Physicochemical Characterization of Bioactive Polyacrylic Acid

624

Biomacromolecules 2008, 9, 624–633

Physicochemical Characterization of Bioactive Polyacrylic Acid Organogels as Potential Antimicrobial Implants for the Buccal Cavity David S. Jones,*,† Brendan C. O. Muldoon,†,§ A. David Woolfson,† Gavin P. Andrews,† and F. Dominic Sanderson† Medical Polymers Research Institute, School of Pharmacy, The Queen’s University of Belfast, Medical Biology Centre, 97, Lisburn Road, Belfast, BT9 7BL, Northern Ireland, United Kingdom, and GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom Received May 30, 2007; Revised Manuscript Received September 12, 2007

This study describes the formulation and physicochemical characterization of poly(acrylic acid) (PAA) organogels, designed as bioactive implants for improved treatment of infectious diseases of the oral cavity. Organogels were formulated containing a range of concentrations of PAA (3–10% w/w) and metronidazole (2 or 5% w/w, representing a model antimicrobial agent) in different nonaqueous solvents, namely, glycerol (Gly), polyethylene glycol (PEG 400), or propylene glycol (PG). Characterization of the organogels was performed using flow rheometry, compressional analysis, oscillatory rheometry, in vitro mucoadhesion, moisture uptake, and drug release, methods that provide information pertaining to the nonclinical and clinical use of these systems. Increasing the concentration of PAA significantly increased the consistency, compressibility, storage modulus, loss modulus, dynamic viscosity, mucoadhesion, and the rate of drug release. These observations may be accredited to enhanced molecular polymer entanglement. In addition, the choice of solvent directly affected the physicochemical parameters of the organogels, with noticeable differences observed between the three solvents examined. These differences were accredited to the nature of the interaction of PAA with each solvent and, importantly, the density of the resultant physical cross-links. Good correlation was observed between the viscoelastic properties and drug release, with the exception of glycerol-based formulations containing 5 and 10% w/w PAA. This disparity was due to excessive swelling during the dissolution analysis. Ideally, formulations should exhibit controlled drug release, high viscoelasticity, and mucoadhesion, but should flow under minimal stresses. Based on these criteria, PEG 400-based organogels composed of 5% or 10% w/w PAA exhibited suitable physicochemical properties and are suggested to be a potentially interesting strategy for use as bioactive implants designed for use in the oral cavity.

Introduction Treatment of local diseases within the oral cavity is frequently performed using either conventional peroral medication or by the use of topical dosage forms.1,2 In light of the ease of application, the greater patient compliance, and the improved efficacy, the use of topical dosage forms is preferred. Conventional dosage forms that are frequently employed for local oral delivery are principally lozenges, mouthwashes, oral gels, and suspensions. These systems provide an initial burst of drug that soon declines to subtherapeutic levels due to the large quantity of drug swallowed with saliva and the poor persistence at the site of application. This release profile may therefore result in poor clinical efficacy.3 Lozenges and mouthwashes have compliance problems due to the dosing regime and are also unsuitable for effective overnight therapy.4 Therefore, it is accepted that the clinical performance of topical drug delivery systems designed for the treatment of oral disorders may be enhanced by increasing the retention of the dosage form at the site of application.5,6 The increased retention of such dosage forms enables controlled and prolonged drug delivery to the required site * To whom correspondence should be addressed. Telephone: +44 28 9097 2011. Fax: +44 28 9024 7794. E-mail: [email protected]. † The Queen’s University of Belfast. † GlaxoSmithKline Pharmaceuticals. § Present address: Warner Chilcott (U.K.) Ltd., Old Belfast Road, Larne BT40 2SH, Northern Ireland, U.K.

within the oral cavity. One approach that has been investigated for the improved retention of dosage forms within the oral cavity is the use of mucoadhesive formulations, systems in which the polymeric components may interact with the mucin-coated oral epithelia.6,7 The success of bioadhesive formulations for the treatment of inflammatory disorders and infection in the oral cavity, for example, periodontal disease, gingivitis, and oral mucositis, has been proven clinically,1,2,8,9 thereby, highlighting the clinical potential of such formulations. A range of types of bioadhesive dosage forms, designed for use in the oral cavity, have been reported, including compacts,8,10 films,11–13 microparticles,14 gels,13,15,16 and semisolids.1,2,17 Clinical success has been associated with the use of bioactive gels and semisolid systems, however, there are problems associated with their use that may preclude their design and development for use in the oral cavity. These include ease of administration and retention at the site of application following the ingress of saliva (particularly for gels). In particular, the retention of gels within the oral cavity is compromised by their expanded polymer structure within the gel state (due to the interaction of the polymer with the aqueous solvent). Within the oral cavity, the interaction with mucin is reduced due to the limited ability of the polymer chains to diffuse into and interact with this substrate.5 Enhancement of the retention of gels may be performed by the dispersion of solid, bioadhesive polymers, which will hydrate and interpenetrate with mucin following application to the oral mucosa.1 However, the dispersion of sufficient polymer particles

10.1021/bm700597e CCC: $40.75  2008 American Chemical Society Published on Web 01/26/2008

Characterization of Bioactive Poly(acrylic acid) Organogels

into gels to achieve the required bioadhesion may compromise the rheological properties of the system, resulting in difficulties in application and spreading onto the mucosa. One interesting approach to the formulation of bioadhesive implants for use in the oral cavity involves the use of organogels. Various types of organogels have been reported, for example, self-assembling liquid amphiphiles,18 water in oil microemulsions,19 and amphiphiles dispersed in a nonaqueous phase.20,21 Organogels may also be formed by the molecular dispersion of a hydrophilic polymer into a nonaqueous phase, the interaction between solute and solvent being mediated by secondary interactions, for example, hydrogen bonding and van der Waal’s interactions. Organogels in this latter category may be rendered bioadhesive by the dispersion of a bioadhesive polymer, for example, poly(acrylic acid), within a nonaqueous (diol or triol) solvent, for example, poly(ethylene glycol), glycerol. Following application onto the oral mucosa, the interaction between the solvent and the polymer may be replaced by an interaction and subsequent entanglement with mucin, thereby, facilitating a bioadhesive interaction. There have been no previous reports of the formulation and characterization of bioactive, hydrophilic organogels designed as bioadhesive implants for the oral cavity. Therefore, this study presents a comprehensive description of the formulation and physicochemical properties of hydrophilic organogels prepared using poly(acrylic acid), a known bioadhesive polymer,5 selected diol and triol solvents, and containing metronidazole, a model antimicrobial agent that is frequently employed for the treatment of periodontal disease.1 In particular, this study presents the rheological, mechanical, mucoadhesion, water uptake, and drug release properties of the metronidazolecontaining poly(acrylic acid) organogels. This study will therefore provide an inclusive examination of the suitability of these organogels as bioactive implants designed for application to the oral mucosa.

Materials and Methods Materials. Poly(acrylic acid) (Carbopol EDT 2050) was a gift from B.F. Goodrich Company (Cleveland, Ohio, U.S.A.). Ethylene glycol, propylene glycol, glycerol, and polyethylene glycol 400 were purchased from Lancaster (Morecambe, England). Porcine mucin and metronidazole were purchased from Sigma-Aldrich (Poole, Dorset, England). All other chemicals were purchased from BDH Chemicals Ltd. (Gillingham, Dorset, England) and were of AnalaR, or equivalent, quality. Methods. Manufacture of BioactiVe Poly(acrylic acid) Organogels. Poly(acrylic acid) (PAA) organogels were prepared by the simultaneous addition of Carbopol EDT 2050 (3, 5, or 10% w/w) and metronidazole (2 or 5% w/w) to the appropriate organic solvent, namely, glycerol (Gly), propylene glycol (PG), or polyethylene glycol 400 (PEG), with the aid of mechanical stirring (2000 rpm). Formulations were stored at 4 °C for 24 h to allow for complete polymer solvation. All samples were then transferred into amber storage vessels, placed in a vacuum to remove incorporated air, and then stored at 4 °C for one week prior to further analysis. Analysis of the Rheological Properties of the BioactiVe Organogels. In this study, the rheological properties of the bioactive organogels were characterized using both destructive (flow) and dynamic (oscillatory rheometry) methods. (i) Oscillatory Rheometry. Oscillatory rheometry of all formulations was performed using a Carri-Med CSL2–100 rheometer (T.A. Instruments, Surrey, England) at 20 ( 0.1 °C using a 4 cm diameter parallel plate geometry and a plate gap of 1 mm, as previously reported.22,23 Prior to analysis, a strain was identified within the linear viscoelastic region and was selected for subsequent frequency sweeps. Initially, samples were carefully applied to the lower plate, compressed between the parallel plates, and retained for 60 min (to facilitate relaxation of

Biomacromolecules, Vol. 9, No. 2, 2008 625 Table 1. Shear Stress Ranges Employed during Continuous Shear Analysis of Metronidazole-Containing Poly(acrylic acid) Organogels

solvent ethylene glycol propylene glycol glycerol PEG 400

drug concentration (% w/w)

3%w/w PAA shear stress (Pa)

5% w/w PAA shear stress (Pa)

10% w/w PAA shear stress (Pa)

0 2 5 0 2 5 0 2 5 0 2 5

200–1500 300–600 200–1000 200–1500 300–600 200–1000 3000–6000 300–600 3000–6000 500–2000 300–600 300–600

1000–2000 700–2500 1000–2500 2000–4500 700–1000 1000–2500 3000–6000 700–1000 3000–6000 2000–4000 700–1000 700–1000

4000–6000 2000–4000 4000–6000 4500–6300 2000–6000 4000–6000 3000–6000 3000–6000 3000–6000 4000–6000 2000–3500 2000–3500

internal stresses that were introduced during sample loading). At least five replicate analyses of each formulation were performed over a frequency range from 0.01 to 1.001 Hz. Calculation of the storage modulus (G′), loss modulus (G″), loss tangent (tan δ), and dynamic viscosity (η′) were performed using proprietary software (TA Instruments, Leatherhead, U.K.). (ii) Continuous Shear Analysis (Flow Rheometry). Flow rheograms for each organogel were obtained using a Carri-Med CSL2–100 rheometer (T.A. Instruments, Surrey, England) in flow mode at 20 ( 0.1 °C, with a plate geometry of 2 cm and a plate gap of 1 mm, as previously reported by the authors.24,25 Samples (n g 5) were applied between the parallel plates and then allowed to equilibrate for 60 min. Rheograms were produced using the loop test, in which the shearing stress was increased gradually from a minimum up to a predetermined maximum within 60 s and then returned to the starting stress under the same conditions. Shearing stresses were selected according to formulation consistency.24,25 The shear stress ranges employed during continuous shear analysis are presented in Table 1. Modeling of the flow properties of the formulations was performed using the Power law, Cross and Sisko models, as previously described by the authors, with the selection of the most appropriate model being determined using regression analysis in conjunction with a one-way analysis of variance and Tukey’s post hoc test.26 Compressional Analysis. The effect of compressional stresses on the mechanical properties of the formulations under examination were determined using a Stable Micro Systems TA-TX2 texture analyzer in compression mode, as previously reported.24,25 Formulations were transferred into McCartney bottles to a fixed height and stored in a vacuum to ensure the removal of entrapped air. A 10 mm polycarbonate probe was depressed into each sample to a depth of 15 mm at a defined rate (10 mm s-1). At least five replicate analyses were performed for each formulation. From the resulting force–distance plots, the compressibility (the work required to compress the sample) was determined. In Vitro Assessment of Mucoadhesion. The mucoadhesion of the various organogels was determined using a Stable Micro Systems TATX2 Texture Analyzer in adhesion mode.1 Initially, flat disks of porcine mucin (13 mm diameter) were prepared by compression (10 tons for 60 s) and then attached on the end of a polycarbonate analytical probe (10 mm diameter) using double-sided adhesive tape. The bottom surface of the mucin disk was then wetted for a defined period (30 s) by immersion in a 5% w/w mucin solution, following which excess mucin solution was removed by blotting. The mucin disk was brought to the surface of the formulation (which was contained in a cylindrical mold) and, upon contact, a downward force of 0.1 N was applied. After 30 s, the probe was removed at a speed of 10 mm s-1, and from the resulting force-time plot, a peak was observed corresponding to the force required to break the mucoadhesive bond. At least five replicate measurements of the mucoadhesive properties of each formulation were performed. Examination of Moisture Uptake. Formulations (2 g) were packed into three-sided molds and then placed into humidity chambers at 25

626 Biomacromolecules, Vol. 9, No. 2, 2008 °C at either 60% or 75% relative humidity. At predetermined time intervals over a 10 day period, formulations (n ) 5) were removed and the mass of moisture absorbed/adsorbed was determined gravimetrically. In Vitro Assessment of Drug Release. The release of metronidazole (2% w/w initial drug loading) from the various organogels was assessed using a Distek Dissolution System 2100C with an autosampler and ultraviolet spectrophotometer. Replicate samples (5 g, n ) 6) were packed into a cylindrical mold located within the dissolution vessel, which contained phosphate buffer saline (PBS) at pH 7.4 and 37 °C, and stirred at 50 rpm. At predetermined intervals, samples of the dissolution medium were removed and filtered through a 0.45 µm filter. The mass of bioactive agent in the various samples was determined using UV spectroscopy (λmax 363 nm) with reference to a predetermined calibration curve, which was linear over the concentration range 5–600 µg mL-1 (r > 0.99). Statistical Analysis. Statistical analyses of the effects of increasing PAA concentration, solvent type, drug loading on formulation viscoelastic properties (G′, G″, tan δ, and η′), consistency (as determined using the Power law model), compressibility, in vitro mucoadhesion, and the mass of drug released at defined periods were performed at four representative frequencies (0.11, 0.53, 0.74, and 1.00 Hz) using a three-way ANOVA (Statview, Abacus Concepts). Furthermore, a fourway ANOVA was performed to examine the effects of polymer concentration, solvent type, time, and relative humidity on moisture uptake. Post hoc comparisons of means were performed using Tukey’s test, with p < 0.05 being accepted to denote significance. Accordingly, individual probability values have not been cited.

Results The effects of solvent composition, polymer concentration and drug concentration on the viscoelastic properties are presented in Figures 1–4 and summarized in Table 2. As may be observed, increasing the concentration of PAA in the organogels, regardless of the solvent type and the concentration of metronidazole, significantly increased the storage modulus, loss modulus, and the dynamic viscosity of the various organogels. Conversely, the effect of polymer concentration on the loss tangent was dependent on both the solvent type and the drug concentration. For example, increasing the concentration of polymer in organogel formulations employing glycerol as the nonaqueous solvent significantly lowered the loss tangent (at higher oscillation frequencies), whereas in formulations containing PEG 400, the loss tangent increased. The loss tangent of propylene glycol containing organogels was directly dependent on the concentration of polymer. Increasing the concentration of PAA from 3 to 5% w/w significantly reduced the loss tangent, whereas a further increase from 5 to 10% w/w PAA significantly increased this parameter. These disparities accounted for the significant statistical interaction between polymer concentration and solvent type in the ANOVA. Increasing the concentration of metronidazole (from 2 to 5% w/w) did not significantly affect the viscoelastic properties (G′, G″, tan δ, and η′) of the various organogels, with the exception of the formulations containing 10% w/w PAA. In these, increasing the concentration of metronidazole from 2 to 5% w/w in formulations containing glycerol significantly decreased G′, G″, and η′; however, the loss tangent was unaffected, whereas in formulations containing PEG 400, increasing the concentration of metronidazole significantly decreased G′ and G″, but the loss tangent and dynamic viscosity were unaffected. Increasing the concentration of metronidazole in formulations containing 10% w/w PAA and propylene glycol did not affect the viscoelastic properties of these organogels. The type of solvent used in the manufacture of organogels significantly affected their viscoelastic properties.

Jones et al.

Specifically, the greatest and lowest storage modulus, loss modulus, and the dynamic viscosity of the formulations were associated with organogels composed of glycerol and propylene glycol, respectively. Conversely, the loss tangent of organogels composed of propylene glycol was significantly greater than for organogels manufactured using PEG and glycerol. Finally, in all formulations, increasing the oscillatory frequency significantly increased G′ and G″ and reduced the dynamic viscosity of all formulations. The initial extent of the increase in the storage and loss moduli with frequency was small, indicative of a plateau in the viscoelastic response. However, at higher oscillatory frequencies (greater than circa 0.08 Hz), a linear region was identified. This is indicative of the terminal zone of the viscoelastic response and reflects a greater comparative increase in the loss modulus than the storage modulus. The effects of deformable torsional and compressional stresses on the flow properties of the organogels under examination are displayed in Table 3. Furthermore, representative flow rheograms are presented in Figure 5. As may be observed, the organogels exhibited pseudoplastic flow with (primarily minimal) thixotropy. Modeling of the up-curve of the flow rheograms was optimally performed using a power law model, as previously reported,25,27 due to the lowest standard error associated with this model. •

η ) kγn-1

(1)

•

where σ is the shearing stress, γ is the rate of shear, k is the consistency, and n is the power law index. The consistency and work of compression (compressibility) of the organogel formulations were dependent on the concentration of polymer, solvent type, and concentration of metronidazole (Table 3). Increasing the concentration of PAA sequentially from 3 to 5 to 10% w/w significantly increased the consistency and work of compression of the organogels. Similarly, the consistency increased as the solvent system used to manufacture the organogels was changed from propylene glycol to PEG 400 to glycerol. Accordingly, the greatest and lowest consistency and work of compression values were exhibited by organogels composed of 10% w/w PAA prepared in glycerol and 3% w/w PAA molecularly dispersed in propylene glycol. The effect of increasing the concentration of metronidazole on the consistency and work of compression of the formulations was dependent on both the solvent used and the concentration of polymer. Increasing the concentration of drug from 2 to 5% w/w did not significantly affect the work of compression and consistency whenever the concentration of polymer in the organogels was either 3 or 5% w/w. Conversely, in systems containing 10% w/w PAA and prepared using glycerol or PEG 400, the work of compression and consistency of organogels containing 5% w/w metronidazole were generally significantly lower than those containing 2% w/w drug, however, no drug-loading effect was noted in formulations containing 10% polymer and PEG 400. Increasing drug concentration in organogels composed of 10% w/w PAA and propylene glycol as the solvent did not significantly affect these parameters. This polymer concentration dependency accounted for the significant interaction term in the ANOVA. The effects of polymer concentration, solvent type, relative humidity, and time on the moisture uptake of the organogel formulations (containing 2% w/w drug) are presented in Table 4. Specifically, increasing both the time of contact (from 1 to 240 h) and the relative humidity (60% to 75%) increased moisture uptake, whereas, alteration of the solvent type used to prepare the organogels from glycerol to PG to PEG 400


Biomacromolecules, Vol. 9, No. 2, 2008 627

Figure 1. The effect of poly(acrylic acid) concentration, metronidazole concentration, and solvent type, namely, glycerol (a), polyethylene glycol (b), and propylene glycol (c) on the mean storage modulus of organogel formulations. Symbols: circles, squares, and diamonds refer to formulations containing 3% w/w, 5% w/w, and 10% w/w polymer, respectively, whereas open and closed symbols refer to metronidazole loadings of 2% w/w and 5% w/w, respectively. Standard deviation values are omitted for clarity, however, the coefficient of variation was less than 0.08 in all cases.

628 Biomacromolecules, Vol. 9, No. 2, 2008

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Figure 3. The effect of poly(acrylic acid) concentration, metronidazole concentration, and solvent type, namely, glycerol (a), polyethylene glycol (b), and propylene glycol (c) on the mean loss tangent of organogel formulations. Symbols: circles, squares, and diamonds refer to formulations containing 3% w/w, 5% w/w, and 10% w/w polymer, respectively, whereas open and closed symbols refer to metronidazole loadings of 2% w/w and 5% w/w, respectively. Standard deviation values are omitted for clarity however the coefficient of variation was less than 0.08 in all cases.

Figure 2. The effect of poly(acrylic acid) concentration, metronidazole concentration and solvent type, namely, glycerol (a), polyethylene glycol (b), and propylene glycol (c) on the mean loss modulus of organogel formulations. Symbols: circles, squares, and diamonds refer to formulations containing 3% w/w, 5% w/w, and 10% w/w polymer, respectively, whereas open and closed symbols refer to metronidazole loadings of 2% w/w and 5% w/w, respectively. Standard deviation values are omitted for clarity, however, the coefficient of variation was less than 0.07 in all cases.

sequentially decreased moisture uptake. Conversely, the concentration of polymer in the organogels did not generally affect the moisture uptake. Furthermore, Table 4 displays the mucoadhesive properties of the various organogel formulations (containing 2% w/w metronidazole). Both increasing the concentration of PAA and substitution of the solvent from propylene glycol to PEG 400 to glycerol sequentially increased the force required to break the adhesive bond between the formulation and the partially hydrated mucin disk. Accordingly, maximum mucoadhesion was observed in the formulation composed of 10% w/w PAA and glycerol as the solvent. In formulations composed of 3% w/w PAA and propylene glycol or PEG 400, no mucoadhesive bond strength was observed, as this was below the limit of detection of the analytical equipment. The release of metronidazole (2% w/w original drug loading) from the various organogels is presented in Figure 6. Furthermore, the time required for the release of 25% of the original

drug loading is summarized in Table 4. The release of the drug from the various organogels was modeled using a Power law model, as described by Peppas,28 from which it was shown that the release exponents (n) of the various systems under examination were less than unity but greater than 0.5. In light of the differences in the release exponents and, hence, the mechanisms of drug release from the different formulations, the time required for the release of 25% of the original drug loading was calculated and employed to discern differences in drug release from the different organogels. The concentration of polymer and type of solvent within the organogel affected drug release. In addition, a statistical interaction was identified between these two factors in the ANOVA and may be accredited to the differing effects of each polymer concentration on drug release from the different organogels. For example, in formulations containing 3% w/w polymer, drug release from organogels composed of propylene glycol and glycerol were statistically similar, whereas the time required for the release of 25% of the original mass of drug from organogels composed of PEG 400 was significantly greater. Conversely, in formulations containing 10% w/w PAA, the time required to release 25% of the original drug loading from organogels composed of glycerol was significantly lower than propylene glycol-based formulations, which were in turn lower than their PEG counterparts.

Discussion In this study, a series of organogels containing PAA (3–10% w/w) and prepared using a range of diol and triol solvents


Figure 4. The effect of poly(acrylic acid) concentration, metronidazole concentration, and solvent type, namely, glycerol (a), polyethylene glycol (b), and propylene glycol (c) on the mean dynamic viscosity of organogel formulations. Symbols: circles, squares, and diamonds refer to formulations containing 3% w/w, 5% w/w, and 10% w/w polymer, respectively, whereas open and closed symbols refer to metronidazole loadings of 2% w/w and 5% w/w, respectively. Standard deviation values are omitted for clarity, however, the coefficient of variation was less than 0.08 in all cases.

(propylene glycol, PEG 400 or glycerol) were formulated as antimicrobial bioactive implants, designed for application to the oral cavity for the treatment of local infection. The clinical utility of these systems depends upon a number of physicochemical properties, in particular, the mucoadhesive, drug release, and rheological properties (both destructive and nondestructive), as these directly influence the performance of topical implants.1 As a result, these properties were extensively measured to facilitate the development of the optimal formulations for the desired clinical purpose. This is the first study that has described the physicochemical properties of these bioactive organogel systems. The rheological properties of formulations designed for implantation into the oral cavity have been reported to be critical to their successful clinical and nonclinical performance.1,22,25 Furthermore, the contribution of the rheological properties of topical formulations to other important physicochemical properties, for example, drug release, mucoadhesion has been noted.1,23,29,30 This highlights the importance of gaining an understanding of the rheological properties of such bioactive systems. In dynamic experiments, the rheological properties of the various organogels exhibited similar responses to increasing oscillatory frequency. Typically, the modulus (storage or loss) exhibited a plateau at lower frequencies, but at higher frequencies, these properties increased. Accordingly, the viscoelastic properties of all formulations conformed to the Maxwell model of viscoelasticity, the increase in modulus at higher frequencies being evidence of the terminal zone within the Maxwell model.31 This feature is not commonly observed with aqueous poly(acrylic acid) gels within the frequency range examined in this


study,32 and accordingly, the organogels under investigation may be appropriately described as viscoelastic solids.33 The effect of increasing the polymer concentration on the viscoelastic properties may be accredited to enhanced polymer chain interactions/entanglements that were correspondingly reflected by increased formulation storage modulus, loss modulus, and dynamic viscosity.29,34,35 The storage modulus was significantly greater than the loss modulus across the frequency range examined, and therefore, tan δ values recorded were less than unity, which indicated a dominant elastic response.35,36 Antimicrobial loaded organogels with a tan δ < 1 over the frequency range examined are desirable if formulations are to resist the stresses experienced in vivo. Conversely, formulations exhibiting tan δ > 1 were predicted to limit the retention time due to the dominant flow response away from the site of application.35 The choice of solvent employed in the manufacture of the bioactive organogels significantly affected their resultant viscoelastic structure. Characteristically, organogels prepared using glycerol as a solvent demonstrated significantly higher formulation storage modulus, loss modulus, and dynamic viscosity than comparator organogels prepared using dihydroxy based solvents (i.e., propylene glycol and PEG 400). It is suggested that the greater number of hydroxy bonding sites on the glycerol molecule enhanced the degree of intermolecular bonding with the PAA polymer chains. Previously, authors have demonstrated the ability of organic solvents to affect the viscoelastic state of gel systems.37–39 Accordingly, the number and functionality of potential binding groups possessed, expressed by the solvent, significantly affected the oscillatory frequency response of the PAA-solvent systems studied. In general, the inclusion of metronidazole within the organogels had minimal effect on the resultant viscoelastic properties, with the exception of organogels composed of 10% w/w PAA and PEG 400 or glycerol, the greater effect being observed with glycerol. Metronidazole possesses functionalities capable of forming intermolecular bonds, which may be responsible for the modification of the rheological response. Previously, Realdon et al.40 demonstrated the sensitivity of the rheological properties of aqueous poly(acrylic acid) gels to drug loading, which was attributed to the ability of the drug substance to form intermolecular bonds that correspondingly altered the conformation of the gel structure. Similarly, Jones et al.41 using Raman spectroscopy demonstrated an interaction between chlorhexidine and formulation polymeric components and accredited the unique rheological and textural properties recorded to this interaction. The effect of increasing the loading of metronidazole from 2 to 5% w/w on the viscoelastic properties of organogels containing 10% w/w PAA and either PEG 400 or glycerol may be explained by the competitive binding effect of metronidazole and PAA for these solvents or by the preferential interaction of metronidazole with the polymer, which in turn influences the solvent–polymer interaction. In organogels containing 10% w/w polymer, there is less free solvent available to facilitate drug solubility, and therefore, competition for secondary interactions occurs. To facilitate metronidazole solubilization, solvent–polymer bonds may have been compromised, and accordingly, the solubilization of metronidazole dislodged solvent molecules from the polymer chains, which resulted in a more intramolecularly bonded (or randomly coiled) structure and, consequently, a decrease in formulation storage modulus and loss modulus was observed.42,43 Furthermore, the observed reduction in formulation viscoelastic properties of the PAA organogels in the presence of the higher concentration of drug may be attributed, at least in part, to the ability of the drug substance to interact with the PAA chains,


Jones et al.

Table 2. Effect of Concentration of Poly(acrylic acid) (PAA; 3, 5, 10% w/w), Metronidazole (0, 2, 5% w/w), and Solvent Composition on the Viscoelastic Properties of Poly(acrylic acid) Organogels mean (( standard deviation) viscoelastic properties at defined frequencies solvent

PAA concn drug concn (% w/w) (% w/w)

glycerol glycerol glycerol glycerol glycerol glycerol PEG 400 PEG 400 PEG 400 PEG 400 PEG 400 PEG 400 PG PG PG PG PG PG

3 3 5 5 10 10 3 3 5 5 10 10 3 3 5 5 10 10

2 5 2 5 2 5 2 5 2 5 2 5 2 5 2 5 2 5

G′ at 0.5 Hz (kPa)

G′ at 1 Hz (kPa)

G′′ at 0.5 Hz (kPa)

G′′ at 1 Hz (kPa)

tan δ at 0.5 Hz

tan δ at 1 Hz

0.43 ( 0.02 0.47 ( 0.02 0.88 ( 0.04 0.91 ( 0.04 2.92 ( 0.04 2.47 ( 0.03 0.18 ( 0.01 0.18 ( 0.00 0.33 ( 0.02 0.36 ( 0.02 1.00 ( 0.01 0.93 ( 0.01 0.12 ( 0.00 0.13 ( 0.01 0.28 ( 0.01 0.27 ( 0.01 0.71 ( 0.01 0.73 ( 0.02

0.52 ( 0.01 0.55 ( 0.02 1.02 ( 0.01 1.11 ( 0.01 3.37 ( 0.03 2.84 ( 0.02 0.20 ( 0.00 0.20 ( 0.01 0.37 ( 0.02 0.41 ( 0.02 1.15 ( 0.01 1.08 ( 0.02 0.14 ( 0.01 0.14 ( 0.00 0.30 ( 0.00 0.30 ( 0.01 0.80 ( 0.03 0.83 ( 0.02

0.18 ( 0.00 0.19 ( 0.01 0.34 ( 0.01 0.34 ( 0.01 1.08 ( 0.01 0.91 ( 0.02 0.06 ( 0.00 0.06 ( 0.00 0.11 ( 0.00 0.12 ( 0.01 0.39 ( 0.00 0.38 ( 0.01 0.04 ( 0.00 0.04 ( 0.00 0.07 ( 0.00 0.07 ( 0.00 0.23 ( 0.01 0.24 ( 0.01

0.22 ( 0.01 0.24 ( 0.01 0.43 ( 0.00 0.43 ( 0.01 1.33 ( 0.02 1.12 ( 0.02 0.07 ( 0.00 0.08 ( 0.01 0.14 ( 0.01 0.15 ( 0.01 0.50 ( 0.01 0.49 ( 0.01 0.05 ( 0.00 0.05 ( 0.00 0.09 ( 0.00 0.09 ( 0.00 0.30 ( 0.01 0.30 ( 0.02

0.41 ( 0.02 0.38 ( 0.02 0.38 ( 0.01 0.35 ( 0.01 0.37 ( 0.01 0.37 ( 0.01 0.32 ( 0.01 0.33 ( 0.01 0.33 ( 0.01 0.32 ( 0.01 0.39 ( 0.01 0.41 ( 0.01 0.31 ( 0.02 0.28 ( 0.01 0.24 ( 0.00 0.25 ( 0.01 0.33 ( 0.01 0.32 ( 0.01

0.45 ( 0.01 0.43 ( 0.01 0.42 ( 0.00 0.38 ( 0.01 0.39 ( 0.00 0.39 ( 0.01 0.37 ( 0.01 0.38 ( 0.01 0.37 ( 0.00 0.37 ( 0.00 0.43 ( 0.01 0.45 ( 0.01 0.35 ( 0.01 0.32 ( 0.01 0.28 ( 0.00 0.29 ( 0.01 0.37 ( 0.01 0.37 ( 0.01

η′ at 0.5 Hz (Pa · s)

η′ at 1 Hz (Pa · s)

53.9 ( 2.8 36.3 ( 1.9 57.0 ( 3.3 38.2 ( 1.7 101.6 ( 3.6 68.4 ( 1.8 101.2 ( 3.7 67.7 ( 2.1 324.6 ( 10.3 211.6 ( 9.2 273.0 ( 6.0 177.6 ( 5.4 17.2 ( 0.3 11.8 ( 0.1 17.9 ( 0.9 12.2 ( 0.6 32.0 ( 0.4 22.0 ( 1.2 34.6 ( 0.1 23.8 ( 0.6 117.2 ( 1.9 79.2 ( 0.9 115.2 ( 2.3 77.5 ( 1.8 11.4 ( 0.5 7.6 ( 0.1 10.6 ( 0.8 7.4 ( 0.3 20.1 ( 0.5 13.6 ( 0.4 20.7 ( 0.5 14.0 ( 0.5 70.0 ( 1.5 47.3 ( 0.9 71.1 ( 1.9 48.1 ( 1.7

Table 3. Effect of Concentration of Poly(acrylic acid) (PAA; 3, 5, 10% w/w), Metronidazole (0, 2, 5% w/w), and Solvent Composition on the Consistency and Compressibility (Work of Compression) of Poly(acrylic acid) Organogels concentration of poly(acrylic acid) (% w/w) 3% w/w PAA solvent propylene glycol PEG 400 glycerol

5% w/w PAA

10% w/w PAA

metronidazole concn (% w/w)

consistency Pa · s

compressibility (N · mm)

consistency Pa · s


consistency Pa · s


2 5 2 5 2 5

56.9 ( 2.6 58.5 ( 4.9 159.9 ( 12.3 154.3 ( 5.8 796.0 ( 20.5 794.9 ( 24.9

3.04 ( 0.11 3.05 ( 0.09 4.86 ( 0.23 4.77 ( 0.14 13.22 ( 1.26 12.07 ( 1.76

313.33 ( 18.74 289.09 ( 24.06 565.44 ( 38.99 616.01 ( 44.04 1655.7 ( 95.02 1589.22 ( 22.03

9.80 ( 1.29 9.82 ( 1.42 10.52 ( 0.52 10.93 ( 0.52 24.94 ( 0.88 23.36 ( 1.22

1550.3 ( 33.2 1610.3 ( 78.7 1720.7 ( 74.8 1524.7 ( 14.4 5990.3 ( 360.0 5149.3 ( 146.9

24.92 ( 0.97 24.62 ( 1.02 28.67 ( 1.29 29.83 ( 3.38 78.83 ( 2.30 71.57 ( 1.24

resulting in a disruption of the viscoelastic network. This has been previously reported for aqueous PAA gels.30 Typically, the bioactive PAA-based organogels demonstrated pseudoplastic flow with a range of thixotropy. Pseudoplastic flow is fundamental property of gel systems and is due to polymer chain alignment and subsequent slippage of adjacent chains following the application of a shearing stress.44 This flow phenotype is a desirable property for implantable drug delivery systems and may be related to both ease of manufacture and ease of application to the buccal cavity.44 In addition, the rapid recovery of the gel structure would assist the retention at the application site.45 In accordance with the viscoelastic properties, formulation consistency and work of compression increased with increasing polymer concentration, which was attributed to increased polymer chain entanglements,25,46 and were affected by solvent type. The functionality and number of potential bonding sites possessed by the various solvents significantly affected formulation consistency and work of compression, reflecting differences in the interaction of the various solvents with the polymer. Good correlation (r > 0.85) was observed between the consistency and the work of compression of the formulations. The compressibility of the formulations is of potential interest as compressional stresses are frequently employed in the administration of bioactive dosage forms to the oral cavity1 and other sites.47 The ability of drug delivery vehicles to adhere to the mucosa is of primary importance in the development of topical implants designed for use in the oral cavity. Therefore, bioadhesive polymers have received considerable attention in the field of controlled drug

delivery.5 Mucoadhesive formulations have been previously used to sustain the residence of drug delivery systems at the desired site of application1,48 with the associated reduced dosing and increased patient compliance. Increasing the polymer concentration increased the mucoadhesive bond strength as a result of the increased functionalities capable of forming intermolecular bonds with mucin glycoproteins.49 Interestingly, the organogels containing 3% w/w polymer, with the notable exception of glycerol-based formulations, were deemed unsuccessful due to the inability to resist the imposed force. The weaker gel structure could be detrimental to applications that experience significant shear stresses in vivo, such as the muscular activity from the tongue and cheeks against the oral mucosa. Additionally, the mucoadhesive properties were dependent on the solvent employed in the manufacture of the organogels. Good correlations were observed between the viscoelastic properties (e.g., storage modulus, loss modulus) and mucoadhesion, in which the more structured organogel networks exhibited greater mucoadhesive interactions. The greater mucoadhesion illustrated by the more structured organogels is due to the greater interpenetration into and interaction with mucin, following the dissociation of solvent–polymer bonds by the ingress of water. The effect of the rheological properties of PAA systems, and in particular the expansion of the polymer chains within the formulation, on the resultant mucoadhesion has been previously reported.8,49 Importantly, the mucoadhesive properties of the bioactive organogels under examination were comparable to those of mucoadhesive semisolids that were reported to show suitable retention in vivo following implantation into the periodontal pocket.1 This highlights the potential utility of the described organogels; particularly those formulated using PEG 400 or glycerol.


Figure 5. The effect of poly(acrylic acid) concentration, metronidazole concentration, and solvent type, namely, glycerol (a), polyethylene glycol (b), and propylene glycol (c) on the flow properties of organogel formulations. Symbols: open and closed symbols refer to the upward and downward flow curves, respectively, whereas circles, squares, and triangles represent formulations containing 3% w/w, 5% w/w, and 10% w/w poly(acrylic acid), respectively. In (a), the formulations contain 5% w/w metronidazole, whereas in (b) and (c), the formulations contain 2% w/w metronidazole. Standard deviation values are omitted for clarity, however, the coefficient of variation was less than 0.07 in all cases.

An important design criteria for bioactive systems designed for implantation into the oral cavity is the ability to offer prolonged and controlled drug delivery to the target site. In this study, the release of metronidazole was determined under sink conditions. While it is appreciated that sink conditions are not frequently encountered within the oral cavity, their use in this study enabled the effects of formulation design on drug release to be examined. This study has highlighted the wide range of drug release properties, which, in a similar fashion to the rheological properties, may be easily manipulated by altering the solvent type and polymer concentration. In general, formulations exhibiting greater rheological structure (e.g., storage modulus) offered greater prolongation of drug release (highlighted by the greater times required to release a defined mass of drug). The inverse relationship between polymer concentration and drug release may be (partly) attributed to the increased


strength of the viscoelastic network, resultant from increased inter/intramolecular entanglements between the polymer chains.29,34,50 While there was a positive correlation between the viscoelastic properties of organogels prepared using diol solvents (PEG 400 and propylene glycol) and drug release, this relationship was not valid for glycerol-based organogels (as depicted by the interaction term in the ANOVA). In this, the greatest mass of drug release at defined time periods was associated with glycerol-based organogels, systems that exhibited greater viscoelastic structure than comparator diol-based systems. These observations may be accredited, at least in part, to the greater structural breakdown of the glycerol-based organogels following the uptake of dissolution fluid within the sink conditions of the release experiment. Accordingly, it may be concluded that the release rate of the drug from the PAAsolvent systems depended upon the nature of the diffusion and moisture sorption processes occurring.51 Formulation moisture sorption indicated that the affinity for moisture was related to the solvent type employed in organogel manufacture. Interestingly, formulations displaying the maximum and minimum moisture sorption correlated with the maximum and minimum drug release. Drug dissolution profiles were modeled using the generalized release equation initially proposed by Peppas28 to gain an understanding of the mechanism of drug release. Typically, formulations composed of 3% w/w PAA (independent of solvent type), 5% w/w PAA formulated in diol solvents, and 10% w/w PAA, formulated in propylene glycol displayed anomalous non-Fickian release mechanism (0.5 < n < 1.0), which indicated that a dual process of polymer erosion/ dissolution and drug diffusion was occurring. The polymer chain dissolution may therefore be attributed to the penetration of the dissolution medium, which manifested itself in swelling and subsequent polymer chain disentanglement.52 The observed drug release behavior in formulations composed of 5% w/w or 10% w/w polymer prepared using glycerol, in which PAA was both dissolved and dispersed in the solvent, may be attributed to the rapid ingression of water into these formulations due to the presence of dispersed polymer. The greater affinity of glycerol based organogels for moisture was confirmed in the moisture uptake study. Conversely, PAA was soluble in PG and PEG containing formulations at all concentrations, and therefore, the swelling of these formulations was markedly reduced. It is worth reflecting on the potential clinical utility of the organogels under investigation. Ideally, formulations should exhibit good flow properties (with limited thixotropy), both under torsional and compressive stresses, as this would enable the formulations to be easily removed from the container and applied to the required site within the oral cavity. In this study, these properties were examined using flow rheometry and compressional analysis. Additionally, the formulations should offer controlled drug release and retention at the site of application to increase patient compliance and to increase the clinical efficacy of the chosen therapeutic agent. In these respects, formulations should ideally exhibit low t25% values in drug release studies and high mucoadhesion. Finally, in light of the contribution of the viscoelasticity of organogels to their clinical and nonclinical performance (e.g., mucoadhesion, flow, and drug release), it would be preferable for the described formulations to offer high elasticity following structural recovery after application. This study has shown that by manipulation of the polymer concentration and solvent type, the physicochemical properties of the organogels may be modified. However, the optimal physicochemical properties were not displayed by a single formulation. Interestingly, it was shown that the viscoelasticity and mucoadhesion (and, hence, clinical retention) of the organogels increased


Jones et al.

Table 4. Effect of Concentration of Poly(acrylic acid) (PAA; 3, 5, 10% w/w) and Solvent Composition on the (Mean ( s.d.) Moisture Uptake, Mucoadhesion, and Drug Release Properties of Metronidazole-Containing (2% w/w) Poly(acrylic acid) Organogels moisture uptake (% w/w weight gain) following storage at: solvent propylene glycol PEG 400 glycerol

concn of PAA (% w/w)

60% RH, 1h

75% RH, 1h

60% RH, 240 h

75% RH, 240 h

drug release time25% (min)

mucoadhesion (N)

3 5 10 3 5 10 3 5 10

6.01 ( 0.14 5.81 ( 0.11 5.43 ( 0.20 3.44 ( 0.18 3.67 ( 0.18 3.22 ( 0.20 6.48 ( 0.17 6.36 ( 0.24 7.68 ( 0.19

6.98 ( 0.40 7.03 ( 0.47 7.51 ( 0.31 5.11 ( 0.12 5.40 ( 0.30 5.14 ( 0.17 13.39 ( 0.38 12.29 ( 0.26 12.43 ( 0.23

11.55 ( 0.22 11.42 ( 0.21 10.93 ( 0.53 7.11 ( 0.34 7.73 ( 0.18 7.43 ( 0.16 15.81 ( 0.39 15.71 ( 0.27 16.65 ( 0.42

17.00 ( 0.11 16.24 ( 0.90 16.62 ( 0.71 10.89 ( 0.78 11.08 ( 0.66 10.79 ( 0.87 23.19 ( 0.95 21.40 ( 0.89 21.99 ( 0.37

124.52 ( 6.23 179.22 ( 8.98 275.25 ( 13.67 266.71 ( 15.11 302.26 ( 14.84 482.26 ( 31.82 112.61 ( 6.98 156.15 ( 10.74 68.19 ( 7.63

not detectable 0.14 ( 0.01 0.27 ( 0.02 not detectable 0.19 ( 0.02 0.34 ( 0.04 0.15 ( 0.01 0.26 ( 0.01 0.43 ( 0.02

as a function of PAA concentration and was maximal for glycerolbased systems. Conversely, the flow rheological properties of organogels were optimal in formulations containing lower concentrations of PAA. Therefore, in the selection of formulations for possible clinical investigation, a compromise is required to ensure that there is an adequate balance of the above considerations. Of great consequence to the clinical performance (and in addition to

the physicochemical properties described previously) is the ability of the formulation to provide controlled release for a prolonged period. All organogels examined in this study exhibited controlled release of the model antimicrobial drug (metronidazole), which may be modified by the choice of concentration of polymer and solvent. The unpredicted relatively rapid release of metronidazole from the glycerol-based organogel containing 10% w/w PAA, in addition to the high viscosity of these formulations, would compromise their clinical utility. Similarly, the controlled drug release, viscoelastic, and mucoadhesive properties of organogels composed of the lower concentrations of PAA are not optimal. Therefore, it is proposed that PEG-based organogels composed of either 5% or 10% w/w PAA possessed the most suitable physicochemical properties, offering high elasticity, mucoadhesion, and controlled and prolonged drug release, while retaining adequate flow properties, both in torsional and compressive modes, to enable administration to the hard or soft surfaces of the oral cavity or into the periodontal pocket.

Conclusion This study examined the physicochemical (rheological, viscoelastic, mucoadhesion, moisture uptake) and drug release properties of poly(acrylic acid) organogels, designed as potential bioactive implants for the improved treatment of diseases of the oral cavity. A range of physicochemical properties was exhibited by the organogels that were manipulated by altering the concentration of PAA (3–10% w/w) and the choice of solvent (propylene glycol, PEG 400, or glycerol). Optimally, formulations designed for administration to the oral cavity should possess appropriate viscoelasticity, flow rheological properties (in both torsional and compressional modes), and mucoadhesion and offer controlled release of the therapeutic agent at the site of application. Based on these design criteria, PEG-containing formulations were identified, in particular, those composed of 5 or 10% w/w PAA, that show particular promise as bioactive implants.

References and Notes

Figure 6. Effect of poly(acrylic acid) concentration and solvent type, namely, glycerol (a), polyethylene glycol (b), and propylene glycol (c) on the cumulative release of metronidazole (2% w/w initial loading). Symbols: circles, squares, and diamonds represent formulations containing 3% w/w, 5% w/w, and 10% w/w poly(acrylic acid), respectively.

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BM700597E

Physicochemical Characterization of Bioactive Polyacrylic Acid

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