Solusomes (novel soluplus® enriched nano-vesicular carriers) for improving the oral bioavailability of Candesartan cilexetil.

Candesartan cilexetil (CAN) is administered for treating hypertension and heart failure. CAN suffers poor oral bioavailability, owing to limited aqueous solubility, and first-pass metabolism. Solusomes (novel Soluplus® enriched nano-vesicular carriers) combine the merits of Soluplus®, and the traditional liposomes. They were explored to increase CAN solubility, allow a high drug release rate, and improve the oral drug bioavailability. Solusomes were developed via thin film hydration technique utilizing lipid (phosphatidylcholine; PC) and polymeric solubilizer (Soluplus®; Solu). S6 system comprising PC (0.1% w/v), CAN and Soluplus® (at 1:5 ratio; w/w), following a 5 min sonication period, was the optimum one with respect to drug entrapment efficiency (83.5 ± 2.6%), drug loading (11.9 ± 0.3%), particle size and shape (377.2 ± 12.1 nm, spherical), zeta-potential (-19.6 ± 2.1 mV), saturated drug solubility (32.09 ± 0.71 µg/mL), drug released % after 1 h (68 ± 0.9%), and stability. Significantly higher Cmax (969.12 ± 46.3 ng/mL), shorter median Tmax (1h), and improved relative bioavailability (≈ 6.8 folds) in rabbits could evidence the potential of S6 system in enhancing oral CAN bioavailability. S6 solusomes act as dual platform to improve the oral drug bioavailability and maintain effective drug concentration for a prolonged period.

Low-Frequency Sonophoresis as an Active Approach to Potentiate the Transdermal Delivery of Agomelatine-Loaded Novasomes: Design, Optimization, and Pharmacokinetic Profiling in Rabbits.

The first melatonergic antidepressant drug, agomelatine (AGM), is commonly used for controlling major depressive disorders. AGM suffers low (< 5%) oral bioavailability owing to the hepatic metabolism. The current work investigated the potential of low-frequency sonophoresis on enhancing transdermal delivery of AGM-loaded novasomes and, hence, bioavailability of AGM. Drug-loaded novasomes were developed using free fatty acid (stearic acid or oleic acid), surfactant (span 60 or span 80), and cholesterol via thin-film hydration technique. The systems (N1-N16) were assessed for zeta potential (ZP), particle size (PS), encapsulation efficiency (EE%), and drug percent released after 0.5 h (Q0.5 h) and 8 h (Q8h), drug-crystallinity, morphology, and ex vivo drug permeation. Skin pre-treatment with low-frequency ultrasound (LFU) waves, via N13-novasomal gel systems, was optimized to enhance ex vivo drug permeation. Influences of LFU mode (continuous or pulsed), duty cycle (50% or 100%), and application period (10 or 15 min) were optimized. The pharmacokinetics of the optimized system (N13-LFU-C4) was assessed in rabbits. N13 was the best achieved novasomal system with respect to PS (471.6 nm), ZP (- 63.6 mv), EE% (60.5%), Q0.5 h (27.8%), Q8h (83.9%), flux (15.5 µg/cm2/h), and enhancement ratio (6.9). N13-LFU-C4 was the optimized novasomal gel system (desirability; 0.997) which involves skin pre-treatment with LFU in a continuous mode, at 100% duty cycle, for 15 min. Compared to AGM dispersion, the significantly (P < 0.05) higher flux (26.7 µg/cm2/h), enhancement ratio (11.9), Cmax (118.23 ng/mL), and relative bioavailability (≈ 8.6 folds) could elucidate the potential of N13-LFU-C4 system in improving transdermal drug permeability and bioavailability.

Nebulization of Risedronate Sodium Microspheres for Potential Attenuation of Pulmonary Emphysema: a Promising New Insight of Alveolar Macrophage Apoptosis.

Risedronate sodium (RS) is a potent nitrogen-containing bisphosphonate which is known to induce osteoclast apoptosis. As a drug repurposing approach, the current work explored the potential of nebulizable RS-chitosan (CS) microspheres to induce alveolar macrophage apoptosis. RS-CS microspheres were assessed for lung deposition, cytotoxicity, and cellular uptake percentage in Calu-3 cells. The potential of nebulizable microspheres for treating elastase-induced emphysema in rats was investigated, compared to RS marketed oral tablets®, with respect to histopathological, immunohistochemical, and flow cytometric studies. The in vitro lung deposition pattern suggested deep alveolar deposition of RS microspheres, with respect to high FPF% and suitable MMAD (66% and 1.506 µm, respectively, at a flow rate of 28.3 L min-1). No apparent cytotoxicity was observed, with a cell viability > 90%. The inhalation of RS-CS microspheres was suggested to inhibit airspace enlargement and lung rarefaction after elastase instillation and reduce the macrophage accumulation in alveolar parenchyma. Immunohistochemical and cytometric analyses revealed significant low expression levels of CD68 and CD11b surface markers, respectively, with significantly (P < 0.05) lower detected numbers of intact alveolar macrophages following inhalation of RS-CS microspheres. The nebulization of RS-CS microspheres could induce apoptosis in alveolar macrophages and be promisingly adopted for attenuation of pulmonary emphysema.

Low-Frequency versus High-Frequency Ultrasound-Mediated Transdermal Delivery of Agomelatine-Loaded Invasomes: Development, Optimization and in-vivo Pharmacokinetic Assessment.

AIM: Agomelatine (AGM) is the first melatonergic antidepressant. It suffers from low oral bioavailability (<5%) due to extensive hepatic metabolism. The current work aimed to develop an alternative AGM-loaded invasomes to enhance transdermal drug bioavailability. METHODOLOGY: AGM-loaded invasomes were developed using two drug: lipid ratios (1:10 or 1:7.5), four terpene types (limonene, cineole, fenchone or citral) and two terpene concentrations (0.75% or 1.5%, w/v). They were characterized for drug entrapment efficiency (EE%), particle size (PS), zeta potential (ZP) and drug released percentages after 0.5h (Q0.5h) and 8h (Q8h). The optimum invasomes (I1, I2 and I4) were evaluated for morphology, drug-crystallinity, and ex-vivo drug flux. The variables influencing sonophoresis of the best achieved invasomal gel system (I2) were optimized including, ultrasound frequency (low, LFU or high, HFU), mode (pulsed or continuous), application period (10 min or 15 min) and duty cycle (50% or 100%). AGM pharmacokinetics were evaluated in rabbits following transdermal application of I2-LFU-C4 system, relative to AGM oral dispersion. RESULTS: The superiority of I2 invasomes [comprising AGM and phosphatidylcholine (1:10) and limonene (1.5% w/v)] was statistically revealed with respect to EE% (78.6%), PS (313 nm), ZP (-64 mV), Q0.5h (30.1%), Q8h (92%), flux (10.79 µg/cm2/h) and enhancement ratio (4.83). The optimum sonophoresis conditions involved application of LFU in the continuous mode for 15 min at a 100% duty cycle (I2-LFU-C4 system). The latter system showed significantly higher Cmax, and relative bioavailability (≈ 7.25 folds) and a similar Tmax (0.5 h). CONCLUSION: I2-LFU-C4 is a promising transdermal system for AGM.

Ethosome-Derived Invasomes as a Potential Transdermal Delivery System for Vardenafil Hydrochloride: Development, Optimization and Application of Physiologically Based Pharmacokinetic Modeling in Adults and Geriatrics.

AIM: The aim of the current work was to develop vardenafil hydrochloride (VRD)-loaded ethosome-derived invasomes as a possible transdermal system which could be used for patients suffering from pulmonary arterial hypertension. METHODS: VRD-loaded ethosomes were developed at three concentrations of phosphatidylcholine (5, 10 and 15 mg/mL) and three percentages of ethanol (20%, 30% and 40%, v/v). The best achieved VRD-loaded ethosomes (ETH9) were optimized to invasomes via incorporation of terpenes (limonene, cineole and a 1:1 mixture) at three concentrations (0.5%, 1% and 2%, v/v). All systems were evaluated for vesicle size, zeta potential, drug entrapment efficiency (EE%), cumulative drug permeated percentages after 0.5hrs (Q0.5h) and 12hrs (Q12h) and steady-state flux (Jss). The optimized system (ETH9-INV8) was further characterized for morphology, histopathology and confocal laser scanning microscopy (CLSM). Physiologically based pharmacokinetic (PBPK) modeling was employed to estimate VRD pharmacokinetic parameters from the optimized transdermal system and an oral aqueous drug dispersion, in adults and geriatrics. RESULTS: The optimized invasomal system (ETH9-INV8) was characterized with spherical vesicles (159.9 nm) possessing negative zeta potential (-20.3 mV), promising EE% (81.3%), low Q0.5h (25.4%), high Q12h (85.3%) and the largest steady-state flux (6.4 µg.cm-2h-1). Following a leave-on period of 12hrs in rats, it showed minor histopathologic changes. CLSM studies proved its ability to deeply permeate rat skin. Lower Cmax values, delayed Tmax estimates and greater AUC0-24h folds in adults and geriatrics (≈ 2.18 and 1.69, respectively) were estimated following the transdermal application of ETH9-INV8 system. CONCLUSION: ETH9-INV8 is a promising transdermal system for VRD.

99mTc-doxorubicin-loaded gallic acid-gold nanoparticles (99mTc-DOX-loaded GA-Au NPs) as a multifunctional theranostic agent.

The development of cancer theranostic nanomedicines is recommended to concurrently achieve and evaluate the therapeutic benefit and progress. The current work aims to develop gallic acid-gold nanoparticles (GA-Au NPs) as a theranostic probe for 99mTc-Doxorubicin (99mTc-DOX) based on the spatiotemporal release pattern induced intra-tumoral (IT) delivery. DOX-loaded GA-Au NPs were developed and identified via UV-Vis spectroscopy. The system was characterized for drug loading efficiency%, particle size, zeta potential, topography, in vitro DOX release and anti-proliferative activity against the MCF-7 cell-line. The factors influencing radiolabeling efficiency of DOX with 99mTc (DOX concentration, stannous chloride concentration, reaction time and pH) were optimized. The in vitro stability in mice serum and in vivo distribution studies in mice of 99mTc-DOX-loaded GA-Au NPs were investigated following IV and IT administration. Dox-loaded GA-Au NPs had a loading efficiency of 91%, a small particle size (≈50 nm), a promising zeta potential (-20 mV) and a sustained drug release profile at pH 5.3. GA-Au NPs exhibited increased anti-proliferative activity, with approximately a four-fold lower IC50 value (0.15 µg/ml) than free DOX. The optimized radiolabeling efficiency of 99mTc-DOX was ≈93%. It showed good physiological stability in mice serum for at least 8 h. The IT delivery of 99mTc-DOX-loaded GA-Au NPs in tumor-induced mice showed dramatic tumor accumulation. A maximum magnitude of 86.73%ID/g was achieved, at 15 min post-injection, with a target/non-target ratio of ≈56. 99mTc-DOX-loaded GA-Au NPs could be used for the selective IT delivery of a chemotherapeutic agent and an imaging agent to a target organ.

Alfuzosin hydrochloride-loaded low-density gastroretentive sponges: development, in vitro characterization and gastroretentive monitoring in healthy volunteers via MRI.

The current work aimed to develop low-density gastroretentive sponges loaded with alfuzosin HCl (ALF) to sustain the rate of drug release, improve its oral bioavailability and deliver it to the main site of absorption. Sponges were developed, according to a 23 full factorial design, by compression of the lyophilized ALF-loaded hydroxypropylmethylcellulose (HPMC) or chitosan (CH) solutions. The influences of the polymer type, grade and concentration on the appearance, topography, porosity, density, in vitro ALF release, floating behavior, swelling, erosion, and mucoadhesive potential of the developed sponges were explored. Based on the desirability value, the best achieved system was selected. The gastroretentive potential of this system was evaluated in healthy male volunteers via MRI. Soft and flexible sponges were developed. They were characterized with interconnecting pores and channels and had excellent floating properties with respect to floating lag time and duration. Compared to HPMC-based sponges, CH-based ones exhibited higher porosity, larger pore diameters, lower bulk densities, higher drug release rates, larger swelling ratios, faster erosion rates and better mucoadhesive properties. MRI of magnetite-loaded best-achieved CH-based system (F8) ascertained the development of a promising gastroretentive system; exhibiting a gastric residence period of at least 5 h.

Spray-Dried Silica Xerogel Nanoparticles as a Promising Gastroretentive Carrier System for the Management of Chemotherapy-Induced Nausea and Vomiting.

PURPOSE: The current work aimed to develop spray-dried silica xerogel nanoparticles (SXNs) as a gastroretentive carrier for the dual delivery of chlorambucil (CHL) and granisetron hydrochloride (GR). As a low-density system, it was proposed to float over gastric fluids; allowing for the retention of CHL in the acidic medium where it is more stable while ensuring the solubility of GR. METHODS: Silica xerogels were developed by sol-gel process, using Tetraethyl orthosilicate (TEOS) water and acetic acid, followed by spray drying. SXNs were evaluated for particle size, zeta potential, entrapment efficiency (EE%), CHL and GR release after 1 hr (P1h) and after 8 hrs (P8h). The best achieved system (SXN4) was evaluated for morphology, pore diameter, total porosity, bulk density, wetting time, floating characteristics. Furthermore, the pharmacokinetics of the loaded drugs were evaluated in rats; relative to an aqueous CHL suspension containing GR. RESULTS: SXN4 system had the highest desirability (0.69); showing spherical nanoparticles (181.63 nm), negative zeta potential (-5.18 mV), promising EE% of 59.39% and 73.94% (for CHL and GR, respectively) and sustained CHL and GR release profiles characterized by low P1h (22.75% and 30.74%) and high P8h (60.36% and 99.33%), respectively. It had a mean pore diameter of 8.622 nm, a total porosity of 62.27%, a bulk density of 0.605 g/mL, a wetting time of 292 sec, zero lag time and a floating duration of at least 8 h. CONCLUSION: The prolongation in the mean residence time (MRT(0-∞)) and the promotion of the relative oral bioavailabilities of both drugs could unravel the potential of this system for the management of chemotherapy-induced nausea and vomiting.

QbD Approach for Novel Crosslinker-Free Ionotropic Gelation of Risedronate Sodium-Chitosan Nebulizable Microspheres: Optimization and Characterization.

Risedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate-chitosan (RS-CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic® F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett-Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 ± 3.39 mV) discrete, spherical microspheres (3.47 ± 0.16 µm) having a high EE% (94.58 ± 0.19%) and prolonged RS release over 12 h (Q12 h, 89.70 ± 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 ± 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS-CS crosslinker-free nebulizable microspheres.

Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride.

Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%) and drug released percentages after 2 h (Q2h) and 24 h (Q24h). The results were statistically analyzed, and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits, in comparison to Levitra® tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q2 h (41.45%) and Q24 h (74.05%). Compared to Levitra® tablets, the significantly (p < 0.01) delayed Tmax, prolonged MRT(0-∞) and higher relative bioavailability (3.7-fold) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability.

Lipomers (Lipid-polymer Hybrid Particles) of Vardenafil Hydrochloride: a Promising Dual Platform for Modifying the Drug Release Rate and Enhancing Its Oral Bioavailability.

Vardenafil hydrochloride is commonly used for the curing of erectile dysfunction. VAR suffers certain limitations: (i) short elimination half-life (4-5 h), (ii) low aqueous solubility (0.11 mg/mL), (iii) susceptibility to extensive first-pass metabolism and drug efflux transporters (P-glycoprotein), and (iv) limited (15%) oral bioavailability. The current study focused on the development of VAR lipomers as promising modified release systems able to enhance oral bioavailability. VAR-lipomers (lipid-polymer complexes) were successfully developed by a modified precipitation technique employing a lipid (polyglyceryl-6-distearate or glyceryl tristearate) and an amphiphilic polymer (Gantrez®). Three VAR:lipid ratios [1:1, 1:2, and 1:3] and three VAR:Gantrez® ratios [4:1, 2:1, and 1:1] were investigated. Solid-state characterization studies involved differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier-transform infrared (FT-IR) spectroscopy. The systems were assessed for particle size, polydispersity index (PDI), zeta-potential, VAR entrapment-efficiency (EE%), morphology, and VAR released % after 2 h (Q2h) and 8 h (Q8h). The best-achieved system (the highest desirability) was promoted for pharmacokinetic studies in fasted rabbits. Statistical analysis of data revealed that L9 system (PGDS, VAR, and Gantrez®; 3:1:1, respectively) had the highest desirability (0.85) with respect to spherical particle size (622.15 nm), PDI (0.11), zeta-potential (-27.90 mV), EE% (62.80%), Q2h (43.45%), and Q8h (77.40%). With respect to Levitra® tablets, the significantly higher relative bioavailability (170%), delayed Tmax, and extended MRT(0-∞) clarified the dual ability of L9 system. Lipomers are emerging systems capable of modifying the rate of VAR release and promoting its oral bioavailability.

Transdermal Delivery of Ondansetron Hydrochloride via Bilosomal Systems: In Vitro, Ex Vivo, and In Vivo Characterization Studies.

Ondansetron hydrochloride (OND) is commonly used for management of postoperative and chemotherapeutic-induced nausea and vomiting. It suffers from low bioavailability (60%) and rapid elimination (t1/2; 3-4 h). The current work aimed to develop OND-loaded bilosomes as a promising transdermal delivery system capable of surmount drug limitations. The variables influencing the development of OND-loaded bilosomes and niosomes (18 systems) via the thin film hydration technique were investigated, including surfactant type (Span®60 or Span®80), surfactant/cholesterol molar ratio (7:0, 7:1, or 7:3), and sodium deoxycholate (SDC) concentration (0, 2.5, or 5%, w/v). The systems were characterized for particle size, polydispersity index, zeta potential, drug entrapment efficiency (EE%), and in vitro permeation. Based on factorial analysis (32·21) and calculations of desirability values, six systems were further subjected to ex vivo permeation through excised rat skin, differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), and transmission electron microscopy. Histopathological and in vivo permeation studies in rats were conducted on the best achieved system (B6) in comparison to drug solution. Higher desirability values were achieved with Span® 60-based bilosomes, surfactant/cholesterol molar ratio of 7:1, and SDC concentration of 2.5% w/v with respect to small vesicle size, polydispersity index and high zeta potential, EE%, and cumulative drug permeation. OND was dispersed in amorphous state as revealed from DSC and PXRD studies. No marked effect was observed in rat skin following application of B6 system while higher ex vivo and in vivo cumulative permeation profiles were revealed. Bilosomal systems were considered as safe and efficient carriers for the transdermal delivery for OND.

Duodenum-triggered delivery of pravastatin sodium: II. Design, appraisal and pharmacokinetic assessments of enteric surface-decorated nanocubosomal dispersions.

CONTEXT: Pravastatin sodium (PVS) is a freely water-soluble HMG-CoA inhibitor that suffers from instability at gastric pH, extensive first pass metabolism, short elimination half-life (1-3 h) and low oral bioavailability (18%). OBJECTIVE: To overpower these drawbacks and to maximize drug absorption at its main site of absorption at the duodenum, enteric surface-coated PVS-loaded nanocubosomal dispersions were presented. MATERIALS AND METHODS: Glyceryl monooleate (GMO)-based dispersions were developed by the fragmentation or the liquid precursor methods using Pluronic® F127 or Cremophor® EL as surfactants. As a challenging enteric-coating approach, the promising dispersions were surface-coated via lyophilization with Eudragit® L100-55; a duodenum-targeting polymer. The drug content, particle size, zeta potential, morphology and release studies of PVS-loaded dispersions were evaluated before and after surface-coating. Compared to an aqueous PVS solution, the pharmacokinetics of the best achieved system (E-F8) was evaluated (UPLC-MS/MS) in rats. RESULTS: The enteric surface-coated nanocubosomal dispersions were more or less spherical in shape and showed high drug-loading, negative zeta potential values and fine-tuned biphasic drug-release patterns characterized by retarded (2 h) and sustained (10 h) phases in pH 1.2 and pH 6.8, respectively. E-F8 system showed significantly (p< 0.05) higher oral bioavailability, delayed Tmax and prolonged MRT0-∞ following oral administration in rats. CONCLUSIONS: The duodenum-triggering potential and the controlled-release characteristics of the best achieved system for smart PVS delivery were revealed.

Laminated sponges as challenging solid hydrophilic matrices for the buccal delivery of carvedilol microemulsion systems: Development and proof of concept via mucoadhesion and pharmacokinetic assessments in healthy human volunteers.

Carvedilol (CVD) suffers from low absolute bioavailability (25%) due to its limited aqueous solubility and hepatic first-pass metabolism. Hydroxypropyl methylcellulose (HPMC) laminated buccal sponges loaded with CVD microemulsions (CVD-ME) were exploited to surmount such limitations. Six pseudoternary-phase diagrams were constructed using Capmul® MCM C8/Capmul® PG8, Tween® 80, propylene glycol and water. Six CVD-ME systems (0.625% w/v) were incorporated into HPMC core sponges backed with Ethocel® layers. The sponges were preliminary evaluated via FT-IR, DSC and XRD. The surface pH, morphology and in vitro drug release studies were evaluated. In vivo mucoadhesion and absorption studies of the best achieved laminated sponges (F4) were assessed in healthy volunteers. CVD-ME systems displayed nano-spherical clear droplets. The sponges showed interconnecting porous matrices through which CVD was dispersed in amorphous state. No intermolecular interaction was detected between CVD and HPMC. The surface pH values were almost neutral. The sponges loaded with CVD-ME systems showed more sustained-release profiles than those loaded with CVD-powder. Compared to Dilatrend® tablets, the significantly (P<0.05) higher bioavailability (1.5 folds), delayed Tmax and prolonged MRT(0-∞) unraveled the dual-potential of F4 sponges for water-insoluble drugs, like CVD, in improving drug oral bioavailability and in controlling drug release kinetics via buccal mucosa.

Long-circulating lipoprotein-mimic nanoparticles for smart intravenous delivery of a practically-insoluble antineoplastic drug: Development, preliminary safety evaluations and preclinical pharmacokinetic studies.

Chlorambucil (CHL) is a water-insoluble antineoplastic drug having a short elimination half-life. It suffers from remarkable differences in pharmacokinetics following oral administration. The current work aimed to assess safety and pharmacokinetics of CHL-loaded, lipoprotein-mimic, nanoparticles (NPs) following intravenous administration. The design of NPs was based on complexation between egg yolk lecithin (EYL) and bovine serum albumin (BSA). The NPs were preliminary evaluated via FT-IR, DSC and P-XRD. The NPs were characterized for particle size, zeta potential, morphology and drug entrapment efficiency (EE%). The best achieved NP dispersion (LP6) and CHL solution were challenged for in vitro hemolytic potential, in vivo vascular irritation studies in rabbits and in vivo pharmacokinetics following intravenous administration in rats. The results confirmed that NPs were stabilized by hydrophobic-attractions and hydrogen-bondings between CHL, BSA and EYL. The amorphous dispersion of CHL within NPs was revealed. LP6 dispersion displayed monodispersed nano-spherical particles (144.33 ± 2.17 nm). It possessed the highest negative zeta potential (-30.55 ± 0.24 mV) and the largest EE% (86.35 ± 2.33%). The significantly (P < 0.05) prolonged MRT(0-∞), longer elimination t50% and reduced plasma clearance highlighted the long-circulating characteristics of LP6. The preliminary safety evaluations and the seven-fold increase in bioavailability elucidated potentiality for smart intravenous delivery of CHL.

Duodenum-triggered delivery of pravastatin sodium via enteric surface-coated nanovesicular spanlastic dispersions: development, characterization and pharmacokinetic assessments.

Pravastatin sodium (PVS) is a hydrophilic HMG-CoA reductase inhibitor that is mainly absorbed from duodenum. PVS has a short elimination half-life (1-3 h), suffers from instability at gastric pH, extensive hepatic first-pass metabolism and low absolute bioavailability (18%). The current work aimed to develop enteric surface-coated spanlastic dispersions as controlled-release duodenum-triggered systems able to surmount PVS drawbacks. PVS-loaded spanlastic dispersions were prepared by ethanol-injection method using span(®) 60. Tween(®) 60 and Tween(®) 80 were explored as edge activators. As a novel approach, the fine spanlastic dispersions were surface-coated with an enteric-polymer (Eudragit(®) L100-55) via freeze-drying. The systems were evaluated, before and after enteric-coating, for particle size, zeta potential, PVS entrapment efficiency (EE%), morphology and PVS release studies. PVS pharmacokinetics from the best achieved system and an aqueous solution were estimated in rats by UPLC-MS/MS. The best achieved enteric surface-coated spanlastic dispersion (E-S6) displayed spherical nanosized vesicles (647.60 nm) possessing negative zeta potential (-6.93 mV), promising EE% (63.22%) and a biphasic drug-release pattern characterized by a retarded-release phase (0.1 N HCl, 2 h) and a controlled-release phase (pH 6.8, 10 h). The higher Cmax, delayed Tmax, prolonged MRT(0-∞), longer elimination t50% and enhanced oral bioavailability unravel E-S6 potential for oral PVS delivery.

Enhancement of the Oral Bioavailability of Fexofenadine Hydrochloride via Cremophor(®) El-Based Liquisolid Tablets.

PURPOSE: The current work aimed to develop promising Fexofenadine hydrochloride (FXD) liquisolid tablets able to increase its oral bioavailability and shorten time to reach maximum plasma concentrations (Tmax). METHODS: Eighteen liquisolid powders were developed based on 3 variables; (i) vehicle type [Propylene glycol (PG) or Cremophor(®) EL (CR)], (ii) carrier [Avicel(®) PH102] to coat [Aerosil(®) 200] ratio (15, 20, 25) and (iii) FXD concentration in vehicle (30, 35, 40 %, w/w). Pre-compression studies involved identification of physicochemical interactions and FXD crystallinity (FT-IR, DSC, XRD), topographic visualization (SEM) and estimation of flow properties (angle of repose, Carr's index, Hausner's ratio). CR-based liquisolid powders were compressed as liquisolid tablets (LST 9 - 18) and evaluated for weight-variation, drug-content, friability-percentage, disintegration-time and drug-release. The pharmacokinetics of LST-18 was evaluated in healthy volunteers relative to Allegra(®) tablets. RESULTS: Pre-compression studies confirmed FXD dispersion in vehicles, conversion to amorphous form and formation of liquisolid powders. CR-based liquisolid powders showed acceptable-to-good flow properties suitable for compaction. CR-based LSTs had appropriate physicochemical properties and short disintegration times. Release profile of LST-18 showed a complete drug release within 5 min. CONCLUSION: LST-18 succeeded in increasing oral FXD bioavailability by 62% and reducing Tmax to 2.16 h.

Phenylalanine-free taste-masked orodispersible tablets of fexofenadine hydrochloride: development, in vitro evaluation and in vivo estimation of the drug pharmacokinetics in healthy human volunteers.

CONTEXT: Fexofenadine hydrochloride (FXD) is a slightly soluble, bitter-tasting, drug having an oral bioavailability of 35%. The maximum plasma concentration is reached 2.6 h (T(max)) post-dose. OBJECTIVE: Developing taste-masked FXD orodispersible tablets (ODTs) to increase extent of drug absorption and reduce Tmax. METHODS: Taste masking was achieved via solid dispersion (SD) with chitosan (CS) or sodium alginate (ALG). Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction were performed to identify physicochemical interactions and FXD crystallinity. Taste-masked FXD-ODTs were developed via addition of superdisintegrants (croscarmellose sodium or sodium starch glycolate, 5% and 10%, w/w) or sublimable agents (camphor, menthol or thymol; 10% and 20%, w/w) to FXD-SDs. ODTs were evaluated for weight variation, drug-content, friability, wetting, disintegration and drug release. Camphor-based (20%, w/w) FXD-ODT (F12) was optimized (F23) by incorporation of a more hydrophilic lubricant (Pruv(®)), visualized via scanning electron microscopy and evaluated for FXD pharmacokinetics in healthy volunteers relative to Allegra(®) tablets. RESULTS: Based on gustatory sensation test, FXD-CS (1:1) and FXD-ALG (1:0.5) SDs were selected. Taste-masked FXD-ODTs had appropriate physicochemical properties. Drug release profiles of F23 and the phenylalanine-containing Allegra(®) ODT were similar (f(2) = 96). Pores were observed following camphor sublimation. The pharmacokinetic studies proved F23 ability to increase extent of FXD absorption and reduce T(max).

Controlled-release triple anti-inflammatory therapy based on novel gastroretentive sponges: characterization and magnetic resonance imaging in healthy volunteers.

The current work aimed to develop novel composite sponges of chitosan (CH)-chondroitin sulfate (CS) as a low-density gastroretentive delivery system for lornoxicam (LOR). This triple anti-inflammatory therapy-loaded matrices are expected to expand and float upon contact with gastric fluids for prolonged times. CH and CS solutions (3%, w/w) were prepared, mixed in different ratios, lyophilized, coated with magnesium stearate and compressed. The CH:CS interpolymer complex (IPC) was evaluated via FT-IR, DSC, and XRD. The compressed-sponges were evaluated for appearance, structure, porosity, pore diameter, density, wetting-time, floating characteristics, adhesion-retention, and LOR-release. The gastroretentivity of the best achieved magnetite-loaded sponges was monitored in healthy volunteers via MRI. The interaction between CH (protonated amino groups) and CS (anionic carboxylate/sulfate groups) proved IPC formation. DSC and XRD studies confirmed loss of LOR crystallinity. The sponges possessed interconnecting porous-network structures. The porosity, mean pore diameter, and bulk density of CH:CS (10:3) IPC sponges were 11.779%, 25.4 nm, and 0.670 g/mL, respectively. They showed complete wetting within seconds, gradual size-expansion within minutes and prolonged adhesion for hours. Controlled LOR-release profiles were tailored over 12h to satisfy individual patient needs. Monitoring of sponges via MRI proved their gastroretentivity for at least 5h.

Brain targeting of olanzapine via intranasal delivery of core-shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies.

Olanzapine (OZ) is atypical antipsychotic drug that suffers from low brain permeability due to efflux by P-glycoproteins and hepatic first-pass metabolism. The current work aimed to develop OZ-loaded micellar nanocarriers and investigate their nose-to-brain targeting potential. OZ-loaded (5mg/ml) micelles (F1-F12) were prepared, using a Pluronic(®) mixture of L121 and P123, adopting thin-film hydration method. The micelles were evaluated for turbidity, particle size, morphology, drug-entrapment efficiency (EE%), drug-loading characteristics, in vitro drug release and ex vivo nasal toxicity in sheep. The in vivo biodistribution and pharmacokinetic studies in the brain/blood following intravenous (i.v.) and intranasal (i.n.) administrations of technetium-labeled OZ-loaded micelles and OZ-solution were evaluated in rats. Spherical micelles ranging in size from 18.97 to 380.70 nm were successfully developed. (1)H NMR studies confirmed OZ incorporation into micelle core. At a drug:Pluronic(®) L121:Pluronic(®) P123 ratio of 1:8:32 (F11), the micelles achieved a conciliation between kinetic and thermodynamic stability, high drug-EE%, controlled drug-release characteristics and evoked minor histopathological changes in sheep nasal mucosa. The significantly (P<0.05) higher values for F11 micelles (i.n.); brain/blood ratio (0.92), drug targeting index (5.20), drug targeting efficiency (520.26%) and direct transport percentage (80.76%) confirm the development of a promising non-invasive OZ-loaded nose-to-brain delivery system.