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7
Application of nanomedicine for
efficient delivery of herbal bioactives
Mabel Moreno
1
, Simón Guerrero
1, 4
, Paula Solar
1
,
Carolina Klagges
1
, Sindy Devis
1
, Carolina Otero
2
,
Hugo Sanchez-Ruderisch
3
and Luis Velásquez
1
1
Universidad SEK, Instituto de Investigación Interdisciplinar en Ciencias Biomédicas SEK
(ICBSEK), Facultad Ciencias de la Salud, Santiago, Chile;
2
Escuela de Química y Farmacia,
Facultad de Medicina, Universidad Andres Bello, Santiago, Chile;
3
Charité-Universitätsmedizin
Berlin, Berlin, Germany;
4
Universidad de Atacama, Facultad de Medicina, Copiapó, Chile
1. Introduction
Nowadays, on e of humanity’s most significant challenges is strengthening primary health-
care based on phytotherapy (see Fig. 7.1) and extending its use to livestock to decrease the
impact of antibiotic resistance and greenhouse. Nanotechnology is emerging as a revolution-
ary tool to address emerging and reemerging infectious diseases [1,2] by (e.g., nanocarriers)
increasing the capability of biomedical compounds, reducing the repeated administration, the
possible toxicities phenomena, and/or improving the bioavailability, which leads to the
improvement of the therapeutic value. The most substantial evidence of this is the wide range
of products on the market [3] that have made it possible to successfully face the current
SARS-COV-2 pandemic. On the other hand, bioactive components of medicinal plants trans-
ported by nanocarriers are emerging as a feasible route to improve their delivery rates
(sinacurcu-min, NanocurcTM, LipocurcTM) [4], leading herbal medicine to the top.
Medicinal plants and their extracts have been the primary source of natural compounds
used in medi cine for centuries (see Fig. 7.1). However, most herbal bioactives are hydropho-
bic and unstable in a biological environment, resulting in their poor bioavailability and, in
turn, their therapeutic efficacy. Herbal-based bioactive principles are preeminent options
due to their well-known ancestral potential therapeutic activities such as hypoglycemic, anti-
diabetic, antioxidant, antimicrobial, antiinflammatory, anticarcinogenic, antimalarial, anti-
cholinergic, antimycobacterium, etc. However, they show several limitations, such as rapid
CHAPTER
159
Phytopharmaceuticals and Herbal Drugs
https://doi.org/10.1016/B978-0-323-99125-4.00009-3 © 2023 Elsevier Inc. All rights reserved.
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metabolism, poor water solubility, instability at biological environment pH, exposure to light
and oxygen, insufficient uptake by tissues, including low intestinal absorption and unspecific
site of action, and undesirable side effects caused by the noncontrolled usage [5e7].
Nanotechnology can be defined as the application of scientific knowledge to manipulate
and control matter in the nanos cale to make use of size- and structure-dependent properties
and phenomena distinct from those associated with individual atoms or molecules or bulk
materials. Note that manipulation includes material synthesis [DD ISO/TS 80004-1:2010,
2.3, BSI-PAS 71:2011].
FIGURE 7.1 Applications of medicinal plants in human beings, a list obtained from European Medicines Agency
(EMA) reports and products on the markets (Altapharma, Bad Heilbrunner, Aktiv, Zirkulin, Herba-Vision, Tetesept,
DocMorris, Mivolis).
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It imposes a powerful technological tool to provide a change in human life in different
ways, especially for overcoming the multiple pharmacological limitations of herbal extracts
and pharmaceutical drugs used in several emerging and reemerging infectious diseases
(ERID), cancer proliferation, antibiotic resistance, some of the major challenges of global
health worldwide [8,9]. This is strongly backed up by the speed formulation of nanodrugs
control and mitigates the organ-specific sequelae of the COVID-19 disease, revealing the
feasibility and viability of developing tailormade medicines. SARS-COV-2 is an infectious
zoonotic disease transmitted from a nonhuman host to humans through vectors or contact
with these hosts. It brings a whole set of post-COVID complications [10e12]. The nanocar-
riers for drug delivery addressed in this chapter will give a roadmap for better release and
availability of the bioactive compound, which could be utilized for post-COVID-19 sequelae
and other illnesses.
New challenges in phytotherapeutics applications point toward developing novel drug de-
livery systems (NDDS) based on nanotechnology [13e16] (see Fig. 7.2) to increase the
FIGURE 7.2 Applications of nanocarriers.
1. Introduction 161
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capability of biomedicals and bioactive herbal compounds and reduce the repeated adminis-
tration, the possible toxicities phenomena, and to improve the bioavailability, which together
leads to the improvement of the therapeutic value. Nanomaterials like nanocarriers, for
instance, liposomes, polymeric nanoparticles (dendrimers, capsules, emulsions), metallic
(e.g., gold), transf erosomes, ethosomes, phytosomes, and magnetic (e.g., magnetite) [10],
are a suitable route to overpass such named limitations due to its small size, relatively
easy functionalization, and slow biodegradability which favor the disruption of the biological
barriers driving to the improvement of the distribution and getting the controlled delivery of
the bioactive compounds [16]. Likewise, the effortless synthesis of polymeric nanoparticles
based on oil-in-water techniques mixed with the low soluble herbal bioactive compounds
(microgels, nanocapsules, and nanoemulsions) permits to perform the improvement of the
stability, solubility, and bioactivity of herbal compounds, for instance, curcumin and phyto-
somes nanoemulsions for cancer treatment [16e18]. Thereby, nanotechnology is imposed like
an innovative oral delivery alternative obtained upon modifying the solubility properties of
bioactive compounds, with other applicability like nanonutraceuticals [19].
2. Herbal bioactive compounds
Since ancient times, humans have observed instinctive animal behavior when they heal
diseases or treat their wounds [20]. They have also learned to distinguish between toxic
and nontoxic species, and they could even differentiate between plants with medicinal ef-
fects and those with no effect [21]. The use of traditional healthcare practice of indigenous
people on human health is k nown as Ethnomedicine [22]. In Chile, the first use of medicinal
plants is located in Monteverde, an archeological site located in the South. Here, they found
Boldo traces, a not endemic species to that place, indicating a therapeutic value of this
plant [23].
Furthermore, before the arrival of Spanish sailors, Mapuches used medicinal herbs within
their therapeutic elements. They were aware of more than 200 plants with medicinal proper-
ties, mo st of which are still currently used for the same purpose [24]. Herbal plants play an
essential role in preventing and treating human diseases. People have been using plants as a
traditional and complementary medicine for thousands of years ago [25], for instance, Ayur-
veda Medicine, Naturopathy, Traditional Chinese Medicine, and Unani Arabic Medicine,
among others. Plants have been associated with the development of human civilization
worldwide. However, plants are considered rich sources of phytochemical ingredients, which
enable them to have medicinal value. In the first centuries of hum an development, drugstores
sold dry plants for therapeutic and poisonous purposes. “Drug ” is the Old French word
drogue or the Dutch word droog, referring to dry barrels containing herbs [26]. The term
“dose-response” was poorly explored during the preclassical era, for instance, in Chinese
in The Herbal Classic of Divine Plowman (2800 BCE). It was Paracelsus who ushered in the
era of “New Chemical Medicine” with the sentence, “Solely the dose determines that a thing
is not a poison,” to defend the use of inorganic substances as therapeutic agents [27].
The modern era of the pharmaceutical industry began with local apothecaries expanding
from their traditional role of distributing botanical medicines (e.g., morphine) to wholesale
manufacturing in the mid-19th century. With the foundation of the chemist and paint
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business, for instance, Gehe & Co. in 1835, and the pharmaceuticals Bayer in 1863, the syn-
thetic chemical industries have ruled the market for centuries.
The first signs of the use of nanotechnology in medicine “nanomedicine” were reported in
1924 by Ramon [28] by the vaccine formulation with micelles made with substances such as
lecithin and diphtheria and tetanus toxins. Since then, several organic and inorganic nanocar-
riers have been developed for vaccine formulat ion, known as “nano vaccines” [29]. In a very
visionary talk, Feynman (1959) said [30,31], “The principles of physics, as far as I can see, do
not speak against the possibility maneuvering things atom by atom traced the future societal
impact of nanotechnology”.
Ethnomedicine also includes nanomaterials, for instance, clays utilized worldwide for cen-
turies by indigenous people as important medicinal (as a dietary supplement or as healing
aid) and cosmetic tools [32]. Clays and other nanomaterials (e.g., nanocarriers) have a signif-
icant commercial value, specifically nanomedicine. The latter, according to the European
Technology Platform on Nanomedicine [33], can be defined as, “Nanomedicine is defined
as the application of nanotechnology to health. It exploits the improved and often novel phys-
ical, chemical, and biological properties of materials at the nanometric scale.”
At this time, society faces poor clinical solutions for many diseases and the rising cost of
healthcare due to an aging population. This has fueled the rapid emergence of nanomedicine
and the revival of herbal medicine. Since the discovery of the Nobel Laureate Tu Youyou
about using Artemisia annua L. for alleviating malaria symptoms was elucidated from an
ancient recipe in Ge Hong’s A Handbook of Prescriptions for Emergencies, ethnomedicine has
gained strength. In the context of redeeming medicinal recipes for scientific analysis, the latter
is to find either herbal bioactive compounds or/and nanom aterials, among others [34].
2.1 Classification and obtention of herbal bioactive compounds
Medicinal plants are characterized by their different components, which are responsible
for primary metabolism (compounds indispensable for the life of the plant), and secondary
metabolism (compounds responsible for color, flavor, and bioactive properties according to
environmental factors such as water availability, temperature, climate, salt, and cultivation
period). Some of these secondary metabolic compounds have been reported to contribute
to a plant’s antioxidant, antibacterial, and antiinflammatory effects [35]. Due to their proper-
ties, many indigenous Chilean plants have been used medicinally and for many other pur-
poses (among antiinflammatory), such as in health foods, antiobesity medications,
antioxidants, anticancer agents, and cosmetics [36,37].
The diverse chemical components of plants are generally abundant and exhibit different
structures. Primary metabolites are found in all plants and play vital functions in obtaining
energy, morphogenesis, and reproduction [38]. Secondary metabolites are considered nones-
sential for life, although they may be fundamental for specific biological functions and for
plant adaptation to the environment. They are compounds of high pharmacological interest
and the des ign basis for many functional foods or supplements [39].
For secondary metabolites obtention, it is necessary to extract them from plant material.
For this, vegetal extract might be processed dry or fresh and duly fragmented, considering
the moment of collection of the vegetal material (It is not the same to collect them in summer
or in winter) [40]. The study of the plant material starts with preextraction and extraction
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protocols, which are essential steps in the processing of bioactive molecules from plant ex-
tracts [40]. Conventional methods, such as Soxhlet extraction and maceration, are commonly
used in small research settings [41 ]. On the other hand, significant advances have been made
in the processing of medicinal plants in current extraction methods; ultrasound-assisted,
microwave-assisted, and supercritical fluid extraction methods, which are advances expected
to increase yields with a lower cost [42,43]. Furthermore, later modifications in purification
methods are continuously established. With such a variety of different methods, the selection
of a proper extraction method needs precise evaluation [42]. Medicinal plants and their sec-
ondary metabolites are known for their antiinflammatory properties, among others, and this
book chapter displays various native Chilean plants whose antiinflammatory effects have
already been evaluated by experimental studies; Aristotelia chilensis and Quillaja saponaria
are some of the examples of our native species analyzed in this chapter.
Aristotelia chilensis (Mol.) Stuntz (Maqui)
Aristotelia chilensis exhibits antiinflammatory properties and immunomodulatory activity
related to atopic-like dermatitis [44]. Moreover, it has been described that this species has
a high anthocya nin pigment, giving the dark violet color characteristic of its berries [45].
A. chilensis is rich in poly-glycosylated derivatives with a high antioxidant capacity. Concern-
ing the antiin flammatory effect, analgesic activity was observed when a dichloromethane
fraction was given. It can be possible that the presence of the pentacyclic triterpenoids ursolic
acid and friedelin together with quercetin 5,3-dimethyl ether can explain this antiinflamma-
tory effect [46]. Moreover, caffeic and ferulic acids found in the infusion fraction might be
responsible for its analgesic effect and the topical arachidonic acid e induced inflammation
as it has been described for these compounds in animal models [45,47].
Quillaja saponaria Mol. (Quillay)
Quillaja saponaria Mol. is a coastal range tree of the foothills of the Andes in semiari d cen-
tral Chile [48]. Its bark has been largely used for hair and wool washing. Moreover, Mapuche
people have used it for toothache relief and to treat inflammation, especially of the respira-
tory tract [49]. Furthermore, this tree has been used since precolonial times as a detergent.
Then, its saponins are used as a foaming and emulsifying agent [50]. Q. saponaria saponins
involve a diverse mixture of glycosides and sugar esters, mainly of the pentacyclic triterpene
quillaic acid. The topical antiinflammatory activity was evaluated using arachidonic acid
(AA) and 12-O-tetradecanoyl phorbol-13 acetate (TPA), which induced inflammation in a
mouse ear assay [51]. In this study, it was demonstrated that saponin aglycone, Quillaic
Acid is a highly effective inhibitor of in vivo inflammation induced by topical application
of either TPA or AA.
2.2 Applications of herbal bioactive compounds
Bioactive molecules can be found in both dried and fresh plant material and in the leaves,
stems, roots, seeds, and/or fruit. Many active extracts or molecules are simple to detect and
isolate, while others, as part of complex mixtures, are difficult to analyze a nd therefore
determine the active compound, as i s the case with many essential oils or resinous sub-
stances. Table 7.1 shows the wide list of products on the markets (Altapharma, Bad
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TABLE 7.1 Medicinal herbs tea, capsules, and supplements in the market (Altapharma, Bad Heilbrunner,
Aktiv, Zirkulin, Herba-Vision, Tetesept, DocMorris, Mivolis).
Composition Name (company)
Active ingredients: birch leaves (Betulal), giant goldenrod (S. gigantea),
ononis (Fabaceae), horsetail (Equisetum arvense). Other ingredients: bitter
fennel (F. vulgare), peppermint leaves (Mentha piperita), licorice root
(Glycyrrhiza glabra).
Bladder and kidney tea (Altapharma)
Active ingredients: ribwort plantain (P. lanceolata), licorice root (Glycyrrhiza
glabra), bitter fennel (F. vulgare), thyme (Thymus vulgaris). Other
ingredients: marshmallow leaves, Icelandic moss (Cetraria islandica (L.)
Acharius s.l., thallus).
Cough and bronchial tea (Altapharma)
Active ingredients: elderflower (Sambucus), thyme (Thymus vulgaris),
willow bark (Salix alba L.). Other ingredients: aniseed (P. anisum),
blackberry leaves, bitter fennel (F. vulgare Amargo), rosehip, thyme herb
(Thymus vulgaris), licorice root (Glycyrrhiza glabra).
Cold tea (Altapharma)
Active ingredients: marshmallow leaves (Althaea officinalis), marshmallow
root (Althaea officinalis), licorice root (Glycyrrhiza glabra), aniseed
(P. anisum).
Throat and pharynx tea (Bad
Heilbrunner)
Active ingredients: ribwort plantain leaves (P. lanceolata). Dry cough tea (Mivolis)
Active ingredients: linden blossom (Tilia), aniseed (P. anisum), thyme
(Thymus vulgaris). Other ingredients: marshmallow leaves, rosehip shells.
Cough and bronchial tea for children
(Altapharma)
Active ingredients: marshmallow leaves (Althaea officinalis/malvavisco),
marshmallow root, liquorice root (Glycyrrhiza glabra), aniseed (P. anisum).
Dry cough tea (Altapharma)
Icelandic moss extract (Cetraria islandica (L.) Acharius s.l., thallus
), bitter
fennel oil (F. vulgare), anise oil (P. anisum).
Herbal dry cough (Tetesept)
Ribwort plantain (P. lanceolata), peppermint oil (Mentha piperita). Ribwort cough syrup (DocMorris)
Eucalyptus oil (Eucalyptus). Nose and head. Eucalyptus oil capsules
(Tetesept)
Active ingredients: birch leaves (Betula), giant goldenrod (S. gigantea),
ononis (Fabaceae), horsetail (Equisetum arvense). Other ingredients: bitter
fennel (F. vulgare), peppermint leaves (Mentha piperita), licorice root
(Glycyrrhiza glabra).
Bladder and kidney tea (Altapharma)
Active ingredients: yarrow herb (Achillea millefolium), aniseed (P. anisum),
bitter fennel (F. vulgare), caraway seeds (C. carvi), chamomile (Asteraceae)
flowers.
Stomach and intestinal tea (Altapharma)
Active ingredient concentration: peppermint leaves (Mentha piperita),
dandelion (Taraxacum), Javanese curcuma (Zingiberaceae), yarrow herb
(Achillea millefolium).
Digestive tea (Altapharma)
Active ingredients: dandelion (Taraxacum). Fat digestive tea (Bad Heilbrunner)
Active ingredients: peppermint leaves (Mentha piperita), dandelion
(Taraxacum), Javanese curcuma (Zingiberaceae), yarrow herb (Achillea
millefolium).
Liver and bile tea (Bad Heilbrunner)
(Continued)
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TABLE 7.1 Medicinal herbs tea, capsules, and supplements in the market (Altapharma, Bad Heilbrunner,
Aktiv, Zirkulin, Herba-Vision, Tetesept, DocMorris, Mivolis).dcont’d
Composition Name (company)
Urtica leaves (Urticaceae), lemongrass (Cymbopogon schoenanthus), horsetail,
ginger.
Base herbal tea (Altapharma)
Lemongrass (Cymbopogon schoenanthus), lemon verbena (Aloysia citrodora),
peppermint (Mentha piperita), orange peel, ginger (Zingiber officinale),
vitamin C, zinc gluconate, lemon peel.
Immune tea (Altapharma)
Thyme (Thymus vulgaris/Tomillo) Thyme tea (Altapharma)
Salvia officinalis (Salvia) Sage tea (Altapharma)
Urtica (Urticaceae) Nettle tea (Altapharma)
Hawthorn leaves (Crataegus rhipidophylla). Hawthorn tea (Bad Heilbrunner)
Hawthorn leaves (Crataegus rhipidophylla), bitter fennel fruits (F. vulgare),
rosemary leaves (Rosmarinus officinalis, Salvia rosmarinus), peppermint
leaves (Mentha piperita), angelica root (Angelica archangelica).
Cardiovascular tea (Bad Heilbrunner)
Lavender flowers (Lavandula spica) Calming tea (Bad Heilbrunner)
Fennel (F. vulgare), Anise (P. anisum), Caraway (C. carvi). Fennel-anise-caraway tea (Altapharma)
Lemongrass (Cymbopogon schoenanthus), Ginger (Zingiber officinale),
Turmeric (Curcuma Longa L/Zingiberaceae), Vitamin D.
Ginger-curcuma tea (Altapharma)
Fennel (F. vulgare), chamomile (Asteraceae), tulsi (Ocimum tenuiflorum),
orange leaf, lemongrass (Cymbopogon schoenanthus), chicory root
(Cichorium intybus), rosehip.
Tulsi (Kings Crown)
Active ingredients: mate (Ilex paraguariensis), blackberry leaves,
peppermint (Mentha
piperita), elderberries, niacin, pantothenic acid,
vitamin B2, vitamin B6, vitamin B1, folic acid, biotin, vitamin B12.
Figure-fit tea (Bad Heilbrunner)
Lemongrass, orange leaves, nettle, fennel, lemon balm, chamomile, lady’s
mantle (Alchemilla mollis), yarrow herb (Achillea millefolium), angelica root
(Angelica archangelica), vitamin B6.
Menstrual tea (Bad Heilbrunner)
Active ingredients: peppermint extract (Mentha piperita), sweet
blackberry leaf extract, passionflower extract (Passiflora incarnata),
lavender flower extract (Lavandula spica). Other ingredients: melatonin and
lavender oil.
Fall asleep tea (Bad Heilbrunner)
Active ingredients: valerian root (Valeriana officinalis), passionflower
(Passiflora incarnata), lemon balm leaves (Melissa officinalis). Other
ingredients: peppermint leaves (Mentha piperita), yarrow (Achillea
millefolium), liquorice root (Glycyrrhiza glabra), chamomile flowers
(Asteraceae).
Sleep and calming tea (Bad
Heilbrunner)
Active ingredients: lemon balm leaves (Melissa officinalis), hop cones
(Humulus lupulus), lavender flowers (Lavandula spica).
Antistress tea (Bad Heilbrunner)
Hemp seed oil, hemp powder (Cannabis). Active hemp oil (Aktiv)
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Heilbrunner, Aktiv, Zirkulin, Herba-Vision, Tetesept, DocMorris, Mivolis), revealing the
excellent p opulation acceptance.
3. Nanocarriers for control drug delivery
Herbal medicine is a significant com ponent of traditional medicine and has been a part of
the treatment of many diseases. Although Asian people have used herbal medicines for de-
cades, the therapeutic efficacy and pharmaceutical application of herbal extracts encounter
difficulties associated with many factors, and even when achieved, a great number of bioac-
tive compounds have been identified and isolated from the medicinal plants, with the likeli-
hood of significant health benefits. The trouble s emerge because the majority of these
compounds suffer from poor bioavailability, low stability, low water solubility, undefined
membrane permeability, and lack of targeting potential. That reduces the biodistribution
and impedes them from approaching the clinical stage. Nowadays, new formulations of
drug delivery systems are immersed in developing pharmaceutical nanocarrier proposals
to overcome the limits of conventional formulations. In the new era of nanoscale develop-
ment, the atoms and molecules work in different patterns and present a diversity of amazing
and appealing applications. Actually, the pharmaceuticals nanocarriers are defined as sys-
tems of submicron size, with or without biodegradable characteristics, and include nanopar-
ticles, nanospheres, nanocapsules, nanoemulsions, and nanosized vesicular carriers such as
the liposomes, niosomes, and extracellular vesicles (EV) such as exosomes [52].
On the different appeal of development areas, all of them must be suitable to increase the
selectivity of the drug and the amount of the drug accumulated in the pathological target
area. Ideally, with excellent bioavailability, diminishing drug degradation in the unwanted
TABLE 7.1 Medicinal herbs tea, capsules, and supplements in the market (Altapharma, Bad Heilbrunner,
Aktiv, Zirkulin, Herba-Vision, Tetesept, DocMorris, Mivolis).dcont’d
Composition Name (company)
Ginkgo leaf extract (Ginkgo biloba). Ginkgo þ B vitamins þ choline/food
supplements (Aktiv)
Ginseng extract (Panax). Ginseng capsules/food supplements
(Aktiv)
Turmeric root extract (Curcumae xanthorrhizae) and curcumin. Curcuma longa with curcumin (Aktiv)
Horse chestnut (Aesculus hippocastanum). Abtei Veins Active Balm (Abtei
Rosskastanien Venen-Dragees)
Artichoke leaf extract (Cynara cardunculus L. (syn. C. scolymus L.)) Artichoke Capsule (Zirkulin)
Dry extract from defatted Cardus marianus (Silybum marianum). Cardus marianus capsule (Tetesept)
Euphrasia and chamomile (Asteraceae). Euphrasia and chamomile eye drops
(Aktiv)
Chamomile (Asteraceae), mallow (Malvaceae). Chamomile plus eye drops (Herba-
Vision)
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