The blanching activities of Betnovate and Celestoderm-V lotions (betamethasone-17-valerate, 0,1%) and Diprosone lotion (betamethasone dipropionate, 0,55%) were determined by measuring their ability to cause blanching of human skin after topical application. Betnovate and Celestoderm-V lotions produced almost identical blanching profiles. Diprosone lotion displayed a statistically significant superior blanching acitivity over both Betnovate and Celestoderm-V lotions over the whole timespan of the trial

Haigh, J M

Kanfer, I

Meyer, I

Kanfer, Isadore

Haigh, John M

Rhodes Repository (SEALS)

The Academy of Pharmaceutical Sciences of the Pharmaceutical Society ofSouth AfricaComparativeblanching activitiesof some topicalcorticosteroidcontaining lotionsbyE. Meyer, I. Kanfer and J.M. Haigh,School of Pharmaceutical Sciences,Rhodes University, Grahamstown, South Africa.Abstract'The blanching activities of Betnovate and Celestoderm- V lotions(betamethasone-17-valerate, 0,1%) and Diprosone lotion (beta-methasone dipropionate, 0,55%) were determined by measuringtheir ability to cause blanching of human skin after topical appli-cation.Betnovate and Celestoderm-V lotions produced almost identicalblanching profiles. Diprosone lotion displayed a statistically sig-nificant superior blanching acitivity over both Betnovate and Ce-lestoderm- V lotions over the whole timespan of the trial.IntroductionIT has been well documented that the blanching assay first de-scribed by McKenzie and Stoughton may be used as a reliable indi-cator of the rate of release of a cortiocosteroid from topically appliedformulations (1). There is also a direct relationship between theblanching activity of a topically applied corticosteroid and its clinicalefficacy (2).This trial was performed to compare the blanching activities of twolotions containing betamethasone-17 -valerate (0,1 %) and one lotioncontaining betamethasone-17,21-dipropionate (0,05%).Occlusion of the sites of application greatly enhances the blanchingeffect due to increased penetration of the corticosteroid into the skin(2), but the trial was performed in both the occluded and unoc-cluded mode because in practice the .unoccluded mode is usedmost often, especially in the case of lotions which are mainly appliedto the scalp and other hairy areas of the body.The structure of the side chains at the 17 and 21 positions is prob-ably responsible for the difference in activity of the two corticoste-roids. McKenzie and Atkinson (3) reported differences in the poten-cies of the 17-propionate and 17-valerate esters relative to fluocino-lone acetonide. Betamethasone-17-propionate was 190% more ef-fective than fluocinolone acetonide and betamethasone-17 -valeratewas 360% more effective than fluocinolone acetonide when evalu-ated by the vasoconstriction assay. It can therefore be concludedthat the 17-valerate is almost twice as potent as the 17-propionate.It has been shown (4) that the effect of betamethasone-17,21-dipro-pionate is superior to that of betamethasone-17-valerate, with re-spect to both the blanching and therapeutic action. This illustratesthe importance of the 21-propionate in the 17,21-dipropionate withrespect to the structure activity relationship of betamethasoneesters (Figure 1).The present study therefore served the purpose of comparing theblanching activities of the two betamethasone-17-valerate contain-ing lotions (Betnovate and Celestoderm-V) to each other and to thebetamethasone-17,21-dipropionate containing lotion (Diprosone).SA Pharmaceutical Journal- November 1981.~~:.Materials and methodsThe three lotions were purchased shortly before the trial at a localpharmacy.Twelve healthy Caucasian volunteers were selected from a panelknown to show a response to topically applied corticosteroids. No. reference was made to sex or steroid sensitivity. The volunteers hadnot received topical or systemic corticosteroids for at least sixweeks prior to the investigation.The lotions 'were applied to the flexor aspect of the forearm in fourdifferent arrangements, each application pattern being chosenrandomly to avoid any bias during application and observation. Fivemicroliters of fhe lotion (equivalent to approximately 4mg) was ap-plied to twelve 7mm square sites on each forearm of the volunteersin a double blind fashion using a micro-pipette. The pipette was alsoused to spread the lotions immediately after application. ~ ,CH20COCH2CH3I=0---OCOCH2CH3CH3BETAMETHASONE DIPROPIONATE(DIPH.OSONE)CH20HI'=0.- --OCO(CH2hC H3CH3BETAMETHASONE 17-VALERATE(BETNOVATE, CELESTODERM-V)Figure 1551AcademyIn the occluded mode the sites were covered with a non-porousplastic covering (Blenderm Surgical tape) and the non-occludedsites were protected by cardboard coverings cut in such a way soas to allow a free flow of air.The residual steroid was removed from all the sites six hours afterapplication by gentle washing with soap and warm water. Thedegree of blanching for each site was recorded independently bythree experienced observers at 7, 8, 9, 10, 12, 14, 16, 18 and 28hours aft~r application using a Q-4scale:0 = normalskin .1 = slight vasoconstriction2 = more intense vasoconstriction3 = general even vasoconstriction with distinct blanching4 = marked vasoconstriction with very distinct blanchingThe methods used to evaluate the results were the area under thecurve (AUG), the number of sites exhibiting blanching, the gradedintensity of vasoconstriction and a paired comparison of adjacentsites (5). Blanching profiles (Rgures 2 and 3) were obtained usingthe percentage of the total possible score and the time in hours afterapplication.R.sults and discussionIn the occluded mode the AUC for Diprosone was greater than thatof Calestoderm-V which was greater than that of Betnovate. In all themethods of analysis there was no significant difference betweenBetnovate and Celestoderm-V (except the graded response at 16hours which was in favour of Celestoderm-V), and Diprosone wassignificantly better in all the methods of analysis at most of the timeintervals - especially at the peak times, i.e. between 8 and 18hours after application.The AUC in the tlnoccluded mode was greatest, for Diprosone with. Betnovate and Celestoderm-V giving very similar values. All theother methods of analysis gave results of Diprosone being signifi-.cantly better thiln Betnovate and Celestoderm-V. No significant dif-ferences were exhibited between Betnovate and Celestoderm-V.803020fJ'0 . .10 HOURS-20Figure 2. Blanching profiles of lotions in theoccluded mode.10552H'30t'.TPS20102"0 10HOURSFigure 3. Blanching profiles of lotions in theunoccluded mode.The main conclusions that can be drawn from this trial are that:(i) Diprosone lotion has a statistically significant superior blanchingactivity over Betnovate lotion and Celestoderm-V lotion, eventhough the concentration of the corticosteroid in Diprosone lotionis half of that of the other two lotions. It would be expected that ifthese lotions were formulated containing the same.concentrationof corticosteroid, the differences in the blanching activitieswould be even more marked.(ii) There are no statistically significant differences between theblanching activities of Betnovate lotion and Celestoderm-Vlotion. This is not necessarily expected as it is a well-establishedfact that the nature of the base affects the release of the activeingredient. Betnovate cream and Celestoderm-V cream shqwsimilar blanching activities, whereas Celestoderm-V ointmenthas a superior activity to that of Betnovate ointment (6); A similarexample of the influence of the base has been observed in thecas.eof fluocinolone acetonide (7).It could be expected, however, that due to the good surfacecoverage, skin contact and spreadibility of lotions, that the corti-costeroid would be released equally well from different lotion~~ 0AcknowledgementsOne of us (E.M.) acknowledges the H. Bradlow Scholarship for post-graduate studies.References1. McKenzie, AW., Stoughton, A.B. (1962) Arch. Derm. 86: 608-6102. McKenzie, AW., (1962) Arch. Derm. 86: 611-6143. McKenzie, AW., Atkinson, R.M. (1964) Arch. Derm. 89: 741-7464. Frederiksson, T., Gip, L., Hamlelt, A (1975) CurroTherap. Res. 18: 324-3315. Coleman, G.L., Kanler, I., Haigh, J.M. (1978) Dermatologica 156: 224-2306. Coleman, G.L. (1977) M.Sc. Thesis, Rhodes University, Grahamstown7. Coleman, G.L., Magnus, AD., Haigh, J.M., Kanter, I. (1979) S. AIr. Med. J.56: 447-448. SA Tydskritvir ApteekV\lese- November 198176I6050"10TPS4-0

Comparative blanching activities of some topical corticosteroid containing lotions

South East Academic Libraries System (SEALS)

The Academy of Pharmaceutical Sciences of the Pharmaceutical Society ofSouth AfricaComparativeblanching activitiesof sometopicalcorticosteroidcontaining lotionsbyE. Meyer, I. Kanfer and J.M. Haigh,School of Pharmaceutical Sciences,Rhodes University, Grahamstown,South Africa.Abstract'The blanching activities of Betnovate and Celestoderm- V lotions(betamethasone-17-valerate, 0,1%) and Diprosone lotion (beta-methasone dipropionate, 0,55%) were determined by measuringtheir ability to cause blanching of human skin after topical appli-cation.Betnovate and Celestoderm-V lotions produced almost identicalblanching profiles. Diprosone lotion displayed a statistically sig-nificant superior blanching acitivityover both Betnovate and Ce-lestoderm-V lotions over the whole timespan of the trial.IntroductionIT has been well documented that the blanching assay first de-scribed by McKenzie and Stoughton may be used as a reliable indi-cator of the rate of release of a cortiocosteroid from topically appliedformulations (1). There is also a direct relationship between theblanching activityof a topically applied corticosteroid and its clinicalefficacy (2).This trial was performed to compare the blanching activities of twolotions containing betamethasone-17-valerate (0,1%) and one lotioncontaining betamethasone-17,21-dipropionate (0,05%).Occlusion of the sites of application greatly enhances the blanchingeffect due to increased penetration of thecorticosteroid intothe skin(2), but the trial was performed in both the occluded and unoc-cluded mode because in practice the .unoccluded mode is usedmost often, especially in the case of lotions which are mainlyappliedto the scalp and other hairy areas of the body.The structure of the side chains at the 17 and 21 positions is prob-ably responsible for the difference in activity of the two corticoste-roids. McKenzie and Atkinson (3) reported differences in the poten-cies of the 17-propionate and 17-valerate esters relativeto fluocino-lone acetonide. Betamethasone-17-propionate was 190% more ef-fective than fluocinolone acetonide and betamethasone-17-valeratewas 360% more effective than fluocinolone acetonide when evalu-ated by the vasoconstriction assay. It can therefore be concludedthat the 17-valerate is almost twice as potent as the 17-propionate.Ithasbeenshown(4)thattheeffectof betamethasone-17,21-dipro-pionateis superiorto thatof betamethasone-17-valerate,with re-spectto boththeblanchingandtherapeuticaction.This illustratestheimportanceof the21-propionateinthe17,21-dipropionatewithrespect to the structureactivityrelationshipof betamethasoneesters(Figure1).The presentstudythereforeservedthepurposeof comparingtheblanchingactivitiesof thetwobetamethasone-17-valeratecontain-ing lotions(BetnovateandCelestoderm-V)toeachotherandtothebetamethasone-17,21-dipropionatecontaininglotion(Diprosone).SA PharmaceuticalJournal- November1981.~~:.Materials and methodsThe threelotionswerepurchasedshortlybeforethetrialat a localpharmacy.TwelvehealthyCaucasianvolunteerswere selectedfroma panelknownto showa responseto topicallyappliedcorticosteroids.No. referencewasmadetosexorsteroidsensitivity.Thevolunteershadnot receivedtopical or systemiccorticosteroidsfor at least sixweekspriorto theinvestigation.The lotions 'were applied to the flexor aspect of the forearm in fourdifferent arrangements, each application pattern being chosenrandomly to avoid any bias during application and observation. Fivemicroliters of fhe lotion (equivalent to approximately 4mg) was ap-plied to twelve 7mm square sites on each forearm of the volunteersin a double blind fashion using a micro-pipette. The pipette was alsoused to spreadthelotionsimmediatelyafterapplication. ~,CH20COCH2CH3I=0---OCOCH2CH3CH3BETAMETHASONE DIPROPIONATE(DIPH.OSONE)CH20HI'=0.- --OCO(CH2hC H3CH3BETAMETHASONE 17-VALERATE(BETNOVATE, CELESTODERM-V)Figure 1551AcademyIn theoccludedmodethesiteswere coveredwitha non-porousplasticcovering(BlendermSurgicaltape) and the non-occludedsiteswereprotectedbycardboardcoveringscut in sucha waysoas toallowa freeflowof air.The residualsteroidwasremovedfromall thesitessix hoursafterapplicationby gentlewashingwith soap and warm water.Thedegreeof blanchingforeachsitewas recordedindependentlybythreeexperiencedobserversat 7, 8, 9, 10,12, 14,16,18 and 28hoursaft~rapplicationusinga Q-4scale:0 = normalskin .1 = slightvasoconstriction2 = moreintensevasoconstriction3 = generalevenvasoconstrictionwithdistinctblanching4 = markedvasoconstrictionwithverydistinctblanchingThe methodsusedto evaluatethe resultsweretheareaunderthecurve(AUG),thenumberof sitesexhibitingblanching,thegradedintensityof vasoconstrictionand a pairedcomparisonof adjacentsites(5).Blanchingprofiles(Rgures2 and3) wereobtainedusingthepercentageofthetotalpossiblescoreandthetimeinhoursafterapplication.R.sults and discussionIn the occluded mode the AUC for Diprosone was greater than thatof Calestoderm-V which was greater than that of Betnovate. In all themethods of analysis there was no significant difference betweenBetnovate and Celestoderm-V (except the graded response at 16hours which was in favour of Celestoderm-V), and Diprosone wassignificantly better in all the methods of analysis at most of the timeintervals - especially at the peak times, i.e. between 8 and 18hours after application.The AUC in the tlnoccluded mode was greatest,for Diprosone with. Betnovate and Celestoderm-V giving very similar values. All theother methods of analysis gave results of Diprosone being signifi-.cantly better thiln Betnovate and Celestoderm-V. No significant dif-ferences were exhibited between Betnovate and Celestoderm-V.803020fJ '0 . .10 HOURS-20Figure 2. Blanching profiles of lotions in theoccluded mode.10552H'30t'.TPS20102"0 10HOURSFigure 3. Blanching profiles of lotions in theunoccluded mode.Themainconclusionsthatcan be drawnfromthistrialarethat:(i) Diprosonelotionhasa statisticallysignificantsuperiorblanchingactivityover Betnovatelotionand Celestoderm-Vlotion,eventhoughtheconcentrationofthecorticosteroidinDiprosonelotionis halfofthatoftheothertwolotions.Itwouldbeexpectedthatiftheselotionswereformulatedcontainingthesame.concentrationof corticosteroid,the differences in the blanchingactivitieswouldbe evenmoremarked.(ii) There are no statisticallysignificantdifferencesbetweentheblanching activitiesof Betnovatelotion and Celestoderm-Vlotion.Thisis notnecessarilyexpectedas it isa well-establishedfactthatthenatureof thebase affectsthereleaseof theactiveingredient.Betnovatecream and Celestoderm-Vcreamshqwsimilarblanchingactivities,whereasCelestoderm-Vointmenthasa superioractivitytothatof Betnovateointment(6);A similarexampleof theinfluenceof thebase hasbeenobservedin thecas.eof fluocinoloneacetonide(7).It could be expected,however,thatdue to the good surfacecoverage,skincontactandspreadibilityof lotions,thatthecorti-costeroidwould be releasedequallywell fromdifferentlotion~~ 0AcknowledgementsOne of us (E.M.) acknowledges the H. Bradlow Scholarship for post-graduate studies.References1. McKenzie,AW., Stoughton,A.B. (1962)Arch.Derm.86: 608-6102. McKenzie,AW., (1962)Arch. Derm.86: 611-6143. McKenzie,AW., Atkinson,R.M. (1964)Arch. Derm.89: 741-7464. Frederiksson,T., Gip, L., Hamlelt,A (1975)CurroTherap.Res. 18: 324-3315. Coleman,G.L.,Kanler,I., Haigh,J.M. (1978)Dermatologica156:224-2306. Coleman,G.L. (1977)M.Sc. Thesis,RhodesUniversity,Grahamstown7. Coleman,G.L., Magnus,AD., Haigh,J.M., Kanter,I. (1979)S. AIr.Med.J.56: 447-448. SA TydskritvirApteekV\lese-November198176I6050"10TPS4-0

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Comparative blanching activities of some topical corticosteroid containing lotions

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