(M1030-03-21) Exploring the Potential of Polyvinyl Acetate Dispersion and PVP-90 to Prevent Alcohol-Induced Dose Dumping in Modified Release Formulations

Purpose: Modified release formulations are designed to ensure drug release is controlled even in the presence of a high percentage of alcohol. This critical quality attributes in the formulation avoids alcohol induced dose dumping (AIDD) when a drug contained in the dosage form is prematurely and excessively released due to the intentional or unintentional abuse of alcohol (1). The AIDD can lead to high drug exposure resulting in safety issues and adverse events. To mitigate this risk, two delivery strategies were utilized to address the issue of the AIDD: first incorporating the drug into a polymeric matrix; and second applying a sustained release polymer coating to protect the core formulation containing the drug. In this study, polyvinyl acetate (PVAc) dispersion combined with various polymeric excipients were evaluated to understand the effect of 20% v/v and 40% v/v alcoholic dissolution media. Additionally, polyvinyl acetate dispersion along with polyvinylpyrrolidone as pore former and triethyl citrate as plasticizer was coated on caffeine tablets to understand release of drug in presence of 0.1N HCl with 20% (v/v) and 40% (v/v) of alcohol.

Methods: The preparation of polymer films for swelling test in 0.1N HCl with 40% (v/v) alcohol was conducted. Briefly, polymeric excipients were weighed and stirred/shaken in water for 12 hours. Then, PVAc dispersion was mixed for more than 30 minutes (magnetic stirrer) with various polymeric excipients/compositions: Kollicoat® Protect, PVP-90, medium molecular weight hydroxypropyl methylcellulose (MW HPMC), and carbomer at two polymer weight ratios: 9:1 and 3:1. The polymer mixture was casted in a film by pouring onto a plastic liner using a 50-mil cast spacer, and then allowed the films to air dry. The dried films were cured in oven at 55 °C for two hours and then cut into square shapes and immersed in 0.1N HCl and 40% ethanol/0.1N HCl (v/v) solution. The film swelling was observed at two and twenty hours. The caffeine containing powder blend was blended in a V-blender for 10 minutes and the tablets were compressed by using a Korsch XL100 Tablet Press at a tablet weight of 300 mg. The tablet contained 10% caffeine, 89.5% Ludipress® polymer and 0.5% magnesium stearate. The tablets were coated (20% weight gain) with a ~20% w/w sustained release dispersion containing PVAc polymer, PVP-90, and plasticizer (% weight ratio 68.1, 25.1 and 6.8) by using O'Hara pan coater with a 12’’ pan. Dissolutions were conducted using a Distek 2100C Dissolution tester, apparatus II, 50 rpm, a temperature of 37 °C and 900 mL dissolution media: 1) 0.1N HCl; 2) 0.1N HCl with 20% alcohol (v/v); 3) 0.1N HCl with 40% alcohol (v/v).<

Results: The film containing PVAc only was insoluble in dilute acid and alkali but showed swelling in presence of 40% alcohol suggesting polymer alone could not mitigate the AIDD issues. To tackle the swelling problem in alcohol, various polymers/ compositions were incorporated in the PVAc film. Figure 1 illustrates the film swelling performance after being immersed in 0.1N HCl and 0.1N HCl with 40% alcohol for 2 hours. Based on the results, PVAc dispersion/PVP-90 (at 3:1 weight ratio) demonstrated less swelling and better integrity in 0.1N HCl with 40% alcohol than the other films (PVAc and carbomer mixture did not form films). Therefore, PVAc dispersion/PVP-90 (3:1, w/w) was selected as the coating polymer for further AIDD evaluations. Figure 2 shows the dissolution results of caffeine tablets with 26.4 mg/cm² coating polymer per tablet (20% weight gain). The data indicated that the coated tablet demonstrated sustained drug release profile and released only 5% in 0.1 N HCl within 2 hours. Interestingly, the release profile was not markedly altered in 0.1N HCl containing 20% and 40% alcohol. The modified release properties of the coated caffeine tablets are still maintained in the first 2 hours, which is acceptable as per the FDA recommendation (2). Additionally, ongoing studies are being conducted to optimize the coating percentage to effectively address the AIDD issue.

Conclusion: This study demonstrated the effectiveness of incorporating polyvinyl acetate dispersion with PVP-90 as a strategy to address AIDD in modified release formulations. The results indicated that the PVAc/PVP-90 combination at 3:1 weight ratio showed less swelling and better integrity in the presence of alcohol. Moreover, the dissolution results of caffeine tablets coated with PVAc/PVP-90 at ~26 mg/cm² showed that the modified release properties were maintained even in the presence of high alcohol concentrations, preventing excessive and premature drug release. The findings of this study suggest that the use of PVAc dispersion/PVP-90 in combination with appropriate polymeric excipients/ compositions can be used as an effective strategy for developing modified release formulations that are resistant to alcohol-induced dose dumping. To fully understand the robustness of coating compositions and achieve reliable modified release formulations, further research and development of this strategy is necessary.

References: [1] D’Souza, S.; Mayock S. and Salt A., AAPS Open, 2017, 3:5
[2] https://www.fda.gov/media/121311/download

Figure 1. Blend film swelling in 0.1N HCl (top vials) and 0.1N HCl with 40% alcohol (bottom vials). A) PVAc + Kollicoat protect (9:1, w/w); B) PVAc + Kollicoat protect (3:1, w/w); C) PVAc + PVP-90 (9:1, w/w); D) PVAc + PVP-90 (3:1, w/w); E) PVAc + MW HPMC (9:1, w/w); F) PVAc + MW HPMC (3:1, w/w).

Figure 2. Dissolution results of caffeine tablets in different dissolution media.