Improving the Dissolution Rate and the Bioavailability of Favipiravir by Solid Dispersion with Curcumin

Favipiravir is an anti-viral agent that inhibits RNA-dependent RNA polymerase of several RNA viruses and is approved for the treatment of influenza in Japan. It has a role as an antiviral drug, an anti-coronaviral (COVID-19) agent but the poor solubility of the favipiravir in the aqueous media of the human body cause a reduction in the effectiveness and bioavailability. In the current work, the favipiravir was formulated for the first time as solid dispersed system with curcumin to improve dissolution property and antiviral activity during treatment of Covid-19. Binary and ternary mix of favipiravir and curcumin with/without soluplus were prepared and characterized by Differential Scanning Calorimetry (DSC), Powder X-ray Diffractometry (PXRD) and Fourier Transform Infrared Spec-troscopy (FTIR) and subjected to the dissolution test by apparatus I according to the European Pharma-copeia. The antiviral activity was measured by its cytotoxicity against A549-hACE2 cells. The results re-vealed that there was a reduction in the crystallinity of both binary and ternary mixtures with an en-hancement of the dissolution in comparison with the pure drug which accompanied by an improvement in the antiviral activity which is promising results that need further .Copyright © 2023, Colegio de Farmaceuticos de la Provincia de Buenos Aires. All rights reserved.

Development of thermosensitive hydrogel of Amphotericin-B and Lactoferrin combination-loaded PLGA-PEG-PEI nanoparticles for potential eradication of ocular fungal infections: In-vitro, ex-vivo and in-vivo studies.

The most prevalent conditions among ocular surgery and COVID-19 patients are fungal eye infections, which may cause inflammation and dry eye, and may cause ocular morbidity. Amphotericin-B eye drops are commonly used in the treatment of ocular fungal infections. Lactoferrin is an iron-binding glycoprotein with broad-spectrum antimicrobial activity and is used for the treatment of dry eye, conjunctivitis, and ocular inflammation. However, poor aqueous stability and excessive nasolacrimal duct draining impede these agens' efficiency. The aim of this study was to examine the effect of Amphotericin-B, as an antifungal against Candida albicans, Fusarium, and Aspergillus flavus, and Lactoferrin, as an anti-inflammatory and anti-dry eye, when co-loaded in triblock polymers PLGA-PEG-PEI nanoparticles embedded in P188-P407 ophthalmic thermosensitive gel. The nanoparticles were prepared by a double emulsion solvent evaporation method. The optimized formula showed particle size (177.0 ± 0.3 nm), poly-dispersity index (0.011 ± 0.01), zeta-potential (31.9 ± 0.3 mV), and entrapment% (90.9 ± 0.5) with improved ex-vivo pharmacokinetic parameters and ex-vivo trans-corneal penetrability, compared with drug solution. Confocal laser scanning revealed valuable penetration of fluoro-labeled nanoparticles. Irritation tests (Draize Test), Atomic force microscopy, cell culture and animal tests including histopathological analysis revealed superiority of the nanoparticles in reducing signs of inflammation and eradication of fungal infection in rabbits, without causing any damage to rabbit eyeballs. The nanoparticles exhibited favorable pharmacodynamic features with sustained release profile, and is neither cytotoxic nor irritating in-vitro or in-vivo. The developed formulation might provide a new and safe nanotechnology for treating eye problems, like inflammation and fungal infections.

Controlled release nanomedicine (CRNM) of aspirin using "biomimetic niosomal nanoparticles (BNNs)”for Covid-19 and cardiovascular treatment: DOE based optimization

Biomimetic strategies can be adopted to improve biopharmaceutical aspects. Subsequently, Biomimetic reconstitutable pegylated amphiphilic lipid nanocarriers have high translational potential for systemic controlled drug delivery;however, such an improvised system for systemic aspirin delivery exploring nanotechnology is not available. Systemic administration of aspirin and its controlled delivery can significantly control blood clotting events, leading to stroke, which has immediate applications in cardiovascular diseases and Covid-19. In this work, we are developing aspirin sustained release pegylated amphiphilic self-assembling nanoparticles to develop reconstitutable aspirin injections by solvent-based co-precipitation method with phase inversion technique that leads to novel "biomimetic niosomal nanoparticles (BNNs).” DOE led optimization is done to develop Design of space for optimized particles. Upon reconstitution of solid powder, the particle size was 144.8 ± 12.90 nm with a surface charge of -29.2 ± 2.24 mV. The entrapment efficiency was found to be 49 ± 0.15%, wherein 96.99 ± 1.57% of the drug was released in 24hr showing super case II transport-based drug release mechanism. The formulation has the least hemolysis while showing significant suppression of platelet aggregation. MTT assay does not show any significant cytotoxicity. This is a potential nanoparticle that can be explored for developing aspirin injection, which is not available.

Biobased polymer SF/PHBV composite nanofiber membranes as filtration and protection materials

With the emergence of the COVID-19, masks and protective clothing have been used in huge quantities. A large number of non-degradable materials have severely damaged the ecological environment. Now, people are increasingly pursuing the use of environmentally friendly materials to replace traditional chemical materials. Silk fibroin (SF) and Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) have received increasing attention because of their unique biodegradability and biocompatibility. In this paper, a series of biodegradable SF/PHBV nanofiber membranes with different PHBV content were fabricated by using electrospinning technology. The morphology of the electrospun SF/PHBV composite nanofiber was observed by scanning electron microscopy (SEM). The average diameters of the pure SF, SF/PHBV (4/1), SF/PHBV (3/1), and SF/PHBV (2/1) nanofibers were 55.16 ± 12.38 nm, 75.93 ± 21.83 nm, 69.35 ± 21.55 nm, and 61.40 ± 12.31 nm, respectively. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) were used to explore the microstructure of the electrospun SF/PHBV composite nanofiber. The crystallization ability of the composite nanofiber was greatly improved with the addition of PHBV. The results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) indicated that the thermal stability of SF was better than PHBV obviously, so SF could improve the thermal stability of the composite materials within a certain range. The mechanical properties of the electrospun nanofiber membranes were evaluated by using a universal testing machine. In general, the elongation of the composite nanofiber membranes decreased, and the breaking strength increased with the addition of PHBV. The small pore size of the nanofiber membranes ensured that they had good application prospects in the field of filtration and protection. When the spinning time was 1 h, the filtration efficiency of SF/PHBV/PLA composite materials remained above 95%. © 2021 The Textile Institute.

Evaluation of the polymorphic forms of ritonavir and lopinavir in raw materials and co-milled systems.

Recently, the U.S. Food and Drug Administration (FDA) approved the first oral antiviral drug to treat mild to moderate cases of coronavirus disease. The combination of nirmatrelvir with an already used protease inhibitor class drug, ritonavir, has led to Paxlovid®. Several studies considered drug repositioning as the first trial for new drugs. The precise identification and quantification of polymorphs in raw materials and finished products are important to researchers involved in pharmaceutical development and quality control processes. In this work, we study the solid-state behavior of the antiretroviral drugs ritonavir and lopinavir in raw materials and in milled compositions. The results indicate that mixtures of ritonavir Forms I and II are found in different batches of raw materials from the same manufacturer; besides three equal crystalline samples, an amorphous batch was found in lopinavir. Furthermore, the milling process of the already amorphous lopinavir seems to facilitate the amorphization of ritonavir as well as the production of some unexpected crystalline forms of ritonavir. A phase transition of ritonavir Form I to Form II is only observed when co-milling with amorphous lopinavir. These findings reveal significant variations in phase purity of raw materials that affect the processing and solid-state properties, representing risks for the product quality.

Microwave treatment to optimize physicochemical properties of modified Busil (Xanthosoma sagittifolium) starch

COVID-19 pandemic encourages the utilization of local food sources to ensure food availability. Busil (Xanthosoma sagittifolium) was readily available and affordable in Banjarnegara Regency in the Province of Central Java in Indonesia. However, the busil starch utilization was still rare due to the low functional properties of the native busil starch. The objective of this study was to explore busil starch physicochemical characterization enhancement after microwave irradiation treatment, especially on the stability of heat processing. This research was conducted in two steps. First, microwave treatment (with a variation of energy and irradiation time) of native busil starch (NBS), and the second was modified busil starch (MBS) physicochemical characterization. A rise in amylose was observed on MBS. SEM analysis was shown MBS granules are breakdown. Through viscosity, final viscosity, setback viscosity, peak time, and the pasting temperature of MBS generally were increased. Meanwhile, peak viscosity and breakdown viscosity of MBS was decreased. Thermal properties of MBS like onset (To), peak (Tp), and conclusion (Tc) temperatures were also increased. The degree of whiteness index (DW) of MBS was decreased. FTIR analysis has shown that microwave treatment did not cause functional group alteration. XRD analysis has also demonstrated no change in the diffraction pattern but a slight change in the crystallinity index. Generally, microwave treatment leads to MBS thermal stability and potentially broaden MBS utilization on food processing product.

Estimating thermodynamic equilibrium solubility and solute-solvent interactions of niclosamide in eight mono-solvents at different temperatures.

Niclosamide is an FDA-approved oral anthelmintic drug currently being repurposed for COVID-19 infection. Its interesting applicability in multiple therapeutic indications has sparked interest in this drug/ scaffold. Despite its therapeutic use for several years, its detailed solubility information from Chemistry Manufacturing & Controls perspective is unavailable. Thus, the present study is intended to determine the mole fraction solubility of niclosamide in commonly used solvents and cosolvents at a temperature range of 298.15-323.15 K. The polymorphic changes from crystalline to monohydrate forms post-equilibration in various solvents were observed. The maximum mole fraction solubility of niclosamide at 323.15 K is 1.103 × 10-3 in PEG400, followed by PEG200 (5.272 × 10-4), 1-butanol (3.047 × 10-4), 2-propanol (2.42 × 10-4), ethanol (1.66 × 10-4), DMSO (1.52 × 10-4), methanol (7.78 × 10-5) and water (3.27 × 10-7). The molecular electrostatic potential showed a linear correlation with the solubility. PEG400 has higher electrostatic potential, and H-bond acceptor count, which forms a hydrogen bond with phenolic -OH of niclosamide and thus enhances its solubility. This data is valuable for the drug discovery and development teams working on the medicinal chemistry and process chemistry of this scaffold.

Preparation, Cellular Uptake, and Cytotoxic Evaluation of Remdesivir-Hydroxypropyl-ß-Cyclodextrin Inclusion Complex

Covid-19 was mainly treated by a broad-spectrum antiviral called Remdesivir. A truncated cone molecular structure of Hydroxypropyl-ß-cyclodextrin can enhance the solubility and cellular uptake of the poorly soluble drug's through biological membranes. This study aimed to synthesize, characterize, observe cellular uptake and evaluate the cytotoxicity of remdesivirhydroxypropyl-ß-cyclodextrin (RDV-HPßCD) inclusion complex. The RDV-HPßCD inclusion complex was synthesized by the solvent evaporation method. Furthermore, the inclusion complex characteristic was evaluated by ultraviolet-visible (UV-Vis) spectrophotometry;particle size analyzer (PSA);Fourier infrared spectrophotometry (FTIR);X-ray diffraction (XRD);and differential scanning calorimetry (DSC). Further, fluorescence microscopy was used to evaluate the cellular uptake and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used in the cytotoxicity study. In the UV-Vis spectrum, both the inclusion complex and pure remdesivir showed a maximum peak at 246 nm. The inclusion complex has a particle size of 1697 ± 738.02 nm with -22.4 ± 1.58 mV of zeta potential. Shifted FTIR spectrum, broad XRD peak, and broad DSC thermogram peak at 72.93 °C indicated the successful formation of the RDV-HPßCD inclusion complex. Furthermore, cellular uptake observation of RDV-HPßCD inclusion complex conjugated to FITC showed better intensity inside the Vero cell than pure remdesivir conjugated to FITC. Further, Inclusion complex showed higher cell viability than pure remdesivir at a certain concentration.

A Biopharmaceutical Perspective on Higher-Order Structure and Thermal Stability of mRNA Vaccines.

Preservation of the integrity of macromolecular higher-order structure is a tenet central to achieving biologic drug and vaccine product stability toward manufacturing, distribution, storage, handling, and administration. Given that mRNA lipid nanoparticles (mRNA-LNPs) are held together by an intricate ensemble of weak forces, there are some intriguing parallels to biologic drugs, at least at first glance. However, mRNA vaccines are not without unique formulation and stabilization challenges derived from the instability of unmodified mRNA and its limited history as a drug or vaccine. Since certain learning gained from biologic drug development may be applicable for the improvement of mRNA vaccines, we present a perspective on parallels and contrasts between the emerging role of higher-order structure pertaining to mRNA-LNPs compared to pharmaceutical proteins. In a recent publication, the location of mRNA encapsulated within lipid nanoparticles was identified, revealing new insights into the LNP structure, nanoheterogeneity, and microenvironment of the encapsulated mRNA molecules [Brader et al. Biophys. J. 2021, 120, 2766]. We extend those findings by considering the effect of encapsulation on mRNA thermal unfolding with the observation that encapsulation in LNPs increases mRNA unfolding temperatures.

Development and in vitro Evaluation of Atazanavir Microcrystals for Intranasal Delivery

Background: Nasal route of drug administration has gained popularity nowadays specially for drugs acting on nasopulmonary area. Atazanavir is an antiviral drug which has proved efficacy in different viral infection including COVID-19. Therefore the hypothesis is, if given through intra nasal route this formulation will be able to prevent the viral infection like COVID-19 by directly acting on the virus at its entry point. Objectives: This study aims to prepare a stable mucoadhesive microcrystal formulation of this antiviral drug with good permeation for intra nasal delivery. Materials and Methods: The formulation was prepared by high-speed homogenization process. Prepared microcrystals were estimated for in vitro drug release and permeation, drug excipient interaction study by DSC, FTIR and in vitro mucoadhesiveness study on agar gel plate. A short-term stability study was conducted on all formulations for 6 months. Results: The melting point and absorbance maxima of atazanavir were found as 200.9°C and 248 nm. The DSC and FTIR study results confirmed no drug excipient interaction was there in the formulation. The particle size of the formulations was found as 5-11 µm in range. Drug release was better and faster from the microcrystals as compare to pure powder drug. The flux for microcrystal formulation was found to be 100 whereas flux for the pure drug powder was 24. Formulations had sufficient mucoadhesive strength due to incorporation of HPMC 400 polymer and they were found stable after six months stability study. Conclusion: Lastly, it can be concluded that this formulation would be a promising system for the delivery through intra nasal route as it showed good drug release and permeation during a short time span in in vitro nasal condition with a particle size range suitable for intranasal delivery. However, further in vivo studies are required to confirm the hypothesis.

Chemical, Thermal, and Rheological Performance of Asphalt Binder Containing Plastic Waste

In order to meet the environmental needs caused by large plastic waste accumulation, in the road construction sector, an effort is being made to integrate plastic waste with the function of polymer into asphalt mixtures;with the purpose of improving the mechanical performance of the pavement layers. This study focuses on the effect of a recycled mixture of plastic waste on the chemical, thermal, and rheological properties of designed asphalt blends and on the identification of the most suitable composition blend to be proposed for making asphalt mixture through a dry modification method. Thermo-gravimetric analysis, differential scanning calorimetry, and Fourier transform infrared spectroscopy analysis were carried out to investigate the effect of various concentrations and dimensions of plastic waste (PW) on the neat binder (NB). The frequency sweep test and the multiple stress creep and recovery test were performed to analyze the viscoelastic behavior of the asphalt blends made up of PW in comparison with NB and a commercial modified bitumen (MB). It has been observed that the presence of various types of plastic materials having different melting temperatures does not allow a total melting of PW powder at the mixing temperatures. However, the addition of PW in the asphalt blend significantly improved the aging resistance without affecting the oxidation process of the plastic compound present in the asphalt blend. Furthermore, when the asphalt blend mixed with 20% PW by the weight of bitumen is adopted into the asphalt mixture as polymer, it improves the elasticity and strengthens the mixture better than the mixture containing MB.

Sulfobutylether-beta-cyclodextrin-enabled antiviral remdesivir: Characterization of electrospun- and lyophilized formulations.

Veklury™ by Gilead Sciences, Inc., containing antiviral drug, remdesivir (REM) has received emergency authorization in the USA and in Europe for COVID-19 therapy. Here, for the first time, we describe details of the non-covalent, host-guest type interaction between REM and the solubilizing excipient, sulfobutylether-beta-cyclodextrin (SBECD) that results in significant solubility enhancement. Complete amorphousness of the cyclodextrin-enabled REM formulation was demonstrated by X-ray diffraction, thermal analysis, Raman chemical mapping and electron microscopy/energy dispersive spectroscopy. The use of solubilizing carbohydrate resulted in a 300-fold improvement of the aqueous solubility of REM, and enhanced dissolution rate of the drug enabling the preparation of stable infusion solutions for therapy. 2D ROESY NMR spectroscopy provided information on the nature of REM-excipient interaction and indicated the presence of inclusion phenomenon and the electrostatic attraction between anionic SBECD and nitrogen-containing REM in aqueous solution.