PLGA/PEG Nanoparticles Loaded with Cyclodextrin-Peganum harmala Alkaloid Complex and Ascorbic Acid with Promising Antimicrobial Activities.

Antimicrobial drugs face numerous challenges, including drug resistance, systemic toxic effects, and poor bioavailability. To date, treatment choices are limited, which warrants the search for novel potent antivirals, including those extracted from natural products. The seeds of Peganum harmala L. (Zygophyllaceae family) have been reported to have antimicrobial, antifungal, and anticancer activities. In the present study, a 2-hydroxy propyl-ß-cyclodextrin (HPßCD)/harmala alkaloid-rich fraction (HARF) host-guest complex was prepared using a thin-film hydration method to improve the water solubility and bioavailability of HARF. The designed complex was then co-encapsulated with ascorbic acid into PLGA nanoparticles coated with polyethylene glycol (HARF-HPßCD/AA@PLGA-PEG NPs) using the W/O/W multiple emulsion-solvent evaporation method. The average particle size, PDI, and zeta potential were 207.90 ± 2.60 nm, 0.17 ± 0.01, and 31.6 ± 0.20 mV, respectively. The entrapment efficiency for HARF was 81.60 ± 1.20% and for ascorbic acid was 88 ± 2.20%. HARF-HPßCD/AA@PLGA-PEG NPs had the highest antibacterial activity against Staphylococcus aureus and Escherichia coli (MIC of 0.025 mg/mL). They also exhibited high selective antiviral activity against the H1N1 influenza virus (IC50 2.7 µg/mL) without affecting the host (MDCK cells). In conclusion, the co-encapsulation of HPCD-HARF complex and ascorbic acid into PLGA-PEG nanoparticles significantly increased the selective H1N1 killing activity with minimum host toxic effects.

Hybrid chitosan-lipid nanoparticles of green tea extract as natural anti-cellulite agent with superior in vivo potency: full synthesis and analysis.

The aim of this work is to exploit the advantages of chitosan (CS) as a nanocarrier for delivery of anti-cellulite drug, green tea extract (GTE), into subcutaneous adipose tissue. Primarily, analysis of herbal extract was conducted via newly developed and validated UPLC method. Ionic gelation method was adopted in the preparation of nanoparticles where the effect lecithin was investigated resulting in the formation of hybrid lipid-chitosan nanoparticles. Optimal formula showed a particle size of 292.6 ± 8.98 nm, polydispersity index of 0.253 ± 0.02, zeta potential of 41.03 ± 0.503 mV and an entrapment efficiency percent of 68.4 ± 1.88%. Successful interaction between CS, sodium tripolyphosphate (TPP) and lecithin was confirmed by Fourier-transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction. Morphological examination was done using transmission electron microscope and scanning electron microscope confirmed spherical uniform nature of GTE load CS-TPP nanoparticles. Ex vivo permeation study revealed permeability enhancing activity of the selected optimal formula due to higher GTE deposition in skin in comparison to GTE solution. Moreover in vivo study done on female albino Wistar rats carried out for 21 days proved successful potential anti-cellulite activity upon its application on rats' skin. Histological examination showed significant reduction of adipocyte perimeter and area and fat layer thickness. Results of the current study demonstrated that the developed GTE-loaded CS-TPP nanoparticle comprised of chitosan and lecithin showed permeability enhancing activity along with the proven lipolytic effect of green tea represent a promising delivery system for anti-cellulite activity.

Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products.

BACKGROUND: FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing. RESEARCH DESIGN AND METHODS: We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed. RESULTS: NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular PolyoxTM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients. CONCLUSIONS: Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.

Distinct Proteins in Protein Corona of Nanoparticles Represent a Promising Venue for Endogenous Targeting - Part II: In vitro and in vivo Kinetics Study.

INTRODUCTION: Nanoparticles (NPs), upon introduction to the biological systems, become wrapped by serum and cellular proteins constituting the protein corona (PC). This PC contributes largely to the NPs' interaction with the biological systems and their subsequent functions. On the one hand, PC can decrease the efficiency of targeting by directing the NPs to the reticuloendothelial system (RES) or by masking the active targeting moieties and decreasing their ability to bind to their target receptors. On the other hand, some components of PC have offered hopes for achieving endogenous targeting. METHODS: In this study, we aimed at the investigation of the role of the PC in determining the behavior of cRGDyk peptide-unconjugated and -conjugated NPs (uNPs and cNPs) exhibiting different physicochemical properties and their interaction with melanoma on in vitro and in vivo levels. Mathematical modeling has been utilized to understand the kinetics of the interaction of NPs with the tumor cells and different organs, respectively. RESULTS: Endocytosis and exocytosis were reported to occur simultaneously for the utilized NPs. The balance was largely dependent on the NPs' physicochemical properties and the role of the PC. In addition, distinct proteins present in the PC (illustrated in the results of the PC analysis in part I) have also determined the patterns of the NPs' distribution in different organs and tissues of the vascular system, the RES system and the target tumot tissue. Vitronectin (VN) was found to mediate higher accumulation in integrin receptor-expressing melanoma cells, while complement 3 protein (C3) and clusterin (CLU), as an opsonin and dysopsonin, respectively, regulated the balance between the RES uptake and blood circulation. DISCUSSION: PC, if properly modulated by tuning NPs' physicochemical properties, can serve as a potential venue for optimum utilization of NPs in cancer therapy.

Distinct Proteins in Protein Corona of Nanoparticles Represent a Promising Venue for Endogenous Targeting - Part I: In vitro Release and Intracellular Uptake Perspective.

INTRODUCTION: Protein corona (PC) deposition on nanoparticles (NPs) in biological systems contributes to a great extent to NPs' fates; their targeting potential, the interaction with different biological systems and the subsequent functions. PC - when properly tuned - can serve as a potential avenue for optimization of NPs' use in cancer therapy. METHODS: Poly-lactic co-glycolic acid (PLGA)-based NPs exhibiting different physicochemical properties were fabricated and characterized. The PC makeup of these NPs were qualitatively and quantitatively analyzed by Western blot and Bradford assay, respectively. The effect of PC on the release of NPs' cargos and the intracellular uptake into B16F10 melanoma cells has been studied. RESULTS: The composition of NPs (polymeric PLGA NPs vs lipid-polymer hybrid NPs) and the conjugation of an active targeting ligand (cRGDyk peptide) represented the major determinants of the PC makeup of NPs. The in vitro release of the loaded cargos from the NPs depended on the PC and the presence of serum proteins in the release medium. Higher cumulative release has been recorded in the presence of proteins in the case of peptide conjugated NPs, cNPs, while the unconjugated formulations, uNPs, showed an opposite pattern. NPs intracellular uptake studies revealed important roles of distinct serum and cellular proteins on the extent of NPs' accumulation in melanoma cells. For example, the abundance of vitronectin (VN) protein from serum has been positively related to the intracellular accumulation of the NPs. CONCLUSION: Careful engineering of nanocarriers can modulate the recruitment of some proteins suggesting a potential use for achieving endogenous targeting to overcome the current limitations of targeted delivery of chemotherapeutic agents.

Zein/Phospholipid Composite Nanoparticles for Successful Delivery of Gallic Acid into aHSCs: Influence of Size, Surface Charge, and Vitamin A Coupling.

PURPOSE: Zein/phospholipid composite nanoparticles (CNPs) were developed as a delivery platform for gallic acid (GA), a polyphenolic compound with reported preclinical antifibrotic activities. However, the therapeutic applicability of GA is hampered owing to its low bioavailability and rapid clearance. Accordingly, we developed GA-loaded CNPs. The effect of their size, surface charge and targeting strategies was investigated and optimized, with the aim of enhancing their ability to deliver GA to the activated hepatic stellate cells (aHSCs) in order to suppress hepatic fibrosis progression. METHODS: Different CNP systems were prepared and characterized with regard to their particle size, zeta potential, and GA entrapment efficiency (EE%). Also, they were statistically optimized via response surface methodology. The optimized systems were investigated with regard to their in vitro GA release, in vitro efficacy on aHSCs, and in vivo biodistribution in healthy rats. RESULTS: The GA-loaded cationic CNPs coupled with vitamin A (GA-CACNP/VA; 192 nm) showed high GA EE% (60% w/w), highest cellular internalization via active targeting, and more selective hepatic distribution, relative to free GA solution, GA-loaded anionic, and GA-loaded cationic systems. Furthermore, GA-CACNP/VA markedly triggered the apoptosis of aHSCs, repressed collagen deposition, and inhibited HSCs' activation to a lesser extent. CONCLUSION: The GA-CACNP/VA was shown to be a promising candidate for specific and controlled delivery of GA to aHSCs, which may provide an effective antifibrotic therapeutic approach.

Impact of Reverse Micelle Loaded Lipid Nanocapsules on the Delivery of Gallic Acid into Activated Hepatic Stellate Cells: A Promising Therapeutic Approach for Hepatic Fibrosis.

PURPOSE: Gallic acid (GA) is a polyphenolic compound with proven efficacy against hepatic fibrosis in experimental animals. However, it suffers from poor bioavailability and rapid clearance that hinders its clinical investigation. Accordingly, we designed and optimized reverse micelle-loaded lipid nanocapsules (RMLNC) using Box-Behnken design that can deliver GA directly into activated-hepatic stellate cells (aHSCs) aiming to suppress hepatic fibrosis progression. METHODS: GA-RMLNC was prepared using soft energy, solvent free phase inversion temperature method. Effects of formulation variables on particle size, zeta potential, entrapment efficiency (EE%) and GA release were studied. In-vivo biodistribution of GA-RMLNC in rats and in-vitro activities on aHSCs were also explored. RESULTS: Nano-sized GA-RMLNCs (30.35 ± 2.34 nm) were formulated with high GA-EE% (63.95 ± 2.98% w/w) and physical stability (9 months). The formulated system showed burst GA release in the first 2 h followed by sustained release profile. In-vivo biodistribution imaging revealed that RMLNC-loaded with rhodamine-B accumulated mainly in rats' livers. Relative to GA; GA-RMLNC displayed higher anti-proliferative activities, effective internalization into aHSCs, marked down-regulation in pro-fibrogenic biomarkers' expressions and elevated HSCs' apoptosis. CONCLUSIONS: These findings emphasize the promising application of RMLNC as a delivery system in hepatic fibrosis treatment, where successful delivery of GA into aHSCs was ensured via increased cellular uptake and antifibrotic activities.

Core in Cup Ethylmorphine Hydrochloride Tablet for Dual Fast and Sustained Pain Relief: Formulation, Characterization, and Pharmacokinetic Study.

Ethylmorphine hydrochloride (EtM) is a derivative of morphine used as analgesic to treat severe pain in case of cancer and bone injury. This study aimed to formulate and evaluate core in cup tablets containing 2 doses of EtM, the cup was formulated as lyophilized oro-dispersible tablet (ODT) for immediate release (IR), and the core was formulated as directly compressed tablet for sustained release (SR). Factorial design was adopted for the optimization of tablets prepared via lyophilized form and direct compression techniques: a 41.22 design was used for the former, while a 32 one was used for the latter. All prepared tablets showed acceptable physical properties which were in accordance with pharmacopeial standards. Two lyophilized ODTs (F9 and F10) formulae were selected as the cup for instant release. While one directly compressed tablet formula (S6) was selected based on the in vitro release profile to represent the sustained core, the outcome was 2 core in cup tablets, namely B1 and B2 which were evaluated for their in vivo absorption and showed a maximum plasma concentration (Cpmax) of 354.12 ± 17.55 ng/mL and 350.82 ± 12.15 ng/mL respectively attained after 3.0 h which were twofolds significantly higher in comparison to the market tablet with Cpmax of only 172.05 ± 12.53 ng/mL attained after 2.20 ± 0.24 h.

In Situ Hexosomal Gel as a Promising Tool to Ameliorate the Transnasal Brain Delivery of Vinpocetine: Central Composite Optimization and In Vivo Biodistribution.

Vascular dementia is a condition characterized by a wretched cerebral circulation which can lead to memory loss. Vinpocetine showed ability to promote the cerebral circulation and depict neuroprotective impacts. However, it suffers from poor bioavailability and requires frequent daily dosing which is not suitable for dementia patients. In our study, these limitations were overcome by the prolonged direct delivery of vinpocetine to the brain utilizing an intranasal in situ hexosomal gel. A central composite design was utilized and the optimum dispersion (consisting of 15% w/w of oleic acid and 5% w/w of pluronic F127) was loaded in an in situ gel system using gellan gum with 1% w/v. The optimized Formulae achieved a controlled drug release over 24 h and the pharmacokinetic data revealed that the Cmax and AUC0-24 in the rats' brain after the intranasal application of the dispersion and in situ gel were significantly higher relative to the vinpocetine solution applied intravenously at the same dose. The potential of both formulae to deliver vinpocetine to the brain directly through the intranasal route was confirmed by the high BTE% of 370.97% and 480.70% and the high DTP% of 73.04% and 79.19% for the dispersion and in situ gel, respectively.

Targeted photodynamic-induced singlet oxygen production by peptide-conjugated biodegradable nanoparticles for treatment of skin melanoma.

BACKGROUND: Photodynamic therapy (PDT) has been determined to be a promising treatment modality in the most resistant tumors such as malignant melanoma. However, the key cytotoxic agent of PDT, -singlet oxygen (1O2) - represents a high risk of photodynamic-associated side effects e.g. skin photosensitization. Recently, controllable photosensitization, where 1O2 is produced on demand, has received increasing attention. In our study, this could be achieved via loading the photosensitizer (PS) in nanoparticles (NPs) decorated with target-specific moieties characterized by 1O2 quenching abilities to specifically locate the PS in the targeted cells and assure that 1O2 is only produced where desired after cellular processing. METHODS: Polymeric and hybrid lipid-polymer NPs were formulated and assayed for their physicochemical properties. This was followed by conjugation with an active targeting ligand, cRGDyk, cyclic (Arginine-Glycine-Aspartic acid-D-Tyrosine-Lysine) peptide. Finally, photodynamic potential of the selected formulations was assayed by quantification of 1O2 production and in vitro cytotoxicity. RESULTS: Three formulations were selected and nominated to be formulations of choice (FOCs); FOC-1 (200 nm, polymeric), FOC-2 (130 nm, polymeric) and FOC-3 (200 nm, hybrid). Physicochemical properties, most importantly particle size and NPs' composition have shown to be the major determinants in targeted NPs' 1O2 production and PDT-mediated cytotoxicity of melanoma. CONCLUSION: Proper selection of formulations intended for PDT application and target-specific ligands could achieve dual targeting; enhanced accumulation of NPs and protection of 1O2 production elsewhere other than target cells.

Gastroretentive Microsponge as a Promising Tool for Prolonging the Release of Mitiglinide Calcium in Type-2 Diabetes Mellitus: Optimization and Pharmacokinetics Study.

Diabetes mellitus is one of the leading causes of death due to the persistent hyperglycemia that leads to potential complications. Lack of patients' adherence to their prescribed medication regimens, due to the requirement of frequent dosing, leads to failure of 40-50% of patients to manage their disease. Thus, microsponges of the novel short half-life mitiglinide calcium (MTG) were formulated using Quasi-emulsion solvent diffusion method, employing Eudragit RS100, ethyl cellulose, and polyvinyl alcohol, then characterized in terms of production yield, entrapment efficiency, particle size, in vitro buoyancy, in vitro drug release, and in vivo pharmacokinetics in rabbits. Optimization was done using response surface methodology; the optimized formulation was investigated by FTIR, DSC, and SEM. Results revealed that the optimized MTG microsponge was successfully formulated with high production yield (61.61% ± 0.6), entrapment efficiency (77.7% ±1.37), and particle size of 192.76 µm and it remained buoyant over simulated gastric fluid for 24 h with high percentage of in vitro buoyancy (91.01% ± 2.5). Moreover, it sustained the in vitro drug release with cumulative % release of 83.74 ± 1.5 after 24 h. This microsponge was highly porous in nature with interconnected pores where MTG was entrapped with good compatibility as confirmed by SEM, DSC, and FTIR analysis; Pharmacokinetic studies showed improvement in Cmax and AUC0-∞ (1.92- and 20.68-fold, respectively) with marked prolongation in MRT and t1/2 (7.22- and 7.97-fold, respectively) than the marketed tablet. Thus, it is a promising approach to improve diabetic patients' compliance by eliminating the necessity of frequent dosing thus attaining better diabetes control.

Synthesis, Characterization and Biocompatibility of N-palmitoyl L-alanine-based Organogels as Sustained Implants of Granisetron and Evaluation of thier Antiemetic Effect.

PURPOSE: To assess the gelation power of N-palmitoyl L-alanine derivatives in injectable oils and to use the best chosen organogel as parenteral implant of granisetron for the treatment of emesis. METHODS: Twelve N-palmitoyl L-alanine derived organogels were developed and evaluated in terms of morphology, thermal properties and in vivo performance. The ability of the selected formula to form in situ gel upon subcutaneous injection in rats and its biocompatibility were monitored over 2 weeks by histopathological examination of the injection site. RESULTS: The acid derivative (N-palmitoyl L-alanine; PA) was superior to ester derivatives. The chosen formula (PA/safflower oil 10% w/v) was successful in forming an in situ gel of granisetron when subcutaneously injected in rats, lasting for 2 weeks and proved to be biocompatible by histopathological examination. Moreover, it exerted an extended antiemetic activity by decreasing the cisplatin-induced pica for a duration of 96 h and reduced preprotachykinin A mRNA expression and Substance P level for up to 4 days (gastric tissue) or 5 days (medulla oblongata) in rats. CONCLUSION: Granisetron organogel could be considered as a safe, sustained-release and supportive anticancer treatment in both acute and chronic emesis as well as an accompanying treatment with chemotherapeutics in cancer cases.

Cromolyn chitosan nanoparticles as a novel protective approach for colorectal cancer.

Colorectal cancer is the third most common cancer in the world. Cromolyn is a mast cell stabilizer and was proposed as an anticancer agent; however its high polarity limits its bioavailability by rapid washing from the body. We formulated 10 cromolyn chitosan nanoparticles (CCSNPs)1 following ionic gelation technique to improve its bioavailability and investigated the protective anticancer effect of the optimum formula against colorectal cancer in dimethylhydrazine-induced model in rats. Rats were divided into seven groups, group-1: normal control, group-2: cromolyn control, group-3: CCSNPs control, groups-4 to 7 received dimethylhydrazine for 16 weeks to induce colorectal cancer. Groups-5 to 7 received cromolyn solution, non-medicated chitosan nanoparticles and CCSNPs, respectively as protective treatments. Optimum CCSNPs (size 112.4 nm, charge +39.9 mV, enclosed 93.6% cromolyn and showed a sustained drug release pattern over 48 h) significantly reduced tumor-signaling molecules and the number of aberrant crypt foci compared to dimethylhydrazine. Histopathological examination of colon samples revealed that CCSNPs exerted an augmented protective anticancer effect by ameliorating tumor pathology compared to cromolyn solution. In conclusion, CCSNPs ameliorated tumor pathology and malignant oncogenic signaling molecules in colorectal cancer tissue. Thus, CCSNPs may provide a novel protective approach in colorectal cancer treatment. Moreover, encapsulating cromolyn in chitosan nanoparticles augmented the protective anticancer effect of the drug.

Microemulsion loaded hydrogel as a promising vehicle for dermal delivery of the antifungal sertaconazole: design, optimization and ex vivo evaluation.

The purpose of the present study was to develop and optimize sertaconazole microemulsion-loaded hydrogel (STZ ME G) to enhance the dermal delivery and skin retention of the drug. Following screening of various oils for maximum drug solubility, 12 pseudoternary phase diagrams were constructed using oils (Peceol®, Capryol® 90), surfactants (Tween® 80, Cremophor® EL), a cosurfactant (Transcutol® P) and water. A 21 × 31 × 21 × 31 full factorial design was employed to optimize a ME of desirable characteristics. The MEs were formulated by varying the oil type, oil concentration, surfactant type and surfactant: cosurfactant ratio. Optimized ME formulae F22 [5% Peceol®, 55% Tween® 80: Transcutol® (1:2), 40% water] and F31 [5% Peceol®, 55% Cremophor® EL: Transcutol® (1:2), 40% water] acquired mean droplet size of 75.21 and 8.68 nm, and zeta potential of 34.65 and 24.05 mV, respectively. Since F22 showed higher STZ skin retention during ex vivo studies (686.47 µg/cm2) than F31 (338.11 µg/cm2); hence it was incorporated in 0.5% Carbopol 934 gel to augment STZ skin retention capability. STZ ME G exhibited higher STZ skin retention (1086.1 µg/cm2) than the marketed product "Dermofix® cream" (270.3 µg/cm2). The antimycotic activity against C.albicans revealed increased zones of inhibition for F22 and STZ ME G (35.75 and 30.5 mm, respectively) compared to Dermofix® cream (26 mm). No histopathological changes were observed following topical application of STZ ME G on rats' skin (n = 9). Overall, the obtained results confirmed that the fabricated formulation could be a promising vehicle for the dermal delivery of STZ.

A pharmaceutical study on lornoxicam fast disintegrating tablets: formulation and in vitro and in vivo evaluation.

Lornoxicam is an anti-inflammatory drug used to relieve rheumatoid arthritis pain, but the low water solubility and bitter taste of the drug present challenges for formulation as fast disintegrating tablets (FDTs). Complexation of the drug with ß-cyclodextrin was initially carried out to increase the drug solubility and to mask its bitter taste. Tablets were prepared by direct compression of drug complex (DC), F-Melt, mannitol, crospovidone, and sodium starch glycolate (SSG). FDTs were characterized in terms of disintegration time (DT) and dissolution. A bioequivalence study was carried out using (Zeficam® tablets (Eva Pharma) as reference with the help of human volunteers (n = 4). The chosen formula (F2, DC 24 mg, F-Melt 88.4 mg, and crospovidone 5 mg) exhibited the shortest in vitro (18 s) and in vivo DT (13 s), and the percent drug released after Q6min was 95.90%. Following administration of F2 and Zeficam®, the respective maximum drug plasma concentrations (Cmax) were 510 and 532.5 ng/mL, at times (Tmax) of 1 and 2.5 h, of mean residence times (MRTs) of 12.25 and 11.35 h and of areas under the plasma curve [AUC(0-24)] of 5080.253 and 4815.775 ng/h/mL. There were significant differences in Tmax and MRT of both treatments (p < 0.05). Moreover, the volunteers found F2 to be palatable. FDTs could be considered as promising dosage forms for lornoxicam as they exhibited a short in vivo DT and an increased rate of drug release and attained a relative bioavailability of 105.49%. This could offer a fast relief of pain accompanying rheumatoid arthritis.

Comparative study of different approaches for preparation of chlorzoxazone orodispersible tablets.

CONTEXT: Muscle spasm is a painful involuntary contraction of muscles, which causes involuntary movement and distortion. Chlorzoxazone is a centrally acting muscle-relaxant with sedative properties, but given orally, it is hepatically metabolized leading to decreased bioavailability. OBJECTIVE: Orodispersible tablets (ODTs) of chlorzoxazone were formulated using two different approaches; by coprocessed excipients (CE) or by liquisolid (LS) technique. MATERIALS AND METHODS: Pharmaburst® 500, Starlac®, Pearlitol flash®, Prosolv® odt and F-melt® were used as coprocessed superdisintegrants, whereas in LS, Avicel® PH101, Microcelac® 100 and Cellactose® 80 were used as carriers, while Aerosil® 200 was the coating material. ODTs were evaluated in terms of weight and thickness variations, drug content, hardness, friability, wetting time, dissolution, disintegration time (DT) and palatability. RESULTS: In vitro DT of CE-ODTs ranged from 26.43 ± 1.693 s to >180 s, whereas it was between 25.42± 0.203 s to >180 s in LS-ODTs. Complete drug release within 15 min was attained by CE1 prepared with 92.5 mg Pharmaburst® 500. In vivo DT of CE1 and LS3 were 19.779 ± 0.810 and 18.105 ± 0.423 s, respectively, using six volunteers. Volunteers found that CE1 had more acceptable taste and was more palatable than LS3. CONCLUSION: It was concluded that chlorzoxazone ODTs could be successfully formulated using either CE or LS techniques and be used as novel dosage forms for pediatrics and geriatrics showing improved drug release. Moreover, CE technique was superior to LS technique in terms of palatability.

A pharmaceutical study on chlorzoxazone orodispersible tablets: formulation, in-vitro and in-vivo evaluation.

CONTEXT: Muscle spasm needs prompt relief of symptoms. Chlorzoxazone is a centrally muscle relaxant. OBJECTIVES: The aim of this study was to prepare chlorzoxazone orodispersible tablets (ODTs) allowing the drug to directly enter the systemic circulation and bypassing the first-pass metabolism for both enhancing its bioavailability and exerting a rapid relief of muscular spasm. MATERIALS AND METHODS: ODTs were prepared by direct compression method using Pharmaburst®500, Starlac®, Pearlitol flash®, Prosolv® odt and F-melt® as co-processed excipients. Three ratios of the drug to the other excipients were used (0.5:1, 1:1 and 2:1). RESULTS AND DISCUSSION: All ODTs were within the pharmacopeial limits for weight and content. ODTs containing Pharmaburst®500 showed the shortest wetting time (∼45.33 s), disintegration time (DT) (∼43.33 s) and dissolution (Q15min 100.63%). By increasing the ratio of CLZ: Pharmaburst®500 from 0.5:1 to 1:1 and 2:1, the DT increased from 26.43 to 28.0 and 43.33 s, respectively. By using Prosolv® odt, ODTs failed to disintegrate in an acceptable time >180 s. DT of ODTs using different co-processed excipients can be arranged as follows: Pharmaburst® 500 < F-melt®

Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer's disease.

BACKGROUND: To sustain the effect of rivastigmine, a hydrophilic cholinesterase inhibitor, nanobased formulations were prepared. The efficacy of the prepared rivastigmine liposomes (RLs) in comparison to rivastigmine solution (RS) was assessed in an aluminium chloride (AlCl(3))-induced Alzheimer's model. METHODS: Liposomes were prepared by lipid hydration (F1) and heating (F2) methods. Rats were treated with either RS or RLs (1 mg/kg/day) concomitantly with AlCl(3) (50 mg/kg/day). RESULTS: The study showed that the F1 method produced smaller liposomes (67.51 ± 14.2 nm) than F2 (528.7 ± 15.5 nm), but both entrapped the same amount of the drug (92.1% ± 1.4%). After 6 hours, 74.2% ± 1.5% and 60.8% ± 2.3% of rivastigmine were released from F1 and F2, respectively. Both RLs and RS improved the deterioration of spatial memory induced by AlCl(3), with RLs having a superior effect. Further biochemical measurements proved that RS and RLs were able to lower plasma C-reactive protein, homocysteine and asymmetric dimethy-larginine levels. RS significantly attenuated acetylcholinesterase (AChE) activity, whereas Na(+)/K(+)-adenosine triphosphatase (ATPase) activity was enhanced compared to the AlCl(3)-treated animals; however, RLs succeeded in normalization of AChE and Na(+)/K(+) ATPase activities. Gene-expression profile showed that cotreatment with RS to AlCl(3)-treated rats succeeded in exerting significant decreases in BACE1, AChE, and IL1B gene expression. Normalization of the expression of the aforementioned genes was achieved by coadministration of RLs to AlCl(3)-treated rats. The profound therapeutic effect of RLs over RS was evidenced by nearly preventing amyloid plaque formation, as shown in the histopathological examination of rat brain. CONCLUSION: RLs could be a potential drug-delivery system for ameliorating Alzheimer's disease.