CA2170505A1 - Compositions and methods for the administration of .delta.-aminolevulinic acid and pharmaceutical equivalents thereof - Google Patents

Abstract

A pharmaceutical composition of increased stability, which comprises ALA or pharmaceutical equivalents thereof and a pharmaceutically acceptable, flexible, finite carrier suitable for administration to the skin or other dermal membrane of a mammal, optionally containing a stabilizing amount of an organic weak proton donor or saccharide containing substance. The pharmaceutically acceptable carrier in solid formulation can be a skin patch, many forms and types of which are known and used in the art. It is preferable that the composition be anhydrous. The formulations appear to improve the fluorescence produced after exposing treated skin to activating light, as compared with the fluorescence produced with ALA in a fluid carrier. In particular, the pattern of fluorescence is more even and uniform over the area of application than with topical creams or salves and may provide increased fluorescence.

Description

SENT BY: 2-27-96 ;10:59A~ ;FOLEY & L~RoMER DC A~ 613 235 2867;# 3/23 ~,- 2170S05 C0MPOSITI0NS AND ~FTu~ns FOR ~E
ADMINISTRATION OF ~-AM~'Cr~VULINIC ACID
AND PHARMACEtlTICAL EQUIYALENT5 ~HEREOF

C~o~s-~eference to Related Aplica~ions This application is a continuation-in-part of PCT/US94/09466, ~iled Au~ust 27, 19~4, whic~ is a contin~a~ion-in-part of Serial ~o. 08/112,330 ~iled ~g~st 27, 1993, which i ~ continuat~on-in-part o~
PC~/US92/01730, ~iled February 27, 19~2, which is a continuation-in-part of U.S. Application Serial No.
07/813,lg6, filed December 23, 1991, now u.s. eatcnt NO.
5,23~,957, which is a.continuation-in-part of U.S. Pa~ent Application 5erial No. 07/661,827, filed FebrUary 27, 1991 and now ~b~n~ed. All of the foregoing applications are hereby incorporated by referQnce.

Ba~ro~ of t~e Invention 5-Aminolevulinic acid, also referred to as ~-aminolevulinic acid ~r 5-amino-4-oxopentanoic aci~, is re~erred to herein as "~LA". ALA has been known for aver 40 years to be a precursor in the metabolic pathWay to heme in humans and to chlorophyll in plants. Until the past ten years ALA has ~een of li~ited usefulneS5, na~ely, use limited to porphyrin research. In 19~, ALA
was proposed for use as a photodyna~ic herbici~le. rt has been discovered recently that ALA can be us~ad by variou~
routes of administratian to detect and treat certain conditions involvin~ rapidly metabolizing cells, namely hyperprDliferative cells. rt is especiall~ us~ful in the lC treat~nt of ~alignant and non-malignant abnor~al qrowt~s.

ALA has been a~ministered by various routes known for use in druq administration, but especially by topical FE~ 2'7 ' 96 10: 55 20~ Yg P~GE . 003 SENT BY: 2-27-96 ;10:59.4M ;FOLEY & L~RDMER DC A~ 61~ 235 2867:# 4~23 ~ 2- 2170505 application to t~he skin and epitheliu~ of various body ca~rlties. Application of ALa results in the ~electiYo accumulation of clinically significant amounts of pro~opo~hyrin IX, another P~G~U~Or in the metabolic pa~hway to heme. Acti~ation of protopo~phyrin IX by ~ight, ~ nA~ on the wavelen~th of the ligh~, will cauae the proto~6r~hyrin IX either to fluorQ~cs (which can be used as t~e ~asis of a de~eGtion m~thod), or to ~ (which can be used as ~he basis of treat~ent fo~ cells that need to be removed).

ALA previously has ~een use~ in clinical te~ting on humans and other ~ in aqueou3 and non-aq~leOUs flu~d vehicles such a~ crea~s ~oil in water e~ulsions) and lotiona for application to the ~kin and orally for ~
~ no~;~ and treatment of skin cA~-er~. ALA ha~ keen used in clinic~l st~ s in a~EG~s solution for applica'cion to the en~ometrial cavity.

~LA has been reportcd to inhibit de~radation of the drug calcitonin by the naoal . ~o~ peptides in U.S. 5,026,825 . Preparations in th- example~ o~ that patent show a combination of calcitonin and ALA in aqueous solution~ ~on~alninq one or more of benzalkonium c~loride, citric acid, sodium citrate, hydrochloric acid, sodiu~ ace~ate and acetic dcid. The or~anic acids and their salts appear to be used a~ burfers, to adjust the pH of the resulting solution to about 4.

ALA has a tendency to decompose in a wide variety of vehicles used in clinical testing inc~uding bot~ water containing vehicles, anhydrous fluid vehicles and water and oil emulsions. In general, the lower the pH of t~e fluid ve~ic~e, t~e more rapid the degradation. Fo~
example, addition of about 10~ by weig~ ALA in the form the hydro~hloride salt into an alkaline solution, left at room temperature, re~ults in almost complete de~radation in a~o~t one week.

FEE 27 ~ 96 10: 55 202~ Y9 P~GE. 004 SENT BY: 2-27-96 ;11:~0.4M :FOLEY & L~RDNER DC A~ 613 235 2867;# 5~23 _3_ 2170505 Precursors or prodrugs of ALA hav~ been reported for use in conditions similar to that a5 reported for A~A.
The Norwegian Radium Hospital ~P~eArch F~undation's PCT
application ~o. W0 951070?7 publishe~ Mar~h 16, 1995 ("~e_~Lsors") and Peng et al. Abstract, Americ~n Society of Photobiolo~y Annual Meeting, 1995 Budapest.

~ he decomposition occurrin~ wlth fluid preparation~, such as wa~er and e~hanol, reported in the scientific literature with u~e of ALA patients, iS sufficient to preclude the llse of ALA in a IJ~G.lu~ to be distribut~d in normal, QXiSting ~h~nols fot the supply of ~ha -ceuticals. Many studles ha~re been performed without suc~ess in an at~e~pt to stabilize ALA, ~lth e~ to extD~ing the ~tability of the chemicaL in a fluid, includinq use of an aqueous solution containing cQrtain antioxidants such a~ ascor~ie acid and sodiun b~sulfite. Thus, there ~emains a need for a stor~g~
stable compo~ition comprising ALA in a for~ suitable for ad~inistration to a patient.

Summarv of thq Invention The invention relates to a pharmaceutical composition of increased stability, which comprises ALA and a pharmaceutically acceptable, flexible, f~nite carrier suita~le or administration to the skin or other dermal 2~ me~brane of a ~a~al, op~onally ~ontaining a stabilizing amoun~ of an organic weak proton donor or a saccharide.

The pharmaceutically ~cceptable oarrier in solid formulation for topical delivery to the skin is de~irably a ~kin patch, many forms and types of which are known and u~ed in the art. It is preferable that ~he composition be prepared without - and essentially contain no - water.
No~ only are these formulations usinq a topical ~olid carrier stable after prolon~e~ stora~e, but use of the ~ormulations appear to i -~ G~e t~e fluore~cence produCed FE~ 27 ' 96 10: 55 202b'~ 5Y9 PP~GE . 005 SENT BY: 2-27-96 ;11:~OA~ :FOLEY & L~RDMER DC A~ 613 235 2867;# 6/23 _4_ 2170505 aPter expo~inq _reated s3cin to actiVAtin~ light, as compared wLth the fluorescenc~ p~c~duced with ALA in a fl~id carrier. Ih particular, the pattern of fluor~scPnre is r~ore even and uniform over the area of application than with topical cream~ or salves, and may even provide increafied ~luores~enc~.

When preparin~ the solid eormulations eor topical administration, additicn o~ a proton d~nor, suoh as a weak orqanic acid, can be used to inc~ease the lon~-tar~
o stability of the patch. suitable organic acid~ are mono-and polycarbaxylic acids such as citric acid, oxalic and ascorbic acids. Weak organic acids are preferred because they are less irritating and less Likely to a~fect the stability of the ALA. ~he additive also can ~e a saccharide. If the solid preparation contains water, it i~ essential to include the stabilizing amount of a proton donor or s~ Arlde c~.n~aining substance.
Anhydrous pr~paration~, however, are preferred.

The terra "stabilizing amoUnt, " when applied to the mild organic proton donor or the saccharide-containing subotance of the present invention, ~eans a concentration suf~icien~ to prevent ~r minimize the degra~ation o~ ALA
over the expected storage time for ~he compvsition, typically 6 months to two years. In general, this amount 2~ should be an a~ount at least equal in weight to the ALA
present, ~lthough concentrations as high as four time~
tt~e weight of A ~ can be used. The ~acc~aride-containing sub~tance can be a co~plex saccharide such as ~tarch, a gum or a poly~AcrhAride or it can be less cor~plex ~ h~ride such as a ~nos~cchari~Q.

The mec:hanism by which the solid topical formulatiOn stabilizes the ALA is unkno~n. ~he -c~Ani by which the weak orqanic proton donor such as the weak organic acid or the ~accharide-containing su~stance increases the 35 stability of AL~ Also is unknown. It canno~ be explained FEB 27 ' 96 10: 56 2026725399 P~GE.006 SENT BY: 2-27-96 ;11:0~.4~ ;FOLEY & L4RoMER DC A~ 613 235 2867;# 7/23 _5_ 2 1 ~ 0 5 0 5 merely as a reducing effect which prevents the oxidation of ALA, since ather anti-oxidants, such as vitamin E, BHT, BHA, ascorbic acid and sodium bisulfite ~sed i~ an aqueous solution, were n~t found to be effective at increasing the sta~ility of ~ . It is unknown w~ether this ef~ect is one of protection by the sacch~ride-containin~ substance of the degradation site~ on ~he ALA.

~ is invention also co~pris~ the method or stabilizing ALA by mixing the sams with an anhydrous, flexi~lQ, finite, phar~aceutically acceptable carrier ~or topical ad~inistration. The carrier also may co~prise a weak organic proton donor or sa~ ride, a ~olid polymer, o~ two or more o~ the foregoing.

Detailed De6crlP~ion of the P~eferred Embodi~ents It now ha~ been found that AL~ can be prepared in a stable formulation fox topical us~ by in~o~GLation into a topical drug del~very carrier, optionally contain~ng a ~ild or~anic proton donor or s~c~-h~ride cont~i~in~
substance. In a preferred e~bodiment, th- delivery carrier is cont~ined in a patch. use o~ topically acting ALA in a patch is unusual since, because of t~e increased costs ass~ciated with manufacture of patches. Typically, b~cause o~ these costs, patches are used only eOr pr~scription druqs inte~e~ for syst~mic effect, but which ~re given topically to avoid dQgradation by ~he llver or to prolong the rate and extent of distribution.

~1 o terDl a ~S-aminolevu ~ inic acid as u~ed herein refers to A~A, pharmaceutically acceptable salts ~hereof and prodru~s, which are considered pharmaceutical equivalents for purpo~e~ of thi~ invention. The nature of such salts and prodrugs are ~nown to ~killed workers in the arts. ~he pharmaceutically accepta~le salt~
include, but are not li~ited to, acid addition salts with inorganic and organic acids as well as ~uaternary FE~ 27 '96 10:56 2026~ Y9 PRGE.007 SENT BY: 2-27-96 ;ll:OlAM :FOLEY & L~RDNER DC A~ 613 235 2867;# 8~23 ,.~
~ -6- 2170505 am~onium salt3 o A~A. 5uitable inorganic salts include hydrochloride, hydrobromide, sulfate, car~onate, hydrogen car~onate, hydrogen sulfate and like inorganic salts known for use ~ith pharmacologically active substances, Suitable organi~ acids are those ~ono- and polycarboxylic dcld~ ~uch a~ citri~ acid, a~corbic acid, oxalic ~cid ~nd benzoic ~cid which are w~ak ~cid- and ~:an al~;o act as a proton donor. A suitabLe ~uaternary ammonium salt i~
oleal~nium chloride and other quaternary ammonium salts that are generally r~co~--ized a~ sa~e and e~fective (nGRAS~) under the food and drug laws ~or application to der~al membranes. See ~fr.~lly ~tlnAr~A~rd~ H. (ed.) cited below.

The other ph,armaceut~cAlly acccptable prodrugs of ALA
include the pharmaceutically acceptable esters - amide~
and other masked form~ or der~vative~ the~eo~ - tha~ are metabolized in vivo to yield ALA ~r a solubilized for~
thereof.

~ecause of the instability of A~A in a strongly acidic milieu, esterification of ALA with an aliphatic alcchol, which i3 normally catalyzed by a stron~ acld, i8 not preferred. ~sterific~tion may, however, be accomplished by an alternate route. For example, the amino group is protecte~ by a carbobenzoxy group ~y ~5 reaction with carbo~enzoxysuccinimide. rhe CBZ-ALA is reacted with a diazo~ such as diazomethane to produce CBZ-ALA ester. The CBZ group is then removed by hydrogenolysis to produce an ALA car~oxylic a~i~ e~ter.
- The y~elds ~y suc~ a procedure are virtually quantitative.

"PharmaceuticAlly acceptable ester~' ~efers t~ those esters which retain, upon hydrolysis of the ester bond in vivo, the biological effectiveness and properties of the carboxylic ~cid and are not biologically or otherwise 35 undesirable. For a desc~iption of pha~aceu~ically FE~ 27 '96 10:56 2026'~ Y9 P~GE.008 SENT BY: 2-27-96 ;11:01.4~ ;FOLEY & L4RDMER DC A~ 613 235 2867;# 9~23 ,- .
~ -7- 2170~0~

acceptable esters as prodrugs, see Bun~g~Ard, H., ed., (19851 Desiqn ~f Prodrugs, Elsevier ~cience Publisher~, Am~terdam. Generally, es~er for~ation can b~
accomplished via canventional synthetic techniqu~s.
(S-e, e.g., March Advanced organic ~hemistry, 3rd Ed., John Wiley & Son~, New York (1985) p. ~157 and references cited therein, and Mark et al., Encyclop~;a of Chemical T-chnology, John Wiley & sons, ~e~ York ~1980~.) The ecter component of the carboxylic acid e~ter will generally compri5e (i~ a C1-C22 alkane that can also con~ain one or more ~ouble bonds and can contain br~n~
car~on chain~ or (ii) a C7-C12 aromatic or heteroaromatic group. This invention.al~o contempla~e~ the use of th~e compositions which are both e~ter~ as described herein 1~ and at the sa~e time are the pharmace~tically acceptable acid ad~ition salts thereof.

"PhArmaceutically acc-ptable amide" refers to those amides which retain, upon hydr~ly6is of the amidQ bond, the biological effectiveness ~nd p~G~er~ies of the carboxylic acid or amine and are not biologically or otherwise ~ndesirable. For a description of pharmaccutically accept~le amidcs a~ prodrugs, see ~undgnArd, H., ed., tl985) Desi~n of Prodrugs, Elsevier Science Publish~s, Amsterdam. These a~ides are typically ~ormed from the corresponding car~oxylic acid and ~n a~ine. G~nerally, amide formation can be accomplished via conventional synthetic techniques. ~See e.g., March Advanced Organic Che i~try~ 3rd ~d., John ~iley & Sons, ~ew York ~1985) p. 1152, and Mark et al., Encyclopedia of C~emical Tec~nology, Jo~n Wiley & son~, New York ~1980~.~ This invention also contemplateS t~
use of those c~ tions ~hich are both ~mide~ as describe~ hcrein and at the same ti~e are the pharmaceu~i.cally acceptable acid addition salts thereof.

The stability of ALA may ~e increased by inc~orating it in~o a solid, pharmaceutically FEE3 27 ' 96 10: 57 2026 ~ Y9 PflGE . 009 SENT BY: 2-27-96 ;11:~1.4~ ;FOLEY & L4RDNER DC A~ 613 235 2867;~10~23 ' ~ -8- 2170S05 acceptable carrier, pre~erably a topical carrier and more pre~`erably in an anhydrous adhesive ~opical carrler. T~e solid carrier can option~lly contain an organic weak proton donor such ~fi a weak or~anic acid, or a sAc~h~lri~e-containin~ substance.

The term "pharmaceutical~y accepta~le carrier~ u~ed here with reference to topical a~11ini~tration refers to the wide variety of carriers known ~or use for applica~ion ~o the skin or body cavity to a dermal membrane. Such carriers are well known in the art.

The ter~ "or~anic.weak proton donor" used here re~ers to an orga~ic substance known to function as a weak ac~d which does not, at the same time, de~r~de the ALA.
W~ether t~e organic substance will degra~e the ALA can be dete~ ea~ily by placing the substance at thQ
cG..centration inten~ed for u8e with the ALA, then analyzing for ~esidual ALA. Suita~le organi~ weak proton do~or~ are organic weak ~cids such as mono- an~
polycar~oxylic acids such as citric acid, oxalic acid, ascorbic acid and benzoic acid. Other suita~le stabilizer~ are gums such as gea~ gu~, xanthan gum, karaya gum, British ~um, starch gum, tragacanth gum, pectin gum and derivatives thereof, ~accharides such as complex saccharides such as ce~lulose, polysaccharides such as dextran and dextri~, and monosaccharides such as dextrose, Eructose, mal~ose, ~-glucose ~nd L-glucose.
corn syrup, composed of d~xtrin and ~lucose is particularly ~se~ul, but its use is limited by the fact that it generally contains w~ter.

The solid topical forms of the pr~sent invention include all the known types of devicQs, including both the adh~sive matrix and reservoir ~evices. Matrix de~ices are prefe~red ~ecause ~he minimization of the num~er of layers of the device results in ease of preparatiOn. The ~atrix devices are prepared by ~ethod~

FEEI 27 '96 10:57 202b'~ 5Y9 PP~GE.010 SENT BY:2-27-96 ;11:01AM :FOLEY & L~RDMER DC A~ 613 235 2867;#11~23 _, 217050~

known in the art. ~rhe most convenient form for manuracture o~ a matrix device is one in w~.ich the A~A i~
dispersed in a pressure sensitive adhesive. ~he matrix devices are preferably prepared using c~ rcially supplied organic solvents containing the poly~er. Th~
add~tional in~redients are added to the mixture and then t~e sol~rents are r~ :v~d to form th-- patch. Thi~s avoid~
t~e use oY or inclucion of water in t~e composition and 'ch~a need to perform a cro~G-linkin~ step a~ter th~
iyjn~ such as is n~ce~ry for emulsion poly~erization.

Pressure sensitiYe adhe~ive~ useful in preparing the preferred topical compositions inclu~e a wide variety o~' polymeric adhesives includingpharmaceutically acceptable acryl~c , vinyl ac~tate, ~ilicon~ and synthetic or natural ru~er adhesiveQ and mixtures thereof. Acrylic adhesive~ includ~ Gelva adhosivev GMS 1430, 788 a~aila~le f rom Mo~C~ to co . and various l)urotak adhesives such as 81-Z852 ~anufac~uL~d by ~ational Starch. Vinylacetate adhesives including Fl-Y~on~ 149 and 150 from Air Produc~s are of li~ited usefulnes~ ~e~ they contain water. Rubber ba~ed adhesive~ such as the Morstiks from Morton Thiokol, Ins. or Vistanex manufactured by ~xxon Chemic~l~ can be ~sed. Numero~s silicone ~ased ~dhesives are available from Dow-Corning. These and other pre~sure sensitive adhesives suitable for topical application ~ill ~e apparent ~o one skilled in the art.

For adhesive ma~rix devices, the polymer ~lend is applied to a suitable backing material impermedble to the drug or t~e ot~er components or the polymer ma~rix. T
bA~k~ng materials, which are preferably water resistant, and occlusive or non-occlusive, can ~n sel~c~ed f~o~ such ~aterial as foam, mHtal foil, polyester, low den~ity polyethylene, copolymers of vinyl chloride and pol~vinylidene chloride and laminates thereof.

FE~ 27 '96 10:57 2026725399 P~GE.011 SENT BY: 2-27-96 ;ll:Oæ~M ;FOLEY & L4RDNER DC A~ 613 235 2867;#12~23 , ~ -10- 21705~$

Where the topical device i5 a reservoir-type device, th~ ALA in a solven~, preferably in a non-aq~eous ~o~vent such as an al~A~eAiol or an organic acid s~ch as citric acid is used to fill the re~ervoir. About 0.1 to about S 2%, prefe~ably about 0.5% of a gelling agent such as hydroxypropyl cellulose, can be added to for~ a gQl. Thc s~lution or qel i5 ret~i no~ in the recerv~ir by a su~table rate con~rolling me~brane such as an et~ylene-viny1 acetate copolymer m m~rane, which membrane preferably ha~ a face layer of ~ pressuxe s-nsit~e adhe~ive as described above. Backing materials are si il Ar to those described abovu for matrix devices.

Both adhe~ive matrix and rese~voir devices contain a release liner imper~eable to the druq and any solvents present in the syste~ in order to proteCt the adhesiYe layer until the patch i8 to be dpplied to the skln.
Typ~cal materials for r~le~e liners are polyester, polyethylene, and polye~hylene coated paper, pre~era~ly ~ilicG.~-coated to facilitate removal.

The adhesive matrices of t~e present inVention contain 0.5 to 50% ALA by weiqht, preferably 5 to ~0%, and most preferably 10 ~o 2~%; 50 ~co 95% adhesi~re, preferably 60 to 90~ and more prefera~ly 70 to 90%. An opt$onal carrierand may contain from 0 to 40% by weight 2S of other components, such as a proton donor, penetrationenhancer and other s~bstances known ~or use in mal formulations. Since the ALA in the solid foxmulation is u~ed for a topical effect, there ig in fact no maximum limitation as to the amount of ALA that ~O can be used in the patch except to the extent that t~e adhesivQness or sta~ility of the patch is affected.

Methods ~or preparing ad~e~ive matrix devlces are known in th~ art. A preferred method for preparing adhe~ive ma~rix topical devices of the present inYe~tion co~prises coating a thin layer of the adhesive polymer FE}3 27 ' 96 10: 57 2026 ~Y9 Pf~GE. 012 SENT BY: 2-27-96 ;11:02.4~ ;FOLEY & LARDNER DC A~ 613 235 2867;#13t23 ~, containin~ the A~A optionally in an anhydrous solvent and optionally containing a mild orqanic proton donor such a~
saccharide co,.taining subs~ance or ~ mild organic acid onto the material to be use~ as a releaso liner, cross-linking t~.e polymer blQnd in th~ case of an adhesive to be cross-~inked, dryinq the rPlPA~e liner cont~in~n~ the polymer mixture, then laminating the ~kt~ m~terial to t~e resultant adhesive layer. The preferred proton donor for the ALA is any liquid material or a ~c~hAride-containing substance or an organic acid such as citric acid in a non-aqueou~ solvent. Additional sub~tan~a which increase the pa~ge of the druq into the skin al-~o can be added. Suitable sized patche~ can then be cut out ~nd th~ pa~ches prefera41y ~ A in protectlve pou~es.

T~ layer of polymer mixture cast on th~ releas~
lin~r accordinq to tho profQrred mRthod of this invention is about S ~ils to about 30 mils thick. The coated layer i3 pre~erably dried at a temperature o~ about 80 d~
Centigrnde. One mil - ~.0254 ~m.

The size of the topical tevice of the present invontion depen~s on ~ dosR o~ ALA ~o be u~ilized, with the preferred patch area being about 2.5 to 20 cm2, preferably 5 to lS cm~. ~he preferred delivery rate for ALA i~ at lea~t 0.1 ~g. pQr cmZ per bour, giving a preferred daily dosage of at le~st 0.25 mg. per day applied to the ~rea of the skin to be diagnosed or treated for about 2-48 hours. ~he optimum concentration of ALA in a patch is at least 0.1-3.0 mg. per c*.

As ~ I.ini~ , the topical device m~st contain a pharmacologically effective amount of ALA. Genera~ly, this is at least 0.25 mq. The duration of application i3 t~at period sufficient to achieve ALA penetration into the diseased tissue and that permits high localiZcd .on~n~ratlons of protoporphyrin IX resultsng from the conversian of ALA. T~is period may be about 3-24 hourS

FEE3 27 ' 96 10: 58 2~ Y9 PRGE . 013 S~ BY: 2-27-96 ;11:0~ ;F0~ & L~ER DC A~ 61~ 235 2867;#14/2a ~, 217050~

~n~, prefera~ly, is 12-~6 hours. The effective amount and duration will vary dqp~ ng on t~e nature of the lesion and may bc determinad empirically by tho6e s~illed in the art by testing localized fluorescence of the S lesion after administration~ If fluorescence is insuf~icient, longer application or higher A~A
concen~rations may be used.

Topical ALA photodynamic therapy (ALA PDT~) involves the exposure of the ALA-treated lesion with light. A
10 suitable wavelength is ~00 nm, 634 nm or 600-700 nm, at an intensity of 10-100 milliwatts per centimeter squared (mW/cm2) to provide a light dose o~ 10-100 Joules/cm~.
Exposure time may vary from 3 to 30 minutes, bUt preferably is about 10 minutes. Upon ~r~ re, activation of proto~o~hyrin IX leads to in s~tu brs~ wn of proto~o~h~rln IX and the generation o~
sin~let oxygen, len~i ng to the destruct~on of diseased cells.

~he target tissues for w~ich the pre~ent invention zO may be used are any visible, cutaneous lesion or Otner undesired rapidly growLng cells. In particular, theso include, kut are not li~ited to, neoplastic, aplastic and hype~plastic sXin condi~ions such as basal cell carcinoma, actinic keratosis, psoriasis and similar conditions.

FEB 27 '96 10:58 2026725399 P~GE.014 SENT BY: 2-27-96 ;11:09AM ;FOLEY & L4RDNER DC A~ 613 235 2867;~15/23 ExamDle 1 The following table show~ typic~l adhesivo ~atrix formulationq of this inventio~. In this table G~S means G~lva multipolymer system, and the percentages shown are percentages by weight:

Golva Multipoly~er Solution - Acrylic Adhe~ive ~, .
w%~/~ %~1~ %~lw ~vlw ~ w~
GMI~ 1430 llO 110 ~0 70 6S R0 AL~ 10 ,10 10 10 10 ~O
citnc ~cid 10 ~- 5 10 5 0 cot~ Symp .- . 5 10 1(1 Il~

G~ 7~ o 90 w 70 60 ~0 S0 Al.A 10 10 10 10 10 10 10 C~ cid 10 S 10 - -- 10 Cora Symp - ~ S lo 30 ~0 3U

GMS 7NY U ~ 7(1 3$ 30 '5 ~5 ~5 GMS 1130 W i j35 30 ~5 '5 IS
a lu ~ v 10 1~ lo 10 Citnc Ach10 . 510 - - 10 C~ S~llp - - 10 1~1 ~O ~0JO

Dw~T Ic1~7-2852110!10 ~n so bO70 70 ! 90 lo a lo lo lu lo lo lo Cilnc Acul IU -- -- lu IU S -- -Con~ S~ 10 ~) ~U '0 15 20 EE~ 27 ' 96 10: 58 202~'Ncl~Y9 PP~GE. 015 SENT BY: 2-27-96 ;11:~3.4N ;FOLEY & L4RDMER DC A~ 613 235 2867;#16~23 ~ -14- 2170~05 ~xamp~e 2 In the following exa~ple the ALA, propylene glycol, locithin an~ glycerin are blended at about 70 to ~O~C
until all t~e drug is dissolYed. The s~lution is then cooled to about 20 to 35~c prior to A~ing t~e karaya gum. Once the karaya gum is added, the final co~posi~ion is applied to a suitable bac~in~ material such as a non-woven polyester film ~or example, ~he ~ilm ~ld under t~e trademark Sont~ra ~loo, m~n~f a~L Qd ~y DuPont de Nemour~, wil~inqt~n, DE~ and w- -~ to about lOo-C to accelera~e the formation of the gel into it~ final, finit~ for~.

5-Aminolevulinic Acid g~w~w~w~w 9~wlw %w~w 9~w~w hlJ~ 2 5 lO Is 20 lS Soh~t(~ glycol~ 10 tO IS 15 IS
Solvem (Ok~c ~id) 10 10 10 10 10 Solvent~Iycenn~ 30 30 ~0 '0 30 Solvent~i~xe~ylalcohol) ~ 10 10 --y~ ~uml 30 ~o 20 20 30 n " ~ an*~m eum) -- -- lo 10 --B~uk~lo~n) 18 15 lo 10 FE~ 27 '96 10:58 2026~ Y9 P~GE.016 SENT BY: 2-27-96 ;11:03AM ;FOLEY & L4RDNER DC A~ 613 235 2867;#17~23 ~ t ~ -15- 2170505 ~xampl e 3 A thirty-two year old fema~- is e3~ s~d with ba~al cell carcinoma. A single le~ion is evident on her rlg~t ~orearm covering approxi~ately 22 mm2, and topical a~inolevulinic acid pho~odyna~ic t~erapy ~ALA PDT~) is prescribed.

A 5 cml ~pica~ patc~ containing 10% ~w~w~ ALA, mAdo according to Example 1 or 2, is applied to the le~ion.
~he patch is l-ft in place for 18 hours, which iB
10 suf~icient to permit adQquate pe~a~ion of ALA in~o the le~ion and f~r the- formation of protoporphyrin IX
("~pIX"), the active end produet of topical ALA
ad~inist~ation. After thQ patch iS re~oved, the lesion i~ wiped with an alcohol sw~b to remo~e any residual adhs~ivs.

Thc lesion is then ~xro-~' to activating UV ll~ht using a cv~el.~ional Woodg la~p to determine if t~e fluor~sc~noe levels, and hence the PpIX levels, are sufficient. Flndin~ the ~evels suitable, the lesion iS
t~en expo~ed t~ a 634 nm wavelen~th light source at 100 mW~cm2 for 15 minutes.

Within 30 minutes, a localized reaCtion is observed, characterized by the rapid onset of redness, erythema and edema ~ the treatment site. ouring thQ next sev-ral days, necrosis of the ~estroyed lesional cells a~ueC, re-ulting Ln the formatlon of a burn-l~ke scab over the former les~on. Durinq the next six weeks, nor~l heali~g of the treated tissue and restoration o~ intact skin is ob~erv~d.

T~e foregoing examples are illustrative emboAi ~nts of th~ invention and are merely exemplary. A person skill~d in the art may make variations and modification without dsparting from the spirit and scope of th EE~ 27 ' 96 10: 59 202t~ Y9 P~GE. 017 SENT BY: 2-27-96 ;11:03.4~ :FOLEY & L4RDMER DC A~ 613 235 2867;~18/23 -lfi- 21705~

invention. All 3~ch modification~ and ~ariati~s are intend-d to b4 ~ncluded within t~e scope of the inventlon as descri~ed in this specification and ~he ~pp~n~
claims.

FEB 27 '96 10:59 202b~ Y9 PflGE.018

Claims (25)

What Is Claimed Is

1. A pharmaceutical composition comprising:
(i) a therapeutically effective amount of a .delta.-aminolevulinic acid or a pharmaceutical equivalent thereof; and (ii) a pharmaceutically acceptable, flexible, finite carrier for dermal application.

2. The composition of claim 1, wherein said pharmaceutical equivalent is an ester of .delta.-aminolevulinic acid.

3. The composition of claim 1, wherein said pharmaceutical equivalent is an amide of .delta.-aminolevulinic acid.

4. The pharmaceutical composition of claim 1, wherein said .delta.-aminolevulinic acid or pharmaceutical equivalent thereof is dispersed throughout the carrier.

5. The pharmaceutical composition of claim 1, wherein said carrier is an adhesive.

6. The pharmaceutical composition of claim 5, wherein said adhesive is a pressure-sensitive adhesive.

7. The pharmaceutical composition of claim 6, wherein said pressure sensitive adhesive is a bio-adhesive.

8. The pharmaceutical composition of claim 6, wherein said pressure sensitive adhesive is a polymeric adhesive selected from the group consisting of an acrylic, a silicone-based adhesive, a vinyl acetate adhesive and a natural or synthetic rubber-based adhesive, or mixtures thereof.

9. The pharmaceutical composition of claim 5, wherein said adhesive additionally contains a stabilizing amount of a saccharide.

10. The pharmaceutical composition of claim 9, wherein said saccharide is selected from the group consisting of dextrans, dextrins, polysaccharides, disaccharides and monosaccharides.

11. The pharmaceutical composition of claim 10, wherein said monosaccharide is selected from the group consisting of dextrose, fructose, D-glucose and L-glucose.

12. The pharmaceutical composition of claim 9, wherein said saccharide is a mixture of a substance selected from the group consisting of dextrins, dextrans and monosaccharides.

13. The pharmaceutical composition of claim 5, wherein said adhesive additionally contains a stabilizing amount of an organic weak proton donor.

14. The pharmaceutical composition of claim 13, wherein said organic weak proton donor is a carboxylic acid.

15. The pharmaceutical composition of claim 14 wherein said carboxylic acid is selected from the group consisting of citric acid, oxalic acid, ascorbic acid and benzoic acid.

16. The pharmaceutical composition of claim 13, wherein said composition is substantially anhydrous.

17. The pharmaceutical composition of claim 13 comprising, in weight percentages, about 0.5% to about 50% .delta.-aminolevulinic acid, and about 10% to about 95% of an adhesive.

18. A method of stabilizing .delta.-aminolevulinic acid or a pharmaceutical equivalent thereof, comprising mixing said .delta.-aminolevulinic acid or said pharmaceutical equivalent thereof with an anhydrous, flexible, finite pharmaceutically acceptable carrier suitable for topical administration.

19. The method of claim 18, wherein a weak organic proton donor is also added to the mixture.

20. The method of claim 19, wherein said weak organic proton donor is a carboxylic acid.

21. The method of claim 18, wherein said carrier is an adhesive.

22. The method of claim 21, wherein said adhesive is a pressure sensitive adhesive.

23. The method of claim 21, wherein said adhesive is selected from the group consisting of bioadhesives and polymeric adhesives.

24. The method of claim 23, wherein said polymeric adhesive is selected form the group consisting of an acrylic, a silicone-based adhesive, a vinyl acetate adhesive, and a natural or synthetic rubber-based adhesive, or mixtures thereof.

25. The use of .delta.-aminolevulinic acid or a pharmaceutical equivalent thereof for the preparation of a transdermal drug delivery device comprising a therapeutically effective amount of said .delta.-aminolevulinic acid or pharmaceutical equivalent thereof in a flexible finite carrier for application to skin or other dermal membrane of a mammal.