Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Senshang Lin

Second Advisor

Bhagwan Rohera

Third Advisor

Emilio Squillante

Abstract

Malaria is a life-threatening disease with a high prevalence worldwide. Mass drug administration (MDA) of ivermectin have been shown to prevent the transmission of malaria. The objective of this investigation is to develop ivermectin-loaded gastro retentive sustained release tablets (GRSRTs), which have the potential to avoid not only frequent administration of MDA but also fluctuation of ivermectin in systemic circulation. Based on the outcomes from screening various materials to be the suitable matrix forming polymer and bio-adhesive polymer mixture of GRSRTs, HPMC K100M, Carbopol 934p and sodium alginate:chitosan (1:1) were selected as formulation variables. Eight formulations of ivermectin-loaded GRSRTs were generated using QbD approach by the JMP® statistical software. Tablet properties (i.e., hardness, friability, weight variation, and drug content), extent of swelling, in vitro bio-adhesive time and strength, in vitro drug release rate, drug release mechanism, the effect of tablet hardness and drug loading dose, and tablet morphology of eight formulations were evaluated. Bio-adhesive time and cumulative amount of drug release were selected as dependent variables. Two regression models were generated to establish the relationships between dependent variables and formulation variables and then used for the optimization of ivermectin-loaded GRSRTs. The model equations regulated the correlations between formulation variables and the cumulative drug release as well as the bio-adhesive time using QbD approach. The optimized ivermectin-loaded GRSRT formulation was generated using model equation. The drug release mechanism of ivermectin-loaded GRSRT is either the membrane type or matrix type depends on the composition of Carbopol and sodium alginate/chitosan as well as drug loading dose. The cumulative drug release of ivermectin-loaded GRSRT depends on the composition of formulation variables and tablet hardness. Observation by a scanning electron microscope on the morphological variations during the period of bio-adhesion to gastric mucosa of a pig showed the mucoadhesion phenomena of ivermectin formulations, and the enhanced intimate contacts between the tablets and gastro mucosa by increasing roughness and spinose projections related with formulation variables. In conclusion, the desired ivermectin-loaded GRSRTs were successfully developed to reduce frequent administration of MDA and maintain steady-state concentration of ivermectin in systemic circulation.

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