(W1230-01-04) Development of a Novel Polymeric Composite Film and Elucidation of Its New Alcohol-Resistant Mechanisms for the Prevention of Alcohol-Induced Dose Dumping

Purpose: Controlled-release dosage forms of opioid drugs are important for pain management, but their misuse affects approximately 16 million people worldwide¹, often through concomitant consumption with alcoholic beverages. Current technologies using guar gum and sodium alginate for mitigating alcohol-induced dose dumping (ADD) face challenges in manufacturing such as high viscosity of coating dispersion, rapid gelation, heterogeneity of films, and non-responsiveness to pH and gastric emptying rate changes in the presence of alcohol². To address these issues, a non-leachable, ethanol-insoluble, and pH-responsive terpolymer nanogel (TPN)³ was exploited as a pore former in ethylcellulose (EC) for the prevention of ADD. The underlying alcohol-resistant mechanism was investigated.

Methods: Relative viscosities of EC dispersion with varying pore former levels, 0% (blank), 10%, and 20% TPN and 10% guar gum were determined using a Cannon-Fenske viscometer. Morphology of blank, 10% TPN-EC, and 10% guar gum-EC films were examined by SEM after immersion in pH 1.2 HCl with 0% or 40% (v/v) ethanol for 4 hr. Permeability studies of five model drugs (theophylline, salicylic acid, propranolol HCl, diltiazem HCl, and naloxone HCl (NAL)) were conducted in pH 1.2 HCl with 0% or 40% (v/v) ethanol for 2 hr. Fourier transform infrared (FTIR) spectroscopy was used to assess drug-polymer interaction in films before and after incubation with and without ethanol.

Results: At up to 10% of total weight, TPN did not affect the viscosity of EC coating suspension, while guar gum increased viscosity by 76-fold. SEM images confirmed the homogeneity and integrity of the TPN-EC film in the presence of 0% and 40% ethanol. Cationic drugs showed substantially lower permeability ratio P_40%/P_0% than that of neutral or anionic drugs due to strong ionic hydrogen bonding between the cationic drugs and the carboxylic groups of TPN. This result was confirmed with FTIR where the C=O peaks of the TPN shifted at 1723 cm^-1 and 1648 cm^-1. As ethanol concentration increased, O-H peak shifted to 3398 cm^-1 and formed a new peak at 1079 cm^-1, which could be attributed to C-N stretching of amine group of NAL.

Conclusion: TPN-containing EC film exhibited superior integrity, processibility, and homogeneity. This work demonstrates that the utilization of ionic complexation between drug and polymer to hinder drug release in presence of alcohol is a promising mechanism for preventing alcohol-induced dose dumping.

References: 1. H. Y. Chang, et al., BMC Med. 2018, 16, 69.
2. Y. Rosiaux, et al., Eur J Pharm Sci., 2013, 85, 1250-1258.
3. K. Chen, et al., Eur J Pharm Sci., 2017, 120, 116-125.