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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5976_Библиотеки_им_академика_М_И_Перельмана
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TABLE 5.1 Published works regarding phyto-complexes of phospholipids, cyclodextrins, and
Chitooligosaccharides.dcont’d
Activity Bioactive Phyto-complex References
Anticancer Didymin b-CD [50]
Curcumin HP-a-CD [51]
Resveratrol HP-b-CD [52]
Genistein b-CD, Ƴ-CD, [53,54]
Betulin GCDG [55]
Vitamin D
3
(cholecalciferol)
b-CD [56]
Curcumin HP- b-CD, M- b -CD [57]
Zerumbone HP-b-CD [58]
Wound healing Eugenol b-cyclodextrin/carboxymethylcellulose
b-CD
[59]
[60]
Catechin b-CD [61]
Embelin b-CD [62]
Ferulic acid HP- b eCD, HP- Ƴ-CD [63]
Antioxidant Chlorogenic acid b-CD [64]
Coumaric acid b-CD [65]
Rosmarinic acid HP- b -CD [66]
Resveratrol b-CD [67]
Epigallocatechin gallate HP- b -CD [68]
Chrysin DM- b -CD [69]
Rutin HP- b -CD [70]
Catechin b-CD [71]
Kaempferol DM- b -CD [72]
Myricetin DM- b -CD [72]
Phenylpropanoids a-CD, b -CD, HP-
b -CD, M-b -CD [73]
Paeonol HP- b -CD [74]
Galangin a-CD, b -CD, Ƴ -CD, HP- b -CD [75,76]
Mangiferin b-CD [77]
Phloretin HP-b-CD, M-b-CD [78]
5. Phyto-complexed systems as a versatile tool for the delivery of plant-based drugs118
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2.1 Molecular complexes
Noncovalent interactions between the substrate and the ligand generate molecular com-
plexes. Small molecule-small molecule complexes, small molecule-macromolecular species,
ion-pairs, dimers, and other self-ass ociated species, and inclusion complexes (ICs) in which
one of the molecules, the “host” forms or possesses a cavity into which it can admit a “guest”
are the examples of complex species included in this category. Although complexes are clas-
sified in a variety of ways, the most common distinctions are made based on the sorts of in-
teractions and species involved, such as metal complexes, molecular complexes, ICs, and ion-
exchange compounds. ICs and molecular complexes between tiny molecules are the most
pharmaceutically valuable structures [91].
2.1.1 Inclusion complexes
ICs are molecular complexes in which a substrate (“guest”) interacts with a cage (“ho st”)
containing one or more ligand molecules. The capacity of “hosts” and “guests” to bind is
mostly due to hydrophobic interactions and the corresponding size and shape differences be-
tween their structures. A single ligand molecule interacts with one or more substrate mole-
cules in CD /PHL, which is one of the most significant molecular complexes.
2.1.2 Cyclodextrin complexes
CDs (Fig. 5.1) are cyclic carbohydrates generated during the breakdown of starch by CD-
glucosyltransferase bacterial enzymes in bacteria (Bacillus macerans) and are employed as
TABLE 5.1 Published works regarding phyto-complexes of phospholipids, cyclodextrins, and
Chitooligosaccharides.dcont’d
Activity Bioactive Phyto-complex References
Antimicrobial Chlorogenic acid b-CD [64]
Chitosan b-CD [79]
Hesperidin HP- b -CD [80]
Gallic acid HP- b-CD, M b -CD [81]
Rutin b -CD [82]
Antilipidemic activity Naringenin b -CD, HP- b -CD [83,84]
Hepatoprotective Angelica sinensis HP-b-CD [85]
Chitooligosaccharide complex
Antioxidant and antibacterial Rutin Chitooligosaccharide [86]
Naringin Chitooligosaccharide [87]
Hesperidin Chitooligosaccharide [88]
Antioxidant Gallic acid Chitooligosaccharide [89]
Antiallergic Gallic acid Chitooligosaccharide [90]
2. Complexation 119
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potential complexing agents to build ICs with poorly water-soluble drugs. These amphiphilic
(cyclic oligosaccharides) molecules are made up of (a-1,4) linked-
D-glucopyranose units with
a lipophilic core cavity and a hydrophilic outer surface.
CDs can form ICs with compounds like phytochemicals, which have a low aqueous solu-
bility. CDs also protect bioactive compounds from various environmental stresses such as
temperature, pH, and light, lowering the concentrations of the compound required to achieve
a desired therapeutic effect and extending shelf life. CDs can also slow or speed up the de-
livery of molecules, changing their behavior. Proteins can also substitute excipients such as
organic solvents and solubilizing chemicals, as well as eliminate toxicological or irritating ef-
fects of the active ingredients.
There are various techniques for forming ICs between CDs and bioactive compounds, and
the process used is clearly based on the features of the guest molecule, the available facilities,
and the cost involved. The “ guest” is included in the CD at the supramolecular level, and so
enthalpy-rich water molecules from the central cavity are replaced by the lipophilic “guest”
or moiety, with no covalent connections broken or established between the IC components
[92]. Th e IC is maintained by hydrophobic forces and van der Waals interactions, as well
as additional factors such ring strain release, changes in the solvent surface, tensions, and
hydrogen bonds, all of which make the IC complex more energetically stable. The IC creation
process is based on a three-dimensional fit between the CD and the “guest” molecule, as well
as specific local interactions between the CD’s surface groups and the guest molecule [72].
Chemical modification of the natives’ hyd roxyl has enhanced their physicochemical qual -
ities and, as a result, the inclusion capacity of their CD in recent years. Each CD’s glucopyr-
anose unit has three reactive hydroxyl groups, each with a varied ratio of reactivity and
function; in the case of b-CD, chemical or enzymatic reactions can modify 21 hydroxyl groups
(Szejtli, 2004). The b-CD derivatives are usually classified according to how they interact with
water molecules, such as hydrophilic, hydrophobic, or ionizable derivatives. The first group
(hydrophilic) has higher water solubility and is ideal for IC formation with poorly water-
soluble “guest” molecules. Hydrophilic CD derivatives include the DM-CD, TMdCD,
hydroxyl alkylated CDs like HPdCD, and branched CDs like Gd CD. Hydrophobic deriva-
tives, such as DEdCD, have the ability to reduce and control the release rate of water-soluble
molecules. Together with polyphenolics, the ionizable CDs, CMdCD, CMEdCD, and SBEd
CD can improve the dissolving rate, the inclusion capacity, and also the lowering of negative
effects of certain molecules [93]. Numbers of researches have culminated into patentable
work for industrial scale up of products. Patents published on complexes of phytochemicals
with CDs are summarized in Table 5.2.
FIGURE 5.1 Conformation and
numbering of the cyclodextrin.
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TABLE 5.2 Patents published on phyto-complexing with cyclodextrins.
Phytoconstituent Inventors Title CD
Publication
date Reference
Silymarin Pipkin, James D., Rajewski,
Roger A., Mainous, Beau
Compositions containing
silymarin and sulfo-alkyl
ether cyclodextrin and
methods of using the same
[US 20200330539 A1]
Sulfonyl
ether b-CD
October 22,
2020
[94]
Silymarin Jianming Chen, Baoan
Gao, Qinqin ZHOU,
Shuiping Zhou, Nan CAI,
Yuansheng Zhang, Chan
Wu, Nong YU, Lina Chen
Silybin injection and
preparation method there for
[WO2016110193A1]
SBE-b-CD July 14, 2016 [95]
Silymarin James D. Pipkin, Roger
Rajewski, Beau MAINOUS
Compositions containing
silymarin and sulfoalkylether
cyclodextrin and methods of
using the same
[WO2016149685A1]
SBE-b-CD September
22, 2016
[96]
Dihydromyricetin Xu Wen feng Dihydromyricetin
cyclodextrin inclusion
compound and preparation
method thereof [CN
104666293A]
Ƴ-CD June 3, 2015 [97]
Retina David Wayne Peter, John
Dillon STANEK, CheriaL.
OROZCO, Shyam K.Gupta
Retinal cyclodextrin acetals
and hemiacetals for clarifying
skin complexion
[EP2755664A2]
Ƴ-CD July 23, 2014 [98]
Artemisinin Mark G Hartell, Apurba K
Bhattacharjee, Rickey P
Hicks, John E Vanhamont,
Wilbur K Milhous
Cyclodextrin complexed
artemisinins [WO2003075904
A2]
b-CD September
18, 2013
[99]
Mangiferin Yang Bo, Han Bin, Yang
Xuemin, Liaoxia Li, Zhao
Yulin
Inclusion compound of
mangiferin and alkaline
Cyclodextrin CN103462975A
a-CD,b-CD,
HP- Ƴ-CD,
SBE-b-CD
December
25, 2013
[100]
Curcumin Philippe Neven, Didier
Serteyn, Jacques Delarge,
Eva Scheer, Robert Kiss,
Veronique Mathieu, Didier
Cataldo, Natacha Rocks
Water-soluble curcumin
compositions for use in
anticancer and
antiinflammatory therapy
[US20110257126A1]
HP-
b-CD,HP-Ƴ-
CD
October 20,
2011
[101]
Tiliroside Corinna Wirth, Ralf
Rosskopf, Herwig
Buchholz
Flavonoid complexes with
cyclodextrins [US7960430B2]
Ƴ -CD,HP-
Ƴ -CD
June 14,
2011
[102]
Dihydroartemisinin Pan Mei, Zheng Qingfour,
Huang Shu-hua
Dihydroartemisinin in beta-
cyclodextrin inclusion
compound, preparation
method thereof, and
antimalarial drug with same
[CN101954090A]
b-CD January 26,
2011
[103]
(Continued)
2. Complexation 121
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2.1.3 Phospholipid complexes
Complexations with PLs have been reported to improve both absorption and penetration
of the active ingredients [34], in comparison to other approaches for changing solubility. The
main molecular building element of cell membranes is lipids, often known as lecithin or phos-
phatidylcholine (PHC). PHLs are natural carriers with medicinal properties of their own.
Choline is required for regular liver function and acts as a hepatoprotective, according to clin-
ical research. Any medication with an active hydrogen atom (eCOOH, eOH, eNH
2
, etc.) can
be esterified to the lipid, with or without the addition of a spacer chain. A hydrogen atom
with an extra electron in its outer shell, which gives it a negative charge, is known as active
hydrogen. This extra electron allows other molecules to react with it. Drugs containing the
carboxylic (eCOOH) group can be esterified without the use of a spacer chain. If the eCOOH
group is absent (but if other active hydrogen atom such as eOH oreNH
2
is present), ester-
ification can be accomplished using a spacer group. The PHL complexation is not influenced
by geometrical variables, unlike CD complexation (size of drugs and its chain length and mo -
lecular weight). Chemical variables are crucial in deciding which types of guest molecules can
interact with PHLs to create ICs. Studies have successfully generated lipid complexation of
proteins like insulin and salmon calcitonin (drugs with a high molecular weight and large
size or chain length) and have found that it improves their biological activity [108]. Chemical
structures of some PHLs are shown in Fig. 5.2.
TABLE 5.2 Patents published on phyto-complexing with cyclodextrins.dcont’d
Phytoconstituent Inventors Title CD
Publication
date Reference
Resveratrol Andre Arigony Souto Resveratrol complex and
process
For the preparation [US
20100204179A1]
b-CD April 12,
2010
[104]
Naringenin Yaakov Nahmias, Martin
L.Yarmush, Raymond T.
Chung
Naringenin complexes and
methods of use thereof [WO
2010042633A2]
b-CD,M- b
-CD,HP- b
-CD
August 15,
2010
[105]
Chitosan Ma Jose Alonso, Fernandez
Marcos, Garcia Futes,
Francesca Maestrelli,
PaolaMura
Nanoparticles Comprising
chitosan and cyclodextrin
[US20080220030A1]
HP-
a-CD,HP-
b-CD,SBE-
b-CD
September
11, 2008
[106]
Z-Ligustilide Qian Zhong ming Wang
ChengYuan, Dujun Rong
Ligustilide cyclodextrin or its
derivatives clathrate, its
preparation method and
pharmaceutical formulation
[CN1732923A]
HP- b -CD February 15,
2006
[107]
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2.1.4 Chitooligosaccharide complex
Chitooligomers, chitosan oligomers, and CHGS (CHGS) (Fig. 5.3) are chitosans with de-
grees of polymerization less than 20 and an average molecular weight less than 3900 Da.
CHGS are produced by depolymerizing chi tin or chitosan using acid hydrolysis, physical
hydrolysis, or enzymatic degradation. Many researchers are interested in using CHGS and its
derivatives for numerous biomedical applications because of their inc reased solubility, good
moisture absorption capacity, good biocompatibility, and low viscosity. Due to its sensitivity
to autooxidation, CHGS should be stored in inert circumstances and at temperatures below
20
C for long-term storage. When antioxidants lik e vitamin C or salts like sodium chloride
are stored alongside CHGS, the shelf life of CHGS is significantly extended [109].
3. Methods for the preparation of phyto-complexes
3.1 Solvent evaporation technique
This approach involves dissolving PHLs/CD and the phytochemical (in 1:1 or 1:2 M ratios
depending on the geometrical fitness of the drug molecule) in a common organic solvent (e.g.,
FIGURE 5.2 Chemical structure of some phospholipids.
3. Methods for the preparation of phyto-complexes 123
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dichloromethane, tetrahydrofuran, methanol, etc.) and then vacuum evaporating the solvent.
If the medicine is in the form of a salt, it must be converted to an acid or basic before being
added to the common solvent. Dry residues or solid powder are collected and put in vacuum
desiccators to obtain the complex [110].
3.2 Physical blending method
Mechanical trituration is used to completely combine the medication and CD (in mortar
for the laboratory scale). The resulting mass is filtered via a sieve (according to the desired
particle size). In industries, the physical mixture is made by combining the medicine with
CDs in a quick mass granulator for a long time [111].
FIGURE 5.3 Structure of (A) chitin; (B) chitosan; (C) chitooligosaccharide (n 9).
5. Phyto-complexed systems as a versatile tool for the delivery of plant-based drugs124
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3.3 Kneading method
To make the paste, the CDs are impregnated with a little quantity of water or a hydroal-
coholic solution. After that, the medicine is mixed into the mixture and kneaded for a set
period of time. The kneaded mixture is next dried and sieved according to the specifications.
In the laboratory, kneading can be done with a mortar and pestle. Kneading may be done on
a huge scale with the help of extruders and other devices [112].
3.4 Coprecipitation technique
In this technique, the medication is introduced to a CD solution and stirred (on a magnetic
stirrer) in a controlled manner. Vacuum filtration was used to separate the generated precip-
itate, which is then dried at room temperature. Through a sudden shift in temperature and
the addition of organic solvent, this approach leaves a drug-CD solution in a very close state
to saturation. However, this approach is not widely employed in industry because of the low
yield, the risk of utilizing organic solvents, and the lengthy preparation time [113].
3.5 Neutralization precipitation method
This process involves dissolving the medication in an alkaline solution, such as sodium/
ammonium hydroxide, and then mixing it with an aqueous solution of CDs to produce a
transparent solution. This clear solution is neutralized with hydrochloric acid solution under
agitation until it reaches the corresponding point. This causes the complex to precipitate,
which is then filtered and dried [114].
3.6 Microwave irradiation method
Drug and CDs are taken in definite molar ratio, dissolved in a mixture of water and
organic solvent (in a specific proportion), kept in a microwave oven for about 1e2 min at
60
C. After this reaction to the residual, uncomplexed free drug and CDs are removed by
adding an adequate amount of solvent mixture to the reaction mixture. The complex is ob-
tained as the precipitate, which is filtered and dried [115].
3.7 Milling/cogrinding method
Using mechanical equipment, a solid binary inclusion compound may be made by grinding
and milling the medicine and CDs. The drug and CDs are well combined, and then the phys-
ical combination is placed in an oscillation mill and processed for the equal period of time.
Alternatively, the drug-CD binary system can be prepared by using the ball milling procedure.
The ball mill, which contains balls of various sizes, is run at a set speed for a certain period of
time before being unloaded and sieved through a 60-mesh sieve. This method is preferable to
other ways in terms of cost and environmental impact since; unlike previous procedures, it
does not involve the use of harmful organic solvents. This method differs from the physical
mixture method where simple blending is sufficient and in cogrinding, extensive combined
attrition and impact effect on powder blend is required [116].
3. Methods for the preparation of phyto-complexes 125
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3.8 Atomization/spray-drying method
In the pharmaceutical industry, spray drying is a popular and commonly used process for
creating a dry powder from a liquid phase. It’s also employed as a preservation technique, as
the lack of water improves storage stability. The mixture is atomized in this procedure, and
the resulting spray is dried with tangentially incoming hot air, resulting in a spray-dried CD
complex. The approach produces complexes with a high efficiency. Furthermore, the product
created using this process produces porous particles of a more consistent size and shape,
which increases the solubility rate of complex drugs [111].
3.9 Lyophilization/freeze-drying method
Lyophilization/freeze-drying is a process that includes molecular mixing of drug and car-
rier in a common solvent as an alternative to solvent evaporation. This approach is utilized to
create amorphous powder with a high degree of drug-PHL or CD interaction. This procedure
involves dissolving the medication plus PHLs or CDs in a small amount of organic solvent/
(s) (such as dimethyl sulfoxide and/or glacial acetic acid) with moderate agitation until a
clear mixture forms. The resulting homogenous solution is then freeze dried under vacuum
for an overnight period at a condenser temperature of 400
C (10 Pa). The resulting complex
is nitrogen flushed and kept at 40
C. This approach was used by Shi et al. to create a new
insulin-PHL complex. This approach can successfully convert thermolabile compounds into
complex forms. The drawbacks of this technique include time-consuming operation with a
poor-flowing powdered product [117].
The solvent evaporation approach is not particularly effective in improving lipid complex
dissolution. As a result, the SCF method may be employed to improve pharmacosome disso-
lution and simplify complicated preparation operations. One of the SCF technologies, the su-
percritical antisolvent process (SAS), is emerging as a viable technology for producing
micronic and submicronic particles with controlled size and size distribution. Carbon dioxide
is utilized as an antisolvent for the solute in the SAS process because it has low critical tem-
perature and pressure, nontoxic, nonflammable, affordable, and easy to remove from poly-
meric materials [118].
The medication and CD or PHLs are dissolved in a suitable solvent, and the solution is
then injected into a pressure vessel under supercritical conditions through a nozzle. When
a solution is sprayed into an SCF antisolvent, the antisolvent diffuses quickly into the liquid
solvent, while the carrier liquid solvent counter diffuses into the antisolvent. Because the
expanded SCF solvent has a lower solvent power than the pure solvent, the mixture becomes
supersaturated, causing the solute to precipitate and the solvent to be transported away by
the SCF flow [119]. Li et al. [118] employed two separate SCF methods, gas antisolvent
and solution-enhanced dispersion by SCF, both of which are part of the SAS proces s, to pre-
pare PHL complexes of puerarin.
4. Characterization of complexes
The CDs and PHL complexes are characterized by the following criteria in addition to the
standard techniques of solubility assessment and dissolution studies. The following
5. Phyto-complexed systems as a versatile tool for the delivery of plant-based drugs126
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approaches are used to confirm the development of a complex or to investigate the reciprocal
interaction between the medicines and the PHLs [ 120].
4.1 Differential scanning calorimetry
Differential scanning calorimetry (DSC) is a quick and accurate approach for determining
drug-excipient compatibility, and it offers the most information regarding potential interac-
tions. In DSC, an interaction is concluded when endothermic peak(s) eliminate with appear-
ance of new peak(s). Interactions can also be interpreted on the basis of the form of the peak
and its start, peak temperature/melting point, and relative peak area or enthalpy change. The
formation of a new endothermic peak, the removal of individual endothermic peaks of
PHLs/CDs, and the reduction in enthalpy are all regarded to be signs of complexation [121].
4.2 X-ray powder diffraction
In the solid state, X-ray diffractometry is also a helpful technique for studying complexes.
In comparison to the physical mixing of the host and guest molecules, the complex should
produce a distinct x-ray powder diffraction pattern. If the complex is crystalline, the single
crystal X-ray pattern can be used to deduce the structure of the complex. Reduced inten-
sity/disappearance of crystalline peaks of drug and PLs suggest amorphization of the
drug in the complex. Amorphization is usually larger in the case of the former than latter,
according to a comparative analysis of PL and CD complexes. The CD complexes have
several crystalline peaks, but the PL complex has only one big diffused peak with lower in-
tensity. Chemical interaction between the drug and the PLs, which is not present in other
lipid-based systems like liposomes, might explain the significant change in its X-ray diffrac-
tion in the PHL complex. Several investigations using the PL complexes of insulin, salmon
calcitonin, ba icalein, chrysophanol, and catechin, among others, back up that statement
[122,123].
4.3 Fourier transform infrared spectroscopy
The formation of the complex can be confirmed by the infrared (I)R spectroscopy by
comparing the spectrum of the complex with the spectrum of the individual components
and their physical mixtures, although the application of IR is limited to guests having char-
acteristic absorption bands, such as carbonyl or sulfonyl groups. In most of the cases, the IR
spectrum of the complex shows a broad peak for hydroxyl group (indicating the interaction
at hydroxyl group) in place of the sharp peak (indicating free hydroxyl group) of eOH group
in the drug. The interaction may also be evident in the shifting of C]O stretching band. In
most cases, however, no change due to complex formation can be observed. Bands due to the
included part of the guest molecule do shift or their intensities are altered, but since the mass
of the guest molecule does not exceed 5%e15% of the mass of the complex, these alterations
are usually obscured by the spectrum of the host. Therefore, no useful information can be ob-
tained [124].
4. Characterization of complexes 127
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