Development of Transdermal Oleogel Containing Olmesartan Medoxomil: Statistical Optimization and Pharmacological Evaluation.

Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM side effects and boost its therapeutic efficacy and bioavailability. OLM oleogel formulations were composed of Tween 20, Aerosil 200, and lavender oil. A central composite response surface design chose the optimized formulation, containing Oil/Surfactant (SAA) ratio of 1:1 and Aerosil % of 10.55%, after showing the lowest firmness and compressibility, and the highest viscosity, adhesiveness, and bioadhesive properties (Fmax and Wad). The optimized oleogel increased OLM release by 4.21 and 4.97 folds than the drug suspension and gel, respectively. The optimized oleogel formulation increased OLM permeation by 5.62 and 7.23 folds than the drug suspension and gel, respectively. The pharmacodynamic study revealed the superiority of the optimized formulation in maintaining normal blood pressure and heart rate for 24 h. The biochemical analysis revealed that the optimized oleogel achieved the best serum electrolyte balance profile, preventing OLM-induced tachycardia. The pharmacokinetic study showed that the optimized oleogel increased OLM's bioavailability by more than 4.5- and 2.5-folds compared to the standard gel and the oral market tablet, respectively. These results confirmed the success of oleogel formulations in the transdermal delivery of OLM.

Repurposing levocetirizine hydrochloride loaded into cationic ceramide/phospholipid composite (CCPCs) for management of alopecia: central composite design optimization, in- silico and in-vivo studies.

Levocetirizine hydrochloride (LVC) is an antihistaminic drug that is repurposed for the treatment of alopecia. This investigation is targeted for formulating LVC into cationic ceramide/phospholipid composite (CCPCs) for the management of alopecia. CCPCs were fabricated by ethanol-injection approach, through a central composite experiment. CCPCs were evaluated by inspecting their entrapment efficiency (EE%), polydispersity index (PDI), particle size (PS), and zeta potential (ZP). The optimum CCPCs were additionally studied by in-vitro, ex-vivo, in-silico, and in-vivo studies. The fabricated CCPCs had acceptable EE%, PS, PDI, and ZP values. The statistical optimization elected optimum CCPCs composed of 5 mg hyaluronic acid, 10 mg ceramide III, and 5 mg dimethyldidodecylammonium bromide employing phytantriol as a permeation enhancer. The optimum CCPCs had EE%, PS, PDI, and ZP of 88.36 ± 0.34%, 479.00 ± 50.34 nm, 0.377 ± 0.0035, and 20.20 ± 1.13 mV, respectively. The optimum CCPC maintained its stability for up to 90 days. It also viewed vesicles of tube shape via transmission electron microscope. The in-silico assessment resulted in better interaction and stability between LVC and vesicle components in water. The ex-vivo and in-vivo assessments showed satisfactory skin retention of LVC from optimum CCPCs. The histopathological assessment verified the safety of optimum CCPCs to be topically applied. Overall, the optimum CCPCs could be utilized as a potential system for the topical management of alopecia, with a prolonged period of activity, coupled with reduced LVC shortcomings.

Formulation and Development of Oral Fast-Dissolving Films Loaded with Nanosuspension to Augment Paroxetine Bioavailability: In Vitro Characterization, Ex Vivo Permeation, and Pharmacokinetic Evaluation in Healthy Human Volunteers.

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.

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies, statistical optimization, ex vivo, and in vivo studies.

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.

Response surface optimization of biocompatible elastic nanovesicles loaded with rosuvastatin calcium: enhanced bioavailability and anticancer efficacy.

Statins are mainly used for the treatment of hyperlipidemia, but recently, their anticancer role was extremely investigated. The goal of this study was to statistically optimize novel elastic nanovesicles containing rosuvastatin calcium to improve its transdermal permeability, bioavailability, and anticancer effect. The elastic nanovesicles were composed of Tween® 80, cetyl alcohol, and clove oil. The nanodispersions were investigated for their entrapment efficiency, particle size, zeta potential, polydispersity index, and elasticity. The optimized elastic nanovesicular dispersion is composed of 20% cetyl alcohol, 53.47% Tween 80, and 26.53% clove oil. Carboxy methylcellulose was utilized to convert the optimized elastic nanovesicular dispersion into elastic nanovesicular gels. Both the optimized dispersion and the optimized gel (containing 2% w/v carboxymethylcellulose) were subjected to in vitro release study, scanning and transmission electron microscopy, histopathological evaluation, and ex vivo permeation. The cell viability assay of the optimized gel on MCF-7 and Hela cell lines showed significant antiproliferative and potent cytotoxic effects when compared to the drug gel. Moreover, the optimized gel accomplished a significant increase in rosuvastatin bioavailability upon comparison with the drug gel. The optimized gel could be considered as a promising nanocarrier for statins transdermal delivery to increase their systemic bioavailability and anticancer effect. Graphical abstract.

Tripling the Bioavailability of Rosuvastatin Calcium Through Development and Optimization of an In-Situ Forming Nanovesicular System.

In situ forming nanovesicular systems (IFNs) were prepared and optimized to improve Rosuvastatin calcium (RC) oral bioavailability through increasing its solubility and dissolution rate. The IFN was composed of Tween® 80 (T80), cetyl alcohol (CA), in addition to mannitol or Aerosil 200. A single simple step was adopted for preparation, then the prepared formulations were investigated by analyzing their particle size (PS), polydispersity index (PDI), Zeta potential (ZP), entrapment efficiency (EE), and flowability properties. D-optimal design was applied to choose the optimized formulations. The maximum desirability values were 0.754 and 0.478 for the optimized formulations containing 0.05 g CA, 0.18 g T80, and 0.5 g mannitol (OFM) or Aerosil (OFA), respectively. In vitro drug release from the optimized formulations showed a significantly faster dissolution rate when compared to the market product. In vivo performance of the optimized formulations in rabbits was investigated after filling them into enteric-coated capsules. Ultimately, OFA formulation achieved a 3 times increase in RC oral bioavailability in comparison with the market product, supporting the hypothesis of considering IFNs as promising nanocarriers able to boost the bioavailability of BCS class II drugs.

Optimization of long circulating mixed polymeric micelles containing vinpocetine using simple lattice mixture design, in vitro and in vivo characterization.

The aim of this study was to increase the in vivo mean residence time of vinpocetine after IV injection utilizing long circulating mixed micellar systems. Mixed micelles were prepared using Pluronics L121, P123 and F127. The systems were characterized by testing their entrapment efficiency, particle size, polydispersity index, zeta potential, transmission electron microscopy and in vitro drug release. Simple lattice mixture design was planned for the optimization using Design-Expert(®) software. The optimized formula was lyophilized, sterilized and imaged by scanning electron microscope. Moreover, the in vivo behavior of the optimized formula was evaluated after IV injection in rabbits. The optimized formula, containing 68% w/w Pluronic L121 and 32% w/w Pluronic F127, had the highest desirability value (0.621). Entrapment efficiency, particle size, polydispersity index and zeta potential of the optimized formula were 50.74 ± 3.26%, 161.50 ± 7.39 nm, 0.21 ± 0.03 and -22.42 ± 1.72 mV, respectively. Lyophilization and sterilization did not affect the characteristics of the optimized formula. Upon in vivo investigation in rabbits, the optimized formula showed a significantly higher elimination half-life and mean residence time than the market product. Finally, mixed micelles could be considered as a promising long circulating nanocarrier for lipophilic drugs.