Gelatin-stabilised microemulsion-based organogels: rheology and application in iontophoretic transdermal drug delivery

Journal of Controlled Release 60 (1999) 355–365

Gelatin-stabilised microemulsion-based organogels: rheologyand application in iontophoretic transdermal drug delivery

1 *Shilpa Kantaria, Gareth D. Rees , M. Jayne LawrenceDepartment of Pharmacy, King’s College London, Manresa Road, Chelsea SW3 6LX, London, UK

Received 12 November 1998; received in revised form 20 March 1999; accepted 31 March 1999

Abstract

Gelatin-containing microemulsion-based organogels (MBGs) have been formulated using pharmaceutically acceptablesurfactants and oils such as Tween 85 and isopropyl myristate. MBG formulations were subject to rheological study and theirutility in transdermal drug delivery examined. Unlike most organogels, MBGs are electrically conducting and have beensuccessfully employed in this study for the iontophoretic delivery of a model drug through excised pig skin. Iontophoresisusing MBGs gave substantially higher release rates for sodium salicylate compared to passive diffusion, and fluxes wereproportional to the drug loading and the current density. MBGs provide a convenient means of immobilising the drug and arerheologically similar to their hydrogel counterparts at comparable gelatin concentrations. MBGs also appear to offerimproved microbial resistance in comparison to aqueous solution or hydrogels. 1999 Elsevier Science B.V. All rightsreserved.

Keywords: Microemulsion-based gel; Transdermal drug delivery; Rheology; Iontophoresis

1. Introduction drug reservoir is formulated as a solution since thiscan limit the ease of clinical administration. The

Iontophoresis has been used extensively in recent development of more convenient reservoir systems isyears as a means of enhancing the rate of transder- clearly desirable and one notable area of interest hasmal drug delivery [1–3], and is particularly effective been the use of drug-containing hydrogels. Formula-in facilitating transport of larger hydrophilic species tion of the drug as a gel rather than a solutionsuch as peptides, proteins and nucleotides which facilitates drug handling and in the case of ion-often exhibit negligible penetration under passive tophoretic delivery, allows the patient to remainconditions. A potential practical drawback of drug ambulant.delivery via iontophoresis, however, occurs when the There has been considerable interest generally in

the development of ‘intelligent’ or responsive hydro-gels which react to a variety of environmental stimuli

*Corresponding author. Tel.: 144-171-333-4808; fax: 144- such as pH, temperature or the presence of a171-351-5307.

particular substrate [4]. For iontophoretic application,E-mail address: [email protected] (M.J. Lawrence)1 particular benefit would accrue from the use ofPresent address: SmithKline Beecham, Research & Develop-

ment, St. George’s Avenue, Weybridge, Surrey KT13 0DE, UK. electro-responsive hydrogels where the aim is to

0168-3659/99/$ – see front matter 1999 Elsevier Science B.V. All rights reserved.PI I : S0168-3659( 99 )00092-9

356 S. Kantaria et al. / Journal of Controlled Release 60 (1999) 355 –365

achieve successful on-off drug release profiles me-diated by an electrical stimulus [5,6]. Mechanistical-ly, this is generally achieved by a change in hydrogelstructure reflected by swelling or de-swelling, andchanges in drug diffusivity within the gel matrix [7].

A disadvantage of any aqueous-based formulationdesigned for the clinical environment is the potentialfor microbial contamination, and hydrogels are noexception [8]. Metabolic action can result in thebreakdown of gel structure, and pH changes andredox reactions can reduce drug efficacy [9,10]. Onemeans of reducing the likelihood of such contamina-tion is to employ alternative gel systems such asthose based on organic solvents (organogels), whichare far less inclined to support microbial growth.Organogels based on microemulsions have receivedparticular attention especially those stabilised bybiosurfactants such as lecithin [11], alkylglucosides[12] or alternative sugar derivatives [13]. One reason

Fig. 1. Proposed MBG structure based on small angle neutronfor this is that microemulsions are thermodynamical- scattering [17].ly stable and the surfactants act as penetrationenhancers. The majority of organogels, however, aremore ‘fluid’ than their hydrogel counterparts and are ducting and therefore have potential application ingenerally soluble in the parent oil. A notable excep- iontophoretic drug delivery.tion are gelatin-containing microemulsion-based or- The aim of the present study is to examine theganogels (MBGs). suitability of new MBG formulations for transdermal

The formation of MBGs from water-in-oil (w/o) iontophoretic drug delivery. Previous MBG formula-microemulsions was first described in 1986 [14,15], tions have been based on hydrocarbon oils, andand they have been subsequently characterised both almost exclusively employed salts of the anionicstructurally [16–18] and in terms of their physico- surfactant bis-2-(ethylhexyl) sulphosuccinate (AOT).chemical properties [17,19,20]. Whilst there are Since the aforementioned combination of oil andmoderate differences between the various proposed surfactant would be unacceptable in the clinicalMBG structures, these can be attributed in the main setting, we have sought to replace both oil andto the different formulations employed by each surfactant with pharmaceutically acceptable alterna-group. The common theme linking the available tives. Iontophoretic transdermal delivery of themodels is that there exists within a macroscopic model drug sodium salicylate has therefore beenhydrophobic continuous phase, an interconnected examined using a variety of MBG formulations, andgelatin network which is hydrated and stabilised the release rates compared with those attainablefrom direct contact with the oil by a monolayer of using passive drug delivery.surfactant. The schematic model proposed by Atkin-son et al. [17,20] in which this network is proposedto coexist with a population of ‘conventional’ w/o 2. Materials and methodsmicroemulsion droplets, is shown in Fig. 1. Incorpo-ration of gelatin into w/o microemulsions provides 2.1. Materialsthe opportunity to formulate gel matrices of compar-able viscosity to those attainable using hydrogels. In Helical silver wire, cation exchange membranes,addition, in contrast to the majority of alternative sodium salicylate, sodium chloride and the sodiumorganogel formulations, MBGs are electrically con- salt of AOT were supplied by BDH. Polyoxyethyl-

S. Kantaria et al. / Journal of Controlled Release 60 (1999) 355 –365 357

enesorbitan monolaurate (Tween 21), polyoxyethyl- amount of dermis, was obtained from the lateral partenesorbitan monooleate (Tween 81) and polyoxy- of the pig ear using a Cobbett skin graft knife. Theethylenesorbitan trioleate (Tween 85) were pur- thickness of the freshly excised skin ranged fromchased from Aldrich, and isopropyl myristate (IPM) 0.069 to 0.089 cm. All skin was stored in silver foilfrom Fluka. Acid-hydrolysed pig-skin gelatin at 2188C and used within 1 month of excision. Skin(Bloom 300) was obtained from Sigma. Distilled samples were hydrated by immersion in normalwater was used throughout. saline for 8 h prior to use.

2.2. Microemulsion and MBG preparation 2.5. Iontophoresis

W/o microemulsions containing the model drug The four-compartment iontophoretic cell used inwere prepared by injection of an aqueous stock these studies has been described elsewhere [21]. Asolution of sodium salicylate to a reverse micellar Thurlby PSU 30V-2A power source was employedsurfactant solution; clear solutions formed after brief throughout. Experiments were conducted at 258Cshaking. MBGs were prepared by addition of solid with electrodes positioned in the outer compartmentsgelatin (up to 0.14 g/g) to a previously prepared w/o of the cell; both the outer and inner chambers of the

3 3microemulsion containing 25% w/w surfactant, 25% cell contained ca. 2 cm of 0.154 mol /dm saline.w/w water and 50% w/w IPM. The temperature was The experimental set-up is shown schematically inthen increased to 558C with constant stirring until Fig. 2.solubilisation of the gelatin was complete. Agitation The hydrated excised skin was placed in betweenwas then stopped and the sample allowed to cool to the two inner chambers, and a cation exchangeroom temperature. Formulations yielding clear, membrane placed between the outer compartmentshomogeneous, non-birefringent gels were classified which bathed the electrodes and isolated the donoras MBGs. Salicylate concentrations quoted in the and receptor compartments from the electrodes. Thetext refer to concentrations in the aqueous phase. cation exchange membrane allows the passage of

current but prevents the transport of extraneous2.3. Rheological studies cations, thereby reducing pH changes and drug

degradation. For solution studies, the sodium salicyl-Rheological measurements were performed using ate solution was poured into the donor compartment

a CarriMed CSL 100 Controlled Stress Rheometer at room temperature. MBGs containing the modelemploying a 4-cm diameter parallel plate geometry.The elastic modulus (G9) and the loss modulus (G0)were determined over a frequency range of 0.01 to10 Hz. A plate gap of 400 mm was employed and thestrain restricted to values below 0.01 Pa to avoidstructural damage to the MBGs. Torque sweeps wereperformed on all samples to confirm the gels werewithin the linear viscoelastic region under the select-ed experimental conditions. MBGs were stored undera layer of the parent oil in sealed containers tominimise evaporation losses. Three different sampleswere tested for each MBG formulation at an incuba-tion temperature of 258C.

2.4. Preparation of pig skin for iontophoresis

Split thickness pig-skin, the part of the skincomposed of the epidermis together with a small Fig. 2. The four compartment iontophoretic cell [21].


drug were introduced into the donor cell at a tants in combination with AOT, but MBGs could nottemperature above the gel-solution transition tem- be formulated using non-ionic surfactants alone.perature and allowed to set overnight. A glass slide Nonetheless, it was possible to replace up to 85% ofwas used to separate the donor compartment from the AOT with non-ionic surfactant on a weight forthe outer compartment and ion-exchange membrane weight basis. The utility of MBGs as drug deliveryduring the gelling process. The glass slide was matrices was considered taking into account theirremoved and the outer compartment filled with saline rheological properties. The drug delivery studiesimmediately prior to measurement. were then performed using aqueous drug solutions

Cathodal iontophoresis (cathode adjacent to the and MBGs stabilised by AOT or 2:1 (w/w)donor chamber and anode adjacent to the receptor Tween:AOT mixtures in IPM.chamber) was employed for the delivery of the The viscoelastic behaviour of the MBGs wassalicylate anion. The applied current density was examined using dynamic oscillatory testing, with

2 2either 0.179 mA/cm or 0.384 mA/cm . Experi- torque sweeps identifying 8 Pa as an appropriatements were conducted over an 8-h period with applied stress for further testing. MBGs appeared by

3hourly removal of 0.50 cm aliquots from the eye to be macroscopically stable, however prelimin-receptor compartment for analysis. The volume ary investigations showed that the MBGs exhibit anchange was made up each time using an equal ageing/curing phenomenon with time. A typicalvolume of fresh saline. The concentration of salicyl- example of this effect is illustrated in Fig. 3 whichate in the receptor compartment was determined shows the elastic modulus, G9, gradually increasingspectrophotometrically at 296 nm with pH moni- over the period of 1 month for an MBG containingtoring over the measurement period. All experiments 0.45 g (8.3% w/w) gelatin. This curing process iswere repeated at least four times. well known for gelatin hydrogels and has been

previously noted for AOT/alkane MBGs [14,15]. Inkeeping with previous studies [14,15,17], compari-

3. Results and discussion sons of rheological behaviour in the various MBGformulations were based on measurements obtained

3.1. Formulation and rheological characterisation from samples subject to a 7-day curing period.of the MBGs

One of the main strategies pursued in the develop-ment of pharmaceutically acceptable MBGs was thesubstitution of hydrocarbon oils used in previousstudies by biocompatible oils such as triglyceride,ethyl oleate or IPM. For the purposes of the presentstudy, IPM was the preferred option as the mi-croemulsion phase behaviour was most favourablefor MBG formation. A second important strategywas to eliminate as far as possible the use of AOT inorder to minimise the likelihood of toxicity prob-lems. To this end, the formulation and phase be-haviour of a variety of non-ionic surfactants wasexamined. The surfactants Tween 21, Tween 81 andTween 85 were found to be most appropriate for ourpurposes being pharmaceutically acceptable andhaving moderately high water and drug solubilisationcapacity. A more detailed account of the phase Fig. 3. A typical example of the curing effect as G9 is monitoredbehaviour studies will be reported elsewhere [22]. over a period of 1 month for an MBG in IPM containing 0.45 gMBGs could be formulated using the Tween surfac- (8.3% w/w) gelatin. Incubation temperature5258C.


The elastic modulus of the MBGs increased withincreasing gelatin concentration for all the systemsstudied. Although this was expected, the dependencewas not linear, G9 reaching a limiting plateau around3000–3500 Pa. The loss modulus, G0, also increasedwith increasing gelatin concentration, however, G0

was always less than G9 for the studied formulationsafter curing. It should be noted that the MBGsformulated here contain moderately high gelatinconcentrations and interestingly, G9 is higher for theorganogels than for hydrogel systems containing thesame overall concentration of gelatin. FormulatingMBGs using different surfactant combinations hadlittle effect on values of G9 and G0 at comparablegelatin concentrations. This lack of variation pre-sumably reflects the fact that the MBG microstruc-tures are very similar in each case.

Addition of sodium salicylate as a model drug tothe MBG formulations had a marked impact onMBG formation and the rheological properties of thefinally formed gel. This is illustrated by Fig. 4a and bwhich shows the effect of salicylate addition on theformation of the Tween 85/AOT/IPM organogel in aplot of G9 and G0 against time. This behaviour istypically representative of all the MBGs studied. It isuseful to consider the crossover point, that is whenG95G0, as representing the transition boundarybetween solution and gel. It is clear that in theabsence of salicylate, G9 rises rapidly with thecrossover point reached after ca. 1000 s. In thepresence of salicylate, the gelation process is clearlyinhibited and the crossover point does not occur untilafter 3000 s. Inclusion of salicylate also has the

Fig. 4. Inhibition of MBG formation by the model drug sodiumeffect of weakening the finally produced gel assalicylate. G9 and G0 are monitored as a function of time for

reflected by the reduction in G9. The degree of Tween 85:AOT(2:1w/w) / IPM MBGs prepared using (a) waterinhibition and the extent of gel weakening were only and (b) 10% (w/w) sodium salicylate in water as the

dispersed phase. Incubation temperature5258C.proportional to the salicylate concentration over themeasured range but was most pronounced at lowergelatin concentrations. This behaviour is illustrated from a simple ‘salt’ effect, since incorporation ofin Fig. 5a and b which shows log G9 versus log of salicylate in hydrogels results in qualitatively similarthe gelatin concentration for the AOT/IPM and the behaviour. In addition, the inclusion of simpleTween 85:AOT(2:1) / IPM systems in the presence electrolytes in both gelatin hydrogels and MBGs isand absence of sodium salicylate. The behaviour of known to retard gelation and weaken the gel bythe Tween 81 and Tween 21 MBG formulations is reducing the propensity of the gelatin to adopt thequalitatively the same as that shown in Fig. 5b for triple helical structure.Tween 85. The theory of rubber elasticity allows for the

It seems likely that the reduction in MBG stability calculation of the concentration of elastic strandsobserved on incorporation of sodium salicylate arises forming the gel network by use of Eq. (1) [17]


formed are shown in Table 1 and illustrates clearlythe influence of gelatin and salicylate concentrationin the various MBG formulations.

3.2. Salicylate flux from AOT /IPM and AOT /Tween /IPM MBGs

The flux of drug from sodium salicylate solutionsand from salicylate-containing MBGs was monitoredas a function of time under passive and iontophoreticconditions. The results summarised in Fig. 6 for theAOT/IPM system are typical of the data obtained.The release profiles show firstly that iontophoresisresults in a marked increase in flux for both thesalicylate solution and the gel-encapsulated drugcompared to that observed under passive conditions.There is essentially no difference in the observedfluxes when comparing MBG and solution underpassive conditions, which is consistent with the skinbarrier playing the rate-determining step in thepermeation process. In contrast, the iontophoreticflux from the salicylate solution is consistentlyhigher than that obtained with the MBG. Thisdisparity most likely reflects the differences in drugdiffusivity in the two types of drug reservoir. Thesteady state flux under iontophoretic conditions wasattained within 2–3 h in all instances.

A summary of the data showing the cumulativerelease after 8 h of salicylate in MBGs and insolution under iontophoretic conditions is given inTable 2. Although the cumulative release from theAOT/IPM gel is slightly higher than for thoseMBGs containing the Tween surfactants, the differ-

Fig. 5. Log G9 versus log of the gelatin concentration for the (a) ence overall between the systems is not marked. ThisAOT/IPM and (b) the Tween 85:AOT(2:1) / IPM systems in the

would suggest that the internal MBG structure is notpresence and absence of sodium salicylate. Incubationgreatly affected by substitution of AOT by Tween, atemperature5258C.conclusion supported by our rheological studies, andthat the mechanism of drug transport is similar in all

G 5 gn RT (1) cases.e v

Here G is the equilibrium value for the plot of G9 3.3. Effect of drug donor concentration ande

against frequency, g is the mobility modulus of the current densitycross-links within the network and is approximatelyunity, n is the number of elastic strands formed, R is The drug release profiles, such as the examplev

the gas constant and T is the temperature in degrees shown in Fig. 6, can be used to calculate the steady2Kelvin. The above equation is valid for viscoelastic state flux (mmol /h cm ) for solutions or MBGs

materials in which G9 is greater than G0 which is the under different delivery or formulation conditions.case here. The calculated number of elastic strands The effect on mean transdermal flux values of


Table 1aNumber of elastically effective strands

15Gel composition Elastically effective strands (310 )

Water only 5% w/w 10% w/wSalicylate Salicylate

AOT/IPM, 0.45 g gelatin 8.4 6.5 5.3AOT/IPM, 0.30 g gelatin 7.9 6.0 4.0AOT/IPM, 0.15 g gelatin 7.2 4.2 3.72:1 Tween 85:AOT/IPM, 0.45 g gelatin 8.1 6.6 5.32:1 Tween 85:AOT/IPM, 0.30 g gelatin 6.8 6.1 3.72:1 Tween 85:AOT/IPM, 0.15 g gelatin 6.6 1.2 0.12:1 Tween 81:AOT/IPM, 0.45 g gelatin 7.0 6.2 3.12:1 Tween 81:AOT/IPM, 0.30 g gelatin 6.3 5.3 3.02:1 Tween 81:AOT/IPM, 0.15 g gelatin 5.7 3.5 0.52:1 Tween 21:AOT/IPM, 0.45 g gelatin 7.6 6.0 4.92:1 Tween 21:AOT/IPM, 0.30 g gelatin 7.0 5.5 4.12:1 Tween 21:AOT/IPM, 0.15 g gelatin 4.9 3.8 1.3Hydrogel, 0.45 g gelatin 7.8 6.9 6.3Hydrogel, 0.30 g gelatin 6.4 6.0 4.7Hydrogel, 0.15 g gelatin 5.2 1.3 0.6

a The number of elastically effective strands formed in MBG formulations and hydrogels as a function of composition. Values derivedusing Eq. (1) [16].

changing the drug donor concentration and the able under equivalent conditions, although standardcurrent density are summarised in Tables 3 and 4. errors were quite high in relation to the measuredUnder passive conditions, the flux from both MBG fluxes. As expected, the salicylate solutions gaveand solution were essentially first order with respect higher fluxes than MBGs under comparable ion-to the donor concentration. Passive drug delivery tophoretic conditions. In the case of aqueous solu-rates from MBG and solution were broadly compar- tions of sodium salicylate, transdermal flux is again

first order with respect to the drug donor concen-tration at the higher current density of 0.384 mA/

2 2cm . At the lower current density of 0.179 mA/cm ,however, the increase in flux with increased donorconcentration was much less marked. Fluxes fromsalicylate solutions were also proportional to theapplied current density, with a first order dependenceobserved at the higher salicylate concentration com-pared to an increase of ca. 50% for the lower drugconcentration.

The changes in transdermal flux from the MBGswhen drug donor concentration and current densityare increased follow a broadly similar trend to thatobserved in aqueous solution. Table 3 shows that at a

2fixed current density of 0.179 mA/cm , there is anaverage increase in flux of just 37% on doubling thedrug concentration in the MBG. Table 4 shows that

2Fig. 6. Drug release profile from an aqueous solution containing at the higher current density of 0.385 mA/cm , an2.14% w/w sodium salicylate, and from an AOT/IPM organogel

average increase in flux of 56% is obtained oncontaining 10% w/w drug in the aqueous phase (2.14% w/wdoubling the drug concentration in the MBG. Atoverall) under passive and iontophoretic delivery conditions.

Incubation temperature5258C. fixed drug concentration, doubling the current den-


Table 2aCumulative release of sodium salicylate after 8 h

Composition MBG drug loading, Iontophoresis Iontophoresisbcurrent density MBG (mmol) soln. (mmol)

AOT/IPM 10.0T85/AOT/IPM 5% w/w, 9.4 1661

2T81/AOT/IPM 0.385 mA/cm 8.3T21/AOT/IPM 7.8

AOT/IPM 15.8T85/AOT/IPM 10% w/w, 15.8 3262


AOT/IPM 7.5T85/AOT/IPM 5% w/w, 6.7 9.860.6


AOT/IPM 7.5T85/AOT/IPM 10% w/w, 6.9 13.560.8


a Summary of cumulative salicylate release after 8 h from MBGs and aqueous solution as a function of formulation, drug loading andcurrent density. Mixed surfactant MBGs contain 2:1 (w/w) Tween:AOT in isopropyl myristate.

b The aqueous solution of drug contains 1.07 or 2.14% w/w of sodium salicylate, equivalent to that in the MBG when the latter areexpressed as overall concentrations. The cumulative release of salicylate from solution under passive conditions after 8 h is 1.560.4 mmol.Incubation temperature5258C.

Table 32 aEffect of drug donor concentration on transdermal flux (iontophoresis current density50.179 mA/cm )

Composition Iontophoresis Iontophoresis Passive Passiveb bMBG soln. MBG soln.

2 2 2 2(mmol/h cm ) (mmol /h cm ) (mmol /h cm ) (mmol/h cm )

AOT/IPM 0.8360.13 1.3560.04 0.1160.05 0.1960.0510% w/w drugAOT/IPM 0.6560.16 1.1760.16 0.0960.08 0.0960.045% w/w drugT21/AOT/IPM 0.7860.07 1.3260.07 0.1060.14 0.1860.0210% w/w drugT21/AOT/IPM 0.5860.14 1.1060.24 0.0660.03 0.0660.075% w/w drugT81/AOT/IPM 0.8060.09 1.3460.05 0.0960.06 0.1860.0410% w/w drugT81/AOT/IPM 0.5460.18 1.0860.03 0.0560.03 0.1260.055% w/w drugT85/AOT/IPM 0.8660.09 1.3060.07 0.1060.06 0.2060.0110% w/w drugT85/AOT/IPM 0.6560.10 1.1560.13 0.0860.04 0.1060.075% w/w drug

a Transdermal flux from MBGs and aqueous solution as a function of formulation and drug loading at constant iontophoretic currentdensity. Mixed surfactant MBGs contain 2:1 (w/w) Tween:AOT in isopropyl myristate.

b The aqueous solution of drug contains 1.07 or 2.14% w/w of sodium salicylate, equivalent to that in the MBG when the latter areexpressed as overall concentrations. Incubation temperature5258C.


Table 42 aEffect of drug donor concentration on transdermal flux (iontophoresis current density50.385 mA/cm )

Composition Iontophoresis Iontophoresis Passive Passiveb bMBG soln. MBG soln.

2 2 2 2(mmol/h cm ) (mmol /h cm ) (mmol /h cm ) (mmol/h cm )

AOT/IPM 1.4160.15 2.8260.39 0.2860.09 0.3660.0410% w/w drugAOT/IPM 0.8460.08 1.5360.12 0.1560.06 0.1660.065% w/w drugT21/AOT/IPM 1.3360.09 2.7460.30 0.1960.06 0.3860.0510% w/w drugT21/AOT/IPM 0.8760.19 1.5260.11 0.0860.07 0.1860.035% w/w drugT81/AOT/IPM 1.3360.18 2.8760.32 0.2560.07 0.3660.0510% w/w drugT81/AOT/IPM 0.8560.17 1.5960.12 0.1060.06 0.1860.075% w/w drugT85/AOT/IPM 1.3860.11 2.8460.38 0.1660.08 0.3660.0510% w/w drugT85/AOT/IPM 0.9360.13 1.5360.09 0.1460.05 0.2160.115% w/w drug

a Transdermal flux from MBGs and aqueous solution as a function of formulation and drug loading at constant iontophoretic currentdensity. Mixed surfactant MBGs contain 2:1 (w/w) Tween:AOT in isopropyl myristate.

b The aqueous solution of drug contains 1.07 or 2.14% w/w of sodium salicylate, equivalent to that in the MBG when the latter areexpressed as overall concentrations. Incubation temperature5258C.

sity resulted in an increase in average flux of 38% prevents the osmotic uptake of large amounts ofand 67%, respectively, for MBGs containing 5% water, which would otherwise disrupt the gel struc-w/w and 10% w/w salicylate in the dispersed ture and modify its physicochemical properties. It isaqueous phase. also notable and encouraging that no deleterious

The drug donor concentration and current density effects were observed when the MBGs were subjectalso had an effect on the lag time observed in the to iontophoresis with current densities up to 0.385

2drug release profiles. Under passive conditions, the mA/cm .lag time was reduced as the drug donor concentration The pH of the donor drug solution and the MBGincreased, typically from 3–4 h to around 2 h. Under was monitored during the course of the experiments.iontophoretic conditions, the lag times were much Under passive conditions the increase in pH was lessshorter (ca. 1 h) and inversely proportional to both than 0.2 from the starting pH of 5.8, which wasdrug donor concentration and current density. expected given the relatively small cumulative re-

lease after 8 h (see Table 2). The increase in pH3.4. The effect on MBGs and pH under iontophoretic conditions was more marked, but

the increases after 8 h were still relatively small atMBGs based on AOT in n-heptane have been 0.77 and ca. 0.6 pH units for the salicylate solution

reported to swell and eventually break down when and the MBGs, respectively. These modest changesplaced in contact with distilled water [19]. It is in pH are unlikely to affect the ionisation state of thetherefore notable that the salicylate-containing drug and are not therefore expected to impact on theMBGs formulated here could be contacted with observed release profiles from drug solutions. In thenormal saline for extended periods without obvious case of MBG drug reservoirs, the complex structureeffect on MBG stability. The excellent stability of of the organogel could be affected by factors such asthese MBGs in saline can be ascribed to achieving a change in pH. This is because of the importance ofbalance of ionic strength in the two phases. This electrostatic interactions which determine, for exam-


ple, the formation of the triple-helix in the gelatin broadly comparable to those attainable using aqueousdrug solutions, and the transdermal flux was propor-network. In the case of the experiments presentedtional to the drug loading and to the iontophoretichere, however, the release profiles obtained usingcurrent density. MBGs would be practically simplerMBGs were very similar indeed to those obtainedto use in the clinical environment, and the presenceusing salicylate solutions, and no obvious changes inof surfactants in the formulation may further enhanceMBG structure were apparent. The impact of thedrug penetration. The greater resistance toward mi-change in pH on drug release from MBGs iscrobial contamination of organogels compared totherefore considered to be negligible.hydrogels should provide an additional benefit.

3.5. MBG resistance to microbial contamination

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Gelatin-stabilised microemulsion-based organogels: rheology and application in iontophoretic transdermal drug delivery