Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres.

Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 µm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤ 5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 µm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine.

Oral delivery of proteins by biodegradable nanoparticles.

Successful administration of therapeutic proteins via the oral route has long eluded the drug delivery community; a variety of factors, both physical and physiological, have hindered the myriad approaches to increasing the bioavailability of orally administered therapeutic proteins, including: 1) pre-systemic degradation by enzymes and 2) poor penetration of the intestinal mucosa and epithelium. Even when bypassing the harsh, acidic environment of the stomach, the intestines pose significant obstacles to systemic uptake. For example, the lining of the gastrointestinal tract comprises a thick wall of epithelial cells covered by a layer of polysaccharides and mucus. In this review, we will discuss the biology underlying intestinal uptake of protein-containing, biodegradable nanoparticles, review insulin delivery as the most accepted model for oral delivery of proteins, and present a variety of new material systems enabling novel approaches to oral protein delivery which we believe will bring to bear the next therapeutic advances in our field.

The infant skin barrier: can we preserve, protect, and enhance the barrier?

Infant skin is different from adult in structure, function, and composition. Despite these differences, the skin barrier is competent at birth in healthy, full-term neonates. The primary focus of this paper is on the developing skin barrier in healthy, full-term neonates and infants. Additionally, a brief discussion of the properties of the skin barrier in premature neonates and infants with abnormal skin conditions (i.e., atopic dermatitis and eczema) is included. As infant skin continues to mature through the first years of life, it is important that skin care products (e.g., cleansers and emollients) are formulated appropriately. Ideally, products that are used on infants should not interfere with skin surface pH or perturb the skin barrier. For cleansers, this can be achieved by choosing the right type of surfactant, by blending surfactants, or by blending hydrophobically-modified polymers (HMPs) with surfactants to increase product mildness. Similarly, choosing the right type of oil for emollients is important. Unlike some vegetable oils, mineral oil is more stable and is not subject to oxidation and hydrolysis. Although emollients can improve the skin barrier, more studies are needed to determine the potential long-term benefits of using emollients on healthy, full-term neonates and infants.

Preparation and characterization of poly(methyl methacrylate) - iron (III) oxide microparticles using a modified solvent evaporation method.

At present, there is widespread interest in developing new, biocompatible microparticles made from polymers such as poly(methyl methacrylate) (PMMA) that could have applications ranging from diagnostic imaging to drug delivery. In these experiments, there were two primary objectives: (1) to stabilize a suspension of iron (III) oxide (alpha-Fe(2)O(3); mean diameter = 100 nm) nanoparticles in a solution of PMMA by using an emulsifier and different mixtures of two miscible solvents; and (2) to fabricate PMMA-alpha-Fe(2)O(3) microparticles by using an oil-in-water (o/w) solvent evaporation method. By accomplishing the first objective, it was hypothesized that the encapsulation efficiency of alpha-Fe(2)O(3) within PMMA microparticles would improve and induce the clustering of alpha-Fe(2)O(3) along the circumferential edges of the microparticles. Of the seven emulsifiers tested, Tween 80 was selected primarily for its hydrophilicity and its ability to produce a stable alpha-Fe(2)O(3) dispersion. As a result, 22 batches of microspheres (11 with Tween 80 and 11 without) were made and the solvent (dichloromethane) to co-solvent (ethyl acetate) ratios were varied. Particles made with solvent mixtures of >50% ethyl acetate (<50% dichloromethane) were more likely to be hollow and had larger mean volumetric particle diameters (>5 microns) than particles made with mixtures containing >50% dichloromethane. Particles made with Tween 80 were larger, more porous, and had alpha-Fe(2)O(3) aligned along the circumferential edges of the particles. The use of solvent mixtures did not improve the encapsulation efficiency of alpha-Fe(2)O(3) but the use of ethyl acetate helped to induce the clustering of alpha-Fe(2)O(3) along the peripheries of the microparticles.

Investigating the effects of surfactants on the size and hydrolytic stability of poly(adipic anhydride) particles.

The present study investigates the effects of surfactants (<0.01% v/v) on the size and hydrolytic stability of poly(adipic anhydride) (pAA) micro- and nanospheres fabricated using a modified phase inversion technique. Overall, surfactants increased the output yield by roughly 20%. Lecithin produced the greatest reduction in the volumetric particle size (dvol) compared to particles fabricated with no surfactant (dvol = 530 +/- 300 nm and 2.2 +/- 1.1 microm, respectively). In addition, sorbitan monooleate produced spheres with smaller numeric diameters (dnum) than the control but appeared to induce aggregation (dvol = 7.7 +/- 12.5 microm). The dnum and dvol were not dependent on the hydrophobicity of the surfactant (R2 = 0.36 and 0.03, respectively) or the apparent surface tension of the non-solvent (NS) phase (R2 = 0.44 and 0.04, respectively). In addition, quantitative DSC and FT-IR analysis confirmed that altering the particle size could also influence the hydrolytic stability of pAA.

Technetium 99m sestamibi myocardial perfusion imaging predicts clinical outcome in the community outpatient setting. The Nuclear Utility in the Community (NUC) Study.

OBJECTIVES: The purpose of this study was to evaluate the prognostic value of community-based myocardial perfusion imaging (MPI) and to assess the incremental value of individual components of (99m)Tc-sestamibi single photon emission computed tomography (SPECT). BACKGROUND: Although the most rapid growth of MPI has been in community outpatient laboratories, its prognostic value has not been validated in this setting. METHOD: We prospectively followed 1,612 consecutive patients undergoing stress (99m)Tc-sestamibi SPECT in an outpatient community laboratory who experienced 71 hard events over 24 +/- 7 months (0.2% lost to follow-up). RESULTS: Patients whose scans were normal incurred an annualized event rate of 0.4%, compared with 2.3% for those with abnormal scans (p < 0.0001). Subset analysis demonstrated comparable risk stratification for women and men, diabetics, patients with normal resting ECGs, and those referred for pharmacologic and exercise stress. After adjusting for pre-test variables, multivariable Cox regression analysis found the most potent independent components of MPI to be, in order of importance, transient ischemic dilation, extent of reversibility, post-stress ejection fraction, extent and severity of the stress perfusion defect, and the overall test result (normal or abnormal). Each 1% decrement of ejection fraction predicted a 3% increase in risk (p = 0.0009). Post-MPI angiography and revascularization increased commensurate with the extent and severity of MPI result. CONCLUSIONS: The prognostic value of perfusion imaging is portable and transferable to the outpatient community setting, with multiple components of MPI providing incremental prognostic information.