Quality by Design (Qbd) as a Tool for the Optimization of Indomethacin Freeze-Dried Sublingual Tablets: In Vitro and in Vivo Evaluation

Abstract

Objective: This study aims to prepare and optimize indomethacin freeze-dried sublingual tablets (IND-FDST) by utilizing a quality by design (QbD) approach to achieve rapid drug dissolution and simultaneously bypassing the GIT for better patient tolerability. Methods: A screening study was utilized to determine the most significant factors which the quality attributes, namely disintegration time and % friability. Then an optimization study was conducted using a full response surface design to determine the optimized formula by varying the amount of the matrix-forming polymer (gelatin) and super disintegrant (croscarmellose sodium (CCS)). The variables' effect on the % friability, disintegration time, wetting time, and amount of drug release after 10 min (%Q10) was studied. The optimized formula was tested for compatibility, morphology as well as stability studies under accelerated conditions in addition to the in vivo pharmacodynamics in rats. QbD was adopted by utilizing a screening study to identify the significant formulation factors followed by a response surface optimization study to determine the optimized IND-FDST formulation. Results: Optimized IND-FDST comprised of gelatin/CCS combination in a ratio of 1:1 possessed adequate %friability (0.73±0.03%), disintegration time (25.40±1.21 seconds), wetting time (3.49±0.68 seconds), and % Q10 (100.99±5.29%) as well as good stability under accelerated conditions. IND-FDST also showed significant inhibition of edema, tumour necrosis factor-alpha, and interleukin-6 release in vivo compared to the oral market product by 70%, 42%, and 65%, respectively. Conclusion: QbD presents a successful approach in the optimization of a successful IND-FDST formula that showed superior in vivo and in vitro characteristics.

Highly Porous and Drug-Loaded Amorphous Solid Dispersion Microfiber Scaffolds of Indomethacin Prepared by Melt Electrowriting

“…51 However, in freeze-dried sublingual tablets, the drug loading has been investigated at around 25 mg per unit. 3 When processing the blend polymer/IND 1:2 (w/w) into scaffolds with 15 layers in each direction (0°and 90°fiber orientation), the sample weight is around 90 mg and, therefore, drug loading is about 60 mg, which would be probably sufficient for a single dose. As MEW is a multi-parameter process and the scaffold design is controlled via the G-code, the dosage of IND in MEW-printed scaffolds could be readily adjusted by, for example, changing the fiber diameter as required.…”

“…1,2 Additionally, sublingual drugdelivery systems are designed for the drug to avoid passing the gastrointestinal tract, reducing potential side effects of the drugs observed with common peroral delivery, such as gastrointestinal ulceration, and limitations of local acidic conditions, as well as enzymatic degradation. 3 Furthermore, these approaches simplify the uptake of the drugs, as they avoid potential swallowing difficulties, 4 improving patient compliance.…”

“…Sublingual or buccal drug delivery approaches have gained increasing attention due to the fast and direct drug uptake in the oral cavity. The sublingual route is known to be one of the most effective ones, as the drug is directly absorbed by the high number of capillaries below the tongue and effectively brought to the blood circulation. , Additionally, sublingual drug-delivery systems are designed for the drug to avoid passing the gastrointestinal tract, reducing potential side effects of the drugs observed with common peroral delivery, such as gastrointestinal ulceration, and limitations of local acidic conditions, as well as enzymatic degradation . Furthermore, these approaches simplify the uptake of the drugs, as they avoid potential swallowing difficulties, improving patient compliance.…”

Highly Porous and Drug Loaded Amorphous Solid Dispersions Microfiber Scaffolds of Indomethacin prepared by Melt Electrowriting

“…38 However, in freeze-dried sublingual tablets, the drug loading has been investigated at around 25 mg per unit. 3 When processing the blend polymer:IND 1:2 (w/w) into scaffolds with 15 alternating layers, the sample weight is around 90 mg and therefore, drug loading is about 60 mg. As MEW is a multi-parameter process and the scaffold design is controlled via the G-code, the dosage of IND in MEW printed scaffolds could be readily adjusted by, for example, changing the fiber diameter as required. The diameter can be varied via the applied pressure and/or the printing speed.…”

“…1,2 Additionally, sublingual drugdelivery systems are designed for the drug to avoid passing the gastrointestinal tract, reducing potential side effects of the drugs observed with common peroral delivery, such as gastrointestinal ulceration, and limitations of local acidic conditions, as well as enzymatic degradation. 3 Furthermore, these approaches simplify the uptake of the drugs, as they avoid potential swallowing difficulties 4 improving patient compliance.…”