Computational Amendment of Parenteral In Situ Forming Particulates' Characteristics: Design of Experiment and PBPK Physiological Modeling.

Lipid and/or polymer-based drug conjugates can potentially minimize side effects by increasing drug accumulation at target sites and thus augment patient compliance. Formulation factors can present a potent influence on the characteristics of the obtained systems. The selection of an appropriate solvent with satisfactory rheological properties, miscibility, and biocompatibility is essential to optimize drug release. This work presents a computational study of the effect of the basic formulation factors on the characteristics of the obtained in situ-forming particulates (IFPs) encapsulating a model drug using a 21.31 full factorial experimental design. The emulsion method was employed for the preparation of lipid and/or polymer-based IFPs. The IFP release profiles and parameters were computed. Additionally, a desirability study was carried out to choose the optimum formulation for further morphological examination, rheological study, and PBPK physiological modeling. Results revealed that the type of particulate forming agent (lipid/polymer) and the incorporation of structure additives like Brij 52 and Eudragit RL can effectively augment the release profile as well as the burst of the drug. The optimized formulation exhibited a pseudoplastic rheological behavior and yielded uniformly spherical-shaped dense particulates with a PS of 573.92 ± 23.5 nm upon injection. Physiological modeling simulation revealed the pioneer pharmacokinetic properties of the optimized formulation compared to the observed data. These results assure the importance of controlling the formulation factors during drug development, the potentiality of the optimized IFPs for the intramuscular delivery of piroxicam, and the reliability of PBPK physiological modeling in predicting the biological performance of new formulations with effective cost management.

Boosting hair growth through follicular delivery of Melatonin through lecithin-enhanced Pickering emulsion stabilized by chitosan-dextran nanoparticles in testosterone induced androgenic alopecia rat model.

The strategy in this work was loading Melatonin (MEL), the powerful antioxidant photosensitive molecule, in novel Pickering emulsions (PEs) stabilized by chitosan-dextran sulphate nanoparticles (CS-DS NPs) and enhanced by lecithin, for treatment of androgenic alopecia (AGA). Biodegradable CS-DS NPs dispersion was prepared by polyelectrolyte complexation and optimized for PEs stabilization. PEs were characterized for droplet size, zeta potential, morphology, photostability and antioxidant activity. Ex-vivo permeation study through rat full thickness skin was conducted with optimized formula. Differential tape stripping trailed by cyanoacrylate skin surface biopsy was executed, for quantifying MEL in skin compartments and hair follicles. In-vivo evaluation of MEL PE hair growth activity was performed on testosterone induced AGA rat model. Visual inspection followed by anagen to telogen phase ratio (A/T) and histopathological examinations were conducted and compared with marketed 5% minoxidil spray "Rogaine ®". Data showed that PE improved MEL antioxidant activity and photostability. Ex-vivo results displayed MEL PE high follicular deposition. In-vivo study demonstrated that MEL PE treated testosterone induced AGA rat group, restored hair loss and produced maximum hair regeneration along with prolonged anagen phase amongst tested groups. The histopathological examination revealed that MEL PE prolonged anagen stage, increased follicular density and A/T ratio by 1.5-fold. The results suggested that lecithin-enhanced PE stabilized by CS-DS NPs was found to be an effective approach to enhance photostability, antioxidant activity and follicular delivery of MEL. Thus, MEL-loaded PE could be a promising competitor to commercially marketed Minoxidil for treatment of AGA.

Pharmaceutical nanotechnology: from the bench to the market.

BACKGROUND: Nanotechnology is considered a new and rapidly emerging area in the pharmaceutical and medicinal field. Nanoparticles, as drug delivery systems, impart several advantages concerning improved efficacy as well as reduced adverse drug reactions. MAIN BODY: Different types of nanosystems have been fabricated including carbon nanotubes, paramagnetic nanoparticles, dendrimers, nanoemulsions, etc. Physicochemical properties of the starting materials and the selected method of preparation play a significant aspect in determining the shape and characteristics of the developed nanoparticles. Dispersion of preformed polymers, coacervation, polymerization, nano-spray drying and supercritical fluid technology are among the most extensively used techniques for the preparation of nanocarriers. Particle size, surface charge, surface hydrophobicity and drug release are the main factors affecting nanoparticles physical stability and biological performance of the incorporated drug. In clinical practice, many nanodrugs have been used for both diagnostic and therapeutic applications and are being investigated for various indications in clinical trials. Nanoparticles are used for the cure of kidney diseases, tuberculosis, skin conditions, Alzheimer's disease, different types of cancer as well as preparation of COVID-19 vaccines. CONCLUSION: In this review, we will confer the advantages, types, methods of preparation, characterization methods and some of the applications of nano-systems.

Preparation of solid dispersion systems for enhanced dissolution of poorly water soluble diacerein: In-vitro evaluation, optimization and physiologically based pharmacokinetic modeling.

Diacerein (DCN), a BCS II compound, suffers from poor aqueous solubility and limited bioavailability. Solid dispersion systems (SD) of DCN were prepared by solvent evaporation, using hydrophilic polymers. In-vitro dissolution studies were performed and dissolution parameters were evaluated. I-Optimal factorial design was employed to study the effect of formulation variables (drug:polymer ratio and polymer type) on the measured responses including; drug content (DC) (%), dissolution efficiency at 15 min (DE (15 min)%) and 60 min (DE (60 min)%) and mean dissolution time (MDT) (min). The optimized SD was selected, prepared and evaluated, allowing 10.83 and 3.42 fold increase in DE (15 min)%, DE (60 min)%, respectively and 6.07 decrease in MDT, compared to plain drug. DSC, XRD analysis and SEM micrographs confirmed complete amorphization of DCN within the optimized SD. Physiologically based pharmacokinetic (PBPK) modeling was employed to predict PK parameters of DCN in middle aged healthy adults and geriatrics. Simcyp® software established in-vivo plasma concentration time curves of the optimized SD, compared to plain DCN. Relative bioavailability of the optimized SD compared to plain drug was 229.52% and 262.02% in healthy adults and geriatrics, respectively. Our study reports the utility of PBPK modeling for formulation development of BCS II APIs, via predicting their oral bio-performance.

Olanzapine Mesoporous Nanostructured Lipid Carrier: Optimization, Characterization, In Vivo Assessment, and Physiologically Based Pharmacokinetic Modeling.

A promising approach has been emerging to enhance dissolution of hydrophobicdrugsby encapsulation in mesoporous silica materials. Olanzapine is a practically insoluble antipsychotic drug which is subjected to excessive first pass effect and shows inadequate oral bioavailability. Therefore, mesoporous silica was used to improve bioavailability of olanzapine incorporated in nano-structured lipid carriers (NLCs). These systems were characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE) and differential scanning calorimetry (DSC) as well asits release profile. The optimized mesoporous NLC system displayed nano-spherical particles (120.56 nm), possessed high entrapment efficiency (88.46%) and the highest percentage of drug released after six hours (75.13%). The biological performance of the optimized system was assessed in comparison with the drug suspension in healthy albino rabbits. The optimized system showed significantly (P < 0.05) prolonged MRT (8.47 h), higher Cmax (22.12± 0.40 ng/ml) and Tmax (2.0 h) values compared to drug suspension. Physiologically based pharmacokinetic (PBPK) model was simulated and verified. All the predicted results were within 0.6 and 1-fold of the reported data. To set a conclusion, in vitro results as well as in vivo pharmacokinetic study and PBPK data showed an enhancement in bioavailability of the optimized NLCs system over the plain drug suspension. These results proved the potentiality of incorporating olanzapine in mesoporous NLC for a significant improvement in oral bioavailability of olanzapine.

The Effect of Liver and Kidney Disease on the Pharmacokinetics of Clozapine and Sildenafil: A Physiologically Based Pharmacokinetic Modeling.

BACKGROUND AND OBJECTIVES: Physiologically based pharmacokinetic (PBPK) modeling permits clinical scientists to reduce practical constraints for clinical trials on patients with special diseases. In this study, simulations were carried out to validate the pharmacokinetic parameters of clozapine and sildenafil using Simcyp® simulator in young male adults and compare the effect of renal or hepatic impairment on the pharmacokinetic parameters of clozapine and sildenafil. Also, the effect of age on pharmacokinetic parameters of both drugs was investigated in healthy population and in patients with renal and hepatic impairment. METHODS: A full PBPK model was built in the simulator for clozapine and sildenafil based on physicochemical properties and observed clinical results. The model used was Advanced, Dissolution, Absorption and Metabolism (ADAM) for both drugs. RESULTS: The PBPK model adequately predicted the pharmacokinetic parameters of clozapine and sildenafil for the healthy adult population. In the simulation results, the bioavailability of both drugs was remarkably raised in both renal and hepatic impairment in young and elderly populations. CONCLUSION: PBPK modeling could be helpful in the investigation and comparison of the pharmacokinetics in populations with specific disease conditions.

Boosting transdermal delivery of atorvastatin calcium via o/w nanoemulsifying system: Two-step optimization, ex vivo and in vivo evaluation.

A nanoemulsion system was designed for Atorvastatin calcium (ATOR) transdermal delivery to overcome its poor bioavailability of (30%) resulting from the extensive first-pass effect and dissolution rate-limited in vivo absorption. Pseudo ternary phase diagrams were developed, and various NE formulae were prepared using oleic acid (OA), Tween 80 as surfactant and PEG 400 as cosurfactant, ethanol and limonene as permeation enhancers (PEs). NEs were characterized for morphology, droplet size, zeta potential and in vitro release. The optimized formulae were assessed for ex vivo transdermal permeation and in vivo pharmacodynamic/pharmacokinetic studies. Hypocholesterolemic effect after 7 days skin treatment was detected and compared to oral ATOR dispersion. Finally, blood plasma levels were measured for 24 h for rats received the selected transdermal NE and transdermal drug in OA. The obtained results suggested the low potentiality of NE systems in transdermal delivery of lipophilic drugs, only the addition of PEs is driving factor for increasing drug flux through full thickness rat skin. In the optimized formula, the presence of ethanol and PEG 400 disrupts SC lipids exhibiting rapid ex vivo release profile compared to other NEs and to ATOR in OA. In contrast, the optimized NE achieved a prolonged plasma profile. Transdermal NE was significantly more efficient than oral administration in lowering cholesterol plasma level and in increasing ATOR bioavailability. In conclusion, data revealed no correlation between ex vivo and in vivo studies explained by the collapse of the follicles in ex vivo skin permeation study, leaving only the lipoidal pathway for NE to pass through, thus only NE components, neither nanosizing nor other reported mechanisms, are the main influencing factors. In vivo experiments suggested that o/w NE changed ATOR pathway to follicular delivery leading to accumulation of NE in follicles and consequently a prolonged plasma profile.

Therapeutic Strategies for Erectile Dysfunction With Emphasis on Recent Approaches in Nanomedicine.

This review addressed erectile dysfunction, regarding pathophysiology and therapeutic strategies. The line of treatment includes phosphodiesterase type-5 inhibitors and other types of therapy like topical and stem-cell transplant. Scientific literature was assessed to investigate the impact of nanotechnology on erectile dysfunction therapy. Various nanotechnology approaches were applied, like vesicular systems, lipid-based carriers, nanocrystals, dendrimers, liquid crystalline systems and nanoemulsions. Smart nano-systems can alter the landscape of the modern pharmaceutical industry by re- investigation of pharmaceutically suboptimal but biologically active entities for treatment of erectile dysfunction which were previously considered undeveloped.