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36 Carbon-Based Nanocarriers for Drug Delivery
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Advancement in Drug
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2
Delivery Systems
2.1 INTRODUCTION TO DRUG DELIVERY SYSTEMS
Drug delivery systems, also known as DDSs, are pharmacological formulations that
assist in the targeted distribution and controlled release of therapeutics in the body.
After being administered, the DDSs will release the drug’s active components that
will reach the point of action after crossing several biological barriers. The fundamental aim of a DDS is to safely extend, contain, and target the therapeutic at the site
of disease. The need for DDSs arises as several drugs are known to exert intolerable
side effects on the body parts where they are not targeted. These side effects occur
from the formulation of the medicine, route of administration, and the reaction of the
body, or often result from the accumulation of high blood plasma drug concentration
with traditional drug administration. To ensure better patient compliance, the steps
that can be taken include limiting the drug quantity and frequency so that the same
effect can be derived from the treatment. It can thus be concluded that the drug’s
effectiveness can be signicantly impacted by the way it is delivered [1,2].
It is preferable to employ a DDS to deliver any drug in the human body to obtain
a controlled release (CR) rate, completely discard any side effects, and achieve the
full therapeutic effect. The physicochemical properties of the therapeutic agent and
the presence of bio-barriers typically inuence the conditions for successful drug
delivery. For the treatment of the same ailment, the properties of the drug can differ
signicantly depending on its size, chemical makeup, hydrophilicity, and capacity to
bind a particular receptor [3]. Thus, it is essential for a delivery system to operate in
the therapeutic drug window with the concentration lying between effectiveness and
toxicity limits. The frequency of dose, drug clearance rates, the method of administration, and the DDS used all affect how long a drug remains in the therapeutic range.
The therapeutic range must lie between the minimal effective concentration (MEC)
and the minimum toxic concentration (MTC). Figure2.1 [1] illustrates the concept
of drug delivery through the variation in the concentration of a drug with respect to
time. Subsequently, few drugs have a range of optimal doses in which the most significant benets are obtained; quantities outside or inside this range can be harmful or
have no therapeutic effect. Another effective method for simulating a drug delivery
is pulsed delivery, which can control the concentration prole by permitting drug
discharge from the drug carrier only when prompted by an external trigger like temperature and pH conditions [1,4].
The dose forms can be liquid,semisolid, or solid. Gaseous dosage forms, like
anesthetics, can also be adopted [5]. Parenteral drug delivery refers to the process
of injecting or infusing medication effectively within the body. There are several distinct types of delivery, including intravenous, subcutaneous, intradermal,
DOI: 10.1201/9781003358114-2 39
40 Carbon-Based Nanocarriers for Drug Delivery
FIGURE 2.1 The Drug Plasma Levels Following a Single Oral Dose of a Drug in the Relevant
Immediate Release (IR), Sustained Release (SR), and Controlled Release (CR) Forms [1].
intramuscular,and intraperitoneal, classied based on the central location of delivery. The majority of semisolid dose forms, such as creamsand gels, are deposited
to the skin before being ingested. Nevertheless, solid dose forms like transdermal
patches as well as liquid dosage forms, like emulsions, can be employed. The dosage
forms can either be modied release (MR) or instant release (IR). Similar to traditional drug delivery, IR dosage forms allow the drug to dissolve in the gastrointestinal contents without delay. Meanwhile, the drugs with delayed and extended release
are both available in MRdosage formulations; the system prevents the drug release
till it reaches the small intestine. Thus, these systems provide a sustained
release (SR) and controlled release (CR) while consequently reducing its administration frequency [1].
The dosingfrequency can bedecreased by lowering thedrug release rate over
a longer period of time with polymer-based matrix or reservoir-controlled release
mechanisms. CR DDSs, on the other hand, are intended to forecast consistent plasma
drug concentrations irrespective of the biological milieu at the site of application.
Hence, unlike SR systems, which control the drug’s release from the pharmaceutical
formulations, CR systems actively modulate the concentration ofthe drug withinthe
body [6,7]. Moreover, SR systems are mostly limited to oral formulations, whereas
CR systems can be supplied via a variety of methods, including transdermal, oral,
and vaginal delivery. For optimal drug uptake, as well as for the drug levels in the
blood and targeted site, the rate of release from the dosage type must serve as the
rate-determining step. From imminent release to prolonged release dosage forms,
the resultant plasma concentration versus time curves attens down more, showing
that the medication is maintained in the therapeutic range for a longer period of time
following only one dosage form delivery. To overcome the problem of uctuating
41Advancement in Drug Delivery Systems
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drug levels associated with conventional dose forms, controlled DDSs have indeed
been developed [1]. Successful formulation development depends on controlled drug
releases and subsequent biodegradation.
The processes for drug release include desorption of surface-bound or adsorbed
medication, migration through a polymer membrane enclosing the drug core,
matrix erosion, conjunction of degradation and diffusion, and reactivity to stimuli
likepH,temperature, orlight. Optimizing the drug’s bioavailability is the responsibility of the formulation researcher. To do this, the medicine’s delivery mechanism
must enable the drug to enter the systemic circulation and, more signicantly, reach
the targeted sites withinthe body, where it may be used without causing unwanted
side effects. Also, the drug needs to be sustainable microbiologically and physically
and chemically consistent with the excipients in the dosage forms. Designing the
delivery methods in a way that can increase patient adherence is important. Instead
of using parenteral medication formulations, it is possible to develop an oral solid
dosage form that enables self-administration of the dose forms.
To allow repeatable medication distribution from the systems and reduce the
impact on the body, such as dietary impacts on drug release, the pharmaceutical
grade of the delivery systems must also be guaranteed in compliance with regulatory
specications. It is also vital to look into whether it is possible to scale up the discovered DDS beyond the laboratory to the industrial scale. The drug is not always
delivered to the target organvia CRmethods. To manage the bioavailability of drugs,
target-specic drug delivery devices must be developed. As a result, several original
ideas have been developed to specically address the requirements of the desirable
DDS. Thus, drug delivery systems have come to light, with researchers focusing
on increasing bioavailability and patient compliance while lowering toxicity and
adverse effects to overcome the major deciencies of conventional drug delivery
methods [3].
This chapter discusses the evolution of the DDS, including its historical aspects
and classications. The classication of the DDS based on the route of entry, release
mechanism, and the recent advancement in the DDS to improve the therapeutic efcacy of the drug molecules using novel DDS approaches are also highlighted in this
chapter. Furthermore, the principles of nanosized delivery systems using nanocarriers and nanoconjugates are elucidated while providing their surface characteristics and signicance to the DDS. The last section briey describes the efcacy of
carbon-based nanomaterials as a drug carrier to deliver their potential in numerous
biomedical applications, including drug delivery.
2.2 HISTORICAL ASPECTS OF DRUG DELIVERY SYSTEMS
Drug delivery history dates back to when humans used to intake medicines by chewing or inhaling plant and animal extracts. Over 1000years ago, the concept of controlled drug delivery came into the picture, with a coating applied on the pills to
improve their taste, which also had an effect on the drug release rate. The rst-ever
drug delivery products providing sustainable release were coated tablets developed
in the late 1940s, where the coating and the drug were alternately stacked such that
the pharmaceutical was released over time. This method not only improved the
42 Carbon-Based Nanocarriers for Drug Delivery
overall efciency of the treatment but also signicantly reduced the drug administration frequency while delaying the release from the stomach to the small intestine.
However, this system had several limitations, like gastric emptying and low dissolution [8,9].
The commercialization of controlled drug delivery products began with the launch
of Spansule® 12hours release technology introduced by Smith, Kline & French
Laboratories. This technology was used rst to develop Dexedrine® and later Contac® 600 with dextroamphetamine sulfate, phenylpropanolamine hydrochloride, and
chlorpheniramine maleate individually [8,10]. Since then, three historical periods
have been identied in the advancement of controlled drug delivery systems, dened
in three distinct generations.
The development of Spansule® marked the rst generation of these drug delivery
systems. The system was designed such that the patient had to take medicine only
twice a day as it gave a sustained drug release for a period of 12hours. It provides
a dissolution-controlled mechanism by regulating the dissolution of the drug core
through a coating barrier. Since then, various other modications have been made to
this technology to synthesize products giving better release proles and more patient
compliance [10]. The rst-generation DDSs were based on oral or transdermal delivery, and the drug release mechanisms were either via dissolution, diffusion, osmosis,
or ion exchange [9,10].
The second-generation DDSs were developed from 1980 to 2010 and were characterized by their zero-order release mechanism. Compared with the number of
formulations synthesized, the second-generation DDSs were not as successful as
the rst. Based on the assumption that maintaining a consistent drug concentration
was better, all research efforts were concentrated on composing a constant rate of
release (zero-order DDSs). After ten years of extensive research, it was announced
that zero-order release kinetics is not strictly necessary for a DDS to be classied
as a sustained release DDS and following this discovery, signicant advancements
were made in this eld. The second-generation DDSs utilized smart polymers and
hydrogels that were sensitive to external factors. Tumor-targeting nanoparticle-based
drug delivery systems were also designed with time; however, all these DDSs had a
shortcoming with their inability to cross biological barriers [9,10].
The third-generation DDSs are currently being constructed to overcome the challenges offered to the second-generation DDSs by biological barriers and characteristics of the drug and the delivery system. Researchers have been focusing on reducing
the side effects, working on the drug’s poor solubility and high molecular weights, and
having better control of the release kinetics. Low water solubility can lead to problems, including decreased bioavailability and higher drug product costs. For instance,
medicines with low water solubility have reduced uptake in the gastrointestinal system when taken orally. Low solubility, on the other hand, might lead to drug precipitation and agglomeration, which can result in some hazardous consequences. As a
result, tremendous endeavors have been undertaken to increase drug solubility [11].
Proteins and polypeptides are examples of bioactive molecules that have a
role in regulating the body’s performance and are thus important for sustaining
health. These drugs must be administered in specied amounts, at the appropriate times, and to specic body sites [12]. These complex molecular drugs are often
43Advancement in Drug Delivery Systems
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administered parenterally; however, due to their large size, the digestive tract is unable
to absorb them. As a result, novel delivery techniques such as pulmonary, nasal, and
transdermal systems have been employed [9].
As previously stated, drug delivery is dened as a mechanism designed to release
a drug at a preset duration and rate. Organizing the carrier to target a certain location
and discharge at a specied pace are two obstacles that one may encounter while
developing an effective carrier. Developing an ideal drug delivery system is a considerable challenge since the drug must be directed to a specic site and released
continuously over time with zero negative impact on the body. With the advancement
in science and technology, various interdisciplinary types of research are being conducted to develop the most efcient and perfectly biocompatible DDSs [10,13].
2.3 CLASSIFICATIONS OF DRUG DELIVERY SYSTEMS
2.3.1 conVenTional DrUg DeliVery sysTems
Traditional drug delivery systems, also known as conventional DDSs, are classical
methods for administering drugs into the body. These methods include simple oral,
inhaled, or intravenous drug administration. Some advantages of these DDSs include
the convenience of administration, accurate measurement of dose, higher shelf life,
dose adjustment, and low cost. They are typically utilized when the objective is to
achieve rapid drug absorption, subsequently facilitating a quick drug release. However, the traditional delivery methods fail to maintain a xed and constant drug
concentration over time. They do not provide a target-specic release and are often
associated with the premature metabolism of drugs and excretion from the body.
One way to address the issue of drug concentration instability is by administering
multiple doses at regular intervals, but this approach has some limitations. Drug concentration in the blood plasma tends to uctuate irregularly, and patients may forget
to take the prescribed dose at the correct time. Given these issues, the need for new
and innovative drug delivery systems has become increasingly apparent [2,14,15].
2.3.2 noVel DrUg DeliVery sysTems
Novel drug delivery systems can solve several drawbacks of traditional drug delivery
methods. They are also referred to as controlled drug delivery systems as they can
improve the efciency of any treatment by enhancing drug potency, improving drug
safety, and enabling the targeted delivery of drugs to specic tissues or cells in the
body. The denition of “controlled release” extends beyond sustainable drug release
but must also exhibit two essential characteristics: predictability and reproducibility.
The advantages of controlled DDSs include drug release at a specic rate, direct
delivery to a particular site, extended residence period, protection from metabolism,
and enhanced bioavailability. Controlled drug delivery systems can be categorized
into four types. The rst type is rate-programmed DDSs, where the system design
is modied to alter the diffusion rate of drug molecules, which further varies the
release rate. The activation-modulated DDSs, a second type of novel DDS, work with
external simulations like physical and chemical processes, which then control the
44 Carbon-Based Nanocarriers for Drug Delivery
drug release process. The third type of controlled DDSs is feedback-regulated DDS.
With this type of DDS, sensors on the devices measure the concentration of certain
biochemical substances, and this concentration controls the drug release. Finally,
site-targeted DDSs are often used for treating diseases like cancer. They deliver a
specic drug dose to a particular site in the body for a set period. Such types of
DDS assist in eliminating side effects of drugs while providing high biocompatibility, improved drug absorption, distribution, and metabolism, maintaining consistent
drug concentration in blood, and cutting down dose frequency and cost [2,15,16].
The rate-programmed DDSs are further classied into polymer-matrix diffusion-controlled, membrane permeation-controlled, hybrid type, and micro- reservoir
partition-controlled DDS. The activation-modulated DDSs can be established
through external and internal stimuli, including physical, chemical, and biological
stimuli. The physical stimuli comprise temperature, pressure, magnetic and electric
elds, along with ultrasound and light waves. At the same time, chemical stimuli
include pH, hydrolysis, and reactive oxygen species (ROS). In addition, the biological stimuli mainly comprise proteins, enzymes, and aptamers. Afeedback-regulated
DDS comprises bio-erosion, bio-responsive and self-modulated DDS, wherein the
drug release is mostly modulated or controlled via biological substances. The targeted DDS mainly primarily works on two mechanisms, namely, the passive and
active targeting mechanisms through systemic targeting and intracellular targeting.
In the case of passive targeting, macromolecules get aggregated selectively over the
targeted tissues due to the enhanced permeability and retention characteristics. In
contrast, the active targetingmechanism occurs as a result of precise interactions
between the target cell’s receptors and nanocarrier [15,17].
2.3.3 BaseD on The roUTe oF aDminisTraTion
2.3.3.1 Oral Administration
Oral drug intake is the most common and conventional method of administration.
It comprises tablets, capsules, and syrup that are taken orally and pass through the
digestive system. It has several advantages, such as the convenience of administration, its noninvasive nature, and its low cost. However, in oral DDSs, there is almost
no control over the drug release, leading to a uctuating concentration in the plasma,
which results in side effects. Besides that, additional drug absorption from standard
formulations may vary signicantlybased on the physicochemical characteristics of
the drug and its carrier type, as well as a number of physiological variables like the
absence or presence of food, pH, gastrointestinal tract motility, etc. Thus, it is essential to design the carrier in a way that it provides controlled release [15,18].
2.3.3.2 Rectal Delivery
The rectal delivery system is inserted through the rectum, which dissolves at body
temperature to release the drug. As it doesn’t involve rst-pass metabolism, it can be
helpful in cases like an unconscious patient. Though this delivery route can be a good
substitute for oral administration, it often leads to patient discomfort. Moreover, it
can be benecial in cases with poorly absorbed drugs in the upper gastrointestinal tract as the medication can bypass the liver, leading to higher bioavailability.
45Advancement in Drug Delivery Systems
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Subsequently, the protection provided to these drugs from enzymatic degradation
can lead to better efcacy. For a drug that requires a high dose, developing an oral
dosage form may be difcult because of problems like low solubility or instability;
thus, rectal administration may be a practical substitute [19].
2.3.3.3 Intravenous Delivery
Intravenous administration is the fastest and most bioavailable method of delivering
a drug into the body’s systemic circulation. It has several advantages, like allowing
the medication to infuse straight into the bloodstream, leading to rapid delivery in
the body; helping control drug levels in the body by enabling precise dosing; providing immediate effect and quick onset of drug action; suitable for drugs containing
irritants; and easy access to the bloodstream for blood sampling and monitoring of
drug levels. However, it has some disadvantages, like infection and tissue damage,
and requires trained personnel for its application [20].
2.3.3.4 Subcutaneous Delivery
In this delivery method, the drug is delivered in subcutaneous tissue in a liquid form.
One of the most signicant advantages of this delivery method is that the drug can
be self-administered by the patient, leading to improved compliance and reduced
expenditure. This delivery method is also less painful than intravenous and intramuscular administration and has fewer chances of infection caused by the treatment.
However, this delivery method is limited to small volumes of the drug, making it
unsuitable for treatments that require high doses. Also, some medications may retain
or degrade at the injection site, causing low treatment efciency [21].
2.3.3.5 Intramuscular Delivery
In intramuscular delivery, a liquid medication is injected via an injector into the muscle tissue. Since the drug is injected directly into the muscle, which can be absorbed
into the bloodstream, this administration technique is appropriate for medications
that are not readily soluble or absorbed through other methods. Additionally, in contrast to the subcutaneous (SC) approach, which can only administer smaller amounts
of the drug due to the constrained space between the skin and underlying tissues,
intramuscular administration enables the administration of a larger volume of the
drug [4,15].
2.3.4 BaseD on The release mechanism
2.3.4.1 Dissolution
The process of dissolution refers to the transfer of molecules of a solute into a solvent
vehicle. In the case of an active agent, this involves moving drug molecules or ions
from a solid phase into the surrounding medium. Examining the rate at which the
drug dissolves from its solid form can predict the drug release rate from a therapeutic
system. When no chemical reaction is involved, a higher level of solubility leads to
a more rapid dissolution rate. When the solvating medium surrounding a solid drug
particle is not saturated, dissolution can occur. The process is inuenced by several
factors, including the solvating medium, the surface area of the solid, the thickness of
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