Effect of alkalizing agent on abuse deterrent potential of multiple-unit ingestion of bilayer abuse-deterrent extended-release tablets using propranolol as model drug for opioids overdose crisis.

The objective of present study is to develop bilayer abuse-deterrent extended-release tablets (ADERTs) using propranolol HCl as model drug for opioids overdose crisis. Bilayer ADERTs were fabricated by direct compression and formulated with polymer matrix in extended-release drug layer coupled with alkalizing and aversive agents in fast-disintegrating pH modifying layer. Various alkalizing agents, like magnesium hydroxide, aluminum hydroxide, calcium carbonate, and calcium hydroxide, were evaluated for their abuse-deterrent potential via in-vitro drug release and extraction studies. Based on the outcomes, magnesium hydroxide was selected as an alkalizing agent, since it raised the pH of dissolving media near to pKa of the drug studied in this investigation. The formulated bilayer ADERTs with magnesium hydroxide provided similar drug release profiles as compared to conventional extended-release tablets for single-unit ingestion. However, upon ingestion of multiple-unit bilayer ADERTs, the fast-disintegrating pH modifying layer increases pH of dissolving media, while extended-release layer increases micro-environmental pH within tablets. Retarding drug release owing to low solubility of basic drug at higher pH was observed. Therefore, the application of alkalizing agent has impact on pH-dependent solubility of drug like opioids and demonstrate its useful potential to be incorporated in bilayer ADERTs for opioids overdose crisis.

Sublingual insulin administration: application of hydroxypropyl beta-cyclodextrin and poloxamer188 as permeation enhancers.

The objective of this investigation is to investigate the feasibility of sublingual insulin administration. Insulin solutions formulated with permeation enhancers (HPßCD/poloxamer 188) and their in-vitro and in-vivo performances were evaluated. Thereafter, insulin fast-dissolving film was further developed to have similar properties, upon dissolving the film, of the optimized insulin solution. In-vitro performance was evaluated via effect of HPßCD and/or poloxamer 188 concentration across cellulose acetate membrane and porcine esophagus. In-vivo performance was evaluated via pharmacodynamic and pharmacokinetic profiles of insulin solution administered. Cumulative amounts of insulin permeated at 60 min formulated with HPßCD (5%), poloxamer 188 (0.5%), and their combination were 1.31, 3.23, and 4.99 IU/cm2, respectively, indicating an additive effect of combination of HPßCD and poloxamer 188. Insulin-induced hypoglycemic effect was observed for insulin solutions with combination of HPßCD and poloxamer 188 after sublingual administration to Sprague-Dawley rats. Microscopic evaluation of porcine oesophageal tissue indicates that HPßCD and poloxamer 188 are safe. Furthermore, the cumulative amount permeated across cellulose acetate membrane at 30 min was 1.13 and 1.00 IU/cm2 for insulin solution and fast-dissolving film, respectively, demonstrating to be similar. In conclusion, the use of HPßCD/poloxamer 188 is feasible for the development of sublingual insulin solutions/films.