In vivo evaluation of pH-sensitive polymeric microparticles for site specific drug delivery to the small intestine and colon

SUMMARY A novel emulsification/solvent evaporation process was developed to formulate prednisoloneloaded Eudragit L and S microparticles as drug delivery vehicles to target different regions of the gastrointestinal tract. Microparticles were characterised in vitro and in vivo. This is the first report of drug absorption form orally administered Eudragit L and S microparticles. INTRODUCTION Delayed release oral dosage forms are designed to target either the small intestine (for gastric irritant or labile molecules) or the colon (for the treatment of localised disorders or delivery of peptides and proteins). The most commonly used method for targeting these regions is to exploit the increasing luminal pH from stomach to colon by applying a pH-sensitive film coating to a core dosage form. The film coating polymer is expected to ionise and dissolve above a threshold pH specific to either the duodenum (pH 5-6) or colonic region (pH 7-7.5). Unfortunately, as the application of pH-sensitive coatings generally renders the dosage form nondisintegrating in the stomach, gastric emptying becomes delayed and variable from both tablets (Khosla et al., 1989) and pellets (Clarke et al., 1993), making the onset of drug action highly unpredictable. Furthermore, pharmacoscintigraphic studies have shown a lag time of 1-1.5 hours post gastric emptying before enteric coated dosage forms disintegrate (Ebel et al., 1993; Wilding et al., 1993), which further impacts onset of action and drug bioavailability. Due to the limited fluid content in the colonic region, pH-sensitive coating dissolution may be further retarded, and tablets intended to deliver drug to the colonic region have been observed, on occasion, to be voided intact. The aim of this research was to formulate pHsensitive microparticles for small intestinal or colonic delivery, which may suspend in the stomach contents therefore emptying rapidly and reproducibly. The large surface area of the pHsensitive microparticles should facilitate rapid drug release above the threshold pH of the pH-sensitive polymer. The in vivo performance of the pHsensitive microparticles was tested in fed rat, given the similarities between rat and man gastrointestinal (GI) transit times and pH. EXPERIMENTAL METHODS A novel but simple emulsification/solvent evaporation method was developed to produce Eudragit L (soluble pH>6) and S (soluble pH>7) prednisolone-loaded microparticles (5:1 polymer:drug), for small intestinal and colonic drug delivery, respectively. Drug encapsulation efficiency was calculated. Microparticles were characterised by SEM, particle size analysis (Malvern Mastersizer), and X-ray diffraction (XRD). In-vitro dissolution experiments were carried out using USP II dissolution apparatus using a pH-change method, simulating gastric to small intestinal and colonic conditions. Eudragit L and S microparticles and micronized prednisolone (control, crystalline drug substance, 5μm particle size) suspensions were administered to rats by oral gavage (2ml, 200mg/kg prednisolone. Plasma samples were collected by tail vein sampling at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours post dose, and the plasma was assayed for prednisolone content by HPLC-MS/MS. RESULTS AND DISCUSSION Prednisolone encapsulation efficiency was ~90% for both polymers. SEM showed microparticles to exhibit excellent morphology, being spherical, nonaggregated and non-porous (Fig. 1). Figure 1: SEM image of Eudragit L100 (left) and S100 (right) microspheres (bar is 100 μm)