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Improvement of physicochemical properties of nanocolloidal carrier loaded with low water solubility drug for parenteral cancer treatment by Response Surface Methodology
Abstract
Nanoemulsions have been used as a drug carrier system, particularly for poorly water-soluble drugs. Sorafenib is a poorly soluble drug and also there is no parenteral treatment. The aim of this study is the development of nanoemulsions for intravenous administration of Sorafenib. The formulations were prepared by high energy emulsification method and optimized by using Response Surface Methodology (RSM). Here, the effect of independent composition variables of lecithin (1.16–2.84%, w/w), Medium-Chain Triglycerides (2.32–5.68%, w/w) and polysorbate 80 (0.58–1.42%, w/w) amounts on the properties of Sorafenib-loaded nanoemulsion was investigated. The three responses variables were particle size, zeta potential, and polydispersity index. Optimization of the conditions according to the three dependent variables was performed for the preparation of the Sorafenib-loaded nanoemulsions with the minimum value of particle size, suitable rage of zeta potential, and polydispersity index. A formulation containing 0.05% of Sorafenib kept its properties in a satisfactory range over the evaluated period. The composition with 3% Medium-Chain Triglycerides, 2.5% lecithin and 1.22% polysorbate 80 exhibited the smallest particle size and polydispersity index (43.17 nm and 0.22, respectively) with the zeta potential of −38.8 mV was the optimized composition. The fabricated nanoemulsion was characterized by the transmission electron microscope (TEM), viscosity, and stability assessment study. Also, the cytotoxicity result showed that the optimum formulations had no significant effect on a normal cell in a low concentration of the drug but could eliminate the cancer cells. The dose-dependent toxicity made it a suitable candidate for parenteral applications in the treatment of breast cancer. Furthermore, the optimized formulation indicated good storage stability for 3 months at different temperatures (4 ± 2 °C, 25 ± 2 °C and 45 ± 2 °C).
... SNEDDSs of different composition were prepared with the following TKIs: brigatinib (BG) [118], dasatinib (DAS) [119], IMA [120,121], sorafenib (SOR) [122,123], and sunitinib (SUN) [124]. Their specific composition and particle size is given in Table 2. ...
According to the WHO, cancer caused almost 10 million deaths worldwide in 2020, i.e., almost one in six deaths. Among the most common are breast, lung, colon and rectal and prostate cancers. Although the diagnosis is more perfect and spectrum of available drugs is large, there is a clear trend of an increase in cancer that ends fatally. A major advance in treatment was the introduction of gentler antineoplastics for targeted therapy–tyrosine kinase inhibitors (TKIs). Although they have undoubtedly revolutionized oncology and hematology, they have significant side effects and limited efficacy. In addition to the design of new TKIs with improved pharmacokinetic and safety profiles, and being more resistant to the development of drug resistance, high expectations are placed on the reformulation of TKIs into various drug delivery lipid-based nanosystems. This review provides an insight into the history of chemotherapy, a brief overview of the development of TKIs for the treatment of cancer and their mechanism of action and summarizes the results of the applications of self-nanoemulsifying drug delivery systems, nanoemulsions, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles and nanostructured lipid carriers used as drug delivery systems of TKIs obtained in vitro and in vivo.
... It is technically challenging to formulate W/O/W NEs with internal and external droplets of less than 100 nm [22] . However, such NEs carrying the drugs have been studied as nanocarriers for oral [23] , transdermal [24] , and parenteral delivery [25] , while NEs carrying hydrophilic drugs have been widely under-studied. 5-Fluorouracil (5-FU) is a drug widely used for the treatment of several types of tumors especially those associated with the neck, breast, lung and colorectal [26,27] . ...
Nanoemulsions (NEs) as multi-compartmentalized systems are extensively considered as versatile drug delivery systems, due to their multifunctional and tuneable physicochemical properties. Here, water-in-oil-in-water (WOW) NEs were formulated using Juglans regia-based Fe3O4/Au-core-shell nanoparticles to encapsulate 5-Fluorouracil (5-FU) for potential colorectal cancer treatment. Response surface methodology, FTIR, TGA, TEM, DLS, VSM, UV-vis spectroscopy, and viscosity measurements were used to characterize the fabricated samples. The analysis confirmed the successful synthesis of Au, Fe3O4, and Fe3O4/Au core-shell nanoparticles with the Juglans regia (J. regia) extract as a green stabilizer and also reducing agent. The NE displayed a spherical-shape and TEM size of∼30 nm. It also exhibited good colloidal stability and multifunctional features related to its components. TGA data indicated that 5-FU increased thermal stability after its loading into the nanoemulsion as a drug carrier. 5-FU release from the NE carrier presented a time-delayed behavior and higher release dosage in media at pH 4 compared to pH 7 within 48 h. When tested against colorectal-derived cell lines, 0.78 µg/mL of 5-FU-loaded Fe3O4/Au core-shell NEs showed potent anticancer activity against HCT116 cancerous cells, while exhibiting low toxicity towards CCD112 normal cells. In conclusion, the synthesized 5-FU-loaded NEs can be potently used as an anticancer drug carrier model, owing to its nano-scale size and other functionalities, which should be further studied.
... Metal nanoparticles such as gold, silver and copper are applicable to use in several industries where each of nanoparticles has different properties depending on the size, shape and other physicochemical properties [6]. Most of the nanoparticles could be used in food packaging [7], wound dressing [8], drug delivery [9] and catalytic application [10]. ...
A study on the effect of size and shape of copper nanoparticles (Cu-NPs) by varying the amount of honey has been done using a facile green synthesis method with the presence of ultrasonic assistance. Several amount of different % w/v of honey (0%, 1%, 5%, 10%, 15% and 20% w/v) that contain carbohydrate which are mainly glucose and fructose, and other polyhydroxyl groups act as stabilizing agent and a weak reducing agent supported by ascorbic acid were used to produce the Cu-NPs. The synthesized Cu-NPs were characterized using UV-visible, XRD and HRTEM to prove the size and shape of the nanoparticles. The best amount of honey used to produce Cu-NPs with uniform particle size and shape is at 15 % w/v. The size is 3.81 ± 1.135 nm and it shows a consistence spherical shape using HRTEM analysis image. UV-visible supported the results from the HRTEM. And XRD shows good diffraction pattern for pure Cu-NPs. It proves that honey has the ability to act as stabilizing agent in controlling the size and shape of nanoparticles.
... The viscosity of all formulas of nano transfersomal dispersion were measured using viscometer at 37 O C for 3 times and the results is shown in table 2.The results showed that in formulas SF1-SF5 (containing SDC as edge activator ) as the ratio of SDC increased the viscosity was decreased because it is anionic surfactant and hydrophilic in nature with low molecular weight [25] . While other formulas containing other types of edge activators including SF6-SF10 (containing different ratios of tween 80) , SF11-S15 ( containing span 80) and SF16-SF20 (containing span 60) showed increasing in the viscosity as the ratio of edge activator was increased because tween 80, span 80 and span 60 are nonionic surfactants that have no charge on the hydrophilic head and increasing their concentration lead to increasing their viscosity due to increase in flow resistance in the batch emulsification process [26] . [27,28] . ...
This work involves investigation and evaluation of the factors that affect the preparation and release of the model class I drug (loxoprofen sodium) to optimize the efficiency of its prepared nano transfersomal dispersion to give rapid onset of action (burst effect) within the first 2 hours that can continue for further four hours. The work involved preparation of twenty formulas of transfersomal dispersion by thin film method which were nano-sized by probe sonication and characterized morphologically by Transmission electronic microscopic (TEM), zeta potential, particle size, polydispersity index (pdI), pH, physical appearance, entrapment efficiency, viscosity, transmittance and in vitro drug release. The selected nano transfersomal formula (SF16) showed pH (7.2), particle size (393 nm), pdI (0.259), zeta potential (-25), entrapment efficiency (91%) and gave a 73% drug release within the first 2 hours of the in vitro test and continued until it gave 86.35% drug release after 4 h. This work succeeded in preparing optimized tansfersomal dispersion for loxoprofen sodium using different soya lecithin / edge activator percent and different types of edge activator. The optimum formula gave an immediate release of the model drug (loxoprofen sodium) and it was ready to be incorporated in any suitable dosage form to give continuous drug release.
... The subsequent mathematical treatment enables the optimization of experimental conditions to get the desired result and also indicates which parameters lead to synergistic or antagonist effects. This approach has been regularly used for the formulation of lipidic vectors [153] and is also increasingly assessed for polymeric systems [154][155][156][157]. To our knowledge, only two examples have performed DOE for PDT vectors. ...
Photodynamic therapy is a technique already used in ophthalmology or oncology. It is based on the local production of reactive oxygen species through an energy transfer from an excited photosensitizer to oxygen present in the biological tissue. This review first presents an update, mainly covering the last five years, regarding the block copolymers used as nanovectors for the delivery of the photosensitizer. In particular, we describe the chemical nature and structure of the block copolymers showing a very large range of existing systems, spanning from natural polymers such as proteins or polysaccharides to synthetic ones such as polyesters or polyacrylates. A second part focuses on important parameters for their design and the improvement of their efficiency. Finally, particular attention has been paid to the question of nanocarrier internalization and interaction with membranes (both biomimetic and cellular), and the importance of intracellular targeting has been addressed.
Sorafenib (SOR) is an oral multikinase inhibitor that effectively hampers the growth and spread of cancer cells by targeting angiogenesis and proliferation. However, SOR tablets (Nexavar) have limited oral bioavailability, ranging from 38% to 49%, due to their low water solubility. To address this issue, cyclodextrins (CDs), widely used to enhance the solubility and stability of lipophilic drugs by encapsulating them within their molecular structure, were considered in this study. We focused on β-cyclodextrin (βCD) and its derivatives, including hydroxypropyl-β-cyclodextrin (HPβCD), dimethyl-β-cyclodextrin (DMβCD), sulfobutylether-β-cyclodextrin (SBEβCD), and compared them with γ-cyclodextrin (γCD) for generating inclusion complexes with SOR. The 200 ns molecular dynamics simulations revealed that SOR could form inclusion complexes with all CDs in two possible orientations: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form), primarily driven by van der Waals interactions. Among the four βCD derivatives studied, SOR exhibited the highest number of atom contacts with SBEβCD and demonstrated the lowest solvent accessibility within the hydrophobic cavity of SBEβCD. These findings correlated with the highest binding affinity of SOR/SBEβCD complex determined by SIE, MM/GBSA, and MM/PBSA methods. Experimental results further supported our computational predictions, in which SBEβCD exhibited a stability constant of 940 M⁻¹ at 25 °C, surpassing βCD's stability constant of 210 M⁻¹. Taken together, our results suggest that the modified CDs, particularly SBEβCD, hold promising potential as an efficient molecular encapsulating agent for SOR, offering improved solubility and stability for this lipophilic drug.
Nanoemulsions have gained increasing attention in recent years as a drug delivery system due to their ability to improve the solubility and bioavailability of poorly water-soluble drugs. This systematic review aimed to collect and critically analyze recent novelties in developing, designing, and optimizing intravenous nanoemulsions appearing in articles published between 2017 and 2022. The applied methodology involved searching two electronic databases PubMed and Scopus, using the keyword "nanoemulsion" in combination with "intravenous" or "parenteral". The resulting original articles were classified by the method of preparation into different categories. An overview of the current methods used for the preparation of such formulations, including high- and low-energy emulsification, was provided. The advantages and disadvantages of these methods were discussed, as well as their potential impact on the properties of the developed intravenous nanoemulsions. The problem of inconsistency in intravenous nanoemulsion terminology may lead to misunderstandings and misinterpretations of their properties and applications was also undertaken. Finally, the regulatory aspects of intravenous nanoemulsions, the state of the art in the field of intravenous emulsifiers, and the future perspectives were presented.
Sorafenib tosylate (SFB) is a multikinase inhibitor that inhibits tumour growth and proliferation for the management of breast cancer but is also associated with issues like toxicity and drug resistance. Also, being a biopharmaceutical class II (BCS II) drug, its oral bioavailability is the other challenge. Henceforth, this report intended to encapsulate SFB into a biocompatible carrier with biodegradable components, i.e., phospholipid. The microemulsion of the SFB was prepared and characterized for the surface charge, morphology, micromeritics and drug release studies. The cell viability assay was performed on 4T1 cell lines and inferred that the IC50 value of sorafenib-loaded microemulsion (SFB-loaded ME) was enhanced compared to the naïve SFB at the concentrations of about 0.75 µM. More drug was available for the pharmacological response, as the protein binding was notably decreased, and the drug from the developed carriers was released in a controlled manner. Furthermore, the pharmacokinetic studies established that the developed nanocarrier was suitable for the oral administration of a drug by substantially enhancing the bioavailability of the drug to that of the free SFB. The results bring forth the preliminary evidence for the future scope of SFB as a successful therapeutic entity in its nano-form for effective and safer cancer chemotherapy via the oral route.
Dysregulation of the tyrosine kinase signaling pathway is closely related to tumor development, and tyrosine kinase inhibitors are important targets for potential anticancer strategies. In particular, sorafenib, as a representative drug of multitarget tyrosine kinase inhibitors, has an important clinical status and is widely used for treating various solid tumors and diabetic complications. However, poor aqueous solubility of sorafenib, poor bioavailability of commonly used oral dose forms, poor accumulation at tumor sites, and severe off-target effects that tend to induce intolerable systemic side effects in patients have greatly reduced its therapeutic efficiency and limited its extensive clinical application. To improve the properties of sorafenib, increase the efficiency of clinical treatment, and overcome the increasingly prominent phenomenon of sorafenib resistance, multiple investigations have been conducted. Numerous studies have reported that the properties of nanomaterials, such as small particle size, large specific surface area, high surface activity and high adsorption capacity, make nanotechnology promising for the construction of ideal sorafenib nanodelivery systems to achieve timed and targeted delivery of sorafenib to tumors, prolong the blood circulation time of the drug, improve the utilization efficiency of the drug and reduce systemic toxic side effects. This review summarizes the progress of research applications in nanotechnology related to sorafenib, discusses the current problems, and expresses expectations for the prospect of clinical applications of sorafenib with improved performance.
Hormones like testosterone and progesterone in the humans play significant role in the regulation of various biological processes like the body growth, reproduction, and others. In last two decades, researchers are using ionic liquids (ILs) extensively in different areas of sciences, and they are a novel class of compounds as well as their polarity can be tuned. ILs are multidisciplinary in nature and can be used in chemistry, materials science, chemical engineering, and environmental science. Further, ILs are being explored to increase the solubility of drugs or biological potential molecules. Testosterone and progesterone are found to be not very polar in nature; therefore, the authors attempt to increase the solubility of testosterone and progesterone via interaction with ILs. It was studied with density functional theory calculations using Gaussian, and an increase in the value of dipole moment is observed for the complex of testosterone/progesterone with the ILs in comparison of individual one. The optimization energy and other thermodynamic energies of the ILs (IL1-IL3), testosterone (T), testosterone-IL (T-IL1 to T-IL3), progesterone (P), and progesterone-ILs (P-IL1 to P-IL3) are found to be negative. Further, the change in free energy for the formation of complexes at room temperature is calculated. Further, the authors have investigated the synergistic effect of testosterone and progesterone against the main protease of new coronavirus using molecular docking. It is observed that the testosterone-IL1 {IL1-3-(2-hydroxyethyl)-1-methyl-1H-imidazol-3-ium 2,4,6-trinitrophenolate} is found to be prominent against the main protease of SARS-CoV-2.
The aim of this study is the development of nanoemulsions for intravenous administration of Sorafenib, which is a poorly soluble drug with no parenteral treatment. The formulation was prepared by a high energy emulsification method and optimized by response surface methodology. The effects of overhead stirring time, high shear rate, high shear time, and cycles of high-pressure homogenizer were studied in the preparation of nanoemulsion loaded with Sorafenib. Most of the particles in nanoemulsion are spherical in shape, the smallest particle size being 82.14 nm. The results of the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole reveal that the optimum formulation does not affect normal cells significantly in low drug concentrations but could remove the cancer cells. Finally, a formulation containing Sorafenib retained its properties over a period of 90 days. With characterization, the study of the formulated nanoemulsion has the potential to be used as a parenteral nanoemulsion in the treatment of cancer. Graphical abstractSchematic figure of high pressure homogenizer device.
Amphiphilic poly(3-hydroxylalkanoate) (PHA) copolymers find interesting applications in drug delivery. The aim of this study was to prepare nucleic acid adsorbed on (PHB-b-PEG-NH2) nanoparticle platform for gene delivery. For this purpose, PHB-b-PEG-NH2 block copolymers were synthesized via transesterification reactions. The copolymers obtained were characterized by Proton Nuclear Magnetic Resonance ((1)H-NMR), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) techniques. The cytotoxic, apoptotic and necrotic effects of these nanoparticles in the MDA 231 human breast cancer cell, the A549 human lung cancer cell and the L929 fibroblast cell lines were also investigated.
Nanoemulsions have attracted great attention in research, dosage form design and pharmacotherapy. This is as a result of a number of attributes peculiar to nanoemulsions such as optical clarity, ease of preparation, thermodynamic stabil-ity and increased surface area. Nanoemulsions also known as submicron emulsions serve as vehicles for the delivery of active pharmaceutical ingredients as well as other bioactives. They are designed to address some of the problems asso-ciated with conventional drug delivery systems such as low bioavailability and noncompliance. The importance of de-sign and development of emulsion nanocarrier systems aimed at controlling and/or improving required bioavailability levels of therapeutic agents cannot be overemphasized. Reducing droplet sizes to the nanoscale leads to some very in-teresting physical properties, such as optical transparency and unusual elastic behaviour. This review sheds light on the current state of nanoemulsions in the delivery of drugs and other bioactives. The morphology, formulation, charac-teristics and characterization of nanoemulsions were also addressed.
Therapeutic agents that inhibit a single target often cannot combat a multifactorial disease such as cancer. Thus, multi-target inhibitors (MTIs) are needed to circumvent complications such as the development of resistance. There are two predominant types of MTIs, (a) single drug inhibitor (SDIs) that affect multiple pathways simultaneously, and (b) combinatorial agents or multi-drug inhibitors (MDIs) that inhibit multiple pathways. Single agent multi-target kinase inhibitors are amongst the most prominent class of compounds belonging to the former, whereas the latter includes many different classes of combinatorial agents that have been used to achieve synergistic efficacy against cancer. Safe delivery and accumulation at the tumor site is of paramount importance for MTIs because inhibition of multiple key signaling pathways has the potential to lead to systemic toxicity. For this reason, the development of drug delivery mechanisms using nanotechnology is preferable in order to ensure that the MDIs accumulate in the tumor
vasculature, thereby increasing efficacy and minimizing off-target and systemic side effects. This review will discuss how nanotechnology can be used for the development of MTIs for cancer therapy with a focus on various nanoparticle formulations. It concludes with a discussion of the future of nanoparticle-based MTIs as well as the continuing obstacles being faced during the development of these unique agents.
Resistance to cancer chemotherapy is a common phenomenon especially in metastatic breast cancer (MBC), a setting in which patients typically have had exposure to multiple lines of prior therapy. The subsequent development of drug resistance can result in rapid disease progression during or shortly after completion of treatment. Moreover, cross-class multidrug resistance limits patient treatment choices, particularly in a setting where treatments options are few. One attempt to minimize the impact of drug resistance has been the concurrent use of two or more chemotherapy agents with unrelated mechanisms of action and differing modes of drug resistance, with the intent of blocking the development of multiple intracellular escape pathways essential for tumor survival. Within the past decade, an array of mechanistically diverse agents has augmented the list of combination regimens that may be both synergistic and efficacious in pretreated MBC. The aim of this paper is to review mechanisms of resistance to common chemotherapy agents and to consider current combination treatment options for heavily pretreated and/or drug-resistant patients with MBC.
Response surface methodology (RSM) was utilized to investigate the influence of the main emulsion composition; mixture of palm and medium-chain triglyceride (MCT) oil (6%-12% w/w), lecithin (1%-3% w/w), and Cremophor EL (0.5%-1.5% w/w) as well as the preparation method; addition rate (2-20 mL/min), on the physicochemical properties of palm-based nanoemulsions. The response variables were the three main emulsion properties; particle size, zeta potential and polydispersity index. Optimization of the four independent variables was carried out to obtain an optimum level palm-based nanoemulsion with desirable characteristics. The response surface analysis showed that the variation in the three responses could be depicted as a quadratic function of the main composition of the emulsion and the preparation method. The experimental data could be fitted sufficiently well into a second-order polynomial model. The optimized formulation was stable for six months at 4 °C.
Response surface methodology was applied to optimize the separation of dl-tryptophan from aqueous solution. dl-tryptophan was extracted into an emulsion liquid membrane containing Aliquat-336 in oleyl alcohol. The carrier concentration (10–30%, by volume), pH (10–14) and initial amino acid concentrations (1–7 mM) were the critical components of the separation optimized. Experiments were performed at 150 rpm stirring rate, for 30 min extraction time with equal volumes of organic and aqueous phases. The response surface equation to predict the extraction yield in the above range of critical components iswhere Y is the response, (extraction yield). Maximum Y (100%) was obtained by employing the following predicted optimum extraction conditions: a pH of 12.46, a carrier concentration of 22.22%, and an initial amino acid concentration of 4.97 mM.
This study reports the development of nanoemulsions intended for intravenous administration of thalidomide (THD). The formulations were prepared by spontaneous emulsification method and optimized with respect to thalidomide (0.01-0.05%, w/w), and hydrophilic emulsifier (polysorbate 80; 0.5-4.0%, w/w) content. The formulations were evaluated concerning physical appearance and drug crystallization; droplet size; zeta potential and drug assay. Only the formulation containing 0.01% THD and 0.5% polysorbate kept its properties in a satisfactory range over the evaluated period (60 days), i.e. droplet size around 200nm, drug content around 95% and zeta potential around -30mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape confirming the results obtained by photon correlation spectroscopy. Drug crystallization observed for higher content (THD 0.05%, w/w) nanoemulsions was investigated. The crystals observed at optical microscopy presented a different crystal habit compared to that of the raw material used. It was speculated whether the kind of THD polymorph employed could influence nanoemulsion formulation. Formulations were prepared with either one of THD polymorphs (β- or α-) and crystals were characterized by fourier transformed infrared spectroscopy (FTIR) and X-ray diffraction (XRD). It was observed that regardless of the polymorph employed (β- or α-), drug crystallization occurs in the α-form. THD solubility in oils was not influenced by the polymorphic form. In addition, the in vitro dissolution profile of the selected formulation (THD 0.01%, w/w; polysorbate 0.5%, w/w) was assessed by bulk-equilibrium reverse dialysis sac technique and demonstrated a release profile similar to that of a THD acetonitrile solution, with around 95% THD being dissolved within 4h. Finally, a pharmacokinetic simulation of an intravenous infusion of 250mL of the selected nanoemulsion suggests that the parenteral administration of a dose as low as 25mg might lead to therapeutic plasma concentrations of thalidomide.
The present study is aimed to characterize the electrostatic parameters of oil in water emulsion droplets composed of MCT (medium chain triglycerides), PL (phospholipids) and Poloxamer and containing increasing concentrations of the cationic lipid oleylamine (OA), in Hepes 20 mM pH 7.4. The initial zeta-potential data suggesting saturation of the droplet surface at high OA concentrations were completed by supplementary analysis: the distribution of the oleylamine within the droplet was determined by reacting the amino groups with the hydrophilic TNBS (trinitrobenzenesulfonic acid), the method being initially standardised with vesicles. In addition, surface potential and pH at the droplet surface were monitored by the pH-sensitive fluorophore 4-heptadecyl-7-hydroxycoumarin. Our results demonstrate that almost all the OA is localised and fully ionised at the droplet surface for all concentrations and that the observed plateau in the zeta-potential values obeys the Gouy-Chapman theory of ion condensation. It is also shown that the slipping plane separation as estimated by the Eversole-Boardman equation is higher that the expected values of 0.2 nm as a result of the relative position of the fluorophore and the outer boundary of the lipid interface thickness and the Poloxamer anchored at the interface only plays a minor role.
The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
The development of novel combination anticancer drug delivery systems is an important step to improve the effectiveness of anticancer treatment in metastatic breast cancer and to overcome increased toxicity of the currently used combination treatments. The aim of this study was to assess efficient targeting, therapeutic efficacy, and bioavailability of a combination of drugs (curcumin and α-tocopheryl succinate) loaded polystyrene–polysoyaoil–diethanol amine nanoparticles. Polystyrene–polysoyaoil–diethanol amine nanoparticles encapsulating two drugs, individually or in combination, were prepared by double-emulsion solvent evaporation method, resulting in particle size smaller than 250 nm with a surface negative charge between −30 and −40 mV. Entrapment efficiency of curcumin and α-tocopheryl succinate in the epigallocatechin gallate–conjugated dual-drug-loaded nanoparticles was found to be 68% and 80%, respectively. The release kinetics of curcumin and α-tocopheryl succinate from the nanoparticles exhibited a gradual and continuous profile followed by an initial burst behavior with a release over 20 days in vitro. Next, we have investigated the anticancer activity of nanoparticles encapsulating both the drugs and individually drug in human breast cancer cells (MDA-MB-231) using double-staining-based cell death analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assessment of cytotoxicity and flow cytometer. In vitro cytotoxicity studies revealed that epigallocatechin gallate–α-tocopheryl succinate/curcumin–polystyrene–polysoyaoil–diethanol amine nanoparticles are more potent than the corresponding α-tocopheryl succinate/curcumin–polystyrene–polysoyaoil–diethanol amine nanoparticles and their single-drug-loaded forms and show a synergistic and breast tumor targeting function. Thus, here, we propose epigallocatechin gallate–conjugated curcumin and α-tocopheryl succinate–loaded polystyrene–polysoyaoil–diethanol amine nanoparticles which effectively inhibit tumor growth and reduce toxicity compared to single-drug chemotherapy.
Response surface methodology (RSM) was used to optimize the formulation of a nanoemulsion for central delivery following parenteral administration. A mixture of medium-chain triglyceride (MCT) and safflower seed oil (SSO) was determined as a sole phase from the emulsification properties. Similarly, a natural surfactant (lecithin) and non-ionic surfactant (Tween 80) (ratio 1:2) were used in the formulation. A central composite design (CCD) with three-factor at five-levels was used to optimize the processing method of high energy ultrasonicator. Effects of pre-sonication ultrasonic intensity (A), sonication time (B), and temperature (C) were studied on the preparation of nanoemulsion loaded with valproic acid. Influence of the aforementioned specifically the effects of the ultrasonic processing parameters on droplet size and polydispersity index were investigated. From the analysis, it was found that the interaction between ultrasonic intensity and sonication time was the most influential factor on the droplet size of nanoemulsion formulated. Ultrasonic intensity (A) significantly affects the polydispersity index value. With this optimization method, a favorable droplet size of a nanoemulsion with reasonable polydispersity index was able to be formulated within a short sonication time. A valproic acid loaded nanoemulsion can be obtained with 60% power intensity for 15 min at 60 °C. Droplet size of 43.21 ± 0.11 nm with polydispersity index of 0.211 were produced. The drug content was then increased to 1.5%. Stability study of nanoemulsion containing 1.5% of valproic acid had a good stability as there are no significant changes in physicochemical aspects such as droplet size and polydispersity index. With the characteristisation study of pH, viscosity, transmission electron microscope (TEM) and stability assessment study the formulated nanoemulsion has the potential to penetrate blood-brain barrier in the treatment of epilepsy.
Fe 3 O 4 /montmorillonite nanocomposite (Fe 3 O 4 /MMT NC) was synthesized for removal of Pb 2+ , Cu 2+ and Ni 2+ ions from aqueous systems. The nanoadsorbent was characterized by X-ray diffraction and transmission electron microscopy and mean diameter of magnetic nanoparticles was about 8.24 nm. The experiments were designed by response surface methodology and quadratic model was used to prediction of the variables. The adsorption parameters of adsorbent dosage, removal time, and initial heavy metal ions concentration were used as the independent variables and their effects were investigated on the heavy metal ions removal. Variance analysis was utilized to judge the adequacy of the chosen models. Optimum conditions with initial heavy metal ions concentration of 510.16, 182.94, and 111.90 mg/L, 120 s of removal time and 0.06 g/0.025 L, 0.08 g/0.025 L, and 0.08 g/0.025 L of adsorbent amount were given 89.72%, 94.89%, and 76.15% of removal efficiency Pb 2+ , Cu 2+ and Ni 2+ ions, respectively. Prediction of models was in good agreement with experimental results and Fe 3 O 4 /MMT NC was found successful in removing heavy metals from their aqueous solutions.
Urocanic acid was conjugated to pullulan to synthesize O-urocanyl pullulan (URPA) with degree of substitution (DS) of 8.2%. URPA nanoparticles prepared by dialysis method had spherical shapes and a mean diameter of 156.8±16.8nm. Adriamycin (ADR) was successfully loaded into URPA nanoparticles and exhibited pH-sensitive in vitro release property. MTT assay showed that ADR-loaded URPA (ADR/URPA) nanoparticles had a significant higher toxicity against drug resistant MCF-7/ADR cells than free ADR, and the reversal index reached up to 9.6. The results of flow cytometry and confocal microscopy showed that URPA nanoparticles efficiently enhanced accumulation and retention of ADR in MCF-7/ADR cells and successfully delivered ADR into cell nucleus. The reversal effect of ADR/URPA nanoparticles on the drug resistance of MCF-7/ADR cells was perhaps related with their cell entry and intracellular drug release mechanisms.
The influence of both the nature of the surfactant and surfactant concentration on the processes of droplet breakup and coalescence in the formation of decane in water sub-micron emulsions in a high-pressure homogenizer were investigated. Emulsions were produced using a Microfluidics inc. M110-S microfluidizer with an impinging jet high-shear chamber. For all the food grade emulsifiers studied, the droplet size decreased with increasing concentration (weight %) reaching a limiting droplet size between 0.5 and 1% for the proteins and ∼1.5% for the Phospholipids. A hydrophobic fluorescent dye (1-undecylpyrene) was used to establish the extent of competition between droplet breakup and coalescence in the emulsification process. For the food proteins and phosphatidylglycerol, droplet coalescence in the process reduced as the amount of emulsifier increased, becoming zero at concentrations of about 0.5–1% i.e. the same concentration as that required to produce the limiting minimum droplet size. For phosphatidylcholine some coalescence in the process was observed up to the highest concentration studied (2%) which is indicative of the fact that it normally stabilises water in oil emulsions so favouring coalescence in the process. The data collected in this study show that in the emulsification process droplet size is determined by both breakup and coalescence events, and that the final droplet size is probably a consequence of multiple breakup events until at higher emulsifier concentrations the droplet size is reached which is limited by the breakup capabilities of the homogenizer. Emulsion stability over 400 h was investigated by measuring changes in the droplet size using dynamic light scattering. For the proteins the increase in droplet volume was shown to be linear with respect to time, indicating an Ostwald ripening process. Although there was coalescence on storage at the lowest concentrations of phospholipid used, there was no observed ripening at any emulsifier concentration showing that phospholipid interfaces are structured in such a way as to resist ripening even though decane has a solubility in water. The ripening rate for whey and β-lactoglobulin were observed to be approximately 10 times higher than the ripening rate calculated using the Lifshitz–Slesov–Wagner (LSW) theory ∼10–20 nm3 s−1. Ripening rates are explained in terms of the nature of the interface formed.
Nanoemulsions are submicron sized emulsions that are under extensive investigation as drug carriers for improving the delivery of therapeutic agents. They are by far the most advanced nanoparticle systems for the systemic delivery of biologically active agents for controlled drug delivery and targeting. Nanoemulsions are the thermodynamically stable isotropic system in which two immiscible liquid (water and oil) are mixed to form a single phase by means of an appropriate surfactants or its mix with a droplet diameter approximately in the range of 0.5-100 um. Nanoemulsion droplet sizes fall typically in the range of 20-200 nm and show narrow size distributions. Nanoemulsion show great promise for the future of cosmetics, diagnostics, drug therapies, and biotechnologies. In this review, the attention is focused to give brief regarding nanoemulsion formulation aspect, method of preparation, characterization techniques with special emphasis on various applications of nanoemulsion in different areas such as in cancer treatment, in drug targeting, as a mucosal vaccine, as a vehicle for transdermal drug delivery and lipophilic drug, as a self-nanoemulsifying and solid self-nanoemulsifying drug delivery system, etc.
The effect of temperature at different pH and ionic strengths on the aggregation kinetics of colloidal montmorillonite particles in aqueous dispersions was investigated. For a given temperature and pH, the rate constant for aggregation increased with increasing ionic strength. At pH≤4 the rate constant for colloid aggregation increased with increasing temperature, regardless of ionic strength. At pH≥10 the aggregation rate constant decreased with increasing temperature as a general trend. In the intermediate pH interval, the aggregation rate constant apparently decreased with increasing temperature except at the highest ionic strength, where it increased with increasing temperature. The aggregation rate constant decreased at alkaline pH compared with the acidic pH range. This effect became more pronounced at higher ionic strengths and higher temperatures but could not be observed at 4 °C. These observations are in qualitative agreement with DLVO calculations taking temperature, pH and ionic strength into account.
Response surface methodology (RSM) was applied to optimize the speed of agitation and the rate of aeration for the maximum production of glucose oxidase (GOD) by Aspergillus niger. A 22 central composite design using RSM was employed in this investigation. A quadratic model for GOD production was obtained. Aeration had more negative effect on GOD production than agitation. Significant negative interaction existed between agitation and aeration. The quadratic term of agitation presented significant positive effect. The maximum level of GOD was achieved when the speed of agitation and the rate of aeration were 756 rev min–1 and 0.9 v/v/m, respectively. The fermentation kinetics of GOD by Aspergillus niger were also studied in a batch system. A simple model was proposed using the Logistic equation for growth, the Luedeking–Piret equation for GOD production and Luedeking–Piret-like equation for glucose consumption. The kinetic model parameters X
0, X
m,
m, , k, Y
X/S, m
S and S
0 is 0.24 mg ml–1, 1.65 mg ml–1 and 0.23 h–1, 3.45 U mg–1, –0.81 U ml–1, 1.60 g g–1, 9.72 g g–1 h–1 and 97.6 g l–1, respectively. The model appeared to provide a reasonable description for each parameter during the growth phase. The production of GOD was growth-linked.
The development of parenteral emulsions continues to play an important role in the formulation and delivery of many drugs. In addition to solubilization and stabilization applications, appropriately designed parenteral emulsions are effective delivery systems for sustained release and targeting of drugs. Control of the strict requirements of globule size and surface charge is important in the design and ultimate stability of the formulation. This review highlights the important issues and suggests strategies to assist the scientist in the development, manufacture and stability of this essential dosage form.
Indomethacin was incorporated in an original emulsion formulation stabilized by a combination of phospholipids and an amphoteric surfactant, lauroamphodiacetate. The solubility of indomethacin in the various emulsion phases was pH-dependent. The pH of the emulsion was adjusted to 3.8 in order to promote localization of the drug in the oil phase and prevent drug ionization. Ionization would increase drug aqueous solubility and result in indomethacin precipitation. Optimal manufacturing conditions were identified yielding an emulsion with a mean droplet size of 110±20 nm and a zeta potential value of −50 mV. The emulsion was found to be chemically and physically stable for more than 5 months at 4°C. The results of the ocular tolerance study in rabbit eye indicated that hourly administration of the emulsion vehicle was well tolerated without any toxic or inflammatory response to the ocular surface during the 5 days of the study. Scanning electron microscopy revealed a normal corneal surface resembling that of the animals treated with physiological saline. The penetration rate of indomethacin through excised rabbit eye cornea from the emulsion and from a marketed product (Indocollyre®) were determined and compared using a novel mounted corneal diffusion assembly. It was shown that the apparent corneal permeability coefficient of indomethacin incorporated in the emulsion was 3.8 times greater than that of indomethacin in the marketed aqueous solution. The increase in corneal drug permeation could be attributed to various causes that are discussed in the manuscript.
Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice.
Sorafenib is slightly absorbed in the gastrointestinal tract due to its poor solubility in water. To improve its absorption, a novel nanoparticulate formulation-nanomatrix was used in the study. The nanomatrix was a system prepared from a porous material Sylysia(®) 350 and a pH sensitive polymer Eudragit(®). The formulations were optimized by orthogonal design (L(9)(3(4))) and their bioavailability were evaluated in rat, comparing to pH-sensitive Eudragit nanoparticles and suspension of sorafenib. In the formulations, the ratio of sorafenib to Eudragit(®) S100 was found to be more important determinant of the sorafenib bioavailability than the ratio of sorafenib to Sylysia(®) 350. As for the bioavailability, the AUC(0-36 h) of sorafenib nanomatrix was 13-33 times to that of sorafenib suspension, but only 16.8% to 40.8% that of Eudragit(®) S100 nanoparticles. This may be resulted from the different drug dispersion degree, release character and bioadhension activity. However, because all the materials used in the nanomatrix formulation are commonly adjuvant, safe, easy to get and cheap, above all, the nanomatrix formulation can solve the stability and scaling up problems in the nanoparticles, it had potential to develop into a product in the future.
In the present study, response surface methodology (RSM) based on central composite design (CCD) was employed to investigate the influence of main emulsion composition variables, namely drug loading, oil content, emulsifier content as well as the effect of the ultrasonic operating parameters such as pre-mixing time, ultrasonic amplitude, and irradiation time on the properties of aspirin-loaded nanoemulsions. The two main emulsion properties studied as response variables were: mean droplet size and polydispersity index. The ultimate goal of the present work was to determine the optimum level of the six independent variables in which an optimal aspirin nanoemulsion with desirable properties could be produced. The response surface analysis results clearly showed that the variability of two responses could be depicted as a linear function of the content of main emulsion compositions and ultrasonic processing variables. In the present investigation, it is evidently shown that ultrasound cavitation is a powerful yet promising approach in the controlled production of aspirin nanoemulsions with smaller average droplet size in a range of 200-300 nm and with a polydispersity index (PDI) of about 0.30. This study proved that the use of low frequency ultrasound is of considerable importance in the controlled production of pharmaceutical nanoemulsions in the drug delivery system.
Thermosensitive core-shell magnetic composite particles with a magnetic silica core and a rich poly (N-vinylcaprolactam) (PNVCL) shell layer were developed for studying the adsorption of bovine serum albumin (BSA) in a batch system. Various analytical and spectroscopic techniques including SEM, FT-IR, VSM and DSC were used to characterize the adsorbents prepared in this study. The combined effects of operating parameters such as initial temperature, pH and initial BSA concentration on the adsorption were analyzed using response surface methodology. The optimum conditions were 40°C, pH 4.68, and initial BSA concentration 2.0 mg/mL. Desorption experiments were conducted by altering the system temperature where a high recovery rate of protein was obtained. The separation process developed here indicates that the dual-responsive smart adsorbent could be an ideal candidate for the separation of protein.
The principal aim of this study was to develop an intravenous formulation of itraconazole (ITZ) using lipid nanoparticles based on binary mixture of liquid and solid lipids. Lipid nanoparticles were developed to provide the controlled release of ITZ as well as to improve the solubility of ITZ. Lipid nanoparticles were prepared with tristearin as a solid lipid, triolein as a liquid lipid, and a surfactant mixture of eggPC, Tween 80 and DSPE-PEG(2000). ITZ was incorporated at the concentration of 20mg/g. Lipid nanoparticles were manufactured by high-pressure homogenization method. The particle size and polydispersity index (PI) of lipid nanoparticles were below 280 nm and 0.2, respectively. Zeta potentials and incorporation efficiencies of lipid nanoparticles were around -30 mV and above 80%, respectively. Lipid nanoparticles containing 1% of liquid lipid showed the smallest particles size and the highest incorporation efficiency. Results from SEM, DSC and PXRD revealed that ITZ in lipid nanoparticles exists in an amorphous state. Release rates were increased as the amount of liquid lipid in lipid core increased, demonstrating that the release of ITZ from lipid nanoparticles could be controlled by modulation of the amount of liquid lipid in lipid core. Pharmacokinetic studies were performed after intravenous administration of lipid nanoparticles in rats at the dose of 5mg/kg. The plasma concentration of ITZ was prolonged after intravenous administration of lipid nanoparticles. It is concluded that binary lipid nanoparticles could control the release and pharmacokinetic parameters of ITZ.
In the present work, we developed water-in-oil (w/o) nanoemulsions for the intravesical administration of cisplatin.
The nanoemulsions were made up of soybean oil as the oil phase and Span 80, Tween 80, or Brij 98 as the emulsifier system. alpha-Terpineol and oleic acid were incorporated as permeation enhancers. The physicochemical characteristics of droplet size, zeta potential, and viscosity were determined. Nanoemulsions were administered intravesically for 1 approximately 4 h to rats in vivo. Animals were subsequently sacrificed, and the bladders were harvested to examine drug accumulation and histology.
Ranges of the mean size and zeta potential were 30 approximately 90 nm and -3.4 to -9.3 mV, respectively. The addition of enhancers further reduced the size of the nanoemulsions. The viscosity of all systems exhibited Newtonian behavior. The cisplatin-loaded nanoemulsions were active against bladder cancer cells. The nanoemulsions with Brij 98 exhibited the complete inhibition of cell proliferation. The encapsulation of cisplatin and carboplatin, another derivative of cisplatin, in nanoemulsions resulted in slower and more-sustained release. The amount of drug which permeated into bladder tissues significantly increased when using carriers containing Brij 98, with the alpha-terpineol-containing formulation showing the best result. The nanoemulsion with alpha-terpineol prolonged the duration of higher drug accumulation to 3 approximately 4 h. At the later stage of administration (3 approximately 4 h), this system increased the bladder wall deposition of cisplatin and carboplatin by 2.4 approximately 3.3-fold compared to the control solution. Histological examination of the urothelium showed near-normal morphology in rats instilled with these nanoemulsions. alpha-Terpineol possibly caused slight desquamation of umbrella cells.
The nanoemulsions are feasible to load cisplatin for intravesical drug delivery.
Virgin coconut oil (VCO)-in-water, nano-emulsion in the form of cream stabilized by Emulium Kappa as an emulsifier, was prepared by using the Emulsion Inversion Point method. A nano-emulsion with droplet size <300 nm was then obtained. VCO has recently become a more popular new material in the cosmetic industries. Emulium Kappa is an ionic emulsifier that contains sodium stearoyl lactylate, the active whitening ingredient was Kojic Dipalmitate. Ostwald ripening is the main destabilizing factor for the nano-emulsion. This decline can be reduced by adding non-soluble oil, namely squalene, to the virgin coconut oil. We tested VCO:squalene in the ratios of 10:0, 9.8:0.2, 9.6:0.4, 9.4:0.6, 9.2:0.8, 9:1 and 8:2 and discovered that squalene's higher molecular weight (above critical molecular weight) resulted in low polarity and insolubility in the continuous phase. The continuous partitioning between the droplets results in the decline of Ostwald ripening. Furthermore, flocculation may occur due to the instability of nano-emulsion, especially for the preparations with little or no squalene at all. The stability of the nano-emulsion was evaluated by the electrophoretic properties of the emulsion droplets. The zeta potential values for the emulsion increased as the percentage of squalene oil increased.
Polymeric micelles are supramolecular, core-shell nanoparticles that offer considerable advantages for cancer diagnosis and therapy. Their relatively small size (10-100 nm), ability to solubilize hydrophobic drugs as well as imaging agents, and improved pharmacokinetics provide a useful bioengineering platform for cancer applications. Several polymeric micelle formulations are currently undergoing phase I/II clinical trials, which have shown improved antitumor efficacy and reduced systemic toxicity. This minireview will focus on recent advancements in the multifunctional design of micellar nanomedicine with tumor targeting, stimulated drug release, and cancer imaging capabilities. Such functionalization strategies result in enhanced micellar accumulation at tumor sites, higher drug bioavailability, as well as improved tumor diagnosis and visualization of therapy. Ultimately, integrated nanotherapeutic systems (e.g., theranostic nanomedicine) may prove essential to address the challenges of tumor heterogeneity and adaptive resistance to achieve efficacious treatment of cancer.
A review about the application of response surface methodology (RSM) in the optimization of analytical methods is presented. The theoretical principles of RSM and steps for its application are described to introduce readers to this multivariate statistical technique. Symmetrical experimental designs (three-level factorial, Box-Behnken, central composite, and Doehlert designs) are compared in terms of characteristics and efficiency. Furthermore, recent references of their uses in analytical chemistry are presented. Multiple response optimization applying desirability functions in RSM and the use of artificial neural networks for modeling are also discussed.
Intravenously injectable o/w emulsions of drugs being poorly soluble in water and simultaneously in oils need to be produced by locating the drug in the interfacial lecithin layer, e.g. amphotericin B. For achieving this, up to now organic solvents were required. The objective was to develop a solvent-free production method for such emulsions. Drug and the pre-formed parenteral emulsion Lipofundin were mixed and subjected to high pressure homogenisation. Drug powder and emulsions were characterised regarding size and physical stability by photon correlation spectroscopy (PCS), laser diffractometry (LD) and zeta potential measurements. Drug incorporation was studied using light microscopy, electron microscopy (EM) and a centrifugation test to separate non-dissolved drug. Amphotericin B and carbamazepine were used as model drugs. The high streaming velocities lead to accelerated drug dissolution and partitioning into the interfacial layer (so-called "solubilisation by emulsification", SolEmuls Technology). The interfacial layer could incorporate (solubilise) a certain amount of drug, revealed by EM pictures. Exceeding this concentration, hybrid dispersions were formed consisting of drug-loaded oil droplets and drug nanocrystals of similar size (approximately 200 nm). Both dispersion types are i.v. injectable opening the opportunity to deliver the drug in a concentrated form at desired low injection volume, e.g. 10 mg/ml.
Previously we have formulated a new cationic emulsion, composed of 3beta [N-(N',N'-dimethylaminoethane) carbamoyl] cholesterol and dioleoylphosphatidyl ethanolamine, castor oil and Tween 80, and it efficiently delivered plasmid DNA into various cancer cells with low toxicity. Chitosan is a natural cationic polysaccharide and is able to form polyelectrolyte complexes with DNA, in which the DNA is condensed and protected against nuclease degradation. Based on these facts, chitosan was used as a condensing agent to enhance the transfection efficiency of cationic emulsion-mediated gene delivery vehicle. The particle size, zeta potential and transmission electron micrographs of DNA/emulsion complexes were observed before and after condensation by chitosan. In vitro transfection efficiency of naked or precondensed DNA/emulsion (pcDNA/E) complexes was investigated in human hepatoma cells (HepG2) using flow cytometer, confocal microscope and western blot. In addition, in vivo gene transfer was also evaluated as GFP mRNA expression by reverse transcriptase-polymerase chain reaction. The size of transfection complexes was reduced after the condensation of DNA by chitosan. Moreover, when the pcDNA/E complexes were administered into the mice, the GFP mRNA expression was prolonged in liver and lung until day 6. These results suggest that the use of chitosan enhance the in vitro transfection efficiency and extend in vivo gene transfer.
The formation of O/W nano-emulsions suitable for pharmaceutical application and the solubilisation of a practically non-water-soluble drug, lidocaine, have been studied in water/non-ionic surfactant/oil systems. Nano-emulsions were prepared by using low-energy emulsification methods, changing the composition at constant temperature. Kinetic stability was assessed by measuring droplet diameter as a function of time. Lidocaine solubilisation was studied in nano-emulsions with high water content. In the water/Cremophor EL/Miglyol 812 system the lowest droplet sizes, from 14 to 39nm at 10/90 and 40/60 oil/surfactant ratios, respectively, and 90% of water content, were obtained with an emulsification method consisting of stepwise addition of water to oil/surfactant mixtures at 70 degrees C. Nano-emulsions of this system showed high kinetic stability. Droplet diameters did not exceed 67nm after a period of at least 7 months. The maximum lidocaine concentration solubilised in nano-emulsions of the water/Cremophor EL/Miglyol 812 system with 90 and 95% of water content was 3.5 and 2.1%, respectively. These values are within the therapeutic range of lidocaine.
This study investigates the submicron lipid emulsion as a potential parenteral drug delivery system for nalbuphine and its ester prodrugs. Submicron emulsions were prepared using egg phospholipid as the main emulsifier, various co-emulsifiers were also incorporated, including Brij 30, Brij 98, and stearylamine. Squalene as the oil phase formed stable emulsions with small particles. Drug release was affected by incorporating various co-emulsifiers and drugs with various lipophilicity. The loading of nalbuphine into lipid emulsions resulted in the slower and sustained release of nalbuphine. Lipid emulsions containing Brij 98 could further enhance the release of prodrugs as compared to the aqueous solution (control) especially for nalbuphine enanthate (NAE). Hemolysis caused by the interaction between erythrocytes and lipid emulsions was investigated. Brij 30 and Brij 98 could shield the hemolytic activity of phospholipids in the oil/water interface, decreasing the acute toxicological potential of the emulsions. The in vivo analgesic activity of various emulsions was examined by a cold ethanol tail-flick test. The analgesic duration and potency were significantly increased by incorporating nalbuphine and NAE into Brij 98-containing emulsions. There was no need for nalbuphine benzoate (NAB) to show a controlled delivery manner by encapsulating into emulsions, since NAB itself could prolong the analgesic duration of nalbuphine due to the slow enzyme degradation. The in vivo analgesic activity correlated well to the profiles of in vivo pharmacokinetic profiles. The study demonstrates the feasibility of using submicron lipid emulsion as the parenteral drug delivery system for nalbuphine and its prodrugs.
Carbamazepine (CBZ), a widely used anticonvulsant drug, is a poorly soluble drug with no parenteral treatment available for patients. This study was aimed at developing a nanoemulsion for CBZ intravenous delivery. The spontaneous emulsification method was used to prepare different formulations containing 2mg/mL CBZ. Likewise, a 2(2) full factorial experimental design was applied to study the influence of two independent variables (type of oil and type of lipophilic emulsifier) on emulsion physicochemical characteristics. The nanoemulsions were evaluated concerning droplet size, zeta potential, viscosity, drug content and association to oily phase. The formulation, which presented the best characteristics required for intravenous administration was selected and refined with respect to the lipophilic emulsifier content (increase from 5% to 6% of soy lecithin). This formulation was characterized and kept its properties in a satisfactory range over the evaluated period (3 months), i.e. droplet size around 150 nm, drug content around 95% and zeta potential around -40 mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape with an amorphous core, whereas the in vitro release profile assessed by dialysis bags demonstrated a release kinetics square root time dependent, with 95% of ca. having been released within 11h.
Despite recent advances in cancer therapy, many malignant tumors still lack effective treatment and the prognosis is very poor. Paclitaxel is a potential anticancer drug, but its use is limited by the facts that paclitaxel is a P-gp substrate and its aqueous solubility is poor. In this study, three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology was evaluated in vitro as a way of enhancing delivery of paclitaxel. Paclitaxel was incorporated both in biotinylated (BP) and non-biotinylated (LP) PEG-PLA nanoparticles by the interfacial deposition method. Small (mean size approximately 110 nm), spherical and slightly negatively charged (-10 mV) BP and LP nanoparticles achieving over 90% paclitaxel incorporation were obtained. The successful biotinylation of nanoparticles was confirmed in a novel streptavidin assay. BP nanoparticles were targeted in vitro to brain tumor (glioma) cells (BT4C) by three-step avidin-biotin technology using transferrin as the targeting ligand. The three-step targeting procedure increased the anti-tumoral activity of paclitaxel when compared to the commercial paclitaxel formulation Taxol and non-targeted BP and LP nanoparticles. These results indicate that the efficacy of paclitaxel against tumor cells can be increased by this three-step targeting method.
Lecithin-based nanoemulsions
- V Klang
- C Valenta
V. Klang, C. Valenta, Lecithin-based nanoemulsions, J. Drug Delivery Sci. Technol.
- Z Izadiyan
Z. Izadiyan et al.
Materials Science & Engineering C 94 (2019) 841-849