Topical composition for photodynamic therapy, occlusive dressing, kit using same, photodynamic therapy material, and method for photodynamic therapy

Abstract

To provide a topical composition for photodynamic therapy, an obstructive dressing material, a kit using them, a material for photodynamic therapy, and a method for photodynamic therapy.SOLUTION: In order to promote infiltration of a topical composition containing 5-aminolevulinic acid (ALA) applied on a treatment site for photodynamic therapy, transepidermal water loss from the treatment site is suppressed to the minimum by covering the treatment site by a low-density polyethylene barrier before phototherapy after the topical composition is applied to the treatment site.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] [Related Applications] This application claims the benefit of priority to U.S. patent application Ser. No. 15 / 869,164, filed Jan. 12, 2018, the entire contents of which are incorporated by reference.

[0002] The present disclosure generally relates to a topical composition comprising 5-aminolevulinic acid (ALA) that is applied to tissue as a treatment site for photodynamic therapy, a low-density polyethylene barrier for covering the topical composition, a kit using the same, a photodynamic therapy material and the use of the low-density polyethylene barrier therefor, the topical composition and the use of the low-density polyethylene barrier therefor, and a method for photodynamic therapy. [Background technology]

[0003] Photodynamic therapy (PDT), photodynamic diagnosis (PD), or photochemotherapy is commonly used to treat and / or diagnose several types of disease in or near the skin or other tissues, such as within body cavities. For example, photodynamic therapy or photodynamic diagnosis can be used to treat or diagnose actinic keratosis on a patient's upper extremities (e.g., the back of the hand or forearm), scalp, or facial area. Furthermore, such techniques can be used to treat and diagnose other indications (e.g., acne, warts, psoriasis, photodamaged skin, cancer) and other areas of a patient (e.g., parts of the arm other than the leg or forearm).

[0004] In one form of photodynamic therapy, a patient is first administered a photoactivator or a precursor of the photoactivator, which accumulates in the tissue to be treated. The area to which the photoactivator is administered is then exposed to visible light, which induces chemical and / or biological changes in the photoactivator. These changes allow the agent to selectively locate, destroy, or alter the target tissue while causing at most mild, reversible damage to other tissues within the treatment area. One example of a photoactivator precursor is 5-aminolevulinic acid ("ALA"), which is commonly used in the photodynamic therapy of actinic keratosis. As used herein, the terms ALA or 5-aminolevulinic acid refer to ALA itself, its precursors, their esters, and their pharmaceutically acceptable salts. Photosensitization following application of a topical composition containing ALA (e.g., a topical solution or emulsion) occurs through the metabolic conversion of aminolevulinic acid to protoporphyrin IX (PpIX), as discussed in more detail below. PpIX is a photosensitizer that accumulates in the skin.

[0005] For photodynamic therapy to be effective, it is desirable to have a power output that can be controlled with respect to intensity and duration, among other factors. Illuminators are typically used to provide uniform light suitable for therapeutic purposes. These devices generally include a light source (e.g., a fluorescent tube or LED), a coupling element that directs, filters, or otherwise conducts the emitted light so that it reaches the intended target in a usable form, and a control system that starts and stops light generation when needed.

[0006] Photodynamic therapy can be performed using certain compositions, such as ALA, in conjunction with the above-described illuminators. Such compositions and / or devices are described, for example, in U.S. Pat. No. 5,954,703 to Golub, entitled "Method and Apparatus for Applying 5-Aminolevulinic Acid," issued September 21, 1999; U.S. Pat. No. 6,223,071 to Lundahl et al., entitled "Photodynamic Therapy and Diagnostic Illumination Device Producing Visible Light of Substantially Uniform Intensity," issued April 24, 2001; U.S. Pat. App. No. 15 / 371,363 to Boyajian et al., entitled "Method and Apparatus for Applying Topical Solutions," published June 8, 2017, as U.S. Publication No. 2017 / 0157379; and U.S. Pat. No. 2017 / 0157379 to Boyajian et al., entitled "Method and Apparatus for Applying Topical Solutions." (5) U.S. Patent Application No. 15 / 292,731, entitled "Adjustable Illuminator for Photodynamic Therapy and Diagnosis," published on April 20, 2017, by Boyajian et al., U.S. Publication No. 2017 / 0106205, and (6) U.S. Patent Application No. 15 / 487,991, entitled "Adjustable Illumination and Methods for Photodynamic Therapy and Diagnosis," published on August 3, 2017, by Boyajian et al., U.S. Publication No. 2017 / 0216616. The entire contents of the aforementioned patents and / or patent applications (1)-(6) are incorporated herein by reference for background information and for the compositions, devices, processes, and techniques related to photodynamic therapy and diagnosis disclosed therein. Summary of the Invention [Problem to be solved by the invention]

[0007] Through research and experimentation in photodynamic therapy techniques, the inventors have found that covering the treatment area with polyethylene (e.g., low-density polyethylene (LDPE)) for a period of time prior to phototherapy is particularly effective in minimizing transepidermal water loss (water loss) from the treatment area. Surprisingly, polymer barriers with an occlusion rate of 65% or greater (e.g., LDPE) were found to be superior to other materials, such as polyurethane and polyvinylidene chloride (PVdC). Low-density polyethylene can be applied to a wide variety of treatment areas, including the arms, legs, chest, back, and head, and can be used with medications other than 5-ALA. [Means for solving the problem]

[0008] According to one aspect of the present disclosure, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy is disclosed. The method includes topically applying ALA to a treatment site to be treated with photodynamic therapy. After the ALA is applied to the treatment site, the method further includes covering the treatment site with a polymer barrier having an occlusion rate of greater than 65%.

[0009] According to another aspect of the present disclosure, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy is disclosed. The method includes topically applying ALA to a treatment site to be treated with photodynamic therapy. The method further includes covering the treatment site with a low-density polyethylene barrier after ALA has been applied to the treatment site. The treatment site is covered with the low-density polyethylene barrier before phototherapy to minimize transepidermal water loss from the treatment site.

[0010] According to yet another aspect of the present disclosure, a method for photodynamic treatment of the stratum corneum is disclosed.The method comprises applying 5-aminolevulinic acid (ALA) to a lesion on the stratum corneum and reducing evaporation from a portion of the stratum corneum, including the area where the lesion is present.The method further comprises heating the area where the lesion is present before or during illumination of the area where the lesion is present.

[0011] According to a further aspect of the present disclosure, a method of using 5-aminolevulinic acid (ALA) and a low-density polyethylene barrier is disclosed, the method comprising contacting a treatment site with a composition comprising ALA to wet the treatment site, and after wetting the treatment site, covering the wet treatment site with a low-density polyethylene barrier.

[0012] According to a further aspect of the present disclosure, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) HCl composition for photodynamic therapy is disclosed. The method includes topically applying the composition to a treatment site to be treated with photodynamic therapy. After the composition has been applied to the treatment site, the method further includes covering the treatment site with a low-density polyethylene barrier prior to phototherapy to minimize transepidermal water loss from the treatment site. The composition provides a mean plasma concentration (C) of ALA of less than about 110 ng / mL when ALA HCl is applied in an amount of 354 mg. max ) value. [Brief explanation of the drawings]

[0013] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, aspects, and advantages will become apparent from the description, drawings, and claims. In the drawings, like reference numerals are used throughout the various views to indicate like elements. The drawings will now be briefly described. [Figure 1A] FIG. 1A illustrates a top view of the body of an illuminator according to an example embodiment. [Figure 1B] FIG. 1B illustrates a top view of the body of an illuminator according to an exemplary embodiment. [Figure 2A] FIG. 2A shows a perspective view of the main body of the illuminator of FIGS. 1A and 1B. [Figure 2B] FIG. 2B shows a perspective view of the main body of the illuminator of FIGS. 1A and 1B. [Figure 3] FIG. 3 shows a perspective view of an illuminator having the body of FIGS. 1A and 1B mounted on a stand. [Figure 4]FIG. 4 shows a representative area that may be treated according to an exemplary embodiment. [Figure 5] FIG. 5 illustrates the evaporative water loss rate for several materials, according to at least one embodiment. [Figure 6] FIG. 6 illustrates occlusion levels for several materials, according to at least one embodiment. [Figure 7] FIG. 7 illustrates the evaporative water loss rate for several materials, according to at least one embodiment. [Figure 8] FIG. 8 illustrates the degree of occlusion for several materials, according to at least one embodiment. [Figure 9] FIG. 9 is a table containing baseline water loss data for the materials referenced in FIGS. [Figure 10] FIG. 10 is a table containing moisture loss data after 3 hours of wear time for the materials referred to in FIGS. [Figure 11] FIG. 11 is a table containing occlusive data for the materials referenced in FIGS. [Figure 12] FIG. 12 is a table containing baseline water loss data for the materials referenced in FIGS. [Figure 13] FIG. 13 is a table containing moisture loss data after 3 hours of wear time for the materials referenced in FIGS. [Figure 14] FIG. 14 is a table containing occlusive data for the materials referenced in FIGS. DETAILED DESCRIPTION OF THE INVENTION

[0014] It will be appreciated that some or all of the figures are schematic diagrams for illustrative purposes, provided for the purpose of illustrating one or more embodiments, with the express understanding that these figures will not be used to limit the scope or meaning of the claims.

[0015] Various embodiments are described below. It should be noted that a particular embodiment is not intended as an exhaustive description or as a limitation on the broader aspects discussed herein. An aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment.

[0016] The following terms are used throughout and are defined below.

[0017] As used in this specification and the appended claims, singular articles such as "a," "an," and "the," and similar references in the context of describing elements (particularly in the context of the claims that follow) are to be construed as inclusive. Both the singular and the plural are used unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "etc."), are intended merely to better illustrate embodiments and do not limit the scope of the claims unless specifically stated. No language in this specification should be construed as indicating any non-claimed element as required.

[0018] The illustrative embodiments described herein may suitably be practiced in the absence of any element or elements not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., should be read expansively and not limitingly. Furthermore, the terms and phrases used herein are used as terms of description and not of limitation, and are not intended to exclude any equivalents of the features shown and described, or portions thereof. It is recognized that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase "consisting essentially of" is understood to include the specifically recited elements and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The expression "comprising" means "including, but not limited to." Thus, other unrecited materials, additives, devices, or steps may be present. Unless otherwise specified, "a" or "an" means one or more.

[0019] Unless otherwise noted, all numbers expressing quantities of properties, parameters, conditions, and the like used in the specification and claims should be understood to be modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are approximations. Any numerical parameters should be construed, at least in light of the number of reported significant digits and by applying ordinary rounding techniques. The term "about," when used before numerical designations, such as temperature, time, amounts, and concentrations, including ranges, indicates approximations that may vary by (+) or (-) 10%, 5%, or 1%.

[0020] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as fully describing and allowing for the same range to be divided into at least one half, one third, one quarter, one fifth, one tenth, etc. As a non-limiting example, each range discussed herein can be readily subdivided into a lower third, middle third, and upper third, etc. Also, as will be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc., are inclusive of the recited numbers and refer to ranges that can be subsequently divided into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual element. [Example]

[0021] According to one embodiment, a topical composition is provided, comprising 5-aminolevulinic acid (ALA) for application to tissue as a treatment site for photodynamic therapy, wherein the treatment site is covered with a low-density polyethylene barrier for a predetermined time after application of the topical composition prior to phototherapy, and the low-density polyethylene barrier is removed before phototherapy is administered to the treatment site.

[0022] According to at least one embodiment, a topical composition is provided, the predetermined time period being 3 hours or less.

[0023] According to at least one embodiment, a topical composition is provided having an ALA concentration of 20% by weight.

[0024] According to at least one embodiment, an occlusive dressing is provided, the occlusive dressing comprising 5-aminolevulinic acid (ALA) for application to tissue as a treatment site for photodynamic therapy, the occlusive dressing covering the treatment site for a predetermined time after application of a topical composition prior to phototherapy, and the occlusive dressing being removed prior to administration of phototherapy to the treatment site.

[0025] According to at least one embodiment, the predetermined time is 3 hours or less.

[0026] According to at least one embodiment, there is no gap between the low density polyethylene barrier and the treatment area.

[0027] According to at least one embodiment, a kit is provided, comprising a low-density polyethylene barrier and a topical composition comprising 5-aminolevulinic acid (ALA).

[0028] According to at least one embodiment, the kit further comprises an illuminator configured to emit light of a uniform intensity.

[0029] According to at least one embodiment, the kit further comprises a netting configured to secure the low density polyethylene barrier in place.

[0030] According to at least one embodiment, the kit further comprises a heater configured to direct heat to the treatment site.

[0031] According to at least one embodiment, the kit further comprises at least one sensor configured to determine the size of the treatment area or the position of the illuminator.

[0032] According to at least one embodiment, the kit further comprises a controller configured to store pre-programmed dosing parameters.

[0033] According to at least one embodiment, a photodynamic therapy material is provided, comprising a topical composition of 5-aminolevulinic acid (ALA) and a low-density polyethylene barrier for covering the topical composition applied to tissue at a treatment site, the low-density polyethylene barrier covering the treatment site for a predetermined time after application of the topical composition prior to phototherapy, and the low-density polyethylene barrier being removed before phototherapy is administered to the treatment site.

[0034] According to at least one embodiment, the predetermined time is 3 hours or less.

[0035] At least one embodiment relates to the use of a low-density polyethylene barrier to facilitate penetration of a topical 5-aminolevulinic acid (ALA) composition into tissue for photodynamic therapy, where the low-density polyethylene barrier facilitates penetration of ALA by minimizing transepidermal water loss from the treatment, and the low-density polyethylene barrier is used to cover the treatment site after topical application of ALA and is removed from the treatment site within 3 hours to allow irradiation of the treatment site with light.

[0036] At least one embodiment relates to the use of a topical 5-aminolevulinic acid (ALA) composition and a low-density polyethylene barrier for photodynamic therapy of tissue, wherein the low-density polyethylene barrier promotes penetration of ALA into tissue by minimizing transepidermal water loss from the treatment site, and the low-density polyethylene barrier is used to cover the treatment site after application of the topical ALA composition, and is removed from the treatment site within 3 hours to allow light irradiation of the treatment site.

[0037] At least one embodiment involves the use of a low density polyethylene barrier where heat is applied to the treatment site while the low density polyethylene barrier covers the treatment site.

[0038] At least one embodiment relates to the use of a topical composition of 5-aminolevulinic acid (ALA) and a low density polyethylene barrier, further comprising applying compressive pressure to the low density polyethylene barrier.

[0039] At least one embodiment relates to the use of a low-density polyethylene barrier to facilitate the conversion of 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) for photodynamic therapy, comprising: The low-density polyethylene barrier facilitates the transfer of the topical 5-ALA composition into tissues for photodynamic therapy by promoting tissue penetration, The low-density polyethylene barrier minimizes transepidermal water loss from the treatment site, thereby facilitating the penetration of 5-ALA into the tissue. The present invention relates to use of a low-density polyethylene barrier, which is used to cover the treatment area after application of a topical ALA composition, and is characterized in that it is removed from the treatment area within 3 hours to allow light irradiation to the treatment area.

[0040] At least one embodiment relates to the use of a topical composition of 5-aminolevulinic acid (ALA) and a low-density polyethylene barrier to facilitate the conversion of ALA to protoporphyrin IX (PpIX) for photodynamic therapy, wherein the low-density polyethylene barrier facilitates the conversion by minimizing transepidermal water loss from the treatment site, thereby promoting penetration of ALA into tissue; The present invention relates to use of a topical composition of ALA and a low-density polyethylene barrier, characterized in that the low-density polyethylene barrier is used to cover the treatment area after application of the topical composition of ALA, and is removed from the treatment area within 3 hours to allow irradiation of the treatment area with light.

[0041] At least one embodiment relates to the use of a topical composition comprising 5-aminolevulinic acid (ALA) for photodynamic therapy of a subject in need of photodynamic therapy, wherein the subject is instructed to cover the treatment area with a low-density polyethylene barrier for a predetermined time after application of the topical composition prior to phototherapy, and the phototherapy is administered to the treatment area after the low-density polyethylene barrier is removed.

[0042] At least one embodiment involves the use of a topical composition in which the low density polyethylene barrier is removed from the treatment site within three hours.

[0043] At least one embodiment relates to the use of an occlusive dressing comprising a low-density polyethylene barrier for photodynamic therapy of a subject in need thereof, wherein the photodynamic therapy comprises applying a topical composition comprising 5-aminolevulinic acid (ALA) to the treatment site, the subject being instructed to cover the treatment site with the low-density polyethylene barrier for a predetermined time period after application of the topical composition prior to phototherapy, and the low-density polyethylene barrier being removed prior to administering phototherapy to the treatment site.

[0044] At least one embodiment involves the use of an occlusive dressing in which the low density polyethylene barrier is removed from the treatment site within three hours.

[0045] According to at least one embodiment, there is provided a method for using a low-density polyethylene barrier to cover a topical composition containing 5-aminolevulinic acid (ALA) that is applied to tissue as a treatment site for photodynamic therapy, the method comprising covering the topical composition applied to the tissue as the treatment site, the low-density polyethylene barrier covering the treatment site for a predetermined time from application of the topical composition prior to phototherapy, and the low-density polyethylene barrier being removed before phototherapy is administered to the treatment site.

[0046] According to at least one embodiment, in a method using a low density polyethylene barrier to coat a topical composition, the predetermined time is 3 hours or less.

[0047] According to at least one embodiment, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy is provided, comprising: topically applying ALA to a treatment area to be treated with photodynamic therapy; after ALA has been applied to the treatment area, covering the treatment area with a low-density polyethylene barrier prior to light therapy to minimize transepidermal water loss from the treatment area; removing the low-density polyethylene barrier within three hours; and then irradiating the treatment area with light.

[0048] According to at least one embodiment, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy involves removing a low-density polyethylene barrier from the treatment site within three hours to avoid excessive irritation while maintaining therapeutic efficacy.

[0049] According to at least one embodiment, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy is provided, the method comprising: topically applying ALA to a treatment area to be treated with photodynamic therapy; and covering the treatment area with a low-density polyethylene barrier after ALA has been applied to the treatment area and prior to phototherapy to minimize transepidermal water loss from the treatment area, wherein the treatment area is on the hand or forearm.

[0050] According to at least one embodiment, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy comprises removing a low-density polyethylene barrier from the treatment site within 3 hours, and then applying 10 J / cm 2 Blue light is irradiated onto the treatment area at a light intensity of .

[0051] According to at least one embodiment, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy includes removing a low-density polyethylene barrier from the treatment area and then applying 10 to 75 J / cm. 2 Red light is irradiated onto the treatment area at a light intensity of .

[0052] According to at least one embodiment, a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy provides a maximum plasma concentration of ALA of less than about 110 ng / mL after application of the ALA.

[0053] According to at least one embodiment, a method of using 5-aminolevulinic acid (ALA) and a low-density polyethylene barrier includes contacting a treatment area with a composition comprising ALA to moisten the treatment area, covering the moistened treatment area with a low-density polyethylene barrier after wetting the treatment area, removing the low-density polyethylene barrier to expose the treatment area, and applying a 10 J / cm 2 and illuminating the exposed treatment area with an illuminator to deliver a dose of blue light.

[0054] According to at least one embodiment, in the method using 5-aminolevulinic acid (ALA) and a low density polyethylene barrier, the low density polyethylene barrier is removed within three hours after the treatment area is covered.

[0055] According to at least one embodiment, the method of using 5-aminolevulinic acid (ALA) and a low-density polyethylene barrier further includes positioning the treatment area between 2 inches and 4 inches from the surface of the illuminator.

[0056] According to at least one embodiment, in a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy, the treatment site is the dorsum of the hand.

[0057] According to at least one embodiment, in a method for enhancing tissue penetration of a topical 5-aminolevulinic acid (ALA) composition for photodynamic therapy, the treatment site is the dorsal surface of the forearm.

[0058] According to at least one embodiment, there is provided a method of using a low-density polyethylene barrier to facilitate the conversion of 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) for photodynamic therapy, the method comprising covering a treatment area with a low-density polyethylene barrier to facilitate the conversion by promoting penetration of an ALA topical composition into tissue, the low-density polyethylene barrier promoting ALA penetration by minimizing transepidermal water loss from the treatment area, the low-density polyethylene barrier being used to cover the treatment area after application of the ALA topical composition and being removed from the treatment area within 3 hours to allow irradiation of the treatment area with light.

[0059] According to at least one embodiment, the method of using a low-density polyethylene barrier to facilitate the conversion of 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) for photodynamic therapy further includes applying heat to the treatment site to promote the conversion.

[0060] According to at least one embodiment, there is provided a method of using a topical 5-aminolevulinic acid (ALA) composition and a low-density polyethylene barrier to facilitate conversion of ALA to protoporphyrin IX (PpIX) for photodynamic therapy of tissue, the method comprising covering a treatment site with a low-density polyethylene barrier, the low-density polyethylene barrier facilitating the conversion by minimizing transepidermal water loss from the treatment site, thereby promoting penetration of ALA, the low-density polyethylene barrier being used to cover the treatment site after application of the topical ALA composition, and the low-density polyethylene barrier being removed from the treatment site within 3 hours to allow irradiation of the treatment site with light.

[0061] According to at least one embodiment, a method of using a 5-aminolevulinic acid (ALA) topical composition and a low-density polyethylene barrier to facilitate conversion of ALA to protoporphyrin IX (PpIX) for photodynamic therapy of tissue further comprises applying heat to the treatment site to promote conversion.

[0062] [Typical lighting fixture] FIGS. 1A-1B and 2A-2B illustrate one embodiment of a configurable illuminator that can be used in accordance with the present disclosure. The illuminator includes a body 100, which preferably includes multiple individual panels (e.g., panels 10a-10e, each rotatably connected via a telescoping hinge 50). As shown in FIGS. 2A-2B, at least one side of the panels may include tabs 23 extending from both the top and bottom of the panel. The tabs 23 are configured so that the sides of adjacent panels are received between the tabs 23, as shown in FIG. 2. Each panel includes an array of light-emitting diodes (LEDs) 60. The number of individual LEDs arranged in a given array is not particularly limited. Alternatively, other types of light sources, such as fluorescent or halogen lamps, may be used. The LED array 60 emits light at appropriate wavelengths according to the intended treatment or to activate specific photoactivatable agents used in therapy or diagnosis.

[0063] In at least one embodiment, when ALA is used as a precursor of a photoactivatable agent for the treatment of actinic keratosis, the LED array 60 preferably emits blue light having a wavelength of 400 nanometers (nm) or greater, e.g., about 430 nm, about 420 nm, or about 417 nm. However, the LED array 60 can also emit visible light in other spectral ranges, such as the green and / or red range between 400 and 700 nm, e.g., about 625 nm to 640 nm, or e.g., 635 nm. For example, the LED array 60 may also emit light having a wavelength of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. Furthermore, the LED array 60 may be configured to emit light continuously, or the LED array 60 may be configured to blink the diodes based on a predetermined interval. Furthermore, the LED array 60 may be configured to emit only one wavelength of light (e.g., blue). Alternatively, the LED array 60 may be configured to emit light of two or more wavelengths. For example, the LED array 60 may be configured to emit alternating blue and red light for therapeutic purposes. In one embodiment, the LED array may also emit red light having a wavelength of 570 to 670 nm.

[0064] In one embodiment of the present disclosure, blue light having a wavelength of about 417 nm is used at 10 mW / cm 2 is irradiated for 1000 seconds at an intensity of 10J / cm 2 However, the intensity may be increased (e.g., doubled) to shorten the treatment time. For example, the intensity can be increased to reduce the treatment time by approximately half. In other embodiments, red light (e.g., red light generated by a 635 nm light emitting diode (LED)) can be used. The red light can have an intensity of, for example, 10-75 J / cm. 2 (For example, 37 J / cm 2 ) can be delivered within, for example, 10 minutes.

[0065] ALA can be applied using an applicator as described below, for example, using a 20% solution of ALA, or by other means, such as a gloved finger or a spatula. ALA can be applied, for example, in liquid or gel form, and can be applied beyond the area of ​​the lesion to be treated. In some applications, materials other than low-density polyethylene may be used, as long as they provide greater than 65% occlusion. In some applications, certain materials can be used, as long as they provide greater than 75% occlusion.

[0066] Referring again to the exemplary illuminator shown in FIGS. 1A-1B, the main body 100 of the illuminator may include a mounting head 40. The mounting head 40 may allow the main body 100 to be mounted on a movable stand 80 shown in FIG. 1, thereby allowing a user to easily move the main body 100 to an appropriate treatment position. The stand 80 includes a base 81 and a vertical support 82. The base 81 may further include a plurality of wheels 87 at its bottom to allow a user to horizontally move the illuminator to an appropriate position. The plurality of wheels 87 may include a plurality of locks to prevent further horizontal movement of the stand 80 once it is positioned. Furthermore, the vertical support 82 may be attached to the base 81 at a pivot point 83.

[0067] At its upper end, the vertical support 82 includes a connecting arm 85 that can serve as a mounting structure for the main body 100. The connecting arm 85 includes a hinge point 86 that allows the main body 100 to move vertically relative to the main body 100. The stand 80 can also include a stabilizing arm 84. Once the stand 80 and main body 100 are positioned, the stabilizing arm 84 can be attached to the main body 100 to prevent undesired movement of the main body 100 during treatment. As further shown in FIG. 3 , a controller and power supply 90 is attached to the stand 80 to provide power to the main body 100 and allow a user to control the main body 100 for treatment purposes. Alternatively, the controller and power supply 90 can be attached directly to the main body 100. To provide a cooling system for the LED array 60, one or more fans 70 can be attached to each panel, as shown in FIG. 3 .

[0068] The controller and power supply 90 may also be connected to multiple panels to adjust the power to the light sources to achieve the desired uniformity and intensity for targeted treatment. The control unit may be implemented as hardware, software, or a combination of both, such as a memory device for storing a computer program and a processor for executing the program. Alternatively, each panel may have a dedicated control unit for adjusting the power to the individual LED arrays on a given panel to allow for fine tuning of the illuminator, which can further increase uniformity and improve efficiency. The LED arrays 60 may also be individually configured to increase the intensity of light emitted from specific diodes to achieve specific lighting effects.

[0069] The illuminator may further include a timer included in the controller and power supply 90, which can indicate to the user the appropriate length of exposure time for a particular treatment. The illuminator may also be programmed with pre-stored light delivery parameters to allow the user to select a desired treatment type. The pre-stored parameters may include, for example, pre-stored settings for exposure time, light intensity, and output wavelength. Based on the treatment selected, the illuminator automatically configures itself to provide the correct amount of illumination by supplying the appropriate power output to achieve the uniformity required for the treatment.

[0070] Alternatively, the illuminator can be provided with a sensor that detects the size of a treatment area placed in front of the illuminator. The sensor then determines the correct light delivery parameters based on the sensed treatment area. The sensor can detect an adjusted position of the illuminator manually set by a user. The detected position of the illuminator can then be used to indicate the intended treatment area. The appropriate dose parameters for the particular treatment area can then be provided based on the detected position set by the user.

[0071] Such adjustable illuminators allow for infinite configurations that can be tailored to the target treatment area. Configurations can range from a planar emitter (as shown in FIGS. 1B and 2B) to a substantially U-shaped configuration (as shown in FIGS. 1A and 2A). Not only can an adjustable illuminator effectively deliver uniform light intensity to a surface such as the face or scalp, but the adjustable illuminator can also provide a device that can be easily configured to treat other parts of a patient's body, particularly those with less curvature, such as the arms and legs, especially the upper extremities. Furthermore, the adjustable illuminator may also be easily positioned to deliver uniform light intensity to larger treatment areas, such as the back or chest.

[0072] The illuminator may illuminate the lesion with red light of uniform intensity for a predetermined period of time. In certain embodiments, the illuminator illuminates the lesion with blue light of uniform intensity for a first predetermined period of time, and then illuminates the lesion with red light of uniform intensity for a second predetermined period of time. For example, in some embodiments, the illuminator illuminates the lesion with low intensity (e.g., about 0.1 J / cm) light to photobleach protoporphyrin IX (PpIX), for example, present on the surface of the patient's skin. 2 ~About 2J / cm 2 ) and irradiate the lesion with blue light (e.g., 417 nm) at a uniform intensity, and then irradiate the lesion with a higher intensity (e.g., approximately 30 J / cm) to activate PpIX present in the deeper layers of the patient's skin. 2 ~About 150J / cm 2 ) to illuminate the lesion with uniform intensity red light (e.g., 635 nm), thereby avoiding potential damage to the upper layers of the patient's skin.

[0073] Furthermore, the total light dose (J / cm 2 ) is the irradiance (mW / cm 2 Since exposure time is equal to 10 mW / cm 2 × time (seconds), an additional parameter that must be controlled to deliver the correct therapeutic light dose is exposure time. This can be achieved by the timer mentioned above. The timer can appropriately control the power delivered to the LED array 60, and the timer can be set by the physician. The data is based on 10 mW / cm 2 2 or about 9.3 to about 10.7 mW / cm 2 10 J / cm delivered from a source with an irradiance density of 2 has been shown to produce clinically acceptable results for the desired treatment areas (e.g., face, scalp, extremities). The adjustable illuminator provides a clinically acceptable 10 J / cm 2 To administer a light dose of 20 mW / cm with an exposure time of 500 seconds (8 minutes 20 seconds), 2 In certain embodiments, lower intensities may be administered with longer exposure times (e.g., 10 J / cm 2 Alternatively, an adjustable illuminator may be used with a light output of 30 mW / cm over the exposure time.2 and higher power ranges such as 10 J / cm 2 The selected light dose may also be administered by additionally or alternatively varying the radiation density over the treatment time.

[0074] In at least one embodiment, a heating element (heat source) can be provided. The heat source can be used to heat the area to be treated. According to one embodiment, a treatment method includes warming up an illuminator to emit heat and exposing the treatment area to the illuminator. The heat promotes the conversion of ALA to porphyrins (e.g., photoporphyrins or protoporphyrins). The relationship between temperature exposure and ALA conversion is nonlinear, and the enzymatic pathway involved in the conversion is highly sensitive to temperature. In at least one embodiment, increasing the temperature by approximately 2°C can approximately double the rate of production of, for example, protoporphyrin IX (PpIX).

[0075] Heat can be applied before or during illumination by the illuminator. For example, ALA can be applied first. The heating element can then be activated to apply heat to the patient's skin for a first treatment period, such as a heat soak, which can be 20 to 30 minutes. During heating, the treatment area can be occluded or unoccluded. In other words, the treatment area can be heated while occluded.

[0076] Following the first treatment period, the light can be applied for a second treatment period, e.g., about 8-15 minutes. In at least one embodiment, the heat source can be an infrared quartz heater. In at least one embodiment, the heat source can include a frame-mounted resistive tape heater or multiple heaters, including at least one selected from the group including an infrared LED, a resistive cartridge heater, a positive temperature coefficient heater, or an infrared quartz heater, as described above. Heat, separate from ambient heat in a clinical setting or byproduct heat from one or more operating mechanisms of the lighting device, can also be intentionally generated and directed to the area to be treated.

[0077] [Administration of 5-ALA] As mentioned above, during photodynamic therapy, the patient receives a total light dose over the course of treatment. The total light dose is measured in J / cm 2 irradiance (mW / cm) over time (seconds) 2 Next, an example of a method for treating precancerous lesions such as actinic keratosis by photodynamic therapy utilizing the above-described adjustable lighting device in combination with ALA will be described.

[0078] Essentially anhydrous ALA is mixed with a liquid diluent immediately prior to use. Anhydrous ALA may be, for example, the hydrochloride salt of aminolevulinic acid (ALA), an endogenous 5-carbon aminoketone. The chemical name for ALA HCl used in the embodiments disclosed herein is 5-amino-4-oxopentanoic acid hydrochloride (molecular weight = 167.59). ALA HCl is highly soluble in water. The structural formula of ALA HCl is: [ka]

[0079] In at least one embodiment, ALA is contained in powder form inside the first ampoule. In the first ampoule, the amount of ALA as a dry solid may be 300-400 mg. In at least one embodiment, the amount of ALA HCl is 354 mg. The second ampoule contains a solution vehicle. The second ampoule contains 1.5 mL of solution vehicle. The solution vehicle includes alcohol (i.e., alcohol as defined by the United States Pharmacopeial Convention) (ethanol content = 48% v / v), water, laureth-4, isopropyl alcohol, and polyethylene glycol.

[0080] The first and second ampoules are contained within a plastic applicator. The first and second ampoules can be crushed, for example, by applying finger pressure or within a device configured to apply pressure to the ampoules. When the ampoules are crushed, the ALA previously contained in the first ampoules comes into contact with the solution contained in the second ampoules and dissolves in the solution vehicle. The applicator provided with the ampoules may be shaken to disperse and dissolve the powdered ALA in the solution vehicle. Once mixed, the resulting solution is applied to the patient within two hours of preparation.

[0081] In some embodiments, ALA may be provided in a composition such as a ready-to-use solution or a reconstitution powder for formulation into a solution, gel, cream, or lotion. In another embodiment, the composition comprises 5-aminolevulinic acid hydrochloride in an amount of about 10% to about 70% w / w of the total weight of the composition, preferably about 20% to about 50% w / w of the total weight of the composition, and more preferably about 30% to about 40% w / w of the total weight of the composition.

[0082] In one embodiment, ALA can be applied as a topical composition at a 20% concentration. In at least one embodiment, the ALA mixture is applied topically to the lesion using a point applicator to bring the ALA into contact with the lesion surface, thereby substantially uniformly wetting the lesion surface with ALA. As used herein, the terms "substantial" or "substantially" can refer to any value within a range defined by up to ±15% variation from the mean. However, in other embodiments, ALA can be applied manually (i.e., by first placing the ALA on the practitioner's gloved fingertips and then gently patting the ALA into the area to be treated) or with an implement such as a spatula.

[0083] [Barrier obstruction] Following application of ALA to the area to be treated (i.e., the lesion), the area to be treated may be occluded with a polymeric barrier. For example, as shown in FIG. 3, a polymeric barrier 200 is wrapped around the area to be treated 300. While the exemplary embodiment shown in FIG. 3 depicts the barrier 200 as surrounding the area 300, it should be understood that in certain embodiments, the barrier 200 may occlude only a portion of the area 300. Furthermore, although the barrier 200 is depicted as being substantially cylindrical (e.g., forming a sleeve around the area 300), the barrier 200 may have a variety of shapes.

[0084] Barrier 200 is shown in Figures 3 and 4 as being spaced from site 300 purely for ease of illustration. However, in at least one embodiment, barrier 200 adheres or adheres to site 300 such that there is substantially no gap between barrier 200 and site 300. The polyethylene barrier may have electrostatic properties that provide a tacky adhesive effect, allowing the barrier to remain near the surface of the skin even for extended periods of time. Such an effect may be particularly enhanced when the skin is wet with a topical solution, i.e., when the treatment site is first wetted with the topical solution and then barrier 200 is applied directly onto the wet treatment site.

[0085] In at least one embodiment, a healthcare professional may provide instructions to a patient (subject of treatment) regarding the application or use of barrier 200. In some embodiments, one or more healthcare professionals may provide and / or receive the instructions. In at least one embodiment, the healthcare professional may be, for example, but not limited to, a pharmacist. By way of example, the healthcare professional may instruct the patient before, during, and after application of barrier 200, e.g., regarding prohibited and permitted activities after barrier 200 has been applied. In some embodiments, the healthcare professional may instruct the subject to place barrier 200 over the treatment site for a predetermined period of time following application of the topical composition prior to phototherapy. In some embodiments, the healthcare professional may instruct the subject to keep barrier 200 over the treatment site. In some embodiments, instead of or in addition to instructing the subject to cover the treatment site, at least one embodiment may instruct the subject to remove barrier 200 after a certain period of time, such as three hours. In some embodiments, the healthcare professional may receive the instructions, for example, from a kit. In some embodiments, the instructions may be provided to the professional and / or the patient. Furthermore, in some embodiments, a medical professional may apply and / or remove the barrier 200 at the direction and / or with the patient's consent.

[0086] Experimental results confirmed that using low density polyethylene (LDPE) for the barrier 200 resulted in lower water loss rates and better occlusion. In particular, embodiments having a low density polyethylene barrier 200 were particularly effective for photodynamic therapy.

[0087] Figure 5 shows the evaporative water loss rate for several materials A-E, as summarized in Table 1 below. The LDPE barrier was found to be particularly conducive to retaining water and making ALA more permeable to the area to be treated. [Table 1]

[0088] The measured water loss rates shown in Figure 5 (and Figure 7, discussed below) are transepidermal water loss rates measured before and after wearing the barrier 200 on the dorsal forearm for 3 hours. Baseline water loss was measured for approximately 30 subjects after a minimum 25-minute acclimation period in a controlled environment with a relative humidity of less than 50% and a temperature of 19-22°C. These measurements correspond to the bars labeled "Before" in Figures 5 and 7. Subjects underwent mild to moderate photodamage to the dorsal forearm. Measurements were performed using a calibrated RG1 evaporometer system (cyberDERM, Broomall, PA) with a DermaLab® transepidermal water loss probe (Cortex Technology of Hadsund, Denmark).

[0089] The vapor pressure gradient estimation method was used. Probes measured temperature and relative humidity at fixed points along the skin, producing values ​​equivalent to evaporative water loss (gm / m 2 This allows for the derivation of the barrier properties (hr). Sampling was performed at 4 inputs / second. Baseline measurements indicate the barrier properties of each subject's stratum corneum before Barrier 200 was applied to the stratum corneum. Measurements taken 3 hours after Barrier 200 application indicate the barrier properties of the material shown in Tables 1-2. Such measurements correspond to the bars labeled "After" in Figures 5 and 7. Each Barrier 200 was cut to cover a 5 cm x 5 cm test site area before application. For testing purposes, the Barrier 200 was secured in place with hypoallergenic medical tape. An area of ​​the subject's skin without the Barrier 200 was measured as a control.

[0090] FIG. 6 illustrates the occlusion for several materials according to at least one embodiment. More specifically, FIG. 6 illustrates the occlusion for the materials shown in FIG. 5, summarized in Table 1 above. Occlusion corresponds to the reduction in the rate of evaporative water loss when the subject wears the barrier 200 compared to the baseline evaporative water loss rate. As shown in FIG. 6, barrier material E, for example, prevented greater than about 85% of water vapor from evaporating from the skin surface. In one embodiment, a polymeric barrier having an occlusion greater than 65% is particularly effective for photodynamic therapy. In one embodiment, a polymeric barrier having an occlusion greater than 75% is particularly effective for photodynamic therapy. The higher occlusion of LDPE materials, such as material E, facilitates the penetration of ALA into tissue by minimizing transepidermal water loss from the treatment site. The tissue may be the subject's skin, particularly the stratum corneum, or other tissue.

[0091] Materials B and C prevented approximately 75% of water vapor from evaporating from the skin surface, as did Material E. Materials A and D, on the other hand, are considered to be semi-occlusive barriers.

[0092] FIG. 7 shows the evaporative water loss rate for several materials according to at least one embodiment. More specifically, FIG. 7 shows the evaporative water loss rate for several materials W-Z and E, as summarized in Table 2 below. Barrier material E was the same material shown in Table 1 and discussed above. Materials W-Z included LDPE and polyvinylidene chloride. [Table 2]

[0093] FIG. 8 illustrates the occlusion for several materials according to at least one embodiment. More specifically, FIG. 8 illustrates the occlusion for the materials shown in FIG. 7, summarized in Table 2 above. As shown in FIG. 8, materials E, W, and Y were significantly more occlusive than materials X and Z. Materials X and Z only blocked approximately 35% of water vapor from evaporating and are therefore essentially semi-occlusive. Material E, due to its flexible nature, easily wraps around the treatment area, which may promote moisture retention.

[0094] FIG. 9 is a table containing baseline water loss data for the materials referenced in FIGS. 5 and 6. In particular, FIG. 9 provides baseline measurements for each subject for each of Materials A-E shown in Table 1, including mean and standard deviation values. FIG. 10 is a table containing water loss data after a three-hour wear time for the materials referenced in FIGS. 5 and 6. FIG. 11 is a table containing occlusion data for the materials referenced in FIGS. 5 and 6. FIG. 12 is a table containing baseline water loss data for the materials referenced in FIGS. 7 and 8. FIG. 13 is a table containing water loss data after a three-hour wear time for the materials referenced in FIGS. 7 and 8. FIG. 14 is a table containing occlusion data for the materials referenced in FIGS. 7 and 8.

[0095] As described above, the barrier 200 is used to occlude at least a portion of the area to be treated, for example, all or part of the dorsum of the hand. In some embodiments, and particularly for larger treatment areas such as the forearm, additional structure can be provided to secure the barrier 200 in place. The low-density polyethylene wrap can be secured in place using the dressing 210 shown in FIG. 4. In one embodiment, the dressing 210 is a surgical net, such as the Surgilast® Tubular Elastic Dressing Retainer manufactured by Derma Sciences Inc. of Plainsboro, New Jersey. The dressing 210 can be a tubular elastic stretch net designed to function as a secondary dressing, applying relatively light pressure to hold the barrier 200 firmly in place without adhesive tape. That is, the secondary dressing 210 can apply slight compressive pressure to the barrier 200. The dressing 210 can be a sleeve that fits over and around the barrier 200. In some embodiments, a secondary dressing and / or tape can be applied. Following application of ALA and occlusion, treatment can be performed according to the exemplary practices described below.

[0096] [Treatment Protocol] Once ALA is applied to the upper limbs, the upper limbs can be occluded for up to 3 hours before phototherapy. For example, the limbs can be occluded for 2 to 3 hours. As described above, ALA is a porphyrin precursor that, when used as part of photodynamic therapy, can treat a variety of conditions, including minimal to moderately thick actinic keratosis of the face, scalp, or upper limbs. Thus, in at least one embodiment, part or all of the face, part or all of the scalp, or part or all of the upper limbs can be covered with an occlusive barrier.

[0097] When ALA is used to treat lesions on the face and scalp without applying an occlusive barrier after application, the formation of photosensitive porphyrins and photosensitization of the treated lesions occurs 14 to 18 hours after application. Between 14 and 18 hours after administration of ALA, the lesions are illuminated with an illuminator. The illuminator can, for example, illuminate the lesions with uniformly intense blue light for a predetermined period of time. According to the preferred treatment, visible light has a nominal wavelength of 417 ± 5 nm.

[0098] When ALA is used to treat lesions on the upper extremities, the illumination time can be significantly shorter than for the face or scalp if an occlusive barrier is applied. The illumination time is approximately 3 hours between (1) application of ALA to the upper extremities and occlusion, and (2) illumination of the upper extremities. Occlusion times exceeding 3 hours in some treatment areas may cause irritation to the skin where ALA is applied. Excessive irritation may be indicated by the presence of itching, wheals, redness, or other signs, including symptoms that persist after the treatment session. In particular, excessive irritation is characterized by adverse skin events such as scaling, crusting, ulceration, rash, crusting, tenderness, and itching. Three hours represents the nominal maximum time the upper extremities should be occluded after application of ALA to avoid such excessive irritation while maintaining therapeutic efficacy. The therapeutic effect is the disappearance of actinic keratosis lesions 12 weeks after PDT. In some embodiments, the time between application of ALA to other body parts (other than the face, scalp, and upper extremities) and illumination may be 3 hours.

[0099] Once the occlusion barrier 200 is removed, light treatment as described above, e.g., 10 J / cm 2 For example, the barrier 200 can be applied and then removed within 3 hours, and the red and / or blue light irradiation can be performed for a dose of 10 J / cm. 2 To deliver a dose of 10 J / cm 2 The exposed area may be irradiated with blue light so that the 2 ~75J / cm 2 In some embodiments, the treatment area may be irradiated with red light at a dose of 0.05 wt. In some embodiments, the light may be irradiated while the treatment area is still occluded. In some embodiments, the light and heat may be irradiated while the treatment area is still occluded.

[0100] To treat facial lesions, the illuminator may be positioned so that the area to be treated is between 2 and 4 inches from the surface of the illuminator, with the patient's nose at least 2 inches from the surface of the illuminator, and the forehead and cheeks within 4 inches of the surface. The sides of the patient's face and the patient's ears should be at least 2 inches from the surface of the illuminator.

[0101] To treat scalp lesions, the illuminator can be positioned so that the area to be treated is between 2 and 4 inches from the surface of the illuminator and the patient's scalp is at least 2 inches from the surface of the illuminator and no more than 4 inches from the surface. The sides of the patient's face and the patient's ears should be at least 2 inches from the surface of the illuminator.

[0102] To treat lesions on the upper extremity, such as the dorsum of the hand or forearm, the illumination device can be positioned so that the area to be treated is between 2 and 4 inches from the surface of the illumination device. An apparatus (e.g., a table) may be used to support the upper extremity during phototherapy to increase patient comfort and stabilize the area to be treated.

[0103] Two open-label pharmacokinetic studies were conducted to evaluate the potential systemic exposure of ALA and protoporphyrin IX (PpIX) when applied topically under occlusion in patients with multiple actinic keratosis (AK) lesions on the upper extremities. According to at least one embodiment, a topical composition of 20% w / w 5-aminolevulinic acid (ALA) was applied topically directly to the patient's upper extremities via an applicator, followed by a 3-hour incubation period covered with an occlusive polyethylene film. Phototherapy was administered after the incubation period. Each subject received 10 mW / cm2 of light. 2 Sent at 10J / cm 2 of visible blue light.

[0104] A total of 29 participants were enrolled in the first of the two studies. Participants were men and non-pregnant women aged 18 years or older. Each eligible subject had at least six Grade 1 or Grade 2 AK lesions in one upper extremity treatment site and at least 12 Grade 1 or Grade 2 AK lesions in the other upper extremity treatment site. Subjects received one treatment and were followed up until week 4 after treatment. The treatment sites designated at baseline throughout the study period were the extensor surfaces of both distal upper extremities (i.e., the dorsal hand / forearm), as defined in the protocol. A total of 14 participants were enrolled in the second of the two studies. Men and non-pregnant women aged 18 years or older who had at least six Grade 1 or Grade 2 AK lesions in one upper extremity treatment site and at least 12 Grade 1 or Grade 2 AK lesions in the other upper extremity treatment site were eligible for this study.

[0105] Topical application of ALA to the upper extremities resulted in lower systemic exposure to ALA and PpIX than intravenous and oral administration. A method according to at least one embodiment includes applying up to two topical solution compositions, each containing approximately 354 mg of ALA. Administration using the topical solution was compared to intravenous and oral administration at an amount of approximately 100 mg of ALA. As noted above, the strength of the ALA was approximately 20% by weight. Topical administration resulted in a mean plasma concentration (C) of ALA of less than approximately 110 ng / mL. max) values. max The term "maximum observed plasma concentration" refers to the maximum observed plasma concentration based on the actual values ​​measured after application of the study drug.

[0106] In particular, after topical application, the geometric mean maximum plasma concentration was approximately 98 ng / mL at a median of 2 hours after application, and the geometric mean area under the curve (AUC t ) was 577 ng*h, with a variability of about 94% to about 170%. After baseline correction, the ALA geometric mean maximum plasma concentration was 80 ng / mL at a median of 2 hours, and the geometric mean AUCt was 282 ng*h / mL. In one embodiment, the topical solution, when applied at a strength of about 20% by weight, exhibits a geometric mean area under the curve (AUCτ) value for ALA of less than about 350 ng·hr / mL. As used herein, "AUC t " refers to the area under the plasma concentration-time curve up to the last quantifiable / non-negative plasma concentration.

[0107] In another study, after topical application, the geometric mean maximum plasma concentration was approximately 61 ng / mL at a median of 2 hours after application, and the geometric mean AUC t The mean ALA geometric mean maximum plasma concentration was 727 ng*h / mL, with a variation of approximately 30% to approximately 152%. After baseline correction, the median ALA geometric mean maximum plasma concentration was 39 ng / mL at 2 hours, and the geometric mean AUC t The estimated bioavailability after topical application of 354 mg of ALA with occlusion was about 1.0%. In one embodiment, the systemic bioavailability after topical administration of 354 mg of ALA HCl is less than about 5%. As used herein, the term "bioavailability" refers to the rate and extent of absorption, and is expressed as AUC τ and C max is determined by the value.

[0108] According to at least one embodiment, a photodynamic therapy method was implemented to treat upper extremity lesions in a multicenter, randomized, parallel-group, assessor-blind, and vehicle-controlled study in 269 patients with 4-15 mild to moderate actinic keratoses. The actinic keratoses were located on the upper extremities, more specifically on the dorsum of the hands and / or forearms between the elbow and the base of the fingers. The subjects ranged in age from 45 to 90 years (mean, 68 years), and 90% had Fitzpatrick Skin Type I, II, or III. Subjects were randomly assigned to treatment in a 1:1 ratio. For each subject, ALA was applied to the lesion on the dorsum of one hand or forearm, and then the dorsum of the hand or dorsum was occluded with a low-density polyethylene barrier for 3 hours. After removal of the low-density polyethylene barrier, 10 J / cm was administered. 2 A dose of blue light of 10mW / cm 2 If damage remained in the treated area, treatment was repeated after 8 weeks.

[0109] Complete clearance (i.e., resolution of actinic keratosis) was achieved by 31% of subjects receiving ALA (i.e., 42 of 135 subjects). Complete clearance was achieved 12 weeks after initial treatment, compared with 13% of subjects receiving only the solution vehicle (i.e., 17 of 134 subjects). A 12-month follow-up evaluation of subjects who achieved complete clearance at 12 weeks showed a 58% recurrence rate for these subjects. The recurrence rate corresponds to the percentage of subjects who achieved complete clearance 12 weeks after treatment but had at least one recurrent lesion during the 12-month follow-up period following the 12-week evaluation.

[0110] Thus, the present disclosure provides methods for photodynamically treating the surface of a patient and occluding the patient's skin as part of the treatment. The patient may be exposed to light to treat actinic keratosis, acne, photodamaged skin, cancer, warts, psoriasis, or other skin conditions.

[0111] While the specification includes details of certain specific implementations, these should not be construed as limitations on the scope of what may be claimed, but rather as descriptions of features unique to particular implementations. Certain features described herein in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various features described in the context of a single embodiment may also be implemented in multiple embodiments separately or in any suitable subcombination. Furthermore, while features may be described above as working in particular combinations and may initially be claimed as such, one or more features from a claimed combination may be cut from the combination, and the claimed combination may be directed to a subcombination or variation.

[0112] It is important to note that the configurations and arrangements of the lighting systems shown in the various exemplary embodiments are exemplary only and not limiting in nature. All changes and modifications that fall within the spirit and / or scope of the described embodiments are desired to be protected. It is to be understood that some features may not be necessary, and embodiments lacking various features are considered to be within the scope of this disclosure, the scope of which is defined by the claims. When the word "a portion" is used, the item may include that item and / or the entire item unless otherwise specified.

[0113] Additional advantages and modifications will readily occur to those skilled in the art. Therefore, the invention in its broader aspects is not limited to the specific details and representative apparatus and methods shown and described herein. Accordingly, various modifications may be made without departing from the spirit and scope of the general inventive concept as defined by the appended claims and their equivalents. [Explanation of symbols]

[0114] 10a~10e Panels 23 tabs 40 Mounting Head 50 Telescopic hinge 60 LED array 70 fans 80 Movable Stand 81 Base 82 Vertical support 83 Pivot Point 84 Stabilizing Arm 85 connecting arm 86 Hinge Point 87 wheels 90 Control Devices and Power Supplies 100 units 200 Barrier 210 Dressing materials 300 parts

Claims

1. an applicator for applying a topical solution containing 5-aminolevulinic acid (ALA) to an area of ​​the skin of the upper extremities containing an actinic keratosis lesion, the applicator containing first and second ampoules, the first ampoules containing powdered ALA and the second ampoules containing a solution vehicle, the topical solution being applied to the surface of the lesion within two hours of preparation; and An occlusive dressing for enhancing tissue penetration of a topical solution containing ALA for photodynamic therapy, the occlusive dressing comprising a low-density polyethylene barrier and configured to provide 65% or greater occlusion at the treatment site. Kit including:

2. 10. The kit of claim 1, wherein the topical composition comprises 20% w / w ALA.

3. The kit of claim 1 , wherein the upper extremity is the dorsum of the hand or the forearm.

4. 10. The kit of claim 1, wherein the volume of the solution vehicle in the second ampoule is 1.5 mL.

5. 10. The kit of claim 1, wherein the solution vehicle comprises alcohol, water, and polyethylene glycol.

6. 2. The kit of claim 1, wherein the first ampoule contains 300 to 400 mg of powdered ALA.

7. Low density polyethylene barrier of 1.11 g / m ２ 10. The kit of claim 1, wherein the kit provides a transepidermal water loss rate of 0.1 s or less.

8. The treatment area was covered with a low density polyethylene barrier of 0.96 g / m ２ 8. The kit of claim 7, which provides a transepidermal water loss rate of 0.1 s or less.

9. The treatment area was covered with a low density polyethylene barrier of 0.67 g / m ２ 8. The kit of claim 7, which provides a transepidermal water loss rate of 0.1 s or less.

10. The kit of claim 1 , wherein the barrier is configured to contact the treatment site.

11. 10. The kit of claim 1, wherein the barrier comprises two layers of barrier, the upper layer applying gentle pressure to hold the lower layer in place.

12. 10. The kit of claim 1, wherein the low density polyethylene barrier is secured with an elastic net.

13. 10. The kit of claim 1, wherein the barrier is covered with a material.

14. 14. The kit of claim 13, wherein the barrier is coated with a material by placing the material on and around the barrier.

15. The kit of claim 1, wherein the occlusive dressing comprises a sleeve.

16. An applicator for applying a topical solution containing 5-aminolevulinic acid (ALA) to areas of the skin of the upper extremities that contain actinic keratosis lesions, wherein the topical solution is provided in the form of a gel; and An occlusive dressing for enhancing tissue penetration of a topical solution containing ALA for photodynamic therapy, the occlusive dressing comprising a low-density polyethylene barrier and configured to provide 65% or greater occlusion at the treatment site. Kit including:

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