Gehanne A.S. Awad

Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery

Transfersomes are highly efficient edge activator (EA)-based ultraflexible vesicles capable of, non-invasively, trespassing skin by virtue of their high, self-optimizing deformability. This investigation presents different approaches for the optimization of Transfersomes for enhanced transepidermal delivery of Diclofenac sodium (DS). Different methods of preparation, drug and lipid concentrations and vesicle compositions were employed, resulting in ultraflexible vesicles with diverse membrane characteristics. Evaluation of Transfersomes was implemented in terms of their shapes, sizes, entrapment efficiencies (EE%), relative deformabilities and in vitro skin permeation. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% (Span 85>Span 80>Na cholate>Na deoxycholate>Tween 80). Whereas, those prepared using 85:15% (w/w) ratio showed highest deformability (Tween 80 was superior to bile salts and spans). Transfersomes were proved significantly superior in terms of, the amount of drug deposited in the skin and the amount permeated, with an enhancement ratio of 2.45, when compared to a marketed product. The study proved that the type and concentration of EA, as well as, the method of preparation had great influences on the properties of Transfersomes. Hence, optimized Transfersomes can significantly increase transepidermal flux and prolong the release of DS, when applied non-occlusively.

Polyethylene glycol conjugated polymeric nanocapsules for targeted delivery of quercetin to folate-expressing cancer cells in vitro and in vivo.

In this work we describe the formulation and characterization of chemically modified polymeric nanocapsules incorporating the anticancer drug, quercetin, for the passive and active targeting to tumors. Folic acid was conjugated to poly(lactide-co-glycolide) (PLGA) polymer to facilitate active targeting to cancer cells. Two different methods for the conjugation of PLGA to folic acid were employed utilizing polyethylene glycol (PEG) as a spacer. Characterization of the conjugates was performed using FTIR and (1)H NMR studies. The PEG and folic acid content was independent of the conjugation methodology employed. PEGylation has shown to reduce the size of the nanocapsule; moreover, zeta-potential was shown to be polymer-type dependent. Comparative studies on the cytotoxicity and cellular uptake of the different formulations by HeLa cells, in the presence and absence of excess folic acid, were carried out using MTT assay and Confocal Laser Scanning Microscopy, respectively. Both results confirmed the selective uptake and cytotoxicity of the folic acid targeted nanocapsules to the folate enriched cancer cells in a folate-dependent manner. Finally, the passive tumor accumulation and the active targeting of the nanocapsules to folate-expressing cells were confirmed upon intravenous administration in HeLa or IGROV-1 tumor-bearing mice. The developed nanocapsules provide a system for targeted delivery of a range of hydrophobic anticancer drugs in vivo.

Phospholipid based colloidal poloxamer-nanocubic vesicles for brain targeting via the nasal route.

In this study, new phospholipid based colloidal nanocubic vesicles encapsulating olanzapine for its brain targeting via the nasal route were developed. The nanocubic vesicles were prepared by incorporating non-ionic copolymers, poloxamer 188 or 407, in the lipid bilayer. The effect of phospholipid:poloxamer molar ratio on the physicochemical properties of the nanocubic vesicles was investigated. The in vivo behavior and brain targeting of these vesicles were evaluated in rats. TEM photographs showed that the vesicles looked spherical before adding poloxamer. However, after poloxamer incorporation, the vesicles showed a predominant cubic shape, except those containing phospholipid:poloxamer in the molar ratio 5:1 which were spherical. DSC study confirmed perturbation of the packing characteristics as well as fluidization of the lipid bilayer by the polymer with consequent formation of the nanocubic structure. The mean diameter of the vesicles was in the range of 363-645 nm. All vesicles were elastic and the elasticity was found to depend on both poloxamer type and concentration. The intranasal nanocubic vesicles were significantly more efficient in targeting olanzapine to the brain compared to the liposomal vesicles with drug targeting efficiency values of 100% and 80%, respectively, and absolute bioavailability of 37.9% and 14.9%, respectively.

Brain delivery of olanzapine by intranasal administration of transfersomal vesicles

The aim of this study was to investigate the presence of a possible direct correlation between vesicle elasticity and the amount of drug reaching the brain intranasally. Therefore, transfersomes were developed using phosphatidylcholine (PC) as the lipid matrix and sodium deoxycholate (SDC), Span® 60, Cremophor® EL, Brij® 58, and Brij® 72 as surfactants. The influence of the type of surfactant and PC-to-surfactant ratio on vesicle morphology, size, membrane elasticity, drug entrapment, and in vitro drug release was studied. The prepared transfersomes were mainly spherical in shape, with diameters ranging from 310 to 885 nm. Transfersomes containing SDC and Span 60 with optimum lipid-to-surfactant molar ratio showed suitable diameters (410 and 380 nm, respectively) and deformability indices (17.68 and 20.76 mL/sec, respectively). Values for absolute drug bioavailability in rat plasma for transfersomes containing SDC and those containing Span 60 were 24.75 and 51.35%, whereas AUC0–360min values in rat brain were 22,334.6 and 36,486.3 ng/mL/min, respectively. The present study revealed that the deformability index is a parameter having a direct relation with the amount of the drug delivered to the brain by the nasal route.

Release Mechanisms Behind Polysaccharides-Based Famotidine Controlled Release Matrix Tablets

Polysaccharides, which have been explored to possess gelling properties and a wide margin of safety, were used to formulate single-unit floating matrix tablets by a direct compression technique. This work has the aim to allow continuous slow release of famotidine above its site of absorption. The floating approach was achieved by the use of the low density polypropylene foam powder. Polysaccharides (κ-carrageenan, gellan gum, xyloglucan, and pectin) and blends of polysaccharides (κ-carrageenan and gellan gum) and cellulose ethers (hydroxypropylmethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose) were tried to modulate the release characteristics. The prepared floating tablets were evaluated for their floating behavior, matrix integrity, swelling studies, in vitro drug release studies, and kinetic analysis of the release data. The differential scanning calorimetry and Fourier transform infrared spectroscopy studies revealed that changing the polymer matrix system by formulation of polymers blends resulted in formation of molecular interactions which may have implications on drug release characteristics. This was obvious from the retardation in drug release and change in its mechanistics.

Anticancer effect of atorvastatin nanostructured polymeric micelles based on stearyl-grafted chitosan

The purpose of this study was to develop a new therapeutic approach for atorvastatin (ATV) adopting nanostructured polymeric micelles for its controlled delivery to the cancer cells. Amphiphilic block copolymers of stearyl chitosan (SC) and sulfated stearyl chitosan (S-SC) that could self assemble to form polymeric micelles with different degree of substitution (DS) were synthesized and characterized. The synthesized chitosan derivatives were able to self assemble and form micelles encapsulating ATV with critical micellar concentrations ranging from 6.9 to 21μg/ml, drug-loading ranging from 40% to 84.1% and encapsulation efficiency ranging from 10.4% to 35%. ATV caused a significant decrease in particle size and zeta potential of both SC and S-SC micelles. Micelles encapsulating ATV exhibited a sustained release and more cytotoxic activity against MCF 7 and HCT 116 cell lines than ATV alone. The 50% cellular growth inhibition (IC50%) of the drug decreased from 10.4 to 3.7 in case of MCF 7 and from 9.4 to 3.4 in case of HCT 116 after its loading in micelles. These results indicate that SC ATV polymeric micelles can be considered as a promising system for site specific controlled delivery of ATV to tumor cells.

Biodistribution of 99mTc‐sunitinib as a potential radiotracer for tumor hypoxia imaging

Tyrosine kinases are groups of enzymes, which are over-expressed in solid tumor cells, representing good targets for different drugs such as sunitinib (N-[2-(diethylamino)ethyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide). The aim of this work was to design and synthesize (99m)Tc-sunitinib radiotracer and to study its tumor binding specificity as a novel selective radiopharmaceutical for tumor hypoxia imaging. The in vivo biodistribution of (99m)Tc-sunitinib in tumor bearing mice showed high target/non-target (T/NT) ratio (T/NT ~ 3 at 60 min post injection). This preclinical high biological accumulation in tumor cells suggests that (99m)Tc-sunitinib is ready to go through the clinical trials as a potential selective radiotracer able to image tumor hypoxia.

Spray dried inhalable ciprofloxacin powder with improved aerosolisation and antimicrobial activity.

In this study, the spray drying technique was used to prepare ciprofloxacin microparticles (CFX-MPs) for pulmonary administration. By virtue of its amphoteric properties, CFX was dissolved in either a slightly alkaline or acidic solution depending on the used polymer. Dextran and chitosan were used to prepare the MPs and modify the release characteristics of the drug. Particle surface modification was done with either DPPC or PEG. The effects of the manufacturing and formulation parameters on the drug-polymer interactions were investigated by thermal analysis and infrared spectroscopy. CFX-MPs showed improved aerosolisation properties and the encapsulated drug possessed high antimicrobial activity against two of the common and resistant respiratory pathogens: Pseudomonas aeruginosa and Staphylococus aureus. MPs were safe on the lung epithelial cells. Modulation of particle characteristics and drug release was possible by altering not only the polymer but also the type of the acid from which the powders were spray dried. MPs prepared with glutamic and aspartic acids showed better characteristics than those prepared with acetic and hydrochloric acids. Dextran modified particles showed improved aerosolisation properties and safety on lung epithelial cells.

Ammonium methacrylate units polymer content and their effect on acyclovir colloidal nanoparticles properties and bioavailability in human volunteers.

Acyclovir (ACV)-Eudragit (EUD) nanoparticles (NPs) were prepared using both EUD RS 100 and RL 100 with different charge density. The effect of charge intensity on particle size, encapsulation efficiency, and in vitro dissolution was assessed. The bioavailability of ACV NP colloids were evaluated in human volunteers, compared with commercial product using a validated LC-MS/MS method with a lower limit of quantification (LLOQ) of 0.02 microg/ml. EUD RL 100 with higher ammonium groups gave smaller NPs than EUD RS 100. The surface charge of the polymer did not affect encapsulation efficiency and in vitro dissolution. In human volunteers, both F2 and F5 colloidal nanosuspensions prepared with EUD RS and RL respectively in drug to polymer ratio 1:3 sustained the oral absorption of ACV, expressed by the significant lower C(max), significant delayed T(max) and the significant higher HVD(t 50%C(max)). The mean C(max) of F2, F5, and Zovirax were 0.61+/-0.06, 0.73+/-0.07 and 0.92+/-0.21 microg/ml respectively. Furthermore, the AUC(0-12) of F2 and F5 was significantly higher than that of Zovirax((R)) with values of 4.37+/-0.88, 5.14+/-0.87 and 3.21+/-0.53 microg/ml h respectively. The higher AUC(0-12) for both F2 and F5 reflected high relative bioavailability of 136.2% and 159.9% respectively compared to commercial ACV tablets.

Comparative effects of different cosurfactants on sterile prednisolone acetate ocular submicron emulsions stability and release.

Pluronic F68 is a nonionic, thermogelling block copolymer showing a high dehydration resistance during autoclaving due to its high cloud point (>100 degrees C). Tween 80 (with cloud point of 72.5 degrees C), is a polyoxyethylene-based cosurfactant, susceptible to temperature because of a decrease in its solubility by temperature increase. This study was done to explore whether or not, when compared with Tween 80, Pluronic F68 could be used blindly as a suitable cosurfactant for the preparation of terminally sterilized ocular submicron emulsions containing a lipid soluble drug, prednisolone acetate (PA). Various oils of variable viscosities were also tried. The results proved that no prediction can be made based on previously known physico-chemical properties alone and that emulsion stability depends on the contribution of the various emulsion components including: oil, surfactant and cosurfactant, in addition to the drug properties.