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Despite potential therapeutic efficacy of resveratrol on colitis and colorectal cancer, rapid absorption and metabolism at the upper gastro-intestinal (GI) tract prevent its clinical application. To overcome this, we attempted to develop colon-specific multi-particulate calcium-pectinate (Ca-pectinate) formulations of resveratrol. However, they were unable to prevent premature drug release at the upper GI tract. Thus, glutaraldehyde (Glu) was used for further cross-linking of the pectin chains. The formulation conditions and procedure were optimized from the in vitro drug release study. The optimized formulation was subjected to in vivo pharmacokinetic study in rats and compared with the unmodified Ca-pectinate and suspension formulation of resveratrol. Spherical particles (∼1 mm diameter) with high drug encapsulation were produced. Low cross-linking solution pH (1.5), minimum Glu concentration (2.5%) and cross-linking time (2 h) were crucial to exhibit colon-specific drug release. As Glu was added in the cross-linking solution, cross-linking between pectin chains and Glu occurred simultaneously during Ca-pectinate network formation, which appeared as a cost-effective formulation technique. Most importantly, the pharmacokinetic study demonstrated in vivo colon-specific drug release from the optimized formulation, while faster drug release was observed from the unmodified and suspension formulations. Hence, the developed formulation has potential to be used as colon-specific delivery system of resveratrol.

Inhalation therapy for infectious lung diseases, such as tuberculosis, is currently being explored, with microspheres being used to target alveolar macrophages. One method of drug encapsulation into polymeric microspheres to form hydrophobic ion-paired (HIP) complexes, and then coprecipitate the complex and polymer using supercritical fluid methodology. For the potent antituberculosis drug, isoniazid (isonicotinic acid hydrazide, INH), to be used in this fashion, it was modified into an ionizable form suitable for HIP. The charged prodrug, sodium isoniazid methanesulfonate (Na-INHMS), was then ion paired with hydrophobic cations, such as alkyltrimethylammonium or tetraalkylammonium. The logarithms of the apparent partition coefficients (log P') of various HIP complexes of INHMS display a roughly linear relationship with the numbers of carbon atoms in the organic counterions. The water solubility of the tetraheptylammonium-INHMS complex is about 220-fold lower than that of Na-INHMS, while the solubility in dichloromethane exceeds 10 mg/mL, which is sufficient for microencapsulation of the drug into poly(lactide) microspheres. The actual logarithm of the dichloromethane/water partition coefficient (log P) for tetraheptylammonium-INHMS is 1.55, compared to a value of - 1.8 for the sodium salt of INHMS. The dissolution kinetics of the tetraheptylammonium-INHMS complex in 0.9% aqueous solutions of NaCl was also investigated. Dissolution of tetraheptylammonium-INHMS exhibited a first-order time constant of about 0.28 min(-1), followed by a slower reverse ion exchange process to form Na-INHMS. The half-life of this HIP complex is on the order of 30 min, making the enhanced transport of the drug across biological barriers possible. This work represents the first use of a prodrug approach to introduce functionality that would allow HIP complex formation for a neutral molecule.

Resveratrol has potential therapeutic efficacy on several lower gastro-intestinal (GI) diseases such as colitis and colorectal cancer. But resveratrol is quickly absorbed and metabolized at the upper GI tract, which renders it unsuitable for this purpose. This study aimed at devising a delayed release formulation of resveratrol as calcium-pectinate (Ca-pectinate) beads and investigated the impact of various formulation parameters on bead characteristics. Ca-pectinate beads were prepared by varying six formulation parameters (cross-linking pH, cross-linker concentration, cross-linking time, drying condition, pectin concentration, and resveratrol concentration). Their effects were investigated on calcium entrapment, moisture content and weight loss during drying, particle shape and size, resveratrol entrapment and loading efficiency, swelling–erosion, and resveratrol retention pattern of formulated beads. Preparative conditions were optimized from these studies and optimized beads were further subjected to morphological examination, drug–polymer interaction, and enzymatic degradation study. Almost all prepared beads were spherical with ∼1 mm diameter. Swelling–erosion and drug retention pattern were changed with formulation variables. Release data of almost all beads showed linearity of the plots for the cumulative percent resveratrol released versus square root of time often after an initial lag period. Observations from the present study revealed that optimized Ca-pectinate beads can encapsulate a very high amount of resveratrol (>97.5%) and can be used for delayed release and site-specific delivery to the lower GI tract. Depending on the formulation parameters, release of resveratrol after 10 h incubation in the intestinal media was 80–100%. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:840–860, 2010

The purpose of this study was to assess the effect of mild heat and heat preconditioning on the uptake and permeability of a P‐glycoprotein (P‐gp) substrate, rhodamine 123 (R123), in a cell culture model of the blood–brain barrier (BBB). An immediate goal was to determine whether prior mild heat treatment could render brain microvessel endothelial cells more resistant to future heat stress and affect BBB drug permeation by future ultrasound‐induced mild heat (USMH) treatment. To address this issue, the expression level of two proteins, P‐gp and heat shock protein 70 (Hsp70), and their effects on uptake of R123 and permeability of R123 and [ 14 C]‐sucrose in combination with mild heat and P‐gp modulator PSC833 during and after mild heat treatment in heat‐preconditioned and heat‐unconditioned bovine brain microvessel endothelial cell (BBMEC) monolayers were studied. Mild heat caused a significant increase in BBB permeability of R123 and [ 14 C]‐sucrose when compared with control and PSC833. Exposure of BBMECs to heat preconditioning caused a slight but insignificant decrease in cellular uptake of R123 both during and immediately after mild heat treatment. Heat preconditioning also caused a slight but insignificant decrease in permeability of R123 and [ 14 C]‐sucrose in BBMEC monolayers during mild heat treatment. Because exposure of BBMEC monolayers to mild heat did not affect P‐gp expression but slightly affected Hsp70 expression, a heat preconditioning that results in a reinforcement of the BBB other than increased expression of P‐gp is suggested. However, heat preconditioning is not sufficient to override the permeation‐enhancing effects of mild heat because mild heat caused a significant increase in R123 uptake and permeability of R123 and [ 14 C]‐sucrose in both heat‐preconditioned and heat‐unconditioned cells. Because Hsp70 is known to play a major role in cellular repair and protective mechanisms, our results would imply a relative benign nature of mild heat treatment. Because heating produced by ultrasonic waves can be controlled and localized to a small volume within the tissue, the present results also suggest that USMH could play a pivotal role in the treatment of brain tumors and other brain‐related diseases.