WO2002030512A1

WO2002030512A1 - Irradiation device for photodynamic therapy

Info

Publication number: WO2002030512A1
Application number: PCT/SE2001/002205
Authority: WO
Inventors: Fredrik Gudmundson
Original assignee: Medeikonos Ab
Priority date: 2000-10-10
Filing date: 2001-10-10
Publication date: 2002-04-18
Also published as: SE0003673D0; AU2001294484A1

Abstract

The invention concerns an irradiation device for treating skin changes, especally skin tumours, by means of photodynamic therapy, which device comprises a radiation unit (1) adapted to generate broad spectrum radiation in a selected wavelength range. Said radiation unit (1) comprises a broad spectrum radiation source (2) and the radiation unit (1) is adapted to generate a high amount of light energy in the selected wavelength range, 580-680 nm, compared with the total generated light energy, Furthermore, a low amount of heat energy in relation to the total generated heat and light energy is obtained. Preferably, the broad spectrum radiation source (2) is a discharge lamp, such as a spectral-shifted sodium discharge lamp. The radiation unit preferably comprises a reflector unit (9) which comprises at least two, preferably four, essentially plane reflecting surfaces, whereby an extensive light image (≥ 50 cm2) with low intensity variation (preferably ≤± 10 %) and a high light intensity (⊃25 mW/cm2) in the selected wavelength range as well as low heat generation is provided. The irradiation device has a simple and compact structure, which allows irradiation of all the skin surfaces of the body with light that is incident at right angles tot he skin surface (3).

Description

IRRADIATION DEVICE FOR PHOTODYNAMIC THERAPY

Field of the Invention

The present invention relates to an irradiation device for photodynamic therapy, which device comprises a radiation unit adapted to generate broad spectrum radiation in a selected wavelength range. Background Art

Applying a compound or composition containing 5-aminolevulinic acid (ALA) to a skin area in which skin changes are suspected is already known. After application, the ALA substance is allowed to act on the skin for e.g. 1-24 h, and in the meantime protoporphyrin IX is formed in the skin area. Protoporphyrin IX is formed or accumulated in a larger amount in the parts of the area which contain a skin change, compared with other skin portions. Protoporphyrin IX is a substance with several useful properties. First, the substance fluoresces, which can be used to detect said skin changes (see Swedish patent application No. 9603095-2). Second, protoporphyrin IX has a phototoxic effect in long-term radiation of the substance. This can be used to cause cell death in the skin area containing protoporphyrin IX and, thus, remove the skin change. The phototoxic effect is currently used for treating skin tumours, so-called photodynamic therapy.

Other phototoxic substances, such as photofrin and ATMPn, are also used in photodynamic therapy. These substances can be applied subcutaneously (locally) or administered intravenously or perorally. Another prior art technique of using the phototoxic effect for treatment is to use a laser as radiation source to irradiate a skin area onto which ALA has been applied. The wavelength of the light emitted by the laser is selected in the 'vicinity of a light absorption peak of protoporphyrin IX, usually about 635 nm. However, it is difficult to use a device containing a laser, especially in the case of extensive skin areas. For treatment of a large skin area, the laser must be successively moved back and forth over the surface, which causes a risk that part of the area will not be radiated and, thus, a risk of insufficient treatment. Moreover, such a treatment takes a long time and requires great accuracy. A further disadvantage is the relatively high cost of a laser.

It is more common to illuminate the skin area being treated by means of a broad spectrum lamp, which covers the entire red part of the visible spectrum, i.e. wavelengths in the range 580-680 nm, whereby a phototoxic reaction takes place in the protoporphyrin IX accumulated in the tumour and the cancer cells are killed.

In most cases, the red part of the visible spectrum, i.e. about 580-680 nm, is used since this radiation has the highest penetration capacity in the skin (see Moan, J, Sorensen, R, Iani, V, Nesland, J M, "The Biophysical

Foundations of Photodynamic Therapy", Endoscopy, 30, 387- 391, 1998) . However, other wavelength ranges within the range of about 350-680 nm, such as blue light and green light, may be used for treating superficial skin changes. To avoid causing the patient pain, especially when irradiating extensive skin areas, for instance about 50-100 cm², and skin areas where the skin is sensitive, the radiation unit may be arranged in such manner that broad spectrum radiation is generated in essentially only a selected wavelength range. The wavelength range is selected so that a relatively high photoabsorption in the phototoxic substance and a relatively low photoabsorption in the photo products are obtained (see Swedish patent application No. 9903057-9) . By using such a device, it has been found that the patient's experience of pain decreases to a considerable extent compared with treatment using a conventional radiation unit. This is due to the fact that the experience of pain largely depends on accumulation of heat in the skin, which in turn is caused by high photoabsorption in the photoproducts .

To obtain the desired result in photodynamic treat- ment of skin cancer with light in the wavelength range 580-680 nm, a light supply of about 10-250 mW/cm² is required. The total dose of light energy supplied should be at least about 10-250 J/cm². However, to obtain the desired effect, a light supply of at least about 70 mW/cm² and about 70 J/cm² is preferred (see Moan, J, Sorensen, R, Iani, V, Nesland, J M, "The Biophysical Foundations of Photodynamic Therapy", Endoscopy, 30, 387-391, 1998). Nonetheless, different types of skin changes may require different amounts of supplied light which means that an irradiation device in which the light intensity can be varied is preferred.

WO 9852205 discloses an irradiation device comprising a halogen lamp and a parabolic reflector. In this device, the light from the halogen lamp is directed to- wards one end of a transparent glass rod, through which it is then passed to be emitted from the other end of the rod. Thus, this device gives a focused light with a high spot intensity. A disadvantage of this device, however, is that it is not possible to irradiate large skin sur- faces. In addition, a certain light intensity loss occurs during the light's passage through the glass rod. This irradiation device also generates a lot of heat.

US 5,441,531 discloses an irradiation device in which infrared radiation passes through a dichroic mirror and a desired radiation < 700 nm is reflected. This device comprises a tungsten-halogen lamp which generates a very wide wavelength spectrum and, thus, unnecessary amounts of heat are generated. Since the device consists of many components, it is very large and cumbersome and also expensive to manufacture. Due to the cumbersome structure of the device not all skin surfaces can be irradiated with light incident at right angles to the skin surface and, thus, a light image with non-uniform light intensity is obtained.

When using light with non-uniform light intensity to irradiate a skin change, there is a risk of certain skin areas getting too little light, i.e. in those places the cell change will remain, as will the risk of the skin change spreading. There is also a risk of some skin areas getting too much light, i.e. the skin will be damaged. It is very difficult to obtain a light with a low intensity variation (i.e. a uniform light) within a variable light intensity region (this is particularly difficult at high light intensities) and in a selected wavelength range, especially when irradiating large skin areas. The variation in intensity should be essentially constant at varying distances (about 0-20 cm) from the lamp to allow supply of a varying radiation dose. Therefore, the light intensity loss should also be minimized. Summary of the Invention

The object of the present invention is to provide an irradiation device for photodynamic therapy, which device provides low intensity variation in combination with i.a. variable light intensity (especially at high light intensities) in a selected wavelength range.

The device according to the present invention com- prises a radiation unit adapted to generate broad spectrum radiation in a selected wavelength range, said radiation unit comprising a broad spectrum radiation source and being adapted so as to provide a large amount of light energy in the selected wavelength range compared with the total generated light energy and a small amount of heat energy compared with the total generated heat and light energy. By using such a device, relatively little or essentially no infrared radiation is obtained, which means that the heat generation will be low. The irradiation device according to the present invention generates ≥ 25 % light energy in a selected wavelength range, for instance 580-680 nm, out of the total generated light energy.

Moreover, preferably ≥ 10 % light energy is generated from the total electric energy supplied. The irradiation device comprises a reflector unit having preferably at least two essentially plane, mutually inclined reflecting surfaces whose reflection properties vary across the total reflecting surface, so that a uniform light image with a variation in light intensity ≤ ± 10 % is achieved.

The mutually inclined reflecting surfaces facing the radiation source preferably have an angle, or angles, < 180°.

The total reflecting surface preferably comprises at least two fields having mutually different blast-cleaned reflection properties. These fields preferably have different surface structures and, thus, different degree of reflection, so that one high-reflective and one low- reflective field are obtained. Preferably, the low-re- flective field is blasted. The low-reflective field is preferably centrered on the total reflecting surface. Moreover, said field is preferably circular.

It is most preferred to have four essentially plane, mutually inclined reflecting surfaces. The mutually in- clined reflecting surfaces facing the radiation source preferably have angles < 180°, and more preferably a central angle of about 124° and two side angles of about 153,5°. A larger number of reflecting surfaces may be used, however, if, for instance, a light image with a larger surface is wanted. In practice, the number of mutually inclined reflecting surfaces could be very large, which would give a reflecting surface which is essentially curved around the radiation source. However, the number of reflecting surfaces is preferably ≤ 10, and it is even more preferred that the reflector unit should comprise four essentially plane, mutually inclined reflecting surfaces, as indicated above. Preferably, the broad spectrum radiation source has a longitudinal extension along a direction substantially perpendicular to the direction of radiation. It is more preferred for the broad spectrum radiation source to con- sist of a discharge lamp, such as a spectral-shifted sodium lamp, which generates radiation with wavelengths between essentially about 580 and 680 nm. Induction lamps may also be used.

According to a preferred embodiment, the irradiation device, which is adapted for photodynamic therapy, generates a uniform, extensive light image with a variable, preferably high, light intensity in the selected wavelength range and with low heat generation.

The irradiation device according to the present invention generates a light image with a variable light intensity in the range of about 40-100 mW/cm², preferably about 70 mW/cm², and preferably a surface ≥ 50 cm², more preferred about 100 cm², so that extensive skin areas can be irradiated. The variation in intensity is preferably about

±7.5 %.

Moreover, the variation in intensity is preferably constant within about 0-20 cm from the broad spectrum radiation source. The selected wavelength range is preferably about 580-680 nm, more preferred about 600-655 nm, and most preferred about 610-635 nm.

Preferably, at least about 50 % light energy is generated in the selected wavelength range, out of the total generated light energy.

Compared with other radiation sources, the radiation source generates little or essentially no infrared radiation, i.e. wavelengths > 780 nm.

The irradiation device may be given a simple and fairly compact structure, which means that the device will be small compared with the surface of the generated light image and will allow access to the entire body of the patient. This is very important since it allows all the skin surfaces of the body to be irradiated with light that is incident at right angles to the skin surface and a uniform light image with a low variation in intensity is obtained.

Advantageously, the irradiation device may be designed so as to require a small power supply compared with the amount of light it generates within the desired wavelength range. This can be achieved by using a low-power radiation source. Thus, the device is energy efficient and cheap to operate. Due to its simple construction it is also relatively inexpensive to manufacture .

Since heat shortens the life of an irradiation de- vice, the inventive device has a longer life than prior- art irradiation devices. Brief Description of the Drawing

The invention will now be further described by means of embodiments and with reference to the accompanying drawing .

Fig. 1 is a basic layout sketch of an embodiment of the irradiation device according to the present invention. Description of Preferred Embodiments The irradiation device shown in Fig. 1 comprises a radiation unit 1. The radiation unit 1 comprises a broad spectrum radiation source in the form of a spectral- shifted sodium discharge lamp 2 with an output of about 600 W. Inside an opening 5 a filter unit 10 is arranged, which filters the light emitted from the discharge lamp 2. The filter unit 10 transmits wavelengths > 580 nm. The filtered light is essentially in the red part of the visible spectrum (about 580-680 nm) . However, the main part of the light energy is in the range of about 610-635 nm.

The light irradiates a surface of about 100 cm² of a skin area 3. The discharge lamp 2 is arranged in a housing 4, which is provided with an exit opening 5 for the light. A front glass 6 covers said opening 5. The discharge lamp 2 comprises a discharge tube 2a and a surrounding outer glass 2b. The housing 4 is articulated to an arm 7, which in turn is articulated to allow easy displacement and positioning of the radiation unit 1 relative to the patient's skin area 3 to be treated. A shutter 8 is arranged adjacent to the opening 5. The radiation unit 1 further comprises a reflector unit 9, which is arranged behind and on the sides of the discharge lamp 2 in the housing 4 to catch all the light and direct it in the forward direction towards the opening 5.

The discharge lamp 2 generates about 50 % light energy in the wavelength range of about 580-680 nm, out of the total generated light energy.

The discharge lamp 2 and the filter unit 10 provide a radiation spectrum which essentially lacks radiation of other wavelengths than those about 600-655 nm, and especially those about 610-635 nm. The device further comprises a frame 11 measuring

10 x 10 cm. The distance of the frame 11 from the radiation unit 1 may be varied. The frame 11 is applied onto the skin area 3 to be irradiated, and in the area defined by the frame 11, the intensity is variable in the range of about 40-100 mW/cm², preferably about 70 mW/cm², with a variation in intensity of ± 7.5-8 % in the entire intensity range. The frame 11 is adjustably arranged adjacent to the radiation device 1 so that the distance between the radiation device 1 and the skin area 3 can be ad- justed and fixed at a predetermined distance.

The combination of variable, preferably high, light intensity in a selected wavelength range and uniform irradiation of a surface is difficult to achieve. It is particularly difficult to achieve when irradiating large skin surfaces, for example about 50-100 cm². However, this is achieved by means of the device according to the embodiment described herein. The light image generated by the irradiation device has a variation in light intensity < ±10 %, preferably about ±7.5-8 %, and a variable light intensity > 25 mW/cm², preferably about 70 mW/cm².

One requirement is that the size and weight of the irradiation device are such that the desired parts of the skin can be easily irradiated. This requirement is fulfilled by the device according to this embodiment. The simple, and thus compact, structure of the irradiation device makes the device small compared with the surface of the generated light image and allows access to the entire body of the patient. This is very important since it allows all the skin surfaces of the body to be irradiated with light that is incident at right angles to the skin surface and a uniform light image with a low intensity variation is obtained.

Light intensity losses should be minimized and, thus, the distance between the radiation source and the skin should be minimized. A precondition is that the radiation has low thermal energy in order to reduce the pain felt by the patient. The device according to the present invention generates very little heat and can thus be held very close to the skin area to be irradiated.

In a halogen lamp, only about 4-6 % of the electric energy is transformed into light emission. In a discharge lamp, about 15-35 % of the electric energy is transformed into light and in an induction lamp the corresponding figure is about 20 %. Thus, discharge and induction lamps are more energy efficient than, for example, a halogen lamp and generates less thermal energy. The generation of heat is also minimized by using a radiation source which, compared to other radiation sources, generates little or essentially no infrared radiation, i.e. wavelengths >780 nm.

To reduce the heat generation it is also of interest to use a radiation source with a minimum output, but with maintained light intensity. High intensity can be achieved by means of a spectral-shifted discharge lamp, i.e. the lamp generates a light spectrum essentially only in the desired wavelength range (about 580-680 nm) . Thus, no output has to be wasted on undesired wavelengths and a high light intensity can be achieved. The output of the lamp can then be about 200-1000 W, preferably about 600 W.

To obtain a perfectly uniform light on an extensive surface placed in front of a discharge lamp by using a parabolic reflector, it is assumed that the discharge lamp is a line source with no extension in space. In practice, the discharge lamp has a certain diameter and, in the case where a parabolic reflector is used, this results in a non-uniform light image. Uniform illumina- tion can be achieved, however, by the reflector unit comprising essentially plane reflecting surfaces that are inclined in such manner that the reflections of the discharge lamp are juxtaposed at regular intervals as seen from a surface in front of the lamp. The reflector unit 9 thus comprises four essentially plane, mutually inclined reflecting surfaces whose reflection properties vary across the total reflecting surface (see Fig. 1) . These surfaces are arranged so that four reflections of the discharge lamp 2 (plus the lamp itself) are obtained at regular intervals as seen from a surface in front of the lamp 2. It thus appears as if the radiation unit 1 consisted of five lamps.

The mutually inclined reflecting surfaces facing the discharge lamp 2 preferably have angles < 180°, and more preferred a central angle of about 124° and side angles β of about 153,5°. These angles give said reflections of the lamp at regular intervals.

The total reflecting surface preferably comprises two fields having mutually different reflection proper- ties. Said fields preferably have mutually different surface structures and thus mutually different degrees of reflection. Degree of reflection means the total amount of light that a surface reflects compared with the amount of light supplied.

The low-reflective field (i.e. the field having the lowest degree of reflection) is preferably circular and centrered on the total reflecting surface, essentially behind the discharge lamp 2, i.e. the low-reflective field corresponds to the area on the total reflecting surface in which light exposure is strongest.

The reflecting surfaces suitably consist of the same material (but may consist of different materials) , such as sheet aluminium, rigid sheetings, stainless sheetings or mirror glass, but said fields on the reflecting surface preferably differ in terms of reflection properties. Low degree of reflection is preferably achieved by means of blasting, but also other surface modification techniques, such as painting, application of adhesive tape or etching are possible. Moreover, the surface may be provided with a divergent agent such as sand particles. A high degree of reflection may preferably be achieved by means of polishing of the reflecting surface.

On the irradiation device shown in Fig. 1, low- reflective and high-reflective fields, respectively, have been obtained by means of blasting and polishing, respectively, of predetermined areas on the reflecting surface (stainless steel sheet) .

The intensity variation of the generated light image (about ±7.5-8 %) is constant within the distance of 0 cm to about 20 cm from the discharge lamp 2 (see Table 1) . The percentage value in Table 1 refers to the difference between the highest and the lowest luminous flux value, respectively, divided by the highest luminous flux value. Measurements have been carried out at three different distances from the discharge lamp 2 (70, 125 and 175 mm) and at the distance from the discharge lamp 2 where the luminous flux is 1000 W/m². Table 1

70 mm 125 mm 175 mm 1000 W/m²

Stainless steel sheet 17 15 15 16 with low-reflective and high-reflective fields, respectively

Mirror glass with 19 11 13 19 low-reflective and high-reflective fields, respectively

Table 2 below shows the distances from the radiation source 2 at which the luminous flux values of 400 and 1000 W/m², respectively, are obtained.

Table 2

Reflector material Distance from the Distance from the radiation source at radiation source at which 1000 W/m² which 400 W/m² is achieved is achieved

[mm] [mm]

Stainless steel sheet 65 150 with low-reflective and high-reflective fields respectively

Mirror glass with 90 280 low-reflective and high- reflective fields, respectively

It will be appreciated that a number of modifications of the above-mentioned disclosed embodiment are possible within the scope of the invention, as defined in the appended claims.

Claims

1. An irradiation device for photodynamic therapy, which device comprises a radiation unit (1) adapted to generate broad spectrum radiation in a selected wavelength range, said radiation unit (1) comprising a broad spectrum radiation source (2) and a reflector unit (9) and ≥ 25 % of the light energy generated by the radiation source (2) being within the selected wavelength range, c h a r a c t e r i s e d in that the reflector unit (9) comprises at least two essentially plane, mutually inclined reflecting surfaces, so that a uniform light image with a variation in light intensity ≤ ±10 % is obtained.

2. An irradiation device according to claim 1, wherein the reflecting surfaces constitute a total reflecting surface with varying reflection properties.

3. An irradiation device according to claim 1 or 2 , wherein the mutually inclined reflecting surfaces facing the radiation source have an angle, or angles, < 180°.

4. An irradiation device according to any one of claims 1-3, wherein the total reflecting surface comprises at least two fields having mutually different reflection properties.

5. An irradiation device according to claim 4, wherein the fields have mutually different surface structures and thus mutually different degrees of reflection, so that one high-reflective and one low-reflective field are obtained.

6. Irradiation device according to claim 5, wherein the low-reflective field is a blasted surface.

7. Irradiation device according to claim 5 or 6, wherein the low-reflective field is centred on the total reflecting surface.

8. Irradiation device according to claim 7, wherein the low-reflective field is essentially circular.

9. Irradiation device according to any one of claims 1-8, in which said reflector unit (9) comprises at least four essentially plane, mutually inclined reflecting surfaces .

10. Irradiation device according to claim 9, in which said reflector unit (9) comprises ≤ 10 essentially plane, mutually inclined reflecting surfaces.

11. Irradiation device according to any one of claims 1-10, wherein the broad spectrum radiation source (2) has a longitudinal extent along a direction substantially perpendicular to the direction of radiation.

12. Irradiation device according to claim 11, in which said broad spectrum radiation source (2) is a discharge lamp.

13. Irradiation device according to claim 12, in which said discharge lamp is a spectral-shifted sodium lamp.

14. Irradiation device according to any one of claims 1-13, which generates a variable light intensity in the range of about 40-100 mW/cm².

15. Irradiation device according to any one of claims 1-14, which generates a light image with a surface area ≥ 50 cm².

16. Irradiation device according to claim 15, which generates a light image with a surface area ≥ 100 cm².

17. Irradiation device according to any one of claims 1-16, wherein the variation in light intensity is about ±7.5 % .

18. Irradiation device according to any one of claims 1-17, wherein the variation in light intensity is constant within about 0-20 cm from the broad spectrum radiation source (2) .

19. Irradiation device according to any one of claims 1-18, wherein the selected wavelength range is about 580-680 nm.

20. Irradiation device according to claim 19, wherein the selected wavelength range is about 600-655 nm.

21. Irradiation device according to any one of claims 1-20, wherein out of the total generated light energy about 50 % light energy is generated in the selected wavelength range.

22. Irradiation device according to any one of claims 1-21, which has a compact structure, so that all the skin surfaces of the body can be irradiated with light that is incident at right angles to the skin surface (3) .