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Indian Journal of Drugs, 2015, 3(1), 11-16
ISSN: 2348-1684
A REVIEW: ADVANCES IN DRUG DELIVERY
Roonal Pritam Kataria
Jai Hind Collge, Department Of Microbiology, A road, Churchgate, Mumbai 400 020
*
For Correspondence:
Jai Hind Collge, Department Of
Microbiology,
A
road,
Churchgate, Mumbai 400 020
Received: 20.12.2014
Accepted: 22.03.2015
Access this article online
Website:
www.drugresearch.in
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ABSTRACT
Drug delivery is the method or process of administering a pharmaceutical compound to
achieve a therapeutic effect in humans or animals. New drug delivery techniques aim to
improve coverall drug performance and efficacy, making patient’s lives easier. Drug delivery
techniques are constantly evolving and improving to breach the biological barriers separating
drugs from their target sites. Advances in drug delivery would not only improve the overall
performance of the drug but are also expected to offer a host of additional advantages such
as ease of administration, increased patient compliance, decreased side effects and cost
reduction. While drug delivery plays an important role in enriching drug performance,
researchers are concentrating on using drug delivery as a means to reduce drug dosage
frequency, preferably through non-invasive methods. Multiple injections required per week
or day could be replaced by once a month dosages or even longer intervals which would
stabilise blood levels of the medications, thereby enhancing treatment outcomes and patient
compliance. Over the past three decades, new approaches have been suggested for the
development of novel carriers for drug delivery. This review describes general concepts and
emerging research in this field of drug delivery
KEY WORDS: Advanced drug delivery system, ease of administration, patient compliance,
cost reduction.
INTRODUCTION
Drug delivery is the method or process of administering
a pharmaceutical compound to achieve a therapeutic
effect in humans or animals. The introduction of drugs
in human body may be accomplished by several
anatomic routes. In order to achieve the therapeutic
purpose, the choice of the most suitable administration
route is of prime importance. Therefore, several factors
must be taken into consideration when administrating a
drug, namely its own properties, the disease to be
treated and the desired therapeutic time. The drugs can
be administrated directly to the target tissue or organ or
can be delivered by systemic routes. Pharmaceutical
treatments started plenty of decades, or even centuries
ago either with the oral administration of solid pills and
liquids, or with injectable active chemical drugs. When
either of these methods is applied, drug dose
maintenance in the body is achieved by repeated
administrations. Despite the effectiveness of these
treatments, it is impossible to control the uniform drug
level over a long period of time. During the past three
decades, new approaches and strategies have been
developed to control several parameters that are
essential for enhancing the treatment performance such
as the rate, period of time and targeting of delivery. This
was the beginning of the so called drug delivery systems
[15]
Drug Delivery Carriers
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The main purpose of using a drug delivery system is not
only to deliver a biologically active compound in a
controlled manner but also to maintain drug level in the
body within therapeutic window. Besides, one can
direct the drug towards a specific organ or tissue
(targeted drug delivery. [34] This can be done by using
suitable drug carriers that could be manipulated in order
to improve the efficiency of drug delivery system. The
carriers can be made slowly degradable, stimuli-reactive
(e.g., pH- or temperature-sensitive), and even targeted
(e.g., by conjugating them with specific antibodies
against certain characteristic components of the area of
interest).
Polymers: The earliest drug delivery systems, first
introduced in the 1970s, were based on polymers
formed from lactic acid. Today, polymeric materials still
provide the most important avenues for research,
primarily because of their ease of processing and the
ability of researchers to readily control their chemical
and physical properties via molecular synthesis.
Polymers are formed by the linkage of a large number of
smaller molecules called monomers. They are made in
different shapes and sizes with drug either attached to it
or inside the polymer construct. Biodegradable
polymers are particularly attractive for application in
DDS since, once introduced into the human body, they
do not require removal or additional manipulation. Their
degradation products are normal metabolites of the
body or products that can be metabolized and easily
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cleared from the body [1, 30]. Moreover, synthetic
polymers offer a wide variety of compositions with
adjustable properties which can be exploited for
administration of drug (chemical, interfacial, mechanical
and biological). Since their preparation is very
reproducible, it is possible to prepare them with the
same specifications quite easily. [33, 44]
Polymers can deliver drugs through dissolution,
diffusion or osmosis. Polymers can be attached to
antibodies to deliver drugs to a specific target. Basically,
two broad categories of polymer systems have been
studied:
reservoir devices which involves the
encapsulation of a pharmaceutical product within a
polymer shell and matrix devices in which a drug is
physically entrapped within a polymer network. Krishna
et al [20] formulated a carboxymethylcellulose-sodium
(CMC-Na) based transdermal system for propranolol, a
beta-adrenoceptor blocker and reported its improved
bioavailability in-vitro and in-vivo with CMC-Na as a
carrier. Murthy et al [28] successfully formulated
transdermal films of terbutaline sulphate using hydroxy
propyl methylcellulose as a matrix for evaluation of
pharmacokinetic and pharmacodynamic parameters in
rabbits
Liposomes: Liposomes are fatty droplets made
artificially in the laboratory by the addition of water
solution to a phospholipid gel. Liposomes are long
circulating macromolecular carriers that encapsulate
active drugs to improve their delivery. The main
mechanism of a liposome is simply fusing to the cell
membrane or through endocytosis. [41] Currently
approved liposomal drug delivery systems provide
stable formulation, provide improved pharmacokinetics,
and a degree of ‘passive’ or ‘physiological’ targeting to
tumor tissue. Liposomal anthracyclines have achieved
highly efficient drug encapsulation, resulting in
significant
anticancer
activity
with
reduced
cardiotoxicity. Mukhopadhyay et al [27] have developed
conjugate of antineoplastic drug daunomycin with
liposome as carrier. This study indicated that the drug
was taken up with high efficiency by multi drug resistant
murine macrophage tumor cell line. Pegylated liposomal
doxorubucin has shown substantial efficacy in breast
cancer treatment both as monotherapy and in
combination with other chemotherapeutics. [35] These
carriers do not directly target tumor cells. Additional
liposome constructs are being developed for the
delivery of other drugs. The next generation of delivery
systems will direct molecular targeting of cancer cells via
antibody-mediated
or
other
ligand-mediated
interactions. Immunoliposomes, in which mAb
fragments are conjugated to liposomes, represent a
strategy for molecularly targeted drug delivery. AntiHER2 immunoliposomes loaded with doxorubicin
displayed potent and selective anticancer activity
IJOD, 2015, 3(1), 11-16
against
HER2-overexpressing
tumors,
including
significantly superior efficacy versus all other treatments
tested (free doxorubicin, liposomal doxorubicin, free
mAb (trastuzumab), and combinations of trastuzumab
plus doxorubicin or liposomal doxorubicin). [31]
Immunoliposomes also appear to be nonimmunogenic
and capable of long circulation even with repeated
administration. Anti-HER2 immunoliposomes are
currently undergoing scale up for clinical studies. [27,
31]
Nanodiamonds: These are 2nms in diameter in single
particle form and can be manipulated to form clusters
with diameters in the 50-100 nms range. This makes
them ideal for drug delivery by shielding and slow
releasing drugs trapped within the clusters. They
provide large surface area and can trap nearly 5- times
drug compared to conventional drug delivery method.
Nanoparticles (including nanospheres and nanocapsules
of size 10-200 nm) are in the solid state and are either
amorphous or crystalline. They are able to adsorb
and/or encapsulate a drug, thus protecting it against
chemical and enzymatic degradation. Nanocapsules are
vesicular systems in which the drug is confined to a
cavity surrounded by a unique polymer membrane,
while nanospheres are matrix systems in which the drug
is physically and uniformly dispersed.
Nanoparticles as drug carriers can be formed from both
biodegradable polymers [21] and non-biodegradable
polymers. Nanoparticles and nanoformulations have
already been applied as drug delivery systems with
great success; and nanoparticulate drug delivery
systems have still greater potential for many
applications, including anti-tumors therapy, gene
therapy, and AIDS therapy, radiotherapy, in the delivery
of proteins, antibiotics, virostatics, and vaccines and as
vesicles to pass the blood-brain barrier. [6, 39]
Administration routes
The choice of a delivery route is driven by patient
acceptability, the properties of the drug (such as its
solubility), access to a disease location, or effectiveness
in dealing with the specific disease. The most important
drug delivery route is the oral route. An increasing
number of drugs are protein- and peptide-based. They
offer the greatest potential for more effective
therapeutics, but they do not easily cross mucosal
surfaces and biological membranes; they are easily
denatured or degraded, prone to rapid clearance in the
liver and other body tissues and require precise dosing.
At present, protein drugs are usually administered by
injection, but this route is less pleasant and also poses
problems of oscillating blood drug concentrations.
Despite these barriers the oral route is still the most
intensively investigated as it offers advantages of
convenience and cheapness of administration, and
potential manufacturing cost savings.
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Inhalable Systems: Preservatives are commonly used in
drug formulations and are well tolerated at low dosages.
But for nasal spray delivery, they can be irritating to the
patient mucosa causing itching and stops or slow down
mucociliary clearance mechanism. Hence they are
generally eliminated from nasal spray formulations. A
specific multidose spraying device called preservative
free systems (PFD) has been developed for intranasal
delivery. Inhaled drug delivery is becoming quite
popular as a drug delivery method today. In addition to
treating simple ailments such as nasal congestion, the
treatment and management of flu, pain, migraine, etc.,
is seeing increased acceptance with this delivery format.
Also, the use of intranasal drug delivery for prophylactic
vaccines is projected to grow significantly. New inhalers
now have features such as dose counters and dosing
feedback mechanisms that help assure the patient that
they’ve received their medication. [7, 29]
Smoking therapeutic drugs: Therapeutic drugs can be
smoked like cigarettes by staccato’s device such that the
inhaled drugs in the form of aerosol hit the blood
stream much quicker than with other techniques and
effects thus seen within seconds. This device quickly
vaporise a drug to form a small particle aerosol which
can then be inhaled by the patient. The drug is then
quickly absorbed through the lungs in the bloodstream.
Aerosol drug delivery to the lungs has long been the
route of choice for the treatment of respiratory
diseases, including asthma and chronic obstructive
airway disease. Metered dose inhalers (MDIs), dry
powder inhalers (DPIs), and nebulizers have been
employed to successfully deliver a wide range of
pharmaceuticals principally to the lungs for local action.
[9, 26]
Microporation: With microporation, a small area of skin
is covered by hundreds of needles that pierce only the
stratum corneum. The microneedles are usually drugcoated projections of solid silicon or hollow drug-filled
metal needles. Because the nerves located deeper in the
skin are not stimulates, the patient does not experience
pain or discomfort. Microneedles were first
conceptualized for drug delivery many decades ago.
They are manufactured in different forms based on their
delivery mode. (i) solid microneedles for skin pretreatment to increase skin permeability. They are
delivered by poke with patch approach - Involves
piercing into the skin followed by application of the drug
patch at the site of treatment. [2] (ii) microneedles
coated with drug that dissolves off in the skin for which
coat and poke approach- of delivery is used, [12] (iii)
Biodegradable polymer microneedles that encapsulate
drug and fully dissolve in the skin when inserted for
delivery [18, 22] and (iv) hollow microneedles for drug
infusion or injection into the skin. [25]
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Microneedles have been used to deliver a broad range
of different low molecular weight drugs, biotherapeutics
and vaccines, including published human studies with a
number of small-molecule and protein drugs and
vaccines. Influenza vaccination using a hollow
microneedle is in widespread clinical use and a number
of solid microneedle products are sold for cosmetic
purposes.[16, 46] Successful application of microneedles
depends on device function that facilitates microneedle
insertion and possible infusion into skin, skin recovery
after microneedle removal, and drug stability during
manufacturing, storage and delivery, and on patient
outcomes, including lack of pain, skin irritation and skin
infection, in addition to drug efficacy and safety. [3, 5,
19]
Iontophoresis: Iontophoresis involves transport of ionic
(charged) molecule into a tissue by passage of a direct
electric current through an electrolyte solution
containing ionic molecule to be delivered using an
appropriate electrode polarity. Typical currents range
from 0.1–1.0 mA/cm2. [10] It can be used for
enhancement of transport of high molecular weight
peptides and nonelectrolytes due to the indirect effect
of electric current i.e. coupled flow of water (ion to
hydrokinesis). An electrode patch containing the drug is
placed on the skin and acts as the working electrode,
which can be either positive or negative depending
upon the characteristics of the drug. Another electrode
is placed elsewhere to complete the circuit. [13] While
the electric field does provide a driving force, delivery is
primarily by passive diffusion through the long-lived
pores due to the short duration of the pulses (typically
milliseconds). Iontophoresis enhances both the rate of
release and the extent of penetration of the salt forms
of the drugs across the skin. Iontophoresis, has a
negligible effect on skin architecture at short treatment
times. This is because of the low-voltage nature of the
applied electric current. [47]
Nanda et al [31] showed that iontophoresis caused a
significant increase in transdermal permeation of
propranolol hydrochloride in vitro through skin. Bhat et
al [4] prepared betamethasone dipropionate ointment
and studied the effect of permeation enhancers such as
surfactants, iontophoresis and sonophoresis using rat
skin. It was seen that in vivo sonophoresis and
iontophoresis enhanced permeation through rat skin.
Kigasawa et al demonstrated that small interfering RNA
(siRNA) was efficiently delivered into rat epidermis by
iontophoresis. [17]
Electroporation: Electroporation uses electricity, to
disrupt cellular membranes. Electric pulses of hundreds
of volts, lasting for 10 μs-10 ms, are typical and result in
the formation of aqueous pores in the lipid bilayers of
the stratum cornea, as well as in the reversible
disruption of cell membranes. [8]
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The electronic patch injector system have been
designed, which can deliver a large dose over an
extended period of time, simplifies administration by
automating processes and equipment, and can move
drug infusion therapies from hospital-based to homebased settings. They offer significant benefits through
the inclusion of electronic systems to control dose rate,
volume and also provide feedback to help compliance.
These injectable devices not only result in ease-of-use
for the patient or administrator, but also potentially
help manufacturers conserve costly drug product. [37]
Eriksson et al [11] have tested safety, clinical efficacy
and immunogenicity of a DNA vaccine coding for rhesus
prostate specific antigen (PSA) delivered by intradermal
injection and skin electroporation. No systemic toxicity
was observed. This work showed that intradermal
vaccination with skin electroporation can be easily
performed with only minor discomfort for the patient.
Medicated tattoos: The temporary tattoos popular with
children and young adults has been modified to contain
active drug for transdermal delivery. A patch of tattoo is
loaded with drug and usually applied on the skin to
transport a specific dose of medication across the skin
and into the blood circulation. [14] The adhesive serves
two functions: It is glue in nature that keeps the patch
adhered to the skin, and it acts as the suspension that
holds the drug. The problems associated with this is the
concentration of the drug within the adhesive directly
affects the "stickiness" of the adhesive so if the large
quantities of drug is to be administered , either the size
of the patch have to be increased or the patch needs to
be reapplied again and again. Several pharmaceuticals
usually combined with substances, like alcohol, within
the patch to improve their penetration via skin in order
to improve absorption. They are also applied to clean
dry skin in the same manner. [43]
Med-Tats is a modification of temporary tattoo which
contains an active drug substance for transdermal
delivery. This technique is useful in the administration of
drug in those children who are not able to take
traditional dosage forms but provides no control of drug
release rates. There is no predetermined duration of
Med-tats. Instead the manufacturer provides a colour
chart that can be compared to the colour of the
patient’s tattoo to determine whether the tattoo should
be removed. [43]
Sonophoresis: Ultrasound, especially in the frequencies
between 20 to 100 KHz, [24] has shown to significantly
increase the permeability of skin for facilitating
transdermal drug delivery. Ultrasound induced
cavitation leads to the formation of localized regions of
high permeability. Skin could either be permeabilized
with short application of ultrasound before the
application of drug or drug and ultrasound could be
applied simultaneously to the skin. Some parameters
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including frequency, intensity, function cycle and
application time, can be adjusted to achieve a safe
reversible breach in the skin. [4, 23]
The SonoPrep R device uses low frequency ultrasound
(55 kHz) for an average duration of 15s to enhance skin
permeability. This battery operated hand held device
consists of a control unit, ultrasonic horn with control
panel a disposable coupling medium cartridge, and a
return electrode. The ability of the SonoPrep device to
reduce the time of onset of action associated with the
dermal delivery of local anaesthetic. The use of other
small, lightweight novel ultrasound transducers to
enhance the in vitro skin transport of insulin has also
been reported by a range of workers. [24, 32]
Smart drugs: Also known as pro-drugs. These
compounds works only when activated by certain
components in the body. Eg. Specific enzyme and hence
will be activated only in tissues that produces the
specific enzymes. [45] Photoillumination, a technique
that uses light to turn a pro-drug into an active
pharmaceutical drug via a photochemical reaction. It
precisely controls the timing and the amount of drug
formed as the process begins when light falls on the
compounds and lasts only as long as the light continues
to shine. Hence can be effectively used to target drug
delivery thereby reducing side effects. A prodrug of
paclitaxel which has a coumarin derivative conjugated
to the amino acid moiety of isotaxel has been
synthesized by Skwarczynski et al in 2006. [42] The
prodrug was selectively converted to isotaxel by visible
light irradiation (430 nm) with the cleavage of coumarin
Dental implants: Dental delivery systems today are used
in two ways: the main application is the local treatment
of diseases affecting the oral cavity itself like
periodontitis or fungal infections. The second is for
systemic drug delivery. A dental prosthesis is introduced
into two fake molars. Saliva enters the reservoir via a
membrane, dissolves part of the solid drug and flows
through a small duct into the mouth cavity, where it is
absorbed by the mucous membrane in the patient’s
cheek. Out of the two sensors, one measures the
volume of liquid that enters the mouth while the other
measures the concentration of medication in the liquid.
This method is helpful for chronically ill patients
suffering from dementia or drug addicts. [40]
CONCLUSION
The need for research into drug delivery systems
extends beyond ways to administer new pharmaceutical
therapies; the safety and efficacy of current treatments
may be improved if their delivery rate, biodegradation,
and site-specific targeting can be predicted, monitored,
and controlled. From both a financial and a global health
care perspective, finding ways to administer injectableonly medications in oral form and delivering costly,
multiple-dose, long-term therapies in inexpensive,
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potent,
and
time-releasing
or
self-triggering
formulations are also needed. The promise of
administration methods that allow patients to safely
treat themselves is as significant as any other health
care development, particularly in developing countries
where doctors, clean syringes, sterile needles, and
sophisticated treatments are few and far between.
With the recent advances, it has been found that oral
types will remain the largest drug delivery category
while parenteral, inhalation and implantable systems
will grow the fastest. And eventually, parenteral
formulations will surpass oral dosages due to changes in
the market trends in the type of molecules that are
being discovered and commercialized. Additionally, selfadministered injectable devices are gaining in popularity
especially for chronic diseases. Inhaled drug delivery
systems are expanding to accommodate everything
from pain medications to autoimmune disease targets
and vaccines. Alternatively excipients, which can be
used in conjunction with novel pharmaceutical
combination devices or via different routes of
administration, are being researched to avoid discarding
promising compounds that can’t be delivered
effectively.
In future, smarter and more novel delivery systems are
being developed. For example, a controlled release
microchip that houses, and delivers on demand, many
different drugs (e.g., “pharmacy on a chip”) has recently
been developed by Richards-Grayson et al. 2003 and
Santini et al. 1999. [36, 38] These systems can
potentially be preprogrammed or externally regulated
to release drugs at any time, pattern, and rate. Such a
system might one day enable novel combination
therapies.
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