The activity of a 0.1% amcinonide cream was compared with those of selected proprietary topical corticosteroid formulations of potencies differing according to the United Kingdom (U.K.) MIMS classification (very potent, potent and moderately potent) using a standard six hour vasoconstrictor assay with multiple reading times. Statistical analysis indicated that 0.1% amcinonide cream feU within the category of a very potent preparation. Three 0.1% amcinonide formulations (cream, combination cream and combination ointment, the last two containing anti-infective agents) were equipotent in the skin-blanching test

Haigh, J M

Woodford, R

Haigh, John M

South East Academic Libraries System (SEALS)

CURRENTTHERAPEUTICRESEARCHVOL. 26, NO.3, SEPTEMBER, 1979BIOAVAILABILITY AND ACTIVITY OF 0.1%AMCINONIDEPREPARATIONS: COMPARISON WITH PROPRIETARY TOPICALCORTICOSTEROID FORMULATIONS OF DIFFERING POTENCIESR. WOODFORD AND J.M. HAIGH*Schoolof Pharmacy,PortsmouthPolytechnic,King Henry I Street,Portsmouth,Hants.,POI 2DZ UnitedKingdomABSTRACTThe activity of a 0.1%amcinonidecreamwas comparedwith thoseofselected proprietary topical corticosteroid formulations of potenciesdiffering accordingto the United Kingdom (U.K.) MIMS classification(very potent, potent and moderatelypotent) usinga standardsix.hourvasoconstrictorassay with multiple reading times. Statisticalanalysisindicatedthat 0.1%amcinonidecreamfeUwithin the categoryof a verypo tent preparation. Three 0.1% amcinonide formulations (cream,combinationcreamand combinationointment,the last two containinganti-infectiveagents)wereequipotentin the skin-blanchingtest.INTRODUCTIONA new topical fluorinated corticosteroid preparation, 0.1% amcinonidecream, has been reported to be as potent as 0.12% betamethasone17-valeratecream in a vasoconstrictorassay1 and as effectiveas 0.1%betamethasone17-valeratecream in a double-blind study involvingvari-ous inflammatory dermatoses.2On the other hand, other vasoconstric-tor trials3,4 have shown a 0.1% amcinonide cream to be markedlysuperior to betamethasone17-valeratecreams of theseconcentrations.Experiments were, therefore, carried out to comparea) the blanchingactivity of 0.1% amcinonide cream with those of selectedU.K. pro-prietary topical corticosteroid preparationsof differing potency, and b)the bioavailability and activity of three formulations, each containing0.1%amcinonide.Seven corticosteroid creams were selected for comparison fromMIMS, which classifies topical steroid preparations as mildly potent,moderatelypotent, potent and verypotent.5 Representativesof the lastthreecategorieswereemployed.* Present address: Faculty of Pharmaceutical Sciences, Rhodes University, 6140 Grahams-town, South Africa.Received for publication on July 14, 1979. Printed in U.S.A.0011-393X/7 9/0900-0301$0.40/0@ 1979, Therapeutic Research Press, Inc. Reproduction in whole or part is not permitted.[ 301 ]BIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONSMATERIALS AND METHODSTopical PreparationsTen corticosteroid preparations were employed. Seven were proprietary formulationsavailable in the U.K. (Betnovate cream, Dermovate cream, Halciderm, Metosyncream, Synalar cream, Temetex cream and Ultradil cream). The other three wereexperimental preparations containing 0.1% of the new topical steroid, amcinonide(amcinonide cream, amcinonide combination cream and amcinonide combinationointment). The corticosteroid compositions are given in Table 1. All products werestored at room temperature for two weeks and approximately 5 grams of eachpreparation were removed and rejected before use.SubjectsTwelve volunteers were selected from an experienced panel as those demonstratingconsistency of response to a standard preparation (Betnovate cream) but withoutreference to their sex or steroid sensitivity. None had received topical corticosteroidapplication for at least three months prior to the study. The results from ten ofthose subjects were selected for statistical analysis.MethodIn the study, 5 mg of the preparations were applied to the washed flexor surface ofeach forearm. The application sites consisted of 7 x 7 mm areaspunched out fromdouble-sided adhesive Blenderm tape, to which the formulations were applied usinga random design. The sites were sealed with impervious Melinex film and leftoccluded for 6 hours. The Melinex and tape were removed and the areas werewashed with soap and water at body temperature and were dried. Readings weretaken in a double-blind manner after 10 minutes (to allow transient erythemaarising from washing to subside) and after 1, 2, 3, 6, 18, 26, 42, 66, 74 and 90hours to provide data points for skin blanching at 6, 7, 8, 9, 12, 24, 32, 48, 72, 80and 96 hours after application.Assessment was made according to a 0-4 scale with half-point ratings for inter-mediate readings:0 =Normal skin1 =Slight vasoconstriction of indistinct outline2 =More intense vasoconstriction3 =General even vasoconstriction with a clear outline of the square4 =More marked vasoconstriction with very distinct blanchingTen volunteers provided a total of 200 application sites.In order to. assessapproximately the retention of steroid in the skin, the sites intwo volunteers were re-occluded with Melinex film for 12 hours eight days aftercommencement of the experiment. Pallor was estimated 5 hours later whenblanching was maximal.RESULTSFor each preparation the data for all volunteecs were converted topercent of the total possiblescore at eachtime period: i.e., if the maxi-mum score per site = 4, then for 2 arms and 10 volunteers,the maxi-[ 302]Table I - Blanchingresponsesto corticosteroidpreparations~ Thecorrected%totalpossiblescores ummedfor all volunteersoverall readingtimes.Obtainedby planimetryof theblanchingprofile.c TheTm/10meanvalueisthesquareroottransformationof sumof correctedscores(Tm)dividedby thenumberof volunteers(10).Theminimumsignificantrangevaluek =0.54(P=0.05),i.e.if theTm/10valueoftwopreparationsdifferbymorethan0.54thereisasignificantd differencebetweenthosepreparations(seeStatisticalTreatmentof Results)Re-occludedfor 12hours,8 daysaftercommencementoftheexperiment.;c~00t::J"'J0I"t::J>Zt::Jc..,~II:>....G1II:aSummed bArea Under Dt"m/10 d% Total% Total the Curve Mean PossiblePossible % x Hours Value Score onPreparation Steroid and % w/w Score Re-occlusionDermovatecream Clobetasolpropionate,0.05 519 3100 6.41 53Amcinonide cream Amcinonide, 0.1 510 2770 6.34 44Halciderm Halcinonide, 0.1 504 2630 6.31 44Amcinonide combination Amcinonide,0.1 501 2680 6.29 44cream""Amcinonide combination Amcinonide, 0.1 489 2760 6.20 530"" ointmentMetosyn Cream Fluocinonide,0.05 414 2640 5.69 19Betnovatecream Betamethasoneas valerate,0.1 393 2570 5.55 19Temetex cream Diflucortolonevalerate,0.1 391 2220 5.51 25Synalar cream Fluocinolone acetonide, 0.025 370 2710 5.35 25Ultradi I cream Fluocortolonepivalate,0.1; 217 1060 4.13 3Fluocortolone hexanoate,0.1100~()(j)(l):0.~ 4'&.ro;2';KBIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONSFigure 1 - Blanching curves for preparations indicated.801100Amcinonidecream60,\\\\\\~Metosyn cream\\~Ultradilcream20Synalarcream20 40 60Time-Hoursmum score=80.For example,amcinonidecreamgavea 6-hourscoreof19.5 out of 80 to providea valueof 24.4% total possiblescore.Thedata were then unified in terms of a standardpreparation,Betnovatecream, as describedpreviously6 in order to relate the results obtainedin this trial to thoseobtainedin previousstudiesemployingboth experi-mental amcinonideformulations4 and an extensiverangeof proprietarypreparations.6,7 The unification correction factor for Betnovatecreamin the present trial is given by: summed % total possible score forBetnovatecreamas obtainedby Barry and Woodford6 / summed% totalpossiblescorefor Betnovatecreamin this study =1.41.The % total possible score data were, therefore,multiplied by 1.41and blanching curves of these results are shown in Figures 1 to 3.Experimental points have been omitted to aid clarity but all points layon or near the curvesas drawn. The profiles shown may be compareddirectly with thosepreparationspreviouslystudied.4,6,7Statistical TreatmentA computer-aidedanalysisof variancewas performed on the results,the[ 304]100\!!0uC/)Q):is~:$t2'cfZR. WOODFORD AND J.M. HAIGHFigure 2 - Blanching curves for preparations indicated.80100Halciderm60:remetexcream40120! Amc:inrnidecombinationcream20 40 60Time-Hourscomputerprogrambeing written so that the datacould be analysedwithout transformationor in one of five (x-I, x-lh, log x, x¥2andx2)transformations.8,4Testsfor non-additivity9indicateda preferenceforthe "squareroot transformation"dataandtherandomisedblockdesignvarianceanlaysiswas calculatedusingthosevalues.Highly significantdifferenceswere found to exist betweenthe preparations(F =37.06,P < 0.01), while the minimum significantrange value k in theStudentizedrangetest!0.4 at the 5% significancelevelwas 0.54 (10preparationsand 81 degreesof freedom).Hencethe non-significantrangefor e.g.amcinonidecombinationcream=6.29:!: 0.54=6.83to5.75.If the Tm/l0 meanvalues(TableI) of two preparationsdifferbymorethan0.54thereis a significantdifferencebetweenthoseformula-tions.SteroidReservoirFormationin theSkinRe-occlusionof the appiicationsites in two volunteers(statisticalanalysiswas,therefore,inapplicable)providedanestimateof thesteroidreservoirin the skin. Theseresultsareshownas % totalpossiblescoreonre-occlusion(TableI).[ 305]Q)auC/)~.iijrn&.BIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONSFigure 3- Blanchingcurvesfor preparationsindicated.AmcinonidecombinationointmentDermovatecream\\\\" """""""Betnovatecream""-"-"-"- , ", , "10020 40 60Time- HoursDISCUSSIONAll of the preparationsstudied in this trial produced obvious vasocon-striction, the shapesof the blanching curves for the amcinonide andproprietary formulations (Figures 1 to 3) being similar to those pre-viously reported.4,6.7In this trial the rather high valueof the Betnovatecreamcorrectionfactor was a little surprising.Examination of the individual volunteers'results suggestedthat this was due to rather low responsesto Betnovatecream (and the other preparations)in three volunteers,thus producing alow total for Betnovatecream in this trial. However, the valuesof thecorrected % total p~ssiblescores summed for all volunteers over allreading times (Table I) were very similar to those previously reported,e.g., amcinonide cream = 510 (509 in a previous trial).4 Dermovatecream = 519 (512 previously),6 Metosyn cream = 414 (409 pre-viously.)6 An exceptionwas amcinonidecombination cream,which pro-vided a value about 7% higher than in the previous study.4 This mayhave been due to the slight modification in the composition of theamcinonidecombination Greamcomparedto that employedin the 1977[ 306]R. WOODFORD AND J.M. HAIGHFigure 4 - Histogram of sum of % total possible scores for preparations indicated.Figure 5 - Histogram of areas under the blanching curve for preparations indicated.Fmnulation:2x'*''W8"£~::>ffi100~[ 307 ]ro1EE'* ffi E'0 t; .0E8<:.Q1;; 1;;<: <:I I IEtl EIEco§ OJ EOJ " E11 I" " " t; OJ Eco11" OJ,, " " t; e!E " "1;; § <: <: ! x0 '" " roc c "' Q:jI :Q g.8 ro.E c, '" 5« «I (f)i EE.0 ".8 81;;<:E isE co§ § EOJ " Ee! t; " E " OJ E" OJ "" " " "" t;1;; u :12 E " ".E§ §c! !ji5 0 , :a ucE .(3 g ro .(38 E c E .!.1'" 5« « (f) «FormulationBIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONStrial.4 The similarities in different trials noted for the proprietarypreparationsfurther inspires confidence in our standardvasoconstrictortest.11The corrected % total possible score valuesfor the most activepreparations(Dermovate cream, Halciderm.cream and the amcinonideformulations) at the 12-hour reading time were somewhatgreaterthan100. Becausethe blanchingcurves were <;lrawnto a maximumvalueof100% (Figs. 1 to 3) the areaunder the curvevalues(Table I and Fig. 5)for the amcinonide,Halciderm and Dermovatepreparationswereratherlower, comparedto the less potent formulations, than might otherwisebe expected.A ranking basedon the sum of the corrected% total pos-sible score values (Fig. 4) suggestedthat the corticosteroidpreparationscomprised three potency groups: this was confirmed by statisticalanalysis(Table I).TableII- Blanchingresponsestopreparationscontaining0.1%amcinonic1...ePreparationaBioavailabilityIi) Iii)Amcinonide creamAmcinonide combination creamAmcinonide combination ointment1.000.980.961.000.971.00aDefined by the relationships(") summed % total possible score for preparationI summed % total possible score for most active preparation("') "areaunderthecurve"for preparationII "area under the curve" for most active preparationTable III - Potencyclassificationof topicalcorticosteroidcreamsCreamaTm/10 MeanValue bSignificanceCpotencyClassificationDermovateHalcidermAmcinonideAmcin.combination6.416.316.346.29Nosignificantdifferencebetweencreams(P=0.05)verypotentMetosynBetnovateTemetexSynalarUltradil5.695.555.515.354.13No significantdifferencebetweencreamsIi>=0.05)potentmoderatelypotenta TableI, k =0.54 IP =0.05)b As determinedby theblanchingtest.Significantdifferencesexistbetweenthethreepotencygroups.c MIMSclassificationfor topicalsteroidsThe three amcinonideformulations providedsimilar steroid bioavail-ability (Table II) and were statistically equivalentto each other and to[ 308]R. WOODFORD AND J.M. HAIGHthe Dermovateand Halciderm preparations(Table I). Table III lists thecreams studied in decreasingTm/10 mean values and shows that thehydrophilic amcinonide preparationswere significantly more active inthe 6-hour occluded blanchingtest than selectedpotent creamson theU.K. market: both amcinonide cream and amcinonide combinationcream were apparently equivalent to the very potent products ex-amined, and produced approximatelysimilar reservoirsof steroid in theskin.CONCLUSIONS1. 0.1% amcinonidecreamwas significantly more active (P =0.05) ina standardsix-hour occludedvasoconstrictorassaythan four "recog-nized as potent" U.K. proprietary topical corticosteroid creams(Betnovate,Metosyn, Synalarand Temetex).0.1% amcinonide cream was statistically equivalent to two verypotent U.K. proprietarycreams,Dermovateand Halciderm.Three 0.1% amcinonide formulations (cream, combination creamand combination ointment, the last two containing anti-infectiveagents)were equipotent in the skin-blanchingtest.2.3.AcknowledgementsOne of us (J.M.H.) acknowledgesa bursary from the South AfricanCouncil for Scientific and Industrial Research.References:1. Ishihara, M.: Studies on the vasoconstrictor activity of amcinonide, a newsynthetic topical corticosteroid. Nishinihon J. Derm. 38:286, 1976.2. Sanchez, J.L.: Amcinonide, a new topical steroid. Curro Therap. Res. 24:458,1978.3. Data on file, Japan-Lederle Co. Ltd., 1975: through ref. 1.4. Woodford, R., and Barry, B.W.: Activity and bioavailability of amcinonide andtriamcinolone acetonide in experimental and proprietary topical preparations.Curro Therap. Res. 21:877, 1977.5. MIMS (Monthly Index of Medical Specialities) 21 (6): 234, 1979.6. Barry, B.W., and Woodford, R.: Comparative bioavaitability of proprietarytopical corticosteroid preparations; vasoconstrictor assays on thirty creams andgels.Br. J. Derm. 91:323, 1974.7. Barry, B.W., and Woodford, R.: Comparative"bioavailability and activity of pro-prietary topical corticosteroid preparations; vasoconstrictor assayson thirty-oneointments. Br. J. Derm. 93:563, 1975.[ 309 ]BID AVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONS8. Tukey, J.W.: On the comparative anatomy of transformations. Ann. Math.Stats. 28:602, 1957.9. Harter, H.L., and Lum, M.D.: An interpretation and extension of Tukey's onedegree of freedom for non-additivity. Aeronautical Research Laboratory, U.S.Air Force ARL 62-313: p. 1, 1962.10. Goldstein, A.: Biostatistics: An introductory text. Macmillan, New York,Chapter 2, 1964.11. Barry, B.W., and Woodford, R.: Activity and bioavailability of topical steroids.In vivo/in vitro correlations for the vasoconstrictor test. J. Clin. Pharm. 3:43,1978.[ 310 ]

Bioavailability and activity of 0.1% amcinonide preparations: comparison with proprietary topical corticosteroid formulations of differing potencies

Rhodes Repository (SEALS)

CURRENTTHERAPEUTICRESEARCHVOL. 26, NO.3, SEPTEMBER, 1979BIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDEPREPARATIONS: COMPARISON WITH PROPRIETARY TOPICALCORTICOSTEROID FORMULATIONS OF DIFFERING POTENCIESR. WOODFORD AND J.M. HAIGH*School of Pharmacy, Portsmouth Polytechnic,King Henry I Street,Portsmouth, Hants., POI 2DZ United KingdomABSTRACTThe activity of a 0.1% amcinonide cream was compared with those ofselected proprietary topical corticosteroid formulations of potenciesdiffering according to the United Kingdom (U.K.) MIMS classification(very potent, potent and moderately potent) using a standard six.hourvasoconstrictor assay with multiple reading times. Statistical analysisindicated that 0.1% amcinonide cream feU within the category of a verypo ten t preparation. Three 0.1% amcinonide formulations (cream,combination cream and combination ointment, the last two containinganti-infective agents) were equipotent in the skin-blanching test.INTRODUCTIONA new topical fluorinated corticosteroid preparation, 0.1% amcinonidecream, has been reported to be as potent as 0.12% betamethasone17-valerate cream in a vasoconstrictor assay 1 and as effective as 0.1%betamethasone 17 -valerate cream in a double-blind study involving vari-ous inflammatory dermatoses.2 On the other hand, other vasoconstric-tor trials3,4 have shown a 0.1% amcinonide cream to be markedlysuperior to betamethasone 17-valerate creams of these concentrations.Experiments were, therefore, carried out to compare a) the blanchingactivity of 0.1% amcinonide cream with those of selected U.K. pro-prietary topical corticosteroid preparations of differing potency, and b)the bioavailability and activity of three formulations, each containing0.1% amcinonide.Seven corticosteroid creams were selected for comparison fromMIMS, which classifies topical steroid preparations as mildly potent,moderately potent, potent and very potent.5 Representatives of the lastthree categories were employed.* Present address: Faculty of Pharmaceutical Sciences, Rhodes University, 6140 Grahams-town, South Africa.Received for publication on July 14, 1979. Printed in U.S.A.0011-393X/7 9/0900-0301$0.40/0@ 1979, Therapeutic Research Press, Inc. Reproduction in whole or part is not permitted.[ 301 ]BIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONSMATERIALS AND METHODSTopical PreparationsTen corticosteroid preparations were employed. Seven were proprietary formulationsavailable in the U.K. (Betnovate cream, Dermovate cream, Halciderm, Metosyncream, Synalar cream, Temetex cream and Ultradil cream). The other three wereexperimental preparations containing 0.1% of the new topical steroid, amcinonide(amcinonide cream, amcinonide combination cream and amcinonide combinationointment). The corticosteroid compositions are given in Table 1. All products werestored at room temperature for two weeks and approximately 5 grams of eachpreparation were removed and rejected before use.SubjectsTwelve volunteers were selected from an experienced panel as those demonstratingconsistency of response to a standard preparation (Betnovate cream) but withoutreference to their sex or steroid sensitivity. None had received topical corticosteroidapplication for at least three months prior to the study. The results from ten ofthose subjects were selected for statistical analysis.MethodIn the study, 5 mg of the preparations were applied to the washed flexor surface ofeach forearm. The application sites consisted of 7 x 7 mm areas punched out fromdouble-sided adhesive Blenderm tape, to which the formulations were applied usinga random design. The sites were sealed with impervious Melinex film and leftoccluded for 6 hours. The Melinex and tape were removed and the areas werewashed with soap and water at body temperature and were dried. Readings weretaken in a double-blind manner after 10 minutes (to allow transient erythemaarising from washing to subside) and after 1, 2, 3, 6, 18, 26, 42, 66, 74 and 90hours to provide data points for skin blanching at 6, 7, 8, 9, 12, 24, 32, 48, 72, 80and 96 hours after application.Assessment was made according to a 0-4 scale with half-point ratings for inter-mediate readings:0 = Normal skin1 = Slight vasoconstriction of indistinct outline2 = More intense vasoconstriction3 = General even vasoconstriction with a clear outline of the square4 = More marked vasoconstriction with very distinct blanchingTen volunteers provided a total of 200 application sites.In order to. assess approximately the retention of steroid in the skin, the sites intwo volunteers were re-occluded with Melinex film for 12 hours eight days aftercommencement of the experiment. Pallor was estimated 5 hours later whenblanching was maximal.RESULTSFor each preparation the data for all volunteecs were converted topercent of the total possible score at each time period: i.e., if the maxi-mum score per site = 4, then for 2 arms and 10 volunteers, the maxi-[ 302 ]Table I - Blanching responses to corticosteroid preparations~ The corrected % total possible scores summed for all volunteers over all reading times.Obtained by planimetry of the blanching profile.c The Tm/10 mean value is the square root transformation of sum of corrected scores (Tm) divided by the number of volunteers (10). Theminimumsignificantrange valuek = 0.54 (P = 0.05), i.e. if the Tm/10 valueof two preparationsdiffer by more than 0.54 there isa significantd difference between those preparations (see Statistical Treatment of Results)Re-occludedfor 12 hours, 8 days after commencementof the experiment.;c~00t::J"'J0I"t::J>Zt::Jc..,~II:>....G1II:aSummed b Area Under Dt"m/10 d% Total% Total the Curve Mean PossiblePossible % x Hours Value Score onPreparation Steroid and % w/w Score Re-occlusionDermovate cream Clobetasol propionate, 0.05 519 3100 6.41 53Amcinonide cream Amcinonide, 0.1 510 2770 6.34 44Halciderm Halcinonide, 0.1 504 2630 6.31 44Amcinonide combination Amcinonide, 0.1 501 2680 6.29 44cream""Amcinonide combination Amcinonide, 0.1 489 2760 6.20 530"" ointmentMetosyn Cream Fluocinonide, 0.05 414 2640 5.69 19Betnovate cream Betamethasone as valerate, 0.1 393 2570 5.55 19Temetex cream Diflucortolone valerate, 0.1 391 2220 5.51 25Synalar cream Fluocinolone acetonide, 0.025 370 2710 5.35 25Ultradi I cream Fluocortolone pivalate, 0.1; 217 1060 4.13 3Fluocortolone hexanoate, 0.1100~()(j)(l):0.~ 4'&.ro;2';KBIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONSFigure 1 - Blanching curves for preparations indicated.801100Amcinonide cream60,\\\\\\~Metosyn cream\\~Ultradil cream20Synalar cream20 40 60Time -Hoursmum score = 80. For example, amcinonide cream gave a 6-hour score of19.5 out of 80 to provide a value of 24.4% total possible score. Thedata were then unified in terms of a standard preparation, Betnovatecream, as described previously6 in order to relate the results obtainedin this trial to those obtained in previous studies employing both experi-mental amcinonide formulations4 and an extensive range of proprietarypreparations. 6,7 The unification correction factor for Betnovate creamin the present trial is given by: summed % total possible score forBetnovate cream as obtained by Barry and Woodford6 / summed % totalpossible score for Betnovate cream in this study = 1.41.The % total possible score data were, therefore, multiplied by 1.41and blanching curves of these results are shown in Figures 1 to 3.Experimental points have been omitted to aid clarity but all points layon or near the curves as drawn. The profiles shown may be compareddirectly with those preparations previously studied.4,6, 7Statistical TreatmentA computer-aided analysis of variance was performed on the results, the[ 304 ]100\!!0uC/)Q):is~:$t2'cfZR. WOODFORD AND J.M. HAIGHFigure 2 - Blanching curves for preparations indicated.80100Halciderm60:remetex cream40120! Amc:inrnide combinationcream20 40 60Time-Hourscomputer program being written so that the data could be analysedwithout transformation or in one of five (x-I, x-lh, log x, x¥2 and x2)transformations.8,4 Tests for non-additivity9 indicated a preference forthe "square root transformation" data and the randomised block designvariance anlaysis was calculated using those values. Highly significantdifferences were found to exist between the preparations (F = 37.06,P < 0.01), while the minimum significant range value k in theStudentized range test! 0.4 at the 5% significance level was 0.54 (10preparations and 81 degrees of freedom). Hence the non-significantrange for e.g. amcinonide combination cream = 6.29 :!: 0.54 = 6.83 to5.75. If the Tm/l0 mean values (Table I) of two preparations differ bymore than 0.54 there is a significant difference between those formula-tions.Steroid Reservoir Formation in the SkinRe-occlusion of the appiication sites in two volunteers (statisticalanalysis was, therefore, inapplicable) provided an estimate of the steroidreservoir in the skin. These results are shown as % total possible scoreon re-occlusion (Table I).[ 305 ]Q)auC/)~.iijrn&.BIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONSFigure 3- Blanching curves for preparations indicated.Amcinonide combinationointmentDermovate cream\\\\" """" " " "Betnovate cream""-"-"-"- , ", , "10020 40 60Time - HoursDISCUSSIONAll of the preparations studied in this trial produced obvious vasocon-striction, the shapes of the blanching curves for the amcinonide andproprietary formulations (Figures 1 to 3) being similar to those pre-viously reported.4, 6.7In this trial the rather high value of the Betnovate cream correctionfactor was a little surprising. Examination of the individual volunteers'results suggested that this was due to rather low responses to Betnovatecream (and the other preparations) in three volunteers, thus producing alow total for Betnovate cream in this trial. However, the values of thecorrected % total p~ssible scores summed for all volunteers over allreading times (Table I) were very similar to those previously reported,e.g., amcinonide cream = 510 (509 in a previous trial).4 Dermovatecream = 519 (512 previously),6 Metosyn cream = 414 (409 pre-viously.)6 An exception was amcinonide combination cream, which pro-vided a value about 7% higher than in the previous study. 4 This mayhave been due to the slight modification in the composition of theamcinonide combination Gream compared to that employed in the 1977[ 306 ]R. WOODFORD AND J.M. HAIGHFigure 4 - Histogram of sum of % total possible scores for preparations indicated.Figure 5 - Histogram of areas under the blanching curve for preparations indicated.Fmnulation:2x'*''W8"£~::>ffi100~[ 307 ]ro1EE'* ffi E'0 t; .0E8<:.Q1;; 1;;<: <:I I IEtl EIEco§ OJ EOJ " E11 I" " " t; OJ Eco11" OJ,, " " t; e!E " "1;; § <: <: ! x0 '" " roc c "' Q:jI :Q g.8 ro.E c, '" 5« «I (f)i EE.0 ".8 81;;<:E isE co§ § EOJ " Ee! t; " E " OJ E" OJ "" " " "" t;1;; u :12 E " ".E§ §c! !ji5 0 , :a ucE .(3 g ro .(38 E c E .!.1'" 5« « (f) «FormulationBIOAVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONStrial. 4 The similarities in different trials noted for the proprietarypreparations further inspires confidence in our standard vasoconstrictortest.1 1The corrected % total possible score values for the most activepreparations (Dermovate cream, Halciderm. cream and the amcinonideformulations) at the 12-hour reading time were somewhat greater than100. Because the blanching curves were <;lrawn to a maximum value of100% (Figs. 1 to 3) the area under the curve values (Table I and Fig. 5)for the amcinonide, Halciderm and Dermovate preparations were ratherlower, compared to the less potent formulations, than might otherwisebe expected. A ranking based on the sum of the corrected % total pos-sible score values (Fig. 4) suggested that the corticosteroid preparationscomprised three potency groups: this was confirmed by statisticalanalysis (Table I).Table II- Blanching responses to preparations containing 0.1% amcinonic1...ePreparationaBioavailabilityIi) Iii)Amcinonide creamAmcinonide combination creamAmcinonide combination ointment1.000.980.961.000.971.00aDefined by the relationships(") summed % total possible score for preparationI summed % total possible score for most active preparation("') "area under the curve" for preparationII "area under the curve" for most active preparationTable III - Potency classification of topical corticosteroid creamsCreamaTm/10 MeanValue bSignificanceCpotencyClassificationDermovateHalcidermAmcinonideAmcin. combination6.416.316.346.29No significantdifferencebetween creams(P = 0.05)very potentMetosynBetnovateTemetexSynalarUltradil5.695.555.515.354.13No significantdifferencebetween creamsIi> = 0.05)potentmoderatelypotenta Table I, k = 0.54 IP = 0.05)b As determined by the blanching test. Significant differences exist between the three potencygrou ps.c MIMS classification for topical steroidsThe three amcinonide formulations provided similar steroid bioavail-ability (Table II) and were statistically equivalent to each other and to[ 308 ]R. WOODFORD AND J.M. HAIGHthe Dermovate and Halciderm preparations (Table I). Table III lists thecreams studied in decreasing Tm/10 mean values and shows that thehydrophilic amcinonide preparations were significantly more active inthe 6-hour occluded blanching test than selected potent creams on theU.K. market: both amcinonide cream and amcinonide combinationcream were apparently equivalent to the very potent products ex-amined, and produced approximately similar reservoirs of steroid in theskin.CONCLUSIONS1. 0.1% amcinonide cream was significantly more active (P = 0.05) ina standard six-hour occluded vasoconstrictor assay than four "recog-nized as potent" U.K. proprietary topical corticosteroid creams(Betnovate, Metosyn, Synalar and Temetex).0.1% amcinonide cream was statistically equivalent to two verypotent U.K. proprietary creams, Dermovate and Halciderm.Three 0.1% amcinonide formulations (cream, combination creamand combination ointment, the last two containing anti-infectiveagents) were equipotent in the skin-blanching test.2.3.AcknowledgementsOne of us (J.M.H.) acknowledges a bursary from the South AfricanCouncil for Scientific and Industrial Research.References:1. Ishihara, M.: Studies on the vasoconstrictor activity of amcinonide, a newsynthetic topical corticosteroid. Nishinihon J. Derm. 38:286, 1976.2. Sanchez, J.L.: Amcinonide, a new topical steroid. Curro Therap. Res. 24:458,1978.3. Data on file, Japan-Lederle Co. Ltd., 1975: through ref. 1.4. Woodford, R., and Barry, B.W.: Activity and bioavailability of amcinonide andtriamcinolone acetonide in experimental and proprietary topical preparations.Curro The rap. Res. 21:877, 1977.5. MIMS (Monthly Index of Medical Specialities) 21 (6): 234, 1979.6. Barry, B.W., and Woodford, R.: Comparative bioavaitability of proprietarytopical corticosteroid preparations; vasoconstrictor assays on thirty creams andgels. Br. J. Derm. 91:323, 1974.7. Barry, B. W., and Woodford, R.: Comparative"bioavailability and activity of pro-prietary topical corticosteroid preparations; vasoconstrictor assays on thirty-oneointments. Br. J. Derm. 93:563, 1975.[ 309 ]BID AVAILABILITY AND ACTIVITY OF 0.1% AMCINONIDE PREPARATIONS8. Tukey, J.W.: On the comparative anatomy of transformations. Ann. Math.Stats. 28:602, 1957.9. Harter, H.L., and Lum, M.D.: An interpretation and extension of Tukey's onedegree of freedom for non-additivity. Aeronautical Research Laboratory, U.S.Air Force ARL 62-313: p. 1, 1962.10. Goldstein, A.: Biostatistics: An introductory text. Macmillan, New York,Chapter 2, 1964.11. Barry, B.W., and Woodford, R.: Activity and bioavailability of topical steroids.In vivo/in vitro correlations for the vasoconstrictor test. J. Clin. Pharm. 3:43,1978.[ 310 ]

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Bioavailability and activity of 0.1% amcinonide preparations: comparison with proprietary topical corticosteroid formulations of differing potencies

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