Integrating Ayurvedic philosophy with modern technologies for drug research and development: A critical need of mechanistic insights for wider acceptability

Abstract

Ayurveda is a holistic science emphasizing healing and maintaining harmony and balance in the body. Medicines from natural resources and in pre-defined dosage forms are integral parts of successful Ayurvedic treatment in various diseases including complex ailments, such as cancer. Ayurvedic medicines are cocktails of several active phyto-compounds and/or natural resources and no isolated/purified molecules are used in the treatment. However, various unique methods employed using natural media, such as water, lipids, buttermilk, and lemon juice, just to name a few, lead to the elimination of unwanted constituents/impurities and enhance the bioavailability and efficacy of the drug. Such plausible alterations, selection, and/or retention of signature phytocompounds in the raw materials, during the process, and in the final drug need to be studied for precise product identification and analysis. Critical standardization of the manufacturing procedures is, therefore, mandatory for quality fidelity, assurance, and optimum efficacy. Moreover, the simultaneous multi-level and/or multi-targeted actions of Ayurvedic medicines against various dysfunctions due to their complex nature makes it extremely challenging to understand the mechanistic aspects during pre-clinical and clinical studies.

The present article focuses on probable challenges and ideal roadmaps for standardization and characterization of such herbal as well as metallic-mineral Ayurvedic medicines being used for various simple and complex diseases like cancer and their treatments. It is emphasized that Ayurvedic manufacturing procedures should be followed meticulously and the finished product be characterized thoroughly using advanced pharmaceutical and analytical techniques. It is also accentuated that detailed monographs or dossiers including shelf-life studies need to be officially published for knowledge dissemination and worldwide acceptance. Finally, safety and efficacy studies as per modern pharmacology ought to be conducted in suitable animal models for the judicious use of these medicines. Mainstream or adjuvant treatment of dreadful diseases such as cancer with Ayurvedic medicines will only be fruitful through rational experimentation and ethical reporting.

The Ayurvedic system of medicine is an integral part of Indian healthcare for thousands of years. In the past few decades, it has emerged as a science of life that teaches the prevention and curation of several diseases. Quality of medicines, one of the important four pillars of treatment- Chikitsa Chatushpaad (doctor, medicine, medical attendant and patient) contributes to the quarter of the treatment success [1]. In the olden days, Ayurvedic physicians used to prepare medicines for daily use in their in-house pharmacy wherein the quality parameters were based on organoleptic and morphometric properties and experience. Later, with the advent of modern pharmaceutical industries, Ayurvedic drug industries started their journey using the same rules and regulations. The Good Manufacturing Practices under Schedule T are specifically designed for Ayurvedic medicines [2]. Ayurveda is mostly practiced using retrospective knowledge from the classical texts while some practitioners add new formulations based on their wisdom and experience. In both cases, it becomes mandatory to characterize the herbal and herbal-metallic-mineral formulations to understand the mechanism of the action of these drugs.

1. Challenges and workflow for characterizing medicinal plants used in ayurvedic formulations

Critical and systematic standardization and characterization of Ayurvedic medicines is the first key step for their global appreciation and acceptance. However, harnessing the natural resources and especially the very herbal nature of Ayurvedic medicines poses several challenges during these steps (Fig. 1).

Fig. 1.

Ayurvedic drug standardization: Challenges with medicinal plants.

The Ayurvedic Pharmacopeia has been published three decades ago with identity, purity, and strength as key quality factors while, the strategy by the World Health Organization and general guidelines by the Ministry of AYUSH, Government of India [3] for standardized and characterized herbal/natural/Ayurvedic medicines have been established a decade ago. However, they also need to be updated as and when newer analytical and diagnostic technologies become available, e.g. molecular markers for herb identification, mass spectrometry for complete metabolic profiling, etc. These can be summarized as depicted in Fig. 2 and be contemplated as an outline to be followed for each Ayurvedic herbal medicine by the manufacturer.

Fig. 2.

Work plan for medicinal plants in Ayurvedic formulations.

2. In-process and final product characterization of ayurvedic formulations

In the recent past and currently, many proprietary formulations are being developed in several pharmaceuticals/nutraceuticals/cosmeceuticals/phytopharmaceuticals for several ailments ranging from acid-peptic disease to cancer. For instance, lipid-based formulations are important in Ayurvedic treatment modalities for both, internal and external applications. Single herbs or polyherbal oil and ghee preparations are used in several diseases. Even in cancer treatment, these formulations are employed in suitable dosage forms [4]. A single herb Yashtimadhu/Glycyrrhiza glabra (GG) processed oil and ghee preparations can be quoted as an example which are reported to be useful in radiotherapy-induced side effects in various types of cancers, especially head and neck cancers. It was experimentally proved that these lipids selectively disperse or dissolve certain phytocompounds beneficial for therapeutic effects. Though Glycyrrhizin is the signature molecule of GG, it got eliminated during the manufacturing process (Taila and Ghruta Siddhi). On the contrary, these processed lipids, when analyzed by HPLC, revealed the presence of Glabridin and 18-beta glycyrrhetinic acid, which are responsible for the radio-protective effect [5]. These can actually be referred to as de-glycyrrhized natural products. However, other molecules from GG should also be screened for their presence/absence/modification in these lipid formulations.

Similarly, many such reported lipid formulations useful in cancer or any other disease treatment need to be thoroughly characterized for respective host plant signature/alternate/altered molecules for a better understanding of their mechanistic aspects. Such reports make it extremely important and mandatory to assess all the finished products as specified in Fig. 3.

Fig. 3.

Roadmap for process standardization and finished product characterization.

Another important attribute of some Ayurvedic medicines is their use in topical applications, such as gargles (Gandush). As per the indications, usually, decoctions or any liquid media are used for gargles. Decoctions of herbs are most useful in inflammatory, wound/ulcers, or infection conditions where specific phytocompounds when exposed to the oral cavity result in therapeutic effects [6]. The polyherbal nature of formulation is often essential to cover a wide spectrum of actions, let it be anti-microbial, anti-inflammatory, anti-oxidative, wound/ulcer healing, etc. In such cases, the pharmaceutical process carried out to prepare the final dosage form may cause selection and/or alteration of the phytocompounds that are present in the parent herb. Identifying the bioactive compounds in the finished product becomes crucial to understand the mechanism of action as seen in pre-clinical and clinical research. For instance, curcumin is insoluble in water [7] and cannot be the only targeted molecule for analysis and therapeutic effect when turmeric is used in the decoction form. Other compounds from turmeric also necessarily need to be identified and characterized for the observed/reported therapeutic effect.

3. Workflow and characterization of metallic and mineral-based ayurvedic medicines

Metallic and mineral drugs are also routinely used in Ayurvedic treatment modalities and need to be characterized thoroughly. In a study for reducing chemotherapy side effects in cancer patients, several classical and proprietary herbo-mineral metallic formulations have been used [8]. Moreover, several Indian and US patents have been filed and published for such a combination of medicines. For example, calcium carbonate groups of medicines (Sudha Varga Bhasma) are one of the widely used medicines in Ayurveda. Conch, cowry, pearl, coral, mother pearl, gypsum, etc. are converted to palatable forms in these medicines. Pharmaceutical studies have shown that such conversion leads to physical and chemical changes due to trituration, grinding, and incineration processes. For example, conch, an aragonite form of calcium carbonate, gets converted to calcite form after incineration at a temperature between 650 and 850 °C. Beyond this temperature, the carbonate gets converted to oxide [9]. In cancer, the tumor micro-environment is found to be responsible for its growth and spread. Cellular alkalinity has been shown to reduce tumor size and is considered to be unfavorable for tumor metastasis [10]. Theoretically, 40% calcium in 1 g of calcium carbonate is the highest daily dose of calcium being used in cancer patients, responsible for maintaining the cellular pH by carbonate ion mechanisms. For this purpose, CaO being an exothermic molecule is not a suitable compound. Another recent research has successfully demonstrated that CaCO₃ nanoparticles are a suitable drug carrier for citronellyl acetate, a neuroprotective drug useful in Alzheimer's disease [11]. Recently reported Zinc oxide-based Jasada Bhasma nanoparticles [12] for biocompatibility and Heerak Bhasma for the treatment of Dalton's lymphoma [13] are commendable examples of thorough characterization and pre-clinical studies. Thus, a separate but specific roadmap for such metallic and mineral finished products could be designed and followed as illustrated in Fig. 4.

Fig. 4.

Work plan for minerals and metals as well as their processing.

Our research and manufacturing laboratory has been working on several drug entities from Ayurveda, such as Swarna Bhasma/nano-microparticulate medicine of metallic gold [14], Swarna Gairik i.e., red ochre roasted in cow's ghee [15] and Trailokyachintamani Rasa (a complex herbo-mineral metallic formulation) [16] on similar principles.

4. Challenges in clinical studies of ayurvedic medicines

In the last decade, AYUSH clinical studies have been registered prospectively in the Clinical Trials Registry of India but the analysis of these studies proposes prospective and randomized clinical trials of Ayurvedic formulations for robust results [17]. Recent randomized clinical studies of herbal mouthwash formulations in radiation-induced mucositis and other symptoms of oral cavity cancer patients have provided subjective assessment [18,19]. However, thorough metabolomic analysis of herbal decoctions while post-treatment changes in oral microbiota and salivary biomarkers can be further studied to support the clinical findings. Similarly, several clinical trials exploring mechanisms of immune-boosting/modulation have shown to enhance the immune system, via natural killer cells and T helper cells [20]. Even during the COVID-19 pandemic several Ayurvedic medicines were used and reported to be useful [21]. However, all such medicines should undergo thorough characterization, batch-to-batch consistency and safety assessment [22].

Work plans or procedures mentioned herein have several challenges or limitations concerning expertise and costs. Even Schedule E1 caution drugs like Ahiphena/Papaver somniferum, Vatsanabh/Aconitum chasmanthum, Arka/Calotropis procera, etc. possessing anticancer activity [23] are used either singly or in formulations but need critical attention for standardization, characterization, quality, safety, posology and clinical studies. Ayurveda research for both classical as well as patent and proprietary formulations needs attention towards factors such as improved research methodologies, use of reverse pharmacology, interdisciplinary research, proactive government sector, upgradation of the Ayurvedic pharma sector, etc. for global acceptability [24].

5. Discussion

For the globalization of Ayurveda, the task of drug standardization and research should be a top priority for all the leading Ayurvedic institutes. The establishment of the Global Centre for Traditional Medicine in India is a step forward in this journey. Cancer itself is a complex disease and treatment also needs to be based on complex drugs like phytocompound-loaded Ayurvedic medicines. Hence, strenuous efforts are necessary to achieve this goal. The mechanistic studies on cancer could only be planned and understood by thorough knowledge of the characteristics of the Ayurvedic medicines used. The roadmaps mentioned here should be followed for each marketed product being used for cancer treatment either as an adjuvant or a mainstream treatment.

Funding sources

None

Conflict of interest

None

Data statement

None

Declaration of generative AI in scientific writing

The authors did not use generative AI to draft the manuscript.

Author contributions

SC, VG, VD, SS conceptualized the work while SC and VG conceived and designed the flow charts. SC wrote the original draft while all authors revised and approved the final draft.