In-vitro and in-vivo evaluation of enteric-coated starch-based pellets prepared via extrusion/spheronisation.
Pellet cores containing modified starch (high-amylose, crystalline and resistant starch) as the main excipient were enteric-coated with an Eudragit L30 D-55 based dispersion. The polymer weight gain was from 15% to 30% (w/w). Pellet cores were prepared using piroxicam (2.5% w/w, poor water solubility) and anhydrous theophylline (2.5% and 25% w/w, coarse and micronised powder, medium water solubility) as model drugs. Next to the water solubility, particle size and concentration of the model drugs, the influence of sorbitol (0% and 10%, w/w) and drying method (oven and fluid-bed) on pellet yield, size (Feret mean diameter), sphericity (aspect ratio, AR and two-dimensional shape factor, e(R)), friability, surface morphology and drug release were evaluated. Binder (HPMC) and granulation liquid (water) concentration were optimised to obtain maximum yield (size fraction between 900 and 1400 microm) and acceptable sphericity (AR<1.2). Pellet friability was <0.01% for all formulations, while the mean pellet diameter was lower for pellets with sorbitol and the ones dried in an oven. Mercury intrusion porosimetry combined with scanning electron microscopy revealed an influence of drying method and sorbitol level on the surface structure: the surface of fluid-bed dried pellets without sorbitol and with 2.5% of model drug was cracked, which correlated with a Hg-intrusion peak at the 6-80 microm pore size range. Due to improved mechanical properties of the wet mass, sorbitol addition smoothened the pellets as the main peak of Hg-intrusion shifted to a smaller pore size range. Using a higher drug concentration and micronised theophylline shifted the main peak of Hg-intrusion further towards the smaller pore size range. Oven-dried pellets showed no Hg-intrusion and no cracks were observed. When applying the highest coating thickness (30% weight gain), all theophylline pellet formulations were successfully coated (<10% drug release after 2h in acid dissolution medium), while pellets with the lowest coating thickness (15% weight gain) released from 5% to about 30% theophylline. The extent of drug release depended on the pellet composition and drying method as these factors determined the surface properties. Piroxicam release in acid medium was less than 1% irrespective of the surface characteristics, due to its poor water solubility. In basic medium (phosphate buffer, pH 6.8) all pellets released the drug in less than 45 min. The bioavailability of coated and uncoated piroxicam pellets was determined after oral administration to six dogs. Values of AUC(0-->72h), C(max) and t(max) after oral administration of piroxicam pellets to dogs were not significantly different from the values obtained for immediate release capsules (P>0.05).
Dukić-Ott
Aleksandra
A
Laboratory of Pharmaceutical Technology, Ghent University, Harelbekestraat 72, Ghent, Belgium.
De Beer
Thomas
T
Remon
Jean Paul
JP
Baeyens
Willy
W
Foreman
Paul
P
Vervaet
Chris
C
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003890:Desiccation; D004285:Dogs; D005079:Excipients / Q000737:chemistry*; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D010316:Particle Size; D010894:Piroxicam / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011108:Polymers / Q000737:chemistry*; D016062:Porosity; D012995:Solubility; D013012:Sorbitol / Q000737:chemistry; D013213:Starch / Q000737:chemistry*; D013499:Surface Properties; D013608:Tablets, Enteric-Coated; D013678:Technology, Pharmaceutical / Q000379:methods*; D013806:Theophylline / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry
C477852:Eudragit L 30 D-55; D005079:Excipients; D008689:Methacrylates; D011108:Polymers; D013608:Tablets, Enteric-Coated; D014867:Water; D010894:Piroxicam; D013012:Sorbitol; D013213:Starch; D013806:Theophylline