome of different studies on permeability, pharmacokinetic, pharmacodynamic and safety profile of the drugs delivered topically through nanoemulgel. Rationality of use along with the major challenges to overcome for nanoemulgel formulation has been discussed.
Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and 31P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 ± 0.83 µg/ml/cm2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin-6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In-vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation.
The aim of this study was to develop a nanostructured lipid carrier (NLC)-based hydrogel and study its potential for the topical delivery of 5-fluorouracil (5-FU). Precirol(®) ATO 5 (glyceryl palmitostearate) and Labrasol(®) were selected as the solid and liquid lipid phases, respectively. Poloxamer 188 and Solutol(®) HS15 (polyoxyl-15-hydroxystearate) were selected as surfactants. The developed lipid formulations were dispersed in 1% Carbopol(®) 934 (poly[acrylic acid]) gel medium in order to maintain the topical application consistency. The average size, zeta potential, and polydispersity index for the 5-FU-NLC were found to be 208.32±8.21 nm, -21.82±0.40 mV, and 0.352±0.060, respectively. Transmission electron microscopy study revealed that 5-FU-NLC was <200 nm in size, with a spherical shape. In vitro drug permeation studies showed a release pattern with initial burst followed by sustained release, and the rate of 5-FU permeation was significantly improved for 5-FU-NLC gel (10.27±1.82 μg/cm(2)/h) as compared with plain 5-FU gel (2.85±1.12 μg/cm(2)/h). Further, skin retention studies showed a significant retention of 5-FU from the NLC gel (91.256±4.56 μg/cm(2)) as compared with that from the 5-FU plain gel (12.23±3.86 μg/cm(2)) in the rat skin. Skin irritation was also significantly reduced with 5-FU-NLC gel as compared with 5-FU plain gel. These results show that the prepared 5-FU-loaded NLC has high potential to improve the penetration of 5-FU through the stratum corneum, with enormous retention and with minimal skin irritation, which is the prerequisite for topically applied formulations.
To study the effects of varying lipid concentrations, lipid and oil ratio, and the addition of propylene glycol and lecithin on the long-term physical stability of nanostructured lipid nanocarriers (NLC), skin hydration, and transepidermal water loss.
Over the years, in vitro Franz diffusion experiments have evolved into one of the most important methods for researching transdermal drug administration. Unfortunately, this type of testing often yields permeation data that suffer from poor reproducibility. Moreover, this feature frequently occurs when synthetic membranes are used as barriers, in which case biological tissue-associated variability has been removed as an artefact of total variation. The objective of the current study was to evaluate the influence of a full-validation protocol on the performance of a tailor-made array of Franz diffusion cells (GlaxoSmithKline, Harlow, UK) available in our laboratory. To this end, ibuprofen was used as a model hydrophobic drug while synthetic membranes were used as barriers. The parameters investigated included Franz cell dimensions, stirring conditions, membrane type, membrane treatment, temperature regulation and sampling frequency. It was determined that validation dramatically reduced derived data variability as the coefficient of variation for steady-state ibuprofen permeation from a gel formulation was reduced from 25.7% to 5.3% (n = 6). Thus, validation and refinement of the protocol combined with improved operator training can greatly enhance reproducibility in Franz cell experimentation.
Synthetic membranes are composed of thin sheets of polymeric macromolecules that can control the passage of components through them. Generally, synthetic membranes used in drug diffusion studies have one of two functions: skin simulation or quality control. Synthetic membranes for skin simulation, such as the silicone-based membranes polydimethylsiloxane and Carbosil, are generally hydrophobic and rate limiting, imitating the stratum corneum. In contrast, synthetic membranes for quality control, such as cellulose esters and polysulfone, are required to act as a support rather than a barrier. These synthetic membranes also often contain pores; hence, they are called porous membranes. The significance of Franz diffusion studies and synthetic membranes in quality control studies involves an understanding of the fundamentals of synthetic membranes. This article provides a general overview of synthetic membranes, including a brief background of the history and the common applications of synthetic membranes. This review then explores the types of synthetic membranes, the transport mechanisms across them, and their relevance in choosing a synthetic membrane in Franz diffusion cell studies for formulation assessment purposes.
Fungal infections of skin including mycoses are one of the most common infections in skin or skins. Mycosis is caused by dermatophytes, non-dermatophyte moulds and yeasts. Various studies show different drugs to treat mycoses, yet there is need to treat it with applied drugs delivery. This study was designed to prepare a bio curcumin (CMN) nanoemulsion (CMN-NEs) for transdermal administration to treat mycoses. The self-nanoemulsification approach was used to prepare a nanoemulsion (NE), utilizing an oil phase consisting of Cremophor EL 100 (Cre EL), glyceryl monooleate (GMO), and polyethylene glycol 5000 (PEG 5000). Particle size (PS), polydispersity index (PDI), zeta potential (ZP), Fourier transform infrared (FTIR) spectrophotometric analysis, and morphological analyses were performed to evaluate the nanoemulsion (NE). The in vitro permeation of CMN was investigated using a modified vertical diffusion cell with an activated dialysis membrane bag. Among all the formulations, a stable, spontaneously produced nanoemulsion was determined with 250 mg of CMN loaded with 10 g of the oil phase. The average droplet size, ZP, and PDI of CMN-NEs were 90.0 ± 2.1 nm, - 7.4 ± 0.4, and 0.171 ± 0.03 mV, respectively. The release kinetics of CMN differed from zero order with a Higuchi release profile as a result of nanoemulsification, which also significantly increased the flux of CMN permeating from the hydrophilic matrix gel. Overall, the prepared nanoemulsion system not only increased the permeability of CMN but also protected it against chemical deterioration. Both CMN-ME (24.0 ± 0.31 mm) and CMN-NE gel (29.6 ± 0.25 mm) had zones of inhibition against Candida albicans that were significantly larger than those of marketed Itrostred gel (21.5 ± 0.34 mm). The prepared CMN-NE improved the bioavailability, better skin penetration, and the CMN-NE gel enhanced the release of CMN from the gel matrix on mycotic patients.
Glycols stand out as one of the most commonly employed safe and effective excipients for pharmaceutical and cosmeceutical products. Their widespread adoption can be attributed to their exceptional solvency characteristics and their ability to interact effectively with skin lipids and keratin for permeation enhancement. Notably, propylene glycol enjoys significant popularity in this regard. Ongoing research endeavours have been dedicated to scrutinising the impact of glycols on dermal drug delivery and shedding light on the intricate mechanisms by which glycols enhance skin permeation. This review aims to mitigate the discordance within the existing literature, assemble a holistic understanding of the impact of glycols on the percutaneous absorption of active compounds and furnish the reader with a profound comprehension of the foundational facets pertaining to their skin permeation enhancement mechanisms, while simultaneously delving deeper into the intricacies of these processes.
Chemotherapeutic cytotoxic agents such as paclitaxel (PTX) are considered essential for the treatment of various cancers. However, PTX injection is associated with severe systemic side effects and high rates of patient noncompliance. Micelle formulations (MFs) are nano-drug delivery systems that offer a solution to these problems. Herein, we report an advantageous carrier for the transdermal delivery of PTX comprising a new MF that consists of two biocompatible surfactants: cholinium oleate ([Cho][Ole]), which is a surface-active ionic liquid (SAIL), and sorbitan monolaurate (Span-20). A solubility assessment confirmed that PTX was readily solubilized in the SAIL-based micelles via multipoint hydrogen bonding and cation-π and π-π interactions between PTX and SAIL[Cho][Ole]. Dynamic light scattering (DLS) and transmission electron microscopy revealed that in the presence of PTX, the MF formed spherical PTX-loaded micelles that were well-distributed in the range 8.7-25.3 nm. According to DLS, the sizes and size distributions of the micelle droplets did not change significantly over the entire storage period, attesting to their physical stability. In vitro transdermal assessments using a Franz diffusion cell revealed that the MF absorbed PTX 4 times more effectively than a Tween 80-based formulation and 6 times more effectively than an ethanol-based formulation. In vitro and in vivo skin irritation tests revealed that the new carrier had a negligible toxicity profile compared with a conventional ionic liquid-based carrier. Based on these findings, we believe that the SAIL[Cho][Ole]-based MF has potential as a biocompatible nanocarrier for the effective transdermal delivery of poorly soluble chemotherapeutics such as PTX.
The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1H and 13C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs.