Developing a Rational, Optimized Product of Centella asiatica for Examination in Clinical Trials: Real World Challenges

Abstract

Botanical products are frequently sold as dietary supplements and their use by the public is increasing in popularity. However, scientific evaluation of their medicinal benefits presents unique challenges due to their chemical complexity, inherent variability, and the involvement of multiple active components and biological targets. Translation away from preclinical models, and developing an optimized, reproducible botanical product for use in clinical trials, presents particular challenges for phytotherapeutic agents compared to single chemical entities. Common deficiencies noted in clinical trials of botanical products include limited characterization of the product tested, inadequate placebo control, and lack of rationale for the type of product tested, dose used, outcome measures or even the study population. Our group has focused on the botanical Centella asiatica due to its reputation for enhancing cognition in Eastern traditional medicine systems. Our preclinical studies on a Centella asiatica water extract (CAW) and its bioactive components strongly support its potential as a phytotherapeutic agent for cognitive decline in aging and Alzheimer's disease through influences on antioxidant response, mitochondrial activity, and synaptic density. Here we describe our robust, scientific approach toward developing a rational phytotherapeutic product based on Centella asiatica for human investigation, addressing multiple factors to optimize its valid clinical evaluation. Specific aspects covered include approaches to identifying an optimal dose range for clinical assessment, design and composition of a dosage form and matching placebo, sourcing appropriate botanical raw material for product manufacture (including the evaluation of active compounds and contaminants), and up-scaling of laboratory extraction methods to available current Good Manufacturing Practice (cGMP) certified industrial facilities. We also address the process of obtaining regulatory approvals to proceed with clinical trials. Our study highlights the complexity of translational research on botanicals and the importance of identifying active compounds and developing sound analytical and bioanalytical methods for their determination in botanical materials and biological samples. Recent Phase I pharmacokinetic studies of our Centella asiatica product in humans (NCT03929250, NCT03937908) have highlighted additional challenges associated with designing botanical bioavailability studies, including specific dietary considerations that need to be considered.

Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial

“…A growing body of preclinical evidence has established that CAW may serve as a potential treatment for cognitive impairment and AD, but translational studies are needed to assess this extract in older adults with cognitive decline. We have designed a custom C. asiatica -derived product (CAP) containing CAW (2 g or 4 g), along with excipients, for use in future clinical trials examining target engagement and clinical efficacy [ 46 ]. CAP is standardized to contain TTs and CQAs (the active compounds of C. asiatica [ 23 ]) at levels similar to those present in the CAW used in our preclinical studies.…”

“…Two doses (2 g and 4 g) within the range were selected based upon the 200 mg/kg/d and 500 mg/kg/d doses that provided robust cognitive improvements in mice [ 27 , 29 , 38 , 49 , 50 ]. A large-scale dried aqueous extract of C. asiatica (CAW) was prepared using a method scaled up from our preclinical studies at Ashland laboratories (Kearny, NJ, USA), a certified Good Manufacturing Practice (cGMP) facility [ 46 ]. The CAW extract was spray-dried onto a carrier matrix at Ashland laboratories and blended at Oregon’s Wild Harvest (Redmond, OR, USA) with inert agents (excipients) imparting color and flavor, into a powdered formula called C. asiatica water extract product (CAP) [ 46 ].…”

“…A large-scale dried aqueous extract of C. asiatica (CAW) was prepared using a method scaled up from our preclinical studies at Ashland laboratories (Kearny, NJ, USA), a certified Good Manufacturing Practice (cGMP) facility [ 46 ]. The CAW extract was spray-dried onto a carrier matrix at Ashland laboratories and blended at Oregon’s Wild Harvest (Redmond, OR, USA) with inert agents (excipients) imparting color and flavor, into a powdered formula called C. asiatica water extract product (CAP) [ 46 ]. The excipients served to improve the palatability and dispersibility in water for human consumption while imparting a color that could be matched in a placebo for future trials.…”

“…In the present study, we explored the pharmacokinetics of both the TT and CQA components of the C. asiatica crude water extract, CAW, in elderly humans with MCI. CAW was administered at two doses (2 g and 4 g) in a formulated product (CAP) [ 46 ] that was standardized for the content of the TT and CQA components shown in Figure 1 . NRF2 activation in humans following CAP administration was also investigated.…”

Bioanalytical method validation and application to a phase 1, double-blind, randomized pharmacokinetic trial of a standardized Centella asiatica (L.) Urban water extract product in healthy older adults

“…C. asiatica water extract product (CAP): Allometric scaling ( Nair and Jacob, 2016 ) from preclinical mouse studies (200-1,000 mg/kg/day) ( Gray et al, 2014 ; Gray et al, 2015 ; Gray et al, 2016 ; Gray et al, 2018b ; Matthews et al, 2020 ; Zweig et al, 2021 ) was used to identify a dose range of 2–10 g of C. asiatica water extract (CAW) daily for a 70 kg human. Two doses (2 and 4 g CAW) were selected from within the calculated dose range and prepared as described in Wright et al (2021) . Briefly, aqueous extracts of C. asiatica dry herb aerial parts were prepared by Ashland Laboratories (Paterson, NJ, United States), spray dried onto a carrier matrix, and blended with inert flavor and color agents (excipients) making a powdered formula called CAW product (CAP).…”