European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

www.elsevier.com/locate/ejpb

Review article

Poly(ethylene oxide)–poly(propylene oxide) block copolymer micelles

as drug delivery agents: Improved hydrosolubility, stability
and bioavailability of drugs
Diego A. Chiappetta a, Alejandro Sosnik a,b,*

a
Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
b
National Science Research Council (CONICET), Buenos Aires, Argentina

Received 5 March 2007; accepted in revised form 27 March 2007

Available online 31 March 2007

Abstract

The low solubility in biological fluids displayed by about 50% of the drugs still remains the main limitation in oral, parenteral, and
transdermal administration. Among the existing strategies to overcome these drawbacks, inclusion of hydrophobic drugs into polymeric
micelles is one of the most attractive alternatives. Amphiphilic poly(ethylene oxide)–poly(propylene oxide) block copolymers are ther-
moresponsive materials that display unique aggregation properties in aqueous medium. Due to their ability to form stable micellar sys-
tems in water, these materials are broadly studied as hydrosolubilizers for poorly water-soluble drugs. The present review provides a
concise description of the most important applications of PEO–PPO-based copolymers in the Pharmaceutical Technology field as means
for attaining improved solubility, stability, release, and bioavailability of drugs.
 2007 Elsevier B.V. All rights reserved.

Keywords: Poly(ethylene oxide)–poly(propylene oxide) block copolymers; Poloxamer; Poloxamine; Drug solubilization; Drug stability; Bioavailability;
Drug delivery

1. Introduction and scope A main goal of PT is the design of technologically opti-

mal vehicles for the administration of drugs. Innovative
Advances in medicine and related sciences during the processes allowed an enhancement in the organoleptic
last century led to a dramatic increase in lifespan. One of properties of the preparations and the maximization of
the pillars of this revolution has been the development of the stability and bioavailability. However, a still existing
novel therapeutic agents for the treatment of incurable drawback is the low solubility in the physiological aqueous
pathologies. A critical step forward in this process was environment of about 50% of the approved active mole-
the ability to scale up the production of pharmaceuticals, cules, resulting in limited gastrointestinal absorption and
making drugs available for broad portions of the popula- poor bioavailability. Paradoxically, oral administration of
tion. At the same time a constant and pronounced develop- therapeutic agents is the preferred way to achieve the high-
ment in related disciplines took place. Pharmaceutical est patient compliance [1]. Limited solubility also consti-
Technology (PT) is among the areas that are noteworthy. tutes a hurdle in the development of parenteral and even
topical formulations. Since improved solubility usually cor-
relates well with higher bioavailability [2,3], several nano-
technological strategies are being pursued in order to
*
Corresponding author. Department of Pharmaceutical Technology, guarantee the appropriate drug solubilization [4]. Among
Faculty of Pharmacy and Biochemistry, University of Buenos Aires, 956
Junin St., 6th Floor, Buenos Aires CP1113, Argentina. Tel.: +54 11 4964
them, it is worth mentioning nanoparticle engineering
8273. [5–8]. Another important strategy is the design of nanocar-
E-mail address: alesosnik@gmail.com (A. Sosnik). riers such as liposomes [9,10]. Inclusion of hydrophobic

0939-6411/$ - see front matter  2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejpb.2007.03.022
304 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

molecules within polymeric micelles is also between the poly(ethylene oxide)–poly(propylene oxide) (PEO–PPO–
nano-oriented approaches pursued to enhance drug solubi- PEO) block copolymers [37,38]. These polymers belong to
lization, stability and bioavailability. Polymeric micelles are the family of the so-called smart materials. Aqueous solu-
nanoscopic (>100 nm) structures formed by amphiphilic tions display a sol–gel transition upon heating (sometimes
block copolymers composed of hydrophilic and hydropho- around 37 C) that makes them attractive for the design of
bic chains that self-assemble in water, above a certain con- injectable matrices for minimally invasive biomedical appli-
centration named the critical micelle concentration (CMC) cations [39,40]. They can be implanted as low viscosity liq-
[11]. Micelles comprise an inner and outer domain deno- uids and they form a solid implant upon heating. These
mined core and shell, respectively. Due to the hydrophobic materials are non-irritating when applied topically or subcu-
nature of the core, these entities particularly suit for the sol- taneously, produce little irritation following intramuscular
ubilization of water insoluble molecules, protection of or intraperitoneal administration [41] and show good cyto-
unstable agents from chemical degradation and metabolism compatibility when used in contact with different cell types
by biological agents and sustained release in different formu- [42,43]. Even though PEO–PPO–PEO materials are non-
lations [12]. Depending on the specificity and the properties degradable, molecules with a molecular weight in the
of functional groups present in both components, the 10–15 kDa range are usually filtered by the kidney and
interactions core–drug will have a chemical, physical or elec- cleared in urine [44,45]. Kabanov and collaborator studied
trostatic character. Polymeric micelles are safer for paren- the distribution kinetics of Pluronic P85 [21]. Findings
teral administration than solubilizing agents currently in showed that renal clearance of unimers (isolated molecules)
use like polyethoxylated castor oil (Cremophor EL) or poly- was the main route. In addition, a significant portion of P85
sorbate 80 (Tween 80) [13–16]. Polymeric micelles are was reabsorbed back into the blood. Several PEO–PPO
kinetically stable so they dissociate slowly, even at concen- block copolymers were approved by FDA and EPA as
trations below the CMC, extending circulation times in thermo-viscosifying materials and find application as direct
blood [16]. In addition, they display larger cores than surfac- and indirect food additives, pharmaceutical ingredients
tant micelles, leading to higher solubilization capacity than and agricultural products [46–48]. More recently, Kwon
the regular micelles [16]. Micelles with blocks made of et al. evaluated crosslinked PEO–PPO–PEO matrices as an
poly(ethylene oxide) are sterically stabilized (Stealth) and injectable intraocular lens (IOL) material [49]. Two families
undergo less opsonization and uptake by the macrophages are commercially available: (1) the linear and bifunctional
of the reticuloendothelial system (RES), allowing the PEO–PPO–PEO triblocks or poloxamers (Pluronic) and
micelles to circulate longer in blood [17,18]. The importance (2) the branched 4-arm counterparts named poloxamine
of drug efflux transporters (i.e. P-glycoprotein or PGP) in (Tetronic). The molecular structure of both groups of
disease processes and treatment has led to the development derivatives is exemplified in Schemes 1A and B for Pluronic
of inhibitors to these transporters as adjuncts to therapy F127 and Tetronic 1107, respectively. These materials are
[19,20]. PGP modulators are the most well-known mecha- available in a wide range of molecular weights and EO/PO
nism. Some polymeric micelles inhibit the PGP at different ratios (Table 1). The most extensive work was performed
levels and tissues: drug-resistant tumors, GI tract and on the first group. In order to attain relatively stable gels,
blood/brain barrier, providing routes to overcome drug these applications demand polymer concentrations, usually
resistance or lack of drug absorption [21]. For example, around 15 wt% [42,50–52]. Pluronic F127 formulations led
Bogman et al. investigated the effect of several Pluronic to enhanced solubilization of poorly water-soluble drugs
derivatives on the activity of PGP and MDRP2 (a trans- and prolonged release profile for many galenic applications
porter involved in multidrug resistance mechanisms) in (e.g. oral, rectal, topical, ophthalmic, nasal and injectable
two cell lines over-expressing these membrane transporters preparations), though the high permeability of the gels has
[22]. Data suggested that the materials display a trans- limited the clinical application due to short residence times
porter-specific interaction, rather than unspecific membrane in the biological environment [53]. Cohn et al. reported a
permeabilization. Based on this unique combination of number of modifications that allowed the production of gels
advantageous features, the use of polymer-based micelles using concentrations around 5%: (1) the chain extension of
has become one of the most promising pharmaceutical Pluronic with hexamethylenediisocyanate [54,55] and (2)
nanotechnologies [16,23]. the coupling of different PEG and PPG blocks using bifunc-
Among the polymers displaying micelle-formation abil- tional agents such as phosgene and diacyl chlorides [56,57].
ity, it is worth mentioning conjugates of hydrophilic Matrices showed better stability and integrity in aqueous
poly(ethylene glycol) segments with hydrophobic blocks of environment along the time. Also, more stable networks
phospholipids [21,24], poly(L-amino acids) [25–28] and were obtained by the covalent crosslinking of PEO–PPO–
poly(esters) [21,29,30]. Other derivatives were developed by PEO triblocks modified with methacryloyl [58,59] and silane
the group of Attwood and Booth. They synthesized PEO moieties [59,60]. In contrast, the potential of poloxamines
block with other polyethers such as poly(butylene oxide) was less explored. Their main drawback probably stems
(PBO) [31–33], poly(styrene oxide) (PS) [31–34] and from the even higher concentrations required to produce gels
phenylglycidyl ether [35,36]. However, the most broadly (20–30%). Due to the higher functionality compared to their
investigated amphiphilic materials are derivatives of linear derivatives, poloxamines were mainly applied in the
 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317 305

H( ) (O )( )O
O 99 67 O 99 H

poloxamer Pluronic F127

O
O 19 60
H

H O N O
O 60 19 N O H
19 60

H O
O 60 19

+
poloxamine Tetronic 1107

Scheme 1. Molecular structure of PEO–PPO block copolymers. (A) Lineal bifunctional poloxamer Pluronic F127 (MW = 12.6 kDa) and (B) branched 4-
arm poloxamine Tetronic 1107 (MW = 15 kDa), both polymers containing 70 wt% of PEO.

design of crosslinked hydrogels for Tissue Engineering [61], in aqueous media. Afterwards, a thorough and comprehen-
using concentrations under the minimal concentration sive summary of relevant research works is disclosed.
required for gelation [62–64]. PEO–PPO molecules self- Finally, the limitations of these materials, as seen by the
assemble into multi-molecular aggregates having spherical, authors, and the perspectives for the future will be
rod-like or lamellar morphologies. This phenomenon is discussed.
observed at much lower concentrations than those required
for gel formation (<1 wt%) [65]. Fig. 1 presents cryo-TEM 2. Aggregation properties of Pluronic.TM and Tetronic.TM
micrographs of spherical micelles formed by Pluronic F127
and P64 [66]. The brighter core and darker shell are apparent. Micellization of PEO–PPO block copolymers in water
An extensive work applying PEO–PPO micellar systems for depends on (1) compositional parameters and (2) environ-
drug solubilization has been published. These investigations mental features. Due to the relevance of this phenomenon a
mainly focused on poloxamers. However, in the last years the concise description of the parameters affecting the process
interest for the application of poloxamine has gradually is herein included. The works cited are those which even
risen. A remarkable advantage of poloxamine arises from if focused on a limited number of derivatives arrived at
the presence of two tertiary amine groups in the center of conclusions extensive to other materials of the same family.
the molecule. This structure contributes to the thermal sta-
bility and more importantly confers the molecule a dual 2.1. The composition: EO/PO ratio and molecular weight
behavior: temperature and pH sensitiveness [67]. In addi-
tion, these functional groups potentially enable further mod- Alexandridis et al. have shown that micellization is
ifications of the molecule by the introduction of additional strongly driven by an entropy gain and the free energy of
useful moieties, such as quaternary ammonium groups for micellization is mainly a function of the PPO block [68].
improved cell adhesion [64]. The quaternization of polox- This entropy gain is related to the release upon heating
amine renders chains that are positively charged, indepen- of hydration water molecules ordered around the hydro-
dently of the pH of the medium, and may contribute to phobic segment (PPO). The higher the content of PEO
increase or to decrease the core affinity of certain drugs. In (and lower EO/PO ratio) and the lower the molecular
these derivatives, a different aggregation pattern is expected. weight of the polymer, the higher the critical micellar tem-
The micellization process of methylated Tetronic 1107 is perature (CMT) observed [69]. An increase in the content
presently being subject of study in our laboratory. of PPO results in lower CMC and CMT values [70]. Both
The goal of the present review is to provide a concise CMC and CMT values decrease with increasing molecular
and up-to-date summary of the past and recent applica- weight for copolymers displaying similar EO/PO ratios.
tions of PEO–PPO-based copolymers in the Pharmaceuti-
cal Technology field as means for attaining improved 2.2. The temperature
solubility, stability and bioavailability of drugs. Since mic-
ellization is the critical stage for these materials to modify A thorough work on the effect of the temperature on the
the behavior of hydrophobic molecules in aqueous medium micellization of PEO–PPO–PEO has been reported by sev-
and it is directly involved in solubilization and stabilization eral researchers [68–77]. Less hydrophobic copolymers
phenomena, the first part will summarize the main works (higher EO/PO ratio) or lower molecular weight do not
that investigated the aggregation of PEO–PPO molecules aggregate at room temperature but start to form micelles
306 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

Table 1
Description of PEO–PPO block copolymers commercially available
Copolymer MW (Da) Total average number Total average number Total weight Total weight pH (2.5% aqueous)
of EO units of PO units of EO units (Da) of PO units
Pluronic
L10 3200 7.3 49.7 320 2880
L35 1900 21.6 16.4 950 950
F38 4600 83.6 15.9 3680 920
L42 1630 7.4 22.5 325 1305 5.0–7.5
L43 1850 12.6 22.4 555 1295
L44 2200 20.0 22.8 880 1320
L61 2000 4.55 31.0 200 1800
L62 2500 11.4 34.5 500 2000
L64 2900 26.4 30.0 1160 1740
L65 3400 38.6 29.3 1700 1700 6.0–7.4
F68 8400 152.7 29.0 6720 1680 5.0–7.5
F77 6600 105.0 34.1 4620 1980 6.0–7.0
L81 2750 6.3 42.7 275 2475 5.0–7.5
P84 4200 38.2 43.5 1680 2520
P85 4600 52.3 39.7 2300 2300 6.0–7.4
F87 7700 122.5 39.8 5390 2310
F88 11,400 207.3 39.3 9120 2280 6.0–7.0
L92 3650 16.6 50.3 730 2920 5.0–7.5
F98 13,000 236.4 44.8 10,400 2600 6.0–7.4
L101 3800 8.6 59.0 380 3420 5.0–7.5
P103 4950 33.8 59.7 1485 3465
P104 5900 53.6 61.0 2360 3540
P105 6500 73.9 56.0 3250 3250
F108 14,600 265.5 50.3 11,680 2920 6.0–7.4
L121 4400 10.0 68.3 440 3960
L122 5000 22.2 69.0 1000 4000
P123 5750 39.2 69.4 1725 4025
F127 12,600 200.5 65.2 8820 3780
Tetronic
304 1650 15.0 17.1 660 990
701 3600 8.2 55.9 360 3240
704 5500 50.0 56.9 2200 3300
803 5500 37.5 66.4 1650 3850
901 4700 10.7 72.9 470 4230 8.0–10.0
904 6700 60.9 69.3 2680 4020
908 25,000 454.5 86.2 20,000 5000
1107 15,000 238.6 77.6 10,500 4500
1301 6800 15.5 105.5 680 6120
1304 10,500 85.5 108.6 4200 6300
1307 18,000 286.4 93.1 12,600 5400

at higher temperatures. A slight increase of temperature was observed with the increase of neutral salts’ concen-
leads to a sharp CMC decrease and the increase in the aver- tration [79–83]. It should be stressed that studies with
age aggregation number, the micellar size, and the fraction the same cation showed that the properties of the coun-
of polymer molecules in micellar form [73,78]. A similar ter-anion are also relevant. For potassium halides, the
trend was observed with the CMT. effect of on micellization follows the sequence
KCl > KBr > KI [78,79]. In another work it was shown
2.3. The ionic strength and salt nature that while NaCl had a stabilizing effect, NaSCN dis-
played the opposite influence [84]. Pandit and Kisaka
Since many drugs have an ionic character and media reported that salts with multivalent anions, at character-
used for the formulations usually comprise salts for pH istic concentrations, prevent Pluronic F127 solutions
buffering and ionic strength balance, these parameters from forming gels, being an indication of a destabilizing
may critically influence the behavior of PEO–PPO-based effect [85]. For example, phosphate anions increased the
molecules in aqueous medium. Addition of electrolytes transition to higher temperatures. In contrast, with car-
having anions and cations of different sizes and polariz- bonate the CMT of Pluronic F88 moved down to lower
abilities may lead to: (1) ‘salting out’ and stabilizing temperatures [86]. The authors proposed a critical micelle
effect or (2) ‘salting in’ and destabilizing effect [74]. In salt concentration (CMSC) as the salt concentration at
general, a gradual decrease in the CMC and the CMT which the micelles begin to form [86].
 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317 307

Fig. 1. Electron micrograph of a vitrified sample of (A) 10% Pluronic F127 and (B) 10% Pluronic L64 solutions. Scale bar = 100 nm. (Reprinted with
permission from Ref. [66];  Royal Society of Chemistry, 1999.)

2.4. Small organic molecules P123 at different HCl solutions [99]. Findings indicated
that the CMT of Pluronic P123 increased when acid was
Solubilized drugs are expected to modify the aggregation added. This phenomenon could occur due to the enhance-
pattern and the stability of the micelles. Regardless of the rel- ment of the interaction between the alkyl group and the
evance of this parameter on the micellization capability, protonated water molecules. In the case of poloxamine,
most of the works focused more on the aspects related to the presence of a central diamine group in the molecular
drug solubility and less on the reciprocal effect of small structure renders both thermo- and pH-responsiveness.
organic molecules on the structure of the aggregates. Tonto- Only a very limited number of works reporting the micelli-
sakis and co-workers showed that small amounts of o-xylene zation of poloxamine at different pH were previously pub-
increased the tendency of the amphiphile to aggregate on the lished. Accordingly, basic/acid equilibrium appears to have
micellar structure of PEO–PPO–PEO triblocks [87]. Alexan- an important impact upon aggregation [100]. A low pH
dridis et al. reported that urea increased both CMC and protonated amines lead to coulombic repulsion and curtails
CMT [88]. Contrarily, phenol appeared to decrease the aggregation [101]. Poloxamine pKa values are usually in the
CMC due to interactions with PEO chains [89]. When 3.8–4.0 to 8.0 range and varying sized chains of blocks of
another surfactant, sodium dodecyl sulfate (SDS), was PPO and PEO bounded to the ethylenediamine molecule
added to Pluronic F127, the surfactant associated to F127 do not substantially change these values [67]. The shift in
unimers and suppressed micellization completely [90,91]. the pKa of the second amine is caused by the effect of
Naproxen and indomethacin did not affect the CMC, though charge repulsion. At pH 2.5, poloxamine exists in a diprot-
they caused a slight decrease in the size of the micelles and a onated form and aggregation is shifted to a higher temper-
large decrease in the aggregation numbers [92]. The same ature range. An increase in pH leads to a decrease in the
group of investigators evaluated the influence of mamma- temperature range over which aggregation occurs. At pH
lian-cell media on the gelation properties of the same poly- 6.8, the percentage of aggregation increases and it is even
mer [93]. Also pilocarpine hydrochloride decreased the higher at pH > 8 [102]. At physiological pH, there is one
CMC from 0.5% to 0.25% [94]. Short-chain alcohols (i.e. eth- positive charge per poloxamine molecule [100]. Alvarez-
anol) prevented micellization in water [95], while medium- Lorenzo et al. investigated the influence of pH on the
chain and more hydrophobic aliphatic alcohols (i.e. butanol) aggregation of poloxamine T904 [103]. Findings showed
favored aggregation [95–97]. that the aggregation number is altered by a change in pH
or ionic strength. As appreciated in TEM micrographs of
2.5. The concentration T904 30% systems, a great number of significantly small
entities (2 nm) were formed at pH 1 (Fig. 2) [103]. Authors
The concentration of the polymer is another aspect of assigned them to the presence of small micelles, though the
consideration [98]. In general, the higher the concentration described sizes could also correspond to dehydrated uni-
of the polymer, the lower the temperature required to mers (one single polymer molecule) [55]. In contrast, in a
attain micellization [74,78]. more basic medium, the micelles were larger (10–20 nm)
and the size distribution more homogeneous. Another
2.6. The pH aspect of interest is the potential modification of polox-
amine. Sosnik and Sefton reported on the methylation of
Pluronic molecules do not display pH-sensitive moieties Tetronic 1107 with iodomethane for enhanced cell attach-
in their structure. Thus, the study of the pH influence on ment in a modular Tissue Engineering construct [64].
the aggregation behavior of Pluronic was very limited. Due to the permanent cationic character of the modified
Yang et al. investigated the micellization of Pluronic molecule, one could expect a behavior similar to the
308 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

Fig. 2. TEM micrographs of 30% T904 solutions prepared in different media and negatively stained with phosphotungstic acid (110,000·). (Reprinted
with permission from Ref. [103];  Elsevier, 2007.)

pristine poloxamine at low pH (where one or amine groups tration rises above the CMC, a sharp increase in the appar-
are protonated) that displays higher CMC and CMT val- ent solubility is observed as molecules accommodate within
ues than the non-protonated molecule. Studies on micelli- the hydrophobic micellar core. They proposed a simple sol-
zation of this derivative are being pursued these days in ubilization model demonstrating that a turning point
our laboratories. Applications where PEO–PPO block (sharp increase in the gradient) will take place at the
copolymers are used for the stabilization of particles exceed CMC. The equations describing this phenomenon are the
the scope of the present review. However, a noteworthy following [107]:
example where the pH-dependency of poloxamine was
If Cs < CMC
exploited is the stabilization of negatively charged DNA
particles with protonated poloxamine molecules [104]. S apparent
¼ 1 þ K unimer  C S
S
3. Micellar solubilization of poorly water-soluble molecules If Cs > CMC
S apparent
Solubilization properties of the polymeric micelles are ¼ 1 þ K unimer  CMC þ K micelle  ðC S  CMCÞ
usually expressed in terms of micelle–water partition coef- S
ficients defined as the ratio between the concentration of where Sapparent is the aqueous solubility measured in the
the solubilizate inside the micelle and the concentration surfactant solution and S is the solubility in pure water, ex-
of the solubilizate that is molecularly dispersed in the aque- pressed in mol/L. CS is the concentration of surfactant in
ous phase, being the concentration in molarity [105,106]. the aqueous phase, Kunimer and Kmicelle are equilibrium con-
The solubilization capacity can be expressed either in the stants describing the solute–unimers (<CMC) and solute–
form of the volume or mass fraction of the solubilizate in micelles (>CMC) interaction, respectively. In general, solu-
the micellar core, as the number of moles solubilized per bilization is found to increase the micelle core radius and to
gram of hydrophobic block or as the molar solubilization decrease the CMC [105]. The radius increases due to both
ratio (MSR) that is the molar ratio of the moles of guest incorporation of solute molecules and increase in aggrega-
molecule to the moles of polymer molecules in the aggre- tion number. More hydrophobic derivatives (lower EO/PO
gate. The maximal solubilization capability of amphiphilic ratio) display higher solubilization capacity and higher
materials relies on the formation of micelles [101]. Never- changes in the dimensions. In contrast, the shell thickness
theless, Paterson et al. showed improved solubilization of (PEO) is less affected. The effect of the concentration of
naphthalene even below the CMC [107]. Once the concen- the polymer on solubilization is exemplified in Fig. 3 for
 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317 309

weight [108]. Table 2 summarizes the most important stud-

ies on solubilization, stabilization and delivery of hydro-
phobic drugs using PEO–PPO-based polymeric micelles.
Concheiro et al. explored the effect of Pluronic F127
grafted with poly(acrylic acid) blocks. These dual materials
enhanced the solubility (3- to 4-fold increase) of the lactone
form of camptothecin, an antitumoral drug [109]. Also, the
stability of the active form of the drug was improved. The
amount of drug solubilized per PPO was considerably
greater in the Pluronic-PAA solutions than in the parent
Pluronic solution, which suggests that the drug is not only
solubilized by the hydrophobic cores but also by the hydro-
philic PEO–PAA shells of the micelles. An interesting ap-
Fig. 3. Naphthalene solubility enhancement ratio (Sw/S) as a function of proach combining micelle encapsulation with additional
P103 surfactant concentration. d represents the experimental data. means to target the drug release is the comprehensive re-
(Reprinted with permission from Ref. [107];  American Chemical search by Rapoport and colleagues on the design of nano-
Society, 1999.)
carriers for the targeted release of doxorrubicin (Dox) to
tumors [110–116]. This methodology reduced unwanted
naphthalene solubilized in poloxamine 803 at 25 C and drug interactions and nocive effects on healthy tissues
pH of 10.3 [107]. It is worth stressing the low CS initial val- and relies on the encapsulation of the chemotherapeutic
ues at CS < CMC. In contrast, a dramatic increase in the agent within polymeric micelles and the application of local
CS was apparent when micelles were formed. Then, a grad- ultrasonic irradiation on the tumor. Main mechanisms of
ual increase in the polymer led to higher micellar concen- the biological action of ultrasound are related to the gener-
trations and consequently, to higher solubilized solute. ation of thermal energy, perturbation of cell membranes
Therefore, solubilization will be intimately related to the under the action of microconvection or inertia cavitation
micellization process and the parameters governing both and enhanced permeability of blood capillaries [110]. As
phenomena are the same. This can be exemplified for the described by the authors of that work, the encapsulated
temperature: the apparent aqueous solubility of a hydro- drug primarily accumulated in the tumoral cells’ interstit-
phobic solute dramatically rises at higher temperature ium and later on, irradiation of the affected area resulted
[101]. This effect is more pronounced at concentration lev- in a more effective cellular uptake. The mechanism recently
els close to the CMC. This is exemplified in Fig. 4 for two- proposed by the group of Pitt in order to explain the more
model hydrophobes: phenanthrene and pyrene [101]. A efficient release of the drug from the micelles relies on the
similar trend is observed with poloxamine at different destruction of the micelles during the application of ultra-
pH. Since micellization is favored at pH > 8, hence solubil- sound [116]. Micelles are destroyed because of cavitation
ity is. Another important parameter is the hydrophobicity events produced by collapsing nuclei or bubbles in the irra-
of the surfactant molecule. In general, the micelle–water diated area. Once the ultrasonic radiation halts two inde-
partition coefficient increases with increasing polypropyl- pendent mechanisms take place: (1) reassembly of
ene oxide content of the polymer and with molecular micelles and (2) the re-encapsulation of Dox. These two
mechanisms are responsible for maintaining the drug re-
lease at a partial level and for the recovery observed after
insonation ceases. Witt et al. studied the opioid analgesia
enhancement of an opioid peptide and morphine using Plu-
ronic P85 below and above the CMC [117]. Data showed a
clear increase in the peak effect and a prolonged effect. As
previously indicated, the CMC and the partition coefficient
are the major thermodynamic constants determining the
stability of the micellar carrier and the drug release in equi-
librium conditions [118].
One main concern following the use of polymeric
micelles for drug solubilization is the severe dilution they
undergo in the biological environment (sometimes below
the CMC) that results in a decrease in the portion of the
micelle-incorporated drug. The CMC values observed for
these block copolymers are generally in the range from
Fig. 4. Solubility enhancement of phenanthrene and pyrene as a function 5 · 103 to 1 wt%. The rate of dissociation is related to
of temperature at a pH of 5.6 and T803 concentration of 5 mM. composition, physical state and cohesion of the micelle
(Reprinted with permission from Ref. [101]; Elsevier, 2004.) core [119]. It has been demonstrated that the micellar
 310
Table 2
Summary of the most important studies on solubilization, stabilization and delivery of hydrophobic drugs using PEO–PPO-based polymeric micelles
Drug Pharmacological Copolymer Administrationa Observations Reference
activity

D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317
Tropicamide Mydriatic/cycloplegic L-64, P65, F68, P75, F77, Ocular Solubility increased linearly with increasing surfactant concentration. [128]
P84, P85, F87, F88, F127 Higher solubility for higher EO content.
Haloperidol Neuroleptic P85 i.p. 5-fold increase in solubility. [129]
Morphine Central analgesia F127 Ocular Drug was soluble. Prolonged delivery [130]
(CNS)
P85 i.v. Increased analgesia due to both an increase in peak effect, as well as a [117]
prolongation of effect
Estriol HRT L64 – The solubility of estriol increased with Pluronic concentration and [131]
temperature.
L64 – Higher solubilization with higher polymer and salt concentration [132]
F127 modified with PAA – Increased solubility above CMT. Better solubilization in modified polymers [133]
segments than in native Pluronic.
Dichloroplatinum (II) Anticancer F68 Parenteral Stable colloidal suspension. Effective against hormone sensitive MXT-M- [134]
complexes 3.2 breast cancer.
Cyclosporin A Immune-depressant F68 – Thermal analysis of solubilization process. [135]
Epirubicin Anticancer L61, P85, F108 s.c. Lifespan of animals and inhibition of tumor growth considerably increased [136]
with drug/copolymer compositions.
Naproxen NSAID F127 Topical, i.v. Increased solubility. Longer half-life by i.v. [137,138]
Doxorubicin (DOX) Anticancer P105 i.p. Local ultrasonic irradiation of the tumor increased drug accumulation in [110–
the tumor cells. Substantial decrease of the tumor growth rates. 116,120–
122,165]
P105 – Lower rat prostate carcinoma cells’ (MatLu) proliferation in vitro with [139]
micellar system.
Doxorubicin (DOX) Anticancer P85 – A formulation containing the block copolymer Pluronic P85 and [140]
antineoplastic drug doxorubicin (Dox) prevents the development of
multidrug resistance in the human breast carcinoma cell line, MCF7.
F87 modified with PAA – Improved inclusion due to interactions between PAA and drug. [141]
segments
Pilocarpine Miotic F127 Ocular Polymer combined with additives displayed higher solubility. [142,143]
F127 Ocular Base and hydrochloride form. Prolonged activity and higher bioavailability. [94]
Clonazepam Psychotropic F68 – 3.5-fold solubility increase. [144]
Propranolol Hypertension F127 – Improved release profile. [145]
Propranolol Æ HCl F68, F127 Rectal Drug is soluble. Located outside micelles. Improved bioavailability when [146]
combined with mucoadhesives.
Insulin Hormone, glucose F127 Rectal Formulations containing unsaturated fatty acids. Rectal insulin absorption [147]
transport enhanced. Marked hypoglycemia.
Subcutaneous Formulations containing unsaturated fatty acids. Slower and more [50]
prolonged hypoglycemic effect attained in inverse proportion to the
polymer concentration.
Buccal Formulations containing unsaturated fatty acids. Buccal insulin absorption [148]
enhanced. Marked hypoglycemia.
Vancomycin Antibiotic F127 Subcutaneous Controlled release and good preservation of the drug. [149]
Diclofenac NSAID F127 – Study on diethylamine derivative and sodium salt. [150]
F127 Rectal Drug is soluble. Faster absorption. [151]
Ketoprofen NSAID F127 Topical Enhanced permeability with enhancers. [152]
Piroxicam Antiinflammatory F68, F127 Percutaneous Better release profile. [153]
Indomethacin Antiinflammatory F68, F127 Ocular Higher solubility and chemical stability. Prolonged in vitro drug diffusion [154]
and showed high physiological tolerance on rabbit eyes.
Lidocaine/Prilocaine Local anesthetics F68, F127 Topical (mouth) Eutectic mixture. Amount of the active ingredients in the micelle phase [52]
depends on the pH: higher at higher pH (non-ionic drug).
Triamcinolone Glucocorticoid F127 combined with Topical (mouth) Enhanced delivery profile. [155]
carbopol

D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317
Digoxin Heart muscle P85 i.v. Pluronic P85 can enhance the delivery of digoxin to the brain through the [156]
stimulant inhibition of the P-glycoprotein-mediated efflux mechanism.
Griseofulvin Antifungal Synperonic P94b – Lower solubilization ability than polymers with poly(oxybutylene) and [33]
poly(oxyphenylethylene) as hydrophobic block.
Tetronic 904 – Higher solubility at higher pH due to improved micellization [103]
Deslorelin GnHR agonist F127 i.m. Broader peak of luteinizing hormone (LH). Lower peak and delayed [157]
activity with the gel.
Biphalin CNS analgesia P85 i.v. Study to improve BBB transfer. Higher peak effect and longer activity. [117]
Timolol maleate Glaucoma F127 Ocular Drug is soluble. About 2.4-fold improved bioavailability [158]
Tropicamide mydriatic/cycloplegic P85 Ocular Solubility increased 1.9 times, faster peak and longer activity. [159]
Benzoporphyrin Anticancer P123 – No evaluation in vitro or in vivo up-to-date. [160,161]
Estradiol HTR F127 – Effect on release by carbopol matrix. Increased solubility above CMC. [162]
Propofol Anesthetic F68, F127 – Higher solubility. [163]
F68, F127 and mixed Higher solubility in mixed systems [164]
micelles
Fluorescent molecule Anticancer P105 i.p., i.v. Local ultrasonic irradiation of the tumor increased drug accumulation in [165]
model cancerous ovarian tissue.
Camptothecin (CPT) Anticancer F127, L92 and modified – CPT solubility 3- to 4-fold higher. CPT solubilized per PPO greater in the [109]
with PAA blocks Pluronic-PAA than parent, suggesting solubilization by the hydrophobic
cores and hydrophilic shells. Enhanced stability.
F127, F68, P85 – Improved oral absorption estimated in vitro. [27]
Megestrol Hormone Mixture F127/L61 Oral Enhanced bioavailability [166]
replacement therapy
Nystatin Antimycotic F68, F98, P105, F127 Solubility increased from 20 to >350 lM. The higher the polarity of the [167]
molecule the lower the solubility.
Ibuprofen NSAID F68 Oral Ibuprofen in eutectic mixture with menthol. [168]
Paclitaxel (PTX) Anticancer P123 i.v. Pluronic P123 solubilize PTX, prolonged blood circulation time and modify [169]
the biodistribution of PTX. t1/2 was 2.3-fold higher injection. Increased the
uptake of PTX in the plasma, ovary and uterus, lung, and kidney, but
decreased uptake in the liver and brain.
Octaethylporphine F127, F68, P85 – Improved oral absorption estimated in vitro. [170]
Meso-tetraphenyl Photosensitizer for F127 – Improved oral absorption estimated in vitro. [170]
porphine cancer treatment
Rofecoxib NSAID F68, F127 – Improved solubility [171]
Abbreviations: CNS, central nervous system; HRT, hormone replacement therapy; NSAID, non-steroidal anti-inflammatory drugs; BBB, blood–brain barrier.
a
For studies in vivo.
b
Synperonic is another PEO–PPO–PEO triblock trademark (ICI C&P). Synperonic P94 (PEO21–PPO47–PEO21) has a molecular weight of 4600 and 60 wt% PEO.

311
312 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

stability increases with the length of the hydrophobic philic (e.g. F127, P105, F87, P85, and F68) Pluronic block
segment and the overall hydrophobicity of the amphiphile. copolymers [65]. Even though, large aggregates were pri-
Due to the relevance of this phenomenon, the next section marily formed and phase separation apparent during the
will introduce a number of strategies pursued in order to first 24–48 h, sonication (1–2 min) or heating (70 C,
enhance the stability of PEO–PPO polymeric micelles. 30 min) stabilized the dispersions. A combination L121/
F127 (1:1% weight ratio) formed stable dispersions with a
4. Stabilization of micelles small particle size and displayed about 10 times higher sol-
ubilization capacity of a hydrophobic dye compared to that
As previously explained, one of the problems related to of pure F127 micelles. However, results indicated that mix-
the use of micelles for drug solubilization is that the aggre- tures are kinetically stabilized and since they are thermody-
gates disassociate at low concentration (upon dilution in namically unstable they will finally separate.
biological environment) and are no longer able to maintain A novel strategy introduced in the last years is the cross-
hydrophobic drugs in the core. The stability of more linking of the micellar shell. Terminal hydroxyl groups
hydrophilic derivatives is more critically affected. This phe- undergo modification to improve reactivity and are further
nomenon could be explained by the fact that more hydro- reacted with coupling agents or by free radical polymeriza-
phobic polymers display lower CMC and CMT and tion reactions. Two different effects can be observed: (1)
concentrations remain above those values even after high micellar stabilization and (2) tunable shell permeability,
dilution. In order to overcome these disadvantages physi- being the latter critical for drug inclusion and release rates
cally and chemically stabilized micelles were developed. [124]. Only a few works pursuing this approach were
Nevertheless, it is worth mentioning that a prolonged cir- reported. Bae et al. modified two-terminal hydroxyl groups
culation not always leads to an improvement in the thera- of Pluronic F127 with thiol moieties and were exposed after
peutic index of the drug. Kabanov and colleagues well micellization to gold nanoparticles generated in situ [125].
stated that there must be an equilibrated affinity between The resultant shell crosslinked gold–Pluronic micelles
the components so that the effective inclusion of the drug exhibited a temperature-dependent volume transition: their
in the micellar core increases stability and circulation time hydrodynamic diameter decreased from about 160 nm at
of the drug on one hand, and gives place to an effective 15 C to about 60 nm at 37 C as determined by dynamic
release from the carrier within the critical site of action light scattering. Yang and co-workers stabilized Pluronic
on the other [47]. Thus, a very strong interaction core–drug P121 micelles by converting the alcohol groups into alde-
will curtail the gradual release of free drug in a manner that hydes and bridging them with diamines through the forma-
allows therapeutic levels’ attainment. In an early work, tion of Schiff bases [126]. The morphology of the
Rapoport explored three alternatives to stabilize Pluronic aggregates remained spherical in shape and the mean par-
micellar systems [120]: (1) direct radical crosslinking of a ticle sizes of the micelles before and after crosslinking were
reactive monomer (e.g. styrene) in the micellar cores, (2) comparable (100 nm). This modification significantly
inclusion of a small concentration of vegetable oil into reduced the CMC and greatly enhanced the stability of
diluted Pluronic solutions and (3) polymerization of a tem- the micelles. A similar chemistry was employed to
perature-responsive LCST hydrogel in the core of Pluronic shell-crosslink Pluronic F127 micelles with a 6-arm
micelles and the generation of a core-located semi-interpen- amine-terminated PEG [127]. The nanocapsules were used
etrating network. The first route compromised the drug for encapsulation of paclitaxel in an oily core. Regardless
loading capacity of the micelles due to the high crosslinking of the intended modifications, stabilization of PEO–PPO-
density. The second resulted in decreased micelle degrada- based micelles without affecting the sequestration capacity
tion upon dilution due to the expected decrease of the and release profile still remains a challenge.
CMC, while not compromising the drug loading capacity
of oil-stabilized micelles. The last one appeared to be the 5. Limitations and perspectives
most beneficial. The crosslinkable system was based on
poly(N-isopropylacrylamide) [120]. Later on, Pitt and co- Hydrosolubilization of pharmacologically active mole-
workers polymerized N,N-diethylacrylamide in the cules is the critical stage in order to attain bioabsorption
presence of Pluronic P-105 micelles [121,122]. The interpen- and biodistribution. The paradox is that about 50% of
etrating network formed stabilized the micelles at concen- the drugs display from a very limited to negligible water
trations below the critical micellar concentration of free solubility values. In this context, different nanotechnologi-
polymer, though the increased micellar stability was not cal methodologies are being intended. Inclusion into poly-
permanent and disappeared over a time period of days to meric micelles is one of the most attractive. Among them,
weeks. Petrov et al. applied a similar procedure and stabi- PEO–PPO based aggregates are the most broadly investi-
lized Pluronic F68 aggregates by UV-induced free-radical gated. PEO–PPO block copolymers have gained popularity
polymerization of pentaerythritol tetraacrylate in the over the decades due to a number of critical reasons: (1)
micellar core [123]. In order to overcome lack of stability very broad range of compositions (MW, EO/PO ratio),
Kabanov et al. introduced the concept of binary mixing (2) commercial availability (very important in pharmaceu-
of hydrophobic (e.g. L121, L101, L81, and L61) and hydro- tical sciences in order to obviate synthetic procedures), (3)
 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317 313

proven biocompatibility for many of the derivatives and rates of poorly water-soluble drugs, Eur. J. Pharm. Biopharm. 65
minor side effects in vivo and (4) approval by regulatory (2007) 57–67.
[7] R.H. Muller, C. Jacobs, O. Kayser, Nanosuspensions as particulate
institutions (i.e. FDA) to be used in pharmaceutical formu- drug formulations in therapy rational for drug development and
lations. Despite all these advantages, it is worth mentioning what we can expect for the future, Adv. Drug Deliv. Rev. 47 (2001)
that PEO–PPO block copolymers still present a number of 3–19.
limitations that depending on the specific case could curtail [8] J.E. Kipp, The role of nanoparticle technology in the parenteral
the application. The most important has to do with the low delivery of poorly water-soluble drugs, Int. J. Pharm. 284 (2004)
109–122.
stability of the self-assembled nanostructures upon dilution [9] G. Gregoriadis, E.J. Wills, C.P. Swain, A.S. Tavill, Drug carrier
in the bloodstream. This phenomenon is more crucial in potential of liposomes in cancer chemotherapy, Lancet 1 (1974)
derivatives with higher EO/PO ratios. Core and shell-stabi- 1313–1316.
lized micelles were produced by a number of scientists [10] P. Couvreur, C. Vauthier, Nanotechnology: intelligent design to
though agreement exists that the intended modifications treat complex disease, Pharm. Res. 23 (2006) 1417–1449.
[11] K. Kataoka, A. Harada, Y. Nagasaki, Block copolymer micelles for
affected the release profile of the drugs. The limited stabil- drug delivery: design, characterization and biological significance,
ity of the gels in aqueous environment was described Adv. Drug Deliv. Rev. 47 (2001) 113–131.
above. Cohn et al. design several synthetic alternatives to [12] S.R. Croy, G.S. Kwon, Polymeric micelles for drug delivery, Curr.
overcome the high permeability of the matrices that Pharm. Design 12 (2006) 4669–4684.
resulted in short residence times [54–60]. Finally, the more [13] D. Le Garrec, S. Gori, L. Luo, D. Lessard, D.C. Smith, M.-A.
Yessine, M.M. Ranger, J.-C. Leroux, Poly(N-vinylpyrrolidone)-
hydrophilic representatives of this family of compounds block-poly(D,L-lactide) as a new polymeric solubilizer for hydro-
display lower micellization ability at 25 C and lower solu- phobic anticancer drugs: in vitro and in vivo evaluation, J. Control.
bilization capacity. In this context, a series of more hydro- Release 99 (2004) 83–101.
phobic counterparts with similar architecture but where the [14] R.G. Strickley, Solubilizing excipients in oral and injectable formu-
PPO segment was conveniently replaced by a more hydro- lations, Pharm. Res. 21 (2004) 201–230.
[15] L. Van Zuylen, J. Verweij, A. Sparreboom, Role of formulation
phobic one (i.e. poly(butylene oxide) and poly(styrene vehicles in taxane pharmacology, Invest. New Drugs 19 (2001)
oxide)) has been developed by the group of Attwood and 125–141.
Booth [31–36]. Due to the higher hydrophobicity, these [16] G.S. Kwon, Polymeric micelles for delivery of poorly water-soluble
micellar aggregates showed improved solubilization ability compounds, Crit. Rev. Therap. Drug Carrier Syst. 20 (2003)
and stability. 357–403.
[17] G. Barratt, Colloidal drug carriers: achievements and perspectives,
Considering pros and contras, PEO–PPO materials rep- Cell. Mol. Life Sci. 60 (2003) 21–37.
resent a very versatile alternative to enhance formulations [18] S.M. Moghimi, I.S. Muir, L. Illum, S.S. Davis, V. Kolb-Bachofen,
of poorly water-soluble drugs. They have gone a long route Coating particles with a block co-polymer (poloxamine-908) sup-
that includes approval of some of the materials by the presses opsonization but permits the activity of dysopsonins in the
Food and Drug Administration. Since several drawbacks serum, Biochim. Biophys. Acta 1179 (1993) 157–165.
[19] A.H. Dantzig, D.P. de Alwis, M. Burgess, Considerations in the
were overcome at least partially by introducing chemical design and development of transport inhibitors as adjuncts to drug
modifications to their structure, future perspectives will therapy, Adv. Drug Deliv. Rev. 55 (2003) 133–150.
probably need to face the low stability of the aggregates [20] T.M. Fahmy, P.M. Fong, A. Goyal, W.M. Saltzman, Targeted for
in a more extended and comprehensive way. Our group is drug delivery, Mater. Today 8 (2005) 18–26.
dedicating efforts to modify poloxamine molecules in order [21] E.V. Batrakova, S. Li, Y. Li, V.Yu. Alakhov, W.F. Elmquist, A.V.
Kabanov, Distribution kinetics of a micelle-forming block copoly-
to allow further stabilization procedures. mer Pluronic P85, J. Control. Release 100 (2004) 389–397.
[22] K. Bogman, F. Erne-Brand, J. Alsenz, J. Drewe, The role of
References surfactants in the reversal of active transport mediated by multidrug
resistance proteins, J. Pharm. Sci. 92 (2003) 1250–1261.
[1] M.F. Francis, M. Cristea, F.M. Winnik, Polymeric micelles for oral [23] C.O. Rangel Yagui, A. Pessoa Jr., L. Costa Tavares, Micellar
drug delivery: Why and how, Pure Appl. Chem. 76 (2004) 1321– solubilization of drugs, J. Pharm. Pharm. Sci. 8 (2005) 147–163.
1335. [24] R. Vakil, G.S. Kwon, Poly(ethylene glycol)-b-poly(e-caprolactone)
[2] G.L. Amidon, H. Lennernäs, V.P. Shah, J.R. Crison, A theoretical and PEG-phospholipid form stable mixed micelles in aqueous
basis for a biopharmaceutic drug classification: the correlation of media, Langmuir 22 (2006) 9723–9729.
in vitro drug product dissolution and in vivo bioavailability, Pharm. [25] A. Lavasanifar, J. Samuel, G.S. Kwon, Poly(ethylene oxide)-block-
Res. 12 (1995) 413–420. poly-(L-amino acid) micelles for drug delivery, Adv. Drug Deliv.
[3] C. Lipinski, Poor aqueous solubility – an industry wide problem in Rev. 54 (2002) 169–190.
drug delivery, Am. Pharm. Rev. 5 (2002) 82–85. [26] M.L. Adams, A. Lavasanifar, G.S. Kwon, Amphiphilic block
[4] V. Hasirci, E. Vrana, P. Zorlutuna, A. Ndreu, P. Yilgor, F.B. copolymers for drug delivery, J. Pharm. Sci. 92 (2003)
Basmanay, E. Aydin, Nanobiomaterials: a review of the existing 1343–1355.
science and technology, and new approaches, J. Biomater. Sci. [27] Z. Sezgin, N. Yüksel, T. Baykara, Preparation and characterization
Polym. Ed. 17 (2006) 1241–1268. of polymeric micelles for solubilization of poorly soluble anticancer
[5] J. Hu, K.P. Johnston, R.O. Williams III, Nanoparticle engineering drugs, Eur. J. Pharm. Biopharm. 64 (2006) 261–268.
processes for enhancing the dissolution rates of poorly water soluble [28] T. Li, J. Lin, T. Chen, S. Zhang, Polymeric micelles formed by
drugs, Drug Dev. Ind. Pharm. 30 (2004) 233–245. polypeptide graft copolymer and its mixtures with polypeptide block
[6] K.A. Overhoffa, J.D. Engstromb, B. Chenc, B.D. Scherzerd, T.E. copolymer, Polymer 47 (2006) 4485–4489.
Milnerc, K.P. Johnston, R.O. Williams III, Novel ultra-rapid [29] X. Zhang, H.M. Burt, D. Van Hoff, D. Dexter, D. Mangold, D.
freezing particle engineering process for enhancement of dissolution Degen, M. Oktaba, W.L. Hunter, An investigation of the antitumor
314 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

activity and biodistribution of polymeric micellar paclitaxel, Cancer [48] A.H. Kibbe, Handbook of Pharmaceutical Excipients, American
Chem. Pharmacol. 40 (1997) 81–86. Pharmaceutical Association, Washington, DC, 2000, pp. 386–388.
[30] S.K. Agrawal, N. Sanabria-DeLong, J.M. Coburn, G.N. Tew, S.R. [49] J.W. Kwon, Y.K. Han, W.J. Lee, C.S. Cho, S.J. Paik, D. I Cho, J.H.
Bhatia, Novel drug release profiles from micellar solutions of Lee, W.R. Wee, Biocompatibility of poloxamer hydrogel as an
PLA–PEO–PLA triblock copolymers, J. Control. Release 112 (2006) injectable intraocular lens: A pilot study, J. Cataract Ref. Surg. 31
64–71. (2005) 607–613.
[31] C. Booth, D. Attwood, Effects of block architecture and composi- [50] J.M. Barichello, M. Morishita, K. Takayama, T. Nagai, Absorption
tion on the association properties of poly(oxyalkylene) copolymers of insulin from Pluronic F-127 gels following subcutaneous admin-
in aqueous solution, Macromol. Rap. Comm. 21 (2000) 501–527. istration in rats, Int. J. Pharm. 184 (1999) 189–198.
[32] C. Booth, D. Attwood, C. Price, Self-association of block [51] A.B. Saim, Y. Cao, Y. Weng, C.N. Chang, M.A. Vacanti, C.A.
copoly(oxyalkylene)s in aqueous solution. Effects of composition, Vacanti, R.D. Eavey, Engineering autogenous cartilage in the shape
block length and block architecture, Phys. Chem. Chem. Phys. 8 of a helix using an injectable hydrogel scaffold, Laryngoscope 10
(2006) 3612–3622. (2000) 1694–1697.
[33] C.J. Rekatas, S.-M. Mai, M. Crothers, M. Quinn, J.H. Collett, D. [52] M. Scherlund, A. Brodin, M. Malmsten, Micellization and gelation
Attwood, F. Heatley, L. Martini, C. Booth, The effect of hydro- in block copolymer systems containing local anesthetics, Int. J.
phobe chemical structure and chain length on the solubilization of Pharm. 211 (2000) 37–49.
griseofulvin in aqueous micellar solutions of block copoly(oxyalk- [53] G. Dumortier, J.L. Groissord, F. Agnely, J.C. Chaumeil, A review
ylene)s, Phys. Chem. Chem. Phys. 3 (2001) 4769–4773. of poloxamer 407 pharmaceutical and pharmacological characteris-
[34] M. Crothers, Z. Zhou, N.M.P.S. Ricardo, Z. Yang, P. Taboada, C. tics, Pharm. Res. 23 (2006) 2709–2728.
Chaibundit, D. Attwood, C. Booth, Solubilisation in aqueous [54] D. Cohn, A. Sosnik, A. Levy, Improved reverse thermo-responsive
micellar solutions of block copoly(oxyalkylene)s, Int. J. Pharm. polymeric systems, Biomaterials 24 (2003) 3707–3714.
293 (2005) 91–100. [55] D. Cohn, G. Lando, A. Sosnik, S. Garty, A. Levi, PEO–PPO-PEO
[35] P. Taboada, G. Velasquez, S. Barbosa, V. Castelletto, S.K. Nixon, based poly(ether ester urethane)s as degradable thermo-responsive
Z. Yang, F. Heatley, I.W. Hamley, M. Ashford, V. Mosquera, D. multiblock copolymers, Biomaterials 27 (2006) 1718–1727.
Attwood, C. Booth, Block copolymers of ethylene oxide and phenyl [56] D. Cohn, A. Sosnik, Novel reverse thermo-responsive injectable
glycidyl ether: micellization, gelation, and drug solubilization, poly(ether carbonate)s, J. Mat. Sci. Mater. Med. 14 (2003) 175–180.
Langmuir 21 (2005) 5263–5271. [57] A. Sosnik, D. Cohn, Reverse thermo-responsive poly(ethylene
[36] P. Taboada, G. Velasquez, S. Barbosa, Z. Yang, S.K. Nixon, Z. oxide) and poly(propylene oxide) multiblock copolymers, Biomate-
Zhou, F. Heatley, M. Ashford, V. Mosquera, D. Attwood, C. rials 26 (2005) 349–357.
Booth, Micellization and drug solubilization in aqueous solutions of [58] A. Sosnik, D. Cohn, J. San Román, G.A. Abraham, Crosslinkable
a diblock copolymer of ethylene oxide and phenyl glycidyl ether, PEO–PPO–PEO-based reverse thermo-responsive gels as potentially
Langmuir 22 (2006) 7465–7470. injectable materials, J. Biomater. Sci. Polym. Edn. 14 (2003)
[37] S.M. Moghimi, A.C. Hunter, Poloxamers and poloxamines in 227–239.
nanoparticle engineering and experimental medicine, TIBTECH 18 [59] D. Cohn, A. Sosnik, S. Garty, Smart hydrogels for in situ-generated
(2000) 412–420. implants, Biomacromolecules 6 (2005) 1168–1175.
[38] H.M. Aliabadi, A. Lavasanifar, Polymeric micelles for drug delivery, [60] A. Sosnik, D. Cohn, Ethoxysilane-capped PEO–PPO–PEO tri-
Exp. Opin. Drug Deliv. 3 (2006) 139–162. blocks: a new family of reverse thermo-responsive polymers,
[39] I.R. Schmolka, Artificial skin. I. Preparation and properties of Biomaterials 25 (2004) 2851–2858.
pluronic F-127 gels for treatment of burns, J. Biomed. Mater. Res. 6 [61] F. Cellesi, N. Tirelli, J.A. Hubbell, Towards a fully-synthetic
(1972) 571–582. substitute of alginate: development of a new process using thermal
[40] J.Z. Krezanoski, Clear, water-miscible, liquid pharmaceutical vehi- gelation and chemical cross-linking, Biomaterials 25 (2004)
cles and compositions which gel at body temperature for drug 5115–5124.
delivery to mucous membranes, U.S. Patent 4,188,373, 1980. [62] A. Sosnik, B. Leung, A.P. McGuigan, M.V. Sefton, Collagen/
[41] L. Reeve, The poloxamers: their chemistry and medical applica- poloxamine hydrogels: cytocompatibility of embedded HepG2 cells
tions, in: A. Domb, Y. Kost, D. Wiseman (Eds.), Hand- and surface attached endothelial cells, Tissue Eng. 11 (2005)
book of Biodegradble Polymers, Drug Targeting and Delivery, 1807–1816.
vol. 7, Harwood Academic Publishers, London, Great Britain, [63] A. Sosnik, M.V. Sefton, Poloxamine hydrogels with a quaternary
1997, pp. 231–249. ammonium modification to improve cell attachment, J. Biomed.
[42] Y. Cao, A. Rodriguez, M. Vacanti, C. Ibarra, C. Arevalo, C.A. Mater. Res. 75A (2005) 295–307.
Vacanti, Comparative study of the use of poly(glycolic acid), [64] A. Sosnik, M.V. Sefton, Methylation of poloxamine for enhanced
calcium alginate and pluronics in the engineering of autologous cell adhesion, Biomacromolecules 7 (2006) 331–338.
porcine cartilage, J. Biomater. Sci. Polym. Ed. 9 (1998) 475–487. [65] K.T. Oh, T.K. Bronich, A.V. Kabanov, Micellar formulations
[43] A. Sosnik, M.V. Sefton, Semi-synthetic collagen/poloxamine matri- for drug delivery based on mixtures of hydrophobic and
ces for Tissue Engineering applications, Biomaterials 26 (2005) hydrophilic Pluronic block copolymers, J. Control. Release 94
7425–7435. (2004) 411–422.
[44] E.A. Pec, Z.G. Wout, T.P. Johnston, Biological activity of urease [66] Y.-M. Lam, N. Grigorieff, G. Golbeck-Wood, Direct visualisation
formulated in poloxamer 407 after intraperitoneal injection in the of micelles of Pluronic block copolymers in aqueous solution by
rat, J. Pharm. Sci. 81 (1992) 626–630. cryo-TEM, Phys. Chem. Chem. Phys. 1 (1999) 3331–3334.
[45] J.M. Grindel, T. Jaworski, O. Piraner, R.M. Emanuele, M. [67] J. Dong, B.Z. Chowdhry, S.A. Leharne, Surface activity of
Balasubramanian, Distribution, metabolism, and excretion of a poloxamines at the interfaces between air–water and hexane–water,
novel surface-active agent, purified poloxamer 188, in rats, dogs, and Colloids Surf. A. Physicochem. Eng. Aspects 212 (2003) 9–17.
humans, J. Pharm. Sci. 91 (2002) 1936–1947. [68] P. Alexandridis, J.F. Holzwarth, T.A. Hatton, Micellization of
[46] L.E. Bromberg, E.S. Ron, Temperature-responsive gels and ther- poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide)
mogelling polymer matrices for protein and peptide delivery, Adv. triblock copolymers in aqueous solutions: thermodynamics of
Drug Deliv. Rev. 31 (1998) 197–221. copolymer association, Macromolecules 27 (1994) 2414–2425.
[47] A.V. Kabanov, V.Yu. Alkhov, Pluronic block copolymers in drug [69] P. Alexandridis, V. Athanassiou, S. Fukuda, T.A. Hatton, Surface
delivery: From micellar nanocontainers to biological response activity of poly(ethylene oxide)-block–poly(propylene oxide)-block–
modifiers, Crit. Rev. Therap. Drug Carrier Syst. 19 (2002) 1–72. poly(ethylene oxide) copolymers, Langmuir 10 (1994) 2604–2612.
 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317 315

[70] G. Wanka, H. Hoffmann, W. Ulbricht, Phase-diagrams and aggre- [90] F. Hecht, H. Hoffmann, Interaction of ABA block copolymers with
gation behavior of poly(oxyethylene)–poly(oxypropylene)–poly(oxy- ionic surfactants in aqueous solution, Langmuir 10 (1994) 86–91.
ethylene) triblock copolymers in aqueous solutions, Macromolecules [91] P.R. Desai, N.J. Jain, R.K. Sharma, P. Bahadur, Effect of additives
27 (1994) 4145–4159. on the micellization of PEO/PPO/PEO block copolymer F127 in
[71] Y. Deng, G. Yu, C. Price, C. Booth, Thermodynamics of micellization aqueous solution, Colloids and Surf. A: Physicochem. Eng. Aspects
and gelation of oxyethylene oxypropylene diblock copolymers in 178 (2001) 57–69.
aqueous solution studied by light scattering and differential scanning [92] P.K. Sharma, S.R. Bhatia, Effect of anti-inflammatories on Pluron-
calorimetry, J. Chem. Soc. Faraday Trans. 88 (1992) 1441–1446. ic F127: micellar assembly, gelation and partitioning, Int. J. Pharm.
[72] G. Yu, Y. Deng, S. Dalton, Q. Wang, D. Attwood, C. Price, C. 278 (2004) 361–377.
Booth, Micellization and gelation of triblock copoly(oxyethylene/ [93] P.K. Sharma, J.E. Matthew, S.R. Bhatia, Structure and assembly of
oxyprolpylene/oxyethylene), F127, J. Chem. Soc. Faraday Trans. 88 PEO–PPO–PEO co-polymers in mammalian cell-culture media, J.
(1992) 2537–2544. Biomater. Sci. Polym. Ed. 16 (2005) 1139–1151.
[73] P. Linse, M. Malmsten, Temperature-dependent micellization in [94] I. Pepić, N. Jalšenjak, I. Jalšenjak, Micellar solutions of triblock
aqueous block copolymer solutions, Macromolecules 25 (1992) copolymer surfactants with pilocarpine, Int. J. Pharm. 272 (2004)
5434–5439. 57–64.
[74] P. Alexandridis, T.A. Hatton, Poly(ethylene oxide)–poly(propylene [95] J. Armstrong, B. Chowdhry, J. Mitchell, A. Beezer, S. Leharne,
oxide)–poly(ethylene oxide) block copolymer surfactants in aqueous Effect of cosolvents and cosolutes upon aggregation transitions in
solutions and interfaces: thermodynamics, structure, dynamics and aqueous solutions of the poloxamer F87 (poloxamer P237): a high
modeling, Colloids Surf. A 96 (1995) 1–46. sensitivity differential scanning calorimetry study, J. Phys. Chem.
[75] P. Alexandridis, T. Nivaggioli, T.A. Hatton, Temperature effects on 100 (1996) 1738–1745.
structural properties of Pluronic P104 and F108 PEO–PPO–PEO [96] A. Caragheorgheopol, H. Caldararu, I. Dragutan, H. Joela, W.
block copolymer solutions, Langmuir 11 (1995) 1468–1476. Brown, Micellization and micellar structure of a poly(ethylene
[76] T. Nivaggioli, B. Tsao, P. Alexandridis, T.A. Hatton, Microviscosity oxide)/poly(propylene oxide)/poly(ethylene oxide) triblock copoly-
in Pluronic and Tetronic poly(ethylene oxide)–poly(propylene oxide) mer in water solution, as studied by the spin probe technique,
block copolymer micelles, Langmuir 11 (1995) 119–126. Langmuir 13 (1997) 6912–6921.
[77] T. Nivaggioli, P. Alexandridis, T.A. Hatton, A. Yekta, M.A. [97] Y.-L. Su, X.-F. Wei, H.-Z. Liu, Influence of 1-pentanol on the
Winnik, Fluorescence probe studies of Pluronic copolymer solutions micellization of poly(ethylene oxide)-poly(propylene oxide)-
as a function of temperature, Langmuir 11 (1995) 730–737. poly(ethylene oxide) block copolymers in aqueous solutions, Lang-
[78] J.P. Mata, P.R. Majhi, C. Guo, H.Z. Liu, P. Bahadur, Concentra- muir 19 (2003) 2995–3000.
tion, temperature, and salt-induced micellization of a triblock [98] K. Pandya, P. Bahadur, T.N. Nagar, A. Bahadur, Micellar and
copolymer Pluronic L64 in aqueous media, J. Colloid Interf. Sci. solubilizing behaviour of Pluronic L-64 in water, Colloids Surf. A
292 (2005) 548–556. Physicochem. Eng. Aspects 70 (1993) 219–227.
[79] N.J. Jain, V.K. Aswal, P.S. Goyal, P. Bahadur, Micellar structure of [99] B. Yang, C. Guo, S. Chen, J. Ma, J. Wang, X. Liang, L. Zheng, H.
an ethylene oxide–propylene oxide block copolymer: a small-angle Liu, Effect of acid on the aggregation of poly(ethylene oxide)-
neutron scattering study, J. Phys. Chem. B 102 (1998) 8452–8458. poly(propylene oxide)-poly(ethylene oxide) block copolymers, J.
[80] N.J. Jain, V.K. Aswal, P.S. Goyal, P. Bahadur, Salt induced Phys. Chem. B. Condens. Matter Mater. Surf. Interf. Biophys. 110
micellization and micelle structures of PEO/PPO/PEO block (2006) 23068–23074.
copolymers in aqueous solution, Colloids Surf. A 173 (2000) 85–94. [100] J.K. Armstrong, B.Z. Chowdry, M.J. Snowden, J. Dong, S.A.
[81] O.V. Elisseeva, N.A.M. Besseling, L.K. Koopal, M.A. Cohen Leharne, The effect of pH and concentration upon aggregation
Stuart, Influence of NaCl on the behavior of PEO–PPO–PEO transitions in aqueous solutions of poloxamine T701, Int. J. Pharm.
triblock copolymers in solution, at interfaces, and in asymmetric 229 (2001) 57–66.
liquid films, Langmuir 21 (2005) 4954–4963. [101] J. Dong, B.Z. Chowdry, S.A. Leharne, Solubilisation of polyaro-
[82] K. Nakashima, P. Bahadur, Aggregation of water-soluble block matic hydrocarbons in aqueous solutions of poloxamine T803,
copolymers in aqueous solutions: Recent trends, Adv. Colloid Colloids and Surfaces A: Physicochem. Eng. Aspects 246 (2004)
Interface Sci. 123–126 (2006) 75–96. 91–98.
[83] K. Patel, P. Bahadur, C. Guo, J.H. Ma, H.Z. Liu, A. Yamashita, A. [102] J. Dong, J. Armstrong, B.Z. Chowdry, S.A. Leharne, Thermody-
Khanal, K. Nakashima, Salt induced micellization of very hydro- namic modelling of the effect of pH upon aggregation transitions in
philic PEO–PPO–PEO block copolymers in aqueous solutions, Eur. aqueous solutions of the poloxamine, T701, Therm. Acta 417 (2004)
Polym. J., in press. 201–206.
[84] M. Malmsten, B. Lindman, Self-assembly in aqueous block copoly- [103] C. Alvarez-Lorenzo, J. Gonzalez-Lopez, M. Fernandez-Tarrio, I.
mer solutions, Macromolecules 25 (1992) 5440–5445. Sandez-Macho, A. Concheiro, Tetronic micellization, gelation and
[85] N.K. Pandit, J. Kisaka, Loss of gelation ability of Pluronic F127 in drug solubilization: Influence of pH and ionic strength, Eur. J.
the presence of some salts, Int. J. Pharm. 145 (1996) 129–136. Pharm. Biopharm., in press.
[86] G. Mao, S. Sukumaran, G. Beaucage, M.L. Saboungi, P. Thiya- [104] B. Pitard, M. Bello-Roufaı̈, O. Lambert, P. Richard, L. Desigaux, S.
grajan, PEO–PPO–PEO block copolymer micelles in aqueous Fernandes, C. Lanctin, H. Pollard, M. Zeghal, P.-Y. Rescan, D.
electrolyte solutions: effect of carbonate anions and temperature Escande, Negatively charged self-assembling DNA/poloxamine
on the micellar structure and interaction, Macromolecules 34 (2001) nanospheres for in vivo gene transfer, Nucleic Acids Res. 32 (20)
552–558. (2004) e159.
[87] A. Tontisakis, R. Hilfiker, B. Chu, Effect of xylene on micellar [105] R. Nagarajan, Solubilization of ‘‘guest’’ molecules into polymeric
solutions of block-copoly(oxyethylene/oxypropylene/oxyethylene) aggregates, Polym. Adv. Tech. 12 (2001) 23–43.
in water, J. Colloid Interface Sci. 135 (1990) 427–434. [106] G. Riess, Micellization of block copolymers, Prog. Polym. Sci. 28
[88] P. Alexandridis, V. Athanassiou, T.A. Hatton, Pluronic-P105 PEO– (2003) 1107–1170.
PPO–PEO block copolymer in aqueous urea solutions: micelle [107] I.F. Paterson, B.Z. Chowdhry, S.A. Leharne, Investigations of
formation, structure, and microenvironment, Langmuir 11 (1995) naphthalene solubilization in aqueous solutions of ethylene oxide-b-
2442–2450. propylene oxide-b-ethylene oxide copolymers, Langmuir 15 (1999)
[89] L.-Q. Jiang, Y.-Y. Zheng, J.-X. Zhao, Effect of phenol on micelli- 6187–6194.
zation of Pluronic block copolymer F127 and solubilization of [108] P.N. Hurter, T.A. Hatton, Solubilization of polycyclic aromatic
anthracene in the micelle, Fine Chemicals 18 (2001) 731–735. hydrocarbons by poly(ethylene oxide–propylene oxide) block
316 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317

copolymer micelles: effects of polymer structure, Langmuir 8 (1992) [129] A.V. Kabanov, V.P. Ckekhonin, V. Alakhov, E.V. Batrakova, A.S.
1291–1299. Lebedev, N.S. Melik-Nubarov, S.A. Arzhakov, A.V. Levashov,
[109] R. Barreiro Iglesias, L. Bromberg, M. Temchenko, T.A. Hatton, A. G.V. Morozov, E.S. Severin, V.A. Kabanov, The neuroleptic
Concheiro, C. Alvarez-Lorenzo, Solubilization and stabilization of activity of haloperidol increases after its solubilization in surfactant
camptothecin in micellar solutions of pluronic-g-poly(acrylic acid) micelles, FEBS Lett. 258 (1989) 343–345.
copolymers, J. Control. Release 97 (2004) 537–549. [130] G. Dumortier, J.L. Groissord, M. Zuber, G. Couarraze, J.C.
[110] Z.-G. Gao, H.D. Fainb, N. Rapoport, Controlled and targeted Chaumeil, Rheological study of a thermoreversible morphine gel,
tumor chemotherapy by micellar-encapsulated drug and ultrasound, Drug Dev. Ind. Pharm. 17 (1991) 1255–1265.
J. Control. Release 102 (2005) 203–222. [131] Y. Saito, Y. Kondo, M. Abe, T. Sato, Solubilization behavior of
[111] N. Munshi, N. Rapoport, W.G. Pitt, Ultrasonic activated drug estriol in an aqueous solution of pluronic L- 64 as a function of
delivery from Pluronic P-105 micelles, Cancer Lett. 118 (1997) concentration and temperature, Chem. Pharm. Bull. 42 (1994)
13–19. 1348–1350.
[112] N. Rapoport, J.N. Herron, W.G. Pitt, L. Pitina, Micellar delivery of [132] Y. Saito, T. Sato, Effects of inorganic salts on solubilization of
doxorubicin and its paramagnetic analog, ruboxyl, to HL-60 cells: estriol in an aqueous solution of poly(ethylene oxide)/poly(propyl-
effect of micelle structure and ultrasound on the intracellular drug ene oxide)/poly(ethylene oxide) triblock copolymer, Drug Dev. Ind.
uptake, J. Control. Release 58 (1999) 153–162. Pharm. 24 (1998) 385–388.
[113] G.A. Husseini, R.I. El-Fayoumi, K.L. O’Neill, N.Y. Rapoport, [133] L. Bromberg, M. Temchenko, Solubilization of hydrophobic com-
W.G. Pitt, DNA damage induced by micellar-delivered doxorubicin pounds by micellar solutions of hydrophobically modified polyelec-
and ultrasound: comet assay study, Cancer Lett. 154 (2000) 211–216. trolytes, Langmuir 15 (1999) 8627–8632.
[114] G.A. Husseini, N.Y. Rapoport, D.A. Christensen, J.D. Pruitt, W.G. [134] R. Gust, G. Bernhardt, T. Spruss, R. Krauser, M. Koch, H.
Pitt, Kinetics of ultrasonic release of doxorubicin from pluronic Schonenberger, K.-H. Bauer, S. Schertl, Z. Lu, Development of a
P105 micelles, Colloids Surf. B. Biointerfaces 24 (2002) 253–264. parenterally administrable hydrosol preparation of the ‘third
[115] N. Rapoport, Combined cancer therapy by micellar-encapsulated generation platinum complex’ [(±)-1,2-bis(4-fluorophenyl)ethylene-
drug and ultrasound, Int. J. Pharm. 277 (2004) 155–162. diamine]dichloroplatinum(II). Part 1. Preparation and studies on
[116] D. Stevenson-Abouelnasr, G.A. Husseini, W.G. Pitt, Further the stability and antitumor activity, Arch. Pharm. 328 (1995)
investigation of the mechanism of doxorubicin release from P105 645–653.
micelles using kinetic models, Colloids Surf. B. Biointerfaces 55 [135] J. Molpeceres, M. Guzmań, P. Bustamante, M.R. Aberturas,
(2007) 59–66. Exothermic–endothermic heat of solution shift of cyclosporin A
[117] K.A. Witt, J.D. Huber, R.D. Egleton, T.P. Davis, Pluronic P85 related to poloxamer 188 behavior in aqueous solutions, Int. J.
copolymer enhances opioid peptide analgesia, J. Pharm. Exp. Pharm. 130 (1996) 75–81.
Therap. 303 (2002) 760–767. [136] E.V. Batrakova, T.Y. Dorodnych, E.Y. Klinskii, E.N. Kliushnenk-
[118] A.V. Kabanov, E.V. Batrakova, V.Y. Alakhov, Pluronic block ova, O.B. Shemchukova, O.N. Goncharova, S.A. Arjakov, V.Y.
copolymers as novel polymer therapeutics for drug and gene Alakhov, A.V. Kabanov, Anthracycline antibiotics non-covalently
delivery, J. Control. Release 82 (2002) 189–212. incorporated into the block copolymer micelles: in vivo evaluation of
[119] G. Gaucher, M.-H. Dufresne, V.P. Sant, N. Kang, D. Maysinger, J.- anticancer activity, Br. J. Cancer 74 (1996) 1545–1552.
C. Leroux, Block copolymer micelles: preparation, characterization [137] H. Suh, H.W. Jun, Physicochemical and release studies of naproxen
and application in drug delivery, J. Control. Release 109 (2005) in poloxamer gels, Int. J. Pharm. 129 (1996) 13–20.
169–188. [138] H. Suh, W. Jun, M.T. Dziminaskl, G.W. Lu, Pharmacokinetic and
[120] N. Rapoport, Stabilization and activation of Pluronic micelles for local tissue disposition studies of naproxen following topical and
tumor-targeted drug delivery, Colloids Surf. B. Biointerfaces 16 systemic administration in dogs and rats, Biopharm. Drug Dispos.
(1–4) (1999) 93–111. 18 (1997) 623–633.
[121] J.D. Pruitt, G. Husseini, N. Rapoport, W.G. Pitt, Stabilization of [139] T.L. McNealy, L. Trojan, T. Knoll, P. Alken, M.S. Michel, Micelle
Pluronic P-105 micelles with an interpenetrating network of N,N- delivery of doxorubicin increases cytotoxicity to prostate carcinoma
diethylacrylamide, Macromolecules 33 (2000) 9306–9309. cells, Urol. Res. 32 (2004) 255–260.
[122] G.A. Husseini, D.A. Christensen, N.Y. Rapoport, W.G. Pitt, [140] E.V. Batrakova, D.L. Kelly, S. Li, Y. Li, Z. Yang, L. Xiao, D.Y.
Ultrasonic release of doxorubicin from Pluronic P105 micelles Alakhova, S. Sherman, V.Y. Alakhov, A.V. Kabanov, Alteration of
stabilized with an interpenetrating network of N,N-diethylacryla- genomic responses to doxorubicin and prevention of MDR in breast
mide, J. Control. Release 83 (2002) 303–305. cancer cells by a polymer excipient: Pluronic P85, Mol. Pharm. 3
[123] P. Petrov, M. Bozukov, C.B. Tsvetanov, Innovative approach for (2006) 113–123.
stabilizing poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(eth- [141] Y. Tian, P. Ravi, L. Bromberg, T.A. Hatton, K.C. Tam, Synthesis
ylene oxide) micelles by forming nano-sized networks in the micelle, and aggregation behavior of Pluronic F87/poly(acrylic acid) block
J. Mater. Chem. 15 (2005) 1481–1486. copolymer in the presence of doxorubicin, Langmuir 23 (2007)
[124] J. Rodrı́guez-Hernández, F. Chécot, Y. Gnanou, S. Lecomman- 2638–2646.
doux, Toward ‘smart’ nano-objects by self-assembly of block [142] S.D. Desai, J. Blanchard, In vitro evaluation of pluronic F127-based
copolymers in solution, Prog. Polym. Sci. 30 (2005) 691–724. controlled-release ocular delivery systems for pilocarpine, J. Pharm.
[125] K.H. Bae, S.H. Choi, S.Y. Park, Y. Lee, T.G. park, Thermosensitive Sci. 87 (1998) 226–230.
pluronic micelles stabilized by shell cross-linking with gold nano- [143] S.D. Desai, J. Blanchard, Evaluation of Pluronic F127-based
particles, Langmuir 22 (2006) 6380–6384. sustained-release ocular delivery systems for pilocarpine using the
[126] T.-F. Yang, C.-N. Chen, M.-C. Chen, C.-H. Lai, H.-F. Liang, H.-W. albino rabbit eye model, J. Pharm. Sci. 87 (1998) 1190–1195.
Sung, Shell-crosslinked Pluronic L121 micelles as a drug delivery [144] M.A. Hammad, B.W. Muller, Solubility and stability of clonazepam
vehicle, Biomaterials 28 (2007) 725–734. in mixed micelles, Int. J. Pharm. 169 (1998) 55–64.
[127] K.H. Bae, Y. Lee, T.G. Park, Oil-encapsulating PEO–PPO–PEO/ [145] N.K. Pandit, D. Wang, Salt effects on the diffusion and release rate
PEG shell cross-linked nanocapsules for target-specific delivery of of propranolol from poloxamer 407 gels, Int. J. Pharm. 167 (1998)
paclitaxel, Biomacromolecules 8 (2007) 650–656. 183–189.
[128] M.F. Saettone, B. Giannaccini, G. Delmonte, V. Campigli, G. Tota, [146] J.-M. Ryu, S.-J. Chung, M.-H. Lee, C.-K. Kim, C.-H. Kim,
F. La Marca, Solubilization of tropicamide by poloxamers: phys- Increased bioavailability of propranolol in rats by retaining
icochemical data and activity data in rabbits and humans, Int. J. thermally gelling liquid suppositories in the rectum, J. Control.
Pharm. 43 (1988) 67–76. Release 59 (1999) 163–172.
 D.A. Chiappetta, A. Sosnik / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 303–317 317

[147] J.M. Barichello, M. Morishita, K. Takayama, Y. Chiba, S. Tokiwa, [159] C. Carmignani, S. Rossi, M.F. Saettone, S. Burgalassi, Ophthalmic
T. Nagai, Enhanced rectal absorption of insulin-loaded Pluronic F- vehicles containing polymer-solubilized tropicamide: ‘‘in vitro/
127 gels containing unsaturated fatty acids, Int. J. Pharm. 183 (1999) in vivo’’ evaluation, Drug Dev. Ind. Pharm. 28 (2002) 101–105.
125–132. [160] N. Hioka, R.K. Chowdhary, N. Chansarkar, D. Delmarre, E.
[148] M. Morishita, J.M. Barichello, K. Takayama, Y. Chiba, S. Tokiwa, Sternberg, D. Dolphin, Studies of a benzoporphyrin derivative with
T. Nagai, Pluronic F-127 gels incorporating highly purified Pluronics, Can. J. Chem. 80 (2002) 1321–1326.
unsaturated fatty acids for buccal delivery of insulin, Int. J. Pharm. [161] R.K. Chowdhary, N. Chansarkar, I. Sharif, N. Hioka, D. Dolphin,
212 (2001) 289–293. Formulation of benzoporphyrin derivatives in Pluronics, Photo-
[149] M.L. Veyries, G. Couarraze, S. Geiger, F. Agnely, L. Massias, B. chem. Photobiol. 77 (2003) 299–303.
Kunzli, F. Faurisson, B. Rouveix, Controlled release of vancomycin [162] R. Barreiro-Iglesias, C. Alvarez-Lorenzo, A. Concheiro, Controlled
from Poloxamer 407 gels, Int. J. Pharm. 192 (1999) 183–193. release of estradiol solubilized in carbopol/surfactant aggregates, J.
[150] E. Khalil, S. Najjar, A. Sallam, Aqueous solubility of diclofenac Control. Release 93 (2003) 319–330.
diethylamine in the presence of pharmaceutical additives: a com- [163] K.I. Momot, P.W. Kuchel, P. Deo, D. Whittaker, NMR study of the
parative study with diclofenac sodium, Drug Dev. Ind. Pharm. 26 association of propofol with nonionic surfactants, Langmuir 19
(2000) 375–381. (2003) 2088–2095.
[151] Y.J. Park, C.S. Yong, H.M. Kim, J.D. Rhee, Y.K. Oh, C.K. Kim, [164] M.T. Baker, M. Naguib, Propofol: the challenges of formulation,
Effect of sodium chloride on the release, absorption and safety of Anesthesiology 103 (2005) 860–876.
diclofenac sodium delivered by poloxamer gel, Int. J. Pharm. 263 [165] Z. Gao, H.D. Fain, N. Rapoport, Ultrasound-enhanced tumor
(2003) 105–111. targeting of polymeric micellar drug carriers, Mol. Pharm. 1 (2004)
[152] A.F. El-Kattan, C.S. Asbill, N. Kim, B.B. Michniak, Effect of 317–330.
formulation variables on the percutaneous permeation of ketoprofen [166] V. Alakhov, G. Pietrzynski, K. Patel, A. Kabanov, L. Bromberg,
from gel formulations, Drug Deliv. 7 (2000) 147–153. T.A. Hatton, Pluronic block copolymers and Pluronic poly(acrylic
[153] S.-C. Shin, C.-W. Cho, I.-J. Oh, Enhanced efficacy by percutaneous acid) microgels in oral delivery of megestrol acetate, J. Pharm.
absorption of piroxicam from the poloxamer gel in rats, Int. J. Pharmacol. 56 (2004) 1233–1241.
Pharm. 193 (2000) 213–218. [167] S.R. Croy, G.S. Kwon, The effects of Pluronic block copolymers on the
[154] E. Dimitrova, S. Bogdanova, M. Mitcheva, I. Tanev, E. Minkov, aggregation state of nystatin, J. Control. Release 95 (2004) 161–171.
Development of model aqueous ophthalmic solution of indometh- [168] C.S. Yong, M.-K. Lee, Y.-J. Park, K.-H. Kong, J.J. Xuan, J.-H.
acin, Drug Dev. Ind. Pharm. 26 (2000) 1297–1301. Kim, J.-A. Kim, W. Seok, S.S. Han, J.-D. Rhee, J.O. Kim, C.H.
[155] S.-C. Shin, J.-Y. Kim, Enhanced permeation of triamcinolone Yang, C.-K. Kim, H.-G. Choi, Enhanced oral bioavailability of
acetonide through the buccal mucosa, Eur. J. Pharm. Biopharm. 50 ibuprofen in rats by poloxamer gel using poloxamer 188 and
(2000) 217–220. menthol, Drug Dev. Ind. Pharm. 31 (2005) 615–622.
[156] E.V. Batrakova, D.W. Miller, S. Li, V.Y. Alakhov, A.V. Kabanov, [169] L.-M. Han, J. Guo, L.-J. Zhang, Q.-S. Wang, X.-L. Fang,
W.F. Elmquist, Pluronic P85 enhances the delivery of digoxin to the Pharmacokinetics and biodistribution of polymeric micelles of
brain: in vitro and in vivo studies, J. Pharm. Exp. Therap. 296 (2001) paclitaxel with Pluronic P123, Acta Pharmacol. Sin. 27 (2006)
551–557. 747–753.
[157] J.G.W. Wenzel, K.S.S. Balaji, K. Koushik, C. Navarre, S.H. Duran, [170] Z. Sezgin, N. Yuksel, T. Baykara, Investigation of pluronic and
C.H. Rahe, U.B. Kompella, Pluronic F127 gel formulations of PEG-PE micelles as carriers of meso-tetraphenyl porphine for oral
deslorelin and GnRH reduce drug degradation and sustain drug administration, Int. J. Pharm. 332 (2007) 161–167.
release and effect in cattle, J. Control. Release 85 (2002) 51–59. [171] N. Ahuja, O.P. Katare, B. Singh, Studies on dissolution enhance-
[158] A.H. El-Kamel, In vitro and in vivo evaluation of Pluronic F127- ment and mathematical modeling of drug release of a poorly water-
based ocular delivery system for timolol maleate, Int. J. Pharm. 241 soluble drug using water-soluble carriers, Eur. J. Pharm. Biopharm.
(2002) 47–55. 65 (2007) 26–38.