Layer-By-Layer Nanocoating of Antiviral Polysaccharides on Surfaces to Prevent Coronavirus Infections.

In 2020, the world is being ravaged by the coronavirus, SARS-CoV-2, which causes a severe respiratory disease, Covid-19. Hundreds of thousands of people have succumbed to the disease. Efforts at curing the disease are aimed at finding a vaccine and/or developing antiviral drugs. Despite these efforts, the WHO warned that the virus might never be eradicated. Countries around the world have instated non-pharmaceutical interventions such as social distancing and wearing of masks in public to curb the spreading of the disease. Antiviral polysaccharides provide the ideal opportunity to combat the pathogen via pharmacotherapeutic applications. However, a layer-by-layer nanocoating approach is also envisioned to coat surfaces to which humans are exposed that could harbor pathogenic coronaviruses. By coating masks, clothing, and work surfaces in wet markets among others, these antiviral polysaccharides can ensure passive prevention of the spreading of the virus. It poses a so-called "eradicate-in-place" measure against the virus. Antiviral polysaccharides also provide a green chemistry pathway to virus eradication since these molecules are primarily of biological origin and can be modified by minimal synthetic approaches. They are biocompatible as well as biodegradable. This surface passivation approach could provide a powerful measure against the spreading of coronaviruses.

Coarse-Grained Molecular Dynamics (CG-MD) Simulation of the Encapsulation of Dexamethasone in PSS/PDDA Layer-by-Layer Assembled Polyelectrolyte Nanocapsules.

Experimental studies have reported the fundamental and applied science aspects of polyelectrolyte (PE) layer-by-layer (LbL) self-assembly. LbL nanocoating is a simple and robust technique that can be used to modify the surface properties of nearly any material. These modifications take place by adsorption of mere nanometers of PE to impart previously absent properties to the nanocoated substrate. Paper manufacturing, drug delivery, and antimicrobial applications have since been developed. LbL self-assembly has become a very lucrative field of research. Computational modeling of LbL nanocoating has received limited attention. PE simulations often require significant computational resources and make computational modeling studies challenging. In this study, atomic-level PE and dexamethasone models are developed and then converted into coarse-grained (CG) models. This modeling study is based on experimental results that were previously reported. The CG models showed the effect of salt concentration and the number of PE layers on the LbL drug nanocapsule. The suitability of the model was evaluated and showed that this model can serve as a predictive tool for an LbL-nanocoated drug delivery system. It is suggested that this model can be used to simulate LbL drug delivery systems before the experimental evaluation of the real systems take place.

Prevention of biofilm formation by methacrylate-based copolymer films loaded with rifampin, clarithromycin, doxycycline alone or in combination.

PURPOSE: This study reports the incorporation of the antibiotics rifampin, doxycycline and clarithromycin in poly(styrene-co-methyl methacrylate films and their effect on biofilm prevention. BACKGROUND: Invasive procedures in patients such as surgical device, or intravenous or urinary catheter implantation, often results in complicated hospital-acquired nosocomial infections. Biofilm formation is essential to establish these infections on these devices and novel antibiotic delivery approaches are needed for more effective management. METHODS: The films were evaluated in vitro for drug release and for their ability to prevent biofilm formation by methicillin susceptible and methicillin resistant Staphylococcus aureus. Surface tension components, obtained from contact angle measurements, and the morphology of the films evaluated by scanning electron microscopy were also investigated. RESULTS: In this study, antibiotic-loaded methacrylic copolymer films that effectively released rifampin, clarithromycin and doxycycline for up to 21 days prevented biofilm formation when tested in an in vitro bioreactor model. These drug loaded copolymer films provided the advantage by coating materials with a novel surface that was unsuitable for resettling of biofilms once the antibiotic was dissolved from the polymer surface. A combination of rifampin and clarithromycin released from the polymer film provided >99.9% kill of an MRSA inoculate for up to 72 h. CONCLUSION: Results showed that combining multiple drugs in copolymer films with unique surface properties, initial hydrophilicity and increase in roughness, can be an effective way to prevent biofilm formation.

A method to evaluate the effect of contact with excipients on the surface crystallization of amorphous drugs.

Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the ß polymorph from two to five times when samples were stored in a desiccator, while D-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.

Cocrystals of nicotinamide and (R)-mandelic acid in many ratios with anomalous formation properties.

We report a remarkable system of cocrystals containing nicotinamide (NIC) and (R)-mandelic acid (RMA) in numerous stoichiometric ratios (4:1, 1:1 in two polymorphs, and 1:2) with anomalous formation properties. The formation of these cocrystals decreases energy but expands volume, in contrast to most physical processes, but similar to water freezing. The decrease of energy upon cocrystallization agrees with the exothermic mixing of NIC and RMA liquids (a base and an acid). Volume expansion is general for the formation of all NIC cocrystals for which data exist (n = 40): +3.9 Å(3)/molecule or +17 cm(3)/kg on average, corresponding to a 2% expansion. This volume expansion correlates with the shortening and strengthening of hydrogen bonds upon cocrystallization, analogous to water freezing. The NIC-RMA binary phase diagram was constructed that contains the congruent and incongruent melting of six crystalline phases. These results are relevant for understanding the nature of cocrystallization and why some molecules are prolific cocrystal formers.

Poly(amidoamine) dendrimer-mediated synthesis and stabilization of silver sulfonamide nanoparticles with increased antibacterial activity.

Silver sulfadiazine (AgSD) is a topical antibiotic with limited aqueous solubility. In this study, it was shown that poly(amido amine) (PAMAM) dendrimer complexes with SD (SDZ) and silver (Ag) could be used for a bottom-up approach to synthesize highly-soluble AgSD nanoparticles (NPs). These NPs were stabilized against crystal growth by electrostatic layer-by-layer (LBL) coating with various PAMAM dendrimers. Additionally, AgNPs can be incorporated in the dendrimer shells that augmented AgSD release. NP formulation in a cream base provided a topical drug-delivery platform with enhanced antibacterial properties against burn-wound infections, comprising three nanostructures i.e., nano-AgSD, AgNPs as well as PAMAM dendrimers, in one efficient, elegant nanosystem. FROM THE CLINICAL EDITOR: In this paper an elegant silver sulfadiazine-based nanoparticle complex is demonstrated with enhanced antibacterial properties and improved solubility for the treatment of burn-wound infections in a topical crème formulation.

The experimental evaluation and molecular dynamics simulation of a heat-enhanced transdermal delivery system.

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.

Entropy-Driven Liquid-Liquid Phase Separation Transition to Polymeric Micelles.

In recent years, liquid-liquid phase separation (LLPS) has been recognized to act as a precursor to self-assembly in amphiphilic systems. In this study, we propose the use of entropy-driven LLPS to obtain a tunable precursor for polymeric micelle formation. In this new approach, an oligomer is utilized as a nonselective solvent for the block copolymer, allowing for the tuning of entropy and subsequent LLPS. A comprehensive model was developed using mean-field lattice theory to predict the conditions under which LLPS and micellization occur. The degree of polymerization of the solvent was found to have a significant impact on the phase behavior of the system, outweighing enthalpic contributions such as the interaction between the blocks of the copolymer and the solvent. Our model predicts that using a solvent with a degree of polymerization equal to or greater than 5 for a copolymer such as PEG4kDa-b-PLA2.2kDa will result in LLPS prior to complete micellization, regardless of the values of interaction parameters. It also suggests that phase-separated liquid and polymeric micelles can co-exist in such a mixture. We confirmed our model predictions using dynamic light scattering and phase microscopy when PEG200 was used as the solvent. Micellization for PEG4kDa-b-PLA2.2kDa/PEG200/water mixture occurred at 10-12% w/w water content, consistent with the model predictions. Furthermore, the LLPS-to-micelle transition was shown to be reversible by changing the temperature or water content, indicating that the phase-separated liquid may be in thermodynamic equilibrium with polymeric micelles.

Physicochemical properties of amorphous roxithromycin prepared by quench cooling of the melt or desolvation of a chloroform solvate.

Roxithromycin is a poorly soluble antibacterial drug. The aim of this study was to prepare and characterize an amorphous form of roxithromycin. The amorphous form was prepared by desolvation of its chloroform solvate, and by quench cooling a melt of the crystalline monohydrated solid. The X-ray powder diffraction pattern of the desolvated chloroform solvate was indistinguishable from that of the glass prepared by melting, which indicated that it was amorphous. The roxithromycin glass was determined to be a fragile glass, but due to its high Kauzmann temperature (approximately 8°C), it should remain fairly stable upon refrigeration or even at room temperature. It was also determined that this glass remains stable in the presence of moisture with no indication of crystallization.

In Vitro Skin Delivery of Griseofulvin by Layer-by-Layer Nanocoated Emulsions Stabilized by Whey Protein and Polysaccharides.

Griseofulvin is a poorly water-soluble drug administered orally to treat topical fungal infections of the skin and hair. However, oral administration leads to poor and unpredictable drug pharmacokinetics. Additionally, griseofulvin is unstable in the presence of light. A layer-by-layer (LbL) nanocoating approach was employed to curb these shortcomings by stabilizing emulsions, lyophilized emulsions, and reconstituted emulsions with a layer each of whey protein, and either hyaluronic acid, amylopectin, or alginic acid, which captured the drug. The coating materials are biological, environmentally benign, and plentiful. Photostability studies indicated that the LbL particles afforded 6 h of protection of the topical application. In vitro absorption studies showed that griseofulvin concentrated preferentially in the stratum corneum, with virtually no transdermal delivery. Therefore, LbL-nanocoated emulsions, lyophilized particles, and reconstituted lyophilized emulsions can produce a viable topical delivery system to treat superficial fungal infections.

Crystallization of toxic glycol solvates of rifampin from glycerin and propylene glycol contaminated with ethylene glycol or diethylene glycol.

This study was initiated when it was suspected that syringe blockage experienced upon administration of a compounded rifampin suspension was caused by the recrystallization of toxic glycol solvates of the drug. Single crystal X-ray structure analysis, powder X-ray diffraction, thermal analysis and gas chromatography were used to identify the ethylene glycol in the solvate crystals recovered from the suspension. Controlled crystallization and solubility studies were used to determine the ease with which toxic glycol solvates crystallized from glycerin and propylene glycol contaminated with either ethylene or diethylene glycol. The single crystal structures of two distinct ethylene glycol solvates of rifampin were solved while thermal analysis, GC analysis and solubility studies confirmed that diethylene glycol solvates of the drug also crystallized. Controlled crystallization studies showed that crystallization of the rifampin solvates from glycerin and propylene glycol depended on the level of contamination and changes in the solubility of the drug in the contaminated solvents. Although the exact source of the ethylene glycol found in the compounded rifampin suspension is not known, the results of this study show how important it is to ensure that the drug and excipients comply with pharmacopeial or FDA standards.

Preparation and characterization of highly porous direct compression carrier particles with improved drug loading during an interactive mixing process.

The aim of this study was to prepare highly porous carrier particles by emulsion solvent evaporation and compare the loading capacity of these beads with two traditional carriers, sugar beads, and microcrystalline cellulose granules during an interactive mixing process. The porous carrier particles were prepared by an emulsion solvent evaporation process using cellulose propionate as a binder, anhydrous dibasic calcium phosphate, and ion exchange resins as a fillers, and polyethylene glycol as a pore inducer. Micronized furosemide or griseofulvin powder was mixed with the same volume of each carrier in an interactive mixing process. The tableting properties, drug loading per unit volume of carrier, content uniformity of the mixtures, and dissolution of the drugs from the mixtures were measured. The results showed that highly porous microcapsules with desirable hardness equivalent to that of sugar beads and MCC granules were successfully prepared. On average the loading capacity of the new carrier was 310% that of sugar beads and 320% that of MCC granules during an interactive mixing process with very good content uniformity. The tableting properties of the microcapsules were equivalent to that of microcrystalline cellulose granules, and the dissolution of the drugs from interactive mixtures prepared with the new carrier was equivalent to that of drug suspensions. This showed that the prepared microcapsule carrier could be used to improve the loading capacity during an interactive mixing and to prepare tablets by direct compression.

Development of microporous drug-releasing films cast from artificial nanosized latexes of poly(styrene-co-methyl methacrylate) or poly(styrene-co-ethyl methacrylate).

Two sets of copolymers comprising of styrene and either methyl or ethyl methacrylate as comonomer were conveniently synthesized by microemulsion copolymerization. The purified materials were characterized by GPC-MALLS and were shown to form artificial nanolatexes in THF. ATR-FTIR analysis revealed differences in copolymer composition and based on the copolymer properties, a selection of copolymers was chosen to cast drug-loaded, microporous films that exhibit microencapsulation of drug agglomerates. The contact angles of the copolymers suggested potential applications in medical devices to prevent the formation of bacterial biofilms that commonly result in infections. Additionally, the different copolymeric films showed two phases of drug release characterized by a rapid initial drug release followed by a zero-order phase. Depending on the application, one could select the copolymer films that best suited the application i.e. for short-term drug release applications such as urinary catheters or long-term applications such as artificial implants.

Effect of para-sulfonato-calix[n]arenes on the solubility, chemical stability, and bioavailability of a water insoluble drug nifedipine.

This study reports the use of para-sulphonato calix[8]arene to produce stable complexes with improved bioavailability for nifedipine, a calcium-channel blocker that is practically insoluble in water. Thermal analysis and electrospray ionisation mass spectroscopy confirmed that nifedipine formed complexes with the calixarenes in a size dependent way. The most stable, soluble complexes was formed with para-sulphonato calix[8]arene. Complexation was weakest with the calix[4]arene while complexation with the calix[6]arene was intermediate. However, the calix[4 and 6]arenes changed the chemical stability of the drug in solution because significant amounts of the nitroso-pyridine derivative was produced, proposing an interaction between the nifedipine bearing a H substituent at the N-1 position and the calixarenes. This oxidative degradation of the drug was greatest when combined with the calix[6]arene. Simultaneous oral ingestion of the calix[6 or 8]arenes significantly increased the bioavailability of the drug after oral administration in male Sprague-Dawley rats while not influencing CYP3A activities in the liver. The pharmacokinetic parameters of the nifedipine: para-sulfonato calix[8]arene complexes showed it was bioequivalent to a nifedipine PEG-solution. The absolute bioavailability for both formulations was ca. 60 %.

All-atomistic molecular dynamics (AA-MD) studies and pharmacokinetic performance of PAMAM-dendrimer-furosemide delivery systems.

Improvement of problematic dissolution and solubility properties of a model drug, furosemide, was investigated for poly(amidoamine) (PAMAM) dendrimer complexes of the drug. Full and half generation dendrimers with amino and ester terminals respectively, were studied. In vitro release performance of these complexes was investigated at drug loads ranging 5-60% using simulated gastric fluids. Full generation dendrimers accommodated higher drug loads, outperformed half-generation complexes, and free drug. Pharmacokinetic studies in rats indicated that the dendrimer complexes markedly improved in the bioavailability of the drug compared to the unformulated drug. The G3.0-PAMAM dendrimer complex showed a two-fold increase in Cmax and a 1.75-fold increase in AUC over the free drug. Additionally, Tmax was shortened from approximately 25 to 20 min. One of the first all-atomistic molecular dynamics (AA-MD) simulation studies was performed to evaluate low-generation dendrimer-drug complexes as well as its pharmacokinetic performance. AA-MD provided insight into the intermolecular interactions that take place between the dendrimer and drug. It is suggested that the dendrimer not only encapsulates the drug, but can also orientate the drug in stabilized dispersion to prevent drug clustering which could impact release and bioavailability negatively. AA-MD can be a useful tool to develop dendrimer-based drug delivery systems.

Poly(amidoamine) Dendrimers as a Pharmaceutical Excipient. Are We There yet?

Drug solubility could affect the therapeutic use of a drug because the biological activity of a drug is only possible if some fraction of a dissolved drug can permeate and overcome biological membranes to reach its site of action. The solubility-permeation interplay is therefore, probably the most important factor in determining a successful therapeutic outcome of any drug because more than 40% of marketed drugs and more than 70% of pipeline drugs show poor water solubility. Several solubilization techniques are used and include, balancing of pH-pKa properties, employment of cosolvents, and the solubilization by host-guest carriers. A relatively new addition to the polymer plethora of solubilizers are the poly(amidoamine) dendrimers. These highly branched, "tree-like" nanocarriers have a significant solubilization capacity for drugs in their cavities and also potentially via their terminals. Despite their successful solubilization capability, they are still plagued by some undesired properties such as cytotoxicity. Poly(amidoamine) however, seems to be a very lucrative target to develop into a pharmaceutical excipient, which will ultimately be confirmed by an official pharmacopeial monograph.

Dissipative Particle Dynamics Investigation of the Transport of Salicylic Acid through a Simulated In Vitro Skin Permeation Model.

Permeation models are often used to determine diffusion properties of a drug through a membrane as it is released from a delivery system. In order to circumvent problematic in vivo studies, diffusion studies can be performed in vitro, using (semi-)synthetic membranes. In this study salicylic acid permeation was studied, employing a nitrocellulose membrane. Both saturated and unsaturated salicylic acid solutions were studied. Additionally, the transport of salicylic acid through the nitrocellulose membrane was simulated by computational modelling. Experimental observations could be explained by the transport mechanism that was revealed by dissipative particle dynamics (DPD) simulations. The DPD model was developed with the aid of atomistic scale molecular dynamics (AA-MD). The choice of a suitable model membrane can therefore, be predicted by AA-MD and DPD simulations. Additionally, the difference in the magnitude of release from saturated and unsaturated salicylic acid and solutions could also be observed with DPD. Moreover, computational studies can reveal hidden variables such as membrane-permeant interaction that cannot be measured experimentally. A recommendation is made for the development of future model permeation membranes is to incorporate computational modelling to aid the choice of model.

Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes.

The complexation of the practically insoluble drug furosemide (acidic pK(a) 3.22) with lower generation PAMAM dendrimers showed a significant release dependence on the ionization state of the drug. UV and FTIR studies suggested that the drug was localized in the interior of the dendrimer. The dendrimer amine, amide and ester groups, demonstrated pH-dependent ionization as did the drug carboxylic acid group and it was proven that the most efficient drug complexation was achieved in slightly acidic conditions (pH 4.0-6.0). At this pH, amide groups in the dendrimer cavities were at least partially ionized to expose a positive charge whilst the furosemide carboxylic acid ionized to great extent (pH>pK(a)) resulting in electrostatic complexation. Conversely, higher release rates were observed in acidic conditions (pH 1.2) where furosemide was virtually unionized, emphasizing the importance of the drug ionization state in the determination of drug release. Despite the complex interactions between the dendrimer and drug and its effects on release kinetics, the dendrimers resulted in higher solubility of the drug and contributed significantly to the array of available techniques to increase the solubility of poorly water-soluble drugs that are very abundant in industry today. Complexation with low generation PAMAM dendrimers (

Solid State Concerns During Drug Discovery and Development: Thermodynamic and Kinetic Aspects of Crystal Polymorphism and the Special Cases of Concomitant Polymorphs, Co-Crystals and Glasses.

During drug discovery and development the thermodynamics and kinetics of crystal form transitions must be studied and the fundamental properties of polymorphs must be identified. However, despite the accumulation of knowledge and experimental evidence that support the understanding of crystallization, its predictability still presents significant challenges. With the continuous development of new drug delivery technologies, even more complex situations arise such as difficult cases of polymorph selection, co-crystallization of different molecules, and manipulation of the crystallization environment for example amorphous solids. This review covers some fundamental thermodynamics and kinetics of simple system, before the discussions consider at these special cases and how the manipulation of thermodynamic and kinetic processes has increased our knowledge, understanding and application of crystallization science during the drug development process.

Paclitaxel Encapsulated in Halloysite Clay Nanotubes for Intestinal and Intracellular Delivery.

Naturally formed halloysite tubules have a length of 1 µm and lumens with a diameter of 12-15 nm which can be loaded with drugs. Halloysite's biocompatibility allows for its safe delivering to cells at a concentration of up to 0.5 mg/mL. We encapsulated the anticancer drug paclitaxel in halloysite and evaluated the drug release kinetics in simulated gastric and intestinal conditions. To facilitate maximum drug release in intestinal tract, halloysite tubes were coated with the pH-responsive polymer poly(methacrylic acid-co-methyl methacrylate). Release kinetics indicated a triggered drug release pattern at higher pH, corresponding to digestive tract environment. Tablets containing halloysite, loaded with paclitaxel, as a compression excipient were formulated with drug release occurring at a sustained rate. In vitro anticancer effects of paclitaxel-loaded halloysite nanotubes were evaluated on human cancer cells. In all the treated cell samples, polyploid nuclei of different sizes and fragmented chromatin were observed, indicating a high therapeutic effect of halloysite formulated paclitaxel.