Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5368_Библиотеки_им_академика_М_И_Перельмана
.pdf
142 I. F. Uchegbu
https://t.me/med1917
Fig. 7.2 (a) Negative-stained transmission electron micrograph (TEM) of N-cetyl-poly
(ethylenimine) (49% cetylation), cholesterol (4 mg mL
(Wang et al.
cholesterol (4 mg mL
TEM of GCPQ micelles (5 mg mL
N-palmitoyl-poly(propylenimine) dendrimer (DPD5, 10 mg mL
amphiphiles bear an average of five palmitoyl groups per dendrimer molecule (Chooi et al.
(e) negatively stained TEM of an aqueous dispersion of N-cetyl-poly(propylenimine) dendrimer,
cholesterol (5 mg mL
of cylindrical and twisted nanofibers from O-palmitoyl-tyrosyl-dalargin (1 mg mL
(Mazza et al. 2013)
2004), (b) negative-stained TEM of N-cetyl-poly(ethylenimine) (37 mol% cetylation),
-1
: 2 mg mL
-1
, 2.5 mg mL
-1
) vesicles in water (Wang et al. 2004), (c) negatively stained
-1
) in water (Qu et al. 2006), (d) negatively stained TEM of
-1
) discs in water (Qu et al. 2008), (f) negatively stained TEM
-1
: 2 mg mL
-1
) nanoparticles in water
-1
) tubules in water—dendrimer
-1
) in water
2010),
in aqueous media using physical low molecular weight cross-linking agents such as
tripolyphosphate (Shahnaz et al. 2012). Amphiphilic polymer (Fig. 7.1) self-assembly to polymer nanoparticles takes place when the amphiphilic polymer is subjected
to either simple shaking to produce polymeric micelles or probe sonication in the
presence of a drug to produce polymeric nanoparticles (Qu et al. 2006; Lalatsa et al.
2012c; Al-Kulabi et al. 2021).
The amphiphilic polymers have been widely studied and the resulting selfassembly found to be governed by the hydroph obicity of the polymer in the case
of the amphiphilic polyelectrolyte N-cetyl-poly(ethylenimine) (Wang et al. 2004),
with the more hydrophilic polymers forming polymeric micelles, the hydrophobic
polymers forming dense amorphous polymeric particles and the polymers of intermediate hydrophobicity forming polymeric bilayer vesicles (Fig.
micelles arise from N-cetyl-poly(ethylenimine) (Wang et al.
7.2). Polymeric
2004) with a molar
7 Polymeric Nanoparticles 143
https://t.me/med1917
hydrophobic content of less than 45% or a mole% cetyl substitution of less than
8 mole% (Wang et al. 2004). A similar situation has been observed with amphiphilic
block copolymers comprising poly(ethylene glycol) and hydrophobic peptide blocks
[poly(ethylene glycol)-block-pol y(L-amino acids)], in which micelle-forming polymers are formed when 6.5–11.6 mol% of the monomers are hydrophobic (Van
Domeselaar et al.
2003). The self-assembly of poly(Nε-palmitoyl-L-lysine)-graft-
poly(ethylene oxide) amphiphiles into bilayer polymeric vesicles is also governed by
the hydrophobicity of the polymer (i.e. the level of palmit oyl substitution) (Wang
2001b). A vesicle formation index (F ) has been derived for these self-
et al.
assem
blies (Eq.
7.1).
F ¼
H
p
L DP
ð7:1Þ
where H ¼ mol% underivatised po
lymer monomers, L ¼ mole% of hydrophobic
unit derivatised monomers and DP ¼ degree of polymerisation of the polymer
backbone. An F value in excess of 0.168 gives rise to vesicles in the case of poly
(N-ε-palmitoyl-L-lysine)-graft-poly(ethylene oxide) amphiphiles (Wang et al.
2001b), whereas an F in excess of 0.11 gives rise to vesicles in the case of
N-cetyl-poly(ethylenimine) amphiphiles (Wang et al. 2004; Lalatsa et al. 2012c).
F levels below the values given above give rise to dense amorphous polymeric
nanoparticles.
Unlike low molecular weight bilayer vesicle self-assemblies, the size of polymeric vesicles may be set by choosing a polymer of a particular molecular weight as
there is a linear relationship between the square root of the molecular weight and the
resulting vesicle size (Eq. 7.2) for N-palmitoyl-6-O-glycolchitosan amphiphiles
(Wang et al. 2001a).
MW p ¼ 0:78d
where MW ¼ polymer molecular weight, d
þ 107 ð7:2Þ
v
¼ the z-average mean diameter of the
v
resulting polymeric vesicles. There is also a linear relationship between the mol%
polymer hydrophobic substitution (Ct) and the size of both polymeric vesicles (d
Eq. 7.3) and polymer dense amorphous nanoparticles (d
—Eq. 7.4) for the N-cetyl
n
—
v
poly(ethylenimine) polymers (Wang et al. 2004).
d
¼ 1:95 Ct þ 139 ð7:3Þ
v
d
¼ þ ð Þ
2:31 Ct 5:55 7:4
n
Just as the chemistry of the polymer may be used to predict the nature and size of
the resulting polymeric nanoparticles, so also may the drug loading (Qu et al. 2006),
in that more hydrophobic (>10 mole palmitoyl substit ution) and higher molecular
weight (15–20 kDa) GCPQ polymers encapsulate higher levels of the hydroph obic
drug propofol. Additionally, the more hydrophobic N-cetyl-N-monomethyl-N,N-
144 I. F. Uchegbu
https://t.me/med1917
dimethyl-N,N,N-trimethyl-poly(ethylenimine) polymers encapsulate higher levels
of cyclosporine A (Le et al. 2013). In essence, for the delivery of hydrophobic
drugs, it is advisable to select the more hydrophobic and higher molecular weight
polymer variants as these polymers are able to encapsulate higher levels of hydrophobic drug. These more hydrophobic and high molecular weight polymers also
demonstrate some drug delivery advantages.
7.3 Preparation and Characterisation of Polymeric
Nanoparticles
7.3.1 Preparation of Polymeric Nanoparticles
Polymeric nanoparticles exist in a wide range of morphologies (Fig. 7.2). Polymeric
nanoparticles are generally formed from the precipitation of an organic solution of
the polymer in aqueous media. The emulsion-solvent evaporation technique is a
popular method of preparing polymeric nanoparticles from hydrophobic polymers
(Hrkach et al. 2012; Hu et al. 2013) and involves essentially the precipitation of an
organic solvent solution of the polymer in aqueous media. The drug and the polymer
are dissolved in an organic solvent such as dichloromethane and then dispersed in an
aqueous solution containing a hydrophilic surfactant and the emulsion produced by
probe sonication (Hu et al.
combination of probe sonication and high-pressure homogenisation (Kim et al.
2012). The resulting emulsion is then left stirring to evaporate the organic solvent,
with the nanoparticles precipitating out of the oil phase of the oil in water emulsion
and being stabilised from sedimentation by the surfactant in the aqueous phase. In
some cases, an emulsion is not formed and the nanoparticles are precipitated out of a
water-miscible organic phase (e.g. acetone) as the organic solvent is added dropwise
to an aqueous phase (Ensign et al. 2012). In some instances, the drug is added as an
organic solution to an aqueous dispersion of the amphiphilic polymer, and the
organic solvent is subsequently removed by dialysis (Lee et al. 2012).
For amphiphilic polymers, the polymer and solid hydrophobic drug are added to
aqueous media and probe sonicated to produce the drug-loaded polymeric nanoparticle dispersion (Uchegbu et al.
2012b). High-pressure homogenisation (Uchegbu et al. 2021
polymer and drug in aqueous media may also be used to prepare drug-loaded
polymeric nanoparticles. This is the only method of polymer nanoparticle formulation that does not use organic solvents and is ideally suited for transfer to industrial
procedures. Other methods of preparing polyme r nanoparticles include the hydration
of a thin film of the amphiphilic polymer deposited from the evaporation of an
organic solvent solution of the self-assembling polymer (Badr et al.
Water-soluble polymer-based nanoparticles formed by ionic gelation are prepared by
2013) or microfluidisation (Hrkach et al. 2012)or
1998; Cheng et al. 2006; Qu et al. 2006; Lalatsa et al.
) of a dispersion of the
2021, 2022).
a
7 Polymeric Nanoparticles 145
https://t.me/med1917
the addition of a drug and a gelating agent, e.g. tripolyphosphate, to an acid-soluble
polymer such as chitosan (Shahnaz et al. 2012).
Regardless of the method of nanoparticle formulation, unentrapped hydrophilic
drugs are removed by ultracentrifugation (Uchegbu et al.
while unentrapped hydrophobic drug crystals are usually removed by filtration
through 0.45 μM filters (Qu et al.
at all (Siew et al. 2012). For ophthalmic formulations, the sterilisation step may be
combined with the removal of unentrapped drug using filtration through 0.22 μM
filters (Uchegbu et al.
2021).
2006) or if destined for oral delivery not filtered
1998; Shahnaz et al. 2012),
7.3.2 Polymer and Nanoparticle Characterisation
Prior to the preparation of drug-loaded nanoparticles, the polymers themselves are
structurally characterised using nuclear magnetic resonance spectrometry (Wang
et al.
2000), a test for various chemical groups such as the primary amine function
in poly(Nε-palmitoyl-L-lysine)-graft-poly(ethylene oxide) (Wang et al. 2000) may
also carried out. Molecular weight is an important function that has a direct effect on
polymer nanoparticle biological behaviour (Siew et al. 2012; Li et al. 2021) and must
thus be carefully controlled. Polymer molecular weight may be measured using gel
permeation chromatography-multi-angle laser light scattering (GPC-MALLS)
(Wang et al.
TOF) analyses (Chooi et al. 2010). A battery of other chemical tests must precede the
translation of these materials for clinical use and the above list is merely a starting
point.
Amphiphilic polymers self-assemble in aqueous media at a critical concentra-
tion—the critical micellar concentration (CMC) (Alexandridis et al. 1994; Chooi
2013). This self-assembly is normally entropy driven at ambient temperature.
et al.
The water molecules adjacent to the hydrophobic groups in the molecule are at an
entropy deficit and achieve an entropy gain, being free to hydrogen bond in all
geometric dimensions, on polymer aggregation (Chooi et al.
manner to low molecular weight amphiphiles (Tanford 1980). The CMC
(Table 7.1) is important as it is a measure of the stability of the amphiphilic
aggregates and the CMC has an influence on drug loading, with lower CMCs leading
to a higher % w/w drug loading on the nanoparticle (Chooi et al. 2013).
The isothermal calorimetry method is the most sensitive method of determining
an amphiphile’ s CMC and is considered the most accurate as it is chemical probefree (Chooi et al. 2010, 2013; Siew et al. 2012). Once drug-loaded nanoparticles are
formed, they are characterised for particle size, morphology, zeta potential and drug
loading. The particle size distribution is measured using photon correlation spectroscopy and particle zeta potential (Fig. 7.3) measured using electrophoresis
(Uchegbu et al. 2004). Particle size data is reported as the z-average mean diameter
and particle distribution polydispersity (Chooi et al. 2013). Particle morphology is
characterised using electron (Fig. 7.1) or atomic force microscopy. Electron
2001a) or matrix-assisted laser desorption time of flight (MALDI-
2010) in a similar
146 I. F. Uchegbu
https://t.me/med1917
CMC
(isothermal
calorimetry,
μM)
Number of
chitosan
amphiphile arms
Mole %
quaternary
ammonium units
± ±
± ±
± ±
± ±
Mole %
palmitoylation
Table 7.1 The critical micellar concentration of chitosan amphiphiles
Mw/
Mn
Mw
(kDa)
Polymer Polymer
GCPQ24H 12.2 1.197 16.1 1.0 8.3 1.32 N/A 19
GCPQQ24L 11.5 1.447 14.5 2.29 8.1 1.54 N/A 25
GCPQ48H 8.7 1.025 15.5 0.49 11.4 0.64 N/A 20
GCPQ48L 8.2 1.145 9.0 1.27 14.5 4.10 N/A 25
2012)
O
HO
N
O
HO
N
N-palmitoyl, N-dimethyl, N-monomethyl
N-trimethylammonium, 6-O-glycol chitosan—
GCPQ (Siew et al.
33.0 1.093 4.1 7.80 6 0.013
103.3 1.486 2.5 7.8 14 0.009
DAB-
GCPQA30
DAB-
GCPQ70
)
2013
x
OH
OH
O
O
y
N
O
O
3
OH
CH
O
+
N
O
3
O
3
CH
O
z
O
NH
O
HO
O
y
O
O
HO
HO
O
x
2
O
NH
HO
O
w
O
O
HO
HO
O
N-graft-(N,N,N-trimethyl, NN-dimethyl,
N-monomethyl, N-acetyl, N-palmitoyl, 6-O-
glycol chitosan)-diaminobutane poly
(propylenimine) dendrimer (Chooi et al.
CH
x
H
O
y
OH
H
2
O
O
CH
O
OH
N
O
O
O
O
O
OH
+
N
O
OH
3
3
3
CH
CH
CH
OH
2
CH
OH
H
O
O
O
O
O
+
N
O
OH
3
3
O
N
3
CH
CH
OH
CH
O
x
x
OH
O
N
O
O
OH
O
3
y
3
OH
CH
CH
N
+
3
H
O
O
CH
OH
2
CH
O
OH
2
CH
CH
OH
2
NH
NH
N
N
N
2
NH
2
CH
NH
N
N
NH
2
N
NH
2
NH
NH
2
CH
O
OH
OH
2
O
CH
y
O
OH
O
OH
O
O
N
O
HO
O
H
O
O
O
2
NH
N
N
N
2
CH
O
+
N
OH
OH
3
O
3
N
3
O
CH
CH
CH
OH
O
N
+
x
O
O
O
OH
2
OH
y
O
CH
OH
OH
2
O
CH
2
OH
2
NH
CH
NH
2
N
NH
3 CH3
3
N
CH
N
CH
2
NH
NH
N
N
NH
2
NH
2
CH
OH
OH
2
CH
y
O
3
CH
3
3
CH
CH
x
O
N
+
O
H
OH
OH
O
O
N
O
O
O
2
O
O
CH
y
O
H
x
OH
O
2
H
CH
OH
y
3
O
3
CH
O
CH
O
+
N
3
O
x
CH
H
OH
O
O
O
N
O
O
HO
H
O
7 Polymeric Nanoparticles 147
https://t.me/med1917
Fig. 7.3 Particle characterisation—measuring particle size and particle zeta potential
microscopy is an excellent method to use for probing the shape of the particles.
Although it must be stated that the dehydration step of the transmission electron
microscopy technique introduces artefacts such as aggregation. This makes the cryoelectron microscopy or the scanning electron microscopy technique superior for
deducing the three-dimensional structure of the nanoparticles more accurately.
Drug loading is measured by removing unentrapped drug by filtration and
centrifugation or dialysis, as outlined above, extracting the encapsulated drug
(destroying the nanoparticles by the addition of organic solvent) and measuring
the level of encapsulated drug using standard analytical methods such as highperformance liquid chromatography (HPLC) (Qu et al. 2006; Shahnaz et al. 2012).
Indirect methods of analysing drug content include analysing the level of
unentrapped drug and working out the level of drug entrapped by difference
(Sarmento et al. 2007). However for formulations on the clinical development
path, drug content is measured using direct methods such as HPLC (Badr et al.
2021, 2022).
7.4 Application of Polymer Nanoparticles in Pharmacy
and Medicine
Drug-loaded polymer nanoparticles have been employed in pharmacy to achieve a
change in drug biodistribution, as once encapsulated, the drug biodistribution is
governed by the characteristics of the particle, particularly the particle surface
148 I. F. Uchegbu
https://t.me/med1917
chemistry. The polymers most widely used in pharmaceutical formulations are
shown in Fig. 7.1.
Polymeric nanoparticles have been administered by the intravenous, subcutaneous, oral, topical ocular and nasal routes. These are the most common routes of
administration that appear in the literature. Polymeric nanoparticles have been used
to deliver drugs to tumour tissue via the intravenous and subcutaneous routes as well
as deliver drugs to the brain via the nasal and intravenous routes. Polymeric
nanoparticles have also been used to reduce side effects, prolong drug residence
time within ocular tissues and significantly increase the oral bioavailability of
hydrophobic drugs. Examples of these advances are presented in this chapter.
7.4.1 Intravenous
7.4.1.1 Anti-Cancer Drugs
Beneficially altering drug biodistribution such that there is a higher level of drug at
tumour sites, and less drug accumulating in healthy tissue, is one of the ways that
polymer nanoparticles have been exploited. The most successful polymer nanoparticle therapeutic to date is Abraxane. Abraxane was licensed in 2005 for the
treatment of refractory malignant breast cancer. Abraxane is composed of nanocrystalline paclitaxel stabilised by albumin (Fu et al. 2009; Cortes and Saura 2010). The
albumin coating on the nanoparticles has been implicated as being responsible for
the targeting of paclitaxel to metastatic tissue as albumin binds to secreted protein
acidic and rich in cysteine (SPARC) (Cortes and Saura 2010); a protein which
accumulates in the tumour microenvironment and a protein that is associated with
a high metastatic potential in most human cancers (Podhajcer et al.
albumin-stabilised paclitaxel also solves a delivery problem associated with paclitaxel’s poor water solub ility (paclitaxel solubility in water <2 μgmL
was erstwhile formulated with Cremophor EL, a surfactant associated with severe
hypersensitivity reactions in patients (Gelderblom et al.
formulation presents a solution to these anaphylactoid responses to the surfactant
Cremophor EL. These hypersensitivity reactions have led others to seek alternative
paclitaxel formulations; with many such formulations involving the use of polymers
and, as such, Samyang’s Genexol PM was approved in Korea in 2007. Genoxol PM
comprises paclitaxel solubilised in aqueous media within methoxy poly(ethylene
glycol)-block-poly(lactide-co-glycolide) block copolymers (Lee et al. 2018).
Genoxol PM, in combination with cisplatin, was found to be non-inferior in
advanced ovarian cancer patients to a standard formulation of Taxol (Lee et al.
2018) and found to have comparable efficacy, when compared to historical studies
with Abraxane in advanced pancreatic cancer patients; with progression-free survival in this pancreatic cancer study being 8 months (Lee et al. 2023).
Docetaxel, a paclitaxel analogue, has also recently been clinically evaluated in
poly(D,L-lactic acid)-block-methoxypoly(ethylene glycol) block copolymer
2008). The use of
-1
) as paclitaxel
2001). The Abraxane
7 Polymeric Nanoparticles 149
https://t.me/med1917
nanoparticles decorated with a ligand specific for prostate-specific membrane antigen—S,S-2[3-[5-amino-1-carboxy pentyl]-ureido]-pentanedioc acid (ACUPA) and
evaluated in prostate cancer patients (Hrkach et al. 2012 ). This new nanoenabled
docetaxel formulation was found to be superior to docetaxel alone, with respect to
extending the plasma half-life of the drug (Hrkach et al.
Amphiphilic glycol chitosans, in which glycol chitosan is conjugated to palmitoyl
units were first described in 1998 (Uchegbu et al. 1998). GCPQ, a glycol chitosan
amphiphile (Fig. 7.1e) may be used to encapsulate drugs in nanoparticles and these
particles do not accumulate in the liver on intravenous administration (Lalatsa et al.
2012b; Fisusi et al. 2016). As such a GCPQ formulation of lomustine has been found
to be bone marrow sparing as well as showing reduced liver deposition, enabling a
high dose of lomustine to be administered (Fisusi et al. 2016). When applied to an
intracranial tumour model of glioblastoma multiforme, this higher dose resulted in a
significant increase in survival time; increasing survival time by 50% when compared to drug-alone treated controls (Fisusi et al.
administered at the maximum feasible dose. Animal survival time increased from
22 to 33 days when treated with either an ethanolic formulation or a GCPQ
formulation, respectively (Fisusi et al.
observed with GCPQ-cisplatin conjugates (Lerchbammer-Kreith et al. 2023a).
These GCPQ-cisplatin conjugates increase the activity of the drug by 280-fold
in vitro and accumulate in the lung on intravenous administration to healthy animals,
offering the possibility of a method to target lung tumours. Glycol chitosan-cispl atin
conjugates also increase drug activity by 70-fold in vitro and accumulate in the lung
on intravenous administration (Lerchbammer-Kreith et al.
that these polymer-cisplatin in vivo studies were carried out in healthy mouse
models, and it is not yet clear if the conjugates would target lung tumours as well
as target healthy lung tis sue.
Glycol chitosan amphiphiles prepared by derivatising glycol chitosan with
cholanic acid have been found to localise within tumour tissue (Na et al. 2012),
possibly as a result of the enhanced permeation and retention effect first described by
Maeda (1992), in which particulate drugs escape the leaky tumour vasculature to
become entrapped in the tumour tissue. These glycol chitosan nanoparticles, when
loaded with camptothecin were superior in achieving tumouri cidal activity when
compared to the drug in solution (Min et al. 2008).
Chitosan amphiphile nanoparticles have also been targeted to tumour tissue using
octreotide in the form of a stearylamine-poly(ethylene glycol)-octreotide conjugate
used to target N-octyl-6-O-carboxymethyl chitosan nanoparticles to the matostatin
receptor on tumour cells (Zou et al. 2013). The use of the octreotide-targeting ligands
improved tumouricidal activity in mice bearing the MCF-7 tumour cells.
An additional polymer that has been exploited for tumour targe ting is hyaluronic
acid. Hyaluronic acid nanoparticles have been prepar ed from dodecyl hyaluronate
and found to encapsulate drugs and show selectivity for the CD44 receptor. Amphiphilic hyaluronic acid prepared by the reaction of hyaluronic acid with amino 5-beta
cholinic acid and amino poly(ethylene glycol) also forms particles that are able to
deliver the photosensitiser-chlorin e6 to tumour tissue bearing the CD44 receptor,
2016). Tissue targeting has also been
2012).
2016). Drug-alone controls were
2023b). It must be stated
150 I. F. Uchegbu
https://t.me/med1917
generate singlet oxygen within HT-29 tumour tissue, on near infra-red irradiation
and cause tumour regression (Yoon et al. 2012). The nanoparticles have also been
used to image tumour tissue.
Low molecular weight drugs have been employed as constituents of polyionic
complexes (PICs), in which a nanoparticle is formed by electrostatic attractive
forces. An example of this is the formulation of cis-dichlorodiamineplatinum II
(CDDP) with poly(ethylene oxide)-block-poly(α,β-aspartic acid) to yield 20 nm
PICs, which slowly release CDDP over time (Nishiyama et al.
significantly enhance tumour exposure to CDDP (Nishiyama et al.
et al. 2005).
Polymeric micelle cancer drug formulations such as poly(ethylene oxide)-blockpoly(benzyl-L-aspartate) doxorubicin (Kataoka et al. 2000) or poly(ethylene oxide)block-poly(cetyl, benzyl-L-aspartate) formulations (Yokoyama et al. 1998) increase
the blood residence time of the encapsulated drug (Kataoka et al.
micelles to accumulate in the tumour presumably by exploiting the enhanced
permeation and retention effect (Maeda et al.
tumouricidal activity is observed with these polymeric micelles (Yokoyama et al.
1998; Kataoka et al. 2000). A comprehensive review of cancer nanomedicines
appears in other parts of this volume.
7.4.1.2 Anti-Infectives
2000). Ultimately improved
1999, 2003) and
1999; Uchino
2000), enabling the
Specific drug delivery applications of polymeric micelles include the encapsulation
of hydrophobic anti-infectives such as amphotericin B (Adams et al. 2003).
Amphotericin B-loaded poly(ethylene oxide)-block-poly(benzyl-L-aspartate)
micelles decrease the haemolytic activity of amphotericin B and provide a means
by which the aqueous incorporation of the hydrophobic amphotericin B may be
increased by two orders of magnitude (Yu et al.
aspartic acid-based poly(ethylene oxide) block copolymer poly(ethylene oxide)block-poly[N-(6-hexylstearate)-L-aspartamide] when loaded with amphotericin B
combined a reduction in amphotericin B-mediated haemolytic activity with an
equivalent level of efficacy with fungizone in a murine neutropenic model of
disseminated candidiasis (Adams et al.
oxide)-block-poly[N-(6-hexylstearate)-L-aspartamide] amphiphiles (50–70 mole%
stearic acid substitution) were more efficient modulators of haemolytic activity, as
amphiphile hydrophobicity promoted drug retention within the polymeric particles
(Lavasanifar et al. 2002).
2003). The more hydrophobic poly(ethylene
1998). Additionally, a derivatised
7.4.2 Oral
Polymer nanoparticles have been used experimentally to enable the deli very of gut
labile materials and drugs with poor aqueous solubility. Most of these studies are
7 Polymeric Nanoparticles 151
https://t.me/med1917
6000
noitartnecnocAeniropsolcycdoolB
5000
4000
)
-1
3000
(ng mL
2000
1000
0
048121620
Fig. 7.4 GCPQ oral delivery of cyclosporine A: AUC (ng mL
dispersion), 18,997 (neoral), 30,703 (GCPQ nanoparticles). Cmax (ng mL
A dispersion), 1903 (neoral), 3465 (GCPQ nanoparticles) (Siew et al. 2012)
*
*
Time (hours)
Cyclosporine A
dispersion
Neoral
GCPQ nanoparticles
-1
h) ¼ 9065 (cyclosporine A
-1
) ¼ 721 (cyclosporine
24
experimental in nature and have not yet been commercialised. The delivery of
hydrophobic drug compounds is becoming a real problem for the pharmaceutical
industry (Kirkpatrick
2003) as the pharmacophore trends towards a higher Log P and
molecular weight phenotype. There are a number of ways that oral absorption may
be enhanced (Strickley 2004) and various solubilising excipients abound, most of
them micelle-forming and macromolecular in nature. These micelle-forming mac-
200
Le et al.
6
romolecules include the poly(ethylenimine) amphiphiles (Cheng et al.
2013)
d the glycol chitosan-based amphiphiles (Siew et al.
an
2012). Such amphi-
;
philes resul t in polymer nanoparticles once they have been loaded with hydrophobic
drugs such as Cyclosporine A (Fig.
7.4) (Siew et al. 2012). Drug-loaded
nanoparticles arising from such polymeric amphiphiles increase drug bioavailability
by at least threefold when compared to the drug alone and increase the Cmax by as
). T
much as sixfold (Siew et al. 2012
dissolut
ion
the gastrointestinal tract due to the high surface area of the
within
nanoparticle dispersion and the amorphous nature of the drug (Siew et al.
he GCPQ nanoparticles act by increasing
2012).
GCPQ nanoparticles also increase drug absorption by prolonging residence time at
the functional aspects of the gastrointestinal tract due to mucoadhesion (Siew et al.
2012) and promote drug absorption by the particles being taken up by the
enterocytes (Garrett et al.
2012; Lalatsa et al. 2012a) (Fig. 7.5). Furthe
rmore, the
more hydrophobic the nanoparticle-forming polymer in the case of N-cetyl-poly
(ethylenimine)-based nanoparticles, the higher the level of hydrophobic drug loading and the more the drug is absorbed (Le et al.
2013).
Paclitaxel was loaded into N-((2-hydroxy-3-trimethylammonium) propyl)
chitosan nanoparticles made via an oil in water in oil emulsification, followed by
glutaraldehyde cross-linking and these nanoparticles improved survival in non-small
cell lung tumour bearing mice and were superior to Taxol with respect to their
Соседние файлы в папке Библиотека им академика М.И. Перельмана