Therapv

Topical corticosteroid compounding: Effects onphysicochemical stability and skin penetration rateLincoln Krochmal, MD, Jonas C. T. Wang, PhD, B. Patel, PhD, and 1. Rodgers, BSBuffalo, New York

Compoundingcompatibilitystudiesoffourcorticosteroid creamproductsandfourcommonlyadded chemicals are presented. Physical alteration, chemical stability, micropreservativechallenge status, and in vitro skin penetration were evaluated at ambient conditions for 2months.The study was designedto generateuseful,previously unavailable information toaiddispensingpharmacists and dermatologists. (J AM ACAD DERMATOL 1989;21:979-84.)

Uncontrolled compounding of topical medica-tions, especially in the pharmacy, can diminish ther-apeutic efficacy because the interaction of com-pounded agents can affect physicochemical stabilityand skin penetration rate. Current use of topical ste-roids frequently includes compounding with a vari-ety of chemicals aimed at a particular purpose orsymptom (or both). Many products, however, arenot physically, chemically, or microbiologicallycom-patible, although dermatologists may order ad hoccompounding of two products into a single formula-tion. In galenic compounding of topical steroids, thehorny layer's absorptive capacity for the steroid maybe increased or decreased by influencing its struc-tural-functional condition. By changing the pene-tration conditions of the skin, the therapeuticallyeffective concentration of the steroid may be opti-mized or compromised. Changes in physicochemicalstability and micropreservative status caused by thecompounding process also have been given scant at-tention. Typical physicochemical problems that 0c-cur commonly in the compounding process are listedin Table I.

The objective of this study was to demonstrate theproblems associated with extemporaneous com-pounding. Four corticosteroid cream products listedin United States Pharmacopeia (USP)XXI and fourcommonly added chemicals were chosen for study.

From the Pharmaceutical Research and Development Division,Bristol-Myers Co.

Reprint requests: Jonas C. T. Wang, Johnson & Johnson Baby Prod-ucts Co., Grandview Rd., Skillman, NJ 08558.

16/1/10365

Table I. Potential physicochemical problems thatcould occur with extemporaneous compoundingprocess

1. Oxidation or hydrolysis could occur as a resultof exposure to light and moisture during thecompounding process.

2. Changes in pH couldoccur becausesome adju-vants (i.e, salicylic acid, phenol, urea) couldacceleratethe degradation process of the activeagent.

3. Micropreservative capability couldbe damagedbecause the compounding process may dilutethe preservative concentration of the originalproduct or enhance the interaction betweenpreservatives and added chemicals or packag-ing materials.

4. The particle size or crystal form of the activeagent could be changed, which may reduce thebioavailability of the active agent.

5. The physical characteristics of the originalproduct (e.g., viscosity, precipitation, or sedi-mentation) couldbe changed, whichmay causephysical separation duringstorage.

6. Because there is no stability profile for thepreparation after compounding, improper stor-age could accelerate the degradation process ofthe active agent, which may lead to a loss ofpotency.

The corticosteroid cream products were selected be-cause the method for analysis (i.e., high-perfor-mance liquid chromatography [HPLC]) has beenpublished in USP XXI Physical alteration, chemi-cal stability, micropreservative challenge status, andin vitro skin penetration rates were evaluated at am-bient conditions for 2 months.

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*As listed in the United States Pharmacopeia XXI.

EXPERIMENTAL DESIGN

Table II. Compounding products and chemicals

Material and reagentsFourcorticosteroidcream products were selected: 0.2%

hydrocortisone 17-valerate (Westcort cream) (Lot No.EXP1188), 0.1% triamicinolone acetonide (Kenalog)(Lot No. 3L029), 0.05%fluocinonide (Lidex) (Lot No.42819), and 0.25% desoximetasone (Topicort) (Lot No.110234). Four chemicalswere selected:2% salicylic acid,10% urea, 0.25% camphor (reagent grade) + 0.25%menthol +0.25% phenol, and 5% USP coal tar solution(Liquor Carbonis Detergens [LCD]). The salicylic acid,urea, menthol, and phenolwere ACS (American Chem-ical Society) grade.Compounding directions for galenicpreparations

The four selected topical corticosteroid creams wereprepared withfour commonlyadded chemicals (Table II)by a licensed pharmacist with the use of a conventionalcompounding technique. The compounding direction foreach galenic preparation is as follows:

-2% Salicylicacid, 10% urea,and 5 % LCD:Weigh out eachchemical solid or solution. Levigate the solid or solution intoa small amount of glycerinor water to form a smooth paste.Incorporate the paste into the steroid cream geometrically.

-0.25% Camphor+0.25% menthol+ 0.25% phenol.'Weighout phenol, menthol, and camphor. Triturate to form aeutectic mixture. Incorporate the solution into the steroidcream geometrically.

All galenic preparations were packaged in 15 ml am-ber glass jars with black, polyethylene-lined, phenoliccaps and stored at ambient conditions for stability eval-uation.

High-performance liquid chromatographychemical analysis method

The HPLC methods listed in the USP XXI for triam-cinolone acetonide cream (p. 1078), desoximetasonecream (p. 285), hydrocortisone 17-valerate cream (p.508), and fluocinonidecream (p. 436) were adopted in thestudy.

Physical and chemical stability studyPhysical stability was carried out by visual observation

of color, odor, and fluidity as compared with samplesstored at 50 C as a positive control. Both physical andchemical stabilities were evaluated at ambient conditionsbefore compounding and at 24 hours, 1 month, and 2.months after compounding. Microbiologic evaluation in-cluded bacterial count and micropreservative chal-lenge test with the use of USP standard methods after

In vitro human skin permeation studiesSkin samples were obtained from the abdomen or chest

of human donors at autopsy. Skin specimens were imme-diately labeled, wrapped, and placed on ice.Only skin thatappeared grossly normal was used. Historical evidence ofchronic illness, skin disease, or skin injury in the donorwere criteria for exclusion from study. Within 2 hoursof collection, the skin specimens were stored in afreezer at -300 C until needed. Before a skin perme-ation study was begun, a sample was thawed at roomtemperature in normal saline solution. Skin was thenfrozen on the microtome with C02 and sectioned (150to 240 /-lm). The prepared skin section was labeled andstored in normal saline solution at 50 C until used in apermeation study.

Franz diffusion cells (9 mm inner diameter), filled withthe necessary volume of normal saline solution as recep-tor fluid, were adapted for the study. The designatedspecimen of prepared skin section was mounted on eachcell, dermis side down. The membrane was secured withan 0 ring and an open cap for the cell. A 50 mm! sample(a dose to ensure an infinite supply for penetration) of thecompounded cream was then dispensed from a pipettecalibrated in microliters and applied in an even layer ontothe skin section. The receptor fluid was maintained at34 0 0.1 0 C throughout the study. Receptor fluid (200mm-) was collected at 1,2,3,4,7,8,12,24,32, and 48hours for chemical assay with the use of USP HPLCmethods. Original creams alone and galenic preparations2 months after compounding were investigated in the invitro human skin penetration study.

The concentration-time course data collected fromdiffusion studies were analyzed statistically with the useof Tukey's studentized range test.

Commonly addedchemicals

10% Urea

0.25% Camphor +0.25% menthol +0.25% phenol

5% USP coal tarsolution (liquorcarbonisdetergens[LCD]

2% Salicylic acid

0.05% Fluocinonide (Lidex)

Corticosteroid cream products*

0.2% Hydrocortisone17-valerate (Westcort)

0.1% Triamcinolone acetonide(Kenalog)

0.25% Desoximetasone(Topicort)

Volume 21Number 5, Part 1November 1989 Topical corticosteroid compounding and penetration rate 981

Table III. Physicochemical results of compounding studies of four corticosteroid products with fourcommonly added chemicals at ambient conditions for two months

0.2 % Hydrocortisone 0.25 % Desoximetazone 0.1 % Triamcinolone 0.05% Fluocinonide17-valerate cream, pH 4.8 cream, pH 4.4 acetonide cream, pH 6.2 cream, pHS.O

Initial I 1 mo I 2rno Initial lImo I 2 rno Initial lImo I 2 mo Initial lImo I 2 mo10%Urea 91% 89% 89% 80% 81% 81% 75% 67% 55% 90% 74% 66%

pH 5.0 5.3 5.4 4.7 4.8 5,8 8.0 8.6 8.7 6.2 6.8 6.80.25% Camphor+

0.25% menthol+ 101% 102% 100% 102% 106% 102% 99% 105% 100% 99% 105% 100%0.25% phenolpH 4.8 4.9 4.8 4.2 4.4 4.9 6.2 6.7 7.0 5.2 5.1 5.1

2% Salicylic 97% 104% 90% 100% 105% 104% 99% 103% 99% 97% 100% 101%acid

pH 3.2 3.1* 3.3* 3.3 2.9 2.8* 2.6 2.6 2.5 2.7 3.0 3.05% USPLCD 90% 87% 96% 103% 97% 103% 101% -~ 95% 103% 157% 102%

solutionpH 4.9 4.8 5.1 5.5 4.7 S.n 6.4 6.4 6.6 5.4 S.4 5.6

*Uquid separation; can be shaken back to uniform emulsion with mixing.tLiquid separation; cannot be shaken baek to uniform emulsion.

~Not measured.Interfering peaks caused the high value.

initial compounding and again 2 months after com-pounding.RESULTSPhysical and chemical stability study

Results of the stability study are shown in TableIII. After compounding with 10% urea, the decreasein steroid content after 2 months at ambient condi-tions was 10% for hydrocortisone l7-valerate, 20%for desoximetasone, 45% for triamcinolone ace-tonide, and 34% for fluocinonide. The steroid con-centration decreased by more than 10% immedi-ately after it was mixed with urea, suggesting thatchemical degradation had occurred. No significantchemical degradation was observed when the steroidwas compounded with 0.25% camphor + 0.25%menthol +0.25% phenol, 2% salicylic acid, or 5%LCD solution.

No physical incompatibilities were observed inthe compounding of the triamcinolone acetonideand fluocinonide creams. Physical separation wasobserved in the compounding of hydrocortisone 17-valerate and desoximetasone creams with 2% sali-cylic acid; however, with shaking, a uniform emul-sion of each could be obtained with little difficulty.Severe physical separation was observed in thecompounding of desoximetasone cream with 5%LCD solution, and the uniformity of the cream could

not be recovered, even with vigorous shaking. ThepH of topical creams varied slightly by product. Ingeneral, after compounding, 2% salicylicacid acid-ifiescream preparations and reduces the pH by ap-proximately 2 units for all compounded prepara-tions. The pH of the triamcinolone acetonide creamwith 10%urea was exceptionallyhigher than that ofother preparations. Why the pH increased is notknown,but a vehicle-adjuvantinteraction may occurbetween the triamcinolone acetonide vehicle and10% urea. The pH of most of the preparations wasunchanged at ambient conditionsfor 2 months. Pre-servative challenge tests revealed that all galenicpreparations were adequately preserved microbio-logicallyfor up to 2 months after mixingat ambientconditions.

In vitro permeability of human skin to the testgalenic preparations

The in vitro human skin permeation rates for thetest creams and their galenic preparations are shownin Figs. I to 4. The shape of the skin penetrationcurvessuggeststhat under the conditionsused in thestudy penetration is generally not a simple first-order process. With few exceptions the penetra-tion profiles include a time lag to reach steadystate.

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Fig. 2. Amount of desoximetasone penetrated through6.36 X 10-1 cm2 of human skin at 34 0 0.1 0 C. Barsindicate standard error of the mean (n =4). e, 0.25%Desoximetasone + 2% salicylic acid; .6., 0.25%desoximetasone + 0.25% camphor, 0.25% menthol,0.25% phenol; X, 0.25% desoximetasone + 5% LCD; 0,0.25% desoximetasone; D, 0.25% desoximetasone + 10%urea.

triamcinolone acetonide also was observed by com-pounding with 2% salicylic acid. In contrast, pene-tration of triamcinolone acetonide with 10% ureawas twice as high (statistically significant,p -< 0.05)as that of cream alone. Evidence presented byothers 1,2 suggests the mechanism of this penetrationenhancement by urea can be attributed to the inter-action of several factors, including the solubility en-hancement by urea, skin structural-functionalchange by urea, and an increase in the horny layer's'water-binding and absorptive capacity for the ste-roids.

Similar observations were made when fluocino-nidewas compoundedwith 0.25%camphor + 0.25%menthol + 0.25% phenol or 5%USP LCD (Fig. 4).An approximately twofold, statistically significant(p

Volume 21Number 5, Part 1November 1989 Topical corticosteroid compounding and penetration rate 983

0.3

Ol ~f/:i. 0.2-coSc.......

OJc:OJa. /~-.....c:: 0.1:::>0E

t~~0

0 20 40 60 80Time, hr.

Fig. 3. Amount of triamcinolone acetonide penetratedthrough 6.36 X 10-1 cm-of'hamanskln at 340 0.10 C.Bars indicate standard error ofthemean (n = 4).0,0.1%Triamcinolone acetonide + 10% urea; e, 0.1% triamci-nolone acetonide + 2% salicylic acid; 0, 0.1% triamcino-lone acetonide; X, 0.1% triamcinolone acetonide + 0.25%camphor, 0.25% menthol, 0.25% phenol; D.,0.1% triam-cinolone acetonide + 5% LCD.

DISCUSSION

The enhancement of penetration and clinical ef-ficacy of active agents by addition of differentchemicals has been practiced commonly by derma-tologists. Results of our study indicate the physico-chemical stability and skin permeation rate of top-ically applied steroids after galenic preparation bycompounding with commonly added chemicals arevehicle dependent. Results also suggest that it is im-possible to develop universal guidelines to predict theinfluences of extemporaneous compounding pro-cesses because there are many unknown factors.These include vehicle properties, solubility of ste-roids in the vehicles, physicochemical and solubilitychanges after compounding with added chemicals,and changes in the horny layer's water-binding andabsorptive capacity that are involved in the com-pounding process.

Generally, penetration enhancement is expectedfor steroid preparations compounded with salicylicacid.' Similar observations of approximately two-fold to threefold penetration enhancement also werenoted in this study for the four commonly used top-ical steroid creams when compounded with 2% sal-

0.20>:l..-

-0~e 0.1

.....

Q)c: ~EQ)Q........c:::::>0E [-

00 40 60 80Time, hr.

Fig. 4. Amount of fluocinonide penetrated through6.36 X 10- 1 cm2 of human skin at 34 0.1 0 C. Barsindicate standard error of the mean (n == 4)., 0.05%Fluocinonide+ 2% salicylic acid; 0, 0.05% fluocinonide;X, 0.05% fluocinonide+ 5% LCD; D., 0.05%fluocinonide+ 0.25% camphor, 0.25% menthol, 0.25%phenol.

icylic acid. The penetration enhancement of salicylicacid could be due to its keratolytic effect on thehorny layer that reduces the resistance of hornylayer to steroid molecules. No physicochemical sta-bility problem was found in compounding with 2%salicylic acid at ambient conditions for 2 months.

Compounding of 0.25% camphor +0.25% men-thol +0.25% phenol and 5% LCD with four teststeroid creams produced no significant changes inphysicochemical stability or in vitro skinpenetrationrate through human skin.

In contrast to conventional belief, results of ourstudy reveal that 10%urea enhances the penetrationof only triamcinolone acetonide through humanskin, which supports the finding of Wohlrab 1 andFeldmann and Maibach.i No penetration enhance-ment of 10% urea was observed for hydrocortisone17-valerate and desoximetasone. The penetrationenhancement of fluocinonide by 10% urea was notdemonstrated in this study mainly because of itschemical instability. As suggested by others.v 4 ureamay increase the horny layer's water-binding andabsorptive capacity that changes the skinstructural-functional condition and, hence, changes the pene-tration conditions under which the therapeuticallyeffective concentration of the steroid may be opti-mized. Urea's enhancement of steroid penetrationand clinicaleffectiveness,however,alsois dependenton the vehicle." The absorption enhancement alsocould be attributed to the interaction ofseveralother

984 Krochmal et al.

factors, such as the solubility increase by urea or thecomplexation between the steroid and urea, vehicleand urea, or skin and urea. Results of this studydemonstrate that urea is not a universal absorptionenhancer for every steroid.

Results also disclose that compounding should bepracticed with care. Previous knowledge of thecommonly added chemicals is required so that amaximum clinical benefit can be achieved throughthe compounding process.

Journal of theAmerican Academy of

Dermatology

REFERENCES1. Wohlrab W. The influence of urea on the penetration

kinetics of topically applied corticosteroids. Acta DermVenereol (Stockh) 1984;64:233-8.

2. Feldmann RJ, Maibach HI. Percutaneous penetration ofhydrocortisone with urea. Arch Dermatol 1974;109:58-9.

3. Burrows D, Shanks RG, Stevenson CJ. Therapeutics 111-quarterly review. Br J DennatoI1968;80:550-3.

4. Weirich EG. Dermatophannacology of salicylic acid. Der-matologica 1975;151:268-73.

ABSTRACfS

Skin hypersensitivity to IgE reverse reaginic tests in patientswith Brazilian pemphigus foliaceusRocha AMF, Antunes L, Patrus OA. Anais Bras Dermatol1988;63:347-9 (Portuguese)

The IgE immune responsewas assessed by the reverse reaginic test in16patientswith Brazilianendemicpemphigusand in an equalnumberof healthy controlsubjects. In both groupsskin tests wereperformedwiththe useofhousedust, airbornefungi,and dermatophytidantigens.Noneof the patientsor control subjectshad a historyof atopy. Positiveskintest reactionsto house dust and airbornefungiwere morecommonin patients with Brazilianpemphigusfoliaceus in comparison with thecontrol group.The IgE immune response may playa role inthe patho-genesis of Brazilianpemphigusfoliaceus,

Yehudi M. Felman, MD

Postoperative interferon/hydrogel treatment for chronicpersisting giant condylomata acuminataGross G, Roussake A, Pfister H. Hautarzt 1988;39:684-7(German)The local application of recombinant interferonalfa-2c withhydrogel(1 X 106 IV recombinant interferon alfa-Zc per gram of hydrogel),given asan adjuvanttherapy after electrosurgery, ledto a completecure,withoutrelapse, ofpreviously recalcitrantgiant condylomataacuminatasimilarto the Buschke-Ldwenstein tumor in a 19-year-old womanwithHodgkin'sdisease (stage 11/11I). Recombinant interferon alfa-2c-hy-drogel givenas an adjuvant therapyto surgerymay have moreantiviraland antiproliferative effects than immunomodulatory activity. Thisform of interferon alfa is safe and effective and is especially recom-mended in immunocompromised persons with genital human papillo-mavirus infection unresponsive to conventional therapeutic modalities.

Yehudi M. Felman, MD

Hyperpigmented striae after bleomycin therapyMassone L, Pestarino A, Borghi S, et al. Ital DermatoI Venereol1988;123:225-7 (Italian)

Hyperpigmented linear striae appeared on the trunk of a 65-year-oldirianwitha 7-yearhistoryof Hodgkin'sdisease. He had beentreated for

a fewmonthswitha cumulative bleomycin doseof 112mg.Streakingon the skinwas first notedsome weeks after the onsetof veryintensepruritus. Biopsy specimens showed melanotic hyperpigmentation withnochangeinthe morphology of theskin.Theauthorssuggestthat bleo-mycin, accumulated in the skin because ofscratching-induced vasodi-lation, mayreduce epidermal turnover timeand allow a longer periodof contactbetween keratinocytes and melanocytes. This may increasein the transferof melanosomes toepidermal cells. Therapywithcime-tidineinsingledailydoses of800mgreduced the intensity of itching forseveral months.

Yehudi M. Felman, MD

Long-term skin effects of optical radiationWiskemann A. Aktuel Dermatol1988;14:320-2 (German)Long-term effects of excessive sun exposure include alterationof Con-nective tissue(photoaging), multiplesolarkeratoses, skin cancer(pho-tocarcinogenesls), and pigmented lesions (solar lentigines, lentigo ma-ligna,lentigo rnaligna melanoma). Fair-skinned persons are at highestrisk. In hairless mice,connective tissue damageis induced mostby theVVBwaveband and leastby the UVA waveband of simulated globalradiation. Radiant heat from the visible and infrared wavebands alsodamages connective tissue. The actionspectrum forphotocarcinogene-sisin miceresembles that ofultraviolet radiation-induced erythema inhumanbeings. UVAradiation(340nm) produces noskincancerin an-imalexperiments, but radiantheatmayaugment carcinogenesis inmiceor produce skin cancer by itself. Besides carcinogenesis by direct ra-dioexposure, the induction of specific immunotolerance againstpreex-istingtumorcellsbysmallbut accumulating singledoses of UVBradi-ation,as demonstrated by experiments inanimals, mustbe considered.An increased riskof skincancer byexposure to tanningequipment orto phototherapy can be estimatedby the amountof additional ultravi-oletexposures inminimalerythemadoses peryearandcan berestrictedby optimizing the spectra.Alreadyexisting radiationdamage (exceptforskincancer)mayregress iftheskin istotally protectedbysunscreens.Tretinoincream 0.1 % to 0.01% accelerates the regression.

Yehudi M. Felman, MD