5
Use of Theoretical Partition Coefficients Determined From. Solubility Parameters to Predict Permeability Coefficients for 5-Fluorouracil * Elizabeth F. Shere rt z, M.D. , Kenn eth B. Sloan, Ph.D ., and Raquel G. McTi ernan, B.S . De pa rtm ent of Medicin e (Dermatology), Veterans Admini strati on Medica l Ce nt er and the Uni versity of Flo rid a Co ll ege of Medicine (EFS), Gainesv ill e, Department of Medicin al Chemistr y, Uni versity of Fl o ri da Co llege of Pha rm acy (KBS) , Gainesville, and Veterans Admini st ra ti on Medi ca l Ce ntcr (RGM), Gainesv ill e, Flo rid a, U .S. A. Values for experiment al pe rm ea bility coe ffi cient s of5-flu o- rour ac il (5-FU) in 7 sin gle- and 4 t wo -comp onent vehicl es we re dete rmin ed from flu x meas ur eme nt s throu gh hairless mouse s IGn in dif fusion ce ll s and from so lubility dat a. Th e- or etical partition coe ffi cient s of 5-FU be tw een vehicle and s kin we re dete rmin ed from solubility parameters of dru g, vehicle, and skin, and from this theor e ti ca l pe rmea bility coe ffi cients were es timated. Co mp ari son of theoreti ca l w ith experimental va lu es for the perm ea bility coeffi cients showed a good correla ti on for vehicles with solubility parameters be tw een 12-18 For vehicles or mix tur es of ve- I n developing dru g preparations for to pi ca l deli very thr ough the skin, the choice of vehicle fo rmul a ti ons for a given dru g is imp or ta nt to assure adequate delivery of the drug into the skin. The solubility of a dru g in a chosen vehicle is imp orta nt in det e rminin g the rate of deli very into the skin, and this solubility is dependent on ph ys icochemi ca l properti es of the drug molec ul e and of the vehicle. Th e ability to predict percu ta neo us penet ra tion of a drug based on these physicochemi ca l character- istics wo uld potentiall y enhan ce topi ca l dru g develo pm ent by decreasing the need for in vitro and in vivo animal and hum an skin penetration studies. Pr e vi ously, Sloan and associates [11 pro- vided the theoreti ca l bas is and experiment al evidence to show that the experime nt all y dete rmin ed perm ea bility coef fi cient (Kp ) of a drug in a given vehicle should be direc tl y pr oportional to the pro duct of a theoreti ca ll y dete rmin ed partition coe ffi cient (PC) of the dru g (betw een skin and vehicl e) and a constant (C). Th e theoreti ca l equa ti ons for this relati onship are s ummari zed in Tabl e I. The ca lcul ati on of the theoreti ca l PC of the drug bet wee n ve- Manusc ript received Jul y 21, 1986; accept ed for publi ca tion January 21, 1987. This s tud y was supp orted by the Medi ca l Resea rch Se rvice of the Vet- erans Admini strati on and the Dc rm atology Foundati on. * T his wo rk was prese nt ed in pa rt at the 47th Annu al Mee ting of T he Society fo r In ves ti ga ti ve De rm atology, In c., Washin gto n, D.C., M ay 1-4, 1986. Re print req ues ts to: E li za beth F. Shererrz, M. D. , Depa rtm e nt of Med- icine (De rm atology), Box J- 277, JHM Hea lth Ce nt er, Gaincsv ill e, Florida 32610. Abbrevia ti ons: 15: solubility paramcter S-FU: S-flu o ro ur ac il Kp: pe rm ea bility coeff icient PC: partition coe ffi cient hicl es with so lubility parameters in the range of 8-12 incr ea ses in flu x and pe rmeability coe ffi cie nt s were seen co mp ared w ith theoreti ca l pr edic tion s, possibly due to the similarity in so lubility parameters of the vehicles to that of skin (1 0 ca l/c m 3 )!. Th ere was an inverse rela- ti onship betw een 5-FU solubility in the vehicles and flu x or pe rm ea bility coe ffi cient s, with a minimum in flu x and pe rm eability coe ffi cient that co rr es po nd ed approxim ately to the poi nt where the so lubility parameters of dru g and vehicle we re the sa m e. J bt l/es t D enl/atol 89 :1 47-1 51, 1987 hi ck and skin is dete rmin ed from the ratio of the reciprocal of the activity coe ffi cient of the drug in the skin to that in the vehicl e, w hi ch in turn depend s on the diff erence bet wee n the solubility parameter of the drug minu s that of the vehicle squared, and the solubility parameter of the dru g minu s that of the skin squared (Eq. 3, Ta bl e I). Th e solubility par ameter (8) is equal to the square roo t of the cohesive ener gy divided by the molar volume (V). Further, E and V ca n be es timated by s ummin g the ato m ic and gro up co ntributi on for the ener gy of vapo ri zation and molar volum e, r es pec ti vel y [3,4], so that it is possible to ca lculate the solubility parameters of chemi ca ls that have not been dete rmin ed experime nt all y. Th e use of solubility parameters to predict the solubility of chemi ca ls h as been useful in a w ide va ri ety of ap- pli ca ti on s, including the cosme ti cs indus tr y [5] and the phar- maceuti ca l industry [6]. Th e anti pro lif era ti ve age nt 5-fluoro ur ac il (5 -FU) h as been ex- tensively used in topical chemotherapy of cut aneou s prema li gnant and mali gnant le sions [7]. Hyperkeratotic lesions are particularl y re fr actory to topi ca l 5-FU therapy, and la ck of penetration of the drug thr ough the thickened s tr a tum corneum is thoug ht to be the reason for this inefficacy [8]. T hus, it would be helpful to choose a vehicle fo rmul a ti on for 5-FU that wo uld optimize dru g delivery in this situa ti on. H owe ver, so fa r there h as not been a systema ti c e xa mina ti on of vehicles to o ptimi ze delivery of 5-FU . Th e curr ent study, then, inves ti gates the flux of 5-FU fr0 111 no n- polar to very polar vehicl es and the use of the ca lculated PC de ri ved from solubility parameters of 5-FU and diff erent vehicles to atte mpt to find a vehicle that would maximize delivery of 5- FU and to see whether the results wo uld be pr edicted from the th eo re ti ca l rela ti onship outlined in Table I. MATERIALS AND M ET H OD S Materials T he 5-FU was o bt ained fr om Sigma (St. Louis, Mi s- souri ). T he vehicl es we re o bt ained from Aldrich; all we re 99% 0022-202X/8 7/S03.S0 Copy ri g ht © 1987 by T he Society fo r In ves ti gative De rm atology, In c. 147

Use of Theoretical Partition Coefficients Determined … · Ultraviolet spectril were recorded with a Shimadzu UV-160 spectrophotometer. The 18-22 g female hairless mice (SKH-hr-l)

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Use of Theoretical Partition Coefficients Determined From. Solubility Parameters to Predict Permeability Coefficients for 5-Fluorouracil *

Elizabeth F. Sherertz, M.D. , Kenneth B . Sloan, Ph.D., and Raquel G . McTiernan , B.S . Departm ent of Medicine (Derm ato logy), Veterans Administration Med ica l Center and the Uni versity of Flo rida College of Medicine (EFS), Gainesville, Department of Medicin al C hemist ry, Uni versity of Flo rida College of Pharmacy (KBS) , Gainesville, and Veterans Administra tion Medica l Centcr (RGM), Gainesv ille, Flo rida, U .S. A.

Values for experimental permea bility coeffi cients of5-fluo­rouracil (5-FU) in 7 single- and 4 two-component vehicles were determined from flu x measurements through hairless m ouse sIGn in diffusion cells and from solubility data. The­oretical partition coeffi cients o f 5-FU between vehicle and skin were determined from solubility parameters of dru g, vehicle, and skin , and from this theoreti ca l permea bility coeffi cients were estimated . Comparison of theoreti cal w ith experimental values for the permeability coeffi cients showed a good correlation fo r vehicles w ith solubility parameters between 12-18 (ca l /cm3) ~. For vehicles or mixtures o f ve-

In developing drug preparations for topica l deli very through the skin , the choice of vehicle fo rmulations for a given drug is important to assure adequ ate deli very of the dru g into the skin. The solubility o f a dru g in a chosen vehicle is important in determinin g the rate of deli very into the skin , and this

solubility is dependent on ph ys icochemi ca l properti es of the dru g molecul e and o f the vehicl e. The ability to predi ct percutaneous penetra tion of a dru g based on these physicochemi ca l character­istics would potentiall y enhance topical dru g development by decreas ing the need for in vitro and in vivo animal and human skin penetration studies . Previously, Sloan and associates [11 pro­vided the theo retical basis and experimental evidence to show that the experim entall y determined perm ea bility coeffi cient (Kp) of a dru g in a given vehicle should be directl y proporti onal to the produ ct of a theo retica ll y determined partition coeffi cient (PC) of the dru g (between skin and vehicle) and a constant (C). The theoreti cal equati ons for this rel ati onship are summarized in Table I.

T he ca lculati on of the theo retica l PC of the dru g between ve-

Man uscript received July 21, 1986; accepted fo r publica tion J anuary 21, 1987.

T his stud y was supported by the Medical Resea rch Service o f the Vet­erans Administration and the Dcrmato logy Foundation.

* T his work was presented in pa rt at the 47th Annual Meeting of T he Society fo r In ves tiga ti ve Derm ato logy, Inc., Washington, D.C., M ay 1-4, 1986.

Reprint req ues ts to: E li zabeth F. Shererrz, M . D. , Depa rtment o f Med­icine (Derm atology) , Box J-277, JHM Hea lth Center, Gaincsville, Flo rida 32610.

Abbreviations: 15: so lubility paramcter S- FU : S-flu o rouracil Kp: perm eability coefficient PC: partition coeffi cient

hicles with solubility parameters in the range of 8-12 (cal/cm3) ~, increases in flu x and permeability coeffi cients were seen compared with theoretica l predictions, possibly due to the similarity in solubility param eters of the vehicles to that of skin (1 0 cal/cm3)!. There w as an inverse rela­tionship between 5-FU solubility in the vehicles and flu x or perm eability coeffi cients, with a minimum in flu x and permeability coeffi cient that corresponded approximately to the point where the solubility parameters o f drug and vehicle were the sam e. J bt l/est D enl/atol 89:147-151, 1987

hick and skin is determined from the ratio of the reciproca l of the activity coeffi cient of the drug in the skin to that in the vehicle, which in turn depends on the difference between the solubility parameter o f the dru g minus that o f the vehicl e squared , and the solubility parameter of the drug minus that o f the skin squ ared (Eq. 3, T able I). The so lubility parameter (8) is equ al to the square root of the cohesive energy (~E) divided by the molar vo lume (V). Further, E and V can be es timated by summing the atomic and group contribution fo r the energy of va porization and molar volume, res pecti vel y [3,4], so that it is possible to ca lculate the solubility parameters o f chemica ls that have not been determined ex perim entall y. The use o f solubility parameters to predict the solubili ty of chemica ls has been useful in a w ide va riety of ap­plica tions, including the cosmetics industry [5] and the phar­maceuti ca l industry [6].

The anti proliferati ve agent 5-fluorouracil (5-FU) has been ex­tensively used in topical chem otherapy of cutaneous premali gnant and malignant lesions [7]. H yperkerato tic lesions are particularl y refracto ry to topica l 5-FU therapy, and lack of penetration of the drug thro ugh the thi ckened stratum corn eum is thought to be the reason for this inefficacy [8]. T hus, it would be helpful to choose a vehicle fo rmulati on for 5-FU that would optimize drug delivery in thi s situation. However, so fa r there has not been a sys temati c exa mination of vehicles to optimize delivery of 5-FU . The current stud y, then, inves ti ga tes the flu x o f 5-FU fr0111 non­polar to very polar vehicles and the use of the calculated PC deri ved from solubility parameters of5-FU and different vehicles to attempt to find a vehicle that would maximize delivery of 5-FU and to see whether the results would be predicted from the theo reti ca l relationship outlined in Table I.

MATERIALS AND METH ODS

Materials T he 5- FU was obtained fro m Sigma (St. Louis, Mis­souri ). T he vehicles were obtained from Aldri ch; all were 99%

0022-202X/87/S03.S0 Copyright © 1987 by T he Society fo r In ves tigat ive Derm ato logy, Inc.

147

148 SHERERTZ, SLOAN, AND Mc TIERNAN

Table I. . Summary of Theoretical Equations Showing the Relationship of Permeability Coefficient and Partition

Coefficient of a Drug in a Vehicle [1]

Permeability Coefficient (Kp) = Partition Coefficient (PC) x Constant (C)

then log Kp = log PC + log C

I flu x of drug through skin

Wlere Kp = ------=---=--­solubility of drug in vehicle

(1)

(2)

log PC = I(solubility parameter of drug - solubility parameter of vehicle)2

- (solubility parameter of drug - solubility parameter of skin)2]

X (molar volume of drug) (volume fraction of vehicle)2/2.3 RT

or log PC = i(l5i - I5v? - (l5i - 15,)2] Vi<l)2/2 .3 RT (3)

volume fra ction of vehicle and skin (<1» "" 1

and

C = diffusion coefficient of drug = !2 thickness of sk in h,

(4)

<I> = volume fraction; R = 1.98 cal/degree mol; T = 305°K; Solubility parameter of skin (6,) = 10 (cal/c l11' )' 121.

pure and were used as received . The diffusion cells were obtained from Kercso Engineering Consultants, Palo Alto , California, and were 3 cm in diameter (7.06 cm2 skin surface area) with a 40-ml receptor phase volume. A Labline incubator with Variomag stir­rer was used to maintain constant temperature at 32°C and to stir the receptor phases of the cells . Ultraviolet spectril were recorded with a Shimadzu UV-160 spectrophotometer. The 18-22 g female hairless mice (SKH-hr-l) were obtained from Temple University Skin and Cancer Hospital, Philadelphia, Pennsylvania.

Diffusion Cell Studies The suspensions of 5-FU were stirred for 48 h at room temperature before 0.5-ml aliquots were applied to the skin. The 5-FU/vehicle suspensions used are summarized in Table II; the amount of 5-FU used in each was sufficient to assure an excess of 5-FU.

The mouse skin was prepared and diffusion cell sampling was done as previously described [1], with cells run in triplicate for each 5-FU/vehicle suspension. Receptor phase samples for UV spectrophotometric analysis at 265 nm were generally taken at 0, 3, 6, 9, 12, 20, 24, 30, 36, and 48 h after the suspensions were applied. At the end of this 48 h, the donor phase/skin surface was gently washed twice with 10 ml methanol to remove remaining 5-FU. This methanol wash from each diffusion cell was filtered

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

through Whatman #1 filter paper, and analyzed by UV spec­troscopy to determine recovery of 5-FU from the donor phase.

Linear regression analysis of cumulative mg of 5-FU in the receptor phase vs time in h gave a slope in mg/h; ill all cases the correlation coefficients were at least r = 0.99. Fluxes were ob­tained by dividing these slopes by the sk in surface area (7.06 cm2

),

and the permeability coefficients (Kp) were then determined by dividing the flux (mg/cm2 h) by the corresponding solubility of 5-FU (in mg/cm 3 of solution) in that vehicle, as in Eq. 2 of Table I.

Solubility Determinations The solubility of 5- FU in each vehicle was determined in triplicate by stirring an excess of 5-FU (240 mg 5-FU/3 ml vehicle or mixture of vehicles except for 400 mg 5-FU/3ml dimethylformamide) in each vehicle in sealed flasks for 48 h at room temperature (23 ± 1°C). This time period was adequate to insure a saturated solution [9 ,10]. The resulting sus­pensions were allowed to sit at room temperature for 24 h and then were filtered by gravity through Whatman #1 filter paper. Aliquots of the filtrates were diluted with methanol for mea­surement of 5-FU concentration by UV spectroscopy at 265 nm (extinction coefficient 5-FU = 7.13 x 103 liters/mol).

Solubility Parameter and PC Calculations The calculated solubility parameters (0;) were obtained usin g the method of Fe­dors [4], as demonstrated previously [1,11]. For mixed vehicle systems, it was assumed that there was no significant change of volume on mixing, and OV( I + 2) was calculated as the sum of the products of the volume fraction and solubility parameter for each vehicle [9].

RESULTS

The vehicles used in the diffusion cell experiments cover a large range of solubility parameters; some represent vehicles that could be used in therapeutic formulations (e.g., isopropyl myristate, propylene glycol). For the diffusiOl'i experiments, saturated so­lutions of 5-FU were maintained by using suspensions of 5-FU in each vehicle. This assumes that dissolution of 5-FU in the vehicles did not become the rate-limiting step for diffusion . The values for the experimental fluxes, solubility of 5-FU in the ve­hicles , and experimental permeability coefficient (Kp, calculated from Eq. 2 in Table I) are summarized in Table II. The value for flux of 5-FU from 5% Efudex (Roche, Nutley , New Jersey) solution, which contains propylene glycol, is included for com­parison. The values for the flux of 5-FU from single vehicles are all significantly different from each other at the p < 0.05 level by two-sample i-test [12], except for the values of isopropyl myr­istate vs dimethylformamide. The permeability coefficients of 5-FU from single vehicles are also significantly different from each

Table II. Experimental Fluxes, Solubilities, and Permeability Coefficients for the Steady-State Diffusion of 5-Fluorouracil Through Hairless Mouse Skin From the Vehicles.

Flux ± SOl, Permeability

Solubility Coefficient' Vehicles" (mg/cm2 h) (mg/cm 3

) (Kp)

O leic acid (OA) 0.1 ± 0.012 0.74 0.15 ± 0.016 Isopropyl myristatc (IPM) 0.028 ± 0.002 0.0051 5.4 ± 0.39 Octanol (Oct) 0.44 ± 0.014 0.60 0.73 ± 0.023 Oimethylformamide (OMF) 0.025 ± 0.002 62.3 0.00041 ± 0.00003 Propylene glycol (PG) 0.0016 ± 0.00 16.5 0.000097 ± 0.000061 Ethylene glycol (EG) 0.0047 ± 0.0013 19.6 0.00024 ± 0.000066 Formamide (Form) 0.015 ± 0.00 13.7 0.0011 ± 0.00010 O A/PG (1;1) 0.050 ± 0.012 0.98 0.051 ± 0.012 OA/PG (1 :3) 0.050 ± 0.002 4.3 0.012 ± 0.00047 O A/PG (1: 14.5) 0.088 ± 0.005 11. 1 0.0079 ± 0.00045 OCT/PG (1; 1) 0.53 ± 0.32 3.6 0.15±0.089 Efudex 5% solution 0.006 ± 0.002

"For diffusion cell studies, 200 mg 5-FU was used in 5 ml IPM or PG, 800 mg in 5 ml DMF, and 400 m g/5 ml of remaining vehicles. 'Fluxes arc signifi cantly differen t from each other f1 < 0.05 except IPM vs DMF and OA:PG(I ; 1 vs 1: 3) by two-sample I-test. ' Permeability coeffi cients arc significantl y different from each other p < 0.05.

x Intercept (h)

14.2 3.2 2.3 0.0 0.1 1.1 3.8 2.3 1.7 2.3 0.2 1.9

VOL. H~ NO.2 AUGUST 1 ~7

other. Fo r the mixed vehicles , th ere is no sig ni fica nt difference in the Auxes of5- FU from 1 :1 or 1:3 mixtures of o leic acid / propylene glyco l but the remainder are different from each o ther. Thus, the Au x of5-F U from vehi cles in thi s stud y is no t therm odyn ami ca ll y contro lled [1 0].

T he ph ys ica l properties of the vehicles, m o le fraction so lubil­ities of 5-FU in vehicles, and calculatt:d PC arc slimmari zt:d in Tab le III. Based o n the m o le fra ction so lubiliti es of 5-FU in the vehicl es, the peak solubility of 5-FU wou ld bc in a vehi cle ex­hibitin g a 0, betwt:en 14.8-16.1 (cal/cm ' )! if dimeth ylforlll31llid e is excl uded 11 31· T ht: calculated so lu bili ty paraJlleter (0) for 5-FU o f 15 (ca l/cm 3)! (Ta ble IV) fits well in this range . The log PC was calculated from Eq. 3 in Table I, using the 0" for vehicles obtained from the lite rature [3 1 and 8 for 5-FU of 15 (ca l/cmJ)! . A so lubility paramcter of 1 0 (cal/cIll J)! was ust:d for the skin 12]. and the skin thi ckness was considcred to be co nstant w ithin the ran ge of bio logic variabi li ty . These log theoretica l PC va lues are shown in T able II I.

Figure '1 sho ws the plot of th c log of th e t:xperimcntal permc­abilit y coeffi cients (Kp) vs th e solubilit y parameters of the single component vehicles. In thc same fl g urc th e log ca lculated PC for the sa nK vehi cles arc plotted aga inst the so lubili ty parameters. If the ass umptio n made that the vehicles are not ca usi ng any changes in the diffusion coeffici ent is appli ca ble [14, 15]. and if the log PC va lues derived from reg ul ar so luti on th eory realistica ll y describe the partitionin g proccss in th is diffusion cell system, then the difference between each of the log calcul ated PC and the log experim ental Kp shou ld be a constant that co rrcsponds to C = D/hs in Eq. 4 in Table l. The average difference between the log calculated PC and log experimenta l Kp fo r 5-FU in oleic acid , dimethy lformamidc, propylene g lycol, eth ylene glycol, and forl11amide is 2.454 ± 0.24, w hich wou ld g ive a va lue for C = 2.88 X IO - J cm / h . Usin g this va lue for the constant, and assulll­ing that the stratum co rneum thickness provides the main barrier to penetratio n by polar solutes and that this thickness (hs) for hairl ess m o use skin is about 0.0009 Clll [16]. then the diffusion coefficient (D) for 5-FU throu gh skin would be about 7.2 X

10- 10 CI112/S. This va lue is in the expected range for the diffusion coe ffi cient for a Illo lecu le such as 5-FU [171 .

The va lue for the constant noted above excluded the va lues for the log theo retica l PC minus log experimental Kp for isop ro p yl

Table Ill. Physi cal Properties o f Vehicles and Calculated Partition Coeffi cients of 5-Fluorouraci l in Vehicles

Mole Solubility Fraction Pararnctcr" Solu bi lity/' Theoretical'

Vehicles 15,. (cal/cm3)1 X; V(n) log pc;,.,,(n)

O leic acid (OA) 7.6 1. 8 X 10 - 3 1.35 Isopropyl myriseaec 8.5 0.0013 x 10- 3 0.78

(I PM) Oceanol (Oct) 10.3 0.73 x 10 - 3 - 0. 13 Dimcthylformamide 12. 1 70.0 x 10- 3 -0.75

(DMF) Propy lene glycol 14.8 6.1 x lO - J - 1.1 3

(pG) Ethylenc glycol 16.1 8.5 x 10- 3 - 1.08

(EG) Formal1lidc (Form) 17.9 4.6 x 10 - 3 -0.75 OA/ pG( I : I) 9.3" 1. 5 x 10 - 3 0.52 OA/PG(1 :3) 10.6" 4.5 x 10 - 3 0.27 OA/PG(I : 14. 5) 13.5'/ 7.5 x 10 - 3 -0.98 Oct/ PG(1 : 1) 11.7'/ 3.2 X 10 - 3 -0.65

' From 13 1, solubi lity parameter of vehicle = Ii •. 'Calculated from m g icm ' solubility in Table 11 and M , and density of vehicle.

Mole fraction so lu bility of 5-Auorouraeil (i) in a vehi cle I v(n) I = x,,·(nl. ("Partition cocrticicllt for distriburion of 5-Auo ro urncil between sk ill and vehicle is

PCI~,YllI)

'Ca lculated using eq uation described in text 14. 10 1

THEOll ETIC AL PART ITION COEFFIC I ENTS FOR 5-FU 149

Table IV. Gro up Contribution M cthod for Calcu lating Mo lar Volume and Solubility Paramcter (0) of

5-Fluo ro uracil [3]

Atom or Group

Ring closure Double bond CH= C= F (attached co C

atom wi th double bond)

C=O NH

Number of Groups

2 2

Energy of Vaporiza tion (Il E, cal/ mol)

250 400

1030 1030 800

(1000 X 0.8)

8300 4000

lllE = 158 10

Molar Volum c (ll V, cnl"'/ lllo l)

16. -2.2 13.5

- 5.5 18.0

21.6 9.0

_Il V 70.4

Il = (HE/2AV) = ( 158 10170.4)1 = 15(ea l/em 3)1

m y ristate and octano!' Prcv io us studies of the delivery of the­ophylline [11 o r 6-merca p to purinc (unpublished) from isopropyl myristate and octa no l have shown that these vehicles, having solubility parameters close to the valuc of 10 (cal/cm 3)! for (por­cine) skin [2]. appear to ha ve a destructive effect on the barrier fUllct io n of the skin and thus their values for Aux and permeability coefficient do no t tend to fit the predicted rclatio nship . The bro­ken linc in Fig 1 represents the log theo retica l Kp va lues ca lculated from the log theoretical PC minus 2.454. The log expe rim ental Kp va lues for the sin g le component vehicles, other than isopropy l m yrista te and octanol, approx imate this theoretica l curve.

Two two- component vchicle sys tcms werc investiga ted in the diffusio n cell studies to determ ine whether the relationshi p be­tween theoretical PC and permeabili ty coefficient would apply in this se ttin g. Of particul ar interes t to us was the effect of mi xed vehicles usin g the lipid . o leic acid . mi xed with the polar so lvent,

+2

+1

o

LOG

\ 0 \ -1

\ , \ , ,

-2 , ,

-3

-4 OA IPM 7 7.6 8 .5

, , "-

"­"- ....

"- ......... ~ ............. ------..,... o

o

OCT DMF PG EG 10.3 12.1 14.8 16.1

SOLUBILITY PARAMETER

o .; .;

'"

FORM 17.9

./

Figure 1. 5-Fluorouracil in single vehicles. Plot of the log of the theo­retical partition coeffi cients (solid iiI/ C) and permeability coefficicnts (brokel/ lil/ l') vs solubility parameters of the vehicles. Ex perimental va lues for log Kp are shown as indi vidual opel/ (iI·ell's. OA = oleic acid ; [PM = isopropyl myristate; OCT = octanol; DMF = dimcth ylforll1amidc; PC = pro­pylenc glycol; EC = ethylene glycol; FORM = formamide.

150 SHERERTZ. SLOAN. AND M cT IERNAN

propylene g lycol, since studies by Cooper had suggcsted such a mi xcd systcm cou ld enh ance skin perm eability for lipophilic mol­ccules such as sa licy lic acid [1 8] and po lar moleculcs such as acy­clovir \1 9]. Sincc the highes t flu x of 5-FU from any single com­ponent vchicle was rca lizcd from octanol, the effect of a mixture of octano l and propylenc glycol (1 :1) on flu x of 5-FU was also cxa mincd . Thc data for th e cxperim ental flu x, so lubility an d pcrmcability cocfficicnt for cach of these mixed vehicles arc in­cluded in Tablc II , and thc calculatcd solubility parameters and log partition coefficients are shown in Table III. It is notable that the addition of oleic acid to propylcne g lycol in thc vehiclc does modcrately incrcase the flu x of5-FU through sk in in the diffu sion cell system compared with propylcnc glycol alonc but not to o lcic acid alone. This incrcased flu x from thc 2-componcnt vehiclc is associatcd w ith a decrcascd solubility of5-FU in the mi xed vehicle as morc oleic acid is addcd compared with 5-FU in propylene g lycol. T hc flux of 5-FU from oleic acid :propylenc glyco l (1: 14.5),0 = 13.5 (cal/cm3)!, and from octanol:propylcnc g lycol (1: I ), 0 = 11.7 (cal/cm3)! was mu ch g reater than the flu x of 5-FU from a singlc component vchicle at a similar 0 va lue ldimcthyl­formam ide, 0 = 12. 1 (ca l/cm3)!]. This difference may be du c to the vcry hi gh solubility of 5-FU in the dim ethylformamide . On the othcr hand , there was a clea r in vcrse relation between Kp and solubi li ty w hich numcrous investiga tors havc shown before [1 ,20].

D ISCUSSION

Previous studies by Sloan ct al [1,11] on thcophyllinc and sa licy lic acid had show n that from knowledge of thc solubility parameters of vchicl es, drug, and skin , thcoretica l PC of drug betwcen vchicle and skin could bc calculated and that fro m these PC va lues it was possible to predi ct va lues fo r perm ea bility coefficients of the dru g. U sing this pred icted Kp valuc and the solub ility of the drug in the vchicle, the flu x of the drug through thc skin also could be pred ictcd. T hc goal in thc current study was to detcrmine, using this sa mc theorctical relationship, w hcther one could predict w hich vchicle wOLtld givc maxim um delivery of 5-FU .

Fo r single-component vchicles exhibiting a solubili ty parameter rangc of 7.6-18 (cal/cm3)!, the theoreti ca l Kp valucs for 5-FU obtaincd from Eq. 1 generally correlate wcll with thc cxpcri­mental Kp valucs obta ined from diffusion cell expcrim ents and the dctcrmined solu bi lities. Thc cxccption to this is for those vehiclcs, isopropyl myristate (0 = 8.5) and octanol [0 = 10.3, (cal/cm3)!]. which have solubility parametcrs similar to that of skin (21. For these two vchicles, th e cxperimental flu x and Kp wcre mu ch highcr than would bc expcctcd. This is similar to w hat is secn for the diffusion of theophylline (1] and 6-merca p­topurine but not sa licylic acid [11] from th csc vehiclcs . T his result has also been secn previously for thc effect of octano l on butyric acid flu x (21]. It is thou ght th at this enhanced flu x is due to irrcvcrsible damage by isopropyl m yrista te and octanol to the lipids in the stratum corneum , thus altering the barrier function for polar drugs (22]. A scannin g electron mi croscopic study of thc treatcd stratum corneum may help clarify the destructive cffect of such vehicles, and this work is planned. A sccond application of a po lar drug such as theoph ylline to skin in diffu sion cells afte r th ey had bccn prctreated w ith 5-FU , 6-mcrcaptopurine (unpub­lished data) theophylline [1] , o r salicylic acid [11] in isop ropyl m yristate or octanol, or thesc two vehicles alone, dcmonstrates much higher flu x of theoph ylline than would be expected , also supporti ng the idea that isopropyl myristate and octano l arc per­mancntly altering the permeability barrier of the skin toward polar dru gs. It has been suggested by Sloan et al [11] that sa licyli c acid behaves like a nonpolar drug in these (octano l, isopropy l m y­ristate, o lcic acid) lipid-like vehiclcs. If the lipid vchicles damage th e barricr to absorption of polar dru gs by leaching the lipid part of the barrier leaving a more polar barrier, then salicylic acid absorption would no t be enhanced and in fac t should be retarded (11 ].

As the solubility parameter of the vehicle approaches that of 5-FU (0 = 15 (ca l/cm3)!, Table IV), the solubili ty of5-FU in that

THE JOURNAL OF INVESTIGATIV E DERMATOLOGY

vehicle is increased so that flu x and subsequcntl y the permcability coeffi cicnt (Kp) decrease to a minimum (Table II ). M aximum solubility for 5-FU was actuall y scen with d imethylfo rmamidc lov = 12. 1 (ca l/cm3)!] but dimethyl formam ide is such a good solvent bccause it forms strong so lvates and complcxes wi th sol­utes th at it does not fit the relationship between solubility and solubili ty para m etcrs of the vehicles [13] .

The axis of the parabola obtained by plo ttin g the log theorctical PC of 5-FU in the vehicles vs solubility param eter (Fig 1) is OJ = 15(cal/cm3)! sincc this was the OJ used for 5- FU . Thc axis for the expcri mental Kp is also approximately 15 (ca l/cm 3)!, sug­gestin g that this calculatcd OJ for 5-FU approaches a reasonable valuc. T his findin g of incrcased solubili ty and decrcased flu x of a drug w hen its solubility parameter is close to that of the vehicle has been seen previously by our group and others \1 ,11,23]. It suggests that the solubility parameters of drug and vehicle must be suffic ientl y di ffe rent to allow ready releasc of dru g from the vchiclc fo r effici ent percutaneo us penetration [6]. These findings also show the utility of using solubility param etcrs in describing the partitioning process of 5- FU fro m vchicl es wi th widely dif­ferent properties . T he fai rly constant relationship between the th eoretical PC calcu latcd from act ivity coefficients and the ex­perimental permeability coeffici ents also suggests that ass ump­tions made about thc diffusion coeffi cient are justified, except when the so lubili ty parameter of the vehicle is close to that of skin .

There are other theo rctical methods that have bcen put forth to predict skin permeability. Osborne [24] recentl y reviewcd 4 such modcls and comparcd their predictive value w ith expcri­mental flux va lucs for 10 different drugs. Osborne fo und that models using wa ter solubility, molecular weight, and PC data put forth by Bcrner and Coopcr (25]. Michaels and colleagues [26], and Albery and Hadgraft [27,28] werc all useful in predicting flu x through thc skin bar rier, but all bad some limitati ons. D ugard and Scott [20] recently described a m eth od of predicting percu­taneous absorption rates in various vehicles based on mo le fraction solubili ty of the penetrant in a g ivcn vehicle. Generall y, our results fo llow the sa me trend as Dugard and Scott put forth with perme­ability coefficient being in versely proportional to the solu bility of 5-FU in the vehicle; the exceptions being dim ethylformamide (in w hich 5-FU is more soluble than ex pected based on its sol­ubility pa rameter) , and isopropyl myristate and octanol (from which 5-FU ex hibits higher than expected Kp va lues).

In summary, solubility parameters of a drug such as 5-FU and vehicle can be used to calculatc a theoretical PC which, in turn , can bc used to estimate a theoretica l permeability coeffic ient. With this thcoretica l permea bility coefficient and the experimentally determined solu bi lity of 5-FU in a g iven vehicle, a rcasonable determination of flu x can be calculated . This computationalmcthod fo r predi cting skin perm eability compares favorabl y, in our ex­perience, with other methods recently revicwcd [20,24]. and may offer thc potential advantage of decreasing the need for deter­mining cxperim ental PC o r for in vitro anima l skin experim cnts to detcrmine flu x ofinvcst igational drugs through sk in . T hc high­cst flu x of 5-FU from any vehicle was realized with octanol. Although octanol has been found to compro mise the skin 's barrier to pcrmeation \1], othcr vehicles ex hibiting similar physical prop­erties (i.e. , solubility parameters close to th at of sk in) may be fo und that arc not as damagin g as octano l ye t rcta in the abi lity to enhance penetration like octano!'

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3. Barton AFM: Solubility parameters. Chemistry Reviews 75:731-753, 1975

VOL. 89. N O.2 AUGUST 1987

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8. Robinson TA, Kligman AM: Treatment of solar keratoses of the extremities with retinoic acid and 5-fluorouracil. Br J Dermatol 92:703- 706, 1975

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11. Sloan KB, Siver KG, Koch SAM: The effect of the solubility pa­rameters of vehicles on the difflfsion of sa licy lic acid through sk in. J Pharm Sci 75:744-749, 1986

]2. Ryan TA, Joiner BL, Ryan BF: Co mparing twO mea ns, in Minitab Student Handbook. Boston, Duxbury Press, 1976, pp. 134-197

13. Martin A, Paruta AN, Adjei A: Extended Hildebrand solubility approach: methylxanthines in mixed solvents. J Pharm Sci 70: 1115-1] 20, 1981

14. Poulsen B: Design o f topica l drug products: biopharmaceutics, drug design , in Medicinal C hemistry, vol 4. Edited by EJ Aricns. New York , Academic Press, 197 1, pp 147-1 92

] 5. Woodford R, Barry BW: O ptimiza tion of bioavail ability of topica l steroids: thermodynamic control. J In vest Dermatol 79:388-391, 1982

T HEORETIC AL PARTIT ION COEFFIC IENTS FOR 5-FU 151

16. Bronaugh RL, Stewart RF, Congdon ER: Methods for ill "i,,-o per­cutaneous absorption studies. II. Animal models for human skin. Tox icol Appl PhJrmacol 62:481-488. 1982

17. Southwell OS, Barry BW: Penetration enhancers fo r human skin : mode o f action of2-pyrro lidol1c and dimcthylfo rmamidc on par­tition and diffusion of model com pounds wate r, n-alcohol , and caffeine. J In ves t Dermatol 80:507- 514, 1983

18. Cooper ER: In creased skin permcabi li ty for lipophilic molecules. J Pharm Sci 73: 11 53-11 56, 1984

19. Cooper ER, Merritt EW, Smith RL: Effect of fa tty acids and alcohols on the penetration o f acyclovir across human skin ill "i'ro. J Pharm Sci 74:688-689, 1985

20. Du gard PH , Scott RC: A method of predictin g percutaneous ab­sorption rates from vehicle to vehicle: an experimen tal assess ment. Int J Pharm (A mst) 28:219-277, 1986

21. Scheu plein RJ, Ross L: Effects of surfactants and solven ts on the permeability of epidermis. J Soc Cos met C hem 2 1 :853-873, 1970

22. Elias PM, Cooper ER, Korc A, Brown BE: Percutaneous transport in relation to stratum corneum structure and lipid composition. J Invest Dcrmatol 76:297-300, 1981

23. Adjci A, N ewburger J , Stovchansky S, Martin A: Membrane sol­ubility parameters and in situ release of theophylline. J Pharm Sci 73 :742-745, 1984

24. Osborne OW: Computational methods fo r predicting skin perme­ability. Pharmaceutica l Manu factu rin g 3:41-48, 1986

25. Berner B, Cooper ER: Models of skin permeability , in Transdcrmal Delivery of Drugs. Edited by B Berner, AS Keygondus. Boca Raton, FL, CRC Press, in press

26. Michaels AS, C handrasekaran SK. Shaw JE: Drug permeation through human skin: theory and in virro experimental measurement. A mcr­ican Institute of C hemical Engineers Journal 21 :985-996, 1975

27. Albery WJ, Hadgraft J: Percutaneous absorption: theoretical descrip­tion. J Phann Pharmacol 31:129-139, 1979

28. Albery WJ , Hadgraft J: Percutaneous absorption: in " i/lo experi­ments. J Pharm Pharmacal 31:140-147, 1979