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biomolecules (e.g., vitamins A and E), and antioxidants (e.g., CoQ10, lycopene, and
carotenoids) have been incorporated into liposomal membranes to increase their delivery.
Phosphatidylcholine, one of the main ingredients of liposomes, has been widely used for
the topical preparation due to its compatibility with skin lipids [107,108]. The technological
solution, based on the modification and/or derivatization of liposome, has been used by
many researchers to maximize the anticancer effect and targeted release of drug loaded in
liposomes from plant extract. In this context, enhanced anticancer activity against
FR-positive breast cancer cells (MCF-7) was reported using folate receptor-targeted
PEGylated liposome loaded bioactive compounds from Kappaphycus alvarezii [109].
In another research, Fardous et al. investigated the bioavailability and anticancer ef ficacy
of AZD-loaded liposomes against TNBC cell line (MDA-MB-231). They reported significantly
enhanced oral bioavailability and anticancer activity of AZD from liposomes was signifi-
cantly higher than free AZD [110].
Like liposome, proliposome is another promising lipid-based drug delivery system. Prob-
lems linked with liposome aggregation, sedimentation, fusion, phospholipid hydrolysis,
and/or oxidation as well as difficulties in sterilising vast quantities of liposomes have been
overcome by this technology. Dry, free-flowing particles that form a liposomal suspension
in water are known as proliposomes. Since proliposomes are solid, their stability issues
can be rectified without affecting the intrinsic features of the liposomes [111].
In a research reported by Hao et al. ginseng fruit saponins (GFS) extract loaded prolipo-
some was developed using spray drying method to improve the oral bioavailability of
GFS in rats. They reported significantly enhanced bioavailability of the developed novel
preparation [112].
Phytosomes are emerging lipid-based technology that was developed as leading herbal
drug delivery system made by the interchange of standardized plant extracts and phospho-
lipids; primarily phosphatidylcholine in stoichiometric proportion. Phytosome technology
has been effectively used to intensify the bioavailability of many best-selling herbal extracts,
e.g., milk thistle, grape seed, Ginkgo biloba, curcumin, green tea, ginseng, hawthorn, etc. This
novel formulation has significant advantages over other conventi onal formulations of plant
extracts and actives, which include enhancement of solubility, ability to cross the cell mem-
branes, bioavailability, enhancement of stability, protection from toxicity, protection from
physical and chemical degradation, and sustained delivery [113,114].
3.3 Lipid-based particulate system
Drugs can be delivered more efficiently and with fewer side effect s when using systems
that use particulate delivery systems. As the stability of lipid nanoparticles and other
solid-lipid nanocarriers improves, so do transdermal absorption rates, as well as targeted
administration of entrapped or loaded drugs. This is due to the development of lipid nano-
particles and other solid-lipid nanocarriers. Moreover, these systems offer chances for better
understanding of carrier effects with respect to absorption, distribution, and their pharmaco -
kinetics. This, however, needs additional and detailed research addressing particle/particle
lipid interactions and the influence of particle composition on Active Pharmaceutical Ingre-
dients (API) distribution within the body. The first generation of lipid nanoparticles was
introduced as solid lipid nanoparticles (SLN), the second, improved generation as nanostruc-
tured lipid carriers (NLC), lipid nanoparticles, lipid microsphere, and lipid nanocapsules.
4. Lipid-based particulate systems for delivery of plant actives and extracts: Extraction, prospective carriers, and safety issues98
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Identical to the vesicular system, the lipid-based particulate system appeared as products first
on the cosmetic market (Nanopearl). NLCs, lipid nanoparticle, lipid microsphere and lipid
nanocapsules are types of submicron particulate drug delivery system, based on the mixture
of lipids, polymer , and emulsion, which offer the advantages of improved drug loading ca-
pacity, entrapment efficiency, and release properties [33,34]. Additionally, the usual particle
diameters of the lipid particulate system are in the range of approximately 10 nme200mm.
Thus, the nano- and micron-sized lipid-based particulate delivery systems for herbal drugs
have a potential future for enhancing the activity and overcoming problems associated with
plant medicines [43]. In recent years, there has been escalating focus on SLN and NLC because
the SLN and NLC as colloidal drug carriers combinethe advantages of polymeric nanoparticles
and fat emulsion. They possess a solid matrix for controlled release of drug avoiding the burst
release as obtained with fat emulsions. For example, Liu et al. prepared docetaxel ultrasmall
NLC with high-entrapment efficiency due to its highly hydrophobic nature and in vitro release
study also showed a sustained and continuousrelease pattern [115]. The lipid-based particulate
formulations loaded with poorly water-soluble drugs administered through different routes
have been investigated and reported to improve the problems like the bioavailability, stability,
solubility, toxicity, side effects, etc., by many research teams, but there are few reports on lipid-
based particulate system for herbal and plant extracts [115,116].
Recently, Rupalli et al. prepared curcumin-loaded NLCs for enhanced skin retained topical
delivery. They reported, 3.24 fold enhancements in skin permeation and retention by
curcumin-loaded NLC gel as compared to free curcumin [117].
Nanoparticles containing zidovudine and Aloe vera have been created by Joshy and his col-
leagues using an easy method of solvent extraction, which exhibited great stability at both
room temperature and in the refrigerator. These nanoparticles were examined in vitro for
their potential use in the delivery of drugs. C6 glioma cells grown on the nanoparticles
demonstrated increased growth and proliferation without showing any harm in cell culture
trials. These nanoparticles could be used to improve the uptake of antiviral drugs by the brain
and could be used to treat HIV, according to a study on cellular uptake [118]. Lipospheres
containing tacrolimus, curcumin, and thymoquinone were produced by Jain and colleagues
for use in the treatment of psoriatic arthritis by encasing them in gels and thymoquinones in
lipospheres with particle sizes below 70 nm. Controlled release of the medicines and plant
active laden formulation was demonstrated by these lipospheres. On the imiquimod-
induced psoriatic plaque model, the therapeutic efficiency of drug loaded liposphere was
tested by measu ring biochemical markers that showed improvement in the phenotypic
and histological aspects of the treated psoriatic skin. There was reduction in the level of
TNF-a, IL-17, and IL-22 compared to imiquimod group [61,62,119].
4. Lipid-based system as carriers for plant actives and extracts
Numerous plant-based pharmaceuticals have been developed by incorporating whole plant,
plant part, plant extracts, or plant actives.Their health benefits have been established by various
nonclinical and clinical studies. Whole plant or its part expresses undesirable effects together
with clinical effects, so now emphasis is on the use of plant extracts or actives for minimal
side effects. Mostly plant extracts are polar (water-soluble) or nonpolar (water insoluble) in na-
ture. Table 4.1 illustrates some plants constituents (alkaloids, tannins, flavonoids, etc.)
4. Lipid-based system as carriers for plant actives and extracts 99
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of therapeutic importance with their nature. Most of them like tannins, alkaloids, glycosides are
water soluble due to multiple ring molecules, and flavonoids have limited properties to cross
the outer membrane of the skin due to poor miscibility with lipids [120].
Novel lipid-based systems are applicable to incorporate herbal constituents and to resolve
all problems which restrict the use of herbal actives. There are numerous herbal-based med-
icines constituting plant actives and extracts incorporated in novel lipid-based systems,
which showed improved pharmacokinetics and dynamics (Table 4.5).
For example, incorporation of quercetin (poorly soluble drug) into SLN showed sustained
release profile in vitro and enhanced cellular uptake of quercetin by Caco-2 cells. These data
indicated that SLN is a promising delivery system to enhance physicochemical properties of
poorly water-soluble drugs, such as quercetin [10]. Lundberg et al. compared the efficiency of
paclitaxel-loaded lipid emulsion and paclitaxel in Cremophor EL (CrEL)/ethanol. The phar-
macokinetic results showed much higher Area under Curve (AUC), and lower systemic clear-
ance in paclitaxel loaded lipid emulsion than paclitaxel in CrEL/ethanol. This might be due to
exclusive entrapment of lipophilic drug in the oil core of lipid emulsion droplets [121]. Lipid-
based delivery systems are suitable candidates for enhancing the bioavailability and stability
of lipophilic herbal components. Curcumin mainly depends on its solubilization and subse-
quent absorption through cell lining so that it can reach systemic/general circulation. How-
ever, curcumin has extremely low water solubility as well as low bioavailability and
undergoes rapid metabolism on oral delivery. Studies have shown that curcumin can be
encapsulated within complexes formed by using a variety of lipids and nanoemulsions as
a delivery system. The physical stability of lipid nanoemulsion has been found to be higher
than the conventional emulsion leading to an increase in the bioavailability of curcumin [150].
Nanostructured Lipid Carrier (NLC) system as a carter for curcumin is a promising drug de-
livery system for brain cancer therapy that showed increased cytotoxicity of curcumin loaded
NLC than that of curcumin to astrocytoma-glioblastoma cell line (U373MG) in the cancer
cell lines along with high biodistribution of drug concentration in brain after intranasal
administration [151]. Silybin is the major biological active component, responsible for the
antihepatotoxic activity, and other properties like antioxidative, antilipid-peroxidative,
antifibrotic, antiinflammatory, immunoregulatory, and liver regenerating effects. However,
short half-life reduced the utility of this herbal component. Nanostructured lipid carriers
have great potential to improve parenteral delivery of lipophilic agents and herbal
components. The NLC is aptly fit for intravenous delivery due to their nanostructure and
the biocompatibility of lipid excipients. Area under the curve (AUC) and mean residence
time (MRT) of silybin-NLC have shown higher value of silybin in nanostructured lipid
carriers than silybin solution [116].
One of the most fundamental components of cellular membranes is lipids. In terms of
global pharmaceutical planning and marketing, nanoscale lipid-based delivery techniques
have a major impact. A number of lipid particulates offer unique benefits as pharmaceutical
carriers in delivery systems as a result of nanotechnology advanceme nts in lipids. Recent de-
cades have seen the emergence of biocompatible lipid microparticles or lipospheres, SLN,
lipid nanocapsules, and lipid nanoparticles as possible drug carrier vehicles for plant actives.
Lipid particulate systems combine several advantages and avoid the disadvantages of other
colloidal carriers. These systems are mostly classified according to their characteristics, such
as entrapment efficiency, release rate, and the mode of action [44].
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TABLE 4.5 Emulsion, vesicular and particulate lipid-based system incorporating plant actives and extracts.
S.No Formulation
Active
ingredient Application Biological activity Method of preparation
Route of
administration References
I. Lipid based emulsion system
1. Lipid emulsion Paclitaxel Reduce side effects Anticancer O/W Parentral [121]
Vinorelbin Improve efficacy, safety and
reduce toxicity
Antitumor High-pressure
homogenization
Parentral [98]
2. Microemulsion Vincristine Reduce toxicity Antitumor W/O/O Systemic [5]
Phenylethanoid
glycosid
Skin lighteners and sunscreens O/W Transdermal [122]
3. Micelles Berberine Enhance oral bioavailability Hypoglycemic activity W/O Oral [123]
Curcumin Improved bioavailability in
brain
Improved working and cue memory
in alzheimer
Oral [124]
4. Nanoemulsions Paclitaxel Improve efficacy and safety Antitumor O/W Parentral [125]
Quercetin Enhance bioavailability Treat cerebral ischemia Titration method Nasal [126]
II. Lipid based vesicular system
1. Liposomes Colchicines Reduce toxicity Treat liver cirrhosis and liver cancer Mechanical dispersion
techniques
Subcutaneous [127]
Quercetin Reduce oxidation in PC Anti-oxidant activity Solvent evaporation
method
Topically [128]
Curcumin Improve their bioavailability Anticancer activity Extrusion technique Parentral [129]
2. Multivesicular
liposome
Ellagic acid Enhance solubility and
stability
Inhibit the growth of tumors of the
skin, esophagus, and lungs
Sonicationefreezing
eunfreezing method
Intravenous [130]
3. Phytosome Silybin Absorption of silybin
phytosome from silybin is
approximately
Seven times greater
Hepatoprotective, antioxidant for liver
and skin
Silybin phospholipid
Complexation
Oral [131]
Naringenin Prolonged duration of action Antioxidant activity Naringenin-phospholipid
Complex
Oral [131]
Umbelliferone Improved permeability,
solubility
Antioxidant activity Solvent
evaporation method
Transdermal [84]
(Continued)
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TABLE 4.5 Emulsion, vesicular and particulate lipid-based system incorporating plant actives and extracts.dcont’d
S.No Formulation
Active
ingredient Application Biological activity Method of preparation
Route of
administration References
4. Ethosomes Sophora
alopecuroides
Improve bioavailability Improved topical delivery of alkaloid Ph-gradient active
loading method
Topical [132]
Curcumin High deformability, and
consistent stability
Wound healing and bacterial flora
assessments
Ethanol injection and
sonication method
Topical [133]
5. Transferosomes Curcumin Increase permeation Antiinflammatory activity Buffer hydration Topical [134]
Curcumin Increase systemic availability Antiinflammatory activity Sonication method Topical [134]
Capsaicin Enhanced permeability Antiarthritic activity Conventional thin film
hydration method
Topical [135]
III. Lipid based particulate system
1. Lipid
microsphere
Vinorelbine Reduce severe venous
irritation
Wide anti-tumor spectrum of activity High pressure
homogenization
Intravenous [136]
2. Solid lipid
nanoparticle
Curcuminoids Improve stability and
enhance activities
Anti-oxidant, anti-aging effect Emulsification method Topical [137]
Curcumin Improve bioavailability Increased endogenous antioxidant
Defense enzymes
Oral gavages
and
intravenous
[138]
Triptolide Improve penetration Antiinflammatory,
immunosuppressive, antineoplastic
activities
Emulsification technique Topically [139]
Curcumin Produce bioadhesion, Antioxidant activity Coacervation technique Topically [140]
Podophyllotoxin Epidermal targeting effect Anticancer High pressure
homogenization
Topical [141]
Curcumin Increased distribution of
curcumin to the lungs
Antiasthmatic Intraperitoneal [142]
Paclitaxel Increase solubility and
stability
Cytotoxicity against human ovarian
and breast cancer cell lines
Hot homogenization
method
Parenteral [143]
Etoposide Enhancing tumor uptake Anticancer agent Melt-emulsifi
cation and
high pressure
homogenization
Intravenous [144]
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Puerarin Increased oral bioavailability Myocardial ischemia, diabetes
mellitus, and arteriosclerosis
Solvent injection method Oral [9]
Etoposide Improved bioavailability Treatment of neoplasms small cell
lung cancer, testicular cancer, and
lymphomas
Emulsion evaporation
esolidification
Oral [145]
Baicalein Enhanced stability Antiinflammatory Solvent diffusion method Intravenous [146]
Capsaicin Enhanced therapeutic efficacy Treat ovarian cancer Thin-film hydration
technique
Intravenous
route
[147]
4. Lipid
nanocapsule
Paclitaxel Reduced toxicity Anti-tumor effect Coacervation method Pulmonary [148,149]
5. Ethosomes Sophora
alopecuroides
Improved bioavailability Improved topical delivery of alkaloid Ph-gradient active
loading method
Topical [132]
Curcumin High deformability, and
consistent stability
Wound healing and bacterial flora
assessments
Ethanol injection and
sonication method
Topical [133]
6. Transferosomes Curcumin Increased permeation Antiinflammatory activity Buffer hydration Topical [134]
Curcumin Increased systemic
availability
Antiinflammatory activity Sonication method Topical [134]
Capsaicin Enhanced permeability Antiarthritic activity Conventional thin film
hydration method
Topical [135]
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4.1 Common methods of preparation
4.1.1 High pressure homogenization
Muller et al. reported that in this process firstly all lipid-soluble constituents dissolve in
melted lipid, then disperses active component containing lipid melt in hot surfactant solution
till preemulsion is formed. Resulting emulsion is homogenized at 40
C, then cooled up to so-
lidification to consolidated lipid particulates [95]. Quercetin crystals, which have antiinflam-
matory, antioxidant, and anticancer activities, but poor water solubility and oral
bioavailability, were homogenized using high-pressure homogenization. High-pressure ho-
mogenization of quercetin enhanced its water solubility, which could be attributable to the
nanometric suspensions formed and crystallinity loss brought on by mechanical friction
and tensions [152].
4.1.2 Solvent evaporation method
Singh et al. reported that in this technique, all solid components such as drug, solid carrier,
and phospholipids are dissolved in a suitable volatile organic solvent followed by evapo-
rating the organic solvent under reduced pressure so that lipid systems are obtained.
Commonly employed solvents are chloroform, acetone, ethyl acetate, ethanol, or dichlorome-
thane. Two techniques employed in this method are rotary evaporator and mechanical
stirrer [47].
4.1.3 Melt dispersion techniques
This method is generally used for lipophilic drugs, which could be directly dispersed into
lipid melt. It involves dispersion of plant actives in melted solid carrier followed by the addi-
tion of warm buffer solution containing phospholipid with constant mixing and rapid cooling
to obtain the uniform dispersion of lipospheres [153].
4.2 Mechanism of uptake of lipid particulate systems and toxicity
Lipid-based particulate systems are efficient carriers for topical delivery of drugs. There
are two different routes for entry of drug molecule into the skin, i.e., intercellular route
and transcellular route (Fig. 4.3). Intercellular route involves drug pene tration through cell
junctions in between the cells, whereas transcellular route involves drug penetration through
the cells [45, 48 , 49 ].
On topical application of lipid-based particulate system, it gets adsorbed or adhered onto
the surface of the skin followed by percutaneous penetration by either intercellular route or
transcellular route. Lipid-based particulate systems facilitate percutaneous absorption due to
its lipoidal nature and close contact with skin lipids. Another mechanism involves disruption
of the organization of the intercellular lipids of the stratum corneum (SC) by lipid excipients,
which increases the fluidity and thus permits easier drug permeation through the less rigid
environment [154]. In addition, penetration enhancers like lecithin have been reported to
enhance the transdermal delivery by lowe ring the permeability barrier of the skin. Further,
drug releases from lipid particulate carriers following diffusion process with controlled
release of the drug moiety from the lipid matrix. The uptake mechanism of lipid particulate
system through the skin is shown in Fig. 4.3.
4. Lipid-based particulate systems for delivery of plant actives and extracts: Extraction, prospective carriers, and safety issues104
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Lipid systems are efficient and safe carriers for drug delivery and are well tolerated in
living systems since they are constituted from physiological compounds leading to the
metabolic pathways. Further, the small size of these carriers provides an increased surface
area exposed to the interaction with cellular systems, increases its biological activity.
FIGURE 4.3 (A) Passage of lipid particulate systems through normal intact skin (B) mechanism of passage of lipid
particulate system through skin.
4. Lipid-based system as carriers for plant actives and extracts 105
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This enhanced activity can be either positive such as better carrier competence for drugs, bet-
ter penetration of cellular barrier s for drug delivery or negative, which may include toxicity,
induction of cellular dysfunction, etc. The activity might also be a mixture of both positive
and negative [43]. Various studies have been reported for this purpose focusing on nanotox-
icology such as cytotoxicity and genotoxicity analysis. However, such effects often are related
to drug concentration as high concentrations lead to toxicities and lower concentrations
generate the subtler effects [155].
4.3 Proprietary lipid particulate system for plant constituents
Liposome Herbasec and Phytosome are products, which have been developed by Cosme-
tochem and Indena. Both companies produce plant extract and constituents which are incor-
porated in vesicular lipid-based systems of high-production quality. Dr. Rimpler did the
worldwide first application of the NLC technology (lipid-based particulate system) for the
encapsulation of lipophilic active ingredients. Nanopearls containing CoQ10 in concentra-
tions previously unreachable have been developed by him in a stable form that permits
the CoQ10 to be delivered into the skin at the same time. It is now possible to deliver the
skin’s living cells with the energy supply and anti-oxidative benefits of ginger and hibiscus
extracts (Nanopearls) to prevent premature aging. Synthetic and plant-derived polypeptides
restructure the connective tissue while ginger- and hibiscus extracts ensure that the additional
connective tissue is not degraded. Using an emulsion of lecithin and plant-derived oils rich in
unsaturated fatty acids, it restores the skin’s lipid barrier and reduces inflammation in dry
and irritated skin. Microsilver has an antibacterial function, which lowers inflammation
and prevents the skin from becoming recontaminated by the centers of inflammation.
Hemp oil-loaded lipid nanoparticles protect the skin by reducing the rate of transepidermal
water loss (TEWL). The multifunctional active agent defensil, an antiinflammatory, antimi-
crobial active agent combination of phytohormones and omega 3-fatty acids supports the
concept of the system care [156]. In the pharmaceutical market, lipid particulate system
can be made with regulatorily accepted excipients with produ ction technology already avail-
able in the pharmace utical industry.
5. Conclusion
In the field of extensive research, many problems related to novel drug delivery mostly
lipid-based particulate system, their production; requirement, safety, and application need
to be improved. Generally, it focuses on suitable drug delivery system to reduce toxicity,
improve stability, therapeutic activity, and other formulation and processing problems.
Mostly herbal drugs are very bioactive with beneficial therapeutic potential and lipid solubi-
lity. Herbal constituents have several problems like poor absorption, poor bioavailability, and
larger molecule size, but lipid solubility is the major problem to deliver drug molecules via
different routes. Lipid-based particulate delivery system shows better stability, activity, ab-
sorption, and release profile resulting in enhanced bioavailability. Several herbal constituents
have shown great results, when delivered using lipoid particulate system especially for trans-
dermal systems, as the adhesion of lipid systems to the skin leads to the formation of a film,
4. Lipid-based particulate systems for delivery of plant actives and extracts: Extraction, prospective carriers, and safety issues106
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and subsequently, to an occlusive effect with a decrease in transepidermal water loss. More-
over, the hydrating effect in the lipid-rich milieu reduces the irritant effect of the molecules
which is otherwise cytodestructive. Despite extensive literature survey, only few researches
based on clinical studies have been reported for herbal constituents incorporated with lipoid
particulate systems (44). Thus, extensive investigations for delivery of herbal extracts loaded
in lipid-based systems are needed to establish clinical utility, effectiveness, and compliance.
Acknowledgment
The authors are thankful to Director, University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur
(C.G.) for providing necessary facilities relating to present work and UGC-MRP 41e748/2012 (SR); UGC-RA
70e371/2012; DST-FIST for financial assistance for the studies.
Declaration of interest
The authors declare no conflict of interest.
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