Therapeutic potential of cationic bilosomes in the treatment of carrageenan-induced rat arthritis via fluticasone propionate gel.

Arthritis is a debilitating disease that affects the patient's mobility and quality of life. This study focused on the development and optimization of a cationic nanosized bilosomal formula for the efficient transdermal treatment of arthritis. An optimum Fluticasone Propionate-loaded bilosomes (OFP) was developed using the Draper-Lin small composite design based on the optimization of 4 factors and evaluation of entrapment efficiency (Y1), vesicle size (Y2), skin flux (Y3), and skin accumulation (Y4). The OFP was characterized against the drug suspension, loaded into a Carbopol gel, and a histopathological assessment was conducted on a carrageenan-induced rat joint arthritis in comparison with cultivate® cream and traditional gel. Interluekin-1ß and TNF-α levels were also measured. The optimal formula was formulated using 2.99% phospholipon90G, 0.04% sodium deoxycholate, and 0.29% stearylamine, and showed 84.72%, 268.13 nm, 5.89 µg/cm2/h, and 16.21 µg/cm2 /24 h for Y1, Y2, Y3, and Y4, respectively. The thermal analysis of OFP demonstrated a single broad endothermic peak for bilosomes with no detectable peak for the amorphous drug. TEM images revealed the spherical structures of the nanosized OFP, while CLSM demonstrated enhanced permeation efficiency over the drug suspension. The in-vivo study further proved the promising efficacy of the optimum OFP, where a complete recovery of the normal histological structure of a rat joint and normal levels of the inflammatory markers were observed within 20 days following once daily application of the optimum bilosomal gel. Therefore, OFP represents a competent nanocarrier for efficient transdermal management of joint arthritis.

Trimetazidine Dihydrochloride Pulsatile-Release Tablets for the Treatment of Morning Anginal Symptoms: Dual Optimization, Characterization and Pharmacokinetic Evaluation.

OBJECTIVE: This research work aimed to target the early morning peak symptoms of chronic stable angina through formulating antianginal drug, Trimetazidine (TMZ) in a pulsatile-release tablet. METHODS: The core formulae were optimized using 22 .31 factorial design to minimize disintegration time (DT) and maximize drug release after 5 minutes (Q5min). Different ratios of Eudragit S100 and Eudragit L100 were used as a coating mixture for the selected core with or without a second coating layer of hydroxypropyl methylcellulose (HPMC E50). The different formulation variables were statistically optimized for their effect on lag time and drug release after 7 hours (Q7h) using BoxBehnken design. The optimized formula (PO) was subjected to stability study and pharmacokinetic assessment on New Zealand rabbits. RESULTS: The optimal core (F8) was found to have 1.76 min disintegration time and 61.45% Q5min PO showed a lag time of 6.17 h with 94.80% Q7h and retained good stability over three months. The pharmacokinetics study confirmed the pulsatile-release pattern with Cmax of 206.19 ng/ml at 5.33 h (Tmax) and 95.85% relative bioavailability compared to TMZ solution. CONCLUSION: Overall pulsatile-release tablets of TMZ successfully released the drug after a desirable lag time, providing a promising approach for early morning anginal symptoms relief.

Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies.

PURPOSE: Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. MATERIALS AND METHODS: Cubo-gels were prepared by 33 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubo-gel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubo-gel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. RESULTS: The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. CONCLUSION: Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.

Stabilized oral nanostructured lipid carriers of Adefovir Dipivoxil as a potential liver targeting: Estimation of liver function panel and uptake following intravenous injection of radioiodinated indicator.

PURPOSE: Adefovir dipivoxil (AD), a nucleoside reverse transcriptase inhibitor is effective against Hepatitis B virus. Its poor oral bioavailability leads to frequent administration causing severe adverse effects. Thereby the entrapment of AD within lipid nanoparticulate systems is a way of increasing AD oral bioavailability as a result of improving intestinal permeability with efficient liver-targeted delivery together with higher drug stability during storage. METHODS: AD-loaded nanostructured lipid carriers (AD-NLCs) were prepared via solvent emulsification diffusion technique adopting 24 full factorial design to study the effect of lipid percentage, presence of egg yolk lecithin, surfactant type and percentage on entrapment efficiency (E.E.%), particle size and percent in-vitro drug released after 8 h (Q8hrs). RESULTS: Formula (F12) showed E.E.% of 90.5 ± 0.2%, vesicle size of 240.2 ± 2.5 nm and Q8hrs of 58.55 ± 9.4% was selected as the optimum formula with desirability value of 0.757 based on highest EE%, lowest P.S. and Q8hrs. Further evaluation of the optimized formula using radioiodinated rose bengal (RIRB) in thioacetamide induced liver damage in Swiss Albino mice revealed a higher liver uptake of 22 ± 0.01% ID/g (percent injected dose/g organ) and liver uptake/Blood (T/B) ratio of 2.22 ± 0.067 post 2 h of I.V injection of RIRB compared to 9 ± 0.01% ID/g and 0.64 ± 0.017 in untreated group, respectively. CONCLUSION: NLCs could be successfully used as oral drug delivery carriers of the antiviral drug Adefovir Dipivoxil to the liver with higher stability and oral bioavailability. Graphical abstract.

Freeze-Dried Clopidogrel Loaded Lyotropic Liquid Crystal: Box-Behnken Optimization, In-Vitro and In-Vivo Evaluation.

BACKGROUND: Clopidogrel (CLP) suffers from extensive first pass metabolism results in a negative impact on its oral systemic bioavailability. Cubosomes are Lyotropic Liquid Crystalline (LLC) nano-systems comprising monoolein, a steric stabilizer and an aqueous system, it considered a promising carrier for different pharmaceutical compounds. Box-Behnken Design (BBD) is an efficient tool for process analysis and optimization skipping forceful treatment combinations. OBJECTIVE: The study was designed to develop freeze-dried clopidogrel loaded LLC (cubosomes) for enhancement of its oral bioavailability. METHODS: A 33 BBD was adopted, the studied independent factors were glyceryl monooleate (GMO lipid phase), Pluronic F127 (PL F127steric stabilizer) and polyvinyl alcohol powder (stabilizer). Particle Size (PS), Polydispersity Index (PDI) and Zeta Potential (ZP) were set as independent response variables. Seventeen formulae were prepared in accordance with the bottom up approach and in-vitro evaluated regarding PS, PDI and ZP. Statistical analysis and optimization were achieved using design expert software®, then the optimum suggested formula was prepared, in-vitro revaluated, freeze-dried with 3% mannitol (cryoprotectant), solid state characterized and finally packed in hard gelatin capsule for comparative in-vitro release and in-vivo evaluation to Plavix®. RESULTS: Results of statistical analysis of each individual response revealed a quadratic model for PS and PDI where a linear model for ZP. The optimum suggested formula with desirability factor equal 0.990 consisting of (200 mg GMO, 78.15 mg PL F127 and 2% PVA). LC/MS/MS study confirmed significant higher Cmax, AUC0-24h and AUC0-∞ than that of Plavix®. CONCLUSION: The results confirm the capability of developed carrier to overcome the low oral bioavailability.

UPLC/QTOF/MS profiling of two Psidium species and the in-vivo hepatoprotective activity of their nano-formulated liposomes.

Liver diseases are major health problem in Egypt influencing lifestyle and economy. The demand for nutraceutical hepatoprotective agents is crucial to ameliorate the side effects of synthetic drugs. The present study aims to evaluate antioxidant and hepatoprotective activities of extracts of Psidium guajava L. and Psidium cattleianum Sabine leaves and their nano-formulated liposomes against paracetamol-induced liver damage in rats. Secondary metabolites profile of P. guajava and P. cattleianum leaves was investigated using UPLC-PDA-ESI-qTOF-MSn. The nano-liposomes containing Psidium extracts were prepared using thin film hydration method. Biochemical analysis was based on monitoring serum levels of AST, ALT, ALP and total bilirubin. The liver homogenate was used for determination of GSH and MDA. Histopathological alterations were also studied. Metabolic profiling revealed qualitative differences between the two investigated species providing a comprehensive map for the metabolites present in P. guajava and P. cattleianum leaves cultivated in Egypt. The identified metabolites belong to different phytochemical classes; polyphenolics, flavonoids, triterpenes and meroterpenoids. Significant hepatoprotective effects were observed as evident from the decreased levels of AST, ALT, ALP, MDA and total bilirubin as well as restoration of decreased GSH level in the two studied Psidium extracts (250, 500mg/kg b. wt) and their respective nano-liposomes (500mg/kg b. wt), when compared to the diseased group. Nano-liposomes of Psidium guajava leaves (500mg/kg b. wt) greatly restored the normal architecture of the liver in the histopathological study, as regards to standard silymarin. The present study verified the effectiveness of Psidium guajava and Psidium cattleianum leaves extracts and their nano-liposomes in ameliorating the paracetamol-induced hepatotoxicity in rats.

Adefovir dipivoxil loaded proliposomal powders with improved hepatoprotective activity: formulation, optimization, pharmacokinetic, and biodistribution studies.

The present study aimed to prepare proliposomal formulae for improving the oral bioavailability of adefovir dipivoxil (AD), a nucleoside reverse transcriptase inhibitor effective against hepatitis B virus (HBV). The prepared proliposomal formulae were characterized for entrapment efficiency (E.E.%), vesicle size and in vitro drug release after reconstitution to conventional liposomes. The optimized formula (F9) with a maximum desirability value of 0.858 was selected having E.E.% of 71 ± 3.3% with an average vesicle size of 164.6 ± 5 nm. Moreover, the crystallization of AD within the optimized formula investigated via powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) confirmed the presence of the drug in an amorphous state within the lipid vesicles with enhanced stability over a storage period of 12 months. Thioacetamide-induced liver damage in rats evidenced by elevated liver enzymes was significantly improved after treatment with the optimum formula. Pharmacokinetic and biodistribution studies of formula F9 showed a higher accumulation of AD in the liver with enhanced bioavailability compared to AD suspension which highlights its potential advantage for an effective treatment of chronic HBV. Hence, proliposomal drug delivery is considered as a better choice for the oral delivery of AD.

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet.

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5 mg VNP composed of Maisine™ 35-1, Transcutol® HP, and Cremophor® EL was adsorbed on the solid carrier Aeroperl®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel®, HPMC-K4M, PVP-K30, and Lubripharm®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 32*21 full factorial design was adopted. The independent variables were: type of coating material (X1), concentration of coating solution (X2), and number of drills (X3). The dependent variables included % release at 2 h (Y1), at 4 h (Y2), and at 8 h (Y3). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.

Engineering of a novel optimized platform for sublingual delivery with novel characterization tools: in vitro evaluation and in vivo pharmacokinetics study in human.

The aim of this work was to develop a novel and more efficient platform for sublingual drug delivery using mosapride citrate (MSP) as a model drug. The engineering of this delivery system had two stages, the first stage was tuning of MSP physicochemical properties by complexation with pure phosphatidylcholine or phosphatidylinositol enriched soybean lecithin to form MSP-phospholipid complex (MSP-PLCP). Changes in physicochemical properties were assessed and the optimum MSP-PLCP formula was then used for formulation into a flushing resistant platform using two mucoadhesive polymers; sodium alginates and sodium carboxymethylcellulose at different concentrations. Design of experiment approach was used to characterize and optimize the formulated flushing resistant platform. The optimized formulation was then used in a comparative pharmacokinetics study with the market formulation in human volunteers. Results showed a marked change in MSP physicochemical properties of MSP-PLCP compared to MSP. Addition of mucoadhesive polymers to flushing resistant platform at an optimum concentration balanced between desired mucoadhesive properties and a reasonable drug release rate. The optimized formulation showed significantly a superior bioavailability in humans when compared to the market sublingual product. Finally, the novel developed sublingual flushing resistant platform offers a very promising and efficient tool to extend the use of sublingual route and widen its applications.

Ocular ketoconazole-loaded proniosomal gels: formulation, ex vivo corneal permeation and in vivo studies.

CONTEXT: Vesicular drug carriers for ocular delivery have gained a real potential. Proniosomal gels as ocular drug carriers have been proven to be an effective way to improve bioavailability and patient compliance. OBJECTIVE: Formulation and in vitro/ex vivo/in vivo characterization of ketoconazole (KET)-loaded proniosomal gels for the treatment of ocular keratitis. MATERIALS AND METHODS: The effect of formulation variables; HLB value, type and concentration of non-ionic surfactants (Tweens, Spans, Brijs and Pluronics) with or without lecithin on the entrapment efficiency (EE%), vesicle size and in vitro KET release was evaluated. An ex vivo corneal permeation study to determine the level of KET in the external eye tissue of albino rabbits and an in vivo assessment of the level of KET in the aqueous humors were performed. RESULTS AND DISCUSSION: In vivo evaluation showed an increase in bioavailability up to 20-folds from the optimum KET proniosomal gel formula in the aqueous humor compared to drug suspension (KET-SP). The selected formulae were composed of spans being hydrophobic suggesting the potential use of a more hydrophobic surfactant as Span during the formulation of formulae. Factors that stabilize the vesicle membrane and increase the entrapment efficiency of KET (namely low HLB, long alkyl chain, high phase transition temperature) slowed down the release profile. CONCLUSIONS: Proniosomal gels as drug delivery carriers were proven to be a promising approach to increase corneal contact and permeation as well as retention time in the eye resulting in a sustained action and enhanced bioavailability.

Design and evaluation of proniosomes as a carrier for ocular delivery of lomefloxacin HCl.

The current investigation aims to develop and evaluate novel ocular proniosomal gels of lomefloxacin HCl (LXN); in order to improve its ocular bioavailability for the management of bacterial conjunctivitis. Proniosomes were prepared using different types of nonionic surfactants solely and as mixtures with Span 60. The formed gels were characterized for entrapment efficiency, vesicle size, and in vitro drug release. Only Span 60 was able to form stable LXN-proniosomal gel when used individually while the other surfactants formed gels only in combination with Span 60 at different ratios. The optimum proniosomal gel; P-LXN 7 (Span 60:Tween 60, 9:1) appeared as spherical shaped vesicles having high entrapment efficiency (>80%), appropriate vesicle size (187 nm) as well as controlled drug release over 12 h. Differential scanning calorimetry confirmed the amorphous nature of LXN within the vesicles. Stability study did not show any significant changes in entrapment efficiency or vesicle size after storage for 3 months at 4 °C. P-LXN 7 was found to be safe and suitable for ocular delivery as proven by the irritancy test. The antibacterial activity of P-LXN 7 evaluated using the susceptibility test and topical therapy of induced ocular conjunctivitis confirmed the enhanced antibacterial therapeutic efficacy of the LXN-proniosomal gel compared to the commercially available LXN eye drops.

Terbinafine Hydrochloride Trans-ungual Delivery via Nanovesicular Systems: In Vitro Characterization and Ex Vivo Evaluation.

Treating a nail infection like onychomycosis is challenging as the human nail plate acts as a formidable barrier against all drug permeation. Available oral and topical treatments have several setbacks. Terbinafine hydrochloride (TBH), belonging to the allylamine class, is mainly used for treatment of onychomycosis. This study aims to formulate TBH in a nanobased spanlastic vesicular carrier that enables and enhances the drug delivery through the nail. The nanovesicles were formulated by ethanol injection method, using either Span® 60 or Span® 65, together with Tween 80 or sodium deoxycholate as an edge activator. A full factorial design was implemented to study the effect of different formulation and process variables on the prepared TBH-loaded spanlastic nanovesicles. TBH entrapment efficiency percentages, particle size diameter, percentage drug released after 2 h and 8 h were selected as dependent variables. Optimization was performed using Design-Expert® software to obtain an optimized formulation with high entrapment efficiency (62.35 ± 8.91%), average particle size of 438.45 ± 70.5 nm, and 29.57 ± 0.93 and 59.53 ± 1.73% TBH released after 2 and 8 h, respectively. The optimized formula was evaluated using differential scanning calorimetry and X-ray diffraction and was also morphologically examined using transmission electron microscopy. An ex vivo study was conducted to determine the permeation and retainment of the optimized formulation in a human cadaver nail plate, and confocal laser scanning microscope was used to show the extent of formulation permeation. In conclusion, the results confirmed that spanlastics exhibit promising results for the trans-ungual delivery of TBH.

Enhancement of lomefloxacin Hcl ocular efficacy via niosomal encapsulation: in vitro characterization and in vivo evaluation.

The aim of this study is to develop and evaluate niosomal dispersions loaded with the hydrophilic drug; lomefloxacin Hcl (LXN) for the management of ocular bacterial conjunctivitis. LXN-loaded niosomes were prepared by the thin film hydration method following a full factorial formulation design. Two independent variables were evaluated: the type of surfactant (X1) and the surfactant:cholesterol ratio (X2). The dependent variables comprised entrapment efficiency (EE%: Y1), particle size (PS: Y2) and zeta potential (ZP: Y3). The optimum formulation, N-LXN14 (Tw60: CH, 1:1), was spherical in shape and exhibited EE% of 68.41 ± 0.07, PS of 176.0 ± 0.98 and ZP of -40.70 ± 2.20 with a sustained release profile over 8 hours following the Higuchi model. N-LXN14 proved good physicochemical stability under refrigeration up to 3 months. Ocular irritancy test showed no signs of ocular toxicity, confirming the safety and suitability for ocular application. Microbiological evaluation of the antibacterial effect of N-LXN14 was conducted using the susceptibility test and through the induction of topical conjunctivitis by Staphylococcus aureus (S. aureus) followed by topical therapy. Susceptibility test manifested significantly higher percent inhibition of S. aureus and higher AUC0-12 h of N-LXN14 (604.59 ± 0.05) compared to the commercial product (126.25 ± 0.049). Both clinical observation and colony count of the infected eyes after eight days of treatment demonstrated significant improvement in therapeutic response. The infected eyes were completely healed with eradication of S. aureus. In conclusion, the results showed that LXN niosomal dispersions may serve as a promising superior ocular delivery system in the treatment of bacterial conjunctivitis.

Oro-dental mucoadhesive proniosomal gel formulation loaded with lornoxicam for management of dental pain.

Oro-dental diseases are generally associated with pain that is controlled using oral tablets containing NSAIDs. Lornoxicam, a relatively new NSAID, is effective in relieving pain accompanying different oro-dental problems. The aim of the current research is to prepare oro-dental analgesic and anti-inflammatory gel using provesicular approach to deliver lornoxicam directly to the site of action in the oral cavity. Local administration of lornoxicam is expected to be superior to systemic delivery in pain relieving and poses less GIT adverse effects. Different surfactants were utilized to prepare the proniosomal gels that rapidly transform into nano-sized niosomes after hydration with the oral saliva. The effect of the surfactant structure on vesicles size distribution and entrapment efficiency percentage (EE%) was investigated. The proniosomal formulations were incorporated into carbopol hydrogels that were characterized regarding rheological and mucoadhesion properties. Moreover, ex-vivo mucosal membrane permeation studies were conducted for selected proniosomal gels to quantify the permeation parameters and assess the amount of drug deposited within the oral mucosa. Results revealed that mucoadhesive proniosomes formulation prepared using Span 60 was optimal as it was nano-sized and also showed the highest EE%. The transmucosal flux of lornoxicam, from these proniosomal formulations, across the oral mucosa was significantly higher (p < 0.05) than lornoxicam containing carbopol gel and the percent drug diffused increased more than twofolds. The results collectively suggest that the mucoadhesive proniosomal gels can be assertively considered as a promising carrier for transmucosal delivery of lornoxicam into the oral cavity.

Silver sulfadiazine based cubosome hydrogels for topical treatment of burns: development and in vitro/in vivo characterization.

The present study is concerned with the development and characterization of a novel nanaoparticulate system; cubosomes, loaded with silver sulfadiazine (SSD), which is the metallic salt of a sulfonamide derivative, and is considered as the drug of choice for topical treatment of infected burns. Cubosome dispersions were formulated by an emulsification technique using different concentrations of a lipid phase monoolein and the nonionic surfactant, Poloxamer 407, with or without polyvinyl alcohol. The prepared cubosomal dispersions were characterized regarding physical morphology, dimensional distribution, particle size, and in vitro drug release. The optimum formulae were incorporated in a chitosan, carbopol 940 or chitosan/carbopol mixture based hydrogels, to form cubosomal hydrogels (cubogels). The cubogels were characterized regarding in vitro release of SSD, rheological properties, pH, and mucoadhesion. For the optimal cubogel formulae, an in vivo histopathological study was conducted on rats to predict the effectiveness of the newly prepared cubogels in comparison with the commercially available cream (Dermazin®). In vivo histopathological study results showed that prepared cubogels were successful in the treatment of deep second degree burn which may result in better patient compliance and excellent healing results with least side effects in comparison with the commercially available product.

Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation, in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers.

This work aimed to incorporate Dexibuprofen (DXI), the pharmacologically active and more potent form of ibuprofen, into polymeric micelles based tablets with enhanced oral bioavailability. Thin film hydration technique was employed to prepare DXI polymeric micelles using Pluronic® F127 and/or P123 solutions in different ratios (ranging from 1:1 up to 1:10). Prepared micelles were characterized regarding particle size, drug loading and entrapment efficiency. Selected formulae were lyophilized in presence of cryoprotectants and subjected to solid-state characterization as well as scanning and transmission electron microscopy. Subsequently, tablets were prepared and evaluated in-vitro regarding physical properties and drug release. An in-vivo pharmacokinetic study was performed in six healthy human volunteers in comparison to the commercially available tablet of DXI. Solid-state characterization proved that DXI was homogenously dispersed in Pluronic micelles' matrices. Formula TF5 tablets comprising lyophilized micelles (F5; DXI: Pluronic F127 in 1:1 ratio and 0.25% mannitol) showed higher Cmax and earlier tmax values than those of the commercial formula, where the relative bioavailability was calculated to be 160.15%. The experimental evidence in this research leads to the conclusion that polymeric micelles present enabling properties for oral delivery of drugs with low solubility.

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.

Self nano-emulsifying simvastatin based tablets: design and in vitro/in vivo evaluation.

The aim of this work is to improve the oral bioavailability of poorly water soluble drug, simvastatin (SV) through combining the advantages of self-nanoemulsifying systems (SNEs) and tablets. Ternary phase diagram was constructed using Labrafil, Tween 80 and Transcutol, in order to evaluate self-nanoemulsification domain. The particle size distribution and zeta potential of the prepared systems were evaluated using Malvern Zetasizer. Liquisolid powders were prepared using Aeroperl(®) as a coating material and Avicel(®) or Starch 1500 as carrier materials, the powder flow properties were then evaluated. Compressed SV SNE based tablets were evaluated regarding their physical characteristics, in-vitro release properties as well as in-vivo pharmacokinetic evaluation in six healthy human volunteers using a validated LC/MS/MS method. The in-vitro release results revealed that the developed SNE based tablets improved the release of SV significantly, compared to commercially available SV tablets (Zocor(®)). The optimal SV SNE tablet formulation was S3St10 (10% Labrafil, 60% Tween 80, and 30% Transcutol). The in-vivo evaluation of S3St10 revealed that rapid and enhanced absorption of SV could be obtained from the SNE based tablet, with a 1.5 fold increase in bioavailability than that obtained after administration of Zocor(®). Hence such an approach could be promising in improving the bioavailability of SV.

In vitro characterization and growth inhibition effect of nanostructured lipid carriers for controlled delivery of methotrexate.

The present study describes the design and characterization of nanostructured lipid carriers (NLCs) for controlled delivery of methotrexate (MTX). A series of NLCs with or without MTX were prepared using different ratios of liquid-lipid to solid-lipid and type and concentration of surfactants. The effect of different formulation parameters on the physical properties of NLCs, entrapment efficiency of MTX and in vitro drug release was evaluated. In addition, the in vitro delivery and cytotoxicity of MTX-loaded NLCs against human prostate cancer DU-145 cells and ovarian human cancer A2780 cells were investigated. Drug loading capacity, particle size and surface charge of the prepared NLCs and the in vitro MTX release were affected by the formulation parameters. In vitro growth inhibition assay using DU-145 and A2780 cancer cell lines showed that drug-free NLCs maintained cell viability while MTX-loaded NLCs inhibited the growth of both cell lines. In addition, MTX-loaded NLCs showed superior inhibitory effect on cell growth over the free drug especially in A2780 cell lines and a higher cytotoxic effect on DU-145 at higher drug concentration. The results of the current study warrant further exploration for the use NLCs as a controlled delivery system for chemotherapeutic agents.

Novel diphenyl dimethyl bicarboxylate provesicular powders with enhanced hepatocurative activity: preparation, optimization, in vitro/in vivo evaluation.

Diphenyl dimethyl bicarboxylate (DDB) is a hepatocurative agent used for treatment of various liver diseases. However, DDB therapeutic effectiveness is restricted by its low oral bioavailability that arises from its poor solubility and dissolution. Aiming at surmounting the aforementioned restrictions, DDB provesicular dry powders exemplified by proniosomes and proliposomes were prepared using film-deposition technique employing sorbitol as a carrier. Upon dilution with water, the provesicular powders rapidly transformed into vesicular dispersions, either liposomes or niosomes, which were characterized regarding their percent encapsulation efficiency (EE%), vesicle size and distribution, morphology and in vitro drug release. The revealed optimal provesicular powder was exposed to solid state characterization, stability testing and in vivo performance evaluation. Results showed that provesicular powders with acceptable flowability can be prepared using a weight ratio of lipids mixture to sorbitol of 1:20. Proniosomal powder composed of Tween 80:cholesterol:stearylamine in molar ratio 7:3:0.5 loaded on sorbitol was selected as the optimal formulation as it showed the highest EE% and dissolution enhancement for DDB. The elevated levels of liver enzymes in hepatically injured Albino Wister rats were significantly reduced (P<0.05) after oral administration of the optimal proniosomal powder in comparison to free DDB. This improvement was confirmed histopathologically by minimizing the associated hepatic injury. Accordingly, proniosomes can be assertively considered as a promising stable precursor for immediate preparation of niosomal carrier for DDB with enhanced dissolution and hepatocurative activity.