Fabrication and optimization of itraconazole-loaded zein-based nanoparticles in coated capsules as a promising colon-targeting approach pursuing opportunistic fungal infections.

Itraconazole (ITZ), a broad-spectrum antifungal drug, was formulated into colon-targeting system aiming to treat opportunistic colonic fungal infections that commonly infect chronic inflammatory bowel diseases (IBD) patients due to immunosuppressive therapy. Antisolvent precipitation technique was employed to formulate ITZ-loaded zein nanoparticles (ITZ-ZNPs) using various zein: drug and aqueous:organic phase ratios. Central composite face-centered design (CCFD) was used for statistical analysis and optimization. The optimized formulation was composed of 5.5:1 zein:drug ratio and 9.5:1 aqueous:organic phase ratio with its observed particle size, polydispersity index, zeta potential, and entrapment efficiency of 208 ± 4.29 nm, 0.35 ± 0.04, 35.7 ± 1.65 mV, and 66.78 ± 3.89%, respectively. ITZ-ZNPs were imaged by TEM that revealed spherical core-shell structure, and DSC proved ITZ transformation from crystalline to amorphous form. FT-IR showed coupling of zein NH group with ITZ carbonyl group without affecting ITZ antifungal activity as confirmed by antifungal activity test that showed enhanced activity of ITZ-ZNPs over the pure drug. Histopathological examination and cytotoxicity tests ensured biosafety and tolerance of ITZ-ZNPs to the colon tissue. The optimized formulation was then loaded into Eudragit S100-coated capsules and both in vitro release and in vivo X-ray imaging confirmed the success of such coated capsules in protecting ITZ from the release in stomach and intestine while targeting ITZ to the colon. The study proved that ITZ-ZNPs is promising and safe nanoparticulate system that can protect ITZ throughout the GIT and targeting its release to the colon with effectual focused local action for the treatment of colon fungal infections.

Dissolution enhancement of olmesartan medoxomil through polymer-based surface solid dispersion and solidified surfactant techniques.

This study aims to formulate Olmesartan medoxomil (OM) into oral fast-dissolving tablets (FDTs) to improve its solubility and bioavailability via two different techniques; The polymer-based surface solid dispersion (SSD) technique and the solidified surfactant (SS) technique. In the first technique, two polymers were used; polyvinylpyrrolidone (PVP K90) and Poloxamer 407 (Pluronic®F127), while in the second technique the liquid Tween 80 was solidified by adsorption onto Aeroperl®300. The pre-compression and post-compression parameters of the obtained formulations were assessed. The best formulations were subjected to a taste masking evaluation and a short-term stability study. The results demonstrated that, in comparison to the pure drug, the proportion of drug released from each of the prepared FDTs considerably increased. Results of the stability studies showed that the chosen drug formulations remained stable throughout the storage period.

Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide.

Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper-Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y1), zeta potential (Y2), drug entrapment efficiency (Y3), and the cumulative drug release after 24 h (Y4) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles' spherical shape with bilayer structure. Values of dependent variables were 748.6 nm, -48.60 mV, 72.8% and 72.2% for Y1, Y2, Y3 and Y4, respectively. The optimized FLT-loaded niosomes exerted high cytotoxic efficacy against human prostate cancer cell line (PC-3) with an IC50 value of 0.64 ± 0.04 µg/mL whilst, it was 1.88 ± 0.16 µg/mL for free FLT. Moreover, the IC50 values on breast cancer cell line (MCF-7) were 0.27 ± 0.07 µg/mL and 4.07 ± 0.74 µg/mL for FLT-loaded niosomes and free FLT, respectively. The permeation of the optimized FLT-loaded niosomes through the rabbit intestine showed an enhancement ratio of about 1.5 times that of the free FLT suspension. In vivo pharmacokinetic study displayed an improvement in oral bioavailability of the optimized niosomal formulation with AUC and Cmax values of 741.583 ± 33.557 µg/mL × min and 6.950 ± 0.45 µg/mL compared to 364.536 ± 45.215 µg/mL × min and 2.650 ± 0.55 µg/mL for the oral FLT suspension. With these promising findings, we conclude that encapsulation of FLT in cholesterol-loaded nanovesicles enhanced its anticancer activity and oral bioavailability which endorse its use in the management of prostate cancer.

Development and optimization of osmotically controlled drug delivery system for poorly aqueous soluble diacerein to improve its bioavailability.

In an attempt to improve the low oral bioavailability of Diacerein (DCN), the combination of a ternary solid dispersion and an asymmetric osmotic pump system had been designed to enhance solubility and to control DCN delivery. Ternary DCN solid dispersion was prepared by melting fusion method using surfactant polymers, and carrier (Pluronic® PF127, Solutol® HS15, and PEG 35 K) and this DCN solid dispersion powder with the proper amount of excipients were compressed and coated with Opadry®CA to develop a Semi-Permeable and Asymmetric Osmotic Pump tablets. The ternary DCN solid dispersion by using surfactant polymers (Pluronic® F127 and Solutol® HS 15) with a ratio of 1:1 was displayed market significant improvement in saturated solubility (70.2 ± 4.14 µg/ml) and fast dissolution rate (Q60min = 79.28 ± 3.1% and IDR5 min = 5.25 ± 0.19 ml/min) in comparison to pure DCN. Moreover, the optimized asymmetric osmotic pump tablet with following parameters; 3% w/v Opadry® CA coat concentration, 1% w/w HPMC E15 gelling polymer and 35.8%w/w NaCl Osmogen concentration, was displayed control release of DCN at zero-order kinetic (R2 = 0.977) for up to 24 h(s). The in-vivo study conducted on rabbits was revealed a significant enhancement in the bioavailability of the optimized osmotic pump (28.84 ± 3.32 ng.hr/ml) compared to DCN dispersion (10.39 ± 1.45 ng.hr/ml). In conclusion, the approach of enhancing solubility and wet-ability in accompany with optimized asymmetric osmotic pump system could serve as a promising delivery system and a way to improve the bioavailability of poorly aqueous soluble drugs.

Enhancement of pharmacokinetic and pharmacological behavior of ocular dorzolamide after factorial optimization of self-assembled nanostructures.

Dorzolamide hydrochloride is frequently administered for the control of the intra-ocular pressure associated with glaucoma. The aim of this study is to develop and optimize self-assembled nanostructures of dorzolamide hydrochloride and L-α-Phosphatidylcholine to improve the pharmacokinetic parameters and extend the drug pharmacological action. Self-assembled nanostructures were prepared using a modified thin-film hydration technique. The formulae compositions were designed based on response surface statistical design. The prepared self-assembled nanostructures were characterized by testing their drug content, particle size, polydispersity index, zeta potential, partition coefficient, release half-life and extent. The optimized formulae having the highest drug content, zeta potential, partition coefficient, release half-life and extent with the lowest particle size and polydispersity index were subjected to further investigations including investigation of their physicochemical, morphological characteristics, in vivo pharmacokinetic and pharmacodynamic profiles. The optimized formulae were prepared at pH 8.7 (F5 and F6) and composed of L-α-Phosphatidylcholine and drug mixed in a ratio of 1:1 and 2:1 w/w, respectively. They showed significantly higher Cmax, [Formula: see text] and [Formula: see text] at the aqueous humor with extended control over the intra-ocular pressure, when compared to the marketed product; Trusopt®. The study introduced novel and promising self-assembled formulae able to permeate higher drug amount through the cornea and achieve sustained pharmacological effect at the site of action.

Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation.

The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25-68%), water (2-3%), and the mixture of surfactant and cosurfactant (1:1) (24-67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1: 1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p < 0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa.

Topical Delivery of Fenoprofen Calcium via Elastic Nano-vesicular Spanlastics: Optimization Using Experimental Design and In Vivo Evaluation.

The aim of this study was to investigate the potential of surfactant-based nanovesicular system (spanlastics) for topical delivery of fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. FPCa-loaded spanlastics were prepared by thin film hydration (TFH) technique according to a full factorial design to investigate the influence of formulation variables on the drug entrapment efficiency (%EE), particle size (PS), deformability index (DI), and the % drug released after 24 h through the cellulose membrane (Q24h) using Design-Expert® software. The optimized formula (composed of Span 60 and Tween 60 as an edge activator at weight ratio of 8: 2 in presence of Transcutol P as a cosolvent in the hydration media) exhibited the highest %EE (49.91 ± 2.60%), PS of 536.1 ± 17.14 nm, DI of 5.07 ± 0.06 g, and Q24h of 61.11 ± 2.70%; it was also characterized for morphology and physical stability. In vitro release study of FPCa-loaded spanlastic gel and conventional FPCa gel through a synthetic membrane and hairless rat skin were evaluated. The skin permeation study revealed that spanlastic gel exhibited both consistent and prolonged action. Finally, the % inhibition of carrageenan-induced rat paw edema of spanlastic gel was three times higher than the conventional FPCa gel after 24 h. In conclusion, spanlastic-based gel could be a great approach for improving topical delivery of fenoprofen calcium, providing both prolonged and enhanced anti-inflammatory activity in the treatment of arthritis.

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability.

OBJECTIVE: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients. METHODS: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems. RESULTS: The optimum formulations were composed of different ratios of Capryol™ 90 as an oil phase, Cremophor® RH40 as a surfactant, and Transcutol® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19 nm and emulsification time not exceeding 1 min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6-2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies. CONCLUSIONS: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits.

OBJECTIVE: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability. METHODS: Liquid SNEDDS (L-SNEDDS) composed of Capryol™ 90 (oil), Cremophor® RH40 (surfactant), and Transcutol® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits. RESULTS: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in tmax, AUC(0-12), and AUC(0-∞) at p < .05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product. CONCLUSIONS: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.

Insecticidal properties of essential oils against Tribolium castaneum (Herbst) and their inhibitory effects on acetylcholinesterase and adenosine triphosphatases.

Essential oils from 20 Egyptian plants were obtained by using hydrodistillation. The chemical composition of the isolated oils was identified by gas chromatograph/mass spectrometer. Fumigant and contact toxicities of the essential oils were evaluated against the adults of Tribolium castaneum. In fumigation assays, the oil of Origanum vulgare (LC50 = 9.97 mg/L air) displayed the highest toxicity towards the adults of T. castaneum. In contact assays, the oils of Artemisia monosperma (LC50 = 0.07 mg/cm(2)) and O. vulgare (LC50 = 0.07 mg/cm(2)) were the most potent toxicants against the adults of T. castaneum. Biochemical studies showed that the tested oils caused pronounced inhibition of acetylcholinesterase (AChE) and adenosine triphosphatases (ATPases) isolated from the larvae of T. castaneum. The oil Cupressus macrocarpa (IC50 = 12.3 mg/L) was the most potent inhibitor of AChE, while the oil of Calistemon viminals (IC50 = 4.4 mg/L) was the most potent inhibitor of ATPases.

Content uniformity testing: suitability of different approaches for marketed low dose tablets.

CONTEXT: Content uniformity (CU) testing was developed and improved to control the effectiveness and safety of dosage units. Many modifications of compendial CU test have been introduced and several alternatives have been suggested. OBJECTIVES: This study aims to evaluate the degree of suitability of current USP CU test for low dose tablets and to compare the performance of the current test with that of the former USP27-NF22 and other alternatives for different sample sizes. METHODS: All locally marketed risperidone (RSP) tablets were analyzed using newly developed and validated isocratic UPLC method. The CU results were statistically analyzed in groups with sample sizes comparable to the USP sampling plans. RESULTS: Seven out of eleven products failed the different requirements of the former and current USP <905>chapters as well as of several alternative CU tests with several substantial deviations. CONCLUSION: The current USP <905> chapter was found to have some deficiencies that allowed such failed products to exist in the market. The dependence of compendial CU test on two-staged sampling plan and the use of arithmetic mean to calculate the reference and acceptance values were obvious shortcomings.

Effect of formulation parameters on the preparation of superporous hydrogel self-nanoemulsifying drug delivery system (SNEDDS) of carvedilol.

The purpose of this study was to formulate a superporous hydrogel (SPH) containing carvedilol self-nanoemulsifying drug delivery system. Effects of formulation parameters (amount of SPH and 0.1 N HCl used during drug loading) were studied in 3(2) factorial design. Response surface plots showed significant effect of the parameters on hydrogel swelling, carvedilol content, and carvedilol in vitro release. Regression equations were generated to calculate the desirable responses.

Fumigant and contact toxicities of monoterpenes to Sitophilus oryzae (L.) and Tribolium castaneum (Herbst) and their inhibitory effects on acetylcholinesterase activity.

A comparative study was conducted to assess the contact and fumigant toxicities of eleven monoterpenes on two important stored products insects--, Sitophilus oryzae, the rice weevil, and Tribolium castaneum, the rust red flour beetle. The monoterpenes included: camphene, (+)-camphor, (-)-carvone, 1-8-cineole, cuminaldehyde, (L: )-fenchone, geraniol, (-)-limonene, (-)-linalool, (-)-menthol, and myrcene. The inhibitory effect of these compounds on acetylcholinesterase (AChE) activity also was examined to explore their possible mode(s) of toxic action. Although most of the compounds were toxic to S. oryzae and T. castaneum, their toxicity varied with insect species and with the bioassay test. In contact toxicity assays, (-)-carvone, geraniol, and cuminaldehyde showed the highest toxicity against S. oryzae with LC(50) values of 28.17, 28.76, and 42.08 microg/cm(2), respectively. (-)-Carvone (LC(50) = 19.80 microg/cm(2)) was the most effective compound against T. castaneum, followed by cuminaldehyde (LC(50) = 32.59 microg/cm(2)). In contrast, camphene, (+)-camphor, 1-8-cineole, and myrcene had weak activity against both insects (i.e., LC(50) values above 500 microg/cm(2)). In fumigant toxicity assays, 1-8-cineole was the most effective against S. oryzae and T. castaneum (LC(50) = 14.19 and 17.16 mg/l, respectively). Structure-toxicity investigations revealed that (-)-carvone--, a ketone--, had the highest contact toxicity against the both insects. 1-8-Cineole--, an ether--, was the most potent fumigant against both insects. In vitro inhibition studies of AChE from adults of S. oryzae showed that cuminaldehyde most effectively inhibited enzyme activity at the two tested concentrations (0.01 and 0.05 M) followed by 1-8-cineole, (-)-limonene, and (L)-fenchone. 1-8-Cineole was the most potent inhibitor of AChE activity from T. castaneum larvae followed by (-)-carvone and (-)-limonene. The results of the present study indicate that (-)-carvone, 1,8-cineole, cuminaldehyde, (L)-fenchone, and (-)-limonene could be effective biocontrol agents against S. oryzae and T. castaneum.

Preparation and evaluation of self-nanoemulsifying tablets of carvedilol.

The purpose of this study was to combine the advantages of self-nanoemulsifying drug delivery systems and tablets as a conventional dosage form emphasizing the excipients' effect on the development of a new dosage form. Systems composed of HCO-40, Transcutol HP, and medium-chain triglyceride were prepared. Essential properties of the prepared systems regarding carvedilol solubility, a model drug, and self-emulsification time were determined. In order to optimize self-nanoemulsifying drug delivery systems (SNEDDS), formulation dispersion-drug precipitation test was performed in the absence and presence of cellulosic polymers. Furthermore, SNEDDS was loaded onto liquisolid powders. P-glycoprotein (P-gp) activity of the selected SNEDDS was tested using HCT-116 cells. Carvedilol showed acceptable solubility in the selected excipients. It also demonstrated improvement in the stability upon dilution with aqueous media in the presence of cellulosic polymers. Use of granulated silicon dioxide improved the physical properties of liquisolid powders containing SNEDDS. It improved the compressibility of the selected powders and the tested SNEDDS showed marked P-gp inhibition activity. Prepared self-nanoemulsifying tablet produced acceptable properties of immediate-release dosage forms and expected to increase the bioavailability of carvedilol.

Optimization of chlorphenesin emulgel formulation.

This study was conducted to develop an emulgel formulation of chlorphenesin (CHL) using 2 types of gelling agents: hydroxypropylmethyl cellulose (HPMC) and Carbopol 934. The influence of the type of the gelling agent and the concentration of both the oil phase and emulsifying agent on the drug release from the prepared emulgels was investigated using a 2(3) factorial design. The prepared emulgels were evaluated for their physical appearance, rheological behavior, drug release, antifungal activity, and stability. Commercially available CHL topical powder was used for comparison. All the prepared emulgels showed acceptable physical properties concerning color, homogeneity, consistency, spreadability, and pH value. They also exhibited higher drug release and antifungal activity than the CHL powder. It was found that the emulsifying agent concentration had the most pronounced effect on the drug release from the emulgels followed by the oil phase concentration and finally the type of the gelling agent. The drug release from all the emulgels was found to follow diffusion-controlled mechanism. Rheological studies revealed that the CHL emulgels exhibited a shear-thinning behavior with thixotropy. Stability studies showed that the physical appearance, rheological properties, drug release, and antifungal activity in all the prepared emulgels remained unchanged upon storage for 3 months. As a general conclusion, it was suggested that the CHL emulgel formulation prepared with HPMC with the oil phase concentration in its low level and emulsifying agent concentration in its high level was the formula of choice since it showed the highest drug release and antifungal activity.