Abstract
In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q1), the time required for 50% drug release (T50%) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (w/w) and an S/P ratio of 1.64:1 (w/w). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q1) and T50% of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by a reduction of cholinergic transmission
The quality target product profiles (QTPPs) were set up considering the quality characteristics of an injectable RV-in situ-forming microparticles (ISM) system capable of overcoming the limitations of the current RV treatments such as limited oral bioavailability, frequent dosing, adverse effects associated with oral administration, poor patient adherence and serious administration errors
sucrose acetate isobutyrate (SAIB), a highly lipophilic water-insoluble sugar and an FDA-approved food additive, was used as a non-polymeric matrix former in the fabrication of RV-ISM systems to test its ability to control the drug release in situ, while making use of its undeniable favorable properties, such as its high solubility in a wide range of organic solvents which result in the formation of low-viscosity solutions compared to more common polymers, in addition to its biocompatibility, biodegradability, in vivo tolerability and low cost [23]
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by a reduction of cholinergic transmission. Inhibitors of cholinesterase enzymes have emerged as effective agents for the management of AD [2]. RV is rapidly absorbed, its oral bioavailability is limited by first pass metabolism in the intestine and liver mediated by esterase enzymes [4], resulting in inter-patient variation in drug response, ranging from 20% to 60% [4,5]. The oral administration of RV is associated with dose-dependent adverse effects such as nausea, vomiting and diarrhea which negatively affect the tolerability and compliance of the patient [6]
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