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Purpose: The objective of this work was to formulate a delivery system of pDNA encoded p53 gene-loaded chitosan-sodium deoxycholate (CS-DS) nanoparticles, and to evaluate their influence on in vitro cytotoxicity and transfection efficiency of p53 gene. Methods: The prepared pDNA-loaded CS-DS nanoparticles were evaluated for morphology, particle size, zeta potential, entrapment efficiency %, in vitro release, in vitro cytotoxicity, and transfection efficiency. Results: The mean particle size ranged from from 96.5 ± 11.31 to 405 ± 46.39 nm. All nanoparticles had good positive zeta potential values. Entrapment efficiency % ranged from 38.25 ± 3.25 to 94.89 ± 5.67. The agarose gel electrophoresis confirmed the strong binding between plasmid and CS. The in vitro pDNA release from nanoparticles exhibited an initial burst effect followed by a sustained drug release over a period of 6 days. In vitro cytotoxicity against human Caco-2 cells showed low cell cytotoxicity of plain CS-DS nanoparticles, while pDNA-loaded CS-DS nanoparticles showed a cytotoxic effect with increasing nanoparticles' concentration. Gene transfection, analyzed by PCR and ELISA, showed a direct correlation between gene expression and concentration of pDNA. The highest expression of the gene was achieved with pDNA concentration of 9 µg/mL with 5.7 times increase compared to naked pDNA of the same concentration. Conclusion: The obtained results were very encouraging and offer an alternative approach to enhancing the transfection efficiency of genetic material-loaded chitosan-based delivery systems.

Background and purpose: Conventional topical ophthalmic aqueous solutions and suspensions are often associated with low bioavailability and high administration frequency, pulsatile dose and poor exposure to certain ocular parts. The aim of this study was to develop an ophthalmic nanoparticles loaded gel, for delivering prednisolone acetate (PA), to increase dosing accuracy, bioavailability, and accordingly, efficiency of PA in treating inflammatory ocular diseases. Methods: A novel formulation of self-assembled nanoparticles was prepared by the complexation of chitosan (CS) and, the counter-ion, sodium deoxycholate (SD), loaded with the poorly-water-soluble PA. Particle size, zeta potential, encapsulation efficiency (EE) and drug loading content (LC) of prepared nanoparticles were assessed. Moreover, the nanoparticles were characterized using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Drug release and eye anti-inflammatory potential of the prepared novel formulation was investigated. Results: Mean particle size of the nanoparticles have dropped from 976 nm ±43 (PDI 1.285) to 480 nm ±28 (PDI 1.396) when the ratio of CS-SD was decreased. The incorporation of 0.1-0.3% of polyvinyl alcohol (PVA), in the preparation stages, resulted in smaller nanoparticles: 462 nm ±19 (PDI 0.942) and 321 nm ±22 (PDI 0.454) respectively. DSC and FTIR results demonstrated the interaction between CS and SD, however, no interactions were detected between PA and CS or SD. Drug release of PA as received, in simulated tears fluid (pH 7.4), showed a twofold increase (reaching an average of 98.6% in 24 hours) when incorporated into an optimized nanoparticle gel formulation (1:5 CS-SD). Conclusion: The anti-inflammatory effect of PA nanoparticles loaded gel on female guinea pig eyes was significantly superior to that of the micronized drug loaded gel (P < 0.05).

Hany SM Ali,1,2 Ahmed F Hanafy,1,3 Abdulmalik Alqurshi1 1Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Research and Development Department, Al Andalous Pharmaceutical Industries, Cairo, Egypt Introduction: Presenting poorly water-soluble drugs as nanoparticles has shown to be an effective technique in enhancing drug dissolution rate, intrinsic solubility, and thus oral bioavailability. Nevertheless, working with nanoparticles introduces many challenges, one of which is their physical instability. Formulating nanoparticles into a solid dosage form may overcome such challenges and thus unlock the potential benefits of nanosizing. Methods: The current work investigates the possibility of developing a novel solid dosage form, with enhanced dissolution rate, whereby nanocrystals (~400nm) of the class II Biopharmaceutical Classification System drug, glyburide (GBD) were fabricated through combined precipitation and homogenization procedures. Using a novel, but scalable, spraying technique, GBD nanocrystals were loaded onto commonly used tablet fillers, water-soluble lactose monohydrate (LAC), and water insoluble microcrystalline cellulose (MCC). Conventional tableting processes were then used to convert the powders generated into a tablet dosage form. Results: Studies of redispersibility showed considerable preservation of size characteristics of GBD nanocrystals during downstream processing with redispersibility indices of 105 and 118 for GBD–LAC and GBD–MCC, respectively. Characterization by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy showed that the powders generated powders contained nanosized crystals of GBD which adhered to carrier surfaces. Powder flowability was characterized using Hausner ratio (HR) and Carr’s index (CI). GBD–LAC-loaded particles exhibited poor flowability with CI and HR of 37.5% and 1.60, respectively, whilst GBD–MCC particles showed a slightly improved flowability with CI and HR of 26.47% and 1.36, respectively. The novel tablet dosage form met US Pharmacopeia specifications, including drug content, hardness, and friability. Conclusion: Higher dissolution rates were observed from the nanocrystal-based tablets compared to the microsized and commercial drug formulations. Moreover, the novel nanocrystal tablet dosage forms showed enhanced in vivo performance with area under the plasma concentration–time curve in the first 24 hours values 1.97 and 2.24 times greater than that of marketed tablets. Keywords: glyburide, nanocrystals, downstream, tablet, bioavailability, solidification, redispersibility

The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatin's tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitol's recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (ΔrecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7° 2θ. Mannitol's greater affinity for both ions and residual water rather than its affinity for self-association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 μg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 °C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 °C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature, medium volume, and medium composition; naloxone tablet disintegration was extremely rapid, with full disintegration ranging from 5 to 20 s. In conclusion, rapidly disintegrating tablets have been developed which are suitable for proof-of-concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route.

A new robust and reliable high-performance liquid chromatography (HPLC) method with multi-criteria decision making (MCDM) approach was developed to allow simultaneous quantification of atenolol (ATN) and nifedipine (NFD) in content uniformity testing. Felodipine (FLD) was used as an internal standard (I.S.) in this study. A novel marriage between a new interactive response optimizer and a HPLC method was suggested for multiple response optimizations of target responses. An interactive response optimizer was used as a decision and prediction tool for the optimal settings of target responses, according to specified criteria, based on Derringer's desirability. Four independent variables were considered in this study: Acetonitrile%, buffer pH and concentration along with column temperature. Eight responses were optimized: retention times of ATN, NFD, and FLD, resolutions between ATN/NFD and NFD/FLD, and plate numbers for ATN, NFD, and FLD. Multiple regression analysis was applied in order to scan the influences of the most significant variables for the regression models. The experimental design was set to give minimum retention times, maximum resolution and plate numbers. The interactive response optimizer allowed prediction of optimum conditions according to these criteria with a good composite desirability value of 0.98156. The developed method was validated according to the International Conference on Harmonization (ICH) guidelines with the aid of the experimental design. The developed MCDM-HPLC method showed superior robustness and resolution in short analysis time allowing successful simultaneous content uniformity testing of ATN and NFD in marketed capsules. The current work presents an interactive response optimizer as an efficient platform to optimize, predict responses, and validate HPLC methodology with tolerable design space for assay in quality control laboratories.

Some synthesized antitumor derivatives of thiazole based chalcones including thiazolo[2,3-b]quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogues were subjected to be tested against standard microbial strains. Compound 18 showed higher activity against both Gram-positive and Gram-negative bacteria with MIC of 1.0, 1.0, 2.0, 2.0 and 4.0 μg/ml against S. aureus, B. subtilis, M. luteus, E. coli and P. aeuroginosa respectively which is better than ampicillin and very relative to ciprofloxacin standards. Moreover, this compound shows a good anti-biofilm activity against the Gram positive bacteria. Molecular docking studies of synthesized compounds against DHFR enzyme were carried out. Interestingly, active anticancer candidates 22,38, 40 and 41 in addition to most active antimicrobial agents 15, 18 and 20 bind to DHFR with nearly the same amino acid residues as MTX especially mentioning Arg28, Arg70, Asn64 and Lys68 which support our hypothesis that these compounds could act as antitumor or antibacterial via DHFR inhibition. Flexible alignment and surface mapping techniques have further provided lipophilic distributions supporting effective binding to DHFR. ADMET calculations for compounds 15, 18 and 20 suggested that they could be good orally absorbed antibacterial agents while compound 38 could be an orally absorbed anticancer agent with diminished toxicity. The results highlight studied thiazole based chalcones as efficient leads for designing new future antibacterial drug candidates.