Project description:Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control than traditional systemic drug delivery, significantly circumventing drug loss, off-target effects, systemic and organ toxicity, etc., and is widely regarded as the preferred regimen for pulmonary drug delivery. However, very few lung diseases are currently treated with the preferred inhaled formulations, such as asthma, chronic obstructive pulmonary disease and pulmonary hypertension. And there is a lack of appropriate inhaled formulations for other critical lung diseases, such as lung cancer and pulmonary fibrosis, due to the fact that the physicochemical properties of the drugs and their pharmacokinetic profiles do not match the physiology of the lung, and conventional inhalation devices are unable to deliver them to the specific parts of the lung. Phytochemicals of natural origin, due to their wide availability and clear safety profile, hold great promise for the preparation of inhalable formulations to improve the current dilemma in the treatment of lung diseases. In particular, the preparation of inhalable formulations based on nano- and microparticulate carriers for drug delivery to deep lung tissues, which overcome the shortcomings of conventional inhalation therapies while targeting the drug activity directly to a specific part of the lung, may be the best approach to change the current dilemma of lung disease treatment. In this review, we discuss recent advances in nano- and micron-carrier-based inhalation formulations for the delivery of natural products for the treatment of pulmonary diseases, which may represent an opportunity for practical clinical translation of natural products.
Project description:PurposeThe purpose of this study is to show how the Ocular Compartmental Absorption & Transit (OCAT™) model in GastroPlus® can be used to characterize ocular drug pharmacokinetic performance in rabbits for ointment formulations.MethodsA newly OCAT™ model developed for fluorometholone, as well as a previously verified model for dexamethasone, were used to characterize the aqueous humor (AH) concentration following the administration of multiple ointment formulations to rabbit. The model uses the following parameters: application surface area (SA), a fitted application time, and the fitted Higuchi release constant to characterize the rate of passage of the active pharmaceutical ingredient from the ointment formulations into the tears in vivo.ResultsParameter sensitivity analysis was performed to understand the impact of ointment formulation changes on ocular exposure. While application time was found to have a significant impact on the time of maximal concentration in AH, both the application SA and the Higuchi release constant significantly influenced both the maximum concentration and the ocular exposure.ConclusionsThis initial model for ointment ophthalmic formulations is a first step to better understand the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug pharmacokinetic performance in rabbits.
Project description:We report the uptake of a lipophilic fungicide into the cuticle of living leaves of young maize from droplets of a suspension concentrate. The action of a "coffee-ring" effect is demonstrated during fungicide formulation drying, and the fungicide particle distribution is quantified. We develop a simple, two-dimensional model of uptake leading to a "reservoir" of cuticular fungicide. This model allows inferences of physicochemical properties for fungicides inside the cuticular medium. The diffusion coefficient closely agrees with literature penetration experiments (Dcut ≈ 10-18 m2 s-1). The logarithm of the inferred cuticle-water partition coefficient log10 Kcw = 6.03 ± 0.04 is consistent with ethyl acetate as a model solvent for the maize cuticle. Two limiting kinetic uptake regimes are inferred from the model for short and long times, with the transition resulting from longitudinal saturation of the cuticle beneath the droplet. We discuss the strengths, limitations, and generalizability of our model within the "cuticle reservoir" approximation.
Project description:The aim of this study was to develop nutraceutical chewing candy (NCC) formulations based on acetic, alcoholic, and lactofermented apple juice (AJ) products. In addition, different texture-forming (gelatin, pectin) and sweetening (stevia, xylitol) agents were tested. To implement the aim of this study, combinations based on AJ, prepared from fresh and frozen apples, apple cider (C) samples (No.1, No.2, No.3, and No.4), and apple vinegar (V) were used. First, the most appropriate combination was selected by evaluating overall acceptability (OA) and emotions induced for consumers (EIC). In addition, the volatile compound (VC) profile, and physicochemical and antimicrobial characteristics of the developed combinations were analyzed. For AJ fermentation, lactic acid bacteria (LAB) strains possessing antimicrobial properties (LUHS122-L. plantarum and LUHS210-L. casei) were used. AJ prepared from frozen apples had 11.1% higher OA and 45.9%, 50.4%, and 33.3% higher fructose, glucose, and saccharose concentrations, respectively. All the tested C samples inhibited Bacillus subtilis and had an average OA of 6.6 points. Very strong positive correlations were found between AJ and C OA and the emotion 'happy'; comparing lactofermented AJ, the highest OA was obtained for AJ fermented for 48 h with LUHS122, and a moderate positive correlation was found between AJ OA and the emotion 'happy' (r = 0.7617). This sample also showed the highest viable LAB count (7.59 log10 CFU mL-1) and the broadest spectrum of pathogen inhibition (inhibited 6 out of 10 tested pathogens). Further, acetic, alcoholic, and lactofermented AJ product combinations were tested. For the preparation of NCC, the combination consisting of 50 mL of AJ fermented with LUHS122 for 48 h + 50 mL C-No.3 + 2 mL V was selected because it showed the highest OA, induced a high intensity of the emotion 'happy' for the judges, and inhibited 8 out of 10 tested pathogens. Finally, the OA of the prepared NCC was, on average, 9.03 points. The combination of acetic, alcoholic, and lactofermented AJ products leads to the formation of a specific VC profile and increases the OA and antimicrobial activity of the products which could be successfully applied in the food and nutraceutical industries.
Project description:Specific size, shape and surface chemistry influence the biological activity of nanoparticles. In the case of lipophilic nanoparticles, which are widely used in consumer products, there is evidence that particle size and formulation influences skin permeability and that lipophilic particles smaller than 6 nm can embed in lipid bilayers. Since most nanoparticle synthetic procedures result in mixtures of different particles, post-synthetic purification promises to provide insights into nanostructure-function relationships. Here we used size-selective precipitation to separate lipophilic allyl-benzyl-capped silicon nanoparticles into monodisperse fractions within the range of 1 nm to 5 nm. We measured liposomal encapsulation and cellular uptake of the monodisperse particles and found them to have generally low cytotoxicities in Hela cells. However, specific fractions showed reproducibly higher cytotoxicity than other fractions as well as the unseparated ensemble. Measurements indicate that the cytotoxicity mechanism involves oxidative stress and the differential cytotoxicity is due to enhanced cellular uptake by specific fractions. The results indicate that specific particles, with enhanced suitability for incorporation into lipophilic regions of liposomes and subsequent in vitro delivery to cells, are enriched in certain fractions.
Project description:In vivo pharmacokinetic simulations and virtual bioequivalence (BE) evaluation of cilostazol have not yet been described for humans. Here, we successfully developed a physiologically based absorption model to simulate plasma concentrations of cilostazol. In addition, virtual population simulations integrating dissolution of 0.3% sodium dodecyl sulfate water media were executed to evaluate the BE of test and reference formulations. Simulation results show that test and reference formulations were bioequivalent among 28 subjects, but not nine subjects, consistent with clinical studies. The model proved to be an important tool to show potential BE for cilostazol. This finding may facilitate understanding of the potential risks during the development of generic products.
Project description:Inefficient injection of microparticles through conventional hypodermic needles can impose serious challenges on clinical translation of biopharmaceutical drugs and microparticle-based drug formulations. This study aims to determine the important factors affecting microparticle injectability and establish a predictive framework using computational fluid dynamics, design of experiments, and machine learning. A numerical multiphysics model was developed to examine microparticle flow and needle blockage in a syringe-needle system. Using experimental data, a simple empirical mathematical model was introduced. Results from injection experiments were subsequently incorporated into an artificial neural network to establish a predictive framework for injectability. Last, simulations and experimental results contributed to the design of a syringe that maximizes injectability in vitro and in vivo. The custom injection system enabled a sixfold increase in injectability of large microparticles compared to a commercial syringe. This study highlights the importance of the proposed framework for optimal injection of microparticle-based drugs by parenteral routes.
Project description:Currently, sixty-five original sprinkle drug products are available in various dosage forms including tablets, powders, granules, immediate-release capsules, extended-release capsules, delayed-release capsules, and multiparticulate drug delivery systems. By sprinkling on soft food vehicles, these products provide dosing flexibility and convenience of administration, which potentially improve the compliance of patients with dysphagia. Due to these advantages, the growth of sprinkle products picked up since the 1990s, and several regulatory issues regarding this dosage form have been raised and documented. In this article, the types of sprinkle formulations were discussed by dividing them into seven categories, and the commercial products were summarized in terms of the drug substance, pharmaceutical excipients, storage conditions and administration methods. In addition, several US Food and Drug Administration guidelines related to the regulatory issues of sprinkle formulations were reviewed, which led to the conclusion that the future development of this promising dosage form demands integrated guidance for industry rather than scattered information in various documents.
Project description:Humans can easily describe, imagine, and, crucially, predict a wide variety of behaviors of liquids-splashing, squirting, gushing, sloshing, soaking, dripping, draining, trickling, pooling, and pouring-despite tremendous variability in their material and dynamical properties. Here we propose and test a computational model of how people perceive and predict these liquid dynamics, based on coarse approximate simulations of fluids as collections of interacting particles. Our model is analogous to a "game engine in the head", drawing on techniques for interactive simulations (as in video games) that optimize for efficiency and natural appearance rather than physical accuracy. In two behavioral experiments, we found that the model accurately captured people's predictions about how liquids flow among complex solid obstacles, and was significantly better than several alternatives based on simple heuristics and deep neural networks. Our model was also able to explain how people's predictions varied as a function of the liquids' properties (e.g., viscosity and stickiness). Together, the model and empirical results extend the recent proposal that human physical scene understanding for the dynamics of rigid, solid objects can be supported by approximate probabilistic simulation, to the more complex and unexplored domain of fluid dynamics.
Project description:Enabling formulations based on hydroxypropyl-β-cyclodextrins (HPβCD), micellar preparation, and liposomes have been designed to deliver the racemic mixture of a lipophilic cannabinoid type 2 agonist, MDA7. The antiallodynic effects of MDA7 formulated in these three different systems were compared after intravenous (i.v.) administration in rats. Stoichiometry of the inclusion complex formed by MDA7 in HPβCD was determined by continuous variation plot, electrospray ionization-mass spectrometry (ESI-MS) analysis, phase solubility, and nuclear magnetic resonance studies and indicate formation of exclusively 1:1 adduct. Morphology and particle sizes determined by dynamic light scattering and transmission electron microscopy show the presence of a homogeneous population of closed round-shaped oligolamellar MDA7 containing liposomes, with an average size of 118 nm [polydispersity index (PDI) 0.03]. Monodisperse micelles exhibited an average size of 14 nm (PDI 0.09). HPβCD-based formulation administrated in vivo was composed of two discrete particles populations with a narrow size distribution of 3 nm (PDI 0.04) and 510 nm (PDI 0.02). HPβCD-based formulation dramatically improved antiallodynic effect of MDA7 in comparison with the liposomes preparation. Through inclusion complexation and possibly formation of aggregates, HPβCD can enhance the aqueous solubility of lipophilic drugs, thereby improving their bioavailability for i.v. administration.