Journal of Drug Delivery Science and Technology 51 (2019) 224–233

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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Nanoemulsion: Promising nanocarrier system for delivery of herbal T

bioactives
Ranjit K. Harwansha,∗, Rohitas Deshmukha, Md Akhlaquer Rahmanb
a
Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
b
College of Pharmacy, Taif University, Taif, 21974, Saudi Arabia

A R T I C LE I N FO A B S T R A C T

Keywords: The herbal medicines have been popularized throughout the globe since time immemorial. Several plant based
Nanoemulsions therapeutic leads have been produced through integrated approaches. Many herbal bioactives have several
Herbal bioactives health benefits but limited therapeutic potential due to short half-life and low bioavailability profile. Plant
Nano drug delivery system derived molecules are either hydrophilic or lipophilic in nature. Highly hydrophilic bioactives have poor ab-
Nanocarriers
sorption via lipid membrane which slows down their biological efficacy and pharmacokinetics. The large mo-
Bioavailability
lecular size of the plant bioactive compounds also limited their therapeutic uses due to low membrane per-
meability. Nanocarriers have the ability to potentiate the efficacy of herbal bioactives by improving their
solubility, absorption profile, minimizing dose and side effects. The nanoemulsions can channel the herbal
bioactives to the particular target site and maintain blood-plasma concentration for longer periods. However, the
conventional drug delivery system failed to achieve these specific requirements. Nanoemulsions are promising to
improve solubility, stability, permeability and bioavailability of the herbal bioactives through encapsulation.
The present review describes the importance of nanoemulsions for delivery of herbal bioactives and highlights
the various aspects of its formulation consideration, challenges and future perspective for the development of
herbal bioactives.

1. Introduction drug inside the human body. NDDS have the potential to target the
drug/active molecule to particular tissues or sites, also have the ability
Herbal medicines have been used for the treatment of several dis- to get the desired drug concentration over effective treatment period
eases since ancient era. During the last decades, it has become a thrust under therapeutic index [1,2]. Nanosized particles or droplets lead to
area of research for many researchers and innovators throughout the improved solubility and bioavailability of the drug. In this context,
world due to their health benefits. The increasing demand of herbal nanoencapsulation based nanoemulsions are pioneering for en-
medicines as alternative therapies in the Western world needs more capsulating the herbal bioactives and thereby, enhanced solubility and
research in alliance with pharmaceutical nanotechnology for safe and bioavailability. Nanoemulsions are homogeneous, thermodynamically
efficacious medicines. The pharmaceutical application of herbal stable and isotropic system of aqueous, surfactants/co-surfactants (Smix)
bioactives and extracts or phytopharmaceuticals is limited with low and oil phase [3,4]. The nanoemulsion droplet size (o/w and w/o) is
solubility, permeability as well as bioavailability. It has become the reported to be 20–200 nm that is variable based on the composition of
biggest hurdle for the effective use of herbal bioactive compounds the system and the homogenization method used. Nanoemulsion
against various health complications. These drawbacks could be solved structure has been represented in Fig. 1. Upon oral administration,
by the nanoencapsulation process utilizing the nanocarriers which can nanoemulsions dispersed into tiny droplets by self-nanoemulsification
entrap the active moieties inside the lipidic or polymeric core of ex- process in the gastric environment with gastro-intestinal motility [5].
cipients. Therefore, the efficacy of phytopharmaceuticals is based on These nanocarriers can also improve the stability of the en-
effective drug delivery systems [1]. capsulated extract and bioactive of the herbs from gastric degradation
In the recent past, nano drug delivery systems (NDDS) have and results into an extended release of the formulation. They have
emerged as most powerful strategy to deliver bioactive constituent or capability to enhance the membrane diffusion which leads to the

∗
Corresponding author.
E-mail addresses: [email protected], [email protected] (R.K. Harwansh), [email protected] (R. Deshmukh),
[email protected] (M.A. Rahman).

https://doi.org/10.1016/j.jddst.2019.03.006
Received 16 January 2019; Received in revised form 25 February 2019; Accepted 6 March 2019
Available online 11 March 2019
1773-2247/ © 2019 Elsevier B.V. All rights reserved.
R.K. Harwansh, et al. Journal of Drug Delivery Science and Technology 51 (2019) 224–233

Fig. 1. Structure of nanoemulsion [A] oil in water type emulsion (o/w), [B] water in oil type of emulsion (w/o).

sustained effect thereof. For instance, several bioactive and extract of Nanosized droplet offers increased drug absorption and permeation
plants have been reported with nanoemulsion such as neem oil, eu- through the gastrointestinal tract (GIT) due to large interfacial area
calyptus oil, zedoary oil, curcumin, Phaleria macrocarpa, citronella oil, [20].
capsicum oleoresin, berberine, triptolide, etc. [6–14].
The enhanced oral bioavailability and sustained release property of 2.1. Advantage of nanoemulsions as novel nanocarrier
paclitaxel were achieved with nanoemulsions (o/w) as reported by
Choudhury et al. (2014) [15]. In another study, a capsicum oleoresin The advantages offered by nanoemulsions [21] are as follows:
(capsaicin) encapsulated nanoemulsion has been investigated for en-
hancement of its bioavailability. It was obtained due to nanosized • It improves the solubility, dissolution, absorption, bio-membrane
droplets of the formulation [16]. permeation and bioavailability of poorly soluble drugs. This may be
Nanoemulsions have been exploited well for delivery of diverse due to nanosize range and large interfacial area of the droplets.
medicines including pharmaceuticals, phytopharmaceuticals, cosme- • The herbal bioactives can be encapsulated into the nanoemulsion
ceuticals, dietary and nutraceutical for the betterment of human health. matrix so it improves their physical stability.
It can improve the drug's profile like solubility, stability, permeability • The oil or lipids are biocompatible, biodegradable and non-muta-
and bioavailability by encapsulating them into core oil and water of the genic so nanoemulsions are safe for human health.
droplets. It offers a greater advantage for oral administration of the • It offers the site-specific and prolonged release delivery of the
poorly soluble drugs in comparison to conventional delivery systems phytomolecules.
[17]. The specific feature of nanoemulsion as novel carrier system has • Reductions in the dose thereby minimize associated toxicities and
been represented in Fig. 2. provide better therapeutic effects.
The encapsulation of herbal bioactives in novel systems offers dif- • In case of topical application, it avoids first-pass metabolisms hence
ferent advantages in comparison with traditional delivery systems improves plasma drug concentration.
which include stabilization of drug in the aqueous environment of • Offers value added drug delivery system for nutraceutical and
stomach containing food components, protection from gastric de- dietary supplements.
gradation, control the release of active constituents and bioavailability • Facilitating patient compliance.
improvement. Nanosized droplets offer an improved pharmacokinetic
profile of bioactive from herbs. Many authors have shown that reducing 2.2. Formulation aspect of nanoemulsions
the size of the globules leads to an increased surface area which offers
higher drug solubility and absorption profile of the drug. This property Excipients screening are the major steps for the formulation of na-
helps to improve the bio-accessibility and cellular uptake of the active noemulsions. The major excipients for formulation of nanoemulsions
molecules by passive transport through gastrointestinal walls [18]. are oil, Smix and water. Drug solubility study helps to select the best oils
Nanoemulsions are promising for delivery of herbal bioactives in an and surfactants for development of the nanoemulsion formulations. A
effective and efficacious manner. The present review highlights the pseudoternary phase diagram is mainly used for determining the actual
aspects of current status, challenges and future perspective of herbal ratio of water:oil:Smix in the nanoemulsions. The maximum drug solu-
bioactives with implication of nanoemulsions as herbal drug delivery bility, encapsulation efficiency and drug loading in the formulation
systems. depend upon the ratio of ternary system of the formulation [22,23]. The
specific properties of the three components (oil, water and Smix) and
2. Formulation considerations and techniques for nanoemulsion their formulations have been represented in Fig. 3.

Nanoemulsions like self-nanoemulsifying drug delivery systems 2.2.1. Oils

(SNEDDSs) have been popularized for improvement of oral aqueous Oil is a main component of the nanoemulsions. Different oil in-
solubility, dissolution, absorption, therapeutic efficacy, intestinal per- gredients have been represented in Table 1. It helps to facilitate
meability and bioavailability of drugs. SNEDDS is a homogeneous mixer emulsification in association with Smix to increase the solubilization of
of water, surfactant, oil and co-surfactant (Smix). Its droplet size is hydrophobic drug in the oil core of the droplets. It also improves the
ranging between 50 and 300 nm under gentle agitation with GI fluids GIT drug permeation through intestinal lymphatic system. In the case of
[19]. Moreover, nanoemulsions upon agitation with gastric motility get topical formulation, it acts as a permeation enhancer which promotes
further reduced to tiny size droplets (o/w) by self-nanoemulsification. skin permeation of drugs through carriers and attained plasma drug

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Fig. 2. Specific features of nanoemulsion as novel drug delivery system.

concentration for longer periods. Hydrolyzed vegetable oils, medium- 2.2.2. Surfactants
chain and modified long triglycerides are broadly used as excipients in Surfactants are interfacial tension lowering agents in oil and water
nanoemulsions [24,25]. interface of an emulsion. It is generally used in lower concentration to
reduce the oil-water surface tension during fabrication of nanoemul-
sion. Surfactants are nonionic, zwitterionic, cationic and anionic. It

Fig. 3. A hypothetical pseudo-ternary phase diagram of oil, water and Smix with emphasis on emulsification process and various formulations.

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Table 1
Example of oils, surfactants and co-surfactants.
Excipients Description/main fatty acid (FA) composition HLB

Lipids/Oils
Akoline MCM Caprylic/capric glycerides [MAG and DAG of C8 and C10 with small quantities of TAG] 5–6
Beeswax –
Capmul MCM Caprylic/capric glycerides 5–6
Caprylic/capric TAG TAG of C8 and C10 –
Captex 355 Glycerol caprylate caprate [TAG of C8 and C10] –
Corn oil – –
Ethyl oleate Oleic acid ethyl ester 11
Isopropyl myristate FA ester [Isopropyl ester of C14 FA-myristic acid] 11.5
Isostearyl isostearate – 7
Labrafac CCa Caprylic/capric triglyceride [TAG of C8-12 FA] 1
Labrafac™ lipophile WL1349a Medium chain triglycerides 2
Miglyol 812 Medium-chain TAG –
Oleic acid – –
Olive oil - 7
Peanut oil – –
Sesame oil – –
Soyabean oil Soya oil 7
Vegetable oil Long-chain TAG [TAG of C18, C16 and C14 FA] –
Viscoleo Fractionated coconut oil [TAG of C8-12 FA] –
Surfactants
Acconon CC-6 Ethoxylated glycerides 12.5
Acconon MC-8 Caprylocaproyl macrogolglycerides (polyoxyglycerides) and C10:0 and some free PEG 400 14–15
Brij 35 Polyoxyethylene lauryl ether 9.5
Caproyl 90™a Propylene glycol monocaprylate [C8 FA mono-ester of propylene glycol] 6
Caproyl™ PGMCa Propylene glycol caprylate 5
Captex 350a Coconut oil transesterified with C8 and C10 fatty acids –
Cremophor ELa Polyoxy-35-castor oil [Glycerol-PEG ricinoleate, FA ester of PEG] 12–14
Cremophor RH40a Polyoxy-40- hydrogenated castor oil [FA ester of glycerol-PEG, FA ester of PEG, free PEG and ethoxylate glycerol] 14–16
Labrafac™ PGa Propylene glycol dicaprylocaprate 2
Labrafil® M 2125CSa Polyoxyethylated glycerides [Linoleoyl macrogolglycerides] 4
Labrafil® M1944CSa Polyoxyethlated oleic glycerides [Oleoyl macrogolglycerides]; Mainly C18:1 mono- and diester of PEG 300 and MAG, DAG and TAG 4
Labrasola Caprylocaproyl macrogol-8-glycerides [FA C8:0/C10:0 mono and diesters of PEG 400 and MAG, DAG and TAG with mainly C8:0 and 14
C10:0 and some free PEG 400]
Lauroglycol™ 90a Propylene glycol monolaurate [C12 FA mono-ester of propylene glycol] 5
Lauroglycol™ FCCa Propylene glycol laurate 4
Maisine™ 35-1a Glyceryl monolinoleate [MAG and DAG of C18 and C16 FA with small quantities of TAG] 4
Plurol isosteariquea Polyglyceryl-6-Isostearate 10.8
Span 80 Sorbitan monooleate [Sorbitan (Z)-mono-9-octadecenoate] 4.3
TPGS D-alpha Tocopheryl polyethylene glycol 1000 succinate –
Transcutol CGa Diethyleneglycol monoethyl ether 4.2
Transcutol Pa Diethyleneglycol monoethyl ether 4.2
Tween 20 Polysorbate 20 [Polyoxyethylene 20-sorbitan monolaurate]; PEG-sorbitan esterified with C12 FA 16.5
Tween 80 Polysorbate 80 [Polyoxyethylene 20-sorbitan monooleate]; PEG-sorbitan esterified with 80 C18:1 FA 15
Tween 85 Polyxyethylene 20-sorbitan trioleate 11
Co-surfactantsa
Ethanol Ethyl alcohol 7.9
Glycerin – –
Polypylene glycol – –
PEG-400 Polyethylene glycol-400 15.5
Carbitol Diglycol monoethyl ether –

a
Solubilizer, penetration and bioavailability enhancer.

consists of both hydrophilic head and a hydrophobic tail region which ethanol, isopropyl alcohol, ethylene glycol, transcutol P, carbitol,
can act as an emulsifier to produce nanoemulsion. Hydrophilic-lipo- transcutol CG etc. [32].
philic balance (HLB, 3–8 for w/o and 8–18 for o/w) value of the sur-
factants plays an important role in nanoemulsion formulations. 2.2.4. Surfactant and co-surfactant (Smix)
Surfactants (30–60% v/v) are used to produce a stable emulsion. A vide Smix is a mixer of surfactant and co-surfactant which is a de-
category of surfactants has been shown in Table 1 [26,27]. termining factor for producing nanoemulsion. It can work better in a
ratio of oil for selecting the proper region of nanoemulsion in the phase
2.2.3. Co-surfactants diagram. It is generally considered that all of the excipients used in
An alone surfactant cannot lower the surface tension of both oil and nanoemulsion formulation should have generally regarded as safe
water interface efficiently to make the nanoemulsions. Co-surfactants (GRAS) listed components for safety aspect [33–35]. The list of phar-
can work better in combination with a surfactant which is generally maceutically acceptable excipients for the formulation of nanoemulsion
used in development of the nanoemulsions. It can be used in low con- is represented in Table 1.
centration due to severe side effects at higher concentration [28–30].
Mostly applicable surfactants are C3-C8 chain alcohols which increase 2.3. Preparation method of nanoemulsions
the fluidity by reducing the interfacial tension between oil and water
phase [31]. Examples of commonly applicable co-surfactants (Table 1) Nanoemulsions are non-equilibrated formulations, therefore large
are polyethylene glycol 400 (PEG 400), propylene glycol, glycerin, amount of surfactants and energies are required for fabricating suitable

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Fig. 4. Schematics of nanoemulsion preparation.

nanosize emulsions. Generally, spontaneous nano-emulsfication, high solubilization of water and oil molecules by using non-ionic surfactants
or low-energy techniques are used for producing nanodroplets of the like polyethoxylated type. It is a basis of nanoemulsion formulation.
formulation [36,37]. The schematic of nanoemulsion preparation has Generally, nanoemulsions (o/w) are fabricated by mixing the water,
been shown in Fig. 4. The detailed methods of preparation of nanoe- nonionic surfactants and oil in specific concentration at room
mulsion are described below. temperature. Upon heating o/w type nanodroplets changed to w/o
type nanodroplets due to hydrophobic nature of surfactants. At this
2.3.1. Low-energy methods stage, surfactant monolayer has negative curvature [41]. But the
This technique employs low energy for manufacturing of nanoe- curvature becomes zero at low interfacial tension in the range of
mulsions. It is also known as the condensation process of nanoemulsi- 10−2-10−5 mNm−1 which may be due to intermediate HLB value with
fication which occurred due to phase transitions. It includes phase in- respect to temperature [47,48]. At this stage, the ternary system
version temperature (PIT), phase transition and spontaneous- involves formation of lamellar liquid crystalline and bicontinuous
emulsification process [38]. These processes are primarily reliant on the type emulsions (Fig. 3). This system can produce the nanodroplets
inflection of interfacial properties of components like oil, surfactant and upon rapid cooling at above PIT or normal condition. Dilution of
Smix to give suitable formulation. The intrinsic physical and chemical microemulsion with oil/water results in nanoemulsions (w/o or o/w
characteristics and interfacial behavior of the ternary phase played type) and this phenomenon is known as catastrophic phase inversion
crucial role in nanoemulsion production [39,40]. process [38,42].
PIT involves a quick alteration in the curvature of non-ionic sur-
factants at constant the composition and temperature while emulsion 2.3.1.2. Solvent displacement technique. It is spontaneous
inversion point technique employed the changes in composition of the nanoemulsification technique for producing polymeric nanoparticles
formulations at a constant temperature which is broadly used in in- through nano-precipitation concept. Briefly, firstly oily components are
dustry [41–44]. In this method, the internal capacity (energy) of the dispersed into organic solvents like alcohol, diethyl ether, acetone etc.
formulation is applied for producing the fine droplets, so that low-en- Then, it is incorporated into Smix containing water system with
ergy method is very effective for preparing nanoemulsion. For the na- agitation and mixed properly which results in nanodroplets
noemulsification, HLB value, temperature and ingredients ratio of the formation. In last stage, excess amount of solvent is removed by using
formulation are prime factors [45–48]. The low-energy emulsification rotatory vacuum evaporator [44–46,49].
methods are now gaining attention due to their wide application and
benefits as a nanoemulsion formulation and its stability aspects. The 2.3.1.3. Phase inversion composition (PIC) technique. This technique is
detailed discussions about these techniques have been illustrated un- also called as a self-nanoemulsification process. It can produce nano-
derneath. assemblies without utilization of heat and solvent at an environment of
room temperature. Nanoemulsions are the kinetically stable system at
2.3.1.1. PIT technique. PIT is a temperature dependent technique for nanosize (around 50 nm) range. A specific method of preparation

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involves incorporation of surfactant containing aqueous phase into the

oil phase with agitation at a constant temperature. This process
involves phase transition during formation of a bicontinuous
microemulsion or lamellar liquid crystalline phases (Fig. 3). The
quick changes of droplets from micron size to nanosize are known as
the spontaneous nanoemulsification process which may be due to PIC
[43].

2.3.2. High-energy methods

High-energy emulsification process is traditional method but it is
used for the preparation of nanoemulsion formulation. As the name
indicates, this method utilizes high kinetic energy through the me-
chanical instruments for fabricating nanoemulsions. This energy is re-
quired for size reduction of micro-droplets to nano-droplets of the
formulation [50]. Ultrasonicator, microfluidizer and high-pressure
homogenizer are used as high-energy sources for nanoemulsion pro-
duction. Droplet size of the nanoemulsion is affected by working and
operating condition of the equipment [37,51–53].
In nanoemulsion preparation techniques, ultrasonication and
homogenization are the most commonly used methods. Ultrasonicator
employs ultrasonic waves (cavitation forces) via probe required to re-
duce the micron size droplets of emulsion into tiny droplets. In ultra-
sonic-emulsification, the desired nanoemulsions are produced with
varying time and energy input. Ultrasonication employs cavitation and
turbulence for size reduction and nanoemulsfication while homo-
genization utilizes 500 to 5000 psi high pressure for exerting high en-
ergy through hydraulic force and shear, required for producing na-
noemulsion. In homogenization, microemulsions (> 500 μm) are
treated for converting micron-size droplets into nanosize [37]. Micro-
fluidization is another technique used for the preparation of nanoe-
Fig. 5. Oral delivery of herbal bioactive based nanoemulsions.
mulsion. It applies extremely high pressure 20,000 psi for making high
energy through displacement pump. In this process, the micron size
droplets (coarse emulsion) is reduced into fine (nano-sized) droplets marianum) has been famous for its hepatoprotective activity but limited
(nanoemulsions). High-pressure homogenizer, ultrasonicator and mi- with poor oral bioavailability due to low aqueous solubility. This pro-
crofluidizer are well-accepted equipments for nanoemulsions produc- blem is overcome by encapsulating silymarin in nanoemulsion (o/w)
tion at laboratory and industry [51–53]. formulation [59]. Zedoary turmeric oil from Curcuma zedoaria has been
extracted to formulate SNEDDS for oral delivery to enhance its ther-
3. Role of nanoemulsions in delivery of herbal bioactives apeutic effect (antibacterial, antioxidant, hepatoprotective and anti-
tumor) and bioavailability [60]. Colchicine nanoemulsion with eugenol
During the last decade, nanotechnology plays crucial role in pro- was prepared to improve the oral bioavailability, where eugenol was
ducing several nanocarriers for enhancing the therapeutic effect of the incorporated for enhancing the gastrointestinal membrane permeability
herbal drug. It offers several advantages over a conventional delivery [61].
system that it can deliver the herbal bioactive and extract at a con- Topical and transdermal drug delivery systems (TDDS) are alter-
trolled period as required by the body. An objective of the nano-as- native and promising approaches for enhancing therapeutic efficacy
semblies like nanoemulsions (NEs) is to increase the permeability or and bioavailability of low bioavailable drugs through the skin. These
bioavailability of low bioavailable phytopharmaceuticals through the delivery systems can exert a local effect at the site of application and
skin and gastro-intestinal membrane [1,54]. NEs have received atten- systemic effect on blood circulation against dermal diseases. TDDS can
tion toward the oral delivery of herbal drugs especially for enhancing avoid hepatic first-pass metabolism of the drug and produce drug re-
the bioavailability of low bioavailable drugs (Fig. 5). NEs protect the lease in a controlled and sustained manner for a longer period of time
herbal bioactives from gastric degradation by encapsulating them into [62]. The TDDS minimizes the drug-associated side effects, enhances
oil in water (o/w) or water in oil (w/o) nanodroplets. It also improves bioavailability and increases patient compliance [63,64]. Factor af-
the stability of herbal drugs. The scarce solubility of hydrophobic fecting the drug transport through the skin layer includes the site of
moieties of herbs in aqueous media is a major challenge for develop- application, penetration enhancer, contact time, hydration of the skin,
ment of suitable formulation. The nanosized droplet offers favorable skin condition (diseased, abraded and normal), skin age and skin
environment for uptaking of highly lipophilic herbal bioactive mole- temperature. Diffusion is a drug penetration mechanism through the
cules. Drug release from NEs depends upon the partitioning of droplets skin which depends upon the concentration [65]. Drug molecules pe-
into gastrointestinal fluids and their motility. Efficient drug absorption netrate across the skin surface by three potential pathways: inter-
from GI membrane is affected by tiny droplets size and membrane cellular, intracellular (transcellular) and follicular (appendage) route
polarity [55,56]. [63,66] as shown in Fig. 6.
Recently, nanoemulsions of several herbal bioactive molecules have In this context, several herbal bioactives like catechin, epicatechin,
been investigated to achieve the maximum oral bioavailability and (-)-epicatechin gallate, caffeine, curcumin, ferulic acid etc. have been
therapeutic efficacy. In an instance, betulininc acid loaded nanoemul- successfully delivered through the skin in the form of NEs [67–72]. NEs
sion (o/w) for enhanced oral bioavailability and hepatoprotective ac- of these herbal drugs have been studied for improved skin permeability,
tivity has been studied by Harwansh et al. (2017) [56]. Quercetin-na- therapeutic activity and bioavailability [73]. Nanoemulsion based de-
noemulsion (o/w) has been reported for improvement of its oral livery of different herbal bioactives has been represented in Table 2.
bioavailability and in vivo antiobesity effect [57,58]. Silymarin (Silybum

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Fig. 6. Schematic of skin and major routes of drug penetration, (1) via the sweat ducts (intercellular pathway), (2) directly across the stratum corneum (intracellular
pathway) and (3) through the hair follicles and sebaceous gland (folicullar pathway).

4. Challenges and future perspective of herbal bioactives infection and disease are inappropriate to fulfill the need of the com-
munity so much so minimizing undesired action at the target sites are
Herbal bioactives have been popularized worldwide for their several evenly essential. Drug targeting to a particular site like a tumor can be
health effects but there are still challenges like low half-life, low solu- achieved with NEs which can modulate the absorption, distribution,
bility, low permeability as well as poor bioavailability hence, low metabolism and excretion profile of herbal drugs. Commencement and
biological effect. Most of the active principle compounds (40%) pro- development of suitable herbal bioactive formulations are utmost im-
duced through high-throughput techniques having low solubility. These portant for promotion of human health by using nano drug delivery
are major challenges for development of appropriate herbal products approach [88,89].
for management of the disease. It requires continuous research in the Novel drug delivery systems like NEs can overcome the drawbacks
novel carriers for delivery of herbal bioactives to achieve the effective of conventional drug delivery systems. It can potentially increase the
level of blood concentration in the body [1,54]. therapeutic effect of herbal bioactives. Although, clinical implementa-
The fabrication of nanocarrier aims to increase the absorption and tion of herbal drugs still remain challenges as alternative drug therapies
pharmacokinetics of poorly bioavailable herbal bioactives through size for the treatment of diseases. Interaction of drug loaded nanocarriers
reduction, encapsulation and stability. An effective level of drug de- with biological receptors and tissues results in interfering with the
livery is an important aspect to attain the improved therapeutic efficacy immune response is challengeable for clinical transformation to drug
at target site. In case of herbal bioactives, large molecular size and lipid therapies. Another challenge in regard to formulation and development
solubilization are prime rate limiting parameters for bio-membrane of herbal bioactive based NDDS at industrial scale are the feasibility and
permeation. To cross the membrane with enhanced pharmacokinetic availability of the innovative techniques. Nanomedicine drug targeting
profile are biggest challenges in development of herbal formulations. and probing suffered from biocompatibility and toxicological issues
Oil or lipid based nanocarriers (NEs) may be the solution to these which remain challenges and need to be resolved for the fulfilment of
challenges. They can improve the solubility, permeability, GIT ab- international standards of drug therapies [90].
sorption and minimize the food-stuffs effect on rate of absorption of Nanoemulsions are very effective and versatile nanocarrier system
highly lipophilic molecules, thus enhanced bioavailability [87]. used not only for delivery of allopathic drug but also for plant derived
The biological half-life is another major aspect for determining the medicines that have been proved through various platforms for phar-
pharmacological effect of a drug. Shorter half-life compound can maceutical application. It has greater encapsulation efficiency rather
eliminate rapidly as compared to greater half-life bioactives. Liver than the other delivery systems which could be useful for solubilization
metabolism leads to detoxification and fragmentation of the active of poorly soluble compounds, especially hydrophobic moieties. Future
compounds results in low bioavailability. Higher renal filtration and perspective of nanoemulsion based herbal drug delivery delineates di-
elimination rate also lower the bioavailability of herbal drugs. In this verse kind of application including oral, parenteral, ocular, pulmonary,
context, nanoencapsulation with nanocarriers are promising for fabri- topical, transdermal, vaccine, protein and peptides drug targeting. It
cating and overcoming the limitation of herbal bioactives. Several kinds could be promising for delivery of nutraceuticals for several health
of research on herbal bioactive based nanocarriers are being carried out benefits. Nanoemulsions can produce the prolonged and sustained re-
to get the desired therapeutic efficacy at the same dose or reduced dose lease action to maintain the therapeutic level of the drug.
with minimum adverse effects. So nanocarriers like nanoemulsions are Nanoemulsions based novel herbal formulations will lead to maximum
exploited successfully in the herbal drug delivery to gain the maximum economic growth for cosmetic, dietary and nutraceutical and pharma-
therapeutic response. Thus, NEs based many herbal formulations are ceutical companies [55].
being used with molecular mechanism understanding of disease for
therapeutic purposes. Unfavorable drug effects against the cause of

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 Table 2
R.K. Harwansh, et al.

Encapsulation and delivery of bioactive compounds from herbs through the nanoemulsion techniques.
Herbal bioactives Applications Biological activities Special features Route of administrations References

Oleanolic acid (OA) and Dermal controlled release Anti-inflammatory and anti-carcinogenic Mean droplet size 140 ± 47 nm (OA) and Transdermal and in vivo [74]
ursolic acid (UA) activity 201 ± 21 nm (UA)
Ferulic acid Enhanced skin permeability, sustained release action UVA protection efficacy against oxidative Droplet size 102.3 ± 1.14 nm, ZP Transdermal, in vivo [71]
stress, antioxidant -35.2 ± 0.41 mV, 98.88 ± 0.12 %EE
Catechin Enhanced skin permeability and bioavailability, sustained release Photoprotection against UVA induced %EE 99.02 ± 0.13, droplet size Transdermal and oral [75]
oxidative stress 98.6 ± 1.05 nm, ZP -27.3 ± 0.20 mV
Betulinic acid Enhanced gastro-intestinal permeability, bioavailability and Hepatoprotection and antioxidant Droplet size 50.3 ± 0.56 nm, ZP Oral (in vivo) [56]
sustained release action -10.2 ± 0.11 mV; 99.95 ± 0.12 %EE
β-Elemene Improved solubility and enhanced antitumor activity against Anti-tumor Average particle size 52.68 nm and ZP In vitro and in vivo [76]
Hep3B cancer cells -26.43 mV
Emodin Enhanced transcellular permeation, improved oral bioavailability – Droplet size Oral [77]
116 ± 6.5 nm
Zedoary turmeric oil SNEDDS for enhanced bioavailability and therapeutic efficacy Antibacterial, antioxidant, Droplets size 68.3 ± 1.6 nm, ZP Oral [60]
hepatoprotective and antitumor -41.2 ± 1.3 mV
Colchicine Improved intestinal membrane permeability and bioavailability Eugenol as penetration enhancer, Particle size 41.2 ± 7.2 nm Oral [61]
anticancer
Glycyrrhizin Increased percutaneous permeation, sustained release action Useful in the treatment of dermatitis, Droplet size 22 nm Transdermal [4]
eczema, psoriasis, antibacterial and anti-
inflammatory
Berberine Sustained drug release, improved oral bioavailability Anti-inflammatory, anticancer and anti- Droplet size 19.53 ± 1.58 nm, ZP -9.14 mV Oral [13]

231
angiogenic activity
Capsaicin Enhanced oral bioavailability and stability Analgesic, pain reliever anticancer, Particle size 53.4 ± 0.83 nm, ZP Oral [16]
cardiovascular -42.1 ± 0.52 mV
Curcumin Increased solubility, improved oral bioavailability Anticancer, antioxidant, anti-tumor, Droplet median size 11.2 nm In vitro, in vivo oral [78]
antimicrobial, anti-inflammatory
Epigallocatechin Increased absorption Nutraceutical, systemic antioxidant, 50–100 mg dose Oral [79]
anticancer, hypolipidemics
Paclitaxel Sustained release profile, increased bioavailability Anticancer, targeted for breast cancer Absolute oral bioavailability (55.9%) In vitro, [15]
In vivo
Quercetin Enhanced oral bioavailability, reduced dose, enhanced penetration Antiobesity, Antioxidant, anticancer, anti- Particle size 19.3 ± 0.17 nm, ZP Oral and in vivo, intranasal, [57,58,80–82]
in blood brain barrier, increased antioxidant activity and 74 times inflammatory, anti-ageing, anti-wrinkle 0.34 ± 0.13 mV, %EE > 99%, droplet size in vitro, oral, topical
higher drug release, exerted better therapeutic efficacy, enhanced 10–100 nm
skin
Permeability
Resveratrol Improved bioavailability controlled release, pharmacokinetics Antioxidant, anti-inflammatory, anti- Dose 4 mg/kg, particle size 5 μm, %EE 92.5% Oral, in vivo [18,83]
profile tumor
Silymarin Improved bioavailability Hepatoprotective Droplet size 68.22 ± 0.00314 nm, PDI 0.216, Oral, buccal [59]
%EE 69.22 ± 0.6%
β-Carotene Enhanced bioaccessibility and bioavailability, increased stability, Antioxidant, anticancer, cardiovascular Particle size 140–170 nm, 0.5% dose, 66% In vitro [84,85]
sustained release delivery, effective delivery system for GIT disease bioaccessibility
Pterostilbene Improved solubility and Stability. Sustained drug release Anticancer, antidiabetic, and Mean droplet size 55.8 nm In vitro, Oral delivery [86]
cardiovascular diseases

Where, % EE = Entrapment efficiency, ZP = Zeta potential, PDI = Polydispersity index, GIT = Gastrointestinal tract.
Journal of Drug Delivery Science and Technology 51 (2019) 224–233
R.K. Harwansh, et al. Journal of Drug Delivery Science and Technology 51 (2019) 224–233

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