Preparation and Characterization of ACE2 Receptor Inhibitor-Loaded Chitosan Hydrogels for Nasal Formulation to Reduce the Risk of COVID-19 Viral Infection.

The COVID-19 virus is spread by pulmonary droplets. Its high infectivity is caused by the high-affinity binding of the viral spike protein to the ACE2 receptors on the surface of respiratory epithelial cell membranes. The proper hydration of nasal mucosa plays an essential role in defense of bacterial and viral infections. Therefore, a nasal formulation, which can moisture the nasal mucosa and contains the ACE2 receptor inhibitor, can reduce the risk of COVID-19 infection. This article presents a systematic study of the preparation of chitosan hydrogels with dicarboxylic acids (malic and glutaric acid) and their detailed characterization (Fourier transform infrared spectroscopy, determination of cross-linking efficiency, rheological studies, thermal analysis, and swelling kinetics). The results confirm that chemically cross-linked chitosan hydrogels can be synthesized using malic or glutaric acid without additives or catalysts. The adsorption capacity of hydrogels for three different ACE2 inhibitors, as APIs, has also been investigated. The API content of hydrogels and their mucoadhesive property can provide an excellent basis to use the hydrogels for the development of a nasal formulation in order to reduce the risk of SARS-CoV 2 infection.

Synthesis and Characterization of Nano-Sized 4-Aminosalicylic Acid-Sulfamethazine Cocrystals.

Drug-drug cocrystals are formulated to produce combined medication, not just to modulate active pharmaceutical ingredient (API) properties. Nano-crystals adjust the pharmacokinetic properties and enhance the dissolution of APIs. Nano-cocrystals seem to enhance API properties by combining the benefits of both technologies. Despite the promising opportunities of nano-sized cocrystals, the research at the interface of nano-technology and cocrystals has, however, been described to be in its infancy. In this study, high-pressure homogenization (HPH) and high-power ultrasound were used to prepare nano-sized cocrystals of 4-aminosalysilic acid and sulfamethazine in order to establish differences between the two methods in terms of cocrystal size, morphology, polymorphic form, and dissolution rate enhancement. It was found that both methods resulted in the formation of form I cocrystals with a high degree of crystallinity. HPH yielded nano-sized cocrystals, while those prepared by high-power ultrasound were in the micro-size range. Furthermore, HPH produced smaller-size cocrystals with a narrow size distribution when a higher pressure was used. Cocrystals appeared to be needle-like when prepared by HPH compared to those prepared by high-power ultrasound, which had a different morphology. The highest dissolution enhancement was observed in cocrystals prepared by HPH; however, both micro- and nano-sized cocrystals enhanced the dissolution of sulfamethazine.

Solvent dependent 4-aminosalicylic acid-sulfamethazine co-crystal polymorph control.

Despite polymorphism of crystalline active pharmaceutical ingredients (APIs) being a common phenomenon, reports on polymorphic co-crystals are limited. As polymorphism can vastly affect API properties, controlling polymorph generation is crucial. Control of the polymorph nucleation through the use of different solvents during solution crystallization has been used to obtain a desirable crystal polymorph. There have been two reported polymorphic forms of the 4-aminosalicylic acid-sulfamethazine co-crystals. These forms were found to have different thermodynamic stabilities. However, the control of co-crystal polymorph generation using preparation parameter manipulation has never been reported. The aim of this study was to establish the effect of different solvent parameters on the formation of different co-crystal polymorphic forms. Selection of the solvents was based on Hansen Solubility Parameters (HSPs) as solvents with different solubility parameters are likely to interact differently with APIs, ultimately affecting co-crystallization. Eight solvents with different HSPs were used to prepare co-crystals by solvent evaporation at two different temperatures. Through characterization of the co-crystals, a new polymorph has been obtained. The hydrogen bond acceptability seemed to affect the co-crystal form obtained more than the hydrogen bond donation ability. Furthermore, the use of HSPs can be utilized as an easy calculation method in screening and design of co-crystals.

Formulation of Tioconazole and Melaleuca alternifolia Essential Oil Pickering Emulsions for Onychomycosis Topical Treatment.

Onychomycosis is a disease that affects many adults, whose treatment includes both oral and topical therapies with low cure rates. The topical therapy is less effective but causes fewer side effects. This is why the development of an effective, easy to apply formulation for topical treatment is of high importance. We have used a nanotechnological approach to formulate Pickering emulsions (PEs) with well-defined properties to achieve site-specific delivery for antifungal drug combination of tioconazole and Melaleuca alternifolia essential oil. Silica nanoparticles with tailored size and partially hydrophobic surface have been synthesized and used for the stabilization of PEs. In vitro diffusion studies have been performed to evaluate the drug delivery properties of PEs. Ethanolic solution (ES) and conventional emulsions (CE) have been used as reference drug formulations. The examination of the antifungal effect of PEs has been performed on Candida albicans and Trichophyton rubrum as main pathogens. In vitro microbiological experimental results suggest that PEs are better candidates for onychomycosis topical treatment than CE or ES of the examined drugs. The used drugs have shown a significant synergistic effect, and the combination with an effective drug delivery system can result in a promising drug form for the topical treatment of onychomycosis.

Antimicrobial Activity of Different Artemisia Essential Oil Formulations.

The extreme lipophilicity of essential oils (EOs) impedes the measurement of their biological actions in an aqueous environment. We formulated oil in water type Pickering Artemisia annua EO nanoemulsions (AEP) with surface-modified Stöber silica nanoparticles (20 nm) as the stabilizing agent. The antimicrobial activity of AEP and its effects on mature Candida biofilms were compared with those of Tween 80 stabilized emulsion (AET) and ethanolic solution (AEE) of the Artemisia EO. The antimicrobial activity was evaluated by using the minimum inhibitory concentrations (MIC90) and minimum effective concentrations (MEC10) of the compounds. On planktonic bacterial and fungal cells beside growth inhibition, colony formation (CFU/mL), metabolic activity, viability, intracellular ATP/total protein (ATP/TP), along with reactive oxygen species (ROS) were also studied. Artemisia annua EO nanoemulsion (AEP) showed significantly higher antimicrobial activity than AET and AEE. Artemisia annua EO nanoemulsions (AEP) generated superoxide anion and peroxides-related oxidative stress, which might be the underlying mode of action of the Artemisia EO. Unilamellar liposomes, as a cellular model, were used to examine the delivery efficacy of the EO of our tested formulations. We could demonstrate higher effectiveness of AEP in the EO components' donation compared to AET and AEE. Our data suggest the superiority of the AEP formulation against microbial infections.