Green Nanotechnology in the Formulation of a Novel Solid Dispersed Multilayered Core-Sheath Raloxifene-Loaded Nanofibrous Buccal Film; In Vitro and In Vivo Characterization.

Green nanotechnology utilizes the principles of green chemistry to formulate eco-friendly nanocarrier systems to mitigate patients and environment hazards. Raloxifene (RLX) demonstrates poor aqueous solubility (BCS class II) and low bioavailability, only 2% (extensive first-pass metabolism). The aim of this study is to enhance RLX solubility and bioavailability via development of novel solid dispersed multilayered core-sheath RLX-loaded nanofibers (RLX-NFs) without the involvement of organic solvents. A modified emulsion electrospinning technique was developed. Electrospinning of an RLX-nanoemulsion (RLX-NE) with polymer solution (poly vinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and chitosan (CS) in different volume ratios (1:9, 2:8, and 4:6) using D-optimal response surface methodology was adopted. In vitro characterization of RLX-loaded NFs was performed; scanning electron microscope (SEM), thermal analysis, drug content, release studies, and bioadhesion potential. The optimum NFs formula was evaluated for morphology using high-resolution transmission electron microscopy (HRTEM), and ex vivo drug permeation. The superiority of E2 (comprising RLX-NE and PVA (2:8)) over other NF formulae was statistically observed with respect to Q60 (56.048%), Q240 (94.612%), fiber size (594.678 nm), mucoadhesion time 24 h, flux (5.51 µg/cm2/h), and enhancement ratio (2.12). RLX pharmacokinetics parameters were evaluated in rabbits following buccal application of NF formula E2, relative to RLX oral dispersion. E2 showed significantly higher Cmax (53.18 ± 4.56 ng/mL), and relative bioavailability (≈2.29-fold).

Colon targeting of celecoxib nanomixed micelles using pulsatile drug delivery systems for the prevention of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a debilitating condition characterized by chronic inflammation of the colon which can increase the risk of colon cancer. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, showed potential for the prophylaxis against IBD. However, it suffers from poor aqueous solubility and cardiovascular toxicity on prolonged use. Here, CXB solubility was enhanced using nanomixed micelles (NMMs) and then colon targeted in a pulsatile system to minimize systemic side effects. Pluronic P123 NMMs with bile salts or hydrophilic Pluronics were prepared using the thin film hydration technique. NMMs were characterized for particle size, size distribution and zeta potential before and after freeze drying and for solubility enhancement. The freeze dried NMMs were then loaded in pulsatile systems with varying tablet plugs containing time-dependent polymers at different concentrations. The optimum NMM consisted of Pluronic P123 and sodium taurocholate (1:1) and CXB:surfactant mixture ratio of 1:30. The pulsatile capsules, containing a tablet plug made of 75% Carbopol®, achieved the target release profile with 88.35% of the dose released after an 8 hrs lag period. Finally, the optimum NMM/pulsatile system showed protective effect against experimentally-induced colitis compared to conventional capsules and pulsatile capsules filled with pure CXB.

Brain Targeted Intranasal Zaleplon Nano-emulsion: In-Vitro Characterization and Assessment of Gamma Aminobutyric Acid Levels in Rabbits' Brain and Plasma at Low and High Doses.

BACKGROUND: Zaleplon is a pyrazolopyrimidin derivative hypnotic drug indicated for the short-term management of insomnia. Zaleplon belongs to Class II drugs, according to the biopharmaceutical classification system (BCS), showing poor solubility and high permeability. It undergoes extensive first-pass hepatic metabolism after oral absorption, with only 30% of Zaleplon being systemically available. It is available in tablet form which is unable to overcome the previous problems. OBJECTIVE: The aim of this study is to enhance solubility and bioavailability via utilizing nanotechnology in the formulation of intranasal Zaleplon nano-emulsion (ZP-NE) to bypass the barriers and deliver an effective therapy to the brain. METHOD: Screening studies were carried out wherein the solubility of zaleplon in various oils, surfactants( S) and co-surfactants(CoS) were estimated. Pseudo-ternary phase diagrams were constructed and various nano-emulsion formulations were prepared. These formulations were subjected to thermodynamic stability, in-vitro characterization, histopathological studies and assessment of the gamma aminobutyric acid (GABA) level in plasma and brain in rabbits compared to the market product (Sleep aid®). RESULTS: Stable NEs were successfully developed with a particle size range of 44.6±3.4 to 136.9±1.6 nm. CONCLUSION: A NE composed of 10% Miglyol® 812, 40% Cremophor® RH40 40%Transcutol® HP and 10% water successfully enhanced the bioavailability and brain targeting in the rabbits, showing a three to four folds increase than the marketed product.

Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter.

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 23 full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1 h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.