CA2185440A1 - Methods for phototherapeutic treatment of proliferative skin diseases - Google Patents
Methods for phototherapeutic treatment of proliferative skin diseasesInfo
- Publication number
- CA2185440A1 CA2185440A1 CA002185440A CA2185440A CA2185440A1 CA 2185440 A1 CA2185440 A1 CA 2185440A1 CA 002185440 A CA002185440 A CA 002185440A CA 2185440 A CA2185440 A CA 2185440A CA 2185440 A1 CA2185440 A1 CA 2185440A1
- Authority
- CA
- Canada
- Prior art keywords
- skin
- affected
- dha
- affected areas
- sunscreen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/04—Preparations for care of the skin for chemically tanning the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0066—Psoralene-activated UV-A photochemotherapy (PUVA-therapy), e.g. for treatment of psoriasis or eczema, extracorporeal photopheresis with psoralens or fucocoumarins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
Abstract
Method for treating a proliferative skin disorder, such as psoriasis, in a human patient having affected and non-affected areas of skin. The method comprises the steps of: (1) topically applying a sunscreen providing photo-protection to the affected and non-affected areas of skin; (2) waiting for a time period sufficient for the skin of the affected areas to be substantially sloughed off; and, (3) exposing the affected and non-affected areas of skin of the patient to a selected level of optical radiation. The level of radiation is chosen to be sufficient to treat the affected treat of skin and insufficient to cause significant damage to the non-affected areas of skin. The method enhances effectiveness and safety of treatment by providing preferential photo-protection to the non-affected skin areas, and may be used for phototherapy, photochemotherapy, or photodynamic therapy.
Description
'0 95/2.1888 PCT/US95/03130 ~ 21 85440 METHODS FOR PHOTOTHERAPEUTIC ~l~F~MFNT OF PROLIFERATIVE
SKIN DISEASES
Field of the Invention This invention relates to treatment of psoriasis and other proliferative skin diseases using phototherapeutic techniques.
Backaround of the Invention Proliferative skin diseases, such as psoriasis, 10 eczema, mycosis fungoides, actinic keratosis, and lichen planus, are known to effect one to two percent of the U.s. population, with as many as 150,000-260,000 new cases occurring annually ("Research Needs in 11 Major Areas in Dermatology" I. Psoriasis. ~J. Invest. Dermatol.
15 73:402-13, 1979). One method used to treat the rapid proliferation of skin cells is phototherapy, which utilizes optical absorption of ultraviolet (W) radiation by the skin to kill rapidly growing cells and arrest proliferation. At present, both WA and WB therapy, 20 which expose the skin to W radiation between 320-400 nm (WA radiation) or 290-320 nm (WB radiation), are effective and widely used. PWA therapy, a form of photochemotherapy which involves repeated topical application of psoralen or a psoralen-based compound to 25 an affected region of skin, followed by exposure of that region to WA radiation, is also widely used. Another method used to treat proliferative skin diseases, particularly psoriasis and mycosis fungoides, is photodynamic therapy (PDT). In this method, a 30 photosensitizing agent, which is a drug selectively retained in carcinoma cells, is administered to a patient. Following absorption of light (typically between 320-700 nm, r9~ron~;ng on the drug) the photosensitizing agent undergoes a photochemical 35 reaction, resulting in the production of cytotoxic ~o gS/2~888 PCTIUS9S/03130 .
21 ~5440 singlet oxygen which eventually leads to tumor vessel destruction in the skin (Anderson, et al., Arch.
Dermatol. 128:1631-1636, lg92).
Prolonged treatment for proliferative skin 5 diseases using these types of therapies can, however, result in significant acute and chronic adverse effects I nr~ i ng erythema, pruritus, skin cancer, and chronic light-induced damage of the skin (Stern et al., N.l~. .T.
Med. 300:809-812, 1979).
It is therefore desirable to reduce the number of times the skin is exposed to radiation during phototherapy. PWA therapy (Wolff, Pharmacol. ~her.
12:381, 1981), and frequent alternation of PWA therapy with other treatments (Parris et al., ~he Science of 15 Photomedicine, Regan et al., eds., 1982, p. 615) have been suggested as methods to reduce the cumulative number of iterations (typically around 25) required for =
successful treatment. Another method used to decrease the number of phototherapy LL~; LS involves increasing 20 the optical fluence during therapy (Honigsmann et al., l~ermatology in General Medicines, 3rd ed, T.B.
Fitzpatrick et al., eds., 1533-1558, 1987; Ryatt, et al., J. Am. Acad. Dermatol. 9:558-562, 1983). Up to a threef old reduction in the time required f or the af f ected 25 region to clear is possible when isolated plaques are exposed to radiation levels between two and three times the minimal erythema dose (NED), defined as the level of optical f luence resulting in the onset of erythema (Parrish et al., .7. Invest. Dermatol. 76:359-362, 1981).
Because both WA and WB radiation are harmful to normal skin, the tolerable limit of treatment aggre6siveness is ultimately limited by adverse effects resulting from the cumulative exposure of the 6kin to W
radiation. Presently, the level of W radiation is kept WO 95/2-1888 PCT/~JS95103 130 as high as possible during phototherapeutic treatments, just less than the level causing painful sunburn.
In order to reduce the effects of increased exposure to W radiation during phototherapy, it is 5 possible, but impractical, to apply sunscreens to all the non-affected skin areas which aULL~Ulld sites of affected skin; most proliferative skin tl; c-o~c~c involve tens or hundreds of affected regions which are randomly located over the body. In addition, during PDT there is often 10 appreciable uptake of the photosensitizing agent in the non-affected regions of skin, making it desirable to protect these regions from drug-activating radiation.
SummarY of the Invention The present invention f eatures, in general, a 15 method for treating a proliferative 6kin disorder in a human patient having affected and non-affected areas of skin. The term "proliferative skin disorder", as used herein, refers to psoriasis, eczema, actinic keratosis, mycosis fungoides, lichen planus, and other disease6 20 resulting in rapid proliferation of skin cells.
The method of the present invention features the steps of: (a) topically applying a ::,UIIS~,Leell providing photo-protection to the affected and non-affected areas of skin; (b) waiting for a time period sufficient for the 25 skin of the affected areas to be sloughed off to a greater degree than skin of non-2ffected areas; and, (c) ~YpoS;n~ the affected and non-affected areas of skin of the patient to a selected level of optical radiation suf f icient to treat the af f ected areas of skin and 30 insufficient to cause significant damage to the non-af f ected areas of skin .
One essential feature of proliferative skin disorders that is used to advantage in the method of the present invention is that of hYper-proliferation of the 35 epidermis, the outer layer of skin. Affected regions of '0 9512~888 PCTIUS95/03130 21 ~440 skin grow and are sloughed of f at a rate of about ten times than that of non-affected regions. A topically-applied substancè, such as a sunscreen, adhering to the stratum corneum of the affected regions will therefore be 5 sloughed off much faster relative to sunscreen applied to the non-affected regions. After a prede~rr;n~d period of time, this results in the non-af f ected regions of skin retaining a large amount of sunscreen relative to the af f ected regions .
Preferably, between steps (b) and (c), the amount of photo-protection provided by the sunscreen to the affected and/or non-affected areas of the patient's skin is determined, e.g., using a non-invasive optical method involving measuring the reflectance properties of 15 sunscreen-treated skin. In alternate ~mho~ir-ntS, a photosensitizing agent, psoralen, or a psoralen-based ' is administered to the patient prior to step (c) .
The sunscreen preferably contains an active 20 compound, e.g. Dihydroxyacetone ("DHA"), which binds to portions of the stratum corneum to partially absorb optical radiation, most preferably in the spectral region between 290 - 400 nm. When a photosensitizing agent, psoralen, or a psoralen-based compound is administered to 25 the patient, the optical absorption of the active ~ is preferably in the spectral regime between 320 - 700 nm.
In preferred Prhorlir--Ls, the method of the present invention is used to treat psorias~is, mycosis 30 fungoides, eczema, actinic keratosis, or lichen planus.
other features and advantages of the invention will be apparent from the following description of the preferred ~rho~l i ts thereof, and from the claims .
~'0 ~5124888 PCT~S~510313(~
2~ ~5~4~
Brie~ Descri~tion of the Draw n~s Fig . l is a f luorescence microscopy photograph of a frozen sample of biopsied skin taken l day after being stained in vivo with DHA.
Fig. la is a fluorescence microscopy photograph of a frozen sample of biopsied skin taken 3 days after being stained in vivo with DHA.
Fig . lb is a f luorescence microscopy photograph of a frozen sample of unstained, biopsied skin.
Fig. 2 is a graph showing the fluorescence intensity of a skin sample stained with DEIA as a function of the number of tape strippings, each of which remove portions of the stratum corneum.
Fig. 3 shows a plot of the phototoxic protection 15 factor (PPF) as a function of DHA concentration applied to human skin.
Fig. 4 is a graph showing the change in optical density at 350 nm for DHA stained skin samples plotted as a function of the PPF provided by DE~A.
Fig. 5 is a graph showing the loss of fluorescence ~ntensity as a function of time in psoriatic (squares) and normal (triangles) skin samples stained with D~.
Fig. 5a is a graph showing the loss of fluorescence intensity as a function of time in psoriatic (squares) and normal (triangles) skin samples stained with dansyl chloride.
Fig. 6 is a graph showing the difference in fluor~ sc~l~c~ intensity between psoriatic and normal skin samples stained with DHA as a function of time.
Fig. 7 is a graph showing the action spectrum of 8-MOP, which illustrates the effectiveness of each optical wavelength to produce erythema in psoralen sensitized skin samples. The graph also shows the absorption spectrum of DEIA.
De~ Descri~tion of Invention WO 95/21888 PCTII,'S95103130 21 85~40 Su~-S~;-.e_..8 for PhototherApy The sunscreens used during the phototherapeutic method of the invention contain an active compound which exhibits desirable chemical and optical properties. By 5 desirable "chemical" properties is meant that the active compound must be of acceptable low toxicity and be able to adhere to both af f ected and non-af f ected regions of the skin. Furthermore, the active compound should be highly substantive, meaning that it is not easily washed 10 off, and should adhere to elements of the stratum corneum (e.g., keratin, other proteins, lipi~s, etc.) preferably through covalent bonding.
By desirable "optical" properties is meant that, once adhered to the skin, the active compound should have 15 a broad absorption spectrum in the W and/or visible fre~Iuency range, and should have the ability to absorb at least 50% of the incident radiation, and preferably 80 or more. The active compound should also not undergo photodegradation ~ollowing the absorption of light, and 20 should minimize hyperpigmentation of the skin during the phototherapy. Active cnmrolln~7C exhibiting desirable rhPm;cll and optical properties which can be incu~- L~ted into a moisturizing base to form sunscreens according to the invention are listed in Table 1.
25 T~bl~ 1 -- Active C _ A_ for ~ LS
r _ Concentration Absorbance permitted (96 by range (nm) weight) Glyceryl- 3.0 - 5.0 260 - 315 ~mi~obo~70~te WO 9512~888 PCT/US~103130 ~ 21 854~0 Amyl- 1.0 - 5_0 290 - 315 p-dimethylamino benz oate ( Padimate-A) 5 2-Ethyl-hexyl-p- 1. 4 - 8 . 0 290 - 315 dimethylamino benz oate (Padimate-0) 2-Ethoxy- 1. 0 - 3 . 0 270 - 328 10 ethylhexyl-p-methoxycinnamate ( cinnoxate ) 2, 2-Dihydroxy-4- 3 . 0 - 5. 0 260 - 380 methoxybenzophenone 15 (dioxybenzone) 2-Hydro~y-4- 2 . 0 - 6. 0 270 - 350 methoxy:: enzophenone ( oxybenz one ) 2-Elydroxy-4- 5.0 - 10.0 270 - 360 20 methoxyb~n70rh~nnn~
5-sulf onic acid (CIll; cn}-F~n70ne) 3, 3, 5-Trimethyl- 4 . 0 - 15. 0 290 - 315 cyclohexyl -25 salicylate (h~ - s -1 ~te) DillydLu~yclcetone 5.0 - 15.0 320 - 390 A pre~erred active - , .u.-d is D~A
(dillydLu~yllcetone)~ DHA is a colorless, naturally-30 occurring three carbon sugar (T~hn;n~r, Rint~h~mictry, ~'095/21888 PCT/059~103130 21 854~ --Worth Publishers, New York, 1970) which has been used topically f or the past three decades as the active ingredient in many popular "sunless tanning" products.
When applied topically, DHA penetrates superf icially into 5 the stratum corneum where it covalently binds to epidermal proteins via their amino groups, producing a co6metically-acceptable "tan" color which effectively photo-protects against visible light. DE~A also exhibits strong absorption of near ultraviolet optical radiation, 10 and is ~luorescent following the absorption of radiation.
TherApy The application of adherent sunscreens containing active ~u--ds is followed by a period during which preferential loss of skin in the affected regions (i.e., 15 the lesions) occurs because of rapid skin proliferation, leaving these regions with a lower concentration of the sunscreen relative to the non-affected regions. The affected regions of skin are thus left relatively unprotected from optical radiation during phototherapy or 20 PDT. By selectively protecting the non-affected skin, the method of the present invention allows: (1) more aggressive phototherapies, leading to an acceleration of the skin clearing process (Carabott et al., Clin. E~rp.
~ermatol. 14:337-340, 1989); (2) reduction in the 25 o~;~;uLL-:~-ce of sunburn, skin cancers, and other acute side ef f ects; and, ( 3 ) a decrease in the number of treatments nP~"cc~ry f or treating rapidly prolif erating skin (:I jC,~AC~C, thus simplifying the therapy. The method of the present invention therefore makes treatment of 30 affected skin using phototherapy, PDT or photochemotherapy both saf er and more ef f icient .
Sunscreen Interaction with the Stratum Corneum Following topical application, the sunscreens pref erably bind to proteins contained in the top cell 35 layers of the stratum corneum. Alternatively, they may wo 9S/2~888 PCTIU595/03130 g polymerize or bind with other components of the skin, such as lipids. In the case of DHA, this results in the formation of an oxidized compound which exhibits fluorescent behavior following the absorption of light 5 (Ellis Adv. Carbohydrate Chem. 14:63-135, 1959).
In order to determine the depth of staining, samples of psoriatic skin were treated with a single application of a 5% (by weight) solution of DE~ (0.2 cc/9 cm2) and then biopsied. Frozen sections of skin were lO prepared, and the fluorescence of DHA as a function of depth in the skin was measured using standard spectroscopy techniques after 1- and 3-day periods.
Referring now to Figs. l, la, and lb, fluorescence induced in the DHA stained skin after a 1-day period was 15 limited to the upper half of the stratum corneum. The intensity of the fluorescence was significantly reduced after a 3-day period due to sl-~n~h;n~ off of the stratum corneum. The fluorescence intensity of the stained skin samples was ~ ~1 with an unstained control sample in 2 O the study .
The depth of DHA penetration was also measured in a separate study by topically applying a solution of Dl~, waiting a period of time sufficient for DE~ to penetrate the stratum corneum, and finally peeling off layers of 25 skin with an adhesive tape while measuring the intensity o~ the induced fluorescence.
Using a topically-applied sunscreen, a thin layer of DHA was deposited on a section of the forearm of three normal volunteers. After allowing sufficient time for 30 the DHA to diffuse into the stratum corneum (4-6 hours) an adhesive tape was applied to the skin in the region of the applied sunscreen. Peeling of the tape resulted in the removal of approximately one layer of skin cells having a thickness of a~out O . 5 ,~m. The f luorescence 35 intensity of the resultant skin surface was measured non-~'O 951218%8 PCT/11595/03130 invasively after stripping each skin layer using standardspectroscopy techniquQs. The process was repeated, with the induced fluorescence intensity due to the presence of DH~ decreasing with each stripping. Fig. 2 illustrates 5 the linear relationship between the removal of skin layers and loss of fluorescence intensity, indicating that following application, DHA diffuses into the skin and stains the upper corneocyte layers unif ormly .
Complete loss of f luorescence occurred after stripping 10 away 25 layers of skin, equal to a depth of about 10 - 15 m, which is approximately the thickness of the human stratum corneum.
The ideal concentration of active compounds in sunscreens produces a highly photo-protective layer that 15 is bound just at the skin surf ace . Concentrations that are higher lead to excess amounts of the active compound binding within the stratum corneum, resulting in an increasQ in the time required for the active compound to be substantially shed, thus lengthening the time between 20 :,ulls~r~ell application and phototherapy. Although the stratum corneum of psoriatic skin is ~ h od of f at 8 times the rate of normal skin, it is also many times thicker. Therefore, active ~ _ ul-ds which bind throughout the stratum corneum result in a higher level 25 of staining, and may actually take longer to be completely sloughed off.
The desirable concentration of DHA or other active ts in sunscreen is def ined as that necessary to provide substantial photo-protection to normal skin. For 30 DHA, this was detF~rm;np~ by varying the DHA concentration and repeating the experiment described above, and was determined to be between 5 - 15% by weight. With different vehicles or agents which affect DHA staining of skin, lower concentrations may be used. Desirable concentrations of other active compounds in sunscreens are listed in Table l.
Because both the concentration of stratum corneum binding sites and kinetics of sloughing are expected to 5 change during the clearing phase of phototherapy, the concentration of the active compound may have to be selectively adjusted during treatment. Differential loss of the active compound from affected skin regions is typically marked in early treatments, but as the regions 10 clear, the rate of loss decreases and the active c ~- a is retained longer ~ Depending on the patient ~ the frequency of application and concentration of the active ul~d may therefore be changed during the course o phototherapy in accordance with the sloughing rates and 15 binding site changes of the skin. It is a routine matter to make such frequency and concentration adjustments using the guidance given herein.
Alternatively, a photosensitizing agent, psoralen, or a psoralen-based r ,_ ' may be administered to a 20 patient and used in combination with a topically-applied sunscreen ~ The ~ 1 c may be administered in one of the traditional modes (e.g. l orally, parenterally, trAnc~ l ly or triln, - ~l ly) ~ in a sustained-release formulation using a biodegradable, biocompatible polymer, 25 or by on-site delivery using micelles ~ gels and l ir--C~ --. Once administered, a sufficient time period is allowed to pass in order for the ~ to be selectively retained in affected skin regions.
Preferably, the compound is administered so that the 30 ratio of drug retained in the affected and non-affected regions is maximized at approximately the same time that the ratio of the amount of sunscreen covering these regions is minimized. This allows for efficient treatment of the affected regions of s in using PDT.
~'iO 9512-1888 PCTII~S95/03130 2~ 85440 Examples of photosensitizing agents which can be used in the method of the present invention include hematoporphyrin derivative (HPD), porf imer sodium (Photofrin), benzoporphyrin-derivative monoacid ring A
5 (BPD-MA), mono-1-aspartyl chlorin e6 (NPe6), chlor~ ;n~lm sulfonated phthalocyanine, and similar light-absorbing ~ q which are selectively retained in affected skin regions and become activated (i.e., undergo photochemical reactions to produce cytotoxic 10 singlet oxygen) following optical absorption. In addition, 5-aminolevulinic acid (ALA), a naturally-occurring precursor to the biosynth~i z~l porphryin Protoporphyrin IX, may be used a-s a photosensitizing agent. Examples of psoralen-based compounds which can be 15 used in the method of the present invention include 8-MOP
(methoxsalen, xanthotoxin~, 5-methoxypsoralen (5-MOP, bergaptin), 7-methylpyridopsoralen, isopsoralen, and other isomeric and chemical derivative f orms of psoralen .
Determination of OPtical Fluence Levels for Photothera~y The minimal erythema dose (MED) is the fluence, measured as energy per unit area, of radiation necessary to produce delayed erythema in a patient af ter irradiation. After receiving a photosensitizing agent, the amount of radiation needed to produce delayed 25 erythema is called the minimal phototoxic dose (MPD).
The phototoxic protection factor (PPF) refers to the ability of a sunscreen to protect the skin from photosensitized skin reactions, and is def ined as the ratio of the MEDs or MPDs f or skin protected with and 30 without a sunscreen. Thus, the PPF provided by a sunscreen f or a certain skin type can be determined by exposing the skin to W fluence high enough to induce erythema in treated and untreated skin regions, and then det~rmin;n~ the ratio of the optical fluences.
.
WO 95/2~8X8 PCTIU595103130 ~ 2~85440 Because the sunscreen acts as a passive optical attenuating filter, the PPF is also simply related to the transmittance of light through the stratum corneum of protected skin. Following application of a sunscreen, 5 accurate determination of the PPF for a particular skin sample allows the appropriate light level to be selected for phototherapy. Overestimation of the PPF may result in burning of the skin during treatment, while underestimation may reduce the effectiveness of 10 phototherapy, thus prolonging treatment.
The PPF of a skin sample can be accurately detPrm; nP~ using a non-invasive technique involving measuring the diffuse component of reflectance from a patient's skin (Wan et al., J. Photochem. Photobiol.
15 34:493-499, 1981; Kollias et al., 3iological Responses to WA Radlation, F. Ur~ach, ed., Valdenmar Pub. Co., overland Park, KS, 1992). It was determined for DH~
staining of skin that the PPF is approximately equal to the square root of the ratio of diffuse light reflected 20 from the skin before and after application of a sunscreen. The PPF can be expressed by the equation:
pPF = l~Ro/R~
Where Ro and R~ eel~ are the diffuse reflectance components of skin before and after application of a 25 sunscreen, respectively, at the wavelength of interest.
This result can also be expressed logarithmically as log PPF = 1/2 (oD8un8creen ~ ODo) a (/~OD) /2 (2) where OD i6 the apparent optical density of the skin def ined conventionally as OD = --logR (3) ~ ~o ~sl2~888 - PcTlussslo3l3o 21 ~544~ ~ `
where R is the diffuse reflectance at the wavelength of interest f or photoprotection .
The PPF can theref ore be measured by irradiating the surface o~ the 6kin with light having the appropriate 5 wavelength, measuring the reflected light with a suitable photodetector, and then estimating the PPF using equation ( 1 ) above .
A sunscreen including an active compound provides a specific PPF for the skin, and may also stain the skin 10 to a color depending on the skin type of the patient.
These two ~actors can be compared for various skin types, and a "color chart" can be established which correlates the level of staining with the provided PPF. This allows approximation of ~he PPF by simple inspection of the 15 level of skin staining, thus simplifying the procedure used to determine the appropriate level of optical radiation to be used during treatment.
~hO 9512~888 PCr/U595103130 21 8544~
O~tical Irr~A;~tion of the ~k;n Following the determination of the PPF and thc appropriate level of optical irradiation, therapy may be conducted with standard treatment units well known in the 5 art. For WB phototherapy, sources emitting wavelengths less then 320 nm are used. For WA and PWA therapy, such units typically include f luorescent bulbs capable of emitting optical radiation peaked near 355 nm. The intensities of WA doses are typically measured with 10 photodetectors having maximum sensitivities between 350 -360 nm. Within the area of treatment, the intensity of the radiation dose is kept relatively uniform. Infrared wavelengths emitted from the bul~ are typically filtered out bef ore reaching the area of treatment as they can 15 heat the skin, causing discomfort to the patient during the therapy. Further details of the d~ LuS used for phototherapeutic treatments can be found in Honigsmann et al., Dermatolo~y in General Medicines, 3rd ed, T.B.
Fitzpatrick et al., eds., 1728-1754, 1987.
When photosensitizing agents are used in combination with topically-applied sunscreens, the wavelength of the incident optical radiation must lie within the absorption spectrum of the photosensitizing agent. D~r~n~l; n7 on the drug used, this region is typically between 320-700 nm. Preferably, a laser, such as a tunable dye or solid-state laser, a metal vapor laser, or a diode laser, is used as the light source.
I.asers are often the most practical light source for treatment because their high power output at the 30 appropriate drug-activating wavelength can minimize e:~c~O~uLe times. In addition, laser light can easily be coupled into flexible optical fibers to simplify the delivery of light to the treatment region. Other light sources, such as fluuL~scell~ bulbs and solar simulators ~ 0 95l2~888 ~ ,~ 130 21 85440 ~
(Dougherty, et al., cancer ~es. 38:2628-2635, 1978) may also be used.
Experi~entJ~ l Results PPF Variation with the Concentration Pf the Active The ~PF provided by a sunscreen wil~ vary with the concentration of the active compound. In order to determine the dependence of the PPF provided by DHA as a function of concentration, 6 patients having skin types 10 ranging from I-IV were exposed to PWA therapy featuring optical f luence levels high enough to cause erythema .
Solutions containing 5%, 10~6 and 1596 DHI~ (by weight) were used as photo-protectants f or each patient, with a thin layer of solution at each concentration (0.2 cc/9 cm2) 15 applied to a different area of skin in each patient. The MPDs of the different areas were measured by exposing nine l cm2 sites in a single skin area to incrementally increased doses of WA radiation, with the radiation being centered near 365 nm. Comparison of the MPDs from 20 these areas with the MPD from an area free of DHA allowed determination of the PPF, which could then be related to DHA concentration.
Ref erring to Fig . 3, the linear relationship between DHA concentration and PPF illustrates the 25 increase in the protection against erythema provided by increasing concentrations of DHA. The rising slope of the data in the plot also indicates an absence of saturation occurring in the D~ absorption, suggesting that even higher concentrations of DHA may result in 3 0 better protection against WA wavelengths .
The PPF provided by DHA was also predicted using the non-invasive optical mea~u, t described above.
Experiments were conducted on two sunscreens by measuring the fluorescence excitation spectra of skin samples 35 covered with a thin layer of sunscreen. Mea,,uL ts WO 95/2iJ888 PCT~S95103130 ~ 21 85440 were taken non-invasively by scanning the wavelength of an excitation light-source, followed by detection skin f luorescence at a single wavelength (l;~an et al ., .T .
Photochem . Photo~iol . 34: 493-499, 1981) . The sunscreens 5 u6ed f or experiments f eatured as an active compound either DHA or dansyl chloride, a fluorescent molecule commonly used in standard assays of corneocyte sloughing kinetics tTAk Ih~:hi et al., J. Soc. Cosmetic Chem.
38:321-331, 1987; Marks, Cutaneous Investigation in 10 ~ealth and Disease, Leveque ed., Mercel Dekker, Paris, 33-47, 1989). A Spex fluorometer featuring an excitation light source and a monochrometer was f itted with an optical fiber bundle (Spex industries, Edison, NJ) in order to deliver optical radiation to the sample of 15 interest. Excitation wavelengths were chosen to match the peak of the absorption spectra of either DHA (350 nm) or dansyl chloride (335 nm). The excitation light was passed through the monochrometer (4 nm h~n~lr~c~) and into one arm of the fiber bundle, and used to irradiate the 20 skin. Fluorescence from the skin was collected by the same fiber and passed through an emission mono- llL, -ter (4 nm bandpass) and into a detector. Excitation spectra were measured at the peak of the emission spectrum of either DHA (500 nm) or dansyl chloride (465 nm), and were 25 corrected for a weak background of auto-fluorescence due to emission from unstained skin. The same in:,-L L was used to measure skin ref l Prt~nre spectra by setting the excitation and emission monochrometers to the same wavelength. By comparing the incident optical intensity 30 with induced fluorescence or reflected intensity, the optical density of the active compound at the absorbing wavelength was ~lPtPrmi n~(l, Ref erring now to Fig . 4, the change in OD, as defined in equation 3, was detrrm;nPd at 350 nm in 35 various skin sites of living human volunteers stained ~o 9511~888 PCTIUS95/03130 with DHA, and is plotted as a function of the PPF. The PPF was determined by exposing the same skin sites to radiation at 350 nm after ingestion of 8-methoxypsoralen ( 8-MOP) . The solid line in the graph is the f it of the 5 data to equation 2. The agreement between the data and the f it indicates the ability of the skin ref lectance method of the present invention to accurately predict the PPF provided by an applied sunscreen using a simple, non-invasive measurement.
10 Ral)id Desquamation of the Skin Stratum corneum sloughing was investigated by monitoring the time-dependent decrease in f luorescence intensity from the skin after topical application of a sunscreen. Referring now to Figs. 5 and 5a, the time-15 depond~nt fluorescence intensities of psoriatic and non-affected skin samples stained with sunscreens inc111d;n~
either D~1~ or dansyl chloride were compared. The induced f luorescence intensity is decreased faster from psoriatic plaques stained with DHa, with the D~A being completely 20 shed from the skin ~prrn~;r-tely 96 hours after àpplication. In contrast, the dansyl chloride stain takes a longer period of time to be shed from the psoriatic skin. The rapid decrease in the time-dependent fluorescence intensity induced in psoriatic skin stained 25 with DH~ implies a more superf icial binding of DHA to the stratum corneum in comparison with dansyl chloride.
Thus, DE~-containing sunscreens allow for effective phototherapeutic treatments to be carried out over a shorter time period, e.g~, 72 hours after application.
Referring now to Fig~ 6, the difference in induced fluorescence intensity between psoriatic and non-affected skin stained with DHA is shown to be greatest after 72 hours. The level of fluorescence intensity is directly correlated with the concentration of DHA bound to the 35 skin sample. Thus, the peak in the data of Fig. 4 at 72 Wo 95/2i~888 ~ ~ 8 ` 4 4 0 PCr/US95103130 hours implies a time marking the maximum difference between the level of protection provided by DHA to psoriatic and non-affected skin. During a phototherapeutic treatment, an approximately 72-hour time 5 period separating the application of DHA and exposure of the skin to optical radiation will result in the optimization of the conditions for phototherapy. The natural sloughing of f process of the psoriatic tissue leaves affected regions with minimal DHA protection, l0 while non-affected skin is relatively well protected from optical radiation. This allows higher optical fluences to be used during the phototherapy, thus accelerating the treatment of the psoriatic condition. It should be noted that active means for desquamating stratum corneum can be 15 used to increase the rate at which sunscreens containing DHA or other active _ u1.ds are shed from the skin . In particular, alpha-hydroxy acids, such as lactic acid, are effective desquamating agents. When applied before, during, or after application of a highly-subst2ntive 20 sunscreen, the period of time required for los~ of the sunscreen will be reduced. Physical means to remove the skin may also be used.
lJse of nTr~; n Photothera~Y
Referring now to Fig. 7, the absorption spectrum 25 of DHA-stained skin extends from roughly 300-600 nm, and is peaked near 350 nm. The DHA staining i5 a yellow-brown or orange color, and is generally cosmetically acccptable because it mimics natural tanned skin. In Fig. 7, the absorption spectrum is plotted with the 30 action spectrum of 8-MOP, which indicates the effectiveness of each wavelength of light to produce delayed erythema in psoralen-sensitized patients. Thus, during PWA therapy, the skin is typically most sensitive to optical wavelengths near 320 to 330 nm. The overlap 35 of the two spectra indicates that the active and most WO 9512 :8X8 PCTIUS95/03130 harmful optlcal wavelengths used in PWA therapy will be pref erentially absorbed by DHA . The absorption spectrum of other compounds listed in Table 1, in particular 2- _ Ethoxy-ethylhexyl-p-methoxycinnamate (cinnoxate), 2 , 2-5 Dihydroxy-4-methoxybenzophenone (dioxybenzone), 2-Hydroxy-4-methoxybenzophenone (oxybenzone), and 2-Hydroxy-4-methoxybenzophenone-5-sulfonic acid (sulisobenzone) are also peaked near 320 nm. Thus, these compounds will also function as particularly effective 10 photo-protectants during WA phototherapy.
Referring again to the DHA absorption spectrum plotted in Fig. 7, it is evident that conventional DHA
preparations have poor absorbance in the WB range (Levy, J. Am. Acad. Dermatol. 27:989-993, 1992). DHA absorbance 15 is pH dependent, and a colored yellow product has been observed to appear at high, but still safe, pH levels in the human skin. This implies a shift in the absorption ~e~i~LUL~ toward 300 nm for DHA incorporated in high pH
environments . A high pH DHA preparation may theref ore be 20 used in a sunscreen as a WB photo-protectant. An effective sunscreen for WB phototherapy can alsD be made by using an increased concentration of DHA, resulting in a higher optical absorbance at wavelengths near 320 nm.
Alternatively, active compounds such as Glyceryl-25 Am;nnb~n7oate~ Amyl-p-dimethylamino benzoate (Padimate-A), 2-Ethyl-hexyl-p-dimethylamino benzoate (Padimate-O), and 3, 3, 5-Trimethyl-cyclohexyl-salicylate (h' - 1 Ate), which are listed in Table 1, absorb light having wavelengths closer to the WB range. These active 30 _ ,olln~c:, when included in highly-substantive sunscreens, are useful photo-protectants.
Following administration of a photosensitizing agent, there is often appreciable uptake of the drug in the non-affected regions of skin, making it necessary to 35 attenuate optical radiation incident on these regions WO 95/2~8~ PCTnJS95~03130 21 854~3 during therapy . It is theref ore desirable to use a sunscreen containing an active component having substantial optical absorption at the drug-activating wavelength of the light source . Ref erring again to Fig .
5 7, DHA-stained skin exhibits partial optical absorption between 320-600 nm, and thus can be used in combination with a variety of photosensitizing agents for treatment of affected regions of skin. Other active compounds partially absorbing light in this spectral regime could 10 also be used as useful photo-protectants.
~xample 1 - Phototherapeutic Treatment of Psoriasi5 Using ~U~ L~_ ~S Tnt~lu~ir~ DHA
With the information obtained from the above studies, aggressive PWA therapy using ~ulls~:Le:ells 15 ;n~ rl;n~ DHA was initiated in twelve patients having chronic plague psoriasis on greater than 30% of their body surfaces. The subjects had previously failed less aggressive therapies using topical corticosteroids or WB
radiation, and had received no treatments in the previous 2 0 f our weeks . PWA therapy was administered according to standard protocol (Melski et al., .J. Invest. Derlzlatol.
68:328, 1977). On one side of each patient, a solution containing 1596 DHA was applied 72 hours before each treatment to allow for differential qherl~lin~ of DHA from 25 the psoriatic skin. During each visit, skin reflectance was measured in the DHA protected site, and the PPF was estimated. The light dosage applied to the DHA side was increased by a factor equivalent to the PPF value so that non-affected skin on each side of the patient was 30 subjected to the same effective optical fluence. For example, if the dose without DHA was 4 J/cm2, and the DHA
provided a PPF - 5 for the stained site, then a dose of 20 J/cm2 was given to the skin stained with DHA. Because the skin on the DHA side is preferentially sloughed off 35 in the psoriatic regions, these region~ of psoriatic ~'O 95l2~888 PCT~S95/03130 21 ~5440 plaques were therefore subjected-to a substantially higher dose of optical radiation. The Psoriasis Activity and Severity Index (PASI score) (Fredriksson et al., U.
Dermatologica 157:238-244, 1978) was recorded weekly in 5 order to f ollow the clinical response . The study endpoint was 90-100% clearance in all treated sites.
No phototoxic erythema was observed on the DHA
6ide of patients completing the study, despite very high WA doses of up to Z5 Jtcm2 in a single treatment. PPF~s 10 as high as lO were found with mu1tiple repeated applications of DHA. A11 patients reported a persistent .,~ t in the psoriatic condition in the DHA treated site. In the f irst 5 patients, the mean number of treatments n~C-occ~ry for clearance of psoriasis was 15 12.4+5.77. These data, when compared to the unstained control skin necessitating 20-25 treatments for clearance of psoriasis, reflect the; LIV~ Ls of the method of the present invention (Melski et al., J. Invest.
Dermatol. 68:328, 1977). It is apparent from PASI scores 20 that the DHA treated sites cleared faster during the early weeks of treatment. After several treatments, it was noted that psoriatic skin began to retain the DHA
longer than 3 days, producing unwanted WA protection on the plaques due to a decrease in the epidermal turnover 25 rate as the plaques began to heal.
The foregoing descriptions of the preferred method of the present invention has been presented f or purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise 30 form disclo6ed.
.
what is claimed is:
SKIN DISEASES
Field of the Invention This invention relates to treatment of psoriasis and other proliferative skin diseases using phototherapeutic techniques.
Backaround of the Invention Proliferative skin diseases, such as psoriasis, 10 eczema, mycosis fungoides, actinic keratosis, and lichen planus, are known to effect one to two percent of the U.s. population, with as many as 150,000-260,000 new cases occurring annually ("Research Needs in 11 Major Areas in Dermatology" I. Psoriasis. ~J. Invest. Dermatol.
15 73:402-13, 1979). One method used to treat the rapid proliferation of skin cells is phototherapy, which utilizes optical absorption of ultraviolet (W) radiation by the skin to kill rapidly growing cells and arrest proliferation. At present, both WA and WB therapy, 20 which expose the skin to W radiation between 320-400 nm (WA radiation) or 290-320 nm (WB radiation), are effective and widely used. PWA therapy, a form of photochemotherapy which involves repeated topical application of psoralen or a psoralen-based compound to 25 an affected region of skin, followed by exposure of that region to WA radiation, is also widely used. Another method used to treat proliferative skin diseases, particularly psoriasis and mycosis fungoides, is photodynamic therapy (PDT). In this method, a 30 photosensitizing agent, which is a drug selectively retained in carcinoma cells, is administered to a patient. Following absorption of light (typically between 320-700 nm, r9~ron~;ng on the drug) the photosensitizing agent undergoes a photochemical 35 reaction, resulting in the production of cytotoxic ~o gS/2~888 PCTIUS9S/03130 .
21 ~5440 singlet oxygen which eventually leads to tumor vessel destruction in the skin (Anderson, et al., Arch.
Dermatol. 128:1631-1636, lg92).
Prolonged treatment for proliferative skin 5 diseases using these types of therapies can, however, result in significant acute and chronic adverse effects I nr~ i ng erythema, pruritus, skin cancer, and chronic light-induced damage of the skin (Stern et al., N.l~. .T.
Med. 300:809-812, 1979).
It is therefore desirable to reduce the number of times the skin is exposed to radiation during phototherapy. PWA therapy (Wolff, Pharmacol. ~her.
12:381, 1981), and frequent alternation of PWA therapy with other treatments (Parris et al., ~he Science of 15 Photomedicine, Regan et al., eds., 1982, p. 615) have been suggested as methods to reduce the cumulative number of iterations (typically around 25) required for =
successful treatment. Another method used to decrease the number of phototherapy LL~; LS involves increasing 20 the optical fluence during therapy (Honigsmann et al., l~ermatology in General Medicines, 3rd ed, T.B.
Fitzpatrick et al., eds., 1533-1558, 1987; Ryatt, et al., J. Am. Acad. Dermatol. 9:558-562, 1983). Up to a threef old reduction in the time required f or the af f ected 25 region to clear is possible when isolated plaques are exposed to radiation levels between two and three times the minimal erythema dose (NED), defined as the level of optical f luence resulting in the onset of erythema (Parrish et al., .7. Invest. Dermatol. 76:359-362, 1981).
Because both WA and WB radiation are harmful to normal skin, the tolerable limit of treatment aggre6siveness is ultimately limited by adverse effects resulting from the cumulative exposure of the 6kin to W
radiation. Presently, the level of W radiation is kept WO 95/2-1888 PCT/~JS95103 130 as high as possible during phototherapeutic treatments, just less than the level causing painful sunburn.
In order to reduce the effects of increased exposure to W radiation during phototherapy, it is 5 possible, but impractical, to apply sunscreens to all the non-affected skin areas which aULL~Ulld sites of affected skin; most proliferative skin tl; c-o~c~c involve tens or hundreds of affected regions which are randomly located over the body. In addition, during PDT there is often 10 appreciable uptake of the photosensitizing agent in the non-affected regions of skin, making it desirable to protect these regions from drug-activating radiation.
SummarY of the Invention The present invention f eatures, in general, a 15 method for treating a proliferative 6kin disorder in a human patient having affected and non-affected areas of skin. The term "proliferative skin disorder", as used herein, refers to psoriasis, eczema, actinic keratosis, mycosis fungoides, lichen planus, and other disease6 20 resulting in rapid proliferation of skin cells.
The method of the present invention features the steps of: (a) topically applying a ::,UIIS~,Leell providing photo-protection to the affected and non-affected areas of skin; (b) waiting for a time period sufficient for the 25 skin of the affected areas to be sloughed off to a greater degree than skin of non-2ffected areas; and, (c) ~YpoS;n~ the affected and non-affected areas of skin of the patient to a selected level of optical radiation suf f icient to treat the af f ected areas of skin and 30 insufficient to cause significant damage to the non-af f ected areas of skin .
One essential feature of proliferative skin disorders that is used to advantage in the method of the present invention is that of hYper-proliferation of the 35 epidermis, the outer layer of skin. Affected regions of '0 9512~888 PCTIUS95/03130 21 ~440 skin grow and are sloughed of f at a rate of about ten times than that of non-affected regions. A topically-applied substancè, such as a sunscreen, adhering to the stratum corneum of the affected regions will therefore be 5 sloughed off much faster relative to sunscreen applied to the non-affected regions. After a prede~rr;n~d period of time, this results in the non-af f ected regions of skin retaining a large amount of sunscreen relative to the af f ected regions .
Preferably, between steps (b) and (c), the amount of photo-protection provided by the sunscreen to the affected and/or non-affected areas of the patient's skin is determined, e.g., using a non-invasive optical method involving measuring the reflectance properties of 15 sunscreen-treated skin. In alternate ~mho~ir-ntS, a photosensitizing agent, psoralen, or a psoralen-based ' is administered to the patient prior to step (c) .
The sunscreen preferably contains an active 20 compound, e.g. Dihydroxyacetone ("DHA"), which binds to portions of the stratum corneum to partially absorb optical radiation, most preferably in the spectral region between 290 - 400 nm. When a photosensitizing agent, psoralen, or a psoralen-based compound is administered to 25 the patient, the optical absorption of the active ~ is preferably in the spectral regime between 320 - 700 nm.
In preferred Prhorlir--Ls, the method of the present invention is used to treat psorias~is, mycosis 30 fungoides, eczema, actinic keratosis, or lichen planus.
other features and advantages of the invention will be apparent from the following description of the preferred ~rho~l i ts thereof, and from the claims .
~'0 ~5124888 PCT~S~510313(~
2~ ~5~4~
Brie~ Descri~tion of the Draw n~s Fig . l is a f luorescence microscopy photograph of a frozen sample of biopsied skin taken l day after being stained in vivo with DHA.
Fig. la is a fluorescence microscopy photograph of a frozen sample of biopsied skin taken 3 days after being stained in vivo with DHA.
Fig . lb is a f luorescence microscopy photograph of a frozen sample of unstained, biopsied skin.
Fig. 2 is a graph showing the fluorescence intensity of a skin sample stained with DEIA as a function of the number of tape strippings, each of which remove portions of the stratum corneum.
Fig. 3 shows a plot of the phototoxic protection 15 factor (PPF) as a function of DHA concentration applied to human skin.
Fig. 4 is a graph showing the change in optical density at 350 nm for DHA stained skin samples plotted as a function of the PPF provided by DE~A.
Fig. 5 is a graph showing the loss of fluorescence ~ntensity as a function of time in psoriatic (squares) and normal (triangles) skin samples stained with D~.
Fig. 5a is a graph showing the loss of fluorescence intensity as a function of time in psoriatic (squares) and normal (triangles) skin samples stained with dansyl chloride.
Fig. 6 is a graph showing the difference in fluor~ sc~l~c~ intensity between psoriatic and normal skin samples stained with DHA as a function of time.
Fig. 7 is a graph showing the action spectrum of 8-MOP, which illustrates the effectiveness of each optical wavelength to produce erythema in psoralen sensitized skin samples. The graph also shows the absorption spectrum of DEIA.
De~ Descri~tion of Invention WO 95/21888 PCTII,'S95103130 21 85~40 Su~-S~;-.e_..8 for PhototherApy The sunscreens used during the phototherapeutic method of the invention contain an active compound which exhibits desirable chemical and optical properties. By 5 desirable "chemical" properties is meant that the active compound must be of acceptable low toxicity and be able to adhere to both af f ected and non-af f ected regions of the skin. Furthermore, the active compound should be highly substantive, meaning that it is not easily washed 10 off, and should adhere to elements of the stratum corneum (e.g., keratin, other proteins, lipi~s, etc.) preferably through covalent bonding.
By desirable "optical" properties is meant that, once adhered to the skin, the active compound should have 15 a broad absorption spectrum in the W and/or visible fre~Iuency range, and should have the ability to absorb at least 50% of the incident radiation, and preferably 80 or more. The active compound should also not undergo photodegradation ~ollowing the absorption of light, and 20 should minimize hyperpigmentation of the skin during the phototherapy. Active cnmrolln~7C exhibiting desirable rhPm;cll and optical properties which can be incu~- L~ted into a moisturizing base to form sunscreens according to the invention are listed in Table 1.
25 T~bl~ 1 -- Active C _ A_ for ~ LS
r _ Concentration Absorbance permitted (96 by range (nm) weight) Glyceryl- 3.0 - 5.0 260 - 315 ~mi~obo~70~te WO 9512~888 PCT/US~103130 ~ 21 854~0 Amyl- 1.0 - 5_0 290 - 315 p-dimethylamino benz oate ( Padimate-A) 5 2-Ethyl-hexyl-p- 1. 4 - 8 . 0 290 - 315 dimethylamino benz oate (Padimate-0) 2-Ethoxy- 1. 0 - 3 . 0 270 - 328 10 ethylhexyl-p-methoxycinnamate ( cinnoxate ) 2, 2-Dihydroxy-4- 3 . 0 - 5. 0 260 - 380 methoxybenzophenone 15 (dioxybenzone) 2-Hydro~y-4- 2 . 0 - 6. 0 270 - 350 methoxy:: enzophenone ( oxybenz one ) 2-Elydroxy-4- 5.0 - 10.0 270 - 360 20 methoxyb~n70rh~nnn~
5-sulf onic acid (CIll; cn}-F~n70ne) 3, 3, 5-Trimethyl- 4 . 0 - 15. 0 290 - 315 cyclohexyl -25 salicylate (h~ - s -1 ~te) DillydLu~yclcetone 5.0 - 15.0 320 - 390 A pre~erred active - , .u.-d is D~A
(dillydLu~yllcetone)~ DHA is a colorless, naturally-30 occurring three carbon sugar (T~hn;n~r, Rint~h~mictry, ~'095/21888 PCT/059~103130 21 854~ --Worth Publishers, New York, 1970) which has been used topically f or the past three decades as the active ingredient in many popular "sunless tanning" products.
When applied topically, DHA penetrates superf icially into 5 the stratum corneum where it covalently binds to epidermal proteins via their amino groups, producing a co6metically-acceptable "tan" color which effectively photo-protects against visible light. DE~A also exhibits strong absorption of near ultraviolet optical radiation, 10 and is ~luorescent following the absorption of radiation.
TherApy The application of adherent sunscreens containing active ~u--ds is followed by a period during which preferential loss of skin in the affected regions (i.e., 15 the lesions) occurs because of rapid skin proliferation, leaving these regions with a lower concentration of the sunscreen relative to the non-affected regions. The affected regions of skin are thus left relatively unprotected from optical radiation during phototherapy or 20 PDT. By selectively protecting the non-affected skin, the method of the present invention allows: (1) more aggressive phototherapies, leading to an acceleration of the skin clearing process (Carabott et al., Clin. E~rp.
~ermatol. 14:337-340, 1989); (2) reduction in the 25 o~;~;uLL-:~-ce of sunburn, skin cancers, and other acute side ef f ects; and, ( 3 ) a decrease in the number of treatments nP~"cc~ry f or treating rapidly prolif erating skin (:I jC,~AC~C, thus simplifying the therapy. The method of the present invention therefore makes treatment of 30 affected skin using phototherapy, PDT or photochemotherapy both saf er and more ef f icient .
Sunscreen Interaction with the Stratum Corneum Following topical application, the sunscreens pref erably bind to proteins contained in the top cell 35 layers of the stratum corneum. Alternatively, they may wo 9S/2~888 PCTIU595/03130 g polymerize or bind with other components of the skin, such as lipids. In the case of DHA, this results in the formation of an oxidized compound which exhibits fluorescent behavior following the absorption of light 5 (Ellis Adv. Carbohydrate Chem. 14:63-135, 1959).
In order to determine the depth of staining, samples of psoriatic skin were treated with a single application of a 5% (by weight) solution of DE~ (0.2 cc/9 cm2) and then biopsied. Frozen sections of skin were lO prepared, and the fluorescence of DHA as a function of depth in the skin was measured using standard spectroscopy techniques after 1- and 3-day periods.
Referring now to Figs. l, la, and lb, fluorescence induced in the DHA stained skin after a 1-day period was 15 limited to the upper half of the stratum corneum. The intensity of the fluorescence was significantly reduced after a 3-day period due to sl-~n~h;n~ off of the stratum corneum. The fluorescence intensity of the stained skin samples was ~ ~1 with an unstained control sample in 2 O the study .
The depth of DHA penetration was also measured in a separate study by topically applying a solution of Dl~, waiting a period of time sufficient for DE~ to penetrate the stratum corneum, and finally peeling off layers of 25 skin with an adhesive tape while measuring the intensity o~ the induced fluorescence.
Using a topically-applied sunscreen, a thin layer of DHA was deposited on a section of the forearm of three normal volunteers. After allowing sufficient time for 30 the DHA to diffuse into the stratum corneum (4-6 hours) an adhesive tape was applied to the skin in the region of the applied sunscreen. Peeling of the tape resulted in the removal of approximately one layer of skin cells having a thickness of a~out O . 5 ,~m. The f luorescence 35 intensity of the resultant skin surface was measured non-~'O 951218%8 PCT/11595/03130 invasively after stripping each skin layer using standardspectroscopy techniquQs. The process was repeated, with the induced fluorescence intensity due to the presence of DH~ decreasing with each stripping. Fig. 2 illustrates 5 the linear relationship between the removal of skin layers and loss of fluorescence intensity, indicating that following application, DHA diffuses into the skin and stains the upper corneocyte layers unif ormly .
Complete loss of f luorescence occurred after stripping 10 away 25 layers of skin, equal to a depth of about 10 - 15 m, which is approximately the thickness of the human stratum corneum.
The ideal concentration of active compounds in sunscreens produces a highly photo-protective layer that 15 is bound just at the skin surf ace . Concentrations that are higher lead to excess amounts of the active compound binding within the stratum corneum, resulting in an increasQ in the time required for the active compound to be substantially shed, thus lengthening the time between 20 :,ulls~r~ell application and phototherapy. Although the stratum corneum of psoriatic skin is ~ h od of f at 8 times the rate of normal skin, it is also many times thicker. Therefore, active ~ _ ul-ds which bind throughout the stratum corneum result in a higher level 25 of staining, and may actually take longer to be completely sloughed off.
The desirable concentration of DHA or other active ts in sunscreen is def ined as that necessary to provide substantial photo-protection to normal skin. For 30 DHA, this was detF~rm;np~ by varying the DHA concentration and repeating the experiment described above, and was determined to be between 5 - 15% by weight. With different vehicles or agents which affect DHA staining of skin, lower concentrations may be used. Desirable concentrations of other active compounds in sunscreens are listed in Table l.
Because both the concentration of stratum corneum binding sites and kinetics of sloughing are expected to 5 change during the clearing phase of phototherapy, the concentration of the active compound may have to be selectively adjusted during treatment. Differential loss of the active compound from affected skin regions is typically marked in early treatments, but as the regions 10 clear, the rate of loss decreases and the active c ~- a is retained longer ~ Depending on the patient ~ the frequency of application and concentration of the active ul~d may therefore be changed during the course o phototherapy in accordance with the sloughing rates and 15 binding site changes of the skin. It is a routine matter to make such frequency and concentration adjustments using the guidance given herein.
Alternatively, a photosensitizing agent, psoralen, or a psoralen-based r ,_ ' may be administered to a 20 patient and used in combination with a topically-applied sunscreen ~ The ~ 1 c may be administered in one of the traditional modes (e.g. l orally, parenterally, trAnc~ l ly or triln, - ~l ly) ~ in a sustained-release formulation using a biodegradable, biocompatible polymer, 25 or by on-site delivery using micelles ~ gels and l ir--C~ --. Once administered, a sufficient time period is allowed to pass in order for the ~ to be selectively retained in affected skin regions.
Preferably, the compound is administered so that the 30 ratio of drug retained in the affected and non-affected regions is maximized at approximately the same time that the ratio of the amount of sunscreen covering these regions is minimized. This allows for efficient treatment of the affected regions of s in using PDT.
~'iO 9512-1888 PCTII~S95/03130 2~ 85440 Examples of photosensitizing agents which can be used in the method of the present invention include hematoporphyrin derivative (HPD), porf imer sodium (Photofrin), benzoporphyrin-derivative monoacid ring A
5 (BPD-MA), mono-1-aspartyl chlorin e6 (NPe6), chlor~ ;n~lm sulfonated phthalocyanine, and similar light-absorbing ~ q which are selectively retained in affected skin regions and become activated (i.e., undergo photochemical reactions to produce cytotoxic 10 singlet oxygen) following optical absorption. In addition, 5-aminolevulinic acid (ALA), a naturally-occurring precursor to the biosynth~i z~l porphryin Protoporphyrin IX, may be used a-s a photosensitizing agent. Examples of psoralen-based compounds which can be 15 used in the method of the present invention include 8-MOP
(methoxsalen, xanthotoxin~, 5-methoxypsoralen (5-MOP, bergaptin), 7-methylpyridopsoralen, isopsoralen, and other isomeric and chemical derivative f orms of psoralen .
Determination of OPtical Fluence Levels for Photothera~y The minimal erythema dose (MED) is the fluence, measured as energy per unit area, of radiation necessary to produce delayed erythema in a patient af ter irradiation. After receiving a photosensitizing agent, the amount of radiation needed to produce delayed 25 erythema is called the minimal phototoxic dose (MPD).
The phototoxic protection factor (PPF) refers to the ability of a sunscreen to protect the skin from photosensitized skin reactions, and is def ined as the ratio of the MEDs or MPDs f or skin protected with and 30 without a sunscreen. Thus, the PPF provided by a sunscreen f or a certain skin type can be determined by exposing the skin to W fluence high enough to induce erythema in treated and untreated skin regions, and then det~rmin;n~ the ratio of the optical fluences.
.
WO 95/2~8X8 PCTIU595103130 ~ 2~85440 Because the sunscreen acts as a passive optical attenuating filter, the PPF is also simply related to the transmittance of light through the stratum corneum of protected skin. Following application of a sunscreen, 5 accurate determination of the PPF for a particular skin sample allows the appropriate light level to be selected for phototherapy. Overestimation of the PPF may result in burning of the skin during treatment, while underestimation may reduce the effectiveness of 10 phototherapy, thus prolonging treatment.
The PPF of a skin sample can be accurately detPrm; nP~ using a non-invasive technique involving measuring the diffuse component of reflectance from a patient's skin (Wan et al., J. Photochem. Photobiol.
15 34:493-499, 1981; Kollias et al., 3iological Responses to WA Radlation, F. Ur~ach, ed., Valdenmar Pub. Co., overland Park, KS, 1992). It was determined for DH~
staining of skin that the PPF is approximately equal to the square root of the ratio of diffuse light reflected 20 from the skin before and after application of a sunscreen. The PPF can be expressed by the equation:
pPF = l~Ro/R~
Where Ro and R~ eel~ are the diffuse reflectance components of skin before and after application of a 25 sunscreen, respectively, at the wavelength of interest.
This result can also be expressed logarithmically as log PPF = 1/2 (oD8un8creen ~ ODo) a (/~OD) /2 (2) where OD i6 the apparent optical density of the skin def ined conventionally as OD = --logR (3) ~ ~o ~sl2~888 - PcTlussslo3l3o 21 ~544~ ~ `
where R is the diffuse reflectance at the wavelength of interest f or photoprotection .
The PPF can theref ore be measured by irradiating the surface o~ the 6kin with light having the appropriate 5 wavelength, measuring the reflected light with a suitable photodetector, and then estimating the PPF using equation ( 1 ) above .
A sunscreen including an active compound provides a specific PPF for the skin, and may also stain the skin 10 to a color depending on the skin type of the patient.
These two ~actors can be compared for various skin types, and a "color chart" can be established which correlates the level of staining with the provided PPF. This allows approximation of ~he PPF by simple inspection of the 15 level of skin staining, thus simplifying the procedure used to determine the appropriate level of optical radiation to be used during treatment.
~hO 9512~888 PCr/U595103130 21 8544~
O~tical Irr~A;~tion of the ~k;n Following the determination of the PPF and thc appropriate level of optical irradiation, therapy may be conducted with standard treatment units well known in the 5 art. For WB phototherapy, sources emitting wavelengths less then 320 nm are used. For WA and PWA therapy, such units typically include f luorescent bulbs capable of emitting optical radiation peaked near 355 nm. The intensities of WA doses are typically measured with 10 photodetectors having maximum sensitivities between 350 -360 nm. Within the area of treatment, the intensity of the radiation dose is kept relatively uniform. Infrared wavelengths emitted from the bul~ are typically filtered out bef ore reaching the area of treatment as they can 15 heat the skin, causing discomfort to the patient during the therapy. Further details of the d~ LuS used for phototherapeutic treatments can be found in Honigsmann et al., Dermatolo~y in General Medicines, 3rd ed, T.B.
Fitzpatrick et al., eds., 1728-1754, 1987.
When photosensitizing agents are used in combination with topically-applied sunscreens, the wavelength of the incident optical radiation must lie within the absorption spectrum of the photosensitizing agent. D~r~n~l; n7 on the drug used, this region is typically between 320-700 nm. Preferably, a laser, such as a tunable dye or solid-state laser, a metal vapor laser, or a diode laser, is used as the light source.
I.asers are often the most practical light source for treatment because their high power output at the 30 appropriate drug-activating wavelength can minimize e:~c~O~uLe times. In addition, laser light can easily be coupled into flexible optical fibers to simplify the delivery of light to the treatment region. Other light sources, such as fluuL~scell~ bulbs and solar simulators ~ 0 95l2~888 ~ ,~ 130 21 85440 ~
(Dougherty, et al., cancer ~es. 38:2628-2635, 1978) may also be used.
Experi~entJ~ l Results PPF Variation with the Concentration Pf the Active The ~PF provided by a sunscreen wil~ vary with the concentration of the active compound. In order to determine the dependence of the PPF provided by DHA as a function of concentration, 6 patients having skin types 10 ranging from I-IV were exposed to PWA therapy featuring optical f luence levels high enough to cause erythema .
Solutions containing 5%, 10~6 and 1596 DHI~ (by weight) were used as photo-protectants f or each patient, with a thin layer of solution at each concentration (0.2 cc/9 cm2) 15 applied to a different area of skin in each patient. The MPDs of the different areas were measured by exposing nine l cm2 sites in a single skin area to incrementally increased doses of WA radiation, with the radiation being centered near 365 nm. Comparison of the MPDs from 20 these areas with the MPD from an area free of DHA allowed determination of the PPF, which could then be related to DHA concentration.
Ref erring to Fig . 3, the linear relationship between DHA concentration and PPF illustrates the 25 increase in the protection against erythema provided by increasing concentrations of DHA. The rising slope of the data in the plot also indicates an absence of saturation occurring in the D~ absorption, suggesting that even higher concentrations of DHA may result in 3 0 better protection against WA wavelengths .
The PPF provided by DHA was also predicted using the non-invasive optical mea~u, t described above.
Experiments were conducted on two sunscreens by measuring the fluorescence excitation spectra of skin samples 35 covered with a thin layer of sunscreen. Mea,,uL ts WO 95/2iJ888 PCT~S95103130 ~ 21 85440 were taken non-invasively by scanning the wavelength of an excitation light-source, followed by detection skin f luorescence at a single wavelength (l;~an et al ., .T .
Photochem . Photo~iol . 34: 493-499, 1981) . The sunscreens 5 u6ed f or experiments f eatured as an active compound either DHA or dansyl chloride, a fluorescent molecule commonly used in standard assays of corneocyte sloughing kinetics tTAk Ih~:hi et al., J. Soc. Cosmetic Chem.
38:321-331, 1987; Marks, Cutaneous Investigation in 10 ~ealth and Disease, Leveque ed., Mercel Dekker, Paris, 33-47, 1989). A Spex fluorometer featuring an excitation light source and a monochrometer was f itted with an optical fiber bundle (Spex industries, Edison, NJ) in order to deliver optical radiation to the sample of 15 interest. Excitation wavelengths were chosen to match the peak of the absorption spectra of either DHA (350 nm) or dansyl chloride (335 nm). The excitation light was passed through the monochrometer (4 nm h~n~lr~c~) and into one arm of the fiber bundle, and used to irradiate the 20 skin. Fluorescence from the skin was collected by the same fiber and passed through an emission mono- llL, -ter (4 nm bandpass) and into a detector. Excitation spectra were measured at the peak of the emission spectrum of either DHA (500 nm) or dansyl chloride (465 nm), and were 25 corrected for a weak background of auto-fluorescence due to emission from unstained skin. The same in:,-L L was used to measure skin ref l Prt~nre spectra by setting the excitation and emission monochrometers to the same wavelength. By comparing the incident optical intensity 30 with induced fluorescence or reflected intensity, the optical density of the active compound at the absorbing wavelength was ~lPtPrmi n~(l, Ref erring now to Fig . 4, the change in OD, as defined in equation 3, was detrrm;nPd at 350 nm in 35 various skin sites of living human volunteers stained ~o 9511~888 PCTIUS95/03130 with DHA, and is plotted as a function of the PPF. The PPF was determined by exposing the same skin sites to radiation at 350 nm after ingestion of 8-methoxypsoralen ( 8-MOP) . The solid line in the graph is the f it of the 5 data to equation 2. The agreement between the data and the f it indicates the ability of the skin ref lectance method of the present invention to accurately predict the PPF provided by an applied sunscreen using a simple, non-invasive measurement.
10 Ral)id Desquamation of the Skin Stratum corneum sloughing was investigated by monitoring the time-dependent decrease in f luorescence intensity from the skin after topical application of a sunscreen. Referring now to Figs. 5 and 5a, the time-15 depond~nt fluorescence intensities of psoriatic and non-affected skin samples stained with sunscreens inc111d;n~
either D~1~ or dansyl chloride were compared. The induced f luorescence intensity is decreased faster from psoriatic plaques stained with DHa, with the D~A being completely 20 shed from the skin ~prrn~;r-tely 96 hours after àpplication. In contrast, the dansyl chloride stain takes a longer period of time to be shed from the psoriatic skin. The rapid decrease in the time-dependent fluorescence intensity induced in psoriatic skin stained 25 with DH~ implies a more superf icial binding of DHA to the stratum corneum in comparison with dansyl chloride.
Thus, DE~-containing sunscreens allow for effective phototherapeutic treatments to be carried out over a shorter time period, e.g~, 72 hours after application.
Referring now to Fig~ 6, the difference in induced fluorescence intensity between psoriatic and non-affected skin stained with DHA is shown to be greatest after 72 hours. The level of fluorescence intensity is directly correlated with the concentration of DHA bound to the 35 skin sample. Thus, the peak in the data of Fig. 4 at 72 Wo 95/2i~888 ~ ~ 8 ` 4 4 0 PCr/US95103130 hours implies a time marking the maximum difference between the level of protection provided by DHA to psoriatic and non-affected skin. During a phototherapeutic treatment, an approximately 72-hour time 5 period separating the application of DHA and exposure of the skin to optical radiation will result in the optimization of the conditions for phototherapy. The natural sloughing of f process of the psoriatic tissue leaves affected regions with minimal DHA protection, l0 while non-affected skin is relatively well protected from optical radiation. This allows higher optical fluences to be used during the phototherapy, thus accelerating the treatment of the psoriatic condition. It should be noted that active means for desquamating stratum corneum can be 15 used to increase the rate at which sunscreens containing DHA or other active _ u1.ds are shed from the skin . In particular, alpha-hydroxy acids, such as lactic acid, are effective desquamating agents. When applied before, during, or after application of a highly-subst2ntive 20 sunscreen, the period of time required for los~ of the sunscreen will be reduced. Physical means to remove the skin may also be used.
lJse of nTr~; n Photothera~Y
Referring now to Fig. 7, the absorption spectrum 25 of DHA-stained skin extends from roughly 300-600 nm, and is peaked near 350 nm. The DHA staining i5 a yellow-brown or orange color, and is generally cosmetically acccptable because it mimics natural tanned skin. In Fig. 7, the absorption spectrum is plotted with the 30 action spectrum of 8-MOP, which indicates the effectiveness of each wavelength of light to produce delayed erythema in psoralen-sensitized patients. Thus, during PWA therapy, the skin is typically most sensitive to optical wavelengths near 320 to 330 nm. The overlap 35 of the two spectra indicates that the active and most WO 9512 :8X8 PCTIUS95/03130 harmful optlcal wavelengths used in PWA therapy will be pref erentially absorbed by DHA . The absorption spectrum of other compounds listed in Table 1, in particular 2- _ Ethoxy-ethylhexyl-p-methoxycinnamate (cinnoxate), 2 , 2-5 Dihydroxy-4-methoxybenzophenone (dioxybenzone), 2-Hydroxy-4-methoxybenzophenone (oxybenzone), and 2-Hydroxy-4-methoxybenzophenone-5-sulfonic acid (sulisobenzone) are also peaked near 320 nm. Thus, these compounds will also function as particularly effective 10 photo-protectants during WA phototherapy.
Referring again to the DHA absorption spectrum plotted in Fig. 7, it is evident that conventional DHA
preparations have poor absorbance in the WB range (Levy, J. Am. Acad. Dermatol. 27:989-993, 1992). DHA absorbance 15 is pH dependent, and a colored yellow product has been observed to appear at high, but still safe, pH levels in the human skin. This implies a shift in the absorption ~e~i~LUL~ toward 300 nm for DHA incorporated in high pH
environments . A high pH DHA preparation may theref ore be 20 used in a sunscreen as a WB photo-protectant. An effective sunscreen for WB phototherapy can alsD be made by using an increased concentration of DHA, resulting in a higher optical absorbance at wavelengths near 320 nm.
Alternatively, active compounds such as Glyceryl-25 Am;nnb~n7oate~ Amyl-p-dimethylamino benzoate (Padimate-A), 2-Ethyl-hexyl-p-dimethylamino benzoate (Padimate-O), and 3, 3, 5-Trimethyl-cyclohexyl-salicylate (h' - 1 Ate), which are listed in Table 1, absorb light having wavelengths closer to the WB range. These active 30 _ ,olln~c:, when included in highly-substantive sunscreens, are useful photo-protectants.
Following administration of a photosensitizing agent, there is often appreciable uptake of the drug in the non-affected regions of skin, making it necessary to 35 attenuate optical radiation incident on these regions WO 95/2~8~ PCTnJS95~03130 21 854~3 during therapy . It is theref ore desirable to use a sunscreen containing an active component having substantial optical absorption at the drug-activating wavelength of the light source . Ref erring again to Fig .
5 7, DHA-stained skin exhibits partial optical absorption between 320-600 nm, and thus can be used in combination with a variety of photosensitizing agents for treatment of affected regions of skin. Other active compounds partially absorbing light in this spectral regime could 10 also be used as useful photo-protectants.
~xample 1 - Phototherapeutic Treatment of Psoriasi5 Using ~U~ L~_ ~S Tnt~lu~ir~ DHA
With the information obtained from the above studies, aggressive PWA therapy using ~ulls~:Le:ells 15 ;n~ rl;n~ DHA was initiated in twelve patients having chronic plague psoriasis on greater than 30% of their body surfaces. The subjects had previously failed less aggressive therapies using topical corticosteroids or WB
radiation, and had received no treatments in the previous 2 0 f our weeks . PWA therapy was administered according to standard protocol (Melski et al., .J. Invest. Derlzlatol.
68:328, 1977). On one side of each patient, a solution containing 1596 DHA was applied 72 hours before each treatment to allow for differential qherl~lin~ of DHA from 25 the psoriatic skin. During each visit, skin reflectance was measured in the DHA protected site, and the PPF was estimated. The light dosage applied to the DHA side was increased by a factor equivalent to the PPF value so that non-affected skin on each side of the patient was 30 subjected to the same effective optical fluence. For example, if the dose without DHA was 4 J/cm2, and the DHA
provided a PPF - 5 for the stained site, then a dose of 20 J/cm2 was given to the skin stained with DHA. Because the skin on the DHA side is preferentially sloughed off 35 in the psoriatic regions, these region~ of psoriatic ~'O 95l2~888 PCT~S95/03130 21 ~5440 plaques were therefore subjected-to a substantially higher dose of optical radiation. The Psoriasis Activity and Severity Index (PASI score) (Fredriksson et al., U.
Dermatologica 157:238-244, 1978) was recorded weekly in 5 order to f ollow the clinical response . The study endpoint was 90-100% clearance in all treated sites.
No phototoxic erythema was observed on the DHA
6ide of patients completing the study, despite very high WA doses of up to Z5 Jtcm2 in a single treatment. PPF~s 10 as high as lO were found with mu1tiple repeated applications of DHA. A11 patients reported a persistent .,~ t in the psoriatic condition in the DHA treated site. In the f irst 5 patients, the mean number of treatments n~C-occ~ry for clearance of psoriasis was 15 12.4+5.77. These data, when compared to the unstained control skin necessitating 20-25 treatments for clearance of psoriasis, reflect the; LIV~ Ls of the method of the present invention (Melski et al., J. Invest.
Dermatol. 68:328, 1977). It is apparent from PASI scores 20 that the DHA treated sites cleared faster during the early weeks of treatment. After several treatments, it was noted that psoriatic skin began to retain the DHA
longer than 3 days, producing unwanted WA protection on the plaques due to a decrease in the epidermal turnover 25 rate as the plaques began to heal.
The foregoing descriptions of the preferred method of the present invention has been presented f or purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise 30 form disclo6ed.
.
what is claimed is:
Claims (8)
1. Use of a photoprotective sunscreen in the preparation of a medicament for treating a proliferative skin disorder in a human patient having affected and non-affected areas of skin, wherein said disorder results in said affected areas of skin being sloughed off at a greater rate than said non-affected areas of skin, wherein said sunscreen is topically applied to said affected and non-affected areas of skin, following which the user of the medicament waits for a time period sufficient for skin of said affected areas to be sloughed off to a greater degree than skin of said non-affected areas, after which said affected and non-affected areas of skin of said patient are exposed to a selected level of optical radiation sufficient to treat said affected areas of skin and insufficient to cause significant damage to said non-affected areas of skin.
2. The use of claim 1, wherein said sunscreen comprises an active compound which partially binds to portions of said skin.
3. The use of claim 2, wherein said active compound partially absorbs optical radiation having a wavelength between 290 and 400 nm.
4. The use of claim 3, wherein said active compound is DHA.
5. The use of claim 1, further comprising the use of a compound selected from the group consisting of photosensitizing agents, psoralen, and psoralen-based compounds to prepare a medicament for administration to said patient prior to exposure to radiation.
6. The use of claim 5, wherein said sunscreen comprises an active compound which partially binds to portions of said skin.
7. The use of claim 6, wherein said active compound partially absorbs optical radiation having a wavelength between 320 and 700 nm.
8. The use of claim 7, wherein said active compound is DHA.
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| US08/213,126 | 1994-03-15 |
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| CA002185440A Abandoned CA2185440A1 (en) | 1994-03-15 | 1995-03-13 | Methods for phototherapeutic treatment of proliferative skin diseases |
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| EP (1) | EP0756477B1 (en) |
| JP (1) | JPH09511237A (en) |
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| CA (1) | CA2185440A1 (en) |
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| JPS5659710A (en) * | 1979-10-22 | 1981-05-23 | Eisai Co Ltd | Preventive and remedy for psoriasis |
| US4454159A (en) * | 1981-12-28 | 1984-06-12 | Albert Musher | Dermatological treatment preparations |
| FR2524801B1 (en) * | 1982-04-09 | 1985-08-30 | Goupil Jean Jacques | DRUGS CONTAINING A PSORALENE DERIVATIVE |
| US4651739A (en) * | 1985-04-08 | 1987-03-24 | The General Hospital Corporation | Light-induced killing of carcinoma cells |
| US4981681A (en) * | 1988-08-26 | 1991-01-01 | Vittorio Tosti | Lotion mixture and method of treating psoriasis |
| US5122536A (en) * | 1989-10-12 | 1992-06-16 | Perricone Nicholas V | Method for the topical treatment of psoriasis |
| JP2886591B2 (en) * | 1990-01-27 | 1999-04-26 | 協和醗酵工業株式会社 | Cosmetics |
| JP2681527B2 (en) * | 1990-02-15 | 1997-11-26 | ジャパンファインケミカル株式会社 | Topical for promoting cell activity |
| GB9106365D0 (en) * | 1991-03-26 | 1991-05-15 | Bioglan Lab Ltd | An emollient for use with ultraviolet light |
| FR2695036B1 (en) * | 1992-09-03 | 1994-10-28 | Goupil Jean Jacques | Oil containing 5-methoxypsoralen at a concentration of 60 to 100 PPM and its use for the treatment of psoriasis. |
| DE4315866C1 (en) * | 1993-05-12 | 1994-05-05 | Wogepharm Gmbh | Compsns. for photo therapy of skin diseases - contain methoxy-psoralene as photosensitiser, and magnesium salt |
-
1994
- 1994-03-15 US US08/213,126 patent/US5556612A/en not_active Expired - Fee Related
-
1995
- 1995-03-13 WO PCT/US1995/003130 patent/WO1995024888A1/en active IP Right Grant
- 1995-03-13 AU AU19916/95A patent/AU693171B2/en not_active Ceased
- 1995-03-13 DE DE69532160T patent/DE69532160T2/en not_active Expired - Fee Related
- 1995-03-13 CA CA002185440A patent/CA2185440A1/en not_active Abandoned
- 1995-03-13 EP EP95912904A patent/EP0756477B1/en not_active Expired - Lifetime
- 1995-03-13 JP JP7524121A patent/JPH09511237A/en not_active Ceased
- 1995-03-13 AT AT95912904T patent/ATE254447T1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU1991695A (en) | 1995-10-03 |
| EP0756477B1 (en) | 2003-11-19 |
| ATE254447T1 (en) | 2003-12-15 |
| AU693171B2 (en) | 1998-06-25 |
| JPH09511237A (en) | 1997-11-11 |
| EP0756477A1 (en) | 1997-02-05 |
| EP0756477A4 (en) | 1999-05-19 |
| WO1995024888A1 (en) | 1995-09-21 |
| US5556612A (en) | 1996-09-17 |
| DE69532160D1 (en) | 2003-12-24 |
| DE69532160T2 (en) | 2004-08-26 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |