Fabrication and optimization of itraconazole-loaded zein-based nanoparticles in coated capsules as a promising colon-targeting approach pursuing opportunistic fungal infections.

Itraconazole (ITZ), a broad-spectrum antifungal drug, was formulated into colon-targeting system aiming to treat opportunistic colonic fungal infections that commonly infect chronic inflammatory bowel diseases (IBD) patients due to immunosuppressive therapy. Antisolvent precipitation technique was employed to formulate ITZ-loaded zein nanoparticles (ITZ-ZNPs) using various zein: drug and aqueous:organic phase ratios. Central composite face-centered design (CCFD) was used for statistical analysis and optimization. The optimized formulation was composed of 5.5:1 zein:drug ratio and 9.5:1 aqueous:organic phase ratio with its observed particle size, polydispersity index, zeta potential, and entrapment efficiency of 208 ± 4.29 nm, 0.35 ± 0.04, 35.7 ± 1.65 mV, and 66.78 ± 3.89%, respectively. ITZ-ZNPs were imaged by TEM that revealed spherical core-shell structure, and DSC proved ITZ transformation from crystalline to amorphous form. FT-IR showed coupling of zein NH group with ITZ carbonyl group without affecting ITZ antifungal activity as confirmed by antifungal activity test that showed enhanced activity of ITZ-ZNPs over the pure drug. Histopathological examination and cytotoxicity tests ensured biosafety and tolerance of ITZ-ZNPs to the colon tissue. The optimized formulation was then loaded into Eudragit S100-coated capsules and both in vitro release and in vivo X-ray imaging confirmed the success of such coated capsules in protecting ITZ from the release in stomach and intestine while targeting ITZ to the colon. The study proved that ITZ-ZNPs is promising and safe nanoparticulate system that can protect ITZ throughout the GIT and targeting its release to the colon with effectual focused local action for the treatment of colon fungal infections.

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).

Chitosan-coated nanodiamonds: Mucoadhesive platform for intravesical delivery of doxorubicin.

Nanodiamonds (NDs) are an emerging delivery system with a massive surface area qualifying them for efficient loading with various drugs. However, NDs easily scavenge ions upon mixing with physiological media leading to rapid aggregation. Herein, chitosan was employed to endue steric stabilization to NDs and confer adhesiveness to the particles improving their retention in the urinary bladder. The effect of chitosan molecular weight and pH on the particle size and surface charge of chitosan-coated doxorubicin-loaded NDs (Chi-NDX) was investigated. Selected formula exhibited high drug loading efficiency (>90 %), small particle size (<150 nm), good colloidal stability, acid-favored drug release but limited stability in cell culture media. After further stabilization with TPP or dextran sulfate, selected TPP-treated formula displayed more potent cytotoxic effect compared with free doxorubicin and uncoated nanoparticles, and higher drug retention in ex vivo bovine bladder. Therefore, TPP-Chi-NDX is suggested as a promising system for mucosal anticancer delivery.

Coated Lipidic Nanoparticles as a New Strategy for Enhancing Nose-to-Brain Delivery of a Hydrophilic Drug Molecule.

Oral Almotriptan maleate (ALM) is used in the treatment of migraine; however, due to its extreme aqueous solubility, shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. Being flexible and lipophilic in nature, nanostructured lipid carriers (NLCs) represent a promising tool in delivering therapeutic substances to the brain. This investigation is meant to explore the capability of mucoadhesive chitosan-coated NLCs to efficiently deliver ALM to the brain through the nasal route as a non-invasive alternative route for targeting the central nervous system (CNS). D-optimal design was adopted and thirteen different formulae were prepared using hot homogenization and ultrasonication technique; where an accurate amount of the almotriptan was added to the molten lipid mixture followed by the addition of the heated aqueous phase under stirring, then the mixture was subjected to homogenization and ultrasonication. The prepared systems were then assessed for their particle size, PDI (polydispersity index), zeta potential (ZP), and entrapment efficiency (EE). The optimized selected formula; F1; composed of 50/50 Compritol/Labrafil and a co-mixture of 2:1 tween 80: Lauroglycol all coated in chitosan, showed a PS of 255 nm, PDI 0.27, ZP 34.1 mV, and 80% EE. A bi-phasic in vitro drug release pattern was obtained, enhanced mucoadhesive property and ex-vivo permeability through sheep nasal mucosa were attained. The In vivo studies performed on albino rabbits showed significantly higher Cmax results in plasma of the optimized ALM-NLC (1.54 µg/mL) compared to those of IN ALM solution (0.25 µg/mL) and ALM oral tablet market product (0.58 µg/mL). Brain Cmax were found to be 3.64 µg/mL, 0.5 µg/mL and 0.48 µg/mL for IN ALM-NLC, oral ALM market product and, IN ALM solution, respectively. Histopathological examination marked the formula as safe.

Freeze-Dried Self-Nanoemulsifying Self-Nanosuspension (SNESNS): a New Approach for the Preparation of a Highly Drug-Loaded Dosage Form.

Febuxostat suffers from relatively low bioavailability owing to the poor drug solubility and hepatic first-pass effect. This study aimed to prepare highly drug-loaded self-nanoemulsifying self-nanosuspension systems (SNESNS). SNESNS were designed to improve febuxostat's oral bioavailability by enhancing its solubility. Different oil and surfactant/co-surfactant mixtures were used for the preparation of SNESNS. The prepared SNESNS were estimated for their particle size, in vitro drug release and transmission electron microscopy (TEM). Results revealed that the oil mixture of Capryol™ 90:Miglyol® 812 (1:1 w/w) with surfactant/co-surfactant mixture of Cremophor® RH 40/Transcutol® HP loaded with drug in 4-fold greater concentration than its saturated solubility resulted in the formation of SNESNS by dilution under the effect of magnetic stirring. SNESNS were freeze-dried using trehalose as a cryoprotectant. TEM images and the bimodal particle size curve confirmed the formation of the biphasic nanosystems after dilution (nanoemulsion and nanosuspension). Higher Cmax and AUC0-48 values compared to those of the market product Feburic® tablets confirmed the success of the SNESNS as a promising carrier for drugs suffering from poor water solubility like febuxostat.

Nanodiamonds: Minuscule gems that ferry antineoplastic drugs to resistant tumors.

Remarkable efforts are currently devoted to the area of nanodiamonds (NDs) research due to their superior properties viz: biocompatibility, minute size, inert core, and tunable surface chemistry. The use of NDs for the delivery of anticancer drugs has been at the forefront of NDs applications owing to their ability to increase chemosensitivity, sustain drug release, and minimize drug side effects. Accelerated steps towards the move of NDs from bench side to bedside have been recently witnessed. In this review, the effects of NDs production and purification techniques on NDs' final properties are discussed. Special concern is given to studies focusing on NDs use for anticancer drug delivery, stability enhancement and mediated targeted delivery. The aim of this review is to put the results of studies oriented towards NDs-mediated anticancer drug delivery side by side such that the reader can assess the potential use of NDs in clinics and follow up the upcoming results of clinical testing of NDs on animals and humans.

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability.

OBJECTIVE: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients. METHODS: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems. RESULTS: The optimum formulations were composed of different ratios of Capryol™ 90 as an oil phase, Cremophor® RH40 as a surfactant, and Transcutol® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19 nm and emulsification time not exceeding 1 min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6-2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies. CONCLUSIONS: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits.

OBJECTIVE: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability. METHODS: Liquid SNEDDS (L-SNEDDS) composed of Capryol™ 90 (oil), Cremophor® RH40 (surfactant), and Transcutol® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits. RESULTS: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in tmax, AUC(0-12), and AUC(0-∞) at p < .05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product. CONCLUSIONS: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.

Studying the influence of formulation and process variables on Vancomycin-loaded polymeric nanoparticles as potential carrier for enhanced ophthalmic delivery.

Ocular topically applied Vancomycin (VCM) suffers poor bioavailability due to its high molecular weight and hydrophilicity. In the present investigation, VCM-loaded polymeric nanoparticles (PNPs) were developed aiming to enhance its ocular bioavailability through prolonging its release pattern and ophthalmic residence. PNPs were prepared utilizing double emulsion (W/O/O), solvent evaporation technique. 23×41 full factorial design was applied to evaluate individual and combined influences of polymer type, Eudragit® RS100, sonication time, and Span®80 concentration on PNPs particle size, encapsulation efficiency, and zeta potential. Further, the optimized formulae were incorporated in 1% Carbopol®-based gel. In-vivo evaluation of the optimized formulae was performed via Draize test followed by microbiological susceptibility testing on albino rabbits. Results revealed successful formulation of VCM-loaded PNPs was achieved with particle sizes reaching 155nm and up to 88% encapsulation. Draize test confirmed the optimized formulae as non-irritating and safe for ophthalmic administration. Microbiological susceptibility testing confirmed prolonged residence, higher Cmax. with more than two folds increment in the AUC(0.25-24) of VCM-PNPs over control groups. Thus, VCM-loaded PNPs represent promising carriers with superior achievements for enhanced Vancomycin ophthalmic delivery over the traditional use of commercially available VCM parenteral powder after constitution into a solution by the ophthalmologists.

Novel delivery approach for ketotifen fumarate: dissofilms formulation using 3² experimental design: in vitro/in vivo evaluation.

Orally dissolving films (dissofilms) have gained increasing popularity and attention due to their ease of administration and avoidance of first pass metabolism. Ketotifen fumarate (KF) bioavailability is reported to be only ~ 50% due to hepatic first-pass metabolism. Aiming to surmount this drawback and improve patients' compliance, a 3(2) full factorial design was applied to formulate KF Orodispersible films, and to investigate the effects and interactions of the concentrations of the novel film former; Lycoat NG73® and the film modifier; maltodextrin (MDX) on the characteristics of the films prepared using solvent casting technique. The dissofilms were thoroughly evaluated regarding their weight uniformity, content uniformity, moisture uptake, in vivo mouth dissolving time (MDT) and their thermal behavior via differential scanning calorimetry. Statistical analysis revealed the significant influence of Lycoat NG73® concentration on percent elongation, percent KF dissolved after 5 min, and in vivo MDT, while MDX concentration had significant effect only on percent elongation. Further, storage of the optimal selected formula (15% Lycoat NG73 and 0% MDX) at 40 °C/75% relative humidity for 12 weeks caused no significant change in appearance, KF content or drug dissolution profile. Pharmacokinetic study revealed that the orally dissolving films showed significantly higher absorption extent than the reference marketed product, while no significant difference was observed for Cmax.

A pilot human pharmacokinetic study and influence of formulation factors on orodispersible tablet incorporating meloxicam solid dispersion using factorial design.

Meloxicam (MLX) suffers from poor aqueous solubility leading to slow absorption following oral administration; hence, immediate release MLX tablet is unsuitable in the treatment of acute pain. This study aims to overcome such a drawback by increasing MLX solubility and dissolution using PEG solid dispersion (SD), then, to investigate the feasibility of incorporating the SD into orodispersible tablets (ODTs). A 2(3) full factorial design was employed to investigate the influence of three formulation variables on MLX ODTs. The selected factors: camphor (X(1)) as pore-forming material, and croscarmellose sodium (X(2)) as superdisintegrant, showed significant positive influence, while PEG content (X(3)) was proved to negatively affect both disintegration and wetting times. In addition, isomalt increased disintegration and wetting times when compared to mannitol as diluents. The pharmacokinetic assessment of the optimum ODT formulation in healthy human subjects proved that the faster MLX dissolution by using PEG solid dispersion at pH 6.8 resulted in more rapid absorption of MLX. The rate of absorption of MLX from ODT was significantly faster (p = 0.030) with a significantly higher peak plasma concentration (P = 0.037) when compared to the marketed immediate release MLX tablet with a mean oral disintegration time of 17 ± 3 s.

Diazepam-loaded solid lipid nanoparticles: design and characterization.

The aim of the present study was to investigate the feasibility of the inclusion of a water-insoluble drug (diazepam, DZ) into solid lipid nanoparticles (SLNs), which offer combined advantages of rapid onset and prolonged release of the drug. This work also describes a new approach to prepare suppositories containing DZ-loaded SLN dispersions, as potential drug carrier for the rectal route. Modified high-shear homogenization and ultrasound techniques were employed to prepare SLNs. The effect of incorporation of different concentrations of Compritol ATO 888 or Imwitor 900K and Poloxamer 188 or Tween 80 was investigated. Results showed that varying the type or concentration of lipid matrix or surfactant had a noticeable influence on the entrapment efficiencies, particle size, and release profiles of prepared SLNs. Differential scanning calorimetry and X-ray diffraction measurements showed that the majority of SLNs possessed less ordered arrangements of crystals than the corresponding bulk lipids, which was favorable for increasing the drug loading capacity. Transmission electron microscopy and laser diffractometry studies revealed that the prepared nanoparticles were round and homogeneous and 60% of the formulations were less than 500 nm. Additionally, SLN formulations showed significant (P < 0.05) prolonged release than DZ solution. The subsequent step encompassed the preparation and evaluation of SLN-based suppositories utilizing SLN formulations that illustrated optimal release profiles. The in vitro release of DZ from the suppositories prepared using DZ-loaded SLN dispersions (equivalent to 2 mg DZ) was significantly (P < 0.05) extended compared to suppositories containing 2 mg DZ free drug.

Enhancement of famotidine dissolution rate through liquisolid tablets formulation: in vitro and in vivo evaluation.

Although famotidine was reported to be 7.5 and 20 times more potent than ranitidine and cimetidine, respectively, its oral bioavailability is low and variable; due mainly to its poor aqueous solubility. The purpose of this study was to improve famotidine dissolution through its formulation into liquisolid systems and then to investigate the in vitro and in vivo performance of the prepared liquisolid tablets. The new mathematical model was utilized to formulate various liquisolid powder systems. Both DSC and XRD suggested loss of famotidine crystallinity upon liquisolid formulation which was further confirmed by SEM indicating that even though the drug existed in a solid dosage form, it is held within the powder substrate in a solubilized, almost molecularly dispersed state, which contributed to the enhanced drug dissolution properties. All the tested liquisolid tablet formulations showed higher drug dissolution rates (DR) than the conventional, directly compressed tables. In addition, the selected optimal formula released 78.36% of its content during the first 10 min which is 39% higher than that of the directly compressed tablets. Further, the bioavailability study indicated that the prepared optimal liquisolid formula did not differ significantly from the marketed famotidine tablets concerning Cmax, tmax, and AUC(0-8) at P<0.05.