CA2115840A1

CA2115840A1 - Transdermal formulation for administering prazosin

Info

Publication number: CA2115840A1
Application number: CA002115840A
Authority: CA
Inventors: Tsung-Min Hsu; Eric J. Roos
Original assignee: Individual
Current assignee: Cygnus Inc
Priority date: 1991-08-27
Filing date: 1992-08-21
Publication date: 1993-03-04
Also published as: EP0601058A4; EP0601058A1; WO1993003697A1; PT100814A; NZ244064A; AU2514292A; US5688524A; JPH06510290A

Abstract

Prazosin is formulated in solution with a skin permeation enhancer composition of: a sulfhydryl-containing compound, a fatty acid ester, and a polar solvent for transdermal administration to treat hypertension or benign prostatic hypertrophy. The formulation is employed in the form of a skin patch (10) comprising (a) an impermeable backing layer (11), (b) a reservoir (12) of the prazosin-enhancer solution, (c) a porous support member (13) that retains the solution but is not a permeation barrier to the solution, a peripheral adhesive layer (14) for affixing the patch to the skin, and a release liner layer (15).

Description

WO ~3/036~7 ~ .1 L ,`3 ~ ~1 0 P~/US92/06g6~

T~SD~R~L FORMULATION5 FOR ADMINISTERING PRAZO5IN

Description ~-;

Tech:nic~
This irl~re~tion relate~ ~o methods arld formula~ion~ fox admirlistering the drug prazosin ~ransdermally .
....

,, a~~ ~''''`' Prazo . iIl i9 an antihypertensive drug that : -appears ~s~ produce it~ antihypertensive ef f ect by relaxatio~ of pexipheral arter:;ole~ a~ a consequeIlce of post~yDaptic C~!- adrerloreceptor blockade ~ Rece~t studie3 ha~re a~so showIl prazo~in ~o be effective in treating :
benign pro~tatic hypertrophy (~3PH), a chronic bladder -outf low obs ructio~ co~nonly occurr~ in a~i~g male~
The effect of pra~o~in on BPH :i~ appare~ly due to decreas~ng the re~i3tance alo~g the pro~ta~lc urethra by ~ ::
relaxing the mooth m~ le of the pro~a~e.
Prazo~in has a relatively ~hort half-life whi~h require~ thaLt it b~ ad~nini~3tered:~everal ~imes per day by the oral rou~ce. Orally administered pra~osln ha~
i~compl~te bioa~ailability that i8 CaU5ed ~y incomplete ab~orption, d~gradation in the gastroi~te3tiIlal tract, :
30 and fir t pas~ liver metaboli~m. These propertie.q make prazc)~in a candida~e f or tran~dermal admini~ration . In this regard, available data indicate targe~ transdermal deli~rery rate o~ approx~mately 10 ~g~cm2/hr through 20 cm2 of skin to achie~e level~ needed for hyper~ension .

WO93/036g7 ~ ~i 3~ PCr/VS92/~6968 therapy and approximately one-quarter of that rate for BPH therapy.
There are ~everal prior publication~ relating to tran~dermal administration of prazo~in. Japane~e Patent Pub. No. 61178915 propo~ed formulation~ of prazo~in hydrochloride`which contain polypropylene glycol, polyethylene glycol, lecithin, urea, amino acid , or 1-dodecylhexahydro-2~-azepine 2-o~e (Azone) aB
permeation enhancer~. Japane8e P~tent Publ. No. 2202813 10 rela~e3 to the u~e of C1 1~ alkyl e3~ers of gallic acid ~:
a~ percu~aneous permeation eDha~cer and li t~ praæosin ^"
hydrochloride among the drug~ tha~ may be ~ombi~ed therewith. Similarly, U.S. Pa~ents 4,847,250 and ~ 4~970,206 ~ugge~t tha~ tran8derma1 a~mini~ration of 15 prazo~in be enhanced with pyroglutamic acid e~ers. ~-Katz, D~, a~d Toui~ou, ~., 155~ _~D~ _ ~YD
(1991) Vol~ 18~ de~cribe3 ~tudies of the flux of pxazo~ hydrochloride through rabbi~ ear ~kin from twelve diiferent formulation~
Tho~e form~la~ion~ co~ainl~g oleic acid and/or Tran~cutol exhibi~ed the hi3he~3t flux. ~ :
Finally, Tenjarla, S.N. Pharm~_Res. (1990 Vol. 7, No. 9, $-18.9, report~ ~hat prazo~in (PZ) flux ~hrough human ~kin (formula~ion not identi~ied) wa~
25 1.6 ~g/cm2/hr and that "wi~h a ~uitable che~ical ~:
enhancer, ~ra~Qdermal delivery of PZ appear~ promlsing~
An ob~ect of this invention i~ to provide a ~ra~sdermal prazosin formulatio~ tha~ pro~ide3 prazosin at the rate~ re~uired for hypertension and/or BPH
30 therapy. ~:

O~e a~pect of the in~en~ion i~ a method for admi~i tering praz~sin ~o an indi~idual in WO~3/036g7 ,~1 1 J ~'~U P~TtUS~2/06968 therapeutically effecti~e amounts compri ing admini3tering prazo~in tran~dermally to the individual in ~::
combination wi~h a ~kin permeation enhancer composition compri~ing (a) a nontoxic ~ulfhydryl-containi~g compound, (b) a nontoxic fatty acid e~ter; and (c) a nontoxic polar ~olvent to an area of unbroken ~ki~ of about 20 to about 60 cm2 over a multiday period at a rate that provide~ at l~ast abou~ S0 ~g prazo~in per hour.
Another aspect of the in~e~tion i~ a formulation of pxazosin for tra~sdermal administration compri~ing a ~herapeutically effec~ive amou~t of prazo~in in combination wi~h an effectiYe amount of a ~kin penmeation enhancer compo~ition c~mpri~i~g (a) a ~ontoxic ~ulfhydryl-contalni~g compou~d, (b) a nontoxic fatty acid ester; a~d (c~ a nontoxic polar solvent.
A further aspe~t of ~.he invention iq a skin ~
patch for admini~tering prazo~i.n txansdexmally i~ -:
therapeutically effective amOU~lt~ over a multlday period com~risi~g in co~bination (a) an impermeable backing layer;
(b~ a reservoir o~ a solution of prazosi~ in a ~ki~ permeation enhancer co~po~ition compri~i~g~
(i~ a nontoxic ~ulfhydryl-containing compound;
(ii~ a ~o~toxic fatty acid ester; a~d (iii) a no~oxic polar ~olve~t;
(c) a porous ~uppor~ member u~derlying the re~ervoix that retains the 301u~ion but i~ ~ot a ~ubstantial permeatio~ barrier to the ~olutio~; and ;.
(d) means for affixing the patch to the ~kin, ~aid patch ha~ing an effecti~e basal surface area of ~bout 20 to 60 cm2 and providing a prazo~in skin flux via ~aid effective ba~al ~urface area of at least ~bou~ :
50 ~g/hr o~er ~aid multiday period. :

Wl) 93/03697 . f~ 3 PCI/U~ /0696P
- 4 - ::

Brief De~criptiQn of_the Drawln~ :-The drawing ~how~ a cros~ectional ~iew of an e~bodiment of a skin pa~ch for admini~ering prazo~3in -:
tran~dermally according to the pre~en~ invention.
Mod~ f or Carryinq ~u~ the InventiQn Aq u~ed herein, the tenn "tra~sdermal" inte~d~ ~
pa3~age of prazo~3in through unbroken husnan skin i~:Lto : ~ -circulation. :
As used herein, the term " the~apeu ically effec~cive amount " intends that do~e of praæosi~ that provide~ the desired therapy~ In the ca~e of treating 13P~, that do~e will u~ually be in the range of 0.5 ~o 5 mg/day, more usually 1. 5 to 4 mg/day; whereas for 15 treatirlg hyper~en3io~, the do~e will u ually :be about 2 to 20 m~/day, more usually 6 ~o 15 mg/day~
~ Skin flux" as u~ed herei~ i~te~d~ the rate of pas~age of prazo i21 through a defined area of ~kln a~
mea~ured ln itro by the proc d.ure described ir B ~ ple 1, infra.
The term "effectl~e ba~al ~urface area" in end~
the ~urface are of the patch that i~ in co~tact with the ~kin and through which praz03in i~ tran~mitted ~o the kin.
The term "nontoxic" mea~s tha~ the compound referred to doe3 not damage ~he skin or cau~e intolerable ~
level of 9kln irritation. ~-.
"Pxaæo~i~" i~tends the fr~e ba~e ~onm of the ~:
drug a~ well as pharmaceutically acceptable salt~
30 thereof. :~
A "multiday p~riod" intend ~ to 7 day~
The enhancer compo~i~ion that i u~ed in combination with prazosin according to the invention :~
compri~es: a sulfhydryl-co~taining o~g~nic compound, a ;~

W093/0~97 ~ P~T/US92/069~8 atty acid e~ter, and a polar ~olvent. The sulfhydryl- -colltaining compound preferably contain~ a siIlgle -SH
~roup . Examples of sui~able sulfhydryl - containing ~:
compounds are N- (2-mercaptopropionyl) glycine, 5 thioslycerol, thioace~ic acid, ~hio3alicylic acid, .
b~cillami~e (N-2-mercapto-2-methyl-1-oxopropyl~L-cysteine), acetylcy~teine, and mercaptome~thon~. The sulfhydryl-contai~ing compound will typically con~titute 1% to 25~ by weight of the enhancer compo3ition, 10 preferably 2~ to 10~ by weigh~ Compound~ such as :~
glutathio~e/NaOH, ethylene ~iamine ~etrace~ic acid ~:
(EDT~)/NaOH, or other reducing age~t~ may be added to the enhancer composition to preve~ oxidatio~ of the ~ sulfhydryl-co~ai~ing compo~ent. ~ :~
The e~ter component of he enhancer compo~ition -~
will ~ormally be a compound of the formula (C~3-(CH2)m~COO)nR .

where m i~ an integer from 8 to 16, preferably 8 to 12 inclusi~e, n is ~ or ~, and R i~ alkyl of 1 to 3 carbon atom~, inclusive, ~ub~tituted with 0 to 2 hydroxyl group~, inclusive. The preferred esters of thi3 formula are hydro~yalkyl e~er of lauri~ acid, with propylene glycol mo~olaurate (PGML) be~ng particularly preferred.
The ester will normally con3~itute 5~ to ~0~ by weight of::;
the enhancer CQmpO ition.
The polar ~olven~ will ~ormally co~titute 10%
to 90~ by weight of the enhancer com~o ition. ~amples 30 of polar solvent that may be u~ed axe etha~ol, propylene .~;
glycol (PG)I N-methyl-2-pyrrolidone tM-pyrol)o benzyl :
alcohol, 1,4-buta~ediol, 1,3-butanediol, 2,3-buta~ediol~
105-pentanediol, Tran~cu~ol (diethyleneglycol monoe hyl ~;-:~

W093/036g7 ~ PCT~US92/0696 -6- .

ether), and low molecular weight polyethylene glycol (~ 500 m.w.) The prazosin will usually be mixed with the .~ enhancer compo~ition in amou~t~ in the ra~ge of about 5 ~.
5 to 2~0 mg. - `
The drawing illuYtrates an embodiment of a skin ~ `~
, .
p~tch for admin~ering prazo~in ~ran~dermally. The pat~h, generally de3ignated 10, compri~es: an impenmeable backing layer 11; a prazosin-enhancer-~olution re~ervoir :~
10 12; ~ porou4 ~upport member ~3 underlying the reservoir; ~:
a peripheral adhesive layer 14; and a relea~e liner layer 15. The backing is heat ~ealed to the porous Yupport member 13 at 16 about the periphery of the reservoir.
- The backing layer 11 :Eunction3 a~ the primary ~-:
struc~ural element of the device and provide3 the de~ice with much of its mecha~ical (e.g.~ flexi~ilit~, etc.) propertie~. It al80 3erve3 a3 a protecti~e covering to preven~ 1099 of prazo~in/enhancer via tranqmis~ion through the upper surface of the de~ice. Backi~g 11 iY
20 preferably made of a sheet or film of polymer or ~ ;~
polymer-metal film laminate tha~ is ~ub~antially impenmeable to prazosin ~d the enhancer composition. ~`
The layer i~ preferably on the order of 0.1 ~o 0.2 mm i~
thicknes~. Examples of Yuitable backing material~ are ~tyrene-isoprene-styrene block copolymer, polyurethane~
polyi~obutene^po~yurethane lami~ate, tyrene-ethylene~
butylen~-~tyrene copolymer. ;~
The ~upport member 13 i~ a highly porou member that retai~ the liquid fonmulation withi~ the reservoir :: :
(i.e., it deters bulk flow of the formulation ou~ o the reser~oir, but doe~ not deter permeatlon and diffusion of the formulation fro~ the re~ervoir i~to the ~kin).
Nonwo~en fabrics ~uch a ~onwove~ polye~ter~, polyethy~
le~e, polypropylene, a~d other synthetic polymer~ may be `~
~;:

wo ~3/~36g7 ~ 8 ~ O PCT/V~92/0~968 used. The basal ~urface of the nonwoven ~abric may be impregnated with a pharmaceutically acceptable pres~ure- ;~
sen~itive adhesive to facilitate the contac~ of that ..
suxface with the ~kin. The material from which member 13 5 is made should be heat- or otherwise ~ealable to the ~-backing member to provide a barrier to trans~rer~e flow of solution from the reservoir. The baqis weight of the :
support member 13 will usually be 0.001 to 0.OQ3 g/cm2. ~:
The perip~eral adhe~ive layer 14 i~ ~he mean~
by which the patch i~ affixed ~o the skin. This layer i~
made from a pharmaceutically accep~ab~e preq~ure ~enqiti~e adhe~i~e polymer ~uch a~ polydim~thylsiloxane :~
~Silicone), po~yisobu~ene, polyacrylate, polyurethane, . low molecular weight polyeth r block amide copolymer~ ~ ;
~PEBAX copolymer~), tack~ rubber~ such a3 poly~tyrene-i~oprene copolymers, poly~tyrene-butadiene cop~lymer~, and the likeD Ihe thickne~3 of thi~ layer will be in the same range a~ tha~ of ~he support memb r, i,e., about 40 to 100 micron~.
Prior to use, de~ice 10 include~ a relea~e line 15. Ju~t prior to use, ~hi~ layer is removed from the de~ice to expose contact adhe~ive layer 14. The relea~e liner will normally be made from a drug/~ehicle/enhancer impermeable ma~erial (e.g., polyethylene tereph~hal~te or :~
other polye~ rs) ~hat i~ inherently "~trippable" or re~dered ~o by techni~ue~ 8UCh as ~ilico~e or :~
fluorocarbon treatment.
..
The following examples further illu~trate the ~:
i~ention. These e~amples are not intended to limit the invention in any manner.
"~

'.~ ': `
:

WO 93/03697 ~3 ~ PCr!US92/0696 Example In yitro Skin Flux_of Pra~osin Free Base From Yariou~ Li~id Formulat on~
~ ,;~
Skin Permeat~on Studie~
Human cadaver ~kin was used f or ~kin f lux ~tudies. Frozen skin wa~ ~hawed and epiderm~Ll layers (~tra~um cornelam and ~riable epidermis) ~eparated from the full thickne~s ~kin by i~ner~ion in water at 6Q(: for 2 m~nuteY. ~ epidermi~ was mounted carefully betw~en th two halYes of modif ied Franz cell~ . The recei~rer compartmerl~ was filled with pH 5 phosphate buffer. Fi~re . ~ ::
hundred ~l of the candidate formulations (~aturated with ~:
prazo iIl f ree ba~e ) were ~he~ added i~to the donor ~:
compartmerlt ~co ini~iate the skin flux experiment The :;
temperatur~ of the diffu~ion cell co~tent~q wa maintaisled :~
at 32 C . A~ a predetermined ~ime, a 1 ml aliquot wa~
. . ~
withdrawn from the recelver alld replaced with ~re h ~:
buffer. 5a~1es:we e a~sayed by ~PL u~ing a W-detector a~c~ 254 nm. Ade~uate chromatographic resolu'cion wa achie~red using a 13rown-Lee RP-1.8 colum~. The mobile ~ ~:
phase was 30% acetonitrile - 70% 0.025M pho~phate buffer, ~.
.. ~.
p$I 5 ~ O i~o which 2 mg/L triethanol amine (TEA) was added . The retentioIl ~ime wa~ 2 . 5 - 3 . 2: mi~u~e The skin ~.
flux l,ug~ hr) wa determined from~ the 0t~ady-state ~lope of a plot of cumulative amoun~c of ~prazo~in pe~ea~cad ~hrough the ~kin ~ersu~ time.
.~, -.
. ..~ ~., The results o~ the~e ~tudie~ are reported in Tabl~ 1 ~elow.
.

~,~,`'.' ".,~ ."i"-.,,;,.c"~ "", ~f~ ",,,-~ ,, ; ,;,,~,j.,; ;"

~i~.J310 WO 93/03~i97 PCr/US92/0696B
g Tabl e In Vitro Skin Flux 2hi~1es ~/cm2Lh~

5 H2~ n/a PG n/a ~:
Tra~cu~ol n/a PGML 0.05 + 0.02 40~ oleic acid/ 60~ EtOH 0.2Q ~ 0.05 40~ PGML, 60~ EtOH 0.44 ~ O.01 40% oleic acid, ÇO~ PGML 0.12 + O.03 100~ Thioylycerol ~/a 40~ Thioglycerol, 60~ EtOH 0.39 ~ 0.33 .
40~ Thioglycexol, 6Q~ H~O 0.04 ~- 0.01 20~ transcu~ol, 80~ P&ML 0.10 0.02 50~ Thioglycerol, 33~ PGM~, 17% EtOH 6.43 ~ O.59 2~ Thioglycerol, 25~ PGML, 50~ EtOH 30.6 + 1.G
25% N~ mercaptopropionyl)glyci~e, 25~ PGM1~ 50~ ~tOH 31.8 + 10.9 10~ N-(2-mercaptopropionyl)glycine, ~:~
25~ PGML,- 65~ EtOH 11.1 ~ 3.92 5~ N-(2-mercaptopropio~yl)glycine, -~
25% PGM~, 70% EtOH 4.54 ~ 2.20 ~:
40~ PG, 40~ PG ~ , 20:% benzyl ~5 alcohol 5.05 + 3.96 25~ N-~2-mercaptopropionyl)glycine, 25~ PGML, 70~ EtOH 8.67 + O.74 5% N-(2-merc~ptopropionyl)glyci~e, 10% T~ Glutahione, 60~ PG, 2g% PGML 7.48 ~ O.20 -~
2~ N-(2-mercaptopropionyl)glycine, 10~ PGML, 88% PG, 40 mg/ml ba~e 11.5 ~ 3.6 5~ ~-(2-mercaptopropionyl3glycine, 25~ PGML, 70~ PG, ~aturated 9.3 + 2.6 :

WO 93/03697 ~ PCr/US92/0696 -10~

5% N-~2-mercaptopropionyl)glycine, 25~ PGM~, 70% EtOH, sa~uxated 12.8 ~ 5.1 2 ~ N - ( 2 - mercaptopropionyl ) glycine, 10~ PGML, ~8~ PG, saturated 14 . 6 + 1~ 5 5 5~ N-(2-mercaptopropionyl~glycine, 70~ EtOH, 25~ PGML, satura~ed ~8.5 ~ 7.9 5% N-(2-mercaptopropio~yl)glycine, :~
70~ PG, 25~ P~ML, 3aturatecl 20.4 + 4.6 60~ EtOH~ 40% Capric acid, base sat. 3.3 + 0.5 60% Benzyl ~lcohol, 40~ PGM~ 1~1 + O.5 n/a = Skin flux value~ were below 0.01 ~g/cm2/hr ;~

~ A3 i~dicated in T~ble 1, the only formula~ions that provided practical fluxe~ were those ~hat contained a ~ulfhydryl compound, a fatty acid e~ter, and a polar ~olve~ti Rabbit 3ki~ irritatio~ studie~ indica~ed ~.hat the formulatio~ co~taini~g 5~ N-(2-mercap~o propionyl)glycine exhibi~ed ~he lowe~t ~kin irritation of ~:
~ho~e formulations exhibiting practical fluxe~ For that .
rea~on, the 5~ tiopronin fo~nu].ations are pre~erl~ed. ~

Ç~. :
In Vit~$kin Flu of Pr~p~3in_ Hydrochlo~ide from I.iquid Formulat~c~n~

5kin flux q~udies were carried out a3 in -~
~xample 1 o~ ca~dida~e fonmulations of pxaxo~in ~:
hydxochloride (at ~a~uratio~). The results of the~e ~.
qtudies are reported in Table 2 below.
~'- `'`"~
~''` '' ' 3~

WO 93/03697 ,~ O PCr/US92/069fi8 Table 2 In Vitro Skin Flux of Prazosin HCl in Variou~ Vehicles Vehicle~ Flux (~g/cm~/hr) H2O 0 . 04 + 0 . 01 EtOH 0.ûl + 0~01 40~ Oleic acid, 60% EtOH 0 . 36 ~ 0 ~ 02 40~ PGM~, 60~ EtO:H 0 .41 ~ 0 . 02 40~ Thioglycerol, 60g6 EtOH 1. 8~ + O . 50 50~ Thiog~ycerol, 33~ PGML, 17~ EtOH 11. 90 ~ 4 . 50 In V~o Skin Flux~of ~o~in 1~ o~
f rom a Li~uid Rese:~roir~ e 5ki~ Patch ~:
Skin Flux Methodol~
A ~imulated re ervoir ~y~tem wa~ arranged in such a way that a men~rane of a ~olvent based acrylate adhe~ive (Morstik 709) /non-wo~ren ~upport wa~Q mounSed on ~ ~:
2 0 the epidermi~ and then placed betwee~ the two hal~re~ of ~ ~:
modified Franz cell. The adhesi~re/non-woven support membrane wa~ prepared by impregnating the adhe i~re polyrner 901UtiOll in~co ~he non-wove~ suppoxt moun~ced on a relea~e liner and then drawing down ~he polymer ~olution through the nonwo~ren support with a 1-3 mil ca3ting knife ~ ~
to f orm a thin layer membraIle . The merr~rane waR placed ~ 3~:
on the ~kin wi~h the xeleas~ liner removed~ Orl the ~op of the membrane, a candidate formulation ~aturated wi~h prazo~in) wa~ added to initiate the ~kin f lwc study . The remainder of the tudy wa~ carried out a~ an Example 1. ::`

The re3ult~ of the~e ~tudie~ are reported in Table 3 below.

WO 93/036~7 ~ 1 ~- J ~ PCr/US92/0696 Table 3 Formulation Flux (~q/cm2/hr) 5~ N- ~2 -mercaptopropionyl ) glycine, 29% PGML, 50~ EtOH, 4% PG, 10% 3N, NaOH, 2g6 EDTA (pH 6 . 5 ) 6 . 97 + 3 0 50 5~ ~-(2-mercaptopropionyl)glycine, 29~ PGM~, 5~ EtOH, 4~ PG, 2~ gluthaion, 10% 3~ NaOH (pH 5.0~ 5.92 + 1.20 5~ N (2 mercaptopropionyl)glyci~e, 38% PGM~, 57% EtOH (pH 3.0) 2.40 + 0O40 5~ M-(2-mercaptopropionyl)glycine, 5~ TEA, 1~ glutathione, 74~ PG, 14~ PGML 5.6 + O.7 5~ N-t2-mercaptopropio~yl)glycine, 20~ PGML, 75~ M-pyrol 10.9 ~ 0.9 15~ M-pyrol, 10~ PGML, 60~ ~tOH, 5~ N-(2-mercap~opropio~yl)glycine, 10% 2~ NaOH 9.1 + 3.7 5~ N-~2~mercap~opropionyl)glyci~e, 10~ 2N NaOH; 2.5~ glutathio~e, 5.5% PG, 65~ EtQH, 14~ PGMC (pH 6.0) 4.6 + 0.8 ;~

Modificatio~ of the above-de~cribed mode~ for carrying out ~he~in~en~ion ~ha~ are ob~ious to thoqe of ~kill in ~he field~ of chemistry, tran~de ~ l drug deliYery~ and relatP~ fields are inte~ded ~o be within ~':
'che ~cope of the follow~ ng claim3 .
',: ~

3 5 ~
-'

Claims

1. A method for administering prazosin to an individual in therapeutically effective amounts comprising administering prazosin transdermally to the individual over a multiday period in combination with a skin permeation enhancer composition comprising (a) a nontoxic sulfhydryl-containing compound, (b) a nontoxic fatty acid ester; and (c) a nontoxic polar solvent to an area of unbroken skin of about 20 to about 60 cm2 over a multiday period at a rate that provides at least about 50 µg prazosin per hour to the individual.

2. The method of claim 1 wherein the sulfhydryl-containing compound in N-(2-mercaptopropionyl)glycine, thioglycerol, thioacetic acid, thiosalicylic acid, bucillamine, acetylcysteine, or mercaptomenthone, the fatty acid ester is of the formula (CH3-(CH2)m-COO)nR

where m is an integer from 8 to 16, preferably 8 to 12, inclusive, n is 1 or 2, and R is alkyl of 1 to 3 carbon atoms, inclusive, substituted with 0 to 2 hydroxyl groups, inclusive, and the polar solvent is ethanol, propylene glycol, N-methyl-2-pyrrolidone, benzyl alcohol, 1,4-butanediol, or 1,5-pentanediol.

3. The method of claim 1 wherein the sulfhydryl-containing compound is N-(2-mercaptopropionyl)glycine, the polar solvent is ethanol or propylene glycol, and the fatty acid ester is propylene glycol monolaurate.

4. The method of claim 1 wherein the sulfhydryl-containing compound constitutes 1 to 25% by weight of the enhancer composition, the fatty acid ester constitutes 5 to 80% of the enhancer composition, and the polar solvent constitutes 10 to 90% of the enhancer composition.

5. The method of claim 1 wherein the prazosin is being administered to a male individual to treat benign prostatic hypertrophy.

6. The method of claim 1 wherein the prazosin is being administered to treat hypertension and the rate provides at least about 200 µg/hr to the individual.

7. A formulation of prazosin for transdermal administration comprising a therapeutically effective amount of prazosin in combination with a skin permeation enhancer composition comprising (a) a nontoxic sulfhydryl-containing compound, (b) a nontoxic fatty acid ester, and (c) a nontoxic polar solvent.

8. The formulation of claim 7 wherein the sulfhydryl-containing compound in N-(2-mercaptopropionyl)glycine, thioglycerol, thioacetic acid, thiosalicylic acid, bucillamine, acetylcysteine, or mercaptomenthone, the fatty acid ester is of the formula (CH3-(CH2)m-COO)nR

where m is an integer from 8 to 16, preferably 8 to 12, inclusive, n is 1 or 2, and R is alkyl of 1 to 3 carbon atoms, inclusive, substituted with 0 to 2 hydroxyl groups, inclusive, and the polar solvent is ethanol, propylene glycol, N-methyl-2-pyrrolidone, benzyl alcohol, 1,4-butanediol, or 1,5-pentanediol..

9. The formulation of claim 7 wherein the sulfhydryl-containing compound is N-(2-mercaptopropionyl)glycine, the polar solvent is ethanol or propylene glycol, and the fatty acid ester is propylene glycol monolaurate.

10. The formulation of claim 7 wherein the sulfhydryl-containing compound constitutes 1 to 25% by weight of the enhancer composition, the fatty acid ester constitutes 5 to 80% of the enhancer composition, and the polar solvent constitutes 10 to 90% of the enhancer composition.

11. A skin patch for administering prazosin transdermally in therapeutically effective amounts over a multi-day period comprising in combination (a) an impermeable backing layer;
(b) a reservoir of a solution of prazosin in a skin permeation enhancer composition comprising:
(i) a nontoxic sulfhydryl-containing compound;
(ii) a nontoxic fatty acid ester; and (iii) a nontoxic polar solvent;
(c) a porous support member underlying the reservoir that retains the solution but is not a substantial permeation barrier to the solution; and (d) means for affixing the patch to the skin, said patch having an effective basal surface area of about 20 to 60 cm2 and providing a prazosin skin flux via said effective basal surface area of at least about 50 µg/hr over said multi-day period.

12. The skin patch of claim 11 wherein the sulfhydryl-containing compound in N-(2-mercaptopropionyl)glycine, thioglycerol, thioacetic acid, thiosalicylic acid, bucillamine, acetylcysteine, or mercaptomenthone, the fatty acid ester is of the formula (CH3-(CH2)m-COO)nR

where m is an integer from 8 to 16, preferably 8 to 12, inclusive, n is 1 or 2, and R is alkyl of 1 to 3 carbon atoms, inclusive, substituted with 0 to 2 hydroxyl groups, inclusive, and the polar solvent is ethanol, propylene glycol, N-methyl-2-pyrrolidone, benzyl alcohol, 1,4-butanediol, or 1,5-pentanediol.

13. The skin patch of claim 11 wherein the sulfhydryl-containing compound is N-(2-mercaptopropionyl)glycine, the polar solvent is ethanol or propylene glycol, and the fatty acid ester is propylene glycol monolaurate.

14. The skin patch of claim 11 wherein the sulfhydryl-containing compound constitutes 1 to 25% by weight of the enhancer composition, the fatty acid ester constitutes 5 to 80% of the enhancer composition, and the polar solvent constitutes 10 to 90% of the enhancer composition.

15. The skin patch of claim 11 wherein the prazosin is being administered to a male individual to treat benign prostatic hypertrophy.

16. The skin patch of claim 11 wherein the prazosin is being administered to treat hypertension and the rate provides at least about 200 µg/hr to the individual.