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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences



REVIEW: APPROACH ON NOVEL DRUG DELIVERY SYSTEM

Kagalkar A. A
*
, Nitave S. A.

Anil Alias Pintu Magdum Pharmacy College, Dharangutti, India.

ABSTRACT
Tremendous advancements in drug delivery, oral administration of
therapeutic agents still remains the favored route for majority of
clinical applications, due to the excellent accessibility, and patient
compliance as well as the preferred alternative route of drug
administration for non-invasive drug delivery among the other various
routes is Novel drug delivery system. The correlation between drug
intake and a clinical response is complex enough, the choice and
design of the ideal pharmaceutical dosage form of a drug delivery
system would be critically important to reach a progress in superior
drug development. To minimize drug degradation and loss, to prevent
harmful side-effects and to increase drug bioavailability and the
fraction of the drug accumulated in the required zone, various drug
delivery and drug targeting systems are currently under development.
Key words: Drug delivery systems (DDS), controlled release (CR).

INTRODUCTION
The method by which a drug is delivered can have a major effect on its efficacy. Some drugs
have an optimum concentration range within which maximum benefit is derived, and
concentrations above or below this range can be toxic or produce no therapeutic benefit at all.
On the other hand, very slow development in the efficacy of the treatment of severe diseases
has suggested a growing need for a multidisciplinary approach to the delivery of therapeutics
to targets in tissues. From this, new ideas on controlling the pharmacokinetics,
pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and effectiveness
of drugs were generated. These new strategies, often called drug delivery systems (DDS), are
W WO OR RL LD D J J O OU UR RN NA AL L O OF F P PH HA AR RM MA AC CY Y A AN ND D P PH HA AR RM MA AC CE EU UT TI IC CA AL L S SC CI IE EN NC CE ES S
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Article Received on
03 August 2013,

Revised on 30 August 2013,
Accepted on 26 September
2013
*Correspondence for
Author:

* Amrita Kagalkar
Anil Alias Pintu Magdum
Pharmacy College,
Dharangutti, India.
amritakagalkar123@gmail.com
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
based on interdisciplinary approaches that merge polymer science, pharmaceutics,
bioconjugate chemistry, and molecular biology
[1]
.

Oral route of administration is one of the oldest and most widely used routes for the
administration of drug providing convenient method of efficiently achieving both local and
systemic effect. In conventional drug delivery systems, there is little or no control over
release of the drug and effective concentration at the target site can be achieved by irregular
administration of grossly excessive doses. This kind of dosing pattern result is frequently
changing, erratic and sub or supra therapeutic plasma concentrations, leading to marked side
effects in some cases
[2]
.

The rate and extent of absorption of drug from conventional formulations may vary greatly
depending on factors such as physicochemical properties of the drug, presence of excipients,
various physiological factors such as presence or absence of food, pH of gastro intestinal
tract, gastro intestinal motility and so on. Uncontrolled rapid release of drug may also cause
local gastro intestinal or systemic toxicity. Hence better dosage form design and delivery can
minimize many of these problems. Various approaches are made in designing the
formulations, which will overcome the disadvantages of conventional dosage forms, which
include sustained/controlled drug delivery system. There are three main categories of
controlled-release drug delivery system namely Intravenous, Transdermal, and Oral systems.
Oral osmotically controlled release (CR) delivery system provide a uniform
concentration/amount of drug at the site of absorption and thus after absorption, allow
maintenance of plasma concentration within therapeutic range, which minimizes side effects
and also reduces the frequency of administration
[2]
.

Carrier-mediated drug delivery has emerged as a powerful methodology for the treatment of
various pathologies. The therapeutic index of traditional and novel drugs is enhanced by the
increase of specificity due to targeting of drugs to a particular tissue, cell or intracellular
compartment, the control over release kinetics, the protection of the active agent or a
combination of the above. Among various systems considered for this approach. The
development of novel drug delivery techniques has got its own specific challenges. The
selection of the route of administration and the dosage form has to integrate therapeutic
considerations, drug substance properties, selection of excipients technical formulation
feasibility and patient needs. The pharmaceutical industry is altering day to day based on the
varying patient requirements and global developments. The industries have diverted their
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
research focuses from conventional dosage forms to novel drug delivery technologies which
has got significantly improved market requirements. In recent years the pharmaceutical
companies are struggling to maintain a balance between the downward pressure on prices and
significantly raised innovation cost. It is going to be always a green zone for companies
developing novel delivery technologies to maintain their market presence and share. The
introduction of novel delivery systems to an existing molecule should significantly improve
its safety, efficacy and improved patient compliance. Most of the innovator companies have a
parallel research pipeline for biopharmaceuticals and concentrates on protein-peptide base
drug portfolio
[3]
.

The method by which a drug is delivered can have a significant effect on its efficacy. Some
drugs like Ginseng and Rosemary have an optimum concentration range within which
maximum benefit is derived and concentrations above or below this range can be toxic or
produce no therapeutic benefit at all. On the other hand, very slow progress in the efficacy of
the treatment of severe diseases has recommended a growing need for a multidisciplinary
approach to the delivery of therapeutics to targets in tissues. Keeping in view the above facts
new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity,
immunogenicity, biorecognition and efficacy of drugs were generated. These new strategies,
often called drug delivery systems (DDS) are based on interdisciplinary approaches that
combine polymer science, pharmaceutics, bioconjugate chemistry and molecular biology. An
ideal drug delivery system possesses two elements (i) ability to target (ii) to control the drug
release. Targeting will make sure high efficiency of the drug and reduce the side effects
especially when dealing with drugs that are presumed to kill cancer cells but can also kill
healthy cells when delivered to them. The prevention of side effects is achieved by controlled
release of drug. Therefore, different types of delivery system are used for variety of synthetic
drugs, phytomolecules and herbal extracts to ensure better bioavailability and targeted
delivery. Some of these delivery systems are Cubosomes, Colloidosomes, Ethosomes,
Aquasomes, Niosomes, Liposomes and Nanoparticles
[4]
.

To minimize drug degradation and loss, to prevent harmful sideeffects and to increase drug
bioavailability and the fraction of the drug accumulated in the required zone, various drug
delivery and drug targeting systems are currently under development
[5]
.


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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Different types of NDDS
1. Liposomes: Liposomes are small artificial vesicles of spherical shape that can be created
from cholesterol and natural nontoxic phospholipids. Due to their size and hydrophobic
and hydrophilic character, liposomes are promising systems for drug delivery. Liposome
properties differ considerably with lipid composition, surface charge, size, and the
method of preparation. It has been displayed that phospholipids impulsively form closed
structures when they are hydrated in aqueous solutions. Such vesicles which have one or
more phospholipid bilayer membranes can transport aqueous or lipid drugs, depending on
the nature of those drugs. Because lipids are amphipathic in aqueous media, their
thermodynamic phase properties and self assembling characteristics influence
entropically focused confiscation of their hydro-phobic sections into spherical bilayers.
Those layers are referred to as lamellae. Generally, liposomes are definite as spherical
vesicles with particle sizes ranging from30 nm to several micrometers. They consist of
one or more lipid bilayers surrounding aqueous units, where the polar head groups are
oriented in the pathway of the interior and exterior aqueous phases. On the other hand,
self-aggregation of polar lipids is not limited to conventional bilayer structures which rely
on molecular shape, temperature, and environmental and preparation conditions but may
self-assemble into various types of colloidal particles
[6]
.



Fig 1: Structure of liposme.

Advantages
Some of the advantages of liposome are as follows:
Provides selective passive targeting to tumor tissues (Liposomal doxorubicin).
Increased efficacy and therapeutic index.
Increased stability via encapsulation.
Reduction in toxicity of the encapsulated agents.
Site avoidance effect.
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Improved pharmacokinetic effects (reduced elimination, increased circulation life times).
Flexibility to couple with site specific ligands to achieve active targeting.

General Method of Preparation and Drug Loading:
Liposomes are manufactured in majority using various procedures in which the water soluble
(Hydrophilic) materials are entrapped by using aqueous solution of these materials as
hydrating fluid or by the addition of drug/drug solution at some stage during manufacturing
of the liposomes. The lipid soluble (lipophilic) materials are solubilized in the organic
solution of the constitutive lipid and then evaporated to a dry drug containing lipid film
followed by its hydration. These methods involve the loading of the entrapped agents before
or during the manufacturing procedure (Passive loading). However, certain type of
compounds with ionizable groups, and those which display both lipid and water solubility can
be introduced into the liposomes after the formation of intact vesicles (remote loading)
[7]
.



Fig 2: General method of liposomes preparation and drug loading.

2. Colon delivery: Colon delivery refers to targeted delivery of drugs into the lower GI
tract, which occurs primarily in the large intestine (i.e. colon). The site specific delivery of
the of drugs to lower parts of the GI tract is advantageous for localized treatment of several
colonic diseases, mainly inflammatory bowel disease (Crohns disease and ulcerative colitis),
irritable bowel syndrome, and colon cancer. Other potential applications of colonic delivery
include chronotherapy, prophylaxis of colon cancer and treatment of nicotine addiction. It has
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
also gained increased importance not just for the delivery of drugs for the treatment of local
diseases, but also potential site for the systemic delivery of therapeutic proteins and peptides
which are being delivery by injections. The colon is a friendlier environment for proteins
and peptides compared to the upper part of GI tract. Clinically relevant bioavailability may be
achieved if the peptide can be protected from acid and enzymes in the stomach and upper
intestine.

Advantages of CDDS over Conventional Drug Delivery
Chronic colitis, namely ulcerative colitis, and Crohns disease are currently treated with
glucocorticoids, and other anti- inflammatory agents.
Administration of glucocorticoids namely dexamethasone and methyl Prednisolone by
oral and intravenous routes produce systemic side effects including adenosuppression,
immunosuppressant, cushinoid symptoms, and bone resorption.
Thus selective delivery of drugs to the colon could not only lower the required dose but also
reduce the systemic side effects caused by high doses.

Colon specific drug delivery has gained increased importance not just for delivery of the
drugs in the treatment associated with the colon, but also as a potential site for the systemic
delivery of therapeutic peptides and proteins. To achieve successful colon targeted drug
delivery, a drug need to be protected from degradation, release and absorption in the upper
portion of the GI tract and then to be ensured abrupt or controlled release in the proximal
colon. This review mainly compares the primary approaches for CDDS (Colon Specific Drug
Delivery) namely pro-drugs, pH and time dependent systems, and microbial triggered
systems, which achieved limited success and had limitations as compared with newer CDDS
namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled
drug delivery (ORDS-CT) which are unique in terms of achieving in vivo site specificity, and
feasibility of manufacturing process
[8]
.


Fig 3: Design of enteric coated timed-release press coated tablet (ETP Tablet).
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences

3. Cubosomes: Cubosomes are the biocompatible novel approach for the drug delivery
system. The controlled release application of these nanoparticles is of a great significance in
cosmeceutical and pharmaceutical fields. Low cost of the raw materials, flexibility and the
potential for controlled release through functionalization makes them an attractive vehicle for
several in-vivo drug delivery routes. Precursor forms of cubosomes are among the
modification possible to overcome its difficulty in loading of drugs. Cubosomes are the
square and rounded particles with internal cubic lattices visible
[9]
.

Cubosomes are discrete, sub-micron, nanostructured particles of bi-continuous cubic liquid
crystalline phase. Cubosomes are typically produced by high-energy dispersion of bulk cubic
phase, followed by colloidal stabilization using polymeric surfactants. Cubosomes offer a
large surface area, low viscosity and can exist at almost any dilution level. They have high
heat stability and are capable of carrying hydrophilic and hydrophobic molecules. Combined
with the low cost of the raw materials and the potential for controlled release through
functionalization, they are an attractive choice
[9]
.

Bi-continuous cubic phases are optically isotropic, very viscous, and solid like liquid
crystalline substance with cubic crystallographic symmetry. Bicontinous cubic phases consist
of two separate, continuous but non-intersecting hydrophilic regions divided by a lipid
bilayer in to a periodic minimal surface with zero curvature. The bicontinuous nature of such
cubic phases differentiates them from the so-called micellar or discontinuous cubic
containing micelles packed in cubic symmetry
[10]
.

Two main approaches are used to produce cubosome particles. The top-down approach
applies high energy to fragment bulk cubic phase. The bottom-up approach forms cubosomes
from molecular solution by, for example, dilution of an ethanol-monoolein solution. Top-
down or high-energy techniques require formation of cubosomes prior to their use in a
product. Bottom-up techniques avoid high-energy drawbacks and allow formation of
cubosomes in use by a consumer or during product formulation. Both techniques require a
colloidal stabilizer, like the tri-block copolymer Poloxamer 407, to prevent cubosome
aggregation. Cubosome formation by any method, even dispersion of bulk cubic phase,
requires some time for the viscous cubic phase to crystallize from less-ordered precursors.
The mechanism of cubosome formation by high energy dispersion is clearly the
fragmentation of bulk cubic phase into smaller pieces. The dilution process produces
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
submicron cubosomes in the absence of fluid shear by dilution of an isotropic liquid
precursor, but the exact cubosome formation mechanism is not known
[11]
.



Fig 4: Cubosomes
4. Colloidosomes: The capsules are fabricated by the self-assembly of colloidal particles
onto the interface of emulsion droplets. After the particles are locked together to form elastic
shells, the emulsion droplets are transferred to a fresh continuous-phase fluid that is the same
as that inside the droplets. The resultant structures, which we call colloidosomes, are
hollow, elastic shells whose permeability and elasticity can be precisely controlled. The
capsule surfaces are composed of a close-packed layer of colloidal particles, linked together
to form a solid shell; the interstices between the particles form an array of uniform pores,
whose size is easily adjusted over the nanometer to micrometer scale to control the
permeability
[12]
.

Colloidosomes are used as advanced tool for encapsulation of various materials such as
drugs, dyes, cosmetics, biomaterials as filler in catalysis and waste removal. Conventional
methods of preparing a core particle include capillary-based micro fluidic techniques,
precipitation polymerization techniques and inverse suspension polymerization techniques
[13]
.

Fig 5: Colloidosomes
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5. Ethosomes: Ethosome are novel carrier system used for delivery of drugs having low
penetration through the biological membrane mainly skin. Ethosomes are the slight
modification of well established drug carrier liposome. Ethosomes are lipid vesicles
containing phospholipids, alcohol in relatively high concentration and water. Ethosomes are
soft vesicles made of phospholipids and ethanol and water. The size range of ethosomes may
vary from tens of nanometers to microns (). Ethosomes permeate through the skin layers
more rapidly and possess significantly higher transdermal flux in comparison to conventional
liposomes. Ethosomes provides a number of important benefits including improving the
drugs efficacy, enhancing patient compliance and comfort and reducing the total cost of
treatment
[14]
.



Fig 6: Ethosomes
Advantages of ethosomal drug delivery
In comparison to other transdermal & dermal delivery systems, Ethosomal drug delivery has
enhanced permeation of drug through skin.
Delivery of large molecules is possible.
It contains nontoxic raw material in formulation.
High patient compliance: The ethosomal drug is administrated in semisolid form (gel or
cream) hence producing high patient compliance.
The Ethosomal system is passive, noninvasive and is available for immediate
commercialization.
Ethosomal drug delivery system can be applied widely in Pharmaceutical, Veterinary,
Cosmetic fields.
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Simple method for drug delivery in comparison to Iontophoresis and Phonophoresis and
other complicated methods.

Method of preparation
There are two methods which can be used for the formulation and preparation of ethosomes.
Both of the methods are very simple and convenient and do not involve any sophisticated
instrument or complicated process. Ethosomes can be formulated by following two methods.

a) Hot method: In this method disperse phospholipid in water by heating in a water bath at
400 C until a colloidal solution is obtained. In a separate vessel properly mix ethanol and
propylene glycol and heat upto 400c. Add the organic phase into the aqueous phase. Dissolve
the drug in water or ethanol depending on its solubility . The vesicle size of ethosomal
formulation can be decreased to the desire extent using probe sonication or extrusion method.

b) Cold method: This is the most common and widely used method for the ethosomal
preparation. Dissolve phospholipid, drug and other lipid materials in ethanol in a covered
vessel at room temperature with vigorous stirring. Add propylene glycol or other polyol
during stirring. Heat the mixture upto 300 C in a water bath. Heat the water upto 300c in a
separate vessel and add to the mixture and then stir it for 5 min in a covered vessel. The
vesicle size of ethosomal formulation can be decreased to desire extend using sonicatio or
extrusion method. Finally, the formulation should be properly stored under refrigeration
[15]
.

5. Niosomes: Niosomes are formations of vesicles by hydrating mixture of cholesterol and
nonionic surfactants.


Fig 7: Niosome
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Kagalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Advantages of Niosomes
The application of vesicular (lipid vesicles and non-ionic surfactant vesicles) systems in
cosmetics and for therapeutic purpose may offer several advantages.
Niosomal dispersion in an aqueous phase can be emulsified in a nonaqueous phase to
regulate the delivery
rate of drug and administer normal vesicle in external non-aqueous phase.
They are osmotically active and stable, as well as they increase the stability of entrapped
drug.
Handling and storage of surfactants requires no special conditions.
They improve oral bioavailability of poorly absorbed drugs and enhance skin penetration
of drugs.
They can be made to reach the site of action by oral, parenteral route.
[16]


Method of preparation of Niosomes
Niosomes can be prepared by a number of methods
[17] [18]
which are as follows
Ether Injection Method
Hand Shaking Method (Thin Film Hydration Technique)
Reverse Phase Evaporation Technique
Multilamellar vesicles (mlv)
Transmembrane pH gradient Drug Uptake Process.

CONCLUSION
For the last few years, advanced drug delivery systems have been investigated to overcome
the limitation of the conventional systems. Herbal drugs have enormous therapeutic potential
which should be explored through some value added drug delivery systems. Lipid solubility
and molecular size are the major limiting factors for drug molecules to pass the biological
membrane to be absorbed systematically following oral or topical administration. Several
plant extracts and phytomolecules, despite having excellent bio-activity in-vitro actions
demonstrate less or no in-vivo actions due to their poor lipid solubility. The NDDS
innovation is especially relevant to those who are sensitive to drug toxicity and it helps to
avoid gastrointestinal disorders. It produces minimal drug level in the blood serum, with
chances of toxicity. This is a significant advantage for patient who needs medication several
times a day. Administration of NSAIDs by novel drug delivery system at a site of tissue
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injury delays the onset and lowers the intensity of pain at lower doses than usually
administered orally.

REFERENCES
[1] Costas Kaparissides, Sofia Alexandridou, Katerina Kotti and Sotira Chaitidou. Recent
Advances in Novel Drug Delivery Systems, Submitted: July 1
st
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, 2006.
[2] N. B Khavare et al. A Review on key parameters and components in Designing of
Osmotic Controlled Oral Drug Delivery Systems; Indian Journal of Novel Drug
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[3] Dimitrios Misirlis. Development of a novel drug delivery System based on polymeric,
thermoresponsive, Hydrogel nanoparticles.Thesis no 3362; 2005.
[4] Nidhi Mishra, Narayan P Yadav, Phyto-vesicles: conduit between conventional and
novel drug delivery system, Asian Pacific Journal of Tropical Biomedicine (2012) S
1728-S1734.
[5] Priyanka R. Kulkarni, Jaydeep D Yadav, Liposomes: A novel drug delivery system
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[6] Akbarzadeh et al, Liposome: Classification, Preparation, and Applications. Nano-scale
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[7] J.S. Dua1, Prof. A. C. Rana, Dr. A. K. Bhandari , Liposome: Methods of preparation
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[9] Solanki U et al., Overview of cubosomes: A nano particle, International Journal of
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[10] Madhurilatha et al. Overview of cubosomes: a nano particle, IJRPC 2011, 1(3).
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[12] A. D. Dinsmore, Colloidosomes: Selectively Permeable Capsules Composed of
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[13] R. Parthibarajan et al, Colloidosomes drug delivery: a review, IJPBS, Volume 1, Issue
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[18] V. Lokeswara Babu et al, Niosomes vesicular drug delivery system, Int J Pharm
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