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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5680_Библиотеки_им_академика_М_И_Перельмана
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(myrcene, a-terpinene and p-cymene) and in the sesquiterpene hydrocarbon
(a-cubebene).
48
7.8 Modern Techniques Used in the Extraction of
Piper nigrum
A variety of plants contain compounds that can treat human disorders. A key
issue in obtaining high yields of therapeutic products is tha t it requires
thorough recovery using an environmentally safe, reliable and time-saving
extraction technique due to the low levels of therapeutic compounds in
plants. When choosing an extraction method, consideration must be given
to the thermolability of the active chemicals, for which the temperature and
other parameters must be adjusted. Modern extraction techniques utilized
in the extraction of P. nigrum are shown in Figure 7.5, and different ex-
traction methods along with extraction time, yields, advantages and dis-
advantages are listed in Table 7.5.
7.8.1 Hydrotropic Extraction Method
Hydrotropy refers to the phenomenon of water-insoluble or sparsely water-
soluble organic compounds becoming more soluble in aqueous solutions if
hydrotropes are present. Hydrotropes are organic salts that are very water
soluble. Increases in solubility are strongly influenced by hydrotrope con-
centration and are governed by the nature and composition of the solute.
Hydrotrope concentrations can be manipulated to recover a solute, which
means that dilutions with water precipitate the solute out of a hydrotropic
solution. In aqueous solutions,
49
solubility is enhanced by hydrotropic
Figure 7.5 Modern extraction techniques used in the extraction of Piper nigrum.
162 Chapter 7
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Table 7.5 Different extraction methods and their extraction yields.
Extraction methods
Extraction
time Yields Advantages Disadvantages Ref.
Ionic liquid (IL) based
ultrasonication-assisted
extraction. Detection
method: ultra power liquid
chromatography (UPLC
analysis)
Different ionic
liquids time:
30 min
1.96% Cost effective, sensitive, efficient
and eco-friendly technique
Not mentioned 61
Microwave-assisted extraction 2 min
2min
92 1%
94% (extraction
efficiency)
Good reproducibility, minimum
sample manipulation
An additional filtration
assembly to separate the
residue
66
Supercritical fluid extraction
(SFE)
2–5 h
2–5 h
2.25 h
81–98%
6.7–7.6%
1.23% 0.05%
(batch)
1.36% 0.02%
(continuous)
Short processing time, minimal
solid residue
High pressure is required 51
Ultrasound-assisted
extraction
5h
18 min
3.9%
0.58%
Inexpensive Lacking in the uniformity
of the distribution in the
sonication energy
61
Hydrotropic solubilization 2 h 90% to 96% Few purification steps, little
or no foaming unlike the
surfactant solutions
Not mentioned 50
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additives. Amphiphilic hydrotrope molecules can aggregate or accumulate
around hydrophobic molecules.
50
The greatest solubilization power is pos-
sessed by insoluble organic active compounds due to the high extraction
capacity of hydrotropes. Hydrotropic solubilization indicates equilibrium
between hydrophobicity and high solubility in water. Hydrotrope molecules
have difficulties in diffusion into the cellulosic layer, followed by diffusion
into the phospholipid bilayer, because they can enter the dispersed piperine
within the cell previously. Osmotic pressure exerts high pressures on the cell
wall that enhances the concentration of hydrotrope in the water, resulting in
greater penetration of fluid into the cell matrix. This aqueous solution
transported piperine through the external hydrotrope medium to the cellular
matrix, allowing penetration through rapid stages.
49
In an experimental study, a new hydrotrope-based extraction process was
used to selectively extract curcuminoids from turmeric. Another study found
that piperine was preferentially isolated from P. nigrum fruits using sodium
alkyl benzene sulphonates and sodium butyl monoglycol sulfate. The ex-
traction rate with hydrotrope and water is higher because the molecules
penetrate cellular structures and cells. Water-soluble hydrotrope molecules
disrupt the cell wall and bilayer membrane structure, which allows piperine
to be removed more quickly. A hydrotrope solution was used to extract pi-
perine selectively and quickly from black pepper. When it was analysed, the
recovered piperine was 90% pure and free of oleoresins. Extraction is in-
fluenced by a variety of elements, including hydrotrope type/nature/tem-
perature/concentration and particle size.
50
7.8.2 Supercritical Fluid (SCF) Extraction Method
Fluids used in supercritical extraction are heated above their critical point of
temperature. Supercritical fluids display a similar viscosity to gases, despite
having a density close to that of liquids. By contrast, it is only capable of
diffusing gases or liquids. These characteristics allow supercritical fluids to
penetrate solid matrices deeper and faster. Separation techniques have been
created recently due to their low cost and safety; carbon dioxide is the most
commonly used solvent in SCF extraction. Extraction and separation of
compounds are carried out using supercritical fluid. In recent years, this
technique has been used by industries that sell aromatic crops and within
the spice industry as a quick, selective, innovative and clean method.
Pepper oleoresin was extracted using SCF from P. nigrum fruit. Using
Hildebrandt’s solubility equation, the solubility parameters of piperine and
carbon dioxide were calculated for maximal extraction. The effects of
stimulants such as alcohol and methanol were investigated using various
theories. the experimental results were in line with predictions. The max-
imum relative extraction of oleoresin and piperine at 250 bar/50 1C/60 min-
utes was determined to be 61.7 and 87.51 percent. Adding 30 percent (vol/wt)
ethanol as a cosolvent increased the yield from 95.9 to 184.7 percent under
SCF extraction conditions. These oleoresins have demonstrated comparable
164 Chapter 7
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antioxidant, antiinflammatory and antibacterial properties to their respect-
ive control compounds. SCF extraction of pepper uses ethanol as a co-
solvent.
As a solvent, pulverized carbon dioxide (SCCO
2
) was used to extract pepper
oil from ground black pepper. In bench-scale investigations, the extraction
rate was examined in relation to extraction pressure (90, 100 and 150 bar),
temperature (40, 50 1C), and solvent flow rate (1, 2 and 3 kg h
1
). Increasing
the pressure or reducing the temperature improved the extraction rate, as
has been statistically proven. The fluid flow rate had a comparable effect.
51
7.8.3 Ultrasound-assisted Extraction (UAE) Method
In an ultrasound-assisted extraction method, ultrasound is used to create
cavitation when applied to an extraction solvent in contact with a sample.
Ultrasound is used to cause cavitation bubbles (in the solvent) that collapse
and cause pressure and temperature changes. This increases the amount of
mass transfer of analytes into the solvent.
52
There are numerous appli-
cations of ultrasound extraction in the disciplines of chemistry, pharma-
ceuticals, cosmetics and nutrition in the 21st century.
10
Soxhlet extraction
and batch extraction techniques, which are conventional methods, include
solvent wasting, labour intensity and solvent wasting. Due to the disadvan-
tages associated with conventional extraction methods, a new method has
been developed. Microjets are formed and cavitation bubbles collapse to
cause higher cell disruption due to the collapse of asymmetrical bubbles to a
solid surface.
53
Different parameters can distress the reactor, including its
nature, temperature, gas atmosphere, acoustical power, frequency and
geometry. As these bubbles collapse, they create high pressure and tem-
perature of about 1000 bar and 5000k, as well as approximately stimulating
physical effects.
54
The breakage of cell walls, the circulation of liquid and the
reduction in particle size and cell membranes allow mass transfer to take
place.
55
Thus, the plant body progress and cell breakage results in the
penetration of the solvent and, as a result, augmentation of the extraction
yield in UAE is realized. UAE produces higher yields, lower extraction times
and lower temperatures as well as better solvent penetration.
53,56
In order to scale up and improve the extraction method, these factors
make UAE appealing. Certain factors interfere with the effectiveness of ex-
tractions, such as solvent, time of extraction, solid–solvent ratio, duty cycle
and ultrasound power. The polarity index, viscosity, surface tension and
vapor pressure of the solvent are measured to determine an appropriate
solvent.
57
Lower pressure causes fewer bubbles to form, and higher force
implodes the bubbles, thereby extracting the target compound. By increas-
ing the ultrasound power, the bubbles collapse more explosively in a con-
tinuous mode that is not possible with ultrasound, and the material is
degraded as a result. In response to the decline of viscosity,
58,59
an increase
in solubility and development occurs during mass transfer, which is caused
by the thermal product. Rathod and Rathod
60
evaluated the three solvents:
Most Modern Approach to the Phytochemical Evaluation 165
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acetone, ethanol and hexane. The highest yield of 4.5 mg g
1
followed by
ethanol (4.3 mgg
1
) and hexane (4 mg g
1
) was obtained from the solvent
acetone. Because of the lower viscosity of acetone, the yield was better dif-
fused into the solid matrix.
60
Determination of optimal conditions such as
ethanol as extracting solvent, extraction time of 18 min, solid to solvent ratio
of 1 :10, ultrasound power 125 W, 80% duty cycle, ultrasound frequency
25 kHz and temperature 48.9 1C helped to enhance the yield of piperine by
using UAE from fruits of P. longum as evaluated by Rathod and Rathod.
60
The maximum yield was found to be 5.79 mg g
1
.
60
The optimized method
increased the top extraction productivity (from 1.9% to 3.6%) within
the shortest extraction time (from 2 h to 30 min) with average recoveries of
piperine of between 9.4% and 99% and spiking at levels 0.05, 0.1 and
0.2 mg mL
1
with an RSD lower than 5%. In another study, the extraction
yield was 4% in 5 h and 0.6% in 18 minutes.
61
7.8.4 Microwave-assisted Extraction (MAE) Method
Assays that isolate active compounds from medicinal plants use microwave
energy to partition the components of a matrix sample into a solvent. As a
result of its ability to quickly heat the sample solvent mixture, MAE is used
for a wide variety of extraction applications, including the extraction of
thermally unstable analytes.
62
This technology can be used for many dif-
ferent purposes, such as extracting bioactive ingredients from matrices more
quickly, reducing equipment size, reducing temperature gradients and in-
creasing the extraction yields. A microwave energy approach allows you to
extract soluble compounds from various materials into a fluid. By using this
method, the volatiles were also conden sed.
63
As a result of the powerful extraction methods such as MAE, polar mol-
ecules with a high dielectric constant are targeted during the extraction,
which causes rapid soaking and at a power level of 151 W, the solvent loss
decreased to 7.9% while the usage of high microwave powers of 289 and
455 W increased the solvent loss up to 20%.
64
Karpakavalli et al.
65
examined how lower volumes of solvent, shorter dur-
ation and additional yield can be obtained from positive extraction compared
to the reflux method. It showed higher yields of 2.2% of piperine.
65
By adding
40 mL solvent in 150 mL vessels at 250 W extraction experiments were carried
out in duplicate. Meanwhile another study showed an extraction yield of
92 1% and 94% in 2 minutes by adding solvent (40 mL) into 150 mL vessels
at 250 W extraction experiments were carried out in duplicate.
66
7.8.5 Ionic-liquid Extraction Method
In a wide range of applications, ionic liquids (ILs) have been suggested as a
viable medium for separating and extracting bioactive chemicals. Using an
ultrasonic extraction process that uses ionic liquids (ILUAE), white pepper
powder can be extracted. A study has been carried out to determine the
166 Chapter 7
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extraction efficiency of ionic liquids containing a wide range of alkyl chains
and anions. This study found that anions and cations have different extraction
rates. The ILUAE approach using ultrasonics was also optimized for extraction
time and solid–liquid ratio. The new technique increased the extraction effi-
ciency from 1.950 percent to 3.577 percent in less time than traditional heat-
reflux extraction (HRE) and regular UAE (from 2 h to 30 min). The recovery (R
2
)
and reproducibility (RSD, n ¼3)ofthecreatedtechniquewerealsovalidated.
At spike levels of 0.05, 0.10 and 0.2 mg mL
1
, between 93.5 and 987 percent of
piperine was recovered with an RSD of less than 5%. This method is linear for
concentrations within the examined ranges, with R
2
of 0.9994.
61
P. nigrum contains piperine, a bioactive compound that provides several
therapeutic benefits. Piperine has been separated from black pepper using a
microwave-ultrasound extraction method in one study. Piperine extraction
yields were evaluated according to a number of factors, such as particle size,
solvent-to-solids ratio, microwave power and time, and ultrasound tempera-
ture and time. A total of 46.6 mg g
1
piperine was extractedwhile using ethanol
as the solvent with a particle size of 0.15 mm, a solvent-to-solids ratio of 20 : 1,
microwave power of 100 W for 1 minute, and ultrasonic temperature of 50 1C
for 30 minutes. The Soxhlet (39.1 mg g
1
), microwave (38.8 mg g
1
)and
ultrasonic (37.0 mg g
1
) extraction yields were higher as a result, and 81.4% of
the piperine extracted was pure according to an HPLC analysis of the extracted
substance. The structural elucidation of piperine was confirmed using FTIR
and UV-vis after it was purified. Table 7.6 describes the various methods of
Ayurvedic preparations available in Ayurveda that contain an extraction
method to increase the bioavailability of poorly absorbed drugs.
7.9 Clinical Studies on Black Pepper
In human clinical studies, piperine was co-administered with many drugs
primarily to increase the bioavailability. During these trials, piperine was ad-
ministered with other diverse groups of medicines in order to be more potent
and stay in the plasma longer. Human oral bioavailability of phenytoin may be
increased by piperine, which occurs in P. longum, P. nigrum and Z. officinalis.
Piperine was tested to see how it affected the steady-state phenytoin pharma-
cokinetics in patients with uncontrolled epilepsy given a single dose. Ten
patients were divided into two groups, each taking 150 mg or 200 mg of
phenytoin twice daily. After the night dose of phenytoin was delivered, venous
bloodsampleswerecollectedat0,0.5,1,2,4,6,9and12hours.Onthesecond
study day, piperine 20 mg was given with phenytoin, and samples were
Table 7.6 Various methods of Ayurvedic extraction according to Ayurveda.
Method Part Species
Decoction Seeds Piper guineense Linn.
Decoction Leaves Piper guineense
Cold maceration Fruits and leaves Piper guineense
Most Modern Approach to the Phytochemical Evaluation 167
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collected in the same way. A Student’s t-test was used to compare mean plasma
drug concentrations at different time points and pharmacokinetic features
before and after piperine administration. Piperine significantly raised the
mean plasma concentration of phenytoin in both dose groups at most time
periods. The changes in AUC
(0–12 h)
( po0.01), C
max
( po0.001) and K
a
( po0.05)
were all statistically significant, but not the changes in K
el
and T
max
.
67
Piperine dramatically increased phenytoin bioavailability, most likely by
boosting absorption, according to the researchers. Experiments were car-
ried out to identify the scientific foundation for utilizing the trikatu group
of acrids (long pepper, black pepper and ginger) in Ayurvedic therapies.
[
3
H] vasicine and [
3
H] sparteine were utilized as test substances. P. longum
raised vasicine levels in the blood by 233 percent. The active ingredient in
piper species, piperine, increased sparteine blood levels by more than
100 percent.
68
According to these findings, these acrids have the capacity
to improve the bioavailability of a variety of medicines. Trikatu drugs
may increase bioavailability by enhancing absorption from the gastro-
intestinal tract, preventing metabolization/oxidation during the first pas-
sage through the liver after absorption, or utilizing a combination of these
strategies.
The co-administration of theophylline and piperine improved the C
max
,
extensive elimination half-life and AUC. Shoba et al. evaluated a bioavail-
ability of 2000%,
69
and when piperine and curcumin were administered
together the resulting bioactive compound was much more concentrated as
a result. Dexibuprofen and Lipicur
70
were administered in patients with a
diagnosis of lumbar sciatica, lumbar disk herniation, and/or lumber canal
steneosis, or with carpal tunnel syndrome. In both, the condition i.e., the
treatment with the multi-ingredient formula (Lipicur) decreased the neuro-
pathic pain by more than 66%. Additionally, the treatment with dex-
ibuprofen decreased neuropathic pain by about 40%. According to the dose
and time dependence,
71
piperine supplementation may result in enhanced
coenzyme Q10 absorption. When co-supplemented with piperine, phytoa-
lexin resveratrol is more bioavailable. Treatment of DIC with PIP suggestively
enhanced maximum plasma concentration C
max
, the area under the curve
(AUC), half-life time (T
1/2
), and also decreased the elimination rate constant
(K
el
), and apparent oral clearance (CL/F) compared to that of control phase.
69
Consequently, the combination therapy of DIC laterally with PIP may signify
a novel approach to decreased dosage and result in the lessened incidence of
gastrointestinal side effects seen with DIC alone at higher doses. The cere-
bral blood flow increased during task performance compared to placebo and
resveratrol alone, but without negatively affecting mood, cognition or blood
pressure.
72
C
last
values of nevirapine increased by approximately 119.5%,
166.5%, 170.1% and 145.9%, respectively,
73
when given along with etham-
butol and pyrazinamide.
73
As a component of tuberculosis treatment with
Risorine, ethambutol and pyrazinamide, piperine proved to be highly ef-
fective.
74
A better safety profile, an increased sputum conversion rate and a
more rapid cure rate are all characteristics of chronic therapy as compared to
conventional rifampicin therapy, which results in a very powerful interaction
168 Chapter 7
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between the two compounds.
75
The authors studied the effect of piperine on
pharmacokinetics of chlorzoxazone in volunteers and observed significant
interaction between two compounds. In another study, authors found
the same effect of piperine intake on the bioavailability of fexofenadine
and observed that piperine treatment significantly increased C
max
of
fexofenadine and AUC time curve. Combined with piperine, cannabidiol has
a 2.3-fold increase in AUC and a 4-fold increase in C
max
. Diverse clinical trials
related to the use of P. nigrum are listed in Table 7.7.
7.9.1 Piperine Effect on the Digestive Tract
In 40 dysphagia patients, the treatment of dysphagia was randomized and
further divided into two clusters to obtain a piperine dose of about 150 mM
through pure piperine. The trial was demonstrated by Rofes et al.
76
by sup-
plementing the alimentary bolus with piperine that improved the swallow re-
sponse in dysphagic patients. An evaluation was made of the effects of
systemically administered extracts of curcumin, lycopene, and piperine as an
adjunct to scaling and root planing (SRP) in patients with moderate gingi-
vitis.
77
After 21 days of using paired t-tests in both treatments, the group shows
a statistically substantial decrease in clinical parameters, but the test group
showed a greater reduction as compared to the control group (Po0.05). The
results showed that systemically administered antioxidants could cause better
resolution of inflammation when used as an adjunct to SRP.
7.9.2 Vitiligo
Application of P. nigrum fruit extract and pure piperine liniments for 11–12
weeks on skin areas of patients with vitiligo was studied.
78
In another study,
piperine has reported a significant impact on melanocyte proliferation and
found side effects less than synthetic drugs. The objective of the study was fo-
cused to assess the effectof piperine with narrowband ultraviolet B (NB–UVB) on
vitiligo treatment. A total 63 patients with facial vitiligo were randomly divided
into 2 groups in this double–blind clinical trial and treated with piperine and
placebo. Besides, both groups received NB–UVB phototherapy every other day
for 3 months. Based on the clinical results, the combination therapy with
NB–UVB/topical piperine was found more influence on vitiligo as compared to
NB–UVB alone. To conclude the application of NB–UVB and topical piperine has
a notable effect on vitiligo.
79
After 6 months of treatment, 40% of the patients
were symptom-free. Pungent spices have long been implicated as a cause of
gastric mucosal injury; while their long-term effect onthe gastric mucosa remains
less known. In a single-dose study, the results of black pepper on the gastric
mucosa were assessed using double-blind intragastric administration ofthe spice
(1.5 g) to healthy human volunteers, with aspirin (655 mg) as a positive control.
7.9.3 Other Conditions
Treatment with a combination of piperine and curcuminoids w as done for
4 weeks to improve the quality of life (HRQoL). On measuring the oxidative
Most Modern Approach to the Phytochemical Evaluation 169
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Table 7.7 Clinical trials on the effect of piperine.
Effect of piperine No of patients/study design Trial length Treatment, dose and formulation of piperine Ref.
Phenytoin
m AUC
0–12 h
m C
max
m K
a
K
el
and T
max
unchanged
2 groups of 10 patients A single dose Phase I: Group 1 received 150 mg of
phenytoin twice daily. Group 2 received a
200 mg dose of phenytoin twice daily
Phase II: 20 mg of piperine was administered
along with phenytoin (150 or 200 mg)
67
Propranolol and theophylline
Piperine with propranolol:
m C
max
m AUC
Piperine with theophylline:
m C
max
m T
1/2
el
m AUC
6 healthy male volunteers in a
randomized crossover study
7 days Phase I: Group 1 received a single oral dose of
propranolol (40 mg). Group 2 received a
single oral dose of theophylline (150 mg)
Phase II: Piperine 20 mg daily for 7 days
following administration of drugs. One
week was permitted as a washout period
between the two treatments
69
Curcumin: concomitant
administration of piperine (20 mg)
produced much higher
concentrations from 0.25 to 1h
post drug and an increase in
bioavailability of 2000%
10 healthy male volunteers in
a randomized crossover
study
Four weeks Phase I: 2 g of pure curcumin powder
(4 500 mg) was given with 150 mL of water
Phase II: 2 g of pure curcumin powder
combined with 20 mg of pure piperine
powder (4 500 mg curcuminþ 5mg
piperine each) was given with 150 mL
of water
69
Dexibuprofen: multi-ingredient
formula Lipicur containing
piperine reduced neuropathic pain
by more than 66% in both
conditions.
141 subjects affected by
neuropathic pain in an open
randomized control clinical
study
Eight weeks Group 1: received two tablets/day of Seractil
containing dexibuprofen (400 mg per tablet)
Group 2: received two tablets/day of Seractil
plus two tablets/day of Tiobec 400
containing lipoic acid, 400 mg per tablet
70
170 Chapter 7
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The treatment reduced
dexibuprofen use by about 40%
Group 3: received two tablets/day of Seractil
plus two tablets/day of Lipicur containing
400 mg lipoic acid, 400 mg curcumin
phytosome and 4 mg piperine
Coenzyme Q10: m AUC (30%) 12 healthy adult male subjects 21 days Control group: coenzyme Q10 (30 mg per
capsule) þplacebo, administered together
in a single dose (90 mg per day), 14 day
(90 mg per day) and 21 day
supplementation (120 mg of Q10 per day)
Treatment group: coenzyme Q10 þ5mg
piperine
71
Risorine: 89% of the sputum-
positive patients became sputum
negative during the first 2 months
of treatment
33 patients with pulmonary
tuberculosis in a pilot study
6 months Months 1 and 2: daily oral therapy consisting
of one capsule of Risorine, one tablet of
ethambutol (800 mg) and two tablets of
Pyrazinamide (750 mg each)
Months 3–6: daily oral therapy consisting of
one capsule of Risorine
26
Risorine: treatment resulted with:
higher sputum conversion rate
(93%) vs. control group (84%) at 4
weeks. Higher cure rate at the end
of 24 weeks (92%) vs. control group
(82%). Decreased side effects
(3 patients vs. 9 patients in control
group)
216 patients with tuberculosis
in a randomized, triple-
blind, parallel-group,
multicenter, comparative
clinical phase III study
6 months Patients were randomized into: control
group, receiving a conventional anti-TB
therapy (n ¼117) or Treatment group,
receiving a similar regimen þrisorine
(n ¼99)
74
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