Expert Opinion on Drug Delivery

ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20

Formulation strategies to modulate drug release

from poloxamer based in situ gelling systems

Hani Abdeltawab, Darren Svirskis & Manisha Sharma

To cite this article: Hani Abdeltawab, Darren Svirskis & Manisha Sharma (2020): Formulation
strategies to modulate drug release from poloxamer based in situ gelling systems, Expert Opinion
on Drug Delivery, DOI: 10.1080/17425247.2020.1731469

To link to this article: https://doi.org/10.1080/17425247.2020.1731469

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Feb 2020.
Published online: 23 Feb 2020.

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EXPERT OPINION ON DRUG DELIVERY
https://doi.org/10.1080/17425247.2020.1731469

REVIEW

Formulation strategies to modulate drug release from poloxamer based in situ

gelling systems
Hani Abdeltawab, Darren Svirskis and Manisha Sharma
School of Pharmacy, Faculty of Medical & Health Sciences, The University of Auckland, Auckland, New Zealand

ABSTRACT ARTICLE HISTORY

Introduction: Poloxamer based in situ gelling systems offer numerous advantages in drug delivery; Received 29 October 2019
however, their application as prolonged-release delivery platforms is limited mainly due to their weak Accepted 14 February 2020
mechanical properties and the interconnected aqueous network causing fast gel erosion and drug KEYWORDS
diffusion. Poloxamers; in situ gelling
Area covered: The focus of this review is to provide an insightful discussion on the formulation systems; thermo-responsive;
strategies that can be employed to sustain/prolong the drug release from poloxamer based in situ sustained drug delivery;
gelling systems. The review also outlines the formulation factors, influencing drug release from these extended release;
systems. modulating release profile;
Expert opinion: The nature, composition, and concentration of poloxamers are the most critical factors formulation strategies
in defining the rate of drug release from an in situ gelling matrix. Hydrophobic gel matrices have
compact micellar arrangements resulting in slow diffusion and erosion. Depending on the intended
clinical application, gel characteristics can be modulated, either by physical blending or by chemical
crosslinking with additive materials, to slow release and improve residence time at the administration
site. Incorporating drug-loaded particles into poloxamer gels sustains drug release by creating multiple
rate-limiting release barriers. Chemical modification of poloxamers appears to be a promising strategy
to obtain prolonged sustained release for parenteral application without compromising the rheological
properties of the formulation.

1. Introduction temperature [10]. Poloxamers are more soluble at cold tem-

peratures due to the formation of stable hydrogen bonds
Poloxamers are water-soluble tri-block copolymers with amphi-
between the PEO and PPO blocks with water molecules. At
philic and surface-active properties. Poloxamers (Figure 1) are
a critical micelle temperature, the hydrogen bonds destabilize
nonionic polymers, consisting of a central hydrophobic block of
and poloxamers aggregate and self-assemble to form spheri-
poly (propylene oxide) (PPO) and two hydrophilic terminal blocks
cal micelle with hydrophobic propylene oxide (PO) core [1].
of poly (ethylene oxide) (PEO). They have been employed as
The size of the micelles grows until the PO core becomes
dispersants for pigments/inks, detergents, foaming agents and
completely dehydrated. The outer hydrophilic chain of the
as anti-biofouling coatings [1]. Due to their biocompatibility
micelles swells and interact to form three-dimensional gel
poloxamers have been extensively used as excipients in pharma-
structures (Figure 2).
ceuticals such as, dispersing agent, emulsifiers, co-emulsifying
To date, the use of poloxamers in drug delivery is chal-
agents, solubilizing agent, tablet lubricant, and wetting agent
lenged by their limited ability to sustain drug release. Many
[2,3]. Over the last two decades, poloxamers based delivery plat-
poloxamer-based gels described, rapidly lose their integrity in
forms have grabbed the attention of formulation scientists and
an aqueous environment, causing fast release of loaded drug
have been widely employed as drug carriers in ophthalmic [4],
[11–13]. In addition, hydrophilic low molecular weight thera-
vaginal [5] and rectal drug delivery [6] due to the ease of admin-
peutics can rapidly diffuse through the interconnected porous
istration and the ability to provide controlled release of drug
network structure of the gels causing an initial burst release
following gelation [7,8].
and fast drug diffusion [14]. Furthermore, their relatively poor
Poloxamer-based delivery systems are attractive, as they
mucoadhesive properties result in short residence time and
can deliver both hydrophilic and hydrophobic drugs and exhi-
rapid clearance from the application site [6]. This raises con-
bit thermo-responsive sol-to-gel transition behavior at concen-
cerns around the safety (initial burst release) and efficacy
trations above a critical value. They can be formulated to be
(fluctuation in drug-plasma concentration) of the poloxamer
liquid at room temperature, which allows for ease of adminis-
based in situ gel delivery systems [15]. As a result, controlled
tration, with gelation occurring as temperature rises, such as
drug delivery for prolonged or extended duration is not yet
at the body temperature, forming a semisolid gel depot. The
achievable through these poloxamer-based systems alone.
polarity of PEO – PPO blocks changes with increase in the
Increasingly, research is focussing on tailoring the composition

CONTACT Manisha Sharma manisha.sharma@auckland.ac.nz School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private
Bag, Auckland 92019, New Zealand
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 H. ABDELTAWAB ET AL.
Article highlights
● Poloxamers are attractive thermo-responsive in situ gelling systems
for drug delivery; they are liquids at room temperature, facilitating
their administration followed by a transformation to a gel state at
physiological temperature to provide sustained release.
● The use of poloxamers as sustained release drug delivery systems is
mainly limited by their rapid erosion and fast drug diffusion.
● Various approaches have been employed for sustaining drug release
from poloxamers based in situ gelling systems such as, physical
blending, chemical crosslinking with additives, incorporation of drug-
loaded particulates and chemical modification of poloxamers.
● The choice of suitable approach to achieve sustained release depends
on the desired release profile and duration of action, and route of
administration.
This box summarizes key points contained in the article.
of the poloxamer-based formulations to modulate the release
profile of the drug-loaded moieties.
Formulation scientists have made various attempts to
achieve controlled, extended release (beyond few days to
weeks) from these systems by chemical modification or by
developing a composite system [16,17]. It is expected that
developing such modified composite systems will enhance
patient adherence to treatment in the future.
Several reviews have been published in the past, focussing
on the use of poloxamers for delivering [1,18] ocular drugs [4],
oral chemotherapeutics [19], drug-resistant respiratory che-
motherapeutics [20], gene delivery [21,22] and for multi-drug
resistance reversal [23–25]. To the best of our knowledge, this
is the first review, which focusses on various formulation
strategies employed to alter the drug release from poloxamer
based in situ gelling systems. This manuscript aims to provide
Figure 1. Chemical structure of poloxamers showing its amphiphilic nature. x and y are the average number of repeating units of each blockchain (for poloxamer
188 x is 76 and y is 29, while for poloxamer 407 x is 100, while y is 65) [9].
Figure 2. Sol-to-gel transition of poloxamer as a function of temperature. CMC: critical micelle concentration.
a comprehensive discussion on the release mechanism gov-
erning each of these formulation approaches along with its
limitations. The authors also suggest a potential approach for
future investigation, which is hypothesized to reduce the drug
initial burst release.
2. Mechanisms of drug release
Understanding the mechanisms controlling drug release from
poloxamers based in situ gel systems is an essential step
toward modulating their release profile. Drug release from
poloxamer based in situ gels is controlled by both diffusion
and gel erosion [1] as presented in Figure 3. However, the
rate-determining step for release varies according to the com-
position of the gel matrix and the physicochemical properties
of the loaded drug [14].
2.1. Drug diffusion
Drug diffusion from poloxamer-based gels plays a dominant
role especially for small hydrophilic molecules due to the
presence of a continuous aqueous channel within the gel
microstructure [26]. The physicochemical properties of the
loaded drug such as its molecular weight, hydrophilicity/lipo-
philicity balance play a significant role in controlling the diffu-
sion process [26]. Gilbert et al. demonstrated that increasing
the length of the alkyl chain on the benzoate ester (methyl,
ethyl, propyl, and butyl) results in reduction in drug release
rate [27]. This is thought to be due to the increase in the
lipophilicity of the drug, with longer alkyl chains, resulting in
increased affinity toward the lipophilic micellar cores and thus
slow diffusion from the in situ gel matrix. On the other hand,
small hydrophilic drugs tend to exist in the aqueous channels

Figure 3. Mechanisms of drug release from poloxamer based in situ gelling systems. Yellow dots represent drug molecules.
and thus diffuse rapidly to the surrounding environment
[26,28]. Likewise, the gel matrix supramolecular arrangement,
micellar volume, micellar entanglement, and the extent of
aqueous channel network affect the drug diffusion from
poloxamer based in situ gelling systems [27,29–31].
2.2. Gel erosion
The micellar packing arrangement of poloxamers rapidly dissoci-
ates in the presence of excess aqueous media leading to the
degradation of the gel matrix. The erosion process of poloxamer-
based gels is not fully described in the literature. However, it is
proposed that micelles at the surface dissolute into the release
media, leading to gel erosion and drug release [32,33]. Further
studies may be required to assess the contribution of bulk ero-
sion as a result of water influx to the matrix core. Gel erosion is
the major release mechanism under two situations. First, when
the loaded drug molecule has a high molecular weight and/or is
hydrophobic, and second when the mechanical strength of the
formed in situ gel is poor/weak, causing release of the loaded
drug with the degradation of the gel matrix [14,34].
Zhang et al. demonstrated that the release of polyethylene
glycol (40 kDa) from poloxamer based in situ gels following
either intramuscular or subcutaneous injection is erosion con-
trolled [14]. Low mobility of the large molecules through the
internal aqueous channels to the external environment can
explain these results. Similarly, hydrophobic drugs have higher
affinity toward the core of poloxamers micelles, and it is
expected that their release is mainly erosion controlled. The
release of meloxicam and nonoxynol-9, two hydrophobic
drugs, was reported to be erosion controlled, and followed zero-
order release kinetics [35,36]. Likewise, the release of acyclovir,
a practical water-insoluble antiviral drug, from poloxamer 407
was mainly controlled by gel erosion. However, the addition of
carrageenan into poloxamers modified the release pattern to be
diffusion controlled, which is attributed to the significant
EXPERT OPINION ON DRUG DELIVERY 3
enhancement in gel strength and reduction in erosion rate [34].
The gel erosion might also contribute to the release of the small
hydrophilic organic drugs as demonstrated by Yang L et al. [26].
The author reported that the release of caffeine from poloxamer-
based gel was governed by both diffusion and gel erosion. This
can be explained by the partitioning of the drug between the
aqueous regions and poloxamer micellar core due to its organic
component. On the other hand, Moore et al. concluded that the
lipophilic/hydrophilic balance of a drug and molecular weight
have no significant effect on the release mechanism [37]. They
studied the release of three drugs; propranolol HCl (hydrophilic),
metronidazole (hydrophobic) and cephalexin (moderately
hydrophobic) from poloxamers and demonstrated that drug
release was a function of gel erosion irrespective of the varying
physiochemical properties of the studied drugs. These contra-
dictory findings might be attributed to the experimental design,
as they used large dissolution medium (20 g gel in 800 ml
deionized water, at stirring rates of 20–80 rpm). Poloxamer gels
being aqueous in nature tends to degrade faster in larger
volumes of dissolution medium as compared to small volumes.
Indeed, these findings signify the importance of experimental
design and its impact on the outcomes of the study.
When comparing literature, it becomes obvious that there
is considerable variations in both experimental design and
methodology used, which makes it challenging to draw any
conclusive outcomes from the studies. Yang et al. and Moore
et al. studied drug release from poloxamers using large
volumes of dissolution media and reported gel erosion as
the dominant mechanism of release [26,37]. Whereas Inal
and Yapar studied the drug release in small volumes and
concluded that release is governed through diffusion [35].
Similarly, the type/polarity of release medium can also influ-
ence the release mechanism. In general, release studies are
performed in aqueous medium; however, some studies have
reported the use of non-aqueous release medium such as
isopropyl myristate [38,39]. The solubility of poloxamers in
4 H. ABDELTAWAB ET AL.
isopropyl myristate is very limited and therefore drug release
is mainly through diffusion.
Another challenge in describing the drug release mechan-
ism from poloxamer-based gelling systems is the selection of
appropriate mathematical model. Though many studies have
reported that drug release from poloxamers follows Fickian
diffusion and can be well described by Higuchi model [28,31],
others demonstrated that release strictly follows zero-order
kinetics [36,37]. Few attempts have been made to develop
a predictive mathematical model, describing the drug release
from poloxamers based gels [26,37]. They have used large
volumes of dissolution media (300- and 800-ml deionized
water) and are therefore more appropriate to understand
drug release following oral administration of poloxamers
based delivery systems, where the gel encounter large
volumes of gastric fluids. Future studies are required to take
into consideration other clinical applications of poloxamers
based in situ gels.
To summarize, drug release from poloxamer based in situ
gelling systems is controlled by both diffusion and gel erosion.
The physicochemical properties of both the loaded drug and
the matrix, along with the experimental conditions of the
release study determine the dominant mechanism of drug
release. Due to the wide applications of poloxamers, it is
difficult to generalize a mathematical model that accurately
predicts the drug release from poloxamer-based gels. Instead,
clinical application should be considered, when designing in-
vitro release experiments to simulate the in-vivo condition as
closely as possible, for the reliability of the results.
3. Factors influencing drug release from poloxamer
based in situ gelling systems
As discussed, the release of drug from poloxamer based in situ
gelling systems is through both drug diffusion and gel erosion.
Thereby, it is important to understand the formulation factors
controlling both gel erosion and drug diffusion.
Comprehensive understanding of these factors will guide us
toward the development of poloxamer-based systems with
the ability to provide extended or prolonged drug release.
3.1. Gel microstructures
The gel microstructure consists of a number of entangled
micelles forming cubic/hexagonal 3D gel structure with interpe-
netrating aqueous channels. The number, size, and arrangement
of micelles critically control the porosity of the three-dimensional
gel structure, which in turn influence the diffusion of drugs to the
surrounding environment [27,29–31].
An increase in the micellar diameter and/or number of
micelles per unit volume reduces inter-micellar distance and
promotes a high degree of micellar entanglement. This will
result in greater tortuosity in the aqueous channels and reduc-
tion in the aqueous phase, which will ultimately slowdown the
rate of drug diffusion [14,29]. Various formulation factors, such
as total poloxamer concentration, blending with additive
material and chemical modification of poloxamers, affect the
gel microstructure and network porosity. Blending of
hyaluronic acid (HA) into poloxamer 407 (P407) increased the
average micellar diameter from 15 to 400 nm, and a subse-
quent reduction in piroxicam release rate was observed [40].
Likewise, the chemical modification of poloxamers by synthe-
sizing disulfide multi-blocks increased the average micellar
diameter from 12 to 600 nm, with a significant extension in
time required for complete gel erosion from 6 h to 12 days
[41]. The increase in total poloxamer concentration also
reduced the drug diffusion and sustained the release profile
[27,30,42].
3.2. Mechanical and rheological properties
Mechanical and rheological properties are crucial formulation
attributes for sustaining the release from poloxamer based
in situ gels [35]. Enhancement of these properties can lead
to a significant reduction in gel erosion and drug diffusion
rates, thus sustaining the release profile [43,44]. In general,
poloxamer based in situ gels are highly porous structures with
interpenetrating aqueous channels contributing to fast ero-
sion of the gel matrix. Creating a tightly packed micellar
structure while initiating increased intermolecular interactions,
will enhance the overall strength of the gel matrix and will
alter the rheological properties.
Increasing the PPO/PEO ratio can significantly promote gel
strength, reduce the erosion rate, and slowdown drug release,
and vice versa [35,45]. Zhang et al. showed an inverse relation-
ship between the concentration of the relatively hydrophobic
P407 and the gel erosion rate; P407 (25% w/v) was completely
eroded over 6 h compared to 70% and 40% erosion for 30%
w/v and 35% w/v P407 concentration, respectively [43]. This is
explained by the increased hydrophobic interaction, causing
reduction in the aqueous channels and enhancing the gel
mechanical properties. On the other hand, Liu et al. observed
that increasing the ratio of the poloxamer 188 (P188) (1% to
6%) in the blend of P407-P188 enhanced the gel erosion rate
[36]. The hydrophilic PEO tends to disrupt the hydration cor-
ona around the hydrophobic PPO core; consequently, a higher
number of water molecules exist around PPO. The high ratio
of water molecules reduces the gel strength and facilitates its
erosion [35].
Blending/crosslinking of poloxamers with additive materials
can significantly enhance the mechanical and rheological prop-
erties of poloxamer based in situ gelling systems, thus reducing
the gel erosion and drug release rates [46–48]. This can be
attributed to the formation of intermolecular bonds between
the additive material and poloxamers, creating a tightly packed
system. Of note, the enhancement of mechanical and rheological
properties is associated with the concentration and molecular
weight of the additive material [47,49].
Though enhancing rheological properties is usually
a successful approach to sustain the release profile from
poloxamer based in situ gelling systems, these properties
must be critically considered in the development of in situ
gels for parenteral and ophthalmic application as they affect
the syringe-ability, injectability, and spread-ability of these
systems. Formulations with viscosities higher than 300 mPas
are difficult to inject intramuscularly [50]. Xuan J et al. demon-
strated that increasing the poloxamer concentration and/or

blending with additives can significantly retard the syringe-
ability due to the increased viscosity. Likewise, Lin et al.
observed that blending of alginates (≥0.7%) into P407 (14%)
renders the formulation unsuitable for ophthalmic administra-
tion due to the high viscosity and poor spread-ability [51]. Of
note, the absence of standard methods for the determination
of these properties is a challenge toward comparing the
results, and for setting acceptance criteria of each property.
4. Strategies for sustaining/prolonging drug release
from poloxamer based in situ gelling systems
Despite the advantages of poloxamer based in situ gelling
systems in drug delivery, their employment as sustained/pro-
longed release delivery platforms is limited by their rapid
erosion and drug diffusion as well as short residence time at
the site of administration [48,51–53]. These challenges are
explained by the poor mechanical strength, highly porous
gel network structure and the poor mucoadhesive properties.
Therefore, different formulation strategies have been
employed to overcome these limitations and prolong drug
release from poloxamer based in situ gelling systems as dis-
cussed in the following sections.
4.1. Physical blending with other additive(s)
Physical blending of poloxamers with another polymer has
been widely investigated to alter drug release from poloxamer
based in situ gel systems (Table 1). Interaction of polymer
additives with poloxamers alters the gel microstructure, sig-
nificantly affecting gel porosity, mechanical and rheological
properties. These interactions occur as a result of hydrophobic
interactions, hydrogen bonding and/or due to supra-
molecular interactions (association of polymers by intermole-
cular forces) [54]. These physicochemical changes modulate
the gel erosion and drug diffusion rates, thus altering the drug
release characteristics of the in situ gels. Various additives such
as chitosan [55], HA [48], alginates [47], cellulose derivatives
[46], carrageenan [34,56–58], heparin [59,60], linoleic acid [61]
and gellan gum [62] have been widely used by researchers to
modulate the release profile from poloxamer based in situ
gelling systems. Similarly, the incorporation of salts such as
sodium chloride into poloxamer gels has demonstrated
a significant promotion in gel strength and subsequent exten-
sion in release profile [63]. In this section, the effects of blend-
ing additives with poloxamers are discussed.
4.1.1. Hyaluronic acid
Hyaluronic acid (HA) is a biocompatible and biodegradable nat-
ural polysaccharide [64]. It has been used in several applications
especially joint lubrication [65] and ocular drug delivery [64]. The
blending of HA into poloxamer solutions increases gel strength
and reduces network porosity, due to hydrogen bonding
between HA and poloxamers, consequently sustaining drug
release and reducing the initial burst release of loaded drug
[48]. Mayol et al. reported that incorporation of HA into
a poloxamer gel (10% P188–15% P407) reduced acyclovir release
EXPERT OPINION ON DRUG DELIVERY 5
in the eye as a function of its concentration; the cumulative
release over 6 h was reduced from 50% to 20% by the addition
of 1% HA and to 10% by the incorporation of 2% HA [48]. In
addition, an increase in mucoadhesive forces and residence time
has been reported. Similarly, the incorporation of HA to P407
reduced the cumulative piroxicam released over 50 h from 50%
to only 20% [40]. The HA-P407 system sustained the in-vitro
release up to 10 days and the half-life (t1/2) following intra-
articular injection increased from 24 h (poloxamer without HA)
to 86 h (poloxamer with HA). Likewise, Nascimento et al. demon-
strated that the blending HA into poloxamers (P407 or P407-
P108) reduced the release of lidocaine compared to HA free
formulation [29].
4.1.2. Chitosan
Chitosan are biocompatible and biodegradable natural polymers
[66]. They form pH-responsive hydrogels; exhibit sol-to-gel tran-
sition as a response to pH change [66]. Chitosan blending with
poloxamer-based gel reduces the drug release rate by enhancing
the gel strength via formation of inter-micellar bridges [28,67]. In
addition, it prolongs the residence time at the administration site
and thus is advantageous in mucosal applications [67,68]. These
changes are associated with chitosan concentration [69–71] and
molecular weight [72].
Sridhar et al. demonstrated that chitosan has increased the
intra-nasal residence time of a poloxamer gel by 3.2 fold [67]. In
addition, the release profile extended from 6 to 16 h. Likewise,
the incorporation of chitosan into poloxamers promoted the
intra-nasal residence time and prolonged the in-vitro release of
metoclopramide hydrochloride to more than 6.5 h compared to
only 2.5 h with poloxamer formulation [73]. Qian et al. demon-
strated that chitosan (0.5%) slightly reduced the in-vitro release
rate of tacrine, compared to poloxamer binary system (P407-
P188) [74]. Chitosan blending with P407 prolonged the in-vitro
release of ketorolac tromethamine from 1 to 12 h. An in-vivo
study in rabbits following intravesical administration demon-
strated increased residence time [68]. In ophthalmic applications,
chitosan reduced ofloxacin release rate; 60% drug was released
over 3 h from the composite preparation compared to more than
90% release within 1 h from poloxamer [69]. In addition, chitosan
increased the ocular residence time of poloxamers by 4 fold as
demonstrated by Gratieri T et al. [55]. This significant increase in
residence time is explained by the enhanced mucoadhesive
forces, which increased from 0.08 N to 0.1 N by the addition of
chitosan.
Chitosan have been used in combination with other additives
to retard the release rate from poloxamer gelling systems. Ur-
Rehman et al. demonstrated that incorporation of chitosan and
sodium tri-polyphosphate reduced the release rate of different
drugs (namely metoprolol, doxycycline, and flufenamic acid)
from P407 as a function of chitosan concentration [70]. Likewise,
incorporation of chitosan to a blend of P407 (17% w/v)-
cyclodextrin (10% w/v) reduced the fexofenadine released over
6 h from 74% to 54.5% [71]. The reduced in-vitro release rate is
explained by the enhanced gel strength and viscosity of the
composite; the consistency index (shear stress/(shear rate * flow
behavioral index)) increased from 1539.4 to 1886.8, respectively.
 6

Table 1. Physical blending and chemical crosslinking formulation strategies to sustain the drug release from poloxamer based in situ gels.
Poloxamer(s)
H. ABDELTAWAB ET AL.

composition Additives (concentration) Drug Route of Administration Modification/change in drug release profile Ref.
Physical Blending
P407 (15 wt.%)-P188 Hyaluronic acid (2 wt.%) Acyclovir Ophthalmic Reduction of in-vitro cumulative release over 6 hours from 50% to 20% [48]
(10 wt.%)
P407 (20 wt.%) Hyaluronic acid (1 wt.%) Piroxicam Intraarticular Reduction in in-vitro cumulative release over 50 hours from 50% to 20% [40]
P407 (18 wt.%) Chitosan (0.1 wt.%) Selegiline hydrochloride Intra-nasal Sustained release profile from 6 to 16 hours, with increased intranasal residence time [67]
P407 (18 wt.%) Chitosan (0.5 wt.%) Metoclopramide Intranasal Sustained release profile from 2.5 to 6.5 hours [73]
hydrochloride
P407 (20 wt.%)- P188 Chitosan (0.5 wt.%) Tacrine Intranasal Reduction in cumulative release over 90 minutes from 60% to 45% [74]
(1 wt.%)
P407 (17 wt.%) Chitosan (3 wt.%) Ketorolac Intravesical Sustained release profile from 1 to 12 hours, with increased residence time [68]
P407 (15 wt.%) Chitosan (0.33 wt.%) Ofloxacin Ophthalmic Reduction in cumulative release, over 1 hour, from 100% to 40% [69]
P407 (20 wt.%) Methylcellulose (4 wt.%) Etidronate Parenteral (intraplantar) Sustained release profile from 5 days to more than 28 days [46]
P407 (18 wt.%)- P188 Hydroxy ethyl cellulose (0.5 wt.%) Ciprofloxacin Ophthalmic Reduction in the cumulative release, over 8 hours, from 88% to 58% [81]
(13 wt.%)
P407 (20 wt.%) Alginate (0.1 wt.%) Pilocarpine Ophthalmic Sustained release profile from 4 to 6 hours, with significant increase in the AUC [51]
P407 (20 wt.%) Alginate (0.63 wt.%) Selegiline Transdermal Reduction in cumulative amount released over 48 hours, from 44 to 32 μg/cm2 [84]
P407 (18 wt.%) Alginate (0.5 wt.%) Nimesulide Rectal Only formulations containing alginate was retained inside the rabbit’s rectum without leakage, [85]
with reduced release rate.
P407 (15 wt.%)- P188 Sodium chloride (0.8 wt.%) Diclofenac sodium Rectal Reduction in the cumulative release, over 6 hours, from 50% to 25% [88]
(17 wt.%)
P407 (17, 18 and Sodium chloride (1 wt.%) Salbutamol Buccal Sustained release profile from 30 minutes to 1 hour [89]
19 wt.%)
Chemical Crosslinking
P407 (20 wt.%) Hyaluronic acid (1.18%, 6.87% and Ciprofloxacin Ophthalmic Release profile was sustained to 5, 20 and 23 hours, compared to only 3 hours for the P407 [64]
13.99% wt.%) system
P407 (25% w/v) Hyaluronic acid (1% w/v) Plasmid DNA Parenteral Release profile was sustained to more than 20 days, compared to only 3 days for poloxamers [90]
P407(18 wt.%)- P188 Chitosan (1.1 wt.%) 5-fluorouracil Intratumor Release profile was sustained from 5 to 52 hours, with significant reduction in initial burst [91]
(15 wt.%) release
P407 (5% w/v) Carboxy methylcellulose (2.5% w/v) Nepafenac Ophthalmic Release profile was sustained to 80 hours, compared to 24 hours for PBS/drug solution (no data [93]
provided for CMC free poloxamers).
P407 (20% w/v) Alginate * Selegiline Transdermal Cumulative amount released at 48 hours was reduced from 44 to only 14 µg/cm2. [84]
P407* Alginate* Lidocaine Parenteral The crosslinked hydrogel significantly increased the time of post-operative pain control in rats [96]
for 8 hours.
Concentration is not reported.
 EXPERT OPINION ON DRUG DELIVERY 7

Chitosan-methyl cellulose-P407 ternary composite significantly

[102]

[108]
[105]

[109]

[104]
Ref.

[17]
[7]
sustained the in-vivo release of the soluble antigen ovalbumin
compared to non-modified poloxamer [75].

Significant reduction in release rate; cumulative release over 48 hours was reduced from 85% to 60%, with

Prolonged the onset time of chemically induced convulsion in rats by 7.5 and the death time by 14 times,
Significant reduction in the release rate over the first 24 hours; composite formulation released only 40%,
4.1.3. Cellulose derivative
Cellulose-based polymers are highly abundant and biocompa-

Release profile was sustained to 14 days, compared to only 3 hours for the microspheres alone.
tible polymers that have diverse applications in pharmaceuti-

Hypoglycemia extended for 3 days, compared to only 10 hours for the hydrogel/insulin group
cals, cosmetics, and nutritional products [76]. Blending of
cellulose derivatives with poloxamer solutions has been
applied to slow drug release by increasing gel strength and
reducing erosion rates [46]. In addition, certain cellulose deri-
vatives, such as hydroxyl propyl methylcellulose (HPMC) and
Modification/change in release profile

hydroxyl ethyl cellulose (HEC), enhance the mucoadhesive

forces, thus increasing the residence time of poloxamer-
based formulations [77]. These changes are strongly governed
Cumulative release over 5 days was reduced from 97% to 77%.

by the type, concentration, and molecular weight of the cellu-

lose derivative being used.
Rangabhatla et al. demonstrated that blending of methylcel-
lulose (MC) with P407 significantly reduced the gel erosion and
Release profile was sustained from 5 to 30 days.

etidronate release rates; release profile was extended from 5 days

increased ocular residence time by 23%.

to 4 weeks [46]. Similarly, Wang W et al. reported that MC

compared to 100% from poloxamers.

blending into P407 reduced the release rate of the Chinese

Table 2. Incorporation of drug-loaded particulates as a formulation strategy to sustain the drug release from poloxamer based in situ gels.

medicine, Cortex Moutan [78]. Dewan et al. demonstrated that

compared to the control group.

grafting of MC into poloxamers increased gel strength and visc-

osity resulting in a reduction in drug release rates as a function of
its molecular weight [49].
Carboxy methylcellulose (CMC) and HPMC blending with P407
decreased the in-vitro release constant of ceftiofur from 0.3 to 0.24
and 0.28 µg/min, respectively [43]. HPMC blending with P188
prolonged the residence time and reduced the icariin released
over 40 h from 70% to 30% [77]. Similarly, Yu et al. demonstrated
that blending sodium carboxy methylcellulose (Na CMC) and
HPMC with P188 significantly retarded the initial burst release
administration

Subcutaneous
Route of

and extended the release profile of florfenicol from 65 to 120

Intraarticular

Diclofenac sodium Intraarticular

Ophthalmic

Intratumor
Intra-nasal

Parenteral

and 128 h, respectively [79]. Hydroxypropyl cellulose (HPC) and

HPMC reduced the release rates of vancomycin from poloxamer-
based gels (61%, 72%, and 80% release within 24 h for HPC-P407
(5%-15%w/w), HPMC-P407 (10%-10% w/w), and P407 (20% w/w)
Coated crystalline

respectively) [80].
Clondronate

Clonazepam
Flurbiprofen
Drug

HEC addition to a binary system of P407 18% and P188 13% w/

Paclitaxel

insulin
Copper

w significantly reduced the ciprofloxacin HCL release over 8 h in-

vitro from 88% to 58% and promoted the mucoadhesive force by
threefold [81]. On the other hand, Marcos et al. demonstrated that
PLGA nanoparticles

14% poloxamer 123 blended with 2% HEC did not significantly

nanoparticles
Particulate

microspheres
Bioactive glass

sustain the release of griseofulvin [82]. However, the addition of

Microcrystals

10% α-cyclodextrin (αCD) to the binary system enhanced the

Liposomes

Liposomes
Liposomes
Chitosan

solubility of griseofulvin, improved rheological and mucoadhesive

properties of the gel by forming a supramolecular network struc-
ture and thus provided sustained release for up to 3 weeks. The
P407 (20 wt.%)-P188 (9 wt.%)-SA or
P407 (18 wt.%)-chitosan (0.25 wt%)

failure of the binary system to sustain the drug release was

justified by the system’s phase separation at physiological tem-
P407 (30 wt.%)-P188 (10 wt.%)

Polyether urethane (chemically

P127 (15 wt.%)-SA (0.75 wt.%)
P407 (20 wt.%)-P188 (5 wt.%)

perature, which led to a highly porous system. The elastic modulus

of the ternary system was approximately 2 and 2.5 times that of
Poloxamer composition

the poloxamer-HEC composite and poloxamers alone,

modified P407)

HPMC (2 wt.%)

respectively.
P407 (18 wt.%)

4.1.4. Alginates
Alginates are anionic mucoadhesive biocompatible polymer
with strong mucoadhesive properties [83]. The physical
8 H. ABDELTAWAB ET AL.
blending of alginate with poloxamer solutions can slow drug
release from in situ gels by reducing erosion and increasing
the residence time [51]. Lin et al. reported that the alginates
reduced the release of pilocarpine from poloxamer in situ gels
in a concentration-dependent manner due to an increase in
gel strength and residence time following ocular administra-
tion [51]. Chen et al. reported that blending alginate into P407
slowed the gel degradation (10% compared to 20% over
2 days for P407 system) and reduced the transdermal release
rate of Selegiline (cumulative amount released was 32 µg/cm2
compared to 44 µg/cm2 from P407) [84]. Yuan et al. demon-
strated that alginates significantly reduced the in-vitro release
of nimesulide from 18% w/w P407 rectal in situ forming gel
and improved its adhesion to the rectal membrane [85].
4.1.5. Salts as additives
Salts such as sodium chloride and sodium phosphate (mono
or dihydrogen) crosslink with poloxamers and significantly
enhance the mechanical and mucoadhesive properties of
in situ gels [35,63,86,87]. Studies have shown a 60-fold
increase in gel strength and a 10-fold increase in mucoadhe-
sive properties following the addition of salts [63]. The
enhancement of mechanical properties is expected to reduce
the drug release rate. However, studies have demonstrated
that sodium salts tend to show ‘pore-forming effects’ after
a certain time, when exposed to aqueous environment due
to their high-water affinity. Salts tend to diffuse out of the gel
matrix leaving pores in the matrix, allowing media to enter the
gel matrix and thus increasing the drug diffusion and gel
erosion rates [35].
Yong et al. demonstrated that sodium chloride increased gel
strength of a P407-P188 liquid suppository by 67-fold. In addition,
the mucoadhesive forces and retention inside the rabbit’s rectum
increased proportionally with the sodium chloride concentration
[86]. The authors did not report the release profile; however, the
longer rectal retention time is expected to contribute into sustain-
ing the drug release profile. Yuan Y et al. observed that sodium
chloride efficiently reduced nimesulide release rate from P407
(18%) based liquid suppository; cumulative drug release over
7 h was reduced from 90% to 70% [85]. Park et al. demonstrated
Figure 4. Schematic representation of poloxamers chemical crosslinking with additive polymers, crosslinking occurs between the hydrophilic corona of poloxamer
micelles and the additive polymer with the aid of a crosslinker, with a potential to increase the gel strength and hinder the drug diffusion.
that sodium chloride significantly increased the gel strength of the
liquid suppository base (P407 15%-P188 17%) and reduced the
cumulative release over 6 h from 50% to 25% [88]. Likewise,
sodium chloride sustained salbutamol sulfate release from P407
to 1 h, compared to only 30 min from sodium chloride-free for-
mulation [89]. On the other hand, the addition of sodium chloride
to poloxamer-based gel did not significantly alter the release of
meloxicam from the binary system (P407-P188) in the initial 3 h,
though, faster release was observed afterward due to the ‘pore-
forming effect’ discussed above [35].
To conclude, physical blending of poloxamers is a successful
approach for sustaining the drug release and improving the
mechanical properties of poloxamer based gelling systems. This
approach can significantly reduce gel erosion through increasing
the gel strength. In addition, it may hinder drug diffusion rates
because of the reduced network porosity. Furthermore, it might
increase the residence time at the application site due to the
enhancement of mucoadhesive properties by some additives.
The enhancement of mucoadhesive properties provides this
approach suitable for mucosal applications such as ophthalmic,
nasal, rectal, and vaginal applications. The proper choice of the
polymer type, molecular weight and concentration is critical in
achieving the set goals without affecting formulation inject-
ability, spread-ability, or applicability. Physical blending is
a suitable approach to sustain drug release from several hours
up to few days. Noteworthy, the duration of the release will vary
with respect to the site of administration.
4.2. Crosslinking with another polymer(s)
The crosslinking of poloxamers with other polymers (Figure 4)
is another approach for modulating the drug release from
poloxamer based in situ gels (Table 1). Crosslinking results in
the preparation of compact gels with increased strength and
reduced erosion [90,91]. As shown in Figure 1, poloxamers
have two hydroxyl groups at chain ends. This reactive group
can be exploited for crosslinking with other polymers. The
reaction can be triggered by a chemical agent or by photo-
activation (photocrosslinking via UV exposure) [54]. However,
the impact of crosslinking on the overall gel properties is

associated with the degree of crosslinking, which should be
carefully considered as per the desired application [90,91]. In
addition, the safety of the crosslinker is equally important,
particularly with long-term exposure [92].
The concentration of the additive polymer significantly
affects the prolongation in drug release. Cho et al. demon-
strated that, at fixed crosslinker concentration, the gel
mechanical properties and ciprofloxacin release were asso-
ciated with the HA concentration. The release profile was
sustained for 5, 20, and 23 h by the addition of 1.18%,
6.87%, and 13.99% HA, respectively [64]. Chun et al. demon-
strated the impact of degree of crosslinking on drug release
rate from HA-P407 composite formulations. Gel formulations
irradiated for 5 min and 20 min, demonstrated 100% and 50%
release, respectively, over a 20-day period [90].
Chung TW et al. used glutaraldehyde to crosslink chitosan with
poloxamers, and demonstrated a significant reduction in the initial
burst release of 5-fluorouracil with sustained release up to
52 h [91]. These changes can be justified by the viscosity incre-
ment of crosslinked formulation (30-fold the viscosity of poloxa-
mer solution) and the enhanced swelling ratio (13.2 times the
swelling ratio of non-cross-linked solution). Of note, the modula-
tion in rheological properties and release pattern was associated
with glutaraldehyde concentration [91]. Similarly, crosslinking of
carboxyl methyl chitosan with poloxamer by glutaraldehyde suc-
cessfully prolonged the release of nepafenac for up to 80 h [93].
The photocrosslinking of chitosan and poloxamer through
gamma radiation also enhanced the viscosity and mechanical
strength of the composite formulation [94]. Alginates can be
crosslinked with poloxamers using calcium salts (biologically safe
crosslinkers). Huang et al. demonstrated that the addition of
calcium to the blend (poloxamer-sodium alginate-HPMC and
iodixanol) significantly reduced the gel erosion over 5 h from
Figure 5. Schematic representation of potential mechanisms of drug release from drug-loaded particulate carriers incorporated in poloxamer-based gels; (a): Drug-
loaded particulates are shielded from the external environment by the gel matrix. Pathway 1 occurs when the particulates maintain their integrity inside the gel
matrix (b): Gel erosion and water influx into the matrix subjects particulates to the dissolution medium (c): Particulates dissolute and drug is released. Pathway 2
occurs if the drug-loaded particles dissolute at a faster rate than gel erosion (d): Particulates dissolute leading to drug release inside the aqueous channels (e): Gel
erosion causing the release of drug left in the matrix.
EXPERT OPINION ON DRUG DELIVERY 9
100% to zero [95]. In addition, the composite demonstrated better
flow-ability at room temperature. Noteworthy, these effects were
proportional to the calcium ion concentration [95]. Likewise, Chen
et al. demonstrated that grafting of alginate into poloxamer was
more efficient in sustaining selegiline release compared to either
their physical blend or P407 single system [84]. Choi GJ et al.
showed that a lidocaine-loaded poloxamer-alginate-calcium
chloride in situ forming gel significantly sustained its effect and
provided control over the post-operative pain in mice compared
to calcium-free formulation [96].
To conclude, crosslinking of poloxamers with other poly-
mers sustain the drug release via reducing the gel erosion and
drug diffusion rates. In addition, the additive polymer may
enhance the mucoadhesive forces and residence time.
Depending on the degree of crosslinking, this approach
might be suitable to extend the drug release over one to
several days. Attention should be given to the safety of the
crosslinker and rheological properties of the final formulation.
4.3. Incorporating particulates into poloxamer based
in situ gel systems
Encapsulating active drug into micro or nanoparticles and
dispersing them in poloxamer solutions (Figure 5) is another
promising approach to sustain the drug release and combat
the initial burst release from poloxamer based in situ gelling
systems [97]. Different particulates carriers such as nanoparti-
cles [7,98–101], liposomes [102], microspheres [103] and
microcrystals [104] have been dispersed in poloxamer in situ
gel matrix (Table 2). It has been observed that the gel matrix
prevents the wettability of the drug-loaded particulates and
thus consequently reduces the diffusion of drug from these
hybrid systems. Slow diffusion of drug could also be attributed
10 H. ABDELTAWAB ET AL.
to the presence of a double barrier offered by both particulate
carrier and gel matrix.
Various types of nanoparticles have been incorporated into
poloxamer-based formulations for sustaining the release profile
as lipid nanoparticles [98,99], poly (lacto-glycolic acid) (PLGA)
nanoparticles [100] and heparin-chitosan nanoparticles [101].
The anti–inflammatory effects of clodronate were significantly
prolonged when drug-loaded chitosan nanoparticles were dis-
persed in poloxamer solution and administered intra-articularly
[7]. Küçüktürkmen et al. demonstrated that incorporating drug-
loaded PLGA nanoparticles into chitosan (0.25%)-P407 (18%)
blend sustained the intra-articular release of diclofenac up to
30 days compared to 1 and 5 days for the nanoparticles and
blend, respectively [17]. Unfortunately, the authors did not
report gel erosion study and therefore the exact mechanism
behind prolonged drug release is unclear. Hence, a question
might be raised whether the drug was released while the gel
maintained its integrity, or the gel was eroded within 5 days as
well. Similarly, paclitaxel loaded nanocrystals dispersed in P407
demonstrated longer release profiles and intra-tumor residence
time compared to drug-loaded nanocrystals or the marketed
product Taxol® (Taxol is a paclitaxel non-aqueous solution for
parenteral administration) [8]. Clonazepam loaded nanostruc-
tured lipid carriers dispersed in P407-SA composite significantly
prolonged the onset of pentylenetetrazole-induced convulsion
by 1.5 times and the death time by 5 times compared to the
control/placebo group in Swiss albino mice animal models
[105]. In addition, the loading of supramagentic iron oxide
nanoparticle into this hybrid system further prolonged the
onset time by 7.5 times and the death time by 14 times com-
pared to the control group. Orasugh JT et al. have demon-
strated that cellulose nanocrystals and cellulose nanocrystals
grafted collagen significantly sustained the release of pilocar-
pine and ketorolac tromethamine, respectively, from poloxa-
mer based in situ gelling systems [106,107].
Liposomes are commonly investigated nano-carriers in
drug delivery. Their incorporation into poloxamer has been
successfully employed for sustaining the drug release. Pachis
et al. reported that a liposome-P407 (18 wt.%) hybrid system
significantly reduced the flurbiprofen release to 60% com-
pared to 85% from poloxamer over 48 h [102]. In addition,
the ocular residence time increased by 23% compared to
liposomes alone or poloxamer alone and by 73% compared
to drug solution. A hybrid system consisting of liposomes and
poloxamers has also been employed for the delivery of the
anti-cancer agent paclitaxel [108]. Incorporating paclitaxel-
loaded liposomes into P407-P188 demonstrated slower
release rate; 52% and 77% over 2 and 5 days compared to
80% and 97% release from the drug-loaded liposomes over
the same periods. Similar results were demonstrated in-vivo;
41.61% of the drug was recovered from the tumor in the
hybrid system group compared to only 3.7% from the lipo-
some group after 2 days. Furthermore, better efficacy, higher
local concentration, and enhanced safety profile were
achieved with the hybrid system.
Similarly, microspheres have also been used in sustaining
drug release from poloxamer matrix. Pontremoli observed that
copper-containing bioactive glass microspheres loaded in
polyether urethane (chemically modified P407) sustained the
release profile of copper to 2 weeks compared to only 3 h for
the microspheres [109]. On the contrary, an Eudragit RS100
microspheres-P407 hybrid system did not significantly alter
the in-vivo release of roxithromycin [103]; the microsphere
released 79% compared to 75% drug release from the hybrid
system over the same time period (168 h). This may be due to
the fast gel erosion which resulted in rapid wetting of the
microspheres. Unfortunately, the study did not report the
concentration of P407 which limits the ability to draw conclu-
sions from the study.
Microcrystal dispersion in poloxamer solutions has been
employed to prolong drug release profile and improve bioac-
tivity of drug. Yang et al. compared the hypoglycemic activity
of parenteral insulin solution, Lantus injection in hydrogel,
insulin microcrystals in hydrogel and coated insulin microcrys-
tals in hydrogel [104]. They demonstrated that insulin solution
resulted in rabbits’ death, which can be explained by the burst
release of insulin and subsequent severe hypoglycemia.
Coated insulin microcrystals in P407/SA or P407/HPMC
resulted in prolonged hypoglycemia for more than 3 days,
unlike the Lantus group, which showed hypoglycemia for
only 4 h followed by normal blood glucose for 20 h. The
results demonstrated that both coated microcrystals and
uncoated microcrystals in hydrogel system are promising stra-
tegies for controlling the release pattern.
To conclude, the incorporation of drug-loaded particulates
in poloxamer based in situ gelling systems significantly pro-
longed the drug release profile. The release pattern can be
finely tuned by controlling both poloxamers concentration
and the particulate size and composition. This technique limits
the degradation rate of the incorporated particulates through
limiting their wettability. This approach is suitable for achiev-
ing drug release over several days to few weeks following
intramuscular or subcutaneous injections.
4.4. Modulating the molecular weight of poloxamers
Despite the advantages of the various approaches discussed
above to sustain drug release from poloxamer gels, they are
limited by the significant increase in the formulation viscosity
in the sol state [110]. Consequently, they might not be the best
choice for parenteral and ophthalmic administration. To achieve
sustained/prolonged release by improving the gel strength with-
out enhancing formulation viscosity, a new strategy has been
introduced. This involves modulating the molecular weight of
poloxamers by chemical synthesis of multi-block copolymers
[41,111]. This technique produces low viscosity poloxamers solu-
tions for easy administration, transforming into strong gels at
body temperature, with reduced drug diffusion and gel erosion
rates [110–113].
Ahn et al. demonstrated that chemical modification of polox-
amers (molecular weight; 31,000 g/mol) significantly reduced the
erosion rates; only 15% erosion was observed over 3 weeks
compared to complete degradation in less than 3 days for non-
modified P407 [111]. Likewise, the chemical modification of
poloxamer 85 has increased the time required for complete
erosion from 1 to 16 days [111]. Similarly, Cohn et al. established
that by synthesizing poloxamer-based poly (ester urethane)

copolymer in varying molecular weights the erosion profile can
be tailored for up to 8 months [114].
Chung HJ demonstrated that multi-block poloxamers
linked by D-lactide and L-lactide oligomers reduced the ero-
sion rate and sustained the release of human growth hormone
(hGH) over 13 days compared to only 1 day for the non-
modified poloxamer [115]. Likewise, Sosnik A et al. reported
increased gel strength and slow degradation for ethoxysilane
capped P407 thus prolonging the release profile to more than
2 weeks [16].
Modulation of poloxamer molecular weight by chemical
synthesis is a promising strategy to achieve sustained drug
release over several weeks. A superior advantage of this tech-
nique is that the formulations flow-ability at room tempera-
ture is maintained, which allows for ease of administration.
Further studies are required to confirm the results in in-vivo
conditions.
4.5. Enhancing drug–poloxamer interaction
Enhancing the interaction between the drug moiety and the
poloxamer can be an effective approach in retarding the fast
drug diffusion and limiting the initial burst release associated
with poloxamer based in situ gel systems [116]. Gilbert et al.
demonstrated that the more hydrophobic drug moieties have
lower diffusion coefficients compared to the less hydrophobic
ones [27]. The reduction in diffusion coefficient through
enhanced drug–polymer interaction is understood by the
energy required to break down the physical or chemical
bonds between the drug and polymer and thus slowing
drug diffusion. This advantage can be further exploited for
sustaining drug release from poloxamer-based gels.
Drug–poloxamer interactions can be enhanced by the
choice of the drug chemical form. The gel matrix consists of
micelles arranged compactly with aqueous channels in
between as shown in Figure 2. The drug molecules partition
between these compartments based on their lipophilic/hydro-
philic balance; water-soluble drugs (salt form) tend to stay in
hydrophilic corona of the micelles and diffuse readily through
the aqueous channels to the external environment. On the
contrary, base forms of the drug with higher lipophilic proper-
ties demonstrate higher affinity toward the micelle core, thus
it will be shielded from the external environment and the drug
release from a gel matrix will be a function of its erosion rate.
Drug chemical structure and its potential to interact with
poloxamers might be considered. Drug moieties with larger
organic components/more cyclic rings tend to concentrate
into the micelles core. Previous studies done by the research
team demonstrated covalent intermolecular interaction
between poloxamers and the drug lidocaine using Fourier
transform infrared spectroscopy, which might be one of the
contributing factors in achieving slow sustained release of the
drug over a period of 3 days [117].
Hence, it is hypothesized that enhancing the intermolecular
interaction between drug and poloxamers might be a promising
strategy to reduce the initial burst release and retain the drug
inside the gel matrix for longer periods. Future studies are
required to test this hypothesis and assess its benefits.
EXPERT OPINION ON DRUG DELIVERY 11
5. Conclusion
Despite the attractive features of poloxamer based in situ
gelling systems for drug delivery, their rapid erosion and fast
drug diffusion are major challenges toward sustained drug
release. A variety of strategies have been reported to extend
drug release; however, the desired release profile and the
route of administration for specific clinical application will
dictate the choice of the appropriate strategy.
Drug release from poloxamers is controlled by both drug
diffusion and gel erosion, which in turn is dependent on the
gel microstructure, mechanical and rheological properties. The
gel strength is a crucial parameter in formulation vulnerable to
high mechanical strain such as intra-articular and intramuscu-
lar injections. The mucoadhesive forces are an important fac-
tor when considering nasal, rectal, and vaginal applications.
Attention should be given to the viscosity and flow-ability of
ophthalmic and injectable formulations.
Several strategies have been used to sustain drug release
from poloxamer-based gelling systems; physical blending and
crosslinking with polymeric additive can promote the mechan-
ical, rheological, and mucoadhesive properties. Incorporating
particulates creates multiple barriers and thus slowdown the
drug release. Poloxamer multi-block synthesis could be
a promising approach to achieve sustained release for
extended duration. It is also hypothesized that enhancing
drug–poloxamer interactions will significantly reduce the
initial burst release and provide prolonged release. This
approach needs further investigation.
6. Expert opinion
The unique ability of poloxamers to transform from sol-to-gel
form in response to temperature makes them attractive drug
delivery platforms. However, their application as a sustained-
release delivery system for an extended duration is limited by
the poor mechanical strength and high porosity, causing fast
gel erosion and drug diffusion. Several formulation strategies
have been investigated to overcome these limitations.
It has been observed that poloxamer composition plays
a critical role in modulating the release profile from these
in situ gelling systems. The concentration and ratio of the
hydrophobic block (PPO) and hydrophilic block (PEO) directly
influences the overall gel properties and thus dictates the
drug release rates. Therefore, it is recommended that by
increasing the concentration of hydrophobic component in
poloxamers such as in poloxamer 407, can significantly
enhance the gel strength thereby reducing the gel erosion
and drug diffusion rates. However, careful consideration
should be given to sol-to-gel transition temperature as this
will significantly decrease with increasing hydrophobicity of
the poloxamer composition. Desired gelation temperature can
be achieved by incorporating small concentrations of polox-
amers with dominant PEO blocks. Attention should be given
to the total poloxamer concentration, as per the intended
clinical application, because this will significantly affect the
viscosity and flowability of the final formulation.
Physical blending of poloxamer with other additives may
be helpful in extending the release profile from several hours
12 H. ABDELTAWAB ET AL.
up to few days, while crosslinking of poloxamers with poly-
meric additives may offer more extended release profile. This
is explained by the presence of stronger bonds and bridging
between poloxamers and the additive polymer. Some addi-
tives as alginate and sodium chloride significantly enhance the
formulation mucoadhesive properties, which is beneficial for
mucosal applications. Modulation in physical properties and
release profile is associated with the additive concentration
and molecular weight. Hence, the physical properties such as
formulation’s viscosity, flow-ability, and spread-ability should
be studied simultaneously along with the drug release studies.
Incorporating a drug-loaded particulate can sustain the
release profile from these in situ gelling systems from few
days to weeks depending upon the particles properties and
poloxamer matrix. Thereby, the size, composition, and wett-
ability of the dispersed particulates are critically important in
achieving the desired release profile. In addition, the poloxa-
mer matrix composition and strength has a significant role in
shielding the particulates from external environment. The
drug-loading efficiency and the affinity/interaction with parti-
culates should aptly considered.
Chemically synthesized multi-block poloxamers tend to
provide sustained release from weeks to months, which is
suitable in conditions requiring drug release over extended
periods. This approach develops a highly strong gel matrix
with significantly slow erosion rate, without altering the visc-
osity in the sol state. These chemically modified poloxamers
therefore are more suitable for the development of sustained-
release injectable formulations. Nonetheless, poloxamers
obtained after chemical modification are considered new com-
pounds by regulators and therefore the safety and toxicity of
the newly synthesized compounds need to be thoroughly
investigated.
It is hypothesized that enhancing the drug–poloxamer
interaction might significantly limit the initial burst release
and sustain the release of the loaded drug. This approach is
simple and can be easily adopted by selecting the suitable
form of the drug. More lipophilic drug form will demonstrate
higher affinity toward the micellar core, and thus rapid diffu-
sion could be avoided. On the contrary, the more hydrophilic
drug forms tend to partition in the aqueous channels and
diffuse outside the gel matrix rapidly.
Though several studies have demonstrated sustained
release of drugs from poloxamer based in situ gels, there is
considerable variation and a lack of standardization in the
experimental design and methodologies used to characterize
these systems. This variation makes it difficult to directly com-
pare the results of different studies and to fully understand
release mechanisms. In addition, the lack of information
regarding important parameters such as molecular weight,
concentration, and particle size of the additives, makes it
difficult to form meaningful and translatable conclusions
based on the data available in the existing literature.
Researchers in this field should, as far as possible, generate
robust data sets using established methodologies and report
all the experimental parameters available.
It is also recommended that the potential site of adminis-
tration must be critically considered at the initial stage of
formulation development. Since the sol-to-gel transition of
poloxamers is temperature driven, the release profile of the
loaded drug is likely to be greatly affected by the temperature
at the administration site. The physiological temperature var-
ies between different body regions. For example, the normal
temperature of intra-articular joint, skin, corneal, intra-
muscular and vaginal cavity is reported as 32.6°C, 32.7°C,
35.7°C, and 38.2°C, respectively [118–121]. In addition, the
temperature may increase or decrease based on the clinical
condition; for example, intra-articular temperature of healthy
subjects is around 32.6°C, whereas the temperature in case of
osteoarthritis and rheumatoid arthritis is recorded as 33.5°
C and 35.1°C, respectively. On the other hand, the intra-
articular temperature at the time of knee surgery drops
down to 29.9°C [118]. Thus, attention must be given to the
temperature at the application site as per the desired clinical
application. The volume and composition of the biological
fluids at the application site is another important factor to
be considered in the development of a sustained release
poloxamer based in situ gelling systems, as it significantly
affects the gel erosion rate. Our previous findings demon-
strated that poloxamer based gelling systems erode faster in
human synovial fluid compared to the phosphate buffer saline
[122]. Future studies are required to further assess the effect of
these factors on the drug release from poloxamer based in situ
gelling systems.
Poloxamer based in situ gelling systems have promising
potential as drug delivery platforms and will continue to
gain interest in the field of modified release drug delivery. It
is postulated that an increasing number of sustained release,
targeted/localized poloxamer-based delivery systems will
come into light within the coming decade.
Funding
The authors are thankful to the New Zealand Pharmaceutical Education
Research Fund [NZPERF] [Reference number – 3719172] and The
University of Auckland for financial support.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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