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372
14.5.2 Ex Vivo Evaluation ofInhalation Devices
The ow rates and inhalation proling of the IDD devices can be assessed through ex
vivo evaluation techniques. To examine the dosage effectiveness of the uticasone
propionate Diskus and budesonide Turbuhaler inhalers, Burnell etal. (2001), ana-
lyzed and compared the inhalation proles created with patients having severe
obstructive pulmonary disease. They used the term ex vivo to characterize data
produced by combining in vivo parameters with in vitro analytical techniques while
analyzing the performance of the two inhalers. To evaluate the ex vivo efcacy of the
250mg Diskus inhaler and the 200mg dose Turbuhaler inhaler, they recorded the
ow rates and inhalation proles using an inhalation prole recorder (IPR). Then,
they used this data in the electronic lung device (ELD), an inhalation simulator. To
validate and feed the data into the ELD, they analyzed these inhalers’ pressure drop
and ow parameters and compared them with regular batches. A computer-controlled
piston in the ELD replicates the IPR’s subject prole. After each inhalation, the
inhaler was separated from the ELD, and all surfaces that have come into contact
with the dosage were cleaned with an appropriate solvent. High- performance liquid
chromatography was then used to analyze the liquids from various parts and stages
of the Andersen cascade impactor. The TED and FPF of the medication were esti-
mated using approved and validated techniques (Burnell etal. 2001).
The ex vivo evaluation of IDDs nds the use of precision-cut lung slices (PCLS)
and isolated perfused lungs (IPLS) to study the kinetics of the drugs, toxicity assess-
ment, and therapeutic effect (Gagnadoux et al. 2008). From post-mortem, lung
slices arecollected in the size range of 100–300 μm. The slicesare further intro-
duced in the culture media to maintain the anatomical and functional physiology of
Table 14.4 (continued)
Models (Ehrmann
etal. 2020; Sakagami
2020; Cidem etal.
2020; Secher etal.
2020)
Advantages
Disadvantages
Isolated perfused
lungs (IPLS)
• It keeps lung tissue
functioning
• A multicellular response to
drug stimuli is made possible by
an intact lung
• Inhalable delivery devices are
suitable for direct administration
of inhalation medication therapy
• Possibility of carefully
regulating pharmacological
stimulus
• The experimental design is
more controllable than the use of
animals in studies
• Limitation with lung perfusion
• More time-consuming process
• Minimal disease models
• They are often sourced from rat
or rabbit origin, which differs from
humans based on tracheobronchial
anatomy and structural
composition
A. Kumar et al.
373
the slices. It helps to realize the functional properties of the lung and how it reacts
to drug molecules (heterocellular and heterogenicity) of the lungs. PCLS are created
from rodents, sheep, and human lung tissue. The isolated perfused lung model
(IPLS) is another exvivo preclinical model to assess the safety and kinetics of the
lungs. The whole lungs are isolated from the rodent or rabbit and transferred into an
articial thoracic chamber simply called thorax in physiologically relevant environ-
mental conditions. The advantage and disadvantage of each type are described in
Table14.4 (Ehrmann etal. 2020; Sakagami 2020; Cidem etal. 2020). The advances
in preclinical exvivo models include organs on chips and 3D organoids.
14.5.3 In Vivo Evaluation ofInhalation Devices
Various studies reported the use of whole animals for testing inhalational biophar-
maceuticals for their pharmacokinetics and pharmacodynamics (PKPD) studies.
The use of animals from small rodents (rats, mice, Guinea pigs) to larger animals
(rabbits, dogs, and monkeys) has been revealed (Secher etal. 2020; Tandel et al.
2018). Genetically modied animal models are also gaining importance in success-
fully studying the drug resistance and therapeutic proling of the drugs. Gamma
scintigraphy approaches have evaluated and compared drug delivery from various
inhalers depending on the characteristic features of the inhaled drugs (Chrystyn
2007). Borgstrom etal.’s study demonstrates lung deposition of 27% and 28% ter-
butaline and budesonide, respectively, induced by the Turbohaler, which is increased
in individuals with no airway obstruction. These studies establish the importance of
ex vivo and in vitro laboratory techniques in forecasting the consequences that
would occur in vivo in humans (Borgström etal. 1994).
14.6 Conclusion andFuture Perspective
IDD has shown prominent therapeutic results in preventing and mitigating pulmo-
nary diseases over the past years. The prominent IDDs are nebulizers, DPI, and
MDI, which provide the disease’s applicability. These are well known for delivering
drugs and even complex vaccines, insulin, genes, and protein or peptides for pulmo-
nary diseases. However, biological and device-oriented challenges restrict or dimin-
ish the therapeutic potential of IDD.Technological advancements have driven the
evolution of newly designed devices to address the challenges associated with con-
ventional IDD devices. The advanced technology also includes micro-sized and
nano-sized advancements. The evaluation of TED, FPF, aerodynamic particle size,
etc. is crucial to reect the performance of the IDD devices. More physiologically
relevant lung models have been designed and considered for lung deposition stud-
ies, toxicity assessment, and biological performance. The future direction includes
more efcient IDD to overcome the complications for geriatric and pediatric
patients.
14 A Technological Update onInhalation Drug Delivery Devices
374
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15
Herbal Formulations: Development,
Challenges, Testing, Stability,
andRegulatory Guidelines
ShivamRamdasPawar, ParthPatel, andKeertiJain
Abstract
Herbal formulations consist of herbal medications in the form of plant extracts,
enhanced fractions, or biomarker components. Herbal preparations offer distinct
benets due to their enhanced absorption and lower toxicity. There is a scarcity
of literature that specically discuss the typical difculties encountered in prepa-
ration ofherbal formulations, such as the process of choosing the appropriate
kind or class of formulations for an extract or a phytochemical. This chapter
focuses on herbal formulation development from a selection of suitable formula-
tions to getting the regulatory approval of diverse herbal nanoformulations. This
chapter intends to present the latest progress in many types of herbal nanomedi-
cines, such as polymeric herbal nanoparticles, solid lipid nanoparticles, micelles,
liposomes, dendrimers, nanoemulsions, and nanosuspension. Further, the testing
methodologies to maintain the quality of herbal medicine and associated chal-
lenges to meet the desired quality are discussed in brief. Additionally, regulatory
considerations required to meet the quality and safety standards are also sum-
marized. A combination of herbal medicine with nanotechnology can be an
essential instrument to get better therapeutic performance of herbal medicine.
Despite the problems associated with the quality, uniformity, and stability of
traditional herbal medicine, there is great potential for nanotechnology-based
herbal formulations to treat a range of diseases. Overall, herbal nanomedicines
havebeen showing promisingtherapeutic potential making them a promising
alternative ofsynthetic pharmaceutical and traditional herbal formulations.
S. R. Pawar · P. Patel · K. Jain (*)
Drug Delivery and Nanomedicine Research Laboratory, Department of Pharmaceutics,
National Institute of Pharmaceutical Education and Research (NIPER), Raebareli,
Lucknow, Uttar Pradesh, India
e-mail: keertijain.02@niperraebareli.edu.in
380
Keywords
Herbal medicine · Nanotechnology · Ayurveda · Regulatory guidelines · Drug
delivery
Abbreviations
GCMS Gas chromatography-mass spectroscopy
HPLC High-performance liquid chromatography
HPTLC High-performance thin-layer chromatography
ICPMS Inductively coupled plasma-mass spectroscopy
LCMS Liquid chromatography-mass spectroscopy
SFC Supercritical uid chromatography
WHO World Health Organization
15.1 Introduction
Plants have provided food and everyday essentials for humans since immemorial
times. They are used in a variety of ways, from papermaking to building making,
from spices or fragrances to preventative and therapeutic measures for a range of
medical problems (Haslam etal. 1989). The World Health Organization (WHO) has
dened herbal medicines as “herbs, herbal materials, herbal preparations and n-
ished herbal products that contain as active components elements of plants, or other
plant materials, or combinations” (Sammons et al. 2016). Many civilizations,
including India’s Ayurvedic medicine, Chinese medicine, Japan’s Kampo medicine,
Australia’s Aboriginal medicine, and New Zealand’s TeRongoa, have their distinc-
tive ways of using traditional herbal medicines as a remedy for treatment of many
diseases (Barnes etal. 2016).
The years of expertise in designing and developing drugs from medicinal plants
have taught us to learn from nature and our predecessors. When Tu Youyou was
granted the Nobel Prize in Physiology and Medicine in 2015 for discovering the
antimalarial compound artemisinin from Artemisia annua L. (Qinghao), it became
evident how valuable traditional herbal remedies could turn out to be (Tu 2011). The
evolution of herbal medicine has also been closely linked to science, economics,
and culture throughout history. There are now many different and meaningful ideas
about the current reliance and preference for traditional medicinal products, thanks
to the development of modern medicine and industrialization (Leonti and Verpoorte
2017; Sharma etal. 2018). Hence, herbal medicinal products received a signicant
share in the international pharmaceutical market, and the demand for the same is
gradually increasing as people are aware of the benets of herbal medicines. The
size of the global herbal medicine market was projected at USD 151.91 billion in
S. R. Pawar et al.
381
2021 and is expected to increase at a noteworthy compound annual growth rate
(CAGR) of 11.16% from USD 168.86 billion in 2022 to USD 437.59 billion by
2030 (Global Herbal Medicine Market 2024).
Early research on nanotechnologies in medicine mostly focused on applying
nanoscale technology to improve the effects of well-known medications. Then, the
area grew rapidly in the preparation of multifunctional and customized nanomedi-
cine, which was made possible due to the versatile properties and adaptability of
nanomaterials. Multifunctional nanomedicine refers to the integration of various
capabilities into a single nanoformulation, such as biomedical imaging, biosensing,
diagnostics, and treatment (das Neves etal. 2020; Ahmad etal. 2022). Customization
by applying patient- and disease-specic features can enhance the therapeutic ben-
ets of nanomedicines in the treatment of different ailments. A deeper understand-
ing of the critical features that affect the interplay of nanomaterial with mucus and
tissues is highly signicant for the logical design of more effective nanomedicines
and to anticipate any undesirable consequences of acute or chronic exposure to
nanoparticulate matter. To logically develop more effective nanomedicines and to
foresee any unfavorable effects of acute or chronic exposure to nanoparticulate mat-
ter, a greater understanding of the fundamental aspects that govern the interaction of
nanomaterial with mucus and tissues is very crucial. The capacity of nanoparticles
to enormously enhance the therapeutic value of medication made the best bet for
any formulation scientist (Thorley and Tetley 2013; Saini etal. 2022).
The last 10years have witnessed the use of many herbal drugs in nanoformula-
tions; however, there is still a dearth of knowledge about the best way to formulate
nanoparticles for a given class of phytoconstituents or extracts, how to develop
herbal nanomedicines systematically, how to characterize formulations, etc. Thus,
in the current chapter, we have summarized the development, characterization
methods, and regulatory requirements for herbal formulation development. Many
ofthe currently availablemarketed nanoformulationshave provided potential thera-
peutic benets in clinical application over traditional medications. Hence, the co-
application of nanotechnology and traditional herbal medicine makes sense and
may provide suitable results in future. This may broaden the scope of nanotechnol-
ogy with signicant improvement in the therapeutic potential of herbal medicine.
Thus, in the following section, we have discussed about some nanoformulations of
herbal of medicines.
15.2 Nanoformulations ofHerbal Medicines
A wide range of innovative herbal nanoformulations, such as polymeric nanoparticles,
nanocapsules, liposomes, phytosomes, nanoemulsions, microspheres, transferosomes,
and ethosomes, have been documented by the scientic community. These novel for-
mulations have signicant advantages compared to traditional formulations of plant
actives and extracts. These advantages include increased solubility, improved bioavail-
ability, protection against toxicity, enhanced pharmacological activity, improved
15 Herbal Formulations: Development, Challenges, Testing, Stability, and…
382
stability, better distribution in tissue macrophages, sustained delivery, and protection
against chemical degradation of herbal medicine. The different types of herbal formu-
lations are discussed in the following subsections.
15.2.1 Herbal Nanoemulsion
It is a thermodynamically stable mixture of oil and aqueous phase, in which one
phase is homogenously dispersed in another phase and it was stabilized by using
proper surfactant. In pharmacy, o/w nanoemulsion is widely used because lipophilic
core of emulsion can efciently deliver the lipophilic drug molecule to the desired
site (Suthar etal. 2023; Juneja etal. 2022). Currently, nanoemulsion is emerging as
an unprecedented nanocarrier for the delivery of herbal medicine and herbal oils.
Instinctually, herbal medicine is comparatively less potent than synthetic active
pharmaceutical molecules, which require higher doses to obtain the same therapeu-
tic effect (Pardhi etal. 2022). Further, some volatile herbal oils have therapeutic
value, but it became difcult to directly administer the oil due to poor patient com-
pliance. Here, nanoemulsion can be used to solve these problems due to its oil-
containing lipophilic core showing high drug loading efciency and ability to easily
accommodate the herbal volatile oil. For instance, Saranya and colleagues formed a
eucalyptus oil nanoemulsion and evaluated its antibacterial efcacy against
Staphylococcus aureus (Suthar etal. 2022). The ndings of the microbial study
demonstrated that all microbiological viability had been lost within 15min of treat-
ment. In addition, the ability to heal wounds was evaluated on Wistar rats, which
showed a higher rate of wound recovery compared to the neomycin-treated control
group, due to signicant enhancement in the bioavailability of eucalyptus oil via
nanoemulsion (Sugumar etal. 2014). Additionally, Nagi etal. (2017) assessed the
pharmacokinetic properties of a silymarin-loaded nanoemulsion formulated using a
high-pressure homogenization process. The avonoid silymarin is derived from the
seeds of the milk thistle, known as Silybum marianum. Although it has substantial
hepatoprotective capabilities, its low bioavailability limits its clinical applications.
According to the pharmacokinetic study of silymarin-loaded nanoemulsion, the
apparent permeability constant of silymarin rises signicantly, which indicates that
the silymarin in the nanoemulsion formulation has a higher oral bioavailability
(Nagi etal. 2017). These researches showed that the nanoemulsion can signicantly
improve the bioavailability of herbal oils and herbal medicines.
15.2.2 Herbal Nanoparticles
Nanoparticles include the nanosized particles of polymers, lipids, or a combination
of both. Each of them has its advantages and disadvantages. For instance, polymers
provide exibility to formulation scientists to tailor-made drug release, easy pro-
cessing, and thermostability (Patel etal. 2023; Jain 2018), whereas lipids provide
better biocompatibility, biodegradability, and permeation prole than polymers.
S. R. Pawar et al.