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Tripathy / AJPSR volume 2 issue 2 , Feb 2012

Available online at www.ordonearresearchlibrary.com

ISSN 2249-4898

Review Article

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH


THE PHARMACEUTICAL APPLICATIONS OF CARBOMER
Ikhwan Hadi Bin Suhaime, Minaketan Tripathy* , Mohamed Salama Mohamed, Abu Bakar Abdul Majeed.
Faculty of Pharmacy, Puncak Alam Campus, Universiti Teknologi Mara, Malaysia-42300.
Received: 21 Dec. 2011; Revised: 22 Jan.. 2012; Accepted: 23 Feb.. 2012 Available online: 5 Mar 2012

ABSTRACT
Carbomer is a versatile polymer having wide applications in the field of pharmaceutical sciences. This review
article constitutes a brief physicochemical introduction of carbomer along with an exhaustive discussion on its
applications in in-situ gelation, ophthalmic drug delivery, transfection of protein chain, oral delivery, enzyme
inhibition and thickener in cell culture medium and for microemulsions. The toxicity of carbomer is also
highlighted.
KEYWORDS: Carbomer, in-situ gelation, ophthalmic gel, transfection of protein chain, enzyme inhibition,
thickner.

INTRODUCTION
Carbomer is a commercial name for poly(acrylic acid) with uses ranging from thickening agents
to drug delivery vehicle targeting specific site in the body. Its molecular weight ranges from 2-30
x 106 with aqueous dispersion pH ranging from 2.8 3.2 according to the types of resin being
used to prepare the solution1,2. It is a weak acid with pKa >5. In the dry state, the carbomer
chains will appear in a spiral form, but will slowly unwind when solubilizing agents was added
which can be observed by the increase in viscosity of the solution3. The unwinding of the coils
can proceed through two mechanisms. The first mechanisms start when the carboxylic acid
groups on the chain was neutralize with an appropriate base. This will increase the electrostatic
repulsion between the chains causing the coil to come apart. The chain would then intertwine
with each other resulting in a 3D matrix that causes an instantaneous formation of highly viscous
gel. The second mechanism occurs by the addition of hydroxyl donor structure such as polyols to
the carboxyl group. The combination of the carboxyl with hydroxyl group produce a thickening
affect due to formation of hydrogen bonds in the structure. This mechanism is a time dependant
mechanism. Studies conducted on the rheology of carbomer have found that the viscosity of the
solution is a function of pH and the concentration. Taberner et. al. (2002) theorized the viscosity
of the carbomer solution can be calculated using the equation below3:

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Where:
m = viscosity of the solution
C = concentration of the solution

Figure 1: Structure of acrylic acid monomer

Source: Perale et. al. (2011)56


This theory was also confirmed by other studies such as an observation made by Iglesias et. al.
(2001) whereby the viscosity of the solution have been found to decrease when low
concentration solution was studied. One of the probable cause mentioned by Iglesias et. al.
(2001) is that the expansion of the polymer chains was diluted due to large amount of solvent
available4. Taberner et. al. (2002) have also observed that carbomer compound can withstand
brief exposure to high temperature. This property makes it an excellent candidate for drug carrier
that involves sterilization process during the manufacturing3.
sterilization process during the manufacturing3.
In situ gelation
Most of the current literature describes carbomer being used as a drug carrier that targets a
specific site in the body. These targets include ocular, oral, transdermic, rectal and nasal5, 6, 7, 8, 9.
This wide range of usage is attributed to the ability of carbomer solution to form in situ gel in
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physiological condition that can control the drug release and also protect the drug. Study shows
that addition of alkaline compound, solvation, and electrostatic repulsion between the anionic
groups causes the gel formation10.
Another factor that can induce an in situ gelation of carbomer is the pH change of the medium.
Kim et. al. (2003) have observed that carbomer solution viscosity would increase when it is
exposed to a neutral pH, but the viscosity would not change in the acidic medium. One of the
hypotheses given is that in acidic media, the carbomer structure does not swell due to strong
hydrogen bonding between the polymer chains. While in neutral medium, the chain would
dissociates causing an increase in viscosity while forming a gel12.
The carbomer gel is classified as a non-newtonian pseudoplastic11. Study by Iglesias et. al.
(2001) have found that the gel shows a change in viscosity under a shear stress. The study also
describes the gel behavior in two stages4. The first stages are the initial rearrangement of the
polymeric chains towards the flow lines corresponds to the pseudoplastic region. The second
stage is the shear thickening behavior. This behavior is induced by the disintegration of the
interpolymeric bridges that causes the disintegration of the 3D network structure13. The second
factor is due to surfactant desorption. The second factor is most likely to happen when the
concentration of the surfactant is above the critical micelle concentration14.
The affect of surfactant towards carbomer gel differs between the surfactant used. Surfactant
such as sodium dodecyl sulphate (SDS) causes a decrease in consistency of the carbomer
systems at pH 4 and 7.4. However the carbomer is able to retain its in situ gelation properties.
The decrease in viscosity is mainly due to salt effect15. The small molecular size and anionic
character of SDS causes an increase in the ionic strength of the medium. This will produce a
shielding affect among the anionic charges of carbopol chain causing it to shrink16. This
shrinkage causes the decrease in viscosity of the system. When the system was expose to a
neutral environment, the anionic charges will be neutralized and cause the swelling of the
system. This will increase the free volume among carbomer microgel. This expansion makes the
microstructure of the carbomer gel to be less tortuous and release the drug incorporated into the
gel structure.

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Figure 2: Stability data of Azithromycin in hydrogel C974-AZI50 (


buffered solution (

) and phosphate

) as a function of time

Source: Esteban et. al. (2009)16

Commercially, there are various derivatives of carbomer available depending on the use.
According to Ceuelman et. al. (2002) the most common carbomer derivatives being used for
pharmaceutical usage is C974P NF, C980 NF and C1342 NF17. The C974 NF is a benzene-free
alternative of C934P NF. C980 NF is the most efficient thinkening agent among the three
derivatives. It is currently being used to treat dry eye syndrome. While the C1342 NF posses the
longest alkyl acrylate chain among the three. It also has an increased resistance towards
dissolved ions and can be used to coat liposomes for ocular administration. The study also
compared the order of elasticity among the three derivatives before and after sonication. Before
sonication, C1342 NF is the most elastic followed by C980 NF and C974P NF. After sonication,
only C980 NF is able to maintain its elasticity. The sonication process resulted in a decrease of
the elasticity of the polymer network and the increase in the critical concentration to form
secondary bonds due to the decrease of molecular weight caused by the scission of the polymer
chain.
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Among other reason for its commercial value is its long shelf life. Esteban et. al. (2009) research
yields that cabomer gel loaded with Azithromycin have a low degradation rate. This would
enhance the formulation efficacy and availability16 .
Ophthalmic gel

Figure 3: % drug release profile vs time obtained for the formulation based on the ternary system
(a) TZ/G/PAA and (b) TZ/HCS/PAA
Source: Sandri et. al. (2006)20

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One of the applications of carbomer is being used as viscous eyedrop formulations. The
formulation use an anionic mucoadhesive such as polyacrylic acid (PAA) for delivery of
tetrahydrozoline hydrochloride (TH) which is a decongestant drug widely used for treating
allergic conjunctivitis19. This study conducted by Sandri et. al. (2006) compare the effect of
using polyacrylic acid for tetrahydrozoline hydrochloride delivery against other in situ gelation
polymer20. The study found that when PAA is coupled with gelatin, the gel formed would only
have a slight turbidity, while when coupled with chitosan the gel formed would have a marked
opalescence. This is caused by a lower ionic interaction between the PAA with gelatin compared
to the interaction between PAA and chitosan. The stronger interaction between PAA and
chitosan might cause a higher neutralization effect on the polymer charge and a minor reduction
in the flexibility of the polymer chain. The gelatin also act as a counter ions for PAA which
makes it less sensitive to the ionic strength of the lachrymal fluid making it a much more suitable
mucoadhesive enhancer for PAA.
The study also shows that gelatin is able to inhibit the release of TZ in distilled water, and in
simulated lachrymal fluid although in a lower degree. The lower degree of inhibition in
simulated lachrymal fluid is due to the effects of the ions in the solution that lowers the viscosity
of the gel and thus lowering the inhibition effect of the gel system on the release of TZ. The
gelatin is also able to enhance the resistance of the PAA gel towards wash away effect due to
ion effect in the medium solution20.
Another studies on the application of poly acrylic acid for ophthalmic application is done by Qi
et. al. (2007)22. This study focuses on the effect of adding low concentration of carbomer
CP1342 to a poloxamer system of P407/P188. The study found that when low amount of CP1342
was added to P407/P188 system, the rheological properties of the solution did not change when
tested in physiological environment. Whereas the mucoadhesive forces of the system was
significantly enhanced compared to its individual solution in the same environment. The
enhancement of the mucoadhesive force is due to the formation of hydrogen bonds between the
CP1342 and the mucin layer. The mucin layer is composed of protein or polypeptide core with
carbohydrate side chains branching out. It can form electrostatic, hydrophobic interaction and
hydrogen bonds more efficiently with polymer containing many hydrophobic functional groups
such as the carboxyl group, hydroxyl group and the sulfate23. Thus the addition of carbomer was
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able to increase the mucoadhesivity of the gel. Even though there is a decrease in the degree of
mucoadhesivity when drug molecule was incorporated into the system; the decrease is much
lower compared to a gel containing only P407/P188 system.

Figure 4: Rheological profile of pH-triggered in situ gelling system at pH 7.4


Source: Srividya et. al. (2001)21

The study also highlighted the increase in drug retaining ability of the combined system in invivo and in vitro testing. It has found that the gel could control the drug release to provide longer
exposure of up to 5 hour.
Some research combines two types of polymer to improve the rheology and the efficacy of drug
delivery to the eye. Research by Srividya et. al. (2001) uses a combination of Carbopol and
hydroxypropylmethylcellulose for delivery of ofloxacin to the eye21. Ofloxacin is a second
generation fluoroquinolone derivatives that is being used for treating external ophthalmic
infection such as acute and subacute conjunctivitis, bacterial keratitis and keratoconjunctivitis24.
The combination of these two polymers was able to undergo gelation when the pH was increased
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from 6.0 to the physiological pH of 7.4. Even though the formulation required a Methocel
E50LV for viscosity enhancing effect, it is able to sustained drug release for 8 hour. Further
study on the stability of the system, indicates that the formulation is stable under accelerated
temperature for at least 3-month period. The use of viscosity enhancing agents is to reduce the
concentration necessary for rapid gelation in the eye. The high concentration of polymer in the
formulation can result in a highly acidic solution that may not be effectively neutralized by the
buffering action in the tear fluid. Another important point for any formulation is the effect of
sterilization on the stability of the formulation. Srividya et. al. (2001) chooses to do a thermal
sterilization via autoclaving21. The sterilization process did not affect the pH, gelling capacity
and viscosity of the formulation although there were haziness observed due to precipitation of
hydroxypropylmethylcellulose at high temperature. However, the original clarity was regained
after it was left overnight. The polymer did not affect the antimicrobial activity of ofloxacin and
did not cause any irritation or ocular damage, thus making it a viable alternative for delivery of
ofloxacin to the eye21.
Transfection of protein chain
Another application for carbomer is for protein chain transfection which is used in many
biochemical drugs for gene therapy. This technique is particularly important because it is critical
to deliver the drug without any degradation by lysosomal enzymes. It is also important because it
reduces the risk of immunogenicity and toxicity compared to using a viral delivery vector. The
reason it is being used for this application is that it can disrupt lipid bilayer membrane at pH
lower than 6.5 but non-disruptive at pH 7.4. This is shown in its ability to hemolyse the red
blood cell suspended in acidic buffers completely at pH 6.1 in 1 hour with concentration as low
as 3-5 g/ml. this effect however was not observed when the pH was 7.4. This effect have can
also be enhanced when it was complexed with protein streptavidin via biotin25. In the study by
Kyriakides et. al. (2002), the researcher employs in vitro hemolyses and cell culture studies to an
in vivo murine excisional wound healing models26. It uses angiogenesis inhibitor
thrombospondin-2 (TSP2) to alter the wound healing ability of the organism27. This study found
that poly (propylacrylic acid) (PPAA) can increase in vivo transfection and can alter the healing
response of the targeted area. This proves that PPAA can be used to enhance the efficacy of
transfecting drug.
Another study by Krashias et. al. (2010) highlighted that carbomer can be used as an adjuvant in
veterinary vaccines for several disease such as swine parvovirus and circovirus type 2,
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staphylococcus aureus in sheep. It is also being used for experimental contraceptive vaccine and
equine influenza virus vaccine in horses28,29,30,31,32,33. In this study, Krashias et. al. (2010) have
found that carbopol is effective in protecting mice from disease and death from lethal influenza
infection in an in vivo study. The study also highlighted that carbopol can reduce the growth of
an aggressive melanoma cell line. For this particular study, Krashias et. al. (2010) have shown
that carbopol can enhance the adaptive immune response by enhancing Th1-biased antibody
production and T cell response. It is postulated that carbopol is much more effective compared to
alum in enhancing the immune response. It is also does not neutralize antibodies used for HIV-1
vaccination marked by no detectable interaction with gp14028. The enhancement effect is also
occurred in the production of IL-2 and IFN- from T-cell34, 35. This cytokines is associated with
anti-tumor activity. Krashias et. al. (2010) found that mice primed with B16F10 in carbopol are
able to produce specific antibodies and retarded the tumor growth28.
Oral delivery
Among the problem associated with any preparation of oral delivery drug, is the degradation of
the drug due to proteolytic enzymes and the acidic environment in the stomach. It is also limited
by the low peneteration of protein across the intestine-blood stream barrier36, 37. Kim & Peppas
(2003) found that acrylic acid in the form of poly (methacrylic acid) can act as a suitable drug
carrier12. The reason is for its applicability is its change in physical structure in differing
environment. In acidic medium, the gels are in a collapsed form due to hydrogen bonding. This
prevents the drug loaded in the gel to diffuse out and being degraded by the stomach acid. When
the gel reaches the intestine, the environment pH has increased and the complexes in the gel
dissociate and swell causing an increase in pore size. The increase in pore size allows the loaded
drug to diffuse out

38,39,40,41,42,43,44,45

. Furthermore, the carbomer gelation is affected by the

calcium ion in the environment. Thus, when the poly (methacrylic acid) gelates it will bind
calcium ion to its structure and depletes the calcium present in the environment. This will
decrease the proteolytic activity of calcium-dependant enzyme such as trypsin and decrease the
rate of enzyme degradation of the drug

46, 47

. The depeletion of calcium ion also increases the

paracellular permeability of epithelial cell monolayers by increasing the opening size of the tight
junction between two epithelial cells 48,49. The rate of release and the location of the release can
be altered by changing the glucose content in the complex 4.
Enzyme inhibitor

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Another major application of carbomer is being used as an enzyme inhibitor. Lueen et. al.
(1996) found that proteolytic enzyme such as trypsin, -chymotrypsin, carboxypeptidase, and
cytosolic leucine aminopeptidase can be inhibited by polymer such as carbomer 934P50. The
inihibition was found to be pH dependant and is most significant at pH 4.5 and 7.5. The
inhibition could occur by the depletion of cation such as Ca2+ and Zn2+ or by the direct binding of
the polymer to the enzyme structure. Enzyme such as trypsin and -chymotrypsin are Ca2+ dependant endoproteases while carboxypeptidase A, microsomal and cytosolic aminopeptidase
belong to the group of Zn2+-dependant exopeptidase. The inhibition of these enzymes occurs due
to higher binding capabilities of carbomer to the cation compared to the enzyme. The study
shows that at higher pH values, the binding capabilities of carbomer increases. This is due to the
dissociation of the carboxylic group which will form a polyanionic polymer that will salt out in
the presence of cations. The estimation of cations binding for 1 gram of polymer, the carboxylic
group consists of 13.9 mmol it will bind to 500 to 600 mg Zn2+ and about 250 mg Ca2+ at neutral
pH. Thus, at neutral pH the ratio of cation binding to the carboxylic acid is between 1:1.8 and
1:1.4 (Zn2+: carboxylic acid) and 1:2.3 (Ca2+: carboxylic acid). Another mechanism for enzyme
inhibition is the direct binding of polymer to the enzyme. The binding is not a result of
mucoadhesive behavior but from the interaction of enzyme structure as a hydrophilic
macromolecule with the mucoadhesive polymer. This interaction obstructs the active site of the
enzyme thus preventing it from denaturing proteins.
This concept has been applied into another study by Morishita et. al. (2004)51. The study uses
microparticle created from poly (methacrylic acid) a carbomer derivatives grafted with poly
(ethylene glycol) for delivery of insulin via the oral route. The microparticle system has been
found able to protect insulin from degradation due to stomach acid and enzyme degradation50.
This is because in acidic environment, the microparticle structure will remain in a collapsed state
thus preventing the incorporated insulin from diffusing out to the environment52, 53, 54. When the
microparticle reaches the neutral environment of the small intestine, the microparticle will swell
due to ionization of the carboxyl group thus releasing the insulin from the microparticle. The
ionization requires the presence of cation such as Ca2+ which will effective inhibit the activity of
Ca2+-dependant enzyme such as enzyme. This will cause a decrease in enzymatic degradation
thus increasing the bioavailability of the insulin. The swelled microparticles also have enhanced
mucoadhesive properties due to presence of adhesion promoter such as PEG chains55. This will
cause the microparticle to come in close contact with the mucus layer on the intestine wall. This
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close proximity will also ensure higher uptake by the cell lining and also a decrease in enzyme
attack.
Other application
Some other application of carbomer derivatives is being used as a cell culture medium and
thickeners agents. Perale et. al. (2011) suggested that using a polyacrylic acid and agarose, a
common polysaccharide for tissue culture56. This system exhibit an adequate 3D environment
that is able to host different kind of cells like human mesenchymal stem cells, murine microglial
and astrocytes cells. It also allows the delivery of different drug with release kinetic that can be
manipulated at will for the therapeutics request. For this application, the use of in situ gelation
method have the advantage of able to increase the therapeutics potential and able to limit the side
effect by confining the drug or cells in a target space in the central nervous system. This method
also allows minimal surgical invasiveness and reduced cell loss due to excessive mechanical
stress. This also allows the possibility of microinvasive intraparenchymal hydrogel placement in
vivo for local delivery purposes. In this study, Perale et. al. (2011) found that there was very
little cell necrosis and removal of degraded hydrogel material by activated phagocytic microglia.
The lack of cell necrosis and a method of removing the material naturally, suggested the possible
biocompatibility of the system56.
Another application for carbomer and its derivatives is being used for microemulsion thickeners
without the loss of stability. Mou et. al. (2008) studies the effect of adding carbomer to a
microemulsion57. The study shows that the additions of carbomer 940 to nanoemulsions have no
significant alteration on the droplet size of the nanoemulsion. This lack of interaction proves that
carbomer does not affect the stability of the nanoparticles. The increase in viscosity is caused by
the formation of the gel network. This network also entraps the nanoparticle in the gel network
causing the nanoparticle to have an enhanced stability.
Toxicity
There have been no adverse reaction observe when carbomer is being used for ophthalmic
formulation. Studies such as by Debbasch et. al. (2002) have shown no observable adverse
reaction exhibited by carbomer58. The study shows that carbomer alone does not possess any
cytotoxicity, but when preservative such as benzalkonium chloride (BAC) was added to the
formulation; there have been a significant decrease in the cell viability. This behavior however
was less significant compared to BAC alone. Debbasch et. al. (2002) then conclude that
carbomer have a protective characteristic that was able to decrease the toxicity of BAC. This
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protective action works by preventing exposure of BAC to corneal surface58. However, irritation
or burning sensation on the eye has been reported by Edsman et. al. (1996)18. These irritations
have been found due to a low concentration of the carbomer solution making it less elastic and
easily flow into the cornea. This however can be easily remedied by increasing the concentration
of the carbomer solution or by using other additives such as glycerol18.
The same can also be said for oral formulation of carbomer. Multiple studies such as by Kim et.
al. (2003), Esteban et. al. (2009) and Santus et. al. (1997) did not observe any cytotoxicity caused
by the use of carbomer. However, the carbomer formulation has been found to inhibit the activity
of certain Ca-dependant enzyme. It also cause an increase in the tight junction leading to an
enhance absorption of protein such as insulin through the intestine cell wall lining12,59,60.

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