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CHAPTER 7
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APPLICATIONS OF NATURAL
PRODUCTS IN DRUG DELIVERY
CONTENTS
7.1. Introduction .................................................................................... 212
7.2. Drug-Delivery Systems ...................................................................214
7.3. Impact of Drug-Delivery Systems in Natural Product Research ....... 215
7.4. Impact of Drug-Delivery Systems in Biotherapeutics Developments 220
References .............................................................................................224
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Natural Compounds: An Introduction
7.1. INTRODUCTION
New and improved drugs are essential because of the increasing challenge of
drug resistance. For new drugs, biotherapeutics, and natural products give a
massive resource; nevertheless, problems, containing the time and cost taken
for outdated drug discovery procedures and the successive lack of outlay
from the pharmaceutical industry, are related to these areas. New methods
are giving compounds with suitable activity at a greater rate. Whereas the
preparation of these collective with drug-delivery systems gives a capable
method for increasing the drug developments existing in modern medicine.
In this chapter, numerous classes of drug-delivery systems are defined, and
the rewards they carry to small molecule and biotherapeutic targeting are
emphasized. This is a striking method to the pharmaceutical industry, and
the increasing trend in the study in this area is studied (Parveen et al., 2012;
Aqil et al., 2013).
Novel medicines are continually being repurposed or developed,
directed to preventing or curing diseases or situations where therapeutic
product obtainability is decient, or to decrease disadvantages, advance
life quality, decrease the load on the charge of healthcare systems, whereas
meaningfully spreading patients’ lives. Nevertheless, R&D (research and
development), drug discovery can be a widespread process lasting over
7–10 years, along with an average cost of $2.6 billion for each effective
drug that spreads the market (Peters, 2014). These signicant time and
cost factors initiate from the technical, scientic, and controlling tasks
that are required to fully comprehend the drug mechanisms of action and
physiological connections for compound diseases at the molecular level.
Attaining practicable commercial success afterward needs investment in
vastly sophisticated technologies, progressive manufacturing procedures,
and advanced research methods to challenge the ever-growing cost and time
of the whole process (Figure 7.1) (Cragg et al., 2009; Mack et al., 2011).
Applications of Natural Products in Drug Delivery
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Figure 7.1: Sources of drug-delivery system.
Source: https://pure.strath.ac.uk/ws/portalles/portal/69481017/Obeid_
TD2017_Delivering_natural_products_and_biotherapeutics_to_improve.pdf.
213
For a long time, traditional medicine has been used, and in recent few
years, its usage has improved in evolving countries, whereas pharmaceutical
corporations have involved combinatorial and synthetic technologies in
errand of drug discovery programs depend on natural products. Nevertheless,
there is a requirement for novel medicines because rising drug resistance has
reduced antibiotics to nearly useless, and recent medicine is fronting a crisis
(Obeid et al., 2017).
When high-throughput screening shows potential excellent in vitro
therapeutic properties, there will be an obstacle that hinders the development
of the natural-derived candidate molecule market. When evaluated in vivo
or clinically, this therapeutic property appears to be inactive and toxic. Or
non-selective (Alzahrani et al., 2016). One way to solve these problems is to
increase the bioavailability and effectiveness of these compounds or to reduce
their toxicity by loading them into different types of delivery systems. These
can deliver therapeutic agents to specic parts of the body at a specic rate
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and have the potential to include multiple molecules with different effects
in a single delivery system. Our research team has extensive experience in
natural products and the development of drug delivery systems. Recently, we
have extended the scope of research to the development of biotherapeutics
(Al Qaraghuli and Ferro, 2017). In this chapter, we discuss how to combine
these research areas to meet the needs of producing new and better drugs,
thereby beneting these research areas. Also, there is evidence that delivery
systems can help reduce drug resistance and therefore play a vital role in
expanding the treatment options available in modern medicine (Gebril et
al., 2014).
Natural Compounds: An Introduction
7.2. DRUG-DELIVERY SYSTEMS
Drug delivery is related to the usage of a vehicle or delivery tool to transport
a therapeutic agent and at a specific location, release it at a precise rate.
Lately, for the treatment of several diseases, there has been a substantial
boom in the usage of delivery systems to carry therapeutic agents with
several successful results (Miele et al., 2012). Drug-delivery systems can
be employed to enable the delivery of small compounds along with large
molecules like polymers, nucleic acids, peptides, and poorly water-soluble
therapeutic agents from synthetic or natural sources (Hans and Lowman,
2002). Several kinds of delivery systems have been efficiently employed.
These contain lipid-based nanoparticles like solid-lipid particles, liposomes,
niosomes, and micelles; polymeric nanoparticles like atelocollagen and
chitosan; dendrimers; inorganic nanoparticles like metal-based nanoparticles,
carbon nanotubes, silica nanoparticles, and quantum dots (Pelaz et al.,
2017). Polymeric nanoparticles such as poly (lactic-co-glycolic acid),
polyvinyl alcohol, polyethylene glycol, polycaprolactone, poly-l-lactic acid,
and chitosan) and liposomes contain the most tested in blend with natural
products. Because of their biodegradability and biocompatibility, the prior
is the most frequently applied as well as the comfort by which they can be
functionalized? In terms of surface charge, size distribution, particle size,
stability, shape, and encapsulation proficiency all these delivery systems can
be considered (Figure 7.2) (Watkins et al., 2015; Obeid et al., 2017).
Applications of Natural Products in Drug Delivery
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Figure 7.2: Diagram of drug delivery systems.
215
Source: https://link.springer.com/protocol/10.1007/978-1-59745-210-6_1.
In evolving new medicines in spite of the advantages of the use of
delivery systems, some challenges still need to be addressed before their
wide application becomes commonplace; these are related to the fast
elimination of the delivery system by the reticuloendothelial system,
especially for charged molecules (Desai, 2012). Furthermore, inammation
and toxicity can create tissue damage because of the usage of different forms
of delivery systems (Allen and Cullis, 2013). As far as the delivery system
is concerned, it has to be secured and to fulll the regulatory considerations
such as manufacturing processes involved, like controlled drug release,
physicochemical characterization, stability, manufacturing costs, large-scale
production, and storage (Zamboni et al., 2012).
7.3. IMPACT OF DRUG-DELIVERY SYSTEMS IN
NATURAL PRODUCT RESEARCH
The major source of natural products is the plant kingdom, which has
powered the process of drug discovery and caused an excess of small
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Natural Compounds: An Introduction
drug-like molecules to intricate polymers (Atanasov et al., 2015; Shen,
2015). Further natural sources contain microbes, fungi, marine organisms,
and invertebrates (like reptiles and insects). Among the years 2000–2006,
the natural products field was projected to yield or be elaborate in R&D
of around 50% of almost all small drug molecules, and 10 among the 44
appropriate small molecules through the controlling authorities in 2014 were
resulting from natural sources (Cragg and Newman, 2001). Conservatively,
the natural products that are mined from source materials, fractionated,
concentrated, and purified. At the initial stages of study, in order to isolate
pure natural products, various methods are employed, and the advantages
and disadvantages of these have been expansively reviewed somewhere else
(Newman and Cragg, 2007). In order to extract constituents, the Soxhlet
solvent extraction, infusions or maceration are employed. For chemical
structure clarification this is generally followed by NMR and TLC analysis,
and MS as an assenting system; these are some instances of the core methods
that are generally employed, together with open-column chromatography
(such as vacuum liquid separation and gel filtration). For more isolation
and separation of pure compounds, new chromatography is employed
(Sasidharan et al., 2011; Bucar et al., 2013). Techniques like MALDI-TOF
MS are generally used to find a specific compound’s location inside tissues.
From various natural sources, the compounds isolated in this method have
reliably revealed useful therapeutic potential in opposition to various diseases
such as diabetes, hypertension, cancer, and infections. In assessing isolated
and extracts compounds, various bioassays are used to regulate the potential
therapeutic activity existing (Niwasabutra et al., 2016). Novel technologies
like molecular biology have been presented in this field for the widespread
estimation of mechanisms of action. From these latter approaches, we will
be able to know which genes are affected and so assistance in modifying the
succeeding research to exact disease pathways. To improve the development
and understanding of any possible lead molecules like Metabolomics is
employed (Figure 7.3).
Applications of Natural Products in Drug Delivery
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217
Figure 7.3: Different types of the delivery system, appropriate for use with
biotherapeutics and natural products.
Source: https://pure.strath.ac.uk/ws/portalles/portal/69481017/Obeid_
TD2017_Delivering_natural_products_and_biotherapeutics_to_improve.pdf.
For natural product research, the usage of progressive methods has
improved the rate of identication of bioactive compounds, nevertheless,
in marketable products, this has not taken as an increase. There are diverse
reasons for this. Some problems like bioavailability in vivo, solubility,
hydrophilicity, chemical, and physical instability. Furthermore, rst-pass
metabolism, poor pharmacokinetics, accretion in tissues, or low targeting
efciency can encumber therapeutic advantage. Drug-delivery systems
can be used to increase pharmacological activity and bioavailability of
molecules by permitting them to cross cellular membranes of target cells.
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Natural Compounds: An Introduction
From the mixture of drug-delivery systems, diseases that have proted along
with natural products contain cancer, diabetes, infections neurodegenerative
diseases (Chen et al., 2009; Ali et al., 2013).
Curcumin is one of the most widely considered natural compounds
compressed into diverse delivery systems to advance the bioavailability
of various tissues. On applications of curcumin, there is a lot of literature
available (Balunas and Kinghorn, 2005; Sikarwar et al., 2008).
To improve therapeutic activity and alleviate components, the drugdelivery systems have also been employed. For instance, vital oils are
frequently susceptible and unstable to degradation, therefore, encapsulation
into colloidal systems is required. The multilamellar liposomes are being
employed by Sinico et al. to improve the therapeutic activity of Artemisia
arborescent vital oil against Herpes simplex virus type 1. They came to
know that by improving the cytoplasmic viral hindrance penetration of the
active components of the plant the oil improved in vitro activity (Alonezi
et al., 2016; Ganesan et al., 2017). To compress a methanolic extract of
Ocimum sanctum chitosan is being applied by Rajendran et al. (n.d.). This
preparation was shown to have substantial antibacterial activities contrary
to Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli, and
Staphylococcus aureus related with the free unencapsulated extract (Bilia,
2012). From this study, the one problem that can be emphasized is the
widespread usage of extracts as contrasting to pure compounds that creates
a challenge from a regulatory viewpoint, as comparative quantities of the
active(s) may not be identied. Though, frequently numerous compounds
existing in extracts act synergistically and, so it is important to comprehend
contrary effects and synergy along with the mechanisms of action when
combination extracts of unidentied conguration and batch-to-batch
variation through delivery systems (Hou and Zhou, 2008; Nam et al., 2016).
Frequently, compounds happen to be biologically active, though,
they are also extremely water-soluble nonetheless have poor absorption
(such as terpenoids, tannins, and avonoids) and in a few instances like
polysaccharides that contain high molecular weight. This when tested in
vivo reduces, making them incapable to easily cross lipid membranes,
resultant in loss of biological activity and poor absorption. Furthermore,
few compounds are greatly poisonous when bare to normal cells. Delivery
systems, in this way, can be used to decrease toxicity, improve absorption,
and improve the selectivity of a few of these compounds (Pandey et al.,
2009; Chuan et al., 2015).
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