Ivermectin orally disintegrating tablets: development, in vitro characterization and preliminary in vivo evaluation

JUAN, CANDELA DANA; RODRIGUEZ, DAIANA; CEBALLOS, LAURA; LANUSSE, CARLOS; GALLO, LOREANA; GONZALEZ VIDAL, NOELIA

Rosario, Santa Fe, Argentina

Congreso; 7ma Reunión Internacional de Ciencias Farmacéuticas (RICiFa 2023); 2023

Universidad Nacional de Rosario y Universidad Nacional de Córdoba

Orally disintegrating tablets (ODTs) are solid dosage forms, characterized by their stability and appropriate dosing, specifically designed for rapid disintegration in the oral cavity. These tablets are particularly useful in pediatric and elderly patients, or those with swallowing difficulties1. In many cases, suitable pharmaceutical dosage forms may not be commercially available for pediatrics, leading to the denomination of “orphan formulations”2. In this study, through Experimental Design (DoE), several formulations of ivermectin (IVM) ODTs were developed. The most promising formulation was reformulated with the incorporation of a sublimating agent and subjected to a sublimation process, in order to obtain porous ODTs3. The purpose of this work was to analyze the critical quality properties of the developed porous formulation and compare with non-porous one.The ODTs consisted of IVM (4 mg), mannitol, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, strawberry essence, and aspartame, with addition of ammonium bicarbonate (sublimating agent) for porous ODTs. Drug-excipient compatibility was assessed using FT-IR. Critical quality properties, including uniformity of content and in vitro dissolution, were evaluated. Stability was assessed under accelerated conditions (40 ± 2°C, 75 ± 5% relative humidity) along three months of storage, and a preliminary in vivo absorption study was performed in rats.In non-porous ODTs, critical properties were disintegration time (32.4 ± 2.0 s), hardness (5.6 ± 0.2 Kp), and friability (0.83 ± 0.09 %), with a maximum drug dissolved at 30 min of 72.0 ± 2.8 %. Porous tablets demonstrated a great improvement in disintegration times (16.9 ± 1.0 s) and dissolution behavior (96.0 ± 6.8 % at 5 min), with adequate hardness and friability. Therefore, all following tests were conducted over porous ODTs. The FT-IR spectra showed no evidence of drug-excipient incompatibility. The average IVM content ranged from 95.9 % to 104.2 % of the theoretical value, which fulfill specifications of Farmacopea Argentina4. The formulation exhibited excellent stability behavior, as there were no changes in the appearance, diameter, weight, or content uniformity. Significant differences were observed in hardness, friability, and disintegration time, but with no further clinical implication (i.e., hardness remained within appropriate values - from 2.6 Kp to 3.0 Kp, the maximum disintegration time was 24 s, and friability increased up to 1.3 %). Dissolution profiles did not show significant differences after one and three months of storage. The ODTs met the dissolution criteria proposed by the US Pharmacopeia5, and more than 85% of the drug is dissolved within 30 minutes. The preliminary in vivo evaluation in rats revealed that IVM was rapidly absorbed and detected at least 25 hours post-treatment. The average time to reach maximum blood concentration (Tmax) was 4.5 ± 1.9 hours.In conclusion, the results of this study demonstrated the excellent quality properties of porous IVM ODTs, which could improve pediatric treatment of parasitosis and give response to “orphan formulations” requirements.