Richard P. Batycky

Formulation and physical characterization of large porous particles for inhalation

AbstractPurpose. Relatively large (>5 µm) and porous (mass density < 0.4 g/cm3) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. Methods. Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler TM device in vitro in both an Andersen cascade impactor and an AerosizerTM.. Results. By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 µm, and tap densities between 0.04 and 0.6 g/cm3. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the AerosizerTM most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1−3 µm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. Conclusions. Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.

A theory of molecular absorption from the small intestine

Abstract A theory of molecular absorption from the small intestine is outlined on the basis of macrotransport analysis. Certain features of the transport process that have not been previously considered in the literature are quantitatively described. These include complex interrelationships between lumen and membrane diffusion, convection, degradation and absorption mechanisms — and overall axial convection, dispersion, degradation and absorption rates. Therapeutic molecules are assumed to be introduced in the form of a bolus into the duodenum. They subsequently convect and diffuse through the duodenum, jejunum, and ileum. Absorption into the systemic circulation across the epithelial barrier, as well as possible degradation or aggregation in the lumen or at the apical epithelial membrane, contribute to the disappearance of the therapeutic as the bolus travels through the lumen in an oral to caudal direction. Space- and time-varying lumen concentrations are predicted, as are time-varying systemic concentrations following introduction of the bolus. The inputs to the model are primarily anatomical or physicochemical characteristics that are either known or can be measured for a given therapeutic and animal model. A detailed parametric study is made, elucidating the individual roles of permeability and degradation rates. This leads to a simple paradigm for determining the two unknowns of the model (the membrane permeability and degradation rate constant) from systemic absorption data; it is shown that the membrane permeability constant can alternatively be estimated by independent in vitro measurements. Comparisons with published experimental systemic concentrations are made for molecules ranging from small lipophilic substances, such as ibuprofen, to polypeptides, such as calcitonin, and proteins, such as insulin. The deduced epithelial permeability values show reasonable agreement with values determined using alveolar epithelia and Caco-2 cell monolayers. By contrast, the membrane permeability values deduced from a simplified model of absorption from the small intestine show relatively poor agreement with experimental values. The model may be useful as a numerical simulation tool for predicting (estimates of) oral dose–response relationships in animals and humans given relatively limited in vivo data.

The macrotransport properties of aerosol particles in the human oral-pharyngeal region

Abstract A method is described for evaluating the mean velocity, dispersion coefficient and deposition rate constant characterizing aerosol transport in a finite, computationally tractable, three-dimensional domain of the human lungs. The methodology is applied specifically to deduce (mesoscale) transport coefficients in an anatomically realistic human mouth and throat. In this method aerosol particles are introduced into a numerically simulated airflow in the vicinity of the entrance region of the airway unit (e.g. the mouth); the aerosol bolus is inspired such that it travels through the airway unit before being expired. The exhaled concentration of nondeposited aerosols is determined numerically, and used to deduce the three aerosol transport coefficients. The deduced transport coefficients, representing “mesoscale” averages of the microscale simulated flow, are determined as functions of air flow rate, particle size, bolus parameters, and dimensionality; these values are then incorporated into a mesoscale lung model and used to simulate macroscale aerosol transport behavior in the lungs. Special attention is given to the numerical simulation of an aerosol bolus inspired into the lungs. The calculated half-width, mode and deposition fraction agree favorably with recent macrotransport simulations, minus the upper airway generation. In these comparisons, the major influence of the upper airways is to increase aerosol deposition. Half-width and deposition fraction are also significantly affected by lung size.

OSMOTICALLY DRIVEN INTRACELLULAR TRANSPORT PHENOMENA

A theory of cell–volume response to abrupt or gradual changes in extracellular osmotic conditions is outlined. The coupled transport of water and impermeable and semipermeable solutes is considered. Semipermeable solutes, including relatively small lipophilic molecules, like glycerol or urea, are permitted to absorb to the membranes of internal organelle bodies, where they diffuse with a configuration–specific lateral diffusion coefficient. Impermeable solutes (such as salts) are excluded from internal organelles, resulting in a significant osmotically inactive cell–volume fraction. Cell–volume expansion or contraction in response to anisosmotic conditions is shown to depend strongly on the internal absorption behaviour of semipermeable solutes, as well as upon membrane permeation parameters. The results of the analysis lay the foundations for accurate determination of membrane permeability variables, of importance to a variety of cellular transport processes, including those involved in cell cryopreservation.

Thermal macrotransport processes in porous media. A review

This paper reviews recent work by the authors involving nonconservative convective-conductive internal energy transport phenomena in porous media. Where appropriate, these heat-transfer results are contrasted and compared with their classical mass-transfer counterparts. Commonalities as well as differences are pointed out, arising from the distinction between molecular diffusivity vs thermal diffusivity. Differences raise from the fact that the latter — in contrast with the former — is a composite material property (derived jointly from separate thermal conductivity and volumetric heat capacity properties). This contrasts with the case of molecular diffusivity, which is a fundamental rather than composite material property. Both adiabatic and nonadiabatic systems are studied, with the latter characterized by a rate of heat loss to the surroundings described by a ‘Newtons law of colling’ heat transfer coefficient, h. Taylor dispersion theory is used to effect the coarse-graining of the thermal problem posed by the microscale equations, thereby producing a macroscale or effective-medium theory of the mean thermal transport process. Various porous media, each possessing a spatially periodic skeletal geometry, are analyzed. General expressions are presented for the macroscale thermal propagation velocity vector Ū∗ (which is not generally equal to the interstitial Darcy-scale velocity V∗ of the flowing fluid) and effective thermal dispersivity dyadic α∗ in terms of the prescribed microscale data. Additionally, in the nonadiabatic case, an expression is obtained for a third macrotransport coefficient, H∗, representing the effective or overall macroscale heat-transfer coefficient, and distinct from the microscale heat-transfer coefficient h. (The former, macrotransport coefficient represents the same type of macroscale material property as arises in so-called ‘fin’ heat-transfer problems.) Furthermore, it is shown that when solving the transient nonadiabatic microtransport equation for the mean temperature T, parameterized by the effective-medium phenomenological coefficients H∗, H∗ and α∗, it becomes necessary to employ a fictitious mean initial temperature distribution in place of the true mean distribution, the latter deriving from the initial microscale distribution. A paradigm is outlined for calculating this fictitious mean initial temperature field from the prescribed initial microscale temperature field. One illustrative example addressed is that of heat conduction in a quiescent composite medium. Specifically, we show that although a composite medium may be composed of two separately homogeneous materials, each possessing identical (and isotropic) thermal diffusivities α, the effective thermal dispersivity α∗ of the composite medium may nevertheless differ from the constant diffusivity α characterizing the individual phases by many orders of magnitude; moreover, in contrast to the scalar, isotropic nature of the individual microscale diffusivities α, the effective macroscale dispersivity α∗ will generally be anisotropic, possessing a value dependent upon which (if either) of the two homogeneous phases is continuous and which is discontinuous! Detailed results are also summarized for the effective thermal dispersivity dyadic for two-dimensional homogeneous Darcy flow through the interstices of a packed bed composed of circular cylinders in various lattice configurations. In the adiabatic fluid case (corresponding to the cylinders being insulated), results for Ū∗ and α∗ are given for the effective thermal dispersivities in terms of the Peclet number, bed porosities and, where relevant, Reynolds number (Re). While most of the numerical data pertain to the Stokes flow case, Re = 0, a few calculations at Reynolds number up to about 100 are also presented. In the comparable nonadiabatic case (corresponding to noninsulated circular cylinders functioning as heat sources or sinks), numerical results are also presented for the Darcy-scale thermophysical parameters H∗, H∗ and α∗. In microscale phenomenological data, these calculations show that Ū∗ and α∗ for nonadiabatic systems may differ sensibly from their adiabatic counterparts, as they now also depend functionally upon the heat transfer coefficient h.