Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutics

Diacerine (DCN) is an anti-osteoarthritic drug with low bioavailability.In an attempt to overcome this drawback,thirty nine ternary solid dispersion formulae were designed by ordinary fusion method using carrier polymers such as either Pluronic® F127(PF127), Solutol®HS15 or Polyethylene Glycol 35K (PEG 35K)with different weight ratio and constant weight of drug. They were optimizedby face-centered central composite statistical design and evaluated for the saturated solubility, initial dissolution rate in 5minutes (IDR5min) and cumulative drug release at 40 and 60 minutes(Q40min, Q60min respectively) as responses. Then rotatable central composite design was conducted to optimize the release profile of osmotic pump tablets that contained optimum DCN solid dispersion. Furthermore the in-vivo performance of the optimized osmotic formula was assessed on healthy rabbits.The optimized solid dispersion formula was DCN:PF127:Solutol®HS 15 with ratio 1:1:1; that showed the significant improvement in the initial dissolution rate with approximately4.86±0.95æg % / min of the drug released in the first 5 min, 67.635±3.1 %, 80.28±4.5 % at Q40min and Q60minrespectively. Furthermore the saturated solubility of optimized DCN solid dispersion;was 62.91±4.8 æg/ml; more than pure DCN which corresponds to a 5.9 fold difference.On optimization of asymmetric osmotic pump tablets, it was found that the drug release was inversely proportional to coat concentration of the membrane and concentration of gelling polymer, while it was directly proportional to the amount of osmogen. The optimized formula had the following parameters; coat concentration (Opadry® CA) was 3%w/v, gelling polymer (HPMC E15) was 1%w/w and osmogen concentration (NaCl) was 35.8%w/w. The results also displayed the reliability of this system to control the release of drug at zero order kinetic for up to 24 hours. The in vivo studies conducted on rabbits revealed a significant enhancing in bioavailability of the optimized osmotic pump (28.84±3.32 ng.hr/ml) compared to pure DCN (10.39±1.45 ng.hr/ml)

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