Haloperidol (Hal) is one of the widely used antipsychotic drugs. When orally administered, it suffers from low bioavailability due to hepatic first pass metabolism. This study aimed at developing Hal-loaded penetration enhancer-containing spanlastics (PECSs) to increase transdermal permeation of Hal with sustained release. PECSs were successfully prepared using ethanol injection method showing reasonable values of percentage entrapment efficiency, particle size, polydispersity index and zeta potential. The statistical analysis of the ex vivo permeation parameters led to the choice of F1L – made of Span^® 60 and Tween^® 80 at the weight ratio of 4:1 along with 1% w/v Labrasol^® – as the selected formula (SF). SF was formulated into a hydrogel by using 2.5% w/v of HPMC K4M. The hydrogel exhibited good in vitro characteristics. Also, it retained its physical and chemical stability for one month in the refrigerator. The radiolabeling of SF showed a maximum yield by mixing of 100 µl of diluted formula with 50 µl saline having 200 MBq of ^99mTc and containing 13.6 mg of reducing agent (NaBH₄) and volume completed to 300 µl by saline at pH 10 for 10 min as reaction time. The biodistribution study showed that the transdermal ^99mTc-SF hydrogel exhibited a more sustained release pattern and longer circulation duration with pulsatile behavior in the blood and higher brain levels than the oral ^99mTc-SF dispersion. So, transdermal hydrogel of SF may be considered a promising sustained release formula for Hal maintenance therapy with reduced dose size and less frequent administration than oral formula.

Glaucoma is the second cause of blindness worldwide. Frequent administration of traditional topical dosage forms may lead to patient incompliance and failure of treatment. Our study aims to formulate proniosomal gel formulations that sustain the release of the water-soluble anti-glaucoma drug Dorzolamide-HCl (Dorz). Proniosomal gel formulations were prepared using coacervation phase separation method according to a 5² full factorial design. The effects of Cholesterol and surfactant (Span 40) amounts (independent variables) on the percentage entrapment efficiency (EE%), particle size (PS), and the percent of drug released after 8 h (Q8h) (dependent variables (DVs)) were investigated. An optimized formulation (OF) was chosen based on maximizing EE% and Q8h and minimizing PS. An intraocular pressure (IOP) pharmacodynamic study was performed in rabbits to evaluate the in-vivo performance of the OF-gel compared to the marketed Trusopt^® eye drops. The results showed that the independent variables studied significantly affected EE%, PS, and Q8h. OF was the one containing 60 mg Cholesterol and 540 mg Span 40. It had desirability of 0.885 and its actually measured DVs deviated from the predicted ones by a maximum of 4.8%. The in-vivo pharmacodynamic study showed that OF could result in higher reduction in IOP, significantly sustain that reduction in IOP and increase Dorz bioavailability compared to Trusopt^® eye drops. Thus the OF-gel is very promising for being used in glaucoma treatment.

Febuxostat (FXS) is a potent antigout drug with poor water solubility and relative high first-pass effect leading to moderate oral bioavailability (<49%). This study aimed to increase FXS solubility and bioavailability by optimizing sublingual fast-dissolving films (SFs) containing a selected FXS self-nano-emulsifying system (s-SNES) previously prepared by our team. The s-SNES was loaded into SFs by solvent casting technique. A full factorial design (3²) was applied to study the effects of polymer and plasticizer types on mechanical characteristics and the dissolution profile of FXS from the SFs. Numerical optimization was performed to select the SF having highest desirability according to predetermined characteristics. The optimized SF (O-SF) contained 1 g of s-SNES, polyvinylpyrrolidone K30 (6%w/v), polyethylene glycol 300 (20%w/w of polymer wt.), and Avicel PH101 (0.5%w/v). O-SF showed good permeation of FXS through sheep sublingual tissue. Storage of O-SF for three months showed no significant change in the FXS dissolution profile. In-vivo performance of O-SF in rabbits was compared to that of oral marketed tablets (Staturic^® 80 mg). A cross-over design was applied and pharmacokinetic parameters were calculated after ensuring absence of sequence effect. Statistical analysis revealed better performance for O-SF with significantly higher C_max, AUC_0–24, AUC_0–∞, apparent t_1/2 together with lower t_max, and apparent k_el than marketed tablets. Relative bioavailability of O-SF compared to the marketed tablet was found to be 240.6%. This confirms the achievement of the study aims of improving dissolution rate and bioavailability of FXS using a patient-wise convenient formula.

This study aimed to illustrate the use of D-optimal mixture design (DOMD) for optimization of an enhancer containing Dapsone niosomal formula for acne topical treatment. Mixture components (MixCs) studied were: Span 20, Cholesterol, and Cremophor RH. Different responses were measured. Optimized formula (OF) was selected to minimize particle size and maximize absolute zeta potential and entrapment efficiency. Optimized formula gel (OF-gel) was prepared and characterized. OF-gel in vivo skin penetration using confocal laser scanning microscopy and activity against Cutibacterium acnes in acne mouse model were studied. Based on DOMD results analysis, adequate models were derived. Piepel and contour plots were plotted accordingly to explain how alteration in MixCs L-pseudo values affected studied responses and regions for different responses’ values. The OF had suitable predicted responses which were in good correlation with the actually measured ones. The OF-gel showed suitable characterization and in vivo skin penetration up to the dermis layer. In vivo acne mouse-model showed that OF-gel-treated group (OF-gel-T-gp) had significantly better recovery (healing) criteria than untreated (UT-gp) and Aknemycin^®-treated (A-T-gp) groups. This was evident in significantly higher reduction of inflammation percent observed in OF-gel-T-gp than both UT-gp and A-T-gp. Better healing in OF-gel-T-gp compared with other groups was also verified by histopathological examination. Moreover, OF-gel-T-gp and A-T-gp bacterial loads were non-significantly different from each other but significantly lower than UT-gp. Thus, DOMD was an adequate statistical tool for optimization of an appropriate enhancer containing Dapsone niosomal formula that proved to be promising for topical treatment of acne.

Objectives: This study aims to illustrate the applicability of combined mixture-process variable (MPV) design and modeling for optimization of nanovesicular systems.Methods: The D-optimal experimental plan studied the influence of three mixture components (MCs) and two process variables (PVs). The MCs were phosphatidylcholine (A), sodium glycocholate (B) and lercanidipine hydrochloride (C), while the PVs were glycerol amount in the hydration mixture (D) and sonication time (E). The studied responses were Y1: particle size, Y2: zeta potential and Y3: entrapment efficiency percent (EE%). Polynomial equations were used to study the influence of MCs and PVs on each response. Response surface methodology and multiple response optimization were applied to optimize the formulation with the goals of minimizing Y1 and maximizing Y2 and Y3.Results: The obtained polynomial models had prediction R2 values of 0.645, 0.947 and 0.795 for Y1, Y2 and Y3, respectively. Contour, Piepel’s response trace, perturbation...