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Journal of Multidisciplinary Engineering Science and Technology (JMEST)
ISSN: 2458-9403
Vol. 6 Issue 12, December - 2019, Special Issue
www.jmest.org
JMESTN42353067 100
Strategies for the Development of Mitragyna
speciosa (Kratom) Leaves Extract Loaded with
Solid Lipid Nanoparticles
Sharifah Nurfadhlin Afifah Syed Azhar1,
Siti Efliza Ashari1,2
1 Integrated Chemical BioPhysics Research,
Faculty of Science, Universiti Putra Malaysia, 43400
UPM, Serdang, Selangor, Malaysia.
2 Centre of Foundation Studies for Agricultural
Sciences, Universiti Putra Malaysia, 43400 UPM,
Serdang, Selangor, Malaysia.
Email: ctefliza@upm.edu.my
Abstract—Currently, the use of medicinal plants
as an alternative medicine for various treatment
has increased tremendously due to their positive
effects. This include a potential plant-based
source, Mitragyna speciosa (MS) leaves (kratom
leaves). Besides, previous study has reported the
other pharmacological properties of MS which
includes anaesthetic, antinociceptive, analgesic
and stimulant effects. In general, the
pharmacological effects of MS leaves are mainly
attributed to its principal alkaloid called
Mitragynine. The Mitragynine dose employed in
recent studies showed that the dose for analgesic
(30–200 mg/kg), pharmacokinetics (20–50 mg/kg)
and toxicity (200–477 mg/kg) which varied largely
across rodent species. Research has been
reported that Mitragynine has been studied at the
preclinical stage and progressively gaining more
attention as a potential substitute or adjunct drug
therapy for addiction and pain. These properties
are claim to be beneficial in wound healing thus,
proper vehicle mechanism should be applied so
that the MS leaves could benefits fully in the
treatment of wound healing.
Hence, an advanced carrier system technology
such as solid lipid nanoparticles (SLNPs) are
suitable transportation due to their good
biocompatibility, small particle size and low
toxicity which enables for better penetration into
skin. SLNPs are colloidal carriers developed in the
last decade as an alternative system to the
existing traditional carriers such as
nanoemulsions, liposomes and polymeric
nanoparticles. SLNPs also possesses good
stability and is able to control the release of the
incorporated drug. When compared with
polymeric nanoparticles, the physiological lipids-
made SLNPs is definitely better tolerated by the
human body and its lipophilic nature helps it to
penetrate deeper into skin.
Keywords: Mitragyna speciosa, Mitragynine,
Antimicrobial Activity, Solid Lipid Nanoparticle,
Transdermal Drug Delivery
I. INTRODUCTION
Mitragyna speciosa (MS) leaves has been
traditionally consumed as a leaves decoction for its
stimulant effects to counter fatigue, to treat fever,
diarrhea and also wound healing. Besides, Takayama,
2004 and Shellard, 1989 reported the other
pharmacological properties of MS which include
anesthetic, antinociceptive, analgesic and stimulant
effects. In general, the pharmacological effects of MS
leaves are mainly attributed to its principal alkaloid
called mitragynine (Fig. 1) [1,2].
Fig. 1. The chemical structure of Mitragynine,
C23H30N2O4 in Mitragyna speciosa leaves
Since then several pharmacological studies have
been undertaken to evaluate this assertion objectively.
However, the mitragynine dose employed in recent
studies showed that the dose for analgesic (30–200
mg/kg) [3,4,5], pharmacokinetics (20–50 mg/kg)
[6,7,8] and toxicity (200–477 mg/kg) [4,5] which varied
largely across rodent species. Currently, research
studies reported that mitragynine has been studied at
the preclinical stage and progressively gaining more
attention as a potential substitute or adjunct drug
therapy for addiction and pain [9,10]. In addition, the
higher antioxidant properties and antimicrobial of the
leaves make it potentially suitable for wound therapy.
Studies from Parthasarathy et al., 2009, reported that
the MS leaves has shown to have antioxidant
properties with DPPH IC50 values of the aqueous,
alkaloid and methanolic MS extracts were 213.4,
104.81 and 37.08 μg/mL, respectively, total phenolic
content were 66.0 mg, 88.4, 105.6 mg GAE/g,
respectively and total flavonoids were 28.2, 20.0 and
91.1 mg CAE/g respectively. In addition, the MS
leaves extracts showed antimicrobial activity against
Salmonella typhi and Bacillus subtilis. The minimum
inhibitory concentrations (MICs) of MS extracts was
determined by the broth dilution method ranged from
Journal of Multidisciplinary Engineering Science and Technology (JMEST)
ISSN: 2458-9403
Vol. 6 Issue 12, December - 2019, Special Issue
www.jmest.org
JMESTN42353067 101
3.12 to 6.25 mg/mL. The alkaloid extract was found to
be most effective against all of the tested organism
[11].
To improve the transportation of the active matter
in MS leaves, solid lipid nanoparticles (SLNPs) will be
chosen as a carrier system for better penetration into
skin. SLNPs are colloidal particles ranging in size
between 10 to 1000 nm. SLNPs are colloidal carriers
developed in the last decade as an alternative system
to the existing traditional carriers such as
nanoemulsions, liposomes and polymeric
nanoparticles. They are a new generation of
submicron-sized lipid emulsions where the liquid lipid
(oil) has been substituted by a solid lipid. Examples of
solid lipid materials are triglycerides, complex glyceride
mixture and wax. SLNPs also possesses excellent
stability and able to control the incorporated drug
release. When compared with polymeric nanoparticles,
the physiological lipids-made SLNPs is better tolerated
by the human body and its lipophilic nature helps it to
penetrate deeper into the skin [12,13].
Recent research claimed that SLNPs are desirable
in transdermal drug delivery. This is due to its various
sizes and its availability in modifying surface polarity to
boost skin penetration. It is believed that the SLNPs
exhibit mechanical flexion where they can reach
deeper into upper skin regions [14]. The usage of
SLNPs for drug delivery system offered low toxicity
because of the solvent less system used during the
preparation and amenability to large scale production
and sterilization. Moreover, this nanoparticle system
able to facilitate the contact of the active substances
with stratum corneum for its small particle size and
high surface area. Thus, this allow high permeation of
carried substances through the viable skin [15].
II. DESIGN OF ACTIVE INGREDIENTS INCORPORATED
INTO SLNPS
The structure of SLNPs depends on formulation
composition such as lipid, surfactants and active
compounds. Table 1. shows the examples of
ingredients used in solid lipid nanoparticles.
TABLE 1. INGREDIENTS USED IN FORMULATION OF
SOLID LIPID NANOPARTICLES
Ingredients
Concentration
(% w/w)
Reference
Lipid
3.33
[16]
Phospholipids
0.6- 1.5
[17]
Tristearin glyceride
95
[17]
Ploxomer188
1.2- 5
[18]
Cetyl palmitate
10
[19]
Tween 85
0.5
[20]
Tween 80
50
[20]
Ethanol/butanol
2
[21]
There are three design model of active ingredients
incorporated into SLNPs [22]:
a) Homogeneous matrix model
A homogeneous matrix with molecularily dispersed
drug or drug being present in amorphous clusters is
thought to be mainly obtained when applying the cold
homogenization method and when incorporating very
lipophilic drugs in SLN with the hot homogenization
method. In the cold homogenization method, the bulk
lipid contains the dissolved drug in molecularily
dispersed form, mechanical breaking by high pressure
homogenization leads to nanoparticles having the
homogeneous matrix structure. The same will happen
when the oil droplet produced by the hot
homogenization method is being cooled, crystallizes
and no phase separation between lipid and drug
occurs during this cooling process. This model is
assumed to be valid for incorporation of drug
prednisolone, which can show release from 1 day up
to weeks [23].
b) Drug-enriched shell model
An outer shell enriched with active ingredient can be
obtained when phase separation occurs during the
cooling process from the liquid oil droplet to the
formation of a solid lipid nanoparticle. A fast release
can be highly desired when application of SLNPs to
the skin should increase the drug penetration
especially when using the occlusive effect of SLNPs at
the same time [24].
c) Drug-enriched core model
A core enriched with active compound can be formed
when the opposite occurs, which means the active
compound starts precipitating first and the shell will
have distinctly less drug [24].
III. PREPARATION OF SOLID LIPID NANOPARTICLES
A. High pressure homogenization
A powerful technique that pushes a liquid with high
pressure (100–2000 bar) through a narrow gap (in the
range of a few microns). The fluid accelerates on a
very short distance to very high velocity (over 1000
Km/h). Very high shear stress and cavitation forces
disrupt the particles down to the submicron range.
Generally, 5-10% lipid content is used but up to 40%
lipid content has also been investigated. Hot and cold
homogenization are used in these technique.
Hot homogenization is carried out at temperatures
above the melting point of the lipid. A pre-emulsion of
the drug loaded lipid melt and the aqueous emulsifier
phase (same temperature) is obtained by high-shear
mixing device. Higher temperatures give smaller
particle sizes because the viscosity of inner phase
decreased and causes the degradation rate of drug
and the carrier to increases.
Moreover, higher homogenization pressure often
leads to an increase of particle size due to high kinetic
energy of the particles. During cold homogenization
technique, the drug containing lipid melt is cooled and
the solid lipid ground to lipid microparticles. These
lipid microparticles are dispersed in a cold surfactant
Journal of Multidisciplinary Engineering Science and Technology (JMEST)
ISSN: 2458-9403
Vol. 6 Issue 12, December - 2019, Special Issue
www.jmest.org
JMESTN42353067 102
solution yielding a pre-suspension and homogenized
at or below room temperature. This approach is
economical and convenient for lab scale but may give
rise to polydisperse distribution and require intensive
energy process [25].
B. Solvent evaporation
In solvent evaporation method, lipophilic material is
dissolved in a water-immiscible organic solvent such
as cyclohexane which emulsified in an aqueous
phase. Upon evaporation of the solvent, nanoparticles
dispersion is formed by precipitation of the lipid in the
aqueous medium by giving the nanoparticles of 25 nm
mean size. The solution was emulsified in an aqueous
phase by high pressure homogenization. The organic
solvent was removed from the emulsion by
evaporation under reduced pressure (40–60 mbar).
The advantages of using this technique is that it is a
continuous process, scalable and commercially
demonstrated. However, during the process
biomolecule in SLNPs maybe damage due to
extremely intensive energy process [25].
C. Microemulsion based method
This method is based on the dilution of
microemulsions. As micro-emulsions are two-phase
systems composed of an inner and outer phase. They
are made by stirring an optically transparent mixture
at 65-70°C, which typically composed of a low melting
fatty acid like stearic acid, polysorbate 20 as an
emulsifier, butanol as co-emulsifiers and water. The
hot microemulsion is dispersed in cold water (2-3°C)
under stirring. SLNPs dispersion can be used as
granulation fluid for transferring in to solid product
such as tablets and pellets by granulation process.
The high-temperature gradients in the process
facilitate the lipid crystallization and prevent
aggregation. Due to the dilution step, the achievable
lipid contents are considerably lower compared with
the high pressure homogenization method based
formulations. This technique consider to be more
stable and safe energy [25].
IV. ADVANTAGES AND DISADVANTAGES OF SOLID LIPID
NANOPARTICLES AS DRUG CARRIER
The basis to overcome the drawbacks of liquid lipid
into solid lipid based system are mainly because of
they enhance oral bioavailability and reduce plasma
profile variability. Besides, solid lipids suitable for
scale-up production and alternative materials to
polymers. Typically, SLNPs have low toxicity, good
biocompatibility, solvent less and suitable for lipophilic
drugs. The submicron size of the nanoparticles gives
better control over release kinetics of encapsulated
compounds and provide chemical protection of labile
incorporated compounds [25].
However, there are some disadvantages of using
SLNPs which include low drug loading capacity,
unexpected dynamics of polymeric transitions and
particle growth [26,27,28]. Therefore, further studies
on in vitro and in vivo are required to understand
better on the molecular level on SLNPs.
V. RECENT APPLICATIONS OF MEDICINAL PLANTS
INCORPORATED INTO SOLID LIPID NANOPARTICLES
According to research, there has been growing
interest in alternative therapies and the therapeutic
use of natural products, especially those derived from
medicinal plants. The possible pure compounds were
easily obtained, structural modifications to produce
potentially more active and safer drugs could be easily
performed. Today, many pharmaceutical industries
use medicinal plants for drugs delivery system [29]. In
addition, solid lipid nanoparticles are suitable carriers
to transport those medicinal plants due to their
submicron-size, able to incorporate hydrophilic and
lipophilic drugs, non-bio toxicity and easily available
for scale up production [30]. Table 2. depicts recent
medicinal plants loaded with solid lipid nanoparticles
for various application in drug delivery.
TABLE 2. RECENT MEDICINAL PLANTS LOADED WITH
SOLID LIPID NANOPARTICLES FOR VARIOUS
APPLICATIONS IN DRUG DELIVERY
Medicinal plant
Application
Reference
Calendula officinalis
extract
Wound healing in
ophthalmic
formulations
[31]
Tripterygium wilfordii
extract
Anti-inflammatory
in topical delivery
[32]
Nigella sativa L. seed
Cosmetic
[33]
Curcuma longa
Linn.extract
Oral application
[34]
Syzygium
aromaticum extract
Antioxidant in oral
application
[35]
VI. CONCLUSION
In summary, SLNPs are very complex systems with
clear advantages and disadvantages to other colloidal
carriers. SLNPs give better biocompatibility, control
drug release, improve stability and easy to scale up.
Further study needs to be done to understand the
Mitragyna speciosa loaded with SLNPs structure and
dynamics on molecular level in vitro and in vivo
studies.
ACKNOWLEDGMENT
We would like to thank Integrated Chemical
Biophysics Research, Faculty of Science, UPM and
Centre of Foundation Studies for Agricultural, UPM for
support and assistance throughout this research.
Journal of Multidisciplinary Engineering Science and Technology (JMEST)
ISSN: 2458-9403
Vol. 6 Issue 12, December - 2019, Special Issue
www.jmest.org
JMESTN42353067 103
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