The bioavailabilities of three locally manufactured proprietary betamethasone- 17-valerate containing creams and ointments were compared by measuring their abilities to cause blanching of human skin after topical application. The preparations studied were Betnovate Cream and Ointment, Celestoderm-V Cream and Ointment and Persivate Cream and Ointment. Celestoderm-V cream displayed a significantly superior blanching activity over both Betnovate and Persivate creams in' the occluded mode, whereas Persivate cream displayed a significantly superior blanching activity over both Betnovate and Celestoderm-V creams in the unoccluded mode. Persivate ointment was found to produce a significantly superior blanching activity over Betnovate and Celestoderm-V ointments in both the occluded and unoccluded modes of application

Haigh, J M

Kanfer, I

Meyer, E

Meyer, Eric

Haigh, John M

Kanfer, Isadore

Rhodes Repository (SEALS)

(\~D~,~!:';,,~;,.;"" ~ ~ .?'" =,,'academy: akademieComparative bioavailability of somelocally manufactured betamethasonevalerate containing preparationsMeyer E., Haigh J.M., Kanfer 1.*Abstract. The bioavailabilities of three locally manufactured proprietary betametha-sone-17-valerate containing creams and ointments were compared by measuring theirabilities to cause blanching of human skin after topical application. The preparationsstudied were Betnovate Cream and Ointment, Celestoderm-V Cream and Ointment andPersivate Cream and Ointment. Celestoderm-V cream displayed a significantly superiorblanching activity over both Betnovate and Persivate creams in' the occluded mode,whereas Persivate cream displayed a significantly superior blanching activity over bothBetnovate and Celestoderm-V creams in the unoccluded mode.Persivate ointment was found to produce a significantly superior blanching activityover Betnovate and Celestoderm-V ointments in both the occluded and unoccludedmodes of application.The McKenzie and Stoughton blanching assayhas been extensively used as a reliable methodof asssessing the rate of release of corticoste-roids from topicallyapplied formulations (1). It isa well documented and generally accepted fact thatthere is a direct relationship between the blanchingactivity of a topically applied corticosteroid and its clin-ical efficacy (2).Several variables have been found to affect theblanching response of a topically applied corticosteroidpreparation. Occlusion of the sites of application by aplastic covering has been found to cause a marked in-crease in blanching due to an increased ease ofpercut a-neous penetration of the corticosteroid after hydrationof the stratum corneum (3). This simple method of in-creasing percutaneous absorption is used successfullyin therapy today for unresponsive dermatoses (4).The different types of pharmaceutical vehicles havealso been found to affect the degree of blanching causedby corticosteroids after topical application (5). Whenointments and creams containing the same steroid inequal concentrations were compared by means of amodified McKenzie and Stoughton blanching assay,the ointment was found to give a significantly greaterblanching response than the cream, especially in theunoccluded mode (6). This increase in the intensity ofblanching is presumably due to the occlusive nature ofthe vehicle. A further observation has been that the re-lease of a steroid from the same type of vehicle candiffer, depending on the formulation (7). Two locallymanufactured proprietary fluocinolone acetonide con-taining creams were found to produce significantly dif-ferent blanching responses (8). This is most likely dueto the solubility of the steroid in the base, a factor thatwould alter the partition coefficient of the steroid be-*School of Pharmaceutical Sciences. Rhodes Uninrsity,Grahamstown, 6140.SA Tydskrif vir Apteekwese- Augustus 1983tween the vehicle and the skin (9). The base effects oflotions have been found to be less significant than thoseof creams and ointments (10).In this study, two trials were mounted, the first tocompare the release of betamethasone-17 -valeratefrom three locally manufactured proprietary creamsand the second to compare the release ofbetametha-sone-17-valerate from three locally manufactured pro-prietary ointments. All the preparations contained0,1 % ofthe steroid. The preparations used were Betno-vate cream and ointment (Glaxo (Pty) Ltd), Celesto-derm-V cream and ointment (Scherag (Pty) Ltd) andPersivate cream and ointment (Lennon Ltd).Materials and methodsThe creams and ointments were purchased shortlybefore the trials from a local pharmacy.The method of experimentation was similar for bothtrials. Twelve healthy Caucasian volunteers were se-lected for each trial from a panel known to show a re-sponse to topically applied corticosteroids. No referencewas made to steroid sensitivity or sex. The volunteershad not received topical or systemic corticosteroids forat least six weeks prior to the investigation.The preparations were applied to the flexor aspect ofthe forearm in four different arrangements, each appli-cation pattern being chosen randomly to avoid any biasduring application and observation. Four stripes of thepreparations (equivalent to approximately 3,2 mg (11) )were applied to twelve 7 mm square sites on each fore-arm of the volunteers in a double-blind fashion bymeans of 1 ml syringes, the needles of which had beencut to about 5 mm in order to facilitate extrusion of thepreparations. The first gram of cream or ointment ofeach tube was discarded and the syringes were filledimmediately prior to use so as to minimize any possibleinteraction between the corticosteroid and the plastic[>445academyakademiematrix of the syringe barrel. The preparations wereevenly spread over the application sites by means of aglass rod.Both trials were performed in both the occluded andunoccluded modes. In the occluded mode the sites werecovered with a non-porous plastic covering (Blendermsurgical tape) and the unoccluded sites were protectedby cardboard coverings cut in such a way so as to allowa free flow of air and held in plac;e by Micropore surgi-cal tape.The measur~ment of the degree of blanching and thestatistical analyses were performed as previously re-ported (0) with the addition of a reading at 32 hoursafter application in both trials and an additional read-ing at 52 hours after application in the trial on oint-ments. The blanching response of topical corticosteroidointments is generally observable for a longer time dueto the increased intensity of blanching.All the preparations were assayed by means of anHPLC technique similar to that described by Coleman(2). .Results and discussionThe HPLC analyses performed indicated that the con-centration of corticosteroid in all the preparationsstudied were within the limits as specified in the V.S.P.(3).Figures 1 - 4 are the blanching profiles obtainedusing the percentage of the total possible score (%TPS)and the time in hours after application.Celestoderm-V cream in the occluded mode wasfound to have a larger area under the curve (AVC) thanPersivate cream which in turn had a larger AVC thanBetnovate cream. In the comparison of adjacent sitesCelestoderm-V cream showed a significantly higherFigure '1 Blanching profiles of creams in the occluded mode.Celestoderm-VPersivateBetnovate5 10 15 20HOURS25 30degree of blanching than both Persivate and Betnovatecreams, with Persivate cream showing a significantlyhigher degree of blanching than Betnovate cream. Thegraded response analyses indicated that the degree ofblanching elicited by Celestoderm- V cream wassignificantly superior to that of Betnovate cream. Simi-lar blanching responses were found in this analysis forCelestoderm-V and Persivate creams. Celestoderm-Vcream, however, exhibited a superior blanching re-sponse over Persivate cream at the peak times of 14, 16and 18 hours after application. No significant differ-ence was found between Betnovate and Persivatecreams. In the unoccluded mode Persivate cream exhi-bited a significantly superior blanching response in allthe methods of analyses than both Betnovate and Ce-lestoderm-V creams. There were no significant differ-ences found between Betnovate and Celestoderm- Vcreams in this mode.Persivate ointment exhibited a larger AVC and wasfound to elicit a statistically significant superiorblanching response than both Betnovate and Celesto-derm-V ointments in all the methods of statisticalanalysis in both the occluded and unoccluded modes ofapplication. No significant differences were observedbetween the blanching abilities of Betnovate and Ce-lestoderm- V ointments.ConclusionThe main conclusions that can be drawn from thisstudy are that:1. Betamethasone-17-valerate is released more effec-tively from Persivate cream and ointment than fromBetnovate cream and ointment in both modes of ap-plication.Figure 2 Blanching profiles of creams in the unoccluded mode.656045555040~. 35...~ 302520151053500 30 355 10 15 20 25HOURSSA Pharmaceutical Journal- August 198375706560555045en40353025201510500446academyakademieFigure 3 Blanching profiles of ointments in the occluded mode.706050PersivateCelestoderm-VBetnovate40tenQ.,I-::.e030201000 5I I I I I I J I I10 15 20 25 30 35 40 45 50 55HOURSFigure 4 Blanching .profiles of ointments in the unoccluded mode.6540~ 35I-~ 30605550452510 15 20 25 30 35 40 45 50 55HOURSSA Tydskrif vir Apteekwese- Augustus 19832. The bioavailability of the steroid from Celestoderm-V cream is Guperiorto both Betnovate and Persivatecreams in the occluded mode, but equivalent to Bet-novate cream in the unoccluded mode.3. There is no statistically significant difference in therelease of the steroid from Betnovate ointment andCelestoderm-V ointment in either mode of applica-tion.The trials therefore served to reinforce the findingsthat the formulation of a topical vehicle can have a sig-nificant effect on the bioavailability of corticosteroids,which could influence the clinical efficacy of the pro-duct.It was further observed that the mode of application(occluded or unoccluded) can alter the comparative bio-availability of a steroid from topical formulations.AcknowledgementsWe gratefully acknowledge the donation of BlendermSurgical Tape and Micropore Surgical Tape from Medi-cal Products Division, 3M Company. Financial assis-tance from The South African Council for Scientific andIndustrial Researchand The Medical Research Councilis also acknowledged.References1. McKenzie, A.W., Stoughton, R.B: (1962)Arch. Derm. 86;608-610.2. Williams, D.I., Wilkinson, D.S., Overton, J., Milne, J.A.,McKenna, W.B., Lyell, A., Church, R: (1964, i) Lancet;1177-1179.3. McKenzie, A.W: (1962)Arch. Derm. 86; 611-614.4. Mailbach, H.I: (1976JDermatologica152 (Suppl. 1);11-25.5. Barry, B.W: (1976)Dermatologica 152 (SuppI.1); 47-65.6. Coleman, G.L., Kanfer, I., Haigh, J.M: (1978)Dermatolo-gica 156; 224-230. .7. Woodford,R., Barry, B.W: (1977) CurroTherap. Res. 21;877-886.8. Coleman, G.L., Magnus, A.D., Haigh, J.M., Kanfer, I:(1979) S. Afr. Med. J. 56; 447-448.9. Ostrenga, J., Haleblian, J., Poulsen, B., Ferrell, B., Muel-ler, N., Shastri, S: (1971)J. Invest. Dermatol. 56; 392-399.10. Meyer, E., Kanfer, I., Haigh, J.M: (1981)S. Afr. Pharm. J.48; 551-552.11. Magnus, A.D., Haigh, J.M., Kanfer, I: (1980) Dermatolo-gica 160; 321-327.12. Coleman, J.L: (1977) M.Sc. Thesis, Rhodes University,Grahamstown. .13. United States Pharmacopoeia XX: (1980) United StatesPharmacopeial Convention, Inc. 12601 Twinbrook Park-way, Rockville, Md. 20852.Could you writefor SAP J7Anyone interested in contributingand expressing views is re-quested to contact:Jennifer KnightPO Box 31360BRAAMFONTEIN 2017Tel: (011)391-752447201510500 5

Comparative bioavailability of some locally manufactured betamethasone valerate containing preparations

South East Academic Libraries System (SEALS)

(\~D~,~!:';,,~;,.;"" ~ ~ .?'" =,,'academy: akademieComparativebioavailabilityof somelocallymanufacturedbetamethasonevaleratecontainingpreparationsMeyerE., Haigh J.M., Kanfer 1.*Abstract. The bioavailabilitiesof threelocallymanufacturedproprietarybetametha-sone-17-valeratecontainingcreamsandointmentswerecomparedbymeasuringtheirabilitiestocauseblanchingof humanskinaftertopicalapplication.ThepreparationsstudiedwereBetnovateCreamandOintment,Celestoderm-V CreamandOintmentandPersivateCreamandOintment.Celestoderm-V creamdisplayedasignificantlysuperiorblanchingactivityoverbothBetnovateandPersivatecreamsin'theoccludedmode,whereasPersivatecreamdisplayeda significantlysuperiorblanchingactivityoverbothBetnovateandCelestoderm-V creamsin theunoccludedmode.Persivateointmentwasfoundtoproducea significantlysuperiorblanchingactivityoverBetnovateand Celestoderm-V ointmentsin boththeoccludedand unoccludedmodesofapplication.TheMcKenzieandStoughtonblanchingassayhasbeenextensivelyusedasa reliablemethodof asssessingtherateof releaseofcorticoste-roidsfromtopicallyappliedformulations(1).It isa well documentedandgenerallyacceptedfactthatthereis a directrelationshipbetweentheblanchingactivityofatopicallyappliedcorticosteroidanditsclin-ical efficacy(2).Severalvariableshavebeenfoundto affecttheblanchingresponseofa topicallyappliedcorticosteroidpreparation.Occlusionof thesitesofapplicationbyaplasticcoveringhasbeenfoundtocausea markedin-creaseinblanchingduetoanincreasedeaseofpercuta-neouspenetrationofthecorticosteroidafterhydrationofthestratumcorneum(3).This simplemethodofin-creasingpercutaneousabsorptionis usedsuccessfullyin therapytodayforunresponsivedermatoses(4).Thedifferentypesofpharmaceuticalvehicleshavealsobeenfoundtoaffecthedegreeofblanchingcausedby corticosteroidsaftertopicalapplication(5).Whenointmentsandcreamscontainingthesamesteroidinequalconcentrationswerecomparedby meansof amodifiedMcKenzieandStoughtonblanchingassay,theointmentwasfoundtogivea significantlygreaterblanchingresponsethanthecream,especiallyin theunoccludedmode(6).This increasein theintensityofblanchingis presumablyduetotheocclusivenatureofthevehicle.A furtherobservationhasbeenthatthere-leaseof a steroidfromthesametypeof vehiclecandiffer,dependingon theformulation(7).Twolocallymanufacturedproprietaryfluocinoloneacetonidecon-tainingcreamswerefoundtoproducesignificantlydif-ferentblanchingresponses(8).Thisis mostlikelyduetothesolubilityofthesteroidin thebase,a factorthatwouldalterthepartitioncoefficientof thesteroidbe-*Schoolof PharmaceuticalSciences.RhodesUninrsity,Grahamstown,6140.SA TydskrifvirApteekwese- Augustus1983tweenthevehicleandtheskin (9).Thebaseeffectsoflotionshavebeenfoundtobelesssignificantthanthoseofcreamsandointments(10).In thisstudy,twotrialsweremounted,thefirst tocomparethe releaseof betamethasone-17-valeratefromthreelocallymanufacturedproprietarycreamsandthesecondto comparethereleaseofbetametha-sone-17-valeratefromthreelocallymanufacturedpro-prietaryointments.All the preparationscontained0,1%ofthesteroid.ThepreparationsusedwereBetno-vatecreamandointment(Glaxo(Pty)Ltd),Celesto-derm-Vcreamandointment(Scherag(Pty)Ltd)andPersivatecreamandointment(LennonLtd).Materials and methodsThe creamsand ointmentswerepurchasedshortlybeforethetrialsfroma localpharmacy.Themethodofexperimentationwassimilarforbothtrials.TwelvehealthyCaucasianvolunteerswerese-lectedforeachtrial froma panelknowntoshoware-sponsetotopicallyappliedcorticosteroids.Noreferencewasmadetosteroidsensitivityor sex.Thevolunteershadnotreceivedtopicalorsystemicorticosteroidsforat leastsixweekspriorto theinvestigation.Thepreparationswereappliedtotheflexoraspectoftheforearmin fourdifferentarrangements,eachappli-cationpatternbeingchosenrandomlytoavoidanybiasduringapplicationandobservation.Fourstripesofthepreparations(equivalenttoapproximately3,2mg(11))wereappliedtotwelve7mmsquaresitesoneachfore-arm of the volunteersin a double-blindfashionbymeansof1mlsyringes,theneedlesofwhichhadbeencuttoabout5mminordertofacilitate xtrusionofthepreparations.The firstgramof creamor ointmentofeachtubewasdiscardedandthesyringeswerefilledimmediatelypriortousesoastominimizeanypossibleinteractionbetweenthecorticosteroidandtheplastic[>445academyakademiematrix of the syringebarrel. The preparationswereevenlyspreadoverthe applicationsitesby meansof aglassrod.Both trials wereperformedin boththe occludedandunoccludedmodes.In theoccludedmodethe siteswerecoveredwith a non-porousplasticcovering(Blendermsurgicaltape)andthe unoccludedsiteswereprotectedby cardboardcoveringscut in sucha way soas toallowa freeflow ofair andheld in plac;eby Microporesurgi-cal tape.The measur~mentofthe degreeofblanchingandthestatistical analyseswereperformedas previouslyre-ported(0) with the additionof a readingat 32 hoursafterapplicationin bothtrials andan additionalread-ing at 52 hours after applicationin the trial on oint-ments.The blanchingresponseoftopicalcorticosteroidointmentsis generallyobservablefora longertimedueto the increasedintensityofblanching.All the preparationswere assayedby meansof anHPLC techniquesimilar to that describedby Coleman(2). .ResultsanddiscussionTheHPLC analysesperformedindicatedthatthecon-centrationof corticosteroidin all the preparationsstudiedwerewithinthelimitsasspecifiedintheV.S.P.(3).Figures1 - 4 are the blanchingprofilesobtainedusingthepercentageofthetotalpossiblescore(%TPS)andthetimein hoursafterapplication.Celestoderm-Vcreamin the occludedmodewasfoundtohavealargerareaunderthecurve(AVC)thanPersivatecreamwhichin turnhada largerAVC thanBetnovatecream.In thecomparisonofadjacentsitesCelestoderm-Vcreamshoweda significantlyhigherFigure'1Blanchingprofilesof creamsin the occludedmode.Celestoderm-VPersivateBetnovate5 10 15 20HOURS25 30degreeofblanchingthanbothPersivateandBetnovatecreams,withPersivatecreamshowinga significantlyhigherdegreeofblanchingthanBetnovatecream.Thegradedresponseanalysesindicatedthatthedegreeofblanchingelicited by Celestoderm-V cream wassignificantlysuperiortothatofBetnovatecream.Simi-larblanchingresponseswerefoundin thisanalysisforCelestoderm-VandPersivatecreams.Celestoderm-Vcream,however,exhibiteda superiorblanchingre-sponseoverPersivatecreamatthepeaktimesof14,16and18hoursafterapplication.No significantdiffer-encewas foundbetweenBetnovateand Persivatecreams.In theunoccludedmodePersivatecreamexhi-bitedasignificantlysuperiorblanchingresponsein allthemethodsofanalysesthanbothBetnovateandCe-lestoderm-Vcreams.Therewerenosignificantdiffer-encesfoundbetweenBetnovateand Celestoderm-Vcreamsin thismode.Persivateointmentexhibiteda largerAVC andwasfound to elicit a statisticallysignificantsuperiorblanchingresponsethanbothBetnovateandCelesto-derm-V ointmentsin all the methodsof statisticalanalysisin boththeoccludedandunoccludedmodesofapplication.No significantdifferenceswereobservedbetweentheblanchingabilitiesofBetnovateandCe-lestoderm-V ointments.ConclusionThe mainconclusionsthat canbe drawnfromthisstudyarethat:1. Betamethasone-17-valerateis r leasedmoreeffec-tivelyfromPersivatecreamandointmenthanfromBetnovatecreamandointmentin bothmodesofap-plication.Figure2 Blanchingprofilesofcreamsin theunoccludedmode.656045555040~. 35...~ 302520151053500 30 355 10 15 20 25HOURSSA PharmaceuticalJournal- August198375706560555045en40353025201510500446academyakademieFigure3 Blanchingprofilesofointmentsintheoccludedmode.706050PersivateCelestoderm-VBetnovate40tenQ.,I-::.e030201000 5I I I I I I J I I10 15 20 25 30 35 40 45 50 55HOURSFigure4 Blanching.profilesof ointmentsin theunoccludedmode.6540~ 35I-~ 30605550452510 15 20 25 30 35 40 45 50 55HOURSSA TydskrifvirApteekwese- Augustus19832. The bioavailabilityof thesteroidfromCelestoderm-V creamis Guperiorto bothBetnovateand Persivatecreamsin theoccludedmode,but equivalentto Bet-novatecreamin the unoccludedmode.3. Thereis nostatisticallysignificantdifferencein thereleaseof the steroidfrom BetnovateointmentandCelestoderm-V ointmentin either modeof applica-tion.The trials thereforeservedto reinforcethe findingsthat theformulationofa topicalvehiclecanhavea sig-nificant effecton thebioavailability of corticosteroids,which couldinfluencethe clinical efficacyof the pro-duct.It wasfurther observedthat the modeof application(occludedor unoccluded)canalter thecomparativebio-availability ofa steroidfromtopicalformulations.AcknowledgementsWe gratefullyacknowledgethe donationof BlendermSurgicalTapeandMicroporeSurgicalTapefromMedi-cal ProductsDivision, 3M Company.Financial assis-tancefromThe SouthAfrican CouncilforScientificandIndustrial ResearchandThe MedicalResearchCouncilis also acknowledged.References1. McKenzie,A.W.,Stoughton,R.B:(1962)Arch.Derm.86;608-610.2. Williams,D.I.,Wilkinson,D.S.,Overton,J., Milne,J.A.,McKenna,W.B.,Lyell,A., Church,R: (1964,i) Lancet;1177-1179.3. McKenzie,A.W:(1962)Arch.Derm.86;611-614.4.Mailbach,H.I:(1976JDermatologica152(Suppl.1);11-25.5. Barry,B.W:(1976)Dermatologica152(SuppI.1);47-65.6. Coleman,G.L.,Kanfer,I., Haigh,J.M: (1978)Dermatolo-gica156;224-230. .7. Woodford,R.,Barry,B.W:(1977)CurroTherap.Res.21;877-886.8. Coleman,G.L., Magnus,A.D., Haigh,J.M., Kanfer,I:(1979)S.Afr. Med.J. 56;447-448.9. Ostrenga,J., Haleblian,J., Poulsen,B.,Ferrell,B.,Muel-ler,N.,Shastri,S:(1971)J. Invest.Dermatol.56;392-399.10.Meyer,E.,Kanfer,I.,Haigh,J.M: (1981)S.Afr.Pharm.J.48;551-552.11.Magnus,A.D.,Haigh,J.M., Kanfer,I: (1980)Dermatolo-gica160;321-327.12.Coleman,J.L: (1977)M.Sc. Thesis,RhodesUniversity,Grahamstown. .13. United StatesPharmacopoeiaXX: (1980)United StatesPharmacopeialConvention,Inc. 12601Twinbrook Park-way,Rockville,Md. 20852.Could you writefor SAP J7Anyone interested in contributingand expressing views is re-quested to contact:JenniferKnightPO Box31360BRAAMFONTEIN 2017Tel: (011)391-752447201510500 5

http://vital.seals.ac.za:8080/vital/access/services/Download/vital:6399/SOURCEPDF

Comparative bioavailability of some locally manufactured betamethasone valerate containing preparations

Abstract

Similar works

Full text

Available Versions

Rhodes Repository (SEALS)

South East Academic Libraries System (SEALS)