OA16922A - Irradiation apparatus. - Google Patents

Abstract

A portable, self-contained, irradiation apparatus for photodynamic treatment of the vulva and/or the anus which comprises: a treatment surface 2 capable of conforming to the area of the vulva and/or anus to be treated, an illumination system 4 for directing light onto a treatment area of the vulva and/or anus and a power source 18 for the illumination system; wherein the illumination system is arranged to provide light at fluence rates of 50 mW/cm2 or below.

Description

IRRADIATION APPARATUS

This invention relates to an irradiation apparatus for photodynamic therapy of diseases, lésions and conditions of the vulva and/or the anus.

Conditions affecting the vulva include female génital warts and Vulvar Intraepithélial Neoplasia (VIN). The anus can be affected by Anal Intraepithélial Neoplasia (AIN). AIN is similar to VIN and may be treated in a similar fashion.

Female génital warts, VIN and AIN are often caused by persistent human papillomavirus (HPV) infection and are becoming increasingly common in young women. The human papillomavirus (MPV) is a virus that can infect the skin and mucus membranes in humans. More than 100 different types of HPV hâve been Identified. Several HPV types are transmitted through sexual activity and are pathogentc or hâve oncogenic potential. HPV is estimated to be the most common sexually transmitted infection in the US. Several hundred million women worldwide are Infected with HPV once in their life-time (70-80%), with the highest prevalence, 20-30%, occurring in young women 20-25 years of âge..

Moderato to severe VINs (VIN2-3) and moderato to severe AIN are referred to as precancerous conditions stnce if left untreated for a long period cancer can develop. Anal and cervical cancer are a life-threatentng diseases. Cervical cancer is today the third most common cancer form among women world wide. Sclentists agréé that there is a strong corrélation between the development of cancers and persistent HPV infections including vulval and anal HPV infections.

No standard treatment for conditions of the vulva such as female génital warts and VIN is available but surgery Is being used in the absence of therapeutic options. This often has to be repeated due to high récurrence rates. Multiple surgical treatments can cause vulval disfigurement and loss of sexual function. Alternative treatments include topical application of Imiqulmod (Aldara®). an Immune response modifier that is applied multiple times per week for several months. However, this treatment is cumbersome due the need for multiple repeated applications, there can be severe adverse réactions and the treatment gave conflicting results (see C.J. Jayne et al„ J Reprod Med 2002; 47(5), 395-398).

Photodynamic therapy (PDT) has been used as an experimental treatment for VIN and female génital warts. PDT is a therapeutic modality using a combination of light and a photosensitiser. When illuminated at a suitable wavelength the photosensitiser or PDT drug reacts with tissue oxygen to form oxygen radicale that Internet with cellular organelles including the mitochondria and cell membranes. These interactions cause cell necrosis or apoptosis (programmed cell death). PDT is today used clintcally for the treatment of several diseases,

-2Including various skin diseases. Through necrosis and apoptosis of the lésions, PDT will increase the level of antigens and immunological “danger signais including heat shock proteins. This will stimulate the patient immune system and Increase the level of cytotoxic cells (CD8+) that will further contribute to a satisfactory treatment response.

Typical products for use In skin PDT are Metvix® (Galderma, Switzerland) and Levulan® (Dusa Pharmaceuticals Inc, Wilmington, USA).

At présent, treatment of VIN with PDT Is an investigational procedure. Most published studies hâve used local application of 5-aminolevulinic acid (5-ALA). P. L Martin-Hirsch et al. (Lancet 1998; 351 (9113), 1403) describe the topical use of 5-ALA (20% w/w In Unguentum Merck) VIN patients. After local analgesia and Incubation of 5-ALA over 4 hours, the lésions were exposed to non-laser light with a wavelength of 630 nm. Treatment with a light dose of 50 J/cm² showed an unacceptably low response rate while treatment with a light dose of 100 J/cm² showed a clearance rate of 40-60%. P. Hillemanns et al. (Int J. Cancer; 85 (2000), 649-653) report about 25 patients with 111 lésions of VIN 1-3 who were topically treated with 10 mi 5-ALA solution (20% w/w In saline). After an incubation under occlusion for 4-5 hours, the lésions were exposed to an argonIon-laser-pumped dye laser providing light at 635 nm. A total light dose of 100 J/cm² was applied, with an irradiance (fluence rate) of 150 mW/cm². Patients were repeatedly treated with PDT and a complété response was achieved In 52% of the patients. A. Zawislak et al. (Photodiagnosis and Photodynamlc Therapy (2009), 6, 28-40) describe the topical use of a bioadhesive patch (3x5 cm) which contained a dose of 38 mg/cm² of 5-ALA in dry form. The patch remained in situ for 4-6 hours and PDT was carried out with a non-laser lamp with a wavelength of 630 nm over 20-30 min providing a light dose of 100 J/cm². Local anesthésia was available to the patients during and after PDT. Patients were repeatedly treated with PDT. A clearance rate of 52% was achieved.

Such dearance rates are similar to those of laser évaporation or local exdsion mostly because ofthe multifocal nature ofVIN disease. However, considerably shorter healing times and no scarring was observed.

A range of other photosensitisers than 5-ALA and Its dérivatives are known from the scientific literature. One type of such compounds Is per se toxic to target cells or species or hâve light emitting properties when exposed to light Such compounds hâve a relatively large molecular weight and are often complex molécules like phthalocyanines, chlorines, porphyrins and psoralens. Another, more clinically useful, type of compounds are photosensitiser precursors that per se are not phototoxic, but are converted to photosensitisers, e.g. endogenous porphyrins like protoporphyrin IX (PplX) in vivo, upon having entered cells. Such compounds are typicaliy 5-ALA and dérivatives of 5-ALA like 5-ALA esters, and will be referred to hereafter as precursors.

-3Known methods and apparatuses for PDT treatment of the vulva can cause severe pain during photoactivation and for a few days afterwards. Patients are usually either treated after systemic or local analgesia (intravenous oplates or spinal anesthésia) or with repeated interruption of Illumination (e.g. pulsed or fractionated illumination). Thus, the treatments can involve subjecting the patient to several hours of treatments, Including application of the photosensltising formulation and Illumination. The patients will hâve to visit the gynaecologist to hâve the formulation applied. Typically, they then hâve to stay suplne for 3-5 hours and then to see the gynaecologist again for Illumination. In addition, many of the patients will not respond sufficiently to the first treatment and will therefore hâve to go through the procedure one or several times..

PDT of VIN Is typically carried out by Illumination provided by commerdally available, external light sources such as xénon arc lamps (Paterson lamp), LED lamps and lasers..

US 2002/0029071 disdoses LED-based PDT probes wherein the LEDs are arranged on the surface of a cylîndricai Intralumtnal probe and on the surface of a spherical head of an intralumînal probe, respectively (Fig. 24 and 25). The probes are for vulval and cervical use. The LEDs give a necessary fluence rate of at least 30 mW/cm² in the red région of the spectrum. The devices are suggested for use in a method of treatment of gynaecological diseases (e.g. VIN). After application of a photosensitiser or a precursor like 5-ALA and incubation thereof, the VIN lésions are exposed to light from the device for 15 to 30 minutes.

As will be appredated, ail of these light sources require operation by a medical practitioner and so will normally be used within a medical Institution, such as a hospital or GP surgery. The patient must remain still during the length of the illumination, which Is Inconvénient and limite the practical length of each treatment session, ln addition, the photosensitiser or precursor must be applied to the treatment area prior to use of the apparatus. It Is usual with current methods for the patient to wait several hours between application of the photosensitiser/precursor and illumination.

There is hence a need for an improved PDT treatment of VIN and similar intraepithélial neoplasla related to body surfaces, like anal intraepithélial neoplasla (AIN).

According to one aspect the présent Invention provides a portable, self-contained irradiation apparatus for photodynamlc treatment of the vulva and/or the anus, the apparatus comprising: a treatment surface capable of conforming to the area of the vulva and/or anus to be treated, an Illumination system for directing light onto a treatment area ofthe vulva and/or anus, and a power source for the Illumination system; wherein the Illumination system Is arranged to provide light at fluence rates of 50 mW/cm² or below.

A significant advantage of the présent invention is that illumination is carried out at very low fluence rates. Fluence rate (or irradiance) refers to the radiant power incident on a unit area and Is

-4measured in units of W/cm². illumination using low fluence rates, I.e. below 50 mW/cm², is known to strongly reduce the patient discomfort (pain) during illumination (see WO 2008/084241 by Photocure ASA) and the following days that require general local or anaesthesia, and may also improve the PDT effect by ailowing a continuous build-up of endogenous porphyrins (from precursors) and to prevent oxygen déplétion during illumination (S. Jacques et al., “PDT with ALA/PplX is enhanced by prolonged light exposure putatïvely by targeting mïtochondria, SPIE Proceedings Vol. 2972, Optical Methods for Tumor Treatment and Détection, ed. T. Dougherty, San José, February 1997, and M. Seshadri et al., Clin Cancer Res 14(9), 2796-2805 (2008)).

In preferred embodiments the Illumination system Is arranged to apply illumination for periods In excess of an hour, preferably for more than two hours, and more preferably for more than four hours, e.g. five hours or six hours. As discussed below, the fluence rate and treatment time may be set based on a desired light dose and based on the severity of the condition to be treated.

The apparatus is more effective due to the use of low fluence rates, preferably applied over a longer period. This apparatus is also more patient friendly since it enables treatment ofthe vulva and/or anus without the patient being required to remain at a medical facility during treatment. The use of the apparatus will often involve only one visit to the medical facility where a suitable apparatus, e.g. in ternis of size of the treatment surface may be selected and/or the VIN or AIN lésions may be prepared for the PDT treatment, after which the patient is free to leave. The patient may be able to apply the apparatus themselves. Prolonged ongoing treatment can occur while the patient continues with normal daily activities or overnight, and when the treatment Is completed the patient can remove the apparatus for themselves, without the need for a further visit to a medical facility other than a visit to détermine treatment success and possible foilow-up treatments which are usually necessary but again can be carried out with the apparatus at home by the patient themselves. Thus, the apparatus provides Increased comfort and minimises disruption to the patients other activities.

The energy consumption per unit time of the illumination system should be such that the heating of tissue does not resuit in undue discomfort or damage to the patient. The irradiation may be applied at a total light dose level of 10 to 200 J/cm², for example at 20 to 150 J/cm² and preferably 30 to 100 J/cm², optionally 20 to 40 J/cm², e.g. 37 J/cm² or 40 J/cm², and this light dose Is preferably spread overseveral hours. The Illumination system is arranged to provide, In use, a fluence rate below 50 mW/cm’, for example a fluence rate in the range of 0.5 to 40 mW/cm², preferably below 30 mW/cm’, and most preferably in the range of 2 to 20 mW/cm², e.g. 5 mW/cm², 6 mW/cm², 8 mW/cm² or 10 mW/cm², This low fluence rate spreads the total light dose over a period of several hours, which can be longer than conventional PDT illumination times as applied In

-5a clinic or similar. As mentioned above this is bénéficiai both in terms of significantly reduced discomfortforthe patientand improved efficacyofthe treatment.

The apparatus may include a heat exchanger for removing heat from the treatment surface and/or from the treatment area. The heat exchanger may comprise a thermally conductive path from the treatment surface to a cooler part of the apparatus, for example an opposite surface of the apparatus or to an outer part of the apparatus. The thermally conductive path may comprise a métal, such as copper or aluminium and may advantageously be formed using conductors also used in the electrical connections for the illumination system. The heat exchanger may include or be connected to a heat sink for transfer of heat to the air. The apparatus may be provided with a material for storage of sensible and/or latent heat. A phase change material may be Included in thermal conductive relationship with the treatment surface and/or treatment area to remove heat from the treatment area. Preferably the phase change material is a material that changes state at a température dose to or slightly above normal body température. By selecting a phase change material that changes state at a température dose to or slightly above normal body température it ls possible to remove large amounts of heat from the treatment area without the user perceiving any increase in température.

In a preferred embodiment, however, the apparatus does not indude a heat exchanger. With fluence rates below 50 mW/cm², more preferably with fluence rates in the range of 2 to 20 mW/cm², any excess heat which is generated when the apparatus is in use will diffuse into the tissue without causlng problems or discomfort.

The illumination System comprises at least one light source, preferably at least one LED and more preferably an array of more than one LEDs or fibre optic light guides, which may be supplied with light by at least one LED. The term LED is Intended to cover any form of light emitting diode, for example OLEDs (organic light emitting diode) or LECs (light emitting electrochemical cells, as described In A. Sandstrôm et al., Nat. Commun. 3, 2012,1002). A preferred embodiment comprises an array of 3-80 LEDs, more preferably 10 to 50 LEDs. LEDs are known for providing appropriate wavelengths of light for PDT and can be arranged to provide the low fluence rates used in the apparatus of the Invention. The at least one LED may be posîtioned on or extend out of the treatment surface. In such embodiments it is not necessary for the light to pass through the treatment surface and hence no constraints are placed on Its opadty. However, In a preferred embodiment the at least one LED is posîtioned under the treatment surface in such a way that the light provided by the LEDs passesthrough thetreatment surface ontothe area oftreatmentofthe vulva and/or anus.

The wavelength of light used for Irradiation may be selected to achieve an effîcacious photodynamlc effect and hence the LEDs are selected for their abllity to émit wavelengths of light

-6sultable for this effect. In one preferred embodiment the at least one LED emits, In use, light having wavelengths in the range of 300 to 800 nm, for example light In the range 500 to 700 nm. In a most preferred embodiment, especially if the apparatus is used together with a composition comprising a precursor selected from 5-ALA or a dérivative thereof, e.g. an ester thereof, such wavelengths are used that are readily absorbed by protoporphyrin IX (PplX), the photosensitiser compound 5-ALA and its dérivatives are converted into, when having entered the cells of the tlssue which is treated. PplX absorbs at various wavelengths, with a maximum absorption at about 405 nm and further smaller peak absorptions at about 514 nm, 540 nm, 575 nm and 630 nm. Although the maximum absorption is at about 405 nm, light of such wavelength ls not preferably used for PDT with 5-ALA or dérivatives thereof, since it does not penetrate well into tissue. Hence in a preferred embodiment, in which the apparatus is used together with a composition comprising a precursor selected from 5-ALA or a dérivative thereof, e.g. an ester thereof, the illumination system, preferably the at least one LED, is selected to émit light in the range of 600 to 670 nm, preferably light of about 630 nm. The illumination may consist only of the one or more wavelengths or ranges of wavelengths mentioned above.

In some preferred embodiments the illumination system comprises filters to ensure that only light within a certain wavelength range, such as those mentioned above, ls emitted from the apparatus. In one embodiment, the treatment surface may be designed to work as a filter, I.e. such that only light having these preferred wavelengths is transmitted. in another preferred embodiment, the illumination system comprises at least one light source, preferably LED which emits a monochromatlc light of the desired wavelength, Le. 630 nm ± 5 nm.

Preferably the apparatus is self-contalned in the sense that It ls capable of independent operation while the apparatus ls applied to the vulva and/or anus. The power source ls hence preferably being integrated with the apparatus and arranged to be carried with the apparatus when the treatment surface is, in use, applied to the treatment area of the patient. Advantageously, the use of low fluence rates and LED lighting requires only a small power source, which can hence be easily incorporated into the apparatus without making the apparatus too bulky for comfortable use to treat the vulva and/or anus.

The power source preferably comprises one or more batteries. The batteries should preferably operate via electrochemical reactions using chemicals that are not too toxlc for the patient should the apparatus break or leak while in contact with the body. Suitable batteries include lithium batteries e.g. CR2 lithium batteries or équivalents of sufficlent capacity which may also be stored for up to 10 years. A fiat battery, e.g. of the “coin type, is preferably used. The slow loss of charge and small size of lithium ion batteries makes them particularly suited for use as the power supply for the apparatus. In one embodiment, the battery is a primary battery. In another

-7embodiment, the battery is a secondary, i.e. rechargeable battery. The latter embodiment Is of advantage since VIN/AiN patients usuaiiy require multiple, repeated photodynamic treatments in order to achieve full treatment success.

in order to increase the safety of the apparatus, it Is préférable that the apparatus Includes a housing, preferably a flexible housing, and the power source Is sealed within the housing. By sealed It Is meant that the housing Is fluid tight In use to prevent fluids leaking into or out of the housing. The housing may aiso Include other electrical components, such as components for the Illumination system. The housing may comprise two flexible iayers sealed to one another about their periphery, with one flexible layer forming the treatment surface. Altematively the housing may be formed by embedding the power source and/or electrical components within a layer of suitable material, such as a polyuréthane layer or silicone layer. This material may be moulded about the power source and/or electrical components to form the housing and optionally to also form the treatment surface. A preferred embodiment comprises a silicone layer encasing the Illumination system (e.g. encasing LEDs) with a polyuréthane layer on one or both sides of the silicone layer to form a sealed housing.

At its most basic the illumination system can simply comprise electrical connections for the power supply and the at least one LED. With this arrangement the apparatus and thus the illumination system would be activated to switch on the at least one LED when it was desired to begin the treatment. The illumination of the treatment area may continue until the apparatus is switched off and removed, or after a pre-defined and electronically programmed Illumination period or until the power supply Is depleted.

Activation of the illumination system may be triggered by a switch. In order to allow the power source and other éléments of the apparatus enclosed, the switch is preferably enclosed within the apparatus and arranged to be operated whîlst sealed within the apparatus. The switch may be a mechanical switch located beneath a flexible part of the apparatus, for example beneath a flexible layer or a flexible moulded part of the housing. Operation of the switch Is then permitted by the resilience of the flexible part. Altematively the switch may be operated by means of an electrical or magnetic field transmitted through the housing. A magnetlcally operated switch may be implemented by the use of a magnet outside the housing to hold a 'normally closed' reed switch open. When the magnet Is removed the reed switch will dose and this can be used to activate the illumination system.

In a simple system using just a power source and LED type Illumination system It Is hard to control the light dose, as the predse life and power output of the power supply will vary. In addition the illumination provided by the at least one LED will be constant, in order to avold unacceptable

-8heating of tissue, light of low fluence rate Is used and it may also be bénéficiai for the apparatus to be able to provide pulsed light.

Therefore preferably the Illumination System of the apparatus according to the Invention further comprises a control circuit, such as a microcontroller or microprocessor, for regulating the level of Irradiation. The control circuit of the illumination system may be activated by a switch as described above. ln a preferred embodiment the control circuit comprises a timer. The illumination system can then be programmed to begin and/or stop illumination at a pre-determined time. For example, ln order to allow the absorption and conversion of a precursor Into a photosensitiser, e.g. the absorption and build up of porphyrins ln case of a precursor such as 5-ALA or dérivatives thereof, a certain time Is required after application of such a precursor. Hence with the abovediscussed timer, it Is ensured that sufficient time has passed from application of the precursor to the start of Illumination. The length of illumination can also be strictly controlled as the control circuit can be arranged to switch off illumination after a pre-determined time has elapsed which provides the requested light dose. To allow further build-up of endogenous porphyrins from precursors after the first illumination, the apparatus may be programmed to repeat the Illumination (re-PDT) after a certain period of time, e.g. 3 hours.

The control circuit may be arranged to provide pulsed illumination. This can be achieved by providing a fonction generator within a microprocessor. As mentioned above, pulsed light Is advantageous ln ensuring that no unacceptable heating of tissue occurs. ln addition, providing Intervals in illumination enhances tissue oxygénation and the effect of PDT. Further it allows for the re-accumulation of endogenous porphyrins ln surviving ceils that can be treated with repeated illuminations. The frequency and length of the puises can be chosen according to the requirements of the treatment régime and set within the control circuit ln one embodiment, the control circuit can be programmed by the user. This enables the length, strength and illumination pattern to be adjusted to suit individual treatments. Suitable rewritable memory forms include EPROM, EEPROM, flash etc. However, the control circuit memory is preferably read only (ROM) and programmed at the time of manufacture.

Access to the control circuit could be achieved by means of a user Interface on the apparatus. By answering a sériés of questions the user can set the Initial delay period, dosage duration, number and length of light puises etc. The interface may be intégral with the apparatus. Thus, It may comprise small buttons that may be pressed with a suitable tool or reed switches. Each button or switch may activate a given pre-set condition such as light dose, intensity, pulsed/steady light, etc.

It is preferred that ail the electrical components of the illumination system and power source are sealed within the apparatus during use, for example within a housing as discussed above. This

-9improves safety and minimises the possibility of faults caused by fluid incursion. Therefore the control circuit should preferably be sealed within the apparatus.

in some embodiments the user interface may be accessible through a flexible area of the apparatus. Altematively the apparatus may comprise a sealable opening which provides access to the interface, for example an opening within the housing.

The provision of a user interface however increases the size of the apparatus, which may be undesirable in certain applications. Therefore, altematively, the control circuit may comprise a receiver for connection to a remote terminal. In this way spécifie program commands can be communicated from the remote terminal, e.g. a computer, to the control circuit.

In some embodiments the receiver comprises an Input port adapted for connection to a cable. In such embodiments the Input port Is suitably shaped to receive, for example, a USB or other male connector.

The Input port should ideally be sealed during use. Therefore the housing may comprise a plug for Insertion Into the port. The connection comprises seals in order to ensure that the control circuit is sealed within the housing during use.

Altematively the program commands may be transmitted to the apparatus by means of a wireless connection. For example, the receiver may be an infra-red or radio wave receiver. This has the advantage that a physical input port is not necessary and instead the control circuit can be permanently sealed within the apparatus.

Preferably the control circuit further comprises a feedback system. This enables the control circuit to make adjustments In the treatment program to account for déviations In expected LED performance.

For example, the feedback system may comprise a light monitor or other direct or indirect monitor to measure the light dose that has been given to the patient. In such Systems the control circuit may be programmed to switch off the light source, e.g. LED(s), after a pre-determined light dose has been reached rather than a pre-determined time.

Altematively a dosimeter may override the timer in the event that the light source, e.g. LEDs, do not operate as expected. For example, if the power supply Is faulty the output of the LEDs may be reduced. Therefore it will be necessary to continue Illumination beyond the predetermined time in order to obtain a complété light dose. Conversely if the power output of the LEDs is strongerthan anticipated the illumination can be stopped ahead ofthe pre-determined time interval, or the duration of each puise can be shortened to prevent possible overheating of tissue.

Another optîonal feature of the control circuit is one or more performance indicator lights for Informlng the patient whether the apparatus has operated correctly or whether a fault has occurred.

-10The control circuit may be arranged to provide a signal to the patient when treatment Is complété to Indicate that the apparatus can be removed. For example an acoustic and/or Visual signal may be provided, such as an alarm sound and/or a light signal. Alternatively or In addition, a vibration could be used as the signal to Indicate the end of the treatment. Typically the patient would be Informed of the length ofthe treatment and so the signal can be used to confirm an expected end of the treatment and hence need not be overiy Intrusive.

Advantageously, when the control circuit 1s used to tum off the LEDs at the end of the treatment cycle there is no significant ill effect for the patient if the apparatus remains in place for longer than the treatment time. However, it Is expected that patients will wish to know when treatment has ended and the apparatus can be removed.

Preferably some or ail of the above mentioned features of the control circuit are contained In a microprocessor.

In preferred embodiments the treatment surface comprises a flexible sheet incorporatîng the illumination system, for example In the form of LEDs or strips of LEDs or fibre optic light guides, which may be supplied with light by at least one LED and which may be included In a fabric (e.g. Philips Lumalive) or in the form of field-induced polymer électroluminescent lightning (FIPEL) which uses layers of light emitting polymers which contain traces of nanomaterials that glow, when a current Is appiied. The apparatus may comprise a substrate layer, for example of a flexible plastic, for supporting the illumination system and treatment surface. The treatment surface may be an upper surface formed on or formed integrally with the substrate layer, with the illumination System embedded within the substrate layer beneath the treatment surface. The treatment surface and/or the substrate may be formed of polyuréthane or of silicone. The treatment surface Is capable of conforming to the area to be treated and thus in contact with the vulva and/or anus, when the apparatus is In use. In a preferred embodiment, the treatment surface is flexible at least to such a degree that such contact Is achieved. In another preferred embodiment, the treatment surface includes a protrusion which, when the device is in use, is Inserted and located In a body orifice, for example the anus, If the apparatus is used in the treatment of AIN or the vagina, If the apparatus is used in the treatment of VIN. Such a protrusion is preferably of an elongated cylindrical or conlcal shape and of suitable diameter to be in contact with the walls of the orifice, when located In the orifice. When the apparatus Is In use, it extends about 1-3 cm Into the orifice, preferably 1-2 cm. When the apparatus is in use, light from the Illumination system will pass through the treatment surface and hence also through the protrusion. Hence lésions Inside the anus or vagina may be treated concomitantly.

Preferably, the treatment surface Is at least partially transparent so as to allow light from the Illumination System to pass through the surface to provide the required PDT treatment. In some

-11 embodiments the treatment surface may be fully transparent to light having the wavelengths required for PDT treatment and being emitted by the illumination system. However, preferably the material of the treatment surface and/or other material between the treatment surface and the light emitting portion(s) of the illumination system Is arranged to diffuse the light, thereby enabling an even distribution of light from multiple LEDs or from multiple fibre optic light guides. In a preferred embodiment diffusing members as disclosed in US 2009/0198173 are used which reduce the number of light sources, e.g. LEDs, for a given area to be illuminated and thus further decrease the heat generated by the apparatus when in use. Preferably, a transparent or translucent silicone is used as a material for the treatment surface which acts as a diffuser for the emitted light. A silicone layer may surround the illumination system (e.g. LEDs) and extend above the light emitting parts of the illumination system. The silicon layer may be placed on top of a polyuréthane substrate layer. There may be white pigments within the silicone. The use of white pigments assists in reflectlng the light back towards the treated area as well as Increaslng light diffusion. A protecting polyuréthane layer may be placed on top of the silicone layer.

The treatment surface preferably comprises as a top layer a removable and/or cleanable layer, which may for example be a layer located atop the silicone layer or atop a polyuréthane layer that Is on the silicone. The removable layer can be contacted with the patient's body and removed after use. It may be cleaned or It may be a disposable layer that can be replaced by a new layer for subséquent use of the apparatus. The use of a removable layer in this way permits the apparatus to be re-used for multiple treatments of the same patient or for treatment of different patients, after suitabie cleaning. The removable and/or cleanable layer may comprise a polymer foil or film layer. In another preferred embodiment, the treatment surface comprises as a top layer a removable layer which comprises a photosensitiser or precursor, e.g. in the form of a dry composition such as a dry film, preferably such dry compositions comprising 5-ALA or dérivatives thereof as described In PCT/EP2011/061688 by Photocure ASA or as described by A. Zawislak et al. in Photodiagnosis and Photodynamic Therapy (2009), 6,28-40).

The apparatus may comprise a lens system arranged to provide homogenous illumination over the treatment area. The treatment surface may act as the lens system. For exampie, this surface may be formed of silicone or another material comprising surface éléments for diffusing light such as shaped ridges or the like.

The apparatus is preferably arranged to be secured In place with the treatment surface located at the treatment area, such that the patient can continue with normal activities. The apparatus may hence be in the form of a diaper, sanitary napkin, panty liner, or the like, enabling the treatment surface to be comfortably and secureiy held against the vulva and/or the anus. Any

-12suitable shapes and/or structures can be utilised, for example based on conventional diapers, panty liners, sanitary napkins, sanitary pads, incontinence pads and so on.

The apparatus may be arranged to be incorporated within a garment such as a panty, for example by insertion of the apparatus into a reusable or a disposable garment or by provîding the apparatus with an adhesive underside which Is suitable to attach it to a garment such as a panty. The apparatus may take the form of a panty or diaper to be wom instead of or within the patients underwear. The garment may comprise a pouch into which the apparatus can be inserted. Thus, the removable and/or cleanable layer described above may be connected to the garment to form the pouch, with the apparatus being inserted beneath the removable and/or cleanable layer. With this arrangement the removable and/or cieanable layer may be connected to the garment aiong three sides to form the pouch, accessible by the fourth, open, side.

ln preferred embodiments the apparatus includes a coupling for joining the apparatus to the patient or to an undergarment such as a panty. The coupling may comprise a fastener for securing the apparatus about the patient in the manner of a diaper, for example an adhesive or Velcro fastener, or it may be a mechanical fixlng such as a button, hook and eye or similar. Altematively the coupling may comprise a coupling for connection to a garment such as a panty, preferably for connection ln or to the gusset or crotch part of the garment. Thus, the coupling may comprise an adhesive patch or patches for adhering the apparatus to the garment, for example an adhesive on an underside of the apparatus, the underside being a surface opposite the treatment surface, or an adhesive on wings at side portions of the apparatus, for connection to a garment ln a similar manner to wings on known sanitary pads and the like. ln another embodiment, the treatment surface has bioadhesive properties which makes the apparatus stay in place for the time of the treatment (see for Instance A. Zawislak et al. in Photodiagnosis and Photodynamic Therapy (2009), 6, 28-40).

Illumination with low fluence rates as used with the présent apparatus requires that the illumination will hâve to occur over a relatively long time period, e.g. many hours, in order to achieve the desired light dose necessary to achieve a therapeutic effect, and hence is very cumbersome in a clinical (hospital) situation. By provîding a coupling as described above for securely locating the treatment surface at the treatment area the apparatus permits very long treatment times using the advantageous low fluence rates.

To ensure a comfortabie and effective treatment for each patient, the apparatus may be made available in different sizes and/or shapes with a treatment surface of different sizes and/or shapes. Moreover, although the apparatus has been created with the treatment of human patients ln mind, it is also possible it to be used in the treatment of other animais. Therefore the shape of

-13the apparatus and/or treatment surface may be dépendent on the anatomica! structure of the animal on which the apparatus Is Intended for use.

The treatment surface preferably has a size and or shape selected for complementary fit with the treatment area, and Is preferably sized to confront the entire area where PDT Is required, for example size to confront the entire area of the vulva or the entire area of the anus or the combined area of the vulva and anus. The illumination System and treatment surface are preferably arranged such that radiation is emitted toward the treatment area at suffïcient proximity and Intensity to achieve the desired treatment effect.

The apparatus may comprise a handle ortab for gripping the apparatus during application and removal.

The apparatus may be used to provide PDT according to the following method. Firstly a composition comprising a photosensitiser or precursor thereof Is topically applied to the area to be treated by the patient or a physician, where applicable by using a specialised applicator. The composition is preferably in the form of a cream, an ointment, a solution, a spray, a powder, a foam or a lotion. Further, It is preferred that the viscosity of the composition is such that the composition stays at the area It Is applied to for the time of the treatment, also at the elevated températures of the treatment. Altematively, the area of interest Is treated by means of a systematicaliy acting drug. Such a systematicaliy acting drug may be supplied intravenously or orally, for example. Depending on the type of VIN/AIN lésion, it can be necessary that a physician scrapes off the upper keratinized cell layers with a lancet or a ring curette to improve the pénétration of a topicaily applied composition. Prior to application of a topical composition, the area treatment is preferably cleaned to reduce the bacterial flora, e.g. by washing the area with aqueous 0.4% chlorhexidine solution. The apparatus Is then applied to the treatment area, either by the patient at home or by a physician In a hospital/private practice. It may be switched on before or after being applied to the treatment area. The patient can then immediately continue their normal daily routine while the treatment area is receiving Illumination from the apparatus. In this way treatment can occur over a prolongée! period of time without inconvenience to the patient. In a preferred embodiment treatment Is carried out ovemight, e.g. the patient applies the composition comprising a photosensitiser or precursor thereof to the area to be treated then applies the apparatus to said area and goes to bed. Since a lowfluence rate is used, little heat Is generated, pain is significantly reduced and the efficacyofthe treatment is increased. After the treatment Is complété the patient can either retum to the medical facility for removal of the apparatus or preferably remove it themselves. The apparatus or parts thereof can either be discarded or retumed to the medical facility for disposai.

The apparatus may optionaliy comprise a drug delivery System to permit the step of topical application of the drug, i.e. composition comprising a photosensitiser or precursor to be done by

-14application of the apparatus to the patient. The drug delivery system may comprise a drug carrying area on the treatment surface, for example on the removable and/or cleanable layer of the treatment surface or the removable layer itself. This might be a textured surface for carrying a composition of photosensitiser or precursor or the treatment surface or removable and/or cleanable layer itself without any further modifications may act as a drug delivering system. The apparatus may automatically perform the Illumination either immediately upon application or preferably at a later time.

Optionally the drug delivery system further comprises a physical, mechanical or electrical System related to delivery. Such an optional system may Include, for example, filters, membranes, one or more réservoirs arranged to deftver the composition comprising the photosensitiser or precursor based upon a preset plan for drug delivery or based on physical conditions, such as for example pH, osmolality, température, pressure, water content in the surroundings. However, the simplest and In most cases the most preferred drug delivery system Is just a single drug carrying area for holding the composition, and in a most preferred embodiment, the drug delivery system Is the treatment surface or removable and/or cleanable layer itself.

In this preferred embodiment the method of use Is similar to that described above except that the composition is not applied to the treatment area in a separate procedure. Instead the composition is applied to the drug carrying area, which may be the treatment surface or a removable and/or cleanable layer, and is hence applied to the body upon application of the treatment surface of the apparatus to the treatment area. Illumination Is then conducted as described above.

The composition can be supplied together with the apparatus. In such instances the drug delivery system, Le. drug carrying area or réservoir, preferably treatment surface, may be supplied with a cover, such as a foil or cap, to seal the composition within the apparatus until use. Prior to use the cover Is removed so that the composition can be released. Altematively the apparatus can be supplied separately from the composition. This enabies the physicien to choose the optimal composition for a particular case and the physidan or patient to add this to the drug delivery system prior to application of the apparatus.

The composition to be used with the apparatus, whether supplied with the apparatus or applied to the apparatus before use or applied to the treatment area separately, may comprise any suitable photosensitiser or precursor of a photosensitiser.

A range of photosensitisers are known in the scientific iiterature. As discussed above, one type of such compounds are compounds that per se are toxic to target cells or species or hâve light emitting properties when exposed to light. Such compounds hâve relatively large molecular weights and are often complex molécules like phthalocyanines, chlorines, porphyrins or psoralens.

-15Another type are compounds that not per se are toxic or light emitting, but form photosensitisers in vivo. Such compounds - referred to herein as precursors - are 5-ALA and dérivatives of 5-ALA, like

5-ALA esters. Either type of compound, i.e. photosensitisers or precursors can be used or supplied with the présent apparatus.

5-ALA and its dérivatives are amongst the most clinically useful precursors of photosensitisers known in the art. These compounds are converted In the body to porphyrins, e.g. protoporphyrin IX (PplX), which is a photosensitiser that absorbs light and in contact with oxygen generates singlet oxygen. Singlet oxygen is extremely reactive and reacts fast with various cellular biomolecules resulting in cell death.

5-ALA and its dérivatives are wideiy known and used In methods of photodynamic therapy (PDT) for the treatment of various abnormalities or disorders of the skin or other épithélial organs or mucosa, espedally cancers or pre-cancerous lésions, as well as certain non-malignant lésions, e.g. skin diseases such as psoriasis, actinie keratosis (AK) and acné. 5-ALA (Levulan®, Dusa) and 5ALA methyl ester (Metvix®, Galderma, Switzeriand) are commercial therapeutic products for PDT treatment of actinie keratosis and basal cell cardnoma.

The use of 5-ALA and dérivatives thereof, e.g. 5-ALA esters in PDT is well known In the sclentific and patent literature (see, for example, WO 2006/051269, WO 2005/092838, WO 03/011265, WO 02/09690, WO 02/10120 and US 6034267). Ail such dérivatives of 5-ALA and their pharmaceutically acceptable salts are suitable for use with the apparatus herein described and preferably used.

Esters of 5-aminolevulinic acid and N-substituted dérivatives thereof are preferred precursors in a composition for use with the invention. Those compounds in which the 5-amino group is unsubstituted, I.e. the ALA esters, are particularly preferred. Such compounds are generaliy known and described in the literature (see, for example, WO 96/28412 and WO 02/10120 to Photocure ASA).

Esters of 5-aminolevulinic add with substituted or unsubstituted, preferably substituted, alkanols, I.e. alkyl esters or, more preferably, substituted alkyl esters, are espedaily preferred precursors in a composition for use with the invention.

Examples of such precursors indude those of formula (I) and pharmaceutically acceptabie salts thereof:

R² ₂N-CH₂COCH₂-CH₂CO-OR’ (!) wherein

-16R¹ represents a substituted or unsubstituted alkyl group; and

R² each Independently represents a hydrogen atom or a group R¹

As used herein, the term alkyt, unless stated otherwise, Includes any long or short chain, cyclic, straight-chained or branched saturated or unsaturated aliphatic hydrocarbon group. The unsaturated alkyl groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Unless stated otherwise, such alkyl groups may contain up to 40 carbon atoms. However, alkyl groups containing up to 30 carbon atoms, preferably up to 10, particularly preferably up to 8, especially preferably up to 6 carbon atoms are preferred.

In compounds of formula I, the R¹ groups are substituted or unsubstituted alkyt groups. If R¹ Is a substituted alkyl group, one or more substituents are either attached to the alkyt group and/or Interrupt the alkyl group. Suitable substituents that are attached to the alkyl group are those selected from: hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, -SR3, NR’j and -PR\ wherein R³ is a hydrogen atom or a Cm alkyl group. Suitable substituents that interrupted the alkyl group are those seiected from: -O-, -NR3-, -S- or -PRs.

If R¹ is a substituted alkyl group, one or more aryl substituents, i.e. aryl groups, preferably one aryl group, are preferred.

As used herein, the term aryl group* dénotés an aromatic group which may or may not contain heteroatoms like nitrogen, oxygen or sulphur. Aryl groups which do not contain heteroatoms are preferred. Preferred aryl groups comprise up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example, 10 or 6 carbon atoms. Preferred embodiments of aryl groups are phenyl and napthyl, especially phenyl. Further, the aryl group may optionally be substituted by one or more, more preferably one or two, substituents. Preferably, the aryl group is substituted at the meta or para position, most preferably the para position. Suitable substituents Include halo alkyt, e.g. trifluoromethyt, alkoxy, preferably alkoxy groups containing 1 to 6 carbon atoms, halo,

e.g. lodo, bromo, chloro or fluoro, preferably chloro and fluoro, nitro and Cm alkyl, preferably Cm alkyt, Preferred Cm alkyl groups Include methyl, Isopropyl and t-butyl, particularly methyl. Particularly preferred aryl substituents are chloro and nitro. However, still more preferably the aryl group Is unsubstituted.

Preferred such R¹ groups are benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 2-methylbenzyl, 3methylbenzyl, 4-[t-butyl]benzyl, 4-Itrifluoromethyljbenzyl, 4-methoxybenzyl, 3,4-Idi-chlorojbenzyl, 4chlorobenzyt, 4-fluorobenzyl, 2-fIuorobenzyl, 3-fluorobenzyt, 2,3,4,5,6-pentafluorobenzyt, 3nitrobenzyt, 4-nitrobenzyl, 2-phenylethyl, 4-phenylbutyl, 3-pyrldinyl-methyl, 4-dipheny!-methyl and benzyl-5-[(1-acetyloxyethoxy)-carbony!]. More preferred such R1 groups are benzyl, 4isopropylbenzyl, 4-methylbenzyl 4-nitrobenzyl and 4-chlorobenzyl. Most preferred is benzyl.

-17If R¹ Is a substituted alkyl group, one or more oxo substituents are preferred. Preferably, such groups are straight-chained C<-i₂ alkyl groups which are substituted by one, two or three oxo groups. Exampies of such groups Include 3,6-dioxa-1-octyl and 3,6,9-trioxa-1-decyl.

If R¹ Is an unsubstïtuted alkyl group, R¹ groups that are saturated straight-chained or branched alkyl groups are preferred. If R¹ Is a saturated straight-chained alkyl group, Cb1o straightchained alkyl group are preferred. Représentative examples of suitable straight-chained alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl. Particularly preferred are Cm straight-chained alkyl group, most particularly preferred methyl and n-hexyl. If R¹ Is a saturated branched alkyl group, such branched alkyl groups preferably consists of a stem of 4 to 8, preferably 5 to 8 straight-chained carbon atoms which is branched by one or more Cm alkyl groups, preferably Ci-2 alkyl groups. Examples of such saturated branched alkyl groups include 2methylpentyl, 4-methylpentyl, 1 -ethylbutyl and 3,3-dimethyl-1-butyl.

In compounds of formula I, each R² independently represents a hydrogen atom or a group R¹. Particularly preferred for use In the invention are those compounds of formula I in which at least one R² represents a hydrogen atom. In especially preferred compounds each R² represents a hydrogen atom.

The most preferred precursors to be used In a composition together with the devices according to the Invention are compounds of formula I and pharmaceutically acceptable salts thereof, wherein R¹ Is CrCe alkyl, e.g. hexyl, more preferably straight chain Ci-Ce alkyl, e.g. n-hexyl and both R² represent hydrogen, Le. 5-ALA hexyl ester and pharmaceutically acceptable salts thereof, preferably the HCl salts. The most preferred precursor is 5-ALA hexyl ester and the most preferred pharmaceutically acceptable sait of 5-ALA hexyl ester Is the HCl sait.

The composition comprising the photosensitiser or precursor to be used together with the current device can be any type of pharmaceutical formulation and may be prepared by any conventional procedure available In the art (see WO 02/10120 to Photocure ASA). For example, esters of 5-ALA may be prepared by reaction of 5-ALA with the appropriate alcohol in the presence of base. Altematively compounds for use In the Invention may be available commerclaily (e.g. from Photocure ASA, Norway).

Preferred formulations are liquids (aqueous and non-aqueous), solids such as dusting powder, dry compositions such as films (preferably those dry compositions disclosed In

PCT/EP2011/061688), semi-soiids such as creams, ointments, gels or pastes (preferred those seml-solids disclosed in WO 2010/142457), foam formulations or other expandable formulations (for example based on heating to body-temperature) and formulations/systems similar to patches.

The components In the composition (e.g. excipients and additives) are the same components found

-18ln pharmaceutical products on the market, and a listing of such components can be found in handbooks of pharmaceutical excipients.

It is important that the formulation is as such that the composition is absorbed completely Into the tissue to be treated or is transparent in order not to Interfère with the illumination. As noted above, it is also possible to make use of compositions that are applied systematically, for example drugs that are given to the patient intravenously.

Viewed from another aspect the présent invention provides a method of photodynamic therapy of a treatment area on the vulva and/or anus, the method comprising: applying a composition comprising a photosensitiser or precursor to the treatment area; placing an apparatus, preferably an apparatus according to the first aspect, at the treatment area with a treatment surface comprised in said apparatus ln contact with said treatment area; and illumlnating the treatment area using an illumination System provided in said apparatus; wherein the illumination comprises light at fluence rates of 50 mW/cm² or below.

The fluence rate may be as discussed above in relation to the apparatus of the Invention, and the method may comprise the use of an apparatus with any of the features discussed above. The wavelength ofthe light may be as set out above. The method preferably comprises illuminating the treatment area for a period in excess of an hour, preferably two hours or more and preferably over four hours.

The method may include a step of selecting an apparatus of suitable size and/or shape. The apparatus may be selected firstly to suit the patient concemed, and secondly to suit different patient conditions.

The composition may be applied to the treatment area prior to placement of the apparatus as described hereinbefore. The apparatus can be provided separately from the composition or with the composition already contained within a drug delivery system. Altematively the apparatus could be provided in the form of a kit comprising the apparatus and at least one composition comprising a photosensitiser or a precursor of a photosensitiser for use with the apparatus.

Hence viewed from another aspect the présent Invention provides a kit comprising the apparatus according to the invention and at least one composition comprising a photosensitiser or a precursor of a photosensitiser

The présent apparatus and method for photodynamic treatment may be combined with other therapeutic procedures, for example administration of other therapeutic drugs. These therapeutic drugs might be administered into the body prior to or together with placing the apparatus to the treatment area or might be administered through other routes of administration

-19(e.g. oral, Intravascular or topical, e.g. dermal). Typically such drugs include antiviral agents, immune-modulating drugs or combination of such drugs.

Certain prefeaed embodiments ofthe présent invention will now be described by way of example only.

Figure 1 shows an irradiation apparatus in the form of a pad foradhering to the patients underwear;

Figure 2 shows a cross-section of the apparatus in schematic form;

Figure 3 shows an alternative arrangement In which the apparatus Is included In a diaper type garment;

Figure 4 is a close up view of the crotch part of the diaper of Figure 3, illustrating the use of a removable layer; and

Figure 5 shows an Irradiation apparatus using a pouch In the crotch of a garment In place of a removable layer.

As described herein the upper side of the apparatus is the side with the treatment surface, which generaily faces upwards during use, and the lower side is the side opposite the treatment surface.

Figure 1 shows a first arrangement of the irradiation apparatus. The apparatus comprises a fiat but somewhat flexible contlnuous upper treatment surface 2 In the form of a strip or sheet. The treatment surface 2 contains an illumination system 4 with LEDs 6 in strips of LEDs for projecting light from the treatment surface 2. The treatment surface 2 is arranged to confront a treatment area on the vulva and/or anus. In this example apparatus wlngs 8 are provided for coupling the apparatus to the patients underwear. The wings 8 hâve an adheslve on the lower side so that they can be folded about the crotch part of the underwear and secured thereto. Alternatively to the position of the wings in Figure 1, said wings can also be provided at the frontend or at the front-end and back-end of the apparatus. The outer edge 10 of the apparatus can optionally include adhesive or a skin-adhering surface (for example, bio-adhesive material) at the upper surface thereof in order to help the apparatus remain in place. Alternatively, the underslde of the apparatus (not shown) can include an adhesive to help the apparatus to remain in place in a garment, e.g. a panty.

The internai structure of the apparatus is shown as a schematic cross-section in Figure 2.

The apparatus has a layered construction. The upper layer is a polyuréthane iayer 12, which can be formed as an integra! layer with other parts of the apparatus. Polyuréthane Is a suitable material for the upper layer 12 since it Is water-tight and can easily be cleaned. Beneath the upper polyuréthane layer 12 is a silicone layer 14 formed over and about the LEDs 6. The silicone layer

-ΣΟΙ 4 also encases otherelectrical parts ofthe apparatus. Depending on the type of silicone, the silicone layer may help to evenly distribute the light from the LEDs 6. White pigments are included in the silicon layer 14 to diffuse the light, provide a more even distribution of the light and increase the light dose due to back-scattering. On top of the silicon layer 14 and polyuréthane layer 12, there ls a polymer foil/film layer 28 (not shown in Figure 2, described below in relation to Figures 4 and 5) that can be removed and deaned. This can be a removable and/or reusable layer as discussed In relation to Figures 4 and 5 below.

Thus, the apparatus has a treatment surface 2 formed of several parts, Le. layers, Including a substrate silicone layer 14 that holds the LEDs 6, a protecting polyuréthane upper layer 12, and a removable/cleanable polymer film 28 on top of the polyuréthane layer 12. The polymer film layer 28 can include a photosensitiser or precursor, e.g. in the form of a dry composition such as a dry film, preferably such dry compositions comprising 5-ALA or dérivatives thereof as described In PCT/EP2011/061688 by Photocure ASA or as described by A. Zawislak et al. in Photodiagnosis and Photodynamlc Therapy (2009), 6,28-40).

The apparatus further includes a control circuit 16 and power source 18 for the LEDs 6. The control circuit 16 ls encapsulated within the apparatus and may be encased in the silicone layer 14. It is enclosed by an additional flexible polyuréthane layer 20 beneath/behïnd the silicon layer 14. The two polyuréthane layers 12,20 together form a housing and provide a seal for the electrical parts 6,16,18. They are joined at the outer edge 10 ofthe device to form a seal about the outer edge 10. A switch on the control circuit 16 is accessible through the lower flexible layer 20 for tuming the apparatus on and off. The power source 18 comprises fiat (coin type) batteries that are sealed within the apparatus between the two flexible layers 12,20.

The apparatus optionally includes a heat exchanger 22 for removlng heat from the treatment area. The heat exchanger includes thermally conducting parts adjacent to the treatment area in order to convey heat away from the patient.

Figure 3 shows an apparatus incorporated Into a diaper type garment 24. The dîaper 24 can be of any suitable construction. In the example of Figure 3 it includes an elasticated waist and elasticated legs with the waist including two fasteners 26 which would be placed at either side of the body when in use, as with a babies diaper or nappy. The fasteners 26 use hook and loop fasteners (e.g. Velcro®) In this example. The apparatus is fitted In the crotch part of the diaper 24 with the treatment surface 2 facing upward toward the body and the illumination system 4 placed to direct light on the required treatment area. Alternative designs can be provided for illumination of treatment areas on the vulva and/or anus, with the illumination system 4 Included light sources placed at different locations within the diaper 24.

-21 The crotch part of the diaper 24 is shown in an enlarged view in Figure 4 in order to show one arrangement for the polymer film layer 28. In this example it is a removable layer with adhesive properties, which can be positioned on top of the polyuréthane layer 12 by the patient before use of the apparatus and peeled away from the poiyurethane upper layer 12 by pulling in the direction of the arrow shown in the Figure after the treatment is finished. This polymer film layer 28 can hence be removed and discardedafterthe use oftheapparatusfortreatmentofthe patient, with a replacement polymer film layer 28 being used for a subséquent treatment. This type of repiaceable layer 28 can be used with the apparatus of Figure 1 In a similar manner.

Figure 5 shows an enlarged view of the crotch part of a panty 30 with an alternative arrangement in which the removable foi! layer 28 is attached to the crotch part ofthe panty 30 on the long sides 32 and one short side 34. This forms a pouch that allows the insertion of the other parts of the apparatus Into the pouch and beneath the polymer foil layer 28 via the other short side 36, which has an opening. The treatment surface 2 and illumination system 4 are placed facing the foil layer 28 and hence will face the treatment area on the vulva and/or anus when the panty 30 is wom. The foil layer28 In this arrangement Is removable from the remainder ofthe apparatus by taklng the apparatus out of the pouch. Thus, the majority of the parts of the apparatus, including the poiyurethane layers 12,20, power source 18, control circuit 16, illumination system 4 and silicon layer 14, are formed as a separate body which can be re-used with a new polymer foil layer 28. Altematively the panty 30 comprises a non-removable polymer foil layer 28 which can be cleaned before re-use in a subséquent treatment.

The foil layer 28 In this arrangement may be provided separately to the panty 30 with suitable adhesive parts enabling it to be attached to an existing garment on the long sides 32 and one short side 34. Altematively, the panty 30 Is provided with the foil layer 28.

Although Figure 5 shows the pouch arrangement of the polymer foil layer 28 with a panty, it will be understood that It could equally well be used with a diaper 24 as In Figure 3.

Before the light is used the composition comprising a photosensitiser or precursor for the photodynamlc therapy Is applied to the patient. This Is done either by applying It directly to the surface of the treatment area, or systematically by intravenously or orally administered compositions. The composition can be applied to the treatment surface 2 of the apparatus so that It Is applied to the patient when the treatment surface 2 Is placed on the treatment area.

The apparatus is applied to the vulva and/or anus with the treatment surface 2 facing the vulva and/or anus or, if présent, the polymer film 28 In contact with the patients body. The illumination system 4 Is activated when the apparatus Is tumed on, or activated In accordance with a présent timing set by the control circuit 16. Ught Is directed from the LEDs 6 through the silicone layer 14, protective poiyurethane layer 12 and polymer film 28 and onto the desired treatment area

-22at the desired fluence rate. The treatment time Is controlled according to the programmîng of the control circuit 16, or it can also be set by a time of removai ofthe apparatus or by switching it off using the switch. As discussed above, the control circuit 16 for the illumination system 4 can optionally apply a pulsed illumination. After the treatment is complété the apparatus is removed.

The apparatus could be single use, but In this preferred embodiment it is intended to be re-used. The polymer film 28 is cleaned or altematively is removed and discarded with a new film being utilised for a subséquent use ofthe other parts ofthe apparatus.

The arrangements described herein are for illustration only and should not be taken to iimit the scope of protection. The skilled man will appreciate that adjustments could be made without 10 deviating from the scope of the daims. For example, other forms of control drcuît and LED array/fibre optic array can be used. The wings 8 of Figure 1 may be placed more centrally on the apparatus. The polymer film layers 28 of Figures 4 and 5 can be used in combination with the features of any of Figures 1, 2 and 3 or in other alternatives as discussed above.

Claims (34)

1. -23CLAIMS:

   1. A portable, self-contained, irradiation apparatus for photodynamic treatment of the vulva and/or the anus, the apparatus comprising: a treatment surface capable of conforming to the area of the vulva and/or anus to be treated, an illumination system for directing light onto a treatment area of the vulva and/or anus and a power source for the Illumination system; wherein the Illumination system is arranged to provide light at fluence rates of 50 mW/cm² or below.
2. 2. An apparatus as claimed in daim 1, wherein the Illumination system is arranged to apply illumination for periods of several hours
3. 3. An apparatus as claimed in daim 1 or 2, wherein the Illumination system Is arranged to apply illumination with a total light dose level of 10 to 200 J/cm²
4. 4. An apparatus as daimed in daim 1,2 or 3, wherein the fluence rate is in the range of 0.5 to 40 mW/cm², preferably in the range of 2 to 20 mW/cm².
5. 5. An apparatus as daimed in any preceding claim, wherein the Illumination system Is arranged to émit light having or consisting of wavelengths in the range of 300 to 800 nm, for example light in the range 500 to 700 nm.
6. 6. An apparatus as daimed in daim 5, wherein the illumination system is arranged to émit light having or consisting of wavelengths in the range of 600 to 670 nm, most preferably light of about 630 nm.
7. 7. An apparatus as daimed in any preceding daim, wherein the apparatus is capable of independent operation while the apparatus is appiied to the vulva and/or anus and wherein the power source is integrated with the apparatus and arranged to be carried with the apparatus when the treatment surface Is, in use, appiied to the treatment area of the patient.
8. 8. An apparatus as daimed in any preceding daim, wherein the apparatus includes a flexible housing, and the power source and/or other electrical components is/are seaied within the housing.
9. 9. An apparatus as daimed ln any preceding daim, wherein the housing comprises two flexible layers sealed to one another about their periphery.
10. 10. An apparatus as daimed in any preceding daim, wherein the treatment surface comprises a flexible sheet incorporating the illumination system, for example in the form of LEDs.
11. 11. An apparatus as claimed in any preceding daim, comprising a silicone layer encasing light emitting parts of the Illumination system.
12. 12. An apparatus as daimed ln daim 11, wherein the silicone layer is located between the flexible layers.
13. 13. An apparatus as daimed in any preceding daim, wherein the treatment surface is suffidently flexible to allow It to conform to the treatment area and thus maintaln contact with the vulva and/or anus, when the apparatus is in use.
14. 14. An apparatus as daimed in any preceding daim wherein the treatment surface includes a protrusion which, when the apparatus is in use, is inserted and located in a body orifice,

    I.e. the anus or vaglna.
15. 15. An apparatus as daimed in any preceding daim, wherein the treatment surface comprises a removable and/or deanable layer as a top layer.
16. 16. An apparatus as daimed in daim 15, wherein the removable and/or deanable layer is connected to a garment to form a pouch, with the apparatus being insertable beneath the removable and/or deanable layer to be contained within the pouch.
17. 17. An apparatus as daimed in any of daims 1 to 16, wherein the apparatus is arranged to be secured in place with the treatment surface located at the treatment area, when in use, such that the patient can continue with normal adivities.
18. 18. An apparatus as claimed In daim 17, wherein the apparatus comprises a panty or diaper and the panty or dîaper is arranged to hold the treatment surface at the treatment area when wom by the patient.
19. 19. An apparatus as claimed in daim 17, wherein the apparatus indudes a coupling for joining the apparatus to the patient or to an undergarment such as a panty.
20. 20. An apparatus as daimed in daim 19, wherein the coupling comprises an adhesive patch or patches for adhering the apparatus to a garment, for example an adhesive on an underside of the apparatus and/or an adhesive on wings provided at side portions of the apparatus.
21. 21. An apparatus as claimed in any preceding claim, wherein the treatment surface has bioadhesive properties.
22. 22. An apparatus as daimed in any preceding daim, comprising a drug delivery system for carrying a composition comprising a photosensitiser or precursor of a photosensitiser.
23. 23. An apparatus as daimed in any preceding claim in combination with a composition comprising a photosensitiser or precursor of a photosensitiser.
24. 24. An apparatus as daimed in daims 22 and 23, wherein the composition comprises a precursor of a photosensitiser, preferably 5-ALA or a dérivative thereof.
25. 25. An apparatus as daimed in daim 24 wherein the composition comprises a 5-ALA ester, preferably a 5-ALA ester of formula (I) and pharmaceutically acceptable salts thereof:

    R^N-CHîCOCHrCHîCO-OR¹ (I) wherein

    R¹ represents a substituted or unsubstituted alkyl group; and

    R² each independently represents a hydrogen atom or a group R¹
26. 26. A method of photodynamic therapy of a treatment area on the vulva and/or anus, the method comprising: applying a composition comprising a photosensitiser or precursor to the treatment area; placlng an apparatus at the treatment area with a treatment surface composed ln said apparatus in contact with said treatment area; and iliuminating the treatment area using an Illumination System provided ln said apparatus; wherein the Illumination comprises light at fluence rates of 50 mW/cm² or below.
27. 27. A method as claimed in clalm 26, comprising applying illumination for periods of several hours
28. 28. A method as claimed ln claim 26 or 27, comprising applying illumination with a total light dose level of 10 to 200 J/cm²
29. 29. A method as claimed ln claim 26 to 28, comprising applying illumination with a fluence rate Is in the range of 0.5 to 40 mW/cm², preferably ln the range of 2 to 20 mW/cm².
30. 30. A method as claimed in any of daims 26 to 29, wherein the illumination comprises or consists of light having wavelengths in the range of 300 to 800 nm, for example light in the range 500 to 700 nm
31. 31. A method as claimed ln clalm 30, wherein the illumination comprises or consists of light having wavelengths ln the range of 600 to 670 nm, preferably light of about 630 nm.
32. 32. A method as daimed in any of daims 26 to 31, wherein the composition Is applied to the treatment area via a drug delivery system, for example via a layer of composition on the treatment surface.
33. 33. Use of the apparatus of any of daims 1 to 25 ln the method of any of daims 26 to 32.
34. 34. A kit comprising an apparatus as claimed in any of daims 1 to 25 and at least one composition comprising a photosensitiser or precursor of a photosensitiser.

    1/2