Aysu Yurdasiper

Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel

This work examined the effect of sodium carbonate (Na(2)CO(3)) on the topical delivery of methotrexate (MTX) from a loaded nanogel in vitro and the modulation of prostaglandin E(2) (PGE(2)) production in skin ex vivo. A nanogel based on co-polymerised N-isopropylacrylamide (NIPAM) and butylacrylate (BA) was synthesized, characterized and loaded with MTX. Finite doses were then applied to excised porcine epidermal membranes mounted in Franz diffusion cells, followed by the addition of saturated aqueous Na(2)CO(3). For comparison, the addition of half-saturated Na(2)CO(3) was examined along with loaded nanogel alone. The same treatments were applied to Silastic membrane and full-thickness porcine ear skin ex vivo, which was then treated with radioimmunoprecipitation buffer and probed for levels of PGE(2) using a commercial enzyme immunoassay kit. The MTX-loaded nanogel, which demonstrated de-swelling by 7% over the range 25-37°C, provided a MTX flux of 1.4±0.3ngcm(-2)h(-1); this increased to 3.1±0.22ngcm(-2)h(-1) upon the addition of saturated aqueous Na(2)CO(3) (p<0.05). Lag times were 6 and ∼0h, respectively. Similar results were obtained using half-saturated aqueous Na(2)CO(3). No permeation was detected across Silastic membrane. PGE(2) levels for water (control) and saturated aqueous Na(2)CO(3) were similar, but reduced by 33% when the MTX-loaded nanogel was applied, and by 57% when this was followed by the application of saturated aqueous Na(2)CO(3) (p<0.01). A novel mechanism is proposed whereby the change in temperature experienced by the nanogel as it penetrated skin induced de-swelling and expulsion of MTX in situ. The added Na(2)CO(3) lead to further solubilisation and MTX release, hence increasing the concentration gradient, flux and reducing PGE(2) production.

Studies on Mefenamic Acid Microparticles: Formulation, In Vitro Release, and In Situ Studies in Rats

In this study, we investigated the in vitro characteristics of mefenamic acid (MA) microparticles as well as their effects on DNA damage. MA-loaded chitosan and alginate beads were prepared by the ionotropic gelation process. Microsponges containing MA and Eudragit RS 100 were prepared by quasi-emulsion solvent diffusion method. The microparticles were characterized in terms of particle size, surface morphology, encapsulation efficiency, and in vitro release profiles. Most of the formulation variables manifested an influence on the physical characteristics of the microparticles at varying degrees. We also studied the effects of MA, MA-loaded microparticles, and three different polymers on rat brain cortex DNA damage. Our results showed that DNA damage was higher in MA-loaded Eudragit microsponges than MA-loaded biodegradable chitosan or alginate microparticles.

Modification of solid lipid nanoparticles loaded with nebivolol hydrochloride for improvement of oral bioavailability in treatment of hypertension: polyethylene glycol versus chitosan oligosaccharide lactate

Abstract Nebivolol (NB)-loaded solid lipid nanoparticles (SLNs) were prepared and modified with chitosan oligosaccharide lactate (COL) and polyethylene glycol (PEG) stearate for improvement of its oral bioavailability. Compritol, poloxamer and lecithin were used for the preparation of SLNs by homogenisation method. After in vitro characterisation effect of lipase, pepsin, or pancreatin on degradation and release rate were investigated. Cytotoxicity and permeation were studied on Caco-2 cells. As COL concentration increased in SLNs, size and zeta potential increased. PEG concentration was reversely proportional to particle size with no change in zeta potential. Encapsulation efficiencies (EEs) were determined as 84–98%. DSC confirmed solubilisation of NB in lipid matrix. A sustained release with no burst effect was determined. The presence of enzymes affected the release. SLNs did not reveal cytotoxicity and highest permeability was obtained with PEG modification. PEG-modified SLNs could be offered as a promising strategy for oral delivery of NB.

Enhanced delivery of naproxen to the viable epidermis from an activated poly N-isopropylacrylamide (PNIPAM) Nanogel: Skin penetration, modulation of COX-2 expression and rat paw oedema

Stimulus-responsive drug-loaded poly (N-isopropylacrylamide) nanogels were examined as a means of enhancing the delivery of naproxen into skin ex vivo. Following massaging into skin, the epidermis was probed (with and without base activation) for depth penetration and transdermal delivery of drug, and anti-inflammatory activity in the relative levels of COX-2 expression. Rat paw oedema testing was used to determine anti-inflammatory effects in vivo. When activated by sodium carbonate, particle size reduced by 19%. Tape stripping revealed significantly greater delivery of naproxen into the epidermis for the activated nanogel and the steady state flux was enhanced 2.8-fold. With base-activation COX-2 was 50% lower than non-activated, and this trend was confirmed by immunostaining, and by the reduction of rat paw swelling which provided ex vivo - in vivo corroboration. A mechanism of action is proposed. In conclusion, stimulus-responsive nanogels have potential for enhancing dermal drug delivery and therapeutic outcomes in inflammatory skin diseases.

Nanosized Drug Delivery for Enhancement of Oral Bioavailability

Oral delivery is the most preferred way especially for chronic administration of drugs, due to patient convenience and compliance. Hence, it remains as an important and immense segment in the drug market. However, many drug molecules belong to Biopharmaceutics classification systems (BCS) class II (poorly soluble and permeable) and class IV (poorly soluble and impermeable), resulting in low bioavailability, which is the most important limitation of oral delivery. Nanosizing of drugs can lead to a dramatic increase in oral absorption and subsequent bioavailability. Possible factors affecting the transport of these nano carriers across gastrointestinal mucosa are size reduction and surface properties that modify the non-specific or targeted uptake by enterocytes and/or M cells. Benefits of nano sizing can be listed as reduction in variability of absorption, improved absorption for higher doses and rapid formulation development. Therefore, many nanosized systems have been formulated for oral delivery. This chapter presents the requirements in the field of oral delivery and describes the design, characterization and application of various nanosized formulations, such as, vesicular, micellar and particulate systems.