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Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London SW1P 1WG, UK
Handbook of Nanotechnology in Nutraceuticals
Shakeel Ahmed, Tanima Bhattacharya, Annu, Akbar Ali
Phospholipid-Based Nanoplatforms
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https://www.routledgehandbooks.com/doi/10.1201/9781003244721-8
Amrita Chakraborty, Pubali Dhar
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183
8
8
Phospholipid-Based
Nanoplatforms
Evolving as Promising Carriers
for Therapeutic Intervention
Amrita Chakraborty and Pubali Dhar*
HIGHLIGHTS
• Successful utilization of physicochemical properties of phospholipids for fabrication of
various delivery vehicles such as nanoemulsions, liposomes, nanomicelles, solid lipid
nanoparticles, lipospheres, etc.
• Improvement of dermal delivery with the modication of liposomes and invention of trans-
ferosomes and ethosomes as novel carrier systems
• Formulation of phospholipid–drug complexes such as phytosomes and pharmacosomes for
enhancing stability, bioavailability, bioactivity and targeted delivery of therapeutics
8.1 INTRODUCTION
The therapeutic delivery domain, a subject of keen interest, has been addressed by new age scientic
research and used to treat fatal maladies. Experimental trials have revealed that the prophylactic and
* Corresponding author: pubalighoshdhar23 @gmail . com
Handbook of Nanotechnology in Nutraceuticals
CONTENTS
Highlights ....................................................................................................................................... 183
8.1 Introduction .......................................................................................................................... 183
8.2 Phospholipid-Based Nanoemulsion ...................................................................................... 185
8.3 Liposomes: A New Frontier of the Colloidal Drug Carrier System ..................................... 188
8.4 Modied Liposomes: Versatile and Flexible Nanovesicular Vehicles for Transdermal
Delivery ................................................................................................................................ 192
8.4.1 Transferosomes ......................................................................................................... 192
8.4.2 Ethosomes ................................................................................................................. 194
8.5 Phospholipid-Based Solid Lipid Nanoparticles: A Novel Formulation for Various
Routes of Administration...................................................................................................... 196
8.6 Multifunctional Micelles for Targeted Drug Delivery .........................................................200
8.7 Lipospheres as a Biocompatible Delivery System ................................................................204
8.8 Phospholipid–Drug Complexes for Enhancing Stability and Oral Bioavailability .............. 205
8.8.1 Phytosomes ............................................................................................................... 207
8.8.2 Pharmacosomes ........................................................................................................ 209
8.9 Conclusion ............................................................................................................................ 211
Acknowledgement ........................................................................................................................ 212
References ...................................................................................................................................... 212
DOI: 10.1201/9781003244721-8
10.1201/9781003244721-8
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184 Handbook of Nanotechnology in Nutraceuticals
Phospholipid-Based Nanoplatforms
therapeutic effectiveness of key bioactives cannot be fully attained through conventional delivery
approaches due to instantaneous renal ltration, instant removal via the reticulo-endothelial system
(RES), their circuitous movement from the circulation to the specic target area and the harsh acidic
conditions of endo-lysosomes within the cell (Rizvi and Saleh, 2018). To overcome the unsatisfac-
tory outcomes connected with the conventional mode of delivery, today, technological expansion has
directed its focus towards the development of nanostructures as prospective delivery devices for the
enhancement of therapeutic facilities. Nanodelivery strategies have emerged as promising encapsula-
tion techniques due to their nanoscale prole, inated surface area:volume ratio, considerable load
and optimal release properties (Aklakur etal., 2016). The fabrication of stable and safe nanomateri-
als for efcacious therapeutic delivery remains a prime challenge to scientists, as there are very few
excipients with generally regarded as safe (GRAS) status. In accordance with the growing perception
of designing bio-compatible, non-toxic, natural and edible delivery vehicles for the sake of a safe and
healthy lifestyle, biopolymers are increasingly gaining importance (Shit and Shah, 2014). The pref-
erence for edible polymers over synthetic surfactants is because natural biopolymers are produced
entirely from an eco-friendly replenishable reservoir and hence, are anticipated to degrade more
rapidly than other commercial compounds. Despite the fact that polymers are selected as vehicles
because of their less detrimental effects, polyethylene oxide (PEO) polymers present hazards; for
instance, they yield aldehydes after exposure to illumination and oxygen. Aldehydes causing toxicity
may disrupt the physiological system with harmful effects (Chakraborty and Dhar, 2017). In cur-
rent research, phospholipids have generated enormous interest as nanoformulation excipients due to
their unique physio-chemical characteristics and their multi-purpose utilization in both biological
and material spheres. Phospholipids, the main components of the cellular membrane, are amphipa-
thic in nature. In the continuously expanding domain of delivery for remedial agents, the choice
of phospholipids as a vehicle results from their innate biodegradability, inherent biocompatibility,
nutritional merits and cost-efcient maneuverability (Li etal., 2015b). Chemically, phospholipid mol-
ecules consist of a phosphate-bearing polar head group and a non-polar hydrocarbon tail attached
jointly by a glycerol or an alcohol molecule. The “head” is a water-loving moiety due to the presence
of phosphate anions and glycerol, whereas the “tail” is water-repellent, as the long fatty acid tail is
repelled by water and is compelled to cluster in an aqueous milieu (Singh etal., 2017b). The hetero-
geneous trait of the head group is due to the existence of miscellaneous functional groups linked to
the phosphate groups, for example phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidyl-
ethanolamine (PE) or phosphatidylserine (PS). There are two types of phospholipids: natural and
synthetic (Van Hoogevest and Wendel, 2014). Natural phospholipid excipients can be isolated from
various plant origins, such as ax seed, rapeseed, sunower and soybean seed, as well as several
animal sources, like egg yolk, milk and krill. For the food and pharmaceutical industry, natural
phospholipids may be further reconstructed by means of hydrogenation or enzymatic modication.
On the contrary, synthetic phospholipid excipients like polyethylene glycol (PEG)ylated phospholip-
ids and the positively charged phospholipid 1,2‐diacyl‐P‐O‐ethylphosphatidylcholine are synthetic
analogs of natural phospholipids. They can be designed with the help of customized chemical and/
or enzymatic synthesis techniques whereby specic polar head groups or non-polar fatty acids are
incorporated into the phospholipids. Lecithin is one of the major amphiphiles abundantly found in
cell membranes of plants and animals. It is a blend of most of the naturally derived phospholipids, of
which PC is the major component. Phospholipids can form a three-dimensional lamellar crystalline
structure as well as two-dimensional lamellar crystals depending on temperature and/or hydration
extent (Karamanidou etal., 2016). The phase transition is mainly instigated by thermal alteration; by
raising the temperature beyond a certain extent, the hydrocarbon tail becomes liquid, which therefore
promotes a transition from the solid to the liquid state. Phospholipids in the liquid state can form
bilayers, generate various supramolecular structures and adopt different self-organizing molecular
assemblies, such as direct and inverted micelles, emulsions, organogels or liposomes, when dispersed
in aqueous media (Suriyakala etal., 2014). Hydrated phospholipids are thermodynamically stable and
visco-elastic. Phospholipids have exhibited good interfacial properties, which can signicantly inu-
ence emulsion stabilization (Li etal., 2014). Surface-active phospholipids can also cover the surface
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185Phospholipid-Based Nanoplatforms
of crystals to augment the hydrophilic nature of lipophilic drugs and nutraceuticals (Silva etal., 2012).
Along with the physicochemical functionalities, phospholipids have also shown excellent physiologi-
cal benets. Non-allergic natural phospholipids are known to be harmless permeation enhancers and
hence, can be employed to regulate the absorption of active therapeutics through different mecha-
nisms, for example altering the release of the bioactive core, increasing their bioavailability, inu-
encing the intestinal conditions, boosting the lymphatic transport of bioactive agents, dealing with
enterocyte-based metabolism, etc. (Van Hoogevest and Wendel, 2014). Phospholipids can reform the
skin lipid barrier, thereby aiding the transcellular transfer of active agents and performing as pen-
etration enhancers (Vanić, 2015). Besides their immense potential to successfully protect therapeu-
tic molecules from instant degradation in the gastrointestinal environment and reduce undesirable
aftereffects, phospholipids are generally recognized for remarkable hepatoprotection from drugs,
alcohol and other toxic substances (Gundermann etal., 2011). Essential phospholipids have also been
found to exhibit antilipemic and antiatherogenic activity by hindering the elevation of total lipids in
dietetic hypercholesterolemia at both curative and preventive doses (Leuschner etal., 1976). Marine
phospholipids have been reported to have a broad spectrum of health benets through a synergistic
mode that combines the favorable quality of long-chain n-3 polyunsaturated fatty acids (PUFAs) with
the ideal stability and notable permeating abilities of amphiphilic phospholipids within biological tis-
sues (Paul etal., 2018). High-dosage phospholipids can effectively treat neuro-degenerative diseases
(Küllenberg etal., 2012). In this present scenario, this chapter intends to explore the recent evolution
and expansion in the fabrication technologies as well as the versatile ameliorative application spec-
trum of the phospholipid-based nanovehicles. Phospholipids provide several possibilities to engineer
a number of distinct nanocarriers, such as nanoemulsions, nanomicelles, nanoliposomes, solid lipid
nanoparticles, phospholipid–drug complexes, lipospheres, and so on.
8.2 PHOSPHOLIPID-BASED NANOEMULSION
Nanoemulsions are submicron-sized colloidal dispersions containing tiny droplets, i.e., mean radius
ranging between 10 and 100 nm (McClements, 2012). Due to the fairly small-scale droplet size in
comparison with the wavelength of light (r << λ), nanoemulsions seem to be optically transparent,
whereas a conventional emulsions generally appear optically turbid or opaque. Moreover, due to the
very small particle radii, nanoemulsions tend to be kinetically stable against gravitational separa-
tion and aggregation (McClements and Rao, 2011). Generally, the production of nanoemulsions
from natural excipients relies on high-energy emulsication approaches, whereas low-energy tech-
niques utilize the fundamental physicochemical virtues of the excipients for spontaneous emulsi-
cation (Klang and Valenta, 2011). Figure 8.1a illustrates the high-energy approaches for fabricating
a nanoemulsion.
Emulsions are shown to acquire better stability when manufactured with PC as emulsiers com-
pared with PS and PE, since PC is apt to organize a closely packed monolayer interface. The mono-
layer made from PC is in a liquid crystalline phase, while those made from PS and PE are in a liquid
expanded state (Pichot etal., 2013). Zwitterionic phospholipid emulsiers are reported to impart
stability to formulations by acting simultaneously as an electrostatic and a mechanical barrier to
coalescence. An interfacial barrier constructed from, at the minimum, two phospholipid layers is
indispensable to ensure emulsion stability, and the emulsion stability is boosted by multiple layers of
phospholipids around the droplets. Charged phospholipids intensify droplet repulsion, which results
in improved emulsion stability. The selection of the lipid component seems to be a signicant deter-
mining criterion for the pharmacokinetic release of active core from the nanoemulsion. Squalene
has often been documented to be an exceptionally benecial lipophilic biomolecule for the fabrica-
tion of lecithin-stabilized nanoemulsions. Squalene nanoemulsions with varied amounts of lecithin
depicted satisfactory stability and the prolonged release of the hydrophobic drug rifampicin in com-
parison with innumerable oils in vitro (Chung etal., 2001). Multifaceted advantages can be obtained
by utilizing lecithin-stabilized nanoemulsions for therapeutic intervention through parenteral
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186 Handbook of Nanotechnology in Nutraceuticals
delivery. Hydrophobic therapeutics can be easily entrapped in the lipid core, and their poor water
solubility is mitigated, which consequently amplies bioavailability. Egg phospholipid–based nano-
emulsion is found to enhance the analgesic potency and duration of release of nalbuphine and its
prodrugs (Wang etal., 2006). For parenteral delivery, the nanoemulsion encapsulating chlorambucil
was fabricated with an average size below 150 nm and encapsulation efciency >97%. The cytotox-
icity as well as the pro-apoptotic activity of chlorambucil were markedly elevated when delivered in
the nanoemulsion formulation instead of aqueous solution (Ganta etal., 2008). Carbamazepine, an
anticonvulsant drug, was also encapsulated in soy lecithin–based nanoemulsion for intravenous
administration (Kelmann etal., 2007). The nanoemulsion formulation was found to be stable, and
its characteristics were maintained in a reasonably acceptable range over a 3-month time period; for
example, droplet diameter about 150 nm, zeta potential about −40 mV and drug encapsulation about
95%. In vitro release kinetics evaluated by dialysis bags showed that 95% of drug had been released
in less than 11 hours. Nevertheless, a critical criterion limiting the global application of lecithin-
stabilized nanoemulsions via the parenteral route is the fear of hemolysis, which might occur as a
result of the bio-molecular interactions between phospholipids and erythrocytes. Egg phosphatidyl-
choline was reported to bring on moderate toxic effects in mature red blood cells in vitro, which was
increased upon the addition of stearylamine and reduced in the presence of Brij-type surfactants. To
avoid the formation of lyso-derivatives and to control the hemolytic potential of the blood, Masoumi
etal. suggested using Tween 80 as a co-emulsier. A nanoemulsion developed using lecithin and
Tween 80 was found to be stable with small droplet size (Masoumi etal., 2015). On the other hand,
a stable curcumin nanoemulsion can be procured by utilizing hydroxylated lecithin as emulsifying
agent and using the ultrasonication technology simultaneously. The report demonstrated that the
amplitude and ultrasonication time had a profound impact on the droplet diameter and the polydis-
persity index of the fabricated nanoemulsion (Espinosa-Andrews and Páez-Hernández, 2020). A
lecithin-stabilized nanoemulsion aiming at oral administration of primaquine was shown to possess
FIGURE 8.1 (a) High-energy approaches as the most commonly used technology for fabrication of nano-
emulsion. (b) Thin lm hydration as the simplest technique for production of phospholipid-based liposomes.
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187Phospholipid-Based Nanoplatforms
markedly better antimalarial activity and in vivo biodistribution compared with a readily available
drug solution. Compared with the commercially available drug, the formulation was proved to pen-
etrate into the hepatic cells with a drug concentration around 45% or above (Singh and Vingkar,
2008). The use of cefpodoxime proxetil, an oral cephalosporin antibiotic, was limited due to its
inadequate water solubility along with insufcient bioavailability. A lecithin-based nanoemulsion
offered amplied absorption of encapsulated cefpodoxime proxetil, which resulted in superior bio-
availability (97.4%) compared with a suspension, an alcoholic solution and an emulsion encapsulat-
ing active molecule (Nicolaos etal., 2003). Additionally, this formulation was shown to shield the
active component from unintended enzymatic degradation in the intestine. A recent in vivo pharma-
cokinetic investigation in a rat model demonstrated that in a lecithin-based nanoemulsion, the bio-
availability and bioaccessibility of carnosic acid were about 2.2-fold and 12.6-fold higher,
respectively, than those of carnosic acid suspension. Additionally, it was found that the carnosic
acid–loaded nanoemulsion improved the solubility, digestion rate, retention time and sustained
release of carnosic acid during digestion (Zheng etal., 2020). Paclitaxel, a poorly water-soluble che-
motherapeutic agent, is a substrate of the P-glycoprotein efux pump. Tiwari and Amiji loaded the
substance into an oil-in-water nanoemulsion using egg lecithin as emulsier (Tiwari and Amiji,
2006). The fabricated nanoemulsions had an average particle size about 90–120 nm and zeta poten-
tial ranging between −56 and +34 mV. In comparison with an aqueous solution of paclitaxel, the
fabricated nanoformulation yielded a signicantly elevated blood level of paclitaxel in an experi-
mental mouse model. Nanoemulsions are being explored not only for achieving a sustained release
mechanism but also for specic organ targeting. Surface alteration of the emulsion droplets, for
instance with PEG derivatives, can be utilized to achieve long-term residence in circulation as well
as passive targeting to inamed areas and tumors. Lecithin-stabilized nanoemulsions with and with-
out PEG modication were recruited for successful co-loading of paclitaxel and curcumin to con-
quer the multidrug resistance issues in tumor cells by stimulating apoptosis (Ganta and Amiji, 2009).
In vitro studies have shown that ultrasound-mediated delivery of a lecithin-based nanoemulsion
entrapping curcumin demonstrated signicant cellular toxicity against OSCC-4 and OSCC-25 cell
lines (Lin etal., 2012). Vecchione etal. developed a curcumin-loaded nanoemulsion utilizing leci-
thin as a surfactant and functionalized chitosan as a coating agent to regulate the deposition and
bio-molecular interaction of the formulation with the intestinal barrier. The highest level of bioavail-
ability was achieved in the case of the smaller nanoemulsion (average particle size 110 nm) coated
with the highest degree of chitosan modication and co-delivered with piperine (Vecchione etal.,
2016). Lecithin-based nanoemulsions manifested higher permeability and sustained release of res-
veratrol through a Caco-2 cell monolayer than those prepared by the combination of Tween 20 and
glycerol monooleate (Sessa etal., 2014). This is attributed to the fact that the shell layer made of a
mixture of phospholipids of soy lecithin is analogous to the phospholipid bilayer residing in the cell
membrane. Therefore, absorption and entrapment of the lecithin-based nanoemulsion in the micro-
villi is enhanced, resulting in improved transport through the cell membrane. Heo etal. assessed the
impact of nanoemulsication with lecithin on the thermal stability as well as bioavailability of con-
jugated linoleic acid in various free fatty acid and triacylglycerol (TG) forms. Conjugated linoleic
acid (CLA) nanoemulsion in triacylglycerol (TG) form presented a smaller droplet size (70−120 nm)
than CLA nanoemulsion in free fatty acid (FFA) form (230−260 nm). The in vitro bioavailability test
revealed that in both FFA and TG forms, cellular penetration of CLA via the monolayers of Caco-2
human intestinal cells was increased after nanoemulsication. Moreover, a rat feeding study reported
a remarkable increase in CLA level in plasma or small intestinal tissues after administration of a
CLA nanoemulsion, demonstrating improved oral bioavailability of CLA with the assistance of
nanoemulsication (Heo etal., 2016). A lecithin-based nanoemulsion was also fabricated by a spon-
taneous emulsication process for entrapping ferulic acid, one of the most common pharmacologi-
cally active polyphenolic compounds with poor water solubility (Ebrahimi etal., 2013). To facilitate
corneal drug delivery, lecithin-based nanoemulsions can be used as penetration enhancers by
detaching the mucus layer and disrupting the arrangements of tight junction proteins. Ammar etal.
utilized nanoemulsions as a delivery system for dorzolamide hydrochloride in glaucoma therapy
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188 Handbook of Nanotechnology in Nutraceuticals
(Ammar etal., 2009). Differential scanning calorimetry has demonstrated the alteration in uidity
of skin lipids with various lecithin-based nanoemulsion systems. Due to this improved skin lipid
uidity, lecithin might help the encapsulated active compounds to readily penetrate into the dermis.
The formulation can be evenly dispersed on the skin as a result of the tiny particle size along with
the uniform droplet dispersion in a nanoemulsion. The nano range of droplet sizes provides a huge
interfacial area that primarily increases the skin permeation rate of active elements and simultane-
ously extends their residence time in the outermost epidermal layers (Sonneville-Aubrun et al.,
2004). A lecithin-based nanoemulsion loaded with Nile red revealed that a nanoemulsion not only
signicantly improved the skin hydration of a formulation but also strengthened the skin penetration
of Nile red for topical application (Zhou etal., 2010). In another study, a lecithin-based nanoemul-
sion entrapping progesterone was developed, with an excellent skin permeation effect (Klang etal.,
2010). Silva and his team proved that a lecithin-based nanoemulsion was suitable for geneistin deliv-
ery, with mean droplet radii ranging between 230 and 280 nm along with a sustained release prole
(Silva etal., 2009). Enhancement of the percutaneous absorption of urbiprofen was observed after
incorporation of the drug into an egg lecithin–based nanoemulsion (Fang etal., 2004). Komaiko
etal. recently demonstrated sunower phospholipid as a natural emulsier for omega-3 delivery
applicable in the food industry. The study revealed that increased phospholipid concentration in
emulsions reduced the droplet dimensions. The fabricated emulsions were predominantly stabilized
by electrostatic repulsion and consequently, were prone to aggregation in specic environments
where the aqueous milieu had a high ionic strength or the droplets possessed relatively lower net
charges (Komaiko etal., 2016). The lecithin utilized in the food industry is usually extracted from
egg yolk, soybeans, milk, rapeseeds and sunower (Cui and Decker, 2016). The composition of leci-
thin changes according to the method of extraction and renement. Though physicochemically sta-
bilized oil-in-water emulsions were recently shown to be fabricated from sunower lecithins utilizing
both high- and low-energy approaches, researchers also found that the behavior of the emulsion
varied according to the phospholipid composition, especially the PC content in the total emulsier
(Liang etal., 2017). The unsatisfactory stability of emulsion obtained with the pure PC fraction may
be due to the dearth of emulsiers like PE (Van Hoogevest and Fahr, 2019). On the other hand,
hydrogenated soybean phospholipids containing 75% or 90% PC alone were found adequate for
emulsifying lipids with hydrophilic–lipophilic balance (HLB) values ranging between 4 and 11.
Interestingly, the hydrogenated soybean phospholipids with 75% PC was reported to be a slightly
ner emulsier as this intermediate-grade soy phospholipid provided a perfect blend of phospholipid
co-emulsiers varying in their hydrophilic head group. Moreover, compared with saturated and
monoacyl-phospholipids, unsaturated diacyl-lecithins are not adequate when used as a single stabi-
lizer for oil-in-water emulsion. Monoacyl-phospholipids are reported to assemble in a cone-shaped
conguration, which can ideally t the curvature of the interface between oil and water in the emul-
sions due to the presence of substantial surface area from the hydrophilic head group and the tiny
cross-sectional domain from fatty acids. The usage of biocompatible lecithin-stabilized nanoemul-
sions was proved to be suitable for various paths of administration, including sensitive paths such as
oral, intravenous, dermal and ocular administration. Though the complex behavior of phospholipids
in nanoemulsions still remains unclear, a number of innovative strategies are being continuously
explored for further optimization, modication and upgradation of lecithin-based nanoemulsions.
Fabrication techniques, physicochemical characteristics and therapeutic effects of phospholipid-
based nanoemulsions entrapping various active compounds are briey outlined in Table 8.1.
8.3 LIPOSOMES: A NEW FRONTIER OF THE
COLLOIDAL DRUG CARRIER SYSTEM
Liposomes are familiar and extensively explored particulate nanovesicles that have been effectively
recruited for the optimum release and targeted delivery of therapeutics (Akbarzadeh etal., 2013).
Liposomes, spherical sacs surrounded by at least one lipid bilayer, are mainly composed of
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189Phospholipid-Based Nanoplatforms
TABLE 8.1
Method of Fabrication, Physicochemical Characteristics and Therapeutic Effects of Phospholipid-Based Nanoemulsion Entrapping Various
Active Compounds
Type of
phospholipid
excipient
Active
compound Preparation method
Particle size
(nm)
Zeta
potential
(mV)
Entrapment
efficiency
(%) Therapeutic effect References
Hydrogenated L-α
phosphatidylcholine
from egg yolk
Curcumin Modied thin lm hydration
followed by sonication
47–56 – 90 Preserved cytotoxic effect to
cancer cell line
Anuchapreeda
etal., 2012
Soybean lecithin Carbamazepine Spontaneous emulsication 150 −40 95 Improved in vitro release prole Kelmann etal.,
2007
Soybean lecithin Conjugated
linoleic acid
High-pressure homogenization 70–120 −40 – Improved cellular uptake and
oral bioavailability
Heo etal, 2016
Lecithin,
DSPE-PEG2000
Doxorubicin Solvent diffusion 44.5 −25.6 71.2 Efciently accumulated in
targeted tumor tissue
Jiang etal., 2013
Lecithin Aripiprazole High-pressure homogenization 62.23 −31.6 – Expected to treat schizophrenia
efciently
Masoumi etal.,
2015
Egg phosphatidyl
choline,
DSPE-PEG2000
Curcumin Coarse homogenization followed
by ultrasonication
144 −44.53 97.4 Combination therapy blocked
P-gp, inhibited NFκB pathway,
enhanced cytotoxic efcacy and
the apoptotic response
Ganta etal., 2009
Egg phosphatidyl
choline,
DSPE-PEG2000
Paclitaxel Coarse homogenization followed
by ultrasonication
138 −39.74 100 Egg phosphatidyl choline,
DSPE-PEG2000
Paclitaxel
Egg lecithin,
soyabean lecithin
Primaquine High-speed homogenization 96.5 – 95 Improved accumulation in liver
and enhanced oral
bio-availability
Singh etal., 2008
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190 Handbook of Nanotechnology in Nutraceuticals
naturally derived phospholipids. The physicochemical properties of the liposomes, for instance
charge density, steric hindrance, membrane uidity and rate of permeation, have been reported to
decide the molecular interactions of liposomes with blood and specic tissues following administra-
tion. Liposomes are prepared to enclose both lipophilic and hydrophilic materials within the watery
portion of the vesicle or into the phospholipid bilayer itself. Liposomes were rst invented by
Bangham in 1965, and the lm hydration technique, also named the Bangham method, still presents
the easiest and earliest technique in liposome formulation. Figure 8.1b portrays the thin lm hydra-
tion technique for formulating phospholipid liposomes. At present, approximately 12 liposome-
based therapeutics are approved for ameliorative use, and the rest remain in different stages of
clinical trials (Zylberberg and Matosevic, 2016). The stratum corneum, a nely organized lipid
matrix consisting of corneocytes, is one of the crucial obstacles to deeper penetration of therapeu-
tics into the dermis. Pertinent literature reports that liposomal phospholipids can intensify skin
penetration or dermal deposition of therapeutics due to the blending of phospholipids in the lipo-
somes with lipid residing in the bilayers of epidermal cells (Daraee etal., 2016). Tacrolimus was
successfully loaded in a saturated soy lecithin-based liposomal system for topical application. The
in vitro investigation displayed noticeably diminished permeation of tacrolimus in the liposomal
formulation in contrast to free tacrolimus delivered within propylene glycol. An in vivo investiga-
tion in an animal model corresponding to allergic contact dermatitis (ACD) revealed that liposomal
gel loaded with 0.03% tacrolimus displayed indistinguishable efcacy in comparison to commer-
cially available 0.03% tacrolimus ointment (Patel etal., 2010). Orthosiphon stamineus, a medicinal
herb, possesses several active compounds with notable pharmacological attributes. Nonetheless, the
low solubility of these compounds restricts their therapeutic utilization. Soybean phospholipid–
based nanoliposomes containing O. stamineus ethanolic extract have been proved to show improved
solubility, permeability, oral bioavailability and antioxidative efcacy. Transmission electron
microscopy (TEM) along with dynamic light scattering (DLS) suggested the existence of spheri-
cally shaped anionic nanoliposomes possessing a particle size of about 152.5 ± 1.1 nm and zeta
potential of −49.8 ± 1.0 mV, approximately (Aisha etal., 2014). To compare the characteristics and
stability prole of curcumin liposomes, milk fat globule membrane (MFGM) phospholipids and
soybean lecithins were both utilized individually as encapsulants in a thin lm ultrasonic dispersion
method. The curcumin liposomes fabricated with MFGM phospholipids exhibited greater entrap-
ment efciency of around 74%, a smaller particle dimension of about 212.3 nm, a higher zeta poten-
tial value of about −48.60 mV, a higher retention rate as well as a sustained in vitro release prole
compared with soy lecithin–stabilized liposomes. Thus, MFGM phospholipids have proved to be a
potent food-grade encapsulant for the fabrication of curcumin liposomes (Jin etal., 2016). Despite
advantageous antitumor potential, application of L-asparaginase is restricted due to its excessive
tendency to cause clinical hypersensitivity. To handle this situation, L-asparaginase-entrapped lipo-
somes were manufactured using soy lecithin by the thin lm hydration method. The mean particle
dimensions of the fabricated positive, negative and neutral liposomes were shown to be 35.6, 65.8
and 43.2 µm, respectively. The percentage of drug entrapped in neutral, positive and negative lipo-
somes was found to be 1.95%, 2.39% and 2.35%, respectively. An in vitro release study of
L-asparaginase was executed utilizing normal saline as dissolution medium, and the release was
reported to be around 78.29%, 82.04% and 86.88% for positive, negative and neutral liposomes,
respectively. Furthermore, a short-term cytotoxicity study showed that the cytotoxicity concentra-
tion (CTC50) for the liposomal formulation (50 μg) was signicantly lower than that of pure drug
(64 μg) (De and Venkatesh, 2012). The uorescent methyl 6-met hoxy- 3-(4- metho xyphe nyl)- 1H-in
dole- 2-car boxyl ate possesses noteworthy antitumor properties against several established cell lines,
such as human lung cancer cell line (e.g. NCI-H460), human malignant melanoma cell line (e.g.
A375-C5) and human breast cancer cell line (e.g. MCF-7). Various nanoliposome structures com-
prising the uorescent therapeutics were manufactured with egg lecithin (egg PC), cholesterol (Ch),
dipalmitoyl phosphatidylglycerol (DPPG) and distearoyl phosphatidylethanolamine (DSPE) by an
injection/extrusion combined process. The formulations consisting of egg PC/Ch/ DPPG (6.25:3:0.75)
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191Phospholipid-Based Nanoplatforms
as well as egg PC/DPPG/DSPE-PEG (5:5:1) were found to be suitable for administration due to their
small hydrodynamic diameter and highly negative zeta potential along with excellent encapsulation
efciency (Abreu etal., 2011). In another study, a slightly modied method of rapid expansion of
supercritical solutions (RESS) was carried out to enclose essential oil into liposomes following the
oil extraction from Atractylodes macrocephala Koidz (Wen etal., 2010). The mean particle dimen-
sion, drug loading and entrapment efciency of liposomes were found to be 173 nm, 5.18% and
82.18%, respectively. A freshly introduced group of sterol-modied lipids (SML) was employed to
design m-PEGDSPE-containing liposomes, and it was compared with the well-established lipo-
some phospholipid constituents mPEG-DSPE/Hydrogenated Soy PC (HSPC)/cholesterol and
mPEG-DSPE/POPC/cholesterol to nd the impact of the amount of entrapped cis-platinum released
on C26 tumor proliferation in the murine colon carcinoma model. The three liposome formulations
demonstrated better antitumor efcacy against colon cancer in comparison with the naked drug fol-
lowing equivalent dose administration. However, the SML liposome platinum formulation did not
prove to be more effective than the HSPC formulation (Kieler-Fergusonetal., 2017). Egg phospha-
tidylcholine (E-PC) and E-PC/egg phosphatidylglycerol (E-PC/EPG) were also employed to fabri-
cate Carbopol-coated mucoadhesive liposomes for delivery of the antiviral drug acyclovir (ACV).
The incorporation of ACV into liposomes was found to result in markedly enhanced in vitro perme-
ability compared with its aqueous solution (Naderkhani etal., 2014). As a platelet substitute, phos-
pholipid vesicles possessing hemostatic activity were constructed by joining a dodecapeptide H12
and exploited for encapsulating adenosine 5′-diphosphate (ADP). The results of the in vivo investi-
gation clearly demonstrated that the H12-(ADP)-vesicles were capable of releasing ADP, augment-
ing platelet aggregation and exerting substantial hemostatic action in respect of treating prolonged
bleeding (Okamura etal., 2010). Zhao etal. introduced a novel thermosensitive cationic liposomal
delivery system with dipalmitoylphosphatidylcholine and cholesterol for the co-administration of
both therapeutics and genes to the same cell. The initial demonstration of this co-administration
strategy resulted in the intended site-specic delivery potency, the temperature-sensitive release of
doxorubicin (DOX) as well as SATB1 gene silencing. Furthermore, the co-administration of DOX
and SATB1 shRNA (short hairpin RNA) revealed improved inhibitory activity against carcinoma
propagation in a gastric cell line both in vitro and in vivo compared with a single infusion (Peng
etal., 2014). A recent investigation reported that an unconventional liposome was constructed from
a dual drug-tailed phospholipid as a result of coupling a prodrug and a drug carrier. The dual chlo-
rambucil-tailed phospholipid (DCTP), consisting of a hydrophobic tail from two molecules of chlo-
rambucil and a hydrophilic head group from one glycerol-phosphatidylcholine molecule, was
organized to construct liposomes by the thin lipid lm technique without any additives. The DCTP
liposome, a potent vehicle of chlorambucil, demonstrated outstanding loading capacity, remarkable
stability and efcacious in vivo antitumor activity (Fang etal., 2015). A recent study has shown that
a phospholipid-rich portion was successfully utilized to formulate rutin-liposomes as a potent neu-
roprotective agent. The formulation attenuated glutamate-induced cytotoxicity and reduced the for-
mation of intracellular reactive species in SH-SY5Y, a human neuroblastoma cell line (Bernardo
etal., 2019). Phospholipid liposomes functionalized with protein targeted to a specic receptor of
the blood–brain barrier can be exploited for administration of neurotrophic drugs in the newborn
brain (Glukhova etal., 2015). By using a supercritical CO2–based system, liposomes loaded with
multivitamins were successfully prepared from MFGM phospholipid concentrate. These liposomes
were found to restore the nutritional and functional attributes of active biomolecules throughout a
period of prolonged heat treatment (Jash etal., 2020). Despite all the advantages, liposomes face
some obstacles as a versatile delivery device. The amount of drug that can be entrapped within a
liposome is often very low. In addition, oxidation and hydrolysis hamper the stability and shelf life
of liposomes. Moreover, a serious concern is related to the dermal delivery of liposomes encapsulat-
ing therapeutic compounds (Van Hoogevest and Fahr, 2019). Saturated phospholipids having a
phase transition temperature of about 40–60°C exhibit rigidity at the cutaneous temperature of 32
°C So, liposomes comprising saturated phospholipids are reported to shown a lower propensity to
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192 Handbook of Nanotechnology in Nutraceuticals
penetrate the dermis. Unsaturated phospholipids with a phase transition temperature lower than 0
°C can stay in the mobile state at skin temperature. Soybean PCs comprising unsaturated fatty acids
were found effective in forming exible liposomes that can permeate to the deeper site of the dermis
in comparison to rigid liposomes rich in saturated soybean PC. Even exible liposomes comprising
unsaturated phospholipids cannot permeate to a great extent through the skin and are reported to be
degraded in the stratum corneum of the epidermis. Therefore, to achieve the desirable skin penetra-
tion for topical application, the composition and exibility of the phospholipid liposomes can be
rened with the assistance of lysolecithin. Not only is permeability an issue, but also, liposomes,
like all other foreign substances, encounter multiple defense systems. Following the systemic
administration of the delivery vehicle, the reticulo-endothelial system (RES) is found to be the pri-
mary site of liposome accumulation (Sercombe etal., 2015). Plasma proteins have been documented
to have a vital role in vesicular destabilization as well as in clearance of liposomes by the RES via
opsonization. Liposomes evading opsonization cannot escape the enhanced permeation and reten-
tion (EPR) effect. Fusion of PEG polymers and liposomal membrane is a prime idea for enhancing
residence time in circulation and impeding RES clearance via steric stabilization. Cholesterol inter-
nalization within the liposomal membrane imparts the required stability to the liposome by dimin-
ishing the possibility of lipid interchange with other circulating bodies such as red blood cells and
lipoproteins. A thorough understanding of the advancements in liposomal technology to date will
pave the path for further upgrading of the therapeutic delivery avenues by minimizing the clinical
and pre-clinical challenges.
8.4 MODIFIED LIPOSOMES: VERSATILE AND FLEXIBLE
NANOVESICULAR VEHICLES FOR TRANSDERMAL DELIVERY
As conventional liposomes cannot thoroughly permeate the cutaneous layers and remain restricted
to the outermost layers of the stratum corneum, they are of minor importance as vehicles for trans-
dermal administration. Today, different generations of liposomes, such as niosomes (rst genera-
tion), transferosomes (second generation) and ethosomes (third generation), have been developed
with different mechanisms for enhancement of drug delivery to skin. Liposomes, transferosome
and ethosomes are extensively utilized as gel formulations for topical application. The mechanism
behind the dermal entry of liposomes, transferosomes and ethosomes is represented in Figure 8.2
for clear understanding. Table 8.2 shows the comparative analysis of liposomes, transferosomes and
ethosomes.
Liposomes facilitate the topical penetration of therapeutic molecules by distorting the nely
arranged cellular lipids of the stratum corneum. Due to the presence of an edge activator, transfero-
somes conquer the dermal obstacle by increasing the deformability of the lipid bilayer and augment-
ing extracellular transport to t themselves into it. Ethanol uidizes both the lipid bilayers residing
in ethosomal vesicles and the stratum corneum, modifying the organization and diminishing the
density of skin surface lipids, i.e. lipid perturbation.
8.4.1 traNsferosomes
Transferosomes are the second generation of liposomes, ultra-deformable or ultra-exible in nature.
They can readily penetrate the stratum corneum of the epidermis in the presence of a trans-epider-
mal water activity gradient (Chauhan etal., 2017). These are formed by an ideal mixing of phos-
pholipids and edge activator. An edge activator is generally a single-chain surfactant responsible
for the destabilization of the lipid bilayer of the vesicle and enhancement of the vesicle elastic-
ity or uidity. When transferosomes come into close proximity with the skin, evaporation of the
aqueous part from the formulation begins. Transferosome vesicles possess a general inclination to
avoid a dry environment. Hence, the formulations are tempted by the considerable water content of
the skin, leading to the spontaneous transport of the encapsulated vesicles through the cutaneous
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193Phospholipid-Based Nanoplatforms
layer (Solanki etal., 2016). Insulin, a large peptide, is not able to penetrate easily into the dermis.
Insulin entrapped within a transferosomal gel showed acceptable permeation results (in vitro per-
meation ux of 13.50 ± 0.22 μg/cm2/h) through porcine ear skin (Malakar etal., 2012). The in vivo
investigation of an insulin transferosome formulation reported a long-term hypoglycemic effect in
alloxan-treated rats for more than 24 h following transdermal administration. For the treatment of
hypertension, diltiazem HCl entrapped within transferosomes was further enclosed in a gel matrix.
The diltiazem HCl–entrapping transferosomes permeated in and across rat skin successfully and
showed a three- to four-times amplied sustained outcome in comparison with the naked drug (Jain
etal., 2003). The transferosomal gel formulated using soy PC can be used as a potent topical deliv-
ery tool for piroxicam due to the perfect release and permeation of the drug. The transferosomal
gel formulation revealed improved anti-inammatory potential against carrageenan-induced paw
edema (Shaji and Lal, 2014). The transferosome formulation encapsulating Sildenal was created
with vesicle size of about 610 nm along with remarkable entrapment efciency of around 97.21%.
FIGURE 8.2 Possible mechanism behind the entry of bioactive agents across the skin via liposomes, trans-
ferosomes and ethosomes.
TABLE 8.2
Comparative Analysis of Liposomes, Transferosomes and Ethosomes
Characteristics Liposome Transferosome Ethosome
Nature of vesicle Bilayer lipid vesicle Second-generation elastic lipid
vesicle
Third-generation elastic lipid
vesicle
Composition Phospholipids and
cholesterol
Phospholipids and edge
activator
Phospholipids and ethanol
Flexibility Microscopic vesicle,
rigid in nature
Ultra-exible liposome; high
deformability
Elastic liposome; high
deformability and elasticity
Extent of dermal
penetration
Penetration rate is very
low
Can easily penetrate through
paracellular space
Can promptly invade via
paracellular transport
Permeation mechanism Diffusion, fusion,
lipolysis
Deformation of vesicle Lipid perturbation
Route of administration Oral, parenteral,
transdermal, topical
Transdermal and topical Transdermal and topical
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194 Handbook of Nanotechnology in Nutraceuticals
In vitro permeation of the developed transferosomes showed at least a vefold superior permeation
rate compared with the common drug suspension (Ahmed, 2015). Lornoxicam, a potent non-steroi-
dal anti-inammatory drug, was loaded in transferosomes for transdermal delivery (Ranade etal.,
2016). The average vesicle diameter and the average drug encapsulation efciency of the fabricated
transferosomes were about 678 nm and 65.3%, respectively. The in vitro ux obtained for the opti-
mized formulation was 79.1 μg/cm2/h, while that for a formulation without edge activator was found
to be 70.2 μg/cm2/h. In a similar study, transferosomes entrapping pentoxifylline showed an average
vesicle diameter of about 0.69 ± 0.0 49 µm, polydispersity index of about 0.11 ± 0.037, zeta potential
of about −34.9 ± 2.2, vesicles elasticity of about 145 ± 0.6 (mg /s/c m2), drug encapsulation efciency
of about 74.9 ± 1.6% as well as permeation ux of about 56.28 ± 0.19 µg/cm2/h (Shuwaili et al.,
2016). In vivo pharmacokinetics examination revealed that the developed transferosome formula-
tion accelerated pentoxifylline absorption as well as lengthening its half-life compared with the
commercial oral pills. Optimized transferosome formulations loading felodipine showed a particle
size of about 75.71 ± 5.4 nm, polydispersity index of about 0.228 and zeta potential of about −49.8
mV. Besides, the formulation provided maximal loading and entrapment efciency along with a high
deformability index of about 119.68. In comparison to control transdermal solution, 256% ination
in permeation across rat skin (ux = 23.72 ± 0.64) with the fabricated formulation was reported in
an in vitro permeation study. The relative bioavailability of felodipine (358.42%) in a transferosome
formulation compared to oral administration indicates that transdermal administration of trans-
ferosomes yielded a relatively persistent blood concentration with minimum plasma uctuation and
prompt and sustained peak time, in contrast to oral delivery (Yusuf etal., 2014).Transferosomes
encapsulating asenapine maleate were optimized with an average dimension of about 126.0 nm,
polydispersity index of about 0.232, zeta potential of about −43.7 mV and entrapment efciency
around 54.96%. In vivo pharmacokinetic investigation demonstrated a statistical ination in bio-
availability upon transdermal administration in comparison with oral delivery (Shreya etal., 2016).
Exploring the deformability features of transferosomes, transferosomes entrapping Timolol male-
ate were found to rene the corneal transmittance and bioavailability (González-Rodríguez etal.,
2016). Capsaicin-loaded transferosomes demonstrated a superior therapeutic effect against arthritis-
associated inammation compared with the marketed thermogel formulation (Sarwa etal., 2015).
In another study, Clonazepam, a benzodiazepine derivative, was encapsulated in transferosomes
for intra-nasal administration. The optimized formulation was responsible for minor changes in
the nasal mucous layer, revealed in ex vivo cytotoxicity investigation, and a notable lag in the onset
of epileptic seizures upon pentylenetetrazol treatment (Nour etal., 2017). Highly exible lecithin
soybean PL nanotransferosomes were recently engineered as the latest delivery device for trans-
dermal transport of large peptide molecules, i.e., human growth hormone (Shamshiri etal., 2019).
Besides these versatile trans-dermal applications, major drawbacks of transferosomes relate to the
hassle of entrapping lipophilic substances into the vesicular nanostructures while keeping their ex-
ibility and deformability intact (Priyanka and Singh, 2014). Transferosomes are lacking chemical
stability due to their predisposition to oxidative stress. However, the recent successes of transfero-
somes show promise to handle upcoming obstacles and welcome the imminent possibilities for the
establishment of novel delivery techniques with rened stability and penetration. The fabrication
techniques, physicochemical characteristics and therapeutic effects of phospholipid-based trans-
ferosomes entrapping various active compounds are briey outlined in Table 8.3.
8.4.2 ethosomes
Ethosomes represent the third generation of elastic lipid carriers, which are actually ethanol-mod-
ied liposomes comprising hydroalcoholic or hydro/alcoholic/glycolic phospholipid (Garg etal.,
2017). The high concentration of ethanol (20–50%) in ethosomal vesicles may disrupt the skin
lipid’s bilayer structure. Thus, these malleable vesicles can easily penetrate through the paracellular
space and offer continual delivery of therapeutics to targeted sites residing in different layers of
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195Phospholipid-Based Nanoplatforms
TABLE 8.3
Method of Fabrication, Physicochemical Characteristics and Therapeutic Effects of Phospholipid-Based Transferosome Entrapping Various
Active Compounds
Active compound Preparation method
Particle
size (nm)
Zeta potential
(mv)
Entrapment
efficiency (%)
Permeation flux
(μg/cm2/h) Therapeutic impact References
Pentoxifylline Modied vortexing-sonication 690 −34.9 74.9 56.28 Enhanced bioavailability Shuwaili etal.,
2016
Lornoxicam Thin lm hydration 678 −52.5 65.3 79.1 Increased skin
permeability
Ranade etal.,
2016
Felodipine Rotary evaporation-sonication 75.71 −49.8 85.14 23.72 Escalated transdermal
permeation
Yusuf etal.,
2014
Insulin Reverse phase evaporation 625–815 −14.30 56.55–60.23 13.50 ± 0.22 Prolonged hypoglycemic
effect, increased patient
compliance
Malakar etal.,
2012
Asenapine maleate Thin lm hydration 126 −43.7 53.96 7.98 Elevated skin permeation Shreya etal.,
2016
Capsaicin Thin lm hydration 94 −14.5 60.34 6.28 Exhibited superior
antiarthritic activity
Sarwa etal.,
2014
Clonazepam Thin lm hydration 122.5 −22.95 84.22 – Enhanced brain delivery
to treat status
epilepticus
Nour etal.,
2017
Sildenal Lipid lm hydration 610 1.52–3.63 97.21 – Increased skin
permeation
Ahmed, 2015
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196 Handbook of Nanotechnology in Nutraceuticals
skin. A soy lecithin–based ethosomal gel formulation of Clotrimazole was developed to attain zero-
order release kinetics of Clotrimazole and drug entrapment efciency of more than 50% (Parmar
etal., 2016). A soy PC formulation of Diclofenac-loaded ethosomes was optimized with a vesicular
size of about 144 ± 5 nm, zeta potential of about −23.0 ± 3.76 mV, an elasticity of about 2.48 ± 0.75
and entrapment efciency of about 71 ± 4%. The permeation ux of this formulation was found
to be signicantly superior to that of the drug-entrapped conventional liposomal structure, aque-
ous or ethanolic solution. The in vivo investigation revealed that the ethosomal hydrogel showed
markedly superior anti-inammatory potential in comparison to liposomal hydrogel (Jain etal.,
2016). Ethosomal vesicles prepared from lecithin were also explored for enhanced topical delivery
of isotretinoin (David etal., 2013). The entrapment of Etodolac in soy lecithin–based ethosomal
vesicles showed efcacious delivery of active molecules at the desired area, reduced the dose and
therefore, played a vital role in patient compliance (Chintala and Padmapreetha, 2014). Soy lecithin
was also used for an Econazole nitrate–loaded ethosome formulation to attain prolonged release
kinetics, better permeation capacity and improved antifungal activity compared with the pure drug
(Verma and Pathak, 2012). Phospholipid-based piroxicam ethosomes provided several benets in
terms of quick onset and maximal release of the therapeutic molecule while minimizing undesirable
complications. An ethosomal gel entrapping Gliclazide as a topical formulation generated no irrita-
tion, provided higher stability and offered a better hypoglycemic effect in comparison to an oral
drug formulation (Vijayakumara etal., 2014). Osthole-loaded ethosomes formulated as an effective
delivery system with a greater encapsulation efciency of 83.3 ± 4.8% and transdermal ux of about
6.98 ± 1.6 μg/cm2/h intensied drug deposition on the cutaneous layer compared with transfero-
somes (1.5-fold) (Meng etal., 2016). An ethosomal formulation encapsulating Lornoxicam exhib-
ited a small particle size (100 ± 3.9 nm), the highest percentage of drug entrapment (93.96%) and
the highest percentage of drug permeation (74.18%) at the end of 24 hours. The results based on sta-
bility and anti-inammatory activity suggested ethosomal gel as an efcient carrier of Lornoxicam
(Acharya etal., 2016). Epigallocatechin gallate (EGCG), a potent antioxidant obtained from green
tea, was entrapped in ethosomes with a particle size of 129.0 nm, polydispersity index of about
0.05 ± 0.00, zeta potential around −62.6 ± 5.05 mV and maximum entrapment efciency of about
54.39 ± 0.03 which nally aided to increase EGCG penetration (Ramadon etal., 2017). Flurbiprofen-
loaded ethosomes with almost 95% entrapment efciency were found to show improved analgesic
activity as well to inhibit paw edema (Paliwal etal., 2019). In vitro skin permeation methodology
showed a release of about 82.56 ± 2. 11 g/ cm 2 in 24 hours and transdermal ux of about 226.1 μg/
cm2/h. Composite phospholipid ethosomes entrapping curcumin were recently optimized with sev-
eral phospholipid compositions (Li etal., 2021). The outcome of the in vitro skin permeation studies
with the composite phospholipid ethosomal formulations indicated signicantly superior penetra-
tion of curcumin across the cutaneous layer than that of the conventional ethosomes fabricated with
PC or hydrogenated PC. In addition, composite phospholipid ethosomes could disrupt the lipid
organization of the stratum corneum and permit curcumin to permeate effortlessly into the dermis.
Interestingly, all the ethosomal formulations displayed a zero-order release prole for in vitro stud-
ies. Furthermore, ethosomes were found to be more stable against aggregation than liposomes due
to their net negative charge. Comprehensive research on the depth of skin penetration is needed to
encourage the commercial pharmaceutical domain further (Patrekar etal., 2015). Fabrication tech-
niques, physicochemical characteristics and therapeutic effects of phospholipid-based ethosomes
entrapping various active compounds are briey outlined in Table 8.4.
8.5 PHOSPHOLIPID-BASED SOLID LIPID NANOPARTICLES: A NOVEL
FORMULATION FOR VARIOUS ROUTES OF ADMINISTRATION
Solid lipid nanoparticles (SLNs) (colloidal size ranging between 50 and 1,000 nm) are colloidal car-
riers comprised of solid lipids that are stabilized by surface-active agents within an aqueous milieu
(Mishra etal., 2018). The lipid matrix of SLNs is comprised of biological lipids, which may reduce
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197Phospholipid-Based Nanoplatforms
TABLE 8.4
Method of Fabrication, Physicochemical Characteristics and Therapeutic Effects of Phospholipid-Based Ethosomes Entrapping Various
Active Compounds
Active compound Preparation method
Particle
size (nm)
Zeta
potential
(mv)
Entrapment
efficiency (%)
Permeation flux
(μg/cm2/h) Therapeutic impact References
Diclofenac Rotary evaporation-sonication 144 −23.0 71 12.9 Enhanced anti-
inammatory activity
Jain etal., 2015
Methoxsalen Thin lm hydration 281.3 −2.13 67.12 5.8 Enhanced topical delivery
to treat vitiligo
Garg etal.,
2016a
Epigallocatechin gallate Mechanical dispersion 129.0 −62.6 54.39 56.97 Enhanced penetration Ramadon etal.,
2017
Osthole Modied injection 153.36 −9.51 83.3 6.98 Enhanced transdermal
delivery
Meng etal.,
2016
Econazole nitrate Cold method 202.85 −75.1 81.05 0.46 Improved anti-fungal
activity
Verma and
Pathak 2012
Cromolyn sodium Thin lm hydration 133.8 −69.82 49.88 18.49 Enhanced skin
accumulation
Rakesh and
Anoop, 2012
Cetirizine
dihydrochloride
Rotary evaporation-sonication 180.1 −15.7 72.85 16.3 Increased anti-allergic
effect
Goindi etal.,
2014
Glimepiride Rotary evaporation-sonication 61 0.6–9.63 97.12 5.583 Sustained release of drug Ahmed etal.,
2016
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198 Handbook of Nanotechnology in Nutraceuticals
the threat of chronic and acute toxic effects. SLNs can shield the core molecule from undesirable
enzymatic degradation in the digestive tract and thus increase the stability of the incorporated bio-
active (Ekambaram etal., 2012). Moreover, epithelial cells and the lymphoid tissues in Peyer’s
patches can engulf the SLNs to a certain extent (Rostami etal., 2014). Earlier, Heiati etal. prepared
neutral and negatively charged SLNs for azidothymidine palmitate (AZT-P) delivery using trilaurin
(TL) as the solid core material as well as a blend of dipalmitoylphosphatidylcholine (DPPC) and
dimyristoylphosphatidylglycerol (DMPG) as a coating agent. They found that the entrapment and
subsequent retention of AZT-P in SLNs depend primarily upon the phospholipid composition and
the net surface charge of the fabricated structure. The organization of phospholipid bilayer structure
and the capacity of amphiphilic drugs, for example AZT-P, to be incorporated within these two lay-
ers seems to be the factor behind the improved entrapment efciency (EE%) (Heiati etal., 1998).
Egg PC and PEGylated phospholipid were successfully utilized as stabilizers to prepare SLNs
encompassing trimyristin (TM) as the solid lipid core. Irrespective of paclitaxel entrapment, the
satisfactory particle sizes (around 200 nm) and zeta potentials (−38 mV) marked the SLNs as suit-
able for parenteral formulation. An in vitro release study with SLNs demonstrated prolonged release
kinetics of paclitaxel from the formulation. Moreover, paclitaxel-loaded SLNs used to treat MCF-7,
a well-known breast cancer cell line, and OVCAR-3, a commonly used ovarian cancer cell line,
exhibited signicantly higher cytotoxicity compared with those cell lines treated with the widely
accepted CremophorEL-based paclitaxel formulation (Lee etal., 2007). SLNs were successfully
modied with lectin to increase the oral bioavailability of insulin. These delivery systems yielded
remarkable drug entrapment efciency (>60%) and noteworthy protection from gastro-intestinal
degradation (Zhang etal., 2006). In another study, utilizing soybean phosphatidylcholine (SPC) as
an encapsulant, biodegradable nanoparticles entrapping an insulin phospholipid complex were fab-
ricated by a novel reverse micelle–double emulsion technique (Cui etal., 2006). The particle size,
zeta potential, drug loading capacity and entrapment efciency were reported to be about 114.7 ±
4.68 nm, −51.36 ± 2.04 mV, 18.92 ± 0.07% and 97.78 ± 0.37%, respectively. In streptozotocin-
induced diabetic rats, the administration of 20\IU/kg nanoparticles lowered fasting plasma glucose
concentration by 42.6% in less than 8 h of administration with a long-term effect for 12 h. Fluorescent-
labeled insulin was successfully introduced into nebulizer-compatible SLNs aiming at efcacious
pulmonary drug delivery (Liu etal., 2008). The SLNs were found to be uniformly dispersed in the
lung alveoli. These results unearthed the potential of SLNs as a pulmonary delivery tool for insulin
by overcoming in vitro and in vivo stability concerns, enhancing bioavailability as well as augment-
ing hypoglycemic effect. Tween 80 and soybean lecithin were simultaneously utilized as emulsiers
to construct isotretinoin-loaded SLNs (IT-SLNs) for topical delivery (Liu etal., 2007). The in vitro
permeation data showed a signicantly enhanced skin targeting effect with the increased accumula-
tive uptake of isotretinoin. Diacerein-loaded SLNs (DC-SLN)s were fabricated by modied high-
shear homogenization as well as ultrasonication using soy lecithin as a surfactant (Jain etal., 2013).
An in vitro drug release study exhibited controlled release kinetics, and an in vivo pharmacokinetic
study indicated 2.7-fold improvement of oral bioavailability with a reduction in the side effects of
the drug. SLNs encapsulating cisplatin were generated by a micro-emulsication technique with the
help of soy lecithin and stearic acid (Doijad etal., 2008). The entrapment efciency ranged from
47.59% to 74.53%. An in vivo study of cisplatin-loaded SLNs reported that cisplatin is favorably
targeted to the liver, brain and lungs consecutively. Egg PC–based SLNs entrapping penciclovir
with an average diameter of about 254.9 nm have been successfully formulated by a double emul-
sion method (W/O/W) (Lv etal., 2009). SLNs enhanced penciclovir permeation into the deeper site
of the skin due to the SLNs’ impact on diminishing or inhibiting the skin dehydration and hence,
disturbing the lamellar arrangement of the lipids and loosening the structure of the stratum cor-
neum. Similarly, soy lecithin–stabilized SLNs incorporating adapalene were established to be able
to target epidermis (Jain etal., 2014). A rat skin model conrmed that the fabricated system can
evade the systemic uptake of adapalene in cutaneous layers and can accumulate the drug in epider-
mis. Catalase, a potent hydroxyl radical scavenger, is effectively loaded in PC-stabilized SLNs with
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199Phospholipid-Based Nanoplatforms
the sequential application of the double emulsion method and solvent evaporation techniques (Qi
etal., 2011). Catalase loaded into SLNs is found to be protected from proteolysis. The capacity of
catalase to degrade hydrogen peroxide diffusing through the polymer shell was fully retained even
after encapsulation. SLNs were successfully formulated with egg PC and Tween 80 for delivering
all-trans-retinoic acid (ATRA) (Lim and Kim, 2002). The determined mean particle dimension and
the zeta potential of ATRA-loaded SLNs were about 154.9 nm and around −38.18 mV, respectively.
Phospholipid complexes technology was successfully utilized to fabricate diclofenac sodium (DS)-
loaded SLNs, aiming to increase the lipophilicity of the water-soluble drug DS (Liu etal., 2011).
The assistance of phospholipid complexes changed the zeta potential and restricted the rapid core
release from the SLNs, which suggested a multi-layer formation of phospholipid enclosing the solid
lipid core of the SLNs. SLNs are also suitable for formulating low-molecular weight compounds
other than peptide drugs with high molecular weight and poor aqueous solubility, for example pent-
oxifylline (Varshosaz etal., 2010). The bioavailability in rats was found to be notably improved in
comparison to that of pentoxifylline solution. Praziquantel, an anthelmintic drug potent against
atworms, was formulated with an average diameter of about 110 nm, a zeta potential of around
−66.3 mV and an encapsulation efciency of approximately 80% (Yang etal., 2009). The average
residence period of the drug was also markedly augmented after delivery of SLNs, leading to a
twofold amplication in comparison to the administration of tablets. SLNs entrapping the choles-
terol-lowering drug Lovastatin boosted the bioavailability by up to 173% compared with a Lovastatin
suspension in animals (Suresh etal., 2007). Total avonoid extract from Dracocephalum moldavica
L. (TFDM) has been successfully encapsulated in soy lecithin–stabilized SLNs, which are round in
shape with mean particle dimension of about 104.83 nm (Tan etal., 2017). The ndings of pharma-
codynamics revealed a considerably higher protective effect from TFDM-SLNs than from TFDM
alone, possibly due to the infarct area, histopathological study, cardiac enzyme levels and inam-
matory marker analysis in serum. For versatile topical applications, soy PC has been utilized to
encapsulate trans-resveratrol into SLNs (Rigon etal., 2016). The resveratrol-loaded SLNs with a
mean diameter less than 200 nm were found to be more useful than kojic acid at inhibiting tyrosi-
nase without any signicant cellular toxicity towards HaCat keratinocytes. SLNs co-loaded with
ferulic acid (FA) and tocopherol (Toc) were fabricated using soy lecithin with the aid of a hot
homogenization technique (Oehlke etal., 2017). The various formulations entrapping up to 2.8 mg/g
of FA or Toc exhibited unique stability for a minimum of 15 weeks of storage at ambient tempera-
ture with retention and/or enhancement of their antioxidative activity. PC-stabilized PEGylated
Docetaxel-loaded SLNs (DCX-SLNs) exhibited notably superior cellular toxicity towards several
human and murine carcinoma cell lines as well as a stronger antitumor activity in a mouse model,
because the DCX-SLNs markedly augmented the deposition of the DCX at the tumor site (Naguib
etal., 2014). Furthermore, the reduced deposition of DCX in essential organs following intravenous
administration of DCX-SLNs compared with that of DCX in Tween 80/ethanol mixed solution
indicates the utility of DCX-SLNs as a favorable safe formulation. In another study, hydrogenated
soy PC acted as a stabilizer in a curcumin-loaded SLN system (Mulik etal., 2010). Flow cytometric
data analysis afrmed superior anticancer activity of curcumin entrapped in transferrin-mediated
curcumin-loaded SLNs towards the MCF-7 breast cancer cell line in comparison to curcumin solu-
bilized surfactant solution (CSSS). A novel SLN of 4-(N)-docosahexaenoyl 2′, 2′-diuorodeoxycyti-
dine (DHA-dFdC) was recently reported with increased aqueous solubility, chemical stability and
in vivo efcacy. The SLNs were fabricated from lecithin/glycerol monostearate-in-water emulsions
using (TPGS) and Tween 20 as emulsiers (Valdes etal., 2019). The SLNs can be delivered by sev-
eral routes, for example topical, oral, parenteral, ocular, pulmonary, etc. The greatest benets of
lipid vehicles are their excellent stability, biocompatibility, biodegradability, maneuverability and
scalability as well as controlled and rened release kinetics. However, the pitfalls of SLN produc-
tion are their inadequate drug loading capacity, drug exclusion after polymeric transition throughout
storage, comparatively higher aqueous content of the formulation, initial “burst effect”, agglomera-
tion and RES clearance (Geszke-Moritz and Moritz, 2016). The emergence of several promising
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200 Handbook of Nanotechnology in Nutraceuticals
approaches regarding SLNs would promote the development of nanostructured lipid carriers as well
as the second generation of lipid-based nanocarriers. Fabrication techniques, physicochemical char-
acteristics and therapeutic effects of phospholipid-based SLNs entrapping various active compounds
are briey outlined in Ta ble 8.5.
8.6 MULTIFUNCTIONAL MICELLES FOR TARGETED DRUG DELIVERY
Polymeric micelles having a particle size within the 5–50 nm range represent the simplest self-assem-
bly structures in spherical shapes spontaneously formed by amphiphiles in an aqueous solution.
Phospholipids become more water soluble following conjugation with PEG and form micelles above
the critical micellar concentration (CMC) when dispersed in water (Lim etal., 2012). The hydropho-
bic domains of the molecule are arranged in a cluster and directed away from the aqueous medium,
while the hydrophilic parts are directed toward the water. The hydrophilic PEG coating on micelles
imparts stability against aggregation, reduces susceptibility to reticulo-endothelial opsonization,
enhances residence time in circulation and ensures pH-responsive drug release at the active site
(Kalepu and Nekkanti, 2015). PEGylated lipids such as DSPE-PEG (Dist earoy l-sn- glyce ro-3- phosp
hoeth anola mine conjugated to PEG) are also utilized to fabricate sterically stabilized micelles
(SSMs) (Gülçür etal., 2013). Conjugation of PEG to the phospholipid builds a dense brush of highly
hydrated chains, forming a conical structure for each monomer, which consequently promotes self-
assembly of a micellar structure that is not absolutely spherical in shape. Though the peptides display
enormous potential benets and therapeutic capabilities for several clinical disorders, they suffer
from numerous physicochemical and biological concerns, for instance aggregation, chemical degra-
dation in vitro, and immediate proteolysis as well as renal clearance in vivo. Phospholipid micelles
have been used to address these delivery issues by improving their stability against rapid proteolysis
and increasing the circulation time. Human pancreatic peptide loaded into SSMs was found to be
stable against protease activity, and its bioactivity was retained in vitro (Banerjee and Önyüksel,
2012). A novel, self-associated, stable PEGylated phospholipid nanomicelle of vasoactive intestinal
peptide (VIP) having a mean size of ∼18 nm was developed to amplify vasodilation in the in situ
peripheral microcirculation model (Önyüksel etal., 1999). Sterically stabilized micelles are found to
be attractive nanocarriers for encapsulating camptothecin (CPT), a topoisomerase I inhibitor. The
average dimension of CPT-SSM was about ∼14 nm with a narrow size distribution. At a concentra-
tion of 15 mmol/L PEGylated phospholipids, camptothecin solubilization in SSM was found to be
approximately 25-fold superior to a buffer solution of camptothecin (Koo etal., 2005). These micelles
are sufciently small for ample extravasation through the leaky microvessels of tumors, resulting in
substantial drug deposition in tumors as well as minimum drug toxicity to the healthy tissues (Koo
etal., 2006). To achieve active targeting, the surface of CPT-SSM was altered with VIP. For the rst
time, CPT was reported to be effective against collagen-induced arthritis (CIA) at a considerably
lower concentration compared with the standard anticancer dose. Moreover, only one subcutaneous
administration of CPT-SSM-VIP (0.1 mg/kg) to CIA mice alleviated rheumatoid arthritis–associated
joint swelling and inammation for a minimum of 32 days without general systemic toxic effects,
whereas CPT alone required a minimum 10 times higher dose to attain the same result (Koo etal.,
2011). GLP1-SSMs constructed from human glucagon-like peptide 1 (GLP-1) and PEGylated phos-
pholipid micelles were found to exhibit a hydrodynamic size range of ∼15 nm and to exert protection
against acute pulmonary inammation in lipopolysaccharide-treated mice (Lim et al., 2011).
Spontaneous self-association of human neuropeptide Y (NPY) with biocompatible and biodegrad-
able SSMs was found to stabilize and protect the peptide in active monomeric form and thus, to
promote inhibition of cAMP production in SK-N-MC neuroepithelioma cells in vitro (Kuzmis etal.,
2011). 17-Allylamino-17-demethoxy geldanamycin (17-AAG), the heat shock protein 90 (Hsp90)
inhibitor, is already established as an antitumor drug for breast adenocarcinoma treatment, though
insufcient water solubility and hepatotoxicity limit its use worldwide. For active targeting, VIP
surface-grafted SSMs entrapping 17-AAG were developed with particle size range about 16 ± 1 nm
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201Phospholipid-Based Nanoplatforms
TABLE 8.5
Method of Fabrication, Physicochemical Characteristics and Therapeutic Effects of Phospholipid-Based Solid Lipid Nanoparticles
Entrapping Various Active Compounds
Active compound Preparation method
Particle
size (nm)
Zeta
potential
(mV)
Entrapment
efficiency (%)
Route of
administration Therapeutic impact References
Paclitaxel Hot homogenization 200 −38 80 Parenteral Boosted cytotoxicity to
MCF-7 breast carcinoma
cell line
Lee etal., 2007
Praziquantel Ultrasound technique 110 −66.3 80 Oral Increased bioavailability Yang etal., 2009
Lovastatin Hot homogenization 60–119 −16 to −21 99% Intraduodenal Increased bioavailability Suresh etal., 2006
Diacerein High-shear homogenization and
ultrasonication
370–510 −14 to −20 88.1 Oral Improved bioavailability
minimizing side effects
Jain etal., 2013
Adapalene Solvent injection 148.3 −12 89.9 Topical Improved therapeutic
efcacy with minimal
penetration
Jain etal., 2014
Methotrexate Emulsication-solvent diffusion 174.51 10.21 84.3 Intravenous Increased antitumor
efcacy against breast
carcinoma cell line
Garg etal., 2016b
Resveratrol Solvent diffusion-solvent
evaporation
134 −34.3 88.9 Oral Enhanced bioavailability
with sustained release
Pandita etal., 2014
Candesartan
cilexetil
Hot homogenization followed
by ultrasonication
180–220 −28 to −29 91–96 Oral Increased anti-
hypertensive effect
Dudhipala and
Veerabrahma, 2016
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202 Handbook of Nanotechnology in Nutraceuticals
and drug content approximately 97 ± 2%. The conservation of cellular toxicity of these fabricated
nanomicelles to MCF-7 breast cancer cells suggests overexpression of high-afnity receptors for VIP
in these cells (Önyüksel etal., 2009b). Using CdSe/ZnS quantum dots (QD), Rubinstein etal. sug-
gested that a substantial amount of QD-loaded VIP-sterically stabilized mixed micelles (SSMMs) are
deposited at high speed in MCF-7 breast carcinoma cells compared with QD-loaded SSMMs without
grafting (p < 0.05) (Rubinstein etal., 2008). For oral insulin delivery, Wang etal. designed phospho-
lipid-based reverse micelles that are sufciently stable at 4 °C for about 6 months (Wang etal., 2010).
Mixed micelles fabricated from phospholipid and Tween 80 were explored as an injectable drug-
loaded nanovehicle for the naturally derived chemotherapeutic agent plumbagin. The micelles pos-
sessed a particle size range of about 46 nm, zeta potential of about 5.04 mV, entrapment efciency of
approximately 98.38% and 2.1-fold increase in antitumor efcacy against the MCF-7 cell line in vitro
(Bothiraja etal., 2013). Self-association of Polymyxin B with SSMs is found to alleviate the antibac-
terial activity in vitro owing to the presence of PEG layer surrounding the micelle. Hindrance of
electrostatic interactions between positively charged polymyxin B and the negatively charged lipo-
polysaccharide on microbial cell wall is thought to be the reason behind this observation (Brandenburg
etal., 2012). Aerosolized, rehydrated sterically stabilized phospholipid nanomicelles encapsulating
Beclomethasone Dipropionate (BDP) suitable for pulmonary administration were formulated with
adequate reproducibility as well as uniform lung deposition. The droplet dimension and zeta poten-
tial of this formulation were found to be around 19.89 ± 0.67 nm and about 28.03 ± 2.05 mV, respec-
tively. The aerodynamic values of the BDP-SSMs were found to be within the acceptable range, and
the fabricated nanomicelles exhibited prolonged release of BDP (Sahib et al., 2012). Curcumin-
entrapped phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs) were prepared
to improve the solubility and anti-proliferative and apoptotic effects of curcumin. Notably high
encapsulation efciency, lower IC50 values and sustained release kinetics proved curcumin-loaded
micelles to be an effective nanoformulation (Duan et al., 2015). Sirolimus-loaded micelles in the
particle size range of 14 nm were found to reduce vascular stenosis by 42% and to provide better
antirestenosis effects than PEGylated liposomes (Haeri et al., 2013). Inhaled corticosteroids are
anticipated to be suitable for local intervention in chronic obstructive pulmonary disease or asthma.
Still, the administration of poorly aqueous soluble drugs via a nebulizer remains insufcient, and
sufferers have to depend on colossal doses to achieve optimal relief. Administration of PEG5000-
DSPE polymeric micelles entrapping budesonide (BUD-SSMs) was found to considerably reduce
inammatory cell numbers in broncho-alveolar lavage uid at an optimum dose compared with
Pulmicort Respules® (Sahib etal., 2011). For oral 20(S)-protopanaxadiol (PPD) delivery, Xia etal
developed novel mixed micelles comprising PPD–phospholipid complexes and Labrasol® and
assessed their efcacy in antitumor therapies. These formulations were found to markedly increase
solubility, enhance absorption and improve bioavailability (Xia etal., 2013). Baohuoside I is a power-
ful anticancer drug, but its worldwide use is restricted due to its inadequate aqueous solubility and
removal mechanism from the body. To enhance the solubility, increase permeability and restrict
efux of baohuoside I, mixed micelles were successfully fabricated from phospholipid complex and
D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) (Jin etal., 2013). One of the problems
with SSMs is limited solubilization potential, which is controlled by the total number of micelles in
the system. The solubilization potential of SSMs was improved by increasing the hydrophobic core
of each SSM, and thus, a novel delivery system, i.e., SSMMs, was formed through the incorporation
of a water-insoluble phospholipid such as PC. SSMMs containing paclitaxel demonstrated superior
solubilization potential of the drug and greater cellular toxicity towards MCF-7, a breast carcinoma
cell line, in comparison with SSMs (Krishnadas etal., 2003). By contrast, SSMs can solubilize indi-
sulam to a substantially greater extent (at least 40 times) compared with SSMMs (Cesur etal., 2009).
PEG 2000-grafted 1,2-distearoyl phosphoethanolamine (DSPE-PEG2000) alone was utilized to
develop SSMs, and egg PC in addition to DSPE-PEG2000 was used to fabricate SSMMs. The con-
siderable variation in the dissolution potential of SSMs and SSMMs can be explained by assuming
that indisulam settles at the interface between the lipophilic interior and the comparatively
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203Phospholipid-Based Nanoplatforms
hydrophilic exterior. In SSMMs, the majority of this area may be occupied by egg PC molecules,
permitting only a few indisulam molecules to colonize, resulting in reduced drug solubilization in
SSMMs. Using the MCF-7 breast cancer cell line, an in vitro study indicated that indisulam-SSM
was more efcacious than indisulam in dimethyl sulfoxide (DMSO). The multi-drug resistance prop-
erty of breast carcinoma remains a hindrance to successful chemotherapy even now. Nanosized poly-
meric micelles promise better accumulation in tumor via EPR. In drug-sensitive MCF-7cells, SSMMs
(P-SSMMs) as well as VIP-grafted SSMMs (P-SSMM-VIP) encapsulating paclitaxel was found to
markedly inhibit cell proliferation in a dose-dependent manner (p < 0.05). Both nanomicelles were
found to be seven times more efcacious than paclitaxel in DMSO solution(P-DMSO) (Önyüksel
etal., 2009a). On the other hand, in drug-resistant BC19/3 cells, P-SSMM-VIP was found to be mark-
edly more efcacious than both P-SSMM and P-DMSO (two and ve times, respectively; p < 0.05 ).
These observations have proved paclitaxel-loaded SSMM-VIP as a suitable nanocarrier for active
targeting and treating multiple drug-resistant breast cancer. Figure 8.3 shows the possible mechanism
of SSMs inhibiting P-glycoprotein efux and restricting multi-drug resistance in neoplastic cells. In
another study, for loading paclitaxel, novel polymeric micelles were engineered by utilizing PEs and
hyaluronic acid (HA). In vivo real-time imaging indicated accumulation of the micellar system
mostly in heart, liver and spleen (Saadat etal., 2014). Following administration, functional paclitaxel
nanomicelles with particle size in the range of 15 nm considerably increased the intracellular uptake
of paclitaxel, accumulated selectively in mitochondria and endoplasmic reticulum, and showed
intense inhibitory activity against MCF-7 and MCF-7/Adr cells. They also intensively invaded the
interior of the MCF-7 and MCF-7/Adr spheroids and markedly reduced the size of the spheroids.
Freeze-dried nanomicelles (QUE-FD-NMs) entrapping quercetin were recently developed with a
particle size ranging from 20 to 80 nm, a time-dependent slow-release prole, enhanced intracellular
assimilation inside human intestinal Caco-2 cells with minimum cellular toxicity, sublime penetra-
tion across the blood–brain barrier, and last but not least, substantial cytotoxicity to C6 glioma cells.
FIGURE 8.3 Inhibition of P-glycoprotein efux by sterically stabilized phospholipid nanomicelle restricting
the multi-drug resistance property in neoplastic cells.
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204 Handbook of Nanotechnology in Nutraceuticals
QUE-FD-NMs were shown to accumulate in brain tumor tissues and demonstrated profound antitu-
mor effects in glioma-bearing mice (Wang etal., 2016). Labrasol/Pluronic F68 modied phospho-
lipid-based nanomicelles entrapping avonoids were recently designed for targeting brain tumors.
The ndings indicated a uniform distribution of nanomicelles entrapping myricetin in specic tis-
sues, thus improving in vivo antitumor efcacy without exceptional cellular toxicity to Caco-2 cells
(Wang etal., 2020). Monoacyl-phospholipids (lyso-phospholipids), robust cone-shaped surfactants,
can successfully produce micelles in a water dispersion. However, substances comprising monoacyl-
as well as diacyl-phospholipids with about 60% lyso-PC can be regarded as intermediate emulsiers
to produce mixed micelles (Van Hoogevest and Fahr, 2019). Micelles have been extensively explored
as a delivery device due to their pH-responsive release property of therapeutics at targeted tissues and
active targeting strategy utilizing specic ligands. Nowadays, biocompatible nanomicelles as oral
and parenteral formulations are attracting pharmaceutical companies to provide better clinical
support.
8.7 LIPOSPHERES AS A BIOCOMPATIBLE DELIVERY SYSTEM
The greatest drawback of polymeric drug delivery devices, for example nanoemulsions, nanopar-
ticles and nanoliposomes, relates to polymer degradation. Hence, the organic solvent present in the
delivery vehicle may circulate in the physiological system, resulting in various toxicological haz-
ards. To combat these problems, lipid microspheres, also known as lipospheres, have been preferred
as a novel class of lipid-based system for encapsulating therapeutic molecules (Swain etal., 2016).
Lipospheres comprise a solid lipid matrix surrounded by a layer of phospholipids as an external coat
(Jadhav etal., 2014). The bioactive core is dissolved (lipophilic) or dispersed (hydrophobic) in lipo-
spheres. Due to the particle dimensions, with a range from 0.01 to 100 μm in diameter, lipospheres
can successfully deliver both hydrophilic (proteins and peptides) and lipophilic therapeutics into
deep and targeted tissue areas, for instance the central nervous system and cerebrospinal uid, with
enhanced efcacy and stability (Dudala etal., 2014). Nasr etal. formulated lipospheres with soy
lecithin and egg lecithin for topical application of angiotensin-converting enzyme (ACE) and docu-
mented improved drug loading capacity, elevated stability and sustained anti-inammatory potency.
Egg lecithin with a lower amount of unsaturated fatty acid manifested higher entrapment efciency
for aceclofenac than soybean PC consisting predominantly of unsaturated fatty acids, e.g. linoleic
acid (67%). The greater membrane fatty acid unsaturation was found to amplify the membrane
uidity, one of the major criteria determining drug entrapping efciency. Unsaturated fatty acids of
phospholipid chains are unable to pack tightly in comparison to saturated fatty acids, which causes
more leakage of the entrapped core. The percentages of drug released after 8 h from egg lecithin–
based lipospheres were observed to be much lower compared with a system prepared with soybean
lecithin under identical circumstances, since the efux transport of drugs is increased by membrane
fatty acid unsaturation. The anti-inammatory potency of fabricated lipospheres was shown to be
higher than that of commercial products in an experiment on carrageenan-induced rat paw edema.
The lipospheres were also found to be capable of conserving their physical properties during storage
at 2–8 °C (Nasr etal., 2008). Using lecithin as surfactant, Benzocaine lipospheres were prepared to
enhance permeation and drug retention in skin and thus, to improve local anesthetic performance.
The onset of anesthetic effect in rabbit cornea was found to be 6 min with lipospheres in comparison
to 17 min observed with the conventional emulsion system. Furthermore, the anesthetic effect lasted
much longer, for 53 min, with lipospheres in contrast to 11 min and 18 min with conventional emul-
sion (Bhatia etal., 2007). Phospholipon 90H, phospholipin 80H and soy lecithin were employed
for the development of Fenobrate lipospheres to enhance the bioavailability of the drug (Saroja
and Lakshmi, 2013). Phospholipid lipospheres loaded with rifampicin displayed improved efcacy
towards H37Rv strain in vitro. Thus, the ndings have shown the possibilities of lipospheres for
pulmonary administration of rifampicin (Singh etal., 2015). Upendra etal. fabricated Glimepiride
lipospheres with particle size varying about 25.68 ± 0.18 µm, entrapment efciency of 85.37 ±
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205Phospholipid-Based Nanoplatforms
2.50%, drug content of 85.13 ± 2.35% and drug release of 81.19 ± 3.91% within 8 hours (Upendra
etal., 2015). Similarly, for the treatment of diabetes, pioglitazone hydrochloride lipospheres were
optimized with spherical-shaped particles in the size range of 23.74 ± 0.35 μm in diameter, entrap-
ment efciency of 79.69 ± 1.35%, drug content of 94.63 ± 2.10% and drug release of 96.06 ± 0.54%
within 8 hours (Bhosale etal., 2016). Formulated naproxen-entrapped lipospheres were found to be
free-owing and spherical in shape. Drug entrapment efciency and in vitro drug release content
were found to vary from 80% to 90% and from 80% to 85%, respectively (Satheesh etal., 2014).
Ooxacin was also successfully loaded in lipospheres to enhance oral bioavailability, minimize
toxicity and attain better patient compliance. Pharmacokinetics studies performed in rabbits stated
that the lipospheres improved the bioavailability of ooxacin 2.45-fold following oral adminis-
tration (Satheesh etal., 2016). Avramoff etal. formulated pro-dispersion lipospheres for delivery
of cyclosporine to improve bioavailability and thus, potential clinical use (Avramoff etal., 2012).
Lecithin-based lipospheres entrapping lamivudine with particle size ranging from 68.27 to 173. m,
encapsulation efciency of 84.87–88.14% and drug release of 49.72–76.83% were explored for the
treatment of AIDS (Saritha and Ravikumar, 2015). Lipospheres have been effectively utilized for
oral, parenteral and topical delivery. Phospholipon 90H–based ibuprofen lipospheres fabricated by a
homogenization technique exhibited superior anti-inammatory and analgesic activity in compari-
son to a conventional system (Momoh etal., 2015). Novel co-spray-dried rifampicin (RMP) phos-
pholipid lipospheres were considered as a promising carrier system, showing higher peak plasma
concentration and thus, improved antimycobacterial activity compared with pure rifampicin (Singh
etal., 2017a). The fusion of the solid interior with phospholipid at the external surface of lipospheres
presents various satisfactory outcomes compared with conventional microspheres, for instance con-
siderable dispensability in an aqueous environment and distinct release kinetics of the core, con-
trolled by the phospholipid covering (Ganesan and Allimalarkodi, 2015). To overcome the delivery
issues targeting breast carcinoma, lipospheres loading cabazitaxel and thymoquinone together were
fabricated from egg PC aided by a melt dispersion method. Enhanced efcacy of the formulated
lipospheres was reported, probably due to diffusion-controlled release of drugs from the liposphere
matrix for prolonged period followed by faster cellular internalization. Compared with treatment by
a solution of the combination, major morphological alterations in cancer cells, for instance nuclear
fragmentation, enhanced Sub G1 phase arrest and apoptotic cell death, were perceived upon the
administration of drug-loaded lipospheres (Kommineni etal., 2019). Lipospheres showed improved
shelf life and thus, stability as compared with emulsions and liposomes. Lipospheres possessing
a solid matrix can minimize the risk of interaction of core molecules with the encapsulant com-
pared with a conventional system. In the liposphere, the solubilization of the active substance is
not mandatory, since it may be dispersed within the solid matrix. Despite all these advantages,
lipospheres suffer from several drawbacks, such as limited drug entrapment efciency for proteins,
high-pressure–mediated drug degradation, etc. To enhance the efciency of lipospheres as a prom-
ising delivery tool, pharmaceutical scientists should pay attention to the biochemical interaction and
mechanism of action of the encapsulated therapeutics in a physiological system. Fabrication tech-
niques, physicochemical characteristics and therapeutic effects of phospholipid-based lipospheres
entrapping various active compounds are briey outlined in Table 8.6.
8.8 PHOSPHOLIPID–DRUG COMPLEXES FOR ENHANCING
STABILITY AND ORAL BIOAVAILABILITY
Several active constituents demonstrating robust in vitro therapeutic effects suffer from inadequate
oral bioavailability and poor permeability through the physiological barriers. In the absence of a
sufcient amount of drug in the gastro-intestinal (GI) tract, the drug cannot efciently penetrate
through the epithelia of the GI system, leading to insufcient systemic absorption. To overcome
this problem, pharmacosomes and phytosomes have begun to attract attention for the delivery of
conventional commercial drugs and natural phyto-compounds, respectively (Abhinav etal., 2016).
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206 Handbook of Nanotechnology in Nutraceuticals
TABLE 8.6
Method of Fabrication, Physicochemical Characteristics and Therapeutic Effects of Phospholipid-Based Lipospheres Entrapping Various
Active Compounds
Type of phospholipid Active compound Preparation method
Particle size
(µm)
Entrapment
efficiency (%)
Net release
content (%) Therapeutic impact Reference
Soybean lecithin, egg
lecithin
Aceclofenac Melt method, solvent
evaporation method
0.69 94.60 85.52 Augmented anti-
inammatory activity
Nasr etal., 2008
Soy lecithin,
phospholipon 90H,
phospholipon 80H
Fenobrate Melt dispersion
technique
30–45 85.98 87% Elevated activity against
hyperlipidemia
Saroja and
Lakshmi, 2013
Phospholipon 90G Glimepiride Melt dispersion
technique
25.68 85.37 81.19 Expected to increase
anti-diabetic activity
Upendra etal.,
2015
Phospholipon 90G Pioglitazone
hydrochloride
Melt dispersion
technique
23.74 79.69 96.06 Expected to increase
anti-diabetic activity
Bhosale etal.,
2016
Phospholipon 80H Naproxen Melt dispersion
technique
41–48 80–90 80–85 Minimized local side
effects
Satheesh etal.,
2014
Phospholipon 90H Ibuprofen Hot homogenization
technique
101–178 89.4–97.9 75–96.9 Increased anti-
inammatory and
analgesic activity
Momoh etal.,
2015
Lecithin Lamivudine Melt dispersion 68.27–173.47 84.87–88.14 49.72–76.83 Expected to effectively
treat HIV
Saritha and
Ravikumar,
2015
Phospholipon 90H Gentamicin Solvent-melting 271.0–290.1 86.32 83 Enhanced antibacterial
efcacy
Momoh and
Esimone, 2012
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207Phospholipid-Based Nanoplatforms
Figure 8.4 depicts the mechanism of action of the phospholipid–drug complex entering the entero-
cytes and reaching the systemic circulation. PC is the major constituent of the pharmacosome and
phytosome structure formation. Phytosomes and pharmacosomes can self-assemble similarly to
liposomes when dispersed in an aqueous medium, but there are some differences in their chemi-
cal structure. In liposomes, hydrophilic bioactive agents are entrapped in the aqueous inner core,
whereas in phospholipid-based phytosomes and pharmacosomes, weak hydrogen bonds and strong
covalent bonds, respectively, form between the phospholipid and the active compound (Grimaldi
etal., 2016). The comparative representation of phytosomes and pharmacosomes is shown in detail
in Table 8.7.
8.8.1 phytosomes
Active phytocompounds such as polyphenols, avonoids, terpenoids and alkaloids suffer from poor
lipophilicity and bioavailability due to their high molecular weight and multiple ring structure.
These features limit their ability to cross cellular membranes or to be absorbed by simple diffusion.
FIGURE 8.4 Entry of phospholipid–drug complex into the systemic circulation via enterocytes to overcome
the burden of poor bioavailability. Drug–phospholipid complex evades the P-glycoprotein efux and rst-pass
hepatic metabolism that must be faced by naked drug molecules.
TABLE 8.7
Comparative Representation of Phytosomes and Pharmacosomes
Characteristics Phytosomes Pharmacosomes
Bond Weak bonding; hydrogen bond Strong bonding; covalent bond
Drug leakage Less No
Entrapment efcacy Low High
Drug release By bilayer diffusion, surface deposition or
degradation
By hydrolysis
Stability Not very stable, shorter shelf life Highly stable, longer shelf life
Membrane uidity Takes place and inuences the rate of release Does not take place and does not
restrict the rate of release
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208 Handbook of Nanotechnology in Nutraceuticals
Bifunctional PC possesses a hydrophilic choline moiety and a lipophilic phosphatidyl constituent.
In the phyto-phospholipid complex, a weak hydrogen bond is formed between the choline molecule
and the active hydrogen atom of a polar phytoactive constituent. Then, the lipophilic phosphatidyl
constituent joins the hydrophilic choline-bound complex, leading to the formation of a phytosome
(Gnananath etal., 2017). Luteolin–phospholipid complex (LPC) was successfully prepared with a
drug-encapsulating ability of approximately 72.64% and mean particle size of about 152.6 nm. The
aqueous solubility of luteolin in LPC was increased around 2.5-fold compared with that of pure
luteolin. LPC yielded about 95.12% luteolin release through diffusion at the end of 2 h, resulting in
increased therapeutic efcacy in the in vivo system (Khan etal., 2014). Hydrogenated PC has been
explored to fabricate phytosome complexes from Terminalia arjuna bark. In comparison to the
pure extract, the phytosomes have been found to exert a signicantly higher antiproliferative effect
against the MCF-7 breast cancer cell line (Shalini etal., 2015). Rutin-loaded phytosomes prepared
from PC have been documented to show improved physical stability over a 3-week storage period
(Hooresfand etal., 2015). A phospholipid stabilized Centella extract (SCE) phytosome was formu-
lated with a markedly higher aqueous solubility and improved sustained release kinetics. Ex vivo
permeation studies using the everted sac model in intestine revealed the enhancement in permeation
of SCE phytosomes (82.8 ± 3.7 %w/w), and in vivo efcacy assessments with the Morris Water
Maze test depicted a pronounced augmentation in spatial learning and memory in elderly mice
after phytosome treatment (Saoji etal., 2016). Rosmarinic acid–phospholipid complex was found to
demonstrate elevated oral bioavailability as well as improved preventive effects against oxidative
stress–mediated cellular damage compared with unformulated rosmarinic acid (Yang etal., 2015).
Optimized pomegranate extract–phospholipid complex (SPEPC) showed greater permeability than
the pure extract in an everted sac model. Dissolution studies revealed that the phospholipid coat-
ing might restrict the core to be free in intestinal environment and arrest their degradation by
gut microbiome (Vora etal., 2015). For dermal delivery, Phyllanthus emblica extract–phospholipid
complex has shown better skin retention and prolonged antioxidant effect compared with a conven-
tional dosage form (Pereira and Mallya, 2015). The lipophilicity, intestinal absorption and thus, oral
bioavailability of Echinacoside were statistically proved to be functional in an Echinacoside–phos-
pholipid phytosome formulation (Li etal., 2015a). Solidied powder of oleanolic acid–phospholipid
complex was found to be suitable to increase the solubility of oleanolic acid (Yang etal., 2016).
In vitro studies indicated notably superior antioxidant properties of (−)-epigallocatechin gallate
(EGCG)–phospholipid complex compared with butylated hydroxytoluene after a 15-day storage
period (Chen etal., 2015). Silymarin–phospholipid complex was documented to have the best physi-
cal attributes, with average vesicle diameter of about 133.534 ± 8.76 nm, polydispersity index of
around 0.339 ± 0.078, encapsulation efciency of approximately 97.169 ± 2.412%, loading capacity
of about 12.18 ± 0.30% and satisfactory stability (Maryana etal., 2016). A phospholipid complex
was found to be a favorable encapsulant for increasing the oral bioavailability of dihydromyricetin
due to the enhancement of the water solubility of the complex, escalation of absorption, and an
anticipated reduction in hepatic and intestinal metabolism (Zhao et al., 2019). In a recent study,
a piperine–phospholipid complex (PPC) was developed and thoroughly characterized as a novel
nanocarrier to overcome the hindrances associated with the conventional delivery strategies. In
vitro as well as in vivo investigations exhibited notably higher hepatoprotection by the fabricated
PPC than the free piperine due to the improved bioavailability and pharmacokinetic prole (Biswas
etal., 2020). A novel self-nanoemulsifying drug delivery system (SNEDDS) enclosing phospholipid
complex was successfully formulated to enhance the oral bioavailability of norisoboldine through
increasing intestinal lymphatic transport and inhibiting its metabolism in liver (Zhang etal., 2019).
Based on previous reports, phytosomes were considered to protect herbal compounds from digestive
degradation and gut bacteria, provide better absorption and improve bioavailability. On the con-
trary, a recent study utilizing a TNO intestinal model-1 (TIM-1) revealed the impact of phospholipid
on the bioaccessibility of polar compounds (Huang etal., 2019). It showed that complexation with
phospholipids diminished the bioaccessibility of rosmarinic acid in the jejunum whilst conserving
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209Phospholipid-Based Nanoplatforms
it in the ileum of the small intestine. The all-inclusive bioaccessibility of the rosmarinic acid–
phospholipid complex was found to be lower than for rosmarinic acid alone. The enhanced oral
absorption found in the preceding in vivo research may be attributed to the overwhelming power
of improved intestinal permeability over reduced bioaccessibility. Surprisingly, thousands of PC
molecules were found to encompass the water‐soluble component in liposomes. In contrast, the PC
and the active phytoconstituent form phytosomes by complexing in a 1:1 or a 2:1 ratio. Thus, phyto-
somes offer better stability and absorption over liposomes (Karimi etal., 2015). The dose require-
ment is decreased and the therapeutic effect intensied by the use of a phytosomal drug delivery
system. Despite various advantages of phytosomes, some fatal complications have been observed
in phytosomal delivery systems (Singh etal., 2018). Phospholipid (lecithin) has been documented
to promote proliferation in MCF-7, a human breast adenocarcinoma cell line (Chivte etal., 2017).
A crucial drawback of phytosomes is leaching of the phytoactive compounds, which was reported
to reduce the effective concentration. Phytosome formulations can be administered via both oral
and topical routes to achieve maximum bioavailability and thus, benecial efcacy. As the phyto-
some formulation methodology has proved to be a simple one, it can be commercially scaled up for
the pharmaceutical, nutraceutical or cosmetic industry in the near future. Fabrication techniques,
physicochemical characteristics and therapeutic effects of phospholipid-based phytosomes entrap-
ping various active compounds are briey outlined in Table 8.8.
8.8.2 pharmacosomes
Pharmacosomal therapeutic carriers are presently emerging for the rened delivery of several thera-
peutics, such as cancer drugs, non-steroidal anti-inammatory drugs (NSAIDs), etc. A drug with an
active hydrogen atom moiety or a free carboxyl group can be esteried to the hydroxyl group of a
phospholipid molecule, resulting in an amphiphilic prodrug (Kapoor etal., 2018). There are several
advantages of pharmacosomes over liposomes. Unlike liposomes, the volume captured does not
alter the encapsulation efciency of pharmacosomes. In pharmacosomes, there is no requirement
for the monotonous as well as laborious step of eliminating the unbound, unencapsulated drug from
the system, which is necessary for liposomes. As the active molecule is covalently conjugated with
phospholipid in pharmacosomes, the leakage of the active core, which is common in liposomes,
does not occur. Pharmacosomes can be administered through the oral, topical and intra-vascular
route (Pandita and Sharma, 2013). In two different studies, to recover the aqueous solubility and
bioavailability and to minimize the toxic effects of the drugs on the GI system, pharmacosomes
were fabricated by conjugating PC with aceclofenac and ketoprofen in various ratios (Semalty etal.,
2010; Kamalesh etal., 2014). Furosemide pharmacosome formulations were found to exhibit a ve-
fold elevation in dissolution and a pronounced enhancement in permeability in comparison to the
pure drug (Semalty etal., 2014). In vitro release kinetics also indicated a prolonged drug release
prole. The solubility of pranlukast–phospholipid complex was reported to be increased about 150-
fold, resulting in a 20-fold improvement of its bioavailability in comparison to its native crystalline
state (Hao etal., 2015). Unsatisfactory bioavailability of rifampicin due to its inadequate water solu-
bility was recently reported to be overcome by constructing a complex with PC (Singh etal., 2014).
This was observed because of the increased solubility accompanied by the enhanced absorption of
rifampicin. The complex was found to increase the oral bioavailability of rifampicin by enhancing
absorption, thereby decreasing its metabolism. In another recent report, it was found that the low
solubility of atorvastatin could be resolved by forming a phospholipid complex (Qin etal., 2018).
The oral adsorption of atorvastatin–phospholipid complex showed a 2.58-fold increase in plasma
concentration with superior pharmacokinetics compared with Lipitor (a commercial product). A
parallel investigation performed by another batch of researchers was the fabrication of Erlotinib–
phospholipid complex to challenge the drug solubility issues as well as to promote bioavailability
and reduce cytotoxicity (Dora etal., 2017). The developed Erlotinib–phospholipid complex in the
form of nanostructures achieved 1.7-fold higher bioavailability and superior efcacy of Erlotinib
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210 Handbook of Nanotechnology in Nutraceuticals
TABLE 8.8
Method of Fabrication, Physicochemical Characteristics and Therapeutic Effects of Phytosome Complexing with Various Active
Compounds
Type of phospholipid Active compound
Preparation
method
Particle
size (nm)
Zeta-potential
(mV)
Entrapment
efficiency (%) Therapeutic impact References
Phospholipon 90H Luteolin Solvent
evaporation
152.6 −27.6 72.64 Enhanced anti-
inammatory activity
Khan etal., 2014
Phosphatidylcholine Rutin Thin layer
hydration
99–123 −45.2 72–80 Expected to increase
antioxidative property and
bioavailability
Hooresfand etal.,
2015
Soy phosphatidylcholine Silymarin Solvent
evaporation
133.534 – 97.169 Improved oral
bioavailability
Maryana etal.,
2016
Soy phosphatidylcholine Ashwagandha
extract
Ethanol method
and reux
method
98.4 −28.7 90.1 Augmented antioxidative
property
Keerthi etal.,
2014
Phospholipid Evodiamine Solvent
evaporation
246.1 −26.94 – Elevated oral bioavailability Tan etal., 2012
Phosphatidylcholine Quercetin Thin layer
hydration
method
266.6 −29.43 ± 0.75 96.57 Expected to enhance
bioavailability
Lestari etal., 2017
Soy phosphatidylcholine Mitomycin Solvent
evaporation
210.87 −33.38 – Exhibited superior
antitumor activity
Hou etal., 2012
Soy phosphatidylcholine Curcumin Co-solvent
method
185.3 −15.7 92.5 Enhanced tumor
accumulation
Xie etal., 2017
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211Phospholipid-Based Nanoplatforms
due to amorphization and enhanced solubility in comparison to free Erlotinib. A geniposide phar-
macosome formulation was optimized to increase lipophilicity to about 20 times higher than that
of the pure material (Yue etal., 2012). Complex formation of raloxifene with phospholipids dem-
onstrated signicant promise in augmenting therapeutic efcacy because of its rened biopharma-
ceutical properties along with improved oral bioavailability. Van der Waals interactions and other
electrostatic forces were found to be responsible for the complex formation between raloxifene and
phospholipid (Jain et al., 2019). To increase solubility and bioavailability as well as to diminish
GI irritation, an aspirin–phospholipid complex was fabricated. The developed formulation showed
90.93% core release at the end of 10 h in an acidic medium (Semalty etal., 2010). Cholesteryl-
phosphonyl gemcitabine (CPNG), an amphiphilic prodrug of gemcitabine, was fabricated by conju-
gating the drug with cholesterol with the aid of diphenyl phosphonate. The nanoassemblies yielded
three to six times greater cellular toxicity compared with the naked drug, probably due to the phos-
phonyl substitution as well as the amphiphilic nature of CPNG. After bolus intravenous admin-
istration, CPNG nanoassemblies were mostly dispersed throughout the mononuclear phagocyte
system prevailing in liver and spleen. The nanoassemblies entrapping a considerable dose of CPNG
showed markedly superior in vivo chemotherapeutic activity compared with gemcitabine (Li etal.,
2015c). Despite the appreciable stability, greater shelf life and sustained release kinetics in vivo,
pharmacosomes may also suffer from fusion, aggregation and chemical hydrolysis during storage
(Sailaja, 2016). To fabricate pharmacosomes as a productive delivery device, bulk interaction of
the drug with phospholipid is most important. Besides this, research groups across the world have
tried to explore various nanoplatforms manufactured with phospholipid in an effort to conquer all
the above-mentioned obstacles (Kuche etal., 2019). Micro/nanoemulsion, self-emulsifying delivery
devices, micelles and several other nanodelivery tools were employed synergistically with drug–
phospholipid complex to mitigate the bioavailability issues and successfully improve the physico-
chemical attributes of the therapeutic agents.
8.9 CONCLUSION
In the pharmaceutical industry, phospholipids are globally used as surface active agents, coating
agents, wetting agents, carriers, solubilizers and permeation enhancers. But, the physicochemical
properties of heterogeneous phospholipid mixtures obtained from various natural resources may
differ from each other depending on the nature of the water-loving head group as well as the long
fatty acid tail. So, the choice of the right phospholipid excipient to fabricate a novel formulation and
to accommodate the intended benets of the therapeutic agents requires a deep understanding of
the composition of the phospholipid mixture. Therapeutic delivery avenues are currently experienc-
ing a substantial expansion due to the unied interests of researchers, industrialists and governing
bodies. Though natural phospholipids should be chosen as excipients for fabricating nanostructures
due to their countless inherent benecial properties, as mentioned throughout this chapter, current
research is focusing on synthetic phospholipids, possibly due to the fear of undiscovered impurities,
allergens, etc., existing in naturally available phospholipids. Along with the active targeting abil-
ity and the enhanced permeation–retention effect, phospholipid-based nanovehicles are anticipated
to ourish soon as one of the safest and most favorable delivery methods. Because of their crucial
contribution in constructing and maintaining biological interfaces, the interaction of phospholipids
with the physiological system has earned a lot of consideration from contemporary researchers.
Phospholipids, especially PC, can be employed to integrate into the cell membrane, substituting
for cellular phospholipids as well as modifying the uidity of the membrane. The complex bio-
molecular interactivity between the phospholipid vehicle and the membrane phospholipid, as well
as its inuence on cellular signaling, still remains stochastic. Furthermore, detailed comprehension
would also be required to correlate the unique stability of the phospholipid nanostructure and its
sustained release prole. To explore the exciting possibilities in the frontier area of therapeutic
delivery, more holistic study of phospholipid-based nanovehicles will be required.
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212 Handbook of Nanotechnology in Nutraceuticals
ACKNOWLEDGEMENT
The authors would like to convey their wholehearted indebtedness to colleagues and co-researchers,
especially Dr. Tanmoy Kumar Dey, for their constant effort and support.
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