Essential oils are natural products with a complex composition. Terpenes are the most common class of chemical compounds present in essential oils. Terpenes and the essential oils containing them are ...widely used and investigated by their pharmacological properties and permeation-enhancing ability. However, many terpenes and essential oils are sensitive to environmental conditions, undergoing volatilization and chemical degradation. In order to overcome the chemical instability of some isolated terpenes and essential oils, the encapsulation of these compounds in nanostructured systems (polymeric, lipidic, or molecular complexes) has been employed. In addition, nanoencapsulation can be of interest for pharmaceutical applications due to its capacity to improve the bioavailability and allow the controlled release of drugs. Topical drug administration is a convenient and non-invasive administration route for both local and systemic drug delivery. The present review focuses on describing the current status of research concerning nanostructured delivery systems containing isolated terpenes and/or essential oils designed for topical administration and on discussing the use of terpenes and essential oils either for their biological activities or as permeation enhancers in pharmaceutic formulations.
•Copaiba oil nanoemulsions were prepared by two methods.•2IV4-1 fractional factorial design was used to optimize the formulation.•Formulations with high oil content were obtained.•Stability at 4 and ...25°C was monitored for 90 days.•MCT aided fixing the copaiba oil volatile fraction in nanoemulsions.
Copaiba oil has been widely used in popular medicine because of its anti-inflammatory properties. The oil is extracted from trees of the genus Copaifera, found mainly in the Brazilian Amazon. A study was conducted using a 2IV4-1 fractional factorial design to evaluate the effects of oil core and surfactants composition on physicochemical properties of nanoemulsions produced by high-pressure homogenization and spontaneous emulsification. Also, the stability of the formulations stored at 4°C and 25°C was monitored for 90 days. The high-pressure homogenization method proved to be the most efficient technique to obtain stable Copaiba oil nanoemulsions with reduced loss of volatile fraction within 90 days of storage at the recommended temperature (4°C). The most suitable nanoemulsion composition was achieved adding 20% Copaiba oil, 10% medium chain triglycerides, 3% Span 80® and 1% Tween 20®. The use of medium chain triglycerides was shown to be a good strategy to fix volatile fractions of Copaiba oil incorporated into nanoemulsions during preparation and storage.
Mucopolysaccharidoses (MPS) are genetic disorders caused by the accumulation of glycosaminoglycans due to deficiencies in the lysosomal enzymes responsible for their catabolism. Current treatments ...are not fully effective and are not available for all MPS types. Accordingly, researchers have tested novel therapies for MPS, including nanotechnology-based enzyme delivery systems and gene therapy. In this review, we aim to analyze some of the approaches involving nanotechnology as alternative treatments for MPS. Areas covered: We analyze nanotechnology-based systems, focusing on the biomaterials, such as polymers and lipids, that comprise these nanostructures, and we have highlighted studies that describe their use as enzyme and gene delivery systems for the treatment of MPS diseases. Expert opinion: Some protocols, such as the use of polymer-based systems or nanostructured carriers associated with enzymes and nanotechnology-based carriers for gene therapy, along with combined approaches, seem to be the future of MPS therapy.
Nanoemulsions composed of a medium-chain triglyceride oil core stabilized by rapeseed or sunflower lecithins were prepared by spontaneous emulsification and high-pressure homogenization. These ...nanoemulsions are compared with formulations stabilized by egg lecithin. Nanoemulsions obtained by high-pressure homogenization display larger droplet size (230 to 440 nm) compared with those obtained by spontaneous emulsification (190 to 310 nm). The zeta potentials of the emulsions were negative and below -25 mV. Zeta potential inversion occurred between pH 3.0 and 4.0. The results demonstrate the feasibility of preparing lipid emulsions comprising rapeseed or sunflower lecithins by spontaneous emulsification and high-pressure homogenization.
Display omitted
•A liposomal vector was proposed and optimized by Box Behnken design tool.•siRNA was efficiently complexed with liposome at +5/−1 charge ratio.•Optimized liposome demonstrated high ...HCE cells viability in vitro.•Liposome + siRNA and chlorhexidine combination reversed 60% of keratitis in vivo.
Acanthamoeba keratitis is an ophthalmic disease with no specific treatment that specially affects contact lens users. The silencing of serine phosphatase (SP) and glycogen phosphorylase (GP) proteins produced by Acanthamoeba has been shown to significantly reduce the cytopathic effect, although no vehicle was proposed yet to deliver the siRNA sequences to the trophozoites. In this study, PEGylated cationic liposomes were proposed and optimized using Box-Behnken design. The influence of DOTAP:DOPE ratio, DSPE-PEG concentration, and siRNA/DOTAP charge ratio were evaluated over both biological response and physicochemical properties of liposomes. The ratio of DOTAP:DOPE had an effect in the trophozoite activity whereas the charge ratio influenced both size and protease activity. The predicted values were very close to the observed values, yielding a formulation with good activity and toxicity profile, which was used in the following experiments. A murine model of ocular keratitis was treated with siGP + siSP-loaded liposomes, as well as their respective controls, and combined treatment of liposomes and chlorhexidine. After 15 days of eight daily administrations, the liposomal complex combined with chlorhexidine was the only treatment able to reverse the more severe lesions associated with keratitis. There was 60% complete regression in corneal damage, with histological sections demonstrating the presence of an integral epithelium, without lymphocytic infiltrate. The set of results demonstrate the efficacy of a combined therapy based on siRNA with classical drugs for a better prognosis of keratitis caused by Acanthamoeba.
Display omitted
In this study, we investigated the effects of the association of a single plasmid or its co-complexation along with an oligonucleotide on the physicochemical properties of cationic ...nanoemulsions and liposomes intended for gene editing. Formulations composed of DOPE, DOTAP, DSPE-PEG (liposomes), MCT (nanoemulsions), and water were obtained by microfluidization. DSPE-PEG was found to play a crucial role on the size and polydispersity index of nanocarriers. Nucleic acids were complexated by adsorption at different charge ratios. No significant differences were noticed in the physicochemical properties of nanocarriers (i.e. droplet size, polydispersity index, or zeta potential) when a single plasmid or both plasmid and oligonucleotide were adsorbed to the formulations. Transmission electron microscopy photomicrographs suggested round nanostructures with the nucleic acids and DSPE-PEG enfolding the surface. Complexes at +4/−1 charge ratio protected nucleic acids against DNase I degradation. The oligonucleotide seemed to be released from the liposomal complexes, while nanoemulsions only released the plasmid after 24 and 48 h of incubation in DMEM supplemented or not. In vitro experiments demonstrated that complexes were highly tolerable to human fibroblasts, Hep-G2, and HEK-293 cells, demonstrating also an uptake ability of about 30%, 30%, and 90%, respectively, no matter what the formulation or the combination of nucleic acids used. Transfection efficiency of the formulations was around 25% in human fibroblasts, 32% in HEK-293, and 15% in Hep-G2 cells. The overall results demonstrated the behavior of liposomes and nanoemulsions complexed with a plasmid or a mixture of a plasmid and an oligonucleotide, and demonstrated that the association with one or two nucleic acids sequences of different length does not seem to interfere in the physicochemical characteristics of complexes or in the uptake capacity by three different types of cells.
Carbamazepine (CBZ), a widely used anticonvulsant drug, is a poorly soluble drug with no parenteral treatment available for patients. This study was aimed at developing a nanoemulsion for CBZ ...intravenous delivery. The spontaneous emulsification method was used to prepare different formulations containing 2
mg/mL CBZ. Likewise, a 2
2 full factorial experimental design was applied to study the influence of two independent variables (type of oil and type of lipophilic emulsifier) on emulsion physicochemical characteristics. The nanoemulsions were evaluated concerning droplet size, zeta potential, viscosity, drug content and association to oily phase. The formulation, which presented the best characteristics required for intravenous administration was selected and refined with respect to the lipophilic emulsifier content (increase from 5% to 6% of soy lecithin). This formulation was characterized and kept its properties in a satisfactory range over the evaluated period (3 months), i.e. droplet size around 150
nm, drug content around 95% and zeta potential around −40
mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape with an amorphous core, whereas the
in vitro release profile assessed by dialysis bags demonstrated a release kinetics square root time dependent, with 95% of ca. having been released within 11
h.
The benzopyran HP1, a compound isolated from Hypericum polyanthemum, has demonstrated significant opioid-mediated antinociceptive activity after its oral administration. Despite the pharmacological ...potential, the poor aqueous solubility limits the oral absorption of this compound. For this reason, HP1 has been alternatively incorporated in lipid-based drug delivery systems. Given that nanoemulsions showed higher antinociceptive action than the free compound in a previous report, in this study, the main objective was to investigate the intestinal transport mechanisms of this system. The Ussing chamber model and rat jejunum were selected for this purpose. The apparent permeability coefficient of HP1 increased approximately 5.3 times after its incorporation in nanoemulsions. Considering that the absorptive transport of HP1 was significantly higher than the secretory transport, the participation of active transporters was suggested. The amount of HP1 in the acceptor chamber was reduced during permeability assays performed at 4 °C, supporting the hypothesis that active transporters are involved in the intestinal transport of this compound. The amount of free fatty acids released from nanoemulsion was approximately 60% after 90 min, demonstrating that part of this system is disassembled before absorption. Nanoemulsion constituents would be able to form new structures with biological constituents, leading to a rapid solubilization of HP1. A mucoadhesion rate of 50% was achieved by nanoemulsion after 30 min, which would also contribute to explain the higher absorption of this system. The particle size of the nanoemulsion is also compatible with endocytosis-mediated transport. Taken together, these results suggest that nanoemulsions containing HP1 could be efficiently delivered to humans considering that different absorption mechanisms are exploited.
Display omitted
Background
Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by deficiency of the enzyme alpha‐l‐iduronidase (IDUA). MPS I affects several tissues, including the brain, leading to ...cognitive impairment in the severe form of the disease. Currently available treatments do not reach the brain. Therefore, in this study, we performed nasal administration (NA) of liposomal complexes carrying two plasmids encoding for the CRISPR/Cas9 system and for the IDUA gene targeting the ROSA26 locus, aiming at brain delivery in MPS I mice.
Methods
Liposomes were prepared by microfluidization, and the plasmids were complexed to the formulations by adsorption. Physicochemical characterization of the formulations and complexes, in vitro permeation, and mucoadhesion in porcine nasal mucosa (PNM) were assessed. We performed NA repeatedly for 30 days in young MPS I mice, which were euthanized at 6 months of age after performing behavioral tasks, and biochemical and molecular aspects were evaluated.
Results
Monodisperse mucoadhesive complexes around 110 nm, which are able to efficiently permeate the PNM. In animals, the treatment led to a modest increase in IDUA activity in the lung, heart, and brain areas, with reduction of glycosaminoglycan (GAG) levels in serum, urine, tissues, and brain cortex. Furthermore, treated mice showed improvement in behavioral tests, suggesting prevention of the cognitive damage.
Conclusion
Nonviral gene editing performed through nasal route represents a potential therapeutic alternative for the somatic and neurologic symptoms of MPS I and possibly for other neurological disorders.
Noninvasive nasal administration of liposomal vehicle for delivering CRISPR‐cas9/Donor plasmids showed an improvement in behavioral tasks and GAG reduction in MPS I mice due to 0.04–0.06% of gene edited cells, which led to a modest increase in IDUA enzyme activity in several tissues, including some brain areas.
Copaiba oil is used as a popular medicine in the Amazonian forest region, especially due to its anti-inflammatory properties. In this paper, we describe the formulation of hydrogel containing copaiba ...oil nanoemulsions (with positive and negative charges), its skin permeation, and its anti-inflammatory activity in two
in vivo
models: mouse ear edema and rat paw edema. Three hydrogels were tested (Carbopol
®
, hydroxyethylcellulose and chitosan), but only Carbopol
®
and hydroxyethylcellulose hydrogels presented good stability and did not interfere with the nanoemulsions droplet size and polydispersity index. In skin permeation assay, both formulations, positively charged nanoemulsion (PCN) and negatively charged nanoemulsion (NCN), presented a high retention in epidermis (9.76 ± 2.65 μg/g and 7.91 ± 2.46 μg/cm
2
, respectively) followed by a smaller retention in the dermis (2.43 ± 0.91 and 1.95 ± 0.56 μg/cm
2
, respectively). They also presented permeation to the receptor fluid (0.67 ± 0.22 and 1.80 ± 0.85 μg/cm
2
, respectively). In addition, anti-inflammatory effect was observed to NCN and PCN with edema inhibitions of 69 and 67% in mouse ear edema and 32 and 72% in rat paw edema, respectively. Histological cuts showed the decrease of inflammatory factors, such as dermis and epidermis hyperplasia and inflammatory cells infiltration, confirming the anti-inflammatory effect from both copaiba oil nanoemulsions incorporated in hydrogel.
PDF
