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.

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.

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.

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.

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.

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.

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.

Application of halloysite clay nanotubes as a pharmaceutical excipient.

Halloysite nanotubes, a biocompatible nanomaterial of 50-60nm diameter and ca. 15nm lumen, can be used for loading, storage and sustained release of drugs either in its pristine form or with additional polymer complexation for extended release time. This study reports the development composite tablets based on 50wt.% of the drug loaded halloysite mixed with 45wt.% of microcrystalline cellulose. Powder flow and compressibility properties of halloysite (angle of repose, Carr's index, Hausner ratio, Brittle Fracture Index, tensile strength) indicate that halloysite is an excellent tablet excipient. Halloysite tubes can also be filled with nifedipine with ca. 6wt.% loading efficiency and sustained release from the nanotubes. Tablets prepared with drug loaded halloysite allowed for almost zero order nifedipine release for up to 20h. Nifedipine trapped in the nanotubes also protect the drug against light and significantly increased the photostability of the drug. All of these demonstrate that halloysite has the potential to be an excellent pharmaceutical excipient that is also an inexpensive, natural and abundantly available material.

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.

Differences in physicochemical properties to consider in the design, evaluation and choice between microparticles and nanoparticles for drug delivery.

INTRODUCTION: The increase in the development of novel nanoparticle drug delivery systems makes the choice between micro- and nanoscale drug delivery systems ubiquitous. Changes in physical and chemical properties between micro- to nanosized particles give them different properties that influence their physiological, anatomical and clinical behavior and therefore potential application. AREAS COVERED: This review focuses on the effect changes in the surface-to-volume ratio have on the thermal properties, solubility, dissolution and crystallization of micro- versus nanosized drug delivery systems. With these changes in the physicochemical properties in mind, the review covers computational and biophysical approaches to the design and evaluation of micro- and nanodelivery systems. The emphasis of the review is on the effect these properties have on clinical performance in terms of drug release, tissue retention, biodistribution, efficacy, toxicity and therefore choice of delivery system. EXPERT OPINION: Ultimately, the choice between micro- and nanometer-sized delivery systems is not straightforward. However, if the fundamental differences in physical and chemical properties are considered, it can be much easier to make a rational choice of the appropriate drug delivery system size.

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.

Experimental and mesoscale computational dynamics studies of the relationship between solubility and release of quercetin from PEG solid dispersions.

The flavonol quercetin is potentially clinically relevant for its antimicrobial, beneficial cardiovascular effects, cancer treatment amongst others. However, its successful therapeutic application is severely curtailed by its poor water solubility and poor absorption following oral administration. In this study, solid dispersions of quercetin in poly(ethylene glycol) (PEG) at various compositions demonstrated an increase in the solubility, however with time, dissolution profiles show a decrease in dissolved flavonol concentration. The mechanism by which this decrease in solubility occurs was studied experimentally as well as by computational mesocscale particle dynamics simulations. The results suggest that phase separation of the polymer and flavonol during release from the solid dispersion is responsible for the time-dependent decrease in dissolved quercetin. It is suggested that the increase in release of quercetin in a PEG solid dispersion would only be beneficial if it were administered at the site of absorption, e.g. rectal administration, to ensure absorption prior to phase separation. The solid dispersions presented here would greatly improve the pharmaceutical availability of the flavonol at the site of absorption. Computational mesoscopic modeling was successfully applied to study the solid dispersions and corroborate experimental findings.

Photostability of crystalline versus amorphous nifedipine and nimodipine.

True solid-state photostability of the drugs nifedipine and nimodipine was investigated during exposure to UV-visible radiation. Photostability was studied on a small scale as thin films of approximately 1 mg drug, which contained either amorphous or re-crystallised stable phases. High-performance liquid chromatography analysis revealed a greater rate and extent of decomposition for the amorphous phases. Photoexposed amorphous nifedipine exhibited approximately 1.8-fold larger first-order decomposition rate constant (k) relative to its crystalline phase. The increase in k was more significant for photoexposed amorphous nimodipine at approximately sixfold relative to its crystalline phase. Photodecomposition in scaled-up samples of the stable crystalline phases for both drugs was monitored with X-ray diffraction in Bragg-Brentano geometry. The similarities in the calculated photodecomposition extents to results from small scale validated the specificity of the X-ray analysis technique to the photodecomposition region. The considerably faster decomposition rates in small-scale studies were attributed to a maximised surface area (A) for quantity (m0 ) of exposed drug. Kinetic interpretations of true solid-state stability should consider the sample solid dimensions in terms of the direct exposed A and m0 in the photodecomposition region, that is, outer layers in solid.

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.

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.