In situ forming implants (ISIs) based on poly(lactic acid-co-glycolic acid) (PLGA) containing leuprolide acetate/β-cyclodextrin (LA/β-CD) complexes were prepared.Incorporation of LA or complexes did not change T g values of ISIs (48.4-49.6 °C). ISIs containing complexes with more β-CD content showed higher surface and bulk porosity.Higher β-CD portion in complexes improved solvent release, decreased initial burst release and facilitated diffusion out of drug for corresponding ISIs. Complexation of LA with β-CD (1/10, w/w) significantly improved its stability within PLGA matrix before release (total LA release of 91.3%). ISIs did not show any cellular cytotoxic effects against L929 fibroblast cells.
Drug release mechanism of in situ-forming implants (ISIs) based on poly(lactic acid-co-glycolic acid) (PLGA) loaded with leuprolide acetate/β-cyclodextrin (LA/β-CD) complexes via fitting with four diffusion-based semi-empirical models were studied. The release rate constants and release exponent of ISIs were calculated. The main drug release mechanism was Fickian diffusion. The LA diffusion coefficient and release constant were decreased via increasing the portion of β-CD in complexes. The release curve was parabolic, with a higher initial slope and then consistent with the exponential. All ISIs containing LA/β-CD complexes better fitted with the Korsmeyer-Peppas, Weibull and Peppas-Sahlin models rather than first-order model. Furthermore, the effect of LA/β-CD complexation on the degradation of ISIs was studied through scanning electron microscopy (SEM). Results showed that hydrophilic nature of β-CD facilitated the surface erosion of PLGA chains, however after 18 d, ISI-1/10 had still a proper structural strength, due to no hydrolytic degradation of β-CD in this implant.
In the present research, the aqueous stability of leuprolide acetate (LA) in phosphate buffered saline (PBS) medium was studied (pH = 2.0-7.4). For this purpose, the effect of temperature, dissolved oxygen and pH on the stability of LA during 35 days was investigated. Results showed that the aqueous stability of LA was higher at low temperatures. Degassing of the PBS medium partially increased the stability of LA at 4 °C, while did not change at 37 °C. The degradation of LA was accelerated at lower pH values. In addition, complexes of LA with different portions of β-cyclodextrin (β-CD) were prepared through freeze-drying procedure and characterized by Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) analyses. Studying their aqueous stability at various pH values (2.0-7.4) showed LA/β-CD complexes exhibited higher stability when compared with LA at all pH values. The stability of complexes was also improved by increasing the portion of LA/β-CD up to 1/10.
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