Novel Black Seed Polysaccharide Extract-g-Poly (Acrylate) pH-Responsive Hydrogel Nanocomposites for Safe Oral Insulin Delivery: Development, In Vitro, In Vivo and Toxicological Evaluation

Abstract

Oral delivery of insulin has always been a challenging task due to harsh gut environment involving variable pH and peptidase actions. Currently, no Food and Drug Administration (FDA) approved oral insulin formulation is commercially available, only intravenous (IV) or subcutaneous (SC) routes. Therefore, it is really cumbersome for diabetic patients to go through invasive approaches for insulin delivery on daily basis. In the present study, a novel pH-responsive hydrogel nanocomposite (NC) system was developed and optimized for safe oral delivery of insulin. Black seed polysaccharide extract-based hydrogel (BA hydrogel) was formulated by free radical polymerization and loaded with insulin. Blank BA hydrogel was also incorporated with insulin-loaded montmorillonite nanoclay (Ins-Mmt) to form an Ins-Mmt-BA hydrogel NC and compared with the insulin-loaded hydrogel. Swelling, sol-gel analysis and in vitro release studies proved that Ins-Mmt-BA6 hydrogel NC has the best formulation, with 96.17% maximum insulin released in 24 h. Kinetic modeling applied on insulin release data showed the Korsemeyer-Peppas model (R2 = 0.9637) as the best fit model with a super case II transport mechanism for insulin transport (n > 0.89). Energy Dispersive X-ray (EDX) Spectroscopy, Fourier Transformed Infrared (FTIR) spectroscopy and Powdered X-ray diffraction (PXRD) analysis results also confirmed successful development of a hydrogel NC with no significant denaturation of insulin. Toxicity results confirmed the safety profile and biocompatibility of the developed NC. In vivo studies showed a maximum decrease in blood glucose levels of 52.61% and percentage relative bioavailability (% RBA) of 26.3% for an Ins-Mmt-BA hydrogel NC as compared to BA hydrogels and insulin administered through the SC route.

Development of Tofacitinib Loaded pH-Responsive Chitosan/Mucin Based Hydrogel Microparticles: In-Vitro Characterization and Toxicological Screening

“…Vital organs such as heart, lungs, stomach, liver, spleen, brain, kidney, and intestine were removed. Labelled containers containing formalin solution (10%) were used to preserve washed organs and for further histopathological examination [ 72 ].…”

Template-Free Self-Assembly of Hollow Microtubular Covalent Organic Frameworks for Oral Delivery of Insulin

“…The morphological changes of MT-COF-18 Å at different time intervals during its synthesis were investigated to better understand the mechanism behind the formation of hollow tubules. MT-COF-18 Å was synthesized under the same conditions, and the reaction was quenched at specific times (12,24,48, and 72 h) by cooling the resultant to room temperature. SEM images after 12 h indicated the formation of stripelike agglomerates of small individual crystallites, and fibrous aggregates several micrometers in length were also observed (Figure 3A).…”

“…However, this method often results in poor patient compliance and unavoidable physical and mental suffering. , Therefore, noninvasive routes are under intensive investigation. − Oral administration of insulin is considered to be the most advantageous therapy to mimic endogenous insulin secretion by establishing a physiological gradient of portal–peripheral insulin . However, two major barriers must be crossed, including the biochemical barrier (gastric acid and gastrointestinal tract enzymes) and the physical barrier (mucus layer and epithelium). − Nanoparticles find intriguing applications in oral insulin delivery because of their large surface area for drug loading and interactions with the gastrointestinal tract, as well as their versatile modifiability to address oral barriers. − Furthermore, glucose-responsive nanomaterials based on phenylboronic acid and its derivatives have attracted great interest in the construction of self-regulated insulin delivery systems. − However, the development of a full-featured carrier to ensure high loading capacity, intelligent release, efficient protection, and transportation of insulin remains a challenge.…”

Fabrication of Stimuli-Responsive Quince/Mucin Co-Poly (Methacrylate) Hydrogel Matrices for the Controlled Delivery of Acyclovir Sodium: Design, Characterization and Toxicity Evaluation

“…Oral administration of such high doses has severe gastrointestinal effects. On the other hand, IV administration of acyclovir may result in kidney damage [ 19 ].…”