Illumination for photodynamic therapy

Abstract

An illumination system (1) for photodynamic therapy is provided, the illumination system comprising: an illumination source (2) configured to emit electromagnetic radiation (3) to illuminate a target surface (4) during operation; and an electronic control unit (5), wherein the illumination source is configured to be able to vary the intensity of the electromagnetic radiation emitted by the illumination source; and wherein the control unit is operably coupled to the illumination source and configured to control operation of the illumination source according to an illumination protocol during an illumination session performed by the illumination system, the illumination protocol comprising instructions for operating the illumination source during an illumination session in a plurality of different modes, the modes including: a) a first mode, wherein in the first mode, the electronic control unit controls operation of the illumination source to a) a first mode, wherein the intensity of the emitted electromagnetic radiation 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 to maintain the intensity of the electromagnetic radiation emitted by the illumination source constant or substantially constant during the second mode time interval; and c) a third mode, wherein in the third mode, the electronic control unit controls operation of the illumination source to alternate between darkness periods and illumination periods during the third mode time interval, wherein the intensity of the electromagnetic radiation emitted by the illumination source is lower during the darkness periods than during the illumination periods, or wherein the illumination source does not emit electromagnetic radiation during the darkness periods, while the illumination source emits electromagnetic radiation during the illumination periods. Further provided are computer program products and kits for treating diseases, as well as methods for operating an illumination source and methods for treating skin diseases.

Description

Technical Field

[0001] The present disclosure relates to an illumination system for photodynamic therapy, the illumination system including an illumination source configured to emit electromagnetic radiation to irradiate a target surface during operation, and an electronic control unit.

[0002] The present disclosure also relates to a method for operating an illumination source, a computer program product such as a data carrier, a kit for treating a disease, and a method for treating a skin disease.

Background Art

[0003] Photodynamic therapy (PDT) has been widely studied and several approaches have been successfully used in treatment. Generally, there are three requirements for PDT: a photosensitizer, molecular oxygen, and light of a specific wavelength. For dermatological PDT, usually a prodrug, such as aminolevulinic acid (ALA), is topically administered to the skin. Subsequently, the prodrug is then converted by cells, such as neoplastic cells, into the actual photosensitizer. The molecular mechanism of action in PDT is based on the cellular ALA uptake, synthesis, and accumulation of a photosensitizer that can be excited by light of a specific wavelength to result in the formation of reactive oxygen species (ROS) in the presence of oxygen. ROS initiate cell death, for example, in the form of apoptosis, necrosis, and autophagy.

[0004] However, one of the main problems preventing wider acceptance of PDT by patients is the significant amount of pain patients experience during irradiation, ranging from mild discomfort to severe pain and up to the point where treatment has to be discontinued. Furthermore, although PDT is a highly effective treatment, recurrence of some diseases such as actinic keratosis is common, and thus patients often develop another lesion in a different skin area later on, even though the treatment was successful, and require medical intervention again. Moreover, some patients do not heal completely after a single PDT session and require a second session. If the first PDT a patient receives is very painful, the likelihood of starting or completing a second PDT is low, despite the fact that it offers superior efficacy compared to other treatment options. As a result, many patients are less likely to receive treatment or retreatment. This, of course, has a significant negative impact on individual PDT treatments as well as PDT as a whole.

[0005] As a result, pain reduction is of great importance in enhancing the acceptance level of PDT treatment overall and thus increasing the utilization of this excellent treatment.

[0006] Nevertheless, PDT efficacy is also limited by several factors involved, namely, photosensitizers, oxygen, and light. Reduced utilization of some of these factors may prevent ROS formation. Optimized dosage forms, pretreatment, and incubation modalities can ensure proper and abundant deposition of photosensitizers. Furthermore, light must reach the molecules in sufficient amounts, and oxygen needs to be present as an energy acceptor.

[0007] In particular, the light of the illumination at an appropriate wavelength that activates each photosensitizer needs to be made available in a sufficient dose. For topical administration, a frequently used photosensitizer is protoporphyrin IX (PpIX), and most of it is produced in skin cells by administration of a precursor molecule such as ALA. PpIX is activated by light of various different wavelengths, and light of red (approximately 635 nm), blue (approximately 420 nm), yellow (approximately 542 nm), or green (approximately 506 nm) is most frequently used. Generally, the light dose received by a target, for example, the skin to be treated, depends on three main factors. They are the irradiance supplied by the light source, the distance between the target area and the light source, and the duration of the irradiation.

Summary of the Invention

Problems to be Solved by the Invention

[0008] Current practice is to apply the total light dose at short intervals (for example, in the range of 7 - 12 minutes with red light or 15 - 20 minutes with blue light). Usually, this approach limits the occurrence of pain. And photo - bleaching of the photosensitizer will occur to a greater extent at higher light intensities and will limit the therapeutic effect. Photo - bleaching explains the effect by which the photosensitizer is inactivated by a permanent disruption of its chemical structure, for example, by cleavage of covalent bonds. This photo - bleaching effect will occur simultaneously with a temporary oxygen depletion of the target tissue due to a large - scale initial reaction. This causes a sharp reduction in the oxygen required for ROS formation. All photo - bleaching that occurs during the period of oxygen limitation will be unproductive because the amount of cytotoxic singlet oxygen generated is small.

[0009] It should be noted that the above description should not be construed as an admission of prior art. They were made to illustrate the background of the concepts disclosed herein, and they would not yet be generally publicly available.

[0010] The object of the present invention is to provide an improved illumination system for photodynamic therapy, an improved method for operating an illumination source, an improved computer program product such as a data carrier, an improved kit for treating a disease, and / or an improved method for treating a skin disease, which preferably is or is configured to limit the pain burden while conveniently maintaining the acceptable effects of the therapy and / or is or is configured to enhance the effects of the therapy.

Means for Solving the Problems

[0011] Each object will be achieved, inter alia, by the content of the independent claims. Advantageous specific examples and improvements are the content of the dependent claims. However, even more advantageous concepts will be disclosed herein in addition to the matter of the current claims.

[0012] One aspect of the present disclosure relates to an illumination system for photodynamic therapy, the illumination system including an illumination source configured to emit electromagnetic radiation to irradiate a target surface during operation and an electronic control unit, the illumination source being configured to be able to vary the intensity of the electromagnetic radiation emitted by the illumination source; the electronic control unit being operably connected to the illumination source and configured to control the operation of the illumination source according to an illumination protocol during an illumination session executed by the illumination system; and the illumination protocol including instructions for operating the illumination source during the illumination session in a plurality of different modes, the modes being a) a first mode, wherein in the first mode, the electronic control unit controls the operation of the illumination source to continuously or quasi-continuously increase the intensity of the electromagnetic radiation emitted by the illumination source from a base intensity B to a target intensity T within a first mode time interval; b) The second mode, wherein in the second mode, the electronic control unit controls the operation of the illumination source to make the intensity of the electromagnetic radiation emitted by the illumination source constant or substantially constant during a second mode time interval; and c) The third mode, wherein in the third mode, the electronic control unit controls the operation of the illumination source to alternate between a dark period and an illumination period during a third mode time interval comprising wherein the intensity of the electromagnetic radiation emitted by the illumination source is lower during the dark period than during the illumination period, or, during the dark period, the illumination source does not emit electromagnetic radiation, while the illumination source emits electromagnetic radiation during the illumination period. The control unit can be configured to control the operating voltage and / or the operating current supplied to the illumination source in a manner that effects the operation of the illumination source as desired for each mode.

[0013] The proposed lighting system can limit or reduce the perceived pain burden. This is achieved, inter alia, by operating the illumination source during the illumination sessions in the different modes described above, as will be explained in more detail hereinafter. The proposed lighting system and, in particular, the illumination protocol can increase the effectiveness of PDT. Thus, the proposed system and / or protocol can provide an efficient therapy while optimizing pain.

[0014] In the first mode, the intensity of the electromagnetic radiation emitted by the illumination source increases continuously or quasi - continuously from a base intensity B to a target intensity T. The term "quasi - continuously" means that the intensity of the emitted radiation is constant for a maximum duration that is less than or equal to one of the following values: 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second or 500 milliseconds. The term "continuously" means that the intensity of the emitted electromagnetic radiation is constant for a maximum duration that is less than or equal to one of the values associated with "quasi - continuously", preferably one of the following values: 400 milliseconds, 300 milliseconds, 200 milliseconds, 100 milliseconds, 50 milliseconds, 25 milliseconds, 20 milliseconds, 15 milliseconds, 10 milliseconds, 5 milliseconds, 4 milliseconds, 3 milliseconds, 2 milliseconds, 1 millisecond. Since it is characterized or determined by the electrical energy supplied to the illumination source, the corresponding values will be characteristic of an operating voltage and / or current that increases continuously or quasi - continuously.

[0015] A continuous or quasi - continuous increase in intensity can trigger the onset of a mild reaction. An increase in intensity can reduce initial photo - bleaching and / or promote re - oxygenation of the treated skin. Separately, a continuous increase in irradiance may cause sufficient photodynamic effects, including an initial inflammatory reaction that induces vasodilation for better oxygen supply. Here, the process during PDT that results in cell destruction is explained. Therefore, the efficiency of the treatment during the first mode will be ensured.

[0016] Another advantage of the first mode is that a continuous increase in the irradiance on the skin - the irradiance on or of the skin depends on the radiation intensity and the distance between the illumination source and the skin - allows for the application of sensory nerve endings in the skin to the stimulus, balances the sensation of pain, and ultimately reduces the pain burden on the patient. A slow increase in irradiance over intervals of 4 to 10 minutes has proven to be acceptable.

[0017] In the second mode, the intensity of the electromagnetic radiation emitted by the illumination source is constant or substantially constant. The term "substantially constant" means that the maximum deviation from the intensity I is less than or equal to one of the following values: 15%, 10%, 5%. I is a constant intensity during the second mode. I may be equal to T.

[0018] The constant or constant-intensity electromagnetic radiation in the second mode can supply a relatively high irradiance, preferably in a short period of time. It will, for example, due to the limited duration, preferably assist or contribute to maintaining the photodynamic effect that persists without causing an intolerable pain burden.

[0019] In the third mode, the illumination source is operated such that dark periods and illumination periods alternate. The dark periods can allow the activation of neurons to disappear to some extent and can result in a lower pain burden. The illumination periods can allow the achievement of the target light dose for the illumination session. In the illumination periods, the intensity is conveniently greater than in the dark periods. In the dark periods, the illumination source can be operated to emit a lower intensity or no radiation at all.

[0020] Moreover, another advantage of the third mode is the balance ratio of oxygen consumption and oxygen supply. The supply of oxygen during the dark periods can conveniently support the efficiency of the treatment by preventing late oxygen depletion.

[0021] Therefore, the combination of the first, second, and third modes is - the initiation of a gentle reaction that reduces the pain burden, reduces initial photobleaching, and promotes the reoxygenation of the treated tissue, - a sufficient photodynamic effect, including an initial inflammatory reaction that induces vasodilation for better oxygen supply, - To prevent late oxygen depletion, especially during the late stage of said irradiation, for example when using a higher or high influence rate, reoxygenation and thus further photosensitizer activation, and - To achieve a given light dose on the irradiation target while maintaining an effective light dose without causing an unbearable pain burden, resulting in a moderately increased or not increased treatment duration.

[0022] In one specific example, B may be less than or equal to one of the values: 0.5T, 0.45T, 0.4T, 0.35T, 0.3T. Alternatively or additionally, B may be greater than or equal to one of the values: 0.1T, 0.15T, 0.2T, 0.25T, 0.3T. Thus, B is between 0.1T and 0.5T, or between any other range created by combining the values of the two lists.

[0023] Appropriately selecting B enables sufficient application to the stimulation of sensory nerve endings in the skin and can balance the sensation of pain. This results in a reduced pain burden. Furthermore, a sufficient photodynamic effect is achieved or promoted. For example, a B value higher than 0.6T may cause excessive initial pain during said illumination session. A value below 0.1T will only be sufficient to promote a substantial photodynamic effect and / or result in unstable irradiation due to technical limitations.

[0024] In one specific example, the constant or quasi-constant intensity during the second mode will be the target intensity T in the first mode. This will enable a direct transition from the first mode to the second mode. Once the target intensity is reached, the advantage is that the efficiency of the treatment is not threatened by changing said intensity. Furthermore, the direct transition from the first to the second mode reduces the stimulation of the patient's nerves and thus can lower the pain burden.

[0025] In one specific example, the intensity during the illumination period would be T. This would reduce the pain burden. Because the nerve, for example, is already applied to T from the preceding mode of the illumination protocol.

[0026] In one specific example, the maximum intensity among the first mode, the second mode and the third mode would be T. This would similarly reduce the stimulation of the patient's nerve and thus also contribute to the reduction of the pain burden.

[0027] In one specific example, the intensity would linearly increase from B to T in the first mode. The linear increase can be easily adjusted to the pain increase rate, and since the increase is predictable, it makes the patient feel comfortable.

[0028] In one specific example, the intensity would strictly monotonically increase in the first mode. The step increase in intensity is more noticeable to the patient than the strict monotonic increase in intensity. As a result, the strict monotonic increase in intensity is associated with pain reduction.

[0029] In one specific example, the intensity would non-linearly increase in the first mode. At the beginning or start of the first mode, the intensity would increase more slowly later in the first mode. This allows the beneficial effects of the photodynamic effect to appear initially, and the application of the nerve and the initial stage of the intensity are maintained.

[0030] In one specific example, the illumination protocol includes a priming mode. The priming mode is a mode of operation of the illumination source that precedes a first mode. In the priming mode of operation, the intensity of the electromagnetic radiation emitted by the illumination source will be constant or substantially constant over a priming mode time interval. The intensity in the priming mode is P. P is less than or equal to the base intensity B in the first mode. The subject / patient irradiated using the protocol becomes accustomed to the irradiance during the initial operation of the illumination source in the priming mode. When applying the priming mode, the intensity in the first mode following the priming mode increases at a higher rate, linearly and / or without the priming mode, preferably without significantly increasing the pain perceived by the user.

[0031] In one specific example, the illumination source will be operated in a first mode before being operated in a second mode and / or before being operated in a third mode during the illumination session. The first mode can accustom the nerves to the radiation intensity or pain burden during the illumination session. For this purpose, the first mode preferably uses a low intensity initially. Therefore, in order to reduce the sensation of pain, it may be advantageous to execute the first mode before further modes, for example, a mode characterized by an initial light intensity in the first mode that is higher than, for example, B.

[0032] In one specific example, the illumination source will be operated in a second mode during the illumination session, after the first mode, and / or before the third mode. Since the second mode will have a constant intensity, if the second mode is preceded by the first mode which serves to accustom the nerves to the light intensity of the second mode, it is advantageous for pain reduction. Further, it is also convenient to have a mode of constant intensity (second mode) between the increasing intensity (first mode) and the alternation of dark and illumination periods (third mode). This is because the pain burden is highest during the second mode. The next dark and illumination periods can be made less taxing on the user's highest pain at the midpoint of the illumination period. The user may preferably experience moderate pain during the third mode and low initial pain.

[0033] In one specific example, the start of the operation of the illumination source in the first mode defines the start of the illumination session, and the end of the operation of the illumination source in the third mode defines the end of the illumination session. If the priming mode is applied, the start of the operation of the illumination source in the priming mode defines the start of the illumination session.

[0034] In one specific example, all modes selected from the first mode, the second mode, and the third mode of the operation of the illumination source occur once, preferably only once, during the illumination session. Thus, the total duration is maintained to be less than 16 minutes, which most patients and doctors will tolerate, for example, from the perspective of pain burden and time consumption. This duration may include or exclude the operation in the priming mode.

[0035] In one specific example, the illumination system can define a target position, or determine a target position such that a target surface is disposed relative to the illumination source during the illumination session. The target position (i.e., the position of the target surface relative to the illumination source) is defined by a seating surface that contacts a portion of the user's head, such as the forehead or chin, and the portion of the user's head can remain in contact with the seating surface throughout the session. The target position can be located at a place away from the radiation emitting surface of the illumination source. A gas phase medium can be present between the radiation emitting surface of the illumination source, such as the surface of an optical element, such as a diffuser or lens, and the target surface and / or the target position.

[0036] As used herein, the term "target surface" refers to a surface to be irradiated by the electromagnetic radiation emitted by the illumination source.

[0037] The term "target position" refers to the position of the target surface relative to the illumination source. In other words, the target position is a position determined by the design of the illumination device. The target position is the position at which the surface to be irradiated should be disposed relative to the illumination device during the operation of the device, i.e., during the illumination session. For example, at the target position, the radiation generated by the illumination device has, for example, a desired irradiance distribution along the target surface. If the target surface is disposed at a different position relative to the illumination source, the irradiance distribution will be different and / or not suitable for the desired purpose.

[0038] As used herein, the term "seating surface" refers to a surface that is preferably suitable for supporting a portion of the user's body, such as the head, at the target position during operation. The portion of the body includes the target surface to be irradiated using the illumination device. The seating surface is formed by a mechanical support.

[0039] In one specific example, the distance between the radiation emission surface of the illumination source and the target position may be smaller than or equal to any 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 emission surface of the illumination source and the target position may be greater than or equal to any one of the following values: 1 cm, 2 cm, 3 cm, 4 cm, 5 cm. The distance between the radiation emission surface of the illumination source and the target position is between 1 cm and 20 cm, preferably between 5 cm and 8 cm.

[0040] PDT effectiveness is potentially limited by any of the factors involved, namely, photosensitizer, oxygen, and light dose. Generally, the light dose received by a target, such as the treated skin, depends on three main factors. One of them is the distance between the target surface and the light source. That distance has a direct impact on the light dose received by the target. This is because the intensity at a particular location depends on the distance of that location from the illumination source. A distance between 1 cm and 20 cm, preferably between 5 cm and 8 cm, is advantageous. This is because the effect of PDT can be maximized. Furthermore, the perceived pain will be acceptable to patients at the above-mentioned distances, especially for typical applied irradiances.

[0041] In one specific example, the illumination source can include at least one optoelectronic semiconductor chip, such as a light-emitting diode chip, for generating electromagnetic radiation. This enables a reliable, cost-beneficial, and accurately mountable illumination source. The optoelectronic chip can easily adjust the emission wavelength to the required (peak) wavelength, for example, by appropriately processing the active region of the chip, such as by bandgap engineering. Thus, electrical energy can be efficiently converted into radiant energy in the relevant wavelength range.

[0042] In one specific example, the radiation emitted by the illumination source may be incoherent radiation. Compared with coherent radiation, incoherent radiation is easier to handle.

[0043] In one specific example, the radiation emitted by the illumination source may be monochromatic light of, for example, light of a single specific color.

[0044] In one specific example, the electromagnetic radiation will have a peak wavelength in the visible spectrum range, for example, in the spectral range of red, blue, green, or yellow.

[0045] In one specific example, the electromagnetic radiation has a peak wavelength in the red spectral range (hereinafter also referred to as "red light"). The peak wavelength of the illumination source is longer than 500 nm, longer than 600 nm, or longer than 630 nm. The peak wavelength may be shorter than 700 nm. The peak wavelength may be 635 nm. Red light has the advantage that it is high-intensity and can reach regions deep within the body away from the skin more easily than light of shorter wavelengths that is more significantly absorbed in body tissue than red light. Therefore, the present disclosure uses red light as a specific example.

[0046] In one specific example, the illumination system can be configured to irradiate the target surface with a predetermined light dose during the illumination session. The light dose, when the target surface is arranged at the target position with respect to the illumination source during the illumination session, may be greater than or equal to one of the following values: 30 J / cm 2 、35 J / cm 2 、37 J / cm 2 Alternatively or additionally, the light dose, when the target surface is arranged at the target position with respect to the illumination source during the illumination session, may be less than or equal to one of the following values: 45 J / cm 2 、40 J / cm 2 、37 J / cm 2 The above values are particularly maintained for at least red light.

[0047] A sufficient light dose is one of the important requirements for successfully performing PDT. However, when selecting the light dose, the maximum acceptable level of pain for the patient must also be considered. A light dose range between 30 and 45 J / cm 2 , and in particular a light dose of 37 J / cm 2 is recognized as the best compromise between an appropriate therapeutic effect and the pain burden, for example when using red light.

[0048] In another specific example, the electromagnetic radiation has a peak wavelength in the blue spectral range (hereinafter also referred to as "blue light"). The peak wavelength of the illumination source will be between 400 nm and 490 nm, for example 420 nm.

[0049] In one specific example, the illumination system may be configured to irradiate the target surface with a predetermined light dose during the illumination session. The light dose, when the target surface is disposed at the target position relative to the illumination source during the illumination session, may be greater than or equal to one of the following values: 8 J / cm 2 , 9 J / cm 2 , 10 J / cm 2 . Alternatively or additionally, the light dose, when the target surface is disposed at the target position relative to the illumination source during the illumination session, may be less than or equal to one of the following values: 12 J / cm 2 , 11 J / cm 2 , 10 J / cm 2 . The above values are maintained, in particular, for at least blue light.

[0050] A light dose in the range between 8 and 12 J / cm 2 , and in particular a light dose of 10 J / cm 2 is recognized as the best compromise between an appropriate therapeutic effect and the pain burden, for example when using blue light.

[0051] It should be noted that yellow or green light could also be used. This would be particularly true if ALA were used as a prodrug. This is because the photosensitizer PpIX absorbs not only red and / or blue light, but also green and / or yellow light.

[0052] In one specific example, the first mode time interval, the second mode time interval, and / or the third mode time interval may be greater than or equal to one of the following values: 1 minute, 15 minutes, 2 minutes, 2.5 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, 5 minutes. Alternatively or additionally, the first mode time interval, the second mode time interval, and / or the third mode time interval may be less than or equal to one of the following values: 10 minutes, 9.5 minutes, 9 minutes, 8.5 minutes, 8 minutes, 7.5 minutes, 7 minutes, 6.5 minutes, 6 minutes, 5.5 minutes, 5 minutes.

[0053] In one specific example, the first mode time interval and / or the second mode time interval may be shorter than the third mode time interval. Thus, the third mode will provide the largest contribution to the total light dose delivered to the target surface during the illumination session.

[0054] In one specific example, the priming mode time interval may be shorter than the first mode time interval, the second mode time interval, and / or the third mode time interval.

[0055] In one specific example, the priming mode time interval may be less than or equal to one of the following values: 4 minutes, 3 minutes, 2 minutes, 1 minute. Alternatively or additionally, the priming mode time interval may be greater than or equal to one of the following values: 10 seconds, 20 seconds, 30 seconds, 1 minute.

[0056] In a specific example, the first mode time interval may be shorter than the second mode time interval. Thus, the illumination duration at an intensity below T will likely be kept relatively small. Thus, the session duration is not unnecessarily extended.

[0057] In a specific example, the first mode time interval and / or the second mode time interval may be longer than the duration of a single dark period and / or a single illumination period, preferably at least 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, where a day is the duration of a single dark period and / or a single illumination period.

[0058] In a specific example, the duration of one dark period and / or one illumination period may be smaller than or equal to one of the following values: 60 seconds, 50 seconds, 45 seconds, 40 seconds, 35 seconds, 30 seconds, 25 seconds, 20 seconds. Alternatively or additionally, the duration of one dark period and / or one illumination period may be greater than or equal to one of the following values: 15 seconds, 20 seconds, 25 seconds, 30 seconds. A duration range between 15 and 60 seconds is advantageous for taking advantage of the beneficial effects without unnecessarily increasing the treatment duration.

[0059] In a specific example, the durations of different dark periods in the third mode may be equal. In a specific example, the durations of different illumination periods in the third mode may be equal. In a specific example, the duration of the dark period is constant and may be equal to or different from the duration of the illumination period.

[0060] In a specific example, the duration of the dark period may be smaller than the duration of the illumination period. This results in an interruption shorter than that of the illumination during the third mode, which contributes to maintaining the session duration at a desired time.

[0061] In one specific example, the duration of the second mode time interval and / or, together with the durations of the first mode time interval and the second mode time interval, is less than or equal to one of the following values: 12 minutes, 11 minutes, 10 minutes, 9 minutes, 8 minutes. Thus, for example, the first pain relief due to the dark period in the third mode after the second mode will occur when or before the patient experiences the maximum pain. Patients have been reported to perceive the maximum or intolerable pain, for example, about 10 minutes after the start of a PDT session. Therefore, maintaining the second mode or the first and second modes combined together for less than 10 minutes has advantages with respect to pain management.

[0062] In one specific example, the duration of the full illumination session may be less than or equal to one of the following values: 20 minutes, 19 minutes, 18 minutes, 17 minutes, 16 minutes, 15 minutes, 14 minutes, 13 minutes. Session durations up to 20 minutes are usually well - accepted by users without problems.

[0063] In one specific example, the duration of the full illumination session may be greater than or equal to one of the following values: 10 minutes, 11 minutes, 12 minutes, 13 minutes. The duration of the session may be, for example, between 10 minutes and 20 minutes.

[0064] In one specific example, the intensity during each illumination period in the third mode may be the same.

[0065] In one specific example, the intensity during the dark period may be less than or equal to B or equal to zero. Therefore, the re - supply of oxygen will be promoted during the dark period.

[0066] In one specific example, the intensity in a single illumination period may be constant or substantially constant. A constant or substantially constant intensity in a single illumination period contributes to a more predictable photodynamic effect.

[0067] In one specific example, the intensity may vary during different illumination periods. The variation in different intensities would serve to adjust the pain burden or load on the patient being treated. For example, at the start of the third mode, the intensity in the illumination period may be higher than near the end of the third mode.

[0068] In one specific example, the illumination protocol governs the entire illumination session.

[0069] Another aspect of the present disclosure relates to a method for operating an illumination source, where the illumination source is operated according to an illumination protocol during an illumination session, for example, performed by the illumination system described above, and where the illumination protocol includes instructions for operating the illumination source during the illumination session in the different modes described above.

[0070] Furthermore, the present disclosure also relates to a computer program product, such as a data carrier, for example, a non - transitory data carrier, or a data stream, where the computer program product contains machine - readable instructions for operating an illumination source according to the protocol described above when loaded and / or executed, in particular, by a computer system, for example, by its electronic control unit.

[0071] Moreover, another aspect relates to a kit for treating a disease, for example, a skin disease such as a neoplastic skin disease. The kit includes a pharmaceutical suitable for topical administration to the skin of the area to be treated and an illumination system as described above, where the illumination system is configured to irradiate the area of the skin where the substance has been administered.

[0072] In one specific example, the pharmaceutical may be a photosensitizer or a precursor of such an agent that is excited by light in the emission spectrum.

[0073] In one specific example, the pharmaceutical can include 5-aminolevulinic acid. 5-aminolevulinic acid is well studied and is considered a reliable prodrug for generating photosensitizers.

[0074] Another aspect relates to a method for treating skin diseases, including the steps of applying to the surface of the skin in the area to be treated with the pharmaceutical, irradiating the area with an illumination source according to the method as described above, and / or using the illumination system as described above.

[0075] In one specific example, the illumination system, the kit and / or the method can be used to treat skin diseases or disorders. The skin diseases or disorders can be actinic keratosis, basal cell carcinoma, or intraepithelial squamous cell carcinoma a neoplastic skin disease selected from , warts, acne, wound healing disorders 、 chronic wounds, bacteria infectious fungal infections or inflammations of skin diseases patients or may include them.

[0076] It is noted that the present disclosure covers non-therapeutic methods.

[0077] Due to the low pain burden, the illumination system can be widely used for the treatment of various diseases.

[0078] Of course, the above features related to different aspects and specific examples can be combined with each other and with the above features. Thus, the features related to the system also apply to the method and the kit, and vice versa.

[0079] Further features and variations will become apparent from the following description of representative specific examples in connection with the accompanying drawings.

Brief Description of the Drawings

[0080]

Figure 1

Figure 2

Figure 3

Figure 4

[0081] FIG. 1 shows, for example, an illumination system 1 for photodynamic therapy (PDT). The illumination system 1 includes an illumination source 2 configured to emit electromagnetic radiation 3 to irradiate a target surface 4 during operation, and an electrical control unit 5. The target surface 4 may be human skin, such as the skin of the head or other regions to be treated. Further, PDT requires a photosensitizer and molecular oxygen (not shown). Usually, the photosensitizer is obtained by a prodrug (not shown), which is conveniently topically administered to the skin in the target area and then converted to the actual photosensitizer by cells, preferably tumor cells. The prodrug may be 5-aminolevulinic acid (5-ALA), an endogenous precursor for heme biosynthesis.

[0082] The molecular mechanism of action in PDT is based on the cellular uptake, synthesis, and accumulation of the photosensitizer, which is excited by light of a specific wavelength and leads to the formation of reactive oxygen species (ROS) due to the presence of oxygen. These ROS species can initiate cell death in the form of apoptosis, necrosis, and / or autophagy.

[0083] The illumination source 2 is configured to be able to vary the intensity of the electromagnetic radiation 3 emitted by the illumination source 2 and / or that reaching the target surface 4. Moreover, the distance between the target surface 4 and the illumination source 2 of the illumination system 1 is adjustable and can thus vary. However, it is preferred that the target surface 4 has a fixed position relative to the illumination source.

[0084] The illumination source 2 can include one light-emitting diode (LED) or a plurality of light-emitting diodes. In particular, an illumination source such as that sold by Biofrontera AG under the trade name BF-RhodoLED (R) is suitable. The light emitted by the light-emitting diode promotes the formation of reactive oxygen species (ROS). The wavelength of the light emitted by the illumination source may be longer than 400 nm, longer than 500 nm, or longer 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 can be applied to appropriately activate the photosensitizer.

[0085] The illumination system 1 can have a target position, or the target surface 2 can define a target position that is arranged relative to the illumination source 2 during the illumination session. The target position will be defined by a support surface that contacts the user's head, for example, the area of the forehead or jaw. The area can continue to contact the indication surface during the entire session. The target position can be arranged at a certain distance from the radiation exit surface 2 of the illumination source. A gaseous medium may be present between the radiation exit surface 2 of the illumination source, for example, the surface of an optical element, for example, a diffuser or a lens, and the target surface 4 and / or the target position.

[0086] The distance between the radiation exit surface 2 of the illumination source and the target position may be smaller 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 2 of the illumination source and the target position may be larger 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 2 of the illumination source and the target position may be between 1 cm and 20 cm, preferably between 5 cm and 8 cm.

[0087] The illumination source 2 can include at least one optoelectronic semiconductor chip that generates the electromagnetic radiation, for example, a light emitting diode chip. The radiation 2 emitted by the illumination source may be incoherent radiation. It may be, for example, a single color of light of a particular color. The electromagnetic spectrum emitted by the illumination source 2 may have a peak wavelength within the visible spectrum range, for example, within the red or blue spectrum range. The emission spectrum may be narrow. For example, the full width at half maximum (FWHM) of the spectrum may be less than 100 nm, for example, 50 nm or less.

[0088] The electronic control unit 5 is operably connected to the illumination source 2 and is configured to control the operation of the illumination source 2 according to an illumination protocol during an illumination session executed in 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 includes instructions for operating the illumination source 2 during the illumination session in a plurality of different modes, which are disclosed in detail in FIG. 2.

[0089] FIG. 2 shows a diagram of the biaxial illumination protocol, where the first axis represents the duration of radiotherapy in seconds and the second axis represents the low level of light intensity in percent. The illumination protocol will govern the entire illumination session

[0090] During the first mode a that is first executed when using the illumination system 1, the electronic control unit 5 controls the operation of the illumination source 2 such that the intensity of the electromagnetic radiation 3 emitted by the illumination source 2 continuously or quasi - continuously increases from a base intensity B (30%) to a target intensity T (100%) during the first mode time interval.

[0091] As illustrated in FIG. 2, a linear trend is applied that increases the light intensity from 30% to 100% of the light intensity over a period of 5 or 5.5 minutes. Of course, other durations are possible. The intensity at 100% need not be the maximum intensity that can be emitted by the illumination source 2, but rather designates the maximum intensity during said illumination session. Alternatively, the intensity may increase non-linearly in the first mode a (see, for example, FIG. 3). Here, the slope is preferably smaller at first than later, which is advantageous for sensitizing nerve endings.

[0092] The first mode a promotes a slow but continuously increasing irradiance that serves as a trigger for sufficient photodynamic effects, including reducing initial photo-bleaching by predicting the onset of a mild reaction, inducing an initial inflammatory reaction that promotes re-oxygenation of the treated tissue and vasodilation for better oxygen supply. The said photodynamic effect means the process during PDT that causes cell destruction, where photo-bleaching means the effect that a photosensitizer is inactivated by a permanent destruction of its chemical structure, for example, by cleavage of a covalent bond. The said photo-bleaching effect may occur together with a temporary oxygen depletion in the target tissue due to a large-scale initial reaction. This causes a rapid decrease in oxygen and thus limits the formation of ROS. Furthermore, the slower onset phase allows for the application to the stimulation of sensory nerve endings in the skin, thereby reducing the pain perceived by the patient.

[0093] After reaching 100% light intensity, the second mode b follows, and the electronic control unit 5 controls the operation of the illumination source 2 such that the intensity of the electromagnetic radiation 3 emitted by said illumination source remains constant or substantially constant during the 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 can be kept constant for approximately 4.5 minutes. Of course, other durations are possible.

[0094] This second mode b has a relatively short duration and thus, with respect to the pain burden, is much less than the total session duration of 16 minutes, which is considered acceptable by most patients and doctors, and is important for supplying high energy to the target. Separately, the electronic control unit 5 controls the operation of the illumination source 2 to stop the irradiance or to reduce the intensity after 10 minutes, for example, by the first dark period in the next mode (mode c below), and thereby operates the illumination source 2 to cancel an excessive increase in pain.

[0095] 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.

[0096] Next, the second mode b is followed by the third mode c. The third mode c is the final mode of the protocol. In the third mode c, the electronic control unit 5 controls the operation of the illumination source 2 to operate the illumination source 2 so that the dark period and the illumination period alternate at a third mode time interval, for example, 6 minutes. The duration of the third mode is such that the desired light dose received at the target surface is, for example, in particular, at least 37 J / cm for red light 2 or in particular, at least 10 J / cm for blue light 2 and can be adjusted accordingly.

[0097] The intensity of the electromagnetic radiation 3 emitted by the illumination source 2 is lower in the dark period than in the illumination period. In the example shown, the illumination source 2 does not emit electromagnetic radiation in the dark period, and the illumination source 2 emits electromagnetic radiation 3 in the illumination period, where the light intensity of the illumination period is the same as the light intensity of mode 2 and the maximum light intensity of mode 1. The relative intensity can be adjusted as needed.

[0098] This alternating intensity is maintained for approximately four minutes or more in the third mode c. In the example shown in FIG. 3, the protocol includes seven illumination periods and seven dark periods, which, in particular, reduce neuronal activation to some extent and reduce pain. The duration of one dark period in the third mode c is constant and equal to the duration of one illumination period. The duration of one period is 20 seconds each. During the illumination period, the light intensity is kept at 100%. After approximately 14 minutes, the illumination is completely stopped and the third mode c ends. The number of illumination and dark periods may, of course, vary and may be absolute or relative durations. Also, instead of not operating the light source so as not to emit any radiation during the dark period, it is still acceptable to set it to a low intensity, for example, up to 30% of the maximum intensity. The intensity in a single illumination period is constant or substantially constant.

[0099] Thanks to the alternating periods, the target tissue can be subjected to sufficient dark periods to reduce photobleaching and / or promote reoxygenation of the treated tissue, leading to an improvement in effectiveness. Furthermore, the temporary cessation of illumination in the final mode c reduces neuronal activation to some extent. Therefore, the perceived pain is significantly reduced.

[0100] This third mode c continues until the total light dose reaches approximately 37 J / cm 2 The value of 37 J / cm 2 is maintained, in particular, for at least red light. It is beneficial to increase the protocol duration while maintaining the light dose at approximately 37 J / cm 2 This is because it may ensure the most balanced ratio of oxygen consumption and supply.

[0101] Alternatively, the third mode c continues until the total light dose reaches approximately 10 J / cm 2 The value of 10 J / cm 2 is maintained, in particular, for at least blue light. The light dose is approximately 10 J / cm 2It is beneficial to increase the protocol duration while maintaining it. This is because it may guarantee the most balanced ratio of oxygen consumption and supply.

[0102] If yellow or green light is used, the total light dose to be targeted can be adjusted as appropriate.

[0103] The duration of the full illumination session is conveniently maintained at 20 minutes or even less than 16 minutes.

[0104] Fragmentation of illumination with dark intervals alternating with higher-intensity light allows for reoxygenation and thus further photosensitizer activation in the later stages of illumination, especially when using a high fluence rate, in order to prevent late oxygen depletion. As a result, the treatment time limited by pain can be used in a time-efficient manner.

[0105] The durations of the different dark periods in the third mode c are equal and / or constant, similar to the durations of the different illumination periods in the third mode c. Alternatively, the durations may vary between different dark periods and / or different illumination periods. The intensity in the illumination period is the same and can vary, for example, decreasing towards the end of the illumination session. In one specific example, the duration of the dark period may be shorter than the duration of the illumination period. This will contribute to shortening the interruption of the illumination and keeping the session duration at the desired time during the third mode.

[0106] The start of the operation of the illumination source 2 in the first mode a defines the start of the illumination session, and the end of the operation of the illumination source 2 in the third mode c defines the end of the illumination session.

[0107] Figure 3 illustrates a variation of the lighting protocol shown in Figure 2. Here, in the first mode of operation (in mode a), initially, the intensity increases non-linearly at a slower rate than later. At interval a1, the increase may be non-linear, and at the next interval a2, it may be linear. The (constant) slope in the linear section may be greater than or equal to all slopes in the non-linear section. From mode b, the protocol can continue as depicted in Figure 2, for example.

[0108] Figure 4 illustrates another variation of the lighting protocol shown in Figure 2. Here, a priming mode p is included before mode a is initiated. The duration of the priming mode is 3 minutes or less. The intensity during the priming mode may be equal to intensity B discussed in Figure 2. In the specific examples of Figures 3 and 4, the start of the second mode (mode b) is shown as an example of approximately 340 seconds.

[0109] The duration of the entire lighting session may be less than or equal to one of the following values: 20 minutes, 19 minutes, 18 minutes, 17 minutes, 16 minutes, 15 minutes, 14 minutes, 13 minutes. 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 or longer than the second mode time interval.

[0110] Above, several durations have been specified for those modes. However, for each mode - the first mode, the second mode, and / or the third mode - a time interval greater than or equal to one of the following values: 1 minute, 15 minutes, 2 minutes, 2.5 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, 5 minutes may be applied. Alternatively or additionally, for each mode, a time interval less than or equal to one of the following values: 10 minutes, 9.5 minutes, 9 minutes, 8.5 minutes, 8 minutes, 7.5 minutes, 7 minutes, 6.5 minutes, 6 minutes, 5.5 minutes, 5 minutes may be applied. Thus, the lighting protocol can be adjusted for different situations, for example.

[0111] The present disclosure also provides a computer program product, such as a data carrier, for example a non-transitory data carrier, or a data stream, which can contain machine-readable instructions for operating a light source in accordance with the above-described protocol when loaded into a computer system and / or when executed by a computer system, for example by its electronic control unit.

[0112] The lighting system 1 can be used to treat skin diseases or disorders. The skin diseases or disorders include actinic keratosis symptoms basal cell carcinoma, or intraepithelial squamous cell carcinoma a neoplastic skin disease selected from, e.g., acne, pimples, wound healing disorders 、 chronic wounds, bacteria infectious fungal infection or inflammatory skin diseases, or can include them. However, it should be noted that it can also be used for non-therapeutic methods.

[0113] A kit for treating a skin disease, such as a skin disease like a neoplastic skin disease, can include a pharmaceutical suitable for topical administration to the skin in the area to be treated, and the above-described lighting system 1, and the lighting system 1 is configured to irradiate the area of the skin where the substance has been administered. The pharmaceutical can be a photosensitizer or a precursor of a drug that can be excited by light in the radiation spectrum.

[0114] For example, a method for treating a skin disease, such as one of the above, can include the following steps: administering a pharmaceutical, such as the above prodrug, to the skin in the area to be treated; irradiating the area with the light source 2 and / or using the above-described lighting system 1 in accordance with the method.

[0115] Applying the illumination protocol as described above can not only enhance effectiveness, but also be expected to reduce the severity of the pain sensation or the overall pain experienced by the patient / user. A substantial amount of perceived pain is a major problem, but it obscures the fact that PDT is widely accepted by patients. Usually, patients are reported to experience a relatively high amount of pain during the illumination, ranging from mild discomfort to severe pain that may force them to abandon the treatment. This, of course, has a significant negative implication for individual PDT sessions and PDT treatment as a whole.

[0116] The application of the proposed illumination system for photodynamic therapy reduces the pain during PDT to a level that can be well tolerated. In addition, the willingness to undergo the treatment itself and to receive PDT again is greatly improved if this illumination system is adopted.

[0117] PDT is a very effective treatment method, but recurrence of the treated diseases, such as actinic keratosis and other diseases mentioned above in this disclosure, is common. Thus, although the treatment is successful, patients often develop different lesions in different skin areas at a later date and require medical intervention again. Moreover, some patients do not fully recover in a single PDT session and need a second session. If the first PDT they received was painful, the completion of the second PDT will be almost non-existent, despite the fact that it can provide a nested effectiveness compared to other treatment options.

[0118] As a result, the proposed illumination system and protocol enhance the acceptance level for photodynamic therapy.

[0119] One particular lighting system and / or related protocol has been described. However, different systems and protocols should be understood to be equally applicable using the features discussed in the introduction of this disclosure, even if these features are not explicitly shown in connection with the drawings. Thus, the features discussed in the introduction are representative examples of this disclosure that explicitly reference these features.

Description of the Reference Numerals

[0120] 1 Lighting system 2 Light source 3 Electromagnetic radiation 4 Target surface 5 Electronic control unit p Priming mode a First mode b Second mode c Third mode

Claims

1. An illumination system for photodynamic therapy, comprising an illumination source configured to emit electromagnetic radiation having a peak wavelength in the red spectral range to irradiate a target surface during operation, and an electronic control unit, wherein the peak wavelength is longer than 500 nm and shorter than 700 nm, the target surface is the surface of the skin, the illumination source is configured to be able to vary the intensity of the electromagnetic radiation emitted by the illumination source; the electronic control unit is operably connected to the illumination source and is configured to control the operation of the illumination source according to an illumination protocol during an illumination session performed by the illumination system; and the illumination protocol includes instructions for operating the illumination source during the illumination session in a plurality of different modes, the modes being a priming mode preceding the first mode, wherein the priming mode time interval in the priming mode is greater than or equal to 10 seconds and less than or equal to 4 minutes, the intensity of the electromagnetic radiation in the priming mode is constant at P, and P is less than or equal to the base intensity B in the first mode, and the start of the priming mode defines the start of the illumination session; a) a first mode, wherein in the first mode, the electronic control unit controls the operation of the illumination source to continuously or quasi - continuously increase the intensity of the electromagnetic radiation emitted by the illumination source from a base intensity B to a target intensity T within a first mode time interval, and the base intensity B is between 0.1T and 0.5T; b) a second mode, wherein in the second mode, the electronic control unit controls the operation of the illumination source to keep the intensity of the electromagnetic radiation emitted by the illumination source constant at the target intensity T during a second mode time interval; and c) A third mode, wherein in the third mode, the electronic control unit controls the operation of the illumination source such that a dark period and an illumination period alternate during a third mode time interval, where the intensity of the electromagnetic radiation emitted by the illumination source is lower during the dark period than during the illumination period, or the illumination source does not emit electromagnetic radiation during the dark period, while the illumination source emits electromagnetic radiation during the illumination period. including The target surface is arranged at a target position with respect to the illumination source during the illumination session, and the illumination system is configured to irradiate the target surface with a predetermined radiation dose during the illumination session, the radiation dose being between 30 J / cm² and 45 J / cm². An illumination system for photodynamic therapy.

2. The illumination system according to claim 1, wherein the illumination source is operated in a second mode during the illumination session after the first mode and / or before the third mode.

3. The illumination system according to claim 1 or 2, wherein the start of the operation of the illumination source in the first mode defines the start of the illumination session, and the end of the operation of the illumination source in the third mode defines the end of the illumination session.

4. The illumination system according to any one of claims 1 to 3, wherein all modes selected from the first mode, the second mode, and the third mode of the operation of the illumination source occur only once during the illumination session.

5. In the third mode, the intensity of the electromagnetic radiation emitted by the illumination source is a target intensity T. The illumination system according to any one of claims 1 to 4.

6. The illumination system according to any one of claims 1 to 5, wherein the distance between the radiation emission surface of the illumination source and the target position is between 1 cm and 20 cm.

7. The duration of the full illumination session is less than or equal to one of the values: 20 minutes, 19 minutes, 18 minutes, 17 minutes, 16 minutes, 15 minutes, 14 minutes, 13 minutes, the lighting system according to any one of claims 1 to 6.

8. A method for operating an illumination source for photodynamic therapy, wherein the illumination source is operated according to an illumination protocol during an illumination session performed by the illumination system according to any one of claims 1 to 7, the illumination protocol including instructions for operating the illumination source during the illumination session in a plurality of different modes, the modes being A priming mode preceding the first mode, wherein the priming mode time interval in the priming mode is greater than or equal to 10 seconds and less than or equal to 4 minutes, the intensity of the electromagnetic radiation in the priming mode being constant and P, where P is less than or equal to the base intensity B in the first mode, the start of the priming mode defining the start of the illumination session; a) A first mode, wherein in the first mode, the illumination source is operated to continuously or quasi-continuously increase the intensity of the electromagnetic radiation emitted by the illumination source 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 illumination source is operated to keep the intensity of the electromagnetic radiation emitted by the illumination source constant at the target intensity T during a second mode time interval; and c) A third mode, wherein in the third mode, the illumination source is operated such that a dark period and an illumination period alternate during a third mode time interval, wherein the intensity of the electromagnetic radiation emitted by the illumination source is lower during the dark period than during the illumination period, or, during the dark period, the illumination source does not emit electromagnetic radiation, while the illumination source emits electromagnetic radiation during the illumination period including, The target surface is positioned at a target position relative to the illumination source during the illumination session, and the illumination system is configured to irradiate the target surface with a predetermined radiation dose during the illumination session, the radiation dose being between 30 J / cm2 and 45 J / cm2. A method for operating an illumination source.

9. The method according to claim 8, wherein in the third mode, the intensity of the electromagnetic radiation emitted by the illumination source is the target intensity T.

10. A computer program product, the computer program product being a data carrier selected from a non-transitory data carrier and a data stream, the computer program product containing machine-readable instructions for operating an illumination source according to the method of claim 8 when loaded into and / or executed by a computer system.

11. The computer program product according to claim 10, which is executed by an electronic control unit of the computer system selected from a CPU and a microcontroller.

12. A kit for treating a skin disease, a pharmaceutical suitable for topical administration to the skin in the area to be treated, and an illumination system according to any one of claims 1 to 7, the illumination system being configured to irradiate the area of the skin to which the pharmaceutical has been administered. A kit comprising.

13. The kit according to claim 12, wherein the pharmaceutical is a photosensitizer or a precursor of a drug that can be excited by radiation in the emission spectrum.

14. The kit according to claim 12, wherein the skin disease is a neoplastic skin disease selected from actinic keratosis, basal cell carcinoma, or intraepithelial squamous cell carcinoma, a wart, acne, a wound healing disorder, a chronic wound, a bacterial infectious, fungal infectious, or inflammatory skin disease.

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