PEARLITOL® CR-H Co-Processed Mannitol-HPMC: Alcohol and Pancreatin Resistance Studies

Introduction 

Dose dumping is an unintended, rapid drug release of the entire amount or a significant fraction of the drug contained in a modified release dosage form, within a short period of time. As drug release from controlled release dosage forms is modulated by a polymer matrix, there is a risk of dose dumping if the matrix becomes compromised due to concomitant ingestion of alcoholic beverages, or if the polymer matrix is susceptible to physiological enzymatic digestion in the gastrointestinal tract. This may lead to loss in clinical efficacy or drug overdose resulting in potentially fatal adverse events. The objective of this study is to evaluate the robustness of PEARLITOL® CR-H co-processed mannitol-HPMC as a controlled release matrix in the presence of alcohol or pancreatin.   

 

Materials and Methods 

Theophylline 250 mg tablets and diprophylline 200 mg tablets were prepared at drug loads of 62.5% and 50%, respectively, from blends with PEARLITOL® CR-H and 1% magnesium stearate. Tablets were compressed using a 11.28 mm round, flat-faced punch set at 10 kN compression force following Korsch XL-400 simulation with compaction speeds of 63,000 tablets/hour (30 rpm). Dissolution studies were conducted with USP dissolution apparatus II with helical sinker. Alcohol dose dumping test was conducted with 0, 5, 20 and 40 % v/v ethanol in USP simulated gastric fluid, pH 1.2 with theophylline-containing tablets. Quantification of theophylline concentration from dissolution media sampled at various timepoints were conducted via UV spectrophotometer with a wavelength of 272 nm. Pancreatin susceptibility test was performed with USP simulated intestinal fluid in the presence and absence of pancreatin (test versus control) with diprophylline-containing tablets. Samples from various timepoints were first subjected to centrifugal filtration to remove the majority of the pancreatin from the media prior to quantification via chromatographic system. Agilent Eclipse XDB-C18 column, 3.5 µm, 4.6 x 150 mm column with mobile phase of 93:7 phosphate buffer to acetonitrile at 1 mL/min was used for the chromatography separation of residual pancreatin and diprophylline for drug quantification. 
  

Results 

1) Alcohol resistance of PEARLITOL® CR-H 

Tablets made with PEARLITOL® CR-H containing theophylline exhibit similar drug release profiles in the presence of 0, 5, 20 and 40 % v/v ethanol in USP simulated gastric fluid, as shown from dissolution curves and similarity factors (figure 1 and table 1).

 

Figure 1. Alcohol dose dumping test. Drug release profiles of PEARLITOL® CR-H tablets containing 250 mg theophylline in the presence of 0, 5, 10, 20 % v/v ethanol in USP simulated gastric fluid, pH 1.2. 


Table 1. Similarity factors, f1 and f2 calculated for dissolution curves in the presence of 5, 10, 20 % v/v ethanol, versus 0 % v/v ethanol in USP simulated gastric fluid, pH 1.2.

 

2) Pancreatin resistance of PEARLITOL® CR-H 

Tablets made with PEARLITOL® CR-H containing diprophylline exhibit similar drug release profiles in the presence and absence of pancreatin in USP simulated intestinal fluid, as shown from dissolution curves and similarity factors (figure 2 and table 2).

Figure 2. Pancreatin susceptibility test. Drug release profiles of PEARLITOL® CR-H tablets containing 200 mg diprophylline in the presence and absence of pancreatin (test versus control) in USP simulated intestinal fluid. 

Table 2. Similarity factors, f1 and f2 calculated for dissolution curves in the presence and absence of pancreatin in USP simulated intestinal fluid.

Conclusion

PEARLITOL® CR-H demonstrated resistance to alcohol and enzymatic digestion, minimizing the risk of dose dumping. 

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