The Gap in Regulating Pharmaceutical Excipients and its Potential Risks in Taiwan: Using Menthol and Magnesium Stearate as Examples

Abstract

The excipients in drugs are drawing more attention than before Because the variety and the complex of the excipients the clinical evidence of impact from excipients was rare By reviewing the literature the label information and the formulations we found some potential risk of excipients including allergy non-optimal labeling and the interaction between the excipient and the active ingredient In the study we firstly focused on the menthol in external preparations to survey the label information of menthol and related regulatory notes Secondly we explored the interaction between aspirin (acetylsalicylic acid ASA) and magnesium stearate (MgSt) to estimate the impact of excipients on clinical effectiveness Menthol had pharmaceutical activity in a wide concentration range but it was usually claimed as an excipient in Taiwan In 731 external preparations containing menthol menthol being labeled as an active pharmaceutical ingredient (API) or an excipient did not depend on the concentration instead it had stronger correlation to the product classification being general sale list or prescription only medicines The status of menthol in regulation was not clear enough in Taiwan The exposure risk of menthol in cold packs shall be noticed The impact of various menthol strengths in steroid ointments presented another regulatory loophole It would be reasonable to define the menthol as an API or an excipients by their concentration in the product and the compliance shall be improved Magnesium stearate (MgSt) is a widely used excipient in pharmaceutical formulations which should be avoided in aspirin preparations since it hydrolyzes aspirin We hypothesized that aspirin products containing MgSt (MgSt-ASA) would be less effective in preventing thrombosis in the clinical settings A retrospective cohort study on Taiwan’s claims data from 1997 to 2013 was designed to evaluate the risk of all-cause mortality and recurrent ischemic stroke (IS) on patients treated with MgSt-ASA preparations as secondary stroke prevention Patients who were discharged after IS and administered with only MgSt-ASA or non-MgSt-ASA were enrolled Composite events including all-cause mortality ischemic stroke hospitalization and myocardial infarction hospitalization follow-up period under therapy with MgSt-ASA or non-MgSt-ASA preparations was considered as the primary outcome The hazard ratios (HR) were adjusted with the comorbidities and baseline statin and antiplatelet prescriptions by the Cox model A total of 10 051 patients with IS (60% males average age 67) were identified which included 541 patients receiving the MgSt-ASA treatment only and 9 510 patients receiving non-MgSt-ASA preparation only The crude incidence of composite events was 8 68 per hundred person-year and 8 26 and 18 6 per hundred person-year for patients under non-MgSt-ASA and MgSt-ASA treatments respectively There was a higher risk of composite events in patients receiving MgSt-ASA preparations than those receiving non-MgSt-ASA formulations with the adjusted HR being 2 12 at 95% confidence interval of 1 76-2 56 The use of MgSt-ASA preparations was associated with a higher risk of composite events compared with non-MgSt-ASA preparations To review the aspirin formulations under a regulatory intervention is warranted

Date of Award	2019
Original language	English
Supervisor	Yea-Huei Kao (Supervisor)