Topical Compositions and Methods for Photodynamic Therapy

Abstract

Methods and topical compositions for treating skin disorders are provided. The topical compositions include 5-aminolevulinic acid, at least one penetration enhancer, and at least one chelating agent. Additionally, methods and topical compositions are disclosed for use in photodynamic therapy, where the topical compositions are applied to the affected area of ​​a patient for a period ranging from about 15 minutes to about 10 hours.

Description

[Technical field]

[0001] The present invention relates to a topical composition for treating a skin disorder, comprising 5-aminolevulinic acid, at least one penetration enhancer, and at least one chelating agent.The present invention further relates to a topical composition for use in photodynamic therapy.The present invention also relates to a method for treating a skin disorder in photodynamic therapy. [Background technology]

[0002] Photodynamic therapy (PDT), photodynamic diagnosis (PD), or photochemotherapy, generally, is used to treat and / or diagnose several types of diseases on or near the skin, or on or near other tissues, such as those in body cavities. For example, photodynamic therapy or photodynamic diagnosis may be used to treat or diagnose actinic keratosis on the upper extremities (e.g., the back of the hand or forearm), scalp, or facial area of ​​a patient. Additionally, such techniques may be used to treat and diagnose other indications (e.g., acne, warts, psoriasis, photodamaged skin, cancer) and other areas of a patient (e.g., the legs, or parts of the arms other than the forearms).

[0003] During one form of photodynamic therapy, the patient is first administered a photoactivatable drug or a precursor of a photoactivatable drug that accumulates in the tissue to be treated. The area to which the photoactivatable drug is administered is then exposed to visible light, which induces chemical and / or biological changes in the drug. These changes allow the drug to selectively target, destroy, or alter the targeted tissue, while at the same time causing at most mild and reversible damage to other tissues in the treatment area. One example of a precursor of a photoactivatable drug is 5-aminolevulinic acid ("ALA"), a 5-aminoketone compound of formula I: [ka]

[0004] It is usually used in the photodynamic therapy of actinic keratosis. As used herein, the term ALA or 5-aminolevulinic acid refers to ALA itself, its precursors, its esters, and their pharma- ceutically acceptable salts. After application of a topical composition (e.g., topical solution or emulsion or nanoemulsion) containing ALA, photosensitization occurs via metabolic conversion of aminolevulinic acid to protoporphyrin IX (PpIX). PpIX is a photosensitizer that accumulates in the skin. ALA is formed from succinyl-CoA and glycine in the first step of heme synthesis, and to a limited extent can penetrate the skin and cause local accumulation of PpIX, but since the action of ferrochelatase (an enzyme for metallation) is the rate-limiting step of heme synthesis, excess ALA leads to accumulation of the photosensitizer PpIX. When exposed to light of the appropriate wavelength and energy, the accumulated photoactive porphyrin produces a photodynamic reaction, which results in a cytotoxic process depending on the oxygen present at the same time. Absorption of light results in an excited state of the porphyrin molecule, and subsequent spin transfer from the photoreactive porphyrin to an oxygen molecule generates singlet oxygen, which can further react to form superoxide and hydroxyl radicals. Because actinic keratosis lesions, basal cell carcinomas, and squamous cell carcinomas overlying the skin are more permeable to ALA than healthy skin, these changes allow PpIX to then selectively target, destroy, or modify target tissues, while at the same time causing at most mild and reversible damage to other tissues within the treatment area.

[0005] For effective photodynamic therapy, it is desirable to have a power output that can be controlled for intensity and duration, among other factors. Lighting devices are typically used to provide uniform light suitable for therapeutic purposes. These devices generally include a light source (e.g., fluorescent light or LED), connecting elements that direct, filter, or otherwise transmit the irradiated light so that it reaches its intended target in a usable form, and a control system that starts and stops the generation of light as needed.

[0006] Photodynamic therapy can be performed using certain compositions such as ALA in conjunction with the lighting device described above.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 Sep. 21, 1999; (2) U.S. Pat. No. 6,223,071 to Lundahl et al., entitled "Illuminator for photodynamic therapy and diagnosis which produces substantially uniform intensity visible light," issued April 24, 2001; and (3) U.S. Pat. No. 10,814,114 to Boyajian et al., entitled "Method And Apparatus For Applying A Topical Solution." No. 2017 / 066270, issued on April 20, 2017; (5) U.S. Pat. No. 10,589,122 to Boyajian et al., entitled “Adjustable Illuminator For Photodynamic Therapy And Diagnosis,” issued on March 17, 2020; and (6) U.S. Pat. No. 10,603,508 to Boyajian et al., entitled “Adjustable Illuminators and Methods for Photodynamic Therapy and Diagnosis.” This information was disclosed in the “J.N. Clinical Chemistry, 2020 Journal of Clinical Chemistry, 2020, Vol. 13, No. 1, 2020” issue of the Journal of Clinical Chemistry, 2020.

[0007] However, one of the drawbacks of PDT is that patients often experience pain during the illumination phase. Pain associated with PDT is the most serious adverse effect and can lead to interruption or discontinuation of treatment, resulting in refusal to repeat the process at a later date due to intolerable discomfort. This pain is not relieved by any topical anesthetic (other than ice chips and evaporative cooling) and can be so severe that patients refuse to complete the treatment and / or to undergo any further PDT (Warren CB et al. J Am Acad Dermatol 2009;61:1033-43, Ang JM et al. Photodiagnosis Photodyn Ther 2017;19:308-44).

[0008] Therefore, PDT-related pain represents a significant barrier to achieving optimal therapeutic outcomes. Long treatment times, waiting times, and associated pain are causing more and more patients to drop out of therapy. It is believed that a greater amount of photosensitizer must be accumulated before light exposure, and pain is directly proportional to the length of incubation time before irradiation. There is a need in the art to reduce incubation times, shorten clinic stays, and reduce associated pain while maintaining comparable therapeutic outcomes. Summary of the Invention

[0009] The inventors have surprisingly found that topical compositions for photodynamic therapy comprising at least one penetration enhancer and at least one chelator together with a 5-aminoketone compound, when applied to the skin of a patient, also show increased penetration of the 5-aminoketone compound into the skin and increased conversion of the compound to PpIX in the skin. Furthermore, the incubation time in photodynamic therapy is reduced by at least 30% compared to compositions lacking a penetration enhancer and / or a chelator. It has been found that the chelator enhances the accumulation of PpIX. Without being bound by any theory, it is believed that this accumulation of PpIX is enhanced by the chelation of iron, thereby preventing the inactivating effect of ferrochelatase when the metal is incorporated into PpIX, leading to the accumulation of PpIX. Thus, the photosensitizing effect is enhanced.

[0010] The present invention is directed to a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) at least one penetration enhancer; c) at least one chelating agent; d) optionally an antifoaming agent.

[0011] In some embodiments, the present invention is directed to a topical composition for the treatment of a skin condition, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) a vehicle comprising at least one chelating agent; The topical composition is applied to the affected area (eg, skin) of the patient for a period ranging from 15 minutes to 10 hours.

[0012] In some preferred embodiments, the vehicle further comprises an optional antifoaming agent. In another preferred embodiment, the treatment method is photodynamic therapy. In another preferred embodiment, the affected area is irradiated with a light source after applying the composition. In another preferred embodiment, the compound of formula I is in a dry solid form.

[0013] In some embodiments, the present invention is directed to a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the patient's affected area (eg, skin) for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0014] In some embodiments, the at least one penetration enhancer is selected from the group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, and glycosaminoglycans.

[0015] In some embodiments, the at least one chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its pharma- ceutically acceptable salts, such as disodium edetate dehydrate, dipotassium edetate, dipotassium edetate dehydrate, calcium disodium edetate, and diethylenetriaminepentaacetic acid.

[0016] The present invention is directed to a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof; b) propylene glycol; c) EDTA, or a pharma- ceutically acceptable salt thereof; d) optionally an antifoaming agent.

[0017] In some embodiments, the present invention is directed to a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) propylene glycol, (ii) EDTA, and pharma- ceutically acceptable salts thereof; (iii) an optional antifoaming agent; and a vehicle.

[0018] The present invention is also directed to a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) at least one penetration enhancer; c) at least one chelating agent; d) optionally an antifoaming agent.

[0019] In some embodiments, the present invention is also directed to a method for treating actinic keratosis, comprising administering a topical composition to the skin of a patient, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) a vehicle comprising at least one chelating agent; The topical composition is applied to the patient's affected area for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0020] In a preferred embodiment, the method includes a vehicle that optionally includes an antifoaming agent. In another preferred embodiment, the method of treatment is photodynamic therapy. In another preferred embodiment, the compound of formula I is in a dry solid form.

[0021] In some embodiments, the present invention is also directed to a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering a topical composition to the skin of a patient, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the test set-up of the in-vitro skin model used in Examples 2-5. [Diagram 2] FIG. 2 is a graph showing a comparison of the amount of PpIX in receptor fluid for an exemplary formulation of the invention compared to a Reference Listed Drug ("RLD"). [Diagram 3] FIG. 3 is a graph showing skin PpIX retention information for an exemplary formulation of the invention compared to RLD. [Figure 4] FIG. 4 is a graph showing a comparison of the amount of PpIX in receptor fluid and the amount retained on the skin between a formulation containing EDTA and a formulation containing calcium disodium edetate. [Diagram 5] FIG. 5 is a graph showing the effect of temperature on PpIX formulations by determining the amount of PpIX in the receptor fluid. [Figure 6] FIG. 6 summarizes the permeation data for Donor 1 (A), Donor 2 (B), and Donor 3 (C), with the blank data subtracted. [Figure 7] FIG. 7 is a graph showing PpIX content quantified within the skin compartment for donors 1, 2, and 3. [Figure 8] FIG. 8 is a graph showing the effect of PG and EDTA on PpIX levels in the receptor compartment (A) and skin (B) in three donors (donors 1, 2 and 3). [Figure 9] FIG. 9 is a graph showing the effect of Transcutol®, PG and EDTA on PpIX levels in the receptor compartment (A) and skin (B) in three donors (donors 1, 2 and 3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Various embodiments are described below. It should be noted that the specific embodiments are not intended as an exhaustive description of the aspects discussed herein or as a limitation to the broader aspects. An aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment.

[0024] The following terms are used throughout and are defined below.

[0025] As used herein and in the appended claims, singular articles such as "a" and "an" and "the" and similar referents in the context of describing elements (particularly in the context of the claims that follow) are to be construed as inclusive of both the singular and the plural, 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 individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein.

[0026] Unless otherwise stated herein or otherwise clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples or use of exemplary language (e.g., "etc.") provided herein are intended merely to better describe the embodiments and do not pose limitations on the claims unless otherwise expressly stated. No language in this specification should be construed as indicating any non-claimed element as essential to the claims.

[0027] The embodiments illustratively described herein may be suitably practiced without any of the elements and limitations. Thus, for example, terms such as "comprising," "including," and "containing" are to be read expansively and without limitation. Furthermore, the terms and expressions used herein are used as terms of description rather than limitation, and there is no intention in using such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it should be recognized that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase "consisting essentially of" is understood to include the elements specifically recited and 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 materials, additives, devices, or steps not mentioned may be present. Unless otherwise specified, "a" or "an" means one or more.

[0028] Unless otherwise indicated, all numbers expressing quantities of properties, parameters, conditions, etc. used in the specification and claims should be understood to be modified in all instances by the term "about". Thus, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are approximate. Any numerical parameters should be interpreted, at the very least, with the number of significant digits taken into account and by applying ordinary rounding techniques. The term "about", when used before numerical designations such as temperature, time, amount and concentration, including ranges, represents an approximation that may vary by (+) or (-) 10%, 5%, or 1%.

[0029] As will be understood by one of ordinary skill in the art, for all purposes, particularly in terms of providing a description, all ranges disclosed herein also encompass all possible subranges and combinations of subranges. Any range recited is fully described and can be readily recognized as being divisible into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily divided into a lower third, a higher third, a central third, etc. As will also be understood by one of ordinary skill in the art, all terms such as "up to," "at least," "greater than," "less than," etc., include numbers that describe and refer to a range that can then be divided into subranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, a range includes each individual member.

[0030] As used herein, the term "synergistic" is defined to mean a combination of ingredients where the activity of the combination is greater than the addition of the individual activities of each component of the combination.

[0031] According to some embodiments, the present invention provides a topical composition for photodynamic therapy in the treatment of a skin condition, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) at least one penetration enhancer; c) at least one chelating agent; d) optionally an antifoaming agent.

[0032] Preferably, the at least one penetration enhancer is selected from the group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, fatty acid esters, glycol derivatives, glycerides, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, bile salts, and glycosaminoglycans. More preferably, the topical composition of the present invention contains as penetration enhancers dialkyl derivatives of acetamide and formamide, such as dimethylacetamide, dimethylformamide, pyrrolidone derivatives, such as N-methyl-2-pyrrolidone, fatty acids, such as oleic acid, glycol derivatives, such as propylene glycol, and fatty acid esters thereof, such as propylene glycol monocaprylate, propylene glycol monolaurate, azones, such as laurocapram or ln-dodecyl-azacycloheptan-2-one, polysorbates, such as Tween 80, stearoyl macrogolglycerides, oleoyl macrogolglycerides, lauroyi ... macrogolglycerides such as capryl-caproyl macrogolglyceride; polyethylene glycol derivatives such as polyethylene glycol 400; ethoxylated ether derivatives such as diethylene glycol monoethyl, diethylene glycol monomethyl ether, and dipropylene glycol monomethyl ether; glycosaminoglycans such as chondroitin sulfate, keratan sulfate, dermatan sulfide, heparin sulfate, and heparan sulfate.

[0033] The penetration enhancer is present in the composition in an amount ranging from about 10% w / w to about 50% w / w of the composition, including, for example, about 10%, 20%, 30%, 40%, or 50% w / w of the composition, and all ranges and subranges therein. More preferably, the penetration enhancer is present in the composition in an amount ranging from about 20% w / w to about 40% w / w of the composition, including, for example, about 20%, about 30%, or about 40% w / w of the composition, and all ranges and subranges therein.

[0034] In a preferred embodiment, the at least one penetration enhancer is selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives. In another preferred embodiment, the at least one penetration enhancer is selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol (Transcutol®). The propylene glycol is present in the composition in an amount ranging from about 10% w / w to about 50% w / w of the composition, including, for example, about 10%, 20%, 30%, 40%, or 50% w / w of the composition, and all ranges and subranges therein. Preferably, the propylene glycol is present in the composition in an amount ranging from about 20% w / w to about 40% w / w of the composition, including, for example, about 20%, about 30%, or about 40% w / w of the composition, and all ranges and subranges therein. 2-(2-ethoxyethoxy)ethanol (Transcutol®), when used as a penetration enhancer, is present in the composition in an amount ranging from about 2% w / w to about 50% w / w of the composition, including, for example, about 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, or 40% w / w of the composition, and all ranges and subranges therein. Preferably, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount ranging from about 4% w / w to about 10% w / w of the composition, including, for example, about 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / w of the composition, and all ranges and subranges therein.

[0035] In another embodiment, the at least one chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its pharma- ceutically acceptable salts, such as disodium edetate, disodium edetate dehydrate, trisodium edetate, dipotassium edetate, dipotassium edetate dehydrate, calcium disodium edetate, diethylenetriaminepentaacetic acid, and organic acids, such as citric acid, fumaric acid, malic acid, lactic acid, and glycolic acid. Preferably, the at least one chelating agent is disodium edetate.

[0036] At least one chelating agent may be present in the composition in an amount ranging from about 0.01% w / w to about 2% w / w, including, for example, about 0.01%, 0.05%, 0.1%, 0.2%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, 1.0%, 1.1%, 1.2%, 1.25%, 1.4%, 1.5%, 1.75%, 1.80%, 1.90% or 2.0% w / w of the composition, and all ranges and subranges therein. Preferably, the amount ranges from about 0.05% w / w to about 1% w / w, including, for example, about 0.05%, 0.1%, 0.2%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, or 1.0% w / w of the composition, and all ranges and subranges therein.

[0037] EDTA or a pharma- ceutically acceptable salt thereof, when used as a chelating agent, may be present in the composition in an amount ranging from about 0.01% w / w to about 2% w / w of the composition, including, for example, about 0.01%, 0.05%, 0.1%, 0.2%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, 1.0%, 1.1%, 1.2%, 1.25%, 1.4%, 1.5%, 1.75%, 1.80%, 1.90% or 2.0% w / w of the composition, and all ranges and subranges therein. Preferably, the amount ranges from about 0.05% w / w to 1% w / w, including, for example, about 0.05%, 0.1%, 0.2%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, or 1.0% w / w of the composition, and all ranges and subranges therein. In a most preferred embodiment, EDTA or a pharma- ceutically acceptable salt thereof is present in the composition in an amount of about 0.1% w / w to about 0.25% w / w of the composition.

[0038] Surprisingly, it has been found that the combination of chelating agent and penetration enhancer shows synergistic effect on increasing the penetration of 5-ALA and the formation of PpIX.Preferably, the combination of propylene glycol and EDTA or its salt shows synergistic effect on increasing the penetration of 5-ALA and the formation of PpIX.The synergistic effect of the combination of chelating agent and penetration enhancer is further enhanced by adding Transcutol® to the combination of propylene glycol and EDTA or its salt.Preferably, the synergistic effect of the combination of chelating agent and penetration enhancer shows synergistic effect on increasing the penetration of 5-ALA and the formation of PpIX by adding Transcutol® to the combination of propylene glycol and EDTA or its salt.

[0039] In another embodiment, the combination of the chelating agent and the penetration enhancer shows additive effects on increasing the penetration of 5-ALA and the formation of PpIX.Preferably, the combination of propylene glycol and EDTA or its salt shows additive effects on increasing the penetration of 5-ALA and the formation of PpIX.Adding Transcutol® to the combination of the chelating agent and the penetration enhancer further enhances the synergistic effect of this combination.For example, adding Transcutol® to the combination of propylene glycol and EDTA or its salt shows additive effects on increasing the penetration of 5-ALA and the formation of PpIX.

[0040] In one embodiment, the 5-carbon aminoketone compound is 5-aminolevulinic acid (ALA) or a pharma- ceutically acceptable salt thereof. Preferably, the 5-carbon aminoketone compound is the hydrochloride salt of aminolevulinic acid.

[0041] Compounds of Formula I [ka] or a pharma- ceutically acceptable salt thereof is present in the composition in an amount ranging from about 10% w / w to 70% w / w of the composition, for example, about 10%, 20%, 30%, 40%, 50%, 60%, or 70% w / w of the composition.Preferably, in an amount ranging from about 20% w / w to 50% w / w of the composition, for example, about 20%, 25%, 30%, 35%, 40%, 45%, or 50% w / w of the composition.In a most preferred embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof is present in an amount of about 20% w / w.

[0042] The 5-ALA compound or its pharma- ceutically acceptable salt is present in the composition in an amount ranging from about 10% w / w to about 70% w / w of the composition, including, for example, about 10%, 20%, 30%, 40%, 50%, 60%, or 70% w / w of the composition, and all ranges and subranges therein.Preferably, the amount ranges from about 20% w / w to about 50% w / w of the composition, including, for example, about 20%, 25%, 30%, 35%, 40%, 45%, or 50% w / w of the composition, and all ranges and subranges therein.In the most preferred embodiment, the 5-ALA or its pharma- ceutically acceptable salt is present in the composition in an amount of about 20% w / w.

[0043] The composition of the present invention may contain various other inactive ingredients conventionally used in a given product type, provided that they do not unacceptably alter the benefits of the present invention. The inactive ingredients may be selected from alcohol, isopropyl alcohol, polyethylene glycol, propylene glycol, glycerin, diethylene glycol monoethyl ether, or purified water, or a combination thereof. It may further include a surfactant or wetting agent and / or humectant. The surfactant or wetting agent may be selected from the group consisting of laureth-4, sodium lauryl sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, or its octech-1 / deceth-1 sodium sulfate. The humectant may be selected from the group consisting of polyethylene glycol, propylene glycol, hyaluronic acid, or its glycerin.

[0044] In one embodiment, the topical composition of the present invention optionally includes an antifoaming agent. Suitable antifoaming agents may include, but are not limited to, polydimethylsiloxane and other silicones, certain alcohols, stearates, and glycols. Preferably, the antifoaming agent is a cyclic polydimethylsiloxane. More preferably, the antifoaming agent is a cyclomethicone. The antifoaming agent is present in the composition in an amount ranging from about 0.2% w / w to about 1.0% w / w of the composition, including, for example, about 0.2%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, or 1.0% w / w of the composition, and all ranges and subranges therein. Preferably, the antifoaming agent is present in the composition in an amount ranging from about 0.2% w / w to about 0.5% w / w of the composition. More preferably, the antifoaming agent is present in the composition in an amount ranging from about 0.5% w / w of the composition.

[0045] The composition may be prepared by simple mixing of ALA with the vehicle. The vehicle may be prepared by mixing the penetration enhancer, chelating agent, antifoaming agent, and other inactive ingredients in any order. Preferably, the vehicle may be prepared by adding the ingredients to purified water in the following order, adding the chelating agent, and mixing well. To this, a solvent such as ethyl alcohol was added, then propylene glycol, then polyethylene glycol 400, then isopropyl alcohol, then Transcutol®, then laureth-4 was added. After each ingredient was added, the vehicle was mixed. Finally, an antifoaming agent such as cyclomethicone was added to obtain the final mixture. Surprisingly, it was discovered that this order of addition prevents precipitation of the chelating agent such as EDTA.

[0046] In one embodiment, the present invention is directed to a topical composition for the treatment of a skin condition, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) a vehicle comprising at least one chelating agent; The topical composition is applied to the affected skin for a period ranging from 15 minutes to 10 hours.

[0047] In a preferred embodiment, the vehicle comprises an optional antifoaming agent. In another preferred embodiment, the method of treatment is photodynamic therapy. In another preferred embodiment, the affected area is irradiated with a light source after application of the composition. In another preferred embodiment, the composition comprises the compound of formula I in the form of a dry solid.

[0048] In another embodiment, the present invention is directed to a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the affected skin for a period ranging from 15 minutes to 10 hours, and then the affected skin is irradiated with a light source.

[0049] Surprisingly, it has been found that the topical composition of the present invention reduces the incubation time in photodynamic therapy by at least about 30% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time in photodynamic therapy is reduced by at least about 30% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time in photodynamic therapy is reduced by at least about 40% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time in photodynamic therapy is reduced by at least about 50% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time in photodynamic therapy is reduced by at least about 60% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time in photodynamic therapy is reduced by at least about 70% compared to a composition lacking a penetration enhancer and a chelating agent. Preferably, the incubation time during photodynamic therapy is reduced by at least about 80% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time during photodynamic therapy is reduced by at least about 90% compared to a composition lacking a penetration enhancer and a chelating agent.Preferably, the incubation time during photodynamic therapy is reduced by at least about 95% compared to a composition lacking a penetration enhancer and a chelating agent.

[0050] Such a reduction in incubation time is believed to reduce the pain associated with PDT.

[0051] In another embodiment, the present invention provides a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the patient's affected area (eg, skin) for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0052] The topical composition is applied for a period of, for example, 15 minutes, 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours.

[0053] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the patient's affected area for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0054] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the patient's affected area for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0055] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the patient's affected area for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0056] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the affected skin for a period ranging from 15 minutes to 10 hours, and then the affected skin is irradiated with a light source.

[0057] In another embodiment, the present invention provides a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof; b) propylene glycol; c) EDTA, or a pharma- ceutically acceptable salt thereof; d) optionally an antifoaming agent.

[0058] In yet another embodiment, the present invention provides a topical composition for photodynamic therapy in the treatment of skin disorders, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) propylene glycol, (ii) EDTA, and pharma- ceutically acceptable salts thereof; (iii) an optional antifoaming agent; and a vehicle.

[0059] In yet another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) propylene glycol, (ii) 2-(2-ethoxyethoxy)ethanol, (iii) edetate disodium, (iv) an optional antifoaming agent; and a vehicle.

[0060] In yet another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) propylene glycol, (ii) 2-(2-ethoxyethoxy)ethanol, (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0061] In yet another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) propylene glycol in an amount ranging from about 10% w / w to about 50% w / w; (ii) 2-(2-ethoxyethoxy)ethanol in an amount ranging from about 2% w / w to about 50% w / w; (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0062] In yet another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) propylene glycol in an amount ranging from about 10% w / w to about 50% w / w; (ii) 2-(2-ethoxyethoxy)ethanol in an amount ranging from about 2% w / w to about 50% w / w; (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0063] In another preferred embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, or a pharma- ceutically acceptable salt thereof; [ka] b) propylene glycol; c) 2-(2-ethoxyethoxy)ethanol, d) edetate disodium.

[0064] In another preferred embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-aminolevulinic acid in an amount of 20% w / w of the composition; b) propylene glycol in an amount of 20% to 40% w / w of the composition; c) EDTA in an amount of 0.1% to 0.5% w / w of the composition.

[0065] Preferably, the composition further comprises 2-(2-ethoxyethoxy)ethanol in an amount of 4% to 10% w / w of the composition.

[0066] In another preferred embodiment, the composition further comprises cyclomethicone in an amount of 0.2-0.5% w / w of the composition.

[0067] In a further preferred embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I in an amount of 1 to 30% w / w; [ka] or a pharma- ceutically acceptable salt thereof; b) propylene glycol in an amount ranging from about 10% w / w to about 50% w / w; c) 2-(2-ethoxyethoxy)ethanol in an amount ranging from about 2% w / w to about 50% w / w; d) edetate disodium.

[0068] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) ethanol; c) Laureth-4, d) polyethylene glycol; and e) isopropyl alcohol; f) propylene glycol; g) 2-(2-ethoxyethoxy)ethanol, h) edetate disodium; and i) cyclomethicone, j) purified water.

[0069] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) ethanol; (ii) laureth-4, (iii) polyethylene glycol, (iv) isopropyl alcohol; (v) propylene glycol; (vi) 2-(2-ethoxyethoxy)ethanol, (vii) edetate disodium, (viii) cyclomethicone, (ix) purified water, and a vehicle comprising the same.

[0070] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof; b) ethanol; c) Laureth-4, d) polyethylene glycol; and e) isopropyl alcohol; f) propylene glycol; g) 2-(2-ethoxyethoxy)ethanol, h) edetate disodium; and i) cyclomethicone, j) purified water.

[0071] In another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) ethanol; (ii) laureth-4, (iii) polyethylene glycol, (iv) isopropyl alcohol; (v) propylene glycol; (vi) 2-(2-ethoxyethoxy)ethanol, (vii) edetate disodium, (viii) cyclomethicone, (ix) purified water, and a vehicle comprising the same.

[0072] In a most preferred embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of 20% w / w; [ka] b) ethanol in an amount of 10-15% w / w of the composition; c) Laureth-4 in an amount of 5-10% w / w of the composition; d) polyethylene glycol in an amount of 1-5% w / w of the composition; e) isopropyl alcohol in an amount of 2-4% w / w of the composition; f) propylene glycol in an amount of 20-40% w / w of the composition; g) 2-(2-ethoxyethoxy)ethanol in an amount of 2-4% w / w of the composition; h) disodium edetate in an amount of 0.1-0.25% w / w of the composition; i) cyclomethicone in an amount of 0.2-0.5% w / w of the composition; j) purified water.

[0073] In another preferred embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) 5-ALA or a pharma- ceutically acceptable salt thereof in an amount of 20% w / w; b) ethanol in an amount of 10-15% w / w of the composition; c) Laureth-4 in an amount of 5-10% w / w of the composition; d) polyethylene glycol in an amount of 1-5% w / w of the composition; e) isopropyl alcohol in an amount of 2-4% w / w of the composition; f) propylene glycol in an amount of 20-40% w / w of the composition; g) 2-(2-ethoxyethoxy)ethanol in an amount of 2-4% w / w of the composition; h) disodium edetate in an amount of 0.1-0.25% w / w of the composition; i) cyclomethicone in an amount of 0.2-0.5% w / w of the composition; j) purified water.

[0074] In yet another embodiment, the present invention provides a topical composition for use in photodynamic therapy for the treatment of a skin disorder, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) ethanol in an amount of 10-15% w / w of the composition; (ii) laureth-4 in an amount of 5-10% w / w of the composition; (iii) polyethylene glycol in an amount of 1-5% w / w of the composition; (iv) isopropyl alcohol in an amount of 2-4% w / w of the composition; and (v) propylene glycol in an amount of 20-40% w / w of the composition; (vi) 2-(2-ethoxyethoxy)ethanol in an amount of 2-4% w / w of the composition; (vii) edetate disodium in an amount of 0.1 to 0.25% w / w of the composition; and (viii) cyclomethicone in an amount of 0.2 to 0.5% w / w of the composition; and a vehicle.

[0075] In another embodiment, the present invention is directed to a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) at least one penetration enhancer; c) at least one chelating agent; d) optionally an antifoaming agent.

[0076] In another embodiment, the present invention is directed to a method for treating actinic keratosis, comprising administering a topical composition to the skin of a patient, the topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) a vehicle comprising at least one chelating agent; The topical composition is applied to the patient's affected area for a period ranging from 15 minutes to 10 hours, and the affected area is then illuminated with a light source.

[0077] In a preferred embodiment, the method includes a vehicle that optionally includes an antifoaming agent. In another preferred embodiment, the method of treatment is photodynamic therapy. In another preferred embodiment, the compound of formula I is in a dry solid form.

[0078] In yet another embodiment, the present invention is also directed to a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering a topical composition to the skin of a patient, the topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0079] In one embodiment, the method of photodynamic therapy in the treatment of actinic keratosis comprises application of a topical composition for a period of, for example, 15 minutes, 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours.

[0080] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0081] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0082] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0083] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0084] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0085] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The topical composition is applied to the affected area for a period ranging from 15 minutes to 10 hours, and then the affected area is illuminated with a light source.

[0086] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) propylene glycol, (ii) 2-(2-ethoxyethoxy)ethanol, (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0087] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) propylene glycol, (ii) 2-(2-ethoxyethoxy)ethanol, (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0088] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) propylene glycol in an amount ranging from about 10% w / w to about 50% w / w; (ii) 2-(2-ethoxyethoxy)ethanol in an amount ranging from about 2% w / w to about 50% w / w; (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0089] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) propylene glycol in an amount ranging from about 10% w / w to about 50% w / w; (ii) 2-(2-ethoxyethoxy)ethanol in an amount ranging from about 2% w / w to about 50% w / w; (iii) edetate disodium, (iv) an optional antifoaming agent; and

[0090] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a 5-carbon aminoketone compound of formula I, or a pharma- ceutically acceptable salt thereof; [ka] b) propylene glycol; c) 2-(2-ethoxyethoxy)ethanol, d) edetate disodium.

[0091] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a 5-carbon aminoketone compound of formula I in an amount of 1 to 30% w / w; [ka] or a pharma- ceutically acceptable salt thereof; b) propylene glycol in an amount ranging from about 10% w / w to about 50% w / w; c) 2-(2-ethoxyethoxy)ethanol in an amount of about 2% w / w to about 50% w / w; d) edetate disodium.

[0092] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a 5-carbon aminoketone compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof; b) ethanol; c) Laureth-4, d) polyethylene glycol; and e) isopropyl alcohol; f) propylene glycol; g) 2-(2-ethoxyethoxy)ethanol, h) edetate disodium; and i) cyclomethicone, j) purified water.

[0093] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) ethanol; (ii) laureth-4, (iii) polyethylene glycol, (iv) isopropyl alcohol; (v) propylene glycol; (vi) 2-(2-ethoxyethoxy)ethanol, (vii) edetate disodium, (viii) cyclomethicone, (ix) purified water, and a vehicle comprising the same.

[0094] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof; b) ethanol; c) Laureth-4, d) polyethylene glycol; and e) isopropyl alcohol; f) propylene glycol; g) 2-(2-ethoxyethoxy)ethanol, h) edetate disodium; and i) cyclomethicone, j) purified water.

[0095] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) ethanol; (ii) laureth-4, (iii) polyethylene glycol, (iv) isopropyl alcohol; (v) propylene glycol; (vi) 2-(2-ethoxyethoxy)ethanol, (vii) edetate disodium, (viii) cyclomethicone, (ix) purified water, and a vehicle comprising the same.

[0096] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a 5-carbon aminoketone compound of formula I, or a pharma- ceutically acceptable salt thereof, in an amount of 20% w / w of the composition; [ka] b) ethanol in an amount of 10-15% w / w of the composition; c) Laureth-4 in an amount of 5-10% w / w of the composition; d) polyethylene glycol in an amount of 1-5% w / w of the composition; e) isopropyl alcohol in an amount of 2-4% w / w of the composition; f) propylene glycol in an amount of 20-40% w / w of the composition; g) 2-(2-ethoxyethoxy)ethanol in an amount of 2-4% w / w of the composition; h) disodium edetate in an amount of 0.1-0.25% w / w of the composition; i) cyclomethicone in an amount of 0.2-0.5% w / w of the composition; j) purified water.

[0097] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA or a pharma- ceutically acceptable salt thereof in an amount of 20% w / w of the composition; b) ethanol in an amount of 10-15% w / w of the composition; c) Laureth-4 in an amount of 5-10% w / w of the composition; d) polyethylene glycol in an amount of 1-5% w / w of the composition; e) isopropyl alcohol in an amount of 2-4% w / w of the composition; f) propylene glycol in an amount of 20-40% w / w of the composition; g) 2-(2-ethoxyethoxy)ethanol in an amount of 2-4% w / w of the composition; h) disodium edetate in an amount of 0.1-0.25% w / w of the composition; i) cyclomethicone in an amount of 0.2-0.5% w / w of the composition; j) purified water.

[0098] In yet another embodiment, the present invention provides a method for the treatment of actinic keratosis with photodynamic therapy, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) ethanol in an amount of 10-15% w / w of the composition; (ii) laureth-4 in an amount of 5-10% w / w of the composition; (iii) polyethylene glycol in an amount of 1-5% w / w of the composition; (iv) isopropyl alcohol in an amount of 2-4% w / w of the composition; and (v) propylene glycol in an amount of 20-40% w / w of the composition; (vi) 2-(2-ethoxyethoxy)ethanol in an amount of 2-4% w / w of the composition; (vii) edetate disodium in an amount of 0.1 to 0.25% w / w of the composition; and (viii) cyclomethicone in an amount of 0.2 to 0.5% w / w of the composition; and (ix) purified water, and a vehicle comprising the same.

[0099] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30% compared to application of a composition lacking the penetration enhancer and chelating agent.

[0100] Preferably, the penetration of the 5-carbon aminoketone in the patient's skin during photodynamic therapy is increased by at least about 30% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the penetration of the 5-carbon aminoketone in the patient's skin during photodynamic therapy is increased by at least about 40% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the penetration of the 5-carbon aminoketone in the patient's skin during photodynamic therapy is increased by at least about 50% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the penetration of the 5-carbon aminoketone in the patient's skin during photodynamic therapy is increased by at least about 60% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the penetration of the 5-carbon aminoketone in the patient's skin during photodynamic therapy is increased by at least about 70% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the penetration of the 5-carbon aminoketone in the patient's skin during photodynamic therapy is increased by at least about 80% compared to a composition lacking a penetration enhancer and a chelator.

[0101] Preferably, penetration of the 5-carbon aminoketone through a patient's skin during photodynamic therapy is increased by at least about 90% as compared to a composition lacking the penetration enhancer and chelator.

[0102] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30% compared to application of a composition lacking the penetration enhancer and chelating agent.

[0103] Preferably, the method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0104] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30% compared to application of a composition lacking the penetration enhancer and chelating agent.

[0105] Preferably, the method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0106] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30% compared to application of a composition lacking the penetration enhancer and chelating agent.

[0107] Preferably, the method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0108] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30% compared to application of a composition lacking the penetration enhancer and chelating agent.

[0109] Preferably, the method increases penetration of the 5-carbon aminoketone through the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0110] In one embodiment, the method increases the penetration of 5-aminolevulinic acid in a patient's skin by at least about 30% during photodynamic therapy of actinic keratosis, the method comprising applying to an affected area of ​​the patient's skin a pharmaceutical composition comprising 5-aminolevulinic acid, wherein the 5-aminolevulinic acid is present in an amount of about 20% w / w of the pharmaceutical composition.

[0111] In one embodiment, the method increases the penetration of 5-aminolevulinic acid in a patient's skin by at least about 30% during photodynamic therapy of actinic keratosis, the method comprising applying to an affected area of ​​the patient's skin a pharmaceutical composition comprising 5-aminolevulinic acid, wherein the 5-aminolevulinic acid is present in an amount of about 10% w / w of the pharmaceutical composition.

[0112] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer; (ii) at least one chelating agent; (iii) an optional antifoaming agent; and The method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30% compared to application of a composition lacking a penetration enhancer and a chelating agent.

[0113] Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least about 30% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least about 40% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least 50% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least 60% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least 70% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least 80% compared to a composition lacking a penetration enhancer and a chelator. Preferably, the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin during photodynamic therapy is increased by at least 90% compared to a composition lacking a penetration enhancer and a chelator.

[0114] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30% compared to application of a composition lacking a penetration enhancer and a chelating agent.

[0115] Preferably, the method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0116] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of glycol derivatives, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30% compared to application of a composition lacking a penetration enhancer and a chelating agent.

[0117] Preferably, the method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0118] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) a five-carbon aminoketone compound of formula I in dry solid form; [ka] or a pharma- ceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30% compared to application of a composition lacking a penetration enhancer and a chelating agent.

[0119] Preferably, the method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking the penetration enhancer and chelator.

[0120] In yet another embodiment, the present invention provides a method for photodynamic therapy in the treatment of actinic keratosis, comprising administering to the skin of a patient a topical composition comprising: a) 5-ALA, or a pharma- ceutically acceptable salt thereof, in a dry solid form; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) ethylenediaminetetraacetic acid (EDTA) or a pharma- ceutically acceptable salt thereof; (iii) an optional antifoaming agent; and The method increases the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30% compared to application of a composition lacking a penetration enhancer and a chelating agent.

[0121] Preferably, the methods of the present invention increase the conversion of the 5-carbon aminoketone compound to protoporphyrin IX production in the patient's skin by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a composition lacking a penetration enhancer and a chelating agent.

[0122] In one embodiment, the method increases the conversion of 5-aminolevulinic acid to protoporphyrin IX production in the patient's skin by at least about 30% during photodynamic therapy of actinic keratosis, the method comprising applying to an affected area of ​​the patient's skin a pharmaceutical composition comprising 5-aminolevulinic acid, wherein the 5-aminolevulinic acid is present in an amount of about 20% w / w of the pharmaceutical composition.

[0123] In one embodiment, the method increases the conversion of 5-aminolevulinic acid to protoporphyrin IX production in the patient's skin by at least about 30% during photodynamic therapy of actinic keratosis, the method comprising applying to an affected area of ​​the patient's skin a pharmaceutical composition comprising 5-aminolevulinic acid, wherein the 5-aminolevulinic acid is present in an amount of 10% w / w of the pharmaceutical composition.

[0124] The amount of 5-aminolevulinic acid permeation and the amount of 5-aminolevulinic acid converted to PpIX were determined in the in-vitro skin model shown in Figure 1 for formulations containing penetration enhancers and chelators. Formulations 6, 7, 8, 10, 17, and RLD were tested using female abdominal skin in an in-vitro skin model for 5-ALA permeation by determining the amount of PpIX in the receptor fluid and in the skin. For drugs that penetrate the skin in vitro, the amount available to the subcutaneous or deep skin tissue and to the systemic blood circulation is determined. ALA is a natural amino acid that is ultimately converted to PpIX in the skin. As shown in FIG. 2, it was observed that formulation 17, containing propylene glycol ("PG") in an amount of 30% w / w with 4% Transcutol® and EDTA in an amount of 0.2% w / w, showed the greatest permeation with the highest amount of PpIX present in the receptor phase at 20 and 24 hours, followed by formulation 10, containing propylene glycol in an amount of 40% w / w and EDTA in an amount of 0.25% w / w, and formulation 8, containing propylene glycol in an amount of 30% w / w and EDTA in an amount of 0.2% w / w. The formulations containing PG and EDTA showed significantly higher permeation compared to the RLD. The addition of 0.25% EDTA showed 2.5-2.9 times more PpIX in the receptor fluid compared to the RLD.

[0125] In one embodiment, affected areas include the upper extremities (e.g., the hand, upper arm, or dorsal surface of the forearm), the scalp or facial area, and other areas of the patient (e.g., the legs, parts of the arms other than the forearms).

[0126] The method includes applying the topical composition of the present invention to the affected area, incubating with or without a mask, and then irradiating the affected area with a light source.Preferably, the method includes covering the affected area with a mask after applying the topical composition, and then irradiating the affected area with a light source.The mask can be a light-tight occlusive dressing or a moisture-resistant occlusive dressing.Preferably, the mask is a low-density polyethylene barrier or a transparent film dressing.

[0127] In one embodiment, a method for enhancing the penetration of a topical composition of 5-aminolevulinic acid (ALA) into tissue for photodynamic therapy is further provided. The method comprises topically applying ALA to a treatment area to be treated with photodynamic therapy. The method further comprises covering the treatment area with a polymeric barrier having a degree of occlusion of 65% or more after ALA is applied to the treatment area.

[0128] The method preferably includes covering the treatment area with a low-density polyethylene barrier after ALA is applied to the treatment area. The treatment area is covered with a low-density polyethylene barrier before phototherapy to minimize transdermal water loss from the treatment area. For techniques, methods, compositions, and devices related to PDT and PD, see U.S. Patent No. 10,357,567, which is incorporated by reference in its entirety.

[0129] In one embodiment, light sources used in photodynamic therapy include lasers, argon-pumped dye lasers or metal vapor lasers, and frequency-doubled Nd:YAG lasers. Non-laser sources include tungsten filaments, xenon arcs, metal halides, and fluorescent lamps, halogen bulbs, LED light delivery, and direct sunlight.

[0130] For effective treatment, it is desirable to have a uniform output in intensity and color. Typically, lighting devices such as those disclosed in U.S. Patent Nos. 8,758,418, 8,216,289, 8,030,836, 7,723,910, 7,190,109, 6,709,446, and 6,223,071, which are incorporated by reference in their entirety for PDT and PD related techniques, methods, compositions, and devices, and in International Patent Application Publication No. WO 2017 / 066270, are used to provide suitable uniform light for treatment purposes. These devices generally include a light source (e.g., a fluorescent lamp, an LED, or an LED array), connection elements that direct, filter, or otherwise transmit the irradiated light so that it reaches its intended target in a usable form, and a control system that starts and stops the generation of light as needed. The light source preferably includes a plurality of LEDs, for example in an array.

[0131] In at least one embodiment, when ALA is used to treat actinic keratosis, the LED preferably emits blue light having a wavelength of 400 nanometers (nm) or greater, such as about 430 nm, about 420 nm, or about 417 nm. However, the LED may also emit visible light in other ranges of the spectrum, such as the green and / or red range of 400-700 nm, such as about 625 nm-640 nm, or about 635 nm. For example, the LED may also emit light having a wavelength of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. Furthermore, the LED may be configured to emit light continuously, or the LED may be configured to blink the diode based on a predetermined interval. Furthermore, the LED may be configured such that only one wavelength of light (e.g., blue) is emitted. Alternatively, the LED may be configured such that two or more wavelengths of light are emitted from the array. For example, the LED may be configured to emit blue and red light alternately for therapeutic purposes. In one embodiment, the LED array may also emit red light having a wavelength of 570-670 nm.

[0132] In one embodiment of the present disclosure, blue light having a wavelength of about 417 nm is applied at 10 mW / cm 2 The intensity was 10 J / cm for 1000 seconds. 2 However, the intensity is less than 20 J / cm 2 The intensity may also be increased (e.g., doubled) to provide a shorter treatment time. For example, the intensity may be increased to shorten the treatment time by about half. Blue light is preferably applied for a period ranging from 5 to 15 minutes. In other embodiments, red light (e.g., at 635 nm, such as red light generated by a light emitting diode (LED)) may be used. Red light may provide a shorter treatment time, such as 10 to 75 J / cm, for example, within 10 minutes. 2 (For example, 37 J / cm 2 ) dose can be provided.

[0133] In another embodiment, 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 prescribed period of time, and then illuminates the lesion with red light of uniform intensity for a second prescribed period of time. For example, in some embodiments, the illuminator illuminates the lesion with blue light of uniform intensity (e.g., 417 nm) at a low intensity (e.g., about 0.1 J / cm2). 2 ~About 2J / cm 2 ) to photobleach the protoporphyrin IX (PpIX) present on the surface of the patient's skin, and then irradiate the lesion with red light (e.g., 635 nm) of uniform intensity at high intensity (e.g., approximately 30 J / cm 2 ~About 150J / cm 2 ) to irradiate the lesion and activate PpIX present in the deeper layers of the patient's skin, thereby avoiding possible damage to the upper layers of the patient's skin.

[0134] In addition, the total light dose (J / cm 2 ) is the irradiance (W / cm 2A further parameter that is controlled for delivery of the correct therapeutic light dose is the exposure time, since it is equal to the power delivered to the LED array multiplied by the time in seconds. This can be achieved by a timer, which allows for proper control of the power delivered to the LED array and can be set by the physician. Data are based on 10 mW / cm 2 or about 9.3 to about 10.7 mW / cm 2 10 J / cm delivered from a source with an irradiation density of 2 has been shown to produce clinically acceptable outcomes for the desired treatment areas (e.g., face, scalp, extremities). The adjustable illuminator delivers 20 mW / cm for an exposure time of 500 seconds (8 minutes, 20 seconds). 2 Delivering a radiation density of 10 J / cm2, a clinically acceptable 2 In certain embodiments, lower intensities can be used with longer exposure times (e.g., 10 J / cm 2 For a light dose of 10 J / cm2 for an exposure time of 1,000 seconds, the illuminator may be used. Alternatively, the illuminator may be used with a light dose of 10 J / cm2 for the exposure time. 2 yielding a light dose of 30mW / cm 2 etc. The selected light dose may also be administered by additionally or alternatively varying the irradiance density over the treatment time.

[0135] The light may be applied for a second treatment period, for example, about 8-15 minutes, following the first treatment period. In at least one embodiment, a heat source may be used and may be an infrared quartz stove. In at least one embodiment, the heat source may comprise a resistive tape heater or multiple heaters attached to a frame, including at least one selected from the group including an IR LED, a resistive cartridge heater, a positive temperature coefficient heater, or an IR quartz stove, as described above. Heat may be intentionally generated and directed toward the area to be treated, as opposed to ambient heat in the clinical environment or by-product heat from one or more operating mechanisms of the lighting device.

[0136] The method further includes heating the area where the lesion is located prior to or during irradiation of the area. 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.

[0137] According to one embodiment, the treatment method includes heating the illumination device to radiate heat from the illumination device and exposing the treatment area to the illumination device. The heat accelerates the conversion of ALA to porphyrins (e.g., photosensitive porphyrins or protoporphyrins). The relationship between exposure temperature 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 of the tissue by about 2°C can, for example, approximately double the rate of production of protoporphyrin IX (PpIX). Heat may be applied before or during irradiation with the illumination device.

[0138] For example, ALA can be applied first. Then, the heating element can be activated to apply heat to the patient's skin for a first treatment period for a heat soak, which can be, for example, 20-30 minutes. During heating, the treatment area can be shielded or unshielded. In other words, the treatment area can be heated while being shielded.

[0139] The light may be applied for a second treatment period, for example, about 8-15 minutes, following the first treatment period. In at least one embodiment, the heat source may be an infrared quartz stove. In at least one embodiment, the heat source may comprise a resistive tape heater or multiple heaters attached to a frame, including at least one selected from the group including an IR LED, a resistive cartridge heater, a positive temperature coefficient heater, or an IR quartz stove, as described above. Heat may be intentionally generated and directed toward the area to be treated, as opposed to ambient heat in the clinical environment or by-product heat from one or more operating mechanisms of the lighting device.

[0140] In some embodiments, the lighting device may be equipped with a fan or other air distributor that provides a gentle flow of air (e.g., a laminar or other generally uniform flow) that is tangential to the skin surface, which may reduce the sensation of pain.

[0141] The topical composition is prepared by mixing 5-aminolevulinic acid with a vehicle to form a composition ready to be applied to the patient's skin for photodynamic therapy in the treatment of skin diseases including, for example, actinic keratosis, disseminated superficial actinic keratosis (DSAP), or refractory disseminated actinic keratosis, acne (e.g., cystic acne, inflammatory acne, non-inflammatory acne). Skin diseases are not limited to the aforementioned. Skin diseases also include skin abnormalities such as contact dermatitis, rash, housewife's eczema, atopic dermatitis, seborrheic dermatitis, lichen Vidal, prurigo, warts, drug eruptions, photodamaged skin, actinic dermatitis, skin pruritus, psoriasis, acne vulgaris, erythema, as well as cell proliferation disorders including cancer (e.g., non-melanoma cancers including keratinocyte carcinoma or other malignant skin cancers). Skin diseases include, for example, basal cell carcinoma (including invasive basal cell carcinoma, nodular basal cell carcinoma, recurrent nodular basal cell carcinoma, and multifocal basal cell carcinoma), squamous cell carcinoma, Bowen's disease, actinic keratosis, and subcutaneous carcinoma.

[0142] An example of a method for treating precancerous lesions, such as actinic keratosis, by photodynamic therapy with ALA is described herein. Essentially anhydrous ALA is mixed with a vehicle immediately prior to its use. Anhydrous ALA can be, for example, the hydrochloride salt of aminolevulinic acid (ALA), an endogenous 5-carbon aminoketone. In at least one embodiment, ALA is contained in a first ampoule in powder form. A second ampoule contains a vehicle solution. The first and second ampoules are contained in a plastic applicator. The first and second ampoules can be crushed, for example, by finger pressure or by the inside of a device configured to apply pressure to the ampoules. When the ampoules are crushed, the ALA previously contained in the first ampoule comes into contact with the solution previously contained in the second ampoule and dissolves in the vehicle solution. The applicator with these ampoules can be shaken to disperse and dissolve the powdered ALA in the vehicle solution. Once combined, the resulting solution is applied to a patient within 2 hours of preparation.

[0143] In some embodiments, ALA may be provided in a composition such as a ready-to-use solution or reconstituted powder for solution, gel, cream, or lotion formulation. In another embodiment, the composition comprises 5-aminolevulinic acid hydrochloride in an amount of about 10% to about 70% w / w based on the total weight of the composition, preferably about 20% to about 50% w / w based on the total weight of the composition. In one embodiment, ALA may be applied to the topical composition at a concentration of 20%. The ALA mixture is applied topically to the lesion using a point applicator that, in at least one embodiment, controls the dispersion of the ALA mixture so as to achieve substantially uniform wetting of the ALA at the lesion surface by contacting the ALA with the lesion surface. As used herein, the term "substantially" or "substantially" may refer to any value within a range defined by up to ±15% variation from the mean value. However, in other embodiments, ALA may be applied with a finger (i.e., by first placing ALA on the fingertips of a gloved physician and then applying ALA to the area to be treated) or with an implement such as a spatula. Preferably, the treatment method for actinic keratosis of the upper extremities further comprises covering the lesion with a mask after application of the topical composition and before irradiation with a light source. The mask can be a light-resistant occlusive dressing or a moisture-resistant occlusive dressing. The mask is preferably a low-density polyethylene barrier or a transparent film dressing. The mask can be held in place using an elastic net dressing.

[0144] In certain applications, materials other than low density polyethylene may be used as long as they provide at least 65% shielding. In certain applications, certain materials may be used as long as they provide at least 75% shielding. EXAMPLES

[0145] The following examples more particularly illustrate the compositions and methods according to various embodiments described herein and should not be construed as limiting the scope of the present technology in any way.

[0146] Example 1 - Preparation of a Topical Composition The following table provides compositions of representative formulations 1-19 according to embodiments of the present invention. [Table 1]

[0147] Preparation method- The composition contains ALA and is prepared by mixing ALA with a vehicle. First, the vehicle is prepared by mixing each component in the following order: A chelating agent, such as edetate disodium or edetate calcium disodium, is added to purified water and mixed well. Then, ethyl alcohol is added, then propylene glycol is added, then polyethylene glycol 400 is added, then isopropyl alcohol is added, then Transcutol® is added, then laureth-4 is added. After each component is added, the vehicle is mixed. Finally, cyclomethicone is added to obtain the final mixture. For compositions without a chelating agent, the vehicle is prepared by mixing each component in any order.

[0148] Example 2-5-Determination of ALA penetration- Formulations 6, 7, 8, 10, 17, and RLD were tested using a custom in-vitro skin permeation test model (IVPT) 10 shown in Figure 1, which is designed to determine the amount of PpIX in the receptor fluid, the amount accumulated in the skin, and the amount remaining on the skin surface.

[0149] As shown in Figure 1, the IVPT setup used in this study consists of a static Franz cell (2.5 ml) with a donor compartment 12, a membrane 14, and a receptor compartment 16. Human full thickness skin was used in these studies. Skin temperature was maintained at 40 ± 1°C by immersion in a temperature-controlled water bath (44°C) and a stir plate (such as the magnetic stirrer 18 shown in Figure 1) was used to ensure homogeneity of the receptor fluid of 30 mM CPC in phosphate buffered saline (PBS). 5-ALA and placebo formulations were supplied separately and mixed immediately prior to dose application. A dose of 30 mg ± 10% was applied manually per cell and 0.5 ml of receptor fluid was sampled at t0 prior to application to ensure the absence of cellular contamination, followed by two subsequent samples, once after 20 hours (t20) and once after 24 hours (t24). This time point was chosen to maximize the detection of PpIX in the receptor fluid and to examine the effect of blue light irradiation (20 mW, applied for 16.25 min at 20 h) on the conversion of PpIX. At the end of the study, the skin surface of each cell was washed three times with a liquid wash (20% aqueous methanol) and one with a dry wipe. The remaining skin layer was then cut into small pieces and PpIX was extracted using a strong solvent such as dimethyl sulfoxide (DMSO).

[0150] All collected samples were quantified in duplicate for PpIX using fluorescent endpoint detection in a Synergy HTX microplate reader.

[0151] As shown in Figure 2, it was observed that formulation 17 (containing 30% PG, 4% TC, and 0.2% EDTA) showed the highest permeation with the highest amount of PpIX present in the receptor phase at 20 and 24 hours, followed by formulation 10 (containing 40% PG and 0.25% EDTA) and formulation 8 (containing 30% PG and 0.2% EDTA), which in turn was followed by formulation 7 (containing 20% ​​PG and 0.25% EDTA). Formulations containing PG and EDTA showed significantly higher permeation compared to the RLD. The addition of 0.25% EDTA showed 2.5-2.9 times more PpIX in the receptor fluid compared to the RLD.

[0152] Skin PpIX retention was also significantly higher for formulation 17 (4.76 ng / cm), as seen in Figure 3. 2 ) and formulation 10 (3.93 ng / cm 2 ) showed the highest retention value.

[0153] Effect of changing chelating agent Formulation 5 (20% PG + 0.1% EDTA) and formulation 14 (20% PG + 0.1% edetate calcium disodium) were tested for the amount of PpIX in the receptor fluid and in the skin. As shown in Figure 4, no significant differences were found between the formulations.

[0154] Example 3 - Effect of temperature on PpIX formation In this study, formulation 5 (20% PG + 0.1% EDTA) was used to evaluate the effect of skin and cell environmental temperature on PpIX content. The study was repeated at two different temperatures using the same skin donor. The skin temperature in the first study was 32°C and in the second study it was 40°C. All other test conditions, except for temperature, were consistent with the previously described IVPT method. The results of the study can be seen in Figure 5. At 32°C, there is no significant difference between the sample skin after application and the blank skin in terms of PpIX formation. At 40°C, there is a significant difference between the sample skin after application and the blank skin in terms of PpIX formation. In terms of PpIX formation, there is also a significant difference between 32°C and 40°C after application of formulation 4. Considering the above, it is believed that temperature may have a significant effect on the formation of PpIX.

[0155] Additional advantages and modifications will readily occur to those skilled in the art. Thus, the present invention in its broader aspects is not limited to the specific details and representative compositions 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.

[0156] Example 4: In vitro skin penetration test (IVPT) study of PpIX 1. Preparation of Phosphate Buffer Solution (PBS) Ten PBS tablets were placed in a one liter volumetric flask and 800 mL of deionized water was added. The tablets were dissolved in the water with a PTFE coated magnetic stir bar. The stir bar was then removed and the volume was made up to one liter with deionized water.

[0157] 2. Preparation of PBS-CPC (cetylpyridinium chloride) To prepare a 30 mM PBS-CPC solution, approximately 5.37 g of CPC (Sigma-Aldrich) was weighed and transferred to a 500 mL volumetric flask. PBS was added and sonicated for 20 minutes (approximately) to dissolve the CPC and bring to the final volume.

[0158] 3. Preparation of 20% (w / v) 5-aminolevulinic acid (5-ALA) formulation Approximately 70 mg of 5-ALA was weighed into a microcentrifuge tube. 350 μL of placebo formulation was added and the tube was vortexed for 30 seconds to allow the drug to dissolve in the placebo formulation.

[0159] 4. Preparation of 20% Methanol Solution To a reagent bottle was added 100 mL of methanol and 400 mL of deionized water. The solution was mixed using a PTFE-coated magnetic stir bar.

[0160] 5. Penetration Test Permeation studies were performed using human full thickness epidermis (female abdominal). Permeation studies of 5-ALA formulations were performed using vertical static Franz diffusion cells. The average cell surface area was 0.6 cm. 2 and the receptor compartment was filled with 2.25 mL of PBS-CPC (30 mM). The skin was cut using a cork borer and gently rinsed in deionized water to remove excess tissue debris. A piece of filter paper was placed under the skin (dermal side) and between the donor and receptor sides. The two compartments were held tightly together using a metal screw clamp. Franz cell set-up, skin integrity testing, and dose application were performed as follows: - Skin integrity was checked using PBS in both compartments of the cell and using a transcutaneous electrical resistance (TEER) reader. - Cells with skin TEER values ​​<20KΩ were excluded.

[0161] The PBS was removed from both compartments, the receptor compartment was filled with 2.25 mL of PBS-CPC, and the donor compartment was dried with tissue paper. The cell was placed in a water bath, which was set at a temperature of 43.5–45 °C to maintain a skin surface temperature of 40 ± 1 °C. A stirring speed of 350 rpm was used. Skin temperature was monitored periodically using a blank skin. Once the skin temperature reached the target temperature, 30 mg of freshly prepared 20% 5-ALA formulation was applied to the epidermal side of the skin. At 0, 20, and 24 h, a 500 pL sample was taken from the receptor compartment. Each time, this was replaced with the same volume of fresh temperature-equilibrated PBS. The total duration of the penetration study was 24 h. At the 20 h time point, blue light (20 mW) was applied to the cell for 16 min 25 s after sample withdrawal. The number of replicates (n) per formulation was 4–5. Blank cells were used as a control to determine any possible interference. All permeation samples were analyzed using a Synergy HTX microplate reader. 200 μL permeation samples were placed in duplicate in a 96-well plate and analyzed.

[0162] 6. Cleansing and Skin Extraction After 24 hours, the process was carried out as follows: The skin surface was washed three times with 20% methanol solution, then the surface was gently wiped with a cotton swab. Samples were placed in scintillation vials and vortexed for 3 seconds. After washing, the skin was cut into small pieces and placed in an Eppendorf tube containing 1 mL of DMSO. The tube was sonicated for 20 min and subsequently centrifuged at 15000 rpm and 21°C for 10 min. The supernatant solution was analyzed.

[0163] 100 μL of lavage and skin samples were placed in duplicate in a 96-well plate along with 100 μL of blank PBS-CPC (30 mM) and analyzed using a Synergy HTX microplate reader.

[0164] 7. Effect of EDTA concentration at 0.1%, 0.15%, and 0.2% on PpIX The effect of EDTA concentrations of 0.1%, 0.15%, and 0.2% on PpIX production from three different formulation end products was prepared and compared in three different donors. 20 and t 24 An overview of the amounts of PpIX quantified at the time points is shown in Figure 6.

[0165] In addition, FIG. 7 shows the amount of PpIX produced in the skin compartments from the three donors tested, with the data presented in terms of content quantified within the skin compartments from donors 1, 2, and 3.

[0166] Based on the experimental findings, the analysis showed no statistical differences among the three levels of EDTA concentration, supporting that the use of lower EDTA concentrations (<0.2%) may result in comparable PpIX levels compared to 0.2% EDTA.

[0167] Example 5: The effect of varying ingredients in the formulation Tests were conducted to determine the synergistic effects between the components of the composition of the present disclosure.The components of the formulation, namely Transcutol®, propylene glycol (PG) and EDTA, were investigated using five different formulation strategies.The details of the formulation are provided herein in Tables 2a and 2b below. [Table 2] [Table 3]

[0168] Formulation synergy testing was performed on three donors. PpIX levels were quantified in the receptor fluid (after permeation) and in the skin. Comparing the results of formulations D, E, and X, showed synergy between EDTA and PG. Compared to formulation X, which contains only EDTA, PpIX levels in both the receptor compartment (after permeation) and in the skin were significantly higher than formulation D (Figure 8).

[0169] In a second experiment, the synergistic effect between Transcutol®, PG, and EDTA was investigated (Figure 9). The PpIX levels quantified after application of formulation B containing Transcutol®, PG, and EDTA were significantly higher than formulation Y containing only Transcutol®. Comparison of PpIX levels from formulations B and D did not show superiority of formulation B. PG and EDTA may be the main drivers of enhanced PpIX levels, while Transcutol® may delay the release of ALA due to increased retention at the skin surface.

[0170] Although the figures and description may illustrate each step of the method in a particular order, the order of such steps may differ from that shown and described unless otherwise specified above. Also, two or more steps may be performed simultaneously or with partial contemporaneity, unless otherwise specified above.

Claims

1. 1. A topical composition for treating a skin condition, comprising: a) a five-carbon aminoketone compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof; b) a vehicle, The vehicle is (i) at least one penetration enhancer selected from the group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, azone, polysorbates, macrogolglycerides, polyethylene glycol derivatives, and ethoxylated ether derivatives; (ii) at least one chelating agent; and a vehicle comprising: A topical composition, wherein the topical composition is applied for a period of from about 15 minutes to about 10 hours.

2. The topical composition of claim 1, A topical composition, wherein the topical composition increases the conversion of a 5-carbon aminoketone compound to protoporphyrin IX in a patient's skin by at least about 30% compared to administration of a composition lacking a penetration enhancer and a chelating agent.

3. 3. The topical composition of claim 1 or claim 2, wherein the vehicle further comprises an anti-foaming agent.

4. 3. The topical composition of claim 1 or claim 2, wherein the composition is utilized in photodynamic therapy.

5. 3. The topical composition of claim 1 or claim 2, wherein the affected area is irradiated with a light source after application of the composition.

6. 3. The topical composition of claim 1 or claim 2, wherein the compound of formula (I) is in a dry solid form.

7. The topical composition of claim 5, wherein the light source delivers blue light that may be 10-20 J / cm 2 .

8. The topical composition of claim 5, wherein the light source delivers red light that may be from 10 to 75 J / cm 2 .

9. 6. The topical composition of claim 5, wherein the light source delivers sunlight.

10. 3. The topical composition of claim 1 or claim 2, wherein the compound of formula (I) is aminolevulinic acid hydrochloride.

11. (i) the at least one penetration enhancer is selected from the group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; (ii) The topical composition of claim 1 or claim 2, wherein the at least one chelating agent is selected from ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

12. 3. The topical composition of claim 1 or claim 2, wherein the skin disorder is actinic keratosis.

13. The topical composition of claim 1 or claim 2, The topical composition a) a 5-carbon aminoketone compound of formula (I) or a pharmaceutically acceptable salt thereof; 【Chemistry 2】 b) propylene glycol; and c) 2-(2-ethoxyethoxy)ethanol, d) edetate disodium.

14. wherein the compound of formula (I) is present in an amount of about 1% w / w to about 30% w / w of the composition; The compound of formula (I) may be present in an amount of about 20% w / w of the composition; The propylene glycol may be present in an amount of about 10% w / w to about 50% w / w of the composition; The 2-(2-ethoxyethoxy)ethanol may be present in an amount of about 2% w / w to about 50% w / w of the composition; and The edetate disodium may be present in an amount of about 0.1% to 0.25% w / w of the composition.

14. The topical composition of claim 13.

15. 14. The topical composition of claim 13, wherein the composition further comprises an anti-foaming agent, which may be cyclomethicone.

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