Capped flexosomes for prominent anti-inflammatory activity: development, optimization, and ex vivo and in vivo assessments.

This study aimed to formulate diacerein (DCN)-loaded flexosomes for enhanced efficacy against osteoarthritis. A 23 D-optimal design was employed, investigating the impact of surfactant type (A), surfactant concentration (%w/v) (B), and oleylamine amount (mg) (C). Flexosomes were formulated using a rotary evaporator, and Design-Expert® software was utilized to statistically analyze entrapment efficiency (EE%), zeta potential (ZP), poly-dispersity index (PDI), and particle size (PS) to determine the optimum formula. The selection criteria prioritized increased ZP (as absolute value) and EE%, coupled with decreased PDI and PS. Rigorous physicochemical, in vivo, and ex vivo tests were conducted to validate the safety, stability, and activity of the optimal formula. Physicochemical assessments encompassed pH measurement, transmission electron microscopy, differential scanning calorimetry, release profiles, storage effects, and Fourier transform infrared spectroscopy. In vivo tests included permeation studies, histopathology, anti-inflammatory activity, and skin irritancy, while ex vivo tests focused on permeation parameters and skin deposition. The optimum formula demonstrated high desirability (0.931), along with favorable EE% (90.93%), ZP (- 40.4 mV), particle size (188.55 nm), and sustained behavior. Notably, improved in vivo permeation (132 µm), skin deposition (193.43 µg/cm2), and antinociceptive activity (66%) compared to DCN suspension (48 µm, 66.31 µg/cm2, and 26%, respectively) were observed. The optimal formula also exhibited excellent safety and storage characteristics. In conclusion, DCN-loaded flexosomes exhibit significant potential for effectively managing osteoarthritis.

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.

Formulation, optimization, in-vivo biodistribution studies and histopathological safety assessment of duloxetine HCl-loaded ultra-elastic nanovesicles for antidepressant effect after intranasal and transdermal delivery.

Duloxetine hydrochloride (DUL) is a BCS class-II antidepressant drug, acting via serotonin and norepinephrine reuptake inhibition. Despite high oral absorption, DUL suffers limited bioavailability due to extensive gastric and first-pass metabolism. To improve DUL's bioavailability; DUL-loaded elastosomes were developed, via full factorial design, utilizing various span®60: cholesterol ratios, edge activator types and amounts. Entrapment efficiency (E.E.%), particle size (PS), zeta potential (ZP) and in-vitro released percentages after 0.5 h (Q0.5h) and 8 h (Q8h) were evaluated. Optimum elastosomes (DUL-E1) were assessed for morphology, deformability index, drug crystallinity and stability. DUL pharmacokinetics were evaluated in rats following intranasal and transdermal application of DUL-E1 elastosomal gel. DUL-E1 elastosomes [comprising span®60 and cholesterol (1:1) and brij S2 (edge activator; 5 mg)] were optimum with high E.E.% (81.5 ± 3.2%), small PS (432 ± 13.2 nm), ZP (-30.8 ± 3.3 mV), acceptable Q0.5h (15.6 ± 0.9%), and high Q8h (79.3 ± 3.8%). Intranasal and transdermal DUL-E1 elastosomes revealed significantly higher Cmax (251 ± 18.6 and 248 ± 15.9 ng/mL) at Tmax (2 and 4 h) and improved relative bioavailability (≈ 2.8 and 3.1 folds) respectively, in comparison to oral DUL aqueous solution. In-vivo histopathological studies were conducted to ensure the safety of DUL-E1. Elastosomes are promising novel nano-carriers, capable of enhancing the bioavailability of DUL via various routes of administration.

Brain targeting of zolmitriptan via transdermal terpesomes: statistical optimization and in vivo biodistribution study by 99mTc radiolabeling technique.

Zolmitriptan (ZT) is a potent second generation triptan, commonly administered to alleviate migraine attacks. ZT suffers various limitations; massive hepatic first pass metabolism, P-gp efflux transporters susceptibility, and limited (≈40%) oral bioavailability. Transdermal route of administration could be explored to enhance its bioavailability. A 23.31 full factorial design was constructed to developed twenty-four ZT loaded terpesomes via thin film hydration technique. The influence of drug: phosphatidylcholine ratio, terpene type, terpene concentration and sodium deoxycholate concentration on the characterization of the developed ZT-loaded terpesomes was assessed. Particle size (PS), zeta potential (ZP), ZT entrapment efficiency (EE%), drug loading (DL%) and drug released percentages after 6 h (Q6h) were the selected dependent variables. Further morphological, crystallinity, and in-vivo histopathological studies were conducted for the optimum terpesomes (T6). 99mTc-ZT and 99mTc-ZT-T6 gel were radio-formulated for in-vivo biodistribution studies in mice following transdermal application of 99mTc-ZT-T6 gel, relative to 99mTc-ZT oral solution. T6 terpesomes [comprising ZT and phosphatidylcholine (1:15), cineole (1% w/v) and sodium deoxycholate (0.1% w/v)] were optimum with respect to spherical PS (290.2 nm), ZP (-48.9 mV), EE% (83%), DL% (3.9%) and Q6h (92.2%) with desirability value of 0.85. The safety of the developed T6 terpesomes was verified by the in-vivo histopathological studies. 99mTc-ZT-T6 gel showed maximum brain concentration (5 ± 0.1%ID/ g) with highest brain to blood ratio of 1.92 ± 0.1 at 4 h post transdermal application. Significant improvement of ZT brain relative bioavailability (529%) and high brain targeting efficiency (315%) were revealed with 99mTc-ZT-T6 gel, which confirmed successful ZT delivery to the brain. Terpesomes could be safe, successful systems capable of improving ZT bioavailability with high brain targeting efficiency.

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.

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.

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.