Effects of Surfactants On Gel Behavior: Design Implications For Drug Delivery Systems

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Effects of Surfactants on Gel Behavior: Design Implications for Drug Delivery

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Article in American Journal of Drug Delivery · June 2003

DOI: 10.2165/00137696-200301020-00001
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Am J Drug Deliv 2003; 1 (2): 77-101

HEALTHCARE TECHNOLOGY REVIEW 1175-9038/03/0002-0077/$30.00/0
 Adis Data Information BV 2003. All rights reserved.
Effects of Surfactants on Gel Behavior

Design Implications for Drug Delivery Systems
Carmen Alvarez-Lorenzo and Angel Concheiro

Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela,
Santiago de Compostela, Spain
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
1. Polymer Gels as Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
1.1 Rheological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
1.2 Mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
1.3 Drug Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
PAGE PROOF 2
2. Incorporation of Surfactants in Polymer Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

2.1 Polymer/Surfactant Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.1.1 Factors Affecting the Association Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.2 Pharmaceutical Applications of Polymer/Surfactant Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.2.1 Solubilization of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.2.2 Modulation of the Rheological Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
2.2.3 Improvement of Drug Control Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
2.2.4 Promotion of Cutaneous and Mucosal Drug Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Abstract The recent advances in the design and synthesis of new polymeric systems have opened a wide range of
possibilities for the use of gels as drug dosage forms. These systems are able to act not only as simple reservoirs,
but also as controlled-release systems and/or targeting agents for site-specific delivery.
Applications of gels are determined by their drug-loading capability, rheological properties, and the
mechanisms and kinetics of drug release. The incorporation of small proportions of surfactants, which are able to
promote or hinder intra- or interchain polymeric bonds, may modify these properties and be a useful tool for
developing gel-based dosage forms. Polymers and surfactants may interact, depending on their chemical
structure, through ionic, hydrophobic and hydrogen-bonding mechanisms. The strength of the interaction is
strongly affected by pH, ionic strength and presence of other substances, and physiological changes in these
variables. These physiologic parameters affect the performance of polymer/surfactant gels as drug delivery
systems. Surfactants may also promote cutaneous or mucosal drug penetration.
Drug release processes from polymer/surfactant gels depend on the microstructure of the gel and the drug
‘state’ in the system. The drug can be: solubilized in water without interacting with any of the components;
electrostatically or hydrophobically bound to the polymer; or solubilized inside micelles or polymer/surfactant
aggregates. Interactions between surface-active drugs and polymers should also be taken into account because of
their important repercussions on gel behavior. Finally, polymer/surfactant systems have a great potential for gene
78 Alvarez-Lorenzo & Concheiro
therapy, and some polymers that are able to interact with natural surfactants can be used as trap systems of bile
salts for controlling the physiological levels of cholesterol.
The term gel was introduced in the late 1800s to name some Thus, despite being well known systems, their applications as drug
semisolid materials according to phenomenological rather than devices are still growing. Gels are platforms especially able to
molecular criteria.[1] Structurally, a gel consists of small amounts resist the physiological stress caused by skin flexion, blinking and
of inorganic particles or organic macromolecules, mainly entan- mucociliary movement; adopting the shape of the application area
gled polymers, interpenetrated by a relatively large volume of and controlling drug release.[6-9] The versatility of hydrogel-based
liquid;[2] yet it possesses more solid-like than liquid-like character- drug delivery devices makes them able to be adapted to practically
istics. The liquid prevents the polymer network from collapsing all delivery routes,[5,10] and if the properties are not ideal for a
into a compact mass, and the network impedes the liquid from specific application, additives may be added. Additives are com-
flowing away. In consequence, the state of gel may be seen as a monly required to isotonize or to prevent microbiological contami-
form of matter intermediate between a solid and a liquid.[3] nation. In addition, additives allow modification of the rheological
The typical three-dimensional structure characteristic of the behavior or solubilizing capacity, or improvement of the control of
gels comes from the links among the polymer chains.[4] Depending drug release properties of the gels, or the promotion of drug
on the degree of cross-linking (i.e. the ratio between the cross- absorption. Many of these additives are surfactants.[11] Of the
PAGE PROOF 2
-linking points and the length of the polymer chains), gels vary in conventional surfactants, many drugs have amphiphilic character-
consistency from viscous fluids to fairly rigid solids. Physically istics and act, in fact, as surface-active agents that may modify gel
cross-linked gels are formed by simple entanglement of polymer properties (table II).[12,13] Finally, once administered, gels prepared
chains and are, in general, easily spreadable. Simple addition of with or without surfactants may have contact with physiological
more solvent induces dilution of the polymer and the system loses surface-active substances, such as biliary salts, which are natural
its gel behavior. Chemically cross-linked gels, in which the poly- components of the media or the tissues in which the formulations
mer chains are covalently bound to each other during polymer are applied or which they have to pass through.
formation or after polymerization, may be used as highly visco- The changes induced in the gel by the presence of surfactants
elastic macroscopic continuous bases or as small particles, known are, in most cases, extensive. Therefore, a deep knowledge of
as microgels, that may modify their volume in response to changes polymer/surfactant interaction processes is required to optimize
in their environment. These gels swell in water without solution, the composition and the performance of the formulations. The aim
keeping their cross-linking points (table I, figure 1). The differ- of this review is to analyze recent information about interaction
ence in the nature of the cross-linking points, which determines the mechanisms not only between the polymer and the surfactant but
dissolution of the gel when it comes in contact with the physiologi- also with the drug, and the factors that affect the association
cal fluids (physical gels), or to a limited extent, its swelling processes (pH, ionic strength and presence of additives), in order
(chemical gels), notably conditions the performance of the gels to highlight the possibilities that the incorporation of surfactants
and the mechanisms of clearance of the residues from the body. offer to improve the properties of the gels with a view to optimiz-
The gels in which the liquid phase is water are named hydro- ing them as drug delivery systems. For this reason, the effects of
gels. Traditionally, this term was exclusively used to design chem- association phenomena on viscoelasticity, microviscosity, drug
ically cross-linked systems, but nowadays it covers any type of gel solubility, control release and cutaneous and mucosal penetration
in which the liquid phase is water. Hydrogels are of great interest are considered. Examples of some specific applications of particu-
as food components, water super-absorbents, chemical traps, arti- lar relevance are presented.
ficial organs, agents able to immobilize enzymes, and, in the
pharmaceutical field, as contact lenses and drug vehicles or carri- 1. Polymer Gels as Drug Delivery Systems
ers.[5] High water content and the soft consistency of hydrogels
make them resemble natural living tissue more than any other class Since the introduction in the mid 1950s of natural modified
of synthetic biomaterials, and therefore highly biocompatible. polymers, such as cellulose ethers,[17] and synthetic poly(acrylic
 Adis Data Information BV 2003. All rights reserved. Am J Drug Deliv 2003; 1 (2)
Effects of Surfactants on Gel Behavior 79
Table I. Classification of polymer gels based on the cross-linking mechanism of the polymer chains and the method of obtaining[1,4,5]
Mechanism Method Examples

Physical gels (cross-linking after polymerization)
Entanglement or helix formation Helix formation among polymers Agar, gelatin, carrageenan
Ionic bonding Mixing Cationic cellulose-Carbopol
Coordination bonding Chelate reaction Poly(vinyl alcohol)-Cu2+
Hydrogen bonding Freeze drying Poly(acrylic acid)-poly(vinyl alcohol)
Freeze crystallization
Freeze thaw
Polymer complex
Hydrophobic bonding Hydrophobic interaction Albumin
Chemical gels
Covalent bonding during Condensation polymerization (free radical, thermal, Copolymerization between various divinyl or acrylic
polymerization photo, radiation, or plasma polymerization) monomers
Covalent bonding after polymerization Chemically induced Chitosan-aldehyde
Photo induced Poly(vinyl alcohol)-styrilbazolium salt
Radiation induced Poly(vinyl pyrrolidone)
PAGE PROOF 2
Plasma induced Polyethylene
acid) derivatives, such as Carbopol1,[18] hydrophilic polymers Hydrogels present important advantages over conventional
that form gels when dispersed in water have received increasing dosage forms since it is relatively easy to modulate, by choosing
attention as the main components of drug delivery systems. Such an adequate polymer and cross-linking degree, two of the critical
polymers have been shown to be particularly useful for the prepa- parameters determining release kinetics and mechanism: the per-
ration of matrix tablets, which form a physically cross-linked gel meability (mesh size) of the polymer network; and its swelling
layer when they come into contact with the physiological fluids, properties. Two other approaches to optimize the performance of
and are then able to control drug delivery rates.[19,20] Preformed pharmaceutical gels consider: (i) inclusion of drug molecules in
gels obtained by direct dispersion of these polymers in water or by structures of greater size and lower diffusivity (liposomes or
chemical cross-linking of their chains are also very useful as nanoparticles); and (ii) incorporation of additives, especially sur-
controlled release devices.[5] factants.
Gels may act as a simple reservoir of drugs that are released by
diffusion or erosion, or may be used as targeting agents for site- 1.1 Rheological Properties
specific delivery. Two main approaches have been developed:
polymeric systems that modify their structure, by swelling or From a rheological point of view, hydrogels behave as visco-
eroding, in response to changes in the characteristics of the physio- elastic systems. This means that under stress, gels deform and
logical medium (smart hydrogels); and devices in which the drug flow, partially irreversibly, owing to the viscous component, and
is covalently bonded to the polymer via a hydrolytically or enzy- partially reversibly, owing to the elastic component. Adequate
matically labile bond.[5,21] A novel third approach is the develop- selection of the polymers and their cross-linking process makes it
ment of hydrogels that can interact effectively with the drug possible to obtain systems with the required viscous-elastic bal-
through ionic or hydrophobic bonds, the intensity of which de- ance for each specific use, e.g. combining easy application with
pends on specific environmental conditions. This type of hydrogel enough mechanical resistance to remain on the site of application
presents, as an additional advantage, a high loading capacity.[22-24] (table III).
1 The use of tradenames is for product identification purposes only and does not imply endorsement.
a b c
Fig. 1. Schematic drawing of the structure of: (a) a physically cross-linked gel; (b) a continuous chemically cross-linked gel; and (c) a dispersion of
chemically cross-linked microgels.
The rheological properties of physically cross-linked gels tions, which facilitates their application and spreading on the
strongly depend on polymer concentration and polymer/polymer application site. Then, in contact with the body fluids, the formula-
PAGE PROOF 2
interactions. Most of these systems behave as plastic or tion thickens in consistency, increasing resistance to removal from
pseudoplastic fluids (i.e. the viscosity depends on the shear stress). the application site and retarding drug diffusion. Cellulose ethers
Gel formation may occur by simple entanglement of the chains, and some polyoxyethylene-polyoxypropylene-polyoxyethylene
when polymer concentration is high enough, or may be induced by triblock copolymers (Pluronic) increase interpolymer hydropho-
a change in the physicochemical properties of the medium that bic interactions when temperature rises and may provide tempera-
promotes ionic, hydrophobic or hydrogen-bonding interactions. ture-sensitive gels.[7,26] Alginates and gellan gum derivatives
Polymers whose conformation in an aqueous medium depends on (Gelrite) are useful to prepare dispersions that transform into
gels when Ca2+ ions are present in the medium.[27] Also, chemical-
the values of pH, temperature, or salt concentration in the physio-
ly cross-linked microgels, which when dispersed in an aqueous
logical range, are particularly useful to prepare in situ physically
medium resemble physically cross-linked gels, may undergo
cross-linked gels. Coiling and uncoiling of the chains strongly
changes in their volume in response to a change in the physico-
alters the rheological properties of the system. Formulations with
chemical properties of the medium, which are reflected in the
in situ gelling capacity are free-flowing under preparation condi-
consistency and rheological behavior of the dispersion as a whole.
Table II. Critical micellar concentrations (CMC) of some amphiphilic drugs Acrylic microgels, such as Carbopol, are common components
at 25°C of pH-induced in situ gelling systems.[18,26]
Drug CMC (mmol/L) Medium The sol-gel transformation becomes apparent not only as an
Alprenolol[14] 100 Tear fluid augmentation in viscosity (determined in a flow experiment) but
Amitriptyline hydrochloride[15] 63 Distilled water also as an increase in the values of the elastic or storage modulus
Betaxolol[14] 100 Tear fluid (G′) and the viscous or loss modulus (G′′) of the system, when
Clomipramine hydrochloride[16] 23 Distilled water subjected to oscillating stresses. Before cross-linking, or when the
Desipramine hydrochloride[15] 85 Distilled water cross-linking degree is low, G′ and G′′ show, in the linear visco-
Diphenhydramine[14] 120 Tear fluid elastic range, the following dependence on angular frequency (ω):
Fluvastatin[14] 100 Tear fluid G′∝ω2
Ibuprofen sodium[12] 180 Distilled water G′′∝ω
Imipramine hydrochloride[16] 51 Distilled water
At a low frequency, the behavior is mainly viscous; at a high
Nortriptyline hydrochloride[15] 45 Distilled water
frequency, the elastic character of the dispersion is more evident.
In contrast, for a well-structured polymer network, G′ and G′′ Table III. Favorable properties of pharmaceutical gels for particular
become practically independent of angular frequency, G′ being applications[1,25,26]
greater than G′′. This behavior is also characteristic of chemically Application Requirements
cross-linked hydrogels, which are usually more consistent than Buccal Adherent to enamel surfaces
physical gels. For example, for optical applications and implants, Highly thixotropic
the values of G′ and G′′ of hydrogels that combine easy handling Optically clear
and patient comfort with the required physical strength are in the Orally digestible
range 105–108Pa.[28,29] Water soluble
Since the main difference between sol and gel states lies in their
Dermatological Easily removed
macroscopic physical properties – the chemical composition is
Easily spreadable
essentially the same – the evolution of the viscoelastic properties
Greaseless
of a polymeric dispersion during cross-linking is particularly
Nonstaining
useful to characterize the kinetics of the reaction.[30] This informa-
tion is crucial for controlling the production process and optimiz- Thixotropic
ing the performance of any system based on hydrogels.[31,32] Water soluble or miscible
Applying oscillatory rheometry, the influence of molecular struc- Nasal Mucoadhesive

ture and concentration of the polymer, the type of cross-linking Odorless
agent, temperature, pH and other factors can be established. This
PAGE PROOF 2
Viscoelastic
technique has been shown to be useful to optimize the synthesis of Water soluble
biocompatible hydrogels made from natural or transformed Ophthalmic Lubricating
polysaccharides, e.g. cross-linking of chitosan with glutaralde- Mucomimetic
hyde,[32] guar galactomannan with borax,[33] or cationic celluloses
Optically clear
with ethyleneglycol diglycidil ether[34] (figure 2). Oscillatory rhe-
Shear-thickening, nonthixotropic
ometry also makes it possible to evaluate the effect of certain
Viscoelastic (optimum viscosity 5–25 mPa • s)
additives (e.g. surfactants) on the behavior of the gels in contact
Water soluble or miscible
with different biological media.[35]
Oral Orally digestible
1.2 Mucoadhesion Pseudoplastic, thixotropic

Water soluble
Adhesion of the gel to skin and mucosa is necessary either to Rectal Greaseless
retain it on surfaces subject to continuous flexion, blinking or Mucoadhesive
mucociliary movement or to achieve a local high drug concentra-
Thermogellinga
tion, enhancing drug absorption.[36] Blinking and tear drainage
Surgical and medical Lubricating
may be dealt with more efficiently using viscoelastic gels with procedures Maximal contact with mucous membranes
mucoadhesive properties.[37] Long-term adhesion is particularly
Vaginal Acid stable
useful in the local treatment of diseases of the mouth or for buccal
Easy flowing but viscoelastic semisolid for
administration of systemic drugs, in order to overcome gel wash-
rapid distribution throughout and permanence
ing-out induced by copious salivary flow.[38] Mucoadhesive gels in the vaginal space
can also be useful for rectal delivery of peptides or drugs that Greaseless
undergo extensive first-pass metabolism; otherwise, the formula-
Lubricating
tion may migrate upwards to the colon, leading to variation of drug
Mucoadhesive
bioavailability.[39,40]
Thermogellinga
Attachment to the mucosa occurs as a result of, firstly, penetra-
a Not liquefied at body temperature.
tion and entanglement of polymer chains and, secondly, hydrogen-
1000
Elastic modulus (G′) changes in physiological parameters that are characteristics of
Viscous modulus (G″)
certain pathological processes, which figure 3 affect its degree of
100 swelling.[21] These mechanisms are summarized in . Obviously,
Elastic/viscous modulus (Pa)
the better the knowledge of the physiological environment, the

10 greater the possibilities of designing hydrogels with appropriate
drug release profiles.
1
Drug diffusion rates are basically governed by the restrictive
effects of the polymer on drug mobility, whether as a result of a
reduction in free volume or an increase in viscosity.[45,46] Apparent
0.1
viscosity has been widely used as a routine predictor of a gel’s
resistance to diffusion.[47] However, when the proportion of poly-
0.01 mer is low, drug diffusion becomes practically independent of this
0 10 20 30 40 50 60 70
property. This is the case of polysaccharide gels formed at quite
Time (min) low polymer proportions that strongly increase the viscosity but in
Fig. 2. Increases in the elastic (G′) and viscous (G′′) moduli during cross- which both water and small solutes are largely free to diffuse
linking of a cationic cellulose dispersion (3%) with ethyleneglycol diglycidil
without major hindrance. As a consequence, the effects of the
ether (1mL/10mL) at 60°C. The values of G′ and G′′ stabilize once the
process is finished (reproduced from Rodriguez et al.,[34] with permission polymer molecules on the flow properties of the system (i.e. on
PAGE PROOF 2
from Elsevier Science). macroscopic movement) do not necessarily correlate with effects
on diffusion (i.e. movement at the microscopic level). This has led
bonding formation or electrostatic interactions with glycoproteins some researchers to suggest that the microviscosity (i.e. viscosity
of the mucous layer.[41,42] Various types of polymers have been at the microscopic level) should be used as a predictor of the drug
used as bioadhesive components.[41,43,44] In general, bioadhesive diffusion rate.[48,49] Depending on the characteristics of a given
capacity increases with molecular weight and is greater for system, several approaches have been developed to determine
polymers with ionic groups. Chitosan, among the cationic microviscosity.[50,51]
polymers, and Carbopol, among the anionic polymers, are two
It is possible that a gel has optimum rheological properties for
examples of efficient bioadhesive hydrophilic polymers.[36]
persistence in the application area but is unable to retard drug
1.3 Drug Release

Diffusion
dh x
Hydrogels that undergo neither degradation nor significant
changes in volume release the drug mainly by Fickian diffusion.
The degree of cross-linking determines the size of the mesh Swelling
through which the drug moves out. If the hydrodynamic diameter

of the drug is greater than the mesh size, the drug is not released; if Hydration
it is smaller, the release rate depends on the tortuousness of the

External
diffusional path.[5] If the gels interact with physiological fluids and stimuli
undergo extensive structural changes, their volume, their mesh Diffusion
Erosion
size and even their integrity may be altered. Specific conditions of
the environment, such as pH, temperature, nature and concentra-
tion of ions, or enzymatic activity, determine the intensity of such
changes and consequently may affect the drug-release process. In
erodible systems, the drug release rate is controlled by dissolution Fig. 3. Mechanisms potentially involved in the drug release process from a
hydrogel-based formulation: Fickian diffusion; diffusion as a result of hydra-
of the polymer or degradation of polymer/drug bonds. Finally, tion and swelling (or external stimuli); and erosion. dh = diameter; x =
drug release from a stimuli-sensitive gel is a function of small distance.
release. In the case of in situ gelling systems made of Carbopol, a more, the polymer may stabilize ionic surfactant micelles through
200-fold increase in macroviscosity, when pH rises from 4 to 7.4, a dilution charge effect. Association phenomena are influenced by
is accompanied by only a 1.5-fold increase in microviscosity, many factors including the charge density and the hydrophobicity
estimated by light scattering of polystyrene particles.[52] Therefore, of surfactant and polymer,[58,59] the structural conformation and
if the mesh size is too big compared with the hydrodynamic flexibility of the polymer,[59,60] and the presence in the medium of
diameter of diffusant molecules, the dose is delivered quickly, other additives.[35,61]
despite high macroscopic viscosity. To overcome this drawback, The surfactant often interacts cooperatively with the polymer at
the incorporation of drug-loaded liposomes or nanoparticles into a critical aggregation concentration (CAC), forming micelle-like
in situ gelling systems has been explored for ocular delivery.[37] aggregates along the chains. In general, the CAC is lower than the
Another approach is to increase the affinity of the drug to the critical micellar concentration (CMC), especially in the case of
polymer network by adequate selection of the gel composition that charged polymers interacting with oppositely charged surfac-
facilitates polymer/drug interactions, in which surfactant mole- tants.[62] In these systems, even at very low concentrations, indi-
cules may participate. Both approaches allow a combination of vidual surfactant molecules can bind to the polymer through ion-
prolonged residence time with sustained delivery or even specific pairing interactions. Usually, the CAC value is independent of
targeting behavior, if the polymer/drug bonds are broken only polymer concentration while the saturation level of binding de-
when specific conditions occur.[13,22] pends on it.[61] Polymer/surfactant interactions have been dis-
cussed in some general reviews.[56,62,63] An analysis of the most
2. Incorporation of Surfactants in Polymer Gels updated and relevant theoretical and practical aspects, from a
PAGE PROOF 2
pharmaceutical point of view, is now presented.

Polymers and surfactants are commonly used together to im-
prove the formulation process of the gel, to improve its attributes 2.1.1 Factors Affecting the Association Process
as a drug dosage form (wetting, rheological properties, enhancing
Polymer and Surfactant Structure
drug penetration) or to avoid physical-stability problems.[53] The
Physical Gels Formed by Non-Ionic Polymers: Non-ionic
addition of a surfactant may modify the release pattern through a
polymers preferentially interact with non-ionic or anionic surfac-
change in the diffusional path (altering the microviscosity or the
tants. High polymer molecular weight and hydrophobicity seem to
mesh size of the gel), or in the intensity of the drug interactions
be the main causes of association. The higher affinity of non-ionic
with specific groups of the polymer.[11,14] In some topical applica-
polymer for anionic surfactants compared with their affinity for
tions, the rate-limiting step in the absorption process is usually
the cationic ones has been attributed to the different size of their
drug penetration through skin or mucosa rather than release from
hydrated head group, which is larger for the rather bulky cationic
the dosage form, and surfactants may improve drug permeability.
surfactants.[64] The reactivity of non-ionic polymers towards a
Usually, the effect of surfactants on the properties of polymer gels
cationic surfactant can be induced in a highly alkaline (pH >12)
depends strongly on the ratio of the two components; opposing
medium because of the ionization of the polymer hydroxyl groups
effects have been observed when the two components are added in
or adsorption of hydroxyl ions.[63]
different proportions.[52,54]
The affinity of a non-ionic polymer for ionic surfactants corre-
2.1 Polymer/Surfactant Interactions lates with its hydrophilic-lipophilic balance.[63] The reactivity or-
der[63] for non-ionic polymers in the presence of anionic surfac-
When a polymer and a surfactant are incorporated into an tants is PVOH < PEO < methylcellulose < PVAc < PPO ≈ PVP;
aqueous medium, aggregation phenomena usually take place. The with cationic surfactants, the reactivity order is PVP < PEO <
aggregates appear as a consequence of: (i) hydrophobic interac- PVOH < methylcellulose < PVAc < PPO (where PEO = polyethyl-
tions between the nonpolar surfactant tail and the polymer back- ene oxide, PPO = polypropylene oxide, PVAc = polyvinyl acetate,
bone; (ii) hydrogen bonds, if the polymer has a high number of PVOH = polyvinyl alcohol, and PVP = polyvinylpyrrolidone). The
carboxylic acid groups and the surfactant is a proton acceptor; and/ ionizable character of nitrogen atoms of polyvinylpirrolidone,
or (iii) electrostatic interactions between the polar heads of the which provides it with a weak cationic character, explains its
surfactant and the charged groups of the polymer.[54-57] Further- markedly greater affinity for anionic surfactants. The generally
low affinity of hydroxyethylcellulose (HEC) is due to the rigidity mer charge density,[68] showed that the CAC is lower for degrees
of its backbone and to its relatively high hydrophilicity.[65] In fact, of ionization below 0.4. This observation, which is somewhat
introducing at least two hydrophobic tails in each chain of HEC surprising for a system in which an electrostatic interaction is
dramatically increases the binding of ionic surfactants.[54] In more expected, is explained by changes in the conformation of the
hydrophobic cellulose ethers, such as hydroxypropyl methylcel- chains. At low pH, the degree of dissociation of the carboxylic
lulose (HPMC) or ethyl hydroxyethylcellulose (EHEC), the acid groups is low and the polymer adopts a coiled conformation;
counter-ion of the anionic surfactants considerably influences the while at high pH, the chain expands as a result of intrapolymeric
aggregation process.[64] For example, the CAC of potassium dode- electrostatic repulsions. The polymer appears more hydrophobic
cyl sulfate (KDS) with HPMC and EHEC is lower than that of when the chain is in a compact conformation, which favors hydro-
sodium (SDS) or lithium (LiDS) derivatives, and the aggregates phobic interactions with the surfactant. In the coiled conformation,
are larger. This is because K+ ions, despite having the greatest two- or three-dimensional interactions among the hydrocarbon
ionic radius, present the lowest hydrated radius and can come tails of bound surfactants become possible, and compensate for the
closer to the micellar surface and give better screening of the weaker electrostatic stabilization of the aggregates.[68,81] This ex-
surfactant charges.[66] plains that the association is more favorable for copolymers of
Titration microcalorimetry shows that the free energy value of hydrophobic comonomers[73] and surfactants with longer alkyl
non-ionic polymer/ionic surfactant binding is slightly larger than tails.[74,82] On the other hand, the fraction of charged groups of the
that for micellization, reflecting a slightly more favorable pro- polymer neutralized by surfactant ions becomes greater as the
cess.[67] The adsorption of a surfactant onto the non-ionic cellulose degree of ionization increases.[70] For its part, degree of ionization
PAGE PROOF 2
ether chain is endothermic at the beginning, but as the aggregation is also raised by the binding of the surfactant, owing to a counter-
number increases and more clusters are formed on the chains, the ion exchange mechanism.[83] Above pH 6.8, the interactions are
interaction becomes exothermic. The enthalpy cost of confining mainly electrostatic and all cationic surfactants bind similarly,
the nonpolar polymer regions in the mixed micelles is compensat- irrespective of their hydrophobicity.[74] When neutralization is
ed for by a gain in entropy, originated from disorder of the complete, the complex adopts a tightly packed conformation and
hydration water layer and increased freedom of movement of the becomes insoluble in water. Finally, if there is an excess of
nonpolar segments in the mixed micelles.[64,67] surfactant, the aggregates may swell owing to ionic repulsions
Physical Gels Formed by Anionic Polymers: The interactions among the charged groups of the surfactant or to micelle solubili-
between linear poly(acrylic acid) or other anionic synthetic zation of hydrophobic aggregates.[74,82]
polymers and surfactants have been studied by adsorption,[67-70] Association of poly(acrylic acid)s with anionic surfactants is
surface tension,[71] fluorescence,[72-74] dye solubilization[72] and weaker than with cationic surfactants, and its effects are less
conductivity[75,76] methods. The interaction with nonionic surfac- pronounced.[71,84] Nevertheless, a sensitive technique such as titra-
tants is usually weak.[72,76,77] Nevertheless, in the case of ethoxylat- tion microcalorimetry has shown that the electrostatic repulsions
ed compounds, hydrogen bonding between the carboxylic groups can be easily overcome by hydrophobic interactions, especially in
of poly(acrylic acid) and the oxygen atoms of the ethyleneoxide the presence of salts in the medium and if the surfactant is double-
chain induces the aggregation. As the interaction with anionic tailed. Even in the case of single-tailed surfactants, the interaction
surfactants is mainly hydrophobic, it is favored when the polymer is slightly exothermic, suggesting that the polymer stabilizes the
is not ionized. To maintain the electroneutral conditions, the micelles.[35,85]
surfactant is accompanied by its counter-ions, which increase the Physical Gels Formed by Cationic Polymers: In the pharma-
osmotic pressure inside the aggregates and cause their swelling.[78] ceutical and cosmetic industries, chitosan is one of the most
The association process with cationic surfactants may result in widely used cationic polymers.[86] Although chitosan/surfactant
a phase separation near the neutralization point.[79,80] The inter- interactions have received little attention, the information avail-
action of an acrylic polymer with alkyltrimethylammonium bro- able shows that the polymer forms complexes with both anionic
mides (CnTAB with n = 10–16) or alkylpyridinium ions has been and cationic surfactants.[87,88] The amount of anionic surfactant
extensively studied.[68,70,73,74] Experiments carried out in media of bound increases as degree of N-acetylation decreases, which clear-
different pH[69,81] or salt concentration to achieve a constant poly- ly indicates that the electrostatic interaction plays an important
role.[87] On the other hand, the affinity of chitosan to cationic Additionally, an excess of free ionic surfactant increases the ionic
surfactants increases when the polymer is modified hydrophobic- strength of the medium. The balance of these three effects deter-
ally[88] or when anionic substituents are incorporated into the mines the final degree of swelling or shrinking of the gel.[102] The
chitosan chains.[89] absorption of a similarly charged surfactant on a polyelectrolyte
Cationically modified HEC and guar gum are also widely used hydrogel is favorable only when hydrophobic interactions over-
for pharmaceutical and cosmetic purposes. Despite HEC interact- come the electrostatic repulsion between charged groups.[56] At a
ing only very weakly with SDS, when there is a minimum of 0.05 low surfactant proportion, the gel swells as a result of an increase
quaternary ammonium residues per anhydroglucose unit, the sorp- in its internal osmotic pressure, while at high concentrations, the
tion of SDS becomes possible.[90-92] If HEC presents cationic and salt effect may be predominant. In the case of opposite charged
hydrophobic substituents, they interact synergistically with this hydrogel/surfactant systems, both hydrophobic and electrostatic
surfactant, resulting in stronger viscoelastic systems, except in a forces contribute to the interaction. An ion exchange between
narrow precipitation region.[65,93] Hydrophobically modified ca- surfactant and polymer counter-ions results in gel shrinkage.[107]
tionic celluloses are even able to interact with cationic surfac- Despite these general tendencies, the conformation, flexibility and
tants.[94] hydrophobicity of the chains and the local environment of the
Cationic polysaccharide-SDS interactions have been character- ionic groups in the gel and surfactant exert a strong influence on
ized by viscosity, surface tension, conductivity, dialysis or fluores- the structure and stoichiometry of the complex.[99-102] Consequent-
cence techniques.[58,63,79,80,95-97] Recently, Rodriguez et al.[98] re- ly, gel response is difficult to predict. Nevertheless, surfactant-
ported for two cationic hydroxyethylcelluloses (HECs), poly- induced gel phase transitions are related to the binding mechan-
PAGE PROOF 2
quaternium-4 (PQ-4) and polyquaternium-10 (PQ-10), that SDS isms of surfactants with non–cross-linked polymers.
begins to adsorb onto the polymer at a concentration (1.7 mmol/L
SDS) well below the CAC reported for HEC (7.0 mmol/L)[67] and Additives and Salts
other non-ionic cellulose ethers, such as ethyl(hydroxyethyl) cel- The addition of inorganic salts generally favors (lower CAC)
lulose (EHEC) [3.0 mmol/L] or hydroxypropyl methylcellulose the binding of ionic surfactants onto non-ionic or equally charged
(HPMC) [4.5 mmol/L].[64] The process saturated at a surfactant polymers,[85] although the intensity of the effect depends on the
concentration greater than the neutralization point (approximately ability of the ions to modify the structure of water.[108] In contrast,
3.5mol SDS/mol ammonium group), which confirms the concomi- the affinity of surfactants for oppositely charged polymers is
tance of both electrostatic and hydrophobic interactions.[90] In all reduced (greater CAC).[100,109]
cases, the binding process was strongly exothermic in both water For pharmaceutical applications, it is important to delimit the
and NaCl 0.9% aqueous solution. influence of ions on polymer/surfactant systems under physiologi-
Chemically Cross-Linked Hydrogels: The presence of surfac- cal conditions. In a recent study, the aggregation process of
tants in the medium may induce volume-phase transitions in Carbopol 934NF with nonionic (Tween 80 and Pluronic
chemically cross-linked hydrogels, and this response may be used F-127) and ionic surfactants (SDS and benzalkonium chloride) in
as a quick test to establish the mechanism and evaluate the water, in 0.9% NaCl solution, and in artificial lacrimal fluid was
intensity of polymer/surfactant interactions.[56,78,99-102] In the bi- analyzed using titration microcalorimetry.[35] Before being added
omedical field, the practical interest of surfactant-induced phase to the dewar containing water (blank) or Carbopol dispersion, all
transition is especially relevant in the case of microgels constitut- surfactants were above their CMC in the buret (15% weight/
ing colloidal systems, in which their swelling or collapse is re- weight). Therefore, when the surfactant solution was slowly added
sponsible for the behavior of the whole system[52,103-106] (figure 4), into water, the micelles broke up until the concentration in the
especially of its rheological properties as discussed in the follow- dewar reached CMC. For the non-ionic surfactants, the demicel-
ing paragraph. lization process was exothermic (enthalpy change negative), while
In the presence of an ionic surfactant, the hydrophobic poly- for the ionic surfactants an endothermic process was observed. In
mer/surfactant interaction favors interpolymeric associations in- spite of the differences observed in the CMC of the surfactants in
ducing the hydrogel to shrink. Simultaneously, it adds ionic each medium (water, 0.9% NaCl and artificial lacrimal fluid), the
groups to the network, which cause the swelling of the gel. enthalpy of demicellization was similar.
Surfactant concentration
Low Medium High
Surface
- - - - + - - - - - - + - - - - -
- + + - - + + - + - +
+ - + - - + + + -
+ + + + - +
-
-
- -
+ + - + - - + +
+ + + + - - +
-
+ + + + - - - -
- - + + + - - + - + - + +
+ - - - + +
+ + + + +
Sodium
dodecyl
sulfate
Tween 80
Pluronic F-127
PAGE PROOF 2
Benzalkonium
chloride
+ + + + + + + + + +
- - - - - -
- + - + - + - + + - - ++ + + - ++ -
+ + - + + - ++ + + + -
- + - + + + - + + +
- + - -
+ - - + - - - - -
- - + +
+ + - + ++ - ++ - ++ -
+ + - - - - + - + + + + - + +
+ + + + - + + +
- + + + -
- - - - - - - - -
Fig. 4. Schematic drawing of Carbopol/surfactant interaction phenomena and their repercussions on the volume of Carbopol microgel particles in the
aqueous medium. At low surfactant concentration (0.01 g/dL) interpolymer connections are promoted, producing an open three-dimensional network. If
non-ionic surfactant concentration rises, more surfactant molecules sorb into the microgels, intrapolymeric micelles are formed, microgels shrink, and the
interpolymer connections are broken. Ionic surfactants cause the shrinking of Carbopol microgels owing to ionic aggregation (benzalkonium chloride) or
increase in ionic strength (SDS) [reproduced from Barreiro-Iglesias et al.,[52] with permission from Elsevier Science]. SDS = sodium dodecyl sulfate.
Despite the fact that complex formation between nonionic resembles the micellization process of this surfactant and may be
surfactants with Carbopol in water or in 0.9% NaCl takes place not so tight, resulting in favorable entropy. There is an enthalpic
mainly through hydrogen-bond interactions, Pluronic F-127/ cost to introducing the nonpolar regions of polymer in surfactant
Carbopol aggregation is endothermic and occurs thanks to a gain clusters and there may be a small entropic cost due to the localiza-
in entropy, while Tween 80–Carbopol interaction is exother- tion of the chains in the micelle. However, this is compensated by
mic. Enthalpically driven complexation, such as in the case of the entropy gain from a decrease in the degree of structuring of the
Tween 80, is characteristic of a tight host-guest inclusion water molecules around the hydrophobic segments, which restore
through nonpolar interactions, which results in a strong entropy the water hydrogen-bonding structure, increasing the water entro-
loss. The complex formation of Carbopol with Pluronic F-127 py. The interaction processes in 0.9% NaCl were thermodynami-
cally similar to those in water, although slightly less intense. In onto the polymer. Tsianou and Alexandridis[110] observed that the
contrast, in artificial lacrimal fluid the Carbopol/surfactant inter- addition of α- or β-cyclodextrins to an aqueous dispersion of 1.0%
actions are hindered (figure 5a). Although the main component of cationic cellulose did not modify its rheological behavior, sug-
lacrimal fluid is NaCl and the ionic strength of the medium is gesting a lack of interaction between the two components. In
similar to that of 0.9% NaCl, the presence of Ca2+ ions and the contrast, the addition of cyclodextrins (1.25 mmol/L) to gels of
higher pH of lacrimal fluid medium prevent hydrogen-bonding 1.0% cationic cellulose and 2.5 mmol/L SDS caused an important
formation between Carbopol and nonionic surfactants. decrease in its viscosity and elasticity. This effect was explained as
Hydrophobic association with SDS is promoted in 0.9% NaCl, the ability of cyclodextrins to bind surfactant (1 : 1 complexes
owing to a shielding effect of the ionic groups of the polymer. In were obtained), to deactivate the thickening effect caused by its
contrast, the salt makes the complex formation with cationic adsorption onto the polymer, and eventually to destroy the gel
surfactants, such as benzalkonium chloride, difficult. For both (figure 6).
surfactants, association process with Carbopol was exothermic.
In artificial lacrimal fluid, the interaction with SDS disappears 2.2 Pharmaceutical Applications of Polymer/
while an endothermic association with benzalkonium chloride Surfactant Gels
takes place (figure 5b). The repercussions of these phenomena on
the rheological properties of the gels were very significant, which 2.2.1 Solubilization of Drugs
has considerable consequences for the application of these systems The problems that present formulation in gels of poorly soluble
PAGE PROOF 2
as drug dosage forms. drugs may be overcome by incorporating surfactants.[111] At the

The presence in the medium of other additives that can interact end of the 1950s, Saito[109] demonstrated that a number of hydro-
hydrophobically with the surfactant may prevent its aggregation philic polymers strongly enhance the solubility of oil-soluble dyes
Lacrimal fluid
NaCl
Water
Lacrimal fluid
NaCl
Water
a
b
2 6
Lacrimal fluid
0 3
Lacrimal fluid
−2 0
−4 −3
∆H (J/mmol)
∆H (J/mmol)
NaCl 0.9%
−6 NaCl 0.9% −6
−8 −9
Water
−10 −12
Water
−12 −15
0.00 0.05 0.10 0.15 0.20 0.25 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
Tween 80 added (mmol) Benzalkonium chloride added (mmol)
Fig. 5. Calorimetric titration curves obtained during the addition of: (a) 15% Tween 80; or (b) benzalkonium chloride; solution into a dewar containing
0.25% Carbopol dispersion (solid symbols). The corresponding dilution plots of each surfactant were similar in water, 0.9% NaCl, and artificial lacrimal
fluid (open symbols) [reproduced from Barreiro-Iglesias et al.,[35] with permission from Springer-Verlag GmbH & Co.KG].
Anionic surfactant
polypropylene oxide gels;[117] or 17β-estradiol in Carbopol 934/
+ -
-
-
+ SDS and in Carbopol 934/Tween 80 gels (figure 7).[118]
- +
+
2.2.2 Modulation of the Rheological Behavior
Viscoelasticity
- - Addition of small proportions of surfactant to a physically
+
+ -
cross-linked polymer gel opens interesting possibilities to modu-
+ late the rheological properties of the gel. Polymer/surfactant
- systems typically exhibit behavior in which three regions may be
+
Cyclodextrin distinguished depending on the relative proportions of the com-
ponents.[79,119] Below the CAC, no rheological changes are appre-
Fig. 6. Schematic representation of the influence of cyclodextrins on the
interpolymeric association induced by anionic surfactant adsorption on a
ciable. Above the CAC but below the CMC, if the polymer
cationic polymer. concentration is lower than its entanglement concentration, the
surfactant favors the intrapolymeric interactions (each aggregate
in media in which surfactant concentration is below CMC. Subse- involves one polymer molecule), which causes the coiling of the
quently, using fluorescent probes, it has been possible to obtain polymer chain and a decrease in viscosity. Conversely, for poly-
information about the micropolarity inside the aggregates at differ- mer concentrations higher than the entanglement concentration,
PAGE PROOF 2
ent stages.[73,112] The low polarity showed by polymer/surfactant the surfactant molecules can act as binding bridges among differ-
aggregates provides an appropriate medium to take in hydrophobic ent polymer chains, forming interpolymeric complexes, which
molecules. This property makes polymer/surfactant gels partic- promote the appearance of a three-dimensional network increasing
ularly useful to formulate hydrophobic drugs in semisolid homo- the viscosity. Above the saturation level of binding, the surfactant
geneous systems with a low proportion of surfactant and avoids forms micelles that can solubilize hydrophobic regions of the
the use of organic cosolvents.[113,114] This approach has been polymer and the complexes, decreasing the consistency of the
applied to solubilize methyl- and hexyl-nicotine in Carbopol network and the viscosity of the gel.[88,120,121]
941/SDS and in Carbopol 941/Brij 36T gels;[115] proflavin deriv- If the polymers are stimuli-sensitive, the presence of surfactants
atives in poly(acrylic acid)/dodecyl tetrabromide gels;[116] 17β- may strongly alter the in situ gelling behavior, modifying the
estradiol, progesterone or testosterone in poly(acrylic acid)/ intensity of the response and the range in which it occurs. Some
8 Carbopol 934/Tween 80 gel
Tween 80 solution
7
6
Estradiol solubilized (mg/dL)
0
0.075 0.10 0.25 0.50 0.75 1.0 2.0
Tween 80 (mg/mL)
Fig. 7. Solubility of 17β-estradiol in Tween 80 solutions and Carbopol 934/Tween 80 gels.[118]
a 0.3% Carbopol gel at pH 4.0

non-ionic cellulose ethers with a marked hydrophobic character 0.3% Carbopol gel at pH 7.4
(e.g. HPMC, EHEC) precipitate or form in situ gelling systems 0.3% Carbopol/14% Pluronic F-127 gel at pH 7.4
200
when temperature rises. In the first case, cooperative binding of
ionic surfactants usually increases the cloud point.[122] For 150
Shear stress (Pa)

polymers that provide thermoreversible gels, the formation of
micelle-like clusters that interconnect hydrophobic segments in
100
different polymer chains strongly increases the viscosity.[121,123] In
these systems, contrary to the general tendency, surfactant binding
50
is enhanced as temperature rises, which contributes to the thermo-
setting property of these gels. For example, the addition of
0
10 mmol/L cetyltrimethylammonium bromide (CTAB) to 1.0% 0 50 100 150 200
EHEC aqueous dispersion increases the viscosity 15-fold at 25ºC, Shear rate (sec-1)
and 40-fold at 45ºC. A similar effect occurs in the presence of

b Pilocarpine solution
relatively hydrophobic (i.e. with at least 10 carbons in the chain) 0.3% Carbopol gel at pH 7.4
anionic surfactants.[54,124] A strong influence of surfactants on 0.3% Carbopol/14% Pluronic F-127 gel at pH 7.4
1.0
cloud point temperatures of synthetic polymers, such as N-
isopropylacrylamide, has also been reported.[107,125]
0.8
The effect of surfactants on pH-sensitive in situ gelling systems
PAGE PROOF 2
Fraction released
has been also analyzed. In Carbopol/Tween 80 and Carbopol/ 0.6
Pluronic F-127 gels, polymer/surfactant interactions depend

0.4
markedly on the weight ratio, which, as a consequence, affects
their rheological behavior.[52,77,126] The interest of these systems as 0.2
in situ gelling formulations for ocular delivery is outlined in the
results of these papers. In the presence of a non-ionic surfactant 0.0
0 1 2 3 4 5 6
and at acid pH, the viscosity of the dispersion is slightly greater Time (h)
than for the polymer system alone, which may help to prolong Fig. 8. Flow curves of: (a) 0.3% Carbopol gel at pH 4.0 and pH 7.4, and
precorneal residence during the time required for gel formation. At 0.3% Carbopol/14% Pluronic F-127 gel at pH 7.4; and (b) pilocarpine
release from an aqueous solution, 0.3% Carbopol gel at pH 7.4, and 0.3%
pH 7.4, a synergistic effect between the polymer and the surfactant
Carbopol/14% Pluronic F-127 gel at pH 7.4 (reproduced from Lin and
is reflected in increased viscosity or in the achievement of the Sung,[77] with permission from Elsevier Science).
same values of viscosity using a lower proportion of the polymer
(figure 8a). The fact that the addition of surfactant increases the of their aqueous dispersions.[63,65,92] To achieve optimum rheologi-
viscosity at acidic pH, and that it also changes the shear-thickening cal behavior, surfactant concentration and charges ratio should be
behavior of Carbopol for pseudoplastic behavior, may be partic- taken into account. Between the CAC and the CMC, the surfactant
ularly useful for the application of the gels as drug dosage forms to favors the interpolymeric interactions, which results in the forma-
be administered in specific physiological regions (e.g. in- tion of a structured three-dimensional network, with a huge in-
travaginal) of low pH. crease in viscosity and elasticity. There is usually a break in this
Cationic polysaccharides/ionic surfactant systems are receiving region when the surfactant neutralizes the charges of the polymer
considerable attention owing to their wide range of applications in and the aggregates precipitate. Further addition of surfactant
the cosmetic field. Cationic polysaccharides have very attractive makes the formation of micelles that can dissolve the complexes
properties, such as hydrophilicity, biocompatibility, and bioadhe- possible[127] and the viscosity rises again. For a specific macromol-
siveness, but their thickening capacity is usually lower than that of ecular structure, the molecular mass of the cationic cellulose
non-ionic or anionic polysaccharides. To overcome this limitation, conditions the intensity of the changes in the elastic and viscous
the addition of an oppositely charged surfactant may strongly moduli of the gels formed after addition of SDS at proportions
increase the viscosity and the viscous (G′′) and elastic (G′) moduli below the neutralization of polymer charges.[92]
Most published work has been devoted to cationic HECs in abruptly, and the elastic component to vanish. In contrast, PQ-4/
which the ammonium groups are bonded to the hydroxyethyl SDS dispersions had, for all SDS concentrations evaluated (from
substituent (e.g. PQ-10).[65,92] The influence of the nature and 0.1–1%), higher viscous and, especially, elastic moduli than the
distribution of the charges of the polymer on the rheological polymer gel. The maxima for G′ and G′′ (four orders of magnitude
properties of 1% cationic cellulose/SDS gels has been analyzed greater than PQ-4 only dispersions) were observed at the SDS
recently, using a variety of PQ-10 and other PQ-4, which carries concentrations in which the ammonium/sulfonic groups ratio is
the ammonium groups directly grafted to the cellulose backbone close to 1 (figure 9). The different behavior of PQ-4 and PQ-10
while the hydroxyethyl substituent remains unaltered.[98] As re- systems relates to structural reasons. PQ-4 has fewer ammonium
ported previously by several authors,[63,65] PQ-10/SDS dispersions groups, which are included in small chains grafted to the cellulose
presented the highest consistency with low (0.1%) and high (1%) backbone, and more free hydroxyethyl substituents than
SDS concentrations. Near the neutralization point (0.30–0.50% PQ-10.[128] Therefore, although the neutralization of charges
SDS), the precipitation of the system caused G′′ to decrease causes the formation of a neutral polyampholyte, the presence of
SDS concentration 0%
SDS concentration 0.10%
Polyquaternium-4/SDS SDS concentration 0.80%
102 102
PAGE PROOF 2
101 101
Viscous modulus (Pa)
Elastic modulus (Pa)
100 100
10−1 10−1
10−2 10−2
10−3 10−3
10−4 10−4
Polyquaternium-10/SDS
102 102
101 101
Viscous modulus (Pa)
Elastic modulus (Pa)
100 100
10−1 10−1
10−2 10−2
10−3 10−3
10−4 10−4
0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100
Angular frequency (rad/s) Angular frequency (rad/s)
Fig. 9. Influence of sodium dodecyl sulfate (SDS) concentration on the viscous and elastic moduli of two structurally different cationic hydroxyethylcellulose
dispersions (1%).[98]
the free hydroxyethyl groups in PQ-4 provides enough hydrophili- polystyrene particles is not reduced. Therefore, although the mac-
city to avoid the precipitation of the aggregates and contributes to roscopic viscosity of the system increases strongly, its resistance
the establishment of the three-dimensional network. In contrast, in to the diffusion is scarcely modified (figure 10). When more
PQ-10 the ammonium groups are directly bonded to the hydroxy- surfactant molecules are added, the formation of intrapolymeric
ethyl substituents, which may be included in the polyampholyte micelles becomes possible, the interpolymeric connections dimin-
complex during aggregation, promoting precipitation. ish, and the three-dimensional network disintegrates. Despite the
The surfactant-induced shrinking of chemically cross-linked decrease in macroscopic viscosity, the formation of larger Carbo-
hydrogels made of PQ-4 and PQ-10 reflected their different be- pol/surfactant aggregates and the appearance of free micelles
havior. Although the SDS-binding isotherms were very similar, makes the medium more tortuous and the diffusion of polystyrene
PQ-10 hydrogels decreased their volume up to 20 times at the particles becomes more difficult.[131] This last effect is particularly
neutralization point, while PQ-4 hydrogels shrank to only one- relevant when the surfactant is cationic, such as benzalkonium
third of their initial volume under the same conditions.[98] This also chloride, and a strong associative process occurs (see figure 4).
indicates that surfactant concentration determines the mesh size of The repercussions of these phenomena on drug release processes
the hydrogel and, in consequence, if a drug were incorporated, its are discussed in section 2.2.3.
diffusivity could be significantly altered.
a Microviscosity
12 Viscosity
Microviscosity
10
PAGE PROOF 2
In addition to the effects on the bulk properties of the gel, it is

foreseeable that polymer/surfactant interactions will dramatically
Relative viscosity
8
alter the microenvironment in which the solute diffusion occurs.
The formation of polymer/surfactant aggregates or free micelles 6
could modify the size of the water-filled regions or the mobility of
4
the polymer chains. A reduction in the gel free volume or an
increase in the path length restricts the diffusive movement of the 2
drug and decreases its release rate.[129] In separately prepared
polymer or surfactant dispersions, it has been shown that the 0
0.0 0.1 0.2 0.3 0.4 0.5 0.6
effects of the polymer or surfactant concentration on the macro-
Tween 80 (%)
scopic flow properties of the system and the diffusion of the drug
do not necessarily correlate, which suggests the need to take the b
5
microviscosity of the medium into account.[49,130,131] The impor-
tance of this effect in polymer/surfactant systems was demonstra-
4
ted, recording the diffusion coefficients of polystyrene latex nano-
spheres (162nm) in 0.25% Carbopol dispersions containing vari-
3
ous proportions of surfactants,[52] using dynamic light scattering
Relative viscosity
(DLS). Microviscosity was estimated using the expression:

2
η/η0 = D0/D
where η and η0 are the microviscosity (mPa • s) of the polymer
1
dispersion and the viscosity of the water, respectively, and D and
D0 are the diffusion coefficients (cm2/min) for the nanospheres in
0
the presence and absence of polymer, respectively. 0.00 0.01 0.02 0.03 0.04 0.05 0.06
While the addition of low proportions of non-ionic surfactants Benzalkonium chloride (%)
to Carbopol systems creates a three-dimensional network of Fig. 10. Influence of concentration of two surfactants (a) Tween 80 and
(b) benzalkonium chloride, on the viscosity, estimated using flow rheome-
greater consistency, the free volume among the Carbopol parti- try, and microviscosity, estimated by dynamic laser scattering with 162nm
cles is scarcely altered and, in consequence, the diffusion of polystyrene particles of 0.25% Carbopol 934 gels at pH 4.[35]
2.2.3 Improvement of Drug Control Release viscosity. This clearly indicates that it is feasible to control the
release of uncharged drugs from gels by using polymer/micelle
Gels hydrophobic interactions. Drug micellar partition was proposed by
When a drug is formulated in a polymeric gel that incorporates Östh et al.[135] as a way to achieve a sustained release of testoster-
surfactants, the drug may be in different states: (i) the drug is one or hydrocortisone in the nasal mucosa from Carbopol 934P
solubilized in the water and there is no interaction with any of the gels. The addition of Brij 58 to the gel induces the partitioning of
components; (ii) the drug molecules establish electrostatic or the drug inside the micelles without modifying its rheological
hydrophobic interactions with the polymer; (iii) the drug mole- properties. Since testosterone is more hydrophobic than hydrocor-
cules are solubilized inside the micelles or the polymer/surfactant tisone, its affinity for the micelles was higher (log D 3.27 versus
aggregates (figure 11).[11,14] The microstructure of the system and 1.62) and, in consequence, a more significant decrease in the
the interaction state of the drug strongly condition the diffusion diffusion coefficients and transport rates through the nasal mucosa
process.[13,56] occurred for this drug (figure 12b).
No Surface-Active Drugs: If there is no interaction between the On the other hand, the release of charged drugs from Carbo-
drug and the components of the gel, diffusion rate is mainly pol gels may be retarded by adding an oppositely charged
dependent on the rheological changes that the surfactant induces in surfactant.[14] Amphiphilic drugs with amino ionizable groups
the polymer dispersion. This is the reason for the retarded release spontaneously form vesicles with SDS. The same happens when
process found for clonazepam[132] and pilocarpine[77] in Carbo- an anionic drug, fluvastatin, is mixed with benzalkonium mi-
pol/surfactant gels (figure 8b), or timolol maleate in EHEC/ celles.[14] Consequently, electrostatic and hydrophobic interactions
PAGE PROOF 2
alkylbetaine surfactant gels.[133] Nevertheless, it is necessary to between the drug and the surfactant, and hydrophobic interactions
bear in mind that the increase in viscosity is usually followed by a of the drug with the polymer and of mixed vesicle drug/surfactant
decrease in release rate less intense than expected, or may even by with the polymer contribute strongly to decrease the release rate.
followed by an increase in diffusion coefficients. Lu and Jun[134] The size of the vesicles was smallest in the gels containing the
observed that with 20% poloxamer, Carbopol gels had greater most hydrophobic Carbopol 1342, because of a more intense
viscosity but also released methotrexate faster. Similarly, Bar- interaction with the surfactant. These gels showed the lowest
reiro-Iglesias et al.[52] found that gels made of 0.25% Carbopol diffusion coefficients and also a considerable increase in their
and 0.01% surfactant have a considerably higher viscosity than viscous modulus (figure 13).
Carbopol-alone gels, but a similar chloramphenicol diffusion Surface-Active Drugs: Frequently, the drug itself is a surface-
rate. In this last case, the measurement of the microviscosity of the active substance able to interact directly with the polymer through
gels, using DLS of polystyrene latex nanospheres, once again hydrophobic and electrostatic bonds, at concentrations below or
provided useful information to predict the diffusional behavior above their CMC (table II). Consequently, amphiphilic drugs may
more accurately. greatly affect the consistency and the release properties of the gels.
If the drug is hydrophobic, its incorporation into micelles and The intensity of these effects depends on the tendency of the drug
aggregates may have important repercussions on the release pro- to aggregate and on the strength of its hydrophobic and ionic
cess. Paulsson and Edsman[11] showed that the diffusion rate of a interactions with the polymer.[13,136] For example, in the presence
series of p-hydroxybenzoic esters (parabens) through Carbopol of alprenolol, micelle-like aggregates are formed with the lipophil-
gels depends, in the absence of surfactant, on the intensity of the ic chains of Carbopol 1342 at low drug concentrations
hydrophobic interactions with the polymer and, in the presence of (4.5–18 mmol/L); increasing the elastic and viscous moduli of
1% Brij 58 micelles, also on the micellar distribution of each 1.0% Carbopol gels. However, when the drug concentration is
paraben. The most hydrophilic parabens showed a low micellar raised, the viscosity decreases (36 mmol/L) and then the gel col-
distribution (log D <2) and there was no sustained release. In lapses and precipitation occurs (72 mmol/L). At this last concen-
contrast, for the most hydrophobic paraben (butylparaben) the tration, alprenolol amino groups neutralize the carboxylic acid
diffusion coefficient in Carbopol 1342 gel with surfactant was groups of the acrylic polymer. Gels formulated with Carbopol
only 4% of that obtained in the micelle-free formulation (figure 1342 showed a lower alprenolol diffusion rate than those made of
12a), despite the fact that the surfactant caused a decrease in more hydrophilic Carbopol 934 or Gelrite, although in both
these cases there are also carboxylic acid groups available to these studies was particularly useful in designing a chemically
interact with the drug. Therefore, the degree of the lipophilic cross-linked hydrogel able to control the release process of another
modification of the polymer is an important factor to achieve amphiphilic drug, diclofenac sodium, as a function of the pH of the
sustained release. When Brij 58 was incorporated into the gels at a medium.[34] At pH 3, hydrophobic and ionic bonds are strongly
concentration above its CMC, an even slower diffusion rate is promoted and the drug is not released. When the medium is
achieved, especially for the gels made of the most hydrophilic replaced by pH 7.4 phosphate buffer, the strength of the inter-
polymers. These results prove that surface-active drugs may con- action decreases and the drug is released.
tribute to improve the gel properties, avoiding the use of classical A comprehensive study of the potential as periodontal drug
surfactants, which simplifies the formulation and reduces toxico- delivery systems of non-ionic cellulose ether/surface-active anes-
logical risks.[137] thetic drug gels was carried out by Scherlund et al.[140] In the
Most semisynthetic polysaccharides have a structure that is absence of surfactants, upon addition of lidocaine and prilocaine
able to interact with surface-active drugs. Cellulose ethers present (in their uncharged form) to EHEC or hydrophobically modified
a glucosidic backbone that may establish hydrophobic interac- EHEC (HM-EHEC) gels, only a minor interaction with the poly-
tions, while the presence of hydrophilic or charged groups in their mer occurred, which did not significantly modify the rheological
substituents provides the polymer with hydrogen-bonding capa- properties. However, in gels containing SDS or myristoylcholine
city or high affinity for oppositely charged molecules, respective- bromide, the drugs strongly affected surfactant/polymer interac-
ly. This amphiphilic character is clearly seen in the surface-active
a
properties of semisynthetic polysaccharides.[138] Nonsteroidal anti-
PAGE PROOF 2
-
inflammatory drugs, such as ibuprofen sodium, adsorb onto cellu-
lose ethers in the form of mixed polymer/drug micelles, nonco-
-
operatively up to CMC and cooperatively above this concentra-
tion.[12] Near CMC, ibuprofen causes phase separation of EHEC
gels, because of a strong hydrophobic interaction that shrinks the
polymer chains, but above CMC micelles of ibuprofen solubilize
the hydrophobic parts of the polymer. Compared with common
anionic surfactants, such as SDS, in which the CAC is much lower b
-
than the CMC, the ibuprofen adsorption on EHEC is less favorable +
and begins nearer the CMC. Binding of ibuprofen molecules +
+
among themselves is preferred to binding to the polymer. There- + -
fore, ibuprofen first forms micelles into which EHEC distributes.

Although the diffusion of ibuprofen through these gels was not
studied, it is expected that polymer/ibuprofen interactions may
contribute to controlling the release rate, as was shown by Rodri-
guez et al.[139] in related systems.
c
Cationic cellulose ethers and cationic guar gums interact hydro- -
phobically and ionically with ibuprofen, binding up to 15mg drug

per milligram of polymer.[139] This interaction considerably delays -
drug diffusion rate from 1.0% polymer gels compared with water.
Moreover, the addition to the gel of small amounts of SDS, which
causes a slight decrease in viscosity, provokes a reduction in the
values of the diffusion coefficients of almost 50%. As indicated Fig. 11. Schematic drawing of the states of a drug in a polymer/surfactant
gel when the drug molecules are: (a) solubilized in the water and do not
above, in the presence of the surfactant, new bonds are expected
interact with the components of the gel; (b) interact electrostatically or
between the drug and the surfactant and between the mixed hydrophobically with the polymer; and (c) are solubilized inside micelles or
micelles of polymer/drug/surfactant. The information provided by polymer/surfactant aggregates.
a Butylparaben
Ethylparaben way to control drug-release rate; and (iii), as cationic surfactants
Methylparaben
have antibacterial properties, they may contribute to the therapeu-
1.0 p-Hydroxybenzoic acid
Propylparaben tic effect.
The possibility of polymer/surfactant gels as drug carriers is
0.8
being explored for gene therapy. Complexation of DNA with
cationic surfactants or polymers reduces its net negative charge
Fraction released
0.6 and promotes its collapsing, which improves the transfection.[141]

Finally, the affinity of polymers for biological surfactants, such as
bile salts, may be used to reduce cholesterol levels.[142] When
0.4
polymers electrostatically bind bile salts, the emulsification of
cholesterol at the gastrointestinal tract is impeded and, therefore,
0.2 fat uptake is reduced. To prepare efficient formulations able to
‘sequestrate’ large amounts of bile salts, an imprinting molecular
technique can be applied. This consists of synthesizing and cross-
0.0
0 60 120 180 240 300 360 linking the polymer network in the presence of target molecules.
Once target molecules are removed after gel preparation, ‘cavities’
b
of a size, and with the spatial arrangement of chemical groups
1.0
Hydrocortisone from Carbopol 934/1% Brij 58 adequate to interact with target, are formed.[143] This provides the
PAGE PROOF 2
Hydrocortisone from Carbopol 934

Testosterone from Carbopol 934 gel with a high chemical trap capability.
Testosterone from Carbopol 934/1% Brij 58
0.8
Hydrophilic Matrices
The contribution of surfactants to the control of the drug-
Fraction released
0.6
release process through a gel layer was also seen in hydrophilic
matrix tablets.[144,145] When a matrix enters into contact with
0.4 physiological fluids, it absorbs water and swells, and a gel layer is
generated. This gel layer grows towards the nucleus of the tablet,
as water penetrates, at the same time that it is being externally
0.2
eroded by polymer disentanglement. Soluble drugs dissolve in this
layer to diffuse out. Although the gel layer changes its dimensions
0.0 and density over time, in many aspects they resemble the polymer
0 20 40 60 80 100
Time (min)
gels described above. An HPMC matrix including SDS was shown
Fig. 12. Drug release profiles of: (a) p-hydroxybenzoic acid, to release chlorpheniramine maleate more slowly than without
methylparaben, ethylparaben, propylparaben, and butylparaben from surfactant,[144,145] probably because of surfactant/drug ionic inter-
Carbopol 1342 gels with 1% Brij 58; and (b) testosterone and hydrocorti-
actions. Surfactants may also induce considerable modifications in
sone from Carbopol 934 and from Carbopol 934/1% Brij 58 gels. The
most hydrophobic parabens and testosterone have a high micellar distribu- the swelling degree of the gel layer, by establishing interactions
tion, which provides more efficient control of the release (reproduced from with the polymer, which may also alter the drug-release pro-
Paulsson and Edsman,[11] with permission from (a) John Wiley & Sons Inc.,
and the copyright holder Wiley-Liss, Inc., and (b) Östh et al.,[135] with
cess.[146] Recently, Nokhodchi et al.[147] evaluated the influence of
permission from Elsevier Science). nature and concentration of several surfactants or their mixtures on
the release of propranolol from HPMC-Eudragit matrices. Tab-
tions, and the values of G′ and G′′ were quite different from that of lets prepared by direct compression of drug/HPMC K4M/
polymer/surfactant dispersions. Formulations based on these Eudragit RSPO (80/60/60) exhibited a progressive decrease in
systems may be particularly useful because: (i) they have a tem- drug release rate (pH 1.2 and 6.8) when the proportion of SDS in
perature of gelation close to 37ºC, being able to transform into gel the tablet increased up to 20mg (figure 14). These results were
when introduced into the periodontal pocket; (ii) they provide a explained by both drug/surfactant interactions, which decrease
Carbopol 934
Carbopol 934/0.2% benzalkonium
allergenic, and therefore the most acceptable as penetration en-
Carbopol 1342 hancers.[150]
1.0 Carbopol 1342/0.2% benzalkonium
Surfactants may promote topical drug permeability mainly
through two mechanisms: increasing drug partitioning in the skin
0.8 and making drug diffusion through the stratum corneum easi-
er.[150,151] Firstly, the surfactants may penetrate into the intercellu-
lar regions of the stratum corneum, increasing fluidity and, eventu-
Fraction released
0.6
ally, solubilizing and extracting lipid components. Secondly, pen-
etration of surfactants into the intracellular matrix followed by
interaction and binding with keratin filaments may result in a
0.4
disruption of the corneocyte. Shokri et al.[151] observed that skin
penetration of diazepam was optimum using 1% Tween 80 or
0.2 benzalkonium chloride but, for higher concentrations, the penetra-
tion decreased again. This effect is due to micelle formation and
distribution of the drug inside them, which decreases the activity
0.0 of the drug at the absorption site. In the cases of SDS and CTAB,
0 60 120 180 240 300 360
Time (min)
penetration increases when the concentration of the surfactant
rises because of the intense barrier impairment induced by these
PAGE PROOF 2
Fig. 13. Fluvastatin release profiles from Carbopol 934, Carbopol 1342,
Carbopol 934/0.2% benzalkonium, and Carbopol 1342/0.2% surfactants.[137]
benzalkonium gels. Mixed micelles of fluvastatin and benzalkonium show
lower diffusion coefficients, especially when they interact with the hydro- The usefulness of penetration enhancers to optimize the bio-
phobic chains of Carbopol 1342 (reproduced from Paulsson and availability of piroxicam from topical gels and of triamcinolone
Edsman,[14] with permission from Kluwer Academic/Plenum Press Publish-
acetonide from buccal bioadhesive gels was reported by Shin and
ers).
SDS incorporation 0%
SDS incorporation 2.5%
drug solubility, and polymer/surfactant interactions, which in- SDS incorporation 5%
0.9 pH 1.2 pH 6.8 SDS incorporation 10%
crease the viscosity of the gel layer and provide a less porous and
more tortuous pathway. In contrast, cetyltrimethyl ammonium 0.8
bromide scarcely modified the drug-release process owing to the

0.7
low affinity of cationic surfactants for cellulose ethers and cationic
0.6
drugs, which makes a low degree of binding predictable. Finally,
Fraction released
surfactants, particularly those of high hydrophile-lipophile bal- 0.5

ance, may enhance the drug diffusion rate from matrices by
0.4
lowering the interfacial tension between the gel layer and the
dissolution fluid.[148] 0.3
0.2
2.2.4 Promotion of Cutaneous and Mucosal Drug Penetration
In many cases, the limiting step for drug absorption is penetra- 0.1
tion through skin and mucosa, rather than the release from the 0.0
dosage form. For example, Morimoto and Morisaka[149] observed 0 60 120 180 240 300 360 420 480
Time (min)
that the rectal absorption of barbital and aminopyrine from Carbo-
Fig. 14. Effect of sodium dodecyl sulfate (SDS) incorporation on propra-
pol gels is more dependent on the pH of the gel, which deter- nolol hydrochloride release from hydroxypropyl methylcellulose (HPMC)/
mines the non-ionized fraction of the drug, than on the release rate. Eudragit hydrophilic matrix tablets. Drug release rate is reduced by an
increase in gel layer viscosity, owing to polymer/surfactant interactions,
Non-ionic surfactants are particularly useful to enhance oral, rectal
and a decrease in drug solubility owing to drug/surfactant association
and topical absorption of drugs and hormones. Polyoxyethylene (reproduced from Nokhodchi et al.,[147] with permission from Elsevier
alkyl ethers are usually considered the least toxic, irritating and Science).
co-workers.[152,153] The amount of piroxicam permeated from nolone acetonide bioavailability compared with that of gels with-
poloxamer/HPMC gels increased almost 3-fold when 5% polyoxy- out enhancer, and provided relatively constant blood levels[153]
ethylene-2-stearyl ether was added to the formulation (figure 15a). (figure 15b).
A histological analysis of the skin after the diffusion test showed Finally, gels have several potential advantages for the treatment
that the stratum corneum was loosely layered and that intercellular of herpetic mucocutaneous infections compared with systemic
spaces were wide.[152] Carbopol/poloxamer gels containing sodi- formulations; these include targeting of the drug to specific sites of
um deoxycholate showed about a 1.59-fold increase in triamci- infection, higher tissue drug levels, reduced adverse effects, lower
treatment costs, and greater convenience.[154] Piret et al.[155] ob-
Poloxamer/HPMC/polyoxyethylene-2-stearyl ether/HPMC/surfactant
a Poloxamer/HPMC/polyoxyethylene-2-oleyl ether/HPMC/surfactant served how the efficacy of foscarnet, formulated as polyoxypropy-
Poloxamer/HPMC/polyoxyethylene-23-lauryl ether/HPMC/surfactant
0.4 lene/polyoxyethylene gel, against herpes simplex virus considera-
Poloxamer/HPMC
bly improved when SDS (5%) was incorporated. This effect is a
consequence of the efficiency of this surfactant as an absorption
0.3 promoter (figure 16a). Additionally, SDS is a potent inhibitor of
Amount permeated (mg/cm2)
the infectivities of herpes simplex virus strains, which contributes

to a rapid recovery from herpetic mucocutaneous lesions[156,157]
0.2 (figure 16b).
PAGE PROOF 2
3. Conclusions
0.1
For the development of pharmaceutical gel-based drug delivery

systems, surfactants are very useful additives. When a surfactant is
0.0 added to a polymer gel, aggregation phenomena usually occur as a
0 4 8 12 16 20 24
result of hydrophobic interactions or hydrogen bonds between the
b
nonpolar surfactant tail and the polymer backbone, and/or electro-
1000 Carbopol/poloxamer/sodium deoxycholate static interactions between the polar heads of the surfactant and the
Carbopol/poloxamer charged groups of the polymer. These interactions considerably
affect the microscopic structure and the macroscopic behavior of
the gels. The viscoelastic behavior of physically cross-linked gels
Plasma concentration (ng/ml)
100 and the degree of swelling of chemically cross-linked hydrogels

may be modulated by the addition of surfactants of different nature
or at different proportions. Surfactants may even strongly alter the
in situ gelling behavior of stimuli-sensitive systems, modifying the
10 intensity of the response to changes in physiological parameters
and the range in which it occurs. These effects are particularly
useful to provide the formulations with adequate rheological
properties for easy administration and resistance to physiological
1
stress.
0 4 8 12 16 20 24 In addition, polymer/surfactant aggregates have a major role in
Time (h)
the solubilization, control of release, and absorption of the drugs
Fig. 15. Penetration profiles of piroxicam from: (a) poloxamer/hydroxy-
propyl methylcellulose (HPMC) and poloxamer/HPMC/surfactant (polyoxy- incorporated into the gels, when administered by various routes.
ethylene-23-lauryl ether, polyoxyethylene-2-oleyl ether, and polyoxy- Polymer/surfactant aggregates provide a more hydrophobic micro-
ethylene-2-stearyl ether) topical gels; and (b) triamcinolone plasma
environment than surfactant micelles, which is particularly useful
concentration following buccal application of Carbopol/poloxamer or
Carbopol/poloxamer/sodium deoxycholate mucoadhesive gels (repro- to increase the solubility of hydrophobic drugs using low
duced from Shin et al.,[152,153] with permission from Elsevier Science). surfactant proportions. Modification of the tortuousness of the
a
1500
of some gels. Polymer or surfactant complexes with DNA are
Infected
Non-infected promising systems for gene delivery. Finally, the capability of
1250
some polymers to bind natural surfactants makes them potentially
useful as chemical traps. Molecular imprinting technology may
1000
enhance the affinity and selectivity of gels for target molecules.
mmol/g epidermis
The knowledge of the interaction phenomena constitutes a very

750
useful tool to design pharmaceutical gels with optimal physico-
chemical, mechanical, and drug loading and release properties.
500
Acknowledgements
250 This work was financed by the Xunta de Galicia (PGIDT 00PX120303PR
and 01PX1203014IF) and the Ministerio de Ciencia y Tecnología, Spain
(RYC 2001/8). The authors have no conflicts of interest that are directly
0
PFA PFA/SDS relevant to the content of this manuscript.
b
6 Polyoxyethylene-co-polyoxypropylene and 5% SDS References
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Effects of Surfactants on Gel Behavior: Design Implications for Drug Delivery

Article in American Journal of Drug Delivery · June 2003

Carmen Alvarez-Lorenzo Angel Concheiro

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Am J Drug Deliv 2003; 1 (2): 77-101

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Effects of Surfactants on Gel Behavior

Carmen Alvarez-Lorenzo and Angel Concheiro

2. Incorporation of Surfactants in Polymer Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Mechanism Method Examples

Plasma induced Polyethylene

become practically independent of angular frequency, G′ being applications[1,25,26]

Applying oscillatory rheometry, the influence of molecular struc- Nasal Mucoadhesive

1.2 Mucoadhesion Pseudoplastic, thixotropic

the better the knowledge of the physiological environment, the

1.3 Drug Release

through which the drug moves out. If the hydrodynamic diameter

it is smaller, the release rate depends on the tortuousness of the

pharmaceutical point of view, is now presented.

Low Medium High

as drug dosage forms. drugs may be overcome by incorporating surfactants.[111] At the

a 0.3% Carbopol gel at pH 4.0

Shear stress (Pa)

and 40-fold at 45ºC. A similar effect occurs in the presence of

has been also analyzed. In Carbopol/Tween 80 and Carbopol/ 0.6

Pluronic F-127 gels, polymer/surfactant interactions depend

Elastic modulus (Pa)

Elastic modulus (Pa)

In addition to the effects on the bulk properties of the gel, it is

(DLS). Microviscosity was estimated using the expression:

fore, ibuprofen first forms micelles into which EHEC distributes.

phobically and ionically with ibuprofen, binding up to 15mg drug

0.6 and promotes its collapsing, which improves the transfection.[141]

Hydrocortisone from Carbopol 934

bromide scarcely modified the drug-release process owing to the

surfactants, particularly those of high hydrophile-lipophile bal- 0.5

the infectivities of herpes simplex virus strains, which contributes

For the development of pharmaceutical gel-based drug delivery

100 and the degree of swelling of chemically cross-linked hydrogels

The knowledge of the interaction phenomena constitutes a very

4. Osada Y. Polymer gels: crosslink formations. In: Osada Y, Kajinara K, editors.

pharmacokinetics and pressure lowering activity in rabbits. J Ocul Pharmacol

Surf A 1994; 90: 89-94 Woodhead Publishing, 1995: 287-93

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