Wael M. Samy

Albumin-based nanoparticles as potential controlled release drug delivery systems

Albumin, a versatile protein carrier for drug delivery, has been shown to be nontoxic, non-immunogenic, biocompatible and biodegradable. Therefore, it is ideal material to fabricate nanoparticles for drug delivery. Albumin nanoparticles have gained considerable attention owing to their high binding capacity of various drugs and being well tolerated without any serious side-effects. The current review embodies an in-depth discussion of albumin nanoparticles with respect to types, formulation aspects, major outcomes of in vitro and in vivo investigations as well as site-specific drug targeting using various ligands modifying the surface of albumin nanoparticles with special insights to the field of oncology. Specialized nanotechnological techniques like desolvation, emulsification, thermal gelation and recently nano-spray drying, nab-technology and self-assembly that have been investigated for fabrication of albumin nanoparticles, are also discussed. Nanocomplexes of albumin with other components in the area of drug delivery are also included in this review.

Protein-based nanocarriers as promising drug and gene delivery systems

Among the available potential colloidal drug carrier systems, protein-based nanocarriers are particularly interesting. Meeting requirements such as low cytotoxicity, abundant renewable sources, high drug binding capacity and significant uptake into the targeted cells, protein-based nanocarriers represent promising candidates for efficient drug and gene delivery. Moreover, the unique protein structure offers the possibility of site-specific drug conjugation and targeting using various ligands modifying the surface of protein nanocarriers. The current review highlights the main advances achieved in utilizing protein nanocarriers as natural vehicles for drug and gene delivery tasks with respect to types, advantages, limitations, formulation aspects as well as the major outcomes of the in vitro and in vivo investigations. The recently emerged technologies in the formulation of protein nanocarriers including using recombinant proteins as alternatives to native ones and new non-toxic crosslinkers as alternatives to the toxic chemical crosslinkers are also discussed.

Spray-dried casein-based micelles as a vehicle for solubilization and controlled delivery of flutamide: Formulation, characterization, and in vivo pharmacokinetics

Novel casein (CAS)-based micelles loaded with the poorly soluble anti-cancer drug, flutamide (FLT), were successfully developed in a powdered form via spray-drying technique. Genipin (GNP) was used to crosslink CAS micelles as demonstrated by color variation of the micelles. Drug solubilization was enhanced by incorporation within the hydrophobic micellar core which was confirmed by solubility study and UV spectra. Spherical core-shell micelles were obtained with a particle size below 100 nm and zeta potential around -30 mV. At low drug loading, FLT was totally incorporated within micellar core as revealed by thermal analysis. However, at higher loading, excess non-incorporated drug at micelle surface caused a significant reduction in the surface charge density. Turbidity measurements demonstrated the high physical stability of micelles for 2 weeks dependent on GNP-crosslinking degree. In a dry powdered form, the micelles were stable for 6 months with no significant changes in drug content or particle size. A sustained drug release from CAS micelles up to 5 days was observed. After i.v. administration into rats, CAS micelles exhibited a prolonged plasma circulation of FLT compared to drug solution. Furthermore, a more prolonged drug systemic circulation was observed for GNP-crosslinked micelles. Overall, this study reports the application of spray-dried natural protein-based micelles for i.v. delivery of hydrophobic anti-cancer drugs such as FLT.

Novel ionically crosslinked casein nanoparticles for flutamide delivery: formulation, characterization, and in vivo pharmacokinetics.

A novel particulate delivery matrix based on ionically crosslinked casein (CAS) nanoparticles was developed for controlled release of the poorly soluble anticancer drug flutamide (FLT). Nanoparticles were fabricated via oil-in-water emulsification then stabilized by ionic crosslinking of the positively charged CAS molecules below their isoelectric point, with the polyanionic crosslinker sodium tripolyphosphate. With the optimal preparation conditions, the drug loading and incorporation efficiency achieved were 8.73% and 64.55%, respectively. The nanoparticles exhibited a spherical shape with a size below 100 nm and a positive zeta potential (+7.54 to +17.3 mV). FLT was molecularly dispersed inside the nanoparticle protein matrix, as revealed by thermal analysis. The biodegradability of CAS nanoparticles in trypsin solution could be easily modulated by varying the sodium tripolyphosphate crosslinking density. A sustained release of FLT from CAS nanoparticles for up to 4 days was observed, depending on the crosslinking density. After intravenous administration of FLT-CAS nanoparticles into rats, CAS nanoparticles exhibited a longer circulation time and a markedly delayed blood clearance of FLT, with the half-life of FLT extended from 0.88 hours to 14.64 hours, compared with drug cosolvent. The results offer a promising method for tailoring biodegradable, drug-loaded CAS nanoparticles as controlled, long-circulating drug delivery systems of hydrophobic anticancer drugs in aqueous vehicles.

Ionically-crosslinked milk protein nanoparticles as flutamide carriers for effective anticancer activity in prostate cancer-bearing rats

In this study, casein (CAS) nanoparticles were used to encapsulate the hydrophobic anticancer drug, flutamide (FLT), aiming at controlling its release, enhancing its anti-tumor activity, and reducing its hepatotoxicity. The nanoparticles were prepared by emulsification of CAS, at pH below its isoelectric point, and stabilized via ionic-crosslinking with sodium tripolyphosphate (TPP). The nanoparticles were spherical and positively charged with a size below 100 nm and exhibited a sustained drug release up to 4 days. After intravenous administration into prostate cancer-bearing rats for 28 days, FLT-loaded CAS nanoparticles showed a higher anti-tumor efficacy as revealed by a significantly higher % reduction in PSA serum level (75%) compared to free FLT (55%). Moreover, the nanoparticles demonstrated a marked reduction in the relative weights of both prostate tumor and seminal vesicle (43% and 32%) compared to free FLT (12% and 18%), respectively. A significantly higher anti-proliferative, anti-angiogenic, and apoptotic effects was demonstrated by the nanoparticles compared to drug solution as evidenced by their ability to decrease the expression of the proliferative marker (Ki-67) and reduce the level of tumor angiogenic markers (VEGF and IGF-1) as well as their ability to activate caspase-3 with subsequent induction of apoptosis in prostate cancer cells. Conclusively, these novel ionically-crosslinked milk protein nanovehicles offer a promising carrier to allow controlled intravenous delivery of hydrophobic anticancer drugs.

Swellable floating tablet based on spray-dried casein nanoparticles: Near-infrared spectral characterization and floating matrix evaluation.

In this study, spray-dried alfuzosin hydrochloride (ALF)-loaded casein (CAS) nanoparticles were successfully used for the preparation of a swellable floating matrix via direct compression. The developed NIR calibration model was able to assess ALF and CAS levels in five different batches of drug-loaded nanoparticles. The calibration and prediction plots exhibited good linearity with correlation coefficients of more than 0.9. The standard error of calibration and cross-validation was less than 5% of the measured values, confirming the accuracy of the model. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the NIR partial least squares regression model. The un-crosslinked tablet demonstrated a substantial weight gain (317% after 2h) and completely disintegrated after 3-4h whereas both 10 and 40% w/w genipin-crosslinked tablets showed lower weight gain (114 and 42% after 2h, respectively). A rapid floating of the tablets within 5-15min (compared to 45min for the marketed tablet) was observed, with maintained floating for 24h. Marketed and prepared tablets succeeded to prolong ALF release for 24h. The development of drug-loaded CAS nanoparticles using spray-drying represents a new alternative for the preparation of swellable floating tablets for prolonged drug release.

Evaluation of the mechanical properties and drug release of cross-linked Eudragit films containing metronidazole

The mechanical properties of casted Eudragit E-100 films were tested for the combined effect of two cohesion promoters (succinic or citric acid) and triacetin as a plasticizer. The prepared films were elastic, self-adhesive, transparent and pale yellow in colour. Films containing either of the tested cohesion promoters showed a significant reduction in both tensile strength and Youngs modulus on increasing triacetin and/or cohesion promoter concentration. Films containing 7% (w/w) succinic acid and 45% (w/w) triacetin gave the highest elongation of the tested films at any given stress with a maximum of 1050% elongation. Optimal bonding to human skin surface (tack) with the highest peel adhesion (588 cN/cm) was observed with these films denoting good self-adhesive properties. In vitro metronidazole (MN) release from the plasticized Eudragit E-100 films was monitored for the influence of incorporation of cohesion promoters, secondary polymer (Eudragit RL or RS) as well as drug loading. Both cohesion promoters were seen to improve MN release from the films with the maximum drug flux (0.334 mg cm(-2) h(-1)) observed with 1.75% (w/w) succinic acid. The tested secondary polymers were also found to improve MN release from the tested films. The highest MN release was observed with 20% (w/w) Eudragit RL which gave 0.77 mg cm(-2) released after 3 h compared with only 0.34 mg cm(-2) for plain films. MN release from the films was increased by increasing drug load. Calculating the release rate constant (K(r)) showed a linear increase with the increase in drug load.

Biopolymeric nifedipine powder for acceleration of wound healing.

Nine biodegradable polymeric powders of chitosan; with or without gelatin; containing nifedipine (NF), were prepared via spray drying for acceleration of wound healing. The angle of repose of powders ranged from 30° to 40° for F(3) and chitosan/gelatin (C(2)), respectively. Upon spray drying, the mean particle size (PS) of chitosan was greatly reduced from 294 to 3.4 μm, while all formulae showed a PS near 3 μm. Specific surface area of the powders ranged from 0.06 × 10(5) to 2.03 × 10(5)cm(2)g. Powders exposure to glutraldehyde (GA) vapors gave smaller particles with higher densities with F(4) showing a mean PS of 0.4 μm. NF dissolution pattern in PBS, was highest from F(2) with 33% released after 30 min while F(3) showed only 4.5% NF released after the same period. Exposure to GA showed a reduction in NF release especially with F(5) showing 30% release after 3h. Tensile strength of 12 days-post incision wound in rats showed a maximum value of 4.7 kg cm(-2) for F(3) compared with 3.3 kg cm(-2) for the control. Excision wounds treated with F(3) also showed a fully developed epithelium with normal keratinization, and an average wound contraction of 99% compared with 79.5% for the control.

Novel microstructured sildenafil dosage forms as wound healing promoters

Purpose: Study the possible benefit of combining biodegradable polymers with sildenafil citrate (SC) in wound healing. Method: Biodegradable micronized powdered formulations of SC were prepared by spray drying using chitosan (P1) or chitosan/gum Arabic (P2). Powders were characterized by differential scanning calorimetry, Scanning electron microscope, particle size analysis, flow and swelling behavior. The powders were also incorporated into microstructured gels and in vitro SC release from powders and gels was tested. In vivo wound healing acceleration was tested by measuring area contraction of excision wounds and histologically. Post-healing tensile strength (TS) for incision wounds in rats receiving powder formulations was tested. Results: The powders were in the micron-size range showing no SC–polymers interaction. Powders had poor flow with angle of repose (θ) of 41 – 48°, and high moisture uptake reaching 107% for placebo powder Po1. Good excision wound healing was seen with P1 and G1 formulations showing 98.4 and 98.5% reduction in wound area, respectively, compared with 83% for the control. Incision wounds were improved with P1 showing TS value of 6.9 compared with 3.7 kg/cm2 for control. Histological examinations supported. Conclusion: Spray-dried chitosan/SC powder (P1) and its gel form (G1) could be promising wound healing promoters as supported by the histological examinations.

Hybrid polymeric matrices for oral modified release of Desvenlafaxine succinate tablets

Purpose: Desvenlafaxine succinate (DSV) is a water soluble anti-depressant drug, which is rapidly absorbed after oral administration exaggerating its side effects. The current work aimed to prepare controllable release DSV matrix to reduce DSV side effects related to its initial burst. Methods: Fifteen DSV matrix formulations were prepared using different polymers, polymer/drug ratios and matrix excipients and characterized using Differential Scanning Calorimetry (DSC), infrared (IR) spectroscopy, water uptake and in vitro DSV release. The release kinetics were calculated to determine the drug release mechanism. Ex-vivo DSV absorption via rat intestinal mucosal cells and the calculation of the apparent permeability coefficient (Papp) were performed using everted sac technique. Results: Maltodextrin was the best matrix excipient (F7 and F10) showing acceptable decrease in the initial burst compared to the innovator. The addition of negatively charged polymers sodium carboxy methyl cellulose (SCMC) or sodium alginate resulted in an interaction that was proved by DSC and IR findings. This interaction slowed DSV release. F10 showed an excellent absorption of more than 80% of DSV after 4 h and the highest similarity factor with the innovator (84.7). Conclusion: A controllable release pattern of DSV was achieved using Methocel, Maltodextrin and SCMC. The obtained results could be used as a platform to control the release of cationic water soluble drugs that suffer from side effects associated with their initial burst after oral administration.