A Peptoid-like Approach Led to Lactam-Lactam Dimer Formation in 2-Hydroxy-N-alkyl-N-phenyl-nicotinamides and Their Polymorphism and Solvatomorphism.

Four 2-hydroxy-N-alkyl-N-phenyl-nicotinamides (1-4) were synthesized, and their crystal structures were analyzed to investigate the effect of substitution on their crystal packing of N-phenyl-2-hydroxynicotinanilides. In these compounds, substituents were introduced on the amide N, leading to a peptoid-like structure. One solvent-free form and two hydrates were harvested for compound 1, and one anhydrous form and one hydrate were obtained for compound 2. Polymorphism was observed in compounds 3 and 4. The molecules were found to be in the keto form rather than the enol tautomer. Because of steric effects, the molecules took on an E configuration, leading to a hairpin-like geometry. A lactam-lactam dimer synthon was formed in all solvent-free structures, and a tetramer motif was observed for the first time. Dehydration of the two hydrates of 1 and the hydrate of 2 led to their respective solvent-free form. Phase transition between the polymorphs was revealed in compound 3. Theoretical calculations, including conformational energy evaluation, hydrate forming propensity assessment, and lattice energy appraisal, were performed to provide a reasonable explanation for the keto tautomer and the formation of the hydrates of compound 1.

Multiphysics-Informed Pharmacokinetic Modeling of Systemic Exposure of Intramuscularly Injected LNPs.

Lipid nanoparticle (LNP) constructs have been widely developed for gene therapy delivery. Understanding local absorption and presystemic clearance kinetics of LNPs, however, remains limited. This subsequently restrains the prediction and assessment of the systemic exposure of locally injected LNPs. As such, a multiscale computational approach was developed by integrating multiphysics simulation of intramuscular absorption kinetics of LNPs with whole-body pharmacokinetics modeling, bridged by a presystemic lymphatic kinetic model. The overall framework was enabled by utilizing physiological parameters obtained from the literature and drug-related parameters derived from experiments. The multiscale modeling and simulation approach predicted the systemic exposure of LNPs administered intramuscularly, with a high degree of agreement between the predicted and the experimental data. Sensitivity analyses revealed that the local absorption rate, pinocytosis presystemic clearance rate, and lymph flow rate of the presystemic lymphatic compartment had the most significant impacts on Cmax. The study yielded refreshing perspectives on estimating systemic exposures of locally injected LNPs and their safety and effectiveness.

A Perspective on Model-Informed IVIVC for Development of Subcutaneous Injectables.

Subcutaneously administered drugs are growing in popularity for both large and small molecule drugs. However, development of these systems - particularly generics - is slowed due to a lack of formal guidance regarding preclinical testing and in vitro - in vivo correlations (IVIVC). Many of these methods, while appropriate for oral drugs, may not be optimized for the complex injection site physiologies, and release rate and absorption mechanisms of subcutaneous drugs. Current limitations for formulation design and IVIVC can be supported by implementing mechanistic, computational methods. These methods can help to inform drug development by identifying key drug and formulation attributes, and their effects on drug release rates. This perspective, therefore, addresses current guidelines in place for oral IVIVC development, how they may differ for subcutaneously administered compounds, and how modeling and simulation can be implemented to inform design of these products. As such, integration of modeling and simulation with current IVIVC systems can help in driving the development of subcutaneous injectables.

Solvatomorphism and first-time observation of acid-acid catemer in 4-phenylamino-benzoic acids.

To investigate the polymorphism in 4-phenylamino-benzoic acids (4-PABAs) in general, and the effect on the polymorphism of these compounds exerted by substitution in particular, a series of 4-PABAs (1-8) varying in the substitution position and pattern were synthesized, and their polymorphic behavior was investigated for the first time. A relatively comprehensive polymorph screening led to the discovery of two forms, one solvent-free and the other solvate, for compounds 1, 3 and 8, and one form for the other compounds. The crystal structures were determined by single-crystal XRD. All the 4-PABAs in the crystal structures are highly twisted, and all the solvent-free crystals are based on the conventional acid-acid dimer motif, except for 2, which has a rarely observed acid-acid catemer motif. Two of the solvates (1-S and 8-S) have pyridine in the lattice while the other (3-S) has dichloromethane. The observation indicates that neither conformational flexibility or substitution alone nor the combination of both leads to polymorphism in these compounds, which is in dramatic contrast to the polymorphism of fenamic acids. The thermal properties of each system were investigated by differential scanning calorimetry and desolvation of the solvates was studied by thermogravimetric analysis. Hirshfeld surface analysis and molecular dynamics simulation were performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the formation and stability of each crystal form.

Multiphysics modeling and simulation of local transport and absorption kinetics of intramuscularly injected lipid nanoparticles.

Recent clinical applications of mRNA vaccines highlight the critical role of drug delivery, especially when using lipid nanoparticles (LNPs) as the carrier for genetic payloads. However, kinetic and transport mechanisms for locally injected LNPs, such as lymphatic or cellular uptake and drug release, remain poorly understood. Herein, we developed a bottom-up multiphysics computational model to simulate the injection and absorption processes of LNPs in muscular tissues. Our purpose was to seek underlying connections between formulation attributes and local exposure kinetics of LNPs and the delivered drug. We were also interested in modeling the absorption kinetics from the local injection site to the systemic circulation. In our model, the tissue was treated as the homogeneous, poroelastic medium in which vascular and lymphatic vessel densities are considered. Tissue deformation and interstitial fluid flow (modeled using Darcy's Law) were also implemented. Transport of LNPs was described based on diffusion and advection; local disintegration and cellular uptake were also integrated. Sensitivity analyses of LNP and drug properties and tissue attributes were conducted using the simulation model. It was found that intrinsic tissue porosity and lymphatic vessel density affect the local transport kinetics; diffusivity, lymphatic permeability, and intracellular update kinetics also play critical roles. Simulated results were commensurate with experimental observations. This study could shed light on the development of LNP formulations and enable further development of whole-body pharmacokinetic models.

Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

INTRODUCTION: Subcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood. OBJECTIVE: To bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products. METHODOLOGY: We have previously developed a multiscale, multiphysics computational model to simulate lymphatic absorption and whole-body pharmacokinetics of monoclonal antibodies. The same simulation framework was applied in this study to compute the capillary absorption of solubilized small molecule drugs that are injected subcutaneously. Sensitivity analyses were conducted to probe the impact by key simulation parameters on the local and systemic exposures. RESULTS: This framework was capable of determining which parameters had the biggest impact on small molecule absorption in the SC. Particularly, membrane permeability of a drug was found to have the biggest impact on drug absorption kinetics, followed by capillary density and drug diffusivity. CONCLUSION: Our modelling framework proved feasible in predicting local transport and systemic absorption from the injection site of small molecules. Understanding the effect of these properties and how to model them may help to greatly expedite the development process.

Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals.

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPßCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization. Then, the surface of the prepared PTX-NCs was modified using the HPßCD coat (HPßCD-PTX-NCs). The prepared nanocrystals, both coated and uncoated, were characterized in terms of size, polydispersity index, charge, morphology, and stability. Moreover, the nanocrystals were investigated using powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). As well, the in vitro release of PTX from the nanocrystals was determined under conditions similar to the IV route of administration. Furthermore, the tendency of the nanocrystals to induce hemolysis was investigated. Results indicated that the size was about 241.4 and 310.5 nm, the polydispersity index was 0.14 and 0.21, and the zeta potential was about - 22.6 and - 16.4 mV for PTX-NCs and HPßCD-PTX-NCs, respectively. Additionally, the PXRD, FTIR, and DSC profiles can be explained by the NCs' integrity and coat formation. The SEM images showed that both PTX-NCs and HPßCD-PTX-NCs have rod-like structures. Moreover, HPßCD-PTX-NCs had significantly superior in vitro release than both PTX-NCs and PTX. Interestingly, the hemolytic assay showed that HPßCD-PTX-NCs had a more efficient and safer profile than PTX-NCs. This study emphasized that HPßCD could be an interesting candidate for the surface modification of PTX-NCs providing superior properties such as release and safety profiles.

Biological and intracellular fates of drug nanocrystals through different delivery routes: Recent development enabled by bioimaging and PK modeling.

Nanocrystals have contributed to exciting improvements in the delivery of poorly water-soluble drugs. The biological and intracellular fates of nanocrystals are currently under debate. Due to the remarkable commercial success in enhancing oral bioavailability, nanocrystals have originally been regarded as a simple formulation approach to enhance dissolution. However, the latest findings from novel bioimaging tools lead to an expanded view. Intact nanocrystals may offer long-term durability in the body and offer drug delivery capabilities like those of other nano-carriers. This review renews the understanding of the biological fates of nanocrystals administered via oral, intravenous, and parenteral (e.g., dermal, ocular, and pulmonary) routes. The intracellular pathways and dissolution kinetics of nanocrystals are explored. Additionally, the future trends for in vitro and in vivo quantification of nanocrystals, as well as factors impacting the biological and intracellular fates of nanocrystals are discussed. In conclusion, nanocrystals present a promising and underexplored therapeutic opportunity with immense potential.

Kinetic Retraction at the Onset of Concomitant Crystallization and Implication on Polymorphic Formation.

The four-quadrant regimes of attainable polymorph crystallization (FQR-APC) plot was recently developed through numerical simulations of crystallization kinetics of a dipolymorphic system. Retraction in the polymorphic composition of the most stable form in crystallized samples was unveiled a characteristic indication of concomitant polymorphism. Comparisons were made with a recently developed concept, the Ostwald ratio (OR), in light of characterization of polymorphic formation. It was shown that both schemes display a good agreement in describing polymorphic outcomes, despite their distinct theoretical origins.

Understanding Formulation and Temperature Effects on Dermal Transport Kinetics by IVPT and Multiphysics Simulation.

PURPOSE: It is often unclear how complex topical product formulation factors influence the transport kinetics through skin tissue layers, because of multiple confounding attributes. Environmental factors such as temperature effect are also poorly understood. In vitro permeation testing (IVPT) is frequently used to evaluate drug absorption across skin, but the flux results from these studies are from a combination of mechanistic processes. METHOD: Two different commercially available formulations of oxybenzone-containing sunscreen cream and continuous spray were evaluated by IVPT in human skin. Temperature influence between typical skin surface temperature (32°C) and an elevated 37°C was also assessed. Furthermore, a multiphysics-based simulation model was developed and utilized to compute the flux of modeled formulations. RESULTS: Drug transport kinetics differed significantly between the two drug products. Flux was greatly influenced by the environmental temperature. The multiphysical simulation results could reproduce the experimental observations. The computation further indicated that the drug diffusion coefficient plays a dominant role in drug transport kinetics, influenced by the water content which is also affected by temperature. CONCLUSION: The in vitro testing and bottom-up simulation shed insight into the mechanism of dermal absorption kinetics from dissimilar topical products.

Paclitaxel Drug Delivery Systems: Focus on Nanocrystals' Surface Modifications.

Paclitaxel (PTX) is a chemotherapeutic agent that belongs to the taxane family and which was approved to treat various kinds of cancers including breast cancer, ovarian cancer, advanced non-small-cell lung cancer, and acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Several delivery systems for PTX have been developed to enhance its solubility and pharmacological properties involving liposomes, nanoparticles, microparticles, micelles, cosolvent methods, and the complexation with cyclodextrins and other materials that are summarized in this article. Specifically, this review discusses deeply the developed paclitaxel nanocrystal formulations. As PTX is a hydrophobic drug with inferior water solubility properties, which are improved a lot by nanocrystal formulation. Based on that, many studies employed nano-crystallization techniques not only to improve the oral delivery of PTX, but IV, intraperitoneal (IP), and local and intertumoral delivery systems were also developed. Additionally, superior and interesting properties of PTX NCs were achieved by performing additional modifications to the NCs, such as stabilization with surfactants and coating with polymers. This review summarizes these delivery systems by shedding light on their route of administration, the methods used in the preparation and modifications, the in vitro or in vivo models used, and the advantages obtained based on the developed formulations.

Biodistribution and Non-linear Gene Expression of mRNA LNPs Affected by Delivery Route and Particle Size.

PURPOSE: Lipid nanoparticles (LNPs) are widely utilized as means to deliver mRNA molecules. However, metric connections between biodistribution and pharmacokinetics (PK) of the nanoparticle carrier and transgene expression dynamics remain largely unknown. METHODS: LNPs containing mRNAs encoding the firefly luciferase gene were prepared with varying sizes. Biodistributions of injected LNPs in mice were measured by fluorescence bioimaging or liquid chromatography with tandem mass spectrometry. In addition, luciferase expression levels were determined by bioluminescence imaging and enzyme activity assays. RESULTS: Some intramuscularly injected LNPs were found circulating in the system, resulting in accumulation in the liver and spleen, especially when the LNP sizes were relatively small. Bigger LNPs were more likely to remain at the injection site. Transgene expression in the liver was found most prominent compared with other organs and tissues. CONCLUSIONS: Biomolecules such as mRNAs encapsulated in locally injected LNPs can reach other organs and tissues via systemic circulation. Gene expression levels are affected by the LNP biodistribution and pharmacokinetics (PK), which are further influenced by the particle size and injection route. As transfection efficiency varies in different organs, the LNP exposure and mRNA expression are not linearly correlated.

Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics.

Subcutaneously injected formulations have been developed for many biological products including monoclonal antibodies (mAbs). A knowledge gap nonetheless remains regarding the absorption and catabolism mechanisms and kinetics of a large molecule at the administration site. A multiscale pharmacokinetic (PK) model was thus developed by coupling multiphysics simulations of subcutaneous (SC) absorption kinetics with whole-body pharmacokinetic (PK) modeling, bridged by consideration of the presystemic clearance by the initial lymph. Our local absorption simulation of SC-injected albumin enabled the estimation of its presystemic clearance and led to the whole-body PK modeling of systemic exposure. The local absorption rate of albumin was found to be influential on the PK profile. Additionally, nineteen mAbs were explored via this multiscale simulation and modeling framework. The computational results suggest that stability propensities of the mAbs are correlated with the presystemic clearance, and electrostatic charges in the complementarity-determining region influence the local absorption rate. Still, this study underscores a critical need to experimentally determine various biophysical characteristics of a large molecule and the biomechanical properties of human skin tissues.

Preferential Oxycodone Loss of Physically Manipulated Abuse Deterrent Oxycodone HCl Extended Release Tablets Prepared for Nasal Insufflation Studies.

A method to reproducibly mill abuse deterrent oxycodone hydrochloride (HCl) extended release (ER) tablets was developed for a nasal insufflation pharmacokinetic (PK) study. Several comminution methods were explored before determining that a conical mill resulted in controlled milling of tablets to a size range equal to or below 1000 µm. However, milling resulted in significant loss of oxycodone from abuse deterrent oxycodone HCl ER tablets compared to minimal oxycodone loss from oxycodone HCl immediate release (IR) tablets. Characterization of milled tablet powder showed that loss of oxycodone was not attributed to analytical procedures or oxycodone phase change during high intensity milling processes. The content uniformity of oxycodone in the milled tablet powder varied when ER and IR tablets were milled to a particle size distribution equal to or below 500 µm but did not vary when particles were sized above 500 µm to equal to or below 1000 µm. In addition, the initial excipient weight to drug substance weight ratio impacted the amount of oxycodone lost from the respective formulation. However, dissolution demonstrated that when oxycodone HCl ER tablets are milled, differences in excipient weight to drug substance weight ratio and particle size distribution of milled tablets did not result in significantly different release of oxycodone.

Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Sensitivity Analysis.

PURPOSE: A multiphysics simulation model was recently developed to capture major physical and mechanical processes of local drug transport and absorption kinetics of subcutaneously injected monoclonal antibody (mAb) solutions. To further explore the impact of individual drug attributes and tissue characteristics on the tissue biomechanical response and drug mass transport upon injection, sensitivity analysis was conducted and reported. METHOD: Various configurations of injection conditions, drug-associated attributes, and tissue properties were simulated with the developed multiphysics model. Simulation results were examined with regard to tissue deformation, porosity change, and spatiotemporal distributions of pressure, interstitial fluid flow, and drug concentration in the tissue. RESULTS: Injection conditions and tissue properties were found influential on the mechanical response of tissue and interstitial fluid velocity to various extents, leading to distinct drug concentration profiles. Intrinsic tissue porosity, lymphatic vessel density, and drug permeability through the lymphatic membrane were particularly essential in determining the local absorption rate of an mAb injection. CONCLUSION: The sensitivity analysis study may shed light on the product development of an mAb formulation, as well as on the future development of the simulation method.

Intracellular uptake of nanocrystals: Probing with aggregation-induced emission of fluorescence and kinetic modeling.

Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals. Cellular uptake studies were conducted with KB cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The results suggested that THPE nanocrystals could be taken up by KB cells directly, as well as in the form of dissolved molecules. The cellular uptake was found to be concentration- and time-dependent. In addition, the intracellular THPE also could be exocytosed from cells in forms of dissolved molecules and nanocrystals. Kinetic modeling was conducted to further understand the cellular mechanism of THPE nanocrystals based on first-order ordinary differential equations (ODEs). By fitting the kinetic model against experimental measurements, it was found that the initial nanocrystal concentration had a great influence on the dynamic process of dissolution, cellular uptake, and exocytosis of THPE nanocrystals. As the nanocrystal concentration increased in the culture media, dissolution of endocytosed nanocrystals became enhanced, subsequently driving the efflux of THPE molecules from cells.

Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Model Development.

PURPOSE: Many monoclonal antibodies (mAbs) are administered via subcutaneous (SC) injection. Local transport and absorption kinetics and mechanisms, however, remain poorly understood. A multiphysics computational model was developed to simulate the injection and absorption processes of a protein solution in the SC tissue. METHODS: Quantitative relationships among tissue properties and transport behaviors of an injected solution were described by respective physical laws. SC tissue was treated as a 3-dimensional homogenous, poroelastic medium, in which vasculatures and lymphatic vessels were implicitly treated. Tissue deformation was considered, and interstitial fluid flow was modeled by Darcy's law. Transport of the drug mass was described based on diffusion and advection, which was integrated with tissue mechanics and interstitial fluid dynamics. RESULTS: Injection and absorption of albumin and IgG solutions were simulated. Upon injection, a sharp rise in tissue pressure, porosity, and fluid velocity could be observed at the injection tip. Largest tissue deformation appeared at the model surface. Transport of drug mass out of the injection zone was minimal. Absorption by local lymphatics was found to last several weeks. CONCLUSIONS: A bottom-up method was developed to simulate drug transport and absorption of protein solutions in skin tissue base on physical principles. The results appear to match experimental observations.