Purpose: Rivastigmine is a dual inhibitor of acetylcholinesterase and butyrylcholinesterase used for the treatment of mild to moderate dementia of the Alzheimer's type. The oral bioavailability of rivastigmine, ranging from 20 to 60%, is limited by first pass metabolism in the liver and intestine mediated by esterase enzyme which results in inter-patient variation in drug response1,2. Moreover, oral administration of rivastigmine is associated with dose-dependent adverse effects like nausea, vomiting and diarrhea which negatively affect the tolerability and compliance of the patients 3.
Drug-loaded in-situ implants were among different strategies that have been developed to overcome the limited oral bioavailability of rivastigmine. They have provided a prolonged drug release within the therapeutic range for 11 days and a peak plasma levels lying below the toxic threshold and up to five times higher than for the control formulation4. However, the use of in situ implant systems has been limited by a typical initial rapid release of the drug prior to solidification of the polymer, difficult injectability of the highly viscous polymer solution and possible myotoxicity of the organic solvent used5.
The aim of this study was to develop and statistically optimize formulation of in situ microparticles (ISM) containing rivastigmine to achieve depot release after intramuscular injection.
Methods: Drug-loaded ISM were prepared by emulsification followed by ultrasonication using a series of suitable concentrations of sucrose acetate isobutyrate SAIB at different polymer to drug ratio (P/D) (Table 1). The formulae compositions were designed based on a response surface statistical design. The effect of formulation parameters on the in vitro drug release and injectability was investigated. The optimized formulae having the highest drug release time required for 50% release (T50%), percentage of cumulative release after 30 days and injectability were subjected to further investigations including rheological properties, morphology, effect of γ-sterilization and in vitro cell viability.
Results: The percentage of drug release after 1 h (Q1) was considered as an indicator for the burst release. Q1 values of all formulations ranged between 13.3% and 31.1%. Data were statistically analyzed using a quadratic model. It was found that both P/D ratio and SAIB% had significant effects on Q1 with p-values of 0.0004 and 0.0053, respectively (Table 1 and Figure 2). Moreover, there was a significant interaction between the two traced factors. The release profiles of all formulations were following Higuchi diffusion model, except F1 and F2 which had zero order profiles. Release half-life (T50%) was calculated for each formulation and the values lied between 6.74 h and 14.61 h. Quadratic response surface model was the most valid one for the factorial analysis of the obtained values. P/D ratio had a significant and direct effect on the T50% (p-value = 0.0002) while the SAIB% had no significant effect (p-value = 0.1096). Injectability was measured in terms of the injection time in seconds required to inject 1 mL solution through a 19-gauge needle under a constant pressure of 70 mmHg. The injection time ranged from 130 to 300 seconds and the values were significantly affected by the P/D ratio and the SAIB% with p-values of 0.0005 and 0.0013, respectively. P/D ratio significantly increased the injection time while the SAIB% had an inverse effect on the measured response. The optimized ISM formulation was composed of 16/1 P/D ratio and 81% SAIB and it was selected to be having the lowest Q1, injection time and the highest T50%. The average particle size of the optimized ISM formulation was 1.2 ± 0.11 µm (Figure 2A). They had uniformly spherical shape, smooth surfaces with no observed aggregations. The optimized ISM formulation was sterilized using γ-radiation with almost no significant effect on its physical characteristics and drug release profile. The result of cell viability assay showed that 3T3 mouse embryonic fibroblast cells were not affected even at a high concentration of 50% v/v (Figure 2B).
Conclusion: The developed and optimized ISM prepared using SAIB are biocompatible, have suitable low injection force and can allow sustained release of rivastigmine in vitro.
Ibrahim Elsayed– College of Pharmacy, Gulf Medical University
Ahmed Fares– Faculty of Pharmacy, Cairo University
Mariame Hassan– College of Pharmacy, University of Sharjah
Iman Ahmed– College of Pharmacy, University of Sharjah