METHODS: The Multi-Layered Perceptron (MLP) neural network was used to predict the dissolution profiles of theophylline pellets containing different ratios of microcrystalline cellulose (MCC) and glyceryl monostearate (GMS). The concepts of leave-one-out as well as a time-point by time-point estimation basis were used to predict the rate of drug release for each matrix ratio. All the data were used for training, except for one set which was selected to compare with the predicted output. The closeness between the predicted and the reference dissolution profiles was investigated using similarity factor (f2).
RESULTS: The f2 values were all above 60, indicating that the predicted dissolution profiles were closely similar to the dissolution profiles obtained from physical experiments.
CONCLUSION: The MLP network could be used as a model for predicting the dissolution profiles of matrix-controlled release theophylline pellet preparation in product development.
METHODS: Imiquimod-loaded fish oil bigel colloidal system was prepared using a blend of carbopol hydrogel and fish oil oleogel. Bigels were first characterized for their mechanical properties and compared to conventional gel systems. Ex vivo permeation studies were performed on murine skin to analyze the ability of the bigels to transport drug across skin and to predict the release mechanism via mathematical modelling. Furthermore, to analyze pharmacological effectiveness in skin cancer and controlling imiquimod-induced inflammatory side effects, imiquimod-fish oil combination was tested in vitro on epidermoid carcinoma cells and in vivo in Swiss albino mice cancer model.
RESULTS: Imiquimod-loaded fish oil bigels exhibited higher drug availability inside the skin as compared to individual imiquimod hydrogel and oleogel controls through quasi-Fickian diffusion mechanism. Imiquimod-fish oil combination in bigel enhanced the antitumor effects and significantly reduced serum pro-inflammatory cytokine levels such as tumor necrosis factor-alpha and interleukin-6, and reducing tumor progression via inhibition of vascular endothelial growth factor. Imiquimod-fish oil combination also resulted in increased expression of interleukin-10, an anti-inflammatory cytokine, which could also aid anti-tumor activity against skin cancer.
CONCLUSION: Imiquimod administration through a bigel vehicle along with fish oil could be beneficial for controlling imiquimod-induced inflammatory side effects and in the treatment of skin cancer.
METHODS: The designed nano- anticancer formulation was characterized thorough X-ray diffraction (XRD), Fourier transformed infrared (FTIR), transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM) and Brunauer-Emmett-Teller (BET) methods. The nano- anticancer formulation (DTX- CaCO3NP) was evaluated for drug delivery properties thorough in vitro release study in human body simulated solution at pH 7.4 and intracellular lysosomal pH 4.8.
RESULTS: Characterization revealed the successful synthesis of DTX- CaCO3NP, which had a sustained release at pH 7.4. TEM showed uniformly distributed pleomorphic shaped pure aragonite particles. The highest entrapment efficiency (96%) and loading content (11.5%) were obtained at docetaxel to nanoparticles ratio of 1:4. The XRD patterns revealed strong crystallizations in all the nanoparticles formulation, while FTIR showed chemical interactions between the drug and nanoparticles with negligible positional shift in the peaks before and after DTX loading. BET analysis showed similar isotherms before and after DTX loading. The designed DTX- CaCO3NP had lower (p 0.05) effects at 48 h and 72 h. However, the DTX- CaCO3NP released less than 80% of bond DTX at 48 and 72 h but showed comparable effects with free DTX.
CONCLUSIONS: The results showed that the developed DTX- CaCO3NP released DTX slower at pH 7.4 and had comparable cytotoxicity with free DTX at 48 and 72 h in MCF-7 cells.
METHOD: Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy.
RESULTS: Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone.
CONCLUSIONS: The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.
METHODS: In the present study, graphene oxide-polyethylene glycol (GOPEG) nanocarrier is designed and loaded with two anticancer drugs; Protocatechuic acid (PCA) and Chlorogenic acid (CA). The designed anticancer nanocomposite was further coated with folic acid to target the cancer cells, as their surface membranes are overexpressed with folate receptors.
RESULTS: The particle size distribution of the designed nanocomposite was found to be narrow, 9-40 nm. The release profiles of the loaded drugs; PCA and CA was conducted in human body simulated PBS solutions of pH 7.4 (blood pH) and pH 4.8 (intracellular lysosomal pH). Anticancer properties were evaluated against cancerous cells i.e. liver cancer, HEPG2 and human colon cancer, HT-29 cells. The cytocompatbility was assessed on normal 3T3 fibroblasts cells.
CONCLUSION: The size of the final designed anticancer nanocomposite formulation, GOPEG-PCACA-FA was found to be distributed at 9-40 nm with a median of 8 nm. The in vitro release of the drugs PCA and CA was found to be of sustained manner which took more than 100 h for the release. Furthermore, the designed formulation was biocompatible with normal 3T3 cells and showed strong anticancer activity against liver and colon cancer cells.
METHODS: Oligo, low, medium and high molecular weight chitosan nanoparticles were prepared by nanospray drying technique. These nanoparticles were incubated with alveolar macrophages in vitro and had model drug sodium fluorescein added into the same cell culture. The diffusion characteristics of sodium fluorescein and nanoparticle behavior were investigated using fluorescence microscopy, scanning electron microscopy, differential scanning calorimetry and Fourier transform infrared spectroscopy techniques.
RESULTS: The oligochitosan nanoparticles enabled macrophage membrane fluidization with the extent of sodium fluorescein entry into macrophages being directly governed by the nanoparticle loading. Using nanoparticles made of higher molecular weight chitosan, sodium fluorescein permeation into macrophages was delayed due to viscous chitosan diffusion barrier at membrane boundary.
CONCLUSION: Macrophage-chitosan nanoparticle interaction at membrane interface dictates drug migration into cellular domains.
METHODS: Hydrophilic pectin-sulphanilamide films, with or without oleic acid (OA), were subjected to drug release and skin permeation studies. The skins were untreated or microwave-treated, and characterized by infrared spectroscopy, Raman spectroscopy, thermal, electron microscopy and histology techniques.
RESULTS: Skin treatment by microwave at 2450 MHz for 5 min promoted drug permeation from OA-free film without incurring skin damage. Skin treatment by microwave followed by film loaded with drug and OA resulted in permeation of all drug molecules that were released from film. Microwave exerted spacing of lipid architecture of stratum corneum into structureless domains which was unattainable by OA. It allowed OA to permeate stratum corneum and accumulate in dermis at a greater ease, and synergistically inducing lipid/keratin fluidization at hydrophobic C-H and hydrophilic O-H, N-H, C-O, C=O, C-N regimes of skin, and promoting drug permeation.
CONCLUSION: The microwave technology is evidently feasible for use in promotion of drug permeation across the skin barrier. It represents a new approach in transdermal drug delivery.
METHOD: Eight pseudoternary phase triangles, containing ethyl oleate as the oil component and a mixture of two nonionic surfactants and n-alcohol or 1,2-alkanediol as a cosurfactant, were constructed and used for training, testing, and validation purposes. A total of 21 molecular descriptors were calculated for each cosurfactant. A genetic algorithm was used to select important molecular descriptors, and a supervised artificial neural network with two hidden layers was used to correlate selected descriptors and the weight ratio of components in the system with the observed phase behavior.
RESULTS: The results proved the dominant role of the chemical composition, hydrophile-lipophile balance, length of hydrocarbon chain, molecular volume, and hydrocarbon volume of cosurfactant. The best GNN model, with 14 inputs and two hidden layers with 14 and 9 neurons, predicted the phase behavior for a new set of cosurfactants with 82.2% accuracy for ME, 87.5% for LC, 83.3% for the O/W EM, and 91.5% for the W/O EM region.
CONCLUSIONS: This type of methodology can be applied in the evaluation of the cosurfactants for pharmaceutical formulations to minimize experimental effort.
METHODS: Polymeric carriers with different hydrophobic to hydrophilic ratios were used to prepare several electrospun solid dispersion formulations. Physicochemical properties and surface morphology of the samples were assessed using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR), polarized light microscopy, Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD) and Scanning Electron Microscopy (SEM). Dissolution study was conducted in a non-sink condition to assess the drug release.
RESULTS: Incorporation of a higher amount of hydrophilic component showed an improvement in formulating a fully amorphous system based on XRPD, yet the dissolution rate increment showed no significant difference from the lower. Hence, the degree of crystallinity is proven not to be the crucial factor contributing to dissolution rate improvement. The presence of a concomitant hydrophobic component, however, showed ability in resisting precipitation and sustaining supersaturation.
CONCLUSION: Hydrophobicity in a binary carrier system plays an important role in achieving and maintaining the supersaturated state particularly for an amorphous solid dispersion. Graphical Abstract.
METHODS: CMC/PLA/ZnO/CUR nanocomposite films were prepared by the dispersion of CMC and ZnO NPs in solubilized PLA/curcumin medium, followed by solvent casting step. Curcumin is poorly water-soluble and used as the model drug in this study. The films with different contents of CMC, PLA and ZnO NPs were characterized using FTIR, impedance spectroscopy, tensile testing and FESEM imaging. The in vitro drug release of the films was carried out in deionized water under DC electric field of 4.5 V.
RESULTS: The ionic conductivity of the films increased with increasing the CMC concentration of the film. The addition of a small amount of ZnO NPs (2%) successfully restored the tensile properties of the film. In response to the application of the electric field, the composite films released drug with a near-linear profile. There was no noticeable amount of passive diffusion of the drug from the film with the absence of the electric field.
CONCLUSION: The outcome of this study enabled the design of an electric-responsive nanocomposite platform for the delivery of poorly water-soluble/non-ionic drugs. Graphical abstract.
METHODS: It was formulated using high pressure homogenization followed by probe sonication and formulation variables were optimized using Central Composite Design. The particle size (PS), zeta potential (ZP), entrapment efficiency (EE), drug release, cytotoxicity on NIH 3T3 fibroblasts cells and HaCaT keratinocytes cells and efficacy on RAW264.7 cells for optimized formulation was determined.
RESULTS: The PS, ZP and EE were found to be 85.26 nm, -23.7 ± 7.45 mV, 99.2 ± 2.62 % (Mes) and 84 ± 1.51 % (Cur), respectively. The good correlation between predicted and obtained value indicated suitability and reproducibility of experimental design. NLCs showed spherical shape as confirmed by TEM. In vitro drug release profile of prepared formulation showed that Mes exhibited 100 % release at 48 h, whereas Cur exhibited 82.23 ± 2.97% release at 120 h. Both the drugs exhibited sustained release upon incorporation into the NLCs. The absence of any significant cell death during MTT assay performed on NIH 3T3 fibroblasts cells and HaCaT keratinocytes cells indicated that NLCs' were safe for use. Furthermore, significant reduction in nitric oxide level during anti-inflammatory evaluation of formulation on RAW264.7 cells showed excellent potential for the formulation to treat inflammation. The formulation was found stable as no significant difference between the PS, ZP and EE of the fresh and aged NLCs was observed.
CONCLUSION: The outcomes of study deciphered successful formulation of Mes-Cur NLCs.
METHODS: Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields with the data integrated into the analysis of lattice deformation as computed using a statistical approach.
RESULTS: The approach developed comprises three main components. Firstly, the identification of the likely direction of deformation based on lattice unit cell geometry; secondly, the identification of likely lattice planes for deformation through the calculation of the strength and stereochemistry of interplanar intermolecular interactions, surface plane rugosity and surface energy; thirdly, identification of potential crystal planes for cleavage fracture by assessing intermolecular bonding anisotropy. Pentaerythritol is predicted to fracture by brittle cleavage on the {001} lattice planes by strong in-plane hydrogen-bond interactions in the <110>, whereas pentaerythritol tetranitrate is predicted to deform by plastic deformation through the slip system {110} , with both predictions being in excellent agreement with known experimental data.
CONCLUSION: A crystallographic framework and associated workflow for predicting the mechanical deformation of molecular crystals is developed through quantitative assessment of lattice energetics, crystal surface chemistry and crystal defects. The potential for the de novo prediction of the mechanical deformation of pharmaceutical materials using this approach is highlighted for its potential importance in the design of formulated drug products process as needed for manufacture by direct compression.
METHODS: siRNA was conjugated with a thermo-responsive copolymer that was synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and hydrophilic N,N-dimethylacrylamide (DMAA) to permit thermally controlled interaction between siRNA and an intracellular gene silencing-related protein by utilizing the coil-to-globule phase transition of the copolymer. The composition of the copolymer was fine-tuned to obtain lower critical solution temperature (LCST) around body temperature, and the phase transition behavior was evaluated. The cellular uptake and gene silencing efficiency of the copolymer-siRNA conjugates were then investigated in cultured cells.
RESULTS: The siRNA conjugated with the copolymer with LCST of 38.0°C exhibited ~ 11.5 nm of the hydrodynamic diameter at 37°C and ~ 9.8 nm of the diameter at 41°C, indicating the coil-globule transition above the LCST. In line with this LCST behavior, its cellular uptake and gene silencing efficiency were enhanced when the temperature was increased from 37°C to 41°C.
CONCLUSION: By fine-tuning the LCST behavior of the copolymer that was conjugated with siRNA, siRNA activity could be controlled in a thermo-responsive manner around the body temperature. This technique may offer a promising approach to induce therapeutic effects of siRNA selectively in the target site even in the in vivo conditions.
METHODS: A total of six conserved peptides representing B- and T-cell epitopes of Influenza A were identified and they were formulated in either incomplete Freund's adjuvant containing CpG ODN 1826 or being encapsulated in PLGA nanoparticles for the evaluation of immunogenicity in BALB/c mice.
RESULTS: The self-adjuvanting PLGA nanoparticles encapsulating the six conserved peptides were capable of eliciting the highest levels of IgG and IFN- γ producing cells. In addition, the immunogenicity of the six peptides encapsulated in PLGA nanoparticles showed greater humoral and cellular mediated immune responses elicited by the mixture of six naked peptides formulated in incomplete Freund's adjuvant containing CpG ODN 1826 in the immunized mice. Peptide 3 from the mixture of six peptides was found to exert necrotic effect on CD3+ T-cells and this finding indicated that peptide 3 should be removed from the nanovaccine formulation.
CONCLUSION: The study demonstrated the self-adjuvanting properties of the PLGA nanoparticles as a delivery system without the need for incorporation of toxic and costly conventional adjuvants in multi-epitope peptide-based vaccines.