Illumination for photodynamic therapy

Abstract

An illumination system (1) for photodynamic therapy is provided, the illumination system comprising an illumination source (2), which is configured to emit an electromagnetic radiation (3) to illuminate a target surface (4) during operation, and an electronic control unit (5), wherein the illumination source is configured such that the intensity of the electromagnetic radiation emitted by the illumination source can be varied, wherein the electronic control unit is operatively connected to the illumination source and configured to control operation of the illumination source according to an illumination protocol during an illumination session performed with the illumination system, and wherein the illumination protocol comprises instructions to operate the illumination source during the illumination session in a plurality of different modes, the modes comprising: a) a first mode, wherein, in the first mode, the electronic control unit controls operation of the illumination source such that the intensity of the electromagnetic radiation emitted by the illumination source is increased continuously or quasi-continuously from a base intensity B to a target intensity T within a first mode time interval, b) a second mode, wherein, in the second mode, the electronic control unit controls operation of the illumination source such that the intensity of the electromagnetic radiation emitted by the illumination source is constant or substantially constant for a second mode time interval, and c) a third mode, wherein, in the third mode, the electronic control unit controls operation of the illumination source such that the illumination source is operated such that darker phases and illumination phases alternate for a third mode time interval, wherein the intensity of the electromagnetic radiation emitted by the illumination source is lower in the darker phases than in the illumination phases, or wherein, in the darker phases the illumination source does not emit electromagnetic radiation whereas the illumination source emits electromagnetic radiation in the illumination phases. Furthermore, a computer program product and a kit for treating a disease are provided and a method for operating an illumination source and a method for treating a skin disease.

Claims

1. A method for treating a skin disease by photodynamic therapy comprising the following steps: a) applying a pharmaceutical substance to a surface of a skin in a region which is to be treated, wherein the pharmaceutical substance is a photosensitizing drug or precursor to such a drug that is excitable by radiation in an emitted spectrum, leading to the formation of reactive oxygen species that initiate cell death; b) positioning an illumination source relative to the region such that a distance between a radiation exit surface of the illumination source and the region is between 5 cm and 15 cm; and c) irradiating the region with the illumination source, wherein the illumination source is operated according to an illumination protocol during an illumination session, and wherein the illumination protocol comprises instructions to operate the illumination source during the illumination session in a plurality of different modes, the modes comprising: i) a first mode, wherein, in the first mode, the illumination source is operated such that an intensity of an electromagnetic radiation emitted by the illumination source is increased continuously or quasi-continuously from a base intensity B to a target intensity T within a first mode time interval, and wherein a priming mode of 3 min or less precedes the first mode, wherein, in the priming mode, an electronic control unit controls operation of the illumination source such that the intensity P of the electromagnetic radiation emitted by the illumination source is 0.3 T, ii) a second mode, wherein, in the second mode, the illumination source is operated such that the intensity of the electromagnetic radiation emitted by the illumination source is constant or substantially constant for a second mode time interval, and iii) a third mode, wherein, in the third mode, the illumination source is operated such that darker phases and illumination phases alternate for a third mode time interval, wherein, in the darker phases the illumination source does not emit electromagnetic radiation whereas the illumination source emits electromagnetic radiation in the illumination phases.

2. The method of claim 1, wherein a duration of one illumination phase is equal to 60 s and a duration of one darker phase is equal to 30 s.

3. The method of claim 1, wherein B is less than or equal to 0.4 T.

4. The method of claim 1, wherein B is equal to 0.3 T.

5. The method of claim 1, wherein the illumination source is operated in the second mode after the first mode and before the third mode during the illumination session.

6. The method of claim 1, wherein every mode selected from the first mode, the second mode, and the third mode of operation of the illumination source occurs only once during the illumination session.

7. The method of claim 1, wherein the electromagnetic radiation has a peak wavelength in the red spectral range.

8. The method of claim 1, wherein the radiation dose is equal to 37 J/cm.sup.2.

9. The method of claim 1, wherein the duration of the entire illumination session is less than or equal to 18 min.

10. The method of claim 1, wherein the first mode time interval, the second mode time interval, and the third mode time interval is greater than or equal to 3 min.

11. The method of claim 1, wherein the skin disease is a neoplastic skin disease like actinic keratosis, basal cell carcinoma, squamous cell carcinoma in situ, or warts, acne, wound healing disorders/chronic wounds, bacterial and/or fungal infections, inflammatory skin diseases.

12. The method of claim 1, wherein the intensity of the electromagnetic radiation emitted by the illumination source in a continuous time interval covering the priming mode, the first mode and the second mode is continuously greater than zero.

13. An illumination system for photodynamic therapy which is configured to irradiate the region with the illumination source, according to the method of claim 1.

14. A kit for treating a skin disease, comprising: a pharmaceutical substance suitable to be topically applied to a skin in a region to be treated, and the illumination of claim 13, wherein the illumination system is configured to irradiate a region of the skin to which the substance has been applied.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 schematically shows a perspective view of an illumination system and a target surface.

(2) FIG. 2 shows a diagram illustrating an illumination protocol.

(3) FIG. 3 shows a diagram illustrating a variation of the illumination protocol of FIG. 2.

(4) FIG. 4 shows a diagram illustrating yet another variation of the illumination protocol of FIG. 2.

DETAILED DESCRIPTION OF THE INVENTION

(5) FIG. 1 shows an illumination system 1, e.g. for photodynamic therapy (PDT). The illumination system 1 comprises an illumination source 2, which is configured to emit an electromagnetic radiation 3 to illuminate a target surface 4 during operation, and an electric control unit 5. The target surface 4 may be a human skin, for example the skin on a head or another region to be treated. Furthermore, a PDT requires a photosensitizer and molecular oxygen (not explicitly shown). Usually the photosensitizer is obtained by a prodrug (not explicitly shown) which is topically applied to the skin, expediently in the target region, and which is then converted by the cells, preferably by neoplastic cells, into the actual photosensitizer. The prodrug may be 5-aminolevulinic acid (5-ALA), an endogenous precursor for heme biosynthesis.

(6) The molecular mechanism of action in PDT is based on cellular aminolevulinic acid uptake, synthesis, and accumulation of the photosensitizer, which is excited by light of specific wavelengths leading to the formation of reactive oxygen species (ROS), upon the presence of oxygen. These ROS species can initiate cell death in the form of apoptosis, necrosis and/or autophagy.

(7) The illumination source 2 is configured such that the intensity of the electromagnetic radiation 3 emitted by the illumination source 2 and/or the one reaching the target surface 4 can be varied. Moreover, it is possible that the distance between the target surface 4 and the illumination source 2 of the illumination system 1 is adjustable and thus variable. It is, however, preferred, that the target surface 4 has a fixed position relative to the illumination source.

(8) The illumination source 2 may comprise a light-emitting diode (LED) or a plurality of light-emitting diodes. In particular illumination sources such as the ones distributed by the company Biofrontera AG under the tradename BF-RhodoLED® are suitable. The light emitted by the light-emitting diodes promotes the formation of reactive oxygen species (ROS). The wavelength of the light emitted by the illumination source may be greater than 400 nm, greater than 500 nm or greater than 600 nm. For example, the wavelength may be 635 nm, i.e. radiation in the red spectral range. As another example, the wavelength may be 420 nm, i.e. radiation in the blue spectral range. Alternatively, yellow or green radiation may also be applicable to activate the photosensitizer appropriately.

(9) The illumination system 1 may have a target location or may define a target location in which the target surface 2 is to be arranged relative to the illumination source 2 during the illumination session. The target location may be defined by a bearing surface which is contacted by a section of the user's head, e.g. by the forehead or the chin. The section may stay in contact with the bearing surface during the entire session. The target location may be arranged at a distance from a radiation exit surface of the illumination source 2. A gaseous medium may be present between the radiation exit surface of the illumination source 2, e.g. a surface of an optical element, e.g. a diffusor or a lens, and the target surface 4 and/or the target location.

(10) The distance between the radiation exit surface of the illumination source 2 and the target location may be less than or equal to one of the following values: 20 cm, 15 cm 10 cm, 8 cm, 7 cm, 6 cm, 5 cm. Alternatively or additionally, the distance between the radiation exit surface of the illumination source 2 and the target location may be greater than or equal to one of the following values: 1 cm, 2 cm, 3 cm, 4 cm, 5 cm. The distance between the radiation exit surface of the illumination source 2 and the target location may be between 1 cm and 20 cm, preferably between 5 cm and 8 cm.

(11) The illumination source 2 may comprise at least one optoelectronic semiconductor chip for generating the electromagnetic radiation, e.g. a light-emitting diode chip. The radiation emitted by the illumination source 2 may be incoherent radiation. It may be monochromatic, e.g. of light of one specific color. The electromagnetic spectrum emitted by the illumination source 2 may have a peak wavelength in the visible spectral range, e.g. in the red or blue spectral range. The emission spectrum may be narrow. For example, the full width at half maximum of the spectrum (FWHM: Full Width Half Maximum) may be less than 100 nm, e.g. less than or equal to 50 nm.

(12) The electronic control unit 5 is operatively connected to the illumination source 2 and configured to control operation of the illumination source 2 according to an illumination protocol during an illumination session performed with the illumination system 1. The electronic control unit may be part of a computer. The electronic control unit may be a CPU (Central Processing Unit) or a microcontroller. The illumination protocol comprises instructions to operate the illumination source 2 during the illumination session in a plurality of different modes, which are disclosed in detail in FIG. 2.

(13) FIG. 2 shows a diagram of the illumination protocol with two axes, a first axis representing the duration of the radiation treatment in seconds, and a second axis representing the degree of light intensity in percent. The illumination protocol may govern the entire illumination session.

(14) During a first mode a, which is executed first when using the illumination system 1, the electronic control unit 5 controls operation of the illumination source 2 such that the intensity of the electromagnetic radiation 3 emitted by the illumination source 2 is increased continuously or quasi-continuously from a base intensity B (30%) to a target intensity T (100%) within a first mode time interval.

(15) As illustrated in FIG. 2 a linear ramp is applied which increases the light intensity from 30% to 100% light intensity in the course of 5 or 5.5 minutes. Other durations are possible as well, of course. The intensity at 100% need not be the maximum intensity emittable by the illumination source 2 but rather designates the maximum intensity during the illumination session. Alternatively, the intensity may be increased non-linearly in the first mode a (see FIG. 3, for example). Here, it is preferred that initially the slope is less than later on, which may be advantageous to sensitize the nerve endings.

(16) The first mode a enables provision of a moderate reaction onset to reduce initial photobleaching and promote re-oxygenation of the treated tissue and a slow but continuous increase of the irradiance to trigger a sufficient photodynamic effect, including initial inflammatory reactions that induce vasodilation for even better oxygen supply. The photodynamic effect describes the process during PDT which leads to the destruction of cells, wherein photobleaching describes the effect that the photosensitizer is inactivated by permanent disruption of its chemical structure, e.g. by cleavage of covalent bonds. The photobleaching effect may coincide with temporal oxygen depletion in the target tissue due to a massive initial reaction. This leads to a rapid decrease in oxygen and therefore limits the formation of ROS. In addition, the milder initiation phase allows adaptation of sensory nerve endings in the skin to the stimulus, whereby the perceived pain by the patient is reduced.

(17) After reaching 100% light intensity, a second mode b follows, wherein the electronic control unit 5 controls operation of the illumination source 2 such that the intensity of the electromagnetic radiation 3 emitted by the illumination source is constant or substantially constant for a second mode time interval. As shown in FIG. 2, in the second mode b, the maximum light intensity of the first mode a is maintained. The light intensity may be kept constant for approximately 4.5 minutes. Other durations are possible as well, of course.

(18) This second mode b is important to provide high energy to the target in a relatively short time span and thus keeps the overall duration of the session well below 16 minutes, which is considered acceptable by most patients and physicians regarding the pain burden. Apart from that, the electronic control unit 5 controls the operation of the illumination source 2 such that the illumination source 2 is operated so that the irradiance is stopped or the intensity is reduced after 10 minutes, e.g. by the first darker phase in a subsequent mode (mode c which is discussed below), thereby counteracting an excessive increase in pain.

(19) In the second mode b the intensity of the electromagnetic radiation emitted by the illumination source is constant or substantially constant. The intensity during the second mode b may be equal to the target intensity T in the first mode.

(20) Then the second mode b is followed by a third mode c. The third mode c is the last mode of the protocol. In the third mode c, the electronic control unit 5 controls operation of the illumination source 2 such that the illumination source 2 is operated such that darker phases and illumination phases alternate for a third mode time interval, e.g. for 6 minutes. The duration of the third mode may be adjusted such that a desired light dose is received at the target surface e.g. 37 J/cm.sup.2, which is particularly suitable at least for red light, or 10 J/cm.sup.2, which is particularly suitable at least for blue light.

(21) The intensity of the electromagnetic radiation 3 emitted by the illumination source 2 is lower in the darker phases than in the illumination phases. In the example shown, the illumination source 2 does not emit electromagnetic radiation in the darker phases, whereas the illumination source 2 emits electromagnetic radiation 3 in the illumination phases, wherein the light intensity of the illumination phases is identical to the light intensity of mode 2 and the maximum light intensity of mode 1. Of course, the relative intensities may be adjusted as required.

(22) This alternating intensity may be maintained for approximately 4 minutes or more in the third mode c. In the example shown in FIG. 3, the protocol contains seven illumination phases and seven dark phases, which in particular allows for the neuronal activation to wear off to some extent to reduce pain. The duration in the third mode c of one of the darker phases is constant and is equal to the duration of one of the illumination phases. The duration of a phase is 20 seconds each. During the illumination phases the light intensity is kept at 100%. After approximately 14 minutes the illumination is stopped completely and the third mode c is ended. The number of illumination phases and darker phases may vary, of course, as may the absolute or relative duration. Also, instead of not operating the light source to emit no radiation at all during the darker phases, a low intensity, e.g. up to 30% of the maximum intensity may still be tolerable. The intensity in a single illumination phase may be constant or substantially constant.

(23) Due to the alternating phases the target tissue may be provided with enough dark phases to reduce photobleaching and/or to promote re-oxygenation of the treated tissue, which may lead to an increase in efficacy. In addition, the paused illuminations of the last mode c allow for the neuronal activation to wear off to some extent. Therefore the perceived pain is significantly reduced.

(24) This third mode c extends until a total light dose of approximately 37 J/cm.sup.2 may be reached. An increased protocol duration while maintaining a light dose of approximately 37 J/cm.sup.2 is beneficial, as it is likely to ensure a most balanced rate of oxygen consumption and resupply. The value of 37 J/cm.sup.2 particularly holds at least for red light. An increased protocol duration while maintaining a light dose of approximately 37 J/cm.sup.2 is beneficial, as it is likely to ensure a most balanced rate of oxygen consumption and resupply.

(25) Alternatively, the third mode c extends until a total light dose of approximately 10 J/cm.sup.2 may be reached. The value of 10 J/cm.sup.2 particularly holds at least for blue light. An increased protocol duration while maintaining a light dose of approximately 10 J/cm.sup.2 is beneficial, as it is likely to ensure a most balanced rate of oxygen consumption and resupply.

(26) If yellow or green light is used, the targeted total light dose may be adjusted appropriately.

(27) The duration of the entire illumination session is expediently kept below 20 minutes or even 16 minutes.

(28) The fractionation of the illumination by dark intervals alternating with higher intensity light, allows re-oxygenation and thus additional photosensitizer activation, especially in the later phases of the illumination when high fluence rates are used, in order to prevent late oxygen depletion. Consequently, the limited treatment time due to pain can be used in a time-efficient manner.

(29) The durations of different darker phases in the third mode c may be equal and/or constant as depicted as may be the durations of different illumination phases in the third mode c. Alternatively, the durations may vary between different darker phases and/or different illumination phases. The same holds for the intensity in the illumination phases, which may be varied, e.g. reduced towards the end of the illumination session. In an embodiment, the duration of the darker phases may be less than the duration of the illumination phases. This results in shorter interruptions of the illumination during the third mode, which may contribute to keep the session duration at a desired time.

(30) The beginning of the operation of the illumination source 2 in the first mode a may define the start of the illumination session and the end of the operation of the illumination source 2 in the third mode c may define the end of the illumination session.

(31) FIG. 3 illustrates a variation of the illumination protocol shown in FIG. 2. Here, in the first mode of operation (mode a), initially, the intensity is increased non-linearly at a slower rate than later on. In interval a1, the increase may be non-linear, whereas in the subsequent interval a2 it may be linear. The (constant) slope in the linear section may be greater than or equal to every slope in the non-linear section. From mode b, the protocol may be continued as depicted in FIG. 2, for example.

(32) FIG. 4 illustrates another variation of the illumination protocol shown in FIG. 2. Here, a priming mode p is included before mode a is commenced. The duration of the priming mode may be 3 min or less. The intensity P during the priming mode may be equal to the intensity B discussed in FIG. 2. In the embodiments in FIGS. 3 and 4, the onset of the second mode (mode b) is merely as an example shown to be at about 340 s.

(33) The duration of the entire illumination session may be less than or equal to one of the following values: 20 min, 19 min, 18 min, 17 min, 16 min, 15 min, 14 min, 13 min.

(34) The first mode time interval and/or the second mode time interval may be shorter than the third mode time interval. The first mode time interval may be shorter than the second mode time interval or longer.

(35) Above, some durations have been specified for the modes. However, the respective mode—first mode, second mode and/or third mode—may be applied for a time interval which is greater than or equal to one of the following values: 1 min, 1.5 min, 2 min, 2.5 min, 3 min, 3.5 min, 4 min, 4.5 min, 5 min. Alternatively or additionally, the respective mode may be applied for a time interval which is than or equal to one of the following values: 10 min, 9.5 min, 9 min, 8.5 min, 8 min, 7.5 min, 7 min, 6.5 min, 6 min, 5.5 min, 5 min. In this way, the illumination protocol may be adjusted to different situations, for example.

(36) The present disclosure also provides a computer program product, such as a data carrier, e.g. a non-transitory data carrier, or data stream, may contain machine readable instructions which, in particular when loaded in and/or executed by a computer system, e.g. by the electronic control unit 5 thereof, cause the illumination source 2 to be operate according to the above-mentioned protocol.

(37) The illumination system 1 may be used to treat a skin disease or disorder. The skin disease or disorder may be or may comprise a neoplastic skin disease, like actinic keratosis, basal cell carcinoma, squamous cell carcinoma in situ, or warts, acne, wound healing disorders/chronic wounds, bacterial and/or fungal infections or inflammatory skin diseases. However, it should be noted that it may also be used for non-therapeutic methods.

(38) A kit for treating a disease, e.g. a skin disease, such as a neoplastic skin disease may comprise a pharmaceutical substance suitable to be topically applied to the skin in a region to be treated and the illumination system 1 as mentioned above, wherein the illumination system 1 is configured to irradiate a region of the skin to which the substance has been applied. The pharmaceutical substance may be a photosensitizing drug or precursor to such a drug that is excitable by light in the emitted spectrum.

(39) A method for treating a skin disease, e.g. one of the ones mentioned further above may comprise the following steps: applying a pharmaceutical substance, e.g. the prodrug mentioned above, to the surface of the skin in a region which is to be treated; irradiating the region, e.g. with the illumination source 2 according to the method as specified above and/or using the illumination system 1 as specified above.

(40) While applying the illumination protocols as discussed above it is not only expected to increase the efficacy but also to reduce the significance of the pain sensation for the patient/user or the pain perceived overall. A substantial amount of perceived pain is one of the major issues that hinders broad acceptance of PDT by patients. Usually patients report to experience a relatively high amount of pain during the illumination which ranges from mild inconvenience to severe pain up to a point where the treatment has to be aborted. This, of course, has great negative implication for an individual PDT session and PDT treatment as a whole.

(41) The application of the proposed illumination system for photodynamic therapy reduces pain during PDT to a well tolerable level. In addition to this, the acceptance of the treatment itself and the willingness to undergo PDT again is greatly improved when employing this illumination system.

(42) Although PDT is a highly effective treatment method, reoccurrence of the treated disease, e.g. actinic keratosis or another one of the diseases mentioned earlier in this disclosure, is common and thus patients often, although being successfully treated, later develop different lesion at different skin areas and again require medical intervention. Moreover, some patients are not completely cleared after a single PDT session and require a second session. If the first PDT they received was very painful, the completion of a second PDT is highly unlikely despite the fact that it offers supreme efficacy compared to other therapy options.

(43) Consequently, the proposed illumination system and protocol increase the acceptance levels for photodynamic therapy.

(44) One particular illumination system and/or its associated protocol has been described above. However, it should be appreciated that different systems and protocols can be applied as well, especially using features which have been discussed in the introductory section of this disclosure, even if these features are not explicitly described above in conjunction with the figures. Thus, the features discussed in the introductory section are made subject to the exemplary embodiments of this disclosure by explicit reference to these features.

REFERENCE NUMERALS

(45) 1 illumination system 2 illumination source 3 electromagnetic radiation 4 target surface 5 electronic control unit p priming mode a first mode b second mode c third mode