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254 Herbal Pharmacopeia
11.5.2.14 Acoustic Methods
The method involves measuring sound wave attenuation and applying a physical equation to calculate particle size (Devi et al., 2010). When a charged particle interacts with the oscillating electric
eld, it causes the eld to rotate in the direction of the acoustic energy. This rotational movement
yields valuable information about the surface charge (Sandhiya & Ubaidulla, 2020).
11.6 CONCLUSION
Nanoparticles offer a promising drug delivery system with potential for site- specic targeting,
enhanced efcacy, and reduced side effects. Conventional drug delivery systems encounter challenges such as non- targeted delivery, drug wastage, and adverse effects. Nanotechnology is expected
to address these issues. Various nanoparticle production techniques have been explored, each with
its own advantages and disadvantages. Notably, biosynthesis or green synthesis has emerged as a
highly advantageous method due to its simplicity, cost- effectiveness, availability, and environmentally friendly nature. However, thorough investigation of potential nanoparticle toxicity is imperative.
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Enhanced Bioavailability
12
of Herbal Extracts using
Nanocarriers
Marij Noor, Amina Khalid, Muhammad Umair,
Tooba Khan, and Muhammad Imran Khan
Department of Biomedical Sciences, Pak Austria Fachhochschule:
Institute of Applied Sciences and Technology, Haripur, Pakistan
12.1 INTRODUCTION
The healing power of nature has always been a consistent thread within the vast tapestry of human
history, weaving through prehistoric and modern societies alike. Herbal extracts, with their potent
properties and rich heritage, have always been appreciated as nature’s pharmacy. Yet, despite all
their benets the body’s own defenses act as a formidable barrier against them. The journey from
plant to pill is challenged by the interaction of plants’ bioactive compounds and biological barriers,
compromising the overall efcacy. With the advent of nanotechnology, scientists have now unlocked
a way to enhance the bioavailability of herbal medicines. This involves the synthesis of ancient
traditions to modern innovation, changing the dynamics of nature’s healing power. Imagine a tiny,
engineered carrier that will directly deliver the bioactive compounds to their targets, while navigating through the complex terrain of the human body, with unprecedented efciency.
12.1.1 Challenges of herbal extraCts in traditional MediCine
Herbal extracts are used for their medicinal properties and are derived from plants or plant parts.
Since the time of early humankind, they have been acting as biosynthetic chemical laboratories,
often containing several constituents that act together synergistically. ‘Active ingredients’ are the
chemical constituents that provide medicinal benets. However, the use of herbal extracts remains
challenging due to several factors. These factors are poor solubility, instability, low bioavailability,
and variability of the constituents due to environmental and genetic factors, and so on [1].
Herbal extracts may consist of either a single or multiple active compounds. Unlike other drugs,
however, they are thermolabile to volatile, leading to the degradation of active compounds during
storage and processing. Temperature, moisture, light, oxygen, microbial, and trace metal contamination are among the environmental factors that inuence the stability of herbal products [2].
Almost every herbal extract, despite their extraordinary benets in vitro, shows less to no in vivo
results because of their inappropriate molecular size and poor solubility in lipids, which is a major
cause of low absorption and low bioavailability. Procedures such as purication can lead to the loss
of certain chemically related substances involved in synergistic action, thereby compromising the
active compounds’ desired activity. Additionally, water- soluble components cannot cross the lipid
membranes in the intestines, further compromising bioavailability. Scientists have now found a
solution to tackle this problem. As a result, bioavailability is increased using novel delivery systems
for drugs like micelles, liposomes, and polymeric nanoparticles to improve movement across the
barriers and drug release [3].
257
258 Herbal Pharmacopeia
12.1.2 iMportanCe of bioavailability in therapeutiC effiCaCy
The concept of bioavailability is a cornerstone of therapeutic efcacy. It determines the efciency
with which a bioactive compound reaches its site of action in the body. If the therapeutic agent
available produces an intended effect, it is considered to have high bioavailability. By contrast,
drugs with suboptimal levels of bioactive element at the target site will be described as having poor
bioavailability. This will result in reduced efcacy, and an increased likelihood of adverse effects,
necessitating higher or more frequent doses, and compromising patient adherence. Hence, the optimization of bioavailability is crucial in developing drugs from herbal extracts to facilitate precise
dosage adjustments, enhanced patient outcomes, and better pharmacodynamic and pharmacokinetic
proles.
Bioavailability is dened as the measure absorption level of an active constituent present in a
drug and its absorbed rate in the bloodstream from the administered dosage in a patient, reaching the
targeted location to achieve the desired therapeutic outcome. A drug’s bioavailability dictates the
active ingredient percentage present in the organism in comparison with the concentration of drug
administered [4].
For accurate dosage adjustment, knowledge regarding the absorption, transport mechanism,
metabolism, and elimination of the Active Pharmaceutical Ingredient (API) is necessary. Conversely,
the administration of improper medication contributes to the unnecessary utilization of drugs.
Hence, for the patient’s safety and treatment efciency, bioavailability is signicant. To maximize
the bioavailability of medication, scientists utilize certain protocols such as appropriate drug delivery techniques, identifying and managing factors that hinder bioavailability, adjusting drug formulations, optimizing dosages, and monitoring blood levels of drug along with adjustment in the
dosage.
Once the dose is optimized with improved bioavailability, this will result in a reduced required
dose and frequency of dose administration, and therefore improved patient compliance and reduced
chances of side effects [4].
It is necessary to optimize herbal extracts’ pharmacokinetic and pharmacodynamic proles. The
pharmacokinetic prole shows how a drug is absorbed in the bloodstream, distributed, metabolized,
and eliminated from the body. This will help to determine the amount of active ingredients in the
bloodstream at any particular time. Poor bioavailability may be a result of inadequate absorption,
rapid metabolism, or premature elimination, leading to insufcient levels of drug at the targeted site
and reduced therapeutic efciency. Conversely, the pharmacodynamic prole determines the therapeutic effects, harmful side effects, and the mechanism of action. High bioavailability will ensure an
adequate amount of active compound at the target site which will assist in producing the desired
therapeutic effect. It is bioavailability that inuences the onset, duration of action, and intensity.
Adrug with poor bioavailability may not elicit a signicant pharmacodynamic response, causing
inadequate efcacy of the drug [5].
12.1.3 the role of nanoteChnology in addressing bioavailability issues
A nanotechnology- based drug delivery system was introduced to overcome the dilemmas related
to herbal medicines. This acts as a drug carrier, increasing bioavailability and therapeutic efcacy.
This nanoscale system, based on particle size of 0.1μm, has been developed to enhance activity,
minimize dosage requirement, and mitigate adverse effects. The potential of herbal medicines has
signicantly increased using nanotechnology- based drug delivery systems, including the capacity to
convert less soluble, less absorbed, and unstable constituents into effective drugs [6].
Consider a nanobiologist- designed system in a laboratory setting that can perform targeted delivery. It consists of an imaging molecule, ligands for site- specic targeting, an active constituent for
delivery, a destabilizing lipid for drug release at the required site, and, nally, a sensor to probe the
efcacy in real time. The fabrication of this delivery vehicle’s structural components is based on
Enhanced Bioavailability of Herbal Extracts using Nanocarriers 259
structural motifs that undergo self- assembly, targeting ligands and pharmaceutical agents. This is
the vision behind the creation of drug- loaded nanocarriers, which are tuned to trigger the release of
the drug in order to signicantly improve the efcacy of herbal extracts, which will potentially overcome drug resistance. In the case of liposomes, the basic underlying principle revolves around creating defects in the liposome membrane. Membranes sensitive to mild hyperthermia are potential
methods for triggered drug delivery. Additionally, by utilizing external triggering of liposomes, this
method exploits the abnormalities of diseased cells in tumors, upregulated enzymes can cleave the
membranes’ lipids and create defects [7].
12.2 PRINCIPLES OF BIOAVAILABILITY ENHANCEMENT
12.2.1 understanding adMe profiles
Pharmacokinetics refers to the study of the drug’s kinetics, or its active constituent once it enters the
body. It refers to the transient changes that occur in the drug and its metabolites when they get into
the plasma, serum, or whole blood, and, over time, within target tissues and organs. The human body
is a very intricate system; once a drug has entered, it experiences a series of processes: absorption,
distribution, metabolism, and, nally, excretion (ADME). Below we shall discuss each in detail
(Ruiz- Garcia, Bermejo et al. 2008) (Figure 12.1).
12.2.1.1 Absorption
The term absorption is used to describe the process which involves the movement of a certain
amount of drug from the administration site to the main compartment. It depends on the route of
administration. In the case of an orally administered drug, it is rst absorbed from the gastrointestinal tract, and the net absorption is limited by factors including the drug’s physicochemical properties
and the dosage form. Common routes of drug administration are mentioned in Table 12.1. Before
FIGURE 12.1 This diagram illustrates the complex processes of absorption, distribution, metabolism and
excretion which determine the pharmacokinetics of the drugs.
260 Herbal Pharmacopeia
TABLE 12.1
Common Routes of Drug Administration and Characteristics
Route Of
Administration Absorption Pattern Advantages Limitations and Precautions
Intravenous Bypass absorption
Rapid onset of action
Ideal for administering irritating
substances, large volumes or
complex mixtures upon dilution
Subcutaneous Quick action from aqueous
solution
Gradual and prolonged from
respiratory preparation
Intramuscular Quick action from aqueous
solution
Gradual and prolonged from
respiratory preparation
Oral ingestion Depends on different factors Safe, economical, and
Used in emergencies
Allows for dose adjustment
Typically, necessary for
large molecular weight
proteins and peptide drugs
Suitable for poorly soluble
suspension and slowrelease implants
It is ideal for moderate
volumes, oily vehicles,
and certain irritants
Can be self- administered
convenient
Potential risk of adverse effects
Slow administration
Not preferable in case of oily and
poorly soluble drugs
Not suggested in case of large
volumes potential pain or necrosis
from irritating substances
Not allowed during anticoagulant
therapy
May affect the results of certain
diagnostic test like LFT
Requires patient compliance
bioavailability, inconsistent and
incomplete
entering the systemic circulation, the drug must pass through the liver where metabolism and biliary
excretion are likely to occur. Therefore, out of the total concentration of administered and absorbed
dose, a fraction will be diverted or inactivated before reaching the general circulation, followed by
distribution to the site where needed.
12.2.1.1.1 Distribution
Following the process of absorption, the next step involves the distribution of the drug into both
intracellular and interstitial uids. The concentration and rate at which a drug is distributed within
the tissues depend on the drug's physiological and physicochemical characteristics. This process of
distribution is inuenced by factors such as cardiac output, blood ow to specic regions, capillary
permeability, and tissue volume.
A drug is preferably distributed to well- perfused organs such as the liver, kidneys, and brain.
Distribution to muscles, skin, fat, and most viscera occurs more slowly, typically in the second
phase, taking minutes to hours for the drug to reach these tissues until it comes to an equilibrium
with blood [8].
12.2.1.1.2 Metabolism
The concept of metabolism is signicant in the pharmacokinetics of drugs. Metabolism is the process in which specialized enzymatic systems are used for chemically altering a drug. In the case of
certain medications, drugs are initially administered as inactive pro- drugs; therefore, metabolism is
essential to convert the drug into its active form. In certain cases, drug metabolism might lead to a
complete loss or decrease in a drug’s pharmacological activity. The liver is pivotal for the metabolism of most drugs [9].
Two main types of reactions are observed that are involved in drug metabolism: Phase I functionalization reactions and Phase II biosynthetic reactions. The aim of Phase I reactions is to expose or
introduce a functional group to the original compound, as observed in hydrolysis reactions. Likewise,
Phase II conjugation reactions facilitate the creation of covalent bonds between metabolites from
Phase I or a functional group on the parent compound and endogenously produce sulfate, glutathione, glucuronic acid, amino acids, or acetate.
Enhanced Bioavailability of Herbal Extracts using Nanocarriers 261
The system of enzyme engaged in the drugs biotransformation is likely to be seen positioned
rstly in the liver, however some metabolic activity is also detected in other tissues. Organs which
have signicant metabolic capacity include the kidneys, lungs and the GI tract. Drug- metabolizing
activity is predominantly found in the cytosol (Phase II conjugation enzyme systems) and the smooth
ER (prominent location for enzyme systems involved in Phase I), but it can also occur in the mitochondria, plasma membrane and nuclear envelope.
12.2.1.1.3 Excretion
Drugs are removed from the body through excretion in their original form or as metabolites. Organs
other than the lungs, such as the kidneys and liver, exhibit more effective elimination of polar compounds compared to those with high lipid solubility. Consequently, lipid- soluble drugs undergo
metabolism to become more polar compounds for elimination. The kidney is crucial in regarding the
removal of drugs and their respective metabolites. Three processes are involved in renal excretion:
(i) glomerular ltration, (ii) active tubular secretion, and (iii) passive tubular reabsorption.
Regarding the biliary and fecal excretion, there are transporters located in the hepatocytes’ canalicular membrane, facilitating the active secretion of drugs and metabolites into bile. Ultimately,
drugs and its metabolites which reside in bile are discharged into the GI tract during digestion.
Given that there are secretory transporters expressed on the enterocyte’s apical membrane, they may
be involved in directing the drug’s secretion and their metabolites into the intestinal lumen from the
systemic circulation. Subsequently, reabsorption can occur in the intestine, particularly taking into
consideration the conjugated metabolites such as glucuronides, which may necessitate hydrolysis by
enzymes via intestinal ora [8]. The different routes involved in the excretion are mentioned in
Figure 12.2.
12.2.2 faCtors affeCting the bioavailability of herbal CoMpounds
Despite the therapeutic and phytochemical signicance of herbal medicine in improving human
health, its wider application is hindered by the issue of low bioavailability. A compounds
FIGURE 12.2 A diagram of the human body shows the various routes involved in drug excretion from the
body. They include renal clearance, biliary excretion, pulmonary excretion, fecal excretion, breast milk excretion, sweat excretion, and skin excretion.
262 Herbal Pharmacopeia
characteristics are crucial for improving the rate and extent of its absorption, regardless of the route
of administration. Challenges arise when poorly lipid- soluble compounds face restricted permeability across membranes [10]. Due to solubility issues, many herbal products exhibit limited therapeutic efcacy leading to suboptimal bioavailability regardless of their remarkable potential [3].
The effectiveness of any herbal extract depends upon achieving adequate levels of its therapeutically active compound at the desired site [11]. Unfortunately, most bioactive substances designed
for oral intake are predominantly hydrophobic, with compromised water solubility and inadequate
bioavailability. Additionally, poor solubility contributes to reduced absorption in the GI tract, thus
limiting therapeutic effectiveness [12].
It is not possible to accurately predict the bioavailability of a compound; however, Lipinski’s
‘rule of ve’ analysis offers a valuable insight. According to this rule, a compound’s bioavailability
will be better when it possesses no more than ve hydrogen bond donors, ten hydrogen bond acceptors, and a molecular mass not exceeding 500 Da, log p less than or equal to 5, and a maximum of
10 rotatable bonds [13].
12.2.2.1 Absorption within the GI Lumen
Absorption involves the transferring a drug from the administration site into the general circulation.
In the scenario of drugs that are orally administered, the absorption of molecules from the GI tract
relies on the dissolution and permeation across membranes.
12.2.2.1.1 The Solubility of the Herbal Products
A drug’s dissolution is inuenced by several factors which include the compound’s log p value, particle size, pKa, pH levels of gastrointestinal and intestinal uids, and, last but not least, the surface
area. For instance, ellagic acid (EA) [10] resveratrol [8], and curcumin [1] exhibit poor bioavailability as a result of limited solubility in aqueous media [14].
12.2.2.1.2 Absorption via Passive Diffusion
There are various physicochemical factors which are important for the absorption of phytochemicals
via passive diffusion. The unionized molecules tend to transverse the GI lipid barriers; however, this
is no big deal for basic compounds to pass through the intestine. Absorption is also inuenced by
parameters such as the length of the gastrointestinal tract, motility, surface area, and blood ow. For
instance, the log p value serves as a major indicator for diffusion process across biological membrane and their potential partition within lipid membranes [15].
12.2.2.1.3 Inux or Efux via Active Transport
Certain phytomolecules with signicant molecular structure are unable to undergo passive diffusion
for absorption and instead utilize carriers through an active transport mechanism. The plasma membrane has transport proteins that function as pumps, channels, or carriers. For rapid ion permeation
along the electrochemical gradient, channels act as specic pathways, and they need adenosine triphosphate (ATP). Along with that their protein structure consists of an ATP- binding cassette (ABC)
that has a conserved consensus sequence facilitating ATP binding and hydrolysis. Additionally, solute carriers help during the molecule’s transmembrane movement without ATP hydrolysis. In the
case of transporting a single type of molecule, it is classied as a uniporter (e.g. glucose transporter
2 acts as uniporters in the apical (luminal) cell domain), whereas symporters or antiporters move two
molecules simultaneously in the same or an opposite direction [16].
12.2.2.2 Metabolism
The process of metabolism in living organisms involves a series of enzymatic pathways that are supposed to modify the chemical structure of foreign compounds. This process focuses on detoxifying
phytochemicals, converting them into more hydrophilic from lipophilic compounds. Metabolism
may take place either before (in the gastrointestinal tract) or after absorption (within the hepatic
microsomal system).
Enhanced Bioavailability of Herbal Extracts using Nanocarriers 263
12.2.2.2.1 Metabolism Prior to Absorption
The metabolism occurs prior to absorption in the GI tract and is crucial for the compound’s bioavailabilty. The process involves digestive enzymes (such as glycosidase and protease) or gut microora
at the colonic level. For instance, avonoids undergo hydrolysis in the small intestine via glycosidase [17]. Chlorogenic acid (CA) cannot be released by esterase in humans; instead, it is metabolized by the microora of colon for absorption [18].
12.2.2.2.2 Metabolism Post-Absorption
After entering the bloodstream, a drug undergoes rst- pass metabolism in the hepatic microsomal system, generating metabolites with increased polarity that are more readily excreted in bile or urine. A
common oxidation mechanism is mediated by cytochromeP450 (CYP450)-dependent mixed function
oxidase system. This system introduces an atom of oxygen into a non- activated hydrocarbon, leading
to the incorporation of hydroxyl groups or N- , O- , and S- dealkylation of substrates [19].
12.2.2.3 Mechanisms of Action for Nanocarriers
Nanotechnology has signicantly emerged across different scientic elds in the recent decades.
It involves the manipulation of minute particles at a nanoscale. At nanoscales, atoms and molecules exhibit distinctive behaviors, offering a wide array of intriguing applications. To overcome
the constraints of conventional formulations, drug delivery scientists have embraced this paradigm
shift into pharmaceutical nanocarriers. They are submicron- sized drug carriers (greater than 200 nm
in diameter) either with or without biodegradable properties. The broad category of nanocarriers
includes nanospheres, nanocapsules, nanoparticles, nanoemulsions, and nano- sized vesicular carriers such as niosomes and liposomes [20].
The pharmacological activity of drugs is dependent not only on their therapeutic efcacy but also
on their bioavailability. Most of the phytopharmaceuticals exhibit limited water solubility, leading to
reduced permeability across membranes and, consequently, diminished oral bioavailability. The promotion of innovative technologies is creating a vast platform for developing novel delivery systems
for herbal medicine to enhance both therapeutic efcacy and the bioavailability of compounds with
low aqueous solubility [21]. Biomedical applications of nanocarriers are mentioned in Figure 12.3.
Biocompatible
Enhances
Bioavailability
ADVANTAGES OF
NANOCARRIERS
Improves
Stability
Minimizes
Toxicity
FIGURE 12.3 Biomedical applications of using nanocarriers.
Specific
Delivery
Prevents
Presystemic
Metabolism
Site
Dose
Reduction