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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5610_Библиотеки_им_академика_М_И_Перельмана
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Chapter 4
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Solid Drug Nanoparticles
Catherine Unsworth, Alison C. Savage, and Steve P. Rannard
Abbreviations
AIDS Acquired immune deficiency syndrome
API Active pharmaceutical ingredient
BCS Biopharmaceutical Classification System
CDER Center for Drug Evaluation and Research
DLVO Derjaguin, Landau, Verwey, and Overbeek
ESD Emulsion spray drying
ETFD Emulsion templated freeze drying
GMP Good Manufacturing Practice
GRAS Generally regarded as safe
HIV Human immunodeficiency virus
ICH International Council for Harmonisation
IID Inactive Ingredients Database
kg kilograms
m metres
s seconds
SDN/SDNs Solid drug nanoparticle/s
SDS Sodium dodecyl sulfate
SLN Solid lipid nanoparticles
US FDA United States Food and Drug Administration
C. Unsworth · A. C. Savage · S. P. Rannard (*)
Department of Chemistry, University of Liverpool, Liverpool, UK
Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool,
Liverpool, UK
e-mail:
srannard@liverpool.ac.uk
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_4
63
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4.1 Introduction and Brief Historical Perspective
Nanoparticle systems can be used to develop low-cost and improved performance
solutions in order to address some of the limitations of the current therapeutic
options that are used to combat global infectious diseases. Conditions of significant
concern include acute respiratory infections, tuberculosis, malaria and the progression of human immunodeficiency virus (HIV) infection, collectively some of the
current leading causes of death worldwide (Singh et al.
Holmes et al. 2017). Drug delivery, enabled by nanocarrier and active pharmaceutical ingredient (API)-based nanoparticle systems, has been widely researched, and
many successful therapies utilising nanomedicine techniques are now clinically
available (Trezza et al.
2022). Solid drug nanoparticles (SDNs) are formed predominately from the API,
stabilised by polymers, surfactants and sugars and can be dosed as a solid (Giardiello
et al. 2016; McDonald et al. 2014) or dispersed in an aqueous carrier, for example,
water or saline solution, for use in suspended form, for example, in injectable or
pulmonary delivery. (McDonald et al.
SDNs have also been referred to using many different terms, such as nanocrystals,
nanosuspensions, DissoCubes™ and nanodispersions; however, we will use the
term SDN to avoid confusion between crystalline and amorphous API nanoparticles
and their method of manufacture. The term ‘nanocarrier’ is used here to define
sub-micron entities with no intrinsic physiological benefit that are used to either
conjugate or encapsulate drug molecules for the benefit of drug delivery, including
inorganic, organic and polym eric species that have active disease targeting or are
passive in their biological distribution after administration.
2015; Williams et al. 2015; Taki et al. 2022; Miguel et al.
2012; Fu et al. 2019; Tatham et al. 2019)
2017; Qasim et al. 2014;
4.1.1 Advantages of SDNs: Drug Loading
While nanocarrier systems offer specific benefits, such as functionalised tailoring
and site-specific targeting, the encapsulation or conjugation process involves the use
of a sub-micron entity that then dominates the physical mass of the nanoparticle
structure and, therefore, limits the maximum drug loading that can be achieved
(McGuckin et al. 2022). This is particularly important as medicines are dosed based
on mass of API, and a significant amount of any dose will be the inactive nanocarrier
in these systems. Where the nanoparticle is essentially composed of the API of
interest, that is, as a stabilised SDN, the mass of drug per particle may be very high.
For example, Brunaugh et al. encapsulated anthelmintic niclosamide for pulmonary
delivery at a 1 wt% loading (Brunaugh et al.
to produce SDNs of niclosamide for injectable delivery at 60% loading (Hobson
2021). In cases where drug potency is very high, and targeting of disease sites is
et al.
critical to avoid off-target toxicity, for example systemic cytotoxic drug delivery to
solid tumours, nanocarriers are ideal candidates. Where relatively high doses are
2021), whereas Hobson et al. were able
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required, and therapy does not rely on circulating nanoparticles, SDNs offer a more
appropriate opportunity for a range of administration routes. As nanoparticles
consisting essentially of API, SDNs may be formed with relatively low excipient
use, with the potential to minimise related adverse side effects (Lu et al.
2015; Guan
et al. 2022; Pawar et al. 2014). SDNs can be generated through a range of
manufacturing techniques and have been demonstrated to be easily scalable with
many clinically available nanomedicine products in use reliant on SDN technologies
(Trezza et al.
2015; Williams et al. 2015; Taki et
al.
2022; Giardiello et al. 2016;Lu
et al. 2015; Ye et al. 2015; Barenholz 2012; Chen et al. 2011).
4.1.2 Advantages of SDNs: Drug Dissolution Kinetics
Several published estimates suggest that approximately 70% of drugs in development and 40% of drugs in approved medicines exhibit poor aqueous solubility but
good intestinal permeability, falling within the Biopharmaceutical Classification
System (BCS) class II, Fig.
principal limitation of low aqueous solubility is its impact on absorption after oral
administration For a significant physiologi cal benefit, drug molecules must transit
from the gut, where the primary absorption site is the small intestine, into the hepatic
portal vein, survive first past metabolism in the liver at a concentration within the
therapeutic window, and enter the systemic circulation. Subsequent multiple passes
through the liver will lead to clearance. Low solubility in aqueous environments can
4.1 (Lai et al. 2021; Ghadi and Dand 2017). The
Fig. 4.1 Description of
Biopharmaceutical
Classification System (BCS)
classes I-IV and their
relationship to aqueous
solubility and intestinal
permeability (Cheow et al.
2013)
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considerably impact the concentration of drug substance that is available in the gut
for initial absorption.
Although gut absorption of nanoparticles may be possible through Peyer’s
patches, orally dosed SDNs of BCS class II compounds demonstrate several advantages over traditionally formulated therapies, including larger surface area and, as a
result, improved dissolution kinetics that allow saturation solubilities to be achieved
much faster than the dissolution of larger particles (Cheow et al.
2013). Dissolution
rate can be expressed by the Noyes–Whitney equation (Eq. 4.1).
Equation 4.1. The Noyes–Whitney equation expressing dissolution rate
dm
dt
Where dm/dt is solute dissolution rate (kg.s
t is time (s), A is surface area of the solute particle (m
-1
(m.s
), d is the thickness of the boundary layer of the solvent at the surface of the
dissolving substance, C
is concentration in the bulk solvent, Cs is particle surface
b
D
- C
ðÞ
¼ A
C
s
d
b
-1
), m is mass of dissolved material (kg),
2
), D is diffusion coefficient
saturation concentration.
As the particle size of a constant volume of matter is decreased, the total surface
area increases, despite the dimensions and surface area of each particle decreasing.
The fracturing of large particles exposes the inner material and generates new
surfaces. As a quantitative example, a single solid 100 μm particle of API will
generate 125 million nanoparticles with a diameter of 200 nm (based on cubic
particles) with a 500-fold increase in total surface area, Fig. 4.2.
Additionally, the smallest particles, particularly those <100 nm, often possess
higher saturation solubility, which contributes to improved dissolution kinetics. This
is described by the modified Kelvin Ostwald–Freundlich equation (Eq. 4.2) (Owen
and Rannard 2016a; Peltonen 2013).
Equation 4.2. Kelvin Ostwald–Freundlich equation describing the influence
of particle size on dissolution rate
S
2γV
app
ln
S
0
m
¼
RTd
Where S
energy, V
is apparent solubility, S0 is equilibrium solubility, γ is the surface free
app
is the molar volume, R is the universal gas constant, T is temperature, d is
m
the particle diameter.
Improvements to dissolution kinetics can bring considerable improvement to
APIs with narrow windows of absorption (Di et al.
to pharmacokinetic interactions with foods, thereby improving their absorption and
metabolism independent of the fed state of the patient (Schmidt and Dalhoff 2002;
Rangaraj et al. 2019; Rubbens et al. 2018). This has several advantages including
reduced likelihood of adverse drug reactions, lower cost of dosing to meet
2012) and to compounds subject
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Fig. 4.2 Schematic representation of the impact of size reduction. Surface area per particle (blue)
decreases rapidly, whilst the number of particles grows (green) and the total surface area (red)
increases dramatically. Calculation derived from the breakup of a single cubic particle with
dimensions 100 100 100 μm into smaller particles
x x
therapeutic levels and, with respect to long-term dosing, lower interpatient variability, increased patient adherence and lower risk of drug resistance, which is particularly important in conditions such as microbial infection and HIV (Hobson et al.
2019a; Bangsberg et al. 200 4 ).
4.1.3 Advantages of SDNs: Administration Routes
Ongoing research into the formation of SDNs of poorly water soluble drug compounds has demonstrated that it is possi ble to generate nanoparticles and formulations that enable medicines across numerous administration formats, including
topical, oral, inhalable and parenteral delivery routes (Hobson et al. 2021). This
offers many advantages including the ability to deliver APIs directly to the site of
infection; for example pulmonary delivery to the upper respiratory tract (Burgess
2012), or via long-acting therapeutics to facilitate patient adherence by
et al.
avoiding repetiti ve daily oral dosing (Tatham et al.
Surve and Jindal 2020). The high drug loading which may be achievable through
2019; Bakshi et al. 2018;
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SDN technologies may also decrease injection volumes for intramuscular and
subcutaneous administration routes, reducing patient discomfort (Owen and
Rannard 2016b). Optimisation of the choice of stabilising excipients offers the
potential to develop dispersions suitable for a wide range of dosing options.
4.2 Production of Solid Drug Nanoparticles
Techniques used to generate nanoparticles for pharmaceutical purposes are commonly described as either ‘top-down’ or ‘bottom-up’ approaches. In either case, any
harmful solvent phases that may have been used must be removed (Horn and Rieger
2001), and since dried powders offer greater long-term stability and dosing options
than liquid suspensions, solid products are often a common target product
(Junyaprasert and Morakul
removal techni ques often make up multi-step methodologies of SDN production,
and costs may be greatly increased by the need to introduce precursor steps to
material manufacturing strategies (Owen and Rannard
2015). Particle generation techniques and solvent
2016a).
4.2.1 Top-Down Methods for SDN Production
‘Top down’, or attrition, methods involve the size reduction of a material through
physical or mechanical processes (Soares et al. 2018; Boverhof et al. 2015). A very
common attrition method is milling, wherein powders are ground, commonly in the
presence of a liquid, using a milling medium. The approach is industrially relevant
and has successfully translated numerous SDN-derived medicines into the clinic
(Schutz et al.
Milling techniques are not without limitations and amorphous, semi-solid and lowmelting-point APIs are not suited to these approaches. Additionally, reports have
shown that the introduction of impurities resulting from degradation of milling
media, which may be formed from stainless steel, tungsten carbide, zirconium
oxide, or polymers, can present contamination concerns (Floyd and Jain 1996),
particularly where milling time is sustained or speeds are very high. More recently,
cryo-milling has been developed to broaden the capabilities of milling techniques to
temperature or hydrolysis-sensitive compounds.
API particles suspended in a liquid system may alternatively be subjected to highpressure, or high-speed homogenisation to decrease size, deagglomerate and disperse the solid compound into a liquid continuous phase (Karagiannidis et al.
High-pressure homogenisation utilises increases in dynamic pressure within the
liquid phase via a series of valves. Adjustment of the aperture size between a piston
and valve seat varies the shear force within the pumped dispersion leading to
cavitation and the breakdown of suspended solid drug particles. Successive decreasing of the aperture across repeated cycles allows the gradual decrease in particle size
2013; Bobo et al. 2016) without the use of solvents (Li et al. 2016).
2017).
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to be controlled within the required parameters. Homogenisation has also shown
significant commercial success and is capable of rapidly processing large batches;
however, heat generation within the liquid restricts applicability of the technique
within temperature-sensitive APIs (Owen and Rannard
systems are required.
While producing efficient size reduction, the high energy demand of processing
makes attrition techniques costly at production scale. The y may be used as a
preparation step in final product formulation, but control over the particle size is
impacted by processing parameters including, for milling: media, speed, time,
stabilisers and dispersion viscosity; and for homogenisation: co ntrol pressure, number of passes and sample viscosity. Chemical degradation and polymorphic changes
are common where processing parameters are not optimised.
2016a) and intensive cooling
4.2.2 Bottom-Up Methods for SDN Production
‘Bottom-up’ processing of poorly water-soluble APIs involves the condensation,
self-assembly or precipitation of dissolved compounds, allowing for full incorporation of an otherwise hydrophobic component within an aqueous system. The absence
of elevated pressure allows for a greater range of utilisable APIs and stabilising
excipients, with the resulting SDN dispersions often achieving high API/stabilising
excipient ratios within the dispe rsed solids On removal of liquid phases, the solid
composite materials have improved storage stability potential (Owen and Rannard
2016b). Preparation methodologies include emulsion and nanoprecipitation tech-
niques. APIs may be dissolved in a volatile water-immiscible solvent and rapidly
dispersed within an aqueous solution of stabilisers; solvent removal leads to
suspended nanoparticles. Nanoprecipitation utilises API solutions in water-miscible
solvents; addition to an aqueous solution of stabilising excipients leads to supersaturation and nanoscale precipitatio n (Hobson et al.
of the challenges of bottom-up processes is arresting particle growth effectively to
limit particle size and polydispersity, particularly if a specific particle size and form
is being targeted. Appropriate stabiliser screening, along with identifying suitable
solvent systems for condensation and precipitation processes, is therefore of utmost
importance (Giardiello et al. 2016; McDonald et al. 2013).
Bottom-up techniques may employ a water-immiscible organic solvent as the
dissolution medium for the API, or an aqueous solvent, where the API has some
degree of aqueous solubility. While the former is the most commonly exploited, the
latter has gained recent traction under the nominal ‘inverse flash nanoprecipitation’.
(Hobson et al.
heterogeneous systems comprising two or more non-miscible phases, with one
liquid dispersed as nanosca le droplets within another (Chen et al.
input method such as microfluidisation, sonication or simple stirring mixes the
phases and breaks down the droplets to the nanoscale, aiding control of droplet
size. Droplet size and phase separation of the emulsion can also be manipulated
2019a; Markwalter and Prud’homme 2018) Nanoemulsions are
2019a; Lepeltier et al. 2014). One
2011). An energy
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through the addition of non-ionic and amphoteric surfactants. Where a volatile oil
phase is used, for example, chloroform or dichloromethane (Le et al. 2008), evaporation through low-energy input methods such as stirring or venting shrinks the
droplet size and induces supersaturation and particle formation. Emulsion templated
freeze drying (ETFD) and emulsion spray drying (ESD) methods have demonstrated
opportunities for very high loading with respect to the API (Savage et al.
Zhang et al. 2008). Nano
(Badruddoza et al.
nanoparticles of low-melting-point prodrugs which would be not be possible by
attrition techniques (Hobson et al.
Nanoprecipitation (sometimes referred to as solvent shifting or antisolvent precipitation (Liu et al.
growth of particles from a solution by addition of, or to, an antisolvent phase. To
arrest particle growth and prevent aggregation, stabilisers are commonly added to the
precipitation mixture, either within the antisolvent or the starting solvent solution.
Typically, a hydrophobic API is dissolved in a polar solvent which is miscible with
the antisolvent (commonly water, or an aqueous mixture). As the drug solution is
introduced to the antisolvent phase, the ‘good’ solvent environment rapidly mixes or
diffuses into the antisolvent, leading to a dramatic decrease in the solubility of the
dissolved API and supersaturation. According to classical nucleation theory, temporary supers aturation of a solute will lead to instability of the system and spontaneous nucleation events in regions of concentrated solute molecules (Lepeltier et al.
2014). The greater the degree of supersaturation, the larger the number of nucleation
events. To ensure homogenous supersaturation, a high degree of rapid mixing is
required. Liu et al. describe three forms of mixing used during laboratory-scale
nanoprecipitation: (Liu et al.
solutes are added drop by drop; (b) flash nanoprecipitation, first described by
Johnson and Prud’homme (Johnson and Prud’homme 2003), where a mixing rate
faster than that of nucleation and growth of the particles is targeted; and
(c) microfluidic nanoprecipitation.
emulsions may be encapsulated within hydrogel matrices
2016) and have also enabled the generation of semi-solid
2019b).
2020)) describes the spontaneous precipitation, nucleation and
2020) (a) traditional mixing, where hydrophobic
2019;
4.3 Complexities of SDN Production
4.3.1 The Need for Stabilisation
As the average particle size reduces within a dispersed aqueous mixture, the Gibbs
Free Energy of the particulate system increases and particles will tend to aggregate
and assemble towards larger, more chemically stable structures in an attempt to
minimise interfacial tension. It is therefore common that nanoparticles are stabilised
using polymers, surfactants and simple sugars, using steric, electrostatic (charge) or
electrosteric stabilisation. Where electrostatic stabilisation is purely responsible for
dispersion stability, typically through the use of ionic surfactants and polymers, the
zeta potential (ζ) of the SDNs should be less than approximately 30 mV or more
-
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than approximately +30 mV (Peltonen 2013). DLVO (Derjaguin, Landau, Verwey,
and Overbeek) theory, which describes electrostatic stabilisation, states that
non-ionic stabilisers are insufficiently charged to prevent repulsion of particles,
which leads to agglomeration of colloidal systems. Stabilisation in these systems is
controlled by steric action: extended polymeric chains, adsorbed to and surrounding
the particle surface, physically separating the parti cles and impeding attractive van
al
der Wa
dried
for example, buffers and saline solutions.
manufacture from different particle formation techniques tends to vary, indicating
that stabilisation efficiency varies according to technique and, possibly, the API
particle surface chemistry (Peltonen 2013). During nanoprecipitation, for examp le,
stabilisers are used to arrest growth and control particle size and as such stabiliser
type and amount can be used as a tool to tailor particles. Similarly, stabiliser volume
or weight fraction is integral to wet milling. Stabilisers prevent aggregation of
particles, and may control the viscosity of the milling fluid, which influences milling
efficiency; therefore, excipient choice is critical to the outcome. By contrast,
stabilisers are not typically considered critical to size control during the process of
homogenisation but are required to stabilise the resulting suspension for storage.
s interactions. Stabilisation of SDNs may be affected if suspensions are
(e.g.
through
The amount and type of stabiliser required for successful stable dispersion
spray
drying or lyophilisation) and/or redispersed in ionic media,
4.3.2 Choice of Stabilisers and Excipients for SDN
Manufacture
Stabilisers including sucrose, lactose and mannitol may also contribute to
cryoprotection in techniques that use lyophilisation as a drying method
(Trenkenschuh and Friess
spray drying (Littringer et al. 2012;Keetal. 2020). Stabilising excipients can further
improve solubilisation and biological action of drug nanoparticles. For example,
surfactants, like sodium dodecyl sulph ate (SDS), may aid solubilisation through
micelle formation, reducing the crystallinity of the API and leading to faster release
(Peltonen 2013; Lee et al. 2008).
It is wholly incorrect to say that regulators, such as the United States Food and
Drug Administration (US FDA) ‘approve’ polymers and surfactants for use in
medicines, and this myth is widely reported within the literature. Regulators approve
finished clinically proven medicine formulations, and these contain excipients that
have no physiological action but are critical to the success of the medicine. For
example, the FDA Centre for Drug Evaluation and Research (CDER) Inactive
Ingredients Database (IID) lists inactive excipients (e.g. polymers, sugars, surfactants, salts, fats, oils) present in US FDA-approved drug products. Use of such
excipients in the formulation and development of SDNs, and any other candidate
medicine, can
minimise regul
2021), or be used to improve powder quality during
atory complexities during the clinical stages of
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