Delivery of poorly soluble compounds by amorphous solid dispersions.

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Formulation development of sustained-release hydrophilic matrix tablets of zileuton.

The purpose of this paper was to develop a hydrophilic matrix system for extended oral delivery of zileuton, and study the effects of certain formulation, processing, and dissolution variables on in vitro drug release. Tablet formulations with 60-70% drug and varying release rates were prepared by wet granulation using low and medium viscosity grades of hydroxypropylmethocellulose. In vitro drug release was evaluated using USP apparatus 1. The in vitro drug release from all formulations followed zero-order kinetics and was independent of compression force. In general, the release rate decreased with increasing drug load and higher polymer concentration or viscosity. High-shear granulation also resulted in lower release rate. Accelerated release was observed with increased agitation as well as in the dissolution media with higher surfactant concentration and/or ionic strength. No stereoselective release from the matrix system was observed. The hydrophilic matrix system effectively controlled the in vitro release of zileuton. Matrix tablets with desired release rates can be prepared by adjusting various formulation and processing parameters. The matrix system also has the advantage of simple processing and relatively low cost.

Effect of particle dissolution rate on ocular drug bioavailability.

Aqueous ophthalmic drug solutions typically exhibit low bioavailability due to various loss processes such as drainage, tear turnover, nonproductive absorption, and protein binding. Suspensions may improve bioavailability, but because of a short residence time and a low corneal permeability rate constant, the dissolution rate of the drug and its intrinsic solubility must be considered. The relationship between the various parameters affecting the relative dissolution rate have not heretofore been examined with respect to the eye. In the present study, a kinetic model that predicts ocular tissue drug levels for suspensions has been developed and tested using a steroid, fluorometholone, as the test drug suspension. The proposed model is able to predict the effects of particle size, concentration, and changes in drainage rate such that a reasonable a priori prediction of drug levels can be made.

Ocular disposition of topically applied histamine, cimetidine, and pyrilamine in the albino rabbit.

Aqueous solutions of pyrilamine, cimetidine, and histamine were instilled into the eyes of albino rabbits and drug levels determined as a function of time in the cornea, conjunctiva, aqueous humor, and iris-ciliary body. For all three drugs, less than 1% of the applied dose penetrates to the aqueous humor. Moreover, cimetidine and histamine are significantly less bioavailable than pyrilamine. Both cimetidine and histamine appear to bind to precorneal mucin and thus exhibit binding to conjunctival tissue with subsequent low penetration into the cornea and prolonged peak times in the aqueous humor. In addition, both drugs show binding to the iris-ciliary body as well. The influence of solution pH on the penetration of these compounds was also investigated, and a factor of two increase in aqueous levels was noted for the pH range 5-8, which encompasses the pKa's for these compounds.

Corneal metabolism of pilocarpine in pigmented rabbits.

Cornea, aqueous humor, and iris-ciliary body levels of pilocarpine and its metabolite pilocarpic acid were determined in mixed-breed rabbits following topical dosing with 25 microliters of 1 X 10(-2) M pilocarpine. From the time-drug concentration profile it is clear that extensive metabolism of pilocarpine occurs in the cornea of pigmented rabbits. This finding contrasts sharply with similar studies in albino rabbits where relatively low levels of pilocarpine acid were observed. It is estimated that the first-order metabolism rate constant in albino rabbits is approximately two orders of magnitude smaller than in pigmented animals. A significant observation from this finding is the possibility that the reported greater dose requirement for heavily pigmented individuals may not be due to drug-pigment binding alone but also to extensive corneal drug metabolism.