Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles

Prévia do material em texto

Vol.:(0123456789)1 3
Journal of Pharmaceutical Investigation (2017) 47:287–296 
DOI 10.1007/s40005-017-0320-1
REVIEW
Mechanisms of drug release from advanced drug formulations 
such as polymeric-based drug-delivery systems and lipid 
nanoparticles
Gi-Ho Son1 · Beom-Jin Lee2 · Cheong-Weon Cho1 
Received: 30 January 2017 / Accepted: 6 March 2017 / Published online: 3 April 2017 
© The Korean Society of Pharmaceutical Sciences and Technology 2017
Introduction
With the improvement of drug design methods, many 
potentially active substances have been manufactured and 
synthesized. However, most recently developed drugs 
belong to biopharmaceutical classification system (BCS) 
groups 2 or 4, which have low aqueous solubility. Low 
water solubility of drugs limits their absorption in the 
body and reduces their oral bioavailability (Amidon et  al. 
1995). To make these drugs safe and effective for treat-
ment, a number of factors including bioavailability, for-
mulation characteristics, and body disposition must be 
considered. Thus, attempts using micronization, formation 
of complexes with cyclodextrin, solid dispersions, permea-
tion enhancers, and surfactants have been made to solve 
the issues of dissolution and permeation of drugs (Aungst 
1993). The goal of drug release from a carrier is to main-
tain and control the drug concentration in the blood and 
target tissue. The first paper describing a sustained drug-
release system consisting of a polymeric device was pub-
lished in 1964 (Folkman and Long 1964), and a number of 
delayed drug-delivery systems controlled by polymers have 
begun to be investigated.
Several models of release kinetics can be used to illus-
trate drug release from drug-delivery systems, such as the 
drug-release kinetic mechanisms controlled by the barrier 
surrounding the matrix and regulated by drug diffusion 
through a carrier matrix. In addition, degradation or swell-
ing of the carrier matrix and loss of drug–polymer linkage 
can also control the rate of drug release from the carrier 
(Bajpai et  al. 2008; Freiberg and; Zhu 2004). Recently, 
various nanocarriers have been developed to improve the 
effectiveness of drug delivery (Lee and Yeo 2015) (Fig. 1). 
Although the spatial control of drug delivery based on 
nanocarriers has been widely studied (Acharya and Sahoo 
Abstract Drug release from a polymeric nanocarrier is 
affected by several factors including the sort of composi-
tion (drug, polymer, and excipient), the ratio of composi-
tion, physical or chemical interaction between components, 
and manufacturing methods. Depending on the mechanism 
of drug release from the vehicles, it can be divided into four 
categories (diffusion, solvent, chemical interaction, and 
stimulated release). Recently, lipids have attracted great 
interest as carriers for water-insoluble drug delivery. Lipid-
based drug-delivery systems have received a lot of interest 
because of their ability to improve solubility and bioavail-
ability of drugs that are poorly soluble in water. The lipid 
carrier, formulation strategy, and rational drug-delivery 
system should be selected appropriately for a lipid-based 
drug-delivery system to be successful. In this review, the 
general release characteristics and mechanisms of drug 
from nanocarriers will be discussed.
Keywords Drug release · Polymeric nanocarrier · Lipid 
nanoparticles · Release mechanism
Online ISSN 2093-6214
Print ISSN 2093-5552
 * Beom-Jin Lee 
 bjl@ajou.ac.kr
 * Cheong-Weon Cho 
 chocw@cnu.ac.kr
1 College of Pharmacy, Chungnam National University, 99 
Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea
2 College of Pharmacy, Ajou University, Suwon 16499, 
Republic of Korea
http://crossmark.crossref.org/dialog/?doi=10.1007/s40005-017-0320-1&domain=pdf
288 G.-H. Son et al.
1 3
2011; Brannon-Peppas and Blanchette 2004; Lu and Low 
2002; Maeda et  al. 2013; Xu et  al. 2013), the importance 
of controlling drug release from carriers at a nanoscale is 
sometimes neglected because large-scale drug-delivery sys-
tems are well established. However, because nanocarriers 
have a larger surface area per volume and a short diffusion 
distance, the control of drug release from nanoparticles 
faces different challenges compared with classical drug 
carriers.
Drug-release mechanism from polymeric 
nanocarriers
One of the primary goals of controlling drug release is 
to keep the concentration of drug in the blood within the 
therapeutic range (Siegel and Rathbone 2012). Therefore, 
it is ideal to develop drug carriers that have low dosing 
frequency and provide controlled drug release. To achieve 
this, drug-delivery systems that have a zero-order drug-
release profile in which the drug is uniformly released have 
been pursued (Bajpai et  al. 2008; Siegel and Rathbone 
2012). Drug release from a nanocarrier is affected by sev-
eral factors including the sort of composition (drug, poly-
mer, and excipient), the ratio of composition, physical or 
chemical interaction among components, and manufactur-
ing methods. Depending on the mechanism of drug release 
out of the vehicles, drug release can be divided into four 
categories (diffusion, solvent, chemical interaction, and 
stimulated release), as shown in Fig. 2 (Langer and Peppas 
2006; Siegel and Rathbone 2012).
Diffusion-controlled release
Diffusion-controlled drug release occurs in capsule-like 
systems where the drug is dissolved or dispersed in a core 
(Cauchetier et al. 2003). The diffusion of the drug is caused 
by the difference in concentration gradient across the mem-
brane (Crank 1975). Here, the drug is dissolved in the 
central part and then diffuses through the membrane. The 
matrix type nanospheres also have a diffusion-controlled 
release profile, where the drug molecules are evenly dis-
persed in the polymer matrix. Matrix type systems do not 
have membranes that can act as a barrier to diffusion. Thus, 
such systems generally show a high initial release, but over 
time, the release rate decreases as the drug molecule diffu-
sion distance inside the carrier increases.
Solvent-controlled release
Transport of a solvent into drug-delivery systems may 
affect drug-release behavior from the delivery carriers. 
Solvent-controlled release includes osmotic- and swelling-
controlled release (Langer and Peppas 2006). Osmotic-
controlled release occurs in a carrier that is packed with a 
semipermeable polymer membrane, and water flows from 
the carrier with a low concentration of drug to the center of 
the carrier with high drug concentration. As a result of this 
mechanism, drug release with zero-order kinetics occurs 
along a gradient of concentration that is constantly main-
tained across the membrane.
A swelling-controlled system is mainly composed of 
polymer material having a three-dimensional cross-linked 
network structure such as a hydrogel in which mesh size 
controls drug-release behavior. (Lin and Metters 2006; 
Peppas et  al. 2000). Drug release from hydrogels can 
Fig. 1 Various types of phar-
maceutical nanocarriers for 
drug delivery. a nanocapsule; b 
nanosphere; c liposome Drug
Nanocapsule
(a) (b)
Nanosphere
Hydrophilic
drug
Liposome
Hydrophobic
drug
(c)
Fig. 2 Various mechanisms of drug release from nanocarriers. a 
diffusion-controlled release; b solvent-controlled release; c polymer-
degraded release; d pH-sensitive release
289Mechanisms of drug release from advanced drug formulations such as polymeric-based…
1 3
be analyzed by the semiempirical Peppas model (Mt/
M∞ = ktn), where Mt and M∞ are the absolute accumula-
tions of drug released at time t and infinite time, respec-
tively, k is a constant, and n is the release index. This 
equation makes it possible to determine the release mech-
anism (Hayashi et al. 2005; Korsmeyer et al. 1983; Pep-
pas et  al. 2000; Ritger and Peppas 1987; Siepmann and 
Peppas 2001). Swelling-controlled systems can achieve 
zero-order drug release, depending on the initial drug 
distributionof the system (Lee 1984) or polymer compo-
sition (Kaity et al. 2013).
Degradation-controlled release
Drug carriers composed of biodegradable polymers such 
as polyesters, polyamides, and polysaccharides release 
the drug through enzymatic decomposition, which 
degrades ester or amide bonds, or causes hydrolysis (Lee 
et al. 2011; Prabaharan et al. 2009; Yoo and Park 2001). 
A matrix composed of polymers such as polylactic-co-
glycolic acid (PLGA), polylactic acid (PLA), or polycap-
rolactone (PCL) undergoes a degradation process, and 
consequently the overall matrix is degraded simultane-
ously. By contrast, a matrix made from polymeric anhy-
drides or orthoesters typically erodes from the surface to 
the center and then causes degradation of the polymer at 
a faster rate than water diffuses into the matrix (Burk-
ersroda et  al. 2002; Middleton and Tipton 2000). How-
ever, a small-sized matrix, such as those found in nano-
particles, has a very short diffusion length for water and a 
limited crystallization zone. Polymer degradation contin-
ues to accelerate with overall polymer degradation rather 
than only surface erosion (Lee and Chu 2008). Biode-
gradable polymer systems are preferred because they are 
degraded in the body.
pH-controlled release
The release of drugs from nanocarriers that respond to 
stimuli is controlled by a stimulus such as temperature, 
pH, ionic strength, ultrasound, electricity, or magnetic 
fields (Abouelmagd et al. 2014). Such carriers have been 
studied for targeted specific drug delivery because it is 
possible to localize stimulation. For example, nanocarri-
ers connected with pH-sensitive linkers using the weakly 
acidic pH of many solid tumors have been developed 
as site-specific drug-delivery carriers (Min et  al. 2010; 
Talelli et  al. 2010). In heat-sensitive drug-delivery sys-
tems, drugs are released using the phase transition tem-
perature of the heat-induced polymer (Chang et al. 2008; 
Li et al. 2011).
Drug-release mechanisms of drug from lipid based 
nanocarriers
Recently, lipids have attracted a great deal of interest as 
carriers for water-insoluble drug delivery. The availabil-
ity of useful lipid excipients capable of satisfying safety 
aspects and having the ability to increase oral bioavail-
ability has contributed to the development of lipid-based 
formulations. Lipid-based drug-delivery systems attract a 
lot of interest because of their ability to improve solubil-
ity and bioavailability of poorly water-soluble drugs (Pou-
ton 2006). Drug absorption from lipid-based formulations 
depends on many factors including particle size, degree of 
emulsification, rate of dispersion, and drug precipitation in 
dispersion (Jannin et al. 2008; Pouton 2000, 2006). A lipid 
carrier formulation strategy and a rational drug-delivery 
system should be selected appropriately for the lipid-based 
drug-delivery system to be successful (Dahan and Hoffman 
2008).
Lipid based nanocarriers
Self-micro emulsifying drug-delivery systems 
(SMEDDS)
SMEDDS are isotropic, transparent, and thermodynami-
cally stable solutions containing oil, surfactant, and cosol-
vent/cosurfactant. SMEDDS are defined as systems capa-
ble of forming microemulsions of oil-in-water by simply 
adding and gently agitating aqueous media such as gas-
trointestinal (GI) fluids (Mahesh et  al. 2001; Patel et  al. 
2010). Microemulsion is characterized by small droplet 
size (about 200  nm) and wide interface. The drug is dis-
solved in a droplet, and the large surface of the microemul-
sion increases the absorption rate in the body. SMEDDS 
not only promote solubilization of the drug but also have 
an advantage in terms of releasing and absorbing the drug 
(Craig et  al. 1995; Farah and Denis 2001). Thus, if the 
release rate of poorly water-soluble drugs acts as a key 
parameter for absorption, it is expected that SMEDDS will 
improve the rate and extent of absorption, resulting in bet-
ter bioavailability (Gursoy and Benita 2004; Pouton 2000).
When SMEDDS are introduced by an oral route, emul-
sification occurs because of mixing with gastrointestinal 
fluids. Thus, the mixture of surfactant and oil containing 
drugs is reconstituted to small-sized microemulsion drop-
lets. Figure  3 shows the various phases that will appear 
when an aqueous medium is introduced into SMEDDS 
(Rajput et al. 2012).
The emulsified drug containing microemulsion drop-
lets promotes bile secretion and is additionally emulsified 
by bile acid and bile salts. Figure 4 illustrates the process 
290 G.-H. Son et al.
1 3
by which SMEDDS are absorbed after they enter the body. 
The lipid nanodroplets are metabolized by lipase of the 
pancreas and are divided into fatty acid and 2-monoglyc-
erides. Short fatty acids are absorbed by direct diffusion 
through the hepatic portal system, while long fatty acids 
and monoglycerides are resynthesized into triglycerides 
and surrounded by phospholipids, cholesterol, and lipopro-
teins. As a result, chylomicrons eventually are created and 
absorbed through the lymphatic pathway (Agrawal et  al. 
2012).
Liposomes
A liposome has a spherical bilayer structure similar to a cell 
membrane. The lipids predominantly used in the produc-
tion of liposomes are phospholipids having an amphipathic 
hydrophilic head and a hydrophobic tail. These phospholip-
ids form a spherical bilayer structure in the hydrated state, 
with the hydrophobic portion facing inward and the hydro-
philic portion facing outward. The advantage of a liposome 
system is that the hydrophilic material can be buried in the 
hydrophilic space at the center of the liposome, and hydro-
phobic materials can be trapped in the fatty acid inside the 
lipid bilayer. Figure 5 gives an overview of the various type 
of liposomes that can be prepared by modifications, and the 
models of drug-release kinetics from the liposome (Jain 
and Jain 2016).
In general, drug release from liposomes depends on fac-
tors such as drug permeability and thermodynamic param-
eters such as drug distribution across bilayer surfaces. It is 
known that in vitro sink conditions are intended to simulate 
physiological states, and it is not easy to predict the com-
plexity of in vivo release processes (Jain and Jain 2016). To 
establish better in vitro–in vivo correlations, release kinetic 
studies were conducted in mathematical models with 
appropriate approximation. Fugit and Anderson studied the 
release patterns from liposomes in the nonsink environment 
of topotecan, and they observed that drug release and distri-
bution between bilayer and aqueous phases followed first-
order release kinetics. Similar results were obtained after 
a slight correction of the mathematical model when the 
study was performed under sink conditions using dynamic 
dialysis. Under nonsink conditions, mathematical modeling 
was used to study the effect of drug dimerization and the 
zeta potential on the drug distribution across bilayers (Fugit 
and Anderson 2014). Dynamic dialysis is generally used to 
study the kinetics of release from nanocarriers. Usually, the 
drug is released from the nanocomposite and diffuses from 
the dialysis membrane into the receiver portion of the sink 
condition. Control of permeability is an important param-
eter in liposomes because it regulates active release, and 
encapsulation serves to deliver the drug to the desired site 
only. Drug-delivery systems based on liposomes may uti-
lize increased permeability of the phospholipid membrane 
through gel–sol transfer in response to external stimuli 
(e.g., temperature causing drug release at the target site). 
Although numerous studies have reported that liposomes 
can improve drug encapsulation and in vitro release, there 
exists no comprehensive theory on membrane structure and 
drug release or membrane transport (Schaefer et al. 2012). 
Various dynamic models have been used to interpret drug 
release from liposomes (Costa and Sousa Lobo 2001; Fugit 
et  al. 2015; Csuhai et  al. 2015).There are various math-
ematical models for describing drug release from drug-
delivery systems, including the zero-order kinetic model, 
the first-order kinetic model, the Higuchi model, the Hix-
son–Crowell model, the Korsmeyer–Peppas model, and the 
regression model (Hayashi et al. 2005).
Solid lipid nanoparticle (SLN)
Recently, SLN has received much attention as a means of 
increasing site-specific drug delivery and bioavailability. 
Therefore, many studies have been conducted to explore the 
possibility of transport through the small intestinal lymph 
pathway. SLN is a spherical particle typically 10–1000 nm 
Fig. 3 The various phases that result from the addition of water 
phase to SMEDDS
291Mechanisms of drug release from advanced drug formulations such as polymeric-based…
1 3
in diameter, and the core of the solid lipid is stabilized by 
surfactant and can solubilize lipid-soluble drugs and mate-
rials. One of the biggest challenges when studying lipid 
nanoparticles is that burst release may occur in this system. 
A burst release phenomenon was observed in all encap-
sulated drugs in tetracaine and etomidate SLNs prepared 
by hot homogenization or cold homogenization methods, 
respectively (Schwarz 1995). By contrast, delayed release 
was obtained in the study of the incorporation of predni-
solone to SLN. These results confirm the suitability of the 
SLN system for long-term drug release. Importantly, it is 
possible to alter the drug-release profile by controlling the 
lipid matrix, the concentration of the surfactant, and factors 
involved in the production (e.g., temperature) of the lipid 
nanoparticles, and the effect of particle size is negligible. 
In addition, manufacturing parameters such as surfactant 
concentration, temperature, and inherent characteristics of 
the lipid matrix are the greatest determinants of the drug-
release profile from lipid nanoparticles. During nanopar-
ticle manufacturing processes involving high-temperature 
homogenization techniques, the drug is distributed from a 
liquid lipid phase to an aqueous phase. As the solubility of 
the drug increases in the aqueous phase, the amount of drug 
distributed to the aqueous phase will be greater. As temper-
ature and concentration of the surfactant increase, the drug 
saturation solubility of the aqueous phase increases in a 
system composed of water containing surfactant, lipid, and 
drug. In the cooling process of prepared oil-in-water type 
nanoemulsions, the lower temperature of the aqueous phase 
might reduce the solubility of drug. This means that the 
drug is redistributed into the lipid. A schematic diagram of 
this process is shown in Fig. 6 (Muller et al. 2000). When 
the lipid reaches a recrystallization temperature, the solid 
lipid core contains the drug. When the temperature of dis-
persion is lowered, the drug is redistributed to the lipid as 
the solubility of the drug in water is reduced. This is related 
to the pressure exerted on the drug. Because the drug can 
no longer be present in the already crystallized lipid core, 
the drug is consequently concentrated on the surface of 
the SLN or the liquid outer layer. Thus, the extent of burst 
release can be controlled through the surfactant concentra-
tion or the temperature setting during preparation. Higher 
temperature and surfactant concentration increase burst 
release, while production at room temperature does not 
show any burst because it avoids the process of redistribu-
tion of the drug to the aqueous phase and subsequent redis-
tribution to the lipid. SLN without burst release may be 
produced with a surfactant-free process. Based on Mehnert 
and Mader (2001), there are three drug encapsulation mod-
els in SLN; namely, a solid solution model, a core–shell 
model, and a drug-enriched shell and core–shell model 
(Fig. 6).
When lipid nanoparticles are prepared by cold homog-
enization using no drug-solubilizing surfactant, the drug 
Fig. 4 Potential mechanism for absorption enhancement of SMEDDS
292 G.-H. Son et al.
1 3
is evenly dispersed on a molecular basis in the lipid 
matrix, and this SLN matrix is a solid solution. The 
model in which the drug is abundant in the outer shell 
is because of drug redistribution during the cooling pro-
cess. A drug-enriched core is obtained when the drug is 
precipitated before the lipid is recrystallized. This core is 
obtained only when the drug is dissolved in the lipid at 
or near saturation solubility. Cooling of the nanoemulsion 
allows the drug to crystallize before crystallization of the 
lipid, and the molten lipid will be supersaturated with the 
drug. Additional cooling will lead to recrystallization of 
the lipid surrounding the drug core as a membrane. This 
lipid membrane will contain only drug content corre-
sponding to drug saturation solubility at lipid recrystal-
lization temperature. This means that a drug-rich core 
is formed and surrounded by a lipid shell (Muller et  al. 
2000).
Nanostructured lipid carrier (NLC)
Unlike SLN, where the drug is encapsulated in solid lipids, 
NLC refers to a system that encapsulates the drug in a mix-
ture of solid lipid and liquid lipid. In NLC, drug solubili-
zation capacity increases because of liquid oil; thus, this 
system exhibits controlled release characteristics with the 
advantage of high drug loading. In particular, incomplete 
and amorphous types of NLCs provide more flexibility 
to achieve a desired sustained release (Fig.  7). NLC with 
more imperfections in the crystal structure as compared to 
SLNs are prepared using a blend of solid lipid and spatially 
Fig. 5 Liposome modified in miscellaneous ways and various models of release kinetics from liposomes. a cationic or stimuli-sensitive lipo-
some; b release kinetics; c PEGylated or targeted liposomes; d conventional liposomes
293Mechanisms of drug release from advanced drug formulations such as polymeric-based…
1 3
different liquid lipids. These imperfections contribute to 
improved drug loading and reduced drug expulsion during 
storage (O’driscoll and Griffin 2008; Zhuang et al. 2010). 
Therefore, NLC which are lipid nanoparticles or colloidal 
carriers have been explored as potential topical delivery 
vehicle. NLC have been reported to offer several advan-
tages over conventional topical products owing to their 
ability to prolong the drug release, mitigate skin irritation, 
and protect of drug from potential degradable opportuni-
ties. Additionally, the high specific surface area of the par-
ticles ensures excellent contact with the affected site on the 
skin, facilitating the transfer of drug more efficiently (Fang 
et al. 2008).
NLC shows a drug-release pattern consisting of two 
stages: an initial burst release followed by a sustained release 
at a constant rate. The outer shell layer consisting of liquid 
lipids is rich in the drug, which causes an initial burst release. 
Unlike SLN, the outer layer of NLC where liquid lipid is 
abundant can dissolve more lipophilic drugs. Thus, a consid-
erable amount of the drug can be easily loaded on the outer 
shell and released by diffusion or erosion of the matrix. Fol-
lowing this initial rapid release, slow release appears from 
the solid lipid core. The interesting aspect of NLC is that it 
is possible to create a drug-release profile versus oil content 
(Muller et al. 2002).
Drug-release mechanisms
Peppas model
Korsmeyer et al. (1983) attempted to explain drug release as 
a mathematical model (Korsmeyer–Peppas model) expressed 
in terms of a log cumulative drug-release percentage versus 
log time. This model is stated as: Mt/M∞ = Kt
η. Mt/M∞ is 
the fraction of drug released at time t, k is the release rate 
constant, and η is the release index. The η value predicts 
the release mechanism of the drug. In other words, 0.45 ≤ η 
corresponds to the Fickian diffusion model, 0.45 < η < 0.89 
to non-Fickian transport, η = 0.89 to Case II transport, and 
η > 0.89 to Super Case II transport.
Higuchi modelHiguchi (1963) has developed a number of mathematical 
theoretical models to identify the manner in which water-
soluble and lipid-soluble drugs are released from the various 
matrix systems. These models are represented by the follow-
ing equation:
where Qt is the amount of drug released per unit area at 
time t, C is the initial concentration of the drug, Cs is the 
solubility of the drug, and D is the diffusion constant. The 
Higuchi model can be simplified to ft = KH
√
t. KH is the 
ft = Qt =
√
D(2C − Cs)Ct
Fig. 6 Partitioning effects on drug during the production of SLN by a hot homogenization technique and three drug incorporation models [solid 
solution model (left), drug-enriched shell models (middle) and lipid shell (right)]
Fig. 7 Schematic illustration of SLN and NLC structure
294 G.-H. Son et al.
1 3
Higuchi dissolution constant. Thus, Higuchi explained drug 
release as a diffusion process based on Fick’s law (depend-
ing on the square root of time).
First-order release kinetics model
The first-order kinetics model is expressed by the following 
equation: log C = log C0 – kt/2.303. C0 is the initial drug 
concentration, K is the first-order rate constant, and t is the 
time. The release data are shown as the cumulative log per-
centage of remaining drug versus time and a straight line 
with a slope of K/2.303 (Dash et  al. 2010, England et  al. 
2015). Three parameter models for liposomes have been 
reported, which include reversible drug-delivery interac-
tions and first-order release kinetics. This model is simple 
and can be adapted to a wide range of nanocarriers using 
different model parameters (Zeng et al. 2011).
Zero-order release kinetics model
Slow drug release according to zero-order release kinetics 
uses the following equation:
where Dt is the amount of drug dissolved at time t, D0 is the 
initial drug amount in the solution, and k0 is the zero-order 
release rate constant (Dash et  al. 2010). In the zero-order 
release kinetics model, the drug-release data are expressed 
as the cumulative amount of released drug versus time. 
This release model can be useful for transdermal, oph-
thalmic, and poorly soluble drug delivery. The zero-order 
release pattern is ideal for slow and delayed drug delivery 
such as antibiotics, antidepressants, blood pressure regula-
tors, analgesics, and anticancer drugs (Knepp et  al. 1987; 
Fattal et al. 1991).
Weibull release model
The Weibull release rate model is an empirical model 
widely used for both immediate and sustained drug-release 
patterns. Factors affecting overall drug release including 
effective surface area only depend on mass. This model is 
expressed as:
where kM = S, and k′tp = X.
Wei et al. (2014) developed a liposome containing bai-
calin to increase its oral bioavailability. This liposome 
showed delayed release according to the Weibull release 
rate model. In vivo studies have shown that oral bioavail-
ability increased threefold.
D
t
= D
0
+ k
0
t
dw
dt
=
D
h
CskMk�tp
Two-film theory mathematical model
In two-film theory mathematical models, interfacial 
reactions and diffusion resistances are studied to evalu-
ate drug release and nanoparticle permeability from 
nanocrystals and liposomes. Small et al. (2012) used low-
frequency ultrasound (LFUS) to perturb the membrane. 
Liposomes were prepared from POPC (1-palmitoyl-2-ole-
oyl-sn-glycero-3-phosphocholine), dipalmitoylphosphati-
dylcholine (DPPC), and cholesterol. Calcein release from 
large unilamellar vesicles (LUV) was monitored after 
LFUS (20  kHz) exposure following the two-film theo-
retical mathematical model. Interestingly, the increased 
DPPC content increased permeability in response to 
LFUS, while the permeability decreased when the molar 
fraction of POPC and cholesterol increased.
Biomembrane model
Biomembrane models simulate natural cell membranes 
because of similar lipid arrays (Sarpietro et  al. 2013). 
Interactions between physiologically active compounds 
and lipids have been studied using differential scanning 
calorimetry for a variety of purposes including drug 
release from lipid vesicles to biomembrane models. The 
interaction between physiologically active substances and 
biological membranes was observed using heat effect. In 
addition, various parameters (pH, swelling, and cross-
linking characteristics, etc.) have been found to influence 
the release kinetics of bioactive molecules during DSC 
analysis (Sarpietro and Castelli 2011).
Toroidal model
For a liposome, the toroidal model has been well stud-
ied in peptide release (Torchilin and Lukyanov 2003). 
For example, delta-lysin causes concentration gradient 
outflow of entrapped materials in phosphatidylcholine 
(PC) vesicles. When fluorescence energy change was 
used to study efflux effects and peptide-induced lipid flip-
flops, peptide transitions across bilayers were observed 
with instantaneous agitation in the membrane. Sobko 
et al. (2010) reported that the addition of the colicin E1 
channel-forming domain to liposomes results in a lipid 
membrane penetration spread (flip-flop) with simultane-
ous release of fluorescent dye in the liposome. Colicin 
reflects the formation of a large pore that can induce the 
release of colicin in liposomes and can be formed by the 
head moiety of lipid molecules (Sobko et al. 2010).
295Mechanisms of drug release from advanced drug formulations such as polymeric-based…
1 3
Conclusions
The latest nanobased drug-delivery technology not only 
provides increased solubility for poorly soluble drugs but 
also can control drug-release rate and pattern. Through 
studies of release mechanisms of nanocarrier into the body, 
a true “controlled drug-delivery system” could be realized 
in the near future.
Acknowledgements This work was supported by the Basic Sci-
ence Research Program (2016R1A2B4011294) through the National 
Research Foundation of Korea (NRF) funded by the Ministry of Edu-
cation, Science and Technology.
Compliance with ethical standards 
Conflict of interest All authors declare that they have no conflict 
of interest.
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http://dx.doi.org/10.1155/2011/370308
	Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles
	Abstract 
	Introduction
	Drug-release mechanism from polymeric nanocarriers
	Diffusion-controlled release
	Solvent-controlled release
	Degradation-controlled release
	pH-controlled release
	Drug-release mechanisms of drug from lipid based nanocarriers
	Lipid based nanocarriers
	Self-micro emulsifying drug-delivery systems (SMEDDS)
	Liposomes
	Solid lipid nanoparticle (SLN)
	Nanostructured lipid carrier (NLC)
	Drug-release mechanisms
	Peppas model
	Higuchi model
	First-order release kinetics model
	Zero-order release kinetics model
	Weibull release model
	Two-film theory mathematical model
	Biomembrane model
	Toroidal model
	Conclusions
	Acknowledgements 
	References