TRANSDERMAL DRUG

DELIVERY THROUGH
VESICLES

Jolly R. Parikh
Assistant Professor
A. R. College of Pharmacy
Vallabh Vidhyanagar
 TRANSDERMAL DELIVERY

• It is the delivery of drugs by topical

application of drugs on skin.
• Drug is delivered from the outside o
f the skin through its various layers i
nto the bloodstream.
ADVANTAGES OF TRANSDERMAL DELIVERY
• The system avoids the chemically hostile GI environm
ent.
• No GI distress or other physiological contraindications
of the oral route.
• Can provide adequate absorption of certain drugs.
• Increased patient compliance.
• Avoids first-pass effect.
• Allows effective use of drugs with short biological hal
f-life.
• Allow administration of drugs with narrow therapeuti
c windows.
• Provides controlled plasma levels of very potent drug
s.
• Drug input can be promptly interrupted when toxicity
occurs.
 Disadvantages of transdermal
delivery

• Drug that require high blood levels cannot be

administered.
• Drug or drug formulation may cause skin
irritation or sensitization.
• Low permeability of drugs through stratum
corneum the outermost layer of the skin.
 Structure of human skin

• Human skin
– The stratified avascular cellular epider
mis
– An underlying dermis of connective tiss
ue
– Subcutaneous layer
• Possible pathways for a penetrant to cross the skin barrier. (1) across the intact
horny layer, (2) through the hair follicles with the associated sebaceous glands, or
(3) via the sweat glands
Routes of penetration through skin
• There are three potential pathways to deliver the drugs through
skin:
1. Through hair follicles
2. Through sweat ducts
3. Through stratum corneum- Transcellular route

• Fractional appendageal area available for transport is 0.1%.

Therefore this route contributes negligibly to steady state drug
flux.
• This pathway is important for ions and large polar molecules as
well as polymers and colloidal particles which target follicles.
• The intact stratum corneum provides the main barrier to skin
delivery.
Factors influencing the permeation of
drugs through skin
• Skin structure and its properties: Integrity and
thickness of stratum corneum.
• The penetrating molecule and its physical-chemical
relationship to skin and the delivery platform:
Physicochemical properties of penetrant (pKa,
molecular size, stability, binding affinity, solubility,
partition coefficient.
• The platform or delivery system carrying the
penetrant.
• The combination of skin, penetrant, and delivery
system.
• Density of sweat glands and folicles.
• Skin hydration.
• Vehicle effects.
 Barriers to Transdermal delivery
• Structure of stratum corneum is compared with that
of a brick wall of- with the coeneocytes acting as
bricks surrounded by a mortar of intercellular lipid
lamallae.
• The highly organized lipid lamallae plays an essential
role in the barrier properties of stratum corneum.
• Most techniques are aimed to disrupt and weaken the
highly organized intercellular lipids in an attempt to
enhance drug transport across the skin barriers.
 STRATEGIES FOR TRANSDERMAL DELIVERY

Vesicles and Stratum corneum Electrically

Drug/ vehicle Stratum corneum
particles bypassed assisted methods
interaction modified

Liposomes & Micro needle

Drug / prodrug array Ultrasound
Analogues
Hydration

Chemical
High velocity Ablation
potential Iontophoresis
particles
Chemical Enhancers

Ion pair Follicular Magneto

coacervates delivery phoresis

Eutectic systems
Photomechanical
thermal wave
 STRATEGIES FOR TRANSDERMAL DELIVERY
Drug/ vehicle interaction:
• Selection of drug with correct physicochemical properties to
translocate barrier at an acceptable rate.
• Drug should be at its highest thermodynamic activity for maximum
penetration.
• Charged molecules do not penetrate SC but forming ion pair
complex increases permeation into SC lipids.
• Eutectics of drug with terpenes or menthol increases permeation.
Vesicles and particles
• Powder jet systems fires solid particles through SC into lower skin
layers.
Modification of SC:
• Hydration of stratum corneum increases penetration as water opens
up the compact structure of horny layer.
• Penetration enhancers like surfactants, sulphoxides, pyrrolidones,
fatty acid esters improves penetration.
• Solvents enter SC and change its solution properties by altering
chemical environment and thus increasing partitioning of drug into
horny layer.
STRATEGIES FOR TRANSDERMAL DELIVERY
Stratum corneum bypassed: Micro needle array
• Use of solid silicone microneedles[400]/hollow metal needles filled with
drug solution which insert drug below the barrier
• Laser ablation using high powered pulses to vaporize a section of horny
layer so as to produce permeable skin regions or chemical peeling is also
employed
• Follicular delivery: the poly sebaceous unit hair follicle, hair shaft and
sebaceous gland provides a route that bypasses intact SC.
• Electrically assisted methods:
• Application of a preparation topically and massaging with ultrasound
source. Ultrasound energy disrupts lipid packing in SC by cavitations.
• Iontophoresis is electrical delivery of charged molecules into tissues by
passing electric current through a drug containing electrode in contact
with the skin.
• Skin electroporation is creation of transient aqueous pores in the lipid
bilayers of skin by applying short electrical pulses for mili or
microseconds.
• Magnetophoresis is application of magnetic fields to move diamagnetic
materials through skin
• Photomechanical waves: A drug solution is placed on the skin covered by
a black polystyrene target which is irradiated with laser pulse. The
resultant photomechanical wave stresses the horny layer and enhances
drug delivery.
 INTRODUCTION TO VESICULAR SYSTEMS

• Vesicles are water filled colloidal particles

• The walls of these capsules consist of amphiphilic
molecules in bilayer conformation.
• In excess of water these amphiphiles can form
one(unilamellar) or more (multilamellar) concentric
layers.
• Hydrophilic drugs can be incorporated into the internal
aqueous compartment, whereas amphiphilic, lipophilic
and charged drugs can be associated with the vesicle
bilayer by hydrophobic or electrostatic attractions
• A wide variety of lipids and surfactants can be used to
prepare vesicles.
• The basic structure of vesicles is shown in the following
figure:
 GLOSSARY OF VESICULAR SYSTEMS
• Vesicles: water-filled colloidal particles. The walls of these particles
consist of amphiphilic molecules in a bilayer conformation.

• Liposomes: vesicles prepared from mainly phospholipids

• Liquid-state vesicles: the amphiphiles in the bilayers of these vesicles

form a liquid phase.

• Non-ionic surfactant vesicles or niosomes: vesicles prepared from

mainly non-ionic surfactants.

• Deformable non-ionic surfactant vesicles: vesicles prepared from

mainly non-ionic surfactants using a surfactant composition that
results in deformable bilayers.

• Transfersomes1: the walls of these vesicles consist of phospholipids

and an edge activator, which results in deformable bilayers.

• Gel-state vesicles: the amphiphiles in the bilayers of these vesicles

form a gel-phase.
 Rationale for using vesicles in dermal and
transdermal delivery
Vesicles act as
• Act as drug carriers to deliver entrapped drug
molecules into or across the skin.
• Act as penetration enhancers owing to the penetration
of the individual lipid components into the stratum
corneum and subsequently alteration of intercellular
lipid lamellae.
• Vesicles can penetrate the outer layer of the stratum
corneum where desosomal linkages become disrupted
and keratinocytes are less tightly bound.
• Lipid vesicles may fuse with endogenous lipids on the
surface or in outermost layers of stratum corneum. This
fusion is followed by structural changes in the deeper
layers of stratum corneum which are presumed to be
the result of intercellular diffusion of vesicle lipid
components to the deeper layersas well as intercation
with and disruption of endogenous lipid lamallae. This
will lead to increased permeation rates.
ROLE OF LIPOSOMES IN TRANSDERMAL DELIVERY
• Liposomes are simple microscopic vesicles in which lipid bilayer
structures are present with an aqueous volume entirely enclosed
by a membrane composed of lipids.
• Liposomes can enhance drug delivery through skin routes by
various mechanisms:

Liposomes

Permeation Direct transfer of drug Flexible vesicles

enhancer effect between Liposomes and skin

Disruption of Affinity between Transdermal osmotic ingredient

SC lipids Liposomes & Skin

Hydration force
High partitioning
Introduction of liposomes into skin

Drug solubility
 Role of Liposomes
• Liposomes may act as permeation enhancers by penetration of
individual lipid components.
• Phospholipids are able to diffuse into SC and interaction and
enhancer effects are based on lipid mixing of Liposomal
phospholipids with lipid bilayers of skin.
• Phospholipids can disrupt the bilayer fluidity in the SC
decreasing barrier properties of skin.
• Phospholipids in Liposomes may mix with SC lipids creating a
lipid rich environment. This lipid depot in skin is preferred by
lipophilic drugs resulting in enhanced skin uptake.
Phospholipids may also act as solubilizers to increase solubility
of lipophilic drugs such as indomethacin & miconazole.
• The type of phospholipids also play an important role in
transdermal flux of drugs. Egg PC, soybean PC,
Dioleylphosphatidyl ethanolamine increase drug permeation
through skin while distearoyl PC does not. EPC,SPC and DOPE
have low value of gel liquid crystalline phase transition
temperature and they are in a fluid state at skin temp of
32oC.The fluid state phospholipids disturb the rigid bilayer
structure of skin lipids leading to increased drug partitioning.
 Role of Liposomes
• The mechanism of SC liposome interaction have been studied
using DSC, x-ray diffraction, electro paramagnetic resonance,
pluoro micrography, & con focal laser scanning microscopy.
• Most of the investigators have suggested that direct transfer
of drug between phospholipid bilayers of Liposomes and lipid
content of skin causes enhancement of drug delivery via skin.
• Liposomes do not act as permeation enhancers but provide
the necessary physicochemical environment for transfer of
drugs into the skin.
• Liposome penetration into skin largely depends on lipid
composition, thermodynamic state of bilayers and liquid or
gel state of vesicles.
• Liquid state vesicles may act not only on in superficial skin
layers but may also modify intercellular lipid lamallae in
deeper layers of Sc while gel state vesicles interact with
outer most layers in SC.
• Liquid state vesicles are more effective in transporting drugs
across the skin.
 Applications of liposomes in transdermal delivery
Drug Application
Triamcinolone acetonide The application of the liposomal preparations
was associated with greater steroid concentr
ations in the epidermis and dermis
- Retinoic acid Enhanced delivery into the skin has been rep
- Caffeine orted by liposome encapsulation. Liposomal
- Lignocaine delivery results in the formation of a large dr
ug reservoir in the skin which can be used fo
r local treatment.
Hydrocortisone, Increased uptake form liposomes into the cor
fluocinolone acetonide, nified layer of hairless mice and/or guinea pi
inulin (cyclosporine gs.
Liposomal entrapment Specific delivery into the hair follicles of hist
of calcein ,melanin & DNA ocultured mouse skin while aqueous control s
olutions of these molecules showed no drug l
ocalization within the follicle.
•Tretinoin for the treatment of acne Liposomal carriers have been successful in
•Glucocorticoids for the treatment of enhancing the clinical efficacy of all these
atopic eczema. drugs.
•Lignocaine and Tetracaine as anesthetics
Applications of liposomes in transdermal
delivery

• The first marketed topical liposomal dru

g, Pevaryl Lipogel, produced by Cilag A
G, became available in Switzerland in 1
988. The product contains 1% econazol
e in a liposomal gel form.
 Role of Niosomes in transdermal delivery

• Niosomes are vesicular systems composed of

nonionic surfactants instead of phospholipids.
• They are capable of entrapping hydrophobic
and hydrophilic drugs.
Recently niosomes are gaining popularity in the
field of topical and transdermal delivery due to
their following characteristics:
• They increase skin penetration of drugs.
• They can act as a local depot for sustained
release of dermally active compounds.
• They can serve as solubilizing matrix for
hydrophilic and lipophilic type of drugs.
 Mechanism of skin penetration by
niosomes
• Adsorption and fusion of niosomes onto the surface of
the skin leading to high thermodynamic activity
gradient at the interface, which is the driving force for
permeation of lipophilic drugs.
• The effect of vesicles as penetration enhancer reduces
barrier properties of stratum corneum. As surfactants
are the components of niosomes, they increase
transdermal permeation and Percutaneous absorption
by decreasing surface tension, improving wetting of
skin and enhance distribution of drugs.
• The lipid bilayers of niosomes act as a rate limiting
membrane barrier for drugs.
 Proniosomes
• Proniosomes offer a versatile vesicle drug
delivery concept with potential for
delivery of drugs via transdermal route.
• This would be possible if Proniosomes
form niosomes upon hydration with water
from skin following topical application
under occlusive conditions.
• Proniosomes minimizes problems of
niosomes physical stability such as
aggregation, fusion and leaking and
provide additional convenience in
transportation, storage and dosing.
 Applications of niosomes/ Proniosomes in transdermal delivery

Drug Application
Nimesulide Better anti-inflammatory effect when entrapped
in niosomes
Methotrexate Niosomal Methotrexate gel is more efficacious in
the treatment of localized psoriasis
Levonorgestrel Proniosomal transdermal patch bearing
Levonorgestrel produces more effective
contraception.
Ammonium Niosome formulation shows efficacious anti-
glycyrrhizinate inflammatory activity
Ketorolac Increased Permeation form Proniosomes

Captopril Transdermal delivery through niosomes

Celecoxib Niosomal gel formulation possess great potential

for enhanced skin accumulation, prolonging drug
release and improving the site specificity of
celecoxib
 Elastic Vs Rigid vesicles
• Rigid vesicles consist of double chain nonionic
surfactants or lipids.
• Elastic vesicles consist of double chain nonionic
surfactants or lipids and an edge activator.
• Elastic vesicles have superior characteristics as
compared to rigid conventional vesicles both in
terms of skin permeation and skin interaction.
• Elastic vesicles can be produced by incorporation
of surfactants or ethanol into bilayers.
 ETHOSOMES

• The ethosomes are vesicular carrier

comprising of hydro alcoholic or
hydro/alcoholic/glycolic phospholipid in
which the concentration of alcohols or
their combination is relatively high.
 Different Additives Employed In Formulation of
Ethosomes : 
Class Example Uses
Phospholipid - Soya phosphatidyl choline Vesicles forming
- Egg phosphatidyl choline component
- Dipalmitylphosphatidyl
Choline
- Distearyl phosphatidyl
choline
Polyglycol Propylene glycol As a skin
Transcutol RTM Penetration
enhancer
Alcohol Ethanol For providing
Isopropyl alcohol the softness for
vesicle
membrane
As a penetration enhancer
Cholesterol Cholesterol For providing the stability
to vesicle membrane
Morphological characterizations of ethosomal formulation by
Transmission Electron Microscopy (TEM). Magnification (x 80, 000)
 ROLE OF ETHOSOMES IN SKIN PENETRATION
• Touitou discovered and investigated lipid vesicular systems embodying
ethanol in relatively high concentration and named them ethosomes.
• The basic difference between liposomes and ethosomes lies in their
composition.
• The synergistic effect of combination of relatively high concentration
of ethanol (20-50%) in vesicular form in ethosomes was suggested to be
the main reason for their better skin permeation ability.
• The high concentration of ethanol (20-50%) in ethosomal formulation
can disturb the skin lipid bilayer organization. Therefore, when
integrated into a vesicle membrane, it can give an ability to the
vesicles to penetrate the SC.
• Furthermore, due to high ethanol concentration the ethosomal lipid
membrane is packed less tightly than conventional vesicles but
possesses equivalent stability. This allows a softer and malleable
structure giving more freedom and stability to its membrane, which
could squeeze through small openings created in the disturbed SC
lipids.
• In addition, the vesicular nature of ethosomal formulations can be
modified by varying the ratio of components and chemical structure of
the phospholipids. The versatility of ethosomes for systemic delivery is
evident from the reports of enhanced delivery of quite a few drugs like
acyclovir, minoxidil, triphexyphenidyl, testosterone , cannabidol and
zidovudine.
 Proposed Mechanism of Skin Permeation
of Ethosomes
• The figure shows the schematic representation of mechanism of
skin permeation of ethosomes.
• The stratum corneum lipid multilayers at physiological
temperature are densely packed and highly conformationally
ordered.
• Ethosomal formulations contain ethanol in their composition that
interacts with lipid molecules in the polar headgroup regions,
resulting in an increased fluidity of the SC lipids.
• The high alcohol content is also expected to partial extract the
SC lipids. These processes are responsible for increasing inter and
intracellular permeability of ethosomes.
• In addition, ethanol imparts flexibility to the ethosomal
membrane that shall facilitate their skin permeation. The
interdigitated, malleable ethosome vesicles can forge paths in
the disordered SC and finally release drug in the deep layers of
skin.
• The transdermal absorption of drugs could then result from
fusion of ethosomes with skin lipids. This is expected to result in
drug release at various points along the penetration pathway.
Fluorescence photomicrograph of rat skin after application of hydrophilic fluorescence probe
6-carboxyfluorescein from (A) Liposomal formulation (x 100); (B) Ethosomal formulation
(x100) and Rhodamine 123 from (C) Liposomal formulation; (x 100) (D) Ethosomal formulation
(x100). SC = Stratum corneum, E = Epidermis, D = Dermis; FL = Fibrous layer, Ad = Adipose
tissue, Ve = Vesicular stacks
 
 Applications of ethosomes in transdermal delivery
Drug Application of ethosomes
NSAIDS (Diclofenac) Selective delivery of drug to desired
side for prolong period of time
Acyclovir Increase skin permeation
Trihexyphenidyl hydrochloride Improved transdermal flux
Antibiotic Improved skin deposition
Cannabidol
Erythromycin
Bacitracin Improved dermal deposition

Anti-HIV agents Improved transdermal flux

Zidovudine
Lamivudine
Ammonium glycyrrhizinate    Improved dermal deposition exhibiting
sustained release
¯     Improved biological anti-
inflammatory activity
 Tranferosomes
• Tranferosomes are modified Liposomes developed
to increase transdermal permeation of drugs.
• They are more deformable than standard
Liposomes and thus well suited for skin
penetration.
• Deformability is achieved by including surface
active agents in the formula in an appropriate
ratio.
• They consist of phospholipids and an edge
activator which is a surfactant that destabilizes
lipid bilayers of the vesicles and increases
deformability.
• Not only the physicochemical characteristics of
vesicles but also the mode of application of
Tranferosomes play a crucial role in vesicle skin
interactions.
Mechanism of skin penetration by Tranferosomes
• The passage of Tranferosomes across the skin is a function
of vesicle membrane flexibility, hydrophilicity and ability
of vesicle to retain its integrity.
• When Tranferosomes in suspension are applied on the skin
surface the water evaporates from the skin surface and
vesicles begin to dry out.
• Due to high polarity of Tranferosomes ingredients vesicles
get attracted towards areas of higher water content in the
narrow gaps between the adjoining cells in the skin
• This process along with vesicle membrane’s deformability,
enables the Tranferosomes aggregates to open the tiny
pores temporarily through which water normally gets
evaporated between the cells.
• Such newly activated intercellular channels can
accommodate sufficiently deformable vesicles,
maintaining their integrity and changing their shape to fit
the channels and reach regions of higher water content in
the deeper layers of skin in which the vesicles get
distributed between the cells.
• Tranferosomes bypass the cutaneous capillary bed
because they are too large to enter the blood vessels
locally and reach the subcutaneous tissue.
• Ultimately the vesicles arrive into the systemic
circulation via the lymphatic system. The presence of
large number of hydrophilic molecules in
tranferosomes enhances aggregate sensitivity to the
driving force which results from a water
concentration across the skin.
• This process explains the ability of highly deformable
Tranferosomes to cross the skin barrier.
• The difference in skin condition between occlusive
and non-occlusive conditions is of importance for
Tranferosomes penetration.
• Cevc et al suggested that the transport of
Tranferosomes is driven by the osmotic gradient
across the skin. Occlusion would eliminate this
osmotic ingredient and prevent skin penetration.
 Protransferosome gels
• The provesicular approach has been
extended to the tranferosomes, which
are reported to have superior skin
penetration ability.
• Liquid crystalline protransfersome gel
(PTG) will be converted into the ultra
flexible vesicles, tranferosomes also
known as elastic liposomes, in situ by
absorbing water.
 Protransferosome gel

Lamellar liquid crystalline structure of Figure 2. TEM photomicrograph of PTG

protransfersomal gel formulation after hydration (×1,20,000).
(Photomicrograph A, X 400), Scale bar Scale bar = 500 nm.
= 500 μm and vesicular structure of
tranferosomes formed upon hydration
of protransfersomal gel
(photomicrograph ×1000). Scale bar =
1 μm.
 Protransferosome gels
• For optimum drug delivery, a high degree of drug-vesicle association is
essential so that appreciable quantity of drug could be carried by
elastic vesicles across the stratum corneum.
• Subsequently, larger quantities of drugs will be released from the
vesicles, thereby increasing the amount of free drug available for
diffusion into the deeper skin layers. High entrapment efficiency of
protransfersome gel is probably the reason for its better skin
permeation.
• Furthermore, higher skin permeation of PTG could be a result of
better partitioning across the stratum corneum and to deeper layers of
skin under the influence of transepidermal osmotic gradients.
• The osmotic gradient is developed because skin penetration barrier
prevents water loss through the skin and maintains a water activity
difference in viable parts of the epidermis (75% water content) and
nearly completely dry stratum corneum near the surface (15% water
content).
• PTG consists of polar lipids (PC) that have a tendency to attract water
because of the energetically favorable interaction between the
hydrophilic lipid residues and proximal water molecules. Hence, when
PTG is applied on skin surface that is partly dehydrated by water loss
due to evaporation, the lipid vesicles feel this osmotic gradient and
try to escape complete drying by moving along this gradient resulting
in faster partitioning of vesicles into the stratum corneum and other
deeper layers of the skin.
 Applications of Transferosomes in transdermal delivery
• Transferosomes have been widely used as a carrier for the transport of
proteins and peptides. Proteins and peptide are large biogenic
molecules which are very difficult to transport into the body, when
given orally they are completely degraded in the GI tract.
• These are the reasons why these peptides and proteins are still have to
be introduced into the body through injections. Various approaches
have been developed to improve these situations. The bioavaibility
obtained from Transferosomes is some what similar to that resulting
from subcutaneous injection of the same protein suspension.
• Delivery of insulin by transferosomes is the successful means of non
invasive therapeutic use of such large molecular weight drugs on the
skin (Cevc et al, 1990). Insulin is generally administered by
subcutaneous route that is inconvenient. Encapsulation of insulin into
transferosomes (transfersulin) overcomes these entire problems. After
transfersulin application on the intact skin, the first sign of systemic
hypoglycemia are observed after 90 to 180 min, depending on the
specific carrier composition3.
• Transferosomes have also been used as a carrier for interferons, for
example leukocytic derived interferone-α (INF-α) is a naturally
occurring protein having antiviral, antiproliferive and some
immunomodulatory effects. Transferosomes as drug delivery systems
have the potential for providing controlled release of the administered
drug and increasing the stability of labile drugs.
 Applications of Transferosomes in transdermal delivery

• Another most important application of transferosomes is transdermal

immunization using transferosomes loaded with soluble protein like
integral membrane protein, human serum albumin, gap junction protein.
These approach offers at least two advantages, first they are applicable
without injection and second, they give rise to rather high titer and
possibly, to relatively high IgA levels.

• Transferosomes have also used for the delivery of corticosteroids.

Transferosomes improves the site specificity and overall drug safety of
corticosteroid delivery into skin by optimizing the epicutaneously
administered drug dose Transferosomes based cortiosteroids are
biologically active at dose several times lower than the currently used
formulation for the treatment of skin diseases (Cevc et al, 1997).

• Application of anesthetics in the suspension of highly deformable

vesicles, transferosomes, induces a topical anesthesia, under appropriate
conditions, with less than 10 min. Maximum resulting pain insensitivity is
nearly as strong (80%) as that of a comparable subcutaneous bolus
injection, but the effect of transferosomal anesthetics last longer.

• Transferosomes have also been used for the topical analgesics,

anesthetics agents, NSAIDS and anti-cancer agents. 
 References
• Drug Discovery Today: Technologies Vol.2 No.1, 2005.
• AAPS PharmSciTech. 2005; 6(3): E513-E522
• Recent Patents on Drug Delivery & Formulation, 2007, 1, 23-36.
• J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 5(3):220-225,
2002
• Journal of Controlled Release
Volume 54, Issue 2, 31 July 1998, Pages 149-165
• Biomedical Microdevices, Volume 9, Number 4, August 2007 ,
pp. 421-433(13)
• European Journal of Pharmaceutics and Biopharmaceutics Vol.
59, No. 3, pages 485-490 (2005)
• Current Drug Delivery, Volume 4, Number 4, October 2007 , pp.
276-282(7)
• Drug Dev Ind Pharm. 2003 Oct ;29 (9):1013-26 14606665
• Tropical Journal of Pharmaceutical Research, June 2007; 6 (2):
687-693
• http://www.pharminfo.net
• Drug Delivery Technology, October 2005.