Category: Formulation and Quality
Purpose: This study was conducted to develop and evaluate abuse-deterrent compositions based on the crosslinked anionic starch and cellulose derivatives. The crosslinking and the anionic nature of these polymers provide a dual mechanism to deter the intravenous (IV) drug abuse. The crosslinked structure is responsible for the swelling of the polymers in aqueous solutions, and thus entrapment of a portion of the drug solution intended for IV abuse. The anionic nature is responsible for binding to the cationic opioid drug in various solutions, by which the amount of the free drug available for extraction and subsequent injection will be reduced. Furthermore, the effect of pH on the binding efficiency of the polymers to the cationic opioid drug analogue (Dextromethorphan HBr) was investigated.
Methods: The crosslinked carboxymethyl starch (Explotab CLV® obtained from JRS Pharma and washed in-house) and carboxymethyl cellulose (Ac-Di-Sol® SDW-802 obtained from FMC BioPolymer) were individually weighed and mixed with dextromethorphan HBr, DEX (obtained from LETCO) at a ratio of 1:8 drug to polymer. Different extracting solvents most commonly used by abusers (10 mL of water, pH3 solution, 40% ethanol, normal saline, and acetic acid solutions (0.83 M, 0.5 M, and 0.1 M)) were added, and the solutions were vortexed for 30 seconds and then centrifuged at 1500 rpm for 5 minutes. The supernatant (1.0 mL) was filtered through a 0.2 μm syringe filter and diluted up to 10.0 mL solution using the solvents. The concentration (mg/mL) and the amount of drug (mg) in each solution was measured using a UV-Vis spectrophotometer at 276 nm. Finally, the percentage of binding was calculated from the mass balance. The obtained results were compared with control samples of a neutral non-ionized drug (acetaminophen, APAP).
The pH of the samples was determined using a calibrated pH meter. The correlation between the measured pH values and the binding results was determined. Furthermore, the supernatant volume of the centrifuged samples was measured and subtracted from 10 mL (the total volume of the solvent being added) to determine the entrapped volume of the drug solution. The entrapped volume was multiplied by the concentration (mg/mL) of the free drug determined above to calculate the amount of the entrapped drug due to swelling.
Results: The binding efficiency of the polymers to cationic DEX affected by the type of solvent. More than 70% binding was achieved in water and pH3 solution, followed by 53-60% binding in the less polar solvents (40% ethanol and 0.1 M acetic acid), and modest binding (~ 20-35%) in the ionic solvents (normal saline and acetic acid solutions (0.83 M and 0.5 M)). The reduced binding in the less polar solvents is attributed to a lower ionization of the polymers in such solvents and hence limited availability of anionic sites to bind with the cationic drug. The reduced binding in solvents with ionic moieties is attributed to the ionic interference derived from such solvents. On the other hand, the maximum binding of the polymers to neutral APAP was found 7% in all solvents, confirming that the interaction between DEX and the polymers is an electrostatic one. Ac-Di-Sol® SDW-802 showed 10-15% higher binding than Explotab® CLV in the polar solvents (water and pH 3 solution), comparable binding in the hydroalcoholic and acetic acid solutions, while ~ 10% lower binding in normal saline. These results suggest that Ac-Di-Sol® SDW-802 possesses a higher degree of substitution, rendering the cellulose derivative more ionizable in the polar solvents, while also more susceptible to ionic interferences. Increasing the pH of the samples was associated with an improved binding, except in normal saline and 40% ethanol due to the ionic and polarity effects, respectively. Compared to binding, the swelling played a minor role in drug entrapment for most solvents.
Conclusion: crosslinked carboxymethyl starch and carboxymethyl cellulose can effectively be used to impede opioid drug extraction in different solvents for subsequent intravenous abuse. Future work is required to overcome the ionic interference on binding originated from the solvents with ionic moieties.