Drug polymer prediction

Biostable polymers have been chosen for use in the majority of DES that are marketed or in clinical development. The main attractiveness of biostable polymers is their physical stability, inertness toward the drug, and predictable drug kinetics. In Cypher, a blend of poly(ethylene-co-butyl methacrylate) (PEVAc/PBMA) is used as the drug carrier. This hydrophobic polymer, along with additional polymer process steps, effectively controls the release of sirolimus, eluting 80% of the drug over 30 days after implantation. In the case of Taxus, atri-block copolymer of styrene-isobutylene-styrene (SIBS) is used as the hydrophobic polymer matrix that releases 10% of incorporated paclitaxel in the first 30 days (20). 

The pharmacodynamic performance was studied for three drug-polymer matrix systems and comparisons were made between the In vivo and the In vitro results The systems studied were (a) gentamicin In silicone rubber, (b) tetracycline In HEMA/MMA copolymers, and (c) nlrldazole In silicone rubber. In general, the In vitro models fall short of predicting the actual In vivo results accurately, even In those cases where the controlled release of the agent showed positive, desirable results In the test animals. 

Djuris, J. Nikolakakis, I. Ibric, S. Djuric, Z. Kachrimanis, K. Preparation of carbamazepine-Solup-lus solid dispersions by hot-melt extrusion, prediction of drug-polymer miscibility by thermodynamic model fitting. Eur. J. Pharm. Biopharm. 2013, 84(1), 228-237. 

Predictive models for drug-polymer miscibility have been introduced, and they are largely derived from solution thermodynamics. Lattice-based solution models, such as the F-H theory, can be used to assess miscibility in drug-polymer blends, for which the F-H interaction parameter can be considered as a measure of miscibility. In addition, solubility parameter models can be used for this purpose. The methods used to estimate interaction parameters include melting point depression and the determination of solubility parameters using group contribution theory. 

Marsac PJ, Konno H, Taylor LS (2006a) A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm Res 23(10) 2306-2316 Marsac PJ, ShambRn SL, Taylor LS (2006b) Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility. Pharm Res 23(10) 2417-2426 Marsac PJ, Li T, Taylor LS (2009) Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res 26(1) 139-151... 

ASD including the use of in silico solubility parameter (5) calculation (Ghebremeskel et al. 2007), Flory-Huggins (F-H) interaction parameter calculation (Marsac et al. 2006b Zhao et al. 2011), drug-polymer thermodynamic phase diagrams prediction (Tian et al. 2013), crystallization inhibition with molecular dynamic calculation (Pajula et al. 2012), etc. However, in spite of their use and popularity, these theoretical methods have limitations and lack predictability, reliability, and thereby have limited utility. 

Table 53 Predicted and observed best APl-polymer combinations with favorable drug-polymer hydrogen bond interactions for optimal crysttillization inhibition. (Adapted from data by Van Eerdenbragh and Talyor 2011)...

Although solvent-shift method enjoys simplicity and versatility in selection of the polymer, the outcome of this study is somewhat questionable as the organic solvent may interfere with precipitation kinetics and thermodynamics, and may not reflect amorphous solid system. In addition, supersaturation or precipitation inhibition potential of specific polymers is highly concentration dependent. Since local in vivo drug-polymer concentrations are difficult to predict, it is thus challenging to define suitable biorelevant polymer concentrations for in vitro experiments. 

Process and formulation selection flowcharts, which refer predictive physical stability models, rapid chemical stability screens, and biorelevant in vitro performance tests, are used to select a lead SDD formulation (including the drug/polymer ratio) and process parameters (Dobry et al. 2009). 

Ford JL (1986) The current status of solid dispersions. Pharm Acta Helv 61 69-88 Forster A, Hempenstall J, Tucker I, Rades T (2001) The potential of small-scale fusion experiments and the gordon-taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug Dev Ind Pharm 27 549-560... 

Loftsson T, Fririksddttir H, Gumundsdottir TK (1996) The effect of water-soluble polymers on aqueous solubility of drugs. Int J Pharm 127 293-296 Matteucci ME, Miller MA, Williams RO, Johnston KP (2008) Highly supersaturated solutions of amorphous drugs approaching predictions from configurational thermodynamic properties. J Phys Chem B 112 16675-16681. 

In the last few years efforts have been focused on developing theoretical models and methods for the prediction of drug-polymer interactions, and estimation of a drug s saturation solubility in the polymer matrix. A solubility of the drug in the polymer can be defined only in the case of an amorphous soUd solution, where the drug is molecularly dispersed into the polymer matrix, and not in the case of soUd suspensions. 

P.J. Marsac, S.L. Shamblin, and L.S. Taylor, Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility, Pharm Res, 23 (10), 2417-26,2006. 

The qualitative considerations of the previous section regarding the solubility of plasticizers/drug/polymer blends can be transferred into a quantitative prediction of miscibility by calculation of the Flory-Huggins interaction parameter x [48]... 

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