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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5368_Библиотеки_им_академика_М_И_Перельмана
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322 L. Dymock and C. Hoskins
https://t.me/med1917
Examples of
drugs which
have been
Method to increase the drug
Low excipient:
drug ratio
attempted Key advantages Limitations
solubility
l
h
specific
Often drug size/shape
Effective
solubilising agents
Ease of synthesis Non-universal
Clausenidin
2021)
Trimethoprim
(Arti et al.
hydrophobic interior core of
macromolecular structure in a
Hydrophobic drugs are entrapped
as an inclusion complex inside
residual organic solvent
Ease of tailoring Organic synthesis can leave
et al.
(Al-Abboodi
et al. 2021)
Atazanivir
(Nolay
host–guest manner
specific
Often drug size/shape
Effective
solubilising agents
Stable High drug: excipient ratios
2021)
(Hamada et al.
Glabrescione B
2006)
2020)
et al.
Paclitaxel
Ease of synthesis Non-universal
(Buonsenso
et al. 2021)
(Hoskins et al.
hydrophobic interior core of
macromolecular structure in a
as an inclusion complex inside
host–guest manner
2016)
Nano-
Table 13.2 (continued)
systems Examples of the composition
Poly(allylamine) modified wit
cholesteryl, dansyl or palmitoy
Chitosan modified with a range
groups
of hydrophobic pendant groups
Cyclodextrins α-Cyclodextrin (alfadex)
2-
β-Cyclodextrin βCD (betadex)
Sulfobutylether β-cyclodextrin
sodium (Na + SBEβCD
betadex sulfobutyl ether
Hydroxypropyl-β-cyclodextrin
(hydroxypropylbetadex)
sodium)
γ-Cyclodextrin (gammadex) Ramipril (Roy
Calix[4]resorcinarene Propofol
Calixarenes Calix[n]arene Hydrophobic drugs are entrapped
13 Nanotechnology and Hydrophobic Drug Solubilisation 323
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(continued)
Ease of tailoring Organic synthesis can leave
residual organic solvent
(Yang and de
Villiers )2004
Stable High drug: excipient ratios
Doxorubicin
(Lin et al. 2019)
Naproxen
(Barbera et al.
Low physical stability
Increase drug
solubility
Clobetazone
(Pan et al.
2015)
sized spherical particles
Additional stabilisers
Increase dissolu-
Ciprofloxacin
2014)
required such as surfactants,
liposomes, polymeric self-
assemblies
tion rate
Decreased
absorption varia-
2017)
(Pu et al.
Lonidamine
(Chen et al.
in fed/fasted
tion
state
Methotrexate
(Chen et al.
2018)
Fluconazole
2012)
(Ela et al.
2021)
Biocompatible Low drug loading efficiency
2022)
Curcumin (Rad
et al.
in the vesicular membrane
High degree of instability
Can carry both
hydrophobic and
hydrophilic
(Khan et al.
2019)
Time consuming
payloads
No specific stor-
age requirements
(Khan et al.
2020)
Pyrogalloarene Nifedipine
Nano crystals Drug crystals only Crystal volume milled into nano-
Stearyl alcohol Doxorubicin
Niosomes Cetyl alcohol Hydrophobic drugs are entrapped
Oleyl alcohol Rifampicin
324 L. Dymock and C. Hoskins
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Costly
Offer control over
release of drug
)2019
2020)
Bromocriptine
Examples of
drugs which
have been
attempted Key advantages Limitations
(Ghafelehbashi
et al.
(Sita et al.
Method to increase the drug
solubility
Nano-
Table 13.2 (continued)
systems Examples of the composition
Brij Cephalexin
Decyl glucoside
Octyl glucoside
Triton X-100
Nonoxynol-9
Glyceryl laurate
Polysorbates
Spans
Poloxamers
13 Nanotechnology and Hydrophobic Drug Solubilisation 325
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degradation or clearance, which in itself increases the probability of the drug
reaching its target site. Garg et al. formulated the insoluble folate antimetabolite
methotrexate inside the core of a fucosylated solid–lipid nanoparticle to overcome
the drug off-target effects which include bone marrow suppression and drug-induced
hepatic fibrosis (Garg et al.
Gelucire
®
50/13 lipid mix with stearylamine, phospholipid-90 NG and tween-80.
). The lipid nanoparticles wer e composed of a
2016
The particles formed were capable of 87.8% drug encapsulation resulting in particles
of 163 nm. The novel formulation was capable of enhancing drug half-life from 4.4 h
for the free drug to 10.81 h with the lipid particles. This increase in half-life lead to
greater efficacy in vivo in breast cancer models, where after a 4-week drug regime,
umou
only 30% of t
a
twofold decrease from that of the free drug, with 100% survival after 75 days
was
(Fig.
13.3) (Garg et al. 2016).
r burden was observed with the nanoparticle formulation which
As with all oral dosage forms, there is a more complex route for the nano-carrier
to traverse in order to get to their site of need. In drug solubilisation, the rate-limiting
step in the dosage form is the inability for the active ingredient to first dissolve in the
aqueous GI fluid, which later hinders the ability of the drug to cross the biological
epithelium in the stomach. However, once encapsulated inside a nanoparticle this
dissolution step is overcom e. The next major challenge in oral delivery is the large
shift in pH and presence of enzymes in the transit from mouth to intestine, often
these conditions make it extremely challenging for the nano-carriers to survive.
Studies have shown after encapsulation inside nano-carriers that enhanced blood
plasma levels of drug can be detected, meaning the drug has indeed made it into
systemic circulation, but understanding the fate of the nano-carrier itself can be
problematic, as the lipid and polymer-based systems without molecular or fluorescence tags are difficult to track. The question remains as to whether the nano-carrier
itself transports the drug to the small intestine, where enhanced permeation of the
free drug can occur, or whether the nano-carrier itself crosses the epithelial barrier
itself with the drug inside to produce this effect. Anuar et al. recently reported the
development of a nano-emulsion for enhanced solubilisation of poorly soluble
ibuprofen for oral administration (Anuar et al.
2020). The nano-emulsion was
composed of olive oil, sucrose ester L-1695 and glycerol, forming oily droplets of
mean diameter 232 nm with 3% ibuprofen. When the formulation was administered
orally to male Sprague Dawley rats, a 2.2-fold increase in drug absorption into the
bloodstream was experienced, compared with a standard drug in oil system. This
enhanced bioavailability was down to the ability of the drug to be solubilised along
with the nano-carrier’s ability to enhance the permeation across the biological
membranes in the GI tract (Anuar et al. 2020).
Despite oral and intravenous routes being the most popular routes of administration, other drug solubilisation nano-carriers have been employed for other routes
including via inhalation, topical and ocular administration. Griseofulvin is an antifungal agent which is currently administered orally; however, the intra-patient
variability in therapeutic outcome has resulted in investigations into topical local
delivery with the aid of nanotechnology (Ahmad et al.
2019). Tan et al. formulated
hydrophobic griseofulvin into lipid nanoparticles composed of palmitic acid
326 L. Dymock and C. Hoskins
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Fig. 13.3 In vivo therapeutic efficacy of methotrexate-loaded SLNs (SLNs-MTX), fucosylated
methotrexate-loaded SLNs (Fu-SLNs-MTX) compared with a market injection (MTX-Inj) in
DMBA-induced breast cancer models. I. % age tumour burden calculated after 4-weeks drug
regime n = 6 ± SD. II. % survival after drug regime (Garg et al. 2016)
triglycerides and Tween 80 (Tan et al. 2016). The particles contained 0.77%
griseofulvin, with an average diameter of 180 nm. In vitro skin penetration and
retention studies on porcine skin showed that the nanoparticle formulation resulted
in greater skin permeation (penetration flux = 0.067 ± 0.003 mg/cm
fourfold increase in retention on the epidermis, which showed that the nanoformulation was effectively transported across the skin barrier to the site of need,
highlighting the potential of
2
/h), as well as a
nanotechnologies in this area (Tan et al. 2016).
13 Nanotechnology and Hydrophobic Drug Solubilisation 327
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Fig. 13.4 Etoposide concentration in plasma and vitreous after intra-vitreal injection of etoposide
solution (ETO) and etoposide-loaded SLNs (ETO-SLNs) in male Wistar rats, n = 3 ± SD (Ahmad
et al. 2019)
Ahmad et al. reported the encapsulation of etoposide into solid–lipid
nanoparticles composed of Gelucire 44/14 and Compritol ATO 888 (3:1) for ocular
delivery (Ahmad et al. 2019). The particles formed were 239 nm in diameter and
capable of 80.96% encapsulation of etoposide. The half-life of etoposide after intravitreal administration in male Wistar rats was increased from 7.75 h with free drug
compared with 413.95 h of the nanoparticle formulation. The authors conclude that
this was due to the formulation acting as a depot with controlled and sustained drug
release being achieved over longer time periods, with blood plasma concentration of
etoposide being significantly lower with the nanosystem compared to the free drug
(Fig. 13.4). Given the highly potent nature of etoposide as an anticancer therapeutic,
the authors concluded that the nano-formulation was less likely to cause any adverse
side effects compared with those currently experienced with etoposide alone
(Ahmad et al.
2019).
Aside from the delivery route, biological barriers are also important factors which
need to be considered in formulation design. One of the most difficult areas for drugs
to access is within the brain, with the blood brain barrier posing a major barrier to
access. Nanotechnology is also making headway within this arena. Lui et al. developed polymeric-based systems based on cholesterol, poly(ethylene glycol) and
transcriptional activator TAT peptides for targeted delivery of hydrophobic ciprofloxacin across the blood brain barrier (Liu et al. 2008). The aggregates formed were
180 nm in diameter with 7.2% drug encapsulation. The novel formulation was
shown to sustain the antibiotic release rate over 6 h. The formulations were injected
into the hippocampus sections of rats with a fluorescent dye which was observed
only 2 h after intravenous administration. The findings from this study have huge
implications showing that nano-based systems may serve as viable vehicles to
promote permeation across the blood brain barrier for future therapeutics (Liu
et al. 2008).
328 L. Dymock and C. Hoskins
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13.4 Drug Release from Nano-carriers
Drug release mechanisms from the nano-carriers differs depending on the type of
carrier being employed. Generally, drugs diffuse out of the nano-carrier of choice
over sustained time periods, and this release can be tailored according to the
molecular makeup of the carrier itself. This ability to control the release rate of
drugs is highly important in pharmaceutics, as this may offer a single long-term
therapeutic dose route for drugs with short half-lives which may currently be
administered over short and frequent time periods.
Drug release is generally conducted using dialysis assays, whereby formulations
are inserted inside a dialysis membrane which is submerged in a large volume of
water or physiological media which is sampled over set time periods. The large
volume of media mimics ‘sink conditions’ which is the large dilution factor that
would be faced by the nano-carriers when administered in vivo. The drug appearance in the media is normally monitored using techniques such as UV-Vis spectroscopy, High Performance Liquid Chromatography or Fluorescence Spectroscopy.
Here, a release profile is developed which can not only indicate the release rate
kinetics of the drug, but also the stability once placed into large dilution conditions.
These are important factors which may result in nano-carrier optimisation should the
drug release or dump from the vehicle into the surrounding media too rapidly.
Diazepam is a practically insoluble active ingredient which can be administered
via numerous routes. However, its potency and scope for abuse leads it to require
controlled formulation which would reduce dosages required upon patient administration. Bohrey et al. reported the development of a poly(lactic-co-glycolic acid)
(PLGA) delivery system to act as a drug solubilising agent which could also control
the release rate of diazepam (Bohrey et al. 2016). The nanoparticles formed were
230 nm in diameter with a drug encapsulation efficiency of 66%. The authors found
that by mani pulating the preparation variables, the drug release profile from the
nanoparticles could be manipulated, an important consideration in formulation
design (Bohrey et al. 2016).
13.5 Cellular Internalisation
Cellular internalisation and trafficking of nano-carriers is widely regarded as occurring via the endocytotic pathways; however, this is still poorly understood for most
nano-systems. Endocytosis covers a range of different pathways which are outlined
in Fig. 13.5.
Once encapsulated inside nano-carriers, drug uptake studies into cell lines in
culture consistently show that greater quantities of drug enter the cells, and at a much
more rapid rate than the free drug (Nelemans and Gurevich
to the endocytotic pathway, whereby the cell rearranges its membrane structure to
engulf the nano-carriers and to bring them into the cell in a lysosome structure.
2020). This is likely due
13 Nanotechnology and Hydrophobic Drug Solubilisation 329
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Fig. 13.5 Schematic overview of nanoparticle uptake pathways via endocytosis. Multiple different
pathways exist for cellular entry of nanoparticles via endocytosis mechanism: (a) clatharindependent, (b) caveolin-dependent, (c) clatharin and caveolin independent, (d) phagocytosis and
(e) micropinocytosis pathways (Donahue et al.
2019)
Lysosomal escape of the nano-carrie rs is also not well understood, and there is
debate as to whether the nano-carriers themselves undergo lysosomal escape, or
whether the drug releases from the carrier before further entry into the cellular
cytoplasm. Aside from the endocytotic pathways, the nano-carriers may also enter
cells via direct translocation or via paracellular transport mechanisms.
Cellular trafficking of nano-carriers across the cell membrane may be monitored
in culture by adding fluorescent tags onto the nanoparticle surface. Since nanotechnologies are easily tailorable, this is not difficult and usually achieved via very
simple chemistry. However, it is important to note that after addition of a tag, the
properties of the nano-carrier itself may be slightly modified compared with the
non-tagged version. This includes alteration to the surface charge, increased cytotoxicity and the likelihood for protein corona formation on the nano-carrier surface.
Although there are limitations to microscopy studies, drug nano-carrier
internalisation images can give real insight into the location of the drug vs. the
carrier once inside the cell and highlight areas of accumulation. Lin et al. investigated the cellular trafficking of different sizes of PLGA nanoparticles using fluorescent 3,3 0-dioctadecyloxacarbocyanine perchlorate (DIL) dyes in dendritic cells (Lin
2021). In vitro cellular tracking showed that uptake into the cells was affected
et al.
330 L. Dymock and C. Hoskins
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by nanoparticle size. Nanoparticles of 50 nm and 226 nm were compared, and
interestingly the dendritic cells preferred to internalise the larger nanoparticles (Lin
et al. 2021). Although in this study, nanoparticle size directly impacted uptake, this
may change depending on the cell line, nanoparticle type, internalisation route and
presence of targeting moieties. As such, generalisations cannot be drawn, and each
system must be fully evaluated in its own right and in the context of its clinical use to
determine its own unique trafficking fate.
13.6 Biological Testing and Regulation
Biological testing of new drug formulations is of paramount importance. It is
important to understand how the formulation may impact the drug’s behaviour and
the impact of the formulation itself. This includes cytotoxicity testing of the nanocarrier itself alone and in combination with the drug. This is a very important
parameter to understand whether the carrier itself possesses any toxicity which is
undesirable in an excipient, or whether there is an additive or synergistic effect on
toxicity when the drug is in a formulation compared to the free drug alone. This type
of study is generally carried out using the MTT assay, Alamar Blue Assay or Trypan
Blue Exclusion Assay in vitro in appropriate cell lines. Aside from cytotoxicity, the
effects on cellular response such as membrane integrity are also important to
determine whether the nano-carrier or formulation itself may result in membrane
permeation which would also be undesirable or other cell stresses such as production
of reactive oxygen species. These are normally monitored using Lactate Dehydrogenase assays or Reactive Oxygen Species monitoring assays. Other assays to
monitor the immune response or the production of an inflammation response are
also carried out.
As with all pharmaceutical products, after preliminary in vitro testing in vivo
testing is also required. These studies are carried out in order to determine whether
the formulation may have any adverse effects when administered into an animal
which were not expected from the in vitro trials. Maximum tolerated dose will be
determined, which is especially important, as this may have been altered either
positively or negatively once the drug is encapsulated into the nano-carrier. Efficacy
studies will also be carried out to determine whether the nano-formulation performs
better or worse compared to the current clinical treatments, and often when drugs are
administered inside nano-carriers, due to their superior efficiency over traditional
excipients, the dose required for therapeutic outcome may be reduced. Another
important aspect of in vivo testing is to monitor the clearance of the drug from the
system, and to determine whether repeated dosing would cause an accumulation
problem for the patient. The nano-carrier fate itself is often difficult to determine, but
often molecular tags or radiolabels are used to promote greater certainty of the
safety. Only after extensive in vivo testing, would the nano-carrier system progress
further to clinical trial.
13 Nanotechnology and Hydrophobic Drug Solubilisation 331
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13.7 Clinical Success
Table 13.3 summarises some of the technologies currently either being used in the
clinic or undergoing clinical testing and that are based on nanotechnology strategies
for hydrophobic drug solubilisation. As seen in the table, cancer nanomedicines
predominate. This is due to a huge push to overcome the clinical challenges in cancer
treatment and associated funding within this area. However, other successes such as
in Hepatitis may also be seen. The range of drug candidates solubilised is a testament
to the wide-ranging application of the nano-carriers themselves. As there is a
growing understanding in the clinical setting of the benefits of these technologies,
they are rapidly being adopted and adapted for further applications such as in
diabetes treatment, treatment of tropical disease and cardiovascular disease to
name a few.
Table 13.3 Examples of clinically trialled nanotechnology-based formulations for drug
solubilisation
Solubilisation
Name
Doxil Liposome Doxorubicin Ovarian cancer Approved
VYXEOS/
CPX-351
Epaxal Liposome Hepatitis A
PNT2258 Lipid
ARB001467
Abraxane Polymeric Paclitaxel Pancreatic cancer Marketed
AZD2811 Polymeric Aurora B
GenexolPM
NK105 Polymeric Paclitaxel Breast cancer Phase 3 trial
CRLX101 Cyclodextrin Camptothecin Small cell lung cancer In trial
Rapamune Nanocrystals Sirolimus Immunosuppressant Approved
Tricor Nanocrystals Fenofibrate Treatment of high cholesterol
technology
Liposome Cytarabine:
nanoparticle
Lipid
nanoparticle
Polymeric Paclitaxel Head and neck cancer In trials
Drug
solubilised
Daunorubicin
virus
Single-
stranded DNAi
RNAi Hepatitis B In trial
kinase
inhibitor
Use Outcome
HIV-associated Kaposi ’s
sarcoma
Leukaemia Approved
Hepatitis A Approved
Lymphoma Approved
Small cell lung cancer
Breast cancer
Solid tumours In trials
completed
Renal cancer
Ovarian cancer
Approved
and high triglycerides
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