Drug Release from Poly(D, L-Lactide) / SiO2 Composites

The aim was to develop a biodegradable carrier system for toremif ene citrate based on poly(D,L-lactide) and sol-gel derived SiO 2. Two molecular weights of P(D,L-LA) (LMW 130 000 g/mol and HMW 240 000 g/mol) were used in the composites. The release rate of toremifene citrate from P(D,L-LA)/SiO2 composites was evaluated by in vitro dissolution tests. It was shown that it is possible to prepare a controlled release system of toremifene citrate by adding SiO2 particles and/or pores to the used polymer. Release of toremifene citrate can be adjusted from 30 days to 6 months. Introduction Polylactides have been used as matrix materials for drug rel ease [1], but the clear and sudden changes in structure, e.g., steep decrease in molecular weight ca used by enhanced autocatalytic degradation [2], is a problem with respect to the controlled release of drugs. Biodegradable, sol-gel derived SiO2 is known to be biocombatible and it has been used for controlled drug deli very as such [3]. In this work toremifene citrate (TC) was used as a model dr ug in polymer/silica gel composites. Toremifene citrate is an antiestrogenic compound that has been used i n the systemic treatment of hormone-dependent breast cancer. Local hormone therapy after breast cancer surgery could provide targeted and long-lasting disease control. The purpose of this study was to develop a controlled release form ulation of toremifene citrate using biodegradable delivery systems based on poly(D, Llactide) an d sol-gel derived SiO2 composites. Also the effect of pore forming CO 2 treatment and addition of a fast dissolving mesoporous SiO 2 (MCM-41) on composites was investigated. Furthermore, the effect of the molecular weight of poly(D,Llactide) on release rate of toremifene ci trate was studied. Materials and Methods Silica sol was prepared in a mole ratio of TEOS: H 2O: HCl, 1.0: 14.2: 0.0096. Toremifene citrate (Orion Pharma Ltd, Turku, Finland) was added into the clear hydrolyse d silica sol at room temperature. The pH of the sol was adjusted to 2.4 before spray dry ing with a mini spray dryer (B191, Büchi Labortechnik AG, Switzerland). The theoretical drug concentra tion in the silica sol was 2 wt.%, corresponding to 13,4 wt.% drug in spray dried microparticles (MP). Pore structure of calcified, TEOS-derived MCM-41-type SiO 2 was modified by cetyltrimethylammonium bromide/dimethylhexadecyl amine ratio. HMW and LMW P(D,L-LA) polymers were prepared from racemic l a tide (Purac) recrystallised once from ethylacetate. The racemic D,Dand L,L-lactide w as polymerised in melt using tin octoate as catalyst at 140 °C for 5 hours under N 2 atmosphere and mechanical stirring. Solvent casted PDLLA composite films were prepared by dissolving PDLLA in chloroform mixed with SiO2 microparticles and drug. They contained 40 or 60 wt.% of toremifene citrate containing SiO 2 Key Engineering Materials Online: 2003-12-15 ISSN: 1662-9795, Vols. 254-256, pp 489-492 doi:10.4028/www.scientific.net/KEM.254-256.489 © 2004 Trans Tech Publications Ltd, Switzerland All rights reserved. No part of contents of this paper may be reproduced or transmitted in any form or by any means without the written permission of Trans Tech Publications Ltd, www.scientific.net. (Semanticscholar.org-13/03/20,19:47:16) microparticles, corresponding to 6 and 9 wt.% drug content, or 6 wt.% of pur e toremifene citrate. Two composites contained 6 wt.% TC and SiO 2 (20 wt.% microparticles or 5 wt.% MCM-41) separately in the polymer bulk. The HMW P(D,L-LA) composites wer e treated with CO2 at 50 bar for 5, 20 or 36 hours. Composites without CO 2 treatment were used as controls. The fast dissolving mesoporous SiO 2 (MCM-41) was added to LMW P(D,L-LA) composites. Molecular wei ghts were obtained by Size Exclusion Chromatography (SEC). The morphology of the porous LMW P(D,LLA) / SiO2 composites were detected by a scanning electron microscopy (SEM; JEOL, Model JSM-5500, Tokyo, Japan). The release profiles (n=3) of toremifene citrate were st udied using a shaking water bath at 37oC (75 shakes per minute). Simulated body fluid (SBF, pH 7.4) [4] containing 0.5 wt .% sodiumlaurylsulphate (SDS, Sigma) was used as a dissolution medium. The volume of the dissolution medium was 50 ml and the weight of the specimens film was approximately 50 mg with varying specimen volume (35 – 210) mm 3 depending on the influence of the CO 2 treatment on the composite specimen size and morphology. Alternatively, a 5 ml sa ple or the whole sample solution was removed from each flask and replaced immediately with an identical volume of fresh medium. The absorbance values of the dissolution samples were measur ed on a UV-Visible spectrophotometer (Shimadzu, UV-1601) at the maximum absorbance for toremifene ci trate (A278). Results and Discussion The molecular weights of pure polymers were 240 000 g/mol for HMW P (D,L-LA) and 130 000 g/mol for LMW P(D,L-LA). Molecular weights of HMW P(D,L-LA) specimens before and after dissolution are shown in Table 1. Table 1. Molecular weights of HMW P(D,L-LA) specimens before and after dis solution. Composite Before dissolution After dissolution Mw Mn MWD Time Mw Mn MWD P(D,L-LA) + [g/mol] [g/mol] [days] [g/mol] [g/mol] Pure HMW P(D,L-LA) 240 000 TC (6%), 20h, 50 bar 220 100 136 900 1,61 169 23 500 15 200 1,54 TC MP (40%), 20h, 50 bar 197 400 129 800 1,52 169 93 400 65 200 1,43 TC (6%), 5h, 50 bar 203 600 112 100 1,82 169 28 400 16 200 1,75 TC MP (40%), 5h, 50 bar 214 300 129 100 1,66 169 98 600 64 400 1,53 TC (6%), without pores 210 000 119 600 1,68 105 16 700 8 800 1,88 TC MP (40%), without pores 202 000 116 100 1,74 126 143 700 85 800 1,67 TC MP (60%), 36h, 50 bar 247 400 166 100 1,48 Table 2. Changes in molecular weights of some LMW P(D,L-LA) specimens duri ng dissolution. Composite Before dissolution After dissolution Mw Mn MWD Time Mw Mn MWD P(D,L-LA) + [g/mol] [g/mol] [days] [g/mol] [g/mol] Pure LMW P(D,L-LA) 130 000 82 000 1,60 TC MP (40%) 97 298 55 218 1,76 60 52 112 28 933 1,80 TC (6%) + MCM-41 (10%) 60 68 015 40 286 1,69 TC (6%) 2 67 504 38 676 1,75 8 59 899 34 673 1,73 13 44 702 25 208 1,77 27 19 182 9 992 1,92 TC MP (40%) + MCM-41 (5%) 2 124 752 71 503 1,75 8 112 916 70 309 1,61 27 90 763 58 569 1,55 46 92 367 56 667 1,63 60 78 317 49 651 1,58 490 Bioceramics 16