Ahmed Elshafeey

AbstractAgomelatine (AGM) is an antidepressant drug with a low absolute bioavailability due to the hepatic first pass metabolism. AGM-loaded solid lipid nanoparticles were formulated in the form of an in situ gel to prolong the intranasal retention time and subsequently to increase the absorbed amount of AGM. The optimized in situ gel formula had a sol?gel transition temperature of 31?°C?±?1.40, mucociliary transport time of 27?min ±1.41%, released after 1 and 8?h of 46.3%?±?0.85 and 70.90%?±?1.48. The pharmacokinetic study of the optimized in situ gel revealed a significant increase in the peak plasma concentration, area under plasma concentration versus time curve and absolute bioavailability compared to that of the oral suspension of Valdoxan? with the values of 247?±?64.40?ng/mL, 6677.41?±?1996?ng.min/mL, and 37.89%, respectively. It also gave drug targeting efficiency index of 141.42 which revealed more successful brain targeting by the intranasal route compared to the intravenous route and it had direct transport percent index of 29.29 which indicated a significant contribution of the direct nose to brain pathway in the brain drug delivery.

Acyclovir (ACV)-Eudragit (EUD) nanoparticles (NPs) were prepared using both EUD RS 100 and RL 100 with different charge density. The effect of charge intensity on particle size, encapsulation efficiency, and in vitro dissolution was assessed. The bioavailability of ACV NP colloids were evaluated in human volunteers, compared with commercial product using a validated LC-MS/MS method with a lower limit of quantification (LLOQ) of 0.02 μg/ml. EUD RL 100 with higher ammonium groups gave smaller NPs than EUD RS 100. The surface charge of the polymer did not affect encapsulation efficiency and in vitro dissolution. In human volunteers, both F2 and F5 colloidal nanosuspensions prepared with EUD RS and RL respectively in drug to polymer ratio 1:3 sustained the oral absorption of ACV, expressed by the significant lower Cmax, significant delayed Tmax and the significant higher HV Dt 50 % Cmax. The mean Cmax of F2, F5, and Zovirax® were 0.61 ± 0.06, 0.73 ± 0.07 and 0.92 ± 0.21 μg/ml respectively. Furthermore, the AUC0-12 of F2 and F5 was significantly higher than that of Zovirax® with values of 4.37 ± 0.88, 5.14 ± 0.87 and 3.21 ± 0.53 μg/ml h respectively. The higher AUC0-12 for both F2 and F5 reflected high relative bioavailability of 136.2% and 159.9% respectively compared to commercial ACV tablets. © 2009 Elsevier B.V. All rights reserved.

Objectives The purpose of this study was to develop an injectable depot liposphere delivery system with high loading capacity for controlled delivery of donepezil to decrease dosing frequency and increase patient compliance. Methods A 32 full factorial design was employed to study the effect of lipid type and drug-to-lipid ratio on the yield, encapsulation efficiency, mean diameter and the time required for 50% drug release (t50%). The pharmacokinetic behaviour of the lipospheres in rabbits was studied using tandem mass spectrometry. Key findings The yields of preparations were in the range of 66.22-90.90%, with high encapsulation efficiencies (89.68-97.55%) and mean particle size of 20.68-35.94 μm. Both lipid type and drug-to-lipid ratio significantly affected t50% (P < 0.0001), where the lipids can be arranged: glyceryl tripalmitate > compritol > cetyl alcohol, and the drug-to-lipid ratios can be arranged: 1: 40 > 1: 20 > 1: 10. The flow time of lipospheres through 19-gauge syringe needle was less than 6 s indicating good syringeability. The mean residence time of the subcutaneous and intramuscular lipospheres was significantly higher than the solution (almost 20 fold increase), with values of 11.04, 11.34 and 0.53 days, respectively (P < 0.01). Conclusion Subcutaneous and intramuscular delivery of donepezil glyceryl tripalmitate lipospheres achieves depot release, allowing less frequent dosing. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Bilosomes are innovative vesicular carriers containing bile salt with a non-ionic surfactant. Being highly flexible, bilosomes can squeeze themselves through the skin carrying the drug to the action site and improving its skin penetration. The objective of this research was to encapsulate niflumic acid (NA), a non-steroidal anti-inflammatory drug into Brij® integrated bilosomes (BIBs) for effective treatment of osteoarthritis through transdermal delivery. BIBs were formulated using 100 mg of Span 20 with different amounts of sodium cholate (NaC), sodium taurocholate (NaTC), or sodium glycocholate (NaGC) as bile salt, with the addition of 5 mg of Brij-93 or Brij-35. BIBs were prepared utilizing ethanol injection method with the application of (31 × 22) complete factorial design using Design-Expert® software. The optimal BIBs formulation determined was (B5) which contains 5 mg of NaTC used as bile salt and 5 mg of Brij-93. B5 exhibited entrapment efficiency% = 95.21 ± 0.00%, particle size = 373.05 ± 0.07 nm, polydispersity index = 0.27 ± 0.01, and zeta potential = –32.00 ± 0.00 mV. It also had a high elasticity with a spherical shape. B5 gel displayed a sustained release profile with a significantly 2.3 folds’ higher drug permeation percent across rat skin than that permeated from NA gel. Moreover, in vivo anti-osteoarthritic and histopathological studies assured the efficacy and safety of B5 gel and its superiority over NA gel. Generally, the outcomes confirmed the great efficacy of NA loaded BIBs for the topical treatment of osteoarthritis. © 2023 Elsevier B.V.

This study aimed to formulate and statistically optimize cubosomal formulations loaded with voriconazole to enhance and control its ocular bioavailability. The independent variables of the employed central composite face-centered design were the percentages of monoolein and Pluronic F127. Particle size, zeta potential, drug content, entrapment efficiency and drug release parameters were adopted as dependent responses. The conducted factorial analysis resulted in an optimum formulation composed of 15% monoolein and 1.2% Pluronic F127. The optimum cubosomal formulation showed well-dispersed vesicles with a particle size of 160 nm and a relatively high drug loading (0.81%). Then, it was coated with chitosan to further enhance its precorneal residence time. The chitosan-coated formulation showed high mucoadhesive properties, in addition to being safe and biocompatible. Moreover, it showed higher Cmax, Tmax, AUC(0-8), AUC(0-∞), MRT, T1/2 and HVDt50%Cmax when compared to voriconazole suspension. It showed also higher concentration in the vitreous humor when compared to the drug suspension which indicates deeper penetration into the ocular tissue. Finally, the chitosan-coated optimum cubosomal formulation could be considered an efficient ocular nanocarrier for voriconazole.

Famotidine is a potent H2-receptor antagonist most commonly used by elderly patients. Orodispersible tablets (ODT) are gaining popularity over conventional tablets due to their convenience and suitability for patients having dysphagia. The purpose of this study is to prepare famotidine ODT using the economic direct-compression method. A 32 full factorial design was used to evaluate the influence of different excipients on the properties and in vitro dissolution of famotidine ODT. Two factors were studied for their qualitative effects, namely, disintegrants and diluents. Disintegrants were studied in three levels viz. Ac-Di-Sol, sodium starch glycolate (Primojel) and low-substituted hydroxypropyl cellulose (L-HPC). Fillers were studied in three levels viz. mannitol, spray dried lactose and Avicel PH 101. The ODTs were prepared by direct compression and were evaluated for hardness, drug content, uniformity of weight, in vitro disintegration time, oral disintegration time, wetting time and in vitro dissolution. Maximum dissolution and minimum oral disintegration time (11.4 s) were observed in F7 prepared using L-HPC and mannitol. Furthermore, in human volunteers it showed significant increase in bioavailability compared to Servipep® with mean AUC(0-∞) 117.1 ng/ml and 82.71 ng/ml, respectively, and its relative bioavailability was 141.57%. Hence, ODT (F7) could possibly be used to overcome the drawbacks of conventional famotidine tablets in elderly patients with significant increase in oral bioavailability. © 2009 Elsevier Ltd. All rights reserved.

The aim of this study was to evaluate the bioavailability of two aripiprazole tablets, coprecipitate (CP) and nanoparticles (NP) when compared to the market tablets. A single-dose, randomized, three period crossover design under fasting conditions in healthy human volunteers was studied. The dissolution rate of the CP, NP and market tablets was determined. In order to investigate the feasibility of in vitro data as a tool for predicting in vivo results, two types of in vitro-in vivo correlation (IVIVC), level C and multiple level C, were studied. Almost 75% of aripiprazole was dissolved from the nanoparticles tablets within 10 minutes compared with 20% and 46% for coprecipitate and market tablets, respectively. The mean AUC 0-72 value of aripiprazole from the NP tablets (6136.35 ± 421.29 ng.hr/mL) was significantly higher than both CP tablets (3216.12 ± 525.02 ng.hr/mL) and market tablets (5215.57 ± 457.28 ng.hr/mL) (p d" 0.05). The relative bioavailability of aripiprazole after oral administration of the CP and NP tablets was 61.66% and 117.65%, respectively. The higher dissolution rate of NP tablets resulted in rapid absorption of aripiprazole and consequently higher bioavailability. Multiple level C IVIVC showed the bioequivalence of NP and bioinequivalence of the CP tablets in comparison to market tablets.

Famotidine HCl has low bioavailability (40-45%) due to its narrow absorption window and low solubility in intestinal pH. Lipids were utilized in the formulation of novel gastroretentive dosage forms to increase the availability of famotidine HCl at its absorption site. Novel non-swellable gastroretentive lipid disks (D) and swellable compression coated tablets with a lipid core (T) were prepared. Formulae were characterized by friability testing, in-vitro buoyancy, in-vitro drug release and scanning electron microscopy (SEM). Factorial designs of 22× 31 and 32 were planned for the optimization of disks and tablets, respectively, using Design-Expert® software. X-ray imaging was used for the in-vivo visualization of the selected formula in human gastrointestinal tract (GIT). Moreover, a bioavailability study was performed in healthy human volunteers using the optimized disk formula (D10). Results showed that formulae D10 (containing stearyl alcohol and polyethylene glycol in a ratio of 9:1 w/w) and T7 (containing polyethylene oxide only) had highest desirability values (0.684 and 0.842, respectively). Lipids achieved instantaneous floating and sustained the release of famotidine HCl over a prolonged period of time with significant bioavailability enhancement.

Lipotomes were designed to enhance lacidipine's oral bioavailability by improving its solubility and enhancing the oral lymphatic uptake. Lipotomes were prepared using cetyl alcohol and Tween® 80 using a thin film hydration technique. Cetyl alcohol was chosen for imparting a lipophilic environment that would enforce the lymphatic uptake while Tween® 80 would improve drug solubility within the lipotomes. Lipotomes were characterized by analyzing their particle size, solubilization efficiency and in-vitro drug release. Central composite design was applied to statistically optimize the formulations using Design-Expert® software. The optimum formula (OLT) was made up of excipients:drug ratio of 36.59:1 w/w and Tween® 80:cetyl alcohol ratio of 4:1 w/w. OLT was lyophilized and filled into Eudragit® L100 enteric coated capsules. Mannitol (10% w/v) was the ideal cryoprotectant to retain the physicochemical characteristics of the OLT formulation after lyophilization. In conclusion, the selected lyophilized formula (L3) succeeded in enhancing drug's oral bioavailability in human volunteers compared to the commercial product confirming the success of lipotomes as a novel oral nanocarrier for insoluble drugs having extensive first pass metabolism. © 2014 Elsevier B.V.

Background: Favipiravir is an antiviral drug that was recently approved for the management of COVID-19 infection. Aim: This work aimed to develop a new method, using sugaring-out induced homogeneous liquid-liquid microextraction followed by HPLC/UV for the determination of favipiravir in human plasma. Materials & methods: The optimum extraction conditions were attained using 500 μl of tetrahydrofuran as an extractant and 1400 mg of fructose as a phase-separating agent. Results: The developed method was validated according to the US FDA bioanalytical guidelines and was found linear in the range of 25-80,000 ng/ml with a correlation coefficient of 0.999. Conclusion: These results showed that the developed method was simple, easy, valid and adequately sensitive for determination of favipiravir in plasma for bioequivalence studies. © 2022 Newlands Press.

The purpose of this study was to develop and characterize a successful colloidal soft nano-carrier viz. microemulsion system, for the transdermal delivery of an angiotensin II receptor blocker: olmesartan medoxomil. Different microemulsion formulations were prepared. The microemulsions were characterized visually, with the polarizing microscope, and by photon correlation spectroscopy. In addition, the pH and conductivity (σ) of the formulations were measured. The type and structure of microemulsions formed were determined using conductivity measurements analysis, Freezing Differential Scanning Calorimetry (FDSC) and Diffusion-Ordered Spectroscopy (DOSY). Alterations in the molecular conformations of porcine skin were determined using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) biophysical assessment. Olmesartan medoxomil delivery from the investigated formulations was assessed across porcine skin ex-vivo using Franz diffusion cells; the drug was analyzed by liquid chromatography mass spectroscopy (LC/MS/MS). A comparative pharmacokinetic study was done on healthy human subjects between the selected microemulsion and the commercial oral tablets. The physico-chemical and spectroscopic methods revealed the presence of water-in-oil and bicontinuous structures. Biophysical assessment demonstrated various stratum corneum (SC) changes. Olmesartan medoxomil was delivered successfully across the skin with flux achieving 3.65 μg cm-2 h-1. Higher bioavailability compared to commercial oral tablets with a more sustainment behavior was achieved. © 2012 Elsevier B.V. All rights reserved.

AbstractA new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.

The aim of this study was to investigate the influence of the nanocarrier surface charge on brain delivery of a model hydrophilic drug via the nasal route. Anionic and cationic nanostructured lipid carriers (NLCs) were prepared and optimized for their particle size and zeta potential. The optimum particles were incorporated in poloxamer in situ gels and their in vivo behavior was studied in the plasma and brain after administration to rats. Optimum anionic and cationic NLCs of size <200 nm and absolute zeta potential value of ≈34 mV were obtained. Toxicity study revealed mild to moderate reversible inflammation of the nasal epithelium in rats treated with the anionic NLCs (A7), and destruction of the lining mucosal nasal epithelium in rats treated with the cationic NLCs (C7L). The absolute bioavailability of both drug loaded anionic and cationic NLCs in situ gels was enhanced compared to that of the intranasal solution (IN) of the drug with values of 44% and 77.3%, respectively. Cationic NLCs in situ gel showed a non significant higher Cmax (maximum concentration) in the brain compared to the anionic NLCs in situ gel. Anionic NLCs in situ gel gave highest drug targeting efficiency in the brain (DTE%) with a value of 158.5 which is nearly 1.2 times that of the cationic NLCs in situ gel. © 2014 Elsevier B.V.

AbstractThe 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.

The pharmacokinetic and bioavailability of fenoterol, a B2 adrenergic agonist were studied to determine the feasibility of enhanced transdermal delivery. Fenoterol has been widely used to treat asthmatic patients. Two fenoterol formulations were studied; the first was a liquid formulation of fenoterol in Transcutol: Oleic acid in a ratio 1:1(F1), while the second was a matrix system of fenoterol in Duro-tak® 87-2074 adhesive with 10% 1-dodecyl-2-pyrrolidinone as an enhancer (F2). For comparison, control matrix with fenoterol without any enhancer (F3) was also tested. The tested formulations were applied to the shaved back skin of rabbits using HILL TOP CHAMBER® in case of liquid formula. Blood samples were collected via auricle central vein for 24 hours and the plasma concentrations of fenoterol were determined by LC-MS/MS method. Pharmacokinetic parameters were calculated using the WinNonlin computer program. The results showed a maximum concentration of fenoterol in plasma of 514.8 ng/ml after application of the liquid formula while its AUC0-∞ amounted to be 485972(ng*min/ml) with a dose of 3mg/kg. The transdermal matrix prepared with 10% 1-dodecyl-2-pyrollidinone had a Cmax of 219 ng/ml and AUC0-∞ was 124636 (ng*min/ml) which is significantly higher than that obtained after application of the control patch without any enhancer. Therefore, the transdermal systems will offer an efficient drug delivery system for the treatment of bronchial asthma. © 2011 Elshafeey AH, et al.

The current medical practice in treating Hepatocellular carcinoma (HCC) using Drug Eluting Transarterial chemoembolization (DEB-TACE) technique is limited only to hydrophilic ionizable drugs, that can be attached ionically to the oppositely charged beads. This limitation has forced physicians to subscribe the more hydrophobic, first treatment option drugs, like sorafenib systemically via the oral route, thus flooding the patient system with a very powerful, non-specific, multiple-receptor tyrosine kinase inhibitor that is associated with notorious side effects. In this paper, a new modality is introduced, where highly charged, drug loaded liposomes are added to oppositely charged DEBs in a manner causing them to “explode” and the drug is eventually attached to the beads in the lipid patches covering their surfaces; therefore we call them “Explosomes”. After fully describing the preparation process and in vitro characterization, this manuscript delves into an in vivo pharmacokinetic study over 50 New Zealand rabbits, where explosomal loading is challenged vs oral as well as current practice of emulsifying sorafenib in lipiodol. Over 14 days of follow up, and compared to other groups, explosomal loading of SRF on embolic beads proved to cause a slower release pattern with longer Tmax, lower Cmax and less washout to general circulation in healthy animals. This treatment modality opens a new untapped door for local sustained delivery of hydrophobic drugs in catheterized organs. © 2023 Elsevier B.V.

The current study aimed to load terconazole (TCZ), an antifungal agent with low permeability characteristics, into highly deformable bilosomes (HBs) for augmenting its topical delivery. HBs contain edge activator in addition to the constituents of traditional bilosomes (Span 60, cholesterol, and bile salts). More elasticity is provided to the membrane of vesicles by the existence of edge activator and is expected to increase the topical permeation of TCZ. HBs were formulated using ethanol injection technique based on 2⁴ complete factorial design to inspect the impact of various formulation variables (bile salt type and amount, edge activator type, and sonication time) on HBs characteristics (entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP)). The optimum formula (HB14) was decided based on Design-Expert^® software and was utilized for further explorations. HB14 exhibited EE% = 84.25 ± 0.49%, PS = 400.10 ± 1.69 nm, PDI = 0.23 ± 0.01, and ZP = - 56.20 ± 0.00 mV. HB14 showed spherical vesicles with higher deformability index (9.94 ± 1.91 g) compared to traditional bilosomal formula (3.49 ± 0.49 g). Furthermore, HB14 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition studies revealed superior TCZ deposition inside the skin from HB14 compared to traditional bilosomal formula and TCZ suspension. Moreover, histopathological examination in rats assured the safety of HB14 for topical use. Concisely, the obtained outcomes confirmed the pronounced efficacy of HBs for topical delivery of TCZ.

Lacidipine (LCD) is a potent antihypertensive agent. Fatty-based nanovesicles (FNVs) were designed to improve LCD low solubility and bioavailability. LCD-FNVs were formulated according to different proportions of cetyl alcohol, cremophor®RH40, and oleic acid adopting Box-Behnken Design. The optimized LCD-FNVs, composed of cetyl alcohol 48.4 mg, cremophor®RH40 120 mg, and oleic acid 40 mg, showed minimum vesicle size (124.8 nm), maximum entrapment efficiency % (91.04 %) and zeta potential (-36.3 mV). The optimized FNVs were then used to formulate the lyophilized orally fast-disintegrating sponge (LY-OFDS). The LY-OFDS had a very short disintegration time (58 sec), remarkably high % drug release (100 % after 15 mins), and increased the drug transbuccal permeation by over 9.5-fold compared to the drug suspension. In-vivo evaluation of antihypertensive activity in rats showed that the LY-OFDS reduced blood pressure immediately after 5 min and reached normal blood pressure 4.5-fold faster than the marketed oral tablets. In the In-vivo pharmacokinetic study in rabbits, the LY-OFDS showed 4.7-fold higher bioavailability compared with the marketed oral tablet. In conclusion, the LY-OFDS loaded with LCD-FNVs is a safe, and non-invasive approach that can deliver LCD effectively to the blood circulation via the buccal mucosa giving superior immediate capabilities of lowering high blood pressure and increasing the drug bioavailability. © 2024 Elsevier B.V.

The objective of this work was to design a diclofenac epolamine (DE) flash tablets (FTs) intended to dissolve in the mouth saliva, thereby improving the DE bioavailability and reducing its first-pass liver metabolism. Design-Expert software was used to build a 31.22 full factorial design (12 runs). FTs were fabricated using lyophilization process. The dissolution response was selected to pick the optimized run. The results indicate that the optimized run (R1) showed the fastest drug dissolution (total dissolution in 12 min). The predicted run (Rp) showed a desirability of about 0.93. Differential scanning calorimetry(DSC) analysis results showed a decrease in the drug melting point of the R1 formulation. Fourier–transform infrared spectroscopy (FTIR) showed the compatibility of the drug with other components of formulation, X-ray powder diffraction (XRPD) analysis showed the evolution of the drug physical state from a crystalline to an amorphous form and scanning electron microscopy(SEM) divugled the disappearance of drug crystals in gelatin strands. The results of the pharmacokinetic study performed in 6 human volunteers evidenced an increase in the maximum DE concentration in plasma and, consequently, an increased bioavailability of the FT formulation as compared with a reference formulation(Fr). Concisely, the developed FTs (R1) showed promising results which could be able to enhance oral bioavailability, reduce the therapeutic dose of the drug, and abate of the complications accompanied with conventional dosage forms.

Paroxetine (PX) is the most potent serotonin reuptake inhibitor utilized in depression and anxiety treatment. It has drawbacks, such as having a very bitter taste, low water solubility, and undergoing extensive first pass metabolism, leading to poor oral bioavailability (<50%). This work aimed to develop and optimize palatable oral fast-dissolving films (OFDFs) loaded with a paroxetine nanosuspension. A PX nanosuspension was prepared to increase the PX solubility and permeability via the buccal mucosa. The OFDFs could increase PX bioavailability due to their rapid dissolution in saliva, without needing water, and the rapid absorption of the loaded drug through the buccal mucosa, thus decreasing the PX metabolism in the liver. OFDFs also offer better convenience to patients with mental illness, as well as pediatric, elderly, and developmentally disabled patients. The PX nanosuspension was characterized by particle size, poly dispersity index, and zeta potential. Twelve OFDFs were formulated using a solvent casting technique. A 22 × 31 full factorial design was applied to choose the optimized OFDF, utilizing Design-Expert® software (Stat-Ease Inc., Minneapolis, MN, USA). The optimized OFDF (F1) had a 3.89 ± 0.19 Mpa tensile strength, 53.08 ± 1.28% elongation%, 8.12 ± 0.13 MPa Young’s modulus, 17.09 ± 1.30 s disintegration time, and 96.02 ± 3.46% PX dissolved after 10 min. This optimized OFDF was subjected to in vitro dissolution, ex vivo permeation, stability, and palatability studies. The permeation study, using chicken buccal pouch, revealed increased drug permeation from the optimized OFDF; with a more than three-fold increase in permeation over the pure drug. The relative bioavailability of the optimized OFDF in comparison with the market tablet was estimated clinically in healthy human volunteers and was found to be 178.43%. These findings confirmed the success of the OFDFs loaded with PX nanosuspension for increasing PX bioavailability.

In this study an attempt to sustain the oral release of itopride hydrochloride (ITO), a highly water-soluble drug, by microencapsulation using different polymers was carried out. The prepared microcapsules were characterized according to: particle size, encapsulation efficiency, and in vitro drug release and in vivo study in healthy human volunteers. Results showed that the particle size of microcapsules ranged from 591 ± 2 to 886 ± 4 μm and the encapsulation efficiency of ITO inside microcapsules ranged from 63 ± 1 to 90 ± 1%. The optimum formulation had a particle size of 860 ± 11 μm and was able to entrap 90 ± 1% ITO. The in vitro release study showed that 88 ± 1% of ITO was released from the optimum formulation after 12 h using Eudragit RS-100. The pharmacokinetic parameters of the optimum formulation in human volunteers showed that the maximum plasma concentration was 1624 ± 168 ng/mL, AUC 0-∞ was 85835 ± 6116 ng .h/mL, AUC0-48 was 29728 ± 761 ng .h/mL, and the mean residence time was 108 ± 9 h. The relative bioavailability of ITO from the optimum formulation compared to commercial oral tablets Ganaton as a reference standard was 317.9%.

AbstractDuloxetine hydrochloride (DH) is a serotonin–norepinephrine reuptake inhibitor (SSNRI) indicated for the treatment of depression. Duloxetine suffers from reduced oral bioavailability (≈50%) due to hepatic metabolism. This study aims to develop DH buccoadhesive films to improve its bioavailability. DH buccoadhesive films were prepared adopting the solvent casting method using hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA). The prepared films were evaluated for weight uniformity, drug content, surface pH, swelling index, mucoadhesion strength and drug release percentages. Accelerated stability and bioavailability studies in healthy human volunteers were also performed for the selected films. Results of the evaluation tests showed that the optimum physicochemical characters were obtained by the films prepared with 2% HPMC using 10% propylene glycol (F2 films). Accelerated stability studies revealed that DH showed proved stability throughout the experiment time. DH bioavailability from F2 films was determined and compared with that of the marketed oral capsules (Cymbalta® 30 mg). The pharmacokinetic results showed that Cmax for F2 was higher than the market product. In addition, ANOVA analysis showed that a Tmax of F2 film was significantly lower, while, the AUC0–72 of F2 was significantly higher than that of Cymbalta capsules. The percentage relative bioavailability of DH from F2 was found to be 296.39%. Therefore, the prepared buccal films offer an alternative route for the administration of DH with the possibility of improving its bioavailability.

Favipiravir is a potential antiviral medication that has been recently licensed for Covid-19 treatment. In this work, a gadolinium-based magnetic ionic liquid was prepared and used as an extractant in dispersive liquid–liquid microextraction (DLLME) of favipiravir in human plasma. The high enriching ability of DLLME allowed the determination of favipiravir in real samples using HPLC/UV with sufficient sensitivity. The effects of several variables on extraction efficiency were investigated, including type of extractant, amount of extractant, type of disperser and disperser volume. The maximum enrichment was attained using 50 mg of the Gd-magnetic ionic liquid (MIL) and 150 μl of tetrahydrofuran. The Gd-based MIL could form a supramolecular assembly in the presence of tetrahydrofuran, which enhanced the extraction efficiency of favipiravir. The developed method was validated according to US Food and Drug Administration bioanalytical method validation guidelines. The coefficient of determination was 0.9999, for a linear concentration range of 25 to 1.0 × 105 ng/ml. The percentage recovery (accuracy) varied from 99.83 to 104.2%, with RSD values (precision) ranging from 4.07 to 11.84%. The total extraction time was about 12 min and the HPLC analysis time was 5 min. The method was simple, selective and sensitive for the determination of favipiravir in real human plasma. © 2022 John Wiley & Sons, Ltd.