Experimental design, formulation, and in-vivo evaluation of novel anticoagulant Rivaroxaban loaded cubosomes in rats model.

The aim of this study was to develop novel cubosomes as an oral delivery system to improve the permeation and anti-clotting activity of Rivaroxaban (RX). The experimental design (23 full factorial design) was employed to study individual and combined impacts of the assigned formulation variables. The variables RX amount (X1), Poloxamer (PX): GMO (GMO) ratio (X2) and PX/GMO: water ratio (X3) were taken as independent factors, and their effect was examined on entrapment efficiency (Y1), particle size (Y2), and zeta potential. (Y3). The cubosomal vesicle RX-C 3 composed of RX (20 mg), PX: GMO (1:0.5 % w/w), and PX/GMO: water (1:5% w/w) is the optimised formula achieving the required prerequisites. RX-C 3 had shown a vesicle size of 91.2 ± 1.3 nm, entrapment efficiency of 96.27 ± 0.12 %, and zeta potential of -24.1 ± 0.2 mV. The in-vivo studies showed revealed good inhibition of blood clotting, where RX-C 3 significantly increased clotting time by 35% and prothrombin time by 29% compared to Rivarospire®. In conclusion, the present study suggested that oral cubosomes formulations provide prolonged delivery of Rivaroxaban.

Design, formulation and optimization of topical ethosomes using full factorial design: in-vitro and ex-vivo characterization.

The present study aimed to develop lomefloxacin-loaded ethosomal vesicles intended to be applied topically for treating skin infections. Ethosomes were prepared using the cold method. The formulation variables were optimized using 22 factorial design and Design Expert® software for analyzing the data statistically and graphically using response surface plots. Phosphatidylcholine (X1) and ethanol (X2) were chosen as the independent variables, while the dependent variables comprised entrapment efficiency (Y1), vesicles size (Y2) and zeta potential (Y3). The optimized ethosomes were subsequently incorporated into Carbopol® 940 gel and characterized for rheological behaviour, in-vitro release, ex-vivo skin permeation and deposition. The ex-vivo permeation and skin deposition studies showed better results compared to drug solutions. In a nutshell, the ethosomal vesicles were found to be a promising carrier demonstrating enhanced topical delivery of lomefloxacin.

Development of tizanidine loaded aspasomes as transdermal delivery system: ex-vivo and in-vivo evaluation.

New generation of amphiphilic vesicles known as aspasomes were investigated as potential carriers for transdermal delivery of tizanidine (TZN). Using full factorial design, an optimal formulation was developed by evaluating the effects of selected variables on the properties of the vesicles with regards to entrapment efficiency, vesicle size and cumulative percentage released. The optimal formula (TZN-AS 6) consisting of 20 mg TZN, 50 mg ascorbyl palmitate (AP), 50 mg cholesterol (CH) and 50 mg Span 60, represented well dispersed spherical vesicles in the nanorange sizes and exhibited excellent stability under different storage conditions. Ex-vivo permeation studies using excised rat skin showed a 4.4-fold increase of the steady state flux in comparison to the unformulated drug (p < 0.05). The pharmacokinetic parameters obtained from the in-vivo study using Wistar rats, showed that the bioavailability of TZN was enhanced significantly (p < 0.05) when compared to the oral market product of TZN, Sirdalud®. Moreover, skin irritancy tests confirmed that the vesicles were non-invasive and safe for the skin. Based on the results obtained, the optimised aspasomes formula represents a promising Nano platform for TZN to be administered transdermally, thus improving the therapeutic efficacy of this important muscle relaxant.

Evaluation of bilosomes as nanocarriers for transdermal delivery of tizanidine hydrochloride: in vitro and ex vivo optimization.

Bilosomes were developed in order to investigate their efficacy as nanocarriers for transdermal delivery of Tizanidine HCl (TZN), a skeletal muscle relaxant with low oral bioavailability. Full factorial experimental design consisting of 27 combinations was generated to study the effects of surfactant type, surfactant-to-cholesterol ratio and the amount of bile salt on the entrapment efficiency (EE), the vesicle size (VS) and in vitro dissolution of the TZN-loaded bilosomes. The permeation through the stratum cornea was optimized with the vertical diffusion assembly using excised rat skin. The permeation parameters of the selected bilosomes were compared to the unformulated drug and it was shown that TZN-B24 exhibited the highest enhancement ratio (ER = 8.8).The optimal formula (TZN-B24) consisting of span 60 in a ratio with cholesterol of 1:1 and 20 mg of bile salt was obtained by employing the desirability function of Design-Expert® software. The mathematical model used for the optimization was validated by comparing the predicted values of the EE (82.3%) and the VS (165.8 nm) with the experimental values of EE = 84.42% and of VS = 161.95 nm. TZN-B24 displayed high zeta potential which contributed to its good stability. It was evident from the results of this study that incorporating TZN in bilosomes improved significantly its permeation through the skin barrier and thus bilosomes can offer a potential nanoplatform using the transdermal route to improve the bioavailability of the drug.

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.

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.