Osama Abd Elazeem Soliman

Amorphous spironolactone-hydroxypropylated cyclodextrin complexes with superior dissolution and oral bioavailability

Abstract Inclusion complex formations of spironolactone (SP) with four cyclodextrins (parent β- and γ-CyDs and hydroxypropylated β- and γ-CyDs) in aqueous solution and in the solid state were investigated by the solubility method, spectroscopic methods, thermal analysis, powder X-ray diffractometry, and cross polarization/magic angle spinning 13 C-nuclear magnetic resonance spectroscopy. Although the stability constant of the parent CyD complexes was larger than that of the corresponding hydroxypropylated CyD complexes, the solubilizing effect of hydroxypropyl CyDs was greater than that of parent CyDs. The solid complexes of SP were prepared by the spray-drying method in molar ratios of 1:2 and 2:3 (guest/host) with β-CyDs and γ-CyDs, respectively. The CyD complexes maintained an amorphous state for lengthy time periods (over 2 months at 75% relative humidity and 60°C), with the exception of the β-CyD complex which was converted to a crystalline complex after 1 month storage. The dissolution rate of hydroxypropyl CyD complexes was much faster than that of the parent CyD complexes, the rate being in the order of hydroxypropyl-β-CyD ⪢ hydroxypropyl-γ-CyD > γ-CyD > β-CyD > metastable SP forms > stable SP form. Plasma levels of canrenone, a major effective metabolite of SP, were monitored to estimate the absorption-enhancing effect of hydroxypropyl CyDs. The area under the plasma concentration-time curve after oral administration of the hydroxypropyl-β-CyD complex in dogs was 3.6 times that of SP alone, and this enhancement was higher than those of the parent CyD complexes reported previously (Seo, H., Tsuruoka, M., Hashimoto, T., Fujinaga, T., Otagiri, M. and Uekama, K., Enhancement of oral bioavailability of spironolactone by β- and γ-cyclodextrin complexations. Chem. Pharm. Bull. , 31 (1983) 286–291).

Pharmaceutical Nanotechnology Nanoparticle-Based Topical Ophthalmic Formulations for Sustained Celecoxib Release

Celecoxib-loaded NPs were prepared from biodegradable polymers such as poly-ε-caprolactone (PCL), poly(L-lactide) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA) by spontaneous emulsification solvent diffusion method. Different concentrations of polymers, emulsifier, and cosurfactants were used for formulation optimization. Nanoparticles (NPs) were characterized regarding their particle size, PDI, zeta potential, shape, morphology, and drug content. Celecoxib-loaded NPs were incorporated into eye drops, in situ gelling system, and gel and characterized regarding their pH, viscosity, uniformity of drug content, in vitro release, and cytotoxicity. The results of optimized celecoxib-loaded PCL-, PLGA-, and PLA-NPs, respectively, are particle size 119 ± 4, 126.67 ± 7.08, and 135.33 ± 4.15 nm; zeta potential -22.43 ± 2.91, -25.46 ± 2.35, and -31.81 ± 2.54 mV; and encapsulation efficiency 93.44 ± 3.6%, 86.00 ± 1.67%, and 79.04 ± 2.6%. TEM analyses revealed that NPs have spherical shapes with dense core and distinct coat. Formulations possessed uniform drug content with pH and viscosity compatible with the eye. Formulations showed sustained release without any burst effect with the Higuchi non-fickian diffusion mechanism. Cytotoxicity studies revealed that all formulations are nontoxic. Our formulations provide a great deal of flexibility to formulation scientist whereby sizes and zeta potentials of our NPs can be tuned to suit the need using scalable and robust methodologies. These formulations can thus serve as a potential drug delivery system for both anterior and posterior eye diseases.

Natural bioadhesive biodegradable nanoparticles-based topical ophthalmic formulations for sustained celecoxib release: in vitro study

Abstract Background: Our goal was to prepare and evaluate topical ophthalmic formulations containing optimized celecoxib-loaded bioadhesive cationic chitosan or anionic alginate nanoparticles for sustained release of

Water-soluble complex of curcumin with cyclodextrins: Enhanced physical properties for ocular drug delivery

BACKGROUND Curcumin, a natural hydrophobic polyphenol, has been reported to have diverse pharmacological activities. Previous studies have evaluated its efficacy using both oral and transdermal dosage forms. However, two major obstacles-poor aqueous solubility and low stability-severely limited its pharmaceutical use. OBJECTIVE The main objective of this study was to prepare curcumin eye drops that provided sustained release to allow for once daily application in retinitis pigmentosa. METHOD To achieve our goal, curcumin was complexed with β -cyclodextrin and hydroxypropyl-β- cyclodextrin in two molar ratios (1:1 and 1:2) using co-solvent, co-solvent with sonication and freezedrying filtration methods. A total of 12 complexes were prepared, then characterized using differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, solubility assessment and in vitro release studies. RESULTS An improvement in curcumin aqueous solubility relative to pure curcumin was achieved for all 12 complexes. However, the freeze-drying filtration method was superior to all other methods because it produced highly water-soluble drug-CD complexes. Based on our stability analyses, pH 6.8 phosphate buffer containing 1% Tween 80 was selected as the release medium for in vitro release studies because curcumin exhibited high stability in this medium. Our F11 formulation provided sustained release of the drug for more than 96 h with a maximum amount released of drug (21.77±0.26 μg/ml). Our in vitro release data also showed that release of drug from curcumin-CDs inclusion complexes followed a Higuchi non-Fickian diffusion mechanism. CONCLUSION Based on these results, F11 was formulated as eye drops, which provide a promising once daily novel topical delivery of this naturally derived phytochemical.

Stability and Ocular Pharmacokinetics of Celecoxib-Loaded Nanoparticles Topical Ophthalmic Formulations

A spontaneous emulsification and/or solvent diffusion method was used for the preparation of celecoxib-loaded nanoparticles (NPs) using polymers, including chitosan (CS), sodium alginate, poly-ε-caprolactone (PCL), poly-l-lactide, and poly-d,l-lactide-co-glycolide. NPs were incorporated into vehicles (eye drops, in situ gelling system, and gel). Formulations were subjected to an accelerated stability study by storing them at elevated temperatures of 30, 35, and 45°C for 6 months. Formulations were evaluated monthly for general appearance, pH, viscosity, particle size, polydispersity index, zeta potential, and drug content. Gels containing CS-NPs and PCL-NPs were selected for an ocular pharmacokinetics study using Sprague-Dawley rats due to their high stability and long shelf lives (24.56 and 33.76 months, respectively). The gel improved NP stability by keeping it inside its network structure, which protected them from aggregation and interacting with water. Our formulations improved celecoxib bioavailability due to their bioadhesivness, thus preventing their rapid removal. Also, NPs acted as drug reservoirs that adhered to eye surface and continuously released the drug. The availability of celecoxib in all eye tissues and its absence in plasma suggests that our formulation could be used for anterior eye disorders and also for treatment of diseases associated with the posterior eye with no systemic side effects.

Nimodipine Ophthalmic Formulations for Management of Glaucoma

PurposePreparation and evaluation of topical ophthalmic formulations containing nimodipine-CD complexes prepared using HP-β-CD, SBE-β-CD and M-β-CD for the management of glaucoma.MethodsNimodipine-CD complexes were prepared using a freeze-drying method. Two different molar ratios (NMD:CD) were used for each cyclodextrin. The inclusion complexes were characterized using DSC, FTIR, yield (%), drug content and in vitro release characteristics. NMD-CD complexes incorporated into chitosan eye drops and a temperature-triggered in situ gelling system were evaluated for their pH, viscosity and in vitro release characteristics. We determined the intraocular pressure (IOP) lowering effect of NMD-hydroxypropylmethylcellulose (HPMC) eye drops through a single dose response design using C57BL/6J mice. The minimum effective concentration (MEC) of nimodipine was further applied to mice that vary in the parental allele of Cacna1s, the drug target of nimodipine. Cytotoxicity was also evaluated.ResultsOur ophthalmic formulations possessed pH and viscosity values that are compatible with the eye. In vitro release of nimodipine was significantly increased from chitosan eye drops containing NMD-CD complexes compared to uncomplexed drug. Administration of nimodipine can lower IOP significantly after a single drop of drug HPMC suspension. The IOP-lowering response of the MEC (0.6%) was significantly influenced by the parental allele of Cacna1s.ConclusionsNimodipine can be used as a promising topical drug for management of glaucoma through ocular delivery.