ACen sured before and after antibody modification. Table 1 dem- srstrates the characterization parametergof the empty (EAL) aed loaded (PTXAL) liposome forrtivlations. The size of the ‘mmune-liposomes before mAb modification was found be 145.341.5 nm. After fusion of the IgG-PEG-PE micelle ructures into the empty liposomes, particle size did not ef- ‘ected significantly (p>0.05).On the other hand, for the load- ‘2 PTXCILs, the increasement of the particle size was found “= be significant (2<0.05). Also the zeta potentials ofthe for- smulations were around -5 mV before mAb modification for both empty and loaded liposomes. mAb modification of the ‘icosomes led zeta potentials to increase around -10 mY. “Encapsulation of the PTX into the liposomes was achieved “with given preparation method. Encapsulation efficiency “was found to be 15% for PTX. Total amount of 696 tig PTX “was encapsulated into the immune-liposomes, which corre- ponds 10 0.122umol PTX/ uml total phospholip Cl viability did not decrease with the E1L comparing to ‘he control group, which shows that the immuno-liposomes “with non-specific IgG did not show any cytotoxicity against WC cell line, Uptake studies showed that liposomes did ‘por interact with the cell surface. Both non-specific mAb -podified and non-modified liposomes showed nominal cel- “ies uptake. Gendlusion “mas demonstrated that Iks with non-specific IgG can be spepared by using an optimized conjugation technique. “This system seems promising option after combining a spe- “sili antibody and can be used for the delivery of anti-cancer “areas to tumor cells ‘Acknowledgement: ‘hs project was supported by Hacettepe University Re- ‘sexcch Fund-4794, “eferences Gupta, B, Levehenko, T, Mongayt, D.A, Torchilin, VP, Monoclonal antibody 2C5-mediated binding of lipo- somes to brain tumor cells in vitro and in subcutane- ous tumor model in vivo, J Drug Targeting, 13, 337-343, 2008. | i Se — oo P45 COATED ORGANOMODIFIED SILICA XEROGEL MICROPARTICLES FOR COLON SPECIFIC DRUG DELIVERY OF 5-FU Authors: B. Djurdijic! N.Ge8kovski’ G.Petrudevski? M.S. Crearevska! M.G.Dodov" V. Petrovska! M.Cvetkovska? k. Goraginova’ ‘Institute of Pharmaceutical technology, Faculty of Phar- macy, University Ss Cyril and Methodius, Skopje, Macedonia >Research and development, Alkaloid AD, Skopje, Macedonia Institute of Organic and Polymer engineering, Faculty of Technology and Metallurgy, University Ss Cyril and Metho- dius, Skopje, Macedonia Introduction ‘The advantages and necessity of colon targeting to provide more effective therapy for colon related diseases, such as co- lon cancer and inflammatory bowel disease have been well recognized and documented. Therefore, site-specific drug delivery to the colon has attracted considerable attention for the past few years in order to develop drug delivery systems that are able to release drugs specifically in the colon In a predictable and reproducible manner. Because of the distal location of colon in the Gi tract, a colon-specific drug deliv- ery system should prevent drug release in the stomach and, small intestine, and demonstrate an abrupt onset of drug release upon entry into the colon’, Microparticulated carrier systems, in general, are well investigated for targeted and controlled drug delivery. By using organically modified sol gel derived silica xerogels for microparticles preparation and further pH dependent coating of these carriers, direct target- ing to the colon region could be obtained. Here they could adhere to the mucus layer and release the incorporated drug substance thus enabling increased therapeutic efficacy, The purpose of the present study was to prepare coated organi- cally modified silica xerogel microparticles (MP's) loaded with 5-fluorouracil (5-FU) as colon specific drug delivery sys- tem and evaluate its physico-chemical and biopharmaceut cal properties. I September 13 - 15, 2010 Kervansaray Hotel, Lara, Antalya / TurkeyPe Materials and methods Materials The coated MP's were prepared using the following re- agents: tetraethoxysilane (TEOS; Sigma, Germany), 3-ami- nopropyltriethoxysilane (APTES; Sigma, Germany), ethanol 96% (viv) (Merck, Germany), acetic acid (Merck, Germany), S-FU (Ebewe Pharma, Austria), Ethyicellulose 10cP (Colorcon, USA), Eudragit L-100 (Rohm Pharma, Germany) and deion- ised water. All other used chemicals and reagents were of analytical grade. Methods Preparation of uncoated MPS ‘TEOS and APTES were added in the mixture of water, ethanol and acetic acid and continuously stirred for 3h. The molar ratio of the components was TEOS : APTES : water : etha- nol : acetic acid = 0.01 : 0.00027 : 1.2: 1.7: 0.01. Afterwards, 5-FU was dissolved in the mixture (mass ratio 5-FU: xerogel |: 15,6) and the solution was spray dried (Mini spray dryer 8-290 ,Biichi, Switzerland; set conditions: inlet temperature 130°C, aspiration 240 m’/h, Q-flow 50mm, flow rate 4-Smi/ ‘min). Blank MP's were also prepared. Preparation of coated MP's FF The coating polymers, Ethylcellulose and Eudragit L-100 in a mass ratio of 2:3 were dissolved in ethanol (5% w/w total polymer concentration). Afterwards the dried MP's (mass ratio MP's: coating polymers = 1 : 5) were dispersed in the solution on ultrasonic bath (Ultrasons H, Selecta, Spain) for Imin and spray dried under defined process conditions. ‘Morphology study The morphology of the MP's was evaluated by Morphologi- 63S (Malvern Instruments, UK). Particle size analysis ‘The particle size distribution of the prepared MP's was de- termined by laser diffractometry using Mastersizer 2000 (Malvern Instruments, UK). The particle size distribution was expressed in terms of SPAN value factor. Drug content determination In order to determine 5-FU content in the MP's, 20 mg of the MPs were dispersed in 10 ml 1M NaOH under continuous stirring at temperature not exceeding 60°C until clear solu- tion was obtained. 5-FU contentin all prepared formulation was determined by HPLC method (HPLC Agilent 1200 with UV detector; set conditions - mobile phase water : metha- nol :acetic acid = 89:10:1, flow rate Imi/min, column RP C-18, Lichrocart Merck, Germany, volume of injection 20um, UV detection 266 nm), Fourier transform infrared (FT-IR) spectroscopy The FTIR spectra of the prepared microparticles were col lected using Varian 660 FT-IR spectrometer. Each spectrum was acquired in the 4000-400 cm region (20 scans per spectrum, 4 cm* resolution) by KBr pallets method. Invitro drug release studies The dissolution tests were carried out in 10m! buffer solu- tions (1.2 and 7.4) in closed glass tubes on horizontal shaker at 37°C and 50 strokes/min (Unitronik OR, Selecta Spain). [At appropriate intervals, samples (2ml) were withdrawn, fil- tered through 0.451m membrane filter, and assayed by HPLC method (previously described). Results and Discussion ‘The microscopic investigation of the uncoated MPs afford- ed authentication of the samples as spherical and smooth surfaces micro objects (Fig. 1), while the coated samples ap- peared as nearly spherical particles with collapsed center and deformations (Fig. 2), probably developed during the spray drying procedure. The particle size distribution of the prepared samples appeared as unimodal with median vo!- ‘ume diameter 1.878ym for uncoated MP's and 5:020um for coated MP's and SPAN of 1.027 and 2.044, respectively (Fig 3). It Is obvious that the coated MPs have larger diameter and particle size distribution probably due to the surface ad- herence of the coating polymers. Fig. 1. Microscopic image of the uncoated MP's oe Pina es a nae a)POSTER PRESANTATIONS bands originating from the deformation vibrations of the CH, and NH, groups of the alkyl-amino chain (1550-1400 cm) are due to the incorporation of the APTES in the silica framework. The band that appears around 953 cm" is associ- ated with the combination of stretching modes of Si-OH and SLO-R (where R is ~CH,CH,CH,NH, from the incorporated APTES?.For the S-FU loaded MP's (Fig, 4b), additional bands originating from the active ingredient, informative for the bonding properties between the last and the organomodi- fied silica carrier can be found in the: C-H stretching (~ 3000 cm), C-F stretching (751 crn") and N-H bending (643 and '553 cm) region. This is most probably due to the present ‘organomodified layer of the MPs, affording more effective bonding of 5-FU to the silica matrix. The FTHR spectra for the coated MPS (Fig. 5) revealed that the most of the bands, found specific for the organomodified silica network or the active substance, are being heavily overlapped by the bands from the coating polymers, most probably due to the firm surface adherence of the later, Fig, 3. Comparative particle size distribution of uncoated and coated MP's The content of 5-FU in the uncoated MP's was 93.3:0.256 (mg 5-FU/Ig MP5s) and 145520458 for coated MP's. ‘The FTIR spectra of S-FU and the uncoated MP'sare present- ed on Fig. 4. Three bands positioned at 466, 798 and 1090 em’ (Fig. 4 b and c) are representing the SiO, structure, cor- responding to the bending, symmetric and antisymmetric stretching mode of the Si-O-Si species?. 3000 2300 200 Wavenumbericm Fig. 4. FTAR spectra of 5-FU (a), uncoated loaded MP's (b) and uncoated blank MP's (c); ‘The band near 3400 cm’ is originating from the combina- tion of the O-H stretching (water) and N-H stretching vibra- tion of the primary ammine mode of the present APTES. The 3000 7500 200 1500 ‘Wavenumberiem:* Fig. 5. FFIR spectra of Ethylcellulose 10cP (a), coated loaded MPs (b) and Eudragit L-100 (c). Too 500 The dissolution profiles of coated and uncoated MP's in pH 2 and 7.4 are presented in figures 6 and 7. The results revealed that the uncoated MP's demonstrate burst release in the first few hours without any pH dependent behavior. In contrast, the coated MP's showed significant retention of 5-FU in pH 2 due to pH dependent solubility of Eudragit L-100 and damp- ‘ening of the initial burst release relative to the uncoated MP's probably attributable to the hydrophobic nature of the ethylcellulose. ee) PETC ee abead i | | | | Sb released 3. 6. Comparative dissolution profiles of uncoated MP's in pH2and 7.4 Fig. 7. Comparative dissolution profiles of coated MP's in pH and 7.4 ‘Conclusion ‘Overall, the results from this work show that coated organo- ‘modified silica xerogel microparticles could effectively de- liver 5-FU to the colon region and therefore increase the lo- ‘al drug concentration thus enabling efficient therapy with minimized side effects. References 1. Yang L, Chu J, Fix J. A, Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation, int J Pharm 235, 1-15, 2002; 2. Brinker PJ, Scherer G.W,, Sol-Gel Science; The Physics and Chemistry of the Sol-Gel Processing, Academic, San Diego, CA, USA, 1990. P-46 PREPARATION AND COMPREHENSIVE IN VITRO EVALUATION OF GASTRORETENTIVE FUROSEMIDE TABLETS FORMULATED WITH PAA-CYS Authors: Z.AySenyigit’ A.Vetter? T.Giineri! ‘A.Bernkop-Schniirch? Institutions: * Department of Pharmaceutical Technology, Faculty of ‘macy, Ege University, Bornova, 35100, lzmir, Turkey. * Department of Pharmaceutical Technology, Institu Pharmacy, University of Innsbruck, A-6020, Innsbruck, tra, Introduction Prolonged residence time of a delivery system on the gi ‘mucosa leads to an extended period of absorption and sequently of improved bioavailability and greater thera ticbenefit of the drug substance. Drugs that are absorb ‘the proximal part of the gastrointestinal tract and drugs are less soluble in or degraded by the alkaline pH may efit from prolonged gastric retention. In addition, local sustained drug delivery to the stomach may offer nume advantages including improved bioavailability and «! peutic efficacy, and possible reduction of dose size (1) us strategies are pursuit to develop efficient formula for gastroretentive drug delivery such as floating, swe! ‘mucoadhesive and high/low density systems (2) The aim of this study was to investigate the potential of coadhesive poly(acrylic acid)-cysteine (PAA-Cys) matrix lets for gastroretentive delivery systems using furosemi model drug. PAA-Cys was chosen as anionic thiolated j ‘mer and furosemide was chosen as a model drug bec thas a narrow absorption window in the upper part o gastrointestinal tract. Materials And Methods Synthesis of PAA-Cys PAA-Cys used in this study was synthesized according method described previously (3). The covalent attachr of L-cysteine to PAA was achieved by the formation of a bonds between the primary amino group of cysteine the carboxylic acid group of the polymer. 15* International Pharmaceutical Technology Symposium (IPTS 2010)