PLGA and PDMS-based in situ forming implants loaded with rosuvastatin and copper-selenium nanoparticles: a promising dual-effect formulation with augmented antimicrobial and cytotoxic activity in breast cancer cells.

Breast cancer is among the most prevalent tumors worldwide. In this study, in-situ forming implants (ISFIs) containing rosuvastatin calcium were prepared using three types of poly (D, L-lactic-co-glycolic acid) (PLGA), namely, PLGA 50/50 with ester terminal and PLGA 75/25 with ester or acid terminal. Additionally, polydimethylsiloxane (PDMS) was added in concentrations of 0, 10, 20, and 30% w/v to accelerate matrix formation. The prepared ISFIs were characterized for their rheological behaviors, rate of matrix formation, and in-vitro drug release. All the prepared formulations revealed a Newtonian flow with a matrix formation rate between 0.017 and 0.059 mm/min. Generally, increasing the concentration of PDMS increased the matrix formation rate. The prepared implants' release efficiency values ranged between 46.39 and 89.75%. The ISFI containing PLGA 50/50 with 30% PDMS was selected for further testing, as it has the highest matrix formation rate and a promising release efficiency value. Copper-selenium nanoparticles were prepared with two different particle sizes (560 and 383 nm for CS1 and CS2, respectively) and loaded into the selected formulation to enhance its anticancer activity. The unloaded and loaded implants with rosuvastatin and copper-selenium nanoparticles were evaluated for their antibacterial activity, against Gram-positive and negative microorganisms, and anticancer efficacy, against MCF-7 and MDA-MB-231 cell lines. The results confirmed the potency of rosuvastatin calcium against cancer cells and the synergistic effect when loaded with smaller particle sizes of copper-selenium nanoparticles. This formulation holds a considerable potential for efficient breast cancer therapy.

Nanofibrous Polycaprolactone Membrane with Bioactive Glass and Atorvastatin for Wound Healing: Preparation and Characterization.

Skin wound healing is one of the most challenging processes for skin reconstruction, especially after severe injuries. In our study, nanofiber membranes were prepared for wound healing using an electrospinning process, where the prepared nanofibers were made of different weight ratios of polycaprolactone and bioactive glass that can induce the growth of new tissue. The membranes showed smooth and uniform nanofibers with an average diameter of 118 nm. FTIR and XRD results indicated no chemical interactions of polycaprolactone and bioactive glass and an increase in polycaprolactone crystallinity by the incorporation of bioactive glass nanoparticles. Nanofibers containing 5% w/w of bioactive glass were selected to be loaded with atorvastatin, considering their best mechanical properties compared to the other prepared nanofibers (3, 10, and 20% w/w bioactive glass). Atorvastatin can speed up the tissue healing process, and it was loaded into the selected nanofibers using a dip-coating technique with ethyl cellulose as a coating polymer. The study of the in vitro drug release found that atorvastatin-loaded nanofibers with a 10% coating polymer revealed gradual drug release compared to the non-coated nanofibers and nanofibers coated with 5% ethyl cellulose. Integration of atorvastatin and bioactive glass with polycaprolactone nanofibers showed superior wound closure results in the human skin fibroblast cell line. The results from this study highlight the ability of polycaprolactone-bioactive glass-based fibers loaded with atorvastatin to stimulate skin wound healing.

Risedronate-loaded aerogel scaffolds for bone regeneration.

Sugarcane bagasse-derived nanofibrillated cellulose (NFC), a type of cellulose with a fibrous structure, is potentially used in the pharmaceutical field. Regeneration of this cellulose using a green process offers a more accessible and less ordered cellulose II structure (amorphous cellulose; AmC). Furthermore, the preparation of cross-linked cellulose (NFC/AmC) provides a dual advantage by building a structural block that could exhibit distinct mechanical properties. 3D aerogel scaffolds loaded with risedronate were prepared in our study using NFC or cross-linked cellulose (NFC/AmC), then combined with different concentrations of chitosan. Results proved that the aerogel scaffolds composed of NFC and chitosan had significantly improved the mechanical properties and retarded drug release compared to all other fabricated aerogel scaffolds. The aerogel scaffolds containing the highest concentration of chitosan (SC-T3) attained the highest compressive strength and mean release time values (415 ± 41.80 kPa and 2.61 ± 0.23 h, respectively). Scanning electron microscope images proved the uniform highly porous microstructure of SC-T3 with interconnectedness. All the tested medicated as well as unmedicated aerogel scaffolds had the ability to regenerate bone as assessed using the MG-63 cell line, with the former attaining a higher effect than the latter. However, SC-T3 aerogel scaffolds possessed a lower regenerative effect than those composed of NFC only. This study highlights the promising approach of the use of biopolymers derived from agro-wastes for tissue engineering.

PLGA-modified Syloid®-based microparticles for the ocular delivery of terconazole: in-vitro and in-vivo investigations.

The eye is an invulnerable organ with intrinsic anatomical and physiological barriers, hindering the development of a pioneer ocular formulation. The aim of this work was to develop an efficient ocular delivery system that can augment the ocular bioavailability of the antifungal drug, terconazole. Mesoporous silica microparticles, Syloid® 244 FP were utilized as the carrier system for terconazole. Preliminary studies were carried out using different drug:Syloid® weight ratios. The optimum weight ratio was mixed with various concentrations (30 and 60%w/w) of poly (lactic-co-glycolic acid) (PLGA), ester or acid-capped and with different monomers-ratio (50:50 and 75:25) using the nano-spray dryer. Results revealed the superiority of drug:Syloid® weight ratio of 1:2 in terms of yield percentage (Y%), SPAN and drug content percentage (DC%). Furthermore, incorporation of PLGA with lower glycolic acid monomer-ratio significantly increased Y%. In contrast, increasing the glycolic acid monomer-ratio resulted in higher DC% and release efficiency percentage (RE%). Additionally, doubling PLGA concentration significantly reduced Y%, DC%, drug loading percentage (DL%) and RE%. Applying desirability function in terms of increasing DC%, DL% besides RE% and decreasing SPAN, the selected formulation was chosen for DSC, XRD and SEM investigations. Results confirmed the successful loading of amorphized terconazole on PLGA-modified Syloid® microparticles. Moreover, pharmacokinetic studies for the chosen formulation on male Albino rabbits' eyes revealed a 2, 6.7 and 25.3-fold increase in mean residence time, Cmax and AUC0-24-values, respectively, compared to the drug suspension. PLGA-modified Syloid® microparticles represent a potential option to augment the bioavailability of ocular drugs.

Merits and advances of microfluidics in the pharmaceutical field: design technologies and future prospects.

Microfluidics is used to manipulate fluid flow in micro-channels to fabricate drug delivery vesicles in a uniform tunable size. Thanks to their designs, microfluidic technology provides an alternative and versatile platform over traditional formulation methods of nanoparticles. Understanding the factors that affect the formulation of nanoparticles can guide the proper selection of microfluidic design and the operating parameters aiming at producing nanoparticles with reproducible properties. This review introduces the microfluidic systems' continuous flow (single-phase) and segmented flow (multiphase) and their different mixing parameters and mechanisms. Furthermore, microfluidic approaches for efficient production of nanoparticles as surface modification, anti-fouling, and post-microfluidic treatment are summarized. The review sheds light on the used microfluidic systems and operation parameters applied to prepare and fine-tune nanoparticles like lipid, poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles as well as cross-linked nanoparticles. The approaches for scale-up production using microfluidics for clinical or industrial use are also highlighted. Furthermore, the use of microfluidics in preparing novel micro/nanofluidic drug delivery systems is presented. In conclusion, the characteristic vital features of microfluidics offer the ability to develop precise and efficient drug delivery nanoparticles.

Cyclodextrin Stabilized Freeze-Dried Silica/Chitosan Nanoparticles for Improved Terconazole Ocular Bioavailability.

This research assesses the beneficial effects of loading terconazole, a poorly water-soluble antifungal drug in silica/chitosan nanoparticles (SCNs) for ocular delivery. Nanoparticles were fabricated by the simple mixing of tetraethyl ortho silicate (TEOS) and chitosan HCl as sources of silica and nitrogen, respectively, along with alcoholic drug solution in different concentrations. Freeze-dried nanoparticles were fabricated using cyclodextrins as cryoprotectants. SCNs were assessed for their particle size, PDI, yield, drug loading and in vitro release studies. A 23.31 full factorial experimental design was constructed to optimize the prepared SCNs. DSC, XRD, FTIR, in addition to morphological scanning were performed on the optimized nanoparticles followed by an investigation of their pharmacokinetic parameters after topical ocular application in male Albino rabbits. The results reveal that increasing the water content in the preparations causes an increase in the yield and size of nanoparticles. On the other hand, increasing the TEOS content in the preparations, caused a decrease in the yield and size of nanoparticles. The optimized formulation possessed excellent mucoadhesive properties with potential safety concerning the investigated rabbit eye tissues. The higher Cmax and AUC0-24 values coupled with a longer tmax value compared to the drug suspension in the rabbits' eyes indicated the potential of SCNs as promising ocular carriers for poorly water-soluble drugs, such as terconazole.

Nanofibrillated cellulose/glucosamine 3D aerogel implants loaded with rosuvastatin and bioactive ceramic for dental socket preservation.

Recycling of agro-wastes presents a great economic and ecologic value. In this study, TEMPO-oxidized nanofibrillated cellulose (TONFC) originating from sugarcane bagasse pulp was exploited in regenerative medicine. TONFC in combination with glucosamine HCl (G) were used to prepare a 3D aerogel implant loaded with rosuvastatin as an integrative approach for extraction-socket healing. Comparing the prepared devices, aerogel composed of TONFC: G (4:1 wt ratio) had the best mechanical properties and integrity. Strontium borate-based bioactive ceramic particles were prepared and characterized for crystal structure, shape, porosity, and zeta potential. The particles had a crystalline diffraction pattern relative to Sr3B2O6, and they were rod in shape with nanopores with a zeta potential value of -16 mV. The prepared bioactive ceramic (BC) was then added in different concentrations (3 or 6% w/w) to the selected aerogel implant. The BC had a concentration-dependent effect on the aerogel properties as it ameliorated its mechanical performance (compressive strength = 90 and 150 kPa for 3 and 6%, respectively) and retarded drug release (mean release time = 2.34 and 3.4 h for 3 and 6%, respectively) (p < 0.05). The microphotograph of the selected aerogel implant loaded with BC showed a rough surface with an interconnective porous structure. During cell biology testing, the selected implant loaded with the lower BC concentration had the highest ability to increase MG-63 cells proliferation. In conclusion, TONFC is a promising material to formulate rosuvastatin-loaded aerogel implant with the aid of glucosamine and bioactive ceramic for dental socket preservation.

An in vitro / in vivo release test of risedronate drug loaded nano-bioactive glass composite scaffolds.

Three-dimensional (3D) matrices scaffolds play a noteworthy role in promoting cell generation and propagation. In this study, scaffolds prepared from chitosan/polyvinyl alcohol loaded with/without an osteoporotic drug (risedronate) and nano-bioactive glass (nBG) have been developed to promote healing of bone defects. The scaffolds were characterized by scanning electron microscopy (SEM), porosity test as well as mechanical strength. The pattern of drug release and ability to promote the proliferation of Saos-2osteosarcoma cells had also been reported. Osteogenic potential of the scaffolds was evaluated by testing their effect on healing critical-sized dog's mandibular bone defects. Increasing chitosan and nBG in the porous scaffolds induced decrease in drug release, increased the scaffold's strength and supported their cell proliferation, alkaline phosphatase (ALP) activities, as well as increased calcium deposition. Histological and histomorphometric results demonstrated newly formed bone trabeculae inside critical-sized mandibular defects when treated with scaffolds. Trabecular thickness, bone volume/tissue volume and the percentage of mature collagen fibers increased in groups treated with scaffolds loaded with 10% nBG and risedronate or loaded with 30% nBG with/without risedronate compared with those treated with non-loaded scaffolds and empty control groups. These findings confirmed the potential osteogenic activity of chitosan/polyvinyl alcohol-based scaffolds loaded with risedronate and nBG.

Formulation and optimization of sildenafil citrate-loaded PLGA large porous microparticles using spray freeze-drying technique: A factorial design and in-vivo pharmacokinetic study.

The oral administration of sildenafil citrate (SC) for the treatment of pulmonary arterial hypertension is associated with several drawbacks. The study aimed to design and formulate SC-loaded inhalable poly (lactic-co-glycolic acid) [PLGA] large porous microparticles (LPMs) for pulmonary delivery. A factorial design was used to study the effect of the composition of LPMs on physicochemical properties. The study also evaluated the effect of glucose and L-leucine concentration on the formulation. The developed LPMs demonstrated an acceptable yield% (≤48%), large geometric particle size (>5µm) with a spherical and porous surface, and sustained drug release (up to 48 h). Increasing the concentration of poly(ethyleneimine) from 0.5% to 1% in SC-loaded LPMs led to an increase in entrapment efficiency from ~3.02% to ~94.48%. The optimum LPMs showed adequate aerodynamic properties with a 97.68 ± 1.07% recovery, 25.33 ± 3.32% fine particle fraction, and low cytotoxicity. Intratracheal administration of LPMs demonstrated significantly higher lung deposition, systemic bioavailability, and longer retention time (p < 0.05) compared to orally administered Viagra® tablets. The study concluded that SC-loaded LPMs could provide better therapeutic efficacy, reduced dosing frequency, and enhanced patient compliance.

3D printing: An appealing route for customized drug delivery systems.

In the recent decade, three-dimensional (3D) printers started to grow strongly in the field of drug delivery and personalized medicine, as they can tailor dosage forms according to the needs of each individual. This review gives an overview on the basic principles of layer-by-layer building of pharmaceutical dosage forms using different types of 3D printers. Also, the effect of infill percentage and pattern, raster orientation, layer thickness, thermal processing parameters on the printed formulations is highlighted. Additionally, the complex designs constructed by the 3D printers in order to modify the product shape, density, mucoadhesion and drug release are recapitulated. This review summarizes numerous applications for 3D printing in building drug-loaded structures including tablets, scaffolds, implants, microneedles, capsules, films, hydrogels, mouthguards, tubes, stents, vaginal suppositories and rings as well as in pediatric field. Finally, we suggest further investigational researches to aid in the widespread of 3D printing in the industrial pharmaceutical field. The 3D printing technology is expected to revolutionize drug delivery systems through customization of pharmaceutical formulations.

Spray-Dried Rosuvastatin Nanoparticles for Promoting Hair Growth.

In this research, we examined the effect of rosuvastatin calcium-loaded nanoparticles on the hair growth-promoting activity on Albino rats. Nanoparticles were prepared using 2:1 weight ratio of drug to methyl-ß-cyclodextrin with 10, 20, and 30% stabilizers (phospholipid, polyvinyl pyrrolidone K30, and Compritol 888 ATO) using nanospray dryer. Subsequently, the prepared nanoparticles were evaluated for their process yield, particle size, polydispersity index, zeta potential, and in vitro drug release as well as in vivo studies. The dried nanoparticles showed process yield values up to 84% with particle size values ranging from 218 to 6258 nm, polydispersity index values ranging from 0.32 to 0.99, and zeta potential values ranging from - 6.1 to - 11.9 mV. Combination of methyl-ß-cyclodextrin with 10% polyvinyl pyrrolidone K30 accomplished nanoparticles with the lowest particle size (218 nm) and polydispersity index (0.32) values. These nanoparticles had suitable process yield value (70.5%) and were able to retard drug release. The hair growth-promoting activity for the selected nanoparticles revealed the highest hair length values in Albino rats after 14 days of the hair growth study compared with non-medicated nanoparticles, nanoparticles' physical mixture, rosuvastatin solution, and marketed minoxidil preparation groups as well as the control group. The immunohistochemistry images for both selected nanoparticles and marketed minoxidil groups showed a significant increase in the diameter of hair follicle and percent area fraction of cytokeratin 19 in the outer root sheath of hair follicle compared with other tested groups. Rosuvastatin nanoparticles prepared by nanospray drying technique could be a good competitor to minoxidil for hair growth-promoting activity. Graphical abstract.

A Rapid Lysostaphin Production Approach and a Convenient Novel Lysostaphin Loaded Nano-emulgel; As a Sustainable Low-Cost Methicillin-Resistant Staphylococcus aureus Combating Platform.

Staphylococcus aureus is a Gram-positive pathogen that is capable of infecting almost every organ in the human body. Alarmingly, the rapid emergence of methicillin-resistant S.aureus strains (MRSA) jeopardizes the available treatment options. Herein, we propose sustainable, low-cost production of recombinant lysostaphin (rLST), which is a native bacteriocin destroying the staphylococcal cell wall through its endopeptidase activity. We combined the use of E. coli BL21(DE3)/pET15b, factorial design, and simple Ni-NTA affinity chromatography to optimize rLST production. The enzyme yield was up to 50 mg/L culture, surpassing reported systems. Our rLST demonstrated superlative biofilm combating ability by inhibiting staphylococcal biofilms formation and detachment of already formed biofilms, compared to vancomycin and linezolid. Furthermore, we aimed at developing a novel rLST topical formula targeting staphylococcal skin infections. The phase inversion composition (PIC) method fulfilled this aim with its simple preparatory steps and affordable components. LST nano-emulgel (LNEG) was able to extend active LST release up to 8 h and cure skin infections in a murine skin model. We are introducing a rapid, convenient rLST production platform with an outcome of pure, active rLST incorporated into an effective LNEG formula with scaling-up potential to satisfy the needs of both research and therapeutic purposes.

In-situ forming chitosan implant-loaded with raloxifene hydrochloride and bioactive glass nanoparticles for treatment of bone injuries: Formulation and biological evaluation in animal model.

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.

Long lasting in-situ forming implant loaded with raloxifene HCl: An injectable delivery system for treatment of bone injuries.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.

Fabrication Strategies of Scaffolds for Delivering Active Ingredients for Tissue Engineering.

Designing scaffolds with optimum properties is an essential factor for tissue engineering success. They can be seeded with isolated cells or loaded with drugs to stimulate the body ability to repair or regenerate the injured tissues by acting as centers for new tissue formation. Recently, scaffolds gained a significant interest as principal candidates for tissue engineering due to overcoming the autograft or allograft's associated problems. The advancement of the tissue engineering field relies mainly on the introduction of new biomaterials for scaffolds' fabrication. This review presents and criticizes different scaffolds' fabrication techniques with particular emphasis on the fibrous, injectable in situ forming, foam, 3D freeze-dried, 3D printed, and 4D scaffolds. This article highlights on scaffolds' composition which would be beneficial for developing scaffolds that could potentially help to meet the demand for both drug delivery and tissue regeneration.

Design and evaluation of novel inhalable sildenafil citrate spray-dried microparticles for pulmonary arterial hypertension.

Pulmonary delivery of vasodilators is a promising alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). The aim of this study was to design and evaluate hydrogel microparticles as a carrier for sustained pulmonary delivery of sildenafil citrate. Spray dried hydrogel microparticles containing biodegradable sodium carboxymethyl cellulose, sodium alginate, and sodium hyaluronate polymers at variable concentrations were prepared. A design of experiment using the "Extreme Vertices Mixture" design was executed. The design was used to study the influence of polymer concentration and their interactions on the physicochemical properties of the formulations in terms of particle size, particle size distribution, product yield, entrapment efficiency, and in-vitro drug release. Selected formulations were also evaluated for swelling, biodegradation, moisture content, in-vitro aerodynamic performance, and cytotoxicity. In addition, a lung deposition and pharmacokinetic study was conducted in rats to study drug accumulation in lungs and blood after intratracheal administration of the spray dried inhalable hydrogel microparticles in comparison to orally administered Viagra®. The results demonstrated that formulated microparticles had a mean geometric particle size between 2 and 5 µm, entrapment efficiency of >80%, and yield ranging between 47 and 66% w/w. The in-vitro drug release profiles showed a sustained drug release of sildenafil citrate for over 24 h. The statistical design showed a significant influence of the microparticulate composition on the physicochemical properties. Furthermore, selected formulations were evaluated for their aerodynamic properties. The aerodynamic properties included fine particle fraction ranging between 24 and 30%, dose recovery percent of 68-8 5%, and average mass median aerodynamic diameter of 4.6-4.8 µm. The in-vivo pharmacokinetic study showed that inhaled spray dried hydrogel microparticles (M6) formulation had significantly higher lung/blood Cmax, AUC, extended half-life, and mean residence time in comparison to orally administered sildenafil citrate of the same dose. In conclusion, the formulated drug-loaded spray dried hydrogel microparticles showed promising in-vitro and in-vivo results for the pulmonary delivery of sildenafil citrate. The spray dried hydrogel microparticles formulation can be considered as a potential alternative of oral sildenafil citrate for treatment of PAH.

Mesenchymal stem cells associated with chitosan scaffolds loaded with rosuvastatin to improve wound healing.

In this study we explored the role of rosuvastatin calcium in skin regeneration as statins play important role in the field of tissue engineering. Chitosan hydrochloride was crosslinked with different weight ratios of collagen, ß-glycerolphosphate and carboxymethyl cellulose to produce scaffolds by lyophilization technique. Subsequently, the fabricated scaffolds were examined for their morphology, water absorption capacity, water retention, friability and in-vitro drug release as well as in-vivo studies. The results revealed porous 3-D structured scaffolds with maximum water absorption values-ranging between 396 and 2993%. Scaffolds containing carboxymethyl cellulose revealed highest water absorption-values. In-vitro drug release results showed gradual drug release for 60 h with mean dissolution time-values (MDT) between 13 and 21 h. Combination of chitosan, collagen, carboxymethyl cellulose in weight ratio of 40:30:30, respectively achieved gradual disintegration of the scaffold in a simulating medium to an open wound after 4 days. This selected scaffold loaded with rosuvastatin revealed increase proliferation of human dermal fibroblasts compared to placebo scaffold. After 30 days of implantation of selected medicated scaffold loaded with/without mesenchymal stem cells and placebo scaffolds to induced wounds in Albino rats, enhanced skin regeneration and absence of scar formation for drug loaded scaffolds were observed. The histopathological study showed the advantage of stem cells-loaded scaffolds through the normal redistribution of collagen in the epidermal layer. In conclusion, rosuvastatin calcium and stem cells loaded in the tested scaffolds proved their potential effect in enhancing skin healing and regeneration.

Bioavailability Enhancement of Aripiprazole Via Silicosan Particles: Preparation, Characterization and In vivo Evaluation.

The aim of this study was to design a novel carrier for enhancing the bioavailability of the poorly water-soluble drug, aripiprazole (ARP). Silicosan, the applied carrier, was obtained by chemical interaction between tetraethyl orthosilicate (TEOS) and chitosan HCl. Different ARP-loaded silicosan particles were successfully prepared in absence and presence of one of the following surfactants; Tween 80, Poloxamer 407 and cetyltrimethylammonium bromide (CTAB). The prepared ARP-loaded silicosan particles were thoroughly investigated for their structures using FTIR, XRD, and DSC analysis as well as their particle size, zeta potential, flowability, drug content, and in vitro drug release efficiencies. The prepared ARP-loaded silicosan particles were characterized by amorphous structure, high drug entrapment efficiency and a remarkable improvement in the release of aripiprazole in simulated gastric fluid. SEM and EDX revealed that the morphology and silica atom content in the prepared ARP-loaded silicosan particles were affected by the used surfactant in their formulations. The selected ARP-loaded silicosan particles were subjected to in vivo study using rabbits. The obtained pharmacokinetic results showed that the relative bioavailability for orally administered ARP-loaded silicosan particles (SC-2-CTAB) was 66% higher relative to the oral suspension (AUC0-10h was 16.38 ± 3.21 and 27.23 ± 2.35 ng.h/mL for drug powder and SC-2-CTAB formulation, respectively). The obtained results suggested the unique-structured silicosan particles to be used as successful vehicle for ARP.

Design and characterization of emulsified spray dried alginate microparticles as a carrier for the dually acting drug roflumilast.

Roflumilast is a selective inhibitor of phosphodiesterase-4 isoenzyme in lung cells. Having psychiatric adverse reactions when administered orally affects negatively the patients' adherence to the drug. This work aimed to prepare emulsified spray dried alginate microparticles for the pulmonary delivery of roflumilast. Sodium alginate was used as microparticle-forming material, isopropyl myristate as an oil, Tween®80 as surfactant and calcium beta-glycerophosphate as cross-linking agent to enhance the mechanical properties of the particles. The prepared particles were evaluated for their encapsulation efficiency, particle size and in-vitro drug release. From the studied carriers, beta-cyclodextrin (CD) was the best regarding giving formulation with smaller particle size and more sustained drug release. The inhalation profile of CD-based microparticles was investigated using Anderson cascade impactor. The aerosolization profile of CD-based microparticles suggested their efficiency to deliver the drug deep in the lung. The CD-based microparticles possessed more inhibitory effects on the viability of A549 cells and on the pro-inflammatory cytokines (TNF-α, IL-6 and IL-10) compared to the pure drug. Hence, CD-based microparticles could regulate the tumorigenesis besides tumor-associated inflammation. Finally, CD-based microparticles showed more sustained bronchodilatation properties in healthy human volunteers when compared to Ventolin®HFA. CD-based microparticles proved to be a promising carrier for inhaled roflumilast in human.

Lamotrigine loaded poly-ɛ-(d,l-lactide-co-caprolactone) nanoparticles as brain delivery system.

Management of epilepsy requires brain delivery therapy, therefore, this study was aimed to prepare lamotrigine loaded poly-ɛ-(d,l-lactide-co-caprolactone) (PLCL) nanoparticles using spontaneous emulsification solvent diffusion method. Nanoparticles for brain delivery required to have a particle size <200 nm, polydispesity index <0.2 and a sustained drug release properties. For such aim different factors were considered in preparing the nanoparticles as PLCL monomers' ratio, type of organic solvent used to prepare the nanoparticles, amount of PLCL and Pluronic®F127 in the nanoparticles. Prepared nanoparticles were characterized for their shape, particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading capacity, process yield and in-vitro drug release pattern. The in-vivo investigation for brain delivery of selected nanoparticles delivered by intravenous route was investigated in rats and compared to that for oral tablet. The obtained nanoparticles were spherical in shape. The amount of surfactant and PLCL affected the properties of the obtained nanoparticles. Using a mixture of organic solvent in preparing the nanoparticles improved its properties. The nanoparticles prepared using PLCL with monomers' ratio of 25:75, had particle size value of 125 nm, polydispersity index value of 0.184, zeta potential value of -39 mV and encapsulation efficiency value of 99%, was selected to study their efficacy to deliver the drug to the brain. The tested nanoparticles showed higher values of Tmax, Cmax, AUC, and MRT in homogenized rat brain, compared to oral lamotrigine tablet, while the bioavailability of the oral tablet was higher in rat plasma compared to that for the nanoparticles. This reflects that brain was the main distribution site for tested nanoparticles, and plasma was the main distribution site for oral tablets. This confirms the goal of the selected formulation as brain delivery nanoparticles.