Methods for reducing pain during photodynamic therapy of actinic keratosis

Abstract

To provide methods for reducing pain during photodynamic therapy of actinic keratosis, and also to provide methods of treating actinic keratosis with reduced pain during photodynamic therapy of actinic keratosis.SOLUTION: A method of reducing pain during photodynamic therapy of actinic keratoses, comprises: (a) applying a pharmaceutical composition comprising 5-aminolevulinic acid on the affected area of the skin of a patient; (b) illuminating the affected area with a light source with substantially no pre-illumination gap; and (c) maintaining the illumination for at least 30 minutes; wherein the method does not include pre-treatment preparation.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to a method for reducing pain during photodynamic therapy of actinic keratosis. The present invention also relates to a method for treating actinic keratosis in which pain during photodynamic therapy is reduced. 。

Background Art

[0002] Photodynamic therapy (PDT), photodynamic diagnosis (PDD), or photochemotherapy is generally used to treat and / or diagnose certain types of mild diseases inside or in the vicinity of the skin or other tissues such as, for example, tissues in body cavities. For example, photodynamic therapy or photodynamic diagnosis can be used to treat or diagnose actinic keratosis on the patient's scalp or facial area or upper limbs (for example, the back of the hand or forearm). In addition, such techniques can be used for the treatment and diagnosis of other indications (such as acne, warts, psoriasis, photo-damaged skin, cancer) and other parts of the patient's body (for example, parts of the arm other than the leg or forearm). Furthermore, such techniques may be used for the treatment and diagnosis of other indications (such as acne, warts, psoriasis, photo-damaged skin, cancer) and other parts of the patient's body (for example, parts of the arm other than the leg or forearm). can be used.

[0003] PDT is a field therapy that uses a photosensitizing agent and visible light to treat skin cancer and precancer. PDT has been approved by the FDA in the United States for actinic keratosis (AK) (Piacquadio DJ et al. Arch Dermatol 2004;140:41-6), and in Europe for basal cell carcinoma and squamous cell carcinoma (Christensen E et al. J Eur Acad Dermatol Venereol 2010;24:505-12). PDT is applied to skin lesions ​​​​​​administering a topical 5 - aminolevulinic acid (ALA) or its methyl ester (m - ALA), and these prodrugs are then selectively taken up by neoplastic cells and converted to protoporphyrin IX (PpIX) within mitochondria (Ken nedy JC et al. J Photochem Photobiol B 19 92;14:275 - 92). When exposed to visible light, PpIX is activated and the mito chondria are damaged, causing cell death (Anand S et al. Cance r Lett 2012;326:8 - 16). PDT has important clinical advantages, including the ability to simultaneously target multiple AK lesions and eliminate them without leaving scars (Piacquadio DJ et al. Arch Dermatol 2004 ;140:41 - 6, Christensen E et al. J Eur Acad Dermatol Venereol 2010;24:505 - 12, Anand S et al. Cancer Lett 2012;326:8 - 16). However, one drawback of PDT is that patients often experience stabbing pain during the irradiation phase and this PDT - induced pain, which occurs with either blue or red light, cannot be relieved by any topical anesthetic (other than ice chips and evaporative cooling), and thus is severe enough that patients refuse to complete the treatment and / or may decline future PDT treatments (Warren CB et al. J Am Acad Dermato l 2009;61:1033 - 43, Ang JM et al. Photodiag nosis Photodyn Ther 2017;19:308 - 44). Therefore, Moreover, PDT-related pain is a significant barrier to achieving optimal treatment outcomes.

[0004] Some evidence suggests that PDT-related pain is positively correlated with the length of time that ALA is present on the skin (ALA incubation time). Over the past 20 years, practitioners have attempted to gradually shorten the ALA incubation period. For example, recent clinical trials of facial and scalp AK have shown similar lesion clearance rates using ALA incubation times of 1, 2, or 3 hours (Pariser DM et al. Dermatol Surg 2016;42:296-304). However, FDA-approved ALA photodynamic therapy still involves a painful incubation time of 14-16 hours, or a pre-irradiation gap, presumably because shortening the incubation time for pain management may significantly impair the therapeutic effect of photodynamic therapy. Therefore, the FDA has not yet approved photodynamic therapies with a minimal or near-zero pre-irradiation gap. Surprisingly, the inventors of the present invention have found that topical ALA administration followed by exposure to blue light with a near-zero pre-irradiation gap not only produces excellent results against AK lesions, but also results in little or minimal pain to the patient. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0005] A method for reducing pain during photodynamic treatment of actinic keratosis provided herein comprises: (a) administering to an affected area of a patient's skin a pharmaceutical composition comprising 5-aminolevulinic acid; (b) irradiating the affected area with a light source with a including maintaining for at least 30 minutes, and the method does not include pretreatment preparation.

[0006] Also provided herein, a method for treating actinic keratosis is: (a) administering a pharmaceutical composition containing 5-aminolevulinic acid to the affected area of the patient's skin; (b) irradiating the affected area with a light source with substantially no pre-irradiation gap; (c) maintaining the irradiation for at least 30 minutes. including, and the method does not include pretreatment preparation.

Brief Description of the Drawings

[0007]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0008] Hereinafter, various embodiments of the present invention will be described.

[0009] The expression "substantially no pre-irradiation gap" is used to indicate the time difference or time gap between administering a topical composition of 5-aminolevulinic acid to the skin according to the present invention and then irradiating the affected area of the skin with a light source. In line with the object of the present invention, "substantially no pre-irradiation gap" means that the time gap is 10 minutes or less, preferably 8 minutes or less, more preferably 6 minutes or less, and most preferably 5 minutes or less. ​

[0010] As used herein, the phrase "Visual Analog Pain Scale (hereinafter referred to as the VAS pain score)" is defined as a numerical pain scale of up to 11 points, where the patient reports a number (0-10) that most accurately reflects the pain level experienced at that particular moment, with 0 corresponding to no pain and 10 corresponding to the worst possible pain (Br eivik, Harald Scandinavian Journal of Pain 2016;11:150-152).

[0011] As used herein, the phrase "pre-treatment preparation" includes, but is not limited to, curettage, abrasive tape, micro dermabrasion, laser surface treatment, scraping or descaling of the skin over and around actinic keratosis lesions, or pre-administration including topical administration of 5-fluorouracil, topical calcipotriol or any retinoid cream to patients requiring such photodynamic therapy. Any procedures related to skin cleaning using organic solvents such as isopropyl alcohol, ethyl alcohol or acetone or other such suitable solvents or mixtures thereof are not considered pre-treatment .

[0012] In one embodiment of the present invention, side A (test PDT) received topical administration of a 5-aminolevulinic acid composition, followed by continuous irradiation of the affected skin area of the patient for at least 3 0 minutes, or at least 45 minutes, or at least 60 minutes with substantially no pre-irradiation gap.

[0013] In one embodiment of the present invention, side B (control PDT) received topical administration of a 5-aminolevulinic acid composition ​​​​​After receiving local administration and the composition was maintained on the affected area for 1 hour, the patient's skin affected area was irradiated with standard irradiation for 16 minutes and 40 seconds.

[0014] The use of any example provided herein, or exemplary language (e.g., "such as") is merely for the purpose of better explaining the embodiments and, unless otherwise indicated, does not limit the claims.

[0015] In one aspect, the present invention relates to a method for reducing pain during photodynamic therapy of actinic keratosis, the method comprising: (a) administering a pharmaceutical composition comprising 5-aminolevulinic acid to an affected area of a patient's skin; (b) irradiating the affected area with a light source with substantially no pre-irradiation gap; and (c) maintaining the irradiation for at least 30 minutes, and the method does not include pretreatment preparation.

[0016] In certain embodiments, the irradiation is performed for at least 45 minutes.

[0017] In another embodiment, the irradiation is performed for at least 60 minutes.

[0018] In one aspect of the present invention, the irradiation for at least 30 minutes, the irradiation for at least 45 minutes, and / or the irradiation for at least 60 minutes are each achieved by using 1 cycle of 30-minute irradiation, using 1.5 cycles of 30-minute irradiation, or using 2 cycles of 30-minute irradiation. One irradiation cycle as used herein means that the light source is continuously held in the switched-on position for 30 minutes to irradiate the skin affected area.

[0019] In certain embodiments, the present invention relates to a method for reducing pain during photodynamic therapy of actinic keratosis where the pre-irradiation gap is 10 minutes or less. In certain preferred embodiments ​ 1. The pre-irradiation gap is 8 minutes or less. In a more preferred embodiment, the pre-irradiation gap is 6 minutes or less. In the most preferred embodiment, the pre-irradiation gap is 5 minutes or less.

[0020] In one embodiment, the present invention provides a method for reducing pain during photodynamic therapy of actinic keratosis, which comprises administering a pharmaceutical composition containing 5-aminolevulinic acid to the skin lesion of a patient, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v.

[0021] In another embodiment, the present invention provides a method for reducing pain during photodynamic therapy of actinic keratosis, which comprises administering a pharmaceutical composition containing 5-aminolevulinic acid to the skin lesion of a patient, and the therapeutically effective concentration of 5-aminolevulinic acid is 10% w / v.

[0022] In one embodiment, the present invention relates to a method for reducing pain during photodynamic therapy of actinic keratosis, wherein the skin lesion of the patient is irradiated with a light source after administration of ALA. The light source may be selected from any physical light-emitting device that generates wavelengths of blue, red or white. For example, the light source may be an arc lamp, an incandescent lamp (red-hot filament), a fluorescent light source (red-hot gas), a laser (coherent light), a red light source, a halogen laser, a blue light source, or a light-emitting diode (LED).

[0023] In a preferred embodiment, the light source is a blue light source. In a more preferred embodiment, the light source is blue light having a wavelength of about 417 nm and provides a dose of 10 J / cm² at a power density of 10 mW / cm². 2 2It is applied for 1000 seconds at the intensity of. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time.

[0024] In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. 2 In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. 2 In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time. In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, the red light source is red light generated by a light emitting diode (LED) at, for example, 635 nm. The red light can provide a fluence of, for example, 10 - 75 J / cm² (such as 37 J / cm²) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time.

[0025] In one embodiment of the present invention, the VAS pain score achieved from photodynamic therapy is less than 1.0. In a preferred embodiment, the VAS pain score is selected from values less than 0.9, less than 0.8, less than 0.7 or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2 or less than 0.1. In the most preferred embodiment, the VAS pain score is 0.0. In one embodiment of the present invention, the VAS pain score achieved from photodynamic therapy is less than 1.0. In a preferred embodiment, the VAS pain score is selected from values less than 0.9, less than 0.8, less than 0.7 or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2 or less than 0.1. In the most preferred embodiment, the VAS pain score is 0.0. In one embodiment of the present invention, the VAS pain score achieved from photodynamic therapy is less than 1.0. In a preferred embodiment, the VAS pain score is selected from values less than 0.9, less than 0.8, less than 0.7 or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2 or less than 0.1. In the most preferred embodiment, the VAS pain score is 0.0. In one embodiment of the present invention, the VAS pain score achieved from photodynamic therapy is less than 1.0. In a preferred embodiment, the VAS pain score is selected from values less than 0.9, less than 0.8, less than 0.7 or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2 or less than 0.1. In the most preferred embodiment, the VAS pain score is 0.0. In one embodiment of the present invention, the VAS pain score achieved from photodynamic therapy is less than 1.0. In a preferred embodiment, the VAS pain score is selected from values less than 0.9, less than 0.8, less than 0.7 or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2 or less than 0.1. In the most preferred embodiment, the VAS pain score is 0.0. In one embodiment of the present invention, the VAS pain score achieved from photodynamic therapy is less than 1.0. In a preferred embodiment, the VAS pain score is selected from values less than 0.9, less than 0.8, less than 0.7 or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2 or less than 0.1. In the most preferred embodiment, the VAS pain score is 0.0.

[0026] In another aspect, the present invention relates to a method for treating actinic keratosis, the method comprising: (a) administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin; and (b) irradiating the affected area with a light source with substantially no pre-irradiation gap; and (c) maintaining the irradiation for at least one cycle for 30 minutes, the method not including pre-treatment preparation.

[0027] In certain embodiments, the irradiation is performed for at least 45 minutes.

[0028] In another embodiment, the irradiation is performed for at least 60 minutes.

[0029] In certain embodiments, the irradiation for at least 30 minutes, at least 45 minutes or at least 60 minutes is achieved by use of one cycle of 30-minute irradiation, 1.5 cycles of 30-minute irradiation, or two cycles of 30-minute irradiation, respectively. One irradiation cycle as used herein means that the light source is continuously held in the switched-on position for 30 minutes to irradiate the skin affected area. 5 cycles of 30-minute irradiation, or two cycles of 30-minute irradiation. One irradiation cycle as used herein means that the light source is continuously held in the switched-on position for 30 minutes to irradiate the skin affected area. In certain embodiments, the present invention relates to a method for treating actinic keratosis using photodynamic therapy with a pre-irradiation gap of 10 minutes or less. In certain preferred embodiments, the pre-irradiation gap is 8 minutes or less. In more preferred embodiments, the pre-irradiation gap is 6 minutes or less. In the most preferred embodiment, the pre-irradiation gap is 5 minutes or less. In certain embodiments, the present invention comprises administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v.

[0030] In certain embodiments, the present invention relates to a method for treating actinic keratosis using photodynamic therapy with a pre-irradiation gap of 10 minutes or less. In certain preferred embodiments, the pre-irradiation gap is 8 minutes or less. In more preferred embodiments, the pre-irradiation gap is 6 minutes or less. In the most preferred embodiment, the pre-irradiation gap is 5 minutes or less. In certain preferred embodiments, the pre-irradiation gap is 8 minutes or less. In more preferred embodiments, the pre-irradiation gap is 6 minutes or less. In the most preferred embodiment, the pre-irradiation gap is 5 minutes or less. In certain embodiments, the present invention comprises administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v. In certain embodiments, the present invention comprises administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v. In certain embodiments, the present invention comprises administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v.

[0031] In certain embodiments, the present invention comprises administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v. In certain embodiments, the present invention comprises administering a pharmaceutical composition comprising 5-aminolevulinic acid to the affected area of the patient's skin, and the therapeutically effective concentration of 5-aminolevulinic acid is 20% w / v. Provided is a method for treating actinic keratosis using photodynamic therapy.

[0032] In another embodiment, the present invention includes administering a pharmaceutical composition containing 5-aminolevulinic acid to the skin lesion of a patient, and the therapeutically effective concentration of 5-aminolevulinic acid is 10% w / v Provided is a method for treating actinic keratosis using photodynamic therapy.

[0033] In one embodiment, the present invention relates to a method for treating actinic keratosis using photodynamic therapy, wherein the skin lesion of the patient is irradiated with a light source after administration of ALA. The light source may be selected from any physical light-emitting device that generates wavelengths of blue, red or white, for example, the light source may be an arc lamp, an incandescent lamp (red-hot filament), a fluorescent light source (red-hot gas), a laser (coherent light), a red light source, a halogen laser, a blue light source, or a light-emitting diode (LED ) .

[0034] In a preferred embodiment, the light source is a blue light source. In a more preferred embodiment, the light source is blue light having a wavelength of about 417 nm and is applied at an intensity of 10 mW / cm 2 for 1000 seconds to provide a dose of 10 J / cm . In other embodiments, the intensity 2 may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased to such an extent that the treatment time becomes about half of the original treatment time. In another embodiment, the intensity of the light may be reduced (e.g., using a dimming filter) to extend the treatment time.

[0035] In another preferred embodiment, the light source is a red light source. In a more preferred embodiment, Here, the red light source is generated, for example, at 635 nm by a light-emitting diode (LED). The light is red light. The red light can provide a fluence of, for example, 10 - 75 J / cm 2 (37 J / cm 2 etc.) within, for example, 10 minutes. In other embodiments, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity may be increased until the treatment time is about half of the original treatment time. In another embodiment the intensity of the light may be decreased (e.g., using a dimming filter) to extend the treatment time.

[0036] In one embodiment of the present invention, the VAS pain score achieved by treating actinic keratosis using photodynamic therapy is less than 1.0. In a preferred embodiment, the VA S pain score is selected from values less than 0.9, less than 0.8, less than 0.7, or less than 0.6. In a more preferred embodiment, the VAS pain score is selected from values less than 0.5, less than 0.4, less than 0.3, less than 0.2, or less than 0.1. In the most preferred embodiment the VAS pain score is 0.0.

[0037] [Examples] The following examples illustrate specific embodiments of the present disclosure and various ways of using it. These are described for illustrative purposes only and should in no way be construed as limiting the scope of the present disclosure.

[0038] [Example 1] Bilateral controlled randomized clinical trial 1. Method: Study design ​​​​​​This prospective randomized clinical trial was a bilateral controlled study using a contralateral split-body design. Subjects were recruited from the outpatient dermatology clinic of the Cleveland Clinic and given informed consent prior to enrollment.

[0039] Study Population Eligible patients had 7 or more non-hypertrophic actinic keratoses (AKs) with 4 or more lesions on both sides of the face or scalp. Candidates who were using other therapies for AK were excluded. Patients using doxycycline or topical retinoids were asked to discontinue use at least 2 weeks before receiving PDT.

[0040] Randomization In this bilateral study, the left and right halves of the body were compared. The A side (test side) receiving the experimental blue light regimen was selected by a computer-generated block randomization scheme to ensure an equal left / right distribution. The contralateral side was designated as the B side (control side).

[0041] Treatment Intervention On day 1, a 20% solution of ALA (Levulan Kerastick) was applied to the entire face and scalp. The B side was covered with a dark cloth, and immediately afterwards the A side was exposed to blue light (Blu-U, 10 mW / cm2). The light dose on the A side was given according to a dose-escalation scheme, with the first patient cohort receiving blue light for 30 minutes, the second cohort for 45 minutes, and the third cohort for 60 minutes. Sixty minutes after ALA application, the A side was covered and the B side was irradiated for 1000 seconds (16 minutes 40 seconds). After this exposure, a topical emollient with analgesic properties (Aquaphor) was applied to the treatment site, and the patient was instructed to wear a wide-brimmed hat and avoid sunlight for 48 hours before being sent home.

[0042] Results measurement The primary endpoint was the reduction in AK lesion counts between the baseline and 3-month visits. The treatment outcome was defined as AK lesion clearance. Thirteen nonhypertrophic AK lesions (Olssengrass et al., 2011) were assessed using criteria (scaling, erythema, roughness to palpation). Each lesion was marked with a black pen. The photographs were digitally recorded for long-term record. For balding patients, an accurate count of lesions on the face vs scalp was performed. For ease, the original hairline position has been drawn on the photograph.

[0043] Several secondary outcomes were also measured. Pain assessment was performed every 5–10 minutes during irradiation. Patients were asked to report pain on a visual analogue scale (VAS) ranging from 0 to 10. Erythema was photographed on the first day of treatment and on the fourth day after PDT. Each day at home, participants completed a questionnaire recording the presence or absence of 11 different signs and symptoms. (see Table 2).

[0044] statistical analysis The primary outcome was the reduction in AK lesions. The lesion reduction rates for both sides treated by men were calculated, and then the difference between the two reduction rates was calculated. A t-test was used to compare the difference in attrition rates with a non-inferiority margin of 15%. If the reduction rate is 15% or greater than that of the control regimen, the test regimen is considered non-inferior to the control regimen. Subgroup analyses were performed for each study cohort (30, 45, or 60 minutes) and the same Analyses were also performed on scalp data. The VAS scale was scored up to 5 times on the side receiving the experimental regimen. and were evaluated up to three times on the side receiving the control regimen, the secondary evaluation items of the post-treatment pain scale were analyzed using a linear mixed effects model. The model included variables to account for repeated measures and the effects of the design. Adverse events (side effects) were summarized as descriptive statistics. Statistical significance was considered using a p-value < 0.05. All analyses were performed using R 3.5.1 (cran.r-project.org). (cran.r-project.org).

[0045] Justification of sample size The motivation for this study was to evaluate the primary outcome of AK lesion clearance. If the difference in lesion clearance between the two sides was 0% and the SD of this difference was 24%, the sample size of 23 patients would be estimated to have 87% power for a non-inferiority margin of 15% (one-sided alpha = 0.05). Even if the clearance rate on side A was 2% higher than that on side B, the power would be 80%. If the difference in lesion clearance between the two sides was 0% and the SD of this difference was 24%, the sample size of 23 patients would be estimated to have 87% power for a non-inferiority margin of 15% (one-sided alpha = 0.05). Even if the clearance rate on side A was 2% higher than that on side B, the power would be 80%. If the difference in lesion clearance between the two sides was 0% and the SD of this difference was 24%, the sample size of 23 patients would be estimated to have 87% power for a non-inferiority margin of 15% (one-sided alpha = 0.05). Even if the clearance rate on side A was 2% higher than that on side B, the power would be 80%. If the difference in lesion clearance between the two sides was 0% and the SD of this difference was 24%, the sample size of 23 patients would be estimated to have 87% power for a non-inferiority margin of 15% (one-sided alpha = 0.05). Even if the clearance rate on side A was 2% higher than that on side B, the power would be 80%. If the difference in lesion clearance between the two sides was 0% and the SD of this difference was 24%, the sample size of 23 patients would be estimated to have 87% power for a non-inferiority margin of 15% (one-sided alpha = 0.05). Even if the clearance rate on side A was 2% higher than that on side B, the power would be 80%.

[0046] 2. Results: From May 2014 to October 2016, 27 patients were screened. Of these, 3 did not meet the enrollment criteria and 1 was lost to follow-up (Figure 1). Of the remaining 23 patients, 21 were elderly white males (aged 58 - 88 years with a mean age of 69.7 years) and 2 were females (aged 50 and 73 years). Overall, this population had a sufficient number of AK lesions on the face, ranging from 23 to 70 in total, and 0 to 123 on the scalp. Only 7 patients had no AK on the scalp. and 2 were females (aged 50 and 73 years). Overall, this population had a sufficient number of AK lesions on the face, ranging from 23 to 70 in total, and 0 to 123 on the scalp. Only 7 patients had no AK on the scalp. and 2 were females (aged 50 and 73 years). Overall, this population had a sufficient number of AK lesions on the face, ranging from 23 to 70 in total, and 0 to 123 on the scalp. Only 7 patients had no AK on the scalp. and 2 were females (aged 50 and 73 years). Overall, this population had a sufficient number of AK lesions on the face, ranging from 23 to 70 in total, and 0 to 123 on the scalp. Only 7 patients had no AK on the scalp.

[0047] Initially, the results of long blue light exposure to the face were unknown, thus ensuring patient safety For this purpose, a light dose escalation scheme was adopted (Figure 1). For the first patient cohort, the duration of blue light exposure on the A side was limited to 30 minutes. Since the side effect profile among this group was acceptable, subsequent cohorts received light exposure on the A side for 45 minutes (8 patients) or 60 minutes (8 patients). All patients received blue light administration for 1000 seconds on the B side. Erythema, an early indicator of the PDT response, was typically very mild at the end of treatment but increased significantly over the next 1 - 4 days. As shown in Figure 2, punctate erythema (corresponding to inflammatory AK lesions) appeared to be approximately equal on the A and B sides, which was observed in the majority of patients. The main evaluation item, the clinical effect, was defined as the percentage reduction in the number of AK lesions at the 3 - month mark. The data in Table 1 show that the clinical effect was approximately the same on both sides of the face and scalp. This was statistically confirmed (by a non - inferiority test) for both the face and scalp, indicating that the test PDT and the control PDT provided substantially the same therapeutic effect. Furthermore, for either the face or the scalp, there was no statistical difference in the effect among the three test PDT cohorts (30, 45, and 60 minutes) (Table 1). Pain during blue light irradiation was a secondary evaluation item. (Patients reported every 5 - 10 minutes) When averaging the VAS pain scores, the average score on the A side was 0.52 (95% CI = [0, 1.09]), while on the B side it was 3.57 (95% CI = [2.97, 4.16]). This difference had a p - value < 0.001 and was statistically significant.

[0048] As further documentation, Figure 3 reports the maximum pain score. The data in Table 1 show that the clinical effect was approximately the same on both sides of the face and scalp. This was statistically confirmed (by a non - inferiority test) for both the face and scalp, indicating that the test PDT and the control PDT provided substantially the same therapeutic effect. Furthermore, for either the face or the scalp, there was no statistical difference in the effect among the three test PDT cohorts (30, 45, and 60 minutes) (Table 1). For either the face or the scalp, there was no statistical difference in the effect among the three test PDT cohorts (30, 45, and 60 minutes) (Table 1). The pain during blue light irradiation was a secondary evaluation item. (Patients reported every 5 - 10 minutes)

[0049] When averaging the VAS pain scores, the average score on the A side was 0.52 (95% CI = [0, 1.09]), while on the B side it was 3.57 (95% CI = [2.97, 4.16]). This difference had a p - value < 0.001 and was statistically significant. As further documentation, Figure 3 reports the maximum pain score. This difference had a p - value < 0.001 and was statistically significant. As further documentation, Figure 3 reports the maximum pain score. It further shows a significant reduction in pain experienced with test PDT compared to control PDT.

[0050] The inflammatory side effects experienced by patients in the first few days following PDT were also investigated. Table 2 shows the aggregated results of the daily questionnaires filled in by all patients in the first 4 days after treatment. P The inflammatory reaction after PDT was gradually spreading. The maximum values of burning, itching, erythema, stinging and swelling were observed up to 2 days after PDT (Table 2). On days 3 and 4, these parameters began to decrease and were replaced by an increase in crust formation and peeling, reflecting the normal dissipation process after PDT. Importantly, no significant differences were observed between the main inflammatory parameters when comparing side A and side B. These results confirm that test PDT with a substantially absent pre-irradiation gap is not only much less painful than control PDT with a longer pre-irradiation gap, but also brings equally good effects regarding the treatment of actinic keratosis lesions .. .

Table 1

Table 2

Table 3

[0051] Table 4. Relationship between pain scores reported during the test and control PDT irradiations The pain values shown here were reported on a visual analog scale (VAS) of 0 - 10 every 5 - 10 minutes . A value of 10 was defined as intolerable pain.

[0052] Side A (test PDT) Side B (control PDT) Irradiation time (minutes) Irradiation time (minutes)

Table 4

[0053] 3. Investigation: In this study, there was substantially no pre-irradiation gap between ALA administration and irradiation with blue light source. The study design of the trial was a bilateral controlled type in which each patient functioned as his or her own control. The results showed a dramatic reduction in pain on the side that received the "test" PDT regimen with substantially no pre-irradiation gap. An equally important point is the finding that there was no statistical difference in the "test" PDT side with a 1-hour pre-irradiation gap with respect to the treatment response (lesion clearance). The ability to perform PDT painlessly while achieving good lesion clearance should help to optimize the treatment response in some way. First, a single PDT treatment is rarely sufficient for complete AK clearance, which is why PDT clinical trials typically employ two PDT treatments at an 8-week interval (Piacquadio DJ et al. Arch Dermatol 2004;140: 41-6, Pariser DM et al. Dermatol Surg 2016

[0054] 42:296-304) and the European PDT protocol generally recommends two treatments (Braathen LR et al. J Am Acad Dermatol 20 07;56:125-43). The result that the "test" PDT side on the face / scalp of the recipient had extremely high efficacy and no pain means that pain is no longer a problem. almost never sufficient for complete AK clearance, which is why PDT clinical trials typically employ two PDT treatments at an 8-week interval (Piacquadio DJ et al. Arch Dermatol 2004;140: 41-6, Pariser DM et al. Dermatol Surg 2016 cquadio DJ et al.Arch Dermatol 2004;140: 41-6, Pariser DM et al.Dermatol Surg 2016 ;42:296-304) and the European PDT protocol generally recommends two treatments (Braathen LR et al. J Am Acad Dermatol 20 (Braathen LR et al.J Am Acad Dermatol 20 07;56:125-43) for the reason that. The extremely high efficacy and lack of pain on the side of the face / scalp that received the test PDT mean that pain is no longer an issue. highly effective and painless result on one side of the face / scalp of the recipient of the test PDT means that pain is no longer a problem. This helps persuade the patient to undergo multiple PDT sessions. Also, the trial PDT regimen significantly reduces the waiting time at the clinic. Instead of several hours for the pre-irradiation gap, PDT with a substantially non-existent pre-irradiation gap prior to blue light irradiation requires only 45 to 60 minutes, even if a more elaborate explanation of aftercare instructions for the patient is expected. The trial PDT regimen significantly reduces the waiting time at the clinic. Instead of several hours for the pre-irradiation gap, PDT with a substantially non-existent pre-irradiation gap prior to blue light irradiation requires only 45 to 60 minutes, even if a more elaborate explanation of aftercare instructions for the patient is expected. This helps persuade the patient to undergo multiple PDT sessions. Also, the trial PDT regimen significantly reduces the waiting time at the clinic. Instead of several hours for the pre-irradiation gap, PDT with a substantially non-existent pre-irradiation gap prior to blue light irradiation requires only 45 to 60 minutes, even if a more elaborate explanation of aftercare instructions for the patient is expected. This helps persuade the patient to undergo multiple PDT sessions. Also, the trial PDT regimen significantly reduces the waiting time at the clinic. Instead of several hours for the pre-irradiation gap, PDT with a substantially non-existent pre-irradiation gap prior to blue light irradiation requires only 45 to 60 minutes, even if a more elaborate explanation of aftercare instructions for the patient is expected. This helps persuade the patient to undergo multiple PDT sessions. Also, the trial PDT regimen significantly reduces the waiting time at the clinic. Instead of several hours for the pre-irradiation gap, PDT with a substantially non-existent pre-irradiation gap prior to blue light irradiation requires only 45 to 60 minutes, even if a more elaborate explanation of aftercare instructions for the patient is expected.

[0055] The present invention has surprisingly found a method for significantly reducing the pain experienced during photodynamic therapy. The above-described examples show a reduction in pain score compared to a mere 1-hour pre-irradiation gap as a comparator arm, but in the PDT clinical treatment of actinic keratosis where the pre-irradiation gap approved by the FDA is 14 to 16 hours, the reduction in pain score is even more significant, thus ultimately predicting a painless or nearly painless photodynamic treatment for actinic keratosis. The present invention has surprisingly found a method for significantly reducing the pain experienced during photodynamic therapy. The above-described examples show a reduction in pain score compared to a mere 1-hour pre-irradiation gap as a comparator arm, but in the PDT clinical treatment of actinic keratosis where the pre-irradiation gap approved by the FDA is 14 to 16 hours, the reduction in pain score is even more significant, thus ultimately predicting a painless or nearly painless photodynamic treatment for actinic keratosis. The present invention has surprisingly found a method for significantly reducing the pain experienced during photodynamic therapy. The above-described examples show a reduction in pain score compared to a mere 1-hour pre-irradiation gap as a comparator arm, but in the PDT clinical treatment of actinic keratosis where the pre-irradiation gap approved by the FDA is 14 to 16 hours, the reduction in pain score is even more significant, thus ultimately predicting a painless or nearly painless photodynamic treatment for actinic keratosis. The present invention has surprisingly found a method for significantly reducing the pain experienced during photodynamic therapy. The above-described examples show a reduction in pain score compared to a mere 1-hour pre-irradiation gap as a comparator arm, but in the PDT clinical treatment of actinic keratosis where the pre-irradiation gap approved by the FDA is 14 to 16 hours, the reduction in pain score is even more significant, thus ultimately predicting a painless or nearly painless photodynamic treatment for actinic keratosis. The present invention has surprisingly found a method for significantly reducing the pain experienced during photodynamic therapy. The above-described examples show a reduction in pain score compared to a mere 1-hour pre-irradiation gap as a comparator arm, but in the PDT clinical treatment of actinic keratosis where the pre-irradiation gap approved by the FDA is 14 to 16 hours, the reduction in pain score is even more significant, thus ultimately predicting a painless or nearly painless photodynamic treatment for actinic keratosis. The present invention has surprisingly found a method for significantly reducing the pain experienced during photodynamic therapy. The above-described examples show a reduction in pain score compared to a mere 1-hour pre-irradiation gap as a comparator arm, but in the PDT clinical treatment of actinic keratosis where the pre-irradiation gap approved by the FDA is 14 to 16 hours, the reduction in pain score is even more significant, thus ultimately predicting a painless or nearly painless photodynamic treatment for actinic keratosis.

Claims

1. A method for reducing pain during photodynamic therapy of actinic keratosis, comprising: (a) administering a pharmaceutical composition containing 5-aminolevulinic acid to the affected area of the patient's skin; (b) irradiating the affected area with a light source with substantially no pre-irradiation gap; (c) maintaining the irradiation for at least 30 minutes, wherein the method does not include pretreatment preparation.

2. The pharmaceutical composition in step (a) is a 20% w / v solution of 5-aminolevulinic acid, The method according to claim 1.

3. The irradiation in step (b) is performed using a blue light source, The method according to claim 1.

4. The blue light source delivers light in a wavelength range that delivers light of 417 nm ± 5 nm, Claim 3 The method according to.

5. The actinic keratosis is that of the face and / or scalp, The method according to claim 1.

6. The irradiation in step (c) is performed for at least 45 minutes, The method according to claim 1.

7. The irradiation in step (c) is performed for at least 60 minutes, The method according to claim 1.

8. The method results in a significantly reduced VAS pain score compared to photodynamic therapy with a pre-irradiation gap of at least 60 minutes, Any one of claims 1 to 7 The method according to.

9. The VAS pain score is less than 1.0, The method according to claim 8.

10. The VAS pain score is 0.5 ± 0.5, The method according to claim 8.

11. The VAS pain score is 0.0, The method according to claim 8.

12. A method for treating actinic keratosis, comprising: (a) administering a pharmaceutical composition containing 5-aminolevulinic acid to the affected area of the patient's skin; (b) irradiating the affected area with a light source with substantially no pre-irradiation gap; (c) maintaining the irradiation for at least 30 minutes, wherein the method does not include pretreatment preparation.

13. The pharmaceutical composition in step (a) is a 20% w / v solution of 5-aminolevulinic acid, The method according to claim 12.

14. The irradiation in step (b) is performed using a blue light source, The method according to claim 12.

15. The blue light source delivers light in a wavelength range that delivers light of 417 nm ± 5 nm, Claim 14 The method according to.

16. The irradiation in step (c) is performed for at least 45 minutes, The method according to claim 12 ​ ​ ​ 。 **Claim 17** The irradiation in step (c) is performed for at least 60 minutes, the method according to claim 12 。 **Claim 18** The method results in a significantly reduced VAS pain score compared to photodynamic therapy with a pre-irradiation gap of at least 60 minutes The method according to any one of claims 12 to 17 1. **Claim 19** The VAS pain score is less than 1.0, the method according to claim 18 **Claim 20** The VAS pain score is 0.5 ± 0.5, the method according to claim 18 **Claim 21** The VAS pain score is 0.0, the method according to claim 18

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