Abaloparatide prevents immobilization-induced cortical but not trabecular bone loss after spinal cord injury.

Spinal cord injury (SCI) causes severe and resistant sublesional disuse bone loss. Abaloparatide, a modified parathyroid hormone related peptide, is an FDA approved drug for treatment of severe osteoporosis with potent anabolic activity. The effects of abaloparatide on SCI-induced bone loss remain undefined. Thus, female mice underwent sham or severe contusion thoracic SCI causing hindlimb paralysis. Mice then received subcutaneous injection of vehicle or 20 µg/kg/day abaloparatide for 35 days. Micro-computed tomography (micro-CT) analysis of the distal and midshaft femoral regions of the SCI-vehicle mice revealed reduced trabecular fractional bone volume (56%), thickness (75%), and cortical thickness (80%) compared to sham-vehicle controls. Treatment with abaloparatide did not prevent SCI-induced changes in trabecular or cortical bone. However, histomorphometry evaluation of the SCI-abaloparatide mice demonstrated that abaloparatide treatment increased osteoblast (241%) and osteoclast (247%) numbers and the mineral apposition rate (131%) compared to SCI-vehicle animals. In another independent experiment, treatment with 80 µg/kg/day abaloparatide significantly attenuated SCI-induced loss in cortical bone thickness (93%) when compared to SCI-vehicle mice (79%) but did not prevent SCI-induced trabecular bone loss or elevation in cortical porosity. Biochemical analysis of the bone marrow supernatants of the femurs showed that SCI-abaloparatide animals had 2.3-fold increase in procollagen type I N-terminal propeptide, a bone formation marker than SCI-vehicle animals. SCI groups had 70% higher levels of cross-linked C-telopeptide of type I collagen, a bone resorption marker, than sham-vehicle mice. These findings suggest that abaloparatide protects the cortical bone against the deleterious effects of SCI by promoting bone formation.

Synergistic effects of quercetin-loaded CoFe2O4@Liposomes regulate DNA damage and apoptosis in MCF-7 cancer cells: based on biophysical magnetic hyperthermia.

INTRODUCTION: Breast cancer (BC) is the most common malignancy in women globally. Significant progress has been made in developing structural nanoparticles (NPs) and formulations for targeted smart drug delivery (SDD) of pharmaceuticals, improving the precision of tumor cell targeting in therapy. SIGNIFICANCE: Magnetic hyperthermia (MHT) treatment using magneto-liposomes (MLs) has emerged as a promising adjuvant cancer therapy. METHODS: CoFe2O4 magnetic NPs (MNPs) were conjugated with nanoliposomes to form MLs, and the anticancer drug quercetin (Que) was loaded into MLs, forming Que-MLs composites for antitumor approach. The aim was to prepare Que-MLs for DD systems (DDS) under an alternating magnetic field (AMF), termed chemotherapy/hyperthermia (chemo-HT) techniques. The encapsulation efficiency (EE), drug loading capacity (DL), and drug release (DR) of Que and Que-MLs were evaluated. RESULTS: The results confirmed successful Que-loading on the surface of MLs, with an average diameter of 38 nm and efficient encapsulation into MLs (69%). In vitro, experimental results on MCF-7 breast cells using MHT showed high cytotoxic effects of novel Que-MLs on MCF-7 cells. Various analyses, including cytotoxicity, apoptosis, cell migration, western blotting, fluorescence imaging, and cell membrane internalization, were conducted. The Acridine Orange-ethidium bromide double fluorescence test identified 35% early and 55% late apoptosis resulting from Que-MLs under the chemo-HT group. TEM results indicated MCF-7 cell membrane internalization and digestion of Que-MLs, suggesting the presence of early endosome-like vesicles on the cytoplasmic periphery. CONCLUSIONS: Que-MLs exhibited multi-modal chemo-HT effects, displaying high toxicity against MCF-7 BC cells and showing promise as a potent cytotoxic agent for BC chemotherapy.

Development of oral formulation of Lepidium seeds significantly decreases the high blood glucose levels in diabetic rats: in vitro formulation and in vivo antidiabetic performance.

BACKGROUND: Lepidium sativum, Garden Cress (GC), seeds have a lot of natural molecules with a pronounced activity against different disorders. It was reported that GC seeds have the ability to lower the blood glucose level. AIM: The aim of this work was to formulate GC seeds into oral tablets containing a fixed dose of the grounded seeds. Furthermore, the anti-diabetic performance of the prepared tablets was studied in the streptozotocin rats' model in comparison with positive control metformin. METHODS: Micrometrics of GC grounded seeds with different excipients were investigated. Then, GC tablets were prepared via direct compression technique. GC tablets were characterized for their uniformity of dosage unit, friability, hardness, disintegration time, and in vitro release. The antidiabetic effect was studied in rats for a period of 28 days. Glycosylated hemoglobin, liver performance, and lipid levels include total cholesterol (TC), triglycerides (TGs), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were also estimated. In addition, histopathological study of liver and pancreas was also performed. RESULTS: Prosolv®EasyTab produced tablets with higher hardness, lower disintegration time, and fast release. GC tablets significantly lower the elevated blood glucose level. In addition, they have antihyperlipidemic activity, hepatocellular protective role and restore the histology of the liver and pancreas. CONCLUSION: GC tablets could be a promising alternative formulation to control the high blood glucose level in diabetic rats rather than chemically derivatized drugs.

Comparative Study of Lepidium Sativum Orally Administered Seeds, Hydrogel and Atorvastatin on Obesity of Rats Fed on a High Fat Diet.

BACKGROUND: Obesity has become a prevalent issue worldwide, leading to various complications such as hyperlipidemia, diabetes, and cardiovascular problems. Statins as FDA approved anti-hyperlipidemic drugs, still poses some concerns upon their administration. Recently, researchers have looked for natural products as an alternative to manage hyperlipidemia and obesity. AIM: This work aimed to study the hypolipidemic effect of Lepidium Sativum Garden Cress (GC) from different preparations; orally administered seeds, and hydrogel, in comparison to atorvastatin. METHODS: GC hydrogel was prepared from the GC aqueous extract and pharmaceutically evaluated for its pH, spreadability, seeds content, homogeneity, rheology, and in vitro release. The rat's body weight, blood glucose levels, total lipid profile, and liver biomarkers were evaluated on obese rats for one month. In addition, the histopathology study was also performed. RESULTS: GC hydrogel had acceptable pharmaceutical properties and showed a sustained release performance over 24 h. Oral and topical GC significantly reduced the lipid profiles, blood sugar and ALT, AST levels more than the negative control group and comparable to atorvastatin. It was found that oral GC showed a significant effect on the percentage decrease in the rat's body weight than the applied hydrogel. Histopathology study revealed a better outcome in the histological structure of pancreas and liver compared with rats feed on high fat diet post treatment for one month. CONCLUSION: GC orally administered, or topically applied hydrogel could be a promising, safe alternative formulation to atorvastatin in managing hyperlipidemia and normalizing body weight of obese rats.

Impact of the functional coating of silver nanoparticles on their in vivo performance and biosafety.

OBJECTIVE AND SIGNIFICANCE: Silver nanoparticles (AgNPs) have become an interesting therapeutic modality and drug delivery platform. Herein, we aimed to investigate the impact of functional coating on the in vivo performance of AgNPs as an economic and scalable method to modulate their behavior. METHODS: AgNPs were coated with chitosan (CHI) as a model biopolymer using a one-pot reduction-based method, where CHI of two molecular weight ranges were investigated. The resultant CHI-coated AgNPs (AgNPs-CHI) were characterized using UV-VIS spectroscopy, DLS, and TEM. AgNPs were administered intravenously to rats and their biodistribution and serum levels of hepato-renal function markers were monitored 24 h later compared to plain AgNO3 as a positive control. RESULTS: UV-VIS spectroscopy confirmed the successful coating of AgNPs with CHI. DLS revealed the superiority of medium molecular weight CHI over its low molecular weight counterpart. AgNPs-CHI demonstrated a semi-complete clearance from the systemic circulation, a liver-dominated tissue tropism, and limited renal exposure. On the other hand, AgNO3 was poorly cleared from the circulation, with relatively high renal exposure and a non-specific tissue tropism. AgNPs-CHI were well-tolerated by the liver and kidney without signs of toxicity or inflammation, in contrary with AgNO3 which resulted in a significant elevation of Creatinine (CRE), Urea, and Total Protein (TP), suggesting a significant nephrotoxicity and inflammation. CONCLUSIONS: Functional coating of AgNPs with CHI substantially modulated their in vivo behavior, promoting their hepatic selectivity and biotolerability, which can be invested in the development of drug delivery systems for the treatment of liver diseases.

Synthesis and characterization of magnetic Ag-Fe3O4@polymer hybrid nanocomposite systems with promising antibacterial application.

INTRODUCTION: Bacterial infections caused by different strains of bacteria still one of the most important disorders affecting humans worldwide. Polymers nanocomposite systems could be considered as an alternative to conventional antibiotics to eradicate bacterial infections. SIGNIFICANCE: In an attempt to enhance the antibacterial performance of silver and iron oxide nanoparticles, decrease their aggregation and toxicity, a polymeric hybrid nanocomposite system combining both nanoparticles is produced. METHODS: Magnetic Ag-Fe3O4@polymer hybrid nanocomposites prepared using different polymers, namely polyethylene glycol 4000, ethyl cellulose, and chitosan were synthesized via wet impregnation and ball-milling techniques. The produced nanocomposites were tested for their physical properties and antibacterial activities. RESULTS: XRD, FT-IR, VSM, and TEM results confirmed the successful preparation of hybrid nanocomposites. Hybrid nanocomposites have average crystallite sizes in the following order Ag-Fe3O4@CS (8.9 nm) < Ag-Fe3O4@EC (9.0 nm) < Ag-Fe3O4@PEG4000 (9.4 nm) and active surface area of this trend Ag-Fe3O4@CS (130.4 m2g-1) > Ag-Fe3O4@EC (128.9 m2g-1) > Ag-Fe3O4@PEG4000 (123.4 m2g-1). In addition, they have a saturation magnetization in this order: Ag-Fe3O4@PEG4000 (44.82 emu/g) > Ag-Fe3O4@EC (40.14 emu/g) > Ag-Fe3O4@CS (22.90 emu/g). Hybrid nanocomposites have a pronounced antibacterial action against Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus intermedius compared to iron oxide nanoparticles and positive antibacterial drug. In addition, both Ag-Fe3O4@EC and Ag-Fe3O4@CS have a lower MIC values compared to Ag-Fe3O4@PEG and positive control. CONCLUSION: Magnetic Ag-Fe3O4 hybrid nanocomposites could be promising antibacterial nanomaterials and could pave the way for the development of new materials with even more unique properties and applications.

Insight into the Inclusion Complexation of Fluconazole with Sulfonatocalix[4]naphthalene in Aqueous Solution, Solid-State, and Its Antimycotic Activity.

The study aims to assess the interaction between fluconazole and sulfonatocalix[4]naphthalene towards enhancing its dissolution performance and antimycotic activity. A solubility study was carried out at different pH conditions, and the results revealed the formation of a 1:1 molar ratio fluconazole-sulfonatocalix[4]naphthalene inclusion complex with an AL type phase solubility diagrams. The solid powder systems of fluconazole-sulfonatocalix[4]naphthalene were prepared using kneaded and co-evaporation techniques and physical mixtures. DCS, PXRD, TGA-DTG, FT-IR, and in vitro dissolution performance characterize the prepared systems. According to physicochemical characterization, the co-evaporation approach produces an amorphous inclusion complex of the drug inside the cavity of sulfonatocalix[4]naphthalene. The co-evaporate product significantly increased the drug dissolution rate up to 93 ± 1.77% within 10 min, unlike other prepared solid powders. The antimycotic activity showed an increase substantially (p ≤ 0.05, t-test) antimycotic activity of fluconazole co-evaporate mixture with sulfonatocalix[4]naphthalene compared with fluconazole alone against clinical strains of Candida albicans and Candida glabrata. In conclusion, sulfonatocalix[4]naphthalene could be considered an efficient complexing agent for fluconazole to enhance its aqueous solubility, dissolution performance, and antimycotic activity.

Recent updates in COVID-19 with emphasis on inhalation therapeutics: Nanostructured and targeting systems.

The current world health threat posed by the novel coronavirus disease of 2019 (COVID-19) calls for the urgent development of effective therapeutic options. COVID-19 needs daunting routes such as nano-antivirals. Hence, the role of nanotechnology is very critical in combating this nano-enemy "virus." Although substantial resources are under ongoing attention for prevention and care, we would like to start sharing with readers our vision of the role of inhaled nanomaterials and targeting systems that can play an important role in the fight against the COVID-19. In this review, we underline the genomic structure of COVID-19, recent modes of virus transmission with measures to control the infection, pathogenesis, clinical presentation of SARS-CoV-2, and how much the virus affects the lung. Additionally, the recent therapeutic approaches for managing COVID-19 with emphasis on the value of nanomaterial-based technical approaches are discussed in this review. This review also focuses on the safe and efficient delivery of useable targeted therapies using designed nanocarriers. Moreover, the effectiveness and availability of active targeting of certain specific receptors expressed on the coronavirus surfaces via tailored ligand nanoparticles are manipulated. It was also highlighted in this review the role of inhaled medicines including antivirals and repurposed drugs for fighting the associated lung disorders and efficiency of developed vaccines. Moreover, the inhalation delivery safety techniques were also highlighted.

Fluorescent Nanoparticles Coated with a Somatostatin Analogue Target Blood Monocyte for Efficient Leukaemia Treatment.

BACKGROUND: Leukaemia is the most prevalent form of cancer-causing death in a large number of populations and needs prompt and effective treatment. Chemotherapeutics can be used to treat leukaemia, but their pronounced killing effects to other living cells is still an issue. Active targeting to certain specific receptors in leukaemic cells is the best way to avoid damage to other living cells. Leukaemic cells can be targeted using novel nanoparticles (NPs) coated with a specific ligand, such as octreotide (OCD), to target somatostatin receptor type 2 (SSTR2), which is expressed in leukaemic cells. METHODS: Amino-PEGylated quantum dots (QDs) were chosen as model NPs. The QDs were first succinylated using succinic anhydride and then coated with OCD. The reactivity and selectivity of the formulated QDs-OCD were studied in cell lines with well-expressed SSTR2, while fluorescence was detected using confocal laser scanning microscopy (CLSM) and flow cytometry (FACS). Conclusively, QD-OCD targeting to blood cells was studied in vivo in mice and detected using inductively coupled plasma mass spectrometry and CLSM in tissues. RESULTS: Highly stable QDs coated with OCD were prepared. FACS and CLSM showed highly definite interactions with overexpressed SSTR2 in the investigated cell lines. Moreover, the in vivo results revealed a higher concentration of QDs-OCD in blood cells. The fluorescence intensity of the QDs-OCD was highly accumulated in blood cells, while the unmodified QDs did not accumulate significantly in blood cells. CONCLUSION: The formulated novel QDs-OCD can target SSTR2 overexpressed in blood cells with great potential for treating blood cancer.

Effect of Spray Drying on Amorphization of Indomethacin Nicotinamide Cocrystals; Optimization, Characterization, and Stability Study.

Cocrystals have gained a lot of consideration regarding its superior role in enhancement of solubility and dissolution of the included API. Cocrystals could be converted to coamorphous systems via different techniques like milling and quench cooling; however, the use of spray-drying technique has not been investigated before. So, the aim of this study was to explore the effect of spray drying on the amorphization of indomethacin/nicotinamide, INDNIC, as model cocrystals. Spray-drying operating parameters were optimized using the Taguchi design of experiment for maximum powder yield and low moisture content. The obtained INDNIC spray-dried cocrystals were characterized for their degree of crystallinity, morphology, moisture content, and dissolution performance. In addition, stability study was performed at different temperature and humidity conditions. Experimental design results delineate that spray-drying inlet temperature and cocrystal concentrations as the most influential factors for maximum powder yield and low moisture content. Powder X-ray diffraction and differential scanning calorimetry studies revealed the conversion of INDNIC cocrystals to a partial coamorphous or coamorphous structure without dissociation of INDNIC molecular structure. INDNIC coamorphous powders showed a significantly higher release of IND compared with cocrystals and remain physically stable for 2 months when stored in the refrigerator.

Novel sublingual tablets of Atorvastatin calcium/Trimetazidine hydrochloride combination; HPTLC quantification, in vitro formulation and characterization.

BACKGROUND: Ischemic heart disorders and accumulation of lipids in blood vessels could contribute to angina pectoris. Therefore, the aim of this study was to formulate sublingual tablets containing a novel combination of Atorvastatin calcium (ATOR) and Trimetazidine HCl (TMZ) for efficient treatment of coronary heart disorders. METHODS: The dissolution rate of water-insoluble ATOR was enhanced via complexation with sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) and addition of soluplus as a polymeric solubilizer excipient. The solubilized ATOR and TMZ were compressed into a sublingual tablets by direct compression technique and evaluated for their tableting characteristics. In addition, a new validated method based on High Performance Thin Layer Chromatography (HPTLC) was developed for simultaneous determination of both drugs in pure forms and sublingual tablets. RESULTS: The developed HPTLC method showed LODs of 0.056 and 0.013 µg/band and LOQs of 0.17, 0.040 µg/band for TMZ and ATOR, respectively and proved to be linear, accurate, precise and robust. The optimum formulation containing mixture of superdisintegrants; Ac-Di-Sol and crospovidone (4.8% w/w, each) showed the shortest disintegration time (65 s) and enhanced release profiles of both drugs. CONCLUSIONS: The prepared sublingual tablets combining ATOR and TMZ will be a promising dosage form for coronary heart disease patients with an instant action and improved patient compliance.

Development and evaluation of fluorescent gold nanoparticles.

OBJECTIVE: It is difficult to identify the gold nanoparticles (AuNPs) intracellularly due to their non-fluorescent nature. Although gold can quench the fluorescence of any fluorophore, hence it is also difficult to combine gold with a fluorophore such as a semiconductor quantum dots (QDs). The aim of this study was to prepare a single fluorescent stable AuNPs combined with QDs (QDs-Au-NPs) which can be easily detected intracellularly. METHODS: QDs-Au-NPs were prepared via a simple one-step process through controlling the spacing between them using polyethylene glycol (PEG) as space linker in the form of PEGylated QDs. Furthermore, the applicability of this system was evaluated after coating the particles with somatostatin citrate, SST, to active target somatostatin receptors (SSTRs), and identification of the internalized particles via confocal laser scanning spectroscopy. RESULTS: The results showed that the produced Au shell has a thickness of 2.0 ± 0.2 nm and QDs-Au-NPs showed the same fluorescence intensity compared to the unmodified QDs. Additionally, a stable monodisperse QDs-Au-NPs coated with SST were prepared after coating with 11-Mercaptoundecanoic acid. Moreover, cellular uptake study in Human Caucasian breast adenocarcinoma cell lines showed that QDs-Au-SST-NPs could be detected easily using the confocal microscope. In addition, they showed a significant (p ≤ .05) internalization per cell compared to untreated QDs-Au-NPs as detected by flow cytometry. CONCLUSION: It could be concluded that the produced QDs-Au-NPs has a strong fluorescence property like QDs which enable them to be easily detected after cells internalization.

Enalapril maleate orally disintegrating tablets: tableting and in vivo evaluation in hypertensive rats.

The aim of this study was to develop orally disintegrating tablets (ODTs) for enalapril maleate (EnM) to facilitate its administration to the elderly or other patients having dysphagia. Compatibility between EnM and various excipients was studied using differential scanning calorimetry. ODTs of EnM were prepared by direct compression of EnM mixtures with various superdisintegrants. The tablets were evaluated for physical properties including drug content, hardness, friability, disintegration time, wetting time, and drug release. The antihypertensive effect of the optimum EnM ODTs was evaluated in vivo in hypertensive rats and compared with commercial EnM formulation. EnM ODTs had satisfactory results in terms of drug content and friability. Tablet wetting and disintegration were fast and dependent on the used superdisintegrant where croscarmellose showed the fastest wetting and disintegration time of ∼7 s. EnM release from the tablets was rapid where complete release was obtained in 10-15 min. Selected EnM ODTs rapidly and efficiently reduced the rat's blood pressure to its normal value within 1 h, compared with 4 h for EnM commercial formulation. These results confirm that EnM ODTs could find application in the management of hypertension in the elderly or other patients having dysphagia.

Development of Domperidone Solid Lipid Nanoparticles: In Vitro and In Vivo Characterization.

Domperidone (DOP) is extensively applied orally in the management of nausea and vomiting. Upon oral administration, its bioavailability is very poor due to its poor solubility in alkaline media. Therefore, the aim of this work was to investigate DOP-loaded solid lipid nanoparticles (DOP-SLNs) in order to sustain its release pattern and to enhance oral bioavailability. DOP-SLNs were prepared using four different lipids. Prepared DOP-SLNs were characterized for "polydispersity index (PDI), particle size, zeta potential, % entrapment efficiency (% EE), and drug release behavior." Differential scanning calorimetry (DSC) study was carried out to illustrate the physical form of DOP and excipients. The morphology of DOP-SLNs was confirmed by scanning electron microscopy (SEM). Pharmacokinetic study on optimized DOP-SLN in comparison to tablet was performed in rats. The "particle size, PDI, zeta potential, and % EE" of optimized formulation (F5) were recorded as 201.4 nm, 0.071, - 6.2 mV, and 66.3%, respectively. DSC thermograms suggested amorphous state of DOP in various SLNs. Surface morphology of SLNs using SEM suggested spherical shape of the nanoparticles within nanometer size range. In vitro release studies confirmed that all SLN formulations possessed a sustained release over a period of 12 h (51.3% from optimized formulation) in comparison with immediate release from conventional tablets (100% after 90 min). Pharmacokinetic study showed significant enhancement in oral absorption of DOP from optimized SLN in comparison with DOP tablet. The enhancement in relative bioavailability of DOP from optimized SLN was 2.62-fold in comparison with DOP tablet.

Glibenclamide Mini-tablets with an Enhanced Pharmacokinetic and Pharmacodynamic Performance.

In an attempt to decrease the dose, anticipated side effects, and the cost of production of glibenclamide, GLC, a potent oral hypoglycemic drug, the enhancement of the dissolution and hence the oral bioavailability were investigated. Adsorption and co-adsorption techniques using carriers having a very large surface area and surface active agents were utilized to enhance the drug dissolution. Moreover, the Langmuir adsorption isotherms were constructed to identify the type and mechanism of adsorption. The optimized formulation showing the highest in vitro release was compressed into mini-tablet to facilitate drug administration to elderly patients and those having swallowing difficulties. The produced mini-tablets were tested for their mechanical strength and in vitro release pattern. In addition, the pharmacodynamic and pharmacokinetic studies in New Zealand rabbits were performed using the optimized mini-tablet formulation. Mini-tablets containing GLC co-adsorbate with Pluronic F-68 and Laponite RD showed 100 ± 1.88% of GLC released after 20 min. Pharmacodynamic studies in rabbits revealed significantly higher (p ≤ 0.05) hypoglycemic effect with the optimized mini-tablets at a lower GLC dose compared to mini-tablets containing the commercial GLC dose. Moreover, pharmacokinetic analysis showed significantly higher (p ≤ 0.05) AUC, Cmax, and shorter Tmax. The optimized mini-tablet formulation showed 1.5-fold enhancement of the oral bioavailability compared to mini-tablets containing untreated GLC. It could be concluded that the co-adsorption technique successfully enhanced the oral bioavailability of GLC. Furthermore, the produced mini-tablets have a higher oral bioavailability with a lower GLC dose, which could offer economic benefit for industry as well as acceptability for patients.

Somatostatin receptors as a new active targeting sites for nanoparticles.

The delivery of nanoparticles through receptor-mediated cell interactions has nowadays a major attention in the area of drug targeting applications. This specific kind of targeting is mediated by localized receptors impeded into the target site with subsequent drugs internalization. Hence, this type of interaction would diminish side effects and enhance drug delivery efficacy to the target site. Somatostatin receptors (SSTRs) are one type of G protein-coupled receptors, which could be active targeted for various purposes. There are five SSTRs types (SSTR1-5) which are localized at various organs in the body and spread into different tissues. SSTRs could be considered as a promising target to various nanoparticles which is facilitated when nanoparticles are modified through specific ligand or coating to allow better binding. This review discusses the exploration of SSTRs for active targeting of nanoparticles with certain emphasize on their interaction at the cellular level.

New gentle-wing high-shear granulator: impact of processing variables on granules and tablets characteristics of high-drug loading formulation using design of experiment approach.

The aim of this work was to study the application of design of experiment (DoE) approach in defining design space for granulation and tableting processes using a novel gentle-wing high-shear granulator. According to quality-by-design (QbD) prospective, critical attributes of granules, and tablets should be ensured by manufacturing process design. A face-centered central composite design has been employed in order to investigate the effect of water amount (X1), impeller speed (X2), wet massing time (X3), and water addition rate (X4) as independent process variables on granules and tablets characteristics. Acetaminophen was used as a model drug and granulation experiments were carried out using dry addition of povidone k30. The dried granules have been analyzed for their size distribution, density, and flow pattern. Additionally, the produced tablets have been investigated for; weight uniformity, breaking force, friability and percent capping, disintegration time, and drug dissolution. Results of regression analysis showed that water amount, impeller speed and wet massing time have significant (p < .05) effect on granules and tablets characteristics. However, the water amount had the most pronounced effect as indicated by its higher parameter estimate. On the other hand, water addition rate showed a minimal impact on granules and tablets properties. In conclusion, water amount, impeller speed, and wet massing time could be considered as critical process variables. Thus, understanding the relationship between these variables and quality attributes of granules and corresponding tablets provides the basis for adjusting granulation variables in order to optimize product performance.

HIGH SHEAR GRANULATION PROCESS: ASSESSING IMPACT OF FORMULATION VARIABLES ON GRANULES AND TABLETS CHARACTERISTICS OF HIGH DRUG LOADING FORMULATION USING DESIGN OF EXPERIMENT METHODOLOGY.

High shear wet granulation is a significant component procedure in the pharmaceutical industry. The objective of the study was to investigate the influence of two independent formulation variables; polyvinypyrrolidone (PVP) as a binder (X,) and croscarmellose sodium (CCS) as a disintegrant (X2) on the crit- ical quality attributes of acetaminophen granules and their corresponding tablets using design of experiment (DoE) approach. A two factor, three level (32) full factorial design has been applied; each variable was investi- gated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their density, granule size and flowability. Additionally, the produced tablets have been investigated for: break- ing force, friability, disintegration time and t. of drug dissolution. The analysis of variance (ANOVA) showed that the two variables had a significant impact (p < 0.05) on granules and tablets characteristics, while only the binder concentration influenced the tablets friability. Furthermore, significant interactions (p < 0.05) between the two variables, for granules and tablets attributes, were also found. However, variables interaction showed minimal effect for granules flowability as well as tablets friability. Desirability function was carried out to opti- mize the variables under study to obtain product within the USP limit. It was found that the higher desirability (0.985) could be obtained at the medium level of PVP and low level of CCS. Ultimately, this study supplies the formulator with beneficial tools in selecting the proper level of binder and disintegrant to attain product with desired characteristics.

HIGH-SHEAR GRANULATION PROCESS: INFLUENCE OF PROCESSING PARAMETERS ON CRITICAL QUALITY ATTRIBUTES OF ACETAMINOPHEN GRANULES AND TABLETS USING DESIGN OF EXPERIMENT APPROACH.

Application of quality by design (QbD) in high shear granulation process is critical and need to recognize the correlation between the granulation process parameters and the properties of intermediate (granules) and corresponding final product (tablets). The present work examined the influence of water amount (X,) and wet massing time (X2) as independent process variables on the critical quality attributes of granules and corresponding tablets using design of experiment (DoE) technique. A two factor, three level (32) full factorial design was performed; each of these variables was investigated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their size distribution, density and flow pattern. Additionally, the produced tablets have been investigated for weight uniformity, crushing strength, friability and percent capping, disintegration time and drug dissolution. Statistically significant impact (p < 0.05) of water amount was identified for granule growth, percent fines and distribution width and flow behavior. Granule density and compressibility were found to be significantly influenced (p < 0.05) by the two operating conditions. Also, water amount has significant effect (p < 0.05) on tablet weight unifornity, friability and percent capping. Moreover, tablet disintegration time and drug dissolution appears to be significantly influenced (p < 0.05) by the two process variables. On the other hand, the relationship of process parameters with critical quality attributes of granule and final product tablet was identified and correlated. Ultimately, a judicious selection of process parameters in high shear granulation process will allow providing product of desirable quality.

Novel gold nanoparticles coated with somatostatin as a potential delivery system for targeting somatostatin receptors.

Targeting of G-protein coupled receptors (GPCRs) like somatostatin-14 (SST-14) could have a potential interest in delivery of anti-cancer agents to tumor cells. Attachment of SST to different nano-carriers e.g. polymeric nanoparticles is limited due to the difficulty of interaction between SST itself and those nano-carriers. Furthermore, the instability problems associated with the final formulation. Attaching of SST to gold nanoparticles (AuNPs) using the positive and negative charge of SST and citrate-AuNPs could be considered a new technique to get stable non-aggregated AuNPs coated with SST. Different analyses techniques have been performed to proof the principle of coating between AuNPs and SST. Furthermore, cellular uptake studies on HCC-1806, HELA and U-87 cell lines has been investigated to show the ability of AuNPs coated SST to enter the cells via SST receptors. Dynamic light scattering (DLS) indicated a successful coating of SST on the MUA-AuNPs surface. Furthermore, all the performed analysis including DLS, SDS-PAGE and UV-VIS absorption spectra indicated a successful coating of AuNPs with SST. Cellular uptake studies on HCC-1806, HELA and U-87 cell lines showed that the number of AuNPs-SST per cell is signiflcantly higher compared to citrate-AuNPs when quantified using inductively coupled plasma spectroscopy. Moreover, the binding of AuNPs-SST to cells can be suppressed by addition of antagonist, indicating that the binding of AuNPs-SST to cells is due to receptor-specific binding. In conclusion, AuNPs could be attached to SST via adsorption to get stable AuNPs coated SST. This new formulation has a potential to target SST receptors localized in many normal and tumor cells.