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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5607_Библиотеки_им_академика_М_И_Перельмана
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Biomarkers as Targeted Herbal Drug Discovery
Abdelkader et al. (2016) proved in their recent report that L-carnosine
phytosomes could be the better substitute for N-acetyl-L-carnosine (a prodrug)
as a novel drug carrier for the lens an anterior part of an eye. L-carnosine
was incorporated into phytosomes prepared using phosphotidyl choline (in
two molar ratios 1:1 and 1:2) and also in phytosomes prepared dispersing
in them hyaluronic acid (HA) (in 1:2 molar ratio). The widely used solvent
evaporation method was employed to prepare these phytosomes. In these
phytosomes, preparation phospholipids were dispersed in either HA (0.1%
w/v) in phosphate buffered saline or phosphate-buffered saline (pH 7.4) to
obtain phytosomes. These phytosomal preparations were studied for physical
characteristics such as gross morphology which includes size, zeta potential,
spreading coefcient, contact angle, and viscosity of the drug carrier system.
Ex-vivo transcorneal permeation studies and cytotoxicity studies were also
carried out for both the phytosomes utilizing preliminary corneal cells of
humans. L-carnosine-phospholipid (1:2) phytosomes were in the acceptable nanosize and also polydispersity index results were satisfactory. The
viscosity of phytosome containing hayluronic acid increased up to 5-fold
in comparison with plain HA solution and phytosome containing phospholipid respectively. Notably reduced surface tension, low contact angle, and
consequently higher spreadability for both the types of phytosomes were
noted. Ex vivo transcorneal, permeation study results demonstrated notably
managed penetration of L-carnosine through the cornea by these novel drug
carrier systems without any notable inuence on preliminary corneal cell
motility in humans. The results of another important parameter lens incubation study revealed that the lenses of porcine which were kept in incubator
at standard conditions of incubation in high sugar media with and without
L-carnosine demonstrated concentration-dependent marked inhibition of
lens brunescence revealing the capacity for delaying changes that underlie
cataractogenesis which may be directly linked to diabetic procedures.
In another interesting high-level study reported by Zhang et al. (2016)
they designed and developed N-trimethyl chitosan (TMC)-coated liposomes
of cyanidin-3-glycoside (C3G) (C3G-TCL) to attenuate oxidative stress
produced by selenite sodium in rats. C3G-TCL were prepared by reversephase evaporation method and then coated with self-synthesized TMC. The
physicochemical properties such as size, zeta potential, etc., were measured.
The state of the art a gamma scintigraphy study was performed to evaluate
the pre-corneal elimination of the radioactive preparations. The transcorneal
visualization for uorescence-labeled samples was determined by confocal
laser scanning microscopy (CLSM). The in vivo anti-oxidative study using
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C3G-TCL was carried out in rats with selenite-induced cataracts by topical
administration. The round structural morphological characterization of the
formulated vesicles was conrmed by TEM, with an acceptable size and a
zeta potential of the above carrier systems. The encapsulation efciency was
53.7 ± 0.2% as measured by ultraltration. C3G-TCL showed a 3.3-fold incre-
ment in precorneal residence time when compared with that of the 99 mTcsolution. A TMC coating enhanced the transepithelial transport of liposomes
to a depth of 40-mm in the cornea. In addition, C3G-TCL could signicantly
enhance the activity of superoxide dismutase (SOD) and catalase (CAT) in
lens and also demonstrate a considerable reversal of reduced glutathione
activity. The lipid peroxidation (LPO) in lens was strongly prevented when
compared with that of groups treated with uncoated C3G-loaded liposomes.
The coating material TMC for liposomes helps enhance the antioxidative
effect of C3G in vivo through prolonged residence time on the cornea and
improved permeability in the corneal epithelium.
A vehicle with TMC has been developed by He et al. (2013), using various
percentage of quaternization (DQ) as coating substance, vitamin A palmitate
(VAP) incorporated cationic liposomes disseminated within heat-sensitive in
situ gels (ISG) through a poloxamer. TMC-coated with DQ of 20, 40, and
60% respectively, was chosen and disseminated in P407 solution with the
aid of lm dispersion method, resulting in attainment of TMC-coated VAPL
ISG VAP-loaded liposomes (VAPL). The physicochemical characteristics
of the carrier systems such as gross morphology, zeta potential, particle
size, DL efciency, in-vitro drug release and drug retention in the eye were
examined. In vivo parameters like, ocular retention, followed by irritation
in eye and pharmacokinetic inuence on aqueous humor of the system
involving rabbits has been investigated and tested. With the aid of VAPL,
smooth round surface with a nanosize and a negative zeta potential value has
been identied. There was no signicant changes seen in the morphology
and entrapment efciency after the TMC-coating process, however, the zeta
potential was changed to positive, Increase in the mean size, and release of
drug was further hold-up, the process in turns controlled by DQ of TMC.
A small effect has been identied in relation to gel-forming temperature of
Poloxamer solution, and at the P407 concentration of 25% (w/v), by TMCcoated VAPL that resembles the temperature of 34 C, which is just similar
with that of the eye surface when it dissolves with articial tears. The TMC-
coated VAPL ISG showed highly detained drug liberation and gel corrosion
with an adequate linear relation between them, and with an incremental DQ,
the slow delivery of medication and gel corrosion has been exhibited when
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Biomarkers as Targeted Herbal Drug Discovery
compared to that of the oculotect gel and an uncoated VAPL ISG. In both, in
vivo as well as in vitro studies, the TMC-coated VAPL ISG ocular retention
time, was found to be noticeably extended with a positive link with DQ of
TMC. A prolonged tmax, enhanced Cmax and AUC (024) in aqueous humor
of the rabbit eye, recommending the prolonged drug release with a desirable
corneal penetration and absorption when compared with that of the marketed
gels, has been executed by TMC60-coated VAPL ISG. The insignicant side
effect like local irritation has been recognized with that of the TMC-coated
VAPL ISG. The TMC-coated VAPL ISG shows signicant features such as
slow release of the medicament; prolonged retention in the eye, improved
corneal permeation, and favorable bio-safety characteristics is proven to be
effective and can be considered for future studies.
Micro- or nano-emulsions are some of the most rising liquid globules applied
onto the ocular anterior surface with some exclusive nature (enhanced
bioavailability, ocular tissue compatibility, high DL) (Kumar and Sinha,
2014). Emulsions can be defined as biphasic liquid drug delivery systems
where two immiscible liquids are made to become miscible by adding an
emulgent (surfactant or co-surfactant) (Figure 9.1). The emulsion droplets
behave as a drug pool for liberating hydrophilic as well as hydrophobic
agents in the corneal layer. Droplets of emulsions are formed by blending
the oil phase with the aqueous phase and surface-active agents, which
possess lower energy absorption (Vandammee, 2002). Microemulsions
ranging between sizes of 5 nm to 200 nm show immense drug absorption
and also improve the pre-corneal penetration. An effective medication for
overcoming macular degeneration, using a nano-emulsion (NE) system
comprising of isopropyl myristate, triacetin, Tween 80, and ethyl alcohol to
enhance the solubility and permeability of lutein, has been discovered by Lim
et al. (2016). To recognize the self-emulsifying area, a pseudo-ternary phase
structure was established. Eight different formulations were identified and
chosen to characterize each formulation. We notified physical characteristics
including particle size, drug solubility, formulation stability, and turbidity.
The transparent optimized formulations such as NE 5 (NE-5) and NE-8, has
been chosen. The particle size of NE was ca. found to be in a range of 10–12
nm with a narrow size distribution. For about 7 days, there was no separation and change in the particle size was notified. The lutein loading NEs
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demonstrated a significant increase in lutein release and sustained release.
In contradiction, lutein prepared using oil and starch shows restricted drug
release profiles under 5%. The produced lutein NE formulation is proven to
be a possible substituent for lutein delivery systems.
Polymers show different characteristics in their composition. For attaining
favorable ocular drug delivery to the targeted area, the best suitable option is
the polymeric nanoparticles of colloidal nanosized systems (1 nm < d < 1000
nm) (Ghangoria et al., 2016). Based on the structural differences, the polymeric nanoparticles are classified as: nanospheres (NSs) and nanocapsules
(NCs) (Figure 9.1). NSs generally consist of polymeric matrix with three
drug-loading patterns: (i) to encapsulate drugs into the spheres; (ii) to absorb
drugs onto the surface; (iii) to disperse drugs within the polymeric network.
In contrast to nonospheres, nanocapsule score-shell possesses the ability to
dissolve drugs in the core or to absorb drugs on the shell when present in
drug-loading form (Meyer et al., 2012; Tekade et al., 2014).
A stimulus-amenable, in situ-forming, nanoparticle-laden hydrogel for
controlled release of poorly bioavailable drugs into the aqueous humor of
the eye has been established by Kabiri et al. (2018). A composite of HA
and methylcellulose (MC) is used to formulate a hydrogel. Poly (ethylene
oxide) (PEO) and poly (lactic acid) (PLA) are present in the amphiphilic
nanoparticles. The hydrogel composition and nanoparticle content in the
formulation, is recognized by an experimental design and the formulation
accessibly switched between thixotropy and temperature-dependent rheopexy when it was examined in a rheometer under conditions that imitate
the ocular surface, including blinking. These features need to assure that
the formulation coats the cornea via blinking of the eyelid and eases for
application of it as an eye drop instantly before the patient’s bedtime.
We eventually, examined the efcacy of our formulation in whole-eye
experiments through loading the nanoparticulate with cannabigerolic
acid (CBGA). Above 300% enhancement in transcorneal penetration
over control formulation has been established with our formulation. This
research laids the basic way for introduction of new products targeting
treatment of ocular diseases to the market.
A newer nano-carrier formulation composed of Pluronic-F127 sustained
D-Tocopherolpolyethene glycol 1000 succinate nanoparticlulate, which were
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employed for emulsifying greater curcumin concentrations (4.3 mg/mL) in a
promising level has been reported by Davis et al. (2018) study. Characterization with x-ray diffraction and in vitro release studies resulted in restraining
of curcumin to the nano-carrier interior, measuring <20 nm diameter for each
particulate size. Curcumin-stacked nanocatalysts (CN) were found to be as
mainstay of therapy for Cobalt chloride-induced hypoxia and glutamateinduced toxicity in vitro, with CN treatment prominently enhancing R28 cell
feasibility. The topical application of CN twice-daily for three weeks that
has the ability to reduce retinal ganglion cell loss compared to the controls
has been prepared by employing glaucoma-related in vivo models of ocular
hypertension (OHT) and partial optic nerve transaction (PONT). The above
results revealed that the newer topical CN formulation research has been
shown a promising effect for neuroprotective therapy in glaucoma and other
related eye diseases with neuronal pathology. Epigallocatechin-3-gallate
(EGCG), possessing antiangiogenesis activity acting as blocker for human
vascular endothelial cells for corneal neovascularization (NV) therapy has
been proposed by Chang et al. (2017).
In the current research, conjugated complex of arginine-glycine-aspartic
acid (RGD) peptide HA-coating on the gelatin/EGCG self-assembly
nanoparticles (GEH-RGD NPs) was formed to target V3 integrin on human
umbilical vein endothelial cells (HUVECs) and a corneal NV mouse model
was utilized in order to assess the clinical outcome of this nano-drug used
as eye drops. H1NMR and FT-IR has been utilized to establish HA-RGD
conjugation through COOH and amine grouping. The average size for
GEH-RGD NPs was satisfactory to say it is in nanosize with a positive zeta
potential, and EGCG-loading efciency of almost 100%. Images of GEH-A
spherical shape and shell structure in nanosize have been visible with RGD
NPs obtained through a transmission electron microscopy method. At about
30% after 30 hours of duration, a slow-release design of nano-formulation
was notied in the surface plasmon resonance assuring that the GEH-RGD
NPs specically binds to the integrin V3. The GEH-RGD effectively inhibits
HUVEC proliferation, at a reduced EGCG concentration as compared to that
of the EGCG or non-RGD-modied NPs, in the in vitro cell-viability studies.
Besides, GEH-RGD NPs notably inhibits HUVEC migration lowers than
58%, lasting for 24 hours of duration. In the corneal NV mouse, model,
minimal, and thinner vessels were found in the alkali-burned cornea after
treatment with GEH-RGD NP eye drops. Ultimately, this research proved
that the GEH-RGD NPs were favorably designed and produced as vascular
endothelial cell inhibitors with a denite targeting capability. Furthermore,
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it can also be employed for eye drops to inhibit angiogenesis in corneal NV
mice.
A novel penta block (PB) copolymer (PB-1: PCL-PLA-PEG-PLA-PCL)
builded nano-forms suspended in a thermosensitive gelling copolymer
(PB-2: mPEG-PCL-PLA-PCL-PEGm) termed as composite nano-formulation has been developed and synthesized by Agrahari et al. (2016). An
insignicant shatter release effect has been notied by the composite
nanoformulation that was synthesized to provide a sustained delivery of
complex molecules over a longer duration. The posterior segment ocular
diseases such as age-related (wet) macular degeneration, diabetic retinopathy, and diabetic macular edema are managed with the aid of such
a delivery system. The novel PB copolymers were identied by FT-IR
spectroscopy, 1H-NMR spectroscopy and gel permeation chromatography
for identication of functional groups, molecular weight and purity respectively. To determine the crystallinity of copolymers, the X-Ray diffraction
method was employed. The PB-1 nanoparticles (NPs) size distribution was
found to be ~150 nm using nanoparticle tracking analysis, following an
emulsication-solvent evaporation method. The encapsulation efciency
and DL percentage (%) were found to be as 66.64%} 1.75 and 18.17%}
0.39, respectively, (n = 3). For in vitro release studies of IgG-Fab from
composite nanoforms, variant weight percentages (15 wt.% and 20 wt.%)
of the PB-2 copolymer has been used. An insignicant shatter release with
continuous near zero-order has been identied from the composite nano-
forms analyzed up to 80 days of duration. The in vitro cell viability and
biocompatibility studies carried out on ocular (human corneal epithelial
and retinal pigment epithelium) and macrophage (RAW 264.7) cell lines,
revealed that the produced PB copolymer-based composite nanoforms were
safe and effective for clinical applications. Based on the above results, it
can be concluded that the PB copolymer constructed composite nanoforms
can provide a strong platform for therapeutic proteins ocular delivery.
Moreover, the composite nanoformulations may also provide fewer side
effects associated with frequent intravitreal injections.
Spanlastics are considered as newer elastic micro-vesicular carriers
comprises of spans and non-ionic surfactants that possess considerable
elasticity nature in structure and quantity. Hydrophilic, hydrophobic, and
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amphiphilic drugs can be loaded into its multi-lamellar micro-vesicles with
the aid of snaplastics (Figure 9.1). Non-ionic surfactants like tweens play
an eminent role in reducing interfacial tension, enhancing fluid nature, and
deformability that results in improved diffusion of spanlastics (Deol et al.,
2015). Broadly, the application of surfactants is encouraged for expanding
the pores of the bio-membrane encouraging the temporary entry of huge
spanlastics (Kakkar and Kaur, 2011). To facilitate the posterior eye segment
drug delivery, spanlastics is highly recommended and considered favorable
and efficient ophthalmic nanodevice.
Nano-micelles consisting of polymeric and surfactant nano-micelles are
known to be as rising novel carrier systems for posterior eye drug delivery.
Apart from their smaller size, improved drug solubility and stability
(Alvarez et al., 2016), enhanced corneal permeation (Prosperi-Porta et
al., 2016), lower adverse effects and high biocompatibility (Vadlapudi et
al., 2014) aids them to become potential candidates for poorly aqueous
soluble drug delivery system. Fewer amphiphilic molecules when added to
special solvents adapt to self-assemble and results in core-shell monomers
called nano-micelles (Cholkar et al., 2012) (Figure 9.1). A newer curcumin
composed nanomicelle formulation utilizing a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCL-PVA-PEG) graft copolymer has
been demonstrated by Li et al. (2017). Nanomicelle curcumin, formulated,
and optimized, which was further assessed for in-vitro cytotoxicity, cellular
uptake, and antioxidant activity followed by in-vivo ocular irritation,
corneal permeation, and anti-inflammatory efficacy respectively. After the
encapsulation process of the PVCL-PVA-PEG nanomicelles, the solubility,
chemical stability, and antioxidant activity were drastically enhanced. The
nanomicelle curcumin based ophthalmic solution was easy to produce and
the nanomicelles possess adequate stability as well, it also contains better
cellular tolerance. Excellent ocular tolerance in rabbits has been noticed by
Nanomicelle curcumin. The usage of nanomicelles remarkably enhances
the in vitro cellular uptake as well as the in vivo corneal permeation. Addi-
tionally, nanomicelles also intensify the anti-inflammatory efficacy when
compared with that of a free curcumin solution. These findings reveal that
the nanomicelles act as significant topical delivery systems for the ocular
administration of curcumin.
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The Flt1 peptidehyaluronate (HA) conjugates synthesization results in
micelle-like nanoparticulates formation that were utilized to encapsulate
genistein, an inhibitor of tyrosine-specic protein kinases, for the treatment
of ocular NV has been described by Kim et al. (2012). The mean diameter
of genistein-loaded Flt1 peptide HA conjugate micelles was found to be
as 172.0 ± 18.7 nm, with a drug-loading efciency of 4050%. The in vitro
release tests of genistein through a genistein-loaded Flt1 peptide HA conjugate micelles shows the controlled release phenomena for more than 24 hrs.
Furthermore, the in-vitro biological activity of genistein/Flt1 peptide HA
micelles was authenticated via the synergistic anti-proliferation activity
of HUVECs. Besides, we can also afrm the anti-angiogenic activity of
genistein/Flt1 peptide HA micelles from the data revealing a statistically
signicant suppression of corneal NV in silver nitrate cauterized corneas of
SD rats. In diabetic retinopathy rat models, the retinal vascular hyperpermeability was also found to be reduced upon treatment.
The use of phytocomponents in the treatment of ocular diseases has been
widely accepted globally, since several decades. The advancement in the
field of phytochemical and phytopharmacological sciences has permitted
elucidation of the composition and biological activities of several
medicinal plant products. The phytochemical potency majorly depends
on the availability of active compounds. Several biologically active
constituents are highly water-soluble, with a lower systemic absorption, because they are inaccessible to cross the corneal layer resulting
in loss of bioavailability and efficacy. The phytochemical entrapment
with nanoforms might result to ameliorate the action, thus reducing the
desired dose and side effects, and in turn improving activity. Nanoforms,
can deliver the active chemicals at an adequate concentration during the
complete treatment duration, directing it to the desired targeted action
site. Still, there have been many promising challenges for implementation of clinically viable ocular therapies in this area. The management
of nanoform interactions with biological systems represents some of the
current challenges mimicking our novel trial process. Fewer additional
new challenges include probing of targeted efficiency of nanoforms and
satisfying the international standards in relation with their toxicology and
biocompatibility aspects (Table 9.1).
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TABLE 9.1 Phytoconstituent-Based Nanoformulations and Their Biological Activity
Phyto
constituent
Rebaudioside A Micelles RA micelle formulations have
Forskolin NPs Scintigraphy studies indicated
Quercetin Nanostructured
Coumarin-6 Nanostructured
Curcumin Nanostructured Clearance of the formulations was Liu et al.,
Coumarin-6 Nanostructured
Tacrolimus Proglycosomes Studies in rabbits demonstrated
Curcumin Nanostructured
L-carnosine Phytosome
Formulation Inference References
lipid carriers
lipid carriers
lipid carriers significantly delayed in the presence
lipid carriers
lipid carriers
Biomarkers as Targeted Herbal Drug Discovery
Song et al.,
shown potential to improve the
bioavailability of hydrophobic
drugs.
longer retention of CS-PLGA NP’s
while increased effectiveness after
single instillation in reducing the
intraocular pressure was observed.
80.52% of total quercetin was
released from the QN-NLC based
hydrogel (QN-NLC-Gel) within
3 days, revealing QN-NLC-Gel
released drug sustainably.
Increase in drug absorption was
greater in the cornea than in the
conjunctiva.
of CS-NAC and the effect was
positively related to the degree of
thiolation.
Promising oculardrug delivery
systems to achieve prolonged
precorneal retention, higher corneal
permeability and enhanced ocular
bioavailability.
prolonged precorneal retention (up
to 8 h) and manifestly improved
intraocular drug levels, well above
therapeutic levels.
CS-NAC-CUR-NLC possesses a
greater potential as an oculardrugdelivery system
Ex vivo transcorneal permeation
parameters showed significantly
controlled corneal permeation of
L-carnosine without any significant
impact on primary human corneal
cell viability.
2018
Khan et al.,
2018
Yu et al.,
2018
Liu et al.,
2017
2017
Li et al., 2017
Garg et al.,
2017
Li et al., 2016
Abdelkader et
al., 2016
TABLE 9.1 (Continued)
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Phyto
constituent
Curcumin Nanogel The maximal concentration
Tacrolimus Niosomes Pharmacokinetics test showed that
Mangiferin Nanostructured
Curcumin Nanoparticle
Formulation Inference References
(Cmax) was significantly improved
(p < 0.01). The prolonged mean
residence time (p < 0.01) indicated
that CUR-CNLC-GEL is a
controlled release formulation.
area under curve of HA-coated
niosomes was 2.3-fold and 1.2-fold
as that of suspension and non-coated
niosomes, respectively.
Pharmacokinetic study suggested
lipid carriers
a 5.69-fold increase of ocular
bioavailability compared with
solution.
The in vivo study also revealed that
the formulation could significantly
increase curcumin bioavailability in
the aqueous humor.
223 Phytoconstituent-Based Nanotherapeutics
Liu et al.,
2016
Zeng et al.,
2016
Liu et al.,
2012
Lou et al.,
2014
• phytoconstituents
• nanoformulation
• ocular delivery
• liposomes
Abdelkader, H., Longman, M. R., Alany, R. G., & Pierscionek, B., (2016). Phytosome-
hyaluronic acid systems for ocular delivery of L-carnosine. Int. J. Nanomedicine, 11,
2815–2827.
Afify, E. A. M., Elsayed, I., Gad, M. K., Mohamed, M. I., & Afify, M. A. R., (2018).
Enhancement of pharmacokinetic and pharmacological behavior of ocular dorzolamide
after factorial optimization of self-assembled nanostructures. PLoS One, 13(2), e0191415.
Agarwal, R., Iezhitsa, I., Agarwal, P., et al., (2016). Liposomes in topical ophthalmic drug
delivery; An update. Drug Deliv., 23(4), 1075–1091.
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