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CCRD based development of bromocriptine and glutathione nanoemulsion tailored ultrasonically for the combined anti-parkinson effect
Abstract
Bromocriptine Mesylate (BRM) acts as a dopamine receptor agonist along with antioxidant effect and is utilized in the treatment of Parkinson’s disease (PD). Glutathione (GSH) is a thiol- reducing agent having antioxidant properties in the brain. Replenishment of GSH inside the brain can play a major role in the management of PD. Both BRM and GSH suffer from low oral bioavailability and poor absorption. The objective of the present study was to develop BRM and GSH loaded nanoemulsion for the combined and synergistic effect delivered through the intranasal route for the better and effective management of PD. After extensive screening experiments, Capmul PG-8 NF was selected as oil, polyethylene glycol (PEG) 400 as a surfactant and propylene glycol as co-surfactant. Ultrasonication technique was employed for the fabrication of nanoemulsion. Central composite rotatable design (CCRD) was used to obtain the best formulation by optimization. Oil (%), Smix (%), and sonication time (second) were chosen as independent variables for the optimization. Particle size, PDI, zeta potential, % transmittance, pH, refractive index, viscosity and conductivity of the optimized nanoemulsion were found to be 80.71 ± 2.75 nm, 0.217 ± 0.009, -12.60 ± 0.10 mV, 96.00 ± 3.05 %, 6.48 ± 0.28, 1.36 ± 0.03, 30.12 ± 0.10 mPas and 214.28 ± 2.79 μS/cm respectively. Surface morphology demonstrated that nanoemulsion possessed spherical and globular nature of the particle which showed 3.4 times and 1.5 times enhancement in drug permeation in the case of BRM and GSH respectively as compared to suspension. MTT assay done on neuro-2a cell lines revealed that nanoemulsion was safe for intranasal delivery. Behavioural studies were carried out to prove the efficacy of optimized nanoemulsion in PD using forced swimming test, locomotor activity test, catalepsy test, rota-rod test, and akinesia test in Wistar rats. The outcomes of the behavioural studies revealed that BRM and GSH loaded nanoemulsion treatment showed significant improvement in behavioural activities of PD (haloperidol-induced) rats after intranasal administration. This study concluded that BRM and GSH loaded nanoemulsion could be promising for the combined and synergistic anti-parkinson effect for the effective management of PD.
... %transmittance was investigated to assess the droplet size as well as the stability of the formulation because any change in %transmittance leads to a change in droplet size as well as the size distribution of the formulation [21]. The optimized AZL-NE formulation was found to be 93.46 ± 1.13%, which is close to 100, implying that the formulation was transparent, clear, and able to transmit the light. ...
... After that, the obtained mixture was micro-titrated with distilled water to provide an emulsion with coarse droplets. To convert the coarse emulsion into nanoemulsion, ultrasonication was employed for 30-90 s, using the ultrasonic processor of 30 kHz (Hielscher-Ultrasound Technology, Germany) [21]. Ultrasonication may cause cavitation, resulting in heat production; hence, the sonication was performed in seconds [32]. ...
... Then, the DSC was performed over the temperature of 30 to 300 °C, along with a heating rate of 10 °C/min in an air environment. The flow of nitrogen gas was maintained at 60 mL/min [21]. ...
The present research attempted to design and develop a nanoemulsion formulation of azilsartan medoxomil to improve its aqueous solubility and intestinal permeability. Based on the solubility profile, ethyl oleate, tween 80, and Transcutol P were selected as the oil phase, surfactant, and co-surfactant, respectively. Central composite design (CCD) suggested an optimized azilsartan medoxomil- nanoemulsion formulation (optimized AZL-NE formulation) with 1.25% oil, 15.73% Smix, and 90 s ultrasonication time; it was found to have the droplet size, percentage transmittance, and % cumulative drug release (%CDR) of 71.5 nm, 93.46 ± 1.13%, and 90.14 ± 0.94%, respectively. Furthermore, it exhibited a 0.141 polydispersity index, 34.05 mV zeta potential, a 1.413 ± 0.03 refractive index, 6.68 ± 0.22 pH, 28.17 ± 0.52 cps viscosity, and a 96.98 ± 0.94% percentage drug content. Transmission electron microscopy (TEM) assessed the nano-sized spherical shape, and a differential scanning calorimeter (DSC) assessed the solubilization of the drug in the optimized formulation. The %CDR was 1.71 times higher and the % cumulative drug permeation was 2.1 times higher for the optimized AZL-NE formulation than for the drug suspension through an intestinal segment of a rat, which was also supported by confocal laser scanning microscopy (CLSM) studies. Thus, the nanoemulsion formulation of azilsartan medoxomil ensured the enhancement of the drug availability in the body.
... Finally, to obtain the lidocaine-loaded nanoemulsions, the prepared coarse nanoemulsion was sonicated using a UP50H ® ultrasonic processor (Hielscher-Ultrasonics, Teltow, Germany) with 40% amplitude for 60 s. The prepared nanoemulsion was characterized for selected parameters, such as particle size, PDI and percent transmittance to select the optimized nanoemulsion [32]. ...
A wound refers to a cut or blow that may result in primary or secondary infection or even death, if untreated. In the current study, we have explored the wound-healing properties of lidocaine nanogel, owing to its antioxidant and neutrophilic modulatory potential. Initially, the pre-formulation study was performed and then using central composite design (CCD) fabrication and the characterization of lidocaine-loaded nanoemulsion was carried out. After the preparation of a nanogel of lidocaine-loaded nanoemulsion, it was evaluated on various parameters, such as pH, spreadability, extrudability, drug content, in vitro drug release, dermatokinetic study and in vivo skin safety. Based on the pre-formulation study, the maximum solubility of lidocaine was found in oleic acid (324.41 ± 4.19 mg/mL) and in Tween 20 (192.05 ± 8.25 mg/mL), selected as a suitable emulsifier. The refractive index of the optimized nanoemulsion was found to be 1.35 ± 0.04, the electrokinetic potential was recorded as −15.47 ± 0.95 mV. The pH, spreadability and extrudability of nanogel was found to be 6.87 ± 0.51, 73.32 ± 4.59 gm.cm/sec and 107.41 ± 6.42 gm/cm2, respectively. The percentage of the cumulative drug content and drug release from nanogel was found to be 99.94 ± 1.70% and 93.00 ± 4.67%, respectively. Moreover, dermatokinetic study showed significantly (p < 0.0005) improved drug deposition and the in vivo skin safety study showed no sign of dermal erythematous lesion or any visible damage. Stability studies also testified the secureness of nanogel after storage in a prescribed environmental condition. Thus, this study provides substantial evidence for healing wounds effectively and the further evaluation of the in vivo model. The patent related to this work was published in the Indian Official Journal of the Patent Office (Issue number: 20/2022).
... Different O/W NEs were investigated for this administration route. 86,211,212 Cationic NEs have been developed in order to increase the residence time in the nasal cavity for brain targeting. 59,213 In other studies, mucoadhesive agents have been incorporated into the surface of NE droplets for the same purpose. ...
Nanoemulsions (NEs) are thermodynamically unstable systems comprising at least two immiscible liquid phases with diameters within the “nanometric” range, generally under 200 nm. Moreover, NEs do not require a large amount of surfactant and can be diluted with water without changing the droplet size distribution. For the preparation of NEs, the use of low energy emulsification methods or of high-pressure homogenizers can be applied. NEs exhibit a growing interest in various fields, such as chemistry, materials sciences, and in pharmaceutical and medical sciences. In the pharmaceutical field, NEs have been developed to improve the delivery of hydrophobic active principles. The macromolecular surfactants can provide longer and better emulsion stability with respect to the conventional low molecular surfactants, which can be toxic and skin irritants due to much slower desorption kinetics at the interface of the droplet.
... In a S mix ratio of 4:1, the maximum nanoemulsion region was obtained due to an increase in self-emulsification, decreased interfacial tension and rapid dispersion of oil in the aqueous phase. However, with the increment in the S mix to a ratio of 5:1, the nanoemulsion region reduced, which indicated that a further increase in the surfactant concentration did not enhance the emulsification region [66]. In the case of the S mix ratio of 1:2, the decreased nanoemulsion region obtained with slimy liquid phase indicated that more surfactant was necessary to emulsify the oil phase. ...
The solid self-nanoemulsifying drug delivery system (s-SNEDDS) is a growing platform for the delivery of drugs via oral route. In the present work, tamoxifen (TAM) was loaded in SNEDDS with resveratrol (RES), which is a potent chemotherapeutic, antioxidant, anti-inflammatory and P-gp inhibitor for enhancing bioavailability and to obtain synergistic anti-cancer effect against breast cancer. SNEDDS were developed using capmul MCM as oil, Tween 80 as surfactant and transcutol-HP as co-surfactant and optimized by central composite rotatable design. Neusilin US2 concentration was optimized for adsorption of liquid SNEDDS to prepare s-SNEDDS. The developed formulation was characterized and investigated for various in vitro and cell line comparative studies. Optimized TAM-RES-s-SNEDDS showed spherical droplets of a size less than 200 nm. In all in vitro studies, TAM-RES-s-SNEDDS showed significantly improved (p ˂ 0.05) release and permeation across the dialysis membrane and intestinal lumen. Moreover, TAM-RES-s-SNEDDS possessed significantly greater therapeutic efficacy (p < 0.05) and better internalization on the MCF-7 cell line as compared to the conventional formulation. Additionally, oral bioavailability of TAM from SNEDDS was 1.63 folds significantly higher (p < 0.05) than that of combination suspension and 4.16 folds significantly higher (p < 0.05) than TAM suspension. Thus, findings suggest that TAM- RES-s-SNEDDS can be the future delivery system that potentially delivers both drugs to cancer cells for better treatment.
... Finally, in order to obtain the TTO-NO-NE, the prepared coarse NE was sonicated using probe sonicator (SONICS Vibracell TM , Sonics and Materials, Inc, USA) with 40% amplitude for 60 s. The various prepared NEs as per the runs given by the Box-Behnken design was characterized on selected parameters such as globule size and PDI, and an optimized TTO-NO-NE was selected [20]. ...
This study was designed to develop neem oil nanoemulsion of tea tree oil (TTO-NO-NE) using design of experiment based Box–Behnken design, which provided thermodynamic stable NE with globule size of 174 nm, and PDI 0.28, respectively. Whereas the zeta potential of optimized NE has occurred as − 20 mV with spherical and non-segregated in shape. Next, TTO-NO-NE-loaded nanogel and conventional gel were prepared, and initially, a comparative evaluation was performed for homogeneity, pH, spreadability, extrudability, and drug content. Furthermore, in vitro release pattern, ex vivo dermatokinetic profile, in vivo skin safety study, and stability of nanogel was determined. Comparative in vitro release study showed significantly sustained release of drug from nanogel (p < 0.005) when compared to the conventional gel. Simultaneously, a comparative ex vivo dermatokinetic study demonstrated significantly maximum drug deposition for nanogel (p < 0.05) than conventional gel. Moreover, in vivo skin safety study exhibited no signs of toxicity in terms of zero scoring for nanogel and was considered safe for future use. Finally, a stability study showed no significant (p > 0.05) variation in the pH, spreadability, extrudability, and drug content of optimized nanogel, which claims good stability for nanogel after 6 months of storage in prescribed environmental conditions. Thus, it can be concluded that the developed novel nanogel is a promising therapeutic asset that can mitigate dermal infections effectively.
... The biodistribution analysis showed the ability of this system to transfer the drug from the nose to the brain bypassing the BBB, and г-scintigraphy showed a high bromocriptine concentration in the brain of mice treated with BRC-CS-NPs [424]. The significant improvement in the behavioral activity of rats simulating haloperidol-induced Parkinson's disease was also found after intranasal administration of a nanoemulsion loaded with bromocriptine and glutathione GSH (thiol-reducing agent with antioxidant properties) obtained using ultrasound technology [425]. ...
The treatment of central nervous system (CNS) malignancies, including brain cancers, is limited by a number of obstructions, including the blood-brain barrier (BBB), the heterogeneity and high invasiveness of tumors, the inaccessibility of tissues for early diagnosis and effective surgery, and anti-cancer drug resistance. Therapies employing nanomedicine have been shown to facilitate drug penetration across the BBB and maintain biodistribution and accumulation of therapeutic agents at the desired target site. The application of lipid-, polymer-, or metal-based nanocarriers represents an advanced drug delivery system for a growing group of anti-cancer chemicals. The nanocarrier surface is designed to contain an active ligand (cancer cell marker or antibody)-binding structure which can be modified to target specific cancer cells. Glioblastoma, ependymoma, neuroblastoma, medulloblastoma, and primary CNS lymphomas were recently targeted by easily absorbed nanocarriers. The metal- (such as transferrin drug-loaded systems), polymer- (nanocapsules and nanospheres), or lipid- (such as sulfatide-containing nanoliposomes)-based nano-vehicles were loaded with apoptosis- and/or ferroptosis-stimulating agents and demonstrated promising anti-cancer effects. This review aims to discuss effective nanomedicine approaches designed to overcome the current limitations in the therapy of brain cancers and age-dependent neurodegenerative disorders. To accent current obstacles for successful CNS-based cancer therapy, we discuss nanomedicine perspectives and limitations of nanodrug use associated with the specificity of nervous tissue characteristics and the effects nanocarriers have on cognition.
... It was patented in 1921 and first marketed under the brand name Parlodel to treat endocrine related diseases like prolactin hormone suppression 8 . Bromocriptine has been used extensively for clinical purposes for more than 30 years for the treatment of Parkinsonism, hyperprolactinemia, pituitary adenomas and galactorrhoea [9][10][11][12][13] . With the passage of time extensive research evolved with many new potential benefits of the bromocriptine such as treatment of acromegaly 14 , paripartum cardiomyopathy 15 , neuroleptic malignant syndrome 16 , extrapyramidal disorders affected by medications, diabetes mellitus 17 as well as alcohol withdrawal syndrome and much more 18 . ...
Bromocriptine is a sympatholytic dopamine D2 receptor agonist with remarkable bioactivities. It has been used clinically as a prescription drug for more than 30 years to treat hyperprolactinemia associated conditions, parkinson’s disease, acromegaly, prolactinomas and other pituitary hormone dependent adenomas and recently diabetes mellitus as well as various other disorders. Long‐term treatment with bromocriptine has minimal or no harmful effects on renal, hepatic, cardiac or hematologic functions. This review article was planned to study the hypothetical and proposed mechanism of action as well as brief discussion about its safety issues and tolerability. Bromocriptine represents an attractive option with high efficacy and safety profile for hyperprolactinemia associated conditions, acromegaly, Parkinsonism, type 2 diabetes mellitus (T2DM) and for various other diseases in a variety of dosage forms for best possible beneficial effects. It appeared to be an effective and safe addition to the pharmacopoeia of drugs for the treatment of vast variety of diseases as monotherapy or in combination with other drugs.
... The scattering angle was maintained at 90 • , whereas the temperature was maintained around 25 ± 2 • C. For the formulations that were not diluted, distilled water was used as a blank before experimenting. Experiments were performed in triplicate [43,44]. ...
In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via the ultrasonication technique and optimized using a central composite rotatable design (CCRD). The optimized NLC exhibited the following properties: droplet size, 84.17 to 86.71 nm; PDI, 0.258 to 0.271; zeta potential, −8.15 to −8.21 mV; and % EE, 87.58 to 88.21%. The in vitro drug release profile showed the supremacy of the TQ-NGN-NLC in comparison to the NGN suspension, with a cumulative drug release of 82.42 ± 1.88% from the NLC and 38.20 ± 0.82% from the drug suspension. Ex vivo permeation study displayed a 2.21-fold increase in nasal permeation of NGN from the NLC compared to the NGN suspension. DPPH study showed the better antioxidant potential of the TQ-NGN-NLC in comparison to NGN alone due to the synergistic effect of NGN and TQ oil. CLSM images revealed deeper permeation of the NGN-NLC (39.9 µm) through the nasal mucosa in comparison to the NGN suspension (20 µm). Pharmacodynamic studies, such as the forced swim test and the locomotor activity test, were assessed in the depressed rat model, which revealed the remarkable antidepressant effect of the TQ-NGN-NLC in comparison to the NGN suspension and the marketed formulation. The results signify the potential of the TQ-enriched NGN-NLC in enhancing brain delivery and the therapeutic effect of NGN for depression treatment.
... The effectiveness of the SEL and QUR were evaluated on the 15th day by forced swimming test, muscle coordination test, locomotor activity test, akinesia test and catalepsy. The dose (0.04 mg/250 g) of each sample of suspensions and formulation was given to the assigned groups (Ashhar et al., 2021;Gupta et al., 2018;Kumar et al., 2016). ...
In the present study, SEL was loaded in a lipid nanocarrier (LNC) formulation with a P-gp pump inhibitor i.e., Quercetin (QUR) for improving the bioavailability of the SEL in the brain via the oral route. SEL-QUR LNC was formulated using modified emulsiosonication method and optimized using central composite rotatable design (CCRD) design. The results showed that optimized SEL-QUR LNC formulation was spherical with globule size, polydispersity index, entrapment efficiency and zeta potential within the range of 92.46 to 95.34 nm, 0.239 to 0.248, 88.94 to 91.26 %, and -6.21 to -7.75 mV respectively. A 4-fold and 6-fold increase was observed in the permeation of SEL from SEL-QUR LNC across the gut sac in comparison with SEL-QUR and SEL suspensions respectively. CLSM images showed 2-fold deeper permeation of SEL across intestinal membrane demonstrating excellent in vivo prospect of the formulation. The behavioural studies including forced swimming, muscle coordination, locomotor activity, akinesia, and catalepsy were performed in the haloperidol-induced PD rats that demonstrated increased efficacy of the formulation in contrast to the SEL-QUR and SEL suspensions. These studies concluded that developed LNC formulation loaded SEL with P-gp inhibitor had the potential in improving bioavailability of SEL in the brain via oral route.
In this study, the ratio, dosage of surfactants, and emulsification process were selected. The prepared fenpropathrin nanoemulsion exhibited suitable stability and remarkable insecticidal activity against Helicoverpa armigera. The optimal formula in compliance with the standard of FAO was obtained. Fenpropathrin (10 wt.%) and ethoxylated castor oil (EL-10: EL-40 = 2: 1, 9 wt.%) were dissolved, mixed with hydrocarbon solvent (S-200, 8 wt.%) and replenished with deionized water to obtain 100%. The nanoemulsion droplets showed small contact angle and high adhesion work onto corn leaves, indicating that the nanoemulsions exhibited excellent wetting, adhesion and stretching capabilities. Compared with commercial emulsifiable concentrate (EC), the nanoemulsion had lower LC50 (50.01 mg L⁻¹) against the third instar larva of Helicoverpa armigera. This was due to the body of larvae becoming completely darkened, shriveled and incapacitated shortly after treatment. The LC50 of the fenpropathrin nanoemulsion on Eisenia fetida was 96.60 and 47.99 mg kg⁻¹ after 7 and 14 days, respectively. This indicated low toxicity to E. fetida. The L02 cell viability after 24 and 48 h of nanoemulsion treatment was 85.32% and 68.95%, respectively. In addition, the fenpropathrin nanoemulsion showed a lower apoptosis rate against L02 cells (8.52%) than EC (65.35%) after 24 h, indicating that the nanoemulsion had low cytotoxicity against L02 cells. In general, the utilization and environmental performance of pesticides were improved, with less cytotoxicity. This study will facilitate the preparation and application of nanoemulsions for lipophilic pesticide to enhance insecticidal activity, lower cytotoxicity and improve environmental compatibility.
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) are two of the most complex and sophisticated concierges that defend the central nervous system (CNS) by numerous mechanisms. While they maintain the neuro-ecological homeostasis through the regulated entry of essential biomolecules, their conservative nature challenges the entry of most of the drugs intended for CNS delivery. Targeted delivery challenges for a diverse spectrum of therapeutic agents/drugs (non-small molecules, small molecules, gene-based therapeutics, protein and peptides, antibodies) are diverse and demand specialized delivery and disease-targeting strategies. This review aims to capture the trends that have shaped the current brain targeting research scenario. This review discusses the physiological, neuropharmacological, and etiological factors that participate in the transportation of various drug delivery cargoes across the BBB/BCSF and influence their therapeutic intracranial concentrations. Recent research works spanning various invasive, minimally invasive, and non-invasive brain- targeting approaches are discussed. While the pre-clinical outcomes from many of these approaches seem promising, further research is warranted to overcome the translational glitches that prevent their clinical use. Non-invasive approaches like intranasal administration, P-glycoprotein (P-gp) inhibition, pro-drugs, and carrier/targeted nanocarrier-aided delivery systems (alone or often in combination) hold positive clinical prospects for brain targeting if explored further in the right direction.
Synaptic plasticity is an important basis of learning and memory and participates in brain network remodelling after different types of brain injury (such as that caused by neurodegenerative diseases, cerebral ischaemic injury, posttraumatic stress disorder (PTSD), and psychiatric disorders). Therefore, improving synaptic plasticity is particularly important for the treatment of nervous system-related diseases. With the rapid development of nanotechnology, increasing evidence has shown that nanoparticles (NPs) can cross the blood-brain barrier (BBB) in different ways, directly or indirectly act on nerve cells, regulate synaptic plasticity, and ultimately improve nerve function. Therefore, to better elucidate the effect of NPs on synaptic plasticity, we review evidence showing that NPs can improve synaptic plasticity by regulating different influencing factors, such as neurotransmitters, receptors, presynaptic membrane proteins and postsynaptic membrane proteins, and further discuss the possible mechanism by which NPs improve synaptic plasticity. We conclude that NPs can improve synaptic plasticity and restore the function of damaged nerves by inhibiting neuroinflammation and oxidative stress, inducing autophagy, and regulating ion channels on the cell membrane. By reviewing the mechanism by which NPs regulate synaptic plasticity and the applications of NPs for the treatment of neurological diseases, we also propose directions for future research in this field and provide an important reference for follow-up research.
Parkinson's disease (PD) is triggered by the formation of free radicals in dopaminergic neurons, which results in oxidative stress-induced neurodegeneration. The objective of the work was to relieve oxidative stress by employing intranasal delivery of Bromocriptine Mesylate (BRM) and Glutathione (GSH) loaded nanoemulsion for the better management of PD. The depth of permeation of the nanoemulsion was assessed through confocal laser scanning microscopy (CLSM) which revealed higher nanoemulsion permeation in contrast to suspension. Biocompatibility of nanoemulsion was confirmed by nasal cilio toxicity study. The DPPH study showed that the nanoemulsion had significant antioxidant activity. Biochemical estimation studies in Wistar rats were carried out in order to determine the effect of nanoemulsion on oxidative stress. The levels of GSH, superoxide dismutase (SOD), and catalase (CAT) were significantly enhanced; and the level of thiobarbituric acid reactive substances (TBARS) was significantly reduced after the intranasal administration of nanoemulsion in the haloperidol-induced model of PD. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also determined which reduced significantly after the administration of nanoemulsion. The oxidative stress levels were lowered with nanoemulsion, showing the combined antioxidant capability of BRM and GSH. The neuroprotective effect of the prepared nanoemulsion was confirmed by histopathological studies. Pharmacokinetic study revealed a higher concentration of BRM and GSH in the brain of Wistar rats after intranasal administration of nanoemulsion with a higher Brain/Plasma ratio. A higher value of AUC(0-8) of nanoemulsion in the brain after intranasal administration revealed that BRM and GSH remained in the brain for a longer period due to sustained release from nanoemulsion. According to the findings, BRM and GSH loaded nanoemulsion has the potential to provide a combined and synergistic anti-oxidant effect for efficient management of PD.
Phosphatidylcholine-soybean protein isolate (PC-SPI) nanoemulsions were prepared by ultrasonication. The effects of preparation conditions (SPI and PC addition, ultrasonic power and time) on the structural properties of the nanoemulsions and their storage stability were investigated. The results showed that the most optimal adsorption capacity and adsorption tightness at the oil–water interface under optimal conditions (1.5% SPI, 0.20% PC, 500 W ultrasonic power and 9 min ultrasonic time) were exhibited by the SPI-PC conjugate, which demonstrated that this nanoemulsions can be categorized as a high-quality emulsion suitable for research. To test its stability, and the high-quality nanoemulsion of β-carotene was stored. After degradation of the nanoemulsions during storage, β-carotene was released. The β-carotene retention rate of the high-quality emulsion was maintained above 86% at different temperatures in the absence of light for up to 30 days. This study provides new information for the development of transport and stability systems for nanoemulsions.
Replacing synthetic surfactants by natural alternatives when formulating nanoemulsions has gained attention as a sustainable approach. In this context, nanoemulsions based on sweet almond oil and stabilized by saponin from Quillaja bark with glycerol as cosurfactant were prepared by the high-pressure homogenization method. The effects of oil/water (O/W) ratio, total surfactant amount, and saponin/glycerol ratio on their stability were analyzed. The formation and stabilization of the oil-in-water nanoemulsions were analyzed through the evaluation of stability over time, pH, zeta potential, and particle size distribution analysis. Moreover, a design of experiments was performed to assess the most suitable composition based on particle size and stability parameters. The prepared nanoemulsions are, in general, highly stable over time, showing zeta potential values lower than −40 mV, a slight acid behavior due to the character of the components, and particle size (in volume) in the range of 1.1 to 4.3 μm. Response surface methodology revealed that formulations using an O/W ratio of 10/90 and 1.5 wt% surfactant resulted in lower particle sizes and zeta potential, presenting higher stability. The use of glycerol did not positively affect the formulations, which reinforces the suitability of preparing highly stable nanoemulsions based on natural surfactants such as saponins.
Development of nanoemulsion is gaining considerable attention for use in delivering hydrophobic constituents such as clove oil in foods and agriculture system. The small size of the oil droplets in the nanoemulsion system offers many advantages such as high stability, optical clarity, and improved water solubility and bioactivity. This research was aimed at investigating the effect of incorporation of carrier oil and co-solvent on the formation of clove nanoemulsion. Clove oil-loaded nanoemulsions were prepared by a low energy – phase inversion technique involving a carrier oil (medium chain triglyceride/MCT), at different ratios to the clove oil (1:2, 1:1, 2:1), a co-solvent (glycerol) at ratios of 0 and 1:1 to the mixture of clove oil and MCT and a non-ionic surfactant (Tween 80)at a ratio of 1:1, with two concentration levels of mixture of clove oil and MCT (5% and 10%). The formation and characteristics of nanoemulsion were evaluated including particle size, polydispersity index, zeta potential, and freeze-thaw stability, as well as their possible mechanisms of destabilization. Particle sizes ranged from 45.98 to 220 nm with narrow ranges of polydispersity index (0.072 – 0.286) and zeta potentials (-12.8 and - 22.6 mV). Incorporation of carrier oil at low proportions gave smaller size of oil droplets, and the presence co-solvent enhanced nanoemulsion stabilization. Creaming accompanied by oiling- off was found upon destabilization of nanoemulsion with different rate and appearance as influenced by nanoemulsion composition. This study provides important information about stabilization of nanoemulsion by incorporating carrier oil and co-solvent suitable for foods and agrochemical formulation.
Nanoemulsions (NEs) are colloidal dispersions of two immiscible liquids, oil and water, in which one is dispersed in the other with the aid of a surfactant/co-surfactant mixture, either forming oil-in-water (o/w) or water-in-oil (w/o) nanodroplets systems, with droplets 20–200 nm in size. NEs are easy to prepare and upscale, and they show high variability in their components. They have proven to be very viable, non-invasive, and cost-effective nanocarriers for the enhanced transdermal delivery of a wide range of active compounds that tend to metabolize heavily or suffer from undesirable side effects when taken orally. In addition, the anti-microbial and anti-viral properties of NE components, leading to preservative-free formulations, make NE a very attractive approach for transdermal drug delivery. This review focuses on how NEs mechanistically deliver both lipophilic and hydrophilic drugs through skin layers to reach the blood stream, exerting the desired therapeutic effect. It highlights the mechanisms and strategies executed to effectively deliver drugs, both with o/w and w/o NE types, through the transdermal way. However, the mechanisms reported in the literature are highly diverse, to the extent that a definite mechanism is not conclusive.
Purpose:
The present study is an attempt to develop a vitamin E loaded naringenin (NRG) Nanoemulsion (NE) for direct nose-to-brain delivery for better management of Parkinson's disease (PD).
Methods:
The optimized NE was evaluated for efficacy in PD using multiple behavioral studies (including narrow beam test, muscular coordination test, grip strength test, forced swimming test, and akinesia test) in a rat model. Optimized formulation was evaluated for droplet size, polydispersity index (PDI), refractive index, transmittance, zeta potential, and viscosity.
Results:
Optimized NE had a droplet size of 38.70 ± 3.11nm, PDI of 0.14 ± 0.0024, refractive index of 1.43 ± 0.01, transmittance of 98.12 ± 0.07 %, zeta potential of - 27.4 ± 0.14 mV, and viscosity of 19.67 ± 0.25 Pa s. Behavioral studies showed that 6-OHDA induced PD in rats were successfully reversed when administered with NRG NE intranasally along with the levodopa. While the levels of GSH and SOD were significantly higher, levels of MDA were significantly lower in the group treated with NRG NE via intranasal route along with levodopa.
Conclusion:
Encouraging results from current study provide evidence for possible efficacy of a novel noninvasive intranasal delivery system of NRG for management of PD related symptoms.
The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding the first-pass effect and bypassing the BBB. Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity. Nanoemulsions are formulations belonging to the field of nanomedicine. They consist of emulsions (commonly oil in water) stabilized by one or more surfactants—and eventually co-surfactants—delivered in droplets of small dimensions (sizes of 100–300 nm or less) with a high surface area. A mucoadhesive polymer such as chitosan can be added to the formulation to impair rapid nasal clearance. Nanoemulsions represent promising formulations to deliver drugs directly into the brain through the intranasal route. Therefore, they can be used as a possible alternative to oral administration, avoiding problems such as low solubility in water, poor bioavailability, enzymatic degradation and slow onset of action. This review focuses the present situation in literature regarding the use of nanoemulsions for nose-to-brain targeting, with particular attention to recent publications. Nasal nanoemulsions appear to be effective, non-invasive and safe drug delivery systems to achieve brain targeting for the treatment of neurological diseases.
Dopamine antagonist drugs have profound effects on locomotor activity. In particular, the administration of the D2 antagonist haloperidol produces a state that is similar to catalepsy. In order to confirm whether the modulation of the dopaminergic activity produced by haloperidol can act as an unconditioned stimulus, we carried out two experiments in which the administration of haloperidol was repeatedly paired with the presence of distinctive contextual cues that served as a Conditioned Stimulus. Paradoxically, the results revealed a dose-dependent increase in locomotor activity following conditioning with dopamine antagonist (Experiments 1) that was susceptible of extinction when the conditioned stimulus was presented repeatedly by itself after conditioning (Experiment 2). These data are interpreted from an associative perspective, considering them as a result of a classical conditioning process.
Using mixed nonionic surfactants Span/Tween, we investigated the effects of HLB value on the O/W emulsion stability and rheological behaviors. In this study, MS-01 (Span 60 & Tween 60) and MS-02 (Span 80 & Tween 80) was used as mixed nonionic surfactants. We considered required HLB value 10.85 and selected corresponding HLB value range 8–13. The droplet size distributions, droplet morphology, rheological properties, zeta-potential and creaming index of the emulsion samples were obtained to understand the mechanism and interaction of droplets in O/W emulsion. The results indicated that optimal HLB number for O/W emulsions was 10.8 and 10.7, while using MS-01 surfactant and MS-02 surfactant respectively. MS-01 (HLB = 10.8) sample and MS-02 (HLB = 10.7) sample showed smallest droplet size and highest zeta-potential value. Rheological properties are measured to understand rheological behaviors of emulsion samples. All emulsion samples showed no phase separation until 30 days storage time at 25 °C. © 2018 The Korean Society of Industrial and Engineering Chemistry
Which scientist has never heard of glutathione (GSH)? This well-known low-molecular-weight tripeptide is perhaps the most famous natural antioxidant. However, the interest in GSH should not be restricted to its redox properties. This multidisciplinary review aims to bring out some lesser-known aspects of GSH, for example, as an emerging tool in nanotechnologies to achieve targeted drug delivery. After recalling the biochemistry of GSH, including its metabolism pathways and redox properties, its involvement in cellular redox homeostasis and signaling is described. Analytical methods for the dosage and localization of GSH or glutathiolated proteins are also covered. Finally, the various therapeutic strategies to replenish GSH stocks are discussed, in parallel with its use as an addressing molecule in drug delivery.
Objective: The aim of this study was to formulate and in vitro evaluate fast dissolving oral film of practically insoluble bromocriptine mesylate to enhance its solubility and to improve its oral bioavailability by avoiding first pass effect as well as to produce an immediate release action of the drug from the film for an efficient management of diabetes mellitus type II in addition to an improvement of the patient compliance to this patient-friendly dosage form.Methods: The films were prepared by the solvent casting method using hydroxypropyl methylcellulose of grades (E3, E5, E15), polyvinyl alcohol (PVA), pectin and gelatin as film-forming polymers in addition to polyethene glycol 400 (PEG400), propylene glycol (PG) and glycerin were used as a plasticizer. Poloxamer 407 was used as a surfactant, sodium saccharin as a sweetening agent, citric acid as a saliva stimulating agent, vanilla as a flavouring agent and crospovidone as a super disintegrant. The prepared films then tested for physical characterization, thickness, weight uniformity, mechanical characteristics (folding endurance, tensile strength, percent elongation and Young's modulus), surface pH, in vitro disintegration time, drug content and an in vitro drug release.Results: Films were found to be satisfactory when evaluated for physical characterization, thickness, weight uniformity, mechanical tests, in vitro disintegration time, folding endurance, drug content and an in vitro drug release. The surface pH of all the films was found to be neutral or minor change. Films in vitro drug release studies were also done using USP dissolution apparatus type II (paddle type). The in vitro drug release profile in the optimized formulation F14 was gave 86.8 % of drug released at 2 min. The optimized formulation F14 was also showed satisfactory pH (6.2±0.2), drug content (99.2±0.5%), the disintegration time of 9.2±0.1 seconds and the time needed for 80% of medication to be released (T80 %) was 1.35 minute.Conclusion: The bromocriptine mesylate fast dissolving oral film was formulated. The given film disintegrates within nine seconds which release the drug rapidly and gives an action.
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. For decades, the unilateral 6‑hydroxydopamine (6‑OHDA) rat model has been employed to investigate the pathogenesis and therapy of PD. However, the behavior and associated pathological features of the model long term have not previously been described dynamically. In the present study, the unilateral model was established by 6‑OHDA injection in the striatum. The PD rat model was determined 2 weeks following surgery, according to the apomorphine (APO)‑induced rotations, cylinder, rotarod and open field tests. TH‑positive neurons and fibers in the substantia nigra pars compacta (SNpc) and striatum, respectively, and glial activation in the SNpc, determined by glial fibrillary acidic protein (GFAP) expression for astrocytes and CD11b (Mac1) expression for microglia, were detected by immunohistological staining. Correlation analysis was performed to understand the association between PD‑associated behavior and pathology. The behavioral impairment progressively deteriorated during the process of experiment. In addition, the decrease in TH‑positive neurons was associated with an increase in GFAP‑ and Mac1‑positive cells in the SNpc. Linear regression analysis indicated the association between behavioral and pathological changes. The results of the present study indicate that the APO‑induced rotation, cylinder and rotarod tests are all sensitive and reliable strategies to predict the loss of TH+ neurons. These results provide a potential intervention time‑point and a comprehensive evaluation index system for assessment of PD therapeutic strategies using the hemiparkinsonian rat.
Nanoemulsions have attracted much attention due to their applications especially in plant protection field. The aim of this study is to develop and characterize oil-in-water (O/W) phenazine extract nanoemulsions for controlling Ganoderma boninense PER71. To this purpose, a phase diagram (PD) was constructed based on non-ionic surfactant Tween80, oil carrier E2126 and water, and 30 % crude phenazine extract as active ingredient by low-energy method. After constructing PD, six formulations were examined for its thermostability and stability over time as primary screening. Four formulations were selected to proceed in physiochemical characterizations. The characterized formulations have a mean droplet size ranging from 130.54 to 309.9 nm with polydispersity index varied between 0.32-0.97. The larger drop size (309.9 nm) shifted to a smaller size of 130.54 nm with decrease in the concentration of oil carrier Emereen 2126. The zeta potential of all formulation is yet stable with the value ranged from -11.8 to -16 mV. The surface tension was around 30.82 to 30.88 mN/m. The fungicidal effect of the formulated phenazine nanoemulsion was checked against G. boninense PER71. Nanoemulsion with 174.43 nm size was obtained at a ratio 5:5:90, and it was found to be stable in terms of polydispersity index (0.6), zeta potential (-16.0 mV) and surface tension (30.88 mN/m), and effective in controlling G. boninense PER71 at 70.74 %. This is the first time that a phenazine extract nanoemulsion has been reported. The results obtained might corroborate to the application of phenazine extract nanoemulsion as potential candidate for controlling G. boninense PER71.
Glutathione (GSH) is depleted early in the course of Parkinson’s disease (PD), and deficiency has been shown to perpetuate oxidative stress, mitochondrial dysfunction, impaired autophagy, and cell death. GSH repletion has been proposed as a therapeutic intervention. The objective of this study was to evaluate whether intranasally administered reduced GSH, (in)GSH, is capable of augmenting central nervous system GSH concentrations, as determined by magnetic resonance spectroscopy in 15 participants with mid-stage PD. After baseline GSH measurement, 200 mg (in)GSH was self-administered inside the scanner without repositioning, then serial GSH levels were obtained over ~1 h. Statistical significance was determined by one-way repeated measures analysis of variance. Overall, (in)GSH increased brain GSH relative to baseline (P<0.001). There was no increase in GSH 8 min after administration, although it was significantly higher than baseline at all of the remaining time points (P<0.01). This study is the first to demonstrate that intranasal administration of GSH elevates brain GSH levels. This increase persists at least 1 h in subjects with PD. Further dose–response and steady-state administration studies will be required to optimize the dosing schedule for future trials to evaluate therapeutic efficacy.
Parkinson's disease is a neurodegenerative disorder characterized by motor impairment, cognitive decline and psychiatric symptoms. Schinus terebinthifolius Raddi, Anacardiaceae, had been studied for its anti-inflammatory and antioxidant properties, and in this study, the stem bark was evaluated for the neuroprotective effects on behavioral and biochemical alterations induced by administrations of rotenone in rats. Behavioral evaluations were performed using open-field and rotarod. The in vitro and in vivo antioxidant activities were determined by the DPPH radical scavenging activity and lipid peroxidation method respectively. The administration of rotenone (3mg/kg, s.c.) produced hypolocomotion, increase of immobility and muscle incoordination, while the treatment with S. terebinthifolius stem bark extract (150, 300 and 600mg/kg p.o.) for seven days prevented rotenone-induced dysfunctional behavior. Biochemical analysis of the substantia nigra, striatum and cortex revealed that rotenone administration significantly increased lipid peroxidation, which was inhibited by treatment with all doses of S. terebinthifolius. The results suggested neuroprotective effect of S. terebinthifolius possibly mediated through its antioxidant activity, indicating a potential therapeutic benefit of this species in the treatment of Parkinson's disease.
Resveratrol, a potent natural antioxidant, possesses a wide range of pharmacological activities, but its oral bioavailability is very low due to its extensive hepatic and presystemic metabolism. The aim of the present study was to formulate a kinetically stable nanoemulsion (o/w) using vitamin E:sefsol (1:1) as the oil phase, Tween 80 as the surfactant and Transcutol P as the co-surfactant for the better management of Parkinson's disease. The nanoemulsion was prepared by a spontaneous emulsification method, followed by high-pressure homogenization. Ternary phase diagrams were constructed to locate the area of nanoemulsion. The prepared formulations were studied for globule size, zeta potential, refractive index, viscosity, surface morphology and in vitro and ex vivo release. The homogenized formulation, which contained 150 mg ml(-1) of resveratrol, showed spherical globules with an average globule diameter of 102 ± 1.46 nm, a least poly dispersity index of 0.158 ± 0.02 and optimal zeta potential values of -35 ± 0.02. The cumulative percentage drug release for the pre-homogenized resveratrol suspension, pre-homogenized nanoemulsion and post-homogenized nanoemulsion were 24.18 ± 2.30%, 54.32 ± 0.95% and 88.57 ± 1.92%, respectively, after 24 h. The ex vivo release also showed the cumulative percentage drug release of 85.48 ± 1.34% at 24 h. The antioxidant activity determined by using a DPPH assay showed high scavenging efficiency for the optimized formulation. Pharmacokinetic studies showed the higher concentration of the drug in the brain (brain/blood ratio: 2.86 ± 0.70) following intranasal administration of the optimized nanoemulsion. Histopathological studies showed decreased degenerative changes in the resveratrol nanoemulsion administered groups. The levels of GSH and SOD were significantly higher, and the level of MDA was significantly lower in the resveratrol nanoemulsion treated group.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5mg/kg) or its vehicle. Twenty-four hours later, they were intraperitoneally treated with melatonin (10mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD.
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.
Nanoemulsions are of great interest in food industry finding various food applications. However, oil-in-water (o/w) nanoemulsions have been intensively investigated, but there are few studies on w/o nanoemulsions. In the present work the preparation of nanoemulsions with olive oil using non-ionic surfactants (Tween 20, 40, 60, 80, Span 20, 80) without the addition of a co-surfactant was studied and their emulsion properties and stability were examined. The stable nanoemulsions were presented in ternary phase diagrams (oil–water-surfactant) for each surfactant and the emulsifying ability of the efficient surfactants was determined. The nanoemulsions properties were evaluated in relationship to compositional components. From the results of this study it can be concluded that stable olive oil nanoemulsions without use of a co-surfactant were obtained and moreover the most efficient type of emulsifier and its ratio of addition in the system were determined.
Colloidal delivery systems based on microemulsions or nanoemulsions are increasingly being utilized in the food and pharmaceutical industries to encapsulate, protect, and deliver lipophilic bioactive components. The small size of the particles in these kinds of delivery systems (r < 100 nm) means that they have a number of potential benefits for certain applications: enhanced long-term stability; high optical clarity; and, increased bioavailability. Currently, there is considerable confusion about the use of the terms “microemulsions” and “nanoemulsions” in the scientific literature. However, these are distinctly different types of colloidal dispersions: a microemulsion is thermodynamically stable, whereas a nanoemulsion is not. It is therefore important to distinguish between them since this impacts the methods used to fabricate them, the strategies used to stabilize them, and the approaches used to design their functional attributes. This article reviews the differences and similarities between nanoemulsions and microemulsions in terms of their compositions, structure, fabrication, properties, and stability. It also attempts to highlight why there has been so much confusion in this area, and to clarify the terminology used to refer to these two kinds of colloidal dispersion.
Tetrabenazine reduces chorea symptoms associated with Huntington’s disease by depleting monoamines in pre-synaptic vesicles. It exhibit low aqueous solubility and undergoes first pass metabolism due to which it has low oral bioavailability. The aim of present work was to formulate intranasal tetrabenazine loaded nanoemulsion for better management and treatment of hyperkinesia related with Huntington’s disease. A quality by design (QbD) technique was employed as statistical multivariate approach for formulation and optimization of nanoemulsion. Optimized formulation showed droplet size of 106.80 ± 1.96 nm with polydispersity index (PDI) value of 0.198 ± 0.005 and -9.63 ± 0.63 mV zeta potential. Ex-vivo drug permeation studies were carried out and found that the formulation has an augmented permeation by 1.68 times as compared to tetrabenazine suspension. MTT assay on neuro-2a cell lines showed that tetrabenazine loaded nanoemulsion displayed better cell viability than placebo and aqueous drug solution at ½×Cmax, Cmax and 2×Cmax. Pharmacokinetic parameters in brain after intranasal administration of tetrabenazine nanoemulsion were found to be Cmax = 3.497 ± 0.275 µg/ml, AUC0-12 = 29.196 ± 0.870 µg.h/ml and elimination rate constant (ke) = 0.097 ± 0.012 h⁻¹ where as in plasma the pharmacokinetic parameters were Cmax = 1.400 ± 0.084 µg/ml, AUC0-12 = 12.925 ± 0.340 µg.h/ml and ke = 0.061 ± 0.010 h⁻¹. Histopathalogical studies of porcine nasal mucosa showed that nasal mucosa remain intact when treated with tetrabenazine loaded nanoemulsion. Thus it can be concluded from study that optimized nanoemulsion formulation of a tetrabenazine was robust and its delivery through nasal route is a viable alternative to other routes of administration for treatment of hyperkinesia associated with Huntington’s disease.
Parkinson’s disease is caused due to free radical generation in dopamine neurons leading to oxidative stress induced damage. The aim of this work was to ameliorate the free radical induced oxidative stress in rats by using TPGS (Tocopheryl polyethylene glycol 1000 succinate) loaded rutin nanoemulsion after oral administration. For this purpose, pharmacokinetic and pharmacodynamics studies were performed in albino wistar rats. Various behavioural tests (photoactometer test, rota rod, akinesia and catalepsy) and biochemical estimations for determination of GSH, TBARS and SOD were carried out. The results showed an increase in relative bioavailability of rutin after oral administration of nanoemulsion as compared to pure drug suspension. The AUC and Cmax of rutin nanoemulsion after oral administration were 1.8-fold and 1.9-fold higher than those of drug suspension respectively. Pharmacodynamic studies have shown good results with the rutin nanoemulsion than pure drug suspension. The rats treated with the rutin nanoemulsion exhibited significantly greater locomotor activity, better muscle coordination and improvement in cataleptic behaviour than the normal and haloperidol-induced rats (p < 0.001).Treatment with rutin suspension and rutin nanoemulsion helped in improving the stressed condition by increasing the levels of GSH, SOD and decrease in MDA levels in the brain. Anticancer activity was observed in a dose-dependent manner from 1 to 100 μg/ml. IC50 values for rutin suspension and rutin NE were found to be 36.7 and 25.4 µg/ml respectively. The rutin nanoemulsion has proven to be beneficial in ameliorating oxidative stress.
Bromocriptine mesylate (BCM), a dopaminergic agonist administered orally, exhibits retarded bioavailability owing to poor absorption and extreme first-pass metabolism. The objective of the current study was to develop, characterize, and statistically optimize BCM nanoemulsion (BCM-NE) loaded into a gel (BCM-NE gel) to evaluate its potential for improved permeation of BCM through the transdermal route, thereby improving its pharmacokinetic profile. BCM-NE was prepared by o/w spontaneous emulsification method and the effects of different formulation variables on the critical attributes of NE like globule size were investigated by implementing factorial design. The optimized formulation exhibited a mean globule size of 160 ± 6.5 nm, zeta potential of − 20.4 ± 1.23 mV, and drug content of 99.45 ± 1.9%. Ex vivo permeation studies across rat skin exhibited a significant enhancement in permeation, i.e., enhancement ratio (ER) of ~ 7.4 and 5.86 for BCM-NE and BCM-NE gel, respectively, when compared with aqueous BCM suspension gel. In vivo pharmacokinetic studies performed in rats demonstrated a higher and prolonged drug release of BCM from BCM-NE gel when compared to oral aqueous BCM suspension. The AUC0–t for BCM-NE gel and BCM suspension was found to be 562.54 ± 77.55 and 204.96 ± 51.93 ng/ml h, respectively. The relative bioavailability (%F) of BCM was shown to be enhanced 274% by BCM-NE gel. Histopathological studies demonstrated the safety and biocompatibility of the developed system. All the above results proved that the BCM-NE gel could be a superior and patient-compliant alternative to oral delivery in the management of PD.
Zingiber officinale Roscoe leaves oil was hydrodistilled and analyzed by gas chromatography/mass spectrometry for the first time from the Egyptian chemotype. Ninety compounds (96.63% of total peak area) were identified. Methyl cinnamate (29.21%) represented the most abundant oxygenated compound. Monoterpene hydrocarbons (23.83%) were rich in β-pinene (8.59%) and terpinolene (7.46%). δ-Cadinene (7.05%) represented the majority of sesquiterpene hydrocarbons (20.86%). A nanoemulsion (diameter of 151.4 nm) was formulated by a low-energy method using Tween-80 as a surfactant, with a polydispersity index of 0.27, the zeta potential of -13.75 mV and pH value of 4. Transmission electron microscopy (TEM) confirmed the nanometric-sized particles. The formulation was stable by keeping in the refrigerator for one month. The nanoemulsion antimicrobial activity was tested against Streptococcus mutans (compared to clindamycin) with MIC value of 62.5 μL/mL, confirmed by TEM showing bacterial scattering with impaired biofilm formation, and by in-silico molecular docking of methyl cinnamate to the C-terminal region of S. mutans surface protein antigen. To our knowledge, the formulation and its anticariogenic activity validation were carried out for the first time. Thus, ginger leaves oil is rich in valuable phytoconstituents; its nanoemulsion showed efficacy on S. mutans, yet further studies are required for testing its applicability as a gargle.
Objective of the present study was to determine whether the prepared nanoemulsion would be able to deliver selegiline to the brain by intranasal route improving its bioavailability. Antioxidant activity, pharmacokinetic parameters and dopamine concentration were determined. Oxidative stress models which had Parkinson's disease like symptoms were used to evaluate the antioxidant activity of nanoemulsion loaded with selegiline in vivo. The antioxidant activity was evaluated by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and reducing power assay which showed high scavenging efficiency for selegiline nanoemulsion compared to pure selegiline. Biochemical estimation results showed that the levels of antioxidant enzymes including glutathione (GSH) and superoxide dismutase (SOD) were increased whereas the levels of thiobarbituric acid reactive substances (TBARS) was decreased in intranasally administered selegiline nanoemulsion treated group when compared with haloperidol-induced Parkinson's disease group (control). Moreover, selegiline nanoemulsion was found to be successful in decreasing the dopamine loss, indicating that nanoemulsion is a potential approach for intranasal delivery of selegiline to decrease the damage due to free radicals thus avoiding consequent biochemical alterations that arise during Parkinson's disease. Brain:blood ratio of 2.207 ˃ 0.093 of selegiline loaded nanoemulsion (intranasally administered) ˃ selegiline solution (administered intravenously), respectively, at 0.5 h showed direct nose-to-brain delivery of drug bypassing blood brain barrier (BBB). Selegiline-loaded nanoemulsion administered intranasally showed significantly high dopamine concentration (16.61 ± 3.06 ng/ml) as compared to haloperidol-treated rats (8.59 ± 1.00 ng/ml) (p < 0.05). In this way intranasal delivery of selegiline nanoemulsion might play an important role in the better management of Parkinson's disease.
The objective of present study was to develop a nanoemulsion formulation of agomelatine (BCS class II drug) for the solubility enhancement. Capmul MCM, Tween 80 and PEG-400 were selected as oil, surfactant and co-surfactant respectively. The high energy ultrasonication method was used for the preparation of nanoemulsion. Three-factor three-level central composite design was employed to get the best formulation. The independent variables selected for the optimization were % oil, %Smix and sonication time (second). Based on the constraints applied to independent and dependent variables, the optimized formulation was selected with 2% oil, 10% Smix and 45 s sonication time. The experimental values for dependent variables such as hydrodynamic diameter (nm), % transmittance and % CDR were found to be 73.72 ± 2.53 nm, 98.2 ± 0.42%, 84.71 ± 4.05% respectively. TEM and AFM−assisted morphological characterization of optimized Ago-NE was done and it was found with a spherical shape. The PDI, Zeta potential and the refractive index of optimized Ago-NE were found to be 0.137 ± 0.016, −7.40 ± 0.12 mV and 1.423 ± 0.045 respectively. The viscosity, pH and drug content of optimized Ago-NE were found as 25.12 ± 0.67 cP, 6.4 ± 0.17 and 97.83 ± 1.03% respectively. The ex-vivo permeation profile of optimized Ago-NE and agomelatine suspension through goat nasal mucosa were compared till 12 h and % cumulative drug permeated was found to be 90% and 40% respectively. The higher drug permeation profile of optimized Ago-NE confirmed that the solubility of agomelatine has been improved.
The present study was designed to formulate and optimize transdermal risperidone soft lipid vesicles. The formulation optimized with phospholipid, safranal and ethanol were incorporated as permeation and absorption enhancers. The optimized risperidone soft lipid vesicle was further evaluated for skin irritation study, in-vivo pharmacokinetic study and locomotor activity. Three factor three level Box–Behnken design (BBD) was used to statistically optimize soft lipid vesicle using safranal (A), ethanol (B)and phospholipid (C) as independent variable, while their effect was observed for vesicle size (Y1), entrapment efficiency (Y2) and flux (Y3). The optimized risperidone soft lipid vesicle (Ris-opt) showed nanometric vesicle size, high entrapment efficiency and marked enhancement in transdermal flux. The extent of absorption from Ris-opt was greater when compared to oral suspension with relative bioavailability of 177%. The histopathological evaluation revealed developed formulation did not showed skin irritation compared to standard irritant. The significant findings presented here encourage further studies with risperidone soft lipid vesicles for treatment of schizophrenia.
Purpose:
Lipid-based self-emulsifying drug delivery systems (SEDDS) are commonly used for solubilizing and enhancing oral bioavailability of poorly water-soluble drugs. However, their effects on viability of intestine epithelial cells and influence on membrane permeation are poorly understood. The present study was undertaken for safety assessment of lipid-based formulations containing medium-chain fatty acid esters as lipids and polysorbate 80 as the surfactant using the Caco-2 in vitro model. Any possible paracellular permeation enhancement through Caco-2 monolayers by the nontoxic formulations was also investigated.
Methods:
Mixtures of monoglyceride (Capmul MCM EP or 708G) or propylene glycol monoester (Capmul PG-8 NF) of medium chain fatty acids with polysorbate 80, with and without the incorporation of a medium-chain triglyceride (Captex 355), were prepared. After suitable dilution with aqueous culture medium, the formulations were incubated with a series of Caco-2 cultures of different maturity. Cell viability and membrane integrity were assessed. Any effects of nontoxic formulations on the transport of the fluorescent dye, Lucifer yellow, through Caco-2 monolayers were also determined.
Results:
Formulations containing 1:1 ratios of monoglyceride or propylene glycol monoester to triglyceride (30% polysorbate 80, 35% monoglyceride or monoester and 35% triglyceride) were best tolerated by Caco-2 cells. Increased maturity obtained through longer culture durations rendered Caco-2 cells greater tolerance towards lipid-based formulations, and maximum tolerance to lipid-based formulations was observed with Caco-2 monolayers after being cultured for 21-23days. Furthermore, extent of cell membrane rupture caused by lipid-surfactant mixtures correlated positively with levels of cytotoxicity, suggesting a potential underlying mechanism. Permeation studies using Caco-2 monolayer model revealed that certain formulations significantly enhanced paracellular transport activities.
Conclusions:
Lipid-based SEDDS containing mixtures of monoglyceride (or monoester) and triglyceride of medium chain fatty acids formed fine microemulsions and were significantly less toxic than other formulations. Fully differentiated Caco-2 monolayer was more resistant to lipid-surfactant mixtures than less mature cultures. Certain formulations were also capable of enhancing paracellular permeation.
Selegiline is a monoamine oxidase B (MAO-B) inhibitor and is used in the treatment of Parkinson's disease. The main problem associated with its oral administration is its low oral bioavailability (10%) due to its poor aqueous solubility and extensive first pass metabolism. The aim of the present research work was to develop a nanoemulsion loaded with selegiline for direct nose-to-brain delivery for the better management of Parkinson's disease. A quality by design (QbD) approach was used in a statistical multivariate method for the preparation and optimization of nanoemulsion. In this study, four independent variables were chosen, in which two were compositions and two were process variables, while droplet size, transmittance, zeta potential and drug release were selected as response variables. The optimized formulation was assessed for efficacy in Parkinson's disease using behavioural studies, namely forced swimming, locomotor, catalepsy, muscle coordination, akinesia and bradykinesia or pole test in Wistar rats. The observed droplet size, polydispersity index (PDI), refractive index, transmittance, zeta potential and viscosity of selegiline nanoemulsion were found to be 61.43 ± 4.10 nm, 0.203 ± 0.005, 1.30 ± 0.01, 99.80 ± 0.04%, -34 mV and 31.85 ± 0.24 mPas respectively. Surface characterization studies demonstrated a spherical shape of nanoemulsion which showed 3.7 times enhancement in drug permeation as compared to drug suspension. The results of behaviour studies showed that treatment of haloperidol induced Parkinson's disease in rats with selegiline nanoemulsion (administered intranasally) showed significant improvement in behavioural activities in comparison to orally administered drug. These findings demonstrate that nanoemulsion could be a promising new drug delivery carrier for intranasal delivery of selegiline in the treatment of Parkinson's disease.
Introduction:
Polyethylene glycol (PEG) is a polymer of choice in drug delivery systems. This USFDA-approved polymer is popular due to its tunable properties and well-established safety profile; prime requisites considered during the selection of any excipient in formulation development. Areas covered: The individual properties and applications of PEG have been discussed at length in the existing literature. However, guidance on proper selection of PEG grade to cater to one's purpose is lacking. This article focuses on providing preliminary guidelines to formulators on selection of appropriate PEG grade typically based on its physico-chemical properties and role-based application in pharmaceuticals. It should be noted that the aim article is not to deep dive in each area of research. Expert Opinion: Guidance on PEG application and grade of choice is lacking in the available literature. The authors have discussed and provided guidance to formulators on the appropriate PEG grade selection for particular application of PEG based on the available in vitro and in vivo data presented in this review. State-of-the-art use of PEG in therapeutic applications, in clinical status and in commercial use is also summarized. Nevertheless, toxicities related to PEG and its related impurities are discussed at the end of review.
The objective of the present investigation was to optimize and develop quetiapine fumarate (QF) loaded chitosan nanoparticles (QF-NP) by ionic gelation method using Box-Behnken design. Three independent variables viz., X1-Concentration of chitosan, X2-Concentration of sodium tripolyphosphate and X3-Volume of sodium tripolyphosphate were taken to investigate their effect on dependent variables (Y1-Size, Y2-PDI and Y3-%EE). Optimized formula of QF-NP was selected from the design space which was further evaluated for physicochemical, morphological, solid state characterization, nasal diffusion and in-vivo distribution for brain targeting following non-invasive intranasal administration. The average particle size, PDI, %EE and nasal diffusion were found to be 131.08 ± 7.45 nm, 0.252 ± 0.064, 89.93 ± 3.85% and 65.24 ± 5.26% respectively. Neither toxicity nor structural damage on nasal mucosa was observed upon histopathological examination. Significantly higher brain/blood ratio and 2 folds higher nasal bioavailability in brain with QF-NP in comparison to drug solution following intranasal administration revealed preferential nose to brain transport bypassing blood-brain barrier and prolonged retention of QF at site of action suggesting superiority of chitosan as permeability enhancer. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery.
Dopamine agonists (DA) are therapeutic agents that are commonly used in the treatment of Parkinson’s disease (PD). They can reduce undesired motor fluctuations and delay the administration of levodopa therapy. However, this drug family is associated with specific side effects that can significantly diminish the quality of life among PD patients. Some of them impose significant risks for individuals who have a history of cardiovascular diseases, psychosis, and depression, or those older patients who suffer from renal or hepatic insufficiency. Various pharmacokinetic and pharmacodynamic considerations need to be taken into account when administering DA therapy. The goal of this review is to provide a comprehensive, up-to-date overview of DA therapeutic modalities for PD.
The aim of the present research work was to develop asenapine (ASM) loaded nanostructured lipid carriers (ANLC) for the delivery of drugs in the brain by an intranasal route to enhance therapeutic efficacy. A quality by design approach was used for development and optimization of ANLC. A total of five independent variables were selected, in which three were compositions and two were process variables, while particle size and entrapment efficiency were selected as response variables. The final optimized batch was evaluated by various in vitro characterizations as well as in vivo brain and plasma pharmacokinetic studies. Finally, the ANLC was assessed for efficacy and safety profiling for upto three weeks by a behavior model viz. catalepsy, induced locomotor and paw test in Charles Foster rats. The observed particle size, entrapment efficiency and zeta potential of ANLC was found to be 167.30 ± 7.52 nm, 83.50 ± 2.48% and −4.33 ± 1.27 mV, respectively. Surface characterization studies demonstrated a spherical shape with a smooth surface of ANLC which follows the Korsmeyer–Peppas in vitro release kinetic model (r2 = 0.9911, n = 0.53). A brain pharmacokinetic study indicated a significantly higher (p < 0.05) peak drug concentration (Cmax: 74.13 ± 6.73 ng mL−1), area under the drug concentration–time curve (AUC0–24 h: 560.93 ± 27.85 h ng mL−1) and mean residence time (MRT: 7.1 ± 0.13 h) of ANLC compared to ASM in the brain via an intranasal route. The results of behaviour studies of ANLC showed a significant decrease in extra-pyramidal side effects with increasing antipsychotic effect after 1–2 week(s) of treatment. These findings demonstrate that nanostructured lipid carriers could be a new promising drug delivery system for intranasal delivery of asenapine in the treatment of schizophrenia.
Context:
Tramadol is a centrally acting analgesic and requires frequent dosing. Hence, judicious selection of retarding formulations is necessary. Transdermal ethosomal gel delivery has been recognized as an alternative route to oral delivery.
Objective:
The objective was to develop statistically optimized ethosomal systems for enhanced transdermal activity of tramadol vis-à-vis traditional liposomes.
Materials and methods:
Box-Behnken design was employed for optimization of nanoethosomes using phospholipon 90G (A), ethanol (B), and sonication time (C) as independent variables while dependent variables were the vesicle size (Y1), entrapment efficiency (Y2), and flux (Y3). It was prepared by rotary evaporation method and characterized for various parameters including entrapment efficiency, size and transflux. Preclinical assessments were conducted on Wistar rats to measure the performance of developed formulations.
Results:
The optimized formulation provided mean vesicles size, reasonable entrapment efficiency and enhanced flux when compared with liposome (control). In-vivo absorption study showed a significant increase in bioavailability (7.51 times) compared with oral tramadol. The average primary irritancy index was found to be 1.4, indicating it to be non-irritant and safe for use.
Discussion and conclusion:
The results also demonstrated that encapsulated tramadol increases its biological activity due to the superior skin penetration potential. The preclinical study indicates a significant (P < 0.05) extended analgesic effect compared to oral solution using the hot plate test method. The overall results suggest that developed formulation is an efficient carrier for transdermal delivery of tramadol.
Cilostazol (CLZ) is a well known therapeutic agent which is used for antithrombotic activity but suffers from the drawback of poor oral bioavailability. Research studies have explored the utilization of various lipid based formulations like nanoemulsions to overcome such limitations. CLZ nanoemulsions were produced by aqueous titration technique to improve the oral bioavailability. CLZ solubility in oils and emulsifiers was estimated to select the excipients for the formulation. Triacetin and Capryol 90 (1:1) were used as the hydrophobic phase. Amongst various surfactants and co-surfactants, CLZ showed solubility of 4.0 ± 0.2 mg/ml and 8.0 ± 0.04 mg/ml in tween 80 and transcutol P, respectively and therefore they were selected for the formulation of nanoemulsions. Results of droplet size for optimized batch were found to be 93.72 nm. CLZ nanoemulsions exhibited polydispersity index (PDI) of 0.278. Enhanced CLZ release was obtained with nanoemulsions. Pharmacokinetic studies showed that the optimized nanoemulsion (X1) showed 3.29 times improvement in bioavailability in comparison to CLZ suspension.
Asiatic acid, a well-known plant-based neuroprotective pentacyclic triterpenoid, has major limitation for its bioavailability in the brain. The objective of this study is to develop novel bovine serum albumin (BSA) nanoparticles coupled with glutathione (natural tripeptide) to enhance drug delivery to brain.
Asiatic acid-loaded BSA nanoparticles were prepared by using modified desolvation technique. Conjugation of glutathione with asiatic acid-loaded BSA nanoparticle was done by carbodiimide reaction using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC). In-vivo biodistribution study of asiatic acid solution, and conjugated and unconjugated asiatic acid-loaded BSA nanoparticles, at the dose equivalent to 75 mg/kg was evaluated, through intravenous administration to Wistar rats. Asiatic acid has very weak chromophore so high-pressure liquid chromatography-based novel pre-derivatization method was developed using p-toluidine as a coupling agent to improve sensitivity.
The results showed 10-fold more bioavailability of asiatic acid in the brain after 5 h with glutathione-conjugated asiatic acid-loaded BSA nanoparticles as compared with asiatic acid solution with 627.21% drug targeting efficiency to the brain.
The present investigation demonstrated enhanced delivery of asiatic acid using glutathione and hence served as a potential ligand to improve brain targeting efficiency.
© 2015 Royal Pharmaceutical Society.
Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Aim:
The aim of this study was to investigate the brain targeting potential of chitosan-coated oil in water nanoemulsions (CSNE(ROP)) delivered intranasally in haloperidol-induced Parkinson's disease rat models.
Methods:
Chitosan-coated nanoemulsion (CSNE(ROP)) was developed through aqueous titration followed by a high pressure homogenization method.
Results:
Gamma-scintigraphy study showed a significantly high mucoadhesive potential of CSNE(ROP) and least for conventional and homogenized formulations. Confocal study showed deep localization of formulations in the brain confirming the permeation potential of CSNE(ROP). Pharmacokinetic results of CSNE(ROP) in Wistar rat brain and plasma showed a significantly high (p** < 0.005) AUC0→24 and amplified Cmax over i.v treatment group. Neurobehavioral activity (rotarod and swim tests) and biochemical parameters (glutathion, TBARS and SOD) corroborated well with the pharmacokinetic results. The order of dopamine recovery in haloperidol-induced Wistar rats was found to be (i.n)CSNEROP group>(i.n)SolnROP group>(i.v)SolnROP group>haloperidol group.
Conclusions:
Finally, the investigation demonstrated that intranasal delivery of mucoadhesive nanocarrier might play as a potential candidate in the management of Parkinson's disease and related brain disorders.
Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The present work has been carried out to explore the potential of two novel ionic dicephalic-type surfactants, i.e., positively charged N,N-bis[3,3'-(trimethylammonio)propyl]-dodecanamide dimethylsulphate, C-12(TAPAMS)(2) and anionic disodium N-dodecyliminodiacetate, C-12(COONa)(2) for spontaneous formation of biocompatible and stable oil-in-water (o/w) nanoemulsions. Initially, we examined ternary phase diagrams of surfactant-oil-water (SOW) systems containing different ratios of C-12(TAPAMS)(2) or C-12(COONa)(2) as the surfactant entity (S), oleic acid, isopropyl palmitate or isopropyl myristate as the oil phase (O) and the water phase (W) by the titration method. Then, all obtained nanoemulsions were characterized by visual and microscopic observations, as well as dynamic light scattering (DLS) measurements of particle sizes and size distributions. Results of cryo-TEM and DLS showed that the studied droplets making up the nanoemulsions have a nearly monodisperse size distribution (D-H < 100 nm, PdI < 0.2). Backscattered profiles obtained by the turbidimetric technique proved high kinetic stability of the obtained systems whereas Doppler electrophoresis revealed their large positive or negative zeta- potential. In order to test the nanoemulsions biocompatibility under the surfactants concentration, cytotoxicity of the optimized formulations was evaluated in vitro upon two normal human skin cell lines, i.e., cutaneous keratinocytes (HaCaT) and gingival fibroblasts (HGF). The analyzed parameters - oil composition, surfactant type, and surfactant-to-oil ratio - were all found to influence the droplet size, charge and stability of the systems produced. Our results prove that the studied nanoemulsions, stabilized by dicephalic ionic surfactants, may provide new biocompatible colloidal systems, designated mainly for cosmetics, personal and household care products.
The present study was carried out to evaluate Anti Parkinson's Activity of Ethanolic Extract of Nigella sativa seeds (EENS) in Chlorpromazine (CPZ) induced experimental animal model. The effects of ethanolic extracts of Nigella sativa (200 and 400 mg/kg, p.o) was studied using in-vivo parameter like catalepsy. Alongwith iteffect of EENS on Neurochemical parameters (TBARS, GSH, Nitrite and Total Protein) were also assessed. Catalepsy was measured using block method. For neurochemical estimations all groups were given CPZ dosing for 21 days to induce Parkinson's Disease (PD). The cataleptic scores was significantly (P<0.001) found to be reduced, with the Nigella sativa (200 and 400 mg/kg, p.o.). Levodopa + Carbidopa and Nigella sativa increase the depleted level of Reduced Glutathione (GSH) (P<0.001) and Total Protein (P<0.001) and decrease the elevated levels of TBARS (P<0.001) and Nitrite (P<0.001) preferably at higher dose(400 mg/kg) as compared to group II receiving Chlorpromazine. Our results suggest the Anti Parkinson's activity of Nigella Sativa due to its Anti Cataleptic and Neurochemical responses.
Novel nanoemulsion-based drug delivery systems (DDS) have been proposed as alternative and effective approach for the delivery of various types of poorly water-soluble drugs in the last decade. This nanoformulation strategy significantly improves the cell uptake and bioavailability of numerous hydrophobic drugs by increasing their solubility and dissolution rate, maintaining drug concentration within the therapeutic range by controlling the drug release rate, and reducing systemic side effects by targeting to specific disease site, thus offering a better patient compliance. To date, cavitation technology has emerged to be an energy-efficient and promising technique to generate such nanoscale emulsions encapsulating a variety of highly potent pharmaceutical agents that are water-insoluble. The micro-turbulent implosions of cavitation bubbles tear-off primary giant oily emulsion droplets to nano-scale, spontaneously leading to the formation of highly uniform drug contained nanodroplets. A substantial body of recent literatures in the field of nanoemulsions suggests that cavitation is a facile, cost-reducing yet safer generation tool, remarkably highlighting its industrial commercial viability in the development of designing novel nanocarriers or enhancing the properties of existing pharmaceutical products. In this review, the fundamentals of nanoemulsion and the principles involved in their formation are presented. The underlying mechanisms in the generation of pharmaceutical nanoemulsion under acoustic field as well as the advantages of using cavitation compared to the conventional techniques are also highlighted. This review focuses on recent nanoemulsion-based DDS development and how cavitation through ultrasound and hydrodynamic means is useful to generate the pharmaceutical grade nanoemulsions including the complex double or submicron multiple emulsions.
Abstract Polyphenolic bioflavonoid, Rutin possesses wide range of pharmacological activities. However, it shows poor bioavailability when administered orally. The aim of this study was to formulate and compare the potential of nanoemulsions for the solubility enhancement of rutin (RU) by using different techniques. RU-loaded nanoemulsions were prepared by spontaneous emulsification method and high-pressure homogenization (HPH) technique using sefsol 218 and tocopheryl polyethylene glycol 1000 succinate (TPGS) (1:1), solutol HS15 andtranscutol P as oil phase, surfactant and co-surfactant, respectively. The prepared formulations were compared for various parameters like droplet size, percentage transmittance, zeta potential, viscosity, refractive index and in vitro release. The HPH nanoemulsions showed smaller droplet size and increased in vitro release when compared to nanoemulsions prepared by spontaneous emulsification method. The optimized formulation showed spherical globules with average globule diameter of 18 nm and zeta potential of -41 mV. Cumulative percentage drug released obtained for RU, PF6 (spontaneous emulsification formulation F6) and HF6 (HPH formulation F6) were 41.5 ± 0.04%, 49.5 ± 0.06% and 94.8 ± 0.03%, respectively, after 6 h. The permeability of RU from HF6 was found to be ≈4.6 times higher than RU suspension during ex vivo everted gut sac studies. Antioxidant activity was determined by using DPPH assay and reducing power assay method. Results showed a high scavenging efficiency toward DPPH radicals by HF6. Anti-inflammatory effect of RU as determined by carrageenan-induced rat paw edema method was found to be higher (75.2 ± 4.8%) when compared to RU suspension (46.56 ± 3.5%). It can be inferred that TPGS-loaded nanoemulsion of RU serve as an effective tool in increasing solubility and permeability of RU.
The objective of the study was to optimize curcumin nanoemulsion for intranasal delivery using design of experiment. Box-Behnken design was constructed using oil, surfactant and co-surfactant concentration as independent variables and their affect on response y1 (globule size) and y2 (zeta potential) were studied. The ANOVA test identified the significant factors that affected the responses. For globule size, percentage of oil, surfactant and co-surfactant were identified as significant model terms whereas for zeta potential, oil and co-surfactant were found to be significant. Critical factors affecting the responses were identified using perturbation and contour plots. The derived polynomial equation and contour graph aid in predicting the values of selected independent variables for preparation of optimum nanoemulsion with desired properties. Further, 2(4) factorial design was used to study influence of chitosan on particle size and zeta potential. The formulations were subjected to in vitro cytotoxicity using SK-N-SH cell line and nasal ciliotoxicity studies. The developed formulations did not show any toxicity and were safe for intranasal delivery for brain targeting. In vitro diffusion studies revealed that nanoemulsions had a significantly higher release compared to drug solution. Ex vivo diffusion studies were carried out using sheep nasal mucosa fixed onto Franz diffusion cells. Mucoadhesive nanoemulsion showed higher flux and permeation across sheep nasal mucosa.
Background:
Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action.
Objective:
The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems.
Methods:
The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits.
Results:
Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets.
Conclusion:
The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability.
The formation of oil-in-water (O/W) nano-emulsions suitable for pesticidal application has been studied in water/mixture of non-ionic surfactant (C12E3) and anion surfactant (MAPK)/oil (bifenthrin dissolved in dimethylbenzene) systems. The nano-emulsions with constant oil concentration were prepared by using high-energy emulsification methods. Effects of surfactant ratio and total surfactant concentration on the mean droplet size and size distribution of the emulsions were measured by dynamic light scattering. The stability of nano-emulsions prepared with different surfactant ratios of MAPK and C12E3 was tested by two methods: by measuring the change in droplet size as a function of time using dynamic light scattering and by multiple light scattering. The results showed the data acquired by the short-term scan using multiple light scattering technique corresponded with the droplet size variations measured by dynamic light scattering. The optimum concentration and mixing ratio of the two surfactants for the bifenthrin oil-in-water nano-emulsion was 10wt% and 6:4 (MAPK to C12E3) and the quality indicators of this nano-emulsion were up to standard according to FAO standards.
Conventional and microwave-assisted synthesis of ZnO nanorods have been performed with and without using PEG400. ZnO nanorods were synthesized with 50-250 nm of diameter which depends on the used surfactant and methods. Surfactant effects of PEG400 on the size and morphology of ZnO nanorods were investigated. The microwave method was compared to the conventional heating method. Morphologies were investigated by using scanning electron microscopy (SEM). (c) 2008 Elsevier B.V. All rights reserved.
Introduction: The blood--brain barrier (BBB) represents a stringent barrier for delivery of neurotherapeuticsin vivo. An attempt to overcome this barrier is represented by the direct transport of drugs from the nose to the brain along the olfactory and trigeminal nerve pathways. These nerve pathways initiate in the nasal cavity at olfactory neuroepithelium and terminate in the brain. An enormous range of neurotherapeutics, both macromolecules and low molecular weight drugs, can be delivered to the central nervous system (CNS) via this route.
Areas covered:Present review highlights the literature on the anatomy-physiology of the nasal cavity, pathways and mechanisms of neurotherapeutic transport across nasal epithelium and their biofate and various strategies to enhance direct nose to brain drug delivery. The authors also emphasize a variety of drug molecules and carrier systems delivered via this route for treating CNS disorders. Patents related to direct nose to brain drug delivery systems have also been listed.
Expert opinion:Direct nose to brain drug delivery system is a practical, safe, non-invasive and convenient form of formulation strategy and could be viewed as an excellent alternative approach to conventional dosage forms. Existence of a direct transport route from the nasal cavity to the brain, bypassing the BBB, would offer an exciting mode of delivering neurotherapeutic agents.