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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5362_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug Delivery System and Technologies 85
(a)
(b)
Fig. 3 a Schematic illustration for the physical or chemical stimuli-responsive drug delivery
systems. Reproduced with permission from targeting drug delivery. Reproduced with permission
from MDPI Ivyspring International [37] b Stimuli-responsive drug delivery systems trigger cancer
chemotherapy via active and/or passive [36]
in GSH levels between cancer and normal cells enable the design of redox responsive delivery systems. Furthermore, the reactive oxygen species (ROS) responsive
drug delivery system can also be designed to control the drug release in some disease
tissues due to the fact that the concentration of ROS in inflammatory tissues is 10–100
times higher than ROS concentration in healthy tissues [38]. Several enzymes, such as
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lipase, phospholipases, glycosidases, and proteases, are used to accomplish enzymeresponsive drug delivery using biocatalysis in inflammation or cancer tissues. Apart
from the above stimuli, temperature, light, magnetic, and glucose have also been
used to fabricate smart drug delivery. Besides, dual stimuli-responsive drug delivery
systems have also been reported, including pH and thermos responsive systems, light
and thermos responsive systems, pH and redox responsive systems, and so on.
3.3 Intravenous and Extravaneous Drug Delivery
3.3.1 Intravenous Drug Delivery
Intravenous drug delivery is the route that delivers drugs directly to veins via infusion/drips or injections, which is considered as the fastest drug delivery route, that
the drug can be delivered to the body through blood circulation [39]. Conventional
intravenous administration is usually employed for blood transfusion, fluid rehydration, electrolyte balancing, and delivering drugs or medications lastly. The drug
can be injected into the bloodstream directly using intravenous drug delivery, and
the drug will bypass the stomach and gastrointestinal (GI) tract. Intravenous drug
delivery has the advantages of achieving early onset of drug action for a drug that has
low oral bioavailability, and providing the convenience of medical emergencies for
patients or if the drug can cause the irritation of gastrointestinal tract. Furthermore,
the bioavailability of drugs generally arrives at 100% while the drug is employed
in intravenous drug delivery. The treatments delivered to the body using an intravenous drug delivery approach mainly include antibiotics, analgesics, vasodilators,
sedatives, anesthetics, hormones, chemotherapy drugs, parenteral nutrition, and so
on [40]. The modern intravenous infusion system usually consists of a liquid reservoir (bag or syringe), a tube, a flow control, and a percutaneous device (intravascular
catheter). The pressure or flow is usually provided by gravity or a device to propel
the delivered fluid through the infusion system into the blood vessels. The drugs used
in intravenous delivery systems need to be prepared in an aqueous solution to avoid
embolism possibility and prevent the drug precipitation in the body. Intravenous
drug delivery is usually used in situations that require continuous administration
and rapid response with high doses. However, intravenous drug delivery has several
disadvantages, such as the impossibility of drug retrieval after administration, and it
will be difficult to rectify if adverse reactions or errors occur during the administration. During the intravenous administration, the leakage of drugs to the surrounding
tissues can lead to blistering, tissue shedding, and nerve damage.
Drug Delivery System and Technologies 87
3.3.2 Extravaneous Drug Delivery
Except for intravenous drug delivery, other administration routes have gained great
attention over the past few decades, including intranasal, buccal, pulmonary, sublingual, transdermal, vaginal drug delivery, and so on. The different drug delivery
strategyprovides a unique product opportunity according to the disease’s state and the
therapeutic area’s target. In addition, several approved drugs have synergies while
using the combination of different drug delivery technologies, such as intranasal
triptans, which provide quick relief of migraine-related pain (in a few minutes). On
the other side, the self-limits of each drug delivery technology should be considered according to the disease state, dose, patient population, and economics. We
will summarize the disadvantages and advantages of various types of drug delivery
technologies in this section.
3.4 Various Types of Delivery Technologies
3.4.1 Nasal Drug Delivery
Nasal drug delivery was first recorded in the Indian form of medicine, which was
called Ayurveda [41]. The nose is a structurally and physiologically complex part of
the human body. It comprises of the intranasal passage, ciliary hair-like cells, and
mucous membrane. As the sensory organ, the outer part of the nose consists of the
cartilaginous and bony parts. Mucus has the capacity to hold water and accomplish the
transfer of heat efficiently. The mucosal system has been recognized as the “common
mucosal immune system”, which can provide protection against pathogens. The
related immunoglobulins are IgA, IgE, and IgG, and the immune responses are
mainly related to the nasopharynx-associated lymphoid tissue. Oils, powder, steam,
and smoke can be used in nasal drug delivery systems for various local and systemic
diseases, such as common or allergic rhinitis, and local inflammation. Decongestants,
glucocorticoids, or antihistamines, are usually used in nasal drops or sprays in nasal
delivery systems. Nasal drug delivery has several advantages, such as rapid drug
absorption because of the physical conditions of the nose (good blood circulations
of the nasal mucosa), the quick onset of action, the high permeability in the nasal
epithelium, and the better compliance for patients. The physicochemical properties
of the drugs largely determine the design of the nasal drug delivery system. For
instance, large-sized drugs (> kDa) are too lipophilic, that are difficult to penetrate
the mucosa, and the degree of ionization and the stability are greatly influenced by
the pH of the drug, and the nasal mucosa is further irritated. Low molecular weight
drugs and hydrophobic drugs are usually used for designing nasal sprays or drops for
locally treating the inflamed or blocked nose. The topic of drug delivery can reduce
the systemic side effects, such as the typical sleepiness while using antihistamines
administration [42]. For systemic nasal drug delivery, the small lipophilic drug mainly
passes across the nasal epithelium, and goes through the blood system. The drug needs
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to cross the blood–brain barrier (BBB) and arrive at the human brain, and most drugs
are transported to the brain in three routes: (1) route I based on the internalization with
neurons, (2) route II via the gaps between the cells close to the olfactory nerves; (3)
route III uses the transcellular strategy via the basal epithelial cells [43]. BBB consists
of a monolayer network of blood vessels, and plays an important role in preventing
the free transportation of substances from blood circulation to the brain. In addition,
the metabolite removal could be regulated by BBB, and BBB further protects the
brain via preventing the penetration of substances, including pathogens, blood cells,
neurotoxic plasma components, and blood cells. The drugs need to be administered
through the nose to the brain in order to circumvent BBB and the barrier of blood
cerebrospinal fluid. Besides the small active agents that can be absorbed via the nose,
the proteins, stem cells, peptides, nucleotides, and viruses can also be absorbed. Nasal
vaccines can be designed due to their advantages, such as non-invasive,cost-effective
production, and painless to use for patients.
3.4.2 Ocular Drug Delivery
The cases of age-related macular degeneration are increasing every year reported
by The World Health Organization (WHO). In 2020, 76 million cases of glaucoma
were reported, and 146 million cases of diabetic retinopathy were reported. Retinal
diseases are the main reason for the deterioration of vision all over the world [44].
Ocular anatomy is classified into anterior and posterior segments, and the anterior
segment includes the iris, cornea, and lens, and the posterior segment includes the
retina, macula, optic nerve, and vitreous humor. The lens was influenced by the
cataract, and the fluid drainage pathways were greatly impacted by the glaucoma,
and the lens plays a role in light focusing. The absorbed UV light is managed by the
related proteins within the lens for maintaining the oxidative balance. However, the
lens’s ability to repair cellular damage and mitigate oxidative damage is diminished
with aging, and finally results in the aggregation of protein and lens opacities, and,
eventually loose the vision. For age-related macular degeneration, the accumulation
of ROS in the inflammatory environment can cause protein aggregation and drusen
formation. The abnormal blood vessel growth is mainly caused by the overproduction
of VEGF, then the retinal pigment epithelium is impacted, and further leads to the
late stage of macular degeneration. Currently, the approved therapeutics for treating
ocular diseases mainly include steroids, antibiotics, and biological pharmaceuticals.
In the past decade, ocular drug delivery has been greatly investigated. Several routes
of ocular drug delivery, such as suprachoroidal route, topical route, subretinal route,
subconjunctival route, intravitreal injection, and port delivery, could be used for the
treatment of ocular diseases (Fig. 4)[45].Micro/nano-particles (dendrimer,liposome,
polymeric micelles, and so on) and hydrogels can be used as drug carriers to deliver
drugs into the intraocular space efficiently. Recently, the ocular drug delivery system
for anti-VEGF drug encapsulation and release has been significantly expanded. The
Drug Delivery System and Technologies 89
Fig. 4 This scheme illustrates several routes of ocular drug delivery, including suprachoroidal
route, topical route, subretinal route, subconjunctival route, intravitreal injection, and port delivery
system. Reproduced with permission from MDPI [45]
anti-VEGF drugs include aflibercept, ranibizumab, and bevacizumab. The conjugation of micro/nano-particles and hydrogels has been employed in designing ocular
drug delivery system to achieve the sustained release of drug and dose escalation.
3.4.3 Oral Drug Delivery
Oral administered drugs can be targeted to specific areas via the gastrointestinal
(GI) tract. Oral drug delivery is the most commonly used technology due to such
an approach has the advantages of patient preference, easy-large-scale manufacture, and cost-effectiveness. Oral formulations share roughly ninety percent of the
global market of all pharmaceutical products for human use [46]. Oral administration is simple and does not damage the skin and mucous membranes. Generally, the
patients prefer oral formulations to other parenteral routes, including injections and
inhalation. The design of oral formulations still has some challenges, mainly caused
by the physicochemical properties of drugs, including membrane permeability and
poor water solubility [47]. The poor chemical and biological stability of the drug,
and the physiological barriers (pH, efflux transporters, and metabolic enzymes) can
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influence the absorption of drugs using oral delivery. The low oral bioavailability is
mainly due to the drug solubility, especially for hydrophobic drugs [48]. The low
bioavailabilityof oral drugs is related to factors that aregastric irritation, dose proportionality,food effect, slow onset of action, and so on. The aqueous solubility of drugs
could be improved using the design of formulation, including salt selection, surfactant selection, and particle size reduction. Advanced formulation strategies such as
using nanocarriers can address the issues of conventional oral formulations, and the
solubility, permeability, and bioavailability of drugs could be greatly improved.
3.4.4 Sublingual and Buccal Drug Delivery
For treating the special conditions in the oral cavity, such as infections and ulcers,
sublingual and buccal administrations need to be employed (Fig. 5). Due to the
high vascularization in sublingual and buccal mucosal regions, sublingual and
buccal administrations facilitates effective systemic administration. Sublingual drug
delivery is when the drug is placed under the t ongue and released, and buccal drug
delivery places the drug between the cheek and gums to accomplish the drug release
[49]. Sublingual and buccal administrations have a faster onset of action compared
to oral drug delivery [50]. Because of the thinner epithelium, the absorption of the
drug on the sublingual mucosa is relatively faster than that on the buccal mucosa.
In addition, the drug can enter the systemic circulation directly through the blood
vessels, and the drug bypasses the hepatic first-pass metabolic processes. So, sublingual and buccal administrations are very useful for highly soluble drugs, especially
for the drugs that have to undergo high hepatic clearance in the GI tract. In sublingual
and buccal drug deliveries, patients can easily self-administered, and sometimes, the
drug may be split out or swallowed, then the effect will be quickly terminated. Thus,
it may be inconvenient for patients using the sublingual and buccal administrations,
and some technical procedures need to be involved to keep the drug in the specific
areas for better absorption. Drugs that are bitter and unpalatable, or irritable to the
oral mucosa, are difficult to be administrated. Many factors should be considered
for the bioavailability, stability, safety, and efficacy of the drug during the sublingual
and buccal delivery systems, including drug absorption, duration of action of the
formulation, saliva pH, and saliva flow. Various dosage forms have been investigated
for sublingual and buccal drug delivery, including sprays, gels, films, tablets, and
patches.
3.4.5 Pulmonary Drug Delivery
Pulmonary drug delivery technology has been used for centuries. The lungs can
be employed as portals for delivering drugs or vapors to treat local lung diseases,
including respiratory distress syndrome, congestive obstructive pulmonary disease,
asthma, and respiratory infection. Compared to the nasal and buccal/sublingual cavities, the lung has attractive characteristics such as a large usable surface area, modest
Drug Delivery System and Technologies 91
Fig. 5 This scheme illustrates the sublingual and buccal regions. Reproduced with permission from
Frontiers [49]
metabolic capacity, and good epithelial permeability. The inhalation drug product is
usually used in pulmonary drug delivery, and the well-designed device should ensure
accurate dose administration, which results in consistent lung depth deposition. The
appropriate device needs to generate the aerosol with an aerodynamic diameter in
the range of 0.5–5 µm for facilitating deep deposition in the lungs, and the aerosol
loaded in the device has to be reproducible to control the dose delivery accurately,
and the drug in powders or suspension formulations must be dissolved in the lung
lining fluid. Compared to the oral gastrointestinal mucosa, the lungs are much more
permeable to small molecules.
92 W. G uo e t al .
3.4.6 Transdermal Drug Delivery
Transdermal drug delivery technology uses the skin for drug absorption and delivery,
and the drug can be absorbed by blood vessels from the skin to accomplish systemic
circulation [51]. Transdermaldrug delivery technology possessesseveral advantages,
including avoiding first-pass metabolism, less invasive for patients, easy administration, and the potential for frequency reduction. In addition, transdermal drug delivery
systems can be used for hydrophilic and hydrophobic compounds. Due to the large
area, the skin is suitable for drug absorption. However, the stratum corneum as
the first barrier is still challenging for the absorption of drugs. Stratum corneum
is composed of ceramide lipid components and dead keratinocytes, and a dense
structure of “brick-and-mortar” is formed [52]. The administered drugs permeate
the molecular architecture by two routes; trans-epidermal and trans-appendageal.
The skin permeability of drugs could be enhanced by external stimuli, including
mechanical, electrical, and physical stimuli. Active transdermal drug delivery can
be developed using the appropriate equipment, such as iontophoresis, sonophoresis,
electroporation, photomechanical waves, microneedle, and thermal ablation. Moreover, the therapeutic efficacy of drugs in transdermal delivery can be regulated by
the molecular weight of drugs, the affinity of lipophilic and hydrophilic phases, and
ski irritability. The penetration of the drug into the skin is affected by several factors,
such as skin age and area, state of the skin, species differences, application, pretreat
methods, and so on. Based on the purposes of increasing the drug spread across the
skin and the drug solubility into the skin, innovativepassivedelivery approaches were
designed, such as microemulsions, super-strong formulations, and vesicles [53].
3.4.7 Vaginal Drug Delivery
Therapeutics used for vaginal applications appeared in ancient Egypt [54]. Nowadays, the vaginal drug delivery system usually delivers topical-acting drugs, such as
spermicides, antimicrobials, and antimycotics for contraception or hormonal therapy.
Especially, microbicides in vaginal delivery are mainly used for inhibiting sexual
transmission of HIV, HPV, or HSV. The human vagina connects the vulva, cervix,
uterus, and upper reproductive tract, and there are abundant blood vessels in the
vagina [55]. The active substances in the vagina can easily accomplish the firstpass hepatic metabolism, and the drugs, even with high molecular weight, still have
a good permeability on the vaginal epithelium. Several factors have to be considered for designing the vaginal formulation, such as the un-stability of the vaginal
cavity, thickness of the epithelium, vaginal fluid, and acidity and temperature in
the vagina. Various drug delivery systems have been used in the vagina, such as
hydrogels, foams, creams, tablets, suppositories, pellets, capsules, patches, films,
rings, microparticles, and nanoparticles. Various natural or synthetic polymers can
be used for the vaginal drug delivery system, such as cellulose, pectin, alginates,
starch, carrageenans, chitosan, hyaluronic acid, gelatin, gellan gum, xanthan gum,
poloxamers, polyacrylates, polyvinylpyrrolidone, polyethylene glycol, and so on
Drug Delivery System and Technologies 93
[56]. Nie. et al. synthesized the star-shaped four-arm poly (D, L-lactic-co-glycolic
acid)-b-methoxy poly (ethylene glycol) (4sPLGA-mPEG) block copolymer, as the
injectable hydrogels for vaginal drug delivery system (Fig. 6)[57]. The loading
and releasing of gestodene (GSD), indomethacin (IMC), and ethinyl estradiol (EE)
in hydrogels displayed an excellent contraceptive effect, and such drug delivery
can be applied for contraception. The vagina can be used as a drug delivery site,
and the vaginal drug delivery systems in research focus on local action for treating
numerous diseases and conditions, such as infections of viral, bacterial, and viral,
vaginal atrophy and dryness.
Fig. 6 The star-shaped block copolymer hydrogels loaded with ethinylestradiol, gestodene,
and indomethacin, as injectable intravaginal hydrogels, for contraception by injection method.
Reproduced with permission from MDPI [57]
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4 Challenges and Future Perspectives
Compared to conventional drug delivery systems, nanocarrier drug delivery system
has the advantages of targeted property and enhanced efficacy. However, the safety
and toxicity of nanocarriers still need to be considered. For example, the uptake of
nanoparticles in the reticuloendothelial system can lead to the inflammation of tissues
such as brain, liver, and lung because of oxidative stress [58]. Inorganic mesoporous
nanocarriers with mesopores and tunable size for controlled drug delivery systems
could enhance targeting and endosomal release of drugs. Furthermore, by combination with stimuli-responsive polymers, the drug can be released into the target cell
in spatio-temporal controlled release behavior. Nonetheless, the accuracy, repeatability, and precision of the nanocarriers with stimuli-responsive polymers need to
be further improved for the implementation in the clinic. It is very difficult to get
regulatory approval for nanomedicine using nanocarriers with stimuli-responsive
biomaterials, and more regulatory guidelines need to be developed and harmonized
before nanomedicine for further pharmaceutical industry.
The development of lab-on-a-chip (LOC) technology includes small channels and
chamber micro-devices that can control the flow of fluids and deliver the drug to the
specific area efficiently. Based on microfluidics systems and synthetic polypeptides,
the drug release can be programmed via manipulating the structure and properties
of polypeptides [59]. Recently, crosslinked molecular imprinting polymers (MIPs)
have been used as drug carriers because the binding sites of MIPs are specific to
some drug substances like lock and key [60]. The components, including template,
porogen, monomers, crosslinker, and initiator, are used to synthesize MIPs, and used
template acts as a receptor to bind targets, functional in a manner akin to a natural
antibody-antigen system. Thus, the newly designed MIPs can be used for the development of vaccines and biological drug delivery systems. Intelligent biomaterials
show potential in the field of drug delivery technologies, exemplified by intelligent
hydrogels capable of sensing blood glucose levels and delivering a precise dosage
of insulin. However, it is still challenging to develop small biosensor hydrogels with
sufficient mechanical strength. Another technology, quantum dots (QDs), has the
unique quantum confinement effect optical properties and emits fluorescence under
light source excitation, that can act as nanoprobes and carriers in drug delivery
systems. Quantum dots technology in the design of drug delivery can overcome the
limitation of using polymer for tracing the drug, and the fluorescent emission is much
better than that of using organic dyes.
5 Conclusion
In the last few decades, the development of other disciplines has also promoted
the development of drug delivery systems, there have been enormous advancements
in drug delivery systems and technologies, such as nanomedicine, microfluidics,