Soy Matrix Drug Delivery Systems Obtained by Melt-Processing Techniques Cla ´ udia M. Vaz,* ,† Patrick F. N. M. van Doeveren, ‡ Rui L. Reis, †,§ and Anto ´ nio M. Cunha † Department of Polymer Engineering, University of Minho, Campus de Azure ´ m, 4800-058 Guimara ˜es, Portugal, ATO, Agrotechnological Research Institute, PO Box 17, 6700 AA Wageningen, The Netherlands, and 3B’s Research GroupsBiomaterials, Biodegradables and Biomimetics, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal Received February 12, 2003; Revised Manuscript Received July 14, 2003 The aim of this study was to develop new soy protein drug delivery matrix systems by melt-processing techniques, namely, extrusion and injection moulding. The soy matrix systems with an encapsulated drug (theophylline, TH) were previously compounded by extrusion performed at two different pH values, (i) pH 4 (SIpD tp ) and (ii) pH 7 (SID tp ), and further injection-moulded into a desired shape. During the extrusion process the matrixes SID tp were also cross-linked with glyoxal (0.6X-SID tp ) and reinforced with a bioactive filler, hydroxylapatite (SI-HAD tp ). The obtained mouldings were used to study the drug-release mechanisms from the plastic soy-TH matrixes. In an isotonic saline solution (ISS) buffered at pH 5.0 (200 mM acetate buffer), the resulting release kinetics could be described using the Fick’s second law of diffusion. Because the diffusion coefficients were found to be constant and the boundary conditions to be stationary, these systems are drug-diffusion controlled. Conversely, the dominant phenomena in an isotonic saline solution buffered at pH 7.4 (200 mM Tris/HCl buffer) are more complex. In fact, because of the higher polymer solubility, the resulting matrix is time-variant. So, the drug release is affected by swelling, drug diffusion, and polymer dissolution, being faster when compared to ISS-200 mM acetate buffer, pH 5.0. The changes in the formulation composition affecting the correspondent release rates were also investigated. At pH 7.4, increasing the cross-linking degree of the polymer matrix (via reaction with glyoxal or heat treatment) or decreasing the net charge (extruding at pH near its isoelectric point) led to lower release rates. The incorporation of ceramic filler caused the opposite effect. Because of the low solubility of the matrix at pH 5.0, no significant variations were detected with variations in the selected formulations. These systems, based on a nonstandard protein-based material, seem to be very promising to be used as carriers for drug delivery. 1. Introduction The most conventional way to make matrix drug delivery systems is based on the compression of polymer-drug mixtures into a compact form (e.g., slabs and tablets). 1-3 Alternatively, the drugs can be previously granulated with the polymer so that the drug particles are covered with a layer aiming at retarding the respective release process. 4,5 In other studies, drugs have also been incorporated into the polymer granulates using techniques such as (i) solvent evaporation, 6 (ii) polymer solution granulation, 7 (iii) melt granulation, 8 and (iv) sintering. 9 The obtained granulates were then compressed into slabs or tablets. However, the release kinetics was found to be greatly dependent on the compaction properties of the polymer-drug granules. 6-9 Other alterna- tives include the design of matrix drug delivery systems in which the drug particles are dispersed in a melted polymeric phase. A common example is the compression of drug-filled polymeric compounds above the melting point of the polymer to form a solid part containing the drug. 10-12 In this type of device, the release kinetics is controlled by the polymer bulk properties and not by the porosity of the system. A less-frequent methodology is the encapsulation of a drug into a polymer extrudate that will be subsequently shaped in the final geometry by injection moulding. The major advantages over the more-conventional above-described methods are (i) continuity of the production process because the different production steps (mixing, melting, homogeniz- ing, and shaping) are carried out in a single equipment, (ii) cost-effective process because the technique usually offers high throughputs, low material loss, and excellent homoge- neity, (iii) high geometrical freedom, (iv) environmental friendliness because no organic solvent is used during the processing stage, (v) possibility to work in clean room conditions, and (vi) high versatility in terms of materials and formulations. 10,11,13-15 Following this last described approach, soy protein was chosen as the matrix former because of its high availability and biodegradability, 16 good melt processability, 17 high thermal stability, 17 and noncytotoxicity. 18 Its outstanding * To whom correspondence should be addressed. Tel.: + 31 40 247 4839. Fax: + 31 40 244 7355. E-mail: c.m.vaz@tue.nl. † University of Minho, Campus de Azure ´m. ‡ ATO, Agrotechnological Research Institute. § University of Minho, Campus de Gualtar. BATCH: bm6a18 USER: jld69 DIV: @xyv04/data1/CLS_pj/GRP_bm/JOB_i06/DIV_bm034050i DATE: August 8, 2003 10.1021/bm034050i CCC: $25.00 © xxxx American Chemical Society PAGE EST: 9.2 Published on Web 00/00/0000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67