Mathematical modeling of doxorubicin controlled release from smart biopolymer gel microspheres

V.E. BOSIO; M.V. SANTOS; N.E. ZARIZTKY; GR CASTRO

Taipei

Congreso; 5th International Conference on Industrial Bioprocesses; 2012

National Taiwan University of Science and Technology

Doxorubicin (Dox) is currently used for the treatment of hematological malignancies and solid tumors. However, the clinical use of Dox is restricted by acute and sub-acute strong side effects such as congestive heart failure, dilated cardiopathy, dramatic decrease of myeloid cell-lineages, severe immune suppression, nephropathies, alopecia, etc. Drug formulation can modify many parameters of drug release from kinetic to target organs avoiding undesirable side effects. Dox was encapsulated in 35 and 55 % etherification degree (DE) Pectins (Pec) by ionotropic gelation with Ca+2 showing 88 and 66 % Dox loading capacity. Dox kinetic release from Pec 35 and 55 % microspheres showed 90 and 33 % free drug at pH 7.4 (PBS buffer), 37 ºC for 120 min respectively. However at pH 2.0, only 17.0 and 11.0 % free drug from 35 and 55 % Pec microspheres were released at 37 ºC for 120 min respectively. These results were compared with similar systems of release (pH and temperature) but using no-chelating buffers. Matrix morphologies of the microparticles were compared during the controlled release processes with and without chelating agents. Additionally, the Pec 55 % matrix system posses high stability showing a Dox release decrease from 15 to 11 % after one year storage at 4 ºC. Mathematical modeling was applied in order to analyze drug release kinetics from the Pec 35 and 55 % matrices of spherical shape under the different studied conditions. The equation that represents the problem of diffusion-controlled drug release is established by partial differential equations of second order in spatial coordinates in transient state. Analytical solutions were applied for simple geometries such as spheres, assuming a constant diffusion coefficient and well-stirred conditions in the liquid. In addition a numerical approach was also implemented using the finite element method. The numerical and analytical solutions were able to reproduce the drug release into a finite volume of well-stirred liquid by calculating the drug concentration as a function of time in the external fluid. The diffusion coefficient of the drug in the tested matrices under different conditions was determined using experimental results. The models can therefore be applied to simulate different conditions such as initial drug concentration in the matrix, different matrix sizes, etc. It is an attractive alternative since it can evaluate design options prior to the fabrication of the devices and thus can greatly reduce the amount of experimentation required for the development and optimization of controlled release dosage forms.