DEVICE AND METHOD FOR PHOTODYNAMIC THERAPY

FIELD OF THE INVENTION The invention relates to a wearable device comprising a skin covering and a photosensitizer, such as hypericin, for use in photodynamic therapy utilizing natural or artificial light present in conventional everyday surroundings. The invention further relates to kits comprising the device, and methods of photodynamic therapy.

BACKGROUND OF THE INVENTION

Photodynamic therapy (PDT) involves use of photosensitizers (PS; also termed photodynamic agents) for localized treatment of various medical conditions including psoriasis, acne, actinic keratosis, basal cell carcinomas and solid rumors. Photosensitizers are otherwise inert molecules that become chemically activated upon exposure to photoenergy of discrete wavelength, with the wavelength being characteristic for a particular photosensitizer. PDT is primarily administered in a specialized medical setting, using a dedicated apparatus which provides a source of artificial light of selected wavelength to activate in situ a photosensitizer previously administered to the tissue requiring treatment. Photosensitizers are usually topically applied in the form of a soft cream, ointment or gel for treatment of psoriasis and other localized skin disorders. The wavelength is selected to coincide with the absorption peak(s) of the photosensitizer, and the specific light sources can include visible, infrared or ultraviolet light at laser intensities or other doses. PDT usually requires multiple sessions, over the course of which the length of photo exposure may be gradually increased. Duration of the photo exposure may further depend on the size, location and type of tissue involved.

Light activation of a photosensitizer molecule leads to the generation of short lived reactive oxygen species (ROS) including singlet oxygen. These are cytotoxic and elicit necrosis of the target and surrounding area when the tolerance threshold is exceeded. Accordingly, PDT using most photosensitizers can be associated with various adverse side effects, such as burns, swelling, pain, and scarring in the treated tissue as well as in nearby healthy tissue. In addition, patients undergoing PDT are generally required to avoid direct sunlight and bright indoor light due to the risk of excessive

exposure at the critical wavelengths, which can result in additional tissue damage.

Commonly used photodynamic agents for dermatological applications include 5'- aminolevulenic acid (ALA) and methylaminolevulenic acid (MAL). These compounds are not photosensitizers per se, but are precursors of the photosensitizer protoporphyrin IX and convert into that photosensitizer in cells. ALA and MAL are frequently associated with side effects, including reddening, swelling, scaling, itching and changes in skin color, and must be used only under medical supervision.

Hypericin is an aromatic polycyclic dione (perihydroxylated naphthodianthrone; dianthraquinone) compound which has photodynamic properties, and has light absorption peaks at 545 and 589 nm i.e. in the yellow region of the electromagnetic spectrum. Hypericin exhibits numerous biological activities, including inactivation of retroviruses, as described in U.S. Patent No. 5,047,435; inhibition of cytotoxic T cell mediated cytotoxicity, as described in U.S. Patent No. 5,514,714; and inhibition of cancers such as metastatic murine breast adenocarcinoma and anaplastic squamous cell carcinoma, as described in U.S. Patent Nos. 6,001,882 and 6,229,048.

U.S. Patent No. 6,001,882 discloses topical application of hypericin to psoriatic tissue and illumination thereof with a visible or UV-A light source, but does not disclose any particular hypericin formulation or device.

WO 99/06347 discloses use of hypericin for treatment of tumors using PDT for eliciting destruction of tumors in conjunction with light irradiation. WO 01/56558 discloses use of hypericin for treatment of cancer in the absence of light irradiation by inhibiting transduction of signals for cell proliferation and cell progression through the cell replication cycle.

US Patent No. 7,179,495 discloses use of an ointment or cream composition comprising hypericin, hyperforin and a carrier for treating a skin condition, inter alia psoriasis, hyperkeratotic eczema and skin cancer.

US Patent No. 7,166,310 discloses a pharmaceutical composition comprising hyperforin and hypericin, prepared from extract of Hypericum perforatum L., and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated as a geL The extract is reportedly effective in treating skin disorders inter alia psoriasis.

US Patent No. 7,037,534 discloses an antiviral complex, comprising an antiviral

light sensitive compound, inter alia hypericin, a phosphatase enzyme, a water soluble 1,2-dioxetane as a chemiluminescence substrate, and a quaternary ammonium homopolymer as a chemiluminescence enhancer.

US Patent No. 6,830,758 discloses an adhesive patch comprising a flexible backing and a therapeutic formulation, wherein the formulation comprises inter alia a topical psoriasis drug, and a solvent that dissolves the medicament. This disclosure does not cite hypericin or any other photosensitizers among the many psoriasis drugs mentioned.

US Patent No. 5,505,726 discloses an article of manufacture for photodynamic therapy of a dermal lesion, the article comprising a cover means adapted for being sealed to the skin for covering and defining a dermal treatment site and for providing a chamber, a transparent transport means contained within the chamber wherein the transport means contains a hydration agent and a photopharmaceutical, and a light source mounted in the cover which photoactivates the photopharmaceutical. According to the disclosure, the transport means may comprise a hydrogel.

US Patent No. 5,723,148 discloses a topically administrable pharmaceutical composition comprising the photosensitizer zinc phthalocyanine; a lipid carrier, and a gelling agent, such as a cellulosic polymer. Also disclosed is a method of photodynamic therapy for a hyperproliferative skin disease comprising topical application of the composition followed by irradiating the affected skin with visible radiation.

US Patent No. 7,304,201 discloses a phototherapy bandage which includes a flexible light source for providing visible light, a near-infrared light or other light, having substantially similar intensity across the bandage.

There remains an unmet need for formulations of photodynamic agents and methods of PDT which suffer from fewer side effects than known formulations and methods. Furthermore, the prior art does not teach or suggest a wearable light permeable skin covering device for in situ photodynamic therapy which incorporates a photodynamic agent in a formulation that is molded to the contours of the site to be treated, and does not require any specialized light source.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the unexpected discovery that a wearable light permeable skin covering device in conjunction with a photosensitizer formulation can be used for photodynamic therapy (PDT) of skin disorders using natural or artificial sources of light present in conventional surroundings. When advantageously provided as a kit, the wearable skin covering device and the photosensitizer formulation may be used to provide effective levels of PDT ₅ while avoiding the cost and inconvenience of multiple patient visits to specialized PDT clinics. The present invention is also advantageous over prior art wearable or mountable PDT devices which incorporate a light source such as a laser, due to its relative simplicity and lower cost, while avoiding the need to calibrate and maintain the light source.

The formulation included in the device and kit of the present invention is preferably in a solid or semisolid form which may be molded and/or stretched to conform with the contours of specific skin regions requiring PDT. Most preferably, the formulations are both stretchable and flexible so as to be conformable, to enable freedom of movement by the user while undergoing therapy, and to avoid breakage of the gel in response to body movement. Molded formulations are advantageous for providing PDT to non-uniform skin regions such as the elbows or knees, areas which are commonly affected by psoriasis. Upon application of the formulation to a site on the skin and mounting thereupon of the light filtering skin covering, the invention enables a modality of PDT which is obtained in the course of conventional everyday activity, as long as the patient is exposed to artificial or natural light. In addition, the invention utilizes dosages of photosensitizer and light intensity which are considerably less than that used in standard PDT regimens, and accordingly, is associated with reduced incidence of adverse side effects as compared to prior art methods.

Without wishing to be bound by any particular theory or mechanism of action, the efficacy of the invention may be attributed to the use of relatively low doses of photosensitizer, and to the use of light permeable materials in the covering for harnessing wavelengths or wavelength ranges present in natural and artificial light in conventional surroundings. In a particular embodiment, the light permeable materials are transparent and have no particular light filtering properties, i.e. they transmit light

over a broad range of wavelengths. In other embodiments, the light permeable materials have light filtering properties. Selection of a particular light filtering material in accordance with the particular photosensitizer used enables selective transmission through the covering ofthe specific wavelength or range of wavelength which activates the photosensitizer. This selective light transmission may be advantageous for avoiding the transmission of wavelengths which have the potential to interfere with the photoactivation of the photodynamic agent and/or the desired photodynamic effects. Currently preferred embodiments of the invention comprise the photosensitizer hypericin or a pharmaceutically acceptable derivative or salt thereof in a gelatin-based gel carrier, with either a transparent skin covering or with a light filtering skin covering which selectively transmits light of wavelenth in the range 500 to 600 nm.

In a first aspect, the invention provides a kit for photodynamic therapy at a site on the skin of a subject, the kit comprising (a) at least one packaged product comprising a topical pharmaceutical formulation, the formulation comprising at least one photosensitizer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the formulation is capable of spreading, adhering and conforming to a skin surface to which it is applied and is capable of maintaining contact with the skin surface over an extended period of time; and (b) a wearable skin covering adapted to enclose the formulation over the skin surface to which the formulation is applied, wherein the skin covering comprises (i) a covering element for placement over the formulation applied to said skin surface, and (ii) a means for fastening the covering element at said site on the skin. hi particular embodiments, the covering element is transparent, partially transparent or translucent. In a particular embodiment, the covering element is tinted. In a particular embodiment, at least one of the covering element and the formulation comprise at least one light filtering material, hi a particular embodiment, the covering element comprises at least one light filtering material. In another embodiment, the formulation comprises a light filtering material. When a light filtering material is present in both the formulation and the covering element, the light filtering materials may be the same or different, but generally have the same light transmitting properties. In a particular embodiment, the light filtering material transmits light which enables photoactivation of said photosensitizer. In a particular embodiment, the light filtering material transmits light having wavelength in a range selected from the group consisting

of near infrared, visible light and ultraviolet. In a particular embodiment, the light filtering material has a transmission function selected from the group consisting of narrow bandpass (such as about or less than a range of 100 nm), wide bandpass (such as about or greater than a range of 200 nm), short wavelength cutoff (such as at about 400 nm) and long wavelength cutoff (such as at about 800 nm). In a particular embodiment, the light filtering material selectively transmits light having wavelength in the range from 400 to 900 nm. In a particular embodiment, the light filtering material selectively transmits light having wavelength in the range from 500 to 700 nm. In a particular embodiment, the light filtering material selectively transmits light having wavelength in the range from 570 to 650 nm. In a particular embodiment, the light filtering material is selected to reflect and/or absorb light of a wavelength or wavelength range which does not activate the photosensitizer. In a particular embodiment, the light filtering material is selected to reflect and/or absorb light in the UV range. In a particular embodiment, the light filtering material comprises a material selected from the group consisting of an optical gel and a polymeric film. In a particular embodiment, the polymeric film comprises a material selected from the group consisting of polycarbonates, acrylics, nylons, polyesters, polyurethanes, polyolefϊns, cellulose acetates, cellulose triacetates, vinyl acetals, polyimide, vinyl chloride polymers and combinations thereof. In a particular embodiment, the light filtering material is photochromic or thermochromic. In a particular embodiment, the covering element is substantially dome-shaped, which may be advantageous for placement over a joint such as the elbow or knee. In a particular embodiment, the covering element comprises a transparent bandage and the means for fastening comprises an adhesive material. In a particular embodiment, the adhesive material is disposed upon at least one end of the transparent bandage, or in the case of a circular bandage, around the periphery of said bandage. In a particular embodiment, the formulation is disposed upon the adhesive bandage, for example in a central region.

In a particular embodiment, the means for fastening is adapted to circumscribe a limb of the subject. In a particular embodiment, the means for fastening comprises any suitable means such as a strap or a belt or a string that are fastenable and/or adjustable by elements such as hooks and loops fabric, a buckle, clip, clasp, a knot or a combination thereof or other means such as a snap-fastener an elastic stretchable strap, or an adhesive tape.

In a particular embodiment, the skin covering further comprises a means for masking the covering element, wherein the masking means substantially prevents transmission of natural and artificial light through the covering element. In a particular embodiment, the masking means is detachable. In a particular embodiment, the masking means comprises a material selected from fabric and plastic. The masking means advantageously enables the skin covering to remain in place, thereby maintaining an occlusive effect, for periods when exposure to light is not required or desired.

In a particular embodiment, the skin covering further comprises a frame for surrounding or circumscribing a site on the skin onto which the formulation is applied, wherein the frame is disposed between the covering element and the site on the skin, hi a particular embodiment, the frame and the covering element are joined through at least one hinge element and/or at least one snap-in or snap-on element or any other joining element such as a clasp or separable adhesive.

In a particular embodiment, the kit further comprises an occlusive barrier for placement between the formulation and the covering element of the skin covering, which extends beyond the circumference of the covering element so as to occlude the skin site requiring photodynamic therapy. The occlusive barrier may advantageously augment the occlusive effect provided by the covering element.

In a particular embodiment, the occlusive barrier comprises a transparent adhesive patch. In a particular embodiment, the kit is for use in the absence of a dedicated manufactured photoenergy source. As used herein, "a dedicated manufactured photoenergy source" refers to a light source specifically intended and designed for PDT.

In a particular embodiment, the kit comprises more than one packaged product. In a particular embodiment, each packaged product comprises a formulation comprising a distinct photosensitizer. hi a particular embodiment, each packaged product comprises a formulation of the same photosensitizer at a different concentration.

In a particular embodiment, the packaged product is a multi-use package form, hi a particular embodiment, the multi-use package form is a multi-unit blister pack comprising individual molded or moldable gel units. In a particular embodiment, the kit comprises a multiplicity of adhesive bandages wherein the bandages comprise a first region comprising a gel formulation comprising a photosensitizer and a second region comprising an adhesive, hi a particular embodiment, the bandages are transparent. In a

particular embodiment, the bandages comprise a light filtering material.

In a particular embodiment, the formulation is in a form selected from a gel, an ointment, and a cream, or constituents for making the same such as by dissolving or polymerization. In a particular embodiment, the gel is molded to the contours of the skin site to which it is to be applied. In a particular embodiment, the gel is molded to fully or partially occupy the covering element. In a particular embodiment, the gel is stretchable. In a particular embodiment, the gel is a gelatin-based gel. In a particular embodiment, the formulation is selected from a topical formulation and a transdermal formulation. In a particular embodiment, the formulation is transparent or semitransparent. In a particular embodiment, the carrier comprises at least one polymer. In a particular embodiment, the at least one polymer is crosslinked. hi a particular embodiment, the degree of crosslmking is in the range from about 5% to about 100%.

In a particular embodiment, the polymer is selected from a polysaccharide, a polypeptide, a synthetic polymer and combinations thereof. In a particular embodiment, the polymer is selected from alginate; a cellulose derivative; gelatin; gum arabic; guar gum; karaya gum; tragacanth gum; xanthan gum; phthalate; polyacrylic acid; polyethylene glycol; polylactic acid; poly(lactic-co-glycolic acid); polyvinyl alcohol; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylene; polyisobutylene; an acrylic polymer, an acrylic acid polymer; styrene; a styrene isoprene block copolymer; a urethane; a polyurethane; a silicone; butadiene; a styrene butadiene copolymer; a polyacrylate; and combinations thereof. hi a particular embodiment, the polymer is gelatin. In a particular embodiment, the gelatin is crosslinked. A suitable degree of cross linking is in the range from about 5% to about 100%. In a particular embodiment, the gelatin has a Bloom strength in the range of 100 to 400. In particular embodiments, the gelatin is present in an amount of about 0.5 to about 20 %(w/w), or in an amount of about 0.5 to about 2 %(w/w), or in an amount of about 6 to about 16 %(w/w) based on the total weight of the formulation, hi particular embodiments, the gelatin is present in an amount of aboμt 12 %(w/w), based on the total weight of the formulation.

In a particular embodiment, the gel is a semisolid gel or a soft gel. hi a particular embodiment, the gel is a thixotropic gel. In a particular embodiment, the gel is a

hydrogel. In a particular embodiment, the gel is anhydrous. In a particular embodiment, the gel comprises an optical gel having light filtering properties.

In a particular embodiment, the carrier enables diffusion of the photosensitizer from the formulation into the skin at the site onto which the formulation is applied. In a particular embodiment, the carrier comprises at least one solvent. In a particular embodiment, the solvent is selected from water; ethanol; butylene glycol; propylene glycol; isopropyl alcohol; isoprene glycol; glycerin and combinations thereof. In a particular embodiment, the ratio of polymer to solvent is in the range of 1:3 to 1:100. hi a particular embodiment, the carrier comprises a pressure sensitive adhesive. In particular embodiments, the photosensitizer is present in the formulation in an amount of about 0.01 to about 1.0 %(w/w), or in an amount of about 0.05 to about 0.1 %(w/w), or in an amount of about 0.1 to about 0.5 %(w/w), based on the total weight of the formulation. In particular embodiments, the photosensitizer is present in the formulation in an amount of about 0.1 %(w/w), or in an amount of about 0.25 %(w/w), or in an amount of about 0.5 %(w/w), based on the total weight of the formulation, hi a particular embodiment, the photosensitizer is hypericin or a pharmaceutically acceptable derivative or salt thereof. In particular embodiments, the hypericin is present in the formulation in an amount of about 0.1 %(w/w), such as 0.125%, or in an amount of about 0.25 %(w/w), or in an amount of about 0.5 %(w/w), based on the total weight of the formulation. In a particular embodiment, the formulation has a pH in the range 4 to 8. La a particular embodiment, the formulation comprises an emulsion of the photosensitizer and at least one emulsifying agent. In a particular embodiment, the emulsifying agent is selected from a cationic surfactant, an anionic surfactant, an amphoteric surfactant, a nonionic surfactant, and combinations thereof, hi a particular embodiment, the emulsifying agent is present in the formulation in an amount of from about 0.05 to about 10%(w/w), based on the total weight of the formulation. hi a particular embodiment, the photosensitizer comprises hypericin or a pharmaceutically acceptable derivative or salt thereof, the carrier comprises gelatin, and the formulation is in the form of a gel. hi a particular embodiment, the hypericin or a pharmaceutically acceptable derivative or salt thereof is present in an amount of about 0.01 to about 1.0 %(w/w), based on the total weight of the formulation, and the gelatin is present in an amount of about 0.5 to about 20 %(w/w), based on the total weight of

the formulation. In a particular embodiment, the formulation comprises (i) hypericin or a pharmaceutically acceptable derivative or salt thereof in an amount of about 0.05 to about 1.0 %(w/w), based on the total weight of the formulation, and (ii) gelatin in an amount of about 0.5 to about 2.0 %(w/w), or in an amount of about 6 to about 16 %(w/w), based on the total weight of the formulation, wherein the gelatin has a degree of cross linking in the range from about 5% to about 100%, and wherein the pH of the formulation is in the range 4 to 8. In a particular embodiment, the formulation comprises (i) hypericin or a pharmaceutically acceptable derivative or salt thereof in an amount of about 0.125 %(w/w), based on the total weight of the formulation; gelatin in an amount of about 12 %(w/w), and glycerol in an amount of about 10 %(w/w), based on the total weight of the formulation.

In a particular embodiment, the photosensitizer comprises hypericin or a pharmaceutically acceptable derivative or salt thereof, the carrier comprises a polyurethane, and the formulation is in the form of a gel. In a particular embodiment, the formulation further comprises a light filtering material, such as an optical gel. In a particular embodiment, the formulation further comprises a skin permeation enhancer, hi a particular embodiment, the skin permeation enhancer is selected from the group consisting of a keratolytic agent, an essential oil; a detergent; a polymer and combinations thereof, hi a particular embodiment, the keratolytic agent is selected from propylene glycol, lactic acid, urea and salicylic acid. In a particular embodiment, the essential oil is selected from wintergreen, jojoba, coconut, eucalyptus and thyme. Li a particular embodiment, the detergent is selected from sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, a poloxamer, a polysorbate and lecithin, hi a particular embodiment, the polymer is selected from polyethylene glycol and esters thereof.

In a second aspect, the invention provides a device for photodynamic therapy at a site on the skin of a subject, the device comprising (a) a topical pharmaceutical formulation, wherein the formulation comprises at least one photosensitizer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and (b) a wearable skin covering, wherein the skin covering comprises (i) a covering element for placement over the skin surface to which the formulation is applied, and (ii) a means for fastening the covering element at said site on the skin.

In particular embodiments, the covering element is transparent, partially transparent or translucent. In a particular embodiment, the covering element is tinted. In a particular embodiment, at least one of the covering element and the formulation comprise at least one light filtering material. In a particular embodiment, the covering element comprises at least one light filtering material. In another embodiment, the formulation comprises a light filtering material. When a light filtering material is present in both the formulation and the covering element, the light filtering materials may be the same or different, but generally have the same light transmitting properties. In a particular embodiment, the light filtering material transmits light which enables photoactivation of the photosensitizer. In a particular embodiment, the light filtering material transmits light having wavelength in a range selected from the group consisting of near infrared, visible light and ultraviolet. In a particular embodiment, the light filtering material has a transmission function selected from the group consisting of narrow bandpass (such as about or less than a range of 100 nm), wide bandpass (such as about or greater than a range of 200 nm), short wavelength cutoff (such as at about 400 nm) and long wavelength cutoff (such as at about 800 nm). In a particular embodiment, the light filtering material selectively transmits light having wavelength in the range from 400 to 900 nm. hi a particular embodiment, the light filtering material selectively transmits light having wavelength in the range from 500 to 700 nm. hi a particular embodiment, the light filtering material selectively transmits light having wavelength in the range from 570 to 650 nm. In a particular embodiment, the light filtering material is selected to reflect and/or absorb light of a wavelength or wavelength range which does not activate the photosensitizer. hi a particular embodiment, the light filtering material is selected to reflect and/or absorb light in the UV range. In a particular embodiment, the light filtering material comprises an optical gel. In a particular embodiment, the light filtering material comprises a polymeric film, hi a particular embodiment, the polymeric film comprises a material selected from the group consisting of polycarbonates, acrylics, nylons, polyesters, polyurethanes, polyolefins, cellulose acetates, cellulose triacetates, vinyl acetals, polyimide, vinyl chloride polymers and combinations thereof. In a particular embodiment, the light filtering material is photochromic or thermochromic. hi a particular embodiment, the covering element comprises a transparent bandage and the means for fastening comprises an adhesive material, hi a particular embodiment,

the adhesive material is disposed upon at least one end of the transparent bandage, or in the case of a circular bandage, around the periphery of said bandage. In a particular embodiment, the formulation is disposed upon the adhesive bandage, for example in a central region. In a particular embodiment, the covering element is substantially dome- shaped.

In a particular embodiment, the means for fastening is adapted to circumscribe a limb of the subject. In a particular embodiment, the means for fastening comprises elements as described above.

In a particular embodiment, the skin covering further comprises a means for masking the covering element, wherein the masking means substantially prevents transmission of natural and artificial light through the covering element. In a particular embodiment, the masking means is detachable. In a particular embodiment, the masking means comprises a material selected from fabric and plastic.

In a particular embodiment, the skin covering further comprises a frame for surrounding or circumscribing a site on the skin onto which the formulation is applied, wherein the frame is disposed between the covering element and the site on the skin. In a particular embodiment, the frame and the covering element are joined as described above.

In a particular embodiment, the pharmaceutical formulation is a gel formulation. In other embodiments, the formulation is in the form of a cream or an ointment. In a particular embodiment, the gel formulation is molded to the contours of the skin site to which it is to be applied. In a particular embodiment, the gel is stretchable. In a particular embodiment, the gel is a gelatin-based gel. In a particular embodiment, the gel is molded to fully or partially occupy the covering element. In a particular embodiment, the gel formulation is selected from a topical formulation and a transdermal formulation. In a particular embodiment, the gel formulation is transparent or semitransparent. In a particular embodiment, the carrier comprises at least one polymer. In a particular embodiment, the at least one polymer is crosslinked. In a particular embodiment, the degree of crosslinking is in the range from about 5% to about 100%.

Embodiments of the polymer and the carrier are as described above.

In a particular embodiment, the gel is a semisolid gel or a soft gel. In a particular

embodiment, the gel is a thixotropic gel. In a particular embodiment, the gel is a hydrogel. In a particular embodiment, the gel is anhydrous. In a particular embodiment, the gel comprises an optical gel having light filtering properties.

In particular embodiments, the photosensitizer is present in the formulation in an amount of about 0.01 to about 1.0 %(w/w), or in an amount of about 0.05 to about 0.1 %(w/w), or in an amount of about 0.1 to about 0.5 %(w/w), based on the total weight of the formulation. In particular embodiments, the photosensitizer is present in the formulation in an amount of about 0.1 %(w/w), or in an amount of about 0.25 %(w/w), or in an amount of about 0.5 %(w/w), based on the total weight of the formulation. In a particular embodiment, the photosensitizer is hypericin or a pharmaceutically acceptable derivative or salt thereof, hi particular embodiments, the hypericin is present in the formulation in an amount of about 0.1 %(w/w), such as 0.125%, or in an amount of about 0.25 %(w/w), or in an amount of about 0.5 %(w/w), based on the total weight of the formulation. In a particular embodiment, the formulation has a pH in the range 4 to 8. hi a particular embodiment, the formulation comprises an emulsion of the photosensitizer and at least one emulsifying agent. La a particular embodiment, the emulsifying agent is selected from a cationic surfactant, an anionic surfactant, an amphoteric surfactant, a nonionic surfactant, and combinations thereof. La a particular embodiment, the emulsifying agent is present in the formulation in an amount of from about 0.05 to about 10%(w/w), based on the total weight of the formulation. hi a particular embodiment, the photosensitizer comprises hypericin or a pharmaceutically acceptable derivative or salt thereof, and the carrier comprises gelatin, hi a particular embodiment, the hypericin or a pharmaceutically acceptable derivative or salt thereof is present in an amount of about 0.01 to about 1.0 %(w/w), based on the total weight of the formulation, and the gelatin is present in an amount of about 0.5 to about 20 %(w/w), based on the total weight of the formulation, hi a particular embodiment, the formulation comprises (i) hypericin or a pharmaceutically acceptable derivative or salt thereof in an amount of about 0.05 to about 1.0 %(w/w), based on the total weight of the formulation, and (ii) gelatin in an amount of about 0.5 to about 2.0 %(w/w), or in an amount of about 6 to about 16 %(w/w), based on the total weight of the formulation, wherein the gelatin has a degree of cross linking in the range from

about 5% to about 100%, and wherein the pH of the formulation is in the range 4 to 8. In a particular embodiment, the formulation comprises (i) hypericin or a pharmaceutically acceptable derivative or salt thereof in an amount of about 0.125 %(w/w), based on the total weight of the formulation; gelatin in an amount of about 12 %(w/w), and glycerol in an amount of about 10 %(w/w), based on the total weight of the formulation. hi a particular embodiment, the photosensitizer comprises hypericin or a pharmaceutically acceptable derivative or salt thereof, and the carrier comprises a polyurethane polymer. In a particular embodiment, the formulation further comprises a light filtering material, such as an optical gel. In a particular embodiment, the formulation further comprises a skin permeation enhancer. In a particular embodiment, the skin permeation enhancer is selected from the group consisting of a keratolytic agent, an essential oil; a detergent; a polymer and combinations thereof. In a particular embodiment, the keratolytic agent is selected from propylene glycol, lactic acid, urea and salicylic acid. In a particular embodiment, the essential oil is selected from wintergreen, jojoba, coconut, eucalyptus and thyme. In a particular embodiment, the detergent is selected from sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, a poloxamer, a polysorbate and lecithin. In a particular embodiment, the polymer is selected from polyethylene glycol and esters thereof.

In a third aspect, the invention provides a method of administering photodynamic therapy to a subject in need thereof, the method comprising (i) selecting a site on the skin of the subject where the photodynamic therapy is to be administered; (ii) topically applying to the selected site a pharmaceutical formulation comprising at least one photosensitizer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the formulation is capable of spreading, adhering and conforming to a skin surface to which it is applied and is capable of maintaining contact with the skin surface over an extended period of time; (iii) mounting over the skin site a skin covering, such that the covering encloses the formulation applied to the skin site, and (iv) exposing the skin site having said skin covering mounted thereon to natural or artificial light for a period of time effective to achieve a therapeutic effect.

In a particular embodiment, the subject has a skin disorder or clinical signs

thereof, wherein the skin disorder is selected from the group consisting of: psoriasis, acne, actinic keratosis, skin cancer, basal cell carcinoma, eczema, seborrhea and hyperkeratinosis.

In particular embodiments, the skin covering is transparent, partially transparent or translucent. In a particular embodiment, the skin covering comprises an adhesive bandage. In a particular embodiment, the adhesive bandage is transparent. In a particular embodiment, the formulation is disposed upon the adhesive bandage. In a particular embodiment, at least one of the skin covering and the formulation comprise at least one light filtering material. In a particular embodiment, the skin covering comprises at least one light filtering material. In another embodiment, the formulation comprises a light filtering material. When a light filtering material is present in both the formulation and the skin covering, the light filtering materials may be the same or different, but generally have the same light transmitting properties, hi a particular embodiment, the light filtering material is selected to transmit light of a wavelength or wavelength range which activates the photosensitizer. hi a particular embodiment, the light filtering material transmits light having wavelength in a range selected from the group consisting of near infrared, visible light and ultraviolet. hi a particular embodiment, the step of exposing to natural or artificial light is carried out in the course of conventional everyday activity. In a particular embodiment, the natural or artificial light is that provided by conventional surroundings. In a particular embodiment, the step of exposing to light is carried out daily or on alternate days. In a particular embodiment, the step of exposing to light is carried out for 0.5 to 12 hours per day of treatment, hi a particular embodiment, the step of exposing to light is carried out daily or on alternate days over a period from 1 week to 40 weeks, hi a particular embodiment, the daily exposure to light is incrementally increased. Optionally, the step of exposing to light is adjusted with respect to duration and frequency in response to the observed therapeutic effect and/or adverse side effects. In a particular embodiment, the exposing to natural or artificial light is carried out without the use of a dedicated manufactured photoenergy source. hi a particular embodiment, the light filtering material has a transmission function selected from the group consisting of narrow bandpass (such as about or less than a range of 100 run), wide bandpass (such as about or greater than a range of 200 nm),

short wavelength cutoff (such as at about 400 nm) and long wavelength cutoff (such as at about 800 nm). In a particular embodiment, the light filtering material transmits light having wavelength in the range from 400 to 900 nm. In a particular embodiment, the light filtering material transmits light having wavelength in the range from 500 to 700 nm. In a particular embodiment, the light filtering material transmits light having wavelength in the range from 570 to 650 nm. In a particular embodiment, the light filtering material comprises an optical gel. In a particular embodiment, the light filtering material comprises a polymeric film. In a particular embodiment, the polymeric film comprises a material selected from the group consisting of polycarbonates, acrylics, nylons, polyesters, polyurethanes, polyolefins, cellulose acetates, cellulose triacetates, vinyl acetals, polyimide, vinyl chloride polymers and combinations thereof. In a particular embodiment, the light filtering material is photochromic or thermochromic. hi a particular embodiment, the formulation is molded to assume the contours of the skin site to which it is to be applied. In a particular embodiment, the formulation is a stretchable gel. hi a particular embodiment, the gel is a gelatin-based gel.Particular embodiments of the formulation are as hereinbefore described. hi a particular embodiment, the step of mounting comprises use of a fastening element such as an elastic strap or a strap adjusted and fastened by hooks and loops fabric or a buckle, or an adhesive tape. hi a particular embodiment, the method further comprises a step of masking the skin covering with a means which substantially prevents transmission of natural and artificial light through the covering, hi a particular embodiment, the step of masking is carried out prior to step (iv), wherein the masking means is retained in place over the covering for a period of time sufficient to enable diffusion of the photosensitizer from the formulation into the skin, hi a particular embodiment, the step of masking is carried out following the step of exposing the subject to natural or artificial light. In a particular embodiment, the step of masking is carried out for intermittent periods during the step of exposing the skin site to natural or artificial light, for example, on alternate days.

The invention further provides a topical pharmaceutical formulation comprising at least one photosensitizer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the formulation is capable of spreading, adhering and conforming to a skin surface to which it is applied and is capable of

maintaining contact with the skin surface over an extended period of time; and a skin covering for mounting over the skin site such that the covering encloses the formulation applied to the skin site; for photodynamic therapy.

Other objects, features and advantages of the present invention will become clear from the following description and drawings.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates a sectional view of the wearable device according to one embodiment of the invention. Figure 2 illustrates a sectional view of the wearable device according to an additional embodiment the invention, mounted to a skin surface.

Figure 3 illustrates a partially cut-away perspective view of the wearable device including a molded gel formulation according to one embodiment of the invention.

Figure 4 illustrates a perspective view of the covering element and the masking means of the wearable device according to one embodiment of the invention.

Figure 5 illustrates use of a wearable device for carrying out in situ PDT at a site on the elbow of a subject according to one embodiment of the invention.

Figure 6 is a simplified flow chart of a method for in situ PDT according to one embodiment of the invention. Figure 7 is a simplified flow chart of a method for in situ PDT according to another embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a kit, device and method for in situ photodynamic therapy of skin disorders. The invention involves use of a pharmaceutical formulation comprising a photosensitizer, and a covering for placement over the formulation, wherein the covering is light permeable or optionally incorporates a light filtering material. Advantageously, the invention enables administration of photodynamic therapy without the need for specialized light sources or numerous clinic visits, since the covering enables activation of the photosensitizer by transmitting photoenergy from natural and artificial sources present in conventional surroundings. Furthermore, the

invention enables administration of photodynamic therapy while the patient is mobile and performing conventional everyday activities. Accordingly, the invention is particularly beneficial for active patients, and those for whom disruptions in schedule (e.g. to accommodate 2-3 weekly clinic visits for a period of months) would preclude compliance with conventional photodynamic therapy regimens. The use of the invention enables localized exposure of skin areas requiring photodynamic therapy to therapeutically effective doses of light for extended periods of time, and accordingly, the concentration of photosensitizer used in the formulation can be significantly less than that employed for prior art photodynamic therapy regimens. Definitions

As used herein, the singular forms "a", "an" and "the" include plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "a photosensitizer" includes combinations of photosensitizers, and so forth.

As used herein, "photoactivation" refers to a process by which, upon absorption of a quantum of energy corresponding to a photon of light having a given wavelength, a chemical compound, such as a photosensitizer, participates in or undergoes a chemical reaction at a reaction rate which is greater than the corresponding reaction rate in the absence of photoactivation.

As used herein, a "photosensitizer" or pharmaceutically acceptable salt thereof refers to a chemical compound or molecule that is capable of becoming chemically activated upon exposure to electromagnetic radiation i.e. photoenergy, of appropriate wavelength.

As used herein, a "pharmaceutically acceptable carrier" refers to a pharmaceutical diluent, adjuvant, excipient, vehicle or mixture thereof, with which a pharmaceutically active ingredient is combined prior to or in the course of administration to a subject. A pharmaceutically acceptable carrier generally facilitates any one or more of administration, delivery, absorption and pharmacokinetic profile of the pharmaceutically active ingredient with which it is combined, and usually does not have any pharmaceutical activity of its own. hi the context of the present invention, the carrier facilitates molding of the formulation to the contours of the skin site at which photodynamic therapy is to be administered. Furthermore, the carrier facilitates prolonged contact of the formulation on the skin surface, hi the case of a transdermal

formulation, the carrier facilitates absorption of the photodynamic agent through the skin and into the bloodstream.

As used herein, "photodynamic therapy", abbreviated as "PDT", refers to a medical technique involving use of a photosensitizer and a source of light having wavelength appropriate for chemically activating the photosensitizer for localized treatment of malignant or benign diseases. For photodynamic therapy, a photosensitizer is administered to a patient by one of several routes (e.g., topical, oral, intravenous). In some cases, an interval of time may be allowed for the photosensitizer to be absorbed or taken up by the target cells. The target may involve diseased skin lesions or other tissues or organs. Then, the photosensitizer is activated in the presence of oxygen with a specific wavelength (or wavelength range) of light directed toward the target tissue.

As used herein, "in situ photodynamic therapy" refers to a mode of PDT involving topically applied photosensitizer to a target site, in particular on a skin surface.

As used herein, "skin" refers to any of the dermatological tissues comprising mammalian skin, including, but not limited to, epidermis, dermis, and hypodermis.

As used herein, "a site on the skin" refers to any anatomical region covered with skin, as for example, face, back, neck, shoulder, chest, arm, hand, foot, knee, elbow and leg.

As used herein, "light permeable material" refers to a material, optical medium or coating that transmits light, as opposed to one which is opaque i.e is substantially impermeable to light. A particular light permeable material may or may not have light filtering properties.

As used herein, "light filtering material" refers to a homogeneous optical medium or coating that selectively transmits only certain wavelengths of light i.e. photoenergy, while reflecting or absorbing other wavelengths. With respect to the present invention, it is preferable that the light filtering material does not absorb photoenergy of any particular wavelength, due to potentially harmful thermal effects. The light filtering capacity of a particular material may be determined from its spectral energy distribution curve, which describes the percentages of particular wavelengths and/or wavelength ranges transmitted through the material, as well as the overall light transmission through the material. Light filtering materials may be variously classified according to their light transmitting properties. A narrow bandpass material transmits only a narrow range of

wavelengths. A wide bandpass material transmits a broad range of wavelengths. Short wavelength cutoff and long wavelength cutoff materials respectively do not transmit photoenergy of short and long wavelength. A short-wave pass material transmits shorter wavelengths, but not longer wavelengths. A long-wave pass material transmits longer wavelengths, but not shorter wavelengths.

As used herein, "bandpass" refers to the width at half the maximal height of a light spectrum curve.

As used herein, "narrow bandpass" refers to a bandpass about or less than a range of 100 nm, such as 50 nm. As used herein, "wide bandpass" refers to a bandpass about or greater than a range of 200 nm, such as 250 nm.

As used herein, "short wavelength cutoff' refers to light having negligible energy (relative to the rest of the spectrum) at wavelengths about of smaller than 400 nm.

As used herein, "long wavelength cutoff refers to light having negligible energy (relative to the rest of the spectrum) at wavelengths about of greater than 800 nm.

As used herein, a "subject in need thereof refers to a mammalian subject to whom photodynamic therapy is administered according to the invention. The subject may be human or non-human.

As used herein, "natural or artificial light" refers to electromagnetic radiation in any of the near infrared range (e.g. about 750 nm to 2.5 μm), the visible spectrum (e.g. about 380 to 750 nm) or the ultraviolet range (e.g. about 200 nm to 400 nm), or any subrange thereof, which is produced either by the sun or by an artificial light source in conventional surroundings, for example fluorescent white light or sodium lamp light.

As used herein, "photoenergy" refers to electromagnetic radiation, of a particular wavelength or wavelength range, for example, in the visible spectrum.

As used herein, "therapeutic effect" refers to a consequence of a medical treatment, such as photodynamic therapy, the results of which are judged to be desirable and beneficial. In the context of the present invention, a therapeutic effect includes any of substantial amelioration, abrogation, inhibition, slowing, or reversal of the progression, of clinical symptoms and/or pathological signs associated with a skin disorder being treated with photodynamic therapy.

As used herein, "transdermal formulation" refers to a formulation which is applied to the skin, and thereafter the active agent passes through the skin tissue and into the bloodstream, thereby providing a systemic effect.

As used herein, "topical formulation" refers to a formulation which is applied to the skin, and thereafter the active agent provides a local effect at the site at which it is applied.

As used herein, "wearable" refers to the capability of an object to remain substantially fastened or attached to a body site of a subject, even while the subject is mobile or in motion. As used herein, "maintaining contact with the skin surface" refers to the capability of a formulation to remain substantially at the skin site to which it was applied e.g. without undergoing movement in a lateral or descending direction, either while the subject is stationary or mobile.

As used herein, "extended period of time" refers to a period of time which is compatible for carrying out photodynamic therapy using the device and kit of the invention e.g. for a period of hours, days or weeks.

As used herein, "conventional surroundings" refers to indoor and outdoor environments encountered in the course of routine day to day activity of an individual, and expressly excludes an environment which is in close proximity to a dedicated manufactured photoenergy source.

As used herein, "conventional everyday activities" refers to routine day to day activity of an individual, and expressly excludes exposure to a dedicated manufactured photoenergy source.

As used herein, "a dedicated manufactured photoenergy source" refers to a light source specifically intended and designed for PDT.

Unless otherwise specified, percentages stated herein are in relation to the final weight of the total formulation. It is further to be noted that all numerical values stated herein include a standard deviation that is acceptable in the pharmaceutical arts, and appropriate for any particular component or pharmaceutical ingredient.

Device for photodynamic therapy

The present invention provides a wearable device for photodynamic therapy which comprises: (a) a pharmaceutical formulation for topical application to the skin, and (b) a skin covering for mounting over the topically applied formulation. In currently preferred embodiments, at least one of the skin covering and the formulation incorporate a light filtering material. In a particular embodiment, the skin covering comprises at least one light filtering material. In another embodiment, the formulation comprises a light filtering material. When a light filtering material is present in both the formulation and the skin covering, the light filtering materials may be the same or different, but generally have the same light transmitting properties.

The device may contain or be used in conjunction with additional components, for example, a means for fastening the device at the skin site, a means for masking the covering, and a frame for circumscribing the skin site.

Reference is made to Figure 1 which illustrates a sectional view of one embodiment of the wearable device 100. Covering element 102 is placed or mounted over a pharmaceutical formulation 104 comprising a photosensitizer and a carrier, as described herein. The formulation 104 may be in the form of a molded gel as shown. Formulation 104 may be configured to fully occupy the space defined by covering element 102 as shown, but may alternately be configured to partially occupy said space. Alternately or in addition, formulation 104 may be configured to accommodate the contours i.e. "wrap around", of an irregularly shaped body part containing the skin site to be treated, for example the knee. In one embodiment, covering element 102 comprises a light filtering material selected to transmit light of wavelength that activates the photosensitizer present in formulation 104. Preferably, the light filtering material selectively transmits light of wavelength or wavelength range that activates the photosensitizer in formulation 104. In other embodiments, formulation 104 additionally or alternately incorporates a light filtering material such as an organic or inorganic dye, or an optical gel, which similarly enables transmission of light for activating the photosensitizer in formulation 104. Fastening means 106 enables attachment or fastening the device 100 at a site on the skin of a subject, preferably by circumscribing the body part e.g. knee or elbow, containing the skin site. It is to be understood that while covering element 102 is configured in the depicted embodiment as substantially

dome shaped, it may be alternately configured to assume any one of a variety of shapes, such as a rectangular open box. There is no particular upper or lower limit on the thickness or covering element 102 or formulation 104. It may be preferable however, that these elements are of minimal thickness possible (for example in the range from about 0.2 mm to 3 mm) so as to enable minimum interference with daily routine and maximum mobility while the device is worn by the user.

Reference is made to Figure 2 which illustrates a sectional view of an additional embodiment of the device mounted to a skin surface. Frame 108 circumscribes a site on the skin 112 having a lesion to be treated. Pharmaceutical formulation 104 comprising a photosensitizer is disposed on skin site 112 within the limits defined by frame 108. Frame 108 may be of any convenient material, such as a plastic. In this embodiment, covering element 102 and frame 108 are substantially identical in circumference, enabling covering element 102 to be coincidently disposed on the upper surface of frame 108, as shown. Thus, according to this embodiment, covering element 102 does not directly contact the upper skin surface 110 or 112. hi an optional embodiment, covering element 102 and frame 108 are joined through a joining element, such as a hinge, as depicted by number 126 in Fig. 4. hi an alternate embodiment, covering element 102 has a circumference greater than that of frame 108 so that covering element 102 directly contacts the skin surface 110 and surrounds frame 108. and may incorporate a light filtering material having the same light transmitting properties as the light filtering material incorporated into covering element 102 and/or formulation 104. Alternately the frame may block or transmit most wavelengths of light. Formulation 104 is as described for Fig. 1. As explained above, either or both of covering element 102 and formulation 104 may comprise a light filtering material selected to transmit light of wavelength that activates the photosensitizer present in formulation 104. Fastening means 106 enables attachment or fastening of device 100 at a site on the skin of a subject, preferably by circumscribing the body part e.g. knee or elbow, containing the skin site.

Reference is made to Figure 3 which illustrates a perspective and partially cut- away view of an embodiment of device 100. Covering element 102 and fastening means

106 are associated through slots 116 which accommodate the fixed ends 114 of fastening means 106. Adjustable ends 132 enable altering the length of fastening means

106 so that device 100 may be made to fit snugly around a limb such as a leg or arm,

particularly at the knee or elbow joint. Adjustable ends 132 may comprise for example, hooks and loops fabric patches, a snap fastener, a watch strap-like buckle and holes, or any other similar means for fastening the ends of an adjustable strap. In other embodiments, fastening means 106 may have a fixed length, for example a stretchable elastic strap which accommodates and fits snugly around a limb. In additional embodiments, the fixed ends 114 of fastening means 106 are tapered relative to the wider principle portion of fastening means 106. Covering element 102, shown partially cut-away, may comprise a light filtering material selected to transmit light of wavelength that activates the photosensitizer present in formulation 104. In other embodiments, formulation 104 additionally or alternately incorporates a light filtering material such as an organic or inorganic dye, or an optical gel.

Reference is made to Figure 4 which illustrates a perspective view of covering element 102 associated with masking means 120 and frame 108. Masking means 120 comprises terminal attachment areas 122, such as hooks and loops fabric patches. Covering element 102 comprises complementary attachment areas 124 to which masking means 120 may be removably attached via the terminal attachment areas 122. When in place, masking means 120 enables continued occlusion of the skin site by the skin covering device, even after the required time period for exposure to light has been achieved. Frame 108 is associated with covering element 102 via joining element 126, which may be a hinge as shown. Joining element 126 enables articulation of the covering element in an arc, so as to "open" the covering element and thus enable replenishment and/or replacement of pharmaceutical formulation 104 without removal of the skin covering device from the skin site.

Reference is made to Figure 5 which shows device 100, in partial cut-away view, in place on a skin site on the elbow 118 of a subject. Covering element 102, shown partially cut-away, is disposed over pharmaceutical formulation 104 comprising a photosensitizer. Fastening means 106 attaches device 100 so as to immobilize it over the skin site requiring photodynamic therapy i.e. the outer lateral surface. In this embodiment, a light filtering material is incorporated into covering element 102. Incident light from the surroundings is shown either transmitted through 128, or reflected from 132 covering element 102, depending on the wavelength and the light filtering material present in covering element 102.

In addition embodiments, the covering element may ^" be a simple medical-type bandage and the means for fastening may be an adhesive material disposed thereupon, as is known in the art. For example, the adhesive material may be disposed at the terminal ends of the bandage, or in the case of a circular bandage, around the periphery of said bandage, or in any other pattern used in the art. In a particular embodiment, the formulation is disposed upon the adhesive bandage, for example in a central region. In particular embodiments, the bandage is either transparent or incorporates a light filtering material. A transparent bandage may be used in conjunction with a formulation which incorporates a light filtering material, such as an optical gel. Suitable bandages may be made from thin polymeric films, such as polyurethane, polyethylene, polypropylene, or polyvinyl chloride, as is known in the art. Preferably, these materials are uniform in thickness so that they provide a uniform transfer of photoenergy through the bandage. There is no particular limitation on the shape or configuration of the bandage used, but preferably is suitable in size to the skin area being treated. The bandage may preferably have occlusive properties, which may augment the therapeutic effect.

Formulations

The formulation used with the device comprises (i) at least one photosensitizer or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier. Suitably, the formulation is in a form selected from a gel, an ointment, and a cream, and is preferably transparent, although it may be semitransparent. A high degree of transparency is advantageous for permitting transmission of photoenergy through the topically applied formulation to the underlying skin site requiring treatment.

The formulation may be applied directly to the skin from an applicator, or in the case of a gel formulation in a molded shape or configuration, from a storage package.

In a particular embodiment, the formulation is a gel and is molded to the contours of the skin site to which it is to be applied. The formulation of the invention may be provided either in a pre-determined "standard" shape, or may be "custom" molded or stretched immediately prior to use. Stretchable gelatin-based gels, such as those described in Example 1, are useful for providing a "custom-fitted" formulation for applying to a skin site. Alternately, the formulation may be molded to a shape and size so that it fully or partially occupies the covering element of the skin covering device. In

a particular embodiment, the gel formulation is stretchable so that it may

Alternately or in addition, the formulation may be applied to the skin in an area circumscribed or defined by a means of the device, such as a frame, which circumscribes a site on the skin intended for treatment. It is to be expressly understood that while the formulation is topically applied to the skin, the formulation may be either a topical formulation, providing a local effect only, or it may be a transdermal formulation, in which case, at least a portion of the active agent penetrates the skin and passes into the bloodstream, providing a systemic effect. In some embodiments, the formulation incorporates a light filtering material, such as an organic or inorganic dye, or an optical gel. When the formulation comprises a light filtering material, the skin covering may or may not comprise a light filtering material.

Gel formulations Gel formulations are semisolid systems consisting of organic molecules distributed substantially uniformly throughout a liquid vehicle. Gels can be prepared by combining together a liquid vehicle and a gelling agent, optionally while heating, and mixing until homogeneous. The gel mixture may be cast in a mold of desired shape. Suitable gelling agents include gelatin (for example, 1-20%); tragacanth (for example, 2 to 5%); sodium alginate (for example, 2-10%); methylcellulose (for example, 3-5%); sodium carboxymethylcellulose (for example, 2-5%); carbomer (for example, 0.3-5%) or polyvinyl alcohol (for example, 10-20%). Other gelling agents include polyurethanes, methylhydroxy cellulose, polyoxyethylene-polyoxypropylene and hydroxyethyl cellulose. The liquid vehicle is generally aqueous, but alcohols and oils can be used instead of, or in addition to water or any other aqueous liquid.

It is to be expressly understood that in the context of the present invention, a gelling agent and a liquid vehicle are considered components of the carrier of the formulation.

A suitable gelling agent is gelatin. Gelatin strength may be graded according to its "Bloom number" The Bloom number describes the gel strength formed at 10 ⁰ C with a

6.67% solution gelled for 18 hours. In a particular embodiment, the gelatin used in the

invention has a Bloom strength in the range of 100 to 400. In a particular embodiment, the gelatin is present in the formulation in an amount in the range 0.5 to 20%(w/w) ₅ , such as 6 to 16%(w/w), based on the total weight of the formulation. Suitable gelatin- based gels for use in the invention are disclosed in Example 1. While there is no requirement for cross linking, in a particular embodiment, the gelatin may be crosslinked. The cross linking may be achieved by a chemical cross linker, or by a physical method, such as UV irradiation, gamma irradiation, microwave irradiation or a thermal effect. A suitable degree of cross linking is in the range from about 5 to about 100%. In a particular embodiment, the gel is a semisolid gel or a soft gel. In a particular embodiment, the gel is a stretchable gel with elastic properties, for example a gelatin- based gel as described in Example 1, to enable it being stretched over a skin site requiring therapy.

In a particular embodiment, the gel is a thixotropic gel. A thixotropic gel is characterized by having a decreased viscosity i.e. more liquid-like state, when mechanically disturbed, and an increased viscosity i.e. more gel-like state, in the undisturbed state. Thixotropic gels for pharmaceutical formulations are disclosed for example in U.S. Patent Nos. 5,858,330; 5,473,005 and 6,855,733. hi a particular embodiment, the gel is a hydrogel. A hydrogel is a polymer network having a high water content (typically in the order of 99%) and absorbency.

Polymers suitable for forming hydrogels include natural gel-forming polymers such as carrageenan, xanthan gum, gum karaya, gum acacia, locust bean gum and guar gum, and synthetic polymers such as polyvinyl alcohol, sodium polyacrylate and acrylate polylmers. Hydrogels for pharmaceutical formulations are disclosed for example, in U.S. Patent Nos. 7,022,313 and 6,960,617. Polyurethane based hydrogels are disclosed for example, in U.S. Patent Nos. 3,822,23; .3975,350 and 4,454,309. hi a particular embodiment, the gel is an anhydrous gel. Anhydrous gels for pharmaceutical formulations are disclosed for example, in U.S. Patent No. 5,846,550.

Ointment formulations Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, is one that will

enable optimal photoactivation of the photosensitizer contained therein, and, preferably, will provide for other desired characteristics as well, e.g. emolliency or the like. As is known in the art, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or microemulsions, or oil-in- water (O/W) emulsions or microemulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Water-soluble ointment bases may be prepared from polyethylene glycols (PEGs) of varying molecular weight.

Cream formulations

Creams are viscous liquid or semisolid emulsions or microemulsions, either oil- in- water or water-in-oil. Cream bases are water- washable, and contain an oil phase, an emulsifier (used interchangeably with emulsifying agent) and an aqueous phase. The oil phase is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and may contain a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.

The preparation of emulsions or microemulsions, involves use of surfactant (emulsifier), co-surfactant (co-emulsifier), an oil phase and a water phase. Suitable surfactants include any surfactants that are useful in the preparation of emulsions, e.g., emulsifiers that are typically used in the preparation of creams. The co-surfactant is generally selected from the group of polyglycerol derivatives, glycerol derivatives and fatty alcohols. Suitable emulsifier/co-emulsifier combinations include: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprilic and capric triglycerides and oleoyl macrogolglycerides. The water phase includes not only water but also, typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g. PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phase will generally comprise, fatty acid esters, modified vegetable oils, silicone oils, mixtures of

mono- di- and triglycerides, mono- and di-esters of PEG (e.g. oleoyl macrogol glycerides), etc.

Methods of preparing ointment and cream formulations are well known in the art, described for example in Encyclopedia of Pharmaceutical Technology 2 ^nd ed., New York, Marcel Dekker, 2002.

Photosensitizers

The photosensitizer is suitably present in the formulation in an amount of 0.01 to 1.0 %(w/w), based on the total weight of the formulation. In some embodiments, the photosensitizer is present in an amount of 0.05 to 0.1 %(w/w), or in an amount of 0.1 to 0.5 %(w/w), based on the total weight of the formulation. In a currently preferred embodiment, the photosensitizer is hypericin or a pharmaceutically acceptable derivative or salt thereof. Hypericin is an aromatic polycyclic dione (perihydroxylated naphthodianthrone; dianthraquinone) known to have photodynamic properties (Duran et al. (1986) Photochem. Photobiol. 43:677-689; Giese (1980) Photochem. Photobiol. Rev. 5:229-255), with light absorption peaks in the visible range at 545 and 589 nm. In the presence of light (and possibly other sources of energy), hypericin excites oxygen to its singlet state and is capable of generating superoxide radicals which can lead inter alia, to oxidation of tryptophan imidazole groups in proteins and oxidation of fatty acids in biological systems. For use in the present invention, hypericin may be the product of a chemical synthesis, as described for example, in U.S. Patent No. 5,120,412. Alternately, or in addition, hypericin may be an extract of the plant St. John's wort {Hypericum perforatum) which has been depleted of various pigments e.g. chlorophylls and proanthocyanidines, as described for example, in U.S. Patent No. 7,166,310. Suitable extracts may be prepared using as solvents acetone, ethanol or a mixture thereof, and may be further purified using an adsorbing agent such as a resin.

The hypericin may be present in the formulation in an amount of 0.1 %(w/w), or in an amount of 0.25 %(w/w), or in an amount of 0.5 %(w/w), based on the total weight of the formulation. In one embodiment, hypericin is present in the formulation in an amount of about 0.125 %(w/w). Hypericin containing formulations are conveniently prepared from stock solutions containing 0.5% hypericin dissolved in an alcohol, typically ethanol .

Hypericin derivatives are compounds obtained by chemical modification of hypericin, such as pseudohypericin and protohypericin. Hypericin derivatives also include various substituted hypericin derivatives, such as those with alkyl or substituted alkyl group substitutions, O-substitutions, and halogen and sulfonate substitutions. Methods for making protohypericin are disclosed in U.S. Patent No. 5,120,412.

Methods for making pseudohypericin are disclosed in U.S. Patent No. 4,898,891.

According to the invention, "hypericin derivatives" also encompass hypericin analogs, which are compounds having a chemical structure similar to that of hypericin, such as emodin. Hypericin derivatives and analogs are disclosed, for example in U.S. Patent No. 7,195,783.

The invention may employ one or more additional photosensitizers of the following classes: texaphyrins, benzoporphyrin derivatives (e.g. Visudyne ^® ), azaporphyrins, phthalocyanines, purpurins, Rose Bengal, xanthenes, porphycyanines, isomeric porphyrins, pentaphyrins, sapphyrins, phlorins, benzochlorins, hypericins, anthraquinones, rhodanols, barbituric acid derivatives, expanded porphyrins, dipyrromethenes, coumarins, azo dyes, acridines, rhodanine, azine derivatives, tetrazolium derivatives, safranines, indocyanines, indigo derivatives, indigo triazine derivatives, pyrrole derived macrocyclic compounds, naturally occurring or synthetic porphyrins, naturally occurring or synthetic chlorines, naturally occurring or synthetic bacteriochlorins, naturally occurring or synthetic isobacteriochiorins, naphthalocyanines, phenoxazine derivatives, phenothiazine derivatives, chaloorganapyrylium derivatives, triarylmethane derivatives, rhodamine derivatives, fluorescein derivatives, verdin derivatives, toluidine blue derivatives, methylene blue derivatives, methylene violet derivatives, nile blue derivatives, nile red derivatives, phenazine derivatives, pinacyanol derivatives, plasmocorinth derivatives and indigo derivatives. hi a particular embodiment, the photosensitizer comprises hypericin or a pharmaceutically acceptable derivative or salt thereof, and the carrier comprises gelatin, hi a particular embodiment, the hypericin or a pharmaceutically acceptable derivative or salt thereof is present in an amount of 0.01 to 1.0%(w/w), for example 0.125%, based on the total weight of the formulation, and the gelatin is present in an amount of 0.5 to 20 %(w/w), based on the total weight of the formulation. In a particular embodiment,

the formulation comprises (i) hypericin or a pharmaceutically acceptable derivative or salt thereof in an amount of 0.05 to 1.0%(w/w), and (ii) gelatin in an amount of 0.5 to 2.0 %(w/w), or in an amount of 6 to 16 %(w/w)wherein the gelatin has degree of cross linking in the range 5 to 100%, and wherein the pH of the formulation is in the range 4 to 8.

Carriers

For use in the invention, a suitable carrier appropriately has properties e.g. of viscosity, flexibility and adhesiveness, so as enable the formulation to (i) be molded in a shape that assumes the contours of the skin surface to which it is to be applied; (ii) maintain its form or shape, (iii) maintain its contact with the skin surface, and (iv) avoid breakage in response to body movement of the wearer. Psoriatic lesions are often irregular in shape and frequently occur on contoured non-uniform skin surfaces, such as the elbows and knees. Advantageously, the carrier enables the formulation to be molded to a shape or form which assumes the contours of the body surface to which it is to be applied. The ability of the carrier to maintain its shape or form for extended periods is important in the context of the present invention, since the subject method involves delivery of photodynamic therapy over extended periods of time under circumstances of conventional everyday activity. Accordingly, the carrier should also be relatively resistant breakage in response to disturbances and forces, such as body movement and body generated heat. For the same reason, the formulation must be capable of maintaining its contact with the skin for prolonged periods, and accordingly should be substantially stable and resistant to decomposition. However, the carrier must also be sufficiently fluid so as to permit diffusion of the photosensitizer from the formulation to the skin site onto which it is applied. In addition, the carrier must be substantially inert, and not be associated with a tendency to induce allergic and/or inflammatory reactions in skin.

The carrier suitably comprises at least one polymer. The polymer may be crosslinked, for example having a degree of crosslinking in the range 5 to 100%.

A large number of polymers are known in the art for topical and transdermal formulations. Examples of suitable polymers include, but are not limited to, alginate; a cellulose derivative; gelatin; gum arabic; guar gum; karaya gum; tragacanth gum; xanthan gum; phthalate; polyacrylic acid; polyethylene glycol; polylactic acid;

poly(lactic-co-glycolic acid); polyvinyl alcohol; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylene; polyisobutylene; an acrylic polymer, an acrylic acid polymer; styrene; a styrene isoprene block copolymer; a urethane; a polyurethane; a silicone; butadiene; a styrene butadiene copolymer; a polyacrylate; and combinations thereof.

Suitable cellulose derivatives include, but are not limited to, carboxymethyl cellulose; ethyl cellulose; hydroxyethyl cellulose; hydroxylpropyl cellulose; hydroxypropylmethyl cellulose; methyl cellulose; methylhydroxy cellulose; cellulose acetate, and combinations thereof. In a particular embodiment, the polymer is gelatin. In a particular embodiment, the gelatin is crosslinked. The cross linking may be achieved by a chemical cross linker, or by a physical method, such as UV irradiation, gamma irradiation, microwave irradiation or a thermal effect. A suitable degree of cross linking is in the range 5% to 100%. In particular embodiments, the carrier comprises a mixture of different polymers, or a mixture of the same polymer of different molecular weights. hi a particular embodiment, the carrier of the present invention comprises a pressure sensitive adhesive, i.e. a viscoelastic material which adheres instantaneously to a substrate with the application of very slight pressure and remains permanently tacky. An example of a pressure sensitive adhesive is soluble polyvinylpyrrolidone (PVP).

In particular embodiments, the pressure sensitive adhesive comprises a rubber, including natural rubber or a synthetic elastomeric polymer, a silicone or an acrylic material. Suitable rubber adhesives include natural and synthetic polyisoprene, polybutylene and polyisobutylene, styrene/butadiene polymers, styrene-isoprene-styrene block copolymers, hydrocarbon polymers such as butyl rubber, halogen-containing polymers such as polyacrylo-nitrile, polytetrafluoroethylene, polyvinylchloride, polyvinylidene chloride, and polychloropene, and polysiloxanes and other copolymers thereof.

The carrier suitably comprises at least one solvent, such as water; ethanol; butylene glycol; propylene glycol; isopropyl alcohol; isoprene glycol; glycerin and combinations thereof. Li a particular embodiment, the ratio of polymer to solvent is in the range of 1:3 to 1:100.

In a particular embodiment, the formulation has a pH in the range 4 to 8. In a particular embodiment, the formulation comprises an emulsion of the photosensitizer and at least one emulsifying agent. In a particular embodiment, the emulsifying agent is selected from a cationic surfactant, an anionic surfactant, an amphoteric surfactant, a nonionic surfactant, and combinations thereof.

Skin permeation enhancers

According to particular embodiments, the formulation may further comprise a skin permeation enhancer, for improving penetration of the photosensitizer into the skin. A suitable skin permeation enhancer may be selected from a keratolytic agent, an essential oil; a detergent; a polymer and combinations thereof. Suitable keratolytic agents include, but are not limited to, propylene glycol, lactic acid, urea and salicylic acid. Suitable essential oils include, but are not limited to, wintergreen, jojoba, eucalyptus, coconut and thyme. Suitable detergents include, but are not limited to, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, a poloxamer, a polysorbate and lecithin. Suitable polymers include, but are not limited to, polyethylene glycol and esters thereof.

Emulsifiers

According to particular embodiments, the formulation may further comprise an emulsifier, which may be selected from an anionic, cationic or anionic emulsifier. Suitable emulsifiers for the invention are those known in the art for producing oil-in- water and/or water-in-oil type emulsions or microemulsions. An emulsion may be necessary in order to produce a uniform and stable preparation of the photosensitizer and or other components of the formulation. An emulsion with an aqueous external phase may be preferred for skin contact, since is less likely to produce an oily or greasy sensation upon application, as occurs with an emulsion having an oily external phase. The chosen emulsifier, depending upon its chemical nature, will be a component of either the oily or aqueous phase of the emulsion, and assists with any of formation, maintenance and stability of the formulation.

Suitable emulsifiers include sorbitan esters; ethoxylated sorbitan esters; mannitan and xylitan esters; polyglycerol esters; ethoxylated castor oil; ethoxylated hydrogenated castor oil; glycerol stearate; polyglycol or polyglycerol polyhydroxystearates; polyethylene glycol/alkyl glycol copolymers; PEG esters, such as PEG-8 distearate,

PEG-5 glyceryl stearate, PEG-20 stearate, PEG-100 stearate and PEG-6 oleate; amine oxides; sucrose esters; ethoxylated or non-ethoxylated methylglucoside esters; ethoxylated fatty acids; ethoxylated fatty alcohols; cetearylsulfate; aluminum polyoxystearate; magnesium stearate; and aluminum stearate. The surfactant may be present in an amount of about 0.05 to about 10% by weight based on the total weight of the formulation.

Additional excipients

The formulations may include addition excipients, such as preservatives, moiturizers, emollients, pH adjusters, buffering agents, chelating agents, film forming agents, conditioning agents and protectants. Suitable preservatives include, but are not limited to, propylene glycol, diazolidinyl urea, methylparaben, and propylparaben, methylparaben, propylparaben, imidazolidinyl urea, benzyl alcohol, sorbic acid, benzoic acid, sodium benzoate, dichlorobenzyl alcohol, formaldehyde, alpha-tocopherol (vitamin E), sodium ascorbate/ascorbic acid, ascorbyl palmitate, propyl gallate and combinations thereof.

Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, butylene glycol, sodium PCA, a PEG and a methoxy PEG. Suitable emollients include, but are not limited to, PPG- 15 stearyl ether, lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, octyl stearate, mineral oil, isocetyl stearate, myristyl myristate, octyl dodecanol, dimethicone, phenyl trimethicone, cyclomethicone, dimethiconol, cyclomethicone, propylene glycol dicaprylate/dicaprate and combinations thereof.

Coverings and light filtering materials

According to the invention, the covering element of the device is adapted to enclose the formulation over the site on the skin of the subject requiring photodynamic therapy. According to one embodiment, the covering element is for selectively transmitting only light of wavelength(s) which activates the photosensitizer.

Accordingly, the covering element comprises at least one light filtering material, wherein the light filtering material is selected to transmit light which enables photoactivation of the photosensitizer. This is an important property of the covering element, since it avoids the transmission of wavelengths which have the potential to interfere with the photoactivation of the photodynamic agent and/or the desired

photodynamic effects.

The transmission function of the light filtering material may be classified as any one or more of narrow bandpass, wide bandpass, short wavelength cutoff, long wavelength cutoff, short wave pass and long wave pass. In particular embodiments, the light filtering material transmits light having wavelength in the range from 400 to 900 nm, or from 500 to 700 nm, or from 570 to 650 nm. The light filtering material may comprise any suitable material such as an optical gel, glass or a polymer material, such as a polymeric film. Suitable polymeric films include without limitation, polycarbonates, acrylics, nylons, polyesters, polyurethanes, polyolefins, cellulose acetates, cellulose triacetates, vinyl acetals, polyimide, vinyl chloride polymers and combinations thereof.

A suitable polymer is preferably flexible and/or elastic so as to accommodate body movement, for example at the elbow and knees while the device is in place on a user. In particular, deep dyed plastic and polyester light filtering materials, as are known in the art, may be used. A large variety of such products are commercially available, and may be adapted from other optical applications (e.g. co-extruded sandwiched colored filters used for theater and film productions). The light filtering material may be one which responds non-linearly to solar radiation intensity, or chromic. This feature may be useful for reducing the solar flux when the skin site undergoing treatment is expected to be exposed to solar flux for an extended period of time. Alternatively it may be useful to slow down the photodynamic therapy reaction to rates tolerable by the tissue of the region.

The light filtering material may be photochromic or thermochromic.

Photochromic materials may be selected from photochromic glass, photochromic polymer, and switchable photochromic material. An example of a suitable photochromic polymer is allyl diglycol carbonate. The transmission of this material falls from 85% to 33% following exposure to the UV spectrum of direct solar flux.

The covering element and/or the light filtering material may be made of a single sheet or layer, or may be made of multiple small sections tailored into a single layer. The covering element may be coated with the light filtering material or deep dyed with the light filtering material.

The light filtering capacity of a particular material may be determined from its

spectral energy distribution curve, as is known in the art.

In additional embodiments, the covering is transparent having no particular light filtering properties. An example of a transparent covering is a transparent medical bandage, as is known in the art. Additional components of the device

The device conveniently includes a means for fastening the covering element to the site on the skin of the subject. Suitable fastening means include, but are not limited to adhesive tape, a hooks and loops fabric strap, an adjustable belt, an elastic material, cling wrap and combinations thereof. For example, when the device is to be used to administer photodynamic therapy at a site on the arm, the device may be fitted with a hooks and loops fabric strap which attaches around the circumference of the arm. hi the case of a bandage, the fastening means is an adhesive material disposed either at the terminal ends of the bandage or around the periphery, in the case of a circular bandage, or in any other configuration as is known in the art. The device may conveniently include a means for masking the cover, wherein the masking means is substantially reflective of natural and artificial light. The masking means may be detachable or partially detachable. When attached over the covering, the masking means prevents light from transmitting through the covering. Such an option provides for leaving the formulation in place on the skin without light exposure. This may be desired, for example, immediately following application of the formulation to the skin, if there is required an initial period of time for penetration of the formulation into the skin, prior to the initiation of photodynamic therapy. The masking means is also useful, for example to enable intermittent periods of light exposure, during the course of photodynamic therapy. Use of the masking means further enables the device to remain in place following completion of the desired or required time period of light exposure, so as to continue to occlude the skin site being treated. The use of the masking means will be dictated by the particular photosensitizer used, and the treatment regimen selected by the practitioner. The masking means may comprise a material such as fabric or plastic, and may be fitted with fasteners such snaps or hooks and loops fabric patches.

The device may further comprise a frame for surrounding or circumscribing a site on the skin onto which the formulation is applied. The frame is disposed between the

covering element and the site on the skin requiring treatment. Conveniently, the frame and the covering element are joined through a joining element, such as a hinge or foldable element. When present, the joining element provides a convenient means of opening the covering element so as to enable replenishment and/or replacement of the pharmaceutical formulation without removal of the skin covering device from the skin site.

The device may further comprise or be used in conjunction with an occlusive barrier, for example an adhesive patch. Adhesive patches are disclosed for example, in U.S. Patent No. 6,830,758. It is preferred that the occlusive barrier be substantially transparent. The occlusive barrier is most desirably placed between the formulation and the covering element of the ring device, such that the outer borders of the occlusive barrier extend beyond the circumference of the covering element so as to fully occlude the skin site requiring photodynamic therapy. Accordingly, the occlusive barrier augments the occlusion provided by the covering element. Kits

The kit provided by the invention conveniently enables a patient to undego in situ photodynamic therapy on an out-patient mobile basis, with a minimum of visits to a specialized medical setting.

The kit comprises (a) at least one packaged product comprising a topical pharmaceutical formulation, the formulation comprising at least one photosensitizer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and

(b) a wearable skin covering device adapted to enclose the formulation over the skin surface to which the formulation is applied. hi some embodiments, the kit comprises more than one packaged product, for example different formulation products containing distinct photosensitizers for use with different light filtering materials, or formulations comprising the same photosensitizer at different concentrations, for incrementally increasing or decreasing the therapeutic effect. Alternately, the formulation products may differ with respect to the presence and absence of a light filtering material. The packaged product is generally a multi-use package form, such as a tube or other container, optionally comprising an applicator, which may be comprised in the tube cover. Alternately, a multi-use package form provides individual aliquots of the

formulation, for example a multi-unit blister pack providing individual molded gel doses.The formulation may be in the form or a gel, an ointment, or a cream, as hereinbefore described. It may be particularly suitable to provide a molded or stretchable gel which "fits" the contours or an irregularly shaped body site, for example the elbow, containing the skin site for treatment.

The wearable skin covering comprises a covering element for placement over the formulation applied to a skin surface, and a means for fastening the covering element at said site on the skin. The covering element may comprise at least one light filtering material as hereinbefore described. When incorporated into the covering material, the light filtering material is selected to enable transmission of light which activates the particular photosensitizer selected for use.

The covering element is preferably transparent, but may be semitransparent, and may be in any shape or size which permit attachment to a body site. In a particular embodiment, the covering element is substantially dome-shaped, which is advantageous for placement over a joint such as the elbow or knee.Different light filtering covering elements may be provided with the kit so that the device may be adapted for use with distinct photosensitizers activated by different wavelength ranges.

The means for fastening is conveniently adapted to circumscribe a limb of the subject, and may comprise any device such as a hook and loops strap, an adjustable belt, an elastic strap, an adhesive tape and a combination thereof.

In a particular embodiment, the kit comprises a multiplicity of adhesive bandages wherein the bandages comprise a first region comprising a gel formulation comprising a photosensitizer and a second region comprising an adhesive. In a particular embodiment, the bandages are transparent. In a particular embodiment, the bandages comprise a light filtering material.

Optional components of the skin covering device are a masking means and a frame as hereinbefore described.

The kit may further include an occlusive barrier for placement between the formulation and the covering element of the skin covering. The occlusive barrier extends beyond the circumference of the covering element so as to occlude the skin site being treated.

Methods of photodynamic therapy

The invention further provides a method of administering in situ photodynamic therapy to a subject in need thereof. The method comprises the steps of: (i) selecting a site on the skin of the subject where the photodynamic therapy is to be administered; (ii) topically applying to the selected site a pharmaceutical formulation comprising at least one photosensitizer or pharmaceutically acceptable salt thereof, wherein the formulation is capable of spreading, adhering and conforming to the skin surface with which it is in contact and is capable of maintaining the contact over an extended period of time; (iii) mounting over the skin site a skin covering, such that the covering encloses the formulation over the site on the skin, and (iv) exposing the skin site having said skin covering mounted thereon to natural or artificial light for a period of time effective to achieve a therapeutic effect.

While it is to be understood that the method is to be carried out under the supervision of one of skill in the art i.e. a qualified medical practitioner, use of the method can save numerous hours in visits to specialized clinics, as is required for conventional photodynamic therapy regimens. Furthermore, since the method may be carried out over extended periods of time, the dose of photosensitizer used may be significantly less than that routinely used in photodynamic therapy. hi various embodiments, at least one of the skin covering and the formulation comprise at least one light filtering material. In a particular embodiment, the skin covering comprises at least one light filtering material.

Reference is now made to Figure 6, which is a simplified flow chart 200 of a method for in situ photodynamic therapy, in accordance with an embodiment of the present invention. In a selecting step 210, a site on the skin of the subject is designated for treatment.

The method is applicable for a number of skin disorders, including but not limited to psoriasis, acne, actinic keratosis, skin cancer, basal cell carcinoma, eczema, seborrhea and hyperkeratinosis. hi a topical application step 220, the pharmaceutical application comprising a photosensitizer is applied to the skin site designated for treatment. Application may be carried out by placing and/or spreading a formulation in the form of a gel, cream or ointment on the skin site. A gel formulation may be a molded shaped mass provided as

a pre-determined "standard" shape, or it may be "custom" molded or stretched immediately prior to use. Selection of the pharmaceutical formulation, with respect to the photosensitizer and its dosage, is within the ability of one of average skill in the art.

In a mounting step 230, a skin covering is mounted and affixed to the skin site upon which the formulation is applied. This step may conveniently comprise use of a fastening material such as an adhesive tape, a hooks and loops strap, a stretchable elastic strap and combinations thereof. The skin covering may be part of a device as described herein. Alternately, relatively simple materials may be adapted to form the skin covering. In a particular embodiment, the skin covering incorporates a light filtering material selected to transmit light for activation of the photosensitizer. Selection of the combination of the photosensitizer and an appropriate light filtering material is within the ability of one of average skill in the art.

In an exposing step 240, the skin site to which the formulation has been applied and having the covering mounted thereupon is exposed to natural or artificial light so as to enable activation of the photosensitizer. This step is preferably carried out in the course of conventional everyday activity. That is, the natural or artificial light is that provided by conventional surroundings. The duration and frequency of light exposure may be determined by a skilled practitioner in the art. The exposure to light may be, for example, carried out daily or on alternate days. The exposure to light may be, for example, for 0.5 to 12 hours per day of treatment. The exposure to light may be carried out daily or on alternate days over a period from 1 week to 40 weeks. It may be desirable to employ a regimen in which the daily exposure to light is incrementally increased. In a particular embodiment, the exposing to natural or artificial light is carried out without the use of a dedicated manufactured photoenergy source. When the period of PDT is terminated, the skin covering may be removed from the skin site. Alternately, if additional periods of PDT are required, but a "resting" step is required, the skin covering may be retained on the skin site, and masked with a masking means, as described for the embodiment of Figure 7. It is to be explicitly understood that steps 220 and 230 may be performed in reverse order. In particular, use of a skin covering device comprising a frame, as hereinbefore described, will involve first mounting the device over the skin site to be

treated. The frame provided by the device delineates the area upon which the pharmaceutical formulation is to be subsequently applied.

Reference is now made to Figure 7, which is a simplified flow chart 300 of a method for in situ photodynamic therapy, in accordance with another embodiment of the present invention.

In a selecting step 310, a site on the skin of the subject is designated for treatment, essentially as described for step 210 of Figure 6. In a topical application step 320, the pharmaceutical application is applied to the skin site designated for treatment, essentially as described for step 220 of Figure 6. In a mounting step 330, a skin covering is mounted and affixed to the skin site upon which the formulation is applied, essentially as described for step 230 of Figure 6.

In a masking step 340, the skin covering is made essentially opaque by the use of a masking means, such that light from the surrounding does not impinge on or transmit through the skin covering. This step is conveniently performed after application of the formulation so as to enable diffusion of the photosensitizer from the formulation into the skin.

In an exposing step 350, the masking means is removed from the skin covering so as to expose to natural or artificial light the skin site having the covering mounted thereupon. The exposing enables transmission of light through the covering and activation of the photosensitizer for an initial period of PDT. This step is preferably carried out in the course of conventional everyday activity, as previously explained. The duration of light exposure during the initial period of PDT will be readily determined by one of average skill in the art.

In a subsequent masking step 360, the skin covering is again made opaque by the use of a masking means. This is to enable intermittent periods of PDT, optionally with increasing and/or decreasing periods of exposure to light. The duration of the masking step will be determined by a skilled practitioner.

In a subsequent skin exposing step 380, the masking means is removed so as to again enable transmission of light through the covering and activation of the photosensitizer for a subsequent period of PDT. As shown in Figure 7, steps 360 and

380 may be repeated for a number of cycles, in accordance with various embodiments.

That is, the masking step may be carried out for intermittent periods between repeated

steps of exposing to light, for example, on alternate days.

It is to be understood that additional applications of pharmaceutical formulation may be applied to the skin site prior to each subsequent skin exposing step 380. In some embodiments, the formulation may be changed to one containing a different photosensitizer, in which case the skin covering may also be changed to provide an appropriate light filtering material. In other embodiments, the same photosensitizer may be used in subsequent exposing steps, but the concentration of the photosentizer may be increased or decreased. Alterations in the formulation may be decided upon by a skilled practitioner, depending on the clinical outcome of a particular period of PDT. It is to be explicitly understood that steps 320 and 330 may be performed in reverse order, as described for steps 220 and 230 of Figure 6.

The method of the invention may further comprise a step of molding or stretching a gel formulation to assume the contours of the skin site to which it is to be applied. This step is performed prior to or during the topical application of the formulation. This step is particularly important for treatment of skin lesions which are irregular in shape and which occur on contoured surfaces of the body. For example, difficult to treat psoriatic lesions are frequently found on the elbows and knees. Accordingly, for use in the method, the formulation may be provided in a pre-determined "standard" shape, or may be "custom" molded or stretched prior to use. The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the brand concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention.

The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. One skilled in the art can readily devise many

variations and modifications of the principles disclosed herein without departing from the scope of the invention.

EXAMPLES

Example 1. Gelatin formulations of hypericin

Gelatin of various Bloom strengths in the range 125-300 were used in various experiments. Preferred gelatins have Bloom strengths of 225 and 300 (16 mesh each).

To produce the formulation, gelatin (6-16 %) was mixed into a lukewarm solution of ethanol in water (60-70% ethanol). A stock solution of hypericin sodium salt dissolved in pyridine or dimethyl sulfoxide or ethanol was added to the gelatin.

A stretchable gel containing 12% gelatin was produced according to the formulation in Table 1.

Table 1.

The gelatin was gently melted in the ethanol/water by heating to 95 ⁰ C, and then cooled to 55 ⁰ C. Formaldehyde (10%; 1 ml) was added and the mixture stirred. Then 28 ml of 50% ethanol in water (at 55 ⁰ C) containing the hypericin stock was added to achieve a final concentration of 0.125% hypericin in the formulation. The mixture was maintained at 55 ⁰ C and stirred. The formulation was poured into moulds of suitable shape and allowed to achieve a gel consistency.

The obtained gel was suitable for stretching around the elbow region of a human subject without tearing or breaking, and exhibited adherence to the skin. The stretched gel was fastened to the skin surface using adhesive tape applied to the circumference of the stretched gel. The gel was maintained on the elbow for a period of 3 days without losing its shape or adherence to the skin.

Extra strength of the gel can be achieved by drying the gel and cooling at 8 ⁰ C, or by immersion in a crosslinking solution of glutaraldehyde (1-3%) for 24 hours, drying and washing in water with up to 2% glycine, albumin or milk to remove excesss formaldehyde Example 2. Use of a gelatin-based gel formulation of hypericin

A gelatin-based gel containing 0.125% hypericin was prepared as described in Example 1 and attached to guinea pig skin for 24 hours. This treatment resulted in a red stain in the entire depth of the dermis, indicating the ability of the formulation to enable penetration of hypericin to mammalian skin. While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.