Kadria Elkhodairy

Lyophilization monophase solution technique for improvement of the physicochemical properties of an anticancer drug, flutamide

Flutamide (FLT), an anticancer drug for prostatic carcinoma, has poor aqueous solubility and low oral bioavailability. This study describes the ability of beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) to form complexes with flutamide with enhanced solubility and dissolution rate in vitro. FLT-CD lyophilized dispersions (LDs) were prepared via lyophilization monophase solution technique using tertiary butyl alcohol (TBA) as a cosolvent. FLT showed an A(L)-type phase solubility diagram consistent with a linear increase in drug solubility as a function of CD concentration. Gas chromatography indicated that the LDs contain 0.02-0.03% w/w residual TBA. Based on the data from differential scanning calorimetry (DSC) and X-ray diffractometry (XRD), FLT was fully amorphous in 1:5 FLT-HPbetaCD LD as indicated by complete disappearance of FLT endothermic and diffraction peaks. The Fourier transform infrared (FTIR) spectra indicated that a FLT-CD interaction took place in the lyophilized complex. The particle sizes of 1:1 FLT-betaCD and FLT-HPbetaCD LDs were 0.92 and 0.82microm, with a high surface area (484.55 and 705.68m(2)/g) and porosity (769.46 and 1020.99e(-3)ml/g), respectively. The dissolution rate of FLT from its CD complexes was enhanced significantly. After 30min in 0.1N HCl, about 73% and 86% of FLT were dissolved from 1:5 FLT-betaCD and FLT-HPbetaCD LDs, respectively, compared to only 13.45% of pure drug. No endothermic peak corresponding to FLT melting was detected in 1:5 FLT-HPbetaCD LD after storage at 20 degrees C and 45% relative humidity for 90days thus indicating the stability of this binary system. These data suggest that cyclodextrins might be useful adjuncts in preparation of immediate-release formulations of FLT.

Biopolymeric Nanoparticles for Oral Protein Delivery: Design and In Vitro Evaluation

Chitosan (CS) nanoparticles for the oral delivery of the protein, Human Serum Albumin (HSA) were prepared by two techniques (precipitation and ionic gelation) together with two anions (sodium sulfate or tripolyphosphate, TPP). HSA was loaded with CS nanoparticles by adsorption or entrapment loading protocols. The highest HSA association efficiency (93.43%) and loading capacity (58.65%) were obtained using ionic gelation technique with 0.1% w/v TPP as a crosslinker. The particle size of CS-HSA nanoparticles ranged between 100-320 nm with a high specific surface area (703-903 m 2 /g) and porosity (1060.99-1350.95 e -3 ml/g). Incubation of nanoparticles with lysozyme led to a reduction of 243 nm in particle size within 3 h. CS nanoparticles was redispersible after one month storage. CS/TPP nanoparticles prepared by precipitation/protein entrapment technique slowly released 10.34% HSA over 5 days which is suitable for vaccine or protein delivery while 86.54% of HSA was released from nanoparticles prepared by precipitation/ protein adsorption technique after 8 hr which is suitable for rapid drug release. Using ionic gelation technique, CS/ TPP nanoparticles released 22.47-38.65 % HSA over 5 days at 7:1 to 3:1 CS/TPP mass ratio, respectively. Both techniques retained the structural integrity of HSA after preparation and release processes which was proven via gel electrophoresis.

Biopolymeric microparticles combined with lyophilized monophase dispersions for controlled flutamide release

Despite its short half-life, no controlled release formula of flutamide (FLT) was prepared until now. Therefore, 15 chitosan microparticle formulations were prepared for oral prolonged delivery of FLT via ionotropic gelation and emulsification-ionic gelation techniques then characterized for various parameters. FLT was successfully encapsulated into microparticles with loading capacity up to 39.98% and entrapment efficiency up to 97.16% using emulsification technique. Differential scanning calorimetry indicated that FLT was retained in a crystalline form in the microparticles prepared using ionotropic gelation whereas its crystallinity was significantly reduced using emulsification technique. Relationship between formulation variables and release behavior of FLT was explored. Chitosan microparticles prepared by ionotropic gelation showed a slower FLT release with a T(25%) of 7.9h whereas microparticles prepared by emulsification-ionic gelation under the same conditions showed a quick release profile with a T(25%) of 0.3h. Using 3 different hydrophilic carriers, immediate release FLT dispersions were prepared via lyophilization of monophase solution technique then combined with prolonged release chitosan microparticles to develop 6 controlled release formulae of FLT. A wide range of FLT release profiles were generated providing a prolonged release of drug after a suitable initial burst release.

Lyophilization monophase solution technique for preparation of amorphous flutamide dispersions

Flutamide (FLT) is a poorly soluble anticancer drug. Therefore, lyophilized dispersions (LDs) of FLT with polyvinylpyrrolidone (PVP) K30, polyethylene glycol (PEG) 6000, and pluronic F127 were prepared via lyophilization monophase solution technique with the aim of increasing its dissolution rate. FLT showed an AL-type phase solubility diagrams with PVP and PEG, whereas AN-type diagram was obtained with pluronic. The amount of residual tertiary butyl alcohol, determined by gas chromatography, was 0.015–0.021% w/w. Differential scanning calorimetry and X-ray diffractometry revealed that FLT–polymer 1:1 LDs were partially amorphous, whereas the 1:3 and 1:5 LDs were completely amorphous. After 6 months storage, polymers under study inhibited FLT recrystallization maintaining its amorphous form. The particle size of FLT–polymer LDs was between 0.81 and 2.13 μm, with a high surface area (268.43–510.82 m2/g) and porosity (354.01–676.23 e−3 mL/g). Also, the poor flow properties of FLT could be improved but to a limited extent. FLT dissolution was significantly enhanced with the fastest dissolution that was achieved using pluronic. After 30 min, about 66.52%, 78.23%, and 81.64% of FLT was dissolved from 1:5 FLT–PVP, PEG, and pluronic LDs, respectively, compared with only 13.45% of FLT. These data suggest that these polymers might be useful adjuncts in preparation and stabilization of amorphous immediate-release FLT LDs.

Lyophilized flutamide dispersions with polyols and amino acids: preparation and in vitro evaluation

Context: Flutamide (FLT) has poor aqueous solubility and low oral bioavailability. Objective: Lyophilization monophase solution was used for preparing lyophilized dispersions of FLT with polyols and amino acids to increase its poor dissolution. Methods: Physical properties and dissolution behavior of their physical mixtures and lyophilized dispersions were investigated. Results and discussion: The carriers increased the aqueous solubility of FLT but to a limited extent with arginine and glycine showing a linear AL-phase solubility diagrams. Gas chromatography indicated that residual tertiary butyl alcohol was in range of 0.007−0.023% (w/w) in the dispersions. In all dispersions, the crystal structure of FLT was confirmed using differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. However, the percent drug crystallinity was found to decrease with increasing the carrier content. Infrared spectroscopy revealed no interaction between drug and carriers. The particle size of FLT dispersions ranged between 0.61 and 1.81 μm, with a high surface area (293.93−465.37 m2/g) and porosity (447.69−754.33 e-3 mL/g). In addition, the poor flow properties of FLT were improved but to a limited extent. FLT dissolution from the dispersions was enhanced with 46.35% and 36.43% of FLT dissolved after 30 minutes from 1:5 FLT–mannitol and FLT–trehalose dispersions, respectively, compared with only 13.45% of pure FLT. On the other hand, after 30 minutes 38.57% and 46.78% of FLT was dissolved from 1:3 FLT–arginine and FLT–glycine dispersions, respectively. Conclusion: These data suggest that polyols and amino acids might be useful adjuncts in preparation of immediate-release formulations of FLT.

Zein-based Nanocarriers as Potential Natural Alternatives for Drug and Gene Delivery: Focus on Cancer Therapy

Protein nanocarriers possess unique merits including minimal cytotoxicity, numerous renewable sources, and high drug-binding capability. In opposition to delivery carriers utilizing hydrophilic animal proteins, hydrophobic plant proteins (e.g, zein) have great tendency in fabricating controlled-release particulate carriers without additional chemical modification to stiffen them, which in turn evades the use of toxic chemical crosslinkers. Moreover, zein is related to a class of alcohol-soluble prolamins and generally recognized as safe (GRAS) carrier for drug delivery. Various techniques have been adopted to fabricate zein-based nanoparticulate systems including phase separation coacervation, spray-drying, supercritical anti-solvent approach, electrospinning and self-assembly. This manuscript reviews the recent advances in the zein-based colloidal nano-carrier systems such as nanospheres, nanocapsules, micelles and nanofibers with a special focus on their physicochemical characteristics and drug delivery applications.

Hyaluronate/lactoferrin layer-by-layer-coated lipid nanocarriers for targeted co-delivery of rapamycin and berberine to lung carcinoma

The self-tumor targeting polymers, lactoferrin (LF) and hyaluronic acid (HA) were utilized to develop layer-by-layer (LbL) lipid nanoparticles (NPs) for dual delivery of berberine (BER) and rapamycin (RAP) to lung cancer. To control its release from the NPs, BER was hydrophobically ion paired with SLS prior to incorporation into NPs. Spherical HA/LF-LbL-RAP-BER/SLS-NPs 250.5 nm in diameter, with a surface charge of -18.5 mV were successfully elaborated. The NPs exhibited sequential release pattern with faster release of BER followed by controlled release of RAP which enables sensitization of lung tumor cells to the anti-cancer action of RAP. LbL coating of the NPs was found to enhance the drug cytotoxicity against A549 lung cancer cells as augmented by remarkable increase in their cellular internalization through CD44 receptors overexpressed by tumor cells. In vivo studies in lung cancer bearing mice have revealed the superior therapeutic activity of LbL-RAP-BER/SLS-NPs over the free drugs as demonstrated by 88.09% reduction in the average number of microscopic lung foci and 3.1-fold reduction of the angiogenic factor VEGF level compared to positive control. Overall, the developed HA/LF-LbL-coated lipid NPs could be potential carriers for targeted co-delivery of BER and RAP to lung cancer cells.

Biopolymeric Nanoparticles for Targeted Drug Delivery to Brain Tumors

Abstract Glioma is the most invasive form of brain tumor, and usually causes death within months after diagnosis. Delivering a high concentration of drug to the brain is difficult due to the limitations imposed by the blood–brain barrier (BBB) and rapid clearance from the circulation. In recent years, polymeric nanocarriers have attracted a great deal of attention in drug delivery for antiglioma therapy. Natural polymers, including proteins and polysaccharides, are good candidates for fabrication of drug nanocarriers for enhanced glioma targeting. In this chapter, the current status of research on such biopolymeric nanoparticles (NPs) for drug delivery to gliomas has been highlighted. Modification of the NP surface with additional specific brain-targeting ligands or cell-penetrating peptides for enhanced brain delivery are also reviewed. In addition, the mechanisms of NP-mediated drug transport across the BBB are also discussed.

Inhalable lactoferrin–chondroitin nanocomposites for combined delivery of doxorubicin and ellagic acid to lung carcinoma

AIM The use of inhalable nanomedicines can overcome the Enhanced permeation and retention effect (EPR)-associated drawbacks in lung cancer therapy via systemic nanomedicines. METHODS We developed a lactoferrin-chondroitin sulfate nanocomplex for the co-delivery of doxorubicin and ellagic acid nanocrystals to lung cancer cells. Then, the nanocomplex was converted into inhalable nanocomposites via spray drying. RESULTS The resulting 192.3 nm nanocomplex exhibited a sequential faster release of ellagic acid, followed by doxorubicin. Furthermore, the nanocomplex demonstrated superior cytotoxicity and internalization into A549 lung cancer cells mediated via Tf and CD44 receptors. The inhalable nanocomposites exhibited deep lung deposition (89.58% fine particle fraction [FPF]) with powerful antitumor efficacy in lung cancer bearing mice. CONCLUSION Overall, inhalable lactoferrin-chondroitin sulfate nanocomposites would be a promising carrier for targeted drug delivery to lung cancer.

Decorating protein nanospheres with lactoferrin enhances oral COX-2 inhibitor/herbal therapy of hepatocellular carcinoma

AIM Lactoferrin (LF)-targeted gliadin nanoparticles (GL-NPs) were developed for targeted oral therapy of hepatocellular carcinoma. MATERIALS & METHODS Celecoxib and diosmin were incorporated in the hydrophobic matrix of GL-NPs whose surface was decorated with LF by electrostatic interaction for binding to asialoglycoprotein receptors overexpressed by liver cancer cells. RESULTS Targeted GL-NPs showed enhanced cytotoxic activity and increased cellular uptake in liver tumor cells compared with nontargeted NPs. Moreover, they demonstrated superior in vivo antitumor effects including reduction in the expression levels of tumor biomarkers and induction of caspase-mediated apoptosis. Ex vivo imaging of isolated organs exhibited extensive accumulation of NPs in livers more than other organs. CONCLUSION LF-targeted GL-NPs could be considered as an efficient nanoplatform for targeted oral drug delivery for liver cancer therapy.