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x Contributors
SHIVALI KHANDELWAL • Division of Biological Standardization, ICAR-Indian Veterinary
Research Institute, Bareilly, UP, India
S
ANWEER KHATOON
Department of Veterinary Parasitology, CVAS, RAJUVAS, Navania,
•
Rajasthan, India
S. S
IMRAN KOUR
Department of Veterinary Pharmacology and Toxicology, College of
•
Veterinary Science and Animal Husbandry, DUVASU, Mathura, UP, India
A
NIL KUMAR
Department of Zoology, Baba Raghav Das Post Graduate College, Deoria,
•
UP, India
M
ANJULENDRA KUMAR
Department of Zoology, Babasaheb Bhimrao Ambedkar University,
•
Lucknow, UP, India
N
AVE EN KUMAR
P
RADEEP KUMAR
Apollo College of Veterinary Medicine, Jaipur, Rajasthan, India
•
Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research
•
Institute, Izatnagar, Uttar Pradesh, India
S
UDHIR KUMAR
Department of Zoology, Baba Raghav Das Post Graduate College, Deoria,
•
UP, India
V
IJAY KUMAR
Department of Animal Genetics and Breeding, DUVASU, Mathura, Uttar
•
Pradesh, India
R
EDDI LOKESWARI
Department of Veterinary Microbiology, ICAR-Indian Veterinary
•
Research Institute (ICAR-IVRI), Izatnagar, Bareilly, UP, India
M
ILINDMITRA K. LONARE
Department of Veterinary Pharmacology and Toxicology, COVS,
•
GADVASU, Rampura Phul, Punjab, India
B
AVADHARANI MANI
ICAR-Indian Veterinary Research Institute (ICAR-IVRI), Hebbal,
•
Bengaluru, Karnataka, India
M
ANISHA
OUNIL MANKAD
M
Division of Animal Physiology, ICAR-NDRI, Karnal, Haryana, India
•
Department of Nano Biotechnology, Anand Agricultural University,
•
Anand, Gujarat, India
M
AMTA MEENA
Division of Pharmacology and Toxicology, ICAR-Indian Veterinary
•
Research Institute, Bareilly, Uttar Pradesh, India
D
UMALA NAVEEN
Department of Veterinary Microbiology, ICAR-Indian Veterinary
•
Research Institute (ICAR-IVRI), Izatnagar, Bareilly, U.P., India
A
NURADHA NEMA
Assistant Professor, Department of Veterinary Surgery & Radiology,
•
CVSc & AH, Rewa, NDVSU, MP, India
P
RITAM PAL
Division of Animal Genetics and Breeding, ICAR-NDRI, Karnal, Haryana,
•
India
S
ANTANU PAL
Department of Veterinary Microbiology, ICAR-Indian Veterinary Research
•
Institute (ICAR-IVRI), Izatnagar, Bareilly, U.P., India
D
ISHA PANT
Department of Veterinary Pharmacology and Toxicology, College of Veterinary
•
and Animal Sciences, GB Pant University of Agriculture and Technology, Pantnagar,
Uttarakhand, India
K
AMAL PANT
A
BHISHEK PATHAK
Veterinarian, Government of Uttarakhand, Didihaat, Uttarakhand, India
•
Department of Veterinary Pharmacology and Toxicology, Apollo College
•
of Veterinary Medicine, Jaipur, Rajasthan, India
P
OOJA
P
RADEEP KUMAR RAM
S
IVARAMAN RAMANARAYANAN
Department of Animal Genetics and Breeding, DUVASU, Mathura, U.P., India
•
APRI, DRPCAU, Pusa, Samastipur, Bihar, India
•
Department of Veterinary Pharmacology and Toxicology,
•
COVS, Kishanganj, BASU, Patna, Bihar, India
M
ATUKUMALLI USHA RANI
Veterinary Pharmacology & Toxicology, PV Narsimha Rao
•
Telangana Veterinary University, Hyderabad, Telangana, India
Contributors xi
ROSHNI • Livestock Product Technology, NTR College of Veterinary Science, Gannavaram,
Andhra Pradesh, India
J
ADAV SARMA
Department of Veterinary Pharmacology and Toxicology, College of Veterinary
•
Science, Assam Agricultural University, Khanapara, Guwahati, India
L
IPIKA SARMA
Department of Veterinary Physiology, College of Veterinary Science, Assam
•
Agricultural University, Khanapara, Guwahati, Assam, India
S
ONAL SAXENA
Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research
•
Institute, Izatnagar, Uttar Pradesh, India
M
ANJINDER SHARMA
Department of Veterinary Physiology and Biochemistry, COVS, Guru
•
Angad Dev Veterinary and Animal Sciences University, Ludhiana, Punjab, India
M
EEMANSHA SHARMA
Division of Pharmacology and Toxicology, ICAR-Indian Veterinary
•
Research Institute, Bareilly, Uttar Pradesh, India
P
ABBATHI SHIVAKUMAR
Veterinary Pharmacology & Toxicology, PV Narsimha Rao
•
Telangana Veterinary University, Hyderabad, Telangana, India
S
AMEER SHRIVASTAVA
Division of Veterinary Biotechnology, ICAR-Indian Veterinary
•
Research Institute, Izatnagar, Uttar Pradesh, India
S
HVETA SINGH
Department of Veterinary Medicine, College of Veterinary Science, Assam
•
Agricultural University, Khanapara, Guwahati, Assam, India
T
HAKUR UTTAM SINGH
Division of Pharmacology and Toxicology, ICAR-Indian Veterinary
•
Research Institute, Bareilly, Uttar Pradesh, India
N
ABANEETA SMARAKI
CADRAD, ICAR-Indian Veterinary Research Institute, Izatnagar,
•
Bareilly, Uttar Pradesh, India
T
EJPAL
Department of Veterinary Microbiology, ICAR-Indian Veterinary Research
•
Institute (ICAR-IVRI), Izatnagar, Bareilly, U.P., India
P
ANKAJ KUMAR UMAR
Department of Pharmacology and Toxicology, Nanaji Deshmukh
•
Veterinary Science University, Jabalpur, MP, India
V
ISHWA RANJAN UPADHYAY
Division of Animal Physiology and Reproduction, ICAR-
•
NRCC, Bikaner, Rajasthan, India
S
ANJAY VAGHELA
College of Veterinary Science and Animal Husbandry, Kamdhenu
•
University, Anand, Gujarat, India
A
YUSHI VAIDHYA
Division of Pharmacology and Toxicology, ICAR-Indian Veterinary
•
Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
R
AJESH SUDHAKAR WAKCHAURE
RATIBHA YADAV
P
V
ISHAL YADAV
Mata Jijabai Govt PG Girls College, Indore, Madhya Pradesh, India
•
Animal Reproduction, Gynaecology and Obstetrics, ICAR-National Dairy
•
Veterinary Polytechnic, Jagdalpur, Chhattisgarh, India
•
Research Institute, Karnal, Haryana, India
Chapter 1
Introduction to Drug Deliver y System: Past, Present,
and Future Perspectives
Santanu Pal, Dumala Naveen, Tejpal, and Swarup Debroy
Abstract
Recent advancements in molecular pharmacology and a deepened understanding of disease mechanisms
have emphasized the need to precisely target specific cells responsible for disease onset and progression to
prevent side effects and minimize systemic exposure. Drug delivery (DD) involves the strategies, formulations, technologies, and procedures employed to transport a pharmaceutical substance within the body of
both humans and animals to produce the intended therapeutic outcome. The most frequently used delivery
methods include topical (applied to the skin), transmucosal (such as nasal, buccal, sublingual, vaginal,
ocular, and rectal), and inhalation routes. Traditional dosage forms release the drug rapidly, which can lead
to variations in blood drug levels depending on the form of dosage. Current drug delivery systems (DDS)
leverage cutting-edge technology to expedite the delivery of drugs systemically to specific target sites,
thereby maximizing therapeutic efficacy while minimizing unintended accumulation in the body. Consequently, they play a pivotal role in disease management and treatment. Modern DDS present distinct
advantages over conventional delivery systems, owing to their superior performance, automation, precision,
and effectiveness. Utilizing nanomaterials or small-scale devices with multifunctional components, these
systems are characterized by biocompatibility, biodegradability, and high viscoelasticity, resulting in prolonged circulating half-lives. This chapter offers a comprehensive overview of drug delivery systems’
historical progression and technological evolution. It also delves into recent developments in DDS, their
therapeutic applications, challenges in their use, and potential future improvements for enhanced performance and utilization.
Key words Molecular pharmacology, Drug delivery, Therapeutic outcome, Nanomaterials
1 Introduction
Drug delivery involves the process or strategy of administering
pharmaceutical substances to elicit therapeutic effects in humans
or animals. It encompasses a variety of techniques and technologies
aimed at safely and effectively transporting drugs to their intended
site of action within the body. This can include methods such as oral
ingestion, injections, patches, or controlled-release formulations.
The primary goal of drug delivery is to optimize the efficacy, safety,
1
2 Santanu Pal et al.
Table 1
Progression of controlled drug delivery systems from the year 1950 onward [
Sl.
Generation of drug
No.
delivery systems
1. First generation Conventional dosage Capsule, tablet, emulsion,
2. Second generation Modified action systems Enteric coating, repeat/prolong
3. Third generation Controlled delivery systems Osmotically, swelling and diffusion
4. Fourth generation Targeted delivery systems Targeted, modulated, self-regulated
Properties Dosage forms
suspension
action
controlled systems
delivery systems
1]
5. Fifth generation Long-term delivery systems
(6–12 months)
and patient compliance of pharmaceutical treatments. Utilizing an
advanced drug delivery system (ADDS) can rejuvenate an existing
drug molecule, breathing new life into its therapeutic potential
1
[
he slow but steady enhancement in effectively treating severe
]. T
illnesses
approach
tuents
istics
underscores a growing
delivering
of
to
the
medication
medications
deter
and are accountable for the alterations it induces in the body
when ingested. The progress in pharmacology and pharmacokinetics has underscored the significance of drug release in determining
therapeutic efficacy, leading to the emergence of the controlled
release concept. The approval of controlled-release formulations
of drugs initially occurred in the 1950s, sparking notable
because of their considerable advantages over traditional medications (Table
1). These formulations release drugs at a predeter-
mined rate and duration. Moreover, controlled drug delivery
systems remain unaffected by physiological conditions, allowing
them to sustain drug release for extended periods
days to years (Fig.
1) [2]. Traditional approaches are constrained by
factors such as the inadequate solubility of drugs, lack of specificity,
and undesirable release characteristics.
Novel drug delivery systems (NDDS) offer solutions to common issues associated with traditional dosage forms, including high
dosage with low availability, instability, the first-pass effect, fluctuating plasma drug levels, and rapid release of medicinal products.
Through improved performance, protection, patient compliance,
and extended product shelf life, NDDS aims to alleviate these
problems. Nanoparticles find applications across various fields and
are produced through diverse processes. Currently, 95% of experimental drugs exhibit inadequate pharmacokinetic and
Nanorobots, g
biologicals
necessity
to
its
mine
herapy,
ene t
for a multidisciplinar
specific
tissues.
physicochemical
ranging from
consti-
The
character
interest
y
-
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 3
Fig. 1 The efficacy of drugs remains intact if their concentration in the blood
exceeds the minimum effective level, irrespective of variations in pharmacokinetic profiles
biopharmaceutical properties. As a result, it’s imperative to establish medication distribution schemes that specifically target affected
sites without causing harm to healthy tissues. This approach aims to
disperse therapeutic drug molecules ef fectively, reducing required
dosage levels and enhancing therapeutic effectiveness and safety
profiles in novel therapies [
technology trace
back to 1952 when the Spansule® sustained-
3
]. The origins of modern drug delivery
release capsule technology was introduced. This innovation allows
for the gradual release of a drug over 12 hours following oral
administration, achieved by an initial immediate dose followed by
a gradual release of the remaining medication. Before the 1980s,
oral and transdermal formulations were the primary methods for
delivering small-molecule drugs, providing the
ing up
to 24 hours. However, the landscape changed with the
rapeutic effects last-
introduction of Lupron Depot® in 1989, marking the emergence
of long-acting injectable and implantable formulations. These
innovations extended drug delivery durations from days to months,
and in some cases, even years. Notably, these advancements facilitated the long-term delivery of peptide and protein drugs, albeit
restricted to parenteral administration [
PEGylated protein,
Adagen®, in 1990 heralded the onset of the
4]. The advent of the first
PEGylation era. This led to the development of Doxil® (doxorubicin in PEGylated liposome) in 1995, Movantik® (PEGylated
naloxone—naloxegol) in 2014, and Onpattro® (Patisiran—
siRNA in PEGylated lipid nanoparticle) in 2018 [
4]. Both Mylo-
targ™ (an antibody-drug conjugate containing gemtuzumab
4 Santanu Pal et al.
ozogamicin) and Rapamune® (a nanocrystal formulation of sirolimus) were introduced in the year 2000 [
2 The Initial Phase of Drug Delivery Systems
During ancient times, reliance on medicinal plants was common.
While these plants offered benefits, they lacked uniformity, consistency, and precision in drug delivery. Before the adoption of controlled drug delivery methods, pharmaceuticals were typically
manufactured and preserved in pill or capsule for ms. Upon ingestion, these formulations dissolved upon contact with gastrointestinal fluids passed through the intestinal wall and were subsequently
absorbed into the bloodstream via blood capillaries. However,
during this period, there was no capability to regulate the kinetics
of drug release. Several systems incorporating polymers were available, with waxes frequently included alongside drugs to prolong
their mechanisms of action or enhance specific features such as
targeting particular sites. The conventional drug delivery system
consists of cream, ointment, paste, tablets, capsules, pills, solution,
mixture, tinctures, emulsion, suspension, granules, powders,
snuffs, inhalations, aerosols, liniments, lotions, paints, and suppositories, etc. (Fig.
Creams are semi-solid dosage forms known for their soft texture and ease of spreading. They typically consist of over 20% water
and volatile substances, with less than 50% hydrocarbons like waxes
or polyols serving as the base for the drugs. Cream bases are
emulsions categorized into two types: oil-in-water (O/W) creams
2).
4].
Fig. 2 Schematic diagram outlining the available conventional dosage forms
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 5
and water-in-oil (W/O) creams. Oil-in-water (O/W) creams are
composed of tiny oil globules dispersed within a continuous aqueous phase, stabilized by surfactants.
Ointments are semi-solid formulations primarily composed of
oil-based substances, with the base typically being anhydrous and
not mixing with skin secretions. They contain less than 20% water
and volatile substances, with over 50% hydrocarbons (such as waxes
or polyols) serving as the vehicle. This composition results in ointments having a prolonged retention time but lower spreadability.
Paste is essentially an ointment with a higher concentration of
insoluble solids incorporated. The addition of a significant amount
of particulate matter leads to increased stiffness of the formulation.
Compared to ointments, pastes exhibit reduced permeability, less
risk of maceration, and lower heat. Upon application to the skin,
pastes form an effective protective barrier.
Tablets are a solid form of medication that is produced through
compression and wet/dry granulation, resulting in various shapes
such as round, oval, or square. To facilitate effective tableting,
excipients like binders, glidants, and lubricants are commonly
included. Additionally, disintegrants are added to promote the
rapid breakdown of tablets within the digestive system.
Capsules are another form of a solid dosage in which the drug
ingredients are enclosed within a soluble shell. Capsules serve to
conceal the unpleasant taste of their contents and typically exhibit
limited interaction between the drug and excipients. There are two
main types of capsules: Hard-shelled capsules, primarily utilized for
encapsulating dry, powdered components, and soft-shelled capsules, mainly employed for hydrophobic drugs and oily active substances that are either suspended or dissolved in oil.
Pills are solid single-dose forms created by compressing active
pharmaceutical ingredients (API) together with adhesives and
other additives into rounded masses intended for oral
administration.
A s
uppository i
s a small, rounded, or cone-shaped semi-solid
medication form inserted into a bodily opening such as the rectum
or vagina. It dissolves or melts within the body to release the drug,
providing either local or systemic therapeutic effects. Suppositories
typically consist of natural fats like cocoa butter or synthetic compounds like polyethylene glycol (Carbowax), with glycerol serving
as a primary excipient. They are specifically designed for rectal
insertion and offer a rapid onset of action due to the highly vascularized nature of the rectum. Additionally, they bypass the hepatic
first-pass metabolism.
Oral solutions
are clear liquid formulations intended for oral
administration, consisting of one or more active ingredients dissolved in an appropriate solvent system. Oral emulsions are liquid
formulations designed for oral administration, featuring a biphasic
composition where the drug is contained within an oil-in-water
6 Santanu Pal et al.
emulsion, present in either single or dual phases. Oral suspensions
are liquid dosage forms intended for oral administration, consisting
of one or more active pharmaceutical ingredients (APIs) suspended
within a suitable solvent. Although they tend to settle over time,
they can be easily redispersed by shaking to achieve a uniform
suspension. This suspension remains stable enough to ensure accurate dosing. Syrup refers to a concentrated solution of sugar, typica
lly sucrose, in water, within which active pharmaceutical
ingredients (APIs) are
useful for masking the unpleasant taste of medications. An elixir is a
clear liquid intended for oral administration, primarily used for
delivering potent or nauseating drugs by incorporating pleasant
flavors. The formulation includes a significant proportion of ethanol or sucrose as the vehicle, along with antimicrobial preservatives
to
improve stability.
In 1951, Lipowski pioneered a patented oral sustained-release
formulation. He coated pills with enteric polymers (such as beads),
layering the drug and coating alternately. This method resulted in a
slow, consistent, and periodic release of the drug [
Jatzkewitz reported the first therapeutic nanoparticle by preparing
the initial polymer-drug conjugate [
a rapid development of site-specific drug delivery systems, with
continuous updates to strategies, encompassing advancements
such as liposomes (including immunoliposomes and magnetoliposomes), nanoparticles (including magnetic nanoparticles and polymeric nanoparticles), sophisticated polymers (such as dendrimers),
and viral vectors [
dissolved. Flavored syrups are particularly
2]. In 1955,
2]. Following 1970, there was
5].
3 Recent Drug Delivery Systems
In recent years, considerable advancements have been achieved in
the development of drug delivery systems utilizing organic, inorganic, and hybrid nanoparticles as carriers for targeted drug delivery, especially in chemotherapy (Fig.
delivery systems are designed with enhanced characteristics such
as reduced particle size, improved permeability, enhanced solubility, efficacy, precise targeting, stability, decreased toxicity, and prolonged release. A novel drug delivery system (NDDS) encompasses
methods, formulations, technologies, and systems designed to
effectively transport a pharmaceutical substance within the body,
ensuring its safe delivery to achieve the intended therapeutic outcomes [
and biochemical mechanisms. Physical mechanisms, known as controlled drug delivery systems, involve processes such as osmosis,
diffusion, erosion, dissolution, and electron transport. Biochemical
mechanisms consist of monoclonal antibodies, gene therapy, vector
systems, polymer-drug conjugates, and liposomes. Drug carriers
6]. Novel drug delivery systems encompass both physical
These modern drug
3).
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 7
Fig. 3 Various recent drug delivery systems designed for diverse therapeutic
objectives
encompass a variety of options including soluble polymers, microparticles constructed from insoluble or biodegradable natural and
synthetic polymers, microcapsules, cells, cell ghosts, lipoproteins,
liposomes, and micelles. These carriers can be designed to degrade
slowly, respond to stimuli such as pH or temperature changes, and
even be targeted by attaching specific antibodies against characteristic components of the desired area within the body.
4 Drug Delivery via Carriers
Carriers play a crucial role in achieving targeted drug delivery by
serving as essential molecules or systems necessary for effectively
transporting the loaded drug to specific sites within the body. These
engineered vectors are designed to retain the drug either through
encapsulation or by using spacer molecules, and subsequently
transport or deliver it to the vicinity of the target cell. Several
drug delivery systems rely on carriers, including microspheres and
microcapsules, nanoparticles, monoclonal antibodies, prodrugs,
resealed erythrocytes, artificial cells, neutrophils, and vesicular
carriers.
In recent
for drug delivery. Lipid vesicles have proven to be valuable tools in
times, vesicles have emerged as the preferred method
8 Santanu Pal et al.
Table 2
Variations among nanosomal vesicular carriers are outlined [
17]
Sl.
Nanosome Main component Uses Special properties
No.
1. Niosomes Cholesterol, charge-inducing
substances, nonionic
surfactants
2. Liposomes Phospholipids dispersed in
aqueous solution
3. Transferosomes Surfactants, a little alcohol, dye,
and phosphatidylcholine in
buffer solution
4. Ethosomes High concentration of alcohol,
phospholipid, water,
cholesterol, dye
immunology, membrane biology, diagnostic methods, and more
recently, genetic engineering. Vesicles are instrumental in modeling
biological membranes and facilitating the transport and targeted
delivery of active agents. Vesicular drug delivery systems include
phytosomes, aquasomes, liposomes, sphinosomes, transferosomes,
niosomes, ethosomes, and phytosomes (Table
Phytosomes represent a novel drug delivery system where the
hydrophilic bioactive components of herbs are encapsulated and
surrounded by phospholipids. This complex resembles a miniature
cell, leading to improved pharmacokinetic and pharmacodynamic
properties compared to traditional herbal extracts, ultimately
resulting in enhanced bioavailability. The binding of botanical
extracts with phospholipids enhances their absorption in the intestinal tract, thereby increasing their bioavailability.
Aquasomes represent
designed for transporting bioactive molecules, including peptides,
proteins, hormones, antigens, and genes, to specific targeted sites.
These spherical structures typically range from 60 to 300 nanometers in size. Unlike conventional nanoparticles, aquasomes are
three-layered self-assembled structures. They consist of a solid
nanocrystalline core surrounded by an oligomeric film, onto
which biochemically active molecules can be adsorbed with or
without modification. These structures form through
non-covalent and ionic bonds. The solid core provides structural
stability, while the carbohydrate coating prevents dehydration and
stabilizes the bioactive molecules. Aquasomes have demonstrated
efficacy in delivering substances such as insulin, hemoglobin, and
enzymes like serration peptidase.
Carrier of lipophilic and
amphiphilic drugs
Used in targeted oral,
topical, and pulmonary
DD
Penetrate deeper
epidermis layers, used
for transdermal delivery
Controlled transdermal
delivery
Stable, no need for
special storage or
preparation
Unstable, needs
special storage
and preparation
Ultra flexible and
deformable
vesicles
Soft and novel
vesicles
2).
a recent advancement in delivery systems