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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5698_Библиотеки_им_академика_М_И_Перельмана
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TABLE 16.2 Botanical sources, parts used, active constituents with their dose range, pharmacokinetics, and mechanism of action, essential
formulations, and clinical trials of various herbal drugs.dcont’d
Botanical
sources
Part
used
Active
constituents
Dose range and
route
Pharmacokinetics
parameter
Possible
mechanism of
action Properties
Essential
formulation Clinical trials References
Ferula
asafoetida
Rhizome
and root
Umbelliferone 0.034 mmol/g in
the diet for
5 weeks for
anticarcinogenic
activity
The volatile oil in
the gum is
eliminated through
the lungs, making
this an excellent
treatment for
asthma
Ability to inhibit
the generation of
ROS
Oleo gum
resin (highly
soluble in
ethanol)
Solid lipid
nanoparticle
Inhibit the
release of
proinflammatory
mediators via the
NF-kB signaling
pathway
[35]
Larrea
tridentata
Leaf and
flower
Nordihydro-
guaiaretic acid
417 mg/kg Bioavailability 1.75
or 3.50 mmol/L at
60 min.
Reduction of
genotoxic damage
induced by
ethynodioldiacetate
Soluble in hot
water and
organic
solvent
(natural
lignan)
Microemulsion Number of
aberrant cells in
sister chromatic
exchanges as a
function of
NDGA doses
[36]
Nicotiana
tabacum
Root and
leaves
Nicotine Smoked dosage -
0.3e0.8 mg
Onset - 5e60 s A rise in plasma
FFA could be
prevented by the
administration of
nicotinic acid
Alkaloids Lipid emulsion His bundle
electrography
coupled with
programmed
electrical
stimulation was
being used to
investigate atrial,
atrioventricular
nodal, and
ventricular
conduction times
and
refractoriness, as
well as sinus
node function
[37]
Oral dosage - 0.5
e2mg
Duration - 10
e
30 min. (smoked
dosage)
Intranasal dosage
- 0.3e1mg
Onset - 2e15 min.
Duration - 1e2hs
(Oral dosage)
Onset - 20e90 sec.
Duration - 10
e30 min (Intranasal
dosage)
Olea
europaea
Seed Olive oil
(oleic acid)
10 mL/kg orally Plasma levels were
monitored over 12 h
by using
noncompartment
model
The molecule was
rapidly and
extensively
absorbed by the
organs and tissues
studied, with a
preference for renal
absorption.
Vegetable oil Lipid emulsion Up to 2 g/kg
body weight,
show
considerable
toxicity
[38]
16. Novel drug delivery approaches for improving therapeutic applications of berberine and berberine-rich herbal preparations378
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Alkaloids are among the pharmaceutically significant chemical components derived from
plants. Alkaloids are a class of chemical substances that exist naturally and have a large pro-
portion of basic nitrogen atoms. Alkaloids usually have a striking physiological action on
humans or other animals with immense therapeutic potential [39]. Literature supports an
increased surge of interest in the use of alkaloids against a number of chronic diseases like
cancer, hyperlipidemia, diabetes, metabolic syndrome, and coronary artery disease as well
as viral, bacterial, fungal, and parasitic infections.
BER, an isoquinoline alkaloid, has been utilized in Ayurvedic and Chinese medicine for
centuries for its broad range of pharmacological and biochemical effects. The miscellaneous
pharmacological actions exhibited by BER make it prospective as a drug with broad thera-
peutic applications [40]. The isolated and synthetic preparations of BER exist in different
FIGURE 16.1 Various novel delivery systems.
1. Introduction 379
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chemical forms such as BER hydrochloride, BER sulfate, BER citrate, or phosphate. Among
these forms, BER hydrochloride is the most abundant form [40].
BER exhibits low aqueous solubility, poor permeability, and absorption issues resu lting in
its poor oral bioavailability. Significant improvements have been made regarding new drug-
carrier systems for enhancing the plasma level and pharmacological efficacy of BER [41].
Delivery systems such as vesicular systems comprising of liposomes, phytocomplexes, and
nonvesicular systems comprising of particulates, inclusion complex, emulsions, nanoscaf-
folds, and cellular derivatives improve the efficacy of BER [41].
2. Characteristics of BER
2.1 Chemistry
The proto-BER group of isoquinoline alkaloids includes BER, which is a quaternary ammo-
nium salt and structurally a 5,6-dihydro-dibenzo[a,g] quinolizinium (C
20
H
19
NO
5
) derivative
[40]. Variou s plant families, including Berberidaceae, Papaveraceae, and Ranunculaceae,
have reported the presence of BER, which can be obtained from plants such as Berberis
[e.g., Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata
(tree turmeric)], and Hydrastis canadensis (golden seal), Coptis chinensis (Chinese goldthread
or Huang Lian Su), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense (Amur
cork tree), Tinospora cordifolia, Eschscholzia californica (Californian poppy) and Argemone mex-
icana (prickly poppy). BER is generally obtained from the stems, rhizomes, and roots of
plants, as well as their bark [40].
2.2 Pharmacology
BER has been reported to show evidence of a variety of pharmacological activities against
various dreadful disease cond itions (Fig. 16.2) like antidiabetic, antilipid peroxidation, antia-
therosclerotic, neuroprotective, antibacterial, antifungal, antiinflammatory drug and im-
proves polycystic ovary syndrome and gastroenteritis [42e45](Fig. 16.2).
BER hydrochloride has also shown antiproliferative activity and sensitivity improvement
in various cancer cell lines [46]. The existing literature proposes that BER is a nontoxic agent
and does not cause any systemic toxicity [47]. Specific pharmacological properties of BER and
BER-rich herbal preparations are discussed in the following sections.
2.2.1 Anticancer activity
The therapeutic potential of BER as an anticancer agent has been extensively investigated
[48e52]. The possible anticancer potential of BER has constantly been an issue of significant
attention due to its ability to intercalate with nucleic acids. Cell cycle arrest and induction of
apoptosis are just some of the anticancer actions it has. It also inhibits cell migration and in-
vasion by regulating a number of pathways such as the generat ion of reactive oxygen species
and alterations in mitochondrial functions [51]. It also inhibits DNA topoisomerase by bind-
ing to the DNA or the RNA. In addition, it controls matrix metalloproteinase, P53 activity,
and NF-kappa B stimulation [48 e 52 ]. BER’s antiproliferative properties have been attributed
16. Novel drug delivery approaches for improving therapeutic applications of berberine and berberine-rich herbal preparations380
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to its ability to bind to oligonucleotides and to stabilize DNA triplexes or G-quadruplexes by
inhibiting telomerase and topoisomerase, among other mechanisms [53]. BER affects cell di-
vision and arrests the cell cycle in the G0/G1phase, G1phase, and G2/M phase in cancer cells
such as MDAMB-231 and MCF-7 breast cancer cells [54], ovarian carcinoma cell lines
OVCAR-3 and Skov-3 [55], K1735-M2 murine, and WM793 human melanoma cells, human
U2OS [56], thyroid carcinoma 8505C, and TPC1 cells [55], lung cancer H1299 and A549
cell lines [46], Saos-2 and HOS osteosarcoma cells [57] and human colon cancer HCT-8 cells
[58]. It also supports antineoplastic activity against gastric cancer cells and saves the gastric
mucosa from damage by reducing the growth of H. pylori [59e61]. BER kills triple-negative
breast cancer cells through multiple mechanisms including activation of caspase-9, decreased
expression of cyclin A and D [62]. These findings suggest that BER appears to be a generally
safe medication that may be utilized as an anticancer treatment against a variety of malig-
nancies, according to the available research.
2.2.2 Hypoglycemic activity
BER’s hypoglycemic effect s have been studied extensively [63e66], with evidence of insu-
lin sensitization in rats due to AMPK activation [67,68], as well as a greater effect on diabetic
sequelae such as cardiac malfunction and endothelial malfunction in rats [68,69]. BER’s
FIGURE 16.2 Berberine and its associated activities.
2. Characteristics of BER 381
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antioxidant and aldose reductase inhibiting properties may help to alleviate diabetic ne-
phropathy. Upregulation of LDL receptor expression [70], inhibition of liver gluconeogenesis
[71], activation of glycolysis in peripheral tissues [66], induction of AMP-activated protein ki-
nase in adipose and muscle tissues [72], advancement of insulin secretion, and cell regener-
ation promotion of intestinal glucagon-like protein-1 secretion [71,73e75], and amelior ation
of diabetic neuropathic pain are among the mechanisms proposed for BER’s hypoglycemic
action. The glucose-lowering efficacy of BER has been reported to be similar to metformin
and rosiglitazone and due to its low toxic effect, it is used in diabetic patients with chronic
hepatitis [76,77].
2.2.3 Antimicrobial activity
Many bacterial, fungal, viral, trypanosomal, and plasmodial infections, including Staphylo-
coccus aureus, which is a pathogenic agent in numerous infective illnesses frequent in the
musculoskeletal system [78e81], exhibit frailty to BER due to its antimicrobial action. It has
just a negligible effect on Gram-negative bacteria but is more effective against Gram-positive
bacteria. It primarily operates by amassing in bacterial cells and attaching to single- and
double-stranded DNA, causing bacteria to die as a result of DNA damage [82]. Additionally,
it disrupts the bacterial cell surface structure and limits bacterial development [83].
2.2.4 Antiinflammatory and antioxidant activity
BER has antiinflammatory properties that are mediated via the inhibition of the synthesis
of TNF-a, interleukin-6, and chemoattractant protein-1. Additionally, it has an effect on pros-
taglandin E-2 synthesis and exudates development, as well as downregulates the expression
of COX-2 (cyclooxygenase-2), MMP-2, and MMP-9 via the mitogen-activated protein kinase
and nuclear factor-kB signaling pathways [84]. BER reduces oxidative stress by increasing su-
peroxide dismutase, UCP-2, and reducing NADPH oxidase expression via SIRT-1/FOXO or
AMPK (AMP-activated protein kinase) pathway. It also enhances Nrf-2 (Nuclear factor
erythroid-2- related factor-2) pathway activation which is mainly responsible for the antiin-
flammatory and antioxidant activity. It also reduces inflammation by obstructing the
AMPK-dependent MAPK (mitogen-activated protein kinase) pathways [85].
2.2.5 Hypolipidemic activity
BER has also been shown to boost metabolic activity in both animal and human subjects,
according to the literature. As a result of stabilizing low-density lipoprotein mRNA and
increasing the expression of LDL receptors, BER has been shown to reduce cholesterol levels
[86]. By inhibiting the activity of c-Jun N-terminal kinase (JNK), we can prevent the effect of
BER on the LDL receptor. The activating of JNK by BER may be implicated in the induction of
LDLR, according to most of the research [87]. Its mechanism of action is different from con-
ventional statins that decrease the cholesterol level by increasing the low-density lipoprotein
mRNA transcription [70]. BER with plant stanol lowers the cholesterol level by synergistic
action on cholesterol absorption and reduces plasma triacylglycerols in the hypercholesterol-
emic hamsters model [88]. In another study, BER with simvastatin showed improvement in
lipid-lowering efficiency [89]. In clinical studies, BER significantly raised triglycerides by 35%
and 22%, serum cholesterol by 29% and 16%, and LDL-C by 25% and 20% in patients with
dyslipidemia [70,90].
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2.2.6 Hepatoprotective activity
BER demonstrates hepatoprotective activity by free radical scavenging, diminution of
oxidative/nitrosative stress, and also decreases inflammatory responses in the liver like
decreasing TNF-a, COX-2, and i-NOS expression in acute CCl
4
-induced injury [91,92]. In a
clinical study when BER was used in hepatitis B-affected patients, it not only reduced the pro-
duction of the hepatitis B virus but also induced toxicity in host cells [93].
2.2.7 Miscellaneous activity
BER is also used in the treatment of other diseases like depression by altering brain
biogenic amines (norepinephrine, serotonin, and dopamine) and intermingling with the l-
arginine-NO-cGMP pathway [94,95].
BER is also used to get better stomach function, as diaphoretic (sweat inducer), and as anti-
pyretic [96], and for the treatment of psoriasis and other skin diseases by inhibiting hyperprolif-
eration [97]. It also shows antiplatelet, anticerebral ischemic [98], and antiarrhythmic action [99].
2.3 Limitati ons of BER
BER exhibits numerous therapeutic activities which are hampered by certain pharmacoki-
netic limitations by hindering its passage to the site of action for optimum therapeutic
response. This includes poor absorption and low bioavailability after oral administration,
almost reported bioavailability found to be a mere 0.68% and 0.36%. Several studies reported
that its lipophobic nature restricts its movement and most of the portions get metabolized
across the intestinal wall [100]. As per Zhang et al. absorbed BER is transported back into
the intestinal lumen through ATP-binding cassette (ABC) transporters [101,102]. Thus, there
is an urgent need to deliver it more effectively with maximum therapeutic response and min-
imal side effects. A variety of works has been reported involving the amalgamation of BER
with a novel delivery system to increase its oral bioavailability, feasibility, and patient
compliance.
3. Delivery approaches
The acceptance of herbal actives is generally limited due to the poor pharmacokinetic pro-
file of phytoconstituents that leads to poor bioavailability causing delayed pharmacological
action [103]. This condition is simi lar to the case of BER. Two conditions are sought to be
met by the novel drug delivery systems. As a first step, it provides the medication at a
pace that is determined by the body’s demands throughout the course of therapy, and it
transports it straight to the inflamed tissues and/or organs. Conventional delivery technolo-
gies, including sustained release dosage forms, are incapable of meeting any of these require-
ments [2]. In contrast to conventional drug delivery systems, the novel drug delivery method
maintains drug action at a predefined rate that is generally constant (zero-order kinetics),
maintains a suitable drug level in the body, and eliminates serious adverse effects all at
the same time [104,105]. A targeted drug delivery strategy that uses carriers or chemical
derivatization may also be used to localize drug activity in the affected tissue or organ [106].
3. Delivery approaches 383
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With the introduction of this unique approach, there is now a great deal of promise for
enhancing the in vivo bioavailability of herbal medications [107]. Many researchers are
actively involved in designing novel delivery systems including liposomes, transferosomes,
ethosomes, phytocomplexes, nanoparticles, microemulsions, micelles, solid solutions for
delivering plant actives like BER [107109]. They aim to solve multipurpose problems in the
upcoming era especially associated diseases which include the involvement of reactive oxy-
gen species, pollutants, and mutagenic chemicals affecting the quality of life of human
mankind. Various novel delivery systems explored to deliver BER has been summarized in
Table 16.3. These novel systems could be studied for various pharmacokinetic parameters
which could aid in deciding the percentage enhancement of bioavailability in actuality
[107]. The concerned area of novel delivery systems is to cater to drug targeting, maintaining
therapeutic efficacy, and the development of full-fledged safe medications.
A variety of novel strategies has been utilized for the delivery of herbal actives for their
safe and effective delivery to convene the therapeutic benefit of the herbal actives [30].
Novel systems can be classified into vesicular type or nonvesicular type depending on the
type of structural network. Both vesicular and nonvesicular systems have their own advan-
tages with different mechanisms to control the drug release [124 ,125]. Various advantages are
associated with novel delivery systems apart from certain limitations as it requires close
monitoring while formulation in terms of the ratio of constituents, processing variables.
High production cost and stability issues are some more concerns [126].
Advantages of novel approaches include targeting of drugs to the site of action, the
optimal concentration of the drug, improvement in the therapeutic index, effectively recog-
nize target cells, effectively tailored surface ligands, and drug:ligand complex. Minimization
of medication degradation and loss, as well as improvement in drug bioavailability, better
patient compliance as a result of fewer negative effects [127e129].
3.1 Vesicular delivery system
Vesicular systems have been developed to address the difficulties encountered in current
pharmaceutical research when it comes to delivering controlled drug release at the target
location [125,130]. When subjected to an aqueous environment, vesicular systems self-
assemble into one or more concentric bilayers, which are highly organized structures
comprised of one or more concentric bilayers generated by self-assembling of amphiphilic el-
ements [131]. Vesicular systems produce a regulated and continuous release of substances
with the least side effects. As a result, vesicular systems may be controlled in a variety of
ways to influence the rate at which a drug was released from its confinement [131]. Lipo-
somes, phytosomes, and transfersomes are three types of vesicular systems that will be exam-
ined in further detail in the next section.
3.1.1 Liposomes
Liposomes are globular vesicles made up of phospholipid bilayers with an aqueous core
mostly consisting of natural or synthetic lipids that are used to deliver drugs or other sub-
stances. These systems are among the most promising novel systems now available, and
some liposomal products have already been launched with great success
[125,130,132e134]. Phospholipids (primarily phosphatidylcholine) and cholesterol are crucial
16. Novel drug delivery approaches for improving therapeutic applications of berberine and berberine-rich herbal preparations384
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TABLE 16.3 Novel carriers used for the administration of BER in the treatment of various diseases.
S.No Novel system
Formulation
technique Disease Study performed Remark References
I. Vesicular system
1 Liposomes Thin-film
hydration/
extrusion
Hepatic
carcinoma
In vivo performed in a
murine xenograft model
When compared to the untreated tumor control
group, there was a reduction in the size and weight of
tumors seen.
[110,111]
2 Long-
circulating
liposomes
Ionophore
A23187-mediated
ZnSO
4
gradient
method
Only in vitro
study
performed
Influence of different factors
on the encapsulation
efficiency
94.3% 2.1% encapsulation efficiency with mean
diameter 146.9 nm 3.2 nm found when the drug-
to-lipid ratio is kept 1:20.
[112,113]
3 Chitosan-coated
nano-liposomes
Thin-film
hydration
Oral
bioavailability
In vitro and in vivo
characteristics
Delayed-release in the simulated GI environment and
stability improved. Oral delivery increases the
bioavailability of the drug.
[114]
6 Phytosomes Rehydration
methodology
Oral
bioavailability
In vivo study of
bioavailability in rabbits
Relative bioavailability of BER hydrochloride
phytosome was (273.3 3.40)%, compared with raw
material.
[115,116]
II. Non vesicular delivery system
1 Alginate
microspheres
within the
hydrogel
Emulsification/
gelation method
Only in vitro
study
performed
Drug distribution and drug
release
The release found to be fast in the first period and
steady later possesses controlled steady release of
drugs.
[117]
2 Magnetic
gelatin
microsphere
Reverse phase
suspension cold-
condensation
method
Only in vitro
study
performed
Evaluate drug release and
loading
The drug-loading rate was found to be 7.2%, the
entrapment efficiency was 62.6%, and the sustained-
release capacity of the microsphere was found to be
excellent, releasing 83.5% of the whole drug within
7 h, according to the results.
[117]
3 Mucoadhesive
microparticle
Dual-channel
spray gun
technology
Anticancer Oral bioavailability and
pharmacokinetic profile of
studied in sprague dawley
rats
The results of pharmacokinetic tests revealed a
considerable rise in the plasma cmax concentrations
of the drug. When compared to the untreated control
groups, the AUC values were raised by 6.98 and 7.41
times, respectively, resulting in a 49.8% and 53.4%
reduction in tumor sizes.
[118]
(Continued)
3. Delivery approaches 385
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TABLE 16.3 Novel carriers used for the administration of BER in the treatment of various diseases.dcont’d
S.No Novel system
Formulation
technique Disease Study performed Remark References
4 Ethylcellulose/
Chitosan
microspheres
W/o/w emulsion
and solvent
evaporation
Only in vitro
study
performed
Mechanism of drug release in
different pH buffers
In dHCl, a non-fickian diffusion mechanism was
identified, whereas, in PBS, a diffusion-controlled
drug release mechanism based on fickian diffusion
was discovered. As a result, it was discovered that
drug release is triggered by both drug diffusion and
breakdown of the polymeric network.
[119]
5 Nanoparticulate Rotatory-
evaporated film-
ultrasonication
method
Only in vitro
study
performed
Mean diameter, zeta
potential, drug loading, and
entrapment ratio
Stability is shown by the mean diameter of 60.5 nm,
the zeta potential of 29.7 mV, the drug loading of
8.69%, and the entrapment ratio of 97.58% that were
measured.
[53]
6 Solid lipid High-pressure Antitumor
activity
In vitro study over cells MCF-
7
On MCF-7 cancer cells, BH significantly decreased
cell growth and increased the anticancer efficacy of
the compound.
[120]
Nanoparticle Homogenization
method HepG 2, and A549 cancer
cells
7 Fucose-
conjugated
nanoparticles
High-pressure
homogenization
method
Eradication of
helicobacter
pylori
Delivery efficiency and anti-
H. pylori activities
Inhibits H. pylori development at the site of infection,
while also increasing the antibacterial impact of BER.
It also helps to manage gastrointestinal inflammation.
[121]
8 g-Cyclodextrin Cyclodextrin and
BER solution
incubated for 20 h
Germicidal
activity
Antibacterial activity against
S. aureus, B subtilis,
Increased solubility and decreased bitter taste with
antibacterial and antifungal activity were observed.
[122]
Salmonella, and Escherichia
coli and
against Candida albicans
9 Nanoemulsion Quaternary phase
diagram
Anticancer In vivo study performed for
anticancer activity
Anticancer activity was observed. [123]
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components of liposomal drug delivery systems, with cholesterol acting as a fluidity buffer.
Phospholipids are critical components of liposomal drug delivery systems [133]. Despite the
fact that cholesterol does not participate in a bilayer formation, it may be added to phospha-
tidylcholine in amounts up to 1:1 or even 2:1M ratio of cholesterol to phosphatidylcholine to
increase the rigidity of the bilayer structure. To overcome disadvantages of customary lipo-
somes as low encapsulation, poor stability, and remains of organic solvents, liposomes could
be modified in various ways to control the release rate of the drug [132,135]. These systems
could be sensitized to temperature, pH, light, and electromagnetic waves making them ther-
mosensitive, pH-sensitive, photosensitive, and electromagnetic controlled systems, respec-
tively [136e139].
The findings of Chang et al. revealed that PEG stabilized liposomes had extended circula-
tion periods in the body, enhancing the inhibitory activity of BER as against the in vitro
development of HepG2 cells and the in vivo growth of hepatoma tumor in a mouse xenograft
model, respectively [110].
Using the supercritical carbon dioxide (scCO
2
) approach, Junlinet al. created a thermosen-
sitive liposome with embedded fluorescent silver nanoparticles (AgNPs) and fluorescent sil-
ver nanoparticles (AgNPs). BER was set to release from a liposome as a result of a
photothermal effect, and the drug was released as a result of photoinduction with AgNPs
acting as a photothermal switching agent. The findings demonstrated that adjusting the
AgNPs level in the AgNPseliposome and the irradiation period may be used to regulate
the amount and rate of BER released from the liposomes [140].
3.1.2 Phospholipid complexed vesicles (phytocomplexes)
These lipid-based delivery systems, known as phytocomplexes (phytosomes), are designed
for the administration of plant extracts and water-soluble ingredien ts [131,141,142]. The goal
is to raise the solubility of poorly soluble medicines while simultaneously increasing their
bioavailability through politically active absorption through the entire GI tract. It is a
patented technology developed by a leading manufacturer of drugs and nutraceuticals that
allows the incorporation of standardized phytoconstituents or water-soluble bioactive com-
ponents into phospholipids to yield lipid compatible molecular complexes that improve
the absorption and bioavailability of the drugs and nutraceuticals [143]. In contrast to lipo-
somes, it is characterized by the establishment of chemical bonds between the phosphatidyl-
choline and the plant components, resulting in the development of a 1:1 or a 2:1 molecular
complex depending on the chemicals complexed. The increased ability of phytosomes to
permeate the lipoidal biomembrane and eventually reach the systemic circulation, as
opposed to typical herbal extracts, results in greater bioavailability when compared with
other types of herbal extracts [143]. As established by spectroscopy, actives are disseminated
throughout the whole surface of the membrane, and the molecule is fastened to the hydro-
philic head of the phospholipids (phosphate and ammonium group) and the polar functions
of the substrate in the phytovesicles by chemical bonding. phytosomes have been prepared
for numerous herbal extracts such as Ginkgo biloba, green tea, curcumin, etc. Han et al. demon-
strated in vivo activity of phytosomes and found improvement in oral bioavailability of BER
hydrochloride up to 273.3 3.4% in rabbits [144].
3. Delivery approaches 387
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