Partial Permselective Coating Adds an Osmotic Contribution to Drug Release from Swellable Matrixes PIER LUIGI CATELLANI,PAOLO COLOMBO,NIKOLAOS A. PEPPAS, † PATRIZIA SANTI, AND RUGGERO BETTINI* Contribution from Dipartimento Farmaceutico, Universita ` di Parma, via delle Scienze, 43100 Parma, Italy, and Biomaterials and Drug Delivery Laboratories, School of Chemical Engineering, Purdue University, West Lafayette, Indiana 47907-1283 Received January 2, 1998. Final revised manuscript received March 10, 1998. Accepted for publication March 11, 1998. Abstract 0 A swellable matrix tablet is described which is partially coated with cellulose acetate (CA) to obtain a film having the shape of a cup, whose permeability to water and solutes was altered by mixing increasing amounts of poly(ethylene glycol) 400 (PEG). The drug-release mechanism from such systems was assessed by carrying out drug-release experiments both in water and saline solutions. Drug permeability through the polymeric cup and SEM analysis on the films were also performed. It was found that the systems exhibited drug- release kinetics very close to linearity. The mechanisms governing drug release were (i) drug diffusion through the uncoated gel layer, (ii) drug transport through the gel layer due to the osmotic pressure difference, and (iii) drug diffusion through the cup pores. The relative importance of each contribution depended on the amount of PEG in the film. The systems with a cup containing 1%, 13%, and 33% PEG w/w behaved in part as osmotic systems, whereas the system having a permeable cup behaved as a hybrid reservoir system. These modifications of the coating permeability introduce a further possibility of modulating drug-release kinetics and lead to a reduced dependence of swellable matrix tablet release on environmental conditions. Introduction Osmotic pumps are standard dosage forms for constant rate drug delivery. 1 They are reservoir systems and, therefore, defects in the outer membrane (such as pinholes) could affect their performance, giving rise to an undesirable drug-release rate. The risk of unpredicted delivery is reduced using swellable matrix systems. However, as with all diffusion-controlled systems for oral administration, the reliability of the drug dissolution rate in biological fluids from matrixes is affected by the variability of pH and hydrodynamic conditions of the GI tract, which are com- plicated by the fed or fast conditions of the subject. 2 In previous publications, 3 we showed that the release kinetics of buflomedil pyridoxal phosphate (BPP) from matrixes prepared with high viscosity hydroxypropyl meth- yl cellulose (HPMC) exhibited non-Fickian behavior. When disklike HPMC matrixes were coated with an impermeable film on one base and the lateral surface (leaving available for swelling and drug release only the surface of the other side), a release kinetic behavior was obtained 4 which was closer to linear. These partially coated matrixes are a version of the Geomatrix technology 5 and can be depicted as a polymeric cup containing a swellable core, i.e., the matrix. The impermeable cup resisted the pressure of HPMC relaxation and drove the matrix swelling at the uncoated surface in the axial direction. Finally, the release kinetics from the matrix was changed by the presence of the cup, due to the different development of the swollen releasing area. Since the permeability of the cup could be readily modified by selecting an appropriate film-forming polymer or by adding a porosigenic agent, 6 a novel approach was proposed by partially coating the swellable polymer matrix with permselective films. The rationale of using such a film was to improve the drug-delivery performance of partially coated matrixes by adding other supports to their swelling-dependent delivery mechanisms. In this case, drug release would not be limited to the relaxational/ diffusive transport at the uncoated portion of the matrix but would contain other contributions due to the penetra- tion of water and drug transport through the cup. Therefore, the aim of this work was to study the behavior of drug-delivery systems consisting of swellable matrix tablets partially coated with a cellulose acetate film in order to obtain a cup whose permeability to water and solutes would be altered by adding increasing amounts of a water soluble polymer. Such systems combine matrix and reservoir characteristics judiciously and can contribute either an osmotic or additional diffusive support to drug delivery from swellable matrix. The final result of these modifications of coating permeability could be not only a further possibility of modulating drug-release kinetics, but also a reduction of the dependence of the swellable matrix tablet release behavior on environmental conditions. Here, the contribution of the various mechanisms in- volved in the overall drug delivery of the system was assessed, in particular exploring the osmotic effect intro- duced by semipermeable films. Experimental Section Swellable cylindrical matrixes were prepared by granulating 65 parts of buflomedil pyridoxalphosphate (Lisapharma S.p.A., Erba, Italy) (water solubility of 65 g/100 mL) with 24 parts of hydroxypropyl methylcellulose (Methocel K15M, Colorcon, Orping- ton, UK) using a 1:1 acetone:ethanol solution of 5 parts of cellulose acetate phthalate (Eastman Chemical Co., Kingsport, TN) as a binder. After drying and lubrication with 2 parts magnesium stearate and 4 parts talc, the granules were tabletted using a reciprocating tabletting machine (EKO Korsch, Berlin, D) equipped with flat face punches of 7 mm diameter. The matrixes were picked-up from one side by an aspirator (pipet connected to a vacuum pump), and were partially coated on their other base and their lateral surface by carefully dipping them in an organic solution of the film-forming polymers. The dipped matrix was manually rotated until complete film coating was achieved, and the solvent evaporation was completed at 30 °C after 48 h. Thus, one base of the matrix remained uncoated. The polymeric solutions used to coat the swellable matrixes with permselective films were obtained by bringing 6.6 g of cellulose acetate (CA 398-6, Eastman Chemical Co., Kingsport, TN) and specific amounts (corresponding to 1%, 13%, 33%, and 66% w/w * Corresponding author. Phone: (39)-(521)-905089. Fax: (39)-(521)- 905085. E-mail: bettini@ipruniv.cce.unipr.it. † Purdue University. S0022-3549(98)00002-1 CCC: $15.00 726 / Journal of Pharmaceutical Sciences © 1998, American Chemical Society and Vol. 87, No. 6, June 1998 American Pharmaceutical Association Published on Web 05/08/1998