PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER
`
`WORLD INTELLECTUAL PROPE
`
`International 81 llll~llffll~ll~IIIIIHI
`
`WO
`
`9606602A1
`
`(51) International Patent Classification 6 :
`A61K 31/13
`
`Al
`
`(11) International Publication Number:
`
`WO 96/06602
`
`(43) International Publication Date:
`
`7 March 1996 (07.03.96)
`
`(21) International Application Number:
`
`PCT/US95/10879
`
`(74) Agents: MELOY, Sybil et al.; Foley & Lardner, Suite 500,
`3000 K Street, N.W., Washington, DC 20007-5109 (US).
`
`(22) International Filing Date:
`
`28 August 1995 (28.08.95)
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, Fl, GB, GE, HU, IS, JP, KE,
`KG,KP, KR, KZ,LK,LR,LT, LU,LV,MD, MG, MN,
`MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`TJ, TM, TT, UA, UG, US, UZ, VN, European patent (AT,
`BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`ML, MR, NE, SN, TD, TG), ARIPO patent (KE, MW, SD,
`SZ, UG).
`
`(30) Priority Data:
`26 August 1994 (26.08.94)
`PCT/US94/09466
`(34) Countries for which the regional or
`international application was filed:
`
`WO
`
`US et al.
`
`(60) Parent Applications or Grants
`(63) Related by Continuation
`us
`Filed on
`us
`Filed on
`
`(71) Applicant (for all designated States except US): NOVEN
`PHARMACEUTICALS, INC. [US/US]; 11960 S.W. 144th
`Street, Miami, FL 33186 (US).
`
`PCT/US94/09466 (CIP)
`26 August 1994 (26.08.94)
`08/112,330 (CIP) Published
`With international search report.
`27 August 1993 (27 .08.93)
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): MANTELLE, Juan, A.
`[US/US]; 10821 S.W. 92nd Avenue, Miami, FL 33176 (US).
`GOLUB, Allyn, L. [US/US]; Suite 300, 18441 N.W. 2nd
`Avenue, Miami, FL 33169 (US).
`
`(54) Title: COMPOSmONS AND METIIODS FOR THE ADMINIS1RATION OF 6-AMINOLEVULINIC ACID AND PHARMACEU(cid:173)
`TICAL EQUIVALENTS THEREOF
`
`(57) Abstract
`
`A phannaceutical composition of increased stability, which comprises ALA or phannaceutical equivalents thereof and a
`phannaceutically 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 phannaceutically 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.
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`CZ
`DE
`DK
`ES
`Fl
`FR
`GA
`
`Austria
`Austtalia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switz.er land
`COie d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Gennany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`TT
`UA
`us
`uz
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`Viet Nam
`
`

`

`WO96/06602
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`PCT/US95/10879
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`- 1 -
`
`COMPOSITIONS AND METHODS FOR THE
`ADMINISTRATION OF 6-AMINOLEVULINIC ACID
`AND PHARMACEUTICAL EQUIVALENTS THEREOF
`
`5
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`cross-Reference to Belated Applications
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`a continuation-in-part of
`is
`This application
`PCT/US94/09466,
`filed August 27, 1994, which is a
`continuation-in-part of Serial No. 08/112,330 filed
`August 27, 1993, which is a continuation-in-part of
`PCT/US92/0l 730, filed February 27, 1992, which is a
`continuation-in-part of u.s. Application Serial No.
`07/813,196, filed December 23, 1991, now U.S. Patent No.
`5,234,957, which is a continuation-in-part of U.S. Patent
`Application Serial No. 07/661,827, filed February 27,
`1991
`and
`now
`abandoned.
`All of
`the
`foregoing
`applications are hereby incorporated by reference.
`
`Background of the Invention
`
`to as 6-
`5-Aminolevulinic acid, also referred
`aminolevulinic acid or 5-amino-4-oxopentanoic acid, is
`referred to herein as "ALA". ALA has been known for over
`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 been of limited usefulness,
`namely, use limited to porphyrin research.
`In 1984, ALA
`was proposed for use as a photodynamic herbicide. It has
`been discovered recently that ALA can be used by various
`routes of administration to detect and treat certain
`conditions involving rapidly metabolizing cells, namely
`hyperproliferative cells. It is especially useful in the
`treatment of malignant
`and non-malignant
`abnormal
`growths.
`
`ALA has been administered by various routes known for
`use in drug administration, but especially by topical
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`WO96/06602
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`application to the skin and epithelium of various body
`cavities. Application of ALA results in the selective
`accumulation of clinically significant amounts of
`protoporphyrin IX, another precursor in the metabolic
`pathway to heme. Activation of protoporphyrin IX by
`light, depending on the wavelength of the light, will
`cause the protoporphyrin IX either to fluoresce (which
`can be used as the basis of a detection method), or to
`decompose (which can be used as the basis of treatment
`for cells that need to be removed).
`
`ALA previously has been used in clinical testing on
`humans and other mammals in aqueous and non-aqueous fluid
`vehicles such as creams (oil in water emulsions) and
`lotions for application to the skin and orally for the
`diagnosis and treatment of skin cancers. ALA has been
`used
`in clinical studies
`in aqueous solution for
`application to the endometrial cavity.
`
`ALA has been reported to inhibit degradation of the
`drug calcitonin by
`the nasal mucosa peptides
`in
`u.s. 5,026,825 . Preparations in the examples of that
`patent show a combination of calci tonin and ALA
`in
`aqueous solutions containing one or more of benzalkonium
`chloride, citric acid, sodium citrate, hyd_rochloric acid,
`sodium acetate and acetic acid. The organic acids and
`their salts appear to be used as buffers, 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 including both water
`containing-vehicles, anhydrous fluid vehicles and water
`and oil emulsions.
`In general, the lower the pH of the
`fluid vehicle, the more rapid the degradation.
`For
`example, addition of about 10% by weight ALA in the form
`the hydrochloride salt into an alkaline solution, left at
`room temperature, results in almost complete degradation
`in about one week.
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`Precursors or prodrugs of ALA have been reported for
`use in conditions similar to that as reported for ALA.
`The Norwegian Radium Hospital Research Foundation's PCT
`application No. WO 95/07077 published March 16, 1995
`("precursors") and Peng et al. Abstract, American Society
`of Photobiology Annual Meeting, 1995 Budapest.
`
`The decomposition occurring with fluid preparations,
`such as water and ethanol, reported in the scientific
`literature with use of ALA patients, is sufficient to
`preclude the use of ALA in a product to be distributed in
`normal,
`existing
`channels
`for
`the
`supply
`of
`pharmaceuticals.
`Many studies have been performed
`without success in an attempt to stabilize ALA, with
`respect to extending the stability of the chemical in a
`fluid, including use of an aqueous solution containing
`certain antioxidants such as ascorbic acid and sodium
`bisulfite. Thus, there remains a need for a storage
`stable composition comprising ALA in a form suitable for
`administration to a patient.
`
`summary of the Invention
`
`The invention relates to a pharmaceutical composition
`increased stability, which compris~s ALA and a
`of
`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 a saccharide.
`
`The pharmaceutically acceptable carrier in solid
`formulation for topical delivery to the skin is desirably
`a skin patch, many forms and types of which are known and
`used in the art. It is preferable that the composition
`be prepared without - and essentially contain no - water.
`Not only are these formulations using a topical solid
`carrier stable after prolonged storage, but use of the
`formulations appear to improve the fluorescence produced
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`

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`WO96/06602
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`PCT/US95/l 0879
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`-4-
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`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
`even provide increased fluorescence.
`
`When preparing the solid formulations for topical
`administration, addition of a proton donor, such as a
`weak organic acid, can be used to increase the long-term
`stability of the patch. Suitable organic acids are mono(cid:173)
`and polycarboxylic acids such as citric acid, oxalic and
`ascorbic acids. Weak organic acids are pref erred because
`they are less irritating and less likely to affect the
`stability of the ALA.
`The additive also can be a
`saccharide. If the solid preparation contains water, it
`is essential to include the stabilizing amount of a
`proton
`donor
`or
`saccharide-containing
`substance.
`Anhydrous preparations, however, are preferred.
`
`The term "stabilizing amount," when applied to the
`mild organic proton donor or the saccharide-containing
`substance of the present invention, means a concentration
`sufficient to prevent or minimize the degradation of ALA
`over the expected storage time for the composition,
`typically 6 months to two years.
`In general, this amount
`should be an amount at least equal in weight to the ALA
`present, although concentrations as high as four times
`the weight of ALA can be used. The saccharide-containing
`substance can be a complex saccharide such as starch, a
`gum or a polysaccharide or it can be less complex
`saccharide such as a monosaccharide.
`
`The mechanism by which the solid topical formulation
`stabilizes the ALA is unknown. The mechanism by which
`the weak organic proton donor such as the weak organic
`acid or the saccharide-containing substance increases the
`stability of ALA also is unknown. It cannot be explained
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`merely as a reducing effect which prevents the oxidation
`of ALA, since other anti-oxidants, such as Vitamin E,
`BHT, BHA, ascorbic acid and sodium bisulfite used in an
`aqueous solution, were not found to be effective at
`increasing the stability of ALA.
`It is unknown whether
`this effect is one of protection by the saccharide(cid:173)
`containing substance of the degradation sites on the ALA.
`
`the method of
`invention also comprises
`This
`stabilizing ALA by mixing the same with an anhydrous,
`flexible, finite, pharmaceutically acceptable carrier for
`topical administration. The carrier also may comprise a
`weak organic proton donor or saccharide, a solid polymer,
`or two or more of the foregoing.
`
`Detailed Description of the Preferred Embodiments
`
`It now has been found that ALA can be prepared in a
`stable formulation for topical use by incorporation into
`a topical drug delivery carrier, optionally containing a
`mild organic proton donor or saccharide containing
`substance.
`In a pref erred embodiment,
`the deli very
`carrier is contained in a patch. Use of topically acting
`ALA in a patch is unusual since, because of the increased
`costs associated with manufacture of patches. Typically,
`because of
`these costs, patches are used only for
`prescription drugs intended for systemic effect, but
`which are given topically to avoid degradation by the
`liver or to prolong the rate and extent of distribution.
`
`The term a 6-aminolevulinic acid as used herein
`refers to ALA, pharmaceutically acceptable salts thereof
`and prodrugs, which are considered pharmaceutical
`equivalents for purposes of this invention. The nature
`of such salts and prodrugs are known to skilled workers
`in the arts.
`The pharmaceutically acceptable salts
`include, but are not limited to, acid addition salts with
`inorganic and organic acids as well as quaternary
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`

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`WO96/06602
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`PCT/US95/l 0879
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`-6-
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`ammonium salts of ALA. Suitable inorganic salts include
`hydrochloride, hydrobromide, sulfate, carbonate, hydrogen
`carbonate, hydrogen sulfate and like inorganic salts
`known for use with pharmacologically active substances.
`Sui table organic acids are those mono- and polycarboxylic
`acids such as citric acid, ascorbic acid, oxalic acid and
`benzoic acid which are weak acids and can also act as a
`proton donor. A suitable quaternary ammonium salt is
`olealkonium chloride and other quaternary ammonium salts
`that are generally recognized as safe and effective
`("GRAS") under the food and drug laws for application to
`dermal membranes.
`See generally Bundgaard, H.
`(ed.)
`cited below.
`
`The other pharmaceutically acceptable prodrugs of ALA
`include the pharmaceutically acceptable esters - amides
`and other masked forms or derivatives thereof - that are
`metabolized in vivo to yield ALA or a solubilized form
`thereof.
`
`in a strongly
`Because of the instability of ALA
`acidic milieu, esterification of ALA with an aliphatic
`alcohol, which is normally catalyzed by a strong acid, is
`not
`preferred. Esterification may,
`however,
`be
`accomplished by an alternate route.
`For example, the
`amino group is protected by a carbobenzoxy group by
`reaction with carbobenzoxysuccinimide. The CBZ-ALA is
`reacted with a diazoalkane such as diazomethane to
`produce CBZ-ALA ester. The CBZ group is then removed by
`hydrogenolysis to produce an ALA carboxylic acid ester.
`The yields
`by
`such
`a
`procedure
`are virtually
`quantitative.
`
`"Pharmaceutically acceptable ester" refers to those
`esters which retain, upon hydrolysis of the ester bond in
`vivo, the biological effectiveness and properties of the
`carboxylic acid and are not biologically or otherwise
`undesirable.
`For a description of pharmaceutically
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`acceptable esters as prodrugs, see Bundgaard, H., ed.,
`{1985) Design of Prodrugs, Elsevier Science Publishers,
`Amsterdam.
`Generally,
`ester
`formation
`can
`be
`accomplished via conventional synthetic
`techniques.
`(See, e.g., March Advanced organic Chemistry, 3rd Ed.,
`John Wiley & Sons, New York (1985) p. 1157 and references
`cited therein, and Mark et al., Encyclopedia of Chemical
`Technology, John Wiley & sons, New York (1980).)
`The
`ester component of
`the carboxylic acid ester will
`generally comprise {i) a c1-c22 alkane that can also
`contain one or more double bonds and can contain branched
`carbon chains or (ii) a C7-Cl2 aromatic or heteroaromatic
`group. This invention also contemplates the use of those
`compositions which are both esters as described herein
`and at the same time are the pharmaceutically acceptable
`acid addition salts thereof.
`
`"Pharmaceutically acceptable amide" refers to those
`amides which retain, upon hydrolysis of the amide bond,
`the biological effectiveness and properties of
`the
`carboxylic acid or amine and are not biologically or
`otherwise
`undesirable.
`For
`a
`description
`of
`pharmaceutically acceptable amides as prodrugs, see
`Bundgaard, H., ed., (1985) Design of Prodrugs, Elsevier
`Science Publishers, Amsterdam.
`These
`amides are
`typically formed from the corresponding carboxylic acid
`and an amine.
`Generally,
`amide
`formation can be
`accomplished via conventional synthetic techniques. { See
`e.g. , March Advanced Organic Chemistry, 3rd Ed. , John
`Wiley & Sons, New York (1985) p. 1152, and Mark et al.,
`Encyclopedia of Chemical Technology, John Wiley & Sons,
`New York {1980).) This invention also contemplates the
`use of those compositions which are both amides as
`described herein
`and at
`the
`same
`time are
`the
`pharmaceutically acceptable acid addition salts thereof.
`
`35
`
`stability of ALA may
`The
`into
`a
`solid,
`it
`incorporating
`
`by
`increased
`be
`pharmaceutically
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`acceptable carrier, preferably a topical carrier and more
`preferably in an anhydrous adhesive topical carrier. The
`solid carrier can optionally contain an organic weak
`proton donor
`such as
`a weak organic acid, or a
`saccharide-containing substance.
`
`The term "pharmaceutically acceptable carrier" used
`here with reference to topical administration refers to
`the wide variety of carriers known
`for use
`for
`application to the skin or body cavity to a dermal
`membrane. Such carriers are well known in the art.
`
`The term "organic weak proton donor" used here refers
`to an organic substance known to function as a weak acid
`which does not, at the same time, degrade the ALA.
`Whether the organic substance will degrade the ALA can be
`determined easily by placing
`the substance at the
`concentration
`intended for use with
`the ALA,
`then
`analyzing for residual ALA. suitable organic weak proton
`donors are organic weak acids such as mono-
`and
`polycarboxylic acids such as citric acid, oxalic acid,
`ascorbic acid and benzoic acid.
`Other suitable
`stabilizers are gums such as guar gum, xanthan gum,
`karaya gum, British gum, starch gum,
`tragacanth gum,
`pectin gum and derivatives thereof, saccharides such as
`complex saccharides such as cellulose, polysaccharides
`such as dextran and dextrin, and monosaccharides such as
`dextrose, fructose, maltose, D-glucose and L-glucose.
`Corn
`syrup,
`composed of dextrin
`and glucose
`is
`particularly useful, but its use is limited by the fact
`that it generally contains water.
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`The solid topical forms of the present invention
`include all the known types of devices, including both
`the adhesive matrix and reservoir devices. Matrix
`devices are pref erred because the minimization of the
`number of layers of the device results in ease of
`preparation. The matrix devices are prepared by methods
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`for
`form
`The most convenient
`the art.
`in
`known
`manufacture of a matrix device is one in which the ALA is
`dispersed in a pressure sensitive adhesive. The matrix
`devices are preferably prepared using commercially
`supplied organic solvents containing the polymer. The
`additional ingredients are added to the mixture and then
`the solvents are removed to form the patch. This avoids
`the use of or inclusion of water in the composition and
`the need to perform a cross-linking step after the
`mixing, such as is necessary for emulsion polymerization.
`
`Pressure sensitive adhesives useful in preparing the
`preferred topical compositions include a wide variety of
`polymeric adhesives including pharmaceutically acceptable
`acrylics, vinyl acetate, silicone and synthetic or
`natural rubber adhesives and mixtures thereof. Acrylic
`adhesives include Gelva adhesives GMS 1430, 788 available
`from Monsanto Co. and various Durotak adhesives such as
`87-2852 manufactured by National Starch. Vinylacetate
`adhesives
`including Flexbond 149 and 150
`from Air
`Products are of limited usefulness because they contain
`water. Rubber based adhesives such as the Morstiks from
`Morton Thiokol, Ins. or Vistanex manufactured by Exxon
`Chemicals can be used. Numerous silicone based adhesives
`are available from Dow-corning. These and. other pressure
`sensitive adhesives suitable for topical application will
`be apparent to one skilled in the art.
`
`For adhesive matrix devices, the polymer blend is
`applied to a suitable backing material impermeable to the
`drug or the other components of the polymer matrix. The
`backing materials, which are preferably water resistant,
`and occlusive or non-occlusive, can be selected from such
`material as foam, metal foil, polyester,
`low density
`polyethylene,
`copolymers
`of
`vinyl
`chloride
`and
`polyvinylidene chloride and laminates thereof.
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`Where the topical device is a reservoir-type device,
`the ALA in a solvent, preferably in a non-aqueous solvent
`such as an alkanediol or an organic acid such as citric
`acid is used to fill the reservoir. About 0.1 to about
`2%, preferably about o. 5% of a gelling agent such as
`hydroxypropyl cellulose, can be added to form a gel. The
`solution or gel is retained in the reservoir by a
`suitable rate-controlling membrane such as an ethylene(cid:173)
`vinyl acetate
`copolymer membrane, which membrane
`preferably has a
`face layer of a pressure sensitive
`adhesive as des er ibed above.
`Backing materials are
`similar to those described above for matrix devices.
`
`Both adhesive matrix and reservoir devices contain
`a release liner impermeable to the drug and any solvents
`present in the system in order to protect the adhesive
`layer until the patch is to be applied to the skin.
`Typical materials for release liners are polyester,
`polyethylene, and polyethylene coated paper, preferably
`silicon-coated to facilitate removal.
`
`invention
`the present
`The adhesive matrices of
`contain 0.5 to 50% ALA by weight, preferably 5 to 20%,
`and most preferably 10 to 20%; 50 to 95% adhesive,
`preferably 60 to 90% and more preferably 70 to 90%. An
`optional carrierand may contain from o to 40% by weight
`of other components, such as a proton donor, penetration
`enhancer
`and other
`substances
`known
`for use
`in
`Since the ALA in the solid
`transdermal formulations.
`formulation is used for a topical effect, there is in
`fact no maximum limitation as to the amount of ALA that
`can be used in the patch except to the extent that the
`adhesiveness or stability of the patch is affected.
`
`Methods for preparing adhesive matrix devices are
`A preferred method for preparing
`known in the art.
`adhesive matrix topical devices of the present invention
`comprises coating a thin layer of the adhesive polymer
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`
`20
`
`25
`
`30
`
`35
`
`

`

`WO96/06602
`
`PCT/0S95/10879
`
`-11-
`
`containing the ALA optionally in an anhydrous solvent and
`optionally containing a mild organic proton donor such as
`saccharide-containing substance or a mild organic acid
`onto the material to be used as a release liner, cross-
`linking the polymer blend in the case of an adhesive to
`be cross-linked, drying the release liner containing the
`polymer mixture, then laminating the backing material to
`the resultant adhesive layer. The pref erred proton donor
`for the ALA is any liquid material or a saccharide-
`containing substance or an organic acid such as citric
`acid in a non-aqueous sol vent. Additional substances
`which increase the passage of the drug into the skin also
`can be added. suitable sized patches can then be cut out
`and the patches preferably sealed in protective pouches.
`
`The layer of polymer mixture cast on the release
`liner according to the preferred method of this invention
`is about 5 mils to about 3 O mils thick. The coated layer
`is preferably dried at a temperature of about 80 degrees
`Centigrade. One mil= 0.0254 mm.
`
`the topical device of the present
`The size of
`invention depends on the dose of ALA to be utilized, with
`the preferred patch area being about 2. s to 20 cm2
`,
`preferably 5 to 15 cm2• The preferred delivery rate for
`ALA is at least 0.1 µg. per cm2 per hour, giving a
`preferred daily dosage of at least 0.25 mg. per day
`applied to the area of the skin to be diagnosed or
`treated for about 2-48 hours. The optimum concentration
`of ALA in a patch is at least 0.1-3.0 mg. per cm2 •
`
`the topical device must contain a
`As a minimum,
`pharmacologically effective amount of ALA. Generally,
`this is at least o. 25 mg. The duration of application is
`that period sufficient to achieve ALA penetration into
`the diseased tissue and that permits high localized
`concentrations of protoporphyrin IX resulting from the
`conversion of ALA. This period may be about 3-24 hours
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO96/06602
`
`PCT/US95/10879
`
`-12-
`
`and, preferably, is 12-16 hours. The effective amount
`and duration will vary depending on the nature of the
`lesion and may be determined empirically by those skilled
`in the art by testing localized fluorescence of the
`lesion after administration.
`If
`fluorescence
`is
`application
`or
`longer
`higher
`insufficient,
`ALA
`concentrations may be used.
`
`Topical ALA photodynamic therapy (ALA PDT"') involves
`the exposure of the ALA-treated lesion with light. A
`suitable wavelength is 400 nm, 634 nm or 600-700 nm, at
`an intensity of 10-100 milliwatts per centimeter squared
`to provide a light dose of 10-100 Joules/cm2
`(mW/cm2 )
`•
`Exposure
`time may vary
`from 3
`to 30 minutes, but
`preferably
`is about 10 minutes.
`Upon exposure,
`leads to in situ
`activation of
`protoporphyrin
`IX
`breakdown of protoporphyrin IX and the generation of
`singlet oxygen, leading to the destruction of diseased
`cells.
`
`The target tissues for which the present invention
`may be used are any visible, cutaneous lesion or other
`undesired rapidly growing cells.
`In particular, these
`include, but are not limited to, neoplastic, aplastic and
`hyperplastic
`skin conditions
`such as basal cell
`carcinoma, actinic keratosis, psoriasis and similar
`conditions.
`
`s
`
`10
`
`15
`
`20
`
`25
`
`

`

`WO96/06602
`
`PCT/US95/l 0879
`
`-13-
`
`Example 1
`
`The following table shows typical adhesive matrix
`In this table GMS means
`formulations of this invention.
`Gelva multipolymer system, and the percentages shown are
`percentages by weight:
`
`5
`
`Gelva Multipolymer solution= Acrylic Adhesive= GMS
`
`'lw/w
`
`'lw/w
`
`'lw/w
`
`'1,w/w
`
`'lw/w
`
`'lw/w
`
`'lw/w
`
`'lw/w
`
`10
`
`OMS 1430
`
`ALA
`
`Citric Acid
`
`Com Syrup
`
`GMS788
`
`ALA
`
`Citric Acid
`
`Com Syrup
`
`GMS78S
`
`80
`
`10
`
`10
`-
`
`80
`
`10
`
`10
`-
`
`40
`
`90
`
`10
`-
`-
`
`90
`
`10
`-
`-
`
`80
`
`10
`
`5
`
`5
`
`80
`
`10
`
`5
`
`5
`
`70
`
`10
`
`10
`
`10
`
`70
`
`10
`
`10
`
`10
`
`65
`
`10
`
`5
`
`20
`
`60
`
`10
`-
`
`30
`
`80
`
`10
`-
`
`10
`
`.so
`
`10
`-
`
`40
`
`.so
`
`10
`
`10
`
`30
`
`30
`
`25
`
`25
`
`45
`
`15
`
`OMS 1430
`
`ALA
`
`Citric Acid
`
`Com Syrup
`
`20
`
`Du~Talt 87-28.52
`
`ALA
`
`Citric Acid
`
`Com Syrup
`
`80
`
`5
`
`10
`
`5
`
`-
`
`80
`
`10
`-
`
`10
`
`70
`
`5
`
`10
`
`5
`
`10
`
`50
`
`10
`-
`
`40
`
`35
`
`35
`
`10
`
`10
`
`10
`
`50
`
`10
`
`10
`
`30
`
`40
`
`10
`
`10
`
`-
`
`80
`
`10
`
`10
`
`-
`
`30
`
`10
`
`-
`
`30
`
`60
`
`10
`
`10
`
`20
`
`25
`
`10
`
`-
`
`40
`
`70
`
`10
`
`5
`
`15
`
`25
`
`10
`
`10
`
`30
`
`70
`
`10
`
`-
`
`20
`
`45
`
`10
`
`-
`-
`
`90
`
`10
`-
`-
`
`

`

`WO96/06602
`
`PCT/0S95/10879
`
`-14-
`
`Example 2
`
`In the following example the ALA, propylene glycol,
`lecithin and glycerin are blended at about 70 to 90°C
`until all the drug is dissolved. The solution is then
`cooled to about 20 to 35°C prior to adding the karaya
`gum. Once the karaya gum is added, the final composition
`is applied to a suitable backing material such as a non(cid:173)
`woven polyester film (for example, the film sold under
`the trademark Sontara 8100, manufactured by DuPont de
`Nemours, Wilmington, DE) and warmed to about 100°c to
`accelerate the formation of the gel into its final,
`finite form.
`
`5
`
`10
`
`s-Aminolevulinic Acid
`
`ALA
`
`15
`
`Solvent (dipropylene glycol)
`
`Solvent (Oleic acid)
`
`Solvent (glycerin)
`
`Solvent (isocetyl alcohol)
`
`Bioadhesive (karaya gum)
`
`20
`
`Bioadhesive (xantham. gum)
`
`Binder (lecithin)
`
`'Niw/w
`
`'Niw/w
`
`'Niw/w
`
`'Niw/w
`
`'NJw/w
`
`2
`
`10
`
`10
`
`30
`-
`30
`-
`
`18
`
`s
`
`10
`
`10
`
`30
`-
`
`30
`-
`
`IS
`
`10
`
`IS
`
`10
`
`20
`
`10
`
`20
`
`10
`
`10
`
`lS
`
`lS
`
`10
`
`20
`
`10
`
`20
`
`10
`
`10
`
`20
`
`lS
`
`10
`
`30
`-
`
`30
`-
`-
`
`

`

`WO96/06602
`
`PCT/US95/10879
`
`-15-
`
`Example 3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`A thirty-two year old female is diagnosed with basal
`cell carcinoma. A single lesion is evident on her right
`forearm covering approximately 22 mm.2,
`and
`topical
`aminolevulinic acid photodynamic therapy {ALA PDT"') is
`prescribed.
`
`A 5 cm2 topical patch containing 10% (w/w) ALA, made
`according to Example 1 or 2, is applied to the lesion.
`The patch is left in place for 18 hours, which is
`sufficient to permit adequate penetration of ALA into the
`lesion and for
`the
`formation of protoporphyrin
`IX
`the
`active end product of
`topical ALA
`( "PpIX") ,
`administration.
`After the patch is removed, the lesion
`is wiped with an alcohol swab to remove any residual
`adhesive.
`
`The lesion is then exposed to activating UV light
`using a conventional Woods
`lamp to determine if the
`fluorescence levels, and hence the Pp IX levels, are
`sufficient. Finding the levels suitable, the lesion is
`then exposed to a 634 nm wavelength 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 at the treatment site. During the next several
`days, necrosis of the destroyed lesional cells ensues,
`resulting in the formation of a burn-like scab over the
`former lesion. During the next six weeks, normal healing
`of the treated tissue and restoration of intact skin is
`observed.
`
`The foregoing examples are illustrative embodiments
`of the invention and are merely exemplary. A person
`skilled in the art may make variations and modification
`without departing from the spirit and scope of the
`
`

`

`WO96/06602
`
`PCT/0S95/10879
`
`-16-
`
`invention. All such modifications and variations are
`intended to be included within the scope of the invention
`as described in this specification and the appended
`claims.
`
`

`

`WO96/06602
`
`PCT/0S95/10879
`
`-17-
`
`What Is claimed Is
`1.
`A pharmaceutical composition comprising:
`(i) a therapeutically effective amount of a &(cid:173)
`aminolevulinic acid or a pharmaceutical equivalent
`thereof; and
`(ii) a pharmaceutically acceptable, flexible,
`finite carrier for dermal application.
`
`The composition of claim 1, wherein said
`2.
`pharmaceutical equivalent is an ester of 6-aminolevulinic
`acid.
`
`The composition of claim 1, wherein said
`3.
`pharmaceutical equivalent is an amide of 6'-aminolevulinic
`acid.
`
`pharmaceutical composition of claim 1,
`The
`4.
`cS-aminolevulinic acid or pharmaceutical
`wherein said
`equivalent thereof is dispersed throughout the carrier.
`
`The pharmaceutical composition of claim 1,
`5.
`wherein said carrier is an adhesive.
`
`The pharmaceutical composition of claim 5,
`6.
`wherein said adhesive is a pressure-sens_itive adhesive.
`
`The pharmaceutical composition of claim 6,
`7.
`wherein said pressure sensitive adhesive is a bio(cid:173)
`adhesive.
`
`The pharmaceutical composition of claim 6,
`8.
`wherein said pressure sensitive adhesive is a polymeric
`adhesive selected from
`the group consisting of an
`a silicone-based adhesive, a vinyl acetate
`acrylic,
`and
`a natural or synthetic
`rubber-based
`adhesive
`adhesive, or mixtures thereof.
`
`

`

`WO96/06602
`
`PCT/US95/l 0879
`
`-18-
`
`The pharmaceutical composition of claim 5,
`9.
`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(cid:173)
`glucose.
`
`12. The pharm