Mukhergee-vol5no1 3/8/05 4:14 PM Page 96 …Pvt.Ltd.,Mumbai,India.Sorbitan monolaurate-20 (Span 20)...

Sorbitan Monolaurate 20 as aPotential Skin PermeationEnhancer in Transdermal PatchesBiswajit Mukherjee, MPharm, PhD*†

Kanupriya, MPharm†

Sushmita Mahapatra, MPharm*

Surajit Das, BPharm*

Balaram Patra, MPharm*

*Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India†University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Vol. 5, No. 1, 2005 • The Journal of Applied Research96

mg, 2.498 mg, 3.373 mg, 3.716 mg, and4.983 mg, in the formulations PA-1(PVP: EC 1:2), PA-2 (PVP: EC 1:2 withenhancer), PA-3 (PVP: EC 1:3), PA-4(PVP: EC 1:3 with enhancer), PA-5(PVP: EC 3:5), and PA-6 (PVP: EC 3:5with enhancer), respectively. There wasabout a 29% to 30% enhancement ofskin permeation of the drug using Span20. It is concluded here that the formu-lation PA-3 is the slowest in terms ofskin permeation of the prepared trans-dermal matrix patches for diclofenacdiethylamine and that Span 20 may bethe best choice amongst the skin perme-ation enhancers to permeate the drugsteadily. Moreover, extensive electronmicroscopic studies were conducted tounderstand drug distribution in thepatches, drug release from the patches,and the permeation of drug throughskin.

INTRODUCTIONGroundbreaking drug delivery systemsmay allow formulation scientists to uti-lize chemicals that are otherwise diffi-cult to use because of stability, toxicityor bioavailability problems. Drugadministration with specific deliverysystems can potentially facilitate the

KEY WO R D S : matrix type transdermalp a t c h e s, diclofenac diethylamine,sorbitanmonolaurate 20, rat skin

ABSTRACTThe objective of our present work wasto prepare transdermal matrix patchescontaining the drug, diclofenac diethy-lamine with various polymeric combina-tions of polyvinylpyrrolidone andethylcellulose and to study the mecha-nism of release of the drug from thepatches and its skin permeation.Sorbitan monolaurate 20 (Span 20), anon-ionic surfactant was added to theconcentrations (0.1% wt/vol), as a skinpermeation enhancer to the drug,diclofenac diethylamine. In vitro skinpermeation studies, with rat skin, using amodified Keshary-Chien diffusion cell,were carried out to establish the mostfavorable polymeric combination andthe impact of Span 20 was also studied.Extensive electron microscopy studieswere conducted and the underlyingmechanism of drug release from thepatches and its permeation through skinare discussed. Cumulative amounts ofdrug released, per cm2 of patch after 48hours, were found to be 2.6111 mg, 3.53

Mukhergee-vol5no1 3/8/05 4:14 PM Page 96

The Journal of Applied Research • Vol. 5, No. 1, 2005 97

delivery of drugs to the particular site ofaction, while reducing the undesired sideeffects, thus drastically increasing patientcompliance. Nowadays, transdermalpatch-type drug delivery systems areused as a new frontier for the adminis-tration of various drugs. Drugs aredelivered directly to the systemic circu-lation through intact skin, bypassinghepatic “first-pass” metabolism, and pro-vide controlled release of drugs forextended and safe use. The nonsteroidalanti-inflammatory drug, diclofenac, isused either topically or systemically totreat various disorders, such as rheuma-tism, osteoarthritis, osteoporosis, biliarycolic, renal colic, dysmenorrhea, etc.1-6

Ammonium salt (diclofenac diethy-lamine) is widely used for topical appli-cation.7 The drug causes gastric irritationand undergoes hepatic first-pass metab-olism and thus only 50% of drug reachesthe circulation.8 Moreover the drug pos-sesses almost all characteristics neededfor transdermal systemic formulations.Thus, the drug has reasonably been cho-sen to develop a transdermal formula-tion to increase patient compliance. Wehave been working on this delivery sys-tem for quite some time and have shownthat polymeric matrix (PVP: EC 1:2)containing the drug has a potential skinpermeation in vitro release profilethrough the abdominal skin.9 So, herevarious other formulations having poly-meric composition close to the previousbest polymeric combination (PVP: EC1:2) were studied to establish a poten-tially more favorable polymeric combi-nation. The non-ionic surfactant, 0.1%wt/vol sorbitan monolaurate-20 (Span20), was used to study its impact as anenhancer to skin permeation of the drugdiclofenac diethylamine. Moreover,extensive electron microscopic studieswere conducted in an effort to under-stand drug distribution in the patches,drug release from the patches, and thepermeation of the drug through skin.

MATERIAL AND METHODSMaterialsPolyvinyl alcohol (mol wt. 125,000, vis-cosity of 4% aqueous solution at 32˚C,50 cps) was purchased from S.D. FineChemicals Ltd., Boisar, India.Polyvinylpyrrolidone (K value 26-4 35)was purchased from HiMediaLaboratories Pvt. Ltd., Mumbai, India.Ethyl cellulose (ethoxy content, 47.5%-49%; viscosity, 14 cps in 5% wt/wt solu-tion in 80:20 toluene; ethanol, 25˚C) waspurchased from Central Drug HousePvt. Ltd., Mumbai, India. Sorbitanmonolaurate-20 (Span 20) was pur-chased from Loba Chemie Ltd.,Mumbai, India. Diclofenac diethylaminewas given by Kothari Laboratory,Saugor, India. Di-n-butyl phthalate waspurchased from SRL Pvt. Ltd. (Mumbai,India) All chemicals were used asreceived without any further purification.

MethodsProcedure for the preparation of patchesThe patches were developed using theprocedure mentioned earlier.9 In brief,backing membrane was prepared in a4% wt/vol aqueous solution of polyvinylalcohol, placed in cylindrical glass molds,and dried at 60˚C for 6 hours. The drugmatrix was cast using homogeneouslymixed combinations of polyvinylpyrroli-done and ethylcellulose along with thedrug (20% wt/wt of the total weight ofthe polymer) and the plasticizer, di-n-butyl pthalate (20% wt/wt of the totalweight of polymer) on the backingmembrane and dried at 40˚C for 4 hours.When the drug was mixed with the poly-mer-plasticizer mixture, 0.1% wt/volenhancer (Span 20) was added.

Drug-excipient interaction studyThe pure drug, diclofenac diethylamineand a mixture of it with the excipients,PVP, and EC were mixed separatelywith IR grade KBr in the ratio 100 to 1


and the pellets were prepared by apply-ing 5.5 metric tons of pressure in ahydraulic press. These pellets werescanned over a wave number range of4000 to 400 cm-1 in a Magna IR 750series II FTIR instrument (Nicolet,Madison, Wis).

Evaluation of polymeric filmsPhysical characterizations of the pre-pared films were evaluated through thefollowing physical studies: 1) moisturecontent, 2) moisture uptake, and 3) flat-ness (Tables 1 and 2).

Moisture content. The prepared filmswere weighed individually and kept in adessicator containing silica at room tem-perature for 24 hours. The films wereweighed again and again until theyshowed a constant weight. The percentmoisture content was calculated usingthe following formula:Percent moisture content = [Initialweight - Final weight/Final weight] ¥100

Moisture uptake. The weighed film waskept in a dessicator at room tempera-ture for 24 hours. It was then taken outand exposed to 84% relative humidity

using a saturated solution of potassiumchloride in a dessicator until a constantweight was achieved. The percent mois-ture uptake was calculated by using thefollowing formula:Percent moisture uptake = [Finalweight-Initial weight/Initial weight] ¥100

Flatness. One strip was cut one from thecenter and two from each side of thepatches. The length of each strip wasmeasured and the variation in lengthwas measured by determining percentconstriction. Zero percent constrictionwas considered equivalent to one hun-dred percent flatness. Percent constric-tion is defined as follows: Constriction(%) =( l1-l2)/ l1 ¥ 100 where l2 equalsfinal length of each strip, and l1equalsinitial length of each strip.

In vitro release-dissolution studiesIt is desirable to maintain greater drugconcentrations at the surface of stratumcorneum than in the body. This isrequired to achieve a constant rate ofpermeation. The dissolution study, usingUSP Paddle Type DissolutionApparatus, was carried out at 32˚C at 50-rpm frequency of the paddle. PEG 400


Table 1. Composition of the Prepared Film Without Enhancer

S. No. Formulation Code Ratio of PVP: EC Total weight of PVP and EC (mg)

1. PA-1 1:2 500

2. PA-3 1:3 500

3. PA-5 3:5 500

Table 2. Composition of Prepared Film with Enhancer

S. No. Formulation Ratio of PVP: EC Total weight of Enhancer Code polymers PVP (Span 20)

and EC (mg)

1. PA-2 1:2 500 0.1 wt/vol of the polymer





(20% vol/vol) in normal saline was usedas the dissolution media. The patcheswere tied with a thin copper wire andthen placed in a jar. Samples were with-drawn at different time intervals andthen analyzed using a UV spectropho-tometer at 275 nm against blank.Dissolution was carried out for 4 differ-ent sets and corrected absorbance (Ca)was calculated using the formula:

n Vs n-1

Ca = i - 1 Ai + ∑ AiVt i = 1

Ai indicates absorbance of ith reading;Vs, volume of the sample, and Vt, vol-ume of dissolution medium.

The amount of drug was calculated fromthe standard curve and percentage ofdrug released was determined using theformula below:

% of drug released = Da/Dt ¥100

Dt indicates the total amount of drug inthe patch; and Da, the amount of drugreleased.

In vitro skin permeation studyThe in vitro permeation studies werecarried out in a modified Keshary-Chiendiffusion cell with a capacity of 30 mL,using Sprague-Dawley male rat skin.The skin was used after the removal ofadhering fat. A section of skin was cutand placed in the donor compartment,keeping the dorsal side upward, and thepatch was placed on the skin with thedrug matrix side towards the donor sideand backing membrane on the upperside. The holder, containing the skin andthe formulation, was placed on thereceiver compartment of the cell con-taining the dissolution media (ie, PEG400) (20% vol/vol) in normal saline. Thetemperature of the cell was maintained

at 32˚C by circulating water jacket. Thiswhole assembly was kept on a magneticstirrer and the solution was stirred con-tinuously using a magnetic bead. A simi-lar set was run simultaneously withoutusing the patch at the donor compart-ment as a skin control. The sampleswere withdrawn at different time inter-vals and replaced with equal amounts ofdissolution media. Samples were ana-lyzed spectrophotometrically at 275 nmand the amount of drug permeated percm2 of patch was calculated from thestandard curve and plotted against time.The difference between the readings ofdrug skin permeation and skin controlwas used as the actual reading in eachcase.

Scanning electron microscopyThe external morphology of the skinand the transdermal patch (with andwithout enhancer) was analyzed using ascanning electron microscope. The skinwas first fixed with the help of a fixative(ie, 4% glutaraldehyde) in 0.2 mol sodi-um phosphate buffer (pH 7.2-7.4). Theskin was washed with buffer thoroughlyand then subjected to dehydration withacetone. The moisture from the skin wasremoved by using increasing concentra-tions of acetone. The section of the skinwas cut and mounted on stubs using anadhesive tape. The samples placed onthe stubs were coated with gold palladi-um alloy using a fine coat ion sputter(JOEL, fine coat ion sputter JFC-1100).The sections were examined under scan-ning electron microscope (JSM 6100JEOL, Tokyo, Japan). The abdominalskin of the rat was excised and the fatlayer was removed, carefully keeping theunderlying dermal tissues containingcapillary network intact, using a sterilescalpel with the help of a high powermagnifying glass. The process was con-ducted very quickly and the tissue wasimmediately used for experiments.



StatisticsData were analyzed using the standardstatistical methods.

RESULTSSome important physicochemicalparameters of the prepared formulationswere evaluated in this study (Tables 1and 2). The transdermal patches wereexposed to 84% relative humidity andthe percentage moisture uptake of theformulation was determined (Figure 1).It was observed that with an increasingpercentage of hydrophilic polymer, PVP,in the formulations, moisture contentincreased. Interestingly, with the addi-tion of Span 20 in the patches, littleincrease (statistically insignificant) ofmoisture was observed. A similar obser-vation was made in the case of percent-age moisture content (Figure 2).

A transdermal patch should possessa smooth surface and should not con-strict with time, as the flatness studydemonstrated. No constriction wasobserved in any of the prepared formu-lations; all of the surfaces were 100%flat (Table 3). Fourier transform infraredspectroscopy (FTIR) was carried out toassess the interaction between the drugand the excipients (Figures 3a and 3b).Graphs of drug and drug-excipientsshow that there is no interactionbetween the drug and excipients used.

Drug release from polymer matrix anddrug dissolution ensures sustainedreproducibility of rate and duration ofdrug release. Dissolution studies for dif-ferent formulations were carried outusing USP paddle type apparatus usingPEG 400 and normal saline as dissolu-tion fluid at 32˚C. An initial burst effectwas observed in formulations PA-5(PVP: EC 3:5 without enhancer) andPA-6 (PVP: EC 3:5 with enhancer)(Figure 4). In this figure the mean cumu-lative amount released for formulationPA-5 decreases in 4 hours compared to 3hours. The reason could be the widevariation of data of drug release in twoof the experiments, out of 4 performed.However, in Figure 5, which depicts invitro skin permeation, no such discrep-ancies are seen in any of the formula-tions. Hence, an experimental errorduring sampling could be one possiblereason for the decrease in the cumula-tive amount seen in the case of formula-tion PA-5 at the particular time point. Invitro skin permeation study is predictiveof an in vivo performance of a drug. Thisstudy was carried out using different for-mulations in a modified Keshary-Chiencell using rat skin. Mean cumulativeamounts of drug released per cm2 ofpatch after 48 hours were found to be2.6111 mg, 3.53 mg, 2.498 mg, 3.373 mg,3.716 mg, and 4.983 mg, for the formula-

Figure 2. Percentage moisture content ofdiclofenac diethylamine containing differentmatrix films prepared by using different ratiosof polyvinylpyrrolidone and ethyl cellulose.Data shows mean (n = 5) ± SD.

Figure 1. Percentage moisture uptake fromdiclofenac diethylamine containing differentmatrix films prepared by using different ratiosof polyvinylpyrrolidone and ethyl cellulose.Data shows mean (n = 5) ± SD.



tions PA-1 (PVP: EC 1:2), PA-2 (PVP:EC 1:2 with enhancer), PA-3 (PVP: EC1:3), PA-4 (PVP: EC 1:3 with enhancer),PA-5 (PVP: EC 3:5), and PA-6 (PVP: EC3:5 with enhancer), respectively (Figure5). Again percentages of drug releasedper cm2 of the patches after 48 hourswere 13.05%, 17.65%, 12.49%, 16.86%,18.58%, and 24.91%, for the formula-tions PA-1, PA-2, PA-3, PA-4, PA-5, andPA-6, respectively.

The study clearly indicates the skinpermeation enhancement of the drug byusing sorbitan monolaurate 20. About29% to 30% enhancement of skin per-meation is seen (Figure 5). With a littlevariation of ratio of PVP and EC from1:2 to 3:5, an “initial burst effect” wasnoticed (Figure 4). Again, when skinpermeation studies were conducted, therates of skin permeation in those formu-lations (PA-5 and PA-6) were high. Itmay be because the formulations losttheir polymeric chain network and pro-vide an “initial burst” effect and anopening for the drug cluster for fasterrelease through them.

EM ResultElectron microscopic studies were con-ducted to visualize drug penetrationthrough the skin and its distribution inthe matrix patches. The drug distribution

in the matrix patches was a particulatedistribution (Figure 6). The drug and theexcipients were soluble in chloroformand no chemical interaction was noticed,when FTIR results were compared(Figure 3). Figure 7 shows one of thedrug clusters on the skin surface duringits entry through a skin appendage. Thisresult confirms that the drug remains incluster form when it reaches the surface.Figure 8 shows a drug cluster is passingthrough one of the skin appendagesfrom the dorsal side to the ventral sideof the skin. Figure 9 shows that drugclusters reached the ventral side of theskin. These figures clearly indicate thatthe drug, in cluster form, was transport-ed from the dorsal side to the ventralside of the skin. In an experiment with aspecially prepared skin, keeping theblood capillary network intact at theventral side, it was shown that the drugreaches the ventral side of the skin(Figure 10). Again, this shows that thedrug travels in cluster form, even whenit passes through the skin, and that adrug particle reached the surface ofblood capillaries to diffuse the drug mol-ecules in the blood.

DISCUSSIONIn this study, transdermal patch deliverysystems, containing the well-established

Table 3. Determination of Flatness of the Films

Formulation PVP: EC Film length (cm) Amount of constriction Flatness Code in the strips (%)

PA-1 1:2 2.5 ± 0.01* 0 100

PA-2 1:2 with enhancer 2.5 ± 0.01 0 100(Span 20)

PA-3 1:3 2.5 ± 0.005 0 100


PA-5 3:5 2.5 ± 0.004 0 100


*Data represents mean ± SE (n = 6)



nonsteroidal anti-inflammatory anal-gesic drug diclofenac diethylamine(diethylammonium salt of diclofenac) invarious combinations of ethylcellulose-polyvinylpyrrolidone polymeric matriceswith or without sorbitanmonolaurate 20(Span 20) as skin permeation enhancer,were developed for percutaneous stud-ies of transdermal drug delivery systems.The patches were subjected to in vitropermeation and permeation enhance-ment studies through rat skin using amodified Keshary-Chien diffusion cell.Some physicochemical parameters likemoisture content, moisture uptake, andflatness were also carried out to evalu-ate the physicochemical stability of theformulation. An electron microscopicwas used to visualize what actually hap-pens when the drug diffuses through theskin and how it diffuses from the patch

formulations. The drug molecules weredistributed in the form of small clusterswithin the range of 1 to 3 µm. Thoughthe drug, polymers, plasticizer, andenhancer are completely soluble in chlo-roform, the distribution of the drug inthe polymer matrix was in a particulatedistribution (Figure 6). Stability of a for-mulation primarily depends on the com-patibility of the drug with the excipients.Hence, it is important to detect any pos-sible chemical or physical interactions,since they can affect the bioavailabilityand stability of the drug.10

Drug-excipient interactions werestudied using FTIR technique to under-stand the physical and chemical interac-tions that could occur in the drug andexcipients. FTIR study implied that allthe excipients are compatible withdiclofenac diethylamine. Changes in

Figure 3A. IR spectra of pure drug.



areas of peaks occur simply due to mix-ing of components without any physicaland chemical interactions. In our previ-ous study,9 we also found that there wasno chemical interaction betweendiclofenac diethylamine and the sameexcipients using Thin LayerChromatography technique. The inter-molecular forces between drug mole-cules are stronger (ionic in nature), ascompared to those between the drugand the polymers (ie, ionic drug andslightly polar matrix compounds). Drugmolecules through electrostatic forcesmay form soluble polyion drug complexaggregates11 surrounded by polymermolecules, which prevents drug aggre-gate precipitation while in the solution.Simultaneous precipitation of drug com-plexes with polymers takes place duringthe solvent evaporation technique.

As human skin is not easily availablefor experimentation, rat and mouse skinare frequently used for in vitro studiesof skin permeation of drugs.12-14 Theselection of receptor fluid is an impor-tant criterion in the design of in vitrostudies for transdermal drug deliverysystems. Biphasic characteristics of thereceptor fluid are desirable, since drugmolecules are diffused through bothaqueous and nonaqueous heterogeneousmedia. PEG 400, plus water or normalsaline, is commonly chosen to providethe biphasic characteristics to the recep-tor fluid.15 Moreover, PEG 400 is consid-ered to be a non-interacting fluid for thereceptor media.16 Percutaneous absorp-tion of the drug is believed to take placethrough various skin appendages (ie,sweat and sebaceous ducts, hair follicles,etc), at an early stage and at steady

Figure 3B. IR spectra of drug and excipients.



state. These routes are considered signif-icant, with the implication that variousshunt pathways from one part of theskin to the other may result in the ulti-mate skin release profile of the drug.17

The electron microscopic study of thedorsal sides of the skin, used for skinpermeation studies after the applicationof the various patches, depicted no suchdistinctive changes of the skin condition,except some more flat physical surfaceappearances of the skin exposed to theformulation with enhancer (data notshown). This suggests that there is noharmful effect of Span 20, when used asa skin permeation enhancer at the con-centration used in our study, in transder-mal patch form, even after 48 hours ofadministration. Figure 7 shows one ofthe drug polyion complexes (shown byarrow 2) on the skin surface during theirentry through skin appendage (shownby arrow 1). Figure 8 shows a drug clus-ter passing through one of the skinappendages from the dorsal side to theventral side of the skin. Figure 9 showsthat drug clusters reached the ventralside of the skin. These figures clearlyindicate that the drug in cluster formwas transported from the dorsal side tothe ventral side of the skin. Again skinwas specially prepared keeping theblood capillary network intact at theventral side, and the experiment wasconducted to monitor big drug complex-

es after diffusion through the epidermis.Of particular interest was how such abig cluster of drug molecules is absorbedthrough blood capillaries, when the cap-illary diameters are smaller.Interestingly, it was observed that a drugcluster reached the surface of blood cap-illary by diffusing the drug moleculethrough the capillary walls in the blood(Figure 10).

The scanning electron microscopicstudy showed skin permeation of solubledrug clusters through skin appendagesand that small soluble clusters of drugmolecules penetrate through theappendages to blood capillary walls,which then dissolve and penetrate as sol-uble molecules in the blood. This is estab-lished for the first time in this study. Westrongly believe that soluble drug mole-cules of drug clusters not only penetratethrough the intact skin texture, but theyalso permeate through the appendages.Based on this observation, we stronglybelieve that the diffusion of the drugthrough blood capillary walls plays a verysignificant rate-limiting role, as it does inthe passage of the drug through epider-m i s. The skin permeation study may notclearly predict the blood level of the drugin transdermal patch formulations. Th e r eis little doubt that skin permeation can beenhanced by non-ionic surfactants,including sorbitan esters and polyoxyeth-ylene sorbitan esters.1 8 - 2 3

Figure 4. In vitro drug dissolution profiles ofdiclofenac diethylamine from different PVPand EC matrix patches in PEG400+Normalsaline. Data shows mean ± SE (n = 4).

Figure 5. In vitro skin permeation ofdiclofenac diethylamine from different PVPand EC matrix patches, through rat abdomi-nal skin. Data shows mean ± SE (n = 4).



The mechanism of penetrationenhancement effects of the surfactants isprimarily believed to be due to the pro-motion of membrane-vehicle partition-ing tendency of the drug.24 Penetration

of the surfactants into the intracellularlipid phase of the membrane may alsoincrease the degree of fluidity in thisphase resulting in a decreased resistanceto permeation.25 Increase in this flux ofthe drug across the skin is mainly due tosolvent drag effect.26 The penetration ofthe solvent itself, and subsequent drag ofthe drug cluster with it, is the mecha-nism of drug release from the patches.Span 20 increases the quick partitioningof the drug in the solvent16 and smalldrug-polyion complexes (approximately3 µm are dragged by the solvent throughthe appendages, the average diametersof which are about 50 µm. The drivingforce behind this diffusive transport is agradient in the chemical potential.27

Some important physicochemicalparameters of different formulated

Figure 6. SEM photograph of the transdermalpatch shows the distribution of the drug inthe matrix as particulate distribution.

Figure 7. SEM photograph shows one of thedrug particles on the skin surface during theirentry through skin appendage.

Figure 8. SEM photograph shows drug onecluster passing through one of the skinappendages from the dorsal side to the ven-tral side of the skin.

Figure 9. SEM photograph shows a drug clus-ter as such reached at the ventral side of theskin.

Figure 10. SEM photograph shows how a drugcluster proceeds for absorption through thewall of blood capillary at the ventral side ofthe skin.

Mukhergee-vol5no1 3/8/05 4:15 PM 5


patches were evaluated in this study. Themoisture content and moisture uptakeof the various formulations showed thatwith the increase in concentration ofhydrophilic polymer and PVP, both thepercentage of moisture content and thatof moisture uptake increased (Figures 1and 2). Again, 100% flatness (ie, noamount of constriction) was observed(Table 3). This finding demonstrates flatand smooth patch surface, a very impor-tant characteristic of transdermal patchtype formulation. The percentage mois-ture content and moisture uptake wasfound to be maximal for formulationPA-5 and PA-6. A little bit of moisturecontent prevents the brittleness of thepatches, while less moisture uptake indi-cates the stability of the formulation,since a greater amount of moistureuptake indicates bulkiness of the formu-lation. Moreover, the chance of micro-bial growth cannot be ignored. Polymerdissolution and drug release from poly-meric matrix is known to ensure sus-tained release characteristics, as well asreproducibility of rate and duration ofdrug release.28 In this study, we foundthat formulation (PVP: EC 3:5) with orwithout enhancer showed ‘initial burst’release. This may be due to the presenceof higher percentages of hydrophilicpolymer polyvinylpyrrolidone, whichmight need a small “time lag” to estab-lish a concentration profile in the patch-es, resulting in a burst release effect inthe dissolution study.

When in vitro skin permeation ofthe drug from different formulationswas compared, variable cumulative drugrelease profiles were observed in formu-lations PA-1 to PA- 6. Formulations, PA-1 to PA-6, had a zero order profiles ofcumulative amounts of drug release overtime. The formulation PA-3 (PVP: EC1:3) had the slowest release, whereas theformulation PA-6 (PVP: EC-3: 5 withenhancer Span 20) had the fastestrelease of drug, among the formulations

studied (Figure 5). After 48 hours, thepercentages of drug permeated throughthe skin were about 12.5% (PA-3) and25% (PA-6). When the enhancer, Span20, was used in the same composition ofthe formulation PA-3, the percentagedrug release was about 17% instead of12.5% after 48 hours. For formulationPA-5 (ie, the same composition of PA-6without enhancer), the percentage drugrelease was about 18.5% in 48 hours.Therefore, enhancing the capability ofskin permeation of the diclofenacdiethylamine drug by Span 20 is unam-biguous. In fact, when the mean cumula-tive amounts of drug release throughskin were studied, any of the polymericcombinations seem suitable for thepreparation of transdermal matrixpatches containing diclofenac diethy-lamine. Combinations of polymers usedhere provide a sustained release of thedrug in all formulations and theenhancer reasonably increased (about29-30%) the amount of drug releasedfrom the patches through the skin.

CONCLUSIONAll the formulations may be chosen forfurther in vivo studies, except formula-tions PA-5 (PVP: EC 3:5) and PA-6(PVP: EC with enhancer) because theyshow an initial ‘burst effect’. The formu-lation PA-3 (PVP: EC 3:5) showed theslowest and sustained release of thedrug through the skin. Using Span 20,there was about a 29% to 30% enhance-ment of skin permeation of the drug.Again, it is concluded here that the for-mulation PA-3 is the slowest in terms ofskin permeation amongst the preparedtransdermal matrix type patches fordiclofenac diethylamine and Span 20may be an option amongst the skin per-meation enhancers for permeating thedrug steadily through the skin. Further,the study demonstrates that the solventdrags the drug diclofenac diethylaminein the soluble cluster form through the



skin appendages, and they reach the wallof the blood capillaries.

ACKNOWLEDGEMENTWe are thankful to the UniversityGrants Commission, Government ofIndia and Dr. V. Ravi ChandranEndowment Fund for financial supportto carry out the work.

REFERENCES1. Zuckner J. International Experience with

diclofenac in rheumatoid arthritis. Am J Med.1986;4B(suppl):39-42.

2 . Piccinini F, Rovati L, Zanni A , Cagnacci A ,Volpe A , Facchhinetti F. Indirect evidence thatestrogen replacement therapy stimulates nitricoxide synthetase in postmenopausal women.Gyaenacol Endocrinol. 2 0 0 0 ; 1 4 : 1 4 2 - 1 4 6 .

3. Moya RA, Moisa CF, Morales F, Wynter H,Narancis E. Transdermal glyceryl trinitrate inthe management of primary dysmenorrhea.Int J Gynaecol Obstet. 2000;69:113-118.

4. Ku EC, Wasvary JM, Cash WD. Diclofenacsodium (GP 45840, VollarenTM) a potentinhibitor of prostaglandin synthetase.Biochem Pharmacol. 1975;24:641-343.

5. Lundstam S, Tveit E, Kral JG. Prostaglandinsynthesis inhibition by diclofenac sodium inbiliary pain. Eur J Clin Invest. 1983;13:A1.

6. John VA. The pharmacokinetics and metabo-lism of diclofenac sodium (VoltarolTM) inanimals and man. Rheumatol Rehabil.1979;2(suppl):22-37.

7. Riviere JE, Papich MG. Potential and prob-lems of developing transdermal patches forveterinary applications. Adv Drug Del Rev.2001;50:175-203.

8. Zevin S, Jacob P III, Benowitz NL. Nicotine-mecarylaim interaction. Clin Pharmacol Ther.2000;68:58-66.

9. Arora P, Mukherjee B. Design, development,physicochemical and in vitro evaluation oftransdermal patches containing diclofenacdiethylamine. J Pharm Sci. 2001;91:2076-2089.

10. Levy G, Reuning RH. Effect of complex for-mation on drug absorption. I. Complexes ofsalicylic acid with absorbable and nonab-sorbable compounds. J Pharm Sci.1964;53:1471-1475.

11. Merkle HP, Knoch A, Gienger G. Releasekinetics of polymeric laminates for transder-mal delivery: Experimental evaluation andphysical modelling. J Control Release.1985;2:99-110.

12. Shokri J, Nokodchi A, Dashbolaghi A,Hassen-Zadeh D, Ghafourian T, Barzegar MJ.The effects of surfactants on the skin penetra-tion of Diazepam. Int J Pharm. 2001;228(1-2):99-107.

13. Wu PC, Fang JY, Huang YB, Tsai YH. In vitroeffect of penetration enhancers on sodiumnonivamide acetate in rat skin. Biol PharmBull. 1995;18(12):1790-1792.

14. Nokodchi A. The enhancement effects of sur-factants on the penetration of lorazepamthrough rat skin. Int J Pharmacol.2003;250:359-369.

15. Gupta R, Mukherjee B. Development and invitro evaluation of diltiazem hydrochloridetransdermal patches based on povidone-eth-ylcellulose matrices. Drug Dev Ind Pharm.2003;29:1-7.

16. Sartopdar PP, Gaskill JL, Gianinni RP. Effectof PEG 400 on the penetration of drugsthrough human cadaver skin in vitro. J PharmSci. 1986;75:26-28.

17. Johnson ME, Blankschtein D, Linger R.Evaluation of solute permeation through thestratum corneum: Lateral bilayer diffusion asthe primary transport mechanism. J PharmSci. 1997;86:1162-1172.

18. Arellano A, Santoyo S, Martn C, Ygartua P.Surfactant effects on the in vitro percuta-neous absorption of diclofenac sodium. Eur JDrug Met Pharmacokinet. 1998;23:307-312.

19. Ashton P, Hadgraft J, Walters KA. Effects ofsurfactants in percutaneous absorption.Pharm Acta Helv. 1986;61:228-235.

20. Aungst BJ, Rogers NJ, Shefter E.Enhancement of naloxone penetrationthrough human skin in vitro using fatty acids,fatty alcohols, surfactants, sulfoxides andamides. Int J Pharm. 1986;33:225-234.

21. Walters KA, Olejink S, Harris S. Influence ofnon-ionic surfactants on permeation of ion-ized molecules through hairless mouse skin. JPharm Pharmacol. 1984;36:78.

22. Kim J, Lee CH, Choi HK. Transdermal deliv-ery of Physostigmine: Effects of enhancersand pressure sensitive adhesives. Drug DevInd Pharm. 2002;28;833-839.

23. Zhao H, Park DW, Kim S, Lee C, Kim D. Theeffects of pressure sensitive adhesives andstabilizers on the skin permeation ofTestosterone from a matrix type transdermaldelivery system. Drug Dev Ind Pharm.2002;28,1125-1131.

24. Florence AT, Tucker IG, Walters KA.Interaction of non ionic polyoxyethylenealkyl and aryl ethers with membranes andother biological system. In: Rosen MJ, ed.Structure performance relationships in sur-



factants. Washington, DC: ACS; 1984:189-207.ACS Symposium Series, No. 253.

25. Walters KA, Walker M, Olejnik O. Non ionicsurfactant effects on hairless mouse skin per-meability characteristics. J Pharm Pharmacol.1988;40:525-529.

26. Berner B, Mazzenga GC. Ethanol watermutually enhanced transdermal system II:Skin permeation of ethanol and nitroglycer-ine. J Pharm Sci. 1989;78:402-407.

27. Katcahalsky A, Curran PF. Membrane perme -ability to non electrolytes:discontinuous sys -tems in: Nonequilibrium thermodynamics inBiophysics. Cambridge, Mass: HarvardUniversity; 1965:113-132.

28. Martin A, Bustamante P, Chun AHC.Kinetics. In: Physical Pharmacy. New Delhi,India: Waverly Pvt Ltd; 1999:167-287.


Mukhergee-vol5no1 3/8/05 4:14 PM Page 96 …Pvt.Ltd.,Mumbai,India.Sorbitan monolaurate-20 (Span 20)...

Documents

Transcript of Mukhergee-vol5no1 3/8/05 4:14 PM Page 96 …Pvt.Ltd.,Mumbai,India.Sorbitan monolaurate-20 (Span 20)...