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An Examination of the Rheological and Mucoadhesive Properties of Poly(Acrylic Acid) Organogels Designed as Platforms for Local Drug Delivery to the Oral Cavity
PHARMACEUTICS, PREFORMULATION AND DRUG DELIVERY An Examination of the Rheological and Mucoadhesive Properties of Poly(Acrylic Acid) Organogels Designed as Platforms for Local Drug Delivery to the Oral Cavity DAVID S. JONES,1 BRENDAN C.O. MULDOON,1 A. DAVID WOOLFSON,1 F. DOMINIC SANDERSON2 1
School of Pharmacy, Medical Biology Centre, The Queen’s University of Belfast, 97, Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK 2
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 16 February 2006; revised 19 June 2006; accepted 11 July 2006 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20771
ABSTRACT: This study examined the rheological/mucoadhesive properties of poly (acrylic acid) PAA organogels as platforms for drug delivery to the oral cavity. Organogels were prepared using PAA (3%, 5%, 10% w/w) dissolved in ethylene glycol (EG), propylene glycol (PG), 1,3-propylene glycol (1,3-PG), 1,5-propanediol (1,5-PD), polyethylene glycol 400 (PEG 400), or glycerol. All organogels exhibited pseudoplastic flow. The increase in storage (G0 ) and loss (G00 ) moduli of organogels as a function of frequency was minimal, G00 was greater than G00 (at all frequencies), and the loss tangent <1, indicative of gel behavior. Organogels prepared using EG, PG, and 1,3-propanediol (1,3-PD) exhibited similar flow/viscoelastic properties. Enhanced rheological structuring was associated with organogels prepared using glycerol (in particular) and PEG 400 due to their interaction with adjacent carboxylic acid groups on each chain and on adjacent chains. All organogels (with the exception of 1,5-PD) exhibited greater network structure than aqueous PAA gels. Organogel mucoadhesion increased with polymer concentration. Greatest mucoadhesion was associated with glycerol-based formulations, whereas aqueous PAA gels exhibited the lowest mucoadhesion. The enhanced network structure and the excellent mucoadhesive properties of these organogels, both of which may be engineered through choice of polymer concentration/solvent type, may be clinically useful for the delivery of drugs to the oral cavity. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:2632–2646, 2007
Keywords: poly(acrylic acid); organogels; flow rheometry; oscillatory rheometry; creep analysis; diol/triol solvents
Brendan C.O. Muldoon’s present address is Warner Chilcott (UK) Ltd., Old Belfast Road, Larne BT40 2SH, Northern Ireland, UK. Correspondence to: David S. Jones (Telephone: þ44-289097-2011, Fax: þ44-28-9024-7794; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 96, 2632–2646 (2007) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association
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INTRODUCTION It is accepted that local diseases of the oral cavity, for example, periodontal disease, lichen planus, infection, are optimally treated using local drug delivery systems as these will ensure that the
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required concentration of therapeutic agent is maintained at the site of application for the duration of the period of application.1,2 However, the design of local delivery systems for the treatment of such disorders represents a considerable challenge to the pharmaceutical scientist. Following application, dosage forms will be typically exposed to a range of shearing stresses as a result of, for example, chewing, talking.3,4 Moreover, the retention of the dosage form at the site of the application will be further compromised by the presence of saliva and the rapid turnover of mucosal epithelia within the oral cavity.2,4 One strategy that has been employed for the improved retention of dosage forms within the oral cavity involves the use of mucoadhesive polymers, that is, polymers that can interact with mucous-coated, biological surfaces via secondary bonds.5–7 There have been several reports that have illustrated the in vivo retention of mucoadhesive dosage forms. For example, the in vivo retention and associated clinical efficacy of mucoadhesive, tetracycline-containing semi-solid systems for the treatment of periodontal disease have been reported8, whereas the same authors described the clinical efficacy of mucoadhesive, flurbiprofen-containing formulations.9 More recently, Irwin et al.10 examined the prolonged retention and release of chlorhexidine from mucoadhesive compacts following application to the oral cavity. Several polymers have been identified as possessing mucoadhesive properties, for example, poly(acrylic acid) (PAA), cellulose ethers, chitosan, and poly(methylvinylether-co-maleic anhydride),11 however, amongst these, greatest interest has been paid to PAA (Carbopol1). The ability of Carbopols to form mucoadhesive interactions has been attributed to the high proportion of carboxylic acid groups along the polymer backbone, which facilitate hydrogen bonding with the mucous-coated substrate.7,12 A range of mucoadhesive dosage forms based on PAA have been formulated including compacts,10,13 gels,14,15 semi-solids,9,16,17 and films.18 Typically mucoadhesive polyacrylic acid gels are formulated in an aqueous solvent, neutralization of the polymer ensuring polymer hydration and gel formation. Interaction of mucoadhesive polymers with mucin is facilitated by the uptake of biological fluids, for example, saliva, crevicular fluid, into the formulation. The increased mobility of the polymer chains enables polymer chain diffusion into and subsequent interaction with mucin using DOI 10.1002/jps
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secondary interactions, for example, hydrogen bonding, van der Waal’s bonds. However, it is accepted that the mucoadhesive properties of polymeric gels are limited due to the swollen status of the polymer chains in the gel state and the resultant restricted diffusion into and interaction with mucin.10,19 It is suggested that this problem may be resolved (at least in part) by the formulation of the mucoadhesive polymer, for example, PAA within a nonaqueous solvent to form organogels. By the choice of the appropriate solvent, gelation of the polymer will occur by secondary bond formation. Upon contact with mucin, the polymer–solvent bonds will be broken thereby facilitating polymer chain mobility and interaction with mucin. The use of hydrophilic organogels has further advantages for the formulation of topical systems containing water-labile drugs. In the formulation of topical dosage forms, it is accepted that the rheological properties are primary determinants of both the clinical and nonclinical performance, for example, ease of removal from the container, spreadability, and retention on the substrate. Furthermore, following application, the formulations will be exposed to nonshearing stresses as a result of chewing and other oral functions and consequently, knowledge of the transient rheological properties is required to optimize formulation performance. Despite the potential advantages of organogels for topical drug delivery, there have been few studies that have provided a comprehensive examination of the rheological properties of these systems, particularly with respect to properties that will influence their possible in vivo performance. In light of the known (strongly) mucoadhesive properties of PAA, this polymer is an ideal candidate for the formulation of such platforms. Therefore, in this study, the effects of polymer concentration and solvent type on the rheological properties were determined using flow and oscillatory rheometry and creep analysis. An understanding of the chemical interaction between the various solvents and the polymer was performed using FTIR. Furthermore, the mucoadhesive properties of the organogels were examined using the mucin disc method. The information obtained from this study will therefore provide a fundamental understanding of the physicochemical and mucoadhesive properties of the organogels under examination, and will additionally enable the suitability of these systems for use as formulation platform for use in the oral cavity to be assessed. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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and stored at 48C for 1 week prior to further analysis.
Materials
Continuous Shear Analysis of Poly(Acrylic Acid) Organogels
Poly(acrylic acid) (PAA) (Carbopol EDT 2050) was donated by B.F. Goodrich Company (Cleveland, OH). Ethylene glycol (EG), propylene glycol (PG), glycerol, polyethylene glycol 400 (PEG 400), 1, 3-propanediol (1,3-PD), and 1,5-pentanediol were purchased from Lancaster (Morecambe, England). All other chemicals were purchased from BDH Chemicals Ltd. (Gillingham, Dorset, UK) and were of AnalaR, or equivalent, quality.
Continuous shear analysis of each organogel was performed using a Carri-Med CSL2 100 rheometer (T.A. Instruments, Surrey, England) in flow mode at 20 0.18C with a 2 cm stainless steel parallel plate geometry and plate gap of 1 mm. Samples were carefully applied to the lower plate using a spatula to ensure that formulation shearing was minimized and allowed to equilibrate for at least 1 h prior to analysis. Rheograms were produced using the loop test, whereby the shearing stress was increased gradually from a minimum up to a predetermined maximum within 60 s, and then returned to the starting point under the same conditions.4,16 In all cases at least five replicate measurements were performed. The shearing stresses were selected according to formulation consistency as shown in Table 1.16 Upward flow curves were modeled using the Cross model20 (Eq. 1), the Power law (Oswald-de-Waele) model21 (Eq. 2), and the Sisko model22 (Eq. 3) from which theoretical zero shear viscosities or consistencies were derived. 0 ¼ ðk_ Þm ð1Þ 1
Methods Manufacture of Poly(Acrylic Acid) Organogels Poly(acrylic acid) (PAA) organogels were prepared by the addition of Carbopol EDT 2050 (3%, 5%, or 10% w/w) to the vortex produced by the rapid stirring (at 2000 rev/min) of the appropriate organic solvent, namely EG, PG, PEG 400, 1,3-PD, or 1,5-propanediol (1,5-PD) using a Heidolph mechanical stirrer. Formulations were stored at 48C for 24 h to allow for complete polymer solvation. All samples were then transferred into amber ointment jars, placed in a vacuum to remove incorporated air, and then stored at 48C for 1 week prior to further analysis.
where Z is the viscosity, Z0 is the zero rate viscosity, Z1 is the infinite shear viscosity, k is the consistency index, g_ is the shear rate, and m is the slope of the curve at the inflection point.
Formulation of Aqueous PAA Gels Aqueous PAA gels were prepared by the addition of Carbopol EDT 2050 (3%, 5%, or 10% w/w) to the vortex produced by stirring (at 2000 rev/min) the required amount of de-ionized water using a Heidolph mechanical stirrer. The resulting polymer solution was then neutralized using sodium hydroxide (30% w/v) to produce a clear gel. All samples were centrifuged to remove entrapped air
¼ k_ n
ð2Þ
where s is the shearing stress, g_ is the rate of shear, k is the consistency index and n is the power law index. ¼ 1 þ k_ n1
ð3Þ
Table 1. Shearing Stresses Employed in Controlled Stress Rheometry
Solvent Ethylene glycol Propylene glycol Glycerol PEG 1,3-Propanediol 1,5-Pentanediol Water
3% w/w PAA Shear Stress (Pa)
5% w/w PAA Shear Stress (Pa)
10% w/w PAA Shear Stress (Pa)
200–1500 200–1500 3000–6000 500–2000 300–600 300–600 100–200
1000–2000 2000–4500 3000–6000 2000–4000 700–1000 700–1000 200–300
4000–6000 4500–6300 3000–6000 4000–6000 5000–6000 5000–6000 500–600
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where Z is the viscosity, g_ is the rate of shear, k is the consistency and Z1 is the infinite shear viscosity. Oscillatory Rheometry of Poly(Acrylic Acid) Organogels Oscillatory rheometry was performed using a Carri-med CSL2-100 rheometer with a 4 cm stainless steel parallel plate geometry (1 mm plate separation) at 20 0.18C. Samples were removed from their storage container, applied to the lower plate of the rheometer, and allowed to equilibrate (>1 h). Initially, the linear viscoelastic region was determined by torque sweep from 0.1 to 100 Pa at frequencies of 0.01 and 1.0 Hz and was identified as the region where stress was directly proportional to strain, and the storage modulus (G0 ) remained constant, as previously described by the authors.4,23 Oscillatory measurements were performed over a frequency range of 0.01–1.0 Hz (at constant strain 0.006). Calculation of the storage modulus (G0 ), loss modulus (G00 ), loss tangent (tan d), and dynamic viscosity (Z0 ) were performed using proprietary software (TA Instruments, Leatherhead, UK). For all formulations, five replicate analyses were performed. Creep (Transient) Analysis of Poly(Acrylic Acid) Organogels Creep analyses were performed using a CarriMed CSL2 100 rheometer (T.A. Instruments) at 20.0 0.18C in creep mode using a stainless steel parallel plate geometry (4 cm plate diameter) with a plate gap of 1 mm. Stresses were selected from within the linear viscoelastic region. Samples were carefully applied to the rheometer and allowed to rheologically equilibrate for 60 min. The selected stress was applied and maintained for a period of 50 min during which time the compliance was measured. The stress was removed and the sample recovery was recorded for an additional 30 min. This relaxation period was selected to ensure that the terminal portion of the creep curve was linear, thereby ensuring that full extension of the viscoelastic elements had occurred.4,24,25 For each formulation, the relationship between compliance 1/G and time was mathematically modeled using the Burgers model22,26 using proprietary software (TA Instruments). As before, at least five replicate analyses were performed for each formulation. DOI 10.1002/jps
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Fourier Transform Infra-Red Spectroscopy Studies Fourier transform infra-red spectra of PAA powder of 1% w/w dispersions in glycerol, EG, PEG 400, PG, 1,3-PD, 1,5-pentanediol, and deionized water (neutralized) were recorded using a FTIR Nicolet Prote´ge´ 460 Spectrophotometer ESP at 208C over a wavelength range from 500 to 3900 cm1. In Vitro Mucoadhesive Properties of PAA Organogels and Aqueous Gels Mucoadhesion between PAA-based formulations and porcine mucin was determined using a TAXT2 Texture Analyser in adhesion mode, as previously reported.8 Mucin (250 mg) was pressed into discs (diameter 13 mm) using a Carver press under a pressure of 10 tonnes for 60 s. The mucin disc was attached to the cylindrical end of a polycarbonate probe (10 mm diameter) using double-sided adhesive tape. The mucin disc was then wetted for approximately 10 s using a 5% w/w mucin solution with excess solution being removed by blotting. The disc was then brought to the surface of the formulation (contained within a three-sided mould) and upon contact, a downward force of 0.1 N applied. After 30 s, the probe was removed at a speed of 10 mm/s and from the resulting force–time plot, a peak was observed corresponding to the force required to break the mucoadhesive bond.8
Statistical Analysis The effects of concentration of PAA and solvent type (EG, PG, PEG 400, 1,3-PD, 1,5-PD) on the viscoelastic properties (initial compliance J0, residual viscosity Z0, G0 , G00 , Z0 , and tan d) at five representative frequencies (0.06, 0.27, 0.53, 0.74, 1.0 Hz), consistency, and the mucoadhesive bond strength were statistically evaluated using a two-way Analysis of Variance (ANOVA). Evaluation of the validity of the different flow models (power law model, Cross model, and the Sisko model) was performed by regression analysis. Comparison of the correlation coefficients associated with each model was performed using a one-way ANOVA. Post hoc comparisons of the means of individual groups were performed using Tukey’s test.27 In all cases, p 0.05 denoted significance and, accordingly, individual significance values are not included in the main body of the text. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
Figure 1. The effects of solvent type and concentration of poly(acrylic acid) (PAA) on the storage modulus (closed symbols) and loss modulus (open symbols) of PAA organogels. In this, circles, squares, and diamonds refer to gels containing 3%, 5%, and 10% w/w PAA, respectively. The solvent systems investigated were ethylene glycol (EG) (a), propylene glycol (PG) (b), polyethylene glycol (c), glycerol (d), 1,3 propanediol (e), and 1,5 pentanediol (f). Standard deviations have been omitted for clarity, however, in all cases, the coefficient of variation was less than 6%. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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RESULTS The effects of oscillatory frequency, polymer concentration, and solvent type on the storage and loss moduli of PAA organogels are displayed in Figure 1a–f. Furthermore, a summary of the viscoelastic properties of the various PAA organogels at a representative oscillatory frequency (1 Hz) is presented in Table 2. For each formulation the G0 , G00 , and tan d gradually increased with increasing oscillatory frequency. However, within the frequency range under examination, a plateau was observed for all three parameters. The dynamic viscosity (Z0 ) of all formulations decreased and formulation G0 was significantly greater than G00 over the frequency range examined. In all formulations (and independent of solvent type), increasing the concentration of PAA significantly increased the storage and loss moduli and dynamic viscosity. In each solvent system, the effect of polymer concentration on the loss tangent was dependent on solvent type and accounted for one of the statistical interactions in the ANOVA. Specifically, increasing the concentration of polymer significantly
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lowered tan d for gels containing glycerol or 1, 5-PD but not for the other organogel systems. The choice of solvent significantly affected the viscoelastic properties of the organogels at each concentration of PAA. Interestingly, the greatest values of storage modulus, loss modulus, and dynamic viscosity were associated with the glycerol-based organogels containing 10% w/w polymer (3581.0 5.6 Pa, 1388.0 10.5 Pa, and 220.7 1.7 Pa s, respectively, at 1 Hz), whereas the greatest tan d value (at 1 Hz) was associated with the 3% w/w PAA glycerol-based organogels (0.56 0.02). No consistent order was observed concerning the effects of solvents on the viscoelastic properties (G0 , G00 , tan d, and Z0 ), however, in all cases, PEG 400 was second in effect to glycerol and, in general, EG- and PGbased formulations exhibited similar properties. Conversely, 1,5-PD had least effect on the oscillatory rheological properties. Significant differences were observed between the viscoelastic properties of the various organogels and their water-based comparator gels. For example, the storage modulus of all organogels (containing 10% w/w polymer), with the exception of the
Table 2. The Effect of Polymer Concentration and Solvent Type on the Viscoelastic (Dynamic) Properties of Poly(Acrylic Acid) (PAA) Organogels (at a Representative Frequency of 1 Hz) PAA (% w/w)
Solvent
G0 (Pa)
G00 (Pa)
tan d
Z0 (Pa s)
3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10
EG EG EG PG PG PG PEG PEG PEG GLY GLY GLY 1,3-PD 1,3-PD 1,3-PD 1,5-PD 1,5-PD 1,5-PD Watera Watera Watera
144.4 1.4 318.3 15.7 890.2 43.9 109.5 2.4 322.3 2.7 880.4 23.6 179.5 5.0 307.8 2.5 1426.0 32.2 339.9 1.8 985.7 31.6 3581.0 5.6 185.4 2.8 368.1 11.7 878.1 25.1 73.6 2.5 175.6 10.0 493.1 16.6 79.5 2.5 264.0 5.1 841.3 10.2
33.0 0.7 57.2 3.8 208.3 12.5 37.7 0.4 93.8 0.9 297.2 7.5 79.4 1.2 135.2 1.6 644.5 12.1 191.8 1.9 411.2 17.9 1388.0 10.5 45.2 0.7 74.3 8.7 221.6 8.7 35.2 0.5 63.0 2.8 175.4 9.4 11.1 0.5 39.5 2.1 124.0 0.8
0.23 0.02 0.18 0.02 0.23 0.02 0.34 0.01 0.29 0.02 0.34 0.01 0.44 0.01 0.44 0.00 0.45 0.01 0.56 0.02 0.47 0.01 0.39 0.00 0.24 0.01 0.21 0.02 0.25 0.02 0.48 0.01 0.36 0.01 0.36 0.01 0.14 0.01 0.15 0.01 0.15 0.01
8.3 0.1 13.1 0.6 33.1 2.0 10.0 0.1 17.8 0.2 47.3 1.9 12.6 0.2 21.5 0.3 102.5 1.9 30.5 0.3 65.4 2.8 220.7 1.7 7.2 0.1 11.8 0.3 35.2 1.4 5.6 0.1 10.0 0.4 27.9 0.5 1.8 0.1 7.9 0.3 19.7 0.1
EG, PG, PEG, Gly, 1,3-PD, and 1,5-PD refer to ethylene glycol, propylene glycol, glycerol, 1,3 propanediol, and 1,5-propanediol, respectively. a Neutralized using sodium hydroxide. DOI 10.1002/jps
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gels composed of 1, 5-PD, was significantly greater than the G0 of the comparator aqueous gel. Similarly, the loss modulus, dynamic viscosity, and loss tangent of all organogels (containing 10% polymer) were significantly greater than those of the comparator aqueous gel. It should be noted that the relationships depicted above concerning the results at 1 Hz were identical at the other four frequencies, as determined using the ANOVA. The creep and recovery curves of examples of the various formulations are presented in Figure 2a–d.
In all cases, three regions may be identified in both the creep and recovery curves, namely the elastic, viscoelastic, and flow regions. The magnitudes of each of these were dependent on the concentration of polymer and solvent employed in the organogels. Mathematical modeling of the creep compliance curves was performed using nonlinear regression analysis based on the Voigt– Kelvin model. Based on this, the most appropriate model to describe the organogels under examination was a Burgers model composed of two-unit Voigt–Kelvin model with a residual spring and a
Figure 2. The effects of solvent type and concentration of PAA on the creep compliance of PAA organogels. The solvent systems investigated were 1,3 propanediol (a), PG (b), polyethylene glycol (c), and glycerol (d), respectively. Standard deviations have been omitted for clarity, however, in all cases, the coefficient of variation was less than 7%. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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expressed in Table 3. As may be observed, increasing the concentration of PAA significantly decreased the initial compliance and increased the residual viscosity. In addition, the nature of the solvent employed in the manufacture of the organogels directly affected these viscoelastic parameters. Gels formulated using glycerol (at each polymer concentration) exhibited the lowest initial compliance and the largest residual viscosity. Conversely, the largest compliance and lowest residual viscosity were demonstrated by organogels based on 1,5-pentanediol, whereas the effects of PG and EG on these properties were generally similar. For example, the initial compliance and residual viscosity of gels containing 10% w/w PAA and glycerol were 0.51 0.04 N2/m and 4.96 0.76 106 Pa s, respectively, whereas the initial compliance and residual viscosity of 3% w/w PAA gels prepared using 1,5-pentanediol were 11.30 0.09 N2/m and 0.18 0.01 106 Pa s, respectively. Interestingly, the initial compliance and residual viscosity of all organogels, with the exception of those prepared using 1,5-pentanediol, were significantly lower and higher, respectively, than those of aqueous PAA gels. This illustrates the superior elastic nature of the organogels in comparison to the comparator aqueous system.
Figure 3. Mechanical model (Burgers model composed of a residual spring, a residual dashpot, and two Voigt–Kelvin units) used to describe the viscoelastic behavior of the organogel formulations.
residual dashpot, as depicted in Figure 3. Mathematically, the creep response of the materials was defined by: t t gðtÞ 1 1 ¼ JðtÞ ¼ þ 1 e 2 þ G1 G2 where g is the strain, s is the stress, J is the compliance, G is the modulus, t is the retardation time, t is time, Z is the viscosity. The use of the above model enabled the calculation of the initial compliance 1/G and the residual viscosity (Z), derived from the t/Z expression within the Burgers model, the results from which are
Table 3. The Effect of Polymer Concentration and Solvent Type on the Viscoelastic (Transient) and Flow Properties of Poly(Acrylic Acid) (PAA) Organogels
PAA (%w/w)
Solvent
Creep Compliance (m2/N)
Residual Viscosity (Pa s 106)
Consistency (Pa s)n
3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10
EG EG EG PG PG PG PEG PEG PEG GLY GLY GLY 1,3-PD 1,3-PD 1,3-PD 1,5-PD 1,5-PD 1,5-PD Watera Watera Watera
9.93 0.01 2.92 0.30 1.49 0.24 9.71 0.29 4.13 0.11 1.78 0.07 5.41 0.41 2.92 0.33 0.89 0.04 2.80 0.13 1.93 0.03 0.51 0.04 7.74 0.38 3.05 0.13 1.56 0.02 11.30 0.09 5.87 0.67 2.58 0.04 16.10 2.94 3.62 0.08 2.61 0.10
0.51 0.03 1.21 0.01 1.47 0.07 0.50 0.01 1.15 0.08 1.68 0.18 1.03 0.08 2.12 0.23 3.04 0.06 1.67 0.13 2.98 0.06 4.96 0.76 0.79 0.05 1.28 0.04 2.34 0.07 0.18 0.01 0.36 0.04 0.62 0.01 0.39 0.02 1.02 0.03 1.30 0.06
62.7 4.8 260.2 14.9 1264.0 40.3 113.1 3.5 656.0 37.7 1417.0 214.3 190.4 30.6 819.2 19.6 2142.3 351.6 398.4 27.7 1473.3 71.5 4528.3 127.1 68.8 10.4 352.6 23.0 1158.0 72.5 26.2 1.4 92.3 3.5 755.2 35.0 28.8 1.4 225.6 1.9 535.8 6.0
a
Neutralised gels.
DOI 10.1002/jps
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The flow properties of selected organogels are presented in Figure 4. As may be observed all organogels exhibited thixotropy, the nature and magnitude of which were independent of the nature of the solvent employed in the manufacture. To describe the flow rheological behavior of the various aqueous and nonaqueous gels, the flow properties were mathematically modeled using the power, Cross, and Sisko models. Significant differences in the correlation coefficients and residuals of these were observed, with the power model providing the most statistically acceptable model. Therefore, using this model, the consistencies of the various formulations were determined and statistically compared (Tab. 3). Increasing the concentration of polymer was observed to significantly increase the consistency of each system, independent of the nature of the solvent. Moreover, organogels prepared using glycerol exhibited the greatest consistency whereas those composed of 1,5-pentanediol displayed the lowest consistency. For example, the consistency of the organogel prepared using glycerol and containing 10% w/w polymer was 4528.3 127.1 (Pa s)n, whereas the lowest observed consistency was associated with the organogels containing 3% w/w PAA and 1, 5-pentanediol (26.2 1.4 (Pa s)n). In addition, while lower than those for glycerol, the organogels composed of PEG 400 exhibited notably large consistencies. Interestingly, with the general exception of organogels prepared using 1,5pentanediol, the consistency of the organogels was greater than that of comparator aqueous gels of PAA. Of particular interest in the statistical analysis of data were the observed interactions between polymer concentration and solvent type with respect to the various rheological parameters under investigation (G0 , G00 , tan d, Z0 , J0, Z0, k). In these, deviations from the generalized linear model were due to the disproportionate effect of glycerol (primarily) and, secondarily, polyethylene glycol on the rheological parameters.
Figure 4. Rheograms depicting the effects of solvent type and concentration of PAA on the flow properties of PAA organogels. In this, squares, diamonds, and circles, refer to gels containing 3%, 5%, and 10% w/w PAA. The solvent systems investigated were EG (a), PG (b), polyethylene glycol (c), and glycerol (d), respectively. Standard deviations have been omitted for clarity, however, in all cases, the coefficient of variation was less than 6%. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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Table 4. Carbonyl Stretches Obtained From IR Spectral of the Various Poly(Acrylic Acid) Organogels
the force of detachment of the gels containing 3% w/w PAA was below the limit of detection of the method.
Carbonyl Stretch (per cm)
Solvent Poly(acrylic acid) powder Propylene glycol Ethylene glycol PEG 400 Glycerol 13 Propanediol 15 Pentanediol De-ionized water (neutralized)
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1716 1655 1653 1647 1652 1660 1667 1635
The majority of formulations designed for application to the oral cavity have been aqueous based, however, an interest has emerged in the use of nonaqueous formulations for improved drug delivery. Nonaqueous PAA-based mucoadhesive delivery systems have been reported to offer enhanced bioavailability over aqueous-based formulations for the nasal delivery of propanolol hydrochloride.28 The same authors described the effect of nonaqueous solvents on the viscoelastic properties of neutralized PAA gels and concluded that mixed solvent systems offered enhanced retention times.29 It is accepted that the rheological properties of gel/semi-solid dosage forms designed for application to the oral cavity directly affect the clinical and nonclinical performance of these systems4 and accordingly, in the design of formulations designed for application to the oral cavity, a comprehensive characterization of the rheological properties is required. The stresses encountered by topical dosage forms are varied. Typically, administration into the oral cavity, for example, into the periodontal pocket or onto the inflamed gingival, requires the application of shearing stresses that will deform the product to facilitate removal from the container and spreading onto the substrate. Furthermore, excessive thixotropy may impede the retention of the dosage form at the site of application due to the compromised rheological properties. Following recovery after deformation, the dosage form will be exposed to nondeformable stresses that are oscillatory, compressive, and tensional in nature
The carbonyl shifts in the infrared spectra obtained from each organogel under investigation are presented in Table 4. The IR spectra of unsolvated (powdered) PAA exhibited a carbonylstretching absorption at circa 1716 cm1. Conversely, upon solvation with each nonaqueous solvent, the stretching absorption of the carbonyl shifted to approximately 1650 cm1, which was different from that for neutralized PAA gels. Finally, the mucoadhesive properties of the various PAA gels (both aqueous and nonaqueous) are presented in Table 5. As may be observed, increasing the concentration of PAA sequentially increased the force required to detach the formulations from the mucin disc. Furthermore, significant differences were observed in the mucoadhesive properties of PAA when formulated in the various solvent systems. The greatest mucoadhesive properties, 0.42 0.02 N, were associated with glycerol-based organogels containing 10% w/w polymer. Importantly, the lowest force of detachment (and hence mucoadhesion) was observed for aqueous PAA gels. In all solvents, with the exception of the glycerol-based systems,
Table 5. Effect of Polymer Concentration and Solvent Type on the Mucoadhesive Bond Strength of PAA-Based Gel Formulations Force of Detachment of Formulations Containing (N) Solvent Propylene glycol PEG 400 Glycerol Ethylene glycol 1,3 Propanediol 1,5 Pentanediol Water (neutralized)
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3% w/w PAA
5% w/w PAA
10% w/w PAA
Not measurable Not measurable 0.17 0.02 Not measurable Not measurable Not measurable Not measurable
0.13 0.01 0.19 0.02 0.26 0.01 0.13 0.00 0.14 0.01 0.11 0.00 0.09 0.00
0.29 0.04 0.34 0.02 0.42 0.02 0.23 0.02 0.28 0.03 0.18 0.03 0.19 0.02
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due to, for example, mastication, respiration, and musculature movement. In light of this diversity, it is essential that the viscoelastic properties of the formulations be characterized using methods that employ oscillatory and transient stresses, which are representative of the oral cavity. Typically, the viscoelastic properties of gel/semisolid formulations have been reported to affect the resultant performance, for example, mucoadhesion,30 drug release,8 and mucocilliary transport.31 Therefore, this study describes a comprehensive rheological analysis of novel polymeric organogels that are designed as platforms for drug delivery systems for local use in the oral cavity. The information generated in this study will enable the suitability of these formulation platforms to be discerned and will allow suitable candidate systems to be identified. In oscillatory analysis, the viscoelastic properties (G0 , G00 , tan d, and Z0 ) of the organogels were shown to be dependent on oscillatory frequency. In all cases, the formulation storage modulus (G0 ) and loss modulus (G00 ) increased with increasing oscillatory frequency. The magnitude of the storage modulus was significantly greater than the loss modulus for each organogels (and aqueous gel) and hence, the loss tangent was less than unity over the entire frequency range. This indicated the predominance of the elastic character and the existence of the gel state.4,23,32 The relationship between G0 , G00 , and oscillatory frequency was characteristic of the Maxwell model of viscoelasticity.33 In particular, the frequency dependency of the moduli of the organogels under investigation is indicative of physically entangled systems.4,23 Within the range of oscillatory frequencies examined, the organogels existed initially in the plateau region of viscoelasticity (at lower frequencies) and within the terminal portion of this region at high frequencies. This phenomenon has not been reported for aqueous polymeric gels, including PAA, and is therefore a unique feature of these organogels. Further evidence of the viscoelastic properties of the formulations under examination over a long time period was provided by creep analysis. Three regions may be identified in the relationship between the compliance and time of each formulation, namely the instantaneous elastic region, the region of viscous flow, and the region denoting retarded elasticity (viscoelasticity).4,24 Modeling of the creep response was satisfied using a two-unit Burgers model, from which the instantaneous elastic compliance and residual viscosity JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
were determined. The instantaneous elastic compliance of all formulations was recovered upon removal of the applied stress and may be attributed to the elastic stretching of molecular bonds. The Kelvin–Voigt units describe the retarded elastic behavior and may be accredited to the breaking and reforming of secondary bonds (which occur at different rates) thereby resulting in a spectrum of retardation times.4,24 After sufficient time at constant stress, the Voigt units will fully extend and any further deformation will result in a linear increase in compliance, which is attributed to the extension of the residual dashpot as a result of polymer chain disentanglements. The creep curves obtained from PAA–solvent systems approximated to elastic solids with a relatively restricted viscoelastic region and high residual viscosities. The concentration of polymer significantly affected the viscoelastic properties of the various organogels, as determined using both creep analysis and oscillatory rheology. Typically increasing PAA concentration increased G0 , G00 , Z0 , and Zo and decreased elastic compliance (J). This is indicative of an increase in the strength of the viscoelastic structure, due to increased (physical) polymer chain entanglements thereby resulting in an increased resistance to macromolecular reorganization.4 Importantly, this study has uniquely described both the greater range of viscoelastic (dynamic and transient) properties that may be achieved by formulation of PAA as organogels and, additionally, the effect of the choice of solvent on the resultant rheological properties. The mechanism of organogel formation may be attributed to polymer chain expansion resulting from the intermolecular interactions between the polymer and organic solvent used. Molecules of the solvents under examination readily form associates with each other and with other molecules via hydrogen bonds.34 Following consideration of the structures of both PAA and the various solvents and the FTIR spectra, the dominant interaction associated with organogel formation was primarily hydrogen bonding between the carboxyl groups of the polymer and the hydroxy/ethoxy groups of the solvents, although electrostatic, van der Waals, and hydrophobic interactions may also contribute.35 Similarly, Mathur et al.36 described the interactions of poly(methacrylic) acid and polyethylene glycol in this manner. The wavelengths of the carbonyl stretch of the various organogels systems were similar, indicating a similar mechanism of interaction with the polymer. HowDOI 10.1002/jps
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ever, the difference in the carbonyl stretch of the neutralized aqueous system highlighted differences in the mechanism of polymer–solvent interaction. In contrast to comparator organogels, the gelation of PAA in an aqueous solvent is facilitated by neutralization and repulsion of adjacent, ionized carboxylic acid moieties.37,38 Interestingly, as the initial compliance refers to the elastic stretching of bonds, the lower values of initial compliance associated with the various organogels indicate that the intermolecular bond strength of these systems was greater than for their aqueous counterparts. This phenomenon was confirmed by the higher storage modulus of organogel systems. The solvents employed to prepare the organogels were chosen on the basis of their general pharmaceutical acceptability and their related structural properties, the latter facilitating an examination of solvent structure on the rheological properties of organogels. Typically, the viscoelastic properties of organogels formulated using the EG, PG, and 1,3-PD were similar, indicating the similar effect of these solvents on the rheological properties. Therefore, it may be suggested that diols in which the hydroxyl groups are either adjacent or separated by one methylene group may similarly interact with adjacent carboxylic acid groups on each chain of PAA. In so doing expansion of the polymer chains occurs thereby increasing the elastic nature of the gels. Organogels formulated using 1,5-PD exhibited lower viscoelastic properties, which, in light of the above, may be explained by the inability of the hydroxyl groups to adequately interact with adjacent carboxylic acid groups on the polymer due to stearic effects. PEG is a dihydroxy-terminated polyether capable of forming hydrogen bonds both through the hydroxyl groups and the ethereal oxygen atoms. The two terminal hydroxyl groups are separated by approximately 400 ethoxy groups and, particularly in light of the observations concerning the interaction of 1,5-PD with PAA, the stearic limitations would dramatically restrict the interaction of the terminal hydroxyl groups of PEG with adjacent carboxylic acid groups on PAA. The viscoelastic properties of PEG-based organogels were greater than those prepared using other diol solvents and, accordingly, the expansion of polymer chains in the former system was greater. This may be explained, at least in part, by the ability of PEG to interact with adjacent carboxylic acid groups of PAA via a terminal hydroxyl group and an ethoxy group or by DOI 10.1002/jps
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two ethoxy groups.39 Furthermore, the polymeric nature of PEG enables these interactions to simultaneously occur between carboxylic acid groups within adjacent polymer chains, thereby further increasing rheological structuring. The solvent associated with the greatest rheological structuring of PAA was glycerol. In contrast to the other solvents under examination, glycerol is a triol and therefore is theoretically capable of a greater number of interactions with the carboxylic acid moiety of PAA than the low molecular weight diols (EG, PG, 1,3-PD, and 1,5-PD). This would allow glycerol to interact with both adjacent carboxylic acid moieties on a single polymer chain but also simultaneously those on adjacent polymer chains. In so doing, a three-dimensional network may be facilitated, resulting in greater expansion of the polymer structure and hence greater enhancement of the viscoelastic properties of these organogels. With the exception of systems prepared using 1,5-PD, the viscoelastic properties of the organogels were greater than their aqueous counterparts, indicative of greater rheological structuring. The expansion of adjacent polymer chains in aqueous PAA gels is due to electrostatic repulsion. The greater viscoelastic properties of the organogels may be attributed to both the greater expansion of adjacent carboxylic acid groups and the ability of certain solvents to interact with the carboxylic acid groups on adjacent PAA chains (notably glycerol and PEG). It should be noted that, unlike aqueous PAA gels, the organogels described in this study would be expected to be stable in the presence of ionic species, for example, drug molecules. Following exposure to larger stress the organogels exhibited pseudoplastic flow with limited thixotropy. Modeling of the flow properties of the various organogels was performed using the Cross model and two subsets of this model, namely the Power and Sisko models. Based on regression analysis, the Power law model provided the largest coefficient of determination values and accordingly, a log–log relationship between viscosity and shear rate was observed with the range of shearing stresses under examination. In these formulations, increasing shearing stresses resulted in the disentanglement of adjacent polymer chains via bond breaking and subsequent alignment in the direction of imposed shear, which in turn leads to shear thinning behavior.4,16 Similarly, oscillatory analysis revealed a significant decrease in formulation dynamic viscosity with increasing oscillatory frequency which is an indication of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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shear thinning rheological behavior.40 Increasing the PAA concentration within PAA–solvent systems produced a marked increase in formulation consistency, which is due to enhanced entanglement of adjacent polymer chains.4 The observable differences in the consistencies of PAA organogels that had been formulated with the various solvent systems were consistent with the observed differences in the viscoelastic properties. Of particular relevance in this respect was the correlation between the dynamic viscosity (Z0 ) and consistency. The lack of continuity of the relationships between Z0 and frequency (from oscillatory analysis) and between viscosity and shear rate (from flow rheometry) when modeled using the Cox–Merz law provided further evidence of the gel state of the organogels.1 The effects of the different solvents on the flow properties may be attributed to their varied abilities to interact with PAA and hence to facilitate polymer chain expansion (as described above). It is accepted that the retention of products within the oral cavity may be improved by the use of mucoadhesive formulations. In this study, PAA, a polymer with known mucoadhesive properties,41 was formulated within nonaqueous solvent systems and its mucoadhesive properties were characterized. The method used involved the determination of the force of detachment of the formulation from a surface-hydrated mucin disc, as previously reported by the authors.8,42 This study illustrated that alterations in both the concentration of PAA and the nature of the solvent directly influenced the mucoadhesive properties of the organogels. Furthermore, a relationship between formulation elasticity (G0 ) and mucoadhesion was observed, illustrating the importance of the viscoelastic properties (and in particular network structure) on this property. Two important observations should be noted regarding the mucoadhesive properties of the organogels under examination. First, a wide range of mucoadhesive properties were exhibited by the formulations that were affected by changes in polymer concentration and solvent type. Indeed, the organogel formulations that were manufactured using glycerol or PEG 400 were particularly useful in this respect. Second, with the general exception of 1,5-pentanediol (a nonpharmaceutical solvent), the mucoadhesive properties of the organogels were significantly greater than those of comparator aqueous PAA gels. This illustrates the greater mucoadhesive JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
potential of PAA organogels, a hereto-unreported phenomenon. Furthermore, based on previous studies, the mucoadhesive properties of the glycerol and PEG 400-based organogels would be expected to offer good retention within the oral cavity.8 Knowledge of the rheological and mucoadhesive properties of the organogel formulations enables an insight into the potential pharmaceutical utility of these formulations as platforms of drug delivery systems designed for application to the oral cavity. Notably, the shear thinning properties exhibited by the various organogel formulations are advantageous. The formulations will be exposed to high shear rates during application to the oral cavity, resulting in a reduction in apparent viscosity and thereby facilitating successful application. Following recovery, the viscosity will recover to the original (equilibrium) state, which in association with the known mucoadhesive properties of PAA8 will enhance the retention at the site of application. However, of particular interest, are the unique viscoelastic properties of the formulations. It has been reported that the storage modulus is an important contributor to the mucoadhesive properties of topical formulations, typically being associated with increased product retention/mucoadhesion.4,8 Furthermore, the elastic properties of gel formulations have been reported to be important determinants of drug release. Formulations, exhibiting high G0 (and low tan d), will provide greater resistance to both the diffusion of aqueous fluid into the formulation and the subsequent diffusion of the dissolved drug through the gel matrix.8 Therefore, formulations prepared using glycerol (in particular) or PEG will be advantageous in this respect. Formulations that exhibited advantageous elastic properties also possessed higher consistency and dynamic viscosity, which will affect the ease of removal from the container and the ease of application/spreading onto the host substrate. This is particularly relevant for formulations that are designed for delivery into the periodontal pocket using a syringe where the higher consistencies in association with the narrow diameter of the syringeorifice in the syringe may lead to problems in administration. Therefore, in the choice of formulation platform, a compromise may be required between elasticity (high G0 , low tan d) and consistency to produce formulations that may be easily administered to and retention at the required site of administration. DOI 10.1002/jps
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In conclusion, this study has described the formulation and rheological and mucoadhesive characterization of organogels composed of PAA, dispersed within a range of diol and triol solvents. By choice of polymer concentration and, more importantly, solvent type, organogels were prepared that exhibited a wide range of viscoelastic and flow properties, as determined using oscillatory rheometry, creep analysis, and flow rheometry. The combined use of these rheological techniques enabled a unique insight into the structural properties of the organogel systems. It is suggested that the predominantly elastic and mucoadhesive properties of PAA organogels prepared with glycerol (in particular) or PEG may offer promise as platforms of drug delivery to the oral cavity.
REFERENCES 1. Jones DS, Lawlor MS, Woolfson AD. 2002. Examination of the flow rheological and textural properties of polymer gels composed of poly (methylvinylether-co-maleic anhydride) and poly (vinylpyrrolidone): Rheological and mathematical interpretation of textural parameters. J Pharm Sci 91:2090–2101. 2. Jones DS, Lawlor MS, Woolfson AD. 2003. Rheological and mucoadhesive characterization of polymeric systems composed of poly(methylvinyletherco-maleic anhydride) and poly(vinylpyrrolidone), designed as platforms for topical drug delivery. J Pharm Sci 92:995–1007. 3. Jones DS, Woolfson AD, Brown AF. 1998. Viscoelastic properties of bioadhesive chlorhexidine containing semisolids for topical application to the oropharynx. Pharm Res 15:1131–1136. 4. Jones DS, Brown AF, Woolfson AD. 2001. Rheological characterization of bioadhesive, antimicrobial, semisolids designed for the treatment of periodontal diseases: Transient and dynamic viscoelastic and continuous shear analysis. J Pharm Sci 90:1978–1990. 5. Mortazavi SA, Smart JD. 1995. An investigation of some factors influencing the in vitro assessment of mucoadhesion. Int J Pharm 116:223–230. 6. Needleman IG, Martin GP, Smales FC. 1998. Characterisation of bioadhesivenes for periodontal and oral mucosal delivery. J Clin Periodont 25: 74–82. 7. Park H, Robinson JR. 1987. Mechanisms of mucoadhesion of poly(acrylic acid) hydrogels. Pharm Res 4:457–464. 8. Jones DS, Woolfson AD, Brown AF, Coulter WA, McClelland C, Irwin CR. 2000. Design, character-
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9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
2645
isation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. J Control Release 67:357–368. Jones DS, Irwin CR, Woolfson AD, Djokic J, Adams V. 1999. Physiochemical characterisation and preliminary in vivo efficacy of bioadhesive semisolid formulations containing flurbiproen for the treatment of gingivitis. J Pharm Sci 88:592–598. Irwin CR, McCullough KC, Jones DS. 2003. Chlorhexidine-containing mucoadhesive polymeric compacts designed for use in the oral cavity: An examination of their physical properties, in vitro/ in vivo drug release properties and clinical acceptability. J Mater Sci-Mater Med 14:825–832. Woolfson AD, Malcolm RK, McCarron PA, Jones DS. 2002. Bioadhesive drug delivery systems. In: Dumitriu S, editor. Polymeric biomaterials, 2nd edition. New York: Marcel Dekker. pp 1063– 1083. Mortazavi SA, Smart JD. 1994. An in-vitro method for assessing the duration of mucoadhesion. J Control Release 31:207–212. Anlar S, Capan Y, Guven O, Gogus A, Hincal AA. 1994. Formulation and in vitro-in vivo evaluation of buccoadhesive morphine sulfate tablets. Pharm Res 11:231–236. Witschi C, Mrsny RJ. 1999. In vitro evaluation of microparticles and polymer gels for use as nasal platforms for protien delivery. Pharm Res 16:282– 290. Jones DS, Woolfson AD, Brown AF, O’Neill MJ. 1997c. Mucoadhesion, syringeable drug delivery systems for controlled application of metronidazole to the peridontal pocket: In vitro release kinetics, syringeability, mechanical and mucoadhesive properties. J Control Release 49:71–79. Jones DS, Woolfson AD, Brown AF. 1997. Textural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gels. Pharm Res 14:450–457. Jones DS, Woolfson AD, Djokic J, Coulter WA. 1996. Development and mechanical characterization of bioadhesive semi-solid, polymeric systems containing tetracycline for the treatment of periodontal diseases. Pharm Res 13:1734–1738. Woolfson AD, McCafferty DF, McCarron PA, Price JH. 1995. A bioadhesive patch cervical drug delivery system for the administration of 5-fluorouracil to cervical tissue. J Control Release 35: 49–58. Woolfson AD, Malcolm KR, McCarron PA, Jones DS. 2002. Bioadhesive drug delivery systems. In: Dumitriu S, editor. Polymeric biomaterials, 2nd edition. New York: Marcel Dekker. pp 1063– 1083. Cross MM. 1965. Rheology of non-Newtonian flow: A new flow equation for pseudoplastic systems. J Colloid Sci 20:417–437.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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21. Dolz M, Herraez M, Gonzalez F, Diez O, Delegido O, Hernandez MJ. 1998. Flow behavior of Carbopol-940 hydrogels. The influence of concentration and agitation time. Pharmazie 53:126–130. 22. Barnes HA. 2000. A handbook of elementary rheology, 6th edition. Aberystwyth: The University of Wales Institute of Non-Newtonian Fluid. pp 55–61. 23. Jones DS, Woolfson D, Brown AF. 1998. Viscoelastic properties of bioadhesive, chlorhexidine- containing semi-solids for topical application to the oropharynx. Pharm Res 15:1131–1136. 24. Barry BW. 1974. Rheology of pharmaceutical and cosmetic semisolids. In: Bean HS, Beckett AH, Carless JE, editors. Advances in pharmaceutical sciences, Vol 4. USA: Academic Press. pp 1–72. 25. Barry BW, Meyer MC. 1979. The rheological properties of carbopol gels 2. Oscillatory properties of carbopol gels. Int J Pharm 2:27–40. 26. Barnes HA, Hutton HA, Walters JF. 1990. An introduction to rheology. New York: Elsevier Scientific Publishers. 27. Jones DS. 2002. Pharmaceutical statistics, 1st edition. London: The Pharmaceutical Press. 28. Chu JS, Chandrasekharan R, Amidon GL, Weiner ND, Goldberg AH. 1991. Viscometric study of polyacrylic acid systems as mucoadhesive sustained-release gels. Pharm Res 8:1408–1412. 29. Chu JS, Yu DM, Amidon GL, Weiner ND, Goldberg AH. 1992. Viscoelastic properties of polyacrylic acid gels in mixed solvents. Pharm Res 9:1659–1663. 30. Jones DS, Woolfson AD, Brown AF. 1997. Textural, viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. Int J Pharm 151:223–233. 31. Lin SY, Amidon GL, Weiner ND, Goldberg AH. 1993. Viscoelasticity of cellulose polymers and mucociliary transport on frog plates. Int J Pharm 95:57–65.
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32. Chirila TV, Hong Y. 1998. Poly(1-vinyl-2-pyrrolidine) hydrogels as vitreous substitiutes: A rheological study. Polymer Int 46:183–195. 33. Ferry JD. 1980. Viscoelastic properties of polymers, 3rd edition. New York: John Wiley & Sons Inc. 34. Shchipunov YA, Shumilina EV. 1996. Lecithin organogels: Role of polar solvent and nature of intermolecular interactions. Colloid J 58:117–125. 35. Nishi S, Kotaka T. 1985. Complex-forming poly(oxyethylene): Poly(acrylic acid) interpenetrating polymer networks. Preparation structure and viscoelastic properties. Macromolecules 18:1519– 1525. 36. Mathur AM, Hammonds KF, Klier J, Scranton AB. 1998. Equilibrium swelling of poly(methacrylic acid-g-ethylene glycol) hydrogels. Effect of swelling medium and synthesis conditions. J Control Release 54:177–184. 37. Barry BW, Meyer MC. 1979a. The rheological properties of carbopol gels i. Int J Pharm 2:1–25. 38. Craig DQM, Tamburic S, Buckton G, Newton JM. 1994. An investigation into the structure and properties of carbopol 934 gels using dielectric spectroscopy and oscillatory rheometry. J Control Release 30:213–223. 39. Bell LC, Peppas AN. 1996. Swelling/syneresis phenomena in gel-forming interpolymer complexes. J Biomater Sci Polym Ed 7:671–683. 40. Eadli M, Esmail MN, Vatistas GH. 2001. Rheological properties of high concentrations of carboxylmethyl cellulose solutions. J Appl Polym Sci 79: 1787–1801. 41. Edsman K, Hagerstrom H. 2005. Pharmaceutical applications of mucoadhesion for the non-oral routes. J Pharm Pharmacol 57:3–22. 42. Jones DS, Woolfson DA, Brown AF. 1997a. Textural viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. Int J Pharm 151:223–233.
DOI 10.1002/jps
School of Pharmacy, Medical Biology Centre, The Queen’s University of Belfast, 97, Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK 2
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 16 February 2006; revised 19 June 2006; accepted 11 July 2006 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20771
ABSTRACT: This study examined the rheological/mucoadhesive properties of poly (acrylic acid) PAA organogels as platforms for drug delivery to the oral cavity. Organogels were prepared using PAA (3%, 5%, 10% w/w) dissolved in ethylene glycol (EG), propylene glycol (PG), 1,3-propylene glycol (1,3-PG), 1,5-propanediol (1,5-PD), polyethylene glycol 400 (PEG 400), or glycerol. All organogels exhibited pseudoplastic flow. The increase in storage (G0 ) and loss (G00 ) moduli of organogels as a function of frequency was minimal, G00 was greater than G00 (at all frequencies), and the loss tangent <1, indicative of gel behavior. Organogels prepared using EG, PG, and 1,3-propanediol (1,3-PD) exhibited similar flow/viscoelastic properties. Enhanced rheological structuring was associated with organogels prepared using glycerol (in particular) and PEG 400 due to their interaction with adjacent carboxylic acid groups on each chain and on adjacent chains. All organogels (with the exception of 1,5-PD) exhibited greater network structure than aqueous PAA gels. Organogel mucoadhesion increased with polymer concentration. Greatest mucoadhesion was associated with glycerol-based formulations, whereas aqueous PAA gels exhibited the lowest mucoadhesion. The enhanced network structure and the excellent mucoadhesive properties of these organogels, both of which may be engineered through choice of polymer concentration/solvent type, may be clinically useful for the delivery of drugs to the oral cavity. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:2632–2646, 2007
Keywords: poly(acrylic acid); organogels; flow rheometry; oscillatory rheometry; creep analysis; diol/triol solvents
Brendan C.O. Muldoon’s present address is Warner Chilcott (UK) Ltd., Old Belfast Road, Larne BT40 2SH, Northern Ireland, UK. Correspondence to: David S. Jones (Telephone: þ44-289097-2011, Fax: þ44-28-9024-7794; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 96, 2632–2646 (2007) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association
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INTRODUCTION It is accepted that local diseases of the oral cavity, for example, periodontal disease, lichen planus, infection, are optimally treated using local drug delivery systems as these will ensure that the
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required concentration of therapeutic agent is maintained at the site of application for the duration of the period of application.1,2 However, the design of local delivery systems for the treatment of such disorders represents a considerable challenge to the pharmaceutical scientist. Following application, dosage forms will be typically exposed to a range of shearing stresses as a result of, for example, chewing, talking.3,4 Moreover, the retention of the dosage form at the site of the application will be further compromised by the presence of saliva and the rapid turnover of mucosal epithelia within the oral cavity.2,4 One strategy that has been employed for the improved retention of dosage forms within the oral cavity involves the use of mucoadhesive polymers, that is, polymers that can interact with mucous-coated, biological surfaces via secondary bonds.5–7 There have been several reports that have illustrated the in vivo retention of mucoadhesive dosage forms. For example, the in vivo retention and associated clinical efficacy of mucoadhesive, tetracycline-containing semi-solid systems for the treatment of periodontal disease have been reported8, whereas the same authors described the clinical efficacy of mucoadhesive, flurbiprofen-containing formulations.9 More recently, Irwin et al.10 examined the prolonged retention and release of chlorhexidine from mucoadhesive compacts following application to the oral cavity. Several polymers have been identified as possessing mucoadhesive properties, for example, poly(acrylic acid) (PAA), cellulose ethers, chitosan, and poly(methylvinylether-co-maleic anhydride),11 however, amongst these, greatest interest has been paid to PAA (Carbopol1). The ability of Carbopols to form mucoadhesive interactions has been attributed to the high proportion of carboxylic acid groups along the polymer backbone, which facilitate hydrogen bonding with the mucous-coated substrate.7,12 A range of mucoadhesive dosage forms based on PAA have been formulated including compacts,10,13 gels,14,15 semi-solids,9,16,17 and films.18 Typically mucoadhesive polyacrylic acid gels are formulated in an aqueous solvent, neutralization of the polymer ensuring polymer hydration and gel formation. Interaction of mucoadhesive polymers with mucin is facilitated by the uptake of biological fluids, for example, saliva, crevicular fluid, into the formulation. The increased mobility of the polymer chains enables polymer chain diffusion into and subsequent interaction with mucin using DOI 10.1002/jps
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secondary interactions, for example, hydrogen bonding, van der Waal’s bonds. However, it is accepted that the mucoadhesive properties of polymeric gels are limited due to the swollen status of the polymer chains in the gel state and the resultant restricted diffusion into and interaction with mucin.10,19 It is suggested that this problem may be resolved (at least in part) by the formulation of the mucoadhesive polymer, for example, PAA within a nonaqueous solvent to form organogels. By the choice of the appropriate solvent, gelation of the polymer will occur by secondary bond formation. Upon contact with mucin, the polymer–solvent bonds will be broken thereby facilitating polymer chain mobility and interaction with mucin. The use of hydrophilic organogels has further advantages for the formulation of topical systems containing water-labile drugs. In the formulation of topical dosage forms, it is accepted that the rheological properties are primary determinants of both the clinical and nonclinical performance, for example, ease of removal from the container, spreadability, and retention on the substrate. Furthermore, following application, the formulations will be exposed to nonshearing stresses as a result of chewing and other oral functions and consequently, knowledge of the transient rheological properties is required to optimize formulation performance. Despite the potential advantages of organogels for topical drug delivery, there have been few studies that have provided a comprehensive examination of the rheological properties of these systems, particularly with respect to properties that will influence their possible in vivo performance. In light of the known (strongly) mucoadhesive properties of PAA, this polymer is an ideal candidate for the formulation of such platforms. Therefore, in this study, the effects of polymer concentration and solvent type on the rheological properties were determined using flow and oscillatory rheometry and creep analysis. An understanding of the chemical interaction between the various solvents and the polymer was performed using FTIR. Furthermore, the mucoadhesive properties of the organogels were examined using the mucin disc method. The information obtained from this study will therefore provide a fundamental understanding of the physicochemical and mucoadhesive properties of the organogels under examination, and will additionally enable the suitability of these systems for use as formulation platform for use in the oral cavity to be assessed. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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EXPERIMENTAL SECTION
and stored at 48C for 1 week prior to further analysis.
Materials
Continuous Shear Analysis of Poly(Acrylic Acid) Organogels
Poly(acrylic acid) (PAA) (Carbopol EDT 2050) was donated by B.F. Goodrich Company (Cleveland, OH). Ethylene glycol (EG), propylene glycol (PG), glycerol, polyethylene glycol 400 (PEG 400), 1, 3-propanediol (1,3-PD), and 1,5-pentanediol were purchased from Lancaster (Morecambe, England). All other chemicals were purchased from BDH Chemicals Ltd. (Gillingham, Dorset, UK) and were of AnalaR, or equivalent, quality.
Continuous shear analysis of each organogel was performed using a Carri-Med CSL2 100 rheometer (T.A. Instruments, Surrey, England) in flow mode at 20 0.18C with a 2 cm stainless steel parallel plate geometry and plate gap of 1 mm. Samples were carefully applied to the lower plate using a spatula to ensure that formulation shearing was minimized and allowed to equilibrate for at least 1 h prior to analysis. Rheograms were produced using the loop test, whereby the shearing stress was increased gradually from a minimum up to a predetermined maximum within 60 s, and then returned to the starting point under the same conditions.4,16 In all cases at least five replicate measurements were performed. The shearing stresses were selected according to formulation consistency as shown in Table 1.16 Upward flow curves were modeled using the Cross model20 (Eq. 1), the Power law (Oswald-de-Waele) model21 (Eq. 2), and the Sisko model22 (Eq. 3) from which theoretical zero shear viscosities or consistencies were derived. 0 ¼ ðk_ Þm ð1Þ 1
Methods Manufacture of Poly(Acrylic Acid) Organogels Poly(acrylic acid) (PAA) organogels were prepared by the addition of Carbopol EDT 2050 (3%, 5%, or 10% w/w) to the vortex produced by the rapid stirring (at 2000 rev/min) of the appropriate organic solvent, namely EG, PG, PEG 400, 1,3-PD, or 1,5-propanediol (1,5-PD) using a Heidolph mechanical stirrer. Formulations were stored at 48C for 24 h to allow for complete polymer solvation. All samples were then transferred into amber ointment jars, placed in a vacuum to remove incorporated air, and then stored at 48C for 1 week prior to further analysis.
where Z is the viscosity, Z0 is the zero rate viscosity, Z1 is the infinite shear viscosity, k is the consistency index, g_ is the shear rate, and m is the slope of the curve at the inflection point.
Formulation of Aqueous PAA Gels Aqueous PAA gels were prepared by the addition of Carbopol EDT 2050 (3%, 5%, or 10% w/w) to the vortex produced by stirring (at 2000 rev/min) the required amount of de-ionized water using a Heidolph mechanical stirrer. The resulting polymer solution was then neutralized using sodium hydroxide (30% w/v) to produce a clear gel. All samples were centrifuged to remove entrapped air
¼ k_ n
ð2Þ
where s is the shearing stress, g_ is the rate of shear, k is the consistency index and n is the power law index. ¼ 1 þ k_ n1
ð3Þ
Table 1. Shearing Stresses Employed in Controlled Stress Rheometry
Solvent Ethylene glycol Propylene glycol Glycerol PEG 1,3-Propanediol 1,5-Pentanediol Water
3% w/w PAA Shear Stress (Pa)
5% w/w PAA Shear Stress (Pa)
10% w/w PAA Shear Stress (Pa)
200–1500 200–1500 3000–6000 500–2000 300–600 300–600 100–200
1000–2000 2000–4500 3000–6000 2000–4000 700–1000 700–1000 200–300
4000–6000 4500–6300 3000–6000 4000–6000 5000–6000 5000–6000 500–600
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where Z is the viscosity, g_ is the rate of shear, k is the consistency and Z1 is the infinite shear viscosity. Oscillatory Rheometry of Poly(Acrylic Acid) Organogels Oscillatory rheometry was performed using a Carri-med CSL2-100 rheometer with a 4 cm stainless steel parallel plate geometry (1 mm plate separation) at 20 0.18C. Samples were removed from their storage container, applied to the lower plate of the rheometer, and allowed to equilibrate (>1 h). Initially, the linear viscoelastic region was determined by torque sweep from 0.1 to 100 Pa at frequencies of 0.01 and 1.0 Hz and was identified as the region where stress was directly proportional to strain, and the storage modulus (G0 ) remained constant, as previously described by the authors.4,23 Oscillatory measurements were performed over a frequency range of 0.01–1.0 Hz (at constant strain 0.006). Calculation of the storage modulus (G0 ), loss modulus (G00 ), loss tangent (tan d), and dynamic viscosity (Z0 ) were performed using proprietary software (TA Instruments, Leatherhead, UK). For all formulations, five replicate analyses were performed. Creep (Transient) Analysis of Poly(Acrylic Acid) Organogels Creep analyses were performed using a CarriMed CSL2 100 rheometer (T.A. Instruments) at 20.0 0.18C in creep mode using a stainless steel parallel plate geometry (4 cm plate diameter) with a plate gap of 1 mm. Stresses were selected from within the linear viscoelastic region. Samples were carefully applied to the rheometer and allowed to rheologically equilibrate for 60 min. The selected stress was applied and maintained for a period of 50 min during which time the compliance was measured. The stress was removed and the sample recovery was recorded for an additional 30 min. This relaxation period was selected to ensure that the terminal portion of the creep curve was linear, thereby ensuring that full extension of the viscoelastic elements had occurred.4,24,25 For each formulation, the relationship between compliance 1/G and time was mathematically modeled using the Burgers model22,26 using proprietary software (TA Instruments). As before, at least five replicate analyses were performed for each formulation. DOI 10.1002/jps
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Fourier Transform Infra-Red Spectroscopy Studies Fourier transform infra-red spectra of PAA powder of 1% w/w dispersions in glycerol, EG, PEG 400, PG, 1,3-PD, 1,5-pentanediol, and deionized water (neutralized) were recorded using a FTIR Nicolet Prote´ge´ 460 Spectrophotometer ESP at 208C over a wavelength range from 500 to 3900 cm1. In Vitro Mucoadhesive Properties of PAA Organogels and Aqueous Gels Mucoadhesion between PAA-based formulations and porcine mucin was determined using a TAXT2 Texture Analyser in adhesion mode, as previously reported.8 Mucin (250 mg) was pressed into discs (diameter 13 mm) using a Carver press under a pressure of 10 tonnes for 60 s. The mucin disc was attached to the cylindrical end of a polycarbonate probe (10 mm diameter) using double-sided adhesive tape. The mucin disc was then wetted for approximately 10 s using a 5% w/w mucin solution with excess solution being removed by blotting. The disc was then brought to the surface of the formulation (contained within a three-sided mould) and upon contact, a downward force of 0.1 N applied. After 30 s, the probe was removed at a speed of 10 mm/s and from the resulting force–time plot, a peak was observed corresponding to the force required to break the mucoadhesive bond.8
Statistical Analysis The effects of concentration of PAA and solvent type (EG, PG, PEG 400, 1,3-PD, 1,5-PD) on the viscoelastic properties (initial compliance J0, residual viscosity Z0, G0 , G00 , Z0 , and tan d) at five representative frequencies (0.06, 0.27, 0.53, 0.74, 1.0 Hz), consistency, and the mucoadhesive bond strength were statistically evaluated using a two-way Analysis of Variance (ANOVA). Evaluation of the validity of the different flow models (power law model, Cross model, and the Sisko model) was performed by regression analysis. Comparison of the correlation coefficients associated with each model was performed using a one-way ANOVA. Post hoc comparisons of the means of individual groups were performed using Tukey’s test.27 In all cases, p 0.05 denoted significance and, accordingly, individual significance values are not included in the main body of the text. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
Figure 1. The effects of solvent type and concentration of poly(acrylic acid) (PAA) on the storage modulus (closed symbols) and loss modulus (open symbols) of PAA organogels. In this, circles, squares, and diamonds refer to gels containing 3%, 5%, and 10% w/w PAA, respectively. The solvent systems investigated were ethylene glycol (EG) (a), propylene glycol (PG) (b), polyethylene glycol (c), glycerol (d), 1,3 propanediol (e), and 1,5 pentanediol (f). Standard deviations have been omitted for clarity, however, in all cases, the coefficient of variation was less than 6%. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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RESULTS The effects of oscillatory frequency, polymer concentration, and solvent type on the storage and loss moduli of PAA organogels are displayed in Figure 1a–f. Furthermore, a summary of the viscoelastic properties of the various PAA organogels at a representative oscillatory frequency (1 Hz) is presented in Table 2. For each formulation the G0 , G00 , and tan d gradually increased with increasing oscillatory frequency. However, within the frequency range under examination, a plateau was observed for all three parameters. The dynamic viscosity (Z0 ) of all formulations decreased and formulation G0 was significantly greater than G00 over the frequency range examined. In all formulations (and independent of solvent type), increasing the concentration of PAA significantly increased the storage and loss moduli and dynamic viscosity. In each solvent system, the effect of polymer concentration on the loss tangent was dependent on solvent type and accounted for one of the statistical interactions in the ANOVA. Specifically, increasing the concentration of polymer significantly
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lowered tan d for gels containing glycerol or 1, 5-PD but not for the other organogel systems. The choice of solvent significantly affected the viscoelastic properties of the organogels at each concentration of PAA. Interestingly, the greatest values of storage modulus, loss modulus, and dynamic viscosity were associated with the glycerol-based organogels containing 10% w/w polymer (3581.0 5.6 Pa, 1388.0 10.5 Pa, and 220.7 1.7 Pa s, respectively, at 1 Hz), whereas the greatest tan d value (at 1 Hz) was associated with the 3% w/w PAA glycerol-based organogels (0.56 0.02). No consistent order was observed concerning the effects of solvents on the viscoelastic properties (G0 , G00 , tan d, and Z0 ), however, in all cases, PEG 400 was second in effect to glycerol and, in general, EG- and PGbased formulations exhibited similar properties. Conversely, 1,5-PD had least effect on the oscillatory rheological properties. Significant differences were observed between the viscoelastic properties of the various organogels and their water-based comparator gels. For example, the storage modulus of all organogels (containing 10% w/w polymer), with the exception of the
Table 2. The Effect of Polymer Concentration and Solvent Type on the Viscoelastic (Dynamic) Properties of Poly(Acrylic Acid) (PAA) Organogels (at a Representative Frequency of 1 Hz) PAA (% w/w)
Solvent
G0 (Pa)
G00 (Pa)
tan d
Z0 (Pa s)
3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10
EG EG EG PG PG PG PEG PEG PEG GLY GLY GLY 1,3-PD 1,3-PD 1,3-PD 1,5-PD 1,5-PD 1,5-PD Watera Watera Watera
144.4 1.4 318.3 15.7 890.2 43.9 109.5 2.4 322.3 2.7 880.4 23.6 179.5 5.0 307.8 2.5 1426.0 32.2 339.9 1.8 985.7 31.6 3581.0 5.6 185.4 2.8 368.1 11.7 878.1 25.1 73.6 2.5 175.6 10.0 493.1 16.6 79.5 2.5 264.0 5.1 841.3 10.2
33.0 0.7 57.2 3.8 208.3 12.5 37.7 0.4 93.8 0.9 297.2 7.5 79.4 1.2 135.2 1.6 644.5 12.1 191.8 1.9 411.2 17.9 1388.0 10.5 45.2 0.7 74.3 8.7 221.6 8.7 35.2 0.5 63.0 2.8 175.4 9.4 11.1 0.5 39.5 2.1 124.0 0.8
0.23 0.02 0.18 0.02 0.23 0.02 0.34 0.01 0.29 0.02 0.34 0.01 0.44 0.01 0.44 0.00 0.45 0.01 0.56 0.02 0.47 0.01 0.39 0.00 0.24 0.01 0.21 0.02 0.25 0.02 0.48 0.01 0.36 0.01 0.36 0.01 0.14 0.01 0.15 0.01 0.15 0.01
8.3 0.1 13.1 0.6 33.1 2.0 10.0 0.1 17.8 0.2 47.3 1.9 12.6 0.2 21.5 0.3 102.5 1.9 30.5 0.3 65.4 2.8 220.7 1.7 7.2 0.1 11.8 0.3 35.2 1.4 5.6 0.1 10.0 0.4 27.9 0.5 1.8 0.1 7.9 0.3 19.7 0.1
EG, PG, PEG, Gly, 1,3-PD, and 1,5-PD refer to ethylene glycol, propylene glycol, glycerol, 1,3 propanediol, and 1,5-propanediol, respectively. a Neutralized using sodium hydroxide. DOI 10.1002/jps
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gels composed of 1, 5-PD, was significantly greater than the G0 of the comparator aqueous gel. Similarly, the loss modulus, dynamic viscosity, and loss tangent of all organogels (containing 10% polymer) were significantly greater than those of the comparator aqueous gel. It should be noted that the relationships depicted above concerning the results at 1 Hz were identical at the other four frequencies, as determined using the ANOVA. The creep and recovery curves of examples of the various formulations are presented in Figure 2a–d.
In all cases, three regions may be identified in both the creep and recovery curves, namely the elastic, viscoelastic, and flow regions. The magnitudes of each of these were dependent on the concentration of polymer and solvent employed in the organogels. Mathematical modeling of the creep compliance curves was performed using nonlinear regression analysis based on the Voigt– Kelvin model. Based on this, the most appropriate model to describe the organogels under examination was a Burgers model composed of two-unit Voigt–Kelvin model with a residual spring and a
Figure 2. The effects of solvent type and concentration of PAA on the creep compliance of PAA organogels. The solvent systems investigated were 1,3 propanediol (a), PG (b), polyethylene glycol (c), and glycerol (d), respectively. Standard deviations have been omitted for clarity, however, in all cases, the coefficient of variation was less than 7%. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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expressed in Table 3. As may be observed, increasing the concentration of PAA significantly decreased the initial compliance and increased the residual viscosity. In addition, the nature of the solvent employed in the manufacture of the organogels directly affected these viscoelastic parameters. Gels formulated using glycerol (at each polymer concentration) exhibited the lowest initial compliance and the largest residual viscosity. Conversely, the largest compliance and lowest residual viscosity were demonstrated by organogels based on 1,5-pentanediol, whereas the effects of PG and EG on these properties were generally similar. For example, the initial compliance and residual viscosity of gels containing 10% w/w PAA and glycerol were 0.51 0.04 N2/m and 4.96 0.76 106 Pa s, respectively, whereas the initial compliance and residual viscosity of 3% w/w PAA gels prepared using 1,5-pentanediol were 11.30 0.09 N2/m and 0.18 0.01 106 Pa s, respectively. Interestingly, the initial compliance and residual viscosity of all organogels, with the exception of those prepared using 1,5-pentanediol, were significantly lower and higher, respectively, than those of aqueous PAA gels. This illustrates the superior elastic nature of the organogels in comparison to the comparator aqueous system.
Figure 3. Mechanical model (Burgers model composed of a residual spring, a residual dashpot, and two Voigt–Kelvin units) used to describe the viscoelastic behavior of the organogel formulations.
residual dashpot, as depicted in Figure 3. Mathematically, the creep response of the materials was defined by: t t gðtÞ 1 1 ¼ JðtÞ ¼ þ 1 e 2 þ G1 G2 where g is the strain, s is the stress, J is the compliance, G is the modulus, t is the retardation time, t is time, Z is the viscosity. The use of the above model enabled the calculation of the initial compliance 1/G and the residual viscosity (Z), derived from the t/Z expression within the Burgers model, the results from which are
Table 3. The Effect of Polymer Concentration and Solvent Type on the Viscoelastic (Transient) and Flow Properties of Poly(Acrylic Acid) (PAA) Organogels
PAA (%w/w)
Solvent
Creep Compliance (m2/N)
Residual Viscosity (Pa s 106)
Consistency (Pa s)n
3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10 3 5 10
EG EG EG PG PG PG PEG PEG PEG GLY GLY GLY 1,3-PD 1,3-PD 1,3-PD 1,5-PD 1,5-PD 1,5-PD Watera Watera Watera
9.93 0.01 2.92 0.30 1.49 0.24 9.71 0.29 4.13 0.11 1.78 0.07 5.41 0.41 2.92 0.33 0.89 0.04 2.80 0.13 1.93 0.03 0.51 0.04 7.74 0.38 3.05 0.13 1.56 0.02 11.30 0.09 5.87 0.67 2.58 0.04 16.10 2.94 3.62 0.08 2.61 0.10
0.51 0.03 1.21 0.01 1.47 0.07 0.50 0.01 1.15 0.08 1.68 0.18 1.03 0.08 2.12 0.23 3.04 0.06 1.67 0.13 2.98 0.06 4.96 0.76 0.79 0.05 1.28 0.04 2.34 0.07 0.18 0.01 0.36 0.04 0.62 0.01 0.39 0.02 1.02 0.03 1.30 0.06
62.7 4.8 260.2 14.9 1264.0 40.3 113.1 3.5 656.0 37.7 1417.0 214.3 190.4 30.6 819.2 19.6 2142.3 351.6 398.4 27.7 1473.3 71.5 4528.3 127.1 68.8 10.4 352.6 23.0 1158.0 72.5 26.2 1.4 92.3 3.5 755.2 35.0 28.8 1.4 225.6 1.9 535.8 6.0
a
Neutralised gels.
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The flow properties of selected organogels are presented in Figure 4. As may be observed all organogels exhibited thixotropy, the nature and magnitude of which were independent of the nature of the solvent employed in the manufacture. To describe the flow rheological behavior of the various aqueous and nonaqueous gels, the flow properties were mathematically modeled using the power, Cross, and Sisko models. Significant differences in the correlation coefficients and residuals of these were observed, with the power model providing the most statistically acceptable model. Therefore, using this model, the consistencies of the various formulations were determined and statistically compared (Tab. 3). Increasing the concentration of polymer was observed to significantly increase the consistency of each system, independent of the nature of the solvent. Moreover, organogels prepared using glycerol exhibited the greatest consistency whereas those composed of 1,5-pentanediol displayed the lowest consistency. For example, the consistency of the organogel prepared using glycerol and containing 10% w/w polymer was 4528.3 127.1 (Pa s)n, whereas the lowest observed consistency was associated with the organogels containing 3% w/w PAA and 1, 5-pentanediol (26.2 1.4 (Pa s)n). In addition, while lower than those for glycerol, the organogels composed of PEG 400 exhibited notably large consistencies. Interestingly, with the general exception of organogels prepared using 1,5pentanediol, the consistency of the organogels was greater than that of comparator aqueous gels of PAA. Of particular interest in the statistical analysis of data were the observed interactions between polymer concentration and solvent type with respect to the various rheological parameters under investigation (G0 , G00 , tan d, Z0 , J0, Z0, k). In these, deviations from the generalized linear model were due to the disproportionate effect of glycerol (primarily) and, secondarily, polyethylene glycol on the rheological parameters.
Figure 4. Rheograms depicting the effects of solvent type and concentration of PAA on the flow properties of PAA organogels. In this, squares, diamonds, and circles, refer to gels containing 3%, 5%, and 10% w/w PAA. The solvent systems investigated were EG (a), PG (b), polyethylene glycol (c), and glycerol (d), respectively. Standard deviations have been omitted for clarity, however, in all cases, the coefficient of variation was less than 6%. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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Table 4. Carbonyl Stretches Obtained From IR Spectral of the Various Poly(Acrylic Acid) Organogels
the force of detachment of the gels containing 3% w/w PAA was below the limit of detection of the method.
Carbonyl Stretch (per cm)
Solvent Poly(acrylic acid) powder Propylene glycol Ethylene glycol PEG 400 Glycerol 13 Propanediol 15 Pentanediol De-ionized water (neutralized)
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DISCUSSION
1716 1655 1653 1647 1652 1660 1667 1635
The majority of formulations designed for application to the oral cavity have been aqueous based, however, an interest has emerged in the use of nonaqueous formulations for improved drug delivery. Nonaqueous PAA-based mucoadhesive delivery systems have been reported to offer enhanced bioavailability over aqueous-based formulations for the nasal delivery of propanolol hydrochloride.28 The same authors described the effect of nonaqueous solvents on the viscoelastic properties of neutralized PAA gels and concluded that mixed solvent systems offered enhanced retention times.29 It is accepted that the rheological properties of gel/semi-solid dosage forms designed for application to the oral cavity directly affect the clinical and nonclinical performance of these systems4 and accordingly, in the design of formulations designed for application to the oral cavity, a comprehensive characterization of the rheological properties is required. The stresses encountered by topical dosage forms are varied. Typically, administration into the oral cavity, for example, into the periodontal pocket or onto the inflamed gingival, requires the application of shearing stresses that will deform the product to facilitate removal from the container and spreading onto the substrate. Furthermore, excessive thixotropy may impede the retention of the dosage form at the site of application due to the compromised rheological properties. Following recovery after deformation, the dosage form will be exposed to nondeformable stresses that are oscillatory, compressive, and tensional in nature
The carbonyl shifts in the infrared spectra obtained from each organogel under investigation are presented in Table 4. The IR spectra of unsolvated (powdered) PAA exhibited a carbonylstretching absorption at circa 1716 cm1. Conversely, upon solvation with each nonaqueous solvent, the stretching absorption of the carbonyl shifted to approximately 1650 cm1, which was different from that for neutralized PAA gels. Finally, the mucoadhesive properties of the various PAA gels (both aqueous and nonaqueous) are presented in Table 5. As may be observed, increasing the concentration of PAA sequentially increased the force required to detach the formulations from the mucin disc. Furthermore, significant differences were observed in the mucoadhesive properties of PAA when formulated in the various solvent systems. The greatest mucoadhesive properties, 0.42 0.02 N, were associated with glycerol-based organogels containing 10% w/w polymer. Importantly, the lowest force of detachment (and hence mucoadhesion) was observed for aqueous PAA gels. In all solvents, with the exception of the glycerol-based systems,
Table 5. Effect of Polymer Concentration and Solvent Type on the Mucoadhesive Bond Strength of PAA-Based Gel Formulations Force of Detachment of Formulations Containing (N) Solvent Propylene glycol PEG 400 Glycerol Ethylene glycol 1,3 Propanediol 1,5 Pentanediol Water (neutralized)
DOI 10.1002/jps
3% w/w PAA
5% w/w PAA
10% w/w PAA
Not measurable Not measurable 0.17 0.02 Not measurable Not measurable Not measurable Not measurable
0.13 0.01 0.19 0.02 0.26 0.01 0.13 0.00 0.14 0.01 0.11 0.00 0.09 0.00
0.29 0.04 0.34 0.02 0.42 0.02 0.23 0.02 0.28 0.03 0.18 0.03 0.19 0.02
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due to, for example, mastication, respiration, and musculature movement. In light of this diversity, it is essential that the viscoelastic properties of the formulations be characterized using methods that employ oscillatory and transient stresses, which are representative of the oral cavity. Typically, the viscoelastic properties of gel/semisolid formulations have been reported to affect the resultant performance, for example, mucoadhesion,30 drug release,8 and mucocilliary transport.31 Therefore, this study describes a comprehensive rheological analysis of novel polymeric organogels that are designed as platforms for drug delivery systems for local use in the oral cavity. The information generated in this study will enable the suitability of these formulation platforms to be discerned and will allow suitable candidate systems to be identified. In oscillatory analysis, the viscoelastic properties (G0 , G00 , tan d, and Z0 ) of the organogels were shown to be dependent on oscillatory frequency. In all cases, the formulation storage modulus (G0 ) and loss modulus (G00 ) increased with increasing oscillatory frequency. The magnitude of the storage modulus was significantly greater than the loss modulus for each organogels (and aqueous gel) and hence, the loss tangent was less than unity over the entire frequency range. This indicated the predominance of the elastic character and the existence of the gel state.4,23,32 The relationship between G0 , G00 , and oscillatory frequency was characteristic of the Maxwell model of viscoelasticity.33 In particular, the frequency dependency of the moduli of the organogels under investigation is indicative of physically entangled systems.4,23 Within the range of oscillatory frequencies examined, the organogels existed initially in the plateau region of viscoelasticity (at lower frequencies) and within the terminal portion of this region at high frequencies. This phenomenon has not been reported for aqueous polymeric gels, including PAA, and is therefore a unique feature of these organogels. Further evidence of the viscoelastic properties of the formulations under examination over a long time period was provided by creep analysis. Three regions may be identified in the relationship between the compliance and time of each formulation, namely the instantaneous elastic region, the region of viscous flow, and the region denoting retarded elasticity (viscoelasticity).4,24 Modeling of the creep response was satisfied using a two-unit Burgers model, from which the instantaneous elastic compliance and residual viscosity JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
were determined. The instantaneous elastic compliance of all formulations was recovered upon removal of the applied stress and may be attributed to the elastic stretching of molecular bonds. The Kelvin–Voigt units describe the retarded elastic behavior and may be accredited to the breaking and reforming of secondary bonds (which occur at different rates) thereby resulting in a spectrum of retardation times.4,24 After sufficient time at constant stress, the Voigt units will fully extend and any further deformation will result in a linear increase in compliance, which is attributed to the extension of the residual dashpot as a result of polymer chain disentanglements. The creep curves obtained from PAA–solvent systems approximated to elastic solids with a relatively restricted viscoelastic region and high residual viscosities. The concentration of polymer significantly affected the viscoelastic properties of the various organogels, as determined using both creep analysis and oscillatory rheology. Typically increasing PAA concentration increased G0 , G00 , Z0 , and Zo and decreased elastic compliance (J). This is indicative of an increase in the strength of the viscoelastic structure, due to increased (physical) polymer chain entanglements thereby resulting in an increased resistance to macromolecular reorganization.4 Importantly, this study has uniquely described both the greater range of viscoelastic (dynamic and transient) properties that may be achieved by formulation of PAA as organogels and, additionally, the effect of the choice of solvent on the resultant rheological properties. The mechanism of organogel formation may be attributed to polymer chain expansion resulting from the intermolecular interactions between the polymer and organic solvent used. Molecules of the solvents under examination readily form associates with each other and with other molecules via hydrogen bonds.34 Following consideration of the structures of both PAA and the various solvents and the FTIR spectra, the dominant interaction associated with organogel formation was primarily hydrogen bonding between the carboxyl groups of the polymer and the hydroxy/ethoxy groups of the solvents, although electrostatic, van der Waals, and hydrophobic interactions may also contribute.35 Similarly, Mathur et al.36 described the interactions of poly(methacrylic) acid and polyethylene glycol in this manner. The wavelengths of the carbonyl stretch of the various organogels systems were similar, indicating a similar mechanism of interaction with the polymer. HowDOI 10.1002/jps
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ever, the difference in the carbonyl stretch of the neutralized aqueous system highlighted differences in the mechanism of polymer–solvent interaction. In contrast to comparator organogels, the gelation of PAA in an aqueous solvent is facilitated by neutralization and repulsion of adjacent, ionized carboxylic acid moieties.37,38 Interestingly, as the initial compliance refers to the elastic stretching of bonds, the lower values of initial compliance associated with the various organogels indicate that the intermolecular bond strength of these systems was greater than for their aqueous counterparts. This phenomenon was confirmed by the higher storage modulus of organogel systems. The solvents employed to prepare the organogels were chosen on the basis of their general pharmaceutical acceptability and their related structural properties, the latter facilitating an examination of solvent structure on the rheological properties of organogels. Typically, the viscoelastic properties of organogels formulated using the EG, PG, and 1,3-PD were similar, indicating the similar effect of these solvents on the rheological properties. Therefore, it may be suggested that diols in which the hydroxyl groups are either adjacent or separated by one methylene group may similarly interact with adjacent carboxylic acid groups on each chain of PAA. In so doing expansion of the polymer chains occurs thereby increasing the elastic nature of the gels. Organogels formulated using 1,5-PD exhibited lower viscoelastic properties, which, in light of the above, may be explained by the inability of the hydroxyl groups to adequately interact with adjacent carboxylic acid groups on the polymer due to stearic effects. PEG is a dihydroxy-terminated polyether capable of forming hydrogen bonds both through the hydroxyl groups and the ethereal oxygen atoms. The two terminal hydroxyl groups are separated by approximately 400 ethoxy groups and, particularly in light of the observations concerning the interaction of 1,5-PD with PAA, the stearic limitations would dramatically restrict the interaction of the terminal hydroxyl groups of PEG with adjacent carboxylic acid groups on PAA. The viscoelastic properties of PEG-based organogels were greater than those prepared using other diol solvents and, accordingly, the expansion of polymer chains in the former system was greater. This may be explained, at least in part, by the ability of PEG to interact with adjacent carboxylic acid groups of PAA via a terminal hydroxyl group and an ethoxy group or by DOI 10.1002/jps
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two ethoxy groups.39 Furthermore, the polymeric nature of PEG enables these interactions to simultaneously occur between carboxylic acid groups within adjacent polymer chains, thereby further increasing rheological structuring. The solvent associated with the greatest rheological structuring of PAA was glycerol. In contrast to the other solvents under examination, glycerol is a triol and therefore is theoretically capable of a greater number of interactions with the carboxylic acid moiety of PAA than the low molecular weight diols (EG, PG, 1,3-PD, and 1,5-PD). This would allow glycerol to interact with both adjacent carboxylic acid moieties on a single polymer chain but also simultaneously those on adjacent polymer chains. In so doing, a three-dimensional network may be facilitated, resulting in greater expansion of the polymer structure and hence greater enhancement of the viscoelastic properties of these organogels. With the exception of systems prepared using 1,5-PD, the viscoelastic properties of the organogels were greater than their aqueous counterparts, indicative of greater rheological structuring. The expansion of adjacent polymer chains in aqueous PAA gels is due to electrostatic repulsion. The greater viscoelastic properties of the organogels may be attributed to both the greater expansion of adjacent carboxylic acid groups and the ability of certain solvents to interact with the carboxylic acid groups on adjacent PAA chains (notably glycerol and PEG). It should be noted that, unlike aqueous PAA gels, the organogels described in this study would be expected to be stable in the presence of ionic species, for example, drug molecules. Following exposure to larger stress the organogels exhibited pseudoplastic flow with limited thixotropy. Modeling of the flow properties of the various organogels was performed using the Cross model and two subsets of this model, namely the Power and Sisko models. Based on regression analysis, the Power law model provided the largest coefficient of determination values and accordingly, a log–log relationship between viscosity and shear rate was observed with the range of shearing stresses under examination. In these formulations, increasing shearing stresses resulted in the disentanglement of adjacent polymer chains via bond breaking and subsequent alignment in the direction of imposed shear, which in turn leads to shear thinning behavior.4,16 Similarly, oscillatory analysis revealed a significant decrease in formulation dynamic viscosity with increasing oscillatory frequency which is an indication of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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shear thinning rheological behavior.40 Increasing the PAA concentration within PAA–solvent systems produced a marked increase in formulation consistency, which is due to enhanced entanglement of adjacent polymer chains.4 The observable differences in the consistencies of PAA organogels that had been formulated with the various solvent systems were consistent with the observed differences in the viscoelastic properties. Of particular relevance in this respect was the correlation between the dynamic viscosity (Z0 ) and consistency. The lack of continuity of the relationships between Z0 and frequency (from oscillatory analysis) and between viscosity and shear rate (from flow rheometry) when modeled using the Cox–Merz law provided further evidence of the gel state of the organogels.1 The effects of the different solvents on the flow properties may be attributed to their varied abilities to interact with PAA and hence to facilitate polymer chain expansion (as described above). It is accepted that the retention of products within the oral cavity may be improved by the use of mucoadhesive formulations. In this study, PAA, a polymer with known mucoadhesive properties,41 was formulated within nonaqueous solvent systems and its mucoadhesive properties were characterized. The method used involved the determination of the force of detachment of the formulation from a surface-hydrated mucin disc, as previously reported by the authors.8,42 This study illustrated that alterations in both the concentration of PAA and the nature of the solvent directly influenced the mucoadhesive properties of the organogels. Furthermore, a relationship between formulation elasticity (G0 ) and mucoadhesion was observed, illustrating the importance of the viscoelastic properties (and in particular network structure) on this property. Two important observations should be noted regarding the mucoadhesive properties of the organogels under examination. First, a wide range of mucoadhesive properties were exhibited by the formulations that were affected by changes in polymer concentration and solvent type. Indeed, the organogel formulations that were manufactured using glycerol or PEG 400 were particularly useful in this respect. Second, with the general exception of 1,5-pentanediol (a nonpharmaceutical solvent), the mucoadhesive properties of the organogels were significantly greater than those of comparator aqueous PAA gels. This illustrates the greater mucoadhesive JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
potential of PAA organogels, a hereto-unreported phenomenon. Furthermore, based on previous studies, the mucoadhesive properties of the glycerol and PEG 400-based organogels would be expected to offer good retention within the oral cavity.8 Knowledge of the rheological and mucoadhesive properties of the organogel formulations enables an insight into the potential pharmaceutical utility of these formulations as platforms of drug delivery systems designed for application to the oral cavity. Notably, the shear thinning properties exhibited by the various organogel formulations are advantageous. The formulations will be exposed to high shear rates during application to the oral cavity, resulting in a reduction in apparent viscosity and thereby facilitating successful application. Following recovery, the viscosity will recover to the original (equilibrium) state, which in association with the known mucoadhesive properties of PAA8 will enhance the retention at the site of application. However, of particular interest, are the unique viscoelastic properties of the formulations. It has been reported that the storage modulus is an important contributor to the mucoadhesive properties of topical formulations, typically being associated with increased product retention/mucoadhesion.4,8 Furthermore, the elastic properties of gel formulations have been reported to be important determinants of drug release. Formulations, exhibiting high G0 (and low tan d), will provide greater resistance to both the diffusion of aqueous fluid into the formulation and the subsequent diffusion of the dissolved drug through the gel matrix.8 Therefore, formulations prepared using glycerol (in particular) or PEG will be advantageous in this respect. Formulations that exhibited advantageous elastic properties also possessed higher consistency and dynamic viscosity, which will affect the ease of removal from the container and the ease of application/spreading onto the host substrate. This is particularly relevant for formulations that are designed for delivery into the periodontal pocket using a syringe where the higher consistencies in association with the narrow diameter of the syringeorifice in the syringe may lead to problems in administration. Therefore, in the choice of formulation platform, a compromise may be required between elasticity (high G0 , low tan d) and consistency to produce formulations that may be easily administered to and retention at the required site of administration. DOI 10.1002/jps
RHEOLOGICAL CHARACTERIZATION OF POLY(ACRYLIC ACID) ORGANOGELS
In conclusion, this study has described the formulation and rheological and mucoadhesive characterization of organogels composed of PAA, dispersed within a range of diol and triol solvents. By choice of polymer concentration and, more importantly, solvent type, organogels were prepared that exhibited a wide range of viscoelastic and flow properties, as determined using oscillatory rheometry, creep analysis, and flow rheometry. The combined use of these rheological techniques enabled a unique insight into the structural properties of the organogel systems. It is suggested that the predominantly elastic and mucoadhesive properties of PAA organogels prepared with glycerol (in particular) or PEG may offer promise as platforms of drug delivery to the oral cavity.
REFERENCES 1. Jones DS, Lawlor MS, Woolfson AD. 2002. Examination of the flow rheological and textural properties of polymer gels composed of poly (methylvinylether-co-maleic anhydride) and poly (vinylpyrrolidone): Rheological and mathematical interpretation of textural parameters. J Pharm Sci 91:2090–2101. 2. Jones DS, Lawlor MS, Woolfson AD. 2003. Rheological and mucoadhesive characterization of polymeric systems composed of poly(methylvinyletherco-maleic anhydride) and poly(vinylpyrrolidone), designed as platforms for topical drug delivery. J Pharm Sci 92:995–1007. 3. Jones DS, Woolfson AD, Brown AF. 1998. Viscoelastic properties of bioadhesive chlorhexidine containing semisolids for topical application to the oropharynx. Pharm Res 15:1131–1136. 4. Jones DS, Brown AF, Woolfson AD. 2001. Rheological characterization of bioadhesive, antimicrobial, semisolids designed for the treatment of periodontal diseases: Transient and dynamic viscoelastic and continuous shear analysis. J Pharm Sci 90:1978–1990. 5. Mortazavi SA, Smart JD. 1995. An investigation of some factors influencing the in vitro assessment of mucoadhesion. Int J Pharm 116:223–230. 6. Needleman IG, Martin GP, Smales FC. 1998. Characterisation of bioadhesivenes for periodontal and oral mucosal delivery. J Clin Periodont 25: 74–82. 7. Park H, Robinson JR. 1987. Mechanisms of mucoadhesion of poly(acrylic acid) hydrogels. Pharm Res 4:457–464. 8. Jones DS, Woolfson AD, Brown AF, Coulter WA, McClelland C, Irwin CR. 2000. Design, character-
DOI 10.1002/jps
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
2645
isation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. J Control Release 67:357–368. Jones DS, Irwin CR, Woolfson AD, Djokic J, Adams V. 1999. Physiochemical characterisation and preliminary in vivo efficacy of bioadhesive semisolid formulations containing flurbiproen for the treatment of gingivitis. J Pharm Sci 88:592–598. Irwin CR, McCullough KC, Jones DS. 2003. Chlorhexidine-containing mucoadhesive polymeric compacts designed for use in the oral cavity: An examination of their physical properties, in vitro/ in vivo drug release properties and clinical acceptability. J Mater Sci-Mater Med 14:825–832. Woolfson AD, Malcolm RK, McCarron PA, Jones DS. 2002. Bioadhesive drug delivery systems. In: Dumitriu S, editor. Polymeric biomaterials, 2nd edition. New York: Marcel Dekker. pp 1063– 1083. Mortazavi SA, Smart JD. 1994. An in-vitro method for assessing the duration of mucoadhesion. J Control Release 31:207–212. Anlar S, Capan Y, Guven O, Gogus A, Hincal AA. 1994. Formulation and in vitro-in vivo evaluation of buccoadhesive morphine sulfate tablets. Pharm Res 11:231–236. Witschi C, Mrsny RJ. 1999. In vitro evaluation of microparticles and polymer gels for use as nasal platforms for protien delivery. Pharm Res 16:282– 290. Jones DS, Woolfson AD, Brown AF, O’Neill MJ. 1997c. Mucoadhesion, syringeable drug delivery systems for controlled application of metronidazole to the peridontal pocket: In vitro release kinetics, syringeability, mechanical and mucoadhesive properties. J Control Release 49:71–79. Jones DS, Woolfson AD, Brown AF. 1997. Textural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gels. Pharm Res 14:450–457. Jones DS, Woolfson AD, Djokic J, Coulter WA. 1996. Development and mechanical characterization of bioadhesive semi-solid, polymeric systems containing tetracycline for the treatment of periodontal diseases. Pharm Res 13:1734–1738. Woolfson AD, McCafferty DF, McCarron PA, Price JH. 1995. A bioadhesive patch cervical drug delivery system for the administration of 5-fluorouracil to cervical tissue. J Control Release 35: 49–58. Woolfson AD, Malcolm KR, McCarron PA, Jones DS. 2002. Bioadhesive drug delivery systems. In: Dumitriu S, editor. Polymeric biomaterials, 2nd edition. New York: Marcel Dekker. pp 1063– 1083. Cross MM. 1965. Rheology of non-Newtonian flow: A new flow equation for pseudoplastic systems. J Colloid Sci 20:417–437.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
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JONES ET AL.
21. Dolz M, Herraez M, Gonzalez F, Diez O, Delegido O, Hernandez MJ. 1998. Flow behavior of Carbopol-940 hydrogels. The influence of concentration and agitation time. Pharmazie 53:126–130. 22. Barnes HA. 2000. A handbook of elementary rheology, 6th edition. Aberystwyth: The University of Wales Institute of Non-Newtonian Fluid. pp 55–61. 23. Jones DS, Woolfson D, Brown AF. 1998. Viscoelastic properties of bioadhesive, chlorhexidine- containing semi-solids for topical application to the oropharynx. Pharm Res 15:1131–1136. 24. Barry BW. 1974. Rheology of pharmaceutical and cosmetic semisolids. In: Bean HS, Beckett AH, Carless JE, editors. Advances in pharmaceutical sciences, Vol 4. USA: Academic Press. pp 1–72. 25. Barry BW, Meyer MC. 1979. The rheological properties of carbopol gels 2. Oscillatory properties of carbopol gels. Int J Pharm 2:27–40. 26. Barnes HA, Hutton HA, Walters JF. 1990. An introduction to rheology. New York: Elsevier Scientific Publishers. 27. Jones DS. 2002. Pharmaceutical statistics, 1st edition. London: The Pharmaceutical Press. 28. Chu JS, Chandrasekharan R, Amidon GL, Weiner ND, Goldberg AH. 1991. Viscometric study of polyacrylic acid systems as mucoadhesive sustained-release gels. Pharm Res 8:1408–1412. 29. Chu JS, Yu DM, Amidon GL, Weiner ND, Goldberg AH. 1992. Viscoelastic properties of polyacrylic acid gels in mixed solvents. Pharm Res 9:1659–1663. 30. Jones DS, Woolfson AD, Brown AF. 1997. Textural, viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. Int J Pharm 151:223–233. 31. Lin SY, Amidon GL, Weiner ND, Goldberg AH. 1993. Viscoelasticity of cellulose polymers and mucociliary transport on frog plates. Int J Pharm 95:57–65.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 10, OCTOBER 2007
32. Chirila TV, Hong Y. 1998. Poly(1-vinyl-2-pyrrolidine) hydrogels as vitreous substitiutes: A rheological study. Polymer Int 46:183–195. 33. Ferry JD. 1980. Viscoelastic properties of polymers, 3rd edition. New York: John Wiley & Sons Inc. 34. Shchipunov YA, Shumilina EV. 1996. Lecithin organogels: Role of polar solvent and nature of intermolecular interactions. Colloid J 58:117–125. 35. Nishi S, Kotaka T. 1985. Complex-forming poly(oxyethylene): Poly(acrylic acid) interpenetrating polymer networks. Preparation structure and viscoelastic properties. Macromolecules 18:1519– 1525. 36. Mathur AM, Hammonds KF, Klier J, Scranton AB. 1998. Equilibrium swelling of poly(methacrylic acid-g-ethylene glycol) hydrogels. Effect of swelling medium and synthesis conditions. J Control Release 54:177–184. 37. Barry BW, Meyer MC. 1979a. The rheological properties of carbopol gels i. Int J Pharm 2:1–25. 38. Craig DQM, Tamburic S, Buckton G, Newton JM. 1994. An investigation into the structure and properties of carbopol 934 gels using dielectric spectroscopy and oscillatory rheometry. J Control Release 30:213–223. 39. Bell LC, Peppas AN. 1996. Swelling/syneresis phenomena in gel-forming interpolymer complexes. J Biomater Sci Polym Ed 7:671–683. 40. Eadli M, Esmail MN, Vatistas GH. 2001. Rheological properties of high concentrations of carboxylmethyl cellulose solutions. J Appl Polym Sci 79: 1787–1801. 41. Edsman K, Hagerstrom H. 2005. Pharmaceutical applications of mucoadhesion for the non-oral routes. J Pharm Pharmacol 57:3–22. 42. Jones DS, Woolfson DA, Brown AF. 1997a. Textural viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. Int J Pharm 151:223–233.
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