Rheology can be defined as the science that studies de-formation and flow of matter, being nowadays recognized as an important field of research in a wide range of scientific disciplines [1]. Alongside, rheological tests allow obtaining information about the structure of materials and the effect that an applied force or time has on it. In pharmaceutical sciences, rheological studies are commonly utilized with the intention of characterizing manufacturing operations, changes upon storage and transportation, or behavior during administration/utilization of pharmaceutical products [2, 3]. Ultimately, characterization contributes to the assessment of suitability and optimization of design of pharmaceutical sys-tems, namely semisolids, to be used with a specific purpose.
Gels are widely recognized as valuable dosage forms in order to deliver various drugs through the vaginal route. These polymeric systems present several advantages, namely their safety, versatility, easiness of use, low price and ac-ceptability [4]. Also, good mucoadhesive properties are a common feature of vaginal gels, being advantageous when considering their vaginal administration [5]. However, sub-stantial work still needs to be done in order to optimize their performance at clinical and non-clinical levels. Indeed, in-adequately developed or even lack of specific products for vaginal drug delivery may lead to poor clinical outcomes. Rheological properties of vaginal gels partially govern im-portant features, namely their spreadability and retention
*Address correspondence to this author at the Department of Pharmaceuti-cal Technology, Faculty of Pharmacy, University of Porto, Rua Aníbal
characteristics. These features are essential to clinical out-come of vaginal semisolids, particularly those with contra-ceptive and microbicidal activity. Generally, polymeric sys-tems, such as hydrophilic gels, present non-Newtonian, pseudoplastic behavior, which contributes to their spread-ability when applied on a biologic surface; as the degree of pseudoplasticity increases, easiness of spreadability aug-ments [6]. Although gels should distribute easily through the vaginal mucosa, this feature may lead to leakage. Indeed, ideal vaginal gels should present excellent ability to distrib-ute throughout the mucosa in order to fully cover the vaginal surface, combined with adequate retention characteristics which allow the maintenance of the formulation in situ. These features should be verified over the range of shear rate undergone by gels in the vaginal cavity. Vaginal formula-tions experience a range of continuous and transitory shear rates in vivo, due to phenomena such as vaginal surfaces movement, gravity, capillary flow and coitus. This range of biologically relevant flow shear rates has been previously estimated between less than 0.1 s
-1, corresponding to passive
seeping between epithelial surfaces after initial application, to 100 s
-1 and over during squeezing from a tube or vaginal
applicator and throughout coitus [7]. First studies on the shear flow rheological properties of commercially available vaginal gels evidenced these dosage forms non-Newtonian properties, namely their shear-thinning and viscoelastic be-havior. Further reports also showed that several factors can influence the rheology of vaginal gels, namely their compo-sition, temperature (particularly when considering ther-mosensitive formulations), vaginal pH (mostly when consid-ering pH sensitive formulations), fluids present in the vagina (vaginal fluid or semen), coitus, and posture [8-11].
84 Current Drug Delivery, 2009, Vol. 6, No. 1 das Neves et al.
In spite of all the important work that has been already conducted, typical rheological properties of vaginal gels, or even ideal characteristics that these formulations should pre-sent, are still unclear. This need for information is particu-larly relevant when considering dynamic rheological proper-ties. In fact, dynamic oscillation tests are quite important in rheological characterization, representing a more powerful means of revealing the microstructure of viscoelastic materi-als such as polymeric gels. This is possible in great part to the nondestructive nature of these tests. Dynamic tests allow to fully characterize both components of viscoelasticity (i.e. elastic and viscous components) of polymeric gels, being able to reveal with further detail their nature, structure and behavior [1, 3]. Thus, the objective of this work was to study flow and dynamic rheological properties of vaginal hydro-philic polymer gels and to elucidate about the relationship between these characteristics and gels composition/structure. Also, the general influence these rheological properties may have in the formulations ability to accomplish their therapeu-tic/usage purpose is discussed.
MATERIALS AND METHODS
Materials
Polycarbophil (acid form; Noveon®
AA-1) was a kind gift from Lubrizol Advanced Materials, Inc. (Cleveland, OH, USA). Thymus vulgaris L. essential oil (TVEO) was pur-chased from Segredo da Planta (Produtos Naturais e Biológi-cos, Lda., Lisbon, Portugal). The composition of the essen-tial oil sample used in this work was previously assessed by gas chromatography; its six major components were carvac-rol (70.3%), p-cymene (11.7%), -terpinene (3.2%), E-caryophyllene (2.9%), linalool (2.2%), and myrcene (1.7%)
[12]. All other materials were of analytical grade or equiva-lent. Four commercially available products were considered for rheological evaluation, being purchased from local retail-ers in New York, NY, USA, and Monterey, CA, USA. Also, an investigational vaginal gel containing TVEO (TVEO gel) and its placebo formulation (placebo gel) were evaluated. The main features of all vaginal gels are summarized in Ta-ble 1.
Methods
TVEO Gel and Placebo Gel Preparation
TVEO gel was obtained as previously reported [13]. In brief, polycarbophil (3%, w/w) was dispersed in the mixture of chloride acid solution, 1 mM (75%, w/w), and lactic acid (1%, w/w) by mechanical stirring. Following a 24h rest pe-riod at 2-8ºC, the mixture of propylene glycol (15%, w/w), triacetin (1%, w/w), and TVEO (1%, w/w) was incorporated by gentle stirring. Triethanolamine was used to achieve pH 4.2 ± 0.1 and enough purified water was added to complete final weight. Also, the same gel base (placebo gel) was ob-tained similarly without adding TVEO. Both gels were then transferred to glass containers and allowed to rest for one week at 20ºC, away from light, prior to any further studies.
Rheological Measurements
Flow and oscillatory rheological behavior of all gel sam-ples was evaluated using a controlled stress rheometer (AR2000 Advanced Rheometer, TA Instruments, New Cas-tle, DE, USA). Cone-and-plate geometry was utilized with a stainless steel cone with 4.0º angle, 40 mm diameter, and 109 μm truncation. The free surface between cone and plate was coated with low viscosity mineral oil to help minimize
Table 1. Main Features of Tested Vaginal Gels
Commercial
Name
Gelling Agent(s) Other Excipients Active
Substance
Intended Use Company
Conceptrol® Sodium carboxymethyl
cellulose
Lactic acid, methylparaben, povidone, propylene
glycol, sorbic acid, sorbitol solution, water
Nonoxynol-9
(4%)
Contraceptive McNeil-PPC,
Inc.
Gynol II® Sodium carboxymethyl
cellulose
Lactic acid, methylparaben, povidone, propylene
glycol, sorbic acid, sorbitol solution, water
Nonoxynol-9
(2%)
Contraceptive McNeil-PPC,
Inc.
RepHresh® Polycarbophil and
Carbopol® 974P
Glycerin, ethylparaben sodium, methylparaben
sodium, propylparaben sodium, water
– Maintenance of
vaginal pH
LDS Consumer
Products
Replens® Polycarbophil and
Carbopol® 974P
Glycerin, hydrogenated palm oil glyceride, min-
eral oil, methylparaben, sodium hydroxide, sorbic
acid, water
– Vaginal
moisturizer
LDS Consumer
Products
TVEO gela Polycarbophil Propylene glycol, lactic acid, triacetin, hydro-
chloride acid, triethanolamine, water
Thymus vul-
garis L. essen-
tial oil (1%)
Vulvovaginal
candidosis
–
Placebo gela Polycarbophil Propylene glycol, lactic acid, triacetin, hydro-
Rheological Properties of Vaginal Hydrophilic Polymer Gels Current Drug Delivery, 2009, Vol. 6, No. 1 85
the evaporation of water and other volatile compounds. Se-lection of the temperature at which rheological tests take place is an important decision concerning the objective of the obtained information. Variation of viscosity and other rheological features of pharmaceutical fluid systems with temperature can be slim to dramatic [14, 15], and even in some cases unpredictable [16]. Thus, when studying the in-fluence of rheological properties on vaginal formulations spreading and retention features, it is recommendable to per-form these tests at in vivo temperature [8]. According to these objectives, rheological measurements were conducted at body temperature (37.0 ± 0.1ºC). Another aspect about the rheology of vaginal gels is the alterations induced by dilution and interaction with biological fluids, namely vaginal fluid and semen, as shown previously by others [7, 17]. Although of undoubtedly importance, these variables were not taken in consideration in this study, as the diversity of in vivo settings will justify full additional work.
Flow behavior of all gels was tested in a biologically relevant shear rate interval, ranging from 0.01 s
-1 to 100 s
-1.
As for oscillatory characterization, an initial time sweep (30 minutes at 1 Hz) was performed in order to erase any previ-ous shear history and allow the samples to recover their original structure. Dynamic stress sweep was conducted at a constant angular frequency of 1 Hz over a stress range of 0.1 to 1000 Pa, in order to assure that all further determinations were within linear viscoelasticity regime. Oscillatory fre-quency sweep test (mechanical spectrum) was performed between 0.005 and 50 Hz within the linear viscoelasticity zone (0.5 Pa), as shown by oscillatory stress sweep tests. Immediately after determining the mechanical spectrum, a 30 minutes period at low stress (0.5 Pa) and low frequency (1 Hz) was carried out to allow structure recovery of the samples. The degree of structure recovery was assessed by performing a new mechanical spectrum in the range of 0.005 to 50 Hz. All measurements were performed in triplicate.
RESULTS AND DISCUSSION
Flow Measurements
The apparent viscosity (referred simply as viscosity throughout the manuscript) profiles of all gels are presented in Fig. (1). Standard deviations were omitted in all graphs in order to retain clarity of the plots. Reproducibility for all experiments was acceptable, with coefficients of variation lower than 10%. All six gels presented a non-Newtonian, pseudoplastic behavior, which is typical of polymeric sys-tems. This behavior is considered important, as it facilitates spreading upon vaginal administration. No Newtonian flow regimen has been observed either at higher or at lower shear stress values within the considered shear rate interval. Re-sults showed viscosity values from around 700 Pa.s up to 13500 Pa.s at 0.01 s
-1, decreasing down to approximately 1-5
Pa.s at 100 s-1
. Flow results were analyzed using Ostwald-de Wale power law mathematical model (Eq. (1)):
,.1
=n
K Eq. (1)
where is the shear viscosity, K is the consistency index, is the shear rate, and n is the power law index (or flow behavior index). Fitting results, shown in Table 2, confirm the pseu-doplastic behavior (n < 1) of the gels. Sodium car-
boxymethyl cellulose (NaCMC) gels, Conceptrol®
and Gy-nol II
®, showed less pseudoplasticity than acrylic acid poly-
mer (Carbopol®
974P and polycarbophil) gels, presenting a smoother decrease in viscosity values within the considered shear rate range. These results suggest that acrylic acid polymer gels are potentially easier to spread along the vagi-nal mucosa. In the case of consistency, RepHresh
® presented
higher consistency index than all other gels, while NaCMC gels featured only about a fifth of this value. These results support that acrylic acid polymer gels present a more cohe-sive structure than NaCMC based gels. Furthermore, their higher viscosity at low shear rates indicates that these gels may be easier to retain in the vagina.
Apparent viscosity results as a function of shear rate (Fig. 1) were compared with complex viscosity ( *) results as a function of oscillatory frequency ( ) (Fig. 2). Acceptable superimposition of both plots indicates that the Cox-Merz rule [18], ( ) = | * ( )|, is applicable to these gels. Al-though this empirical rule is mostly applicable to polymeric liquids, it is not uncommon for gels used as pharmaceutical dosage forms to verify, with acceptable deviations, this rule. In fact, these gels can be regarded as concentrated polymeric solutions [1]. Even so, larger differences between both plots can be observed for higher values of shear rate/oscillatory frequency, which is understandable taking in consideration the deviation from linear viscoelasticity zone and disruption of samples microstructure.
Oscillatory Measurements
Oscillatory shear stress sweep results are presented in Fig. (3). From the graph plot it is possible to determine the linear viscoelasticity zone, i.e. the range where the applied stress does not affect considerably the three-dimensional structure of the polymer gels. The point where this linear relationship between stress and strain is disturbed is referred as the critical oscillatory stress ( c) [19]. From this point on the gel structure starts being modified. NaCMC gels, along-side with RepHresh
®, presented higher critical oscillatory
stress values (around 7 Pa), which indicates that these gels have a more resistant microstructure, while Replens
®, TVEO
gel and placebo gel showed more modest values (around 1.5 Pa), indicating a more shallow three-dimensional architec- ture. This behavior is typical of chemically cross-linked polymers. This kind of intermolecular interactions is respon- sible for a three-dimensional structure that is more rigid and has lower capability of sustaining strain forces without being disrupted [20]. Nonetheless, these events may be minimized when formulating a gel, as shown in the case of RepHresh
®.
Although the quantitative composition of this gel is un- known, its behavior is most probably due to higher content in acrylic acid polymers than Replens
®, TVEO gel, and placebo
gel [21]. From the same plot (Fig. 3) it is also observable that the complete destruction of the gel structure (cross-over of G´ and G´´ plots) occurs at oscillatory stress values slightly higher than 50 Pa for all samples, except for RepHresh
®. For
this last gel, shattering of the microstructure takes place for oscillatory stress values of approximately 160 Pa. Also, the observed higher values of G´ for all acrylic acid polymer gels, particularly RepHresh
®, indicates that these semisolids
possess a more solid-like, more rigid micro-structure than Conceptrol
86 Current Drug Delivery, 2009, Vol. 6, No. 1 das Neves et al.
Fig. (1). Viscosity profiles as a function of shear rate for tested vaginal gels.
Table 2. Ostwald-de Walde Power Law Parameters in the Considered Shear Rate Range (0.01-100 s-1
) and Yield Stress Values for
Tested Gels
Ostwald-de Walde power law parameters Yield stress (Pa) Gels
Consistency
index (K)
(Pa.sn)
Power law
index (n)
Correlation
coefficient
Shear stress
sweep intersec-
tion
Oscillatory
stress sweep
intersection
Low shear
rate extrapo-
lation
Herschel-
Bulkley model
Conceptrol II® 31.5 0.284 0.9999 2.2 33 2.7 2.11
Gynol II® 28.5 0.300 0.9999 1.7 38 2.1 3.12
RepHresh® 154.8 0.031 0.9997 88 104 34.8 10.1
Replens® 63.1 0.107 0.9999 22 46 17.0 6.62
TVEO gel 76.1 0.109 0.9999 37 60 24.6 8.26
Placebo gel 69.4 0.100 0.9999 30 51 20.7 5.58
force that NaCMC gels present a higher resistance to exter-nal strain forces, as seen in steady-flow experiments, being able to better maintain their structure when submitted to higher strains.
The mechanical spectrum of the gels is presented in Fig. (4). It can be seen that storage modulus (G´) was higher than loss modulus (G´´) for all gels in the frequency range con-sidered (0.005 to 100 Hz), thus indicating that the systems are predominantly elastic. Acrylic acid polymer gels pre-sented G´ values that did not change significantly, being only observed a slight increase in this parameter with increasing
frequency, while NaCMC gels exhibited a considerable in-crease in G´ (higher curve slope). The relative magnitude between storage and loss moduli is given by tan (tan = G´´/G´), being the phase angle. Fig. (5) presents its vari-ability for all six gels along the considered frequency range. Since tan < 1, elastic solid behavior of samples is predomi-nant over viscous liquid behavior, which is typical of gel systems [22, 23]. Values for acrylic acid polymer gels were almost coincident for frequencies equal or smaller than 1 Hz; above this value the predominance of elastic solid behavior noticeably decreased, being this trend slighter for Re-pHresh
®. As for Conceptrol
® and Gynol II
®, both gels pre-
Rheological Properties of Vaginal Hydrophilic Polymer Gels Current Drug Delivery, 2009, Vol. 6, No. 1 87
Fig. (2). Complex viscosity profiles as a function of oscillatory frequency for tested vaginal gels.
Fig. (3). Storage modulus (G´) and loss modulus (G´´) as a function of oscillatory shear stress, at a frequency of 1 Hz, for tested vaginal gels.
sented a minor gap between both moduli when compared with acrylic acid polymer gels and an irregular fluctuation of the tan . This last observation may be due to the complex composition of these commercial systems, which may result in potential alterations and rearrangements of the three-dimensional microstructure as different oscillatory frequen-cies are applied. Nonetheless, both NaCMC gels present similar trends for tan , revealing the similar composition of both gels (Table 1). Higher elastic component (lower values
of tan ) observed for acrylic acid polymer gels, with par-ticular emphasis to RepHresh
®, may favor their ability to
stay in place after being administered [7]. This difference in solid-like behavior may be related to the polymers nature, namely with the type of cross-linking (chemical or physical) established between polymer chains [20]. Polycarbophil and Carbopol 974P are characterized by chemical cross-linking between polymer chains, while NaCMC chains are cross-linked by physical interactions (e.g. chains entanglement).
88 Current Drug Delivery, 2009, Vol. 6, No. 1 das Neves et al.
Fig. (4). Storage modulus (G´) and loss modulus (G´´) as a function of oscillatory frequency (mechanical spectrum), at a shear stress of 0.5
Pa, for tested vaginal gels.
Fig. (5). tan as a function of oscillatory frequency for tested vaginal gels.
Thixotropy and Yield Stress Determination
The mechanical spectrum of all gels after the initial fre-quency sweep, followed by a 30 minutes recovery period at low stress (0.5 Pa) and low frequency (1 Hz), is presented in Fig. (6). Although thixotropy is usually evaluated by the degree of viscosity decrease with time, this type of behavior simply reflects a degradation of the solid structure with shear or stress time [24]. Thus, comparison of both spectra, namely
the original (Fig. 4) and new G´ plots, allows assessing the degree of recovery of the original microstructure of the gels, i.e. thixotropy. Percentage of structure recovery (second spectrum G´: first spectrum G´ ratio) is plotted in Fig. (7). RepHresh
®, Replens
®, and TVEO gel presented higher rela-
tive decrease of G´ (higher thixotropy) while Conceptrol®
, Gynol II
® and placebo gel were able to almost recover their
original structure. Structure recovery was similar for all fre-quency range in the case of acrylic acid polymer gels; a de-
Rheological Properties of Vaginal Hydrophilic Polymer Gels Current Drug Delivery, 2009, Vol. 6, No. 1 89
crease of the original structure recovery with increasing fre-quency was observed for NaCMC gels. This late fact may indicate permanent alterations in these gels that make them unable to recover their original structure with time after shear cessation.
Yield stress ( 0) of a material can be defined as the minimum stress above which flow can be observed. Al-though a controversial rheological parameter [25], yield stress is widely recognized as an influent parameter regard-ing the characterization of vaginal semisolids. For example, yield stress influences semisolids spreadability or retention in the vagina when low forces are applied [26, 27]. Gener-ally, low values of yield stress increase spreadability but decrease retention and vice-versa. The best method to deter-mine this minimum value of stress required for a material to start flowing is not consensual. Indeed, the use of different methodologies is common, this fact often originating diverse values for the same samples. Thus, values of this parameter were determined in this work by four different methods. The most commonly used method is from flow curves (viscosity vs. shear stress). Yield stress is determined by the intersec-tion of the two straight lines defined by the initial steady viscosity zone and the following zone that is characterized by an abrupt decrease in viscosity. The second method by which this parameter was evaluated is similar to the previ-ous. In this case the yield stress is determined from the oscil-latory stress sweep results (referred to as dynamic yield stress). Although unconventional, a dynamic yield stress value can be determined as previously reported by Islam et al. [28]. Extrapolation of the flow curves at very low shear rates (0.001 to 0.01 s
-1) to zero shear rates was also used to
determine the yield value. The fourth method employed was by fitting flow results to the Herschel-Bulkley mathematical model (Eq. (2)):
,.0
nm+=
Eq. (2)
Where is the shear stress, 0 is the yield stress, m is the consistency index, is the shear rate, and n is the power law index. Results are summarized in Table 2. Although absolute values of yield stress for each gel differ substan-tially from method to method, these figures show similar trends in terms of ranking. In this way, RepHresh
® presented
the highest yield stress, while NaCMC gels showed smaller values of this parameter. These results confirm earlier reports [28, 29] that acrylic acid polymer gels possess higher yield stress than NaCMC gels, contributing to their better capabil-ity of staying in place after being administered in the vagina. Additionally, previous work showed that NaCMC disper-sions possess little or no yield stress, thus supporting our findings and the fact that this polymer is the main responsi-ble for the rheological features of Conceptrol
® and Gynol II
®
[29]. Also, there are some considerable differences between acrylic acid polymer gels, namely between TVEO gel and placebo gel, that probably reflect different compositions and/or manufacturing processes.
Rheological Properties and Therapeutic/Usage Purpose
Considering both flow and oscillatory results and previ-ous discussion, it seems that, once flow starts, acrylic acid polymer gels will spread easily in the vaginal mucosa than Conceptrol
® and Gynol II
®, as indicated by yield stress val-
ues, pseudoplastic behavior, and viscosity at low shear rate/oscillatory frequency. Also, viscosity profiles, critical oscillatory stress values and tan values point to the fact that acrylic acid polymer gels structure may allow better reten-tion at low shear rates; at higher shear rates, NaCMC gels might present better retention properties. Although these findings seem to support that acrylic acid polymer gels pre-
Fig. (6). Storage modulus (G´) and loss modulus (G´´) as a function of oscillatory frequency (mechanical spectrum) for tested vaginal gels,
after the initial mechanical spectrum followed by a 30 minutes recovery period at low stress (0.5 Pa) and low frequency (1 Hz).
.
90 Current Drug Delivery, 2009, Vol. 6, No. 1 das Neves et al.
sent better rheological properties than NaCMC gels, this interpretation should not be assumed without considering the therapeutic/usage purpose of each gel. Indeed, both Concep-trol
® and Gynol II
® are used as spermicides, which means
they are submitted to higher shear rates (around 100 s-1
) dur-ing coitus. Their lower relative insensibility to a wide range of shear rates and higher structural resistance to external forces allows better retention during coitus. Also, compara-tively limited spreadability of NaCMC gels is irrelevant if we take in consideration that high shearing observed during vaginal penetration will act as the ultimate responsible for distributing the formulations throughout the vaginal mucosa. Low thixotropic behavior observed for Conceptrol
® and Gy-
nol II®
is also important, particularly in the ability to recover the original microstructure of the gels after vaginal sexual intercourse. In the case of acrylic acid polymer gels, their intended uses (moisturizer, pH buffer, or antifungal) imply that these pharmaceutical systems will play their role mostly under low to intermediate in vivo shear rates. Thus, these last gels capacity of spreading easily under low external forces, due to their noticeable pseudoplastic behavior, is essential in order to cover all vaginal mucosal surface and fulfill their therapeutic purpose. However, it is necessary that these gels may be retained in the vagina for an adequate amount of time without leaking. Higher yield stress and elastic solid behav-ior of acrylic acid polymer gels, when compared to NaCMC gels, contributes significantly to this late objective.
When compared among themselves, acrylic acid polymer gels present some differences, particularly RepHresh
®. Al-
though our results support the notion that polymers nature determines the fundamental rheological behavior of gels [30], it is known that other small qualitative and quantitative changes or manufacturing process variations among products
may lead to significant differences in their performance [31-33]. Moreover, the physical state of acrylic acid polymers (solid particles in suspension or as colloids) and the configu-ration of their chains (coiled or uncoiled) can influence rheological profiles [28, 34]. The impact that small changes have in the rheological properties of vaginal gels is well ex-emplified by the different thixotropic behavior of TVEO gel and its placebo (Fig. 7). The simple addition of a small amount of a hydrophobic component (TVEO 1%, w/w) changes noticeably the ability that the gel has to recover its original structure after being submitted to destructive forces. This fact can be understandable taking in consideration that the essential oil opposes reestablishment of hydrophilic links responsible for the gel three-dimensional structure [35]. Other hypothesis would be the formation of liquid crystals by the non-colloidal phase, i.e. the essential oil, which can contribute to the modification of the original polymeric structure [36]. Also, in order to better compare the viscosity profile of TVEO gel and its placebo formulation, apparent and oscillatory viscosities ratios of both gels were calculated and plotted in Fig. (8). Results showed that TVEO gel vis-cosity is somewhat higher (up to 1.15 times) than placebo gel viscosity throughout the shear rate/oscillatory frequency range considered, being these differences more obvious for apparent viscosity values. It is also noteworthy that there is a slight increase in apparent viscosity ratio for increasing shear rate, while for higher oscillatory frequencies complex viscos-ity rates are quite variable because of deviation from the vis-coelasticity zone. These results suggest the existence of small but potentially biasing rheological differences that should be taken into account when considering their use in clinical trials as active and placebo formulations, in the same manner as previously noticed by Owen and colleagues [37].
Fig. (7). Percentage of structure recovery for tested vaginal gels.
Rheological Properties of Vaginal Hydrophilic Polymer Gels Current Drug Delivery, 2009, Vol. 6, No. 1 91
CONCLUSION
Rheological behavior of vaginal gels strongly depends on their composition, particularly on the type of gelling agent used (acrylic acid polymers or NaCMC), thus potentially influencing the gels ability to spread and to be retained when administered in the vagina. It was found that small variations in gels composition (e.g. presence or absence of an active compound) can result in substantial changes in their features, namely viscosity, yield stress and thixotropy. Also, rheologi-cal properties of studied vaginal gels appear to be well corre-lated with claimed therapeutic/usage purpose. Taken to-gether, our findings suggest that rheology can be a valuable tool in the optimization of vaginal hydrophilic polymer gels, contributing to the knowledge of their spreading and reten-tion properties, and response to external forces undergone in the vaginal canal.
ACKNOWLEDGEMENTS
The authors are grateful to Dr. Branca Teixeira, Dr. Bár-bara Santos, Mr. António Paupério, and Mr. João Paupério for the acquisition of commercially available vaginal gels.
LIST OF ABBREVIATIONS
G´ = Storage moduli
G´´ = Loss moduli
Hz = Hertz
K = Consistency index (Ostwald-de Wale power law model)
m = Consistency index (Herschel-Bulkley model)
mm = Millimeter
μm = Micrometer
n = Power law index (or flow behavior index)
NaCMC = Sodium carboxymethyl cellulose
= Shear viscosity
* = Complex viscosity
Pa = Pascal
s-1
= Reciprocal second
tan = Tangent of the phase angle delta
TVEO = Thymus vulgaris L. essential oil
TVEO gel = Gel containing Thymus vulgaris L. essential oil
0 = Yield stress
c = Critical oscillatory stress
= Oscillatory frequency
= Shear rate
REFERENCES
[1] Barnes, H.A.; Hutton, J.F.; Walters, K. An Introduction to Rheol-
ogy, Elsevier: Amsterdam, 1989. [2] Tamburic, S.; Craig, D.Q.M. The effects of ageing on the rheologi-
cal, dielectric and mucoadhesive properties of poly(acrylic acid) gel systems. Pharm. Res. 1996, 13, 279-83.
[3] Jones, D.S. Dynamic mechanical analysis of polymeric systems of pharmaceutical and biomedical significance. Int. J. Pharm. 1999,
179, 167-78. [4] das Neves, J.; Bahia, M.F. Gels as vaginal drug delivery systems.
Int. J. Pharm. 2006, 318, 1-14. [5] das Neves, J.; Amaral, M.H.; Bahia, M.F. Performance of an in
vitro mucoadhesion testing method for vaginal semisolids: influ-ence of different testing conditions and instrumental parameters.
Eur. J. Pharm. Biopharm. 2008, 69, 622-32. [6] Garg, A.; Aggarwal, D.; Garg, S.; Singla, A.K. Spreading of semi-
solid formulations: an update. Pharm. Tech. 2002, 26, 84-105.
Fig. (8). Apparent and oscillatory viscosities ratios of TVEO gel and placebo gel.
.
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