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have been very considerate toward our
research and academic activities. We also
would like to acknowledge the excellent
assistance of Kristi Anderson, Moosa Omer
Mukthar, and all the editorial staff at
Elsevier.
PREFACExx
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Acknowledgments
We thank all our senior professors and fellow teachers from various institutes and uni-
versities in and out of Indi a for their comments and suggestions, which enabled us to bring
out the book successfully.
xxi
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Prospects of plant-based
therapeutics
SECTION I
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1
Plant-based therapeutics: current
status and future perspectives
Shikha Jha, Klaudi K. Vaiphei and Amit Alexander
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research,
Guwahati, Changsari, Assam, India
1. Introduction
In the history of humanity, herbal medicines have been a constant source of healing agents
in a diseased state. Herbal medicines have clearly risen in popularity and acceptance in devel-
oped and developing countries over the past decade, with herbal remedies now accessible in
drug stores and traditional ayurvedic pharmacies. However, the emergence of synthetic mol-
ecules in the research arena was massively increa sed due to their high efficacy in treating ail-
ments. This surge of application of synthetic drugs has highlighted the flip side of drug
therapy. Synthetic drugs have an adverse impact on health due to their nonbiodegradability
and unpredictability during drug delivery, which is visible in the form of side effects that de-
mand immediate attention [1]. Even after being forefront in treating diseases with synthetic
molecules worldwide, WHO reported that around 70%e90% of the population in developing
nations rely on traditional herbal medicine. These herbal moieties have gained momentum to
flourish in the research and medicine com munity as an active therapeutic moiety within a
short period.
Specific phytoactive commercial and marketing aspects seem to have a promising growth
as they have been used for generations to drive consumers toward their usage. In addition,
many people consider them safer and more cost-effective than synthetic drugs. Overall, the
international trade in herbal medicinal plants and their products was worth $60 billion in
2010 and is expected to grow to $5 trillion by 2050 [2], which highlights that there will be
a tremendous demand for phytoactive products in the upcoming years. As a result, herbal
medicines are frequently viewed as a balanced and moderate approach to healing treatment,
and a higher amo unt of money is spent on them by laymen. This explains why herbal med-
icine sales are booming and account for a significant portion of the global drug market.
CHAPTER
3
Phytopharmaceuticals and Herbal Drugs
https://doi.org/10.1016/B978-0-323-99125-4.00003-2 © 2023 Elsevier Inc. All rights reserved.
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2. Phytopharmaceuticals: revival of traditional medicine in a modern way
In the global perspective, there is a par adigm shift in the perception of end-user regarding
the safety of allopathic medicine, and their cultural belief converges toward herbal-based
therapeutics. Scientist communities and drug manufacturers have found their way back to
unraveling the traditional phytopharmaceuticals and formulating a stable delivery system.
Developing synthetic leads and further formulating drug delivery systems is cumbersome
and expensive. Also, there is a probable chance of failure of therapeutics in clinical trials.
These added risks with a fear of less return-on-investment hold back manufacturers and
funding agencies to invest in research on herbal products. Thus, switching to the most suited
and documented drugs in literature is the only way ahead to meet the drug discovery de-
mand due to increasing cases of new diseased conditions. Another factor that shifts focus
on the herbal drug is the monetary aspect associated with the treatment using synthetic
drugs. The high cost of treatment is generally unaffordable to the economically weaker sec-
tions of society. This collective factor contributes to diving toward drugs of the natural source
even after having high therapeutic efficacy.
Researchers faced difficulties in separating the active compound from complex mixtures of
plant constituents, and the whole process was time-consuming, which halted the develop-
ment of bioactive. The ethnopharmacological approach is a process opted to screen the
already reported traditional herbal drugs [3]. The main objective of this approach is to
develop a standardized herbal medicine from crude drugs [4]. The advent of the latest tech-
nologies in analytics like hyphenated techniques, i.e., LC-MS, GC-NMR, LC-PDA, provides
novel and interesting scaffolds with on-line detection of compounds and isolation from crude
extracts. Modern strategies like metabolomics, chemical fingerprinting, bioassay-guided
isolation have provided access to successful dis coveries of therapeutic leads [5]. Synthesis
of medicinal agents dated back to the discovery of morphine from Papaver somniferum, which
was the first modern drug. This led stone to the discovery of various drugs from natural sour-
ces. Similarly, anticancer drugs such as taxol (Taxus brevifolia), vincristine (Catharanthus
roseus), an antimalarial druglike artemisinin (Artemesia annua), quinine (Cinchona spp.) are
all discovered through natural sources [6]. Out of 59 drugs approved by USFDA, natural
products hold approximately 16% of the total share. Newmann et al. reported that
8%e13% of drugs were of natural origin consisting of natural products and derivatives of
natural products from the year 2010 to 2019 [7]. Maximum products found their use in anti-
cancer drugs. However, there exist drug classes like antihistamines, diuretics, and hypnotics
that have no drug of natural origin due to their inaccessibility to the disease site.
3. Research in natural products
A recent PubMed research with the keyword “Herbal medicinal product” displayed 15,325
results showing tremendous research activity currently in the pipeline for many diseases.
However, this research work is not further reciprocated on an industrial scale. To increase
research and development of herbal medicinal products, the cultivation of these rare species
of herbal plants needs to be enhanced at higher folds. In order to achieve this, the AYUSH
ministry has provided a subsidy of 30%, 50%, and 75% on the cost of cultivation on 140
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medicinal plants [8]. Additionally, Department of Biotechnology (DBT) is forefront in trans-
lational research in converting significant lead into processes and products with the help of
three regulatory networks, namely, US-FDA-Botanical drugs, DGCI-Phytopharmaceutical
Drugs, Proprietary Ayurvedic medicine in AYUSH mode [9].
4. The market trend regarding natural product
Phytopharmaceuticals or herbal medicines have long been regarded as viable alternatives
to modern allopathic medicine worldwide. Even though herbal medicin es are used widely in
society, only a few herbal medicines have been assessed scientifically for their potential in
treating disease. In addition, the efficacy and quality of herbal medicine are also not yet clin-
ically proven. However, herbal products are widely marketed all over the world by various
companies despite being unapproved by regulatory authorities.
According to the Food and Drug Administration (FDA) reports, more than 50,000 adverse
effects are due to herbal and dietary supplements [10]. A traditional medicine (TM) strategy
2014e23 was launched under the World Health Organization (WHO), focusing on broad-
ening the knowledge base and providing guidance on regulatory and quality assurance stan-
dards to promote TM’s safety, efficacy, and quality. It also focuses more on health services
and systems [11]. Therefore, regulatory bodies were formed to regulate the herbal drugs
currently in formulation stage. However, the regulatory scenario differs from country to
country; for example, in the European Union (EU), food supplements of plant origin are
considered foods and must comply with EU General Food Law. In c ontrast, herbal medicinal
products are considered pharmaceuticals. Also, plant food supplements do not require
approval for marketing, but they must be safe for human consumption as per Regulation
(EC) 178/2002.
On the other hand, in the USA, botanicals are under the food category regulated by the
Dietary Supplement and Health Education Act (DSHEA). They can be marketed directly
without the approval of drug regulatory bodies, i.e., the Food and Drug Administration
(FDA). However, it is the manufacturer’s or distributor’ s responsibility to ensure the safety
of the product and labeling compliance. In contrast to the EU and USA, in Canada, natural
health products are regulated by the Natural Health Products Regulations, requiring
premarket approval from the regulatory bodies, i.e., Health Canada, where they provide a
Natural Product Number (NPN) [12].
In India, botanicals, commonly termed Ayurveda, Siddha, or Unani (ASU) drugs, are un-
der the Department of Ayurveda, Unani, Siddha, and Homeopathy (AYUSH). In contrast, the
regulatory requirements of phytopharmaceuticals are under the Central Drugs Standards
Control Organization (CDSCO). These regulatory provisions for phytopharmaceuticals
defined the regulatory submission requirements for scientific data on quality, safety, and ef-
ficacy to evaluate and allow marketing of herbal drugs along the same lines as synthetic or
chemical moieties [11].
The primary ethical challenge of botanicals holds that many people thought them safe as
they are natural. Still, they have specific pharmacological side effects similar to synthetic
drugs. Moreover, some herbal medicines have been associated with various adverse drug re-
actions, such as toxicity, overdose, allergic reactions, herb-drug interactions, and contamina-
tion with other products. As described earlier related to the regulatory issues, people have
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more access to these unlicensed herbal medicines endangering them to more problems and
adverse drug reactions [13].
Despite being differences in the management of plant-based therapeuti cs globally, herbal
medicines and related products continue to gain global acceptance and use at an exponential
rate. Since a previous misconception that herbal medicinal products are safe as they are
derived from natural sources still exists, issues relating to adverse reactions have become
more visible, prevalent, and no longer debatable in recent years. Therefore, regulatory au-
thorities in various countries around the world must be active and implement relevant mea-
sures to safeguard public health by assuring that all herbal medicinal products are safe and of
appropriate quality for sale.
Currently a valuable key player in the herbal product is listed in Table 1.1 has a wide range
of applications from the treatment of infectious disease to complex disorders [14,15]. Interest-
ingly, research on natural products is now not confined to a specified region of traditional
discovery but spread to the Western part of the world. The combinatorial approach of classic
documented literature from India, China, etc., with countries contributing to traditional herb-
al products having a wide range of biodiversity and the research contribution of the Western
world, will help in the development of herbal medicines with a scientific approach.
5. Future perspectives
The powerful tools in drug discovery led to the identification of active phytopharmaceut-
icals. Despite the availability of all sophisticated tools, the market-approved products of plant
therapeutics are meager. The primary reason behind this is the failure of the drug to rea ch the
third phase of a clinical trial due to its lack of efficacy compared to control or place bo [16].
With the help of elucidation performed on the human genome, i.e., postgenomic era, the
screening of herbal drugs is likely to be hastened and become more efficient.
Screening of herbal drugs is an initial step for its approval as a phytomedicine. There are
several properties of active herbal moieties that limit their delivery to the target site at
optimal concentration. These attributes of herbal drugs are instability in highly acidic pH,
presystemic metabolism, and lower solubility. In addition, various active moieties found
are polar molecules, and their sizeable molecular size restrains their absorption. Hence, lower
bioavailability. Incorporating these molecules into novel drug delivery minimizes their pre-
systemic metabolism, degradation, and accumulation at nontargeted sites, the reupon
improving their bioavailability and therapeutic efficacy, further reducing their side effects.
The scientific community developed lipid-based particulate drug delivery systems search-
ing for targeted and controlled release. Lipid as the carrier is an unobjectionable asset in car-
riers’ drug delivery systems due to its biocompatibility, regulatory, and safety profiles.
Vesicular drug delivery systems, particulate drug delivery systems, and biphasic systems
are different novel drug delivery systems (NDDS) that can be used as a carrier system to
deliver herbal therapeutics. Incorporating these therapeutic moieties into NDDS enhances
the entry of drugs at target sites. This is of particular importance in anticancer drug delivery
when delivery through this route increases the therapeutic index of a drug by enh ancing
target to cancerous cells and less toxic to healthy cells [17].
The delivery progression of the herbal drug into the market has been at the forefront for
many years. However, manufacturers have faced numerous issues in many countries in
recognizing bioactives as many herbal medicines showed enhanced in vitro activity but
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TABLE 1.1 Key players in herbal drugs market.
Manufacturer
Herbal
product(s) Active constituent(s) from plant source Indications
Tsumura and Co.,
Japan
Kampo
medicine
Chinese licorice, ginger, ginseng, crow-dipper Gastrointestinal tract
disorders
Dr. Willmar
Schwabe India Pvt.
Ltd., India
Dizester
Succinum
Carum carvi, Cassia angustifolia, Cassia fistula,
Cuminum cyminum, Ferula asafoetida, Foeniculum
vulgare, Mentha piperita, Moringa oleifera, Myristica
fragrans, Terminalia chebula, Trachyspermum ammi,
and Zingiber officinale
Oleum succini
Digestive tonic
Bladder stone, convulsions,
fear, enlarged spleen
Madaus GmbH,
Germany
Legalon
Diacard
Silybum marianum
Valerian, Cactus grandiflorus, Strophanthus gratus,
Crataegus
Liver diseases
Heart diseases
Weleda,
Switzerland
Arnica
massage balm
Herb and
honey cough
elixir
Arnica, birch
Aniseed, elder flower, Iceland moss thallus,
marshmallow root, thyme herb, white horehound
herb
Sprains, muscular pain and
stiffness, rheumatic pain
Dry cough
Blackmores
Limited, Australia
Propolis 1000
grape seed
forte
Propolis
Grape seed extract
Antioxidants
Arkopharma,
France
Spirulina
Cys-control
Spirulina platensis
Cranberry, heather
Dietary supplement
Promote urinary comfort
Sido Muncul,
Indonesia
Tolak angin Cardamom, clove, ginger Dietary supplement
Arizona Natural,
USA
Allirich Garlic Antibacterials
Dabur, India Chyawanprash
Active antacid
Indian gooseberry, Tinospora cordifolia, Asparagus
racemosus, long pepper
Coriander, Acorus calamus, Alpinia galanga,
Andrographis paniculata, Tulsi (holy basil),
Achyranthes aspera, Piper longum
Immunity booster
Flatulence and indigestion
Herbal Africa,
South Africa
Vuka
Digestive tonic
African Helichrysum
Momordica balsamina
Female libido problems
Digestive, liver, and
pancreas tonic
Nature’s Answer,
USA
Echinacea
Milk thistle
seed
Echinacea purpurea, Echinacea angustifolia
Silybum marianum
Promotes immunity
Promotes liver function
(Continued)
5. Future perspectives 7
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