An Explorative Review on Advanced Approaches to Overcome Bacterial Resistance by Curbing Bacterial Biofilm Formation.

The continuous emergence of multidrug-resistant pathogens evoked the development of innovative approaches targeting virulence factors unique to their pathogenic cascade. These approaches aimed to explore anti-virulence or anti-infective therapies. There are evident concerns regarding the bacterial ability to create a superstructure, the biofilm. Biofilm formation is a crucial virulence factor causing difficult-to-treat, localized, and systemic infections. The microenvironments of bacterial biofilm reduce the efficacy of antibiotics and evade the host's immunity. Producing a biofilm is not limited to a specific group of bacteria; however, Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus biofilms are exemplary models. This review discusses biofilm formation as a virulence factor and the link to antimicrobial resistance. In addition, it explores insights into innovative multi-targeted approaches and their physiological mechanisms to combat biofilms, including natural compounds, phages, antimicrobial photodynamic therapy (aPDT), CRISPR-Cas gene editing, and nano-mediated techniques.

Tween 80-Based Self-Assembled Mixed Micelles Boost Valsartan Transdermal Delivery.

Valsartan (Val) is an important antihypertensive medication with poor absorption and low oral bioavailability. These constraints are due to its poor solubility and dissolution rate. The purpose of this study was to optimize a mixed micelle system for the transdermal delivery of Val in order to improve its therapeutic performance by providing prolonged uniform drug levels while minimizing drug side effects. Thin-film hydration and micro-phase separation were used to produce Val-loaded mixed micelle systems. A variety of factors, including the surfactant type and drug-to-surfactant ratio, were optimized to produce micelles with a low size and high Val entrapment efficiency (EE). The size, polydispersity index (PDI), zeta potential, and drug EE of the prepared micelles were all measured. The in vitro drug release profiles were assessed using dialysis bags, and the permeation through abdominal rat skin was assessed using a Franz diffusion cell. All formulations had high EE levels exceeding 90% and low particle charges. The micellar sizes ranged from 107.6 to 191.7 nm, with average PDI values of 0.3. The in vitro release demonstrated a uniform slow rate that lasted one week with varying extents. F7 demonstrated a significant (p < 0.01) transdermal efflux of 68.84 ± 3.96 µg/cm2/h through rat skin when compared to the control. As a result, the enhancement factor was 16.57. In summary, Val-loaded mixed micelles were successfully prepared using two simple methods with high reproducibility, and extensive transdermal delivery was demonstrated in the absence of any aggressive skin-modifying enhancers.

Celecoxib-Loaded Solid Lipid Nanoparticles for Colon Delivery: Formulation Optimization and In Vitro Assessment of Anti-Cancer Activity.

This work aimed to optimize a celecoxib (CXB)-loaded solid lipid nanoparticles (SLN) colon delivery system for the enhancement of anticancer activity. An ultrasonic melt-emulsification method was employed in this work for the preparation of SLN. The physical attributes were characterized for their particle sizes, charges, morphology, and entrapment efficiency (%EE), in addition to DSC and FTIR. The in vitro drug release profiles were evaluated, and the anticancer activity was examined utilizing an MTT assay in three cancer cell lines: the colon cancer HT29, medulloblastoma Daoy, and hepatocellular carcinoma HepG2 cells. All of the prepared SLN formulations had nanoscale particle sizes ranging from 238 nm to 757 nm. High zeta-potential values (mv) within -30 s mv were reported. The %EE was in the range 86.76-96.6%. The amorphous nature of the SLN-entrapped CXB was confirmed from SLN DSC thermograms. The in vitro release profile revealed a slow constant rate of release with no burst release, which is unusual for SLN. Both the F9 and F14 demonstrated almost complete CXB release within 24 h, with only 25% completed within the first 5 h. F9 caused a significant percentage of cell death in the three cancer cell lines tested after 24 h of incubation and maintained this effect for 72 h. The prepared CXB-loaded SLN exhibited unique properties such as slow release with no burst and a high %EE. The anticancer activity of one formulation was extremely significant in all tested cancer cell lines at all incubation times, which is very promising.

Antibacterial Efficacy of Liposomal Formulations Containing Tobramycin and N-Acetylcysteine against Tobramycin-Resistant Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii.

The antibacterial activity and biofilm reduction capability of liposome formulations encapsulating tobramycin (TL), and Tobramycin-N-acetylcysteine (TNL) were tested against tobramycin-resistant strains of E. coli, K. pneumoniae and A. baumannii in the presence of several resistant genes. All antibacterial activity were assessed against tobramycin-resistant bacterial clinical isolate strains, which were fully characterized by whole-genome sequencing (WGS). All isolates acquired one or more of AMEs genes, efflux pump genes, OMP genes, and biofilm formation genes. TL formulation inhibited the growth of EC_089 and KP_002 isolates from 64 mg/L and 1024 mg/L to 8 mg/L. TNL formulation reduced the MIC of the same isolates to 16 mg/L. TNL formulation was the only effective formulation against all A. baumannii strains compared with TL and conventional tobramycin (in the plektonic environment). Biofilm reduction was significantly observed when TL and TNL formulations were used against E. coli and K. pneumoniae strains. TNL formulation reduced biofilm formation at a low concentration of 16 mg/L compared with TL and conventional tobramycin. In conclusion, TL and TNL formulations particularly need to be tested on animal models, where they may pave the way to considering drug delivery for the treatment of serious infectious diseases.

Rapid and Sensitive Liquid Chromatographic Method for Determination of Anastrozole in Different Polymer-Lipid Hybrid Nanoparticles.

Anastrozole, an aromatase inhibitor drug, is used for the treatment of breast cancer in pre- and postmenopausal women. Anastrozole's incorporation into nanoparticulate carriers would enhance its therapeutic performance. To perceive the exact loaded amount of drug in nanocarriers, a valid analytical method is required. The reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated by using the C18 column, 150 × 4.6 mm, 5 µm particle size, in isocratic mobile phase composed of 50:50 V/V (volume/volume) acetonitrile-phosphate buffer (pH 3) flowing at a rate of 1.0 mL/min, and a diode array detector (DAD) set at λmax = 215 nm. The validation parameters such as linearity, accuracy, specificity, precision, and robustness have proven the accuracy of the method, with the relative standard deviation percentage (% RSD) values < 2. The limit of detection of the method was found equal to 0.0150 µg/mL, and the limit of quantitation was 0.0607 µg/mL. The percent recovery of sample was in the range of 98.04-99.25%. The method has the advantage of being rapid with a drug retention time of 2.767 min, specific in terms of resolution of peaks void of interference with any of the excipients, and high reproducibility. This makes it highly applicable for quality control purposes.

Enhancing azithromycin antibacterial activity by encapsulation in liposomes/liposomal-N-acetylcysteine formulations against resistant clinical strains of Escherichia coli.

E. coli is an Enterobacteriaceae that could develop resistance to various antibiotics and become a multi-drug resistant (MDR) bacterium. Options for treating MDR E. coli are limited and the pipeline is somewhat dry when it comes to antibiotics for MDR bacteria, so we aimed to explore more options to help in treating MDR E. coli. The purpose of this study is to examine the synergistic effect of a liposomal formulations of co-encapsulated azithromycin and N-acetylcysteine against E. coli. Liposomal azithromycin (LA) and liposomal azithromycin/N-acetylcysteine (LAN) were compared to free azithromycin. A broth dilution was used to measure the MIC and MBC of both formulations. The biofilm reduction activity, thermal stability measurements, stability studies, and cell toxicity analysis were performed. LA and LAN effectively reduced the MIC of E. coli SA10 strain, to 3 µg/ml and 2.5 µg/ml respectively. LAN at 1 × MIC recorded a 93.22% effectiveness in reducing an E. coli SA10 biofilm. The LA and LAN formulations were also structurally stable to 212 ± 2 °C and 198 ± 3 °C, respectively. In biological conditions, the formulations were largely stable in PBS conditions; however, they illustrated limited stability in sputum and plasma. We conclude that the formulation presented could be a promising therapy for E. coli resistance circumstances, providing the stability conditions have been enhanced.

Physical PEGylation Enhances The Cytotoxicity Of 5-Fluorouracil-Loaded PLGA And PCL Nanoparticles.

PURPOSE: The main goal of this study is to evaluate the impact of physical incorporation of polyethylene glycol (PEG) into 5-fluorouracil (5-FU)-loaded polymeric nanoparticles (NPs). METHODS: The 5-FU-loaded NPs were prepared utilizing a simple double emulsion method using polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA) with or without PEG 6000. The surface charge, particle size, and shape of NPs were evaluated by standard procedures. Both Fourier Transform Infrared Spectroscopy and X-ray diffraction spectra of the 5-FU loaded NPs were compared against the pure 5-FU. The in vitro release profile of 5-FU from the NPs was monitored by the dialysis tubing method. Cell death and apoptosis induction in response to 5-FU NP exposure were measured by MTT and Annexin-V/7-amino-actinomycin D (7-AAD) assays, respectively, in Daoy, HepG2, and HT-29 cancer cell lines. RESULTS: The 5-FU loaded NPs were found to be spherical in shape with size ranging between 176±6.7 and 253.9±8.6 nm. The zeta potential varied between -7.13± 0.13 and -27.06±3.18 mV, and the entrapment efficiency was between 31.96% and 74.09%. The in vitro release of the drug followed a two-phase mode characterized by rapid release in the first 8 hrs followed by a period of slow release up to 72 hrs with composition-based variable extents. Cells exposed to NPs demonstrated a significant cell death which correlated with the ratio of PEG in the formulations in Daoy and HepG2 cells but not in HT-29 cells. Formulations (F1-F3) significantly induced early apoptosis in HT-29 cell lines. CONCLUSION: The physical PEGylation significantly enhanced the entrapment and loading efficiencies of 5-FU into NPs formulated with PLGA and PCL. It also fostered the in vitro cytotoxicity of 5-FU-loaded NPs in both Daoy and HepG2 cells. Induction of early apoptosis was confirmed for some of the formulations.

Formulation and characterization of Phospholipon 90 G and tween 80 based transfersomes for transdermal delivery of eprosartan mesylate.

The objective of the current study was to formulate the eprosartan mesylate loaded transfersomes using different proportions of Phospholipon® 90 G and Tween® 80 (95-75:5-25% w/w). The prepared transfersomes were characterized for their vesicles size, shape, polydispersity index, zeta potential, entrapment efficiency, in vitro skin permeation, confocal laser scanning microscopy, and in vivo skin irritation. Results revealed that the formulated transfersomes were negatively charged, spherical unilamellar structure of 71.18-85.66 nm with entrapment efficiency of 83.00-88.19%, and presented transdermal flux of 1.78-5.02 µg/cm2/h across rat skin. Confocal laser scanning microscopy confirmed that the formulated rhodamine 6 G loaded transfersomes could penetrate deeply and uniformly into rat skin. Additionally, in vivo skin irritation studies revealed that the prepared transfersomes were devoid of any skin irritation potential (erythema and edema). Results of this study revealed that the transfersomes prepared with Tween® 80 could be used to enhance the transdermal delivery of eprosartan mesylate. In conclusion, transdermal transfersomes formulation may prove to be an encouraging drug carrier for eprosartan mesylate and other actives, particularly owing to their simple formulation and unsophisticated scale-up methods.

Formulation and characterization of novel soft nanovesicles for enhanced transdermal delivery of eprosartan mesylate.

The objective of the present work was to formulate, optimize and evaluate the potential of novel soft nanovesicles i.e. nano-transfersomes, containing eprosartan mesylate (EM) for transdermal delivery. Nano-transfersomes of EM were developed using Phospholipon 90G, Span 80 (SP) and sodium deoxycholate (SDC) and characterized for vesicle size, shape, entrapment efficiency, in vitro skin permeation study and confocal laser scanning microscopy. The optimized nano-transfersomes formulation showed vesicles size of 108.53 ± 0.06 nm and entrapment efficiency of 63.00 ± 2.76%. The optimized nano-transfersomes provided an improved transdermal flux of 27.22 ± 0.29 µg/cm2/h with an enhancement ratio of 16.80 over traditional liposomes through Wistar rat skin. Confocal laser microscopy of rat skin treated with the optimized formulation showed that the formulation was eventually distributed and permeated deep into the rat skin. The present investigation has shown that the nature and concentration of surfactants (edge activators) influence immense control on the characteristics of nano-transfersomes. It was concluded that the developed nano-transfersomes surmount the limitation of low penetration ability of the traditional liposomes across the rat skin. Improved drug delivery presented by nano-transfersomes establishes this system as an encouraging dosage form for the delivery of EM via skin route.

Pharmacodynamic study of eprosartan mesylate-loaded transfersomes Carbopol® gel under Dermaroller® on rats with methyl prednisolone acetate-induced hypertension.

The objective of present study was to prepare eprosartan mesylate (EM)-loaded transfersomes Carbopol® gel and characterized for various parameters, including in vitro skin permeation, in vivo antihypertensive study, skin irritation, and histological study. Furthermore, effect of transfersomes gel on angiotensin II type-1 receptor (AT1R) mRNA and protein expressions on smooth vascular muscles of aorta was determined by real-time polymerase chain reaction (RT-PCR) and western blot analysis. The physical evaluation parameters were detected to be in correspondence with reference marketed gel formulation. The transdermal flux, permeability coefficient, and Tlag of EM from transfersomes gel were found to be 26.76 ± 1.66µg/cm2/h, 8.93 ± 0.55 ×10-3 cm/h, and 2.17 ± 0.29h, respectively, across rat skin pretreated with microneedle (Dermaroller®). Pharmacodynamic study showed prolonged and better management of hypertension after the application of transfersomes gel in experimentally induced hypertensive Wistar rats as compared with oral control formulation. The in vivo angiotensin II type-1 blocking efficacy of prepared transfersomes gel and control formulation was also supported with RT-PCR and western blot analysis of AT1R mRNA and protein expressions on smooth vascular muscles of aorta. Skin irritation and skin histological assessment showed that the prepared transfersomes Carbopol® gel was safe to be used for transdermal route. It is concluded that the incorporation of transfersomes into gel formulation offered enhanced skin contact, ease of application, and found to be a suitable drug reservoir for the transdermal delivery of EM for the management of hypertension in Wistar rats.

Optimization of amino acid-stabilized erythropoietin parenteral formulation: In vitro and in vivo assessment.

The aim of this study was to optimize the formulation of erythropoietin (EPO) using amino acids instead of human serum albumin (HSA) and to evaluate its in vivo stability in order to avoid the risk of viral contamination and antigenicity. Different EPO formulations were developed in such a way as to allow studying the effects of amino acids and surfactants on the EPO stability profile. The main techniques applied for EPO analysis were ELISA, Bradford method, and SDS gel electrophoresis. The in vivo stability was evaluated in a Balb-c mouse animal model. The results showed that the presence of surfactant was very useful in preventing the initial adsorption of EPO on the walls of vials and in minimizing protein aggregation. Amino acid combinations, glycine with glutamic acid, provided maximum stability. Formulation F4 (containing glycine, glutamic acid and Tween 20) showed minimum aggregation and degradation and in vivo activity equivalent to commercially available HSA-stabilized EPO (Eprex®).

Identification and Testing of Novel CARP-1 Functional Mimetic Compounds as Inhibitors of Non-Small Cell Lung and Triple Negative Breast Cancers.

The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimetic (CFMs) compounds 4 and 5, and 4.6, a structurally related analog of CFM-4, are potent inhibitors of TNBC and NSCLC cells in vitro. Cell growth suppression by CFM-4 and -4.6 involved interaction and elevated expression of CARP-1/CCAR1 and Death Effector Domain (DED) containing DNA binding (DEDD)2 proteins. Apoptosis by these compounds also involved activation of pro-apoptotic stress-activated kinases p38 and JNK1/2, cleavage of PARP and loss of mitotic cyclin B1. Both the CFMs inhibited abilities of NSCLC and TNBC cells to migrate, invade, and form colonies in suspension, while disrupting tubule formation by the human umbilical vein endothelial cells (HUVECs). Nano-lipid formulation of CFM-4 (CFM-4 NLF) enhanced its serum bioavailability when compared with the free CFM-4. Oral administration of CFM-4 NLF reduced weights and volume of the xenografted tumors derived from A549 NSCLC and MDA-MB-231 TNBC cells. Although no gross tissue or histological toxicities were noticed, the immuno-histochemical analysis revealed increased CARP-1 and DNA fragmentation in tumors of the CFM-4 NLF-treated animals. In conclusion, while stimulation of pro-apoptotic CARP-1 and DEDD2 expression and their binding underscore a novel mechanism of apoptosis transduction by CFM compounds, our proof-of-concept xenograft studies demonstrate therapeutic potential of CFM-4 for TNBC and NSCLC.

Nanostructure-based platforms-current prospective in ophthalmic drug delivery.

The topically applied drugs as drops are washed off from the eye in very short period, resulting in low ocular bioavailability of drugs. Number of approaches have been attempted to increase the bioavailability and the duration of action of ocular drugs. This review provides an insight into various novel approaches; hydrophilic nanogels, solid lipid nanoparticles, and nanosponges applied very recently in the delivery of insoluble drugs, prolonging the ocular residence time, minimize pre-corneal drug loss and, therefore, bioavailability and therapeutic efficacy of the drugs. Despite various scientific approaches, efficient ocular drug delivery remains a challenge for pharmaceutical scientists.

Novel sulpiride-loaded solid lipid nanoparticles with enhanced intestinal permeability.

BACKGROUND: Solid lipid nanoparticles (SLN), novel drug delivery carriers, can be utilized in enhancing both intestinal permeability and dissolution of poorly absorbed drugs. The aim of this work was to enhance the intestinal permeability of sulpiride by loading into SLN. METHODS: A unique ultrasonic melt-emulsification method with minimum stress conditions was used for the preparation of SLN. The mixture of the drug and the melted lipids was simply dispersed in an aqueous solution of a surfactant at a temperature that was 10°C higher than the melting points of the lipids using probe sonication, and was then simultaneously dispersed in cold water. Several formulation parameters were optimized, including the drug-to-lipid ratio, and the types of lipids and surfactants used. The produced SLN were evaluated for their particle size and shape, surface charge, entrapment efficiency, crystallinity of the drug and lipids, and the drug release profile. The rat everted sac intestine model was utilized to evaluate the change in intestinal permeability of sulpiride by loading into SLN. RESULTS: The method adopted allowed successful preparation of SLN with a monodispersed particle size of 147.8-298.8 nm. Both scanning electron microscopic and atomic force microscopic images showed uniform spherical particles and confirmed the sizes determined by the light scattering technique. Combination of triglycerides with stearic acid resulted in a marked increase in zeta potential, entrapment efficiency, and drug loading; however, the particle size was increased. The type of surfactant used was critical for particle size, charge, drug loading, and entrapment efficiency. Generally, the in vitro release profile demonstrated by all formulations showed the common biphasic mode with a varying degree of burst release. The everted sac model showed markedly enhanced sulpiride permeability in the case of the SLN-loaded formulation. The in situ results showed a very good correlation with the in vitro release data. CONCLUSION: Incorporation of sulpiride into SLN results in enhanced intestinal permeability of sulpiride, that may in turn increase overall oral absorption of the drug. The superior attributes of the prepared SLN, specifically the high particle size uniformity and drug loading capacity, is considered novel, especially given the simplicity and modest nature of the sonication method used.

Novel erythropoietin-loaded nanoparticles with prolonged in vivo response.

The aim of this study was to incorporate human recombinant erythropoietin (EPO) in biodegradable polymeric nanoparticles targeting a prolonged-release effect. EPO-loaded poly(DL-lactide-co-glycolide) nanoparticles were prepared using double emulsion method (w/o/w) with least process-related stress on the encapsulated drug. The nanoparticles have been fully characterized including in vitro release profile. The biological activity was assessed in vivo using BALB-c mice. The produced particles appeared spherical in shape with smooth regular surfaces and had an average particle size of 225.9 ± 3.8 nm. The entrapment efficiency was 33.3%. The in vitro release profile exhibited a biphasic mode with a burst of 50% cumulative drug release, followed by a slow rate of release over 24 h, reaching a maximum of 82%. The bioassay results showed that EPO-loaded nanoparticles were able to maintain the physiological activity of EPO for 14 days after single subcutaneous injection compared with pure and marketed EPO formulae (EPREX®).

Theophylline colon specific tablets for chronotherapeutic treatment of nocturnal asthma.

The ultimate goal is to design a new chronotherapeutic system for theophylline (TPH) with high potential benefits in treating nocturnal asthma. TPH core tablets were prepared by wet granulation using a developed formula. Compression coating over core tablets containing 200 mg TPH was done using granulated chitosan with 10% PVP K30. Different formulae F1, F2 and F3 were prepared using coat weights 260, 300 and 360 mg, respectively. The in vitro release characteristics in both variant pH media mimicking the gastrointestinal media and in media containing rat cecal content were monitored. The in vivo performance of the optimum formula was compared with Avolen(®) SR in Beagle dogs. F3 with high coat thickness exhibited a minimal release after 5-h release study. Both F2 and F3 showed more than 50% drug release after 4 h in the rat cecal medium. This reflects the colon selectivity of the system. The C(max) values were found to be 5.49 ± 0.46 and 5.12 ± 0.85 µg/mL for F3 and Avolen(®) SR, respectively, F3 showed higher mean plasma concentration than Avolen(®) SR from the beginning and continued till 7 h post administration indicating high potential as chronotherapeutic treatment of nocturnal asthma.

Direct UPLC-MS-MS validated method for the quantification of 5-aminolevulinic acid: application to in-vitro assessment of colonic-targeted oral tablets.

A reliable, sensitive, specific, and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS-MS) method was developed for the determination of 5-aminolevulinic acid (5-ALA) in orally-administered colonic delivery system. The prepared system is a compression-coated tablet using granulated chitosan as the coat layer. L-Tyrosine (TYR) was used as an internal standard with no need for derivatization. The chromatographic system consisted of Acquity UPLC BEH C18 column and isocratic mobile phase composed of acetonitrile and 0.1% formic acid with a flow rate of 2.5 min. The assay was based on ESI+ mode in a multiple reaction monitoring (MRM) transitions at m/z 132.08 > 86.0 and m/z 132.08 > 114.0 and m/z 182.1 > 91.2 for 5-ALA and TYR, respectively. Limit of quantification was 5.0 ng/mL and the calibration curve was linear (r(2) = 0.994). Within-run precision and between-run repeatability were expressed as relative standard deviation and were lower than 2.5%. The recoveries from control samples were > 95%. The method was successfully applied for evaluation in assay and release profile of 5-ALA colon targeted tablets media containing suspended rat cecal contents pH 6.8 medium (colonic) for colonic delivery.

Optimization of 5-flurouracil solid-lipid nanoparticles: a preliminary study to treat colon cancer.

Solid lipid nanoparticle (SLNs) formulae were utilized for the release of 5-flurouracil (5-FU) inside the colonic medium for local treatment of colon cancer. SLNs were prepared by double emulsion-solvent evaporation technique (w/o/w) using triglyceride esters, Dynasan™ 114 or Dynasan™ 118 along with soyalecithin as the lipid parts. Different formulation parameters; including type of Dynasan, soyalicithin:Dynasan ratio, drug:total lipid ratio, and polyvinyl alcohol (PVA) concentration were studied with respect to particle size and drug entrapment efficiency. Results showed that formula 8 (F8) with composition of 20% 5-FU, 27% Dynasan™ 114, and 53% soyalithicin andformula 14 (20% 5-FU, 27% Dynasan™ 118, and 53% soyalithicin), which were stabilized by 0.5% PVA, as well as F10 with similar composition as F8 but stabilized by 2% PVA were considered the optimum formulae as they combined small particle size and relatively high encapsulation efficiencies. F8 had a particle size of 402.5 nm ± 34.5 with a polydispersity value of 0.005 and an encapsulation efficiency of 51%, F10 had a 617.3 ± 54.3 nm particle size with 0.005 polydispersity value and 49.1% encapsulation efficiency, whereas formula F14 showed a particle size of 343 nm ± 29 with 0.005 polydispersity, and an encapsulation efficiency of 59.09%. DSC and FTIR results suggested the existence of the lipids in the solid crystalline state. Incomplete biphasic prolonged release profile of the drug from both formulae was observed in phosphate buffer pH 6.8 as well as simulated colonic medium containing rat caecal contents. A burst release with magnitudes of 26% and 28.8% cumulative drug released were noticed in the first hour samples incubated in phosphate buffer pH 6.8 for both F8 and F14, respectively, followed by a slow release profile reaching 50% and 52% after 48 hours.

In vitro characterization of carbamazepine-loaded precifac lipospheres.

Lipospheres of carbamazepine were prepared by melt dispersion technique using Precifac ATO 5 in the various drug-lipid ratios. The resulting free-flowing lipospheres were evaluated with respect to surface morphology, particle size distribution, encapsulation efficiency, and in vitro release behavior. The effect of druglipid ratio, the surfactant added, emulsion stabilizer, and stirring speed also were identified as the key variables affecting the formation of discrete spherical lipospheres and drug release rate. The preparation conditions were optimized by using 0.4% w/v span 20 (Hydrophilic-Lipophilic Balance, HLB = 8.6) as a surfactant and 1% w/v gelatin solution as a stabilizer in presence of a high level of water. We found that the ratio of drug to lipid affects the size of the spheres. The incorporation efficiency was found to be high at all loadings. Increasing the lipid:drug ratio produced more spherical, smooth, and round lipospheres. All the prepared lipospheres exhibited slow release profiles dictating the Higuchi mode of release. We saw that the higher the sphere size and the ratio of Precifac, the slower is in vitro drug release.

Intra-gastric performance and bioavailability study of a new per-oral bioadhesive Verapamil HCl matrix tablet in dogs.

In a previous study, we developed a per-oral extended--release bioadhesive matrix tablet for verapamil HCl (VP). The system combined both strong bioadhesion and sustained release properties in vitro. The purpose of this study is to evaluate the in vivo performance of the prepared bioadhesive tablets (B). The conduction of a periodic X-ray imaging of the abdomen of beagle dogs, after administration of B containing 12% barium sulfate, was used to evaluate the intra-gastric performance. The VP concentrations in blood samples taken at specified times after oral administration of B to fasted beagle dogs were determined and compared with those obtained after administration of a commercial sustained release VP tablets (Manidon 120 R). The X-ray images showed that bioadhesive tablets remained almost at the same place in the stomach for at least 6 hours while it disappeared after 1 hour in case of the control tablets. No statistical difference was seen between the Cmax, tmax, AUC, t1/2, and MRT for B compared to Manidon. The Cmax was found to be 51.4 +/- 15.5 and 48.6 +/- 17.9 (ng/ml) for Manidon and B, respectively and the corresponding tmax were 7.0 +/- 1.9 and 6.0 +/- 0, respectively. The AUCO-. for Manidon and B were 949.84 +/- 245.11 and 722.92 +/- 144.42 ng.h/ml, respectively. So, the prepared B tablets can be considered bioequivalent to the commercial Manidon Retard product.