Predicting oral drug absorption in man for compounds absorbed by carrier mediated and passive absorption processes.

Predicting drug absorption and drug absorption variation can considerably aid the selection of c and idates in the drug discovery process as well as identify ways to optimize oral drug delivery in patients. An approach to estimating the fraction dose absorbed in humans is developed based on a macroscopic mass balance analysis. The analysis utilizes membrane absorption parameters, calculated from intestinal perfusion experiments in rats, for drugs absorbed by both carrier mediated and passive adsorption mechanisms. The analysis suggests that the absorption number, An, and the dose to solubility ratio, 1/S$\\sp*$, are key parameters for predicting drug absorption where An = P$\\sp*\\sb{\\rm e}$Gz, P$\\sp*\\sb{\\rm e}$ is the dimensionless effective permeability, and Gz is the Graetz number. Three equations predicting fraction absorbed are developed for the following cases of drug in solution: drug concentration (1) below the solubility, (2) initially exceeding the solubility, and (3) always greater than the solubility. Model compounds used for the correlations included those absorbed by carrier mediated and /or passive absorption processes. Literature values for intestinal wall permeability are used for the passively absorbed compounds whereas the absorption parameters for the carrier mediated compounds were determined from intestinal perfusion experiments in rats. Human fraction dose absorbed (F) data and An showed an excellent correlation. The theoretical analysis, confirmed by experimental results, demonstrates that two of the fundamental parameters controlling drug absorption are the absorption number and the dose to solubility ratio. The $\\beta$-lactam antibiotic intestinal absorption mechanism is characterized using single pass perfusion technique in rats. The membrane absorption parameters, J$\\sp*\\sb{\\rm max}$(maximal flux), K$\\sb{\\rm m}$(Michaelis Constant), and P$\\sp*\\sb{\\rm c}$(carrier permeability) for amoxicillin, cephalexin, cephradine, cefatrizine, cefaclor, and cefadroxil were determined. Analysis of the data using a modified boundary layer method revealed nonpassive membrane transport. Competitive absorption studies performed with $\\beta$-lactam antibiotics, amino acids, and several small peptides suggest that absorption interactions between carrier mediated compounds, including other drugs, peptides or amino acids, may be clinically significant and may account for a second possible mechanism along with delayed gastric emptying for the delay in antibiotic plasma levels.Ph.D.Pharmaceutical sciencesUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161975/1/8821654.pd

Microfluidic Generation of Droplets with a High Loading of Nanoparticles

Microfluidic approaches for controlled generation of colloidal clusters, for example, via encapsulation of colloidal particles in droplets, have been used for the synthesis of functional materials including drug delivery carriers. Most of the studies, however, use a low concentration of an original colloidal suspension (<10 wt %). Here we demonstrate microfluidic approaches for directly making droplets with moderate (10–25 wt %) and high (>60 wt %) particle concentrations. Three types of microfluidic devices, PDMS flow-focusing, PDMS T-junction, and microcapillary devices, are investigated for direct encapsulation of a high concentration of polystyrene (PS) nanoparticles in droplets. In particular, it is shown that PDMS devices fabricated by soft lithography can generate droplets from a 25 wt % PS suspension, whereas microcapillary devices made from glass capillary tubes are able to produce droplets from a 67 wt % PS nanoparticle suspension. When the PS concentration is between 0.6 and 25 wt %, the size of the droplets is found to change with the oil-to-water flow rate ratio and is independent of the concentration of particles in the initial suspensions. Drop sizes from ∼12 to 40 μm are made using flow rate ratios <i>Q</i>_oil/<i>Q</i>_water from 20 to 1, respectively, with either of the PDMS devices. However, clogging occurs in PDMS devices at high PS concentrations (>25 wt %) arising from interactions between the PS colloids and the surface of PDMS devices. Glass microcapillary devices, on the other hand, are resistant to clogging and can produce droplets continuously even when the concentration of PS nanoparticles reaches 67 wt %. We believe that our findings indicate useful approaches and guidelines for the controlled generation of emulsions filled with a high loading of nanoparticles, which are useful for drug delivery applications

Gelation Chemistries for the Encapsulation of Nanoparticles in Composite Gel Microparticles for Lung Imaging and Drug Delivery

The formation of 10–40 μm composite gel microparticles (CGMPs) comprised of ∼100 nm drug containing nanoparticles (NPs) in a poly­(ethylene glycol) (PEG) gel matrix is described. The CGMP particles enable targeting to the lung by filtration from the venous circulation. UV radical polymerization and Michael addition polymerization reactions are compared as approaches to form the PEG matrix. A fluorescent dye in the solid core of the NP was used to investigate the effect of reaction chemistry on the integrity of encapsulated species. When formed via UV radical polymerization, the fluorescence signal from the NPs indicated degradation of the encapsulated species by radical attack. The degradation decreased fluorescence by 90% over 15 min of UV exposure. When formed via Michael addition polymerization, the fluorescence was maintained. Emulsion processing using controlled shear stress enabled control of droplet size with narrow polydispersity. To allow for emulsion processing, the gelation rate was delayed by adjusting the solution pH. At a pH = 5.4, the gelation occurred at 3.5 h. The modulus of the gels was tuned over the range of 5 to 50 kPa by changing the polymer concentration between 20 and 70 vol %. NP aggregation during polymerization, driven by depletion forces, was controlled by the reaction kinetics. The ester bonds in the gel network enabled CGMP degradation. The gel modulus decreased by 50% over 27 days, followed by complete gel degradation after 55 days. This permits ultimate clearance of the CGMPs from the lungs. The demonstration of uniform delivery of 15.8 ± 2.6 μm CGMPs to the lungs of mice, with no deposition in other organs, is shown, and indicates the ability to concentrate therapeutics in the lung while avoiding off-target toxic exposure

Microfluidic Generation of Droplets with a High Loading of Nanoparticles

Microfluidic approaches for controlled generation of colloidal clusters, e.g., via encapsulation of colloidal particles in droplets, have been used for the synthesis of functional materials including drug delivery carriers. Most of the studies, however, use a low concentration of an original colloidal suspension (< 10 wt%). Here we demonstrate microfluidic approaches for directly making droplets with moderate (10–25 wt%) and high (> 60 wt%) particle concentrations. Three types of microfluidic devices, PDMS flow-focusing, PDMS T-junction, and microcapillary devices, are investigated for direct encapsulation of a high concentration of polystyrene (PS) nanoparticles in droplets. In particular, it is shown that PDMS devices fabricated by soft lithography can generate droplets from a 25 wt% PS suspension, whereas microcapillary devices made from glass capillary tubes are able to produce droplets from a 67 wt% PS nanoparticle suspension. When the PS concentration is between 0.6 and 25 wt%, the size of the droplets is found to change with the oil-to-water flow rate ratio and is independent of the concentration of particles in the initial suspensions. Drop sizes from ~12 to 40 μm are made using flow rate ratios Q(oil)/Q(water) from 20 to 1, respectively, with either of the PDMS devices. However, clogging occurs in PDMS devices at high PS concentrations (> 25 wt%) arising from interactions between the PS colloids and the surface of PDMS devices. Glass microcapillary devices, on the other hand, are resistant to clogging and can produce droplets continuously even when the concentration of PS nanoparticles reaches 67 wt%. We believe that our findings indicate useful approaches and guidelines for the controlled generation of emulsions of microparticles that are filled with a high loading of nanoparticles and which are useful for drug delivery applications