Enhancement of ocular anti-glaucomic activity of agomelatine through fabrication of hyaluronic acid modified-elastosomes: formulation, statistical optimisation, in vitro characterisation, histopathological study, and in vivo assessment.

AIM: The aim of this manuscript was to fabricate agomelatine (AGM) loaded elastosomes to improve its corneal permeation and ocular bioavailability. AGM is a biopharmaceutical classification system (BCS) class II with low water solubility and high membrane permeability. It has a potent agonistic action on melatonin receptors, so it is used for glaucoma treatment. METHODS: Elastosomes were made using modified ethanol injection technique according to a 22 × 41 full factorial design. The chosen factors were: edge activators (EAs) type, surfactant percent (SAA %w/w), and cholesterol:surfactant ratio (CH:SAA ratio). The studied responses were encapsulation efficiency percent (EE%), mean diameter, polydispersity index (PDI), zeta potential (ZP), percentage of drug released after two hours (Q2h%), and 24 hours (Q24h%). RESULTS: The optimum formula with the desirability of 0.752 was composed of Brij98 as EA type, 15%w/w SAA%, and 1:1 CH:SAA ratio. It revealed EE% of 73.22%w/v and mean diameter, PDI, ZP, Q2h%, and Q24h% values of 484.25 nm, 0.31, -30.75 mV, 32.7%w/v, and 75.6%w/v, respectively. It demonstrated acceptable stability for three months and superior elasticity than its conventional liposome. The histopathological study ensured the tolerability of its ophthalmic application. Also, it was proven to be safe from the results of the pH and refractive index tests. The in vivo pharmacodynamic parameters of the optimum formula revealed dominance in a maximum % decrease in intraocular pressure (IOP), the area under the IOP response curve, and mean residence time with the value of 82.73%w/v, 820.69%h, and 13.98 h compared to that of the AGM solution (35.92%w/v, 181.30%h, and 7.52 h). CONCLUSIONS: Elastosomes can be a promising option to improve AGM ocular bioavailability.

Development and evaluation of surfactant-based elastic vesicular system for transdermal delivery of Cilostazole: ex-vivo permeation and histopathological evaluation studies.

Cilostazole (CLZ) is an anti-platelet drug that suffers from extensive first pass-metabolism and gastrointestinal side effects. This study aimed to prepare spanlastics for enhancing the transdermal delivery of CLZ to avoid its oral problems. CLZ-loaded spanlastic dispersions were prepared by ethanol injection technique according to a 413121 full factorial design to investigate the effect of formulation variables on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and the percent of drug released after 2 and 24 h (Q2 and 24 h). Spanlastic-loaded gel of the optimized formula was prepared using hydroxypropyl methylcellulose (HPMC K4M). The optimum formula (F13), constitutes of Span60 and CremophoreRH40 at a weight ratio of 80:20 and distilled water for hydration, had the highest desirability value of (0.841) and exhibited the highest EE% of (69.29 ± 0.29%), PS of (452.7 ± 5.94 nm), ZP of (-32.6 ± 0.4 mV), Q 2 h of (33.28 ± 1.45%) and Q24h of (82.37 ± 1.37. F13 was subjected to ex-vivo permeation study and showed a cumulative amount permeated after 48 h(Q48h) equal to (750.71 ± 3 µg/cm2) in comparison to the drug suspension which showed Q48h equal to (190.20 ± 6.3 µg/cm2). Also, F13 showed an increase in the drug flux of (17.84 µg/cm2.h) and enhancement ratio(ER) of (5.71 ± 0.1) in comparison to the drug suspension that showed drug flux of (3.12 ± 0.0 µg/cm2.h). Spanlastics-loaded gel was subjected to an in-vitro release study compared to(F13) spanlastic dispersion and showed a more sustained release effect. In addition, histopathological studies showed no sign of skin alteration confirming safe delivery through the skin. CLZ showed promising results with high potential to be delivered transdermally.

Development and evaluation of proniosomes to enhance the transdermal delivery of cilostazole and to ensure the safety of its application.

Cilostazole (CLZ) is an anti-platelet drug that suffers from extensive first-pass metabolism and gastrointestinal side effects. This study aimed to prepare proniosomes for enhancing the transdermal delivery of CLZ to avoid its oral problems. proniosomes were prepared by a coacervation phase separation technique according to the D-optimal design to investigate the effect of formulation variables on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and the percent of the drug released after 2 and 24 h (Q2 and 24 h). The desirability criterion is set to select the optimum formula. The optimum formula(opt) with a desirability value (0.75), composed of 540 mg Span60 and 59.7 mg of cholesterol, had the highest EE% of (75.125 ± 0.125%), PS of (300.3 ± 0.2 nm), ZP of (-39.35 ± 0.15 mV), Q2h of (24.32 ± 0.13%) and Q24h of (81.175 ± 0.325%). Further, the opt-gel was prepared by using hydroxy propyl methyl cellulose (HPMC K4M). The opt-formula was subjected to an ex-vivo permeation study and showed a marked increase in drug flux of (22.89 ± 0.1 µg/cm2.h). The opt-gel was subjected to an in-vitro release study in comparison with the opt-formula that showed a more sustained release effect. The histopathological examination study confirmed the safety of the topical application of proniosomes. The CLZ-loaded proniosomes showed promising results with high potential to deliver it across the skin.

Hyaluronic acid-enriched bilosomes: an approach to enhance ocular delivery of agomelatine via D-optimal design: formulation, in vitro characterization, and in vivo pharmacodynamic evaluation in rabbits.

Agomelatine (AGO) is a dual-functional drug. It uses as an antidepressant when orally administrated and antiglaucomic when topically applied to the eye. This study aimed to formulate AGO into bilosomal vesicles for glaucoma treatment, as modern studies pointed out the effect of topical AGO on intraocular pressure for the treatment of glaucoma. A modified ethanol injection technique was used for the fabrication of AGO bilosomes according to a D-optimal design. Phosphatidylcholine (PC) to edge activator (EA) ratio, Hyaluronic acid percentage (HA%), and EA type were utilized as independent variables. The measured responses were percent entrapment efficiency (EE%), particle size (PS), polydispersity index, zeta potential, percentage of drug released after 2 h (Q2h%), and 24 h (Q24h%). The optimal bilosomal formula (OB), with the desirability of 0.814 and the composition of 2:1 PC: EA ratio, 0.26% w/v HA and sodium cholate as EA, was subjected to further in vitro characterizations and in vivo evaluation studies. The OB formula had EE% of 81.81 ± 0.23%, PS of 432.45 ± 0.85 nm, Q2h% of 42.65 ± 0.52%, and Q24h% of 75.14 ± 0.39%. It demonstrated a higher elasticity than their corresponding niosomes with a typical spherical shape of niosomes by using transmission electron microscope. It exhibited acceptable stability over three months. pH and Refractive index measurements together with the histopathological study ensured that the OB formula is safe for the eye and causes no ocular irritation or blurred vision. The OB formula showed superiority in the in vivo pharmacodynamics parameters over the AGO solution, so AGO-loaded bilosome could improve ocular delivery and the bioavailability of agomelatine.