A sub-10-nm, folic acid-conjugated gold nanoparticle as self-therapeutic treatment of tubulointerstitial fibrosis.

Nanomedicines for treating chronic kidney disease (CKD) are on the horizon, yet their delivery to renal tubules where tubulointerstitial fibrosis occurs remains inefficient. We report a folic acid-conjugated gold nanoparticle that can transport into renal tubules and treat tubulointerstitial fibrosis in mice with unilateral ureteral obstruction. The 3-nm gold core allows for the dissection of bio-nano interactions in the fibrotic kidney, ensures the overall nanoparticle (~7 nm) to be small enough for glomerular filtration, and naturally inhibits the p38α mitogen-activated protein kinase in the absence of chemical or biological drugs. The folic acids support binding to selected tubule cells with overexpression of folate receptors and promote retention in the fibrotic kidney. Upon intravenous injection, this nanoparticle can selectively accumulate in the fibrotic kidney over the nonfibrotic contralateral kidney at ~3.6% of the injected dose. Delivery to the fibrotic kidney depends on nanoparticle size and disease stage. Notably, a single injection of this self-therapeutic nanoparticle reduces tissue degeneration, inhibits genes related to the extracellular matrix, and treats fibrosis more effectively than standard Captopril therapy. Our data underscore the importance of constructing CKD nanomedicines based on renal pathophysiology.

Evaluation of different screening methods to understand the dissolution behaviors of amorphous solid dispersions.

OBJECTIVE: The objectives of the current study were to understand the dissolution behaviors of amorphous solid dispersions (ASD) using different screening methods and their correlation to the dissolution of formulated products. MATERIALS AND METHODS: A poorly soluble compound, compound E, was used as a model compound. ASDs were prepared with HPMC, Kollidon VA64 and Eudragit EPO using hot-melt extrusion. Different techniques including precipitation, powder, capsule and compact dissolution and the dissolution of formulated products were conducted in USP simulated gastric fluid using a USP II dissolution apparatus. RESULTS AND DISCUSSIONS: It was found that a precipitation study could generally predict powder, capsule and compact dissolution. Yet, it was recommended to run the dissolution at a higher paddle speed or for a longer duration to improve the predictability. It was also recommended to run powder, capsule and compact dissolution at both slow and high speeds to gain insights into wetting, dispersion and the dissolution of a system. Sometimes, capsule or compact dissolution could not be predicted by precipitation or powder dissolution due to plug formation. In this case, properly designed dosage forms were needed to break up this plug to optimize the dissolution profiles. On the contrary, formulations and dissolution conditions would have minimal effects on the dissolution profiles of a fast-dissolving solid dispersion. CONCLUSIONS: Different techniques are available to select the right polymers to optimize dissolution behaviors. However, it is important to understand the merits and limitations of each technique in order to optimize the formulations for amorphous solid dispersions.

A preliminary assessment of the impact of hot-melt extrusion on the physico-mechanical properties of a tablet.

OBJECTIVES: This research aimed at investigating the difference between the powders prior to and after hot melt extrusion. A preliminary assessment was also conducted to gain a better mechanistic understanding of the impact of hot melt extrusion on tabletability. MATERIALS AND METHODS: Kollidon® VA 64 and mannitol were sieved into different particles sizes and used as is or after drying for 24 h. Hot melt extrusion was used to manufacture an amorphous solid dispersion of Kollidon® VA 64 and mannitol. The extrudates were milled and sieved into different particles sizes. Tablets were manufactured from the different powders and their tabletability, compressibility and compactibility determined. RESULTS AND DISCUSSIONS: It was shown that the as received tablets gave higher tabletability compared with the tablets manufactured from the dried or hot melt extruded (HME) powder. Differences in the tabletability between the as received. dried and HME material could be related back to changes in the bonding area and bonding strength as a result of the hot melt extrusion process and/or a loss of moisture because of the high processing temperature. CONCLUSIONS: The reduced tabletability of the HME tablets appeared to be a function of multiple factors. Both the hot melt extrusion process and the moisture content may play significant roles in determining this phenomenon.

Oral delivery of poorly soluble compounds by supersaturated systems.

"New formulation and manufacturing methods are now available to efficiently and effectively increase solubility and maintain the supersaturation of a thermodynamically metastable state".

Drug delivery to the posterior segment of the eye IV: theoretical formulation of a drug delivery system for subconjunctival injection.

PURPOSE: The aim of the current study was to provide insights on the proper design of a dosage form to deliver drugs to the back of the eye, as well as to estimate the likelihood of achieving therapeutic levels by subconjunctival injection. METHODS: Computer simulation of a validated pharmacokinetic model for a subconjunctival injection was performed. The effect of various rate constants, different methods of administration, and other factors, such as solubility, etc., on the vitreous drug levels, were investigated. RESULTS: It was discovered, as expected, that a simple injection is not practical for chronic diseases, since frequent injection is required. A zero-order release system is able to provide a steady vitreous drug level. However, it may not provide vitreous drug levels greater than 1 microg/mL, unless k(10) can be reduced by a factor of 100 via the formulation modifications. A first-order release system gives a vitreous level between that following a simple subconjunctival injection and the injection of a zero-order release system. CONCLUSIONS: A properly designed delivery system, which can solubilize poorly soluble compounds and sustain vitreous drug levels for an extended period of time, is required for effective drug delivery to the back of the eye by subconjunctival injection.

Drug delivery to the posterior segment of the eye II: development and validation of a simple pharmacokinetic model for subconjunctival injection.

The aim of this study was to develop and validate a simple pharmacokinetic model for subconjunctival injection so as to study drug delivery to the posterior segment of the eye using the subconjunctival route. Curve-fitting was performed by ModelMaker 4.0 by applying Tsuji et al.'s in vivo data. It was found that drug elimination from the vitreous chamber was slowed by the existence of a peripheral compartment. The validity of this model was ensured because it gives reasonable predictability at two additional doses. This model is invaluable in studying drug delivery to the back of the eye by subconjunctival injection.

Drug delivery to the posterior segment of the eye III: the effect of parallel elimination pathway on the vitreous drug level after subconjunctival injection.

The aim of the current study was to study the effect of a parallel elimination pathway on the vitreous drug level after simple injection and application of a zero-order release system by computer simulation. It was found that this pathway gives rise to an early peak time regardless of the physicochemical properties of the applied drug. In addition, the parallel elimination pathway is the major determinant of the vitreous drug level after simple subconjunctival injection. For a zero-order release system, release rate is not the only determinant of pharmacokinetics due to the parallel elimination pathway and k13 also plays a significant role in determining steady-state drug levels. The findings of the current study is necessary for the proper design of a drug delivery system for vitreal drug delivery through subconjunctival injection.