Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery

Journal of Controlled Release 67 (2000) 395–408 www.elsevier.com / locate / jconrel

Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery A.D. Woolfson*, R.K. Malcolm, K. Campbell, D.S. Jones, J.A. Russell School of Pharmacy, The Queen’ s University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7 BL, UK Received 25 November 1999; accepted 17 February 2000

Abstract In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o / w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis, demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems.  2000 Elsevier Science B.V. All rights reserved. Keywords: Eutectic; Ibuprofen; Methyl nicotinate; Oscillatory rheometry; Texture profile analysis

1. Introduction A eutectic system is a mixture or solution whose ingredients solidify or liquefy simultaneously [1]. A eutectic mixture is therefore that unique composition of two (or more) components that has the lowest crystallisation temperature in the system [2]. In solid dosage delivery systems, formation of eutectic mixtures is often regarded as problematic. However, mixtures of two solid components that are in the *Corresponding author. E-mail address: [email protected] (A.D. Woolfson)

liquid phase at ambient temperature can offer certain advantages in percutaneous drug delivery systems. Percutaneous drug delivery conventionally requires that the drug be presented to the intact skin surface in a lipophilic form in solution in order to penetrate the skin barrier [3]. In addition, the solution drug concentration in the vehicle should be as close to saturation as possible in order to maximise the concentration gradient across the absorption barrier. A solution of a drug in a lipophilic form is typically achieved by including either a water miscible co-solvent or an emulsified oil phase in which the solid drug is first dissolved in an oil or mixture of

0168-3659 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 00 )00230-3

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oils as solvent. However, both of these measures reduce the thermodynamic driving force of the drug in the vehicle and, therefore, hinder drug penetration by providing a competing phase for drug migration. To overcome this, a higher drug concentration in the vehicle is required. In addition, the use of co-solvents such as ethanol may cause adverse local reactions on the skin and epithelia. One method of improving percutaneous absorption is by liquefying (as opposed to dissolving) an otherwise solid drug at skin temperature. Thus, the addition of a second component to a solid lipophilic drug causes a concentration-dependent depression in the freezing (melting) point of the latter. The range of compositions in such a two-component system, where a single liquid phase is present at skin temperature, depends upon the respective melting points of the components. The eutectic composition is that single composition of the components having the lowest melting point. Eutectic mixtures for enhanced percutaneous drug penetration have previously been reported, of which the best example is the development of the topical local anaesthetic formulation EMLA , a 1:1 eutectic mixture (mp. 188C) of the local anaesthetics lidocaine and prilocaine [4]. However, such systems more commonly employ a solid or liquid excipient as the second component in the system. Thus, in a more recent application of the eutectic concept to percutaneous delivery, Stott et al. [5] reported enhanced transdermal penetration of a model drug, ibuprofen, in the presence of a range of terpene-derived penetration enhancers. In this example, enhanced transdermal delivery is based on the reciprocal relationship between transdermal penetration and penetrant melting point [6], i.e. reduced melting point of the penetrant equates to enhanced skin penetration. In effect, the solute:solute interaction for the penetrant species is reduced and the penetrant solute:solvent interaction is enhanced, where the solvent in this case is the lipid content of the skin stratum corneum, the main barrier to percutaneous drug penetration. The enhanced delivery of the active agent in this and similar cases is not a consequence of the delivery system, since the pure eutectic mixture was used, but is due to the interaction of the eutectic mixture with the skin structure. The simultaneous percutaneous delivery of two

drugs that have different but complementary pharmacological activities and that form a single liquid phase at ambient temperature represents a novel application of the eutectic concept. If the homogeneous liquid oil phase is emulsified directly as the disperse phase of an o / w cream (to prevent dilution within the formulation causing precipitation or continuous-phase solubilisation of disperse phase components), the dilution effect of a formulation solvent is avoided and the thermodynamic activity of both drugs is enhanced. A formulation-driven enhancement of percutaneous delivery can be achieved with such a system. In the present study, therefore, skintemperature liquid mixtures of methyl nicotinate (mp. 418C), a topical rubefacient, and ibuprofen (mp. 778C), a topical non-steroidal anti-inflammatory drug, are reported. Both drugs are used in the treatment of soft-tissue inflammation. Data is presented in respect of penetration fluxes for both drugs across a model lipophilic barrier membrane, following their release from an o / w cream vehicle having an internal liquid oil phase comprising only the two active agents. Previous studies [7–12] on percutaneous delivery applications of eutectic systems have focused primarily on their thermal and / or membrane penetration characteristics. In the present study, involving a series of formulated systems, the effects of drug and viscosity enhancer concentration(s), emulsifying agent and disperse phase type on the rheological and mechanical properties are also determined, using oscillatory rheometry and texture profile analysis.

2. Materials and methods

2.1. Materials Natrosol 250 HHX-Pharm (HEC), a high molecular weight pharmaceutical grade of hydroxyethylcellulose, was kindly donated by Aqualon Ltd. (Warrington, UK). Methyl nicotinate BP and ibuprofen EP were supplied by Givaudan-Lavirotte (France) and Laporte Organics (Italy), respectively. Xanthan gum (Keltrol RD) was obtained from Kelco Inc. (Chicago, USA). Arlatone 2121, a blend of sorbitan stearate and sucrose cocoate, was supplied

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by ICI (Spain). Water was reagent grade 1, prepared by a Milli-Q System (Waters, UK).

was used to prepare emulsion formulations for both the rheological and membrane penetration studies.

2.2. Preparation of HEC-only and methyl nicotinate gels

2.5. Preparation of methyl nicotinate /ibuprofen emulsions

HEC-only aqueous gels (2.5, 3.0, 3.5, 4.0, 4.5, 5.0% w / w, as required) were prepared by dissolving the required amount of HEC in 70 g of water under intensive stirring, adjusting to weight, and homogenising for 2 min at |2000 rev. / min (MSB rotary homogeniser). Samples were then transferred to amber ointment jars, placed in a vacuum to remove incorporated air and stored at 48C prior to use (at the required temperature) within 48 h of manufacture. Methyl nicotinate HEC gels (1.0, 2.5, 5.0, 10.0, 20.0% w / w) were similarly prepared and treated by initially dissolving the required amount of methyl nicotinate in 70 g water.

Oil-in-water emulsion formulations containing the emulsifying agent were prepared by adding Arlatone 2121 (4.0 g) to 70 g of water and heating at 808C with moderate stirring until a homogeneous dispersion was formed. Xanthan gum (100 mg) was then added to the heated aqueous dispersion with stirring before cooling to ambient temperature. The 50% w / w methyl nicotinate / ibuprofen mixture was prepared by adding solid methyl nicotinate to an equal weight of ibuprofen in a glass beaker — the mixture formed a pale golden, transparent liquid within 1 min which was then stirred to ensure visual homogeneity. (Such mixtures are, of course, heterogeneous on the microscopic scale.) This mixture was then added in varying proportions (2.0, 5.0, 10.0, 20.0% w / w, as required) to the cooled aqueous dispersion under intensive stirring, followed by the gradual addition of HEC (2.5, 3.0, 3.5, 4.0, 4.5, 5.0% w / w, as required). The emulsion was then diluted to 100 g with water and homogenised for 2 min. Emulsion formulations without Arlatone 2121 were prepared in a similar manner. All formulations were prepared 24 h prior to analysis, sealed in air-tight containers and stored at 48C.

2.3. Preparation of ibuprofen suspensions Ibuprofen suspensions (1.0, 2.5, 5.0, 10.0, 20.0% w / w, as required) were prepared by addition of the required amount of ibuprofen to 70 g of water. The resulting aqueous suspension was homogenised to break down aggregates before HEC (2.5, 3.0, 3.5, 4.0, 4.5, 5.0% w / w, as required) was gradually added to produce a semi-solid material. The suspension was then adjusted to weight, homogenised for 2 min and treated / stored as for gel samples.

2.6. Oscillatory rheology 2.4. Determination of liquid range Mixtures (2.0 g) of ibuprofen and methyl nicotinate were prepared at 10% w / w intervals across the composition range. The samples were intimately mixed (5 min) in a glass vial with a stainless steel spatula and left to equilibrate at ambient temperature for 24 h. On visual examination at ambient temperature only a single liquid phase was observed for the 50, 60, 70 and 80% methyl nicotinate samples. By contrast, mixtures containing 20, 30, 40 and 90% of methyl nicotinate consisted of a solid and a liquid phase (in varying proportions), while both pure materials remained solid. The 50% liquid mixture

Oscillatory shear experiments in the frequency ramp mode were performed on a Carri-Med CSL 2 100 rheometer using a 6.0-mm-diameter stainless steel parallel plate geometry. The technique measures the induced response (strain) when a sinusoidal stress is applied to the sample. After determination of the linear viscoelastic region, the semisolid formulations were investigated over the 10 to 1000 mHz frequency range at constant temperature (2060.18C), constant displacement (0.01 rads) and employing a gap size of 1.00 mm. Twenty data points were recorded for each rheogram; five replicates were performed for each formulation.

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2.7. Texture profile analysis The compressibility of the pharmaceutical gels was investigated using a Texture Analyser (Model TA-XT2, Stable Micro Systems) in the texture profile analysis (TPA) mode, as reported previously [13,14]. An aluminium analytical probe (diameter 35.0 mm) was twice compressed into each gel at a rate of 10 mm s 21 and to a depth of 3.0 mm, allowing a 15 s delay between consecutive compressions. Five replicates were performed at ambient temperature for each formulation. The compressibility parameter, as measured by the work of compres-

sion, was determined from the area under the curve of the first compression cycle.

2.8. In vitro drug penetration studies through a model barrier membrane The penetration characteristics of the active component(s) of the various systems were determined using a model hydrophobic barrier membrane, polydimethylsiloxane sheeting (SilescolE, thickness 0.15 mm). Penetration experiments were performed using modified Franz diffusion cells, FDC-400, flat flange, 15 mm orifice diameter, mounted in triplicate on an

Fig. 1. The effect of oscillatory frequency and hydroxyethylcellulose concentration on the storage modulus, G9 (A), loss modulus, G0 (B), tan d (C) and dynamic viscosity, h 9 (D) of HEC-only gels. Key: 2.5% w / w HEC (open diamond), 3.0% w / w HEC (open circle), 3.5% w / w HEC (open square), 4.0% w / w HEC (crossed diamond), 4.5% w / w HEC (crossed circle), 5.0% w / w HEC (crossed square). Each datum point represents the mean (6S.D.) of five replicates.

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FDCD-3 diffusion cell drive console providing synchronous stirring at 600 rev. / min (Crown Glass Co., Somerville, NJ.). Temperature maintenance was via water circulation at 328C (from Techne TE-8J circulating water bath) through diffusion cell water jackets. The cell contained 12 ml of phosphate buffered saline, pH 7.4, as the receiving fluid. The test composition (1 g) was applied evenly across the surface of the barrier membrane at the start of the experiment. The receiving fluid in the reservoir was completely replaced with fresh fluid at 15-min intervals from the start of the experiment, thus ensuring sink conditions throughout, with the concentration of the active pharmacological agent in each sample being determined by reverse-phase high performance liquid chromatography (HPLC system:

399

Shimadzu LC-10A; column: Beckmann 5 mm ODS 4.63150 mm; mobile phase: acetonitrile–water 50:50; flow rate: 1.0 ml min 21 ; detection: 220 nm; retention times: methyl nicotinate 3.4 and ibuprofen 9.1 min; linearity: r.0.99 for both analytes between 0 and 150 mg ml 21 ). Thus, the steady-state penetration flux, expressed as mg cm 22 h 21 , appearing in the receiving fluid was determined for each system from the slope of the drug concentration versus time plot via regression analysis of the linear membrane penetration profile.

2.9. Statistical analysis The

effects

of

concentrations

of

hydroxy-

Fig. 2. The effect of oscillatory frequency and methyl nicotinate (MN) concentration on the storage modulus, G9 (A), loss modulus, G0 (B), tan d (C) and dynamic viscosity, h 9 (D) of 3.0% HEC gels. Key: 0% w / w MN (open diamond), 1.0% w / w MN (open circle), 2.5% w / w MN (open square), 5.0% w / w MN (crossed diamond), 10.0% w / w MN (crossed circle), 20.0% w / w MN (crossed square). Each datum point represents the mean (6S.D.) of five replicates.

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ethylcellulose (2.5–5.0% w / w), ibuprofen (0–20.0% w / w) and methyl nicotinate (0–20.0%w / w) on viscoelastic (G9, G0, tan d and h 9) properties at three representative frequencies (0.1142, 0.5307, 0.9010 Hz), and on mechanical properties (compressibility) were evaluated using a three-way analysis of variance (ANOVA). Post-hoc comparisons of mean values were performed using Tukey’s test. In all cases, P,0.05 denoted significance.

3. Results

3.1. Oscillatory rheology For each formulation, the following rheological parameters were measured as a function of oscillatory frequency (n, Hz): storage modulus (G9), loss modulus (G0), tan d and dynamic viscosity (h 9). G9 is a measure of the recoverable energy or the energy

Fig. 3. The effect of hydroxyethylcellulose and disperse phase (DP) concentration on tan d for the ibuprofen suspensions (A), methyl nicotinate gels (B), non-stabilised emulsions (C) and emulsions stabilised with emulsifier (D). Key: 0% w / w DP (open diamond), 1.0% w / w DP (open circle), 2.5% w / w DP (open square), 5.0% w / w DP (crossed diamond), 10.0% w / w DP (crossed circle), 20.0% w / w DP (crossed square). Each datum point represents the mean (6S.D.) of five replicates.

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stored elastically in the system, whereas G0 is a measure of the energy dissipated as viscous flow, representing the real and imaginary parts of the complex dynamic shear modulus, respectively. Tan d is the ratio G0 /G9 and dynamic viscosity is defined as G0 /v, where v is the angular velocity of oscillatory stress (units: rad s 21 ), which is related to the oscillatory frequency by the relationship v 5 2pn. Representative frequency plots are shown in Figs. 1 and 2 for HEC-only and methyl nicotinate gels, respectively. In Fig. 1, for HEC-only gels, G9 and G0 increased with both higher oscillation frequency and greater HEC concentration (Fig. 1A and B, respectively), with G9 . G0 at all but very low frequencies. However, the rate of increase of G9 with increased oscillation frequency was greater than that of G0, as measured by the decrease in tan d (Fig. 1C).

401

Fig. 2 illustrates the effects on rheological parameters of HEC gels of both increased oscillatory frequency and the presence, in increasing concentrations, of a soluble active agent, methyl nicotinate. G9, G0 and h 9 all increased with increasing methyl nicotinate concentration (Fig. 2A, 2B and 2D respectively), while tan d decreased (Fig. 2C). In order to simplify comparison of the rheological behaviour of the different systems, the values of tan d at a single representative frequency (1 Hz) are plotted in Fig. 3 as a function of HEC and disperse phase / solute concentrations. These systems were ibuprofen only suspensions (Fig. 3A), methyl nicotinate gel solutions (Fig. 3B), non-stabilised (no emulsifier present) emulsions in which the disperse oil phase was formed from methyl nicotinate and ibuprofen within the liquid range (Fig. 3C) and otherwise identical emulsions stabilised with an

Table 1 The effect of hydroxyethylcellulose (HEC) concentration, disperse phase type and disperse phase concentration on the relaxation time (s) of the pharmaceutical systems a 2.5% HEC

3.0% HEC

3.5% HEC

4.0% HEC

4.5% HEC

5.0% HEC

% MN 0 1.0 2.5 5.0 10.0 20.0

2.61 2.74 3.79 2.94 3.45 5.49

4.98 5.14 5.49 6.20 6.35 6.64

7.24 8.37 11.36 9.36 13.26 15.92

15.91 .16 .16 12.2 .16 .16

.16 .16 .16 .16 .16 .16

.16 .16 .16 .16 .16 .16

% IBU 0 1.0 2.5 5.0 10.0 20.0

2.61 1.43 2.56 2.45 5.30 5.14

4.98 2.84 3.53 4.82 5.49 7.24

7.24 4.30 4.42 5.14 8.37 9.95

15.91 5.44 7.83 10.25 .16 9.85

.16 .16 12.29 12.73 .16 9.82

.16 .16 12.24 .16 .16 8.09

% w / w (MN1IBU) 0 2.0 5.0 10.0 20.0

2.61 1.89 1.94 2.48 7.95

4.98 2.42 4.07 5.14 .16

7.24 5.13 6.76 6.80 .16

15.91 7.58 10.62 12.24 .16

.16 13.96 13.10 .16 .16

.16 .16 .16 .16 .16

4.15 3.85 6.37 10.62

5.89 7.24 8.37 14.47

12.24 9.36 9.95 .16

.16 9.95 13.26 .16

.16 .16 .16 .16

.16 .16 .16 .16

% w / w (MN1IBU)emuls 2.0 5.0 10.0 20.0 a

MN, methyl nicotinate; IBU, ibuprofen; emuls, surfactant-stabilised emulsion.

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Fig. 4. The effect of hydroxyethylcellulose and disperse phase concentration on the work of compression (as measured by texture profile analysis) of methyl nicotinate gels (A), ibuprofen suspensions (B), non-stabilised (ns) emulsions (C) and emulsions stabilised (s) with emulsifier (D).

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emulsifying agent, Arlatone 2121 (Fig. 3D). In general, both the addition of drug and HEC to the gels caused tan d to decrease, as clearly shown in Fig. 3B, for example. However, although this trend held true for the addition of up to 10% ibuprofen to the 3.5 to 5% HEC gel (Fig. 3A), the tan d value then increased significantly for the 20% ibuprofen suspensions and, in the case of the 5% HEC, 20% ibuprofen suspension, reached a similar value to that of the 5% HEC-only gel. Similar observations were made for the non-stabilised emulsion plot (Fig. 3C). Table 1 shows the relaxation times for the various systems, calculated from the characteristic crossover frequency, where tan d has a value of unity. For the methyl nicotinate gels, the relaxation times increased linearly both with increasing nicotinate concentration and increasing HEC concentration. For the ibuprofen suspension and ibuprofen / methyl nicotinate emulsion formulations, the relaxation times initially decreased on adding the disperse phase before increasing exponentially.

403

Table 2 Representative penetration flux values (6S.D.; n54) across a model polydimethylsiloxane barrier membrane for methyl nicotinate and ibuprofen from single and dual (active) component systems Active component (formulation system)a

Penetration flux mg cm 22 h 21 6S.D.

Methyl nicotinate (1) Methyl nicotinate (2) Methyl nicotinate (3) Ibuprofen (4) Ibuprofen (5) Ibuprofen (6) Ibuprofen (7)

2.47060.097 2.86560.115 2.15760.196 0.16360.015 0.45560.028 0.45760.025 0.04360.003

a

Key to formulation systems (all contained 3.5% HEC; 2.5% MN and 2.5% IBU, where appropriate). (1) Single component HEC solution gel; (2) dual component (with ibuprofen) nonstabilised emulsion; (3) dual component (with ibuprofen) stabilised emulsion; (4) single component HEC suspension; (5) dual component (with methylnicotinate) non-stabilised emulsion; (6) dual component (with methylnicotinate) stabilised emulsion; (7) single component commercial ibuprofen gel (Ibugel  , Dermal).

3.2. Texture profile analysis Fig. 4 shows the compressibility of the various systems, a mechanical parameter derived from texture profile analysis. The compressibilities of all four systems studied, ibuprofen suspensions (Fig. 4A), methyl nicotinate gels (Fig. 4B), non-stabilised dual drug emulsions (Fig. 4C) and dual drug stabilised emulsions (Fig. 4D) increased with increasing HEC concentrations for a specified solute / disperse phase concentration. However, the compressibilities of ibuprofen suspensions were significantly dependent on drug concentration, whereas those of methyl nicotinate gels were not. Dual drug stabilised and non-stabilised emulsions both had compressibilities that were dependent on total drug concentrations, at least up to 10% by weight of total drug. Emulsions formulations containing 20% disperse phase showed a marked decrease in compressibility compared with lower disperse phase concentrations, particularly evident for higher HEC concentrations.

3.3. Drug penetration The mean penetration flux rates across a Silescol 

poly(dimethylsiloxane) membrane for a number of representative ibuprofen and methyl nicotinate formulations are presented in Table 2. The individual penetration profiles were linear in all cases, with no lag time apparent. Methyl nicotinate penetration flux rates were between 6 and 13 greater than those of ibuprofen, and were less dependent on formulation type. However, compared to the suspension formulation, the ibuprofen penetration flux rate is enhanced almost threefold by incorporating it into a dual component emulsion system. Similarly, the ibuprofen penetration flux rates from dual component systems were |10-fold greater than from a commercial ibuprofen topical gel formulation (Ibugel  ). The effect of disperse phase and HEC concentration on the mean penetration flux rates for ibuprofen from stabilised dual-component emulsions is shown in Fig. 5. Increasing the concentration of disperse phase resulted in a proportionate increase in penetration flux rate. The effect of HEC concentration is less clear, with penetration flux rates increasing from 2.5 to 3.5% HEC, and decreasing thereafter. Similar trends were observed for the methyl nicotinate component.

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Fig. 5. The effect of hydroxyethylcellulose and disperse phase ibuprofen concentration on the penetration flux rate of ibuprofen from stabilised emulsion formulations. Key: 1.0% w / w ibuprofen (solid square), 2.5% w / w ibuprofen (open square), 5.0% w / w ibuprofen (solid circle), 10.0% w / w ibuprofen (open circle). Each datum point represents the mean (6S.D.) of three replicates.

4. Discussion Pharmaceutical semi-solids can display a wide range of rheological behaviours. Emulsions and suspensions, for example, can display viscoelastic characteristics depending on the volume fraction, droplet / particle size distribution and viscosity of the dispersed phase. In the case of emulsions, the interfacial rheology of the emulsifier film and the concentration and nature of the emulsifying agent will also modify the rheological behaviour. It is important to develop an understanding of the rheological behaviour of these systems, since this will affect a range of performance parameters, including drug release characteristics, spreadability and retention at the application site, manufacturing operations and ease of expression from the container.

Where a conventional oil-in-water cream is used as a percutaneous delivery system following topical application, a problem arises concerning adequate bioavailability due to the multiphase nature of the formulation. The drug may partition between the internal and external phases of the emulsion, and between the external phase and the skin, thus reducing the thermodynamic activity of the penetrant drug in the vehicle which, in turn, reduces the rate of percutaneous drug penetration [15]. One means of overcoming this is to directly emulsify, as the internal phase of an oil-in-water emulsion, a lipophilic penetrant which is in the liquid phase at ambient temperature. Since few such suitable penetrants exist, the formation of a liquid mixture (at ambient temperature) of two drugs, which can then be directly emulsified, represents an elegant solution

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to the problem [16]. To date, this concept has been applied successfully only to eutectic mixtures of local anaesthetics [17]. In the present study, dual drug formulated systems are described which contain a lipophilic liquid phase (at ambient temperature), which is close to but not necessarily at the eutectic composition of a given system. Such systems may be complex, containing drug in aqueous solution, suspension and in the micellar phase [18]. Given the relatively low concentrations of the internal phase, ,20% w / w, they require an additional viscosity builder in the aqueous phase to impart the necessary pharmaceutical characteristics to the system. As such, their drug release and, consequently, membrane penetration characteristics may be complex and unpredictable, and could be influenced by the rheological properties of the system. Thus, emulsified dual drug systems based on methyl nicotinate and ibuprofen, with hydroxyethylcellulose (HEC) as a viscosity builder, have been developed within the liquid range. To compare membrane penetration characteristics, single drug systems (HEC gels containing either methyl nicotinate in solution or ibuprofen in suspension) were also prepared, along with an HEC non-stabilised system without surfactant emulsifier. The penetration characteristics of methyl nicotinate and ibuprofen from the various test compositions were determined through a model hydrophobic barrier membrane, polydimethylsiloxane, under sink conditions. The most obvious effect on drug penetration flux was seen with the hydrophobic drug component, ibuprofen, which showed approximately a threefold increase in flux when delivered from the dual drug system, compared to delivery from an ibuprofen suspension in an aqueous gel formulation (Table 2). The increase in ibuprofen penetration flux was |10fold when the dual drug systems were compared to a commercial alcoholic gel formulation (Table 2). Solubilisation of ibuprofen in the alcoholic co-solvent within the commercial formulation may provide a competing phase to the lipophilic environment of the stratum corneum, thus markedly reducing drug penetration flux compared to the dual drug systems, in which no competing solvent component was present. Interestingly, ibuprofen penetration flux values from both emulsified and non-emulsified dual drug systems were similar, indicating that the liquid

405

character of the internal oil phase was probably maintained even in the absence of an emulsifier. This suggests that the molecular interactions between ibuprofen and methyl nicotinate in the liquid mixture are sufficiently strong to prevent crystallisation of the ibuprofen and / or significant solubilisation of the methyl nicotinate in the aqueous continuous phase. It is also possible that the stability of the non-emulsified systems are influenced by their rheological properties, as determined by the viscosity enhancer. However, it is likely that emulsification will be necessary to provide physical stability to the emulsion system during long-term storage. By contrast, the effect of the dual drug concept on the penetration flux of methyl nicotinate was less marked, as might be expected from a component having good aqueous and lipophilic solubility properties and, consequently, good transdermal penetration characteristics. Similar enhancements in ibuprofen penetration flux were obtained at different HEC and disperse phase concentrations. The increase in ibuprofen penetration flux rate from the stabilised emulsions with increasing disperse phase concentration (Fig. 5) may be a consequence of two factors. Firstly, there will be a greater volume fraction of disperse phase droplets in contact with the model membrane surface. Secondly, the same concentration of emulsifying agent (4%) was employed in the emulsion formulations, irrespective of the disperse phase concentration, ensuring a thinner, and hence more penetrable, interfacial layer at higher disperse phase concentrations. It is interesting to note that the enhanced pentration flux of ibuprofen from the stabilised emulsions, compared with the suspension formulations, was observed despite the fact that the ibuprofen molecules have to penetrate this interfacial layer. A similar increase occurred in methyl nicotinate penetration flux rate with increasing methyl nicotinate concentration in the disperse phase. Fig. 5 also illustrates the effect of HEC concentration on ibuprofen penetration flux rate from stabilised emulsions. Both ibuprofen and methyl nicotinate components showed an increase in flux between 2.5 and 3.5% HEC, before decreasing at higher HEC concentrations. This decrease is a likely consequence of the increasing viscosity of the aqueous continuous phase, as reflected in oscillatory

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rheology and TPA measurements. The initial increase in penetration flux has not been observed previously, and is only characteristic of the emulsion systems. Methyl nicotinate-only gels showed a small but significant decrease in penetration flux with increasing HEC concentration, while the penetration flux rates of ibuprofen-only suspensions were HEC-independent. The rheological behaviour of 3–12% HEC-only polymer solutions have been studied previously [19]. For this study, the 2.5 to 5.0% w / w HEC concentration range was chosen for investigation since these systems provide mechanical / rheological properties that are most suitable for topical formulations. The magnitudes of oscillatory rheological parameters of these systems will depend upon the oscillation frequency, HEC concentration, drug concentration(s) and the physical nature of the drug(s) within the system. In Fig. 1, the effects of HEC concentration and oscillatory frequencies are demonstrated in the absence of any drug components. Clearly, in this situation, G9 . G0, with the elastic component therefore predominating. Such behaviour is typical of chain entanglement networks, where the critical polymer concentration has been exceeded [20] and neighbouring polymer chains are forced to overlap. The broadly similar magnitudes of G9 and G0 for a given formulation suggest that the systems not only store energy in polymer / polymer interactions, but also dissipate energy through diffusive processes, as is typical of viscoelastic systems. Both of these processes become more efficient at higher frequencies (Fig. 1A and B), conforming to the Maxwell model describing viscoelastic materials, indicating that some of the diffusive modes were restricted by the increasing frequency of oscillation. The viscoelastic properties of the systems are also enhanced with increasing HEC concentration (Fig. 1A), reflected in the increase of G9 and G0, due to an increase in the degree of molecular entanglement of the HEC chains. These interactions hinder self-diffusion, causing microstructural rearrangements to shift to longer times. Thus, tan d values, which are mostly less than 1.0 (Fig. 1C), and the dynamic viscosity h 9 (Fig. 1D), decreased with increasing oscillation frequency and increasing HEC concentration. For methyl nicotinate HEC gels, in which the active agent is highly water soluble, similar rheologi-

cal trends were observed to HEC gel systems without drug components. Fig. 2 demonstrates that an increase in methyl nicotinate concentration produced a larger elastic than viscous response in 3% HEC gel. Similar trends were observed at all other HEC concentrations. However, compared with the methyl nicotinate HEC solution systems, increasing the ibuprofen concentration in HEC suspensions produced a more dramatic increase in the magnitudes of G9, G0 and h 9, as was expected for a solid disperse phase. The ratio G0 /G9, represented by tan d, is plotted as a function of HEC and disperse phase / solute concentration in Fig. 3 for both single drug and dual drug (methyl nicotinate / ibuprofen) systems. The latter case included stabilised emulsion systems, designed to prevent dilution of the lipophilic liquid phase and precipitation of solid drug components, and non-stabilised emulsion systems, which relied entirely on the viscosity characteristics of the external phase to maintain a homogeneous oil dispersion. For these systems, increasing HEC and / or drug concentrations resulted in an increased elastic character being imparted to the formulations, with some exceptions. Interestingly, at higher HEC and drug concentrations, tan d increased markedly, with the viscous component predominating as the loss modulus (G0) increased. This may indicate the stabilising effect, in both surfactant and non-surfactant emulsified systems, of higher concentrations of HEC on systems with higher drug loadings, preventing solidification of drug components from the liquid phase and allowing the viscous characteristics imparted by the disperse phase to predominate. The characteristic frequency at which G9 5 G0 (or where tan d is equal to 1), termed the crossover frequency, is related to the relaxation time of the system by Eq. (1) t r 5 1 / 2pn * 5 1 /v *

(1)

where t r is the relaxation time (s), and n * and v * are the crossover frequency in Hz and rad s 21 , respectively. The relaxation times of the various systems were determined, where possible. Below the crossover frequency G0 . G9, while above that frequency G9 . G0, typical of viscoelastic systems composed of entanglement networks. In the lower frequency re-

A.D. Woolfson et al. / Journal of Controlled Release 67 (2000) 395 – 408

gime, with a relatively long time scale, a system may exhibit more viscous than elastic behaviour, since energy dissipation is greater than the elastic energy stored in the system. The inference is that the system behaves more like a free-flowing fluid than a resilient gel in this frequency range. In the higher frequency regime (relatively short time scale) energy dissipation is not so significant and most of the imparted energy is stored, with a predominantly elastic response. In some cases, the crossover frequencies were below the 0.01 Hz initial frequency and, consequently, the relaxation times were greater than 16 s. For the suspension and emulsion systems, relaxation times initially decreased on adding the disperse phase before increasing again. For example, 3.0% HEC-only gel has t r 54.98. On adding 1% ibuprofen, t r drops to 2.85 before increasing according to a power law to a value of 7.24 for the 20% suspension. The observed decrease in the crossover frequency (or increase in relaxation time) with increasing disperse phase concentration is attributed to stronger elastic interactions between the particles / droplets and a corresponding decrease in their diffusion coefficient. The absolute values of the relaxation times for the emulsion systems reported in this study is several orders of magnitude larger than for some other o / w emulsion systems reported in the literature, where typical values are |0.10 s [21]. The difference is probably due to the influence of HEC, whose viscosity enhancing characteristics severely restrict droplet and particle motion. This, in turn, has potential implications for the release of drugs from these systems and their consequent membrane penetration characteristics. The application of texture profile analysis (TPA) has been reported for the mechanical characterisation of bioadhesive pharmaceutical semi-solid preparations [22]. In TPA, two passes of a solid probe are made into the product, with a pre-defined pause allowed between each pass. From the resultant force–time curve, the mechanical (textural) properties of the product may be calculated. The parameters that may be derived from TPA include the compressibility (work of compression), defined as the force per unit time required to deform the product during the first compression cycle of the probe.

407

The compressibility of all four systems (Fig. 4A– D) increased with increasing HEC concentration for a specific solute / disperse phase concentration, as might be expected. The effect of changing the concentration of disperse phase was, however, more revealing, with methyl nicotinate gels showing a very small dependence on the concentration of methyl nicotinate (Fig. 3A), compared with the large dependence observed for the ibuprofen suspensions (Fig. 6B), confirming that methyl nicotinate is primarily in the solution phase in this system. Compressibilities for the 20% ibuprofen suspensions were particularly high compared to lower concentrations, indicating the likelihood of particulate interactions with decreasing inter-particle space at such high concentrations. Both dual drug emulsion systems showed a general increase in compressibility with increasing oil phase concentrations, at least up to the 10% level. However, at 20% oil phase concentration, the compressibilities of the emulsions decrease dramatically, possibly due to deformation of the structure imparted by HEC.

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