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Inflammatory bowel disease (IBD) is characterized by chronic inflammation along the gastrointestinal tract. For IBD effective treatment, developing an orally administered stable drug delivery system capable of targeting inflammation sites is a key challenge. Herein, we report pH responsive hyaluronic (HA) coated Eudragit S100 (ES) nanoparticles (NPs) for the targeted delivery of budesonide (BUD) (HA-BUD-ES-NPs). HA-BUD-ES-NPs showed good colloidal properties (274.8 ± 2.9 nm and − 24.6 ± 2.8 mV) with high entrapment efficiency (98.3 ± 3.41%) and pH-dependent release profile. The negative potential following incubation in simulated gastrointestinal fluids reflected the stability of HA coat. In vitro studies on Caco-2 cells showed HA-BUD-ES-NPs biocompatibility and enhanced cellular uptake and anti-inflammatory effects as shown by the significant reduction in IL-8 and TNF-α. The oral administration of HA-BUD-ES-NPs in an acetic acid induced colitis rat model significantly mitigated the symptoms of IBD, and improved BUD therapeutic efficacy compared to drug suspension. This was proved via the improvement in disease activity index and ulcer score in addition to refined histopathological findings. Also, the assessment of inflammatory markers, epithelial cadherin, and mi-R21 all reflected the higher efficiency of HA-BUD-ES-NPs compared to free drug and uncoated formulation. We thus suggest that HA-BUD-ES-NPs provide a promising drug delivery platform for the management and site specific treatment of IBD. Graphical Abstract

Hepatocellular carcinoma (HCC) is a prevalent liver cancer representing the fourth most lethal cancer worldwide. Trans-Resveratrol (T-R) possesses a promising anticancer activity against HCC. However, it suffers from poor bioavailability because of the low solubility, chemical instability, and hepatic metabolism. Herein, we developed T-R-loaded nanocochleates using a simple trapping method. Nanocarriers were optimized using a comprehensive in-vitro characterization toolset and evaluated for the anticancer activity against HepG2 cell line. T-R-loaded nanocochleates demonstrated monodispersed cylinders (163.27 ± 2.68 nm and 0.25 ± 0.011 PDI) and −46.6 mV ζ-potential. They exhibited a controlled biphasic pattern with minimal burst followed by sustained release for 72 h. Significant enhancements of Caco-2 transport and ex-vivo intestinal permeation over liposomes, with 1.8 and 2.1-folds respectively, were observed. Nanocochleates showed significant reduction of 24 h IC50 values compared to liposomes and free T-R. Moreover, an efficient knockdown of anti-apoptotic (Bcl-2) and cancer stemness (NANOG) genes was demonstrated. To the best of our knowledge, we are the first to develop T-R loaded nanocochleates and scrutinize its potential in suppressing NANOG expression, 2-folds lower, compared to free T-R. According to these auspicious outcomes, nanocochleates represent a promising nanoplatform to enhance T-R oral permeability and augment its anticancer efficacy in the treatment of HCC.

Weight gain or obesity represents a major health risk and leads to diseases including cancer and heart disease. Most anti-obesity medications have significant side effects, and there are notable challenges concerning their availability in the body to produce an effect. Pterostilbene is a herbal drug with beneficial anti-obesity effects. However, it has problems such as poor solubility which restrict its use. The aim of the study was to formulate pterostilbene in a nano-based delivery system and fully characterize its anti-obesity effect when given orally. We evaluated the safety and anti-obesity effects of pterostilbene nanoparticles in cells and in obese rats fed on a high-fat diet. We also looked at how the body absorbs, distributes and gets rid of these nanoparticles. The prepared nanoparticles were nontoxic, with an improved anti-obesity effect; they decreased cholesterol levels and helped in changing white fat (which stores fat) to brown fat (which burns calories). We conclude that the developed pterostilbene nanoparticles, given orally, are a new and promising anti-obesity strategy given their long-lasting effect on weight loss and the minimal side effects. This may be of great economic and societal impact.

Salma El-Habashy,1 Hoda Eltaher,1 Ahmed Gaballah,2 Radwa Mehanna,3,4 Amal H El-Kamel1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; 2Microbiology Department, Medical Research Institute, Alexandria University, Alexandria, 21561, Egypt; 3Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, 21131, Egypt; 4Center of Excellence for Research in Regenerative Medicine and Applications CERRMA, Faculty of Medicine, Alexandria University, Alexandria, 21131, EgyptCorrespondence: Amal H El-KamelDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 1 Khartoum Square, Azarita, PO Box 21521, Alexandria, EgyptTel +20-10-0508 0510Email amalelkamel@yahoo.comBackground: Besides its antimicrobial action, doxycycline (DX) has lately been repurposed as a small-molecule drug for osteogenic purposes. However, osteogenic DX application is impeded by its dose-dependent cytotoxicity. Further, high-dose DX impairs cell differentiation and mineralization.Purpose: Integrating DX into a biomaterial-based delivery system that can control its release would not only ameliorate its cytotoxic actions but also augment its osteogenic activity. In this work, we managed to engineer novel composite DX–hydroxyapatite–polycaprolactone nanoparticles (DX/HAp/PCL) to modify DX osteogenic potential.Methods: Employing a 23-factorial design, we first optimized HApN for surface-area attributes to maximize DX loading. Composite DX/HAp/PCL were then realized using a simple emulsification technique, characterized using various in vitro methods, and evaluated for in vitro osteogenesis.Results: The developed HApN exhibited a favorable crystalline structure, Ca:P elemental ratio (1.67), mesoporous nature, and large surface area. DX/HAp/PCL achieved the highest reported entrapment efficiency (94.77%± 1.23%) of DX in PCL-based particles. The developed composite system achieved controlled release of the water-soluble DX over 24 days. Moreover, the novel composite nanosystem managed to significantly ameliorate DX cytotoxicity on bone-marrow stem cells, as well as enhance its overall proliferation potential. Alkaline phosphatase and mineralization assays revealed superior osteodifferentiation potential of the composite system. Quantification of gene expression demonstrated that while DX solution was able to drive bone-marrow stem cells down the osteogenic lineage into immature osteoblasts after 10-day culture, the innovative composite system allowed maturation of osteodifferentiated cells. To the best of our knowledge, this is the first work to elaborate the impact of DX on the expression of osteogenic genes: RUNX2, OSP, and BSP. Further, the osteogenicity of a DX-loaded particulate-delivery system has not been previously investigated.Conclusion: Our findings indicate that repurposing low-dose DX in complementary biomaterial-based nanosystems can offer a prominent osteogenic candidate for bone-regeneration purposes.Keywords: bone regeneration, bioactivity, mesenchymal stem cells, drug repositioning, osteodifferentiation

Introduction Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol®888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron®). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.

Introduction Liver fibrosis represents a serious global disease with no approved treatment. Tanshinone IIA (TSIIA) is a phytomedicine with documented activity in treating many hepatic disorders. TSIIA has been reported to have potent anti-inflammatory and antioxidant properties. It can also induce apoptosis for activated hepatic stellate cells, and is thereby considered as a promising herbal remedy for treating fibrotic liver. However, its poor aqueous solubility, short half-life, exposure to the first-pass effect, and low concentration reaching targeted cells constitute the major barriers hindering its effective therapeutic potential. Therefore, this work aimed at enhancing TSIIA systemic bioavailability together with achieving active targeting potential to fibrotic liver via its incorporation into novel modified lipid nanocapsules (LNCs). Methods Blank and TSIIA-loaded LNCs modified with either hyaluronate sodium or phosphatidyl serine were successfully prepared, optimized, and characterized both in vitro and in vivo. Results The developed LNCs showed good colloidal properties (size ≤100 nm and PDI ≤0.2), high drug-entrapment efficiency (>97%) with sustained-release profile for 24 hours, high storage stability up to 6 months, and good in vitro serum stability. After a single intraperitoneal injection, the administered LNCs exhibited a 2.4-fold significant increase in AUC0–∞ compared with the TSIIA suspension (p≤0.01). Biodistribution-study results proved the liver-targeting ability of the prepared modified LNCs, with a significant ~1.5-fold increase in hepatic accumulation compared with the unmodified formulation (p≤0.05). Moreover, the modified formulations had an improved antifibrotic effect compared with both unmodified LNCs and TSIIA suspension, as evidenced by the results of biochemical and histopathological evaluation. Conclusion The modified TSIIA-LNCs could be regarded as promising novel targeted nanomedicines for effective management of liver fibrosis., Graphical Abstract

Acute lung injury (ALI) and its more serious form; acute respiratory distress syndrome are major causes of COVID-19 related mortality. Finding new therapeutic targets for ALI is thus of great interest. This work aimed to prepare a biocompatible nanoformulation for effective pulmonary delivery of the herbal drug; tanshinone-IIA (TSIIA) for ALI management. A nanoemulsion (NE) formulation based on bioactive natural ingredients; rhamnolipid biosurfactant and tea-tree oil, was developed using a simple ultrasonication technique, optimized by varying oil concentration and surfactant:oil ratio. The selected TSIIA-NE formulation showed 105.7 nm diameter and a PDI ∼ 0.3. EE exceeded 98 % with biphasic sustained drug release and good stability over 3-months. In-vivo efficacy was evaluated in lipopolysaccharide (LPS)-induced ALI model. TSIIA-NE (30 µg/kg) was administered once intratracheally 2 h after LPS instillation. Evaluation was performed 7days post-treatment. Pulmonary function assessment, inflammatory, oxidative stress and glycocalyx shedding markers analysis in addition to histopathological examination of lung tissue were performed. When compared to untreated rats, in-vivo efficacy study demonstrated 1.4 and 1.9-fold increases in tidal volume and minute respiratory volume, respectively, with 32 % drop in wet/dry lung weight ratio and improved levels of arterial blood gases. Lung histopathology and biochemical analysis of different biomarkers in tissue homogenate and bronchoalveolar lavage fluid indicated that treatment may ameliorate LPS-induced ALI symptoms thorough anti-oxidative, anti-inflammatory effects and inhibition of glycocalyx degradation. TSIIA-NE efficacy was superior to free medication and blank-NE. The enhanced efficacy of TSIIA bioactive nanoemulsion significantly suggests the pharmacotherapeutic potential of bioactive TSIIA-NE as a promising nanoplatform for ALI.

The versatility of 3D printing has rendered it an indispensable tool for the fabrication of composite hydrogel scaffolds, offering bone biomimetic features through inorganic and biopolymeric components as promising platforms for osteoregeneration. In this work, extrusion-based 3D printing was employed for the realization of osteoconductive composite biopolymer-based hydrogel scaffolds reinforced with hybrid bioactive hydroxyapatite/polycaprolactone nanoparticles (HAp/PCL NPs) for osteoregeneration. The printing technique was optimized for ink printability and viscosity and crosslinking parameters, where a biopolymeric blend of gelatin, polyvinyl alcohol and hyaluronic acid was developed as innovative plain polymeric ink (PPI). Scaffolds were fabricated by 3D printing adopting a biphasic core/shell geometry, where the core phase of the scaffolds was reinforced with HAp/PCL NPs; the scaffolds were then freeze-dried. Novel composite freeze-dried, loaded-core scaffolds, HAp/PCL NPs-LCS-FD exhibited controlled swelling and maintained structural integrity for 28 days. The developed HAp/PCL NPs-LCS-FD also demonstrated double-ranged pore size, interconnected porosity and efficient mechanical stiffness and strength, favorable for osteoconductive actions. Cell infiltration studies, computed tomography and histomorphometry demonstrated that HAp/PCL NPs-LCS-FD afforded osteoconduction, biodegradation, biocompatibility and bone healing in rabbit tibial model, acting as a template for new bone formation. Our findings suggest that HAp/PCL NPs-LCS-FD could offer prominent bone regeneration and could be involved in various bone defects.

Salma El-Sayed Radwan,1 Amal El-Kamel,1 Eiman I Zaki,2 Susi Burgalassi,3 Erica Zucchetti,3 Riham M El-Moslemany1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; 2Department of Histology and Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 3Department of Pharmacy, University of Pisa, Pisa, ItalyCorrespondence: Riham M El-Moslemany 1, Khartoum Square, Azarita, Alexandria, EgyptTel +11 201006020405Email riham.elmoslemany@alexu.edu.egPurpose: Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR.Methods: Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning.Results: Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2± 3.56 nm, 0.221± 0.02 and − 37.3± 1.8 mV, respectively. High EE% (69± 1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy.Conclusion: Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.Keywords: retinopathy, apatinib, bovine serum albumin, hyaluronic, mucopenetration, active targeting

Hydroxyapatite nanoparticles (HApN) are largely employed as osteogenic inorganic material. Inorganic/polymeric hybrid nanostructures can provide versatile bioactivity for superior osteogenicity, particularly as nanoparticles. Herein, we present hybrid biomaterial-based hydroxyapatite/polycaprolactone nanoparticles (HAp/PCL NPs) realized using simple preparation techniques to augment HApN osteogenicity. Using wet chemical precipitation, we optimized HApN crystalline properties utilizing a 23-factorial design. Optimized HApN exhibited typical Ca/P elemental ratio with high reaction yield. Surface area analysis revealed their mesoporous nature and high surface area. Hybrid HAp/PCL NPs prepared using direct emulsification-solvent evaporation maintained HApN crystallinity with no observed chemical interactions. To the best of our knowledge, we are the first to elaborate the biocompatibility and osteogenicity of nanoparticulate hybrid HAp/PCL. Hybrid HAp/PCL NPs outperformed HApN regarding mesenchymal cell proliferation and osteodifferentiation with reduction of possible cytotoxicity. Unlike HApN, hybrid HAp/PCL NPs presented moderate expression of early osteogenic markers, Runx-2 and osteopontin and significantly elevated expression of the late osteogenic marker, bone sialoprotein after 10-day culture. Our results indicate that hybrid bioactive HAp/PCL NPs could offer a more prominent osteogenic potential than plain HApN for bone regenerative applications as a standalone nanoplatform or as part of complex engineered systems.

Objectives: Nutraceuticals are advertised and sold with the label claim of being natural and safe herbal products. Due to the absence of clear regulations and guidelines for safety assessments of these products, nutraceuticals are commonly adulterated in order to increase sales. The objective of the current study was to design a comprehensive evaluation system to assess the safety, efficacy, authenticity according to label claim, and pharmaceutical quality of herbal slimming products in between 2015 and 2017. Methods: We designed a comprehensive assessment system to evaluate the safety, authenticity according to label claim, and pharmaceutical quality of slimming nutraceuticals. Six different popular products were evaluated (Zotreem Plus®, Zotreem Extra®, Malaysian Super Slim®, AB Slim®, Chinese Super Slim®, and Metabolites®). The pharmaceutical evaluation included analyzing the samples via high-performance liquid chromatography to determine any possible adulterants. Additionally, the products’ physical properties were assessed via pharmacopeial tests. Finally, a microbial evaluation and a cross-sectional observational retrospective prevalence study were conducted to assess the products’ safety and efficacy. ­Results: The tested products were found to be adulterated with unreported active pharmaceutical ingredients such as sibutramine, sildenafil, phenolphthalein, and orlistat. Furthermore, they contained heterogeneous amounts of adulterants and exhibited an unsatisfactory pharmaceutical and microbial quality. Finally, the observational survey conducted on users showed that high percentages of participants suffered from common side effects such as depression, diarrhea, and hypertension. Conclusions: These products threaten the health of consumers. There is a need to raise awareness of the lethal consequences of illegal nutraceuticals.

Brimonidine ocular hypotensive effect can be enhanced by increasing residence time and corneal penetration. The current work aimed to formulate, evaluate and compare nanostructured lipid carriers (NLCs) to solid lipid nanoparticles (SLNs) and commercial eye drops for controlled brimonidine delivery. NLCs prepared by modified high shear homogenisation were spherical with a mean size of 151.97 ± 1.98 nm, negative zeta potential (ZP) of -44.2 ± 7.81 mV, % entrapment efficiency (EE) of 83.631 ± 0.495% and low crystallinity index (CI) (17.12%), indicating a better drug incorporation. Moreover, they kept stable during storage at 4 °C for 3 months. Permeability coefficient of NLCs was 1.227 folds higher than that of SLNs. Histological examination revealed localisation of NLCs in the anterior ocular chamber. NLCs revealed the most sustained and highest intraocular pressure (IOP) lowering activity (-13.14 ± 1.28 mmHg) in rabbits. In conclusion, NLCs is a promising approach for IOP reduction compared to eye drops and SLNs.

Currently applied methodologies (acidic or enzymatic chitosanolysis) towards synthesis of Chitosan- Oligosaccharides (COS) are faced with some drawbacks that confine their potential in biotechnological applications. The present work addresses a novel tailored method as an alternate to biosynthesize COS. An empirical statistical-mathematical approach [Plackett-Burman. Design (PBD) followed by Box-Behnken design (BBD)] was employed to optimize COS biosynthesis by an endo -chitosanase non-aflatoxigenic producing Aspergillus sp. section Flavi strain EGY1 DSM 101520 whole cells. Optimal levels localized by BBD for three key determinants were 0.687% (w/v) low molecular weight chitosan (LMWC), 25 °C incubation temperature and 72–96 h incubation time, along with 2.0 gL −1 maximal level of COS, achieving 94.7% model adequacy upon growing the fungus on LMWC-based tap water medium [merely 0.687% (w/v) LMWC]. Batch mode scaling up in the laboratory scale fermenter achieved 5.34 gL −1 of COS after 44 h with 2.67 fold enhancement. Partially acetylated hetero-oligomers with DPs (2–11) of the water-soluble COS were proved by TLC, MALDI-TOF-MS, 1 H NMR, 13 C NMR and FTIR. To the best of the authors' knowledge, the present work is the first study highlighting a novel, robust, cheap, environmentally safe, reproducible approach to biosynthesize COS by fungal whole cells.

3D printing has revolutionized pharmaceutical research, with applications encompassing tissue regeneration and drug delivery. Adopting 3D printing for pharmaceutical drug delivery personalization via nanoparticle-reinforced hydrogel scaffolds promises great regenerative potential. Herein, we engineered novel core/shell, bio-inspired, drug-loaded polymeric hydrogel scaffolds for pharmaceutically personalized drug delivery and superior osteoregeneration. Scaffolds were developed using biopolymeric blends of gelatin, polyvinyl alcohol and hyaluronic acid and integrated with composite doxycycline/hydroxyapatite/polycaprolactone nanoparticles (DX/HAp/PCL) innovatively via 3D printing. The developed scaffolds were optimized for swelling pattern and in-vitro drug release through tailoring the biphasic microstructure and wet/dry state to attain various pharmaceutical personalization platforms. Freeze-dried scaffolds with nanoparticles reinforcing the core phase (DX/HAp/PCL-LCS-FD) demonstrated favorably controlled swelling, preserved structural integrity and controlled drug release over 28 days. DX/HAp/PCL-LCS-FD featured double-ranged pore size (90.4 ± 3.9 and 196.6 ± 38.8 µm for shell and core phases, respectively), interconnected porosity and superior mechanical stiffness (74.5 ± 6.8 kPa) for osteogenic functionality. Cell spreading analysis, computed tomography and histomorphometry in a rabbit tibial model confirmed osteoconduction, bioresorption, immune tolerance and bone regenerative potential of the original scaffolds, affording complete defect healing with bone tissue. Our findings suggest that the developed platforms promise prominent local drug delivery and bone regeneration.

Eudragit-loaded silymarin nanoparticles (SNPs) and their formulation into buccal mucoadhesive tablets were investigated to improve the low bioavailability of silymarin through buccal delivery. Characterisation of SNPs and silymarin buccal tablets (SBTs) containing the optimised NPs were performed. Ex vivo permeability of nominated SBTs were assessed using chicken pouch mucosa compared to SNPs and drug suspension followed by histopathological examination. Selected SNPs had a small size (150 nm), encapsulation effciency (77%) with drug release of about 90% after 6 h. For STBs, all physicochemical parameters were satisfactory for different polymers used. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state. Ex vivo permeation significantly emphasised the great enhancement of silymarin permeation after NPs formation and much more increase after formulating into BTs relative to the corresponding drug dispersion with confirmed membrane integrity. Incorporation of SNPs into BTs could be an efficient vehicle for delivery of silymarin.

The aim of this study was to formulate and evaluate chitosan (CS)/alginate (ALG) nanoparticles (NPs) loaded with furosemide (FSM) in an attempt to enhance its release, permeability and bioavailability. Non-everted gut sac method was used to evaluate the ex vivo permeation of FSM from its suspension and the selected CS/ALG NPs formulation. The pharmacokinetic parameters of FSM subsequent to oral administration of the selected formulation were assessed in rats. In vivo subacute toxicity study of the prepared blank and FSM loaded formulations was evaluated in rats. The selected optimized formulation (F3) showed optimum particle size (PS), polydispersity index (PDI), zeta potential (ZP) and acceptable percentage entrapment efficiency (%EE) of 253.8nm±4.6, 0.25±0.03, -35mV±1 and 96%±1, respectively. The release profile of FSM from the selected formulation was characterized by initial burst effect in 0.1N HCl. Scanning electron microscope (SEM) demonstrated a smooth surface and spherical shape for the lyophilized optimized NPs. Selected CS/ALG NPs (F3) presented a significant enhancement (p≤0.01) in permeation parameters of FSM as well as in Tmax, Cmax, AUC0-24 and AUC0-∞. Subacute toxicity study results revealed that the selected formulation was safe and nontoxic. The histopathological inspection of the stomach and small intestine tissues of the loaded NPs (F3) and blank groups reflected no obvious signs of cellular toxicity or inflammatory reaction. CS/ALG NPs loaded with FSM enhanced both drug release and mucus-penetrating ability leading to an overall increase in FSM bioavailability. In addition, the in vivo subacute toxicity study results indicated the safety of the prepared NPs for oral drug delivery.

The objectives of this study were to formulate, characterize silymarin-loaded Eudragit nanoparticles (SNPs) and evaluate their hepatoprotective and cytotoxic effects after oral administration. SNPs were prepared by nanoprecipitation technique and were evaluated for particle size, entrapment efficiency, TEM, solid-state characterization, and in vitro drug release. The hepatoprotective activity was evaluated after oral administration of selected SNPs in carbon tetrachloride-intoxicated rats. Potential in vivo acute cytotoxicity study was also assessed. The selected SNPs contained 50 mg silymarin and 50 mg Eudragit polymers (1:1 w/w Eudragit RS 100 & Eudragit LS 100). Morphology of the selected SNPs (particle size of 84.70 nm and entrapment efficiency of 83.45% with 100% drug release after 12 h) revealed spherical and uniformly distributed nanoparticles. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state and absence of chemical interaction. The hepatoprotective evaluation of the selected SNPs in CCl4-intoxicated rats revealed significant improvement in the activities of different biochemical parameters (P ≤ 0.01) compared to the marketed product. The histopathological studies suggested that the selected SNPs produced better hepatoprotective effect in CCl4-intoxicated rats compared with the commercially marketed product. Toxicity study revealed no evident toxic effect for blank or silymarin-loaded nanoparticles at the dose level of 50 mg/kg body weight. The obtained results suggested that the selected SNPs were safe and potentially offered enhancement in the pharmacological hepatoprotective properties of silymarin.

Salma E El-Habashy, Ahmed N Allam, Amal H El-Kamel Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Abstract: Nanoparticles (NPs) have long gained significant interest for their use in various drug formulations in order to increase bioavailability, prolong drug release, and decrease side effects of highly toxic drugs. The objective of this investigation was to evaluate the potential of ethyl cellulose-based NPs (EC-NPs) to modulate the release and reduce ulcerogenicity of piroxicam (PX) after oral administration. PX-loaded EC-NPs were prepared by solvent evaporation technique using different stabilizers at three concentration levels. Morphological examination of selected formulas confirmed the formation of spherical NPs with slightly porous surface. Formulation containing poloxamer-stabilized EC-NPs (P188/0.2), having a particle size of 240.26±29.24nm, polydispersity index of 0.562±0.030, entrapment efficiency of 85.29%±1.57%, and modulated release of PX (88% after 12hours), was selected as the optimum formulation. Differential scanning calorimetry demonstrated the presence of PX in an amorphous form in the NPs. Fourier-transform infrared spectroscopy revealed the possible formation of hydrogen bond and the absence of chemical interaction. In vivo study, evaluation of pharmacokinetic parameters, evaluation of gastric irritation potential, and histological examination were conducted after administration of the selected formulation. Time to reach maximum plasma concentration, tmax, of poloxamer-stabilized EC-NPs was significantly higher than that of Feldene® 20mg capsules (P≤0.001). Encapsulation of the acidic, gastric offender PX into NPs managed to significantly suppress gastric ulceration potential in rats (P≤0.05) as compared to that of PX suspension. A reduction of 66% in mean ulcer index was observed. In conclusion, poloxamer-stabilized EC-NPs (P188/0.2) had a significant potential of offsetting deleterious side effects common in PX use. Keywords: polymeric nanoparticles, poloxamer, NSAIDs, pharmacokinetics, gastric irritation&nbsp

Tanshinone IIA (TSIIA) is a promising phytomedicine that has been extensively studied due to its numerous biological activities, especially as an anticancer drug. However, it suffers from poor oral bioavailability owing to low aqueous solubility, poor permeability and exposure to first-pass metabolism. This study endeavored to improve TSIIA oral bioavailability by encapsulation into lipid nanocapsules (LNCs) for the first time. A previously reported phase-inversion method was used to prepare Tanshinone II A loaded LNCs (TSIIA-LNCs) with slight modifications based on a constructed phase diagram. They were then in-vitro characterized and their oral pharmacokinetics were studied in rats. TSIIA-LNCs showed excellent colloidal properties (size; 70 nm, PDI 0.2 and zeta-potential; -13.5 mV), a high percent entrapment efficiency (98%) and a good drug payload (2.6 mg/g). Furthermore, the in-vivo pharmacokinetic study revealed a significant enhancement in both the rate and extent of absorption of TSIIA-LNCs compared with TSIIA suspension with about 3.6-fold increase in AUC

Rana Ihab Reda,1 Ming Ming Wen,2 Amal Hassan El-Kamel1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 2Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt Purpose: The purpose of this study was to formulate ketoprofen (KET)-loaded Eudragit L and Eudragit S nanofibers (NFs) by the electrospinning technique for buccal administration to treat oral mucositis as a safe alternative to orally administered KET, which causes gastrointestinal tract (GIT) side effects. Materials and methods: NFs were prepared by electrospinning using Eudragit L and Eudragit S. Several variables were evaluated to optimize NF formulation, such as polymer types and concentrations, applied voltage, flow rate and drug concentrations. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) and analyses of drug contents, hydration capacity, surface pH, drug release and ex vivo permeation were performed to evaluate the NFs. The selected formulation (F1) was evaluated in vivo on induced oral mucositis in rabbits. Results: SEM revealed that 20% polymer formed smooth and bead-free NFs. DSC results confirmed the amorphous nature of KET in the NFs. FTIR confirmed hydrogen bond formation between the drug and polymer, which stabilized the NFs. Both formulations (F1 and F2) had an acceptable surface pH. The drug loading was >90%. The amount of KET released from NF formulations was statistically significantly higher (P≤0.001) than that released from the corresponding solvent-casted films. The complete release of KET from F1 occurred within 2hours. Ex vivo permeation study revealed that only a small fraction of drug permeated from F1, which was a better candidate than F2 for local buccal delivery. In vivo evaluation of F1 on oral mucositis induced in rabbits demonstrated that F1 reduced the clinical severity of mucositis in rabbits under the current experimental conditions. The attenuated clinical severity was accompanied by a marked reduction in inflammatory infiltrate and re-epithelization of the epithelial layer. Conclusion: Eudragit L100 nanofibers (EL-NF) loaded with KET (F1) suppressed the inflammatory response associated with mucositis, which confirmed the efficacy of local buccal delivery of KET-loaded EL-NF in treating oral mucositis. Keywords: nanofibers, electrospinning, ketoprofen, Eudragit, oral mucositis

Gastroretentive levofloxacin (LVF) floating mini-tablets for the eradication of Helicobacter pylori (H. pylori) were prepared using the matrix forming polymer hydroxypropyl methylcellulose (HPMC K100M), alone or with Carbopol 940P in different ratios by wet granulation technique. Buoyancy of mini-tablets was achieved by an addition of an effervescent mixture consisting of sodium bicarbonate and anhydrous citric acid to some formulations. The prepared mini-tablets were evaluated for weight variation, thickness, friability, hardness, drug content, in vitro buoyancy, water uptake and in vitro release. The optimized formula was subjected to further studies: FT-IR, DSC analysis and in vivo examination in healthy volunteers. The prepared mini-tablets exhibited satisfactory physicochemical characteristics. Incorporation of gas-generating agent improved the floating parameters. HPMC K100M mini-tablet formulation (F1) offered the best controlled drug release (>8h) along with floating lag time 24h. The obtained DSC thermograms and FT-IR charts indicated that there is no positive evidence for the interaction between LVF and ingredients of the optimized formula. The in vivo test confirmed the success of the optimized formula F1 in being retained in the stomach of the volunteers for more than 4h. LVF floating mini-tablets based on HPMC K100M is a promising formulation for eradication of H. pylori.

This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application.

Size increasing (plug-type) levofloxacin hemihydrate (LVF) tablets for eradication of Helicobacter pylori (H. pylori) were prepared using in situ gel forming polymers including: gellan gum, sodium alginate, pectin and xanthan gum. Effect of cross-linkers: calcium and aluminum chloride, on the drug release was also studied. The prepared tablets were evaluated for their physicochemical parameters: weight variation, thickness, friability, hardness, drug content, water uptake and in vitro drug release. The optimized formula was subjected to further studies such as radial swelling test, FT-IR and DSC. Results revealed that LVF release depends not only on the nature of the matrix but also on the type of cross linker used to form this polymeric matrix. The addition of either calcium chloride or aluminum chloride, as cross-linkers, to gellan gum formulations significantly decreased drug release. Other polymers' formulations resulted in increased drug release upon addition of the same cross-linkers. The formula containing xanthan gum without any cross linker showed the most sustained LVF release with an increase in diameter with time, thus acting as a plug-type dosage form. IR spectra and DSC thermograms of LVF, xanthan gum, and a physical mixture of both, indicated that there was no interaction between the drug and the polymer and confirmed the drug stability.

The aim of the present study was to design and evaluate single pulse and floating double pulse valsartan core-in-cup tablets. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH-101, Croscarmellose sodium (CCNa), magnesium stearate & Aerosil. Weight variation, Hardness and Disintegration time were measured for the core tablets. Core-in-cup tablets were formulated using different polymers as a plug layer, including sodium alginate (SA), sodium carboxymethylcellulose (NaCMC) and hydroxypropyl methyl cellulose (HPMC). The floating behavior, water uptake and drug release from the prepared formulations were evaluated. Differential Scanning Calorimetry (DSC) was also performed to detect the possible drug excipient interaction. Stability study of the selected formula was performed at 25 °C & 60% RH and at 40 °C & 75% RH for 3 months. Finally, the existence of the selected formula in the stomach after oral administration to human volunteers was verified via x-ray radiography. The results showed that the release lag time of the tablets increased when the quantity of the plug layer increased thus decreasing the drug release. Plug layer polymers showed a lag time with rank order: SA In conclusion, pulsatile single pulse and floating double pulse stable valsartan core-in-cup tablets were successfully formulated which provided a desirable lag time followed by a rapid drug release.

Ocular drug delivery remains challenging because of the complex nature and structure of the eye. Conventional systems, such as eye drops and ointments, are inefficient, whereas systemic administration requires high doses resulting in significant toxicity. There is a need to develop novel drug delivery carriers capable of increasing ocular bioavailability and decreasing both local and systemic cytotoxicity. Recently, the emergence of lipid-based nanocarriers has provided a viable means of enhancing the bioavailability of ophthalmic formulations. A number of these formulations have been found to be clinically active. Many nanostructured systems have been employed for ocular drug delivery and yielded some promising results. Solid lipid nanoparticles (SLNs) have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids and are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. Also, SLNs allow autoclave sterilization, a necessary step toward formulation of ocular preparations. Recently, nanostructured lipid carriers (NLCs) and lipid drug conjugates (LDCs) have emerged as a new generation of SLNs to overcome problems of low entrapment efficiency and drug expulsion during storage.

The aim of this study was to investigate the potential of prodrugs of some non-steroidal anti-inflammatory drugs (NSAIDs) as colon targeted delivery systems for treatment of inflammatory bowel diseases. Naproxen, sulindac and flurbiprofen (Fbp) were used. The carboxylic group of those drugs was conjugated onto the amino group of l-aspartic acid or the hydroxyl group of alpha- or beta-cyclodextrin (CyD). Prodrugs hydrolysis in buffers of pH range 1.2-7.2 and in rat gastrointestinal tract homogenates and the effect of oral pretreatment of rats with clindamycin on the hydrolysis of the prodrugs was examined. Additionally, the effect of oral administration of Fbp-beta-CyD prodrug on the experimentally induced colitis in rats was evaluated. The in vivo inflammatory response was assessed macroscopically, histologically and by measurement of reduced glutathione (GSH) levels in colon tissues. No significant hydrolysis of the proposed seven prodrugs in buffers having pH range of 1.2-7.2 was observed over 72h. Negligible % of drug released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs was detected in rat stomach contents, intestinal tissues and intestinal contents homogenates. On the other hand, Fbp-alpha-CyD and Fbp-beta-CyD prodrugs released about 60% Fbp within 4h in rat colon homogenate. Oral pretreatment of rats with clindamycin significantly reduced % Fbp released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs. Oral administration of Fbp-beta-CyD to rats after induction of colitis significantly attenuated the severity of the colonic injury and reduced the score of the macroscopic and microscopic damage. Additionally, there was a significant increase in the level of GSH. The present study provided an evidence that Fbp-beta-CyD prodrug may be beneficial in treatment of inflammatory bowel disease.

The aim of the present study was to investigate the suitability of the melt sonocrystallization technique to modify the undesirable properties of the nonsteroidal anti-inflammatory drug (NSAID), flurbiprofen (FBP), e.g., poor flowability, solubility, and dissolution rate and, consequently, poor bioavailability. FBP melt was poured in deionized water at 25°C and sonicated for 4 min at an amplitude of 60% and cycle of 40 s on and 10 s off. The product obtained was evaluated using scanning electron microscopy (SEM), image analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and X-ray powder diffraction (XRPD). Flow properties, intrinsic dissolution rate, solubility, and bioavailability were also evaluated. The particle size of the treated FBP was significantly reduced. Thermal behavior and FT-IR spectra of untreated and treated FBP have shown no significant difference. Low-intensity peaks in the X-ray diffraction of treated FBP were noticed. In addition there was significant enhancement in the flow properties of treated FBP, as indicated by the value of angle of repose and the flow constants calculated from the Kawakita equation. The increased solubility of treated FBP was about 35%. The intrinsic dissolution rate of treated FBP increased by 2-fold. The dissolution rate studies revealed that 90% of the drug was released within 20 min for treated FBP compared with 60% released for the untreated drug. The relative bioavailability of treated FBP was increased by 2-fold compared with untreated drug. The use of melt sonocrystallization technique is a promising technique that may afford powder with improved flow and tablet functionality as well as improved dissolution and bioavailability. Drug Dev Res 69:34–41, 2008 © 2008 Wiley-Liss, Inc.

The main objective of the study was to investigate the effect of permeation enhancers and application of low frequency (LUS) and high frequency ultrasound (HUS) on testosterone (TS) transdermal permeation after application of testosterone solid lipid microparticles (SLM). SLM formulations contained 10% compritol and 5 mg TS /g of SLM. The permeation experiments were performed using Franz diffusion cells and abdomen rat skin. The examined permeation enhancers were 1% oleic acid (OA) or 1 % dodecylamine (DA). HUS (1 MHz) was applied in a continuous mode for 1h at intensity 0.5 W/cm(2). Different intensities and application time of pulsed LUS (20 kHz) were also examined. Additionally, the effect of combination of US and OA or DA was investigated. Skin irritation and histological changes were also evaluated. The results revealed that SLMs have an occlusive effect on the skin. Statistical analysis revealed the following order for the permeation of TS: 1% DA for 30 min>HUS +1% DA for 30 min= HUS=HUS + SLM containing 1% OA> SLM containing 1% OA=control. At total application time of LUS 6, 12, and 15 min the flux increased by 1.86, 4.63, and 4.77 fold, respectively. The enhancement effect of different intensities of LUS was not directly proportional to the magnitude of intensity. Skin exposure to HUS or LUS before application of 1% DA for 30 min had no superior enhancement effect over application of either LUS or HUS alone. Application of drug loaded SLM offered skin protection against the irritation effect produced by TS and 1% DA. Histological characteristics of the skin were affected to various extents by application of enhancers or ultrasound. In general, application of LUS gave higher TS permeation than HUS. However, safe application of LUS should be practiced by careful selection of exposure parameters.

Pectic-Oligosaccharides (POS) have a growing potential in food and feed industries. To satisfy the demand of worldwide markets from POS and avoid the shortcomings of currently applied methodologies encountered in their preparation, the present study highlights a novel robust approach for POS biosynthesis. In the current approach, Aspergillus sp.section Flavi strain EGY1 DSM 101520 was grown on citrus pectin-based medium as a core POS production medium. POS' levels accumulated in the fungal fermentation broth were optimized through a three step sequential statistical mathematical methodology; Plackett-Burman design (PBD), Box-Behnken design (BBD) and canonical analysis. Three key determinants namely citrus pectin, peptone and NaH2PO4 were pointed out by PBD to impose significant consequences (P

The main objective of this study was to develop a local, oral mucoadhesive metronidazole benzoate (MET) delivery system that can be applied and removed by the patient for the treatment of periodontal diseases. Mucoadhesive micromatricial chitosan/poly(epsilon-caprolactone) (CH/PCL) films and chitosan films were prepared. Thermal behavior, morphology, and particle size measurements were used to evaluate the prepared films. The effect of different molar masses of CH and different ratios of medium Mwt molar mass chitosan (MCH):PCL on water absorption, in vitro bioadhesion, mechanical properties, and in vitro drug release was examined. In vivo performance of the selected formulation was also evaluated. Differential scanning calorimetry examination revealed that MET existed mainly in amorphous form. Under microscopic examination, PCL microparticles were homogeneously dispersed in the films. The use of different molar masses of CH and different ratios of (MCH):PCL affected the size of the entrapped particles. Addition of PCL significantly decreased percentage water uptake and bioadhesion force compared with pure CH film. With regard to mechanical properties, the 2-layered film containing 1:0.625 MCH:PCL had the best tensile properties. At fixed CH:PCL ratio (1:1.25), the slowest drug release was obtained from films containing high molar mass CH. On the other hand, the 2-layered film that consisted of 1:0.625 MCH:PCL had the slowest MET release. In vivo evaluation of the selected film revealed that metronidazole concentration in saliva over 6 hours ranged from 5 to 15 microg/mL, which was within and higher than the reported range of minimum inhibitory concentration for metronidazole. A significant in vitro/in vivo correlation under the adopted experimental conditions was obtained.

The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system.Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5 mg TS g(-1). Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24 h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated.The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7-95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM5% GD5% SA5% GB2.5% GM2.5% SA10% GD10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB-2.5 mg TS g(-1) SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB-2.5 mg TS g(-1) stored at 5 degrees C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation.The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.

Asmaa A Ashour,1 Dina Raafat,2 Hanan M El-Gowelli,3 Amal H El-Kamel1 1Department of Pharmaceutics, 2Department of Pharmaceutical Microbiology, 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Background: The growing threat of microbial resistance against traditional antibiotics has prompted the development of several antimicrobial nanoparticles (NPs), including silver NPs (AgNPs). In this article, a simple and eco-friendly method for the synthesis of AgNPs using the cranberry powder aqueous extract is reported.Materials and methods: Cranberry powder aqueous extracts (0.2%, 0.5%, and 0.8% w/v) were allowed to interact for 24 hours with a silver nitrate solution (10 mM) at 30°C at a ratio of 1:10. The formation of AgNPs was confirmed by ultraviolet-visible spectroscopy and their concentrations were determined using atomic absorption spectroscopy. The prepared NPs were evaluated by transmission electron microscopy, measurement of ζ-potential, and Fourier-transform infrared spectroscopy. The in vitro antimicrobial properties of AgNPs were then investigated against several microbial strains. Finally, in vivo appraisal of both wound-healing and antimicrobial properties of either plain AgNPs (prepared using 0.2% extract) or AgNP-Pluronic F-127 gel was conducted in a rat model after induction of a Staphylococcus aureus ATCC 6538P wound infection.Results: The formation of AgNPs was confirmed by ultraviolet-visible spectroscopy, where a surface-plasmon resonance absorption peak was observed between 432 and 438 nm. Both size and concentration of the formed AgNPs increased with increasing concentration of the extracts. The developed NPs were stable, almost spherical, and polydisperse, with a size range of 1.4–8.6 nm. The negative ζ-potential values, as well as Fourier-transform infrared spectroscopy analysis, indicated the presence of a capping agent adsorbed onto the surface of the particles. In vitro antimicrobial evaluation revealed a size-dependent activity of the AgNPs against the tested organisms. Finally, AgNPs prepared using 0.2% extract exhibited a substantial in vivo healing potential for full-thickness excision wounds in rats.Conclusion: AgNPs were successfully synthesized from a silver nitrate solution through a simple green route, using cranberry powder aqueous extract as a reducing as well as capping agent. Keywords: cranberry, silver nanoparticles, antimicrobial properties, wound healing

Nanoparticulate delivery systems have recently been under consideration for topical ophthalmic drug delivery. Brimonidine base-loaded solid lipid nanoparticles and nanostructured lipid carrier formulations were prepared using glyceryl monostearate as solid lipid and were evaluated for their physical stability following sterilization by autoclaving at 121°C for 15min. The objective of this work was to evaluate the effect of autoclaving on the physical appearance, particle size, polydispersity index, zeta potential, entrapment efficiency and particle morphology of the prepared formulations, compared to non-autoclaved ones. Results showed that, autoclaving at 121°C for 15min allowed the production of physically stable formulations in nanometric range, below 500nm suitable for ophthalmic application. Moreover, the autoclaved samples appeared to be superior to non-autoclaved ones, due to their increased zeta potential values, indicating a better physical stability. As well as, increased amount of brimonidine base entrapped in the tested formulations.

Cellulose propionate (CP) microparticles containing captopril (CAP) were prepared by solvent evaporation technique. The effects of polymer molecular weight, polymer composition and drug:polymer ratios on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared captopril microparticles were examined. The anti-hypertensive effect of the selected CAP formulation in comparison with aqueous drug solution was also evaluated in vivo using hypertensive rats. The formulation containing drug:polymer blend ratio 1:1.5 (1:1 low:high molecular weight CP), namely F7, was chosen as the selected formulation with regard to the encapsulation efficiency (75.1%), flow properties (theta=24 degrees, Carr index=5%, Hausner ratio=1.1, packing rate=0.535) and release characteristics. Initial burst effect was observed in the release profile of all examined formulations. DSC and SEM results indicated that the initial burst effect could be attributed to dissolution of CAP crystals present on the surface or embedded in the superficial layer of the matrix. The release kinetics of CAP from most microparticle formulations followed diffusion mechanism. After oral administration of the selected microparticle formulation (F7) to hypertensive rats, systolic blood pressure decreased gradually over 24 h compared to reference drug solution. These results may suggest the potential application of cellulose propionate microparticles as a suitable sustained release drug delivery system for captopril.

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC(0 - infinity), 17.9 and 18.8 micro g x h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.

Environmentally responsive gel formulation for ocular controlled delivery of carteolol hydrochloride (HCl) was developed in an attempt to improve ocular bioavailability and hence decrease its systemic absorption and side effects. The viscosity and the ability of the prepared formulations to deliver carteolol HCl in vitro and in vivo were monitored and compared with an aqueous commercial solution. The effect of polymer concentration and drug concentration on the in vitro release of carteolol HCl was examined. Gelrite formulations showed pseudoplastic behavior with thixotropic characteristics and the viscosity of the prepared systems increased as the concentration of the polymer increased. At fixed drug concentrations, as the Gelrite concentration increased, the drug release decreased. At fixed polymer concentrations, as the drug concentration increased the release of drug increased. Gelrite formulation (0.4% w/w) containing 1% drug showed significantly improved bioavailability compared with the commercial aqueous solution (Arteoptic � R 1%). The developed in situ gel formulation showed potential for use as delivery systems with superior ocular bioavailability of carteolol HCl.

Alginate beads containing diltiazem hydrochloride (DTZ) were prepared by the ionotropic gelation method. The effects of various factors (alginate concentration, additives type, calcium chloride concentration and curing time) on the efficiency of drug loading were investigated. The formulation containing a mixture of 0.8% methylcellulose (MC) and 4% alginate cured in 2% calcium chloride for 6 h was chosen as the best formula regarding the loading efficiency. The release rate of DTZ from various beads formulations was investigated. The release of drug from alginate beads followed two mechanisms; by diffusion and relaxation of the polymer at pH 1.2, whilst diffusion and erosion are at pH 6.8. The in vitro release of DTZ from MC-alginate beads showed an extended release pattern which was compared with that from commercially available sustained-release (Dilzem® SR) and fast release tablets (Dilzem®). Thermal analysis revealed that the drug was molecularly dispersed in the beads matrix. Although the release cha...

Since the discovery of Helicobacter pylori (H. pylori) in the early 1980s, its eradication has been one of the most important global challenges in gastroenterology. Various circumstances make the treatment with antimicrobials particularly difficult. One problem has been that antibiotics commonly used were designed for the treatment of infections throughout the body rather than for delivering high concentrations locally within the stomach. Many gastroretentive dosage forms were developed in order to eradicate the infection, yet additional advancements are still needed to eliminate the infection completely and decrease its prevalence worldwide. An overview on different antimicrobials and a literature survey about different drug delivery systems used in eradication of H. pylori infection are presented in this review.

A sustained release system for ketoprofen designed to increase its residence time in the stomach without contact with the mucosa was achieved through the preparation of floating microparticles by the emulsion-solvent diffusion technique. Four different ratios of Eudragit S100 (ES) with Eudragit RL (ERL) were used to form the floating microparticles. The drug retained in the floating microparticles decreased with increase in ERL content. All floating microparticle formulations showed good flow properties and packability. Scanning electron microscopy and particle size analysis revealed differences between the formulations as to their appearance and size distribution. X-ray and DSC examination showed the amorphous nature of the drug. Release rates were generally low in 0.1 N HCl especially in presence of high content of ES while in phosphate buffer pH 6.8, high amounts of ES tended to give a higher release rate. Floating ability in 0.1 N HCl, 0.1 N HCl containing 0.02% Tween 20 and simulated gastric fluid without pepsin was also tested. The formulation containing ES:ERL1:1 (FIII) exhibited high percentage of floating particles in all examined media.

To enhance the systemic transdermal delivery of papaverine for the treatment of erectile dysfunction, several factors that influence transdermal delivery of papaverine HCl were studied. The effects of membrane types for in vitro permeation study, human skin layers, solvent/cosolvent systems and the penetration enhancers on the transdermal permeation of papaverine HCl were investigated. A combination of caproic acid, ethanol and water in the volume ratio of 50%:30%:20% was chosen as penetration enhancer and incorporated in two gel bases: 18% Pluronic F-127 and 2% Carbopol 940. In vivo skin permeation studies were performed with two loading doses (0.6% and 2%) in rabbits. The flux and permeability coefficient of papaverine HCl through different human skin layers suggested that the major barrier layer for papaverine HCl was residing primarily in the stratum corneum. However, the viable epidermis and dermis layer also contributed certain degrees of diffusion resistance. Differential Scanning Calorimetry study showed that penetration enhancer exhibited a counter effect with papaverine HCl on the temperature and enthalpy in both gels. In vitro drug release study demonstrated significant increases in the steady-state flux, permeability coefficient and enhancement ratio in these gels. Faster drug transports and higher bioavailability were also observed in rabbits. Skin irritation test performed in rabbits demonstrated a mild skin reaction with mean PII scores of 2 and below; however the recovery was fast. In conclusion, caproic acid, ethanol and water in the volume ratio of 50%:30%:20% is an effective penetration enhancer to deliver papaverine HCl transdermally for systemic absorption.

Osteomyelitis is an inflammatory bone disease caused by pyogenic bacteria. The advantages of localized biodegradable therapy for osteomyelitis include high local antibiotic concentration at the site of infection and obviation of the need for removal of the implant after treatment. The purpose of this study was to develop and evaluate a biodegradable implantable delivery system containing gatifloxacin (GAT) for the localized treatment of osteomyelitis, experimentally induced by methicillin resistant Staphylococcus aureus (MRSA). Implants, prepared by solvent casting technique, showed reasonable tensile strength. DSC examination indicated that GAT is present in an amorphous form in the implant. The in vitro release of GAT showed a profile characterized by an initial burst followed by a second stage of gradual delivery over 27 days. The in vivo release study revealed that GAT concentrations achieved during the first 3 weeks after implantation exceeded the MIC of GAT against MRSA by100,000 times. Bacterial tibial bone count performed in rabbits tibia 2 and 4 weeks after implantation of GAT implant in infected bone indicated complete eradication of infection in all treated rabbits as indicated by the significant decrease in bacterial count. The results show that the proposed implant may have a promising role in the therapeutic approach to osteomyelitis.

The global CNS pharmaceutical market is expected to grow significantly, overtaking the cardiovascular therapeutics market in the next 10 years. Although much work has been devoted to finding drugs that can cross the BBB into the brain, no single approach has worked for all drugs. The lack of technology to effectively cross the BBB or the blood-tumor barrier prevents researchers from providing effective therapeutics for most patients with brain disorders. Drug loaded nanoparticles (NPs) can hide the unfavorable drug's physicochemical characteristics, which hinders its ability to cross the BBB. In this study, we investigate the effect of different surfactant coatings, in a single or a blend form, on polymeric NPs loaded with model dyes and drugs on the brain drug uptake. Different NP formulations are conveyed using different cores ((Poly Lactic-co-Glycolic Acid (PLGA) and Chitosan) and coat materials (tweens, poloxamers, thiamine, polyethylene glycol (PEG), propylene glycol (PG) and spans). Chitosan core was formulated via ionic gelation technique. PLGA core was formulated via solvent evaporation technique. Different surfactants with different HLB (Hydrophilic Lipophilic Balance) values were applied as coating materials for the NPs. All NP formulations were characterized with respect to their size; charge, stability, in-vitro drug release to reach the optimal formulation. Female CD-1 mice were used to evaluate the drug brain uptake. Harvesting of the brain takes place within 60 seconds of animal sacrifice. Animals were euthanized, and brain tissue were removed and homogenized. Concentration of Rodamine B (Model dye) in the brain homogenates was analyzed via HPLC. The developed uncoated Chitosan NPs are in the size range of 50-100 nm with small polydispersity Index (PDI) (∼ 0.3) and a reproducible zeta potential of ∼ +19mV. After coating with tween-80 the zeta potential has decreased to -5 mV. The Tween-80 coated NPs were visualized via Transmission Electron Microscope (TEM). The particle size of the coated NP increased over the uncoated one from ∼ 100 nm to (150 - 200 nm). Finally, brain RodamineB concentration was significantly higher in case of tween-80 coated Chitosan and PLGA compared to uncoated NPs. The use of the novel drug carrier systems for drug targeting to brain is a promising alternative to conventional CNS therapy. The currently used polymers in this study are nontoxic, biodegradable, and biocompatible. The surfactant coated NPs for brain drug delivery is a promising technique to enhance brain uptake. The use of the surfactant coat could aid the solubilization of endothelial cell membrane lipids leading to membrane fluidization and enhanced drug permeability at the BBB. Citation Format: Mohamed I. Nounou, Salma Saudi, Ola Elnoweam, Dalia Alian, Amal El-Kamel. Surfactant coated nanoparticles for brain metastases: A brain uptake perspective. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B39.

Metronidazole was formulated in mucoadhesive vaginal tablets by directly compressing the natural cationic polymer chitosan, loosely cross-linked with glutaraldehyde, together with sodium alginate with or without microcrystalline cellulose (MCC). Sodium carboxymethylcellulose (CMC) was added to some of the formulations. The drug content in tablets was 20%. Drug dissolution rate studies from tablets were carried out in buffer pH 4.8 and distilled water. Swelling indices and adhesion forces were also measured for all formulations. The formula (FIII) containing 6% chitosan, 24% sodium alginate, 30% sodium CMC, and 20% MCC showed adequate release properties in both media and gave lower values of swelling index compared with the other examined formulations. FIII also proved to have good adhesion properties with minimum applied weights. Moreover, its release properties (% dissolution efficiency, DE) in buffer pH 4.8, as well as release mechanism (n values), were negligibly affected by aging. Thus, this formula may be considered a good candidate for vaginal mucoadhesive dosage forms.

The purpose of this study was to develop Pluronic F127 (PF127) based formulations of timolol maleate (TM) aimed at enhancing its ocular bioavailability. The effect of isotonicity agents and PF127 concentrations on the rheological properties of the prepared formulations was examined. In an attempt to reduce the concentration of PF127 without compromising the in situ gelling capabilities, various viscosity enhancing agents were added to PF127 solution containing 0.5% TM. The viscosity and the ability of PF127 gels to deliver TM, in vitro, in absence and presence of various viscosity enhancing agents were also evaluated. At the used concentration, some of the examined isotonicity agents had effect on the viscosity of TM gel. However, the viscosity of gel increased as the PF127 concentrations increased. The viscosity of formulations containing thickening agents was in the order of PF-MC 3%>PF-HPMC 2%>PF-CMC 2.5%>PF127 15%. The slowest drug release was obtained from 15% PF127 formulations containing 3% methylcellulose. In vivo study showed that the ocular bioavailability of TM, measured in albino rabbits, increased by 2.5 and 2.4 fold for 25% PF127 gel formulation and 15% PF127 containing 3% methylcellulose, respectively, compared with 0.5% TM aqueous solution.