Kynurenine and its derivatives for treating atrophic scars - Patents.com

Abstract

Disclosed are compositions comprising kynurenine and its derivatives. The compositions are used to reduce the appearance of and treat atrophic acne scars, as are methods thereof. These methods and compositions are contemplated for cosmetic use to reduce the appearance of acne scars. The use of these compounds to reduce the appearance of atrophic scars, or for potential therapeutic use to reduce, reverse, or treat atrophic scars, is also contemplated.

Description

[Technical field]

[0001] The present invention relates to methods for reducing the appearance of acne scars in humans by applying or administering small molecule chemical compounds. Reducing the appearance of acne scars is desirable for aesthetic and cosmetic purposes, and methods and compositions for reducing the appearance of acne scars would be commercially desirable to the cosmetic and pharmaceutical industries, as well as chemical manufacturers. [Background technology]

[0002] The global cosmetics industry is a multi-billion dollar market, with pharmaceutical sales for some skin conditions exceeding $1 billion annually (e.g., psoriasis). A common skin disease is acne vulgaris, commonly referred to as acne, which, according to 1, "affects nearly all adolescents and 12-51% of adults aged 20-49 years." According to Shute, the prevalence of acne in the United States in 2013 was approximately 50 million, with treatment and treatment-related costs equivalent to more than $1 billion (2019). Other estimates put the global prevalence of acne at more than 9% (2), and some studies predict the global market for acne to exceed $7 billion by 2025 (3).

[0003] Acne vulgaris is a non-life-threatening condition that can cause local discomfort and scarring, and can lead to psychological complications (e.g., low self-esteem, distorted body image) and psychiatric complications (e.g., anxiety or depression) (Non-Patent Document 3, Non-Patent Document 2). Acne vulgaris is a multifactorial process generally understood to result from hypersecretion of the sebaceous glands of the skin, resulting in plugging of pilosebaceous follicles on the face (Non-Patent Document 3) or on the face, chest, upper arms and back (Non-Patent Document 4). According to Non-Patent Document 2, patients typically present with comedones (plugged hair follicles), papules (raised lesions) or pustules (pus-filled lesions), and in severe acne cases, may also present with nodules or cysts. The problem with diagnosing and treating acne is that dermatologists disagree on the minimum symptoms required to officially diagnose acne, and more than 25 different systems are currently used to assess the severity of acne (Non-Patent Document 2). Furthermore, "despite the existence of multiple methods to treat acne, there is no consensus regarding the best approach to acne management" (Non-Patent Document 3).

[0004] A common sequela of acne, especially acne vulgaris, is acne scarring (Non-Patent Document 5, Non-Patent Document 1), and many patients have some degree of scarring (Non-Patent Document 4). Various treatments for acne scarring are known with varying degrees of success (Non-Patent Document 5, Non-Patent Document 1). According to Non-Patent Document 5, "Despite advances in the treatment of acne, post-acne scarring remains a common problem."

[0005] Acne scars are divided into two different scar types: hypertrophic scars and atrophic scars (Non-Patent Document 4, Non-Patent Document 1). The most common form of acne scar is the atrophic scar, where there is a net destruction of collagen in the dermis, while hypertrophic or keloid acne scars, where there is a net increase in collagen, are less common (Non-Patent Document 4). Atrophic scars are further subdivided morphologically into boxcar, ice pick or rolling scar types (Non-Patent Document 4, Non-Patent Document 1).

[0006] According to Non-Patent Document 4, boxcar scars account for approximately 20-30% of atrophic scars and are more extensive "circular to oval depressions with clearly demarcated vertical edges," ice pick scars are the most common (60-70%) and are narrow V-shaped epithelial tracts with clearly demarcated edges that extend vertically into the deep dermis or subcutaneous tissue, and rolling scars account for approximately 15-25% of atrophic scars and cause an uneven skin surface that results in surface shadowing and the appearance of uneven skin. Treatments for atrophic scars include removing or damaging parts of the skin, such as skin abrasion, which removes part of the epidermal (outer) layer of the skin, or using lasers to cause localized damage that aims to stimulate dermal fibroblasts to produce new material to replace atrophied collagen and elastin. Other treatment options include microneedling, which induces the deposition of new collagen, subcision, which uses a needle or other instrument to injure the fibrous layer under the dermis and induce the formation of new collagen, and punch excision / elevation, which involves either excising localized areas of atrophic scars and replacing them with grafts or cutting and elevating them to fill depressions in the atrophic scars on the skin's surface, replacing the voids with newly deposited collagen. In some cases, individual atrophic acne scars can also be treated with fillers, where materials are injected into the skin to help fill the atrophic scar sites (Non-Patent Document 4).

[0007] Given the high worldwide prevalence of acne and the common subsequent resultant acne scarring, new compositions and methods for reducing, reversing or treating acne scars or reducing the appearance of acne scars continue to garner commercial and industrial interest for both medical and cosmetic purposes. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Hession et al. (2015) [Non-Patent Document 2] Heng & Chew, 2020 [Non-Patent Document 3] Duru & Orsal, 2021 [Non-Patent Document 4] Connolly et al., 2017 [Non-Patent Document 5] Eitta et al., 2019 Summary of the Invention

[0009] The present invention relates to compositions and methods for reducing or reducing the appearance of atrophic scars in humans by applying or administering small molecule chemical compounds.Acne and acne scars are common problems, with atrophic scars being the most common form of acne scars.Reducing the appearance of atrophic acne scars or treatments that reduce atrophic acne scars is desirable for cosmetic, aesthetic and medical reasons.

[0010] In one embodiment, the invention contemplates a method of reducing the appearance of acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0011] In one embodiment, the invention contemplates a method of treating the appearance of acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0012] In one embodiment, the invention contemplates a method of treating acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0013] In one embodiment, the invention contemplates a method of reversing acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0014] In one embodiment, the invention contemplates a method of preventing acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0015] In one embodiment, the invention contemplates a method of disguising acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0016] In one embodiment, the present invention contemplates a method of treating, reversing, concealing or reducing the appearance of atrophic scars, comprising administering or applying a small molecule compound, the compound being selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid. In one embodiment, the atrophic scars are suspected, likely or confirmed as sequelae of acne. In one embodiment, the atrophic scars are suspected, likely or confirmed as sequelae of acne vulgaris. In one embodiment, the atrophic scar is a sequela of acne vulgaris.

[0017] In one embodiment, the present invention contemplates a compound selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid for use in treating atrophic scars. In one embodiment, the atrophic scar is an atrophic acne scar. In one embodiment, the compound is kynurenic acid for use in treating atrophic scars. In one embodiment, the compound is kynurenic acid for use in treating atrophic acne scars. In one embodiment, kynurenic acid is a component of a composition formulated for topical administration for use in treating atrophic scars or atrophic acne scars. In one embodiment, the compound is kynurenine for use in treating atrophic scars. In one embodiment, the compound is kynurenine for use in treating atrophic acne scars.

[0018] In one embodiment, the compound is a component of a composition formulated for injection and is administered by injection, hi one embodiment, the injection is performed as a subcutaneous, intradermal or intramuscular injection.

[0019] In one embodiment, the compound is a component of a composition formulated for oral delivery, hi one embodiment, the compound is an ingredient in a product intended for oral ingestion.

[0020] In one embodiment, the compound is a component of a composition formulated for topical delivery. In one embodiment, the compound is a component of a composition formulated for topical application. In one embodiment, the compound is a component in a lotion, cream, gel, solution, or suspension intended for topical use. In one embodiment, the compound is 0.05-10% by weight of the lotion, cream, gel, solution, or suspension. In one embodiment, the compound is 0.05-6% by weight of the lotion, cream, gel, solution, or suspension. In one embodiment, the compound is 0.05-3% by weight of the lotion, cream, gel, solution, or suspension. In one embodiment, the compound is 0.1-1% by weight of the lotion, cream, gel, solution, or suspension. In one embodiment, the compound is 0.1-0.5% by weight of the lotion, cream, gel, solution, or suspension. In one embodiment, the compound is 0.25-0.5% by weight of the lotion, cream, gel, solution, or suspension. In one embodiment, the compound is kynurenic acid. In one embodiment, the compound is kynurenine. In one embodiment, kynurenic acid is present at 0.1-1% by weight of the lotion, cream, gel, solution or suspension. In one embodiment, kynurenic acid is present at 0.1-0.5% by weight of the lotion, cream, gel, solution or suspension. In one embodiment, kynurenic acid is present at 0.5% by weight of the lotion, cream, gel, solution or suspension. In one embodiment, kynurenic acid is present at 0.25% by weight of the lotion, cream, gel, solution or suspension. In one embodiment, kynurenic acid is present at 0.1% by weight of the lotion, cream, gel, solution or suspension.

[0021] In some embodiments, application, administration or use of the compound is contemplated as once, twice or three times daily. [Brief description of the drawings]

[0022] [Figure 1A] FIG. 1 is a photographic representation of a target facial skin area of ​​a female subject in her mid-40s with treatment-resistant, stable atrophic scars due to acne prior to application of topical kynurenic acid (0.5% by weight) cream. [Figure 1B] FIG. 1B is a photographic representation of the target facial skin area of ​​the female subject of FIG. 1A after twice-daily use of topical kynurenic acid (0.5% by weight) for 8 weeks. FIG. 1B shows a significant reduction in the appearance of atrophic scars. The dashed black frame in each image highlights the similar target area on the right cheek in both images for comparison. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] I. Definition A number of compounds are provided herein for use in the treatment of atrophic acne scars or for reducing the appearance of atrophic acne scars. In the context of this specification, the term "treatment" may refer to the treatment of existing atrophic acne scars, or alternatively, to treatment that precedes the development or progression of atrophic acne scars to prevent scar development or progression. The compounds described herein may be used alone or may be combined or used in combination with tracer compounds, liposomes, carbohydrate carriers, polymeric carriers, or other agents or additives, as will be apparent to those skilled in the art. In alternative embodiments, such compounds may constitute a drug, in which case such compounds may be present in a pharmacologically effective amount. The compounds may be suitable for administration to a subject in need thereof, in that the subject may benefit from the prevention or treatment of atrophic acne scars. The compounds may include tautomers or stereoisomers.

[0024] As used herein, KA or KynA may be used as an abbreviation for kynurenic acid (CAS number 492-27-3), and XA may be used as an abbreviation for xanthurenic acid (CAS number 59-00-7). L-kynurenine (CAS number 2922-83-0) may be referred to herein as L-Kyn, and D-kynurenine (CAS number 13441-51-5) may be referred to herein as D-Kyn. Unless otherwise indicated, kynurenine includes L-Kyn, D-Kyn, and racemic mixtures thereof (wherein the racemic mixture may be referred to as DL-Kyn or DL-kynurenine, CAS number 343-65-7). The stereochemistry of other amino acids may be similarly indicated as D-, L-, or DL- to refer to racemic mixtures thereof.

[0025] The term "medicament" as used herein refers to a composition that can be administered to a patient or subject and can produce an effect on the patient or subject. The effect can be chemical, biological or physical, and the patient or subject can be a human or a non-human animal, such as a rodent or transgenic mouse, or a dog, cat, cow, sheep, horse, hamster, guinea pig, rabbit or pig. A drug can consist of an active chemical substance alone or in combination with a pharmaceutically acceptable additive.

[0026] The term "pharmaceutical acceptable excipient" may include any physiologically compatible solvents, dispersion media, coatings, antibacterial, antimicrobial or antifungal agents, isotonic and absorption delaying agents, and the like. The excipients may be suitable for intravenous, intraperitoneal, intramuscular, subcutaneous, intrathecal, topical or oral administration. The excipients may include sterile aqueous solutions or dispersions for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such vehicles in the preparation of pharmaceutical preparations is well known in the art.

[0027] The compounds or compositions according to some embodiments can be administered or formulated for administration by any of a variety of known routes. Examples of methods that may be suitable for administering the compounds include oral, intravenous, inhalation, intramuscular, subcutaneous, topical, intraperitoneal, rectal or vaginal suppository, sublingual, and the like. The compounds described herein may be administered as a sterile aqueous solution, or in the form of a lipid-soluble excipient, or another suitable solution, suspension, patch, tablet, or paste. Other methods known in the art for making formulations are described, for example, in "Remington's Pharmaceutical Sciences", (1999). th edition, ed. A. Gennaro, 1995, Mack Publishing Company, Easton, Pa.

[0028] The dosage of the compositions or compounds of some embodiments described herein may vary depending on the route of administration (oral, injection, topical, etc.) and the form in which the composition or compound is administered (solution, controlled release, etc.). Determining the appropriate dosage is within the capabilities of one of ordinary skill in the art. As used herein, an "effective amount", "therapeutically effective amount" or "pharmacologically effective amount" of an agent refers to the amount of agent present at a concentration that results in a therapeutic level of the drug being delivered over the period of use of the drug. This may depend on the mode of delivery, the period of administration, and the age, weight, general health, sex, and diet of the subject receiving the agent. As used herein, an "effective amount" refers to the amount required to produce the desired result. For example, an effective amount of a therapeutic agent is a level that is effective in treating, curing, or alleviating the symptoms of the disease for which the therapeutic agent is administered. Methods for determining effective amounts are known in the art.

[0029] Any terms not directly defined herein shall be understood to have the meaning commonly associated with them as understood in the art of the invention. As used throughout this specification, the following terms shall be understood to have the following meanings unless otherwise indicated:

[0030] II. Biology Scarring is a natural part of the body's repair mechanism, and scarring in the skin can result in atrophic, hypertrophic, or keloid scars (Patel et al., 2014; Sitohang et al., 2021). Hypertrophic and keloid scars result in excessive deposition of collagen (Connolly, 2017), with hypertrophic scars confined to the wound and keloids extending beyond the original wound. In contrast, atrophic scars are characterized by a net loss of collagen and skin depression (Connolly et al., 2017; Nassar et al., 2020; Patel et al., 2014; Sitohang et al., 2021). According to Nassar et al. (2020), "atrophic scars are depressions in the skin resulting from collagen damage during tissue repair, usually after surgery or trauma" (p. 5), and "atrophic scars usually occur during wound healing when collagen production is insufficient" (p. 1). Patel et al. (2014) state that "atrophic scars are histologically defined as scars that show loss of collagen" (p. 2).

[0031] The treatment of atrophic scars resulting from acne remains a challenge for dermatologists, and treatment methods are not standardized (Sitohang et al., 2021). Common treatments involve stimulating the deposition of new collagen through techniques such as controlled injury to the tissue (e.g., microneedling, laser, chemical or mechanical skin abrasion) or the addition of filler materials (Connolly et al., 2017; Hession et al., 2015; Patel et al., 2014).

[0032] Although it is not necessary to understand the mechanism of the invention and is not intended to be bound by any particular theory, the use of kynurenine and other kynurenine pathway metabolites, including kynurenic acid, has been previously described for the treatment of fibroproliferative disorders, namely hypertrophic scars and keloids (US Pat. No. 9,737,523). Fibroproliferative disorders are characterized by excessive accumulation of extracellular matrix, and kynurenine (including kynurenic acid) has been shown to increase expression of MMP-1 and MMP-3 enzymes in dermal fibroblasts (US Pat. No. 9,737,523, Figures 2 and 3, respectively), and downregulate expression of collagen 1 and fibronectin by dermal fibroblasts (US Pat. No. 9,737,523, Figures 10 and 16, respectively). Topical application to skin tissue using a rabbit ear hypertrophic scar model confirmed the results with dermal fibroblasts, showing that kynurenine reduces collagen and increases MMP-1 compared to controls (US Pat. No. 9,737,523, Figure 13). As shown in US Pat. No. 9,737,523, this combination of upregulation of known matrix degrading enzymes (i.e., MMP-1 and MMP-3) with simultaneous downregulation of collagen 1 effectively reverses hypertrophic scars in animal models and hypertrophic keloid scars in the skin of human subjects (BirchBioMed Inc., 2021). However, these data teach away from the use of kynurenines, including kynurenic acid, in the treatment of atrophic scars. Atrophic scars are characterized by a net loss of collagen and other matrix proteins ("atrophy"), whereas, in contrast, hypertrophic or keloid scars display the opposite characteristics with a net increase, typically excess ("hypertrophy"), of collagen and other matrix proteins. As shown in U.S. Pat. No. 9,737,523, upregulation of known matrix degrading enzymes (i.e., MMP-1 and MMP-3) while simultaneously downregulating dermal collagen 1 is predicted to promote net loss of dermal matrix and enhance local atrophy.Briefly, one of skill in the art would reasonably expect that an increase in catabolic enzymes (i.e., MMP-1 and MMP-3) and a decrease in matrix anabolic proteins (collagen 1) would exacerbate atrophic scarring.

[0033] III. Methods of Use and Formulations of the Compounds In one embodiment, the invention contemplates a method of reducing the appearance of acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0034] In one embodiment, the invention contemplates a method of treating the appearance of acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0035] In one embodiment, the invention contemplates a method of treating acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0036] In one embodiment, the invention contemplates a method of reversing acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0037] In one embodiment, the invention contemplates a method of preventing acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0038] In one embodiment, the invention contemplates a method of disguising acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0039] In one embodiment, the invention contemplates a method of preventing acne scars, atrophic acne scars or post-acne atrophic scars comprising administering or applying a small molecule compound, wherein the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

[0040] In one embodiment, the present invention contemplates a method of treating, reversing, concealing or reducing the appearance of atrophic scars, comprising administering or applying a small molecule compound, the compound being selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid. In one embodiment, the atrophic scars are suspected, likely or confirmed as sequelae of acne. In one embodiment, the atrophic scars are suspected, likely or confirmed as sequelae of acne vulgaris. In one embodiment, the atrophic scar is a sequela of acne vulgaris.

[0041] In one embodiment, the present invention contemplates a small molecule compound selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid for the treatment of atrophic scars, atrophic acne scars or post-acne atrophic scars.

[0042] In one embodiment, the present invention contemplates a small molecule compound selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid for reducing the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars.

[0043] In one embodiment, the present invention contemplates a compound selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid for use in treating atrophic scars. In one embodiment, the atrophic scar is an atrophic acne scar. In one embodiment, kynurenic acid for use in treating atrophic scars. In one embodiment, the compound is kynurenic acid for use in treating atrophic acne scars. In one embodiment, kynurenic acid is a component of a composition formulated for topical administration for use in treating atrophic scars or atrophic acne scars. In one embodiment, kynurenic acid is a component of a composition formulated for topical administration for use in concealing atrophic scars or atrophic acne scars. In one embodiment, kynurenic acid is a component of a composition formulated for topical administration used as a cosmetic treatment for atrophic scars or atrophic acne scars. In one embodiment, kynurenic acid is a component of a composition formulated for topical administration used as a cosmetic to reduce the appearance of atrophic scars or atrophic acne scars. In one embodiment, the compound is kynurenine for use in treating atrophic scars. In one embodiment, the compound is kynurenine for use in treating atrophic acne scars.

[0044] In one embodiment, the compound is a component of a composition formulated for injection and is administered by injection, hi one embodiment, the injection is performed as a subcutaneous, intradermal or intramuscular injection.

[0045] In one embodiment, the compound is a component of a composition formulated for oral delivery, hi one embodiment, the compound is an ingredient in a product intended for oral ingestion.

[0046] In one embodiment, the compound is a component of a composition formulated for topical delivery. In one embodiment, the compound is a component of a composition formulated for topical application. In one embodiment, the compound is a component in a lotion, cream, gel, solution or suspension for topical use.

[0047] In some embodiments, application, administration or use of the compound is considered to be 1-5 times per day. In some embodiments, application, administration or use of the compound is considered to be 1, 2 or 3 times per day. In some embodiments, application, administration or use is considered to be topical.

[0048] In one embodiment, the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid and is a component of a composition formulated for topical use or application.

[0049] In one embodiment, the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid and is a component of a composition formulated as a cream, gel, lotion, foam, suspension or ointment.

[0050] In one embodiment, the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid, and kynurenic acid, and is formulated with one or more additional pharmaceutical compositions, wherein said pharmaceutical compositions include a retinoid or retinoid-like compound (e.g., tretinoin, adapalene, tazarotene), an antibiotic (e.g., clindamycin or erythromycin), which may be further combined with benzoyl peroxide, azelaic acid, or salicylic acid.

[0051] In one embodiment, the compound is selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid, and kynurenic acid, and is combined with one or more additional non-prescription drugs, wherein the non-prescription drug is covered by an FDA OTC monograph. Non-limiting examples of such non-prescription agents include salicylic acid, benzoyl peroxide, allantoin, cocoa butter, dimethicone, glycerin, petrolatum, live yeast cell derivative (LYCD), zinc stearate, zinc acetate, zinc carbonate, zinc oxide, mineral oil, resorcinol, balsam of Peru, shark liver oil, and tannic acid.

[0052] In one embodiment, the compound is kynurenic acid and is present at 0.1% to 1% by weight of a composition for topical use or topical application. In one embodiment, the compound is kynurenic acid and is present at 0.25% to 0.5% by weight of a composition for topical use or topical application. In one embodiment, the compound is kynurenic acid and is present at 0.5% by weight of a composition for topical use or topical application. In one embodiment, the compound is kynurenic acid and is present at 0.5% by weight of a lotion. In one embodiment, the compound is kynurenic acid and is present at 0.5% by weight of a cream. In one embodiment, the compound is kynurenic acid and is present at 0.1% to 2% by weight of a composition for topical use or topical application used to reduce the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars. In one embodiment, the compound is kynurenic acid and is present at 0.1% to 2% by weight of a composition used as a cosmetic to reduce the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars.

[0053] In one embodiment, the present invention contemplates the use of kynurenic acid in the manufacture of a cosmetic or pharmaceutical product for reducing the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars. In one embodiment, the present invention contemplates topical formulations containing trace amounts to 2% by weight of kynurenine, kynurenic acid or xanthurenic acid and the use of said formulations for reducing the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars. In one embodiment, the present invention contemplates topical formulations containing trace amounts to 2% by weight of kynurenine, kynurenic acid or xanthurenic acid and the use of said formulations for reducing the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars. In one embodiment, the present invention contemplates topical formulations containing 0.1-0.75% by weight of kynurenine, kynurenic acid or xanthurenic acid and the use of said formulations for reducing the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars. In one embodiment, the invention contemplates a topical formulation containing 0.25-0.5% by weight of kynurenine, kynurenic acid or xanthurenic acid and said formulation being used to reduce the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars.In one embodiment, the invention contemplates a topical formulation containing 0.1-0.75% by weight of kynurenic acid and said formulation being used to reduce the appearance of atrophic scars, atrophic acne scars or post-acne atrophic scars. EXAMPLES

[0054] IV. Working Examples A. Formulations for Topical Use I. Topical creams were made as follows: kynurenic acid was solubilized in 1M NaOH phosphate buffer solution, the pH was adjusted to 5.5 at room temperature, and the KynA solution was then added to a dermatological formulation base (Glaxal Base™, WellSpring, Ont., Canada) with constant mixing, and the pH was adjusted to 6 before packaging in a poly bottle. Topical creams were made with 0.15%, 0.25%, 0.4% and 0.5% kynurenic acid by weight (Papp et al., 2018).

[0055] II. Other compounded creams are known in the art, one example is VersaPro™ Cream Base (product number 2529, MEDISCA Pharmaceutique Inc., Richmond, BC, Canada). Using VersaPro™ Cream Base, dry kynurenic acid powder was hand mixed into a cream with a mortar and pestle to a final mass of 0.5%.

[0056] III. Moisturizing cream containing kynurenic acid A 0.5% by weight kynurenic acid moisturizing cream was made by combining water, petrolatum, cetearyl alcohol, light mineral oil, ceteareth-20, TroyCare™ EPP37, sodium dihydrogen phosphate dihydrate, kynurenic acid, sodium hydroxide, hydrochloric acid, sodium chloride, and disodium hydrogen phosphate dihydrate. A 0.25% by weight kynurenic acid moisturizing cream was made by combining the same ingredients (water, petrolatum, cetearyl alcohol, light mineral oil, ceteareth-20, TroyCare™ EPP37, sodium dihydrogen phosphate dihydrate, kynurenic acid, sodium hydroxide, hydrochloric acid, sodium chloride, and disodium hydrogen phosphate dihydrate), but the amount of kynurenic acid was reduced to 0.25% of the final product weight.

[0057] B. Use of topical kynurenic acid (0.5% by weight) to reduce the appearance of acne scars A woman in her mid-40s presented with significant atrophic acne scarring on her face that she self-reported had been resistant to treatment for over 20 years. She was administered a topical cream containing 0.5% kynurenic acid by mass twice daily for 3 months at the sites of her atrophic acne scarring, with each application covering 1 cm of skin. 2 Approximately 17 μg kynurenic acid per dose. Early skin healing can be followed by visual inspection of the site. Subjects reported a noticeable reduction in the perceived appearance of their atrophic acne scars as early as after approximately two weeks. Subjects also reported receiving unsolicited feedback from others that the appearance of their acne [atrophic scars] was significantly less noticeable. Example images of "before" and "during" use are shown as Figure 1.

[0058] C. Use of topical kynurenic acid (0.5% by weight) to reduce the appearance of acne scars A man approximately 70 years of age with atrophic acne scars on his face self-reported that his scars were "mature," "stable," and "lasting for more than 3 years." He was administered a topical cream containing 0.5% kynurenic acid by mass, applied to 1 cm of skin. 2 A single application of approximately 2.5-5 μg kynurenic acid per application was applied once daily for two months. The subjects reported that the holes and depressions in their atrophic acne scars appeared to be less visible, less noticeable, and filling in over the two-month period. The subjects also reported that others commented that their atrophic acne scars appeared to be less visible and less noticeable.

[0059] D. Use of topical kynurenine for hypertrophic scars A topical kynurenine cream at 0.05% by weight has been described in the literature for use in the treatment of hypertrophic scars in vivo (Li et al., 2014; Poormasjedi-Meibod et al., 2014) and the method of manufacture and topical application of the cream are incorporated by reference.

[0060] References TIFF2024516316000002.tif221166

[0061] TIFF2024516316000003.tif51160

[0062] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0063] Although the present invention has been described with reference to certain preferred embodiments, it is to be understood that the invention may be embodied in other specific forms or variations thereof without departing from its special or essential characteristics. The above-described embodiments are therefore considered in all respects to be illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.

Claims

1. 1. A small molecule compound selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid for use in the treatment of atrophic acne scars or post-acne atrophic scars.

2. The small molecule compound of claim 1 , wherein the small molecule compound is administered or applied as a component of a composition formulated for topical use.

3. The low molecular weight compound of claim 2 , wherein the composition is formulated as a cream.

4. The low molecular weight compound according to claim 2 , wherein the compound is kynurenic acid and the composition is formulated as 0.5% kynurenic acid by weight.

5. The low molecular weight compound according to claim 2, wherein the compound is kynurenine and the composition is formulated as 0.05% kynurenine by weight.

6. The small molecule compound of claim 1, wherein the small molecule compound is administered or applied once or twice daily.

7. The method of claim 1, wherein the small molecule compound is administered or applied topically to skin having an atrophic scar.

8. 1. A small molecule compound for use in the preparation of a cosmetic product for treating atrophic acne scars or post-acne atrophic scars, the small molecule compound being selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

9. The small molecule compound of claim 8 , wherein the small molecule compound is administered or applied as a component of a composition formulated for topical use.

10. The low molecular weight compound of claim 9 , wherein the composition is formulated as a cream.

11. The low molecular weight compound according to claim 9 , wherein the compound is kynurenic acid and the composition is formulated as 0.5% kynurenic acid by weight.

12. The low molecular weight compound according to claim 9, wherein the compound is kynurenine and the composition is formulated as 0.05% kynurenine by weight.

13. The small molecule compound of claim 8, wherein the small molecule compound is administered or applied once or twice daily.

14. A small molecule compound selected from the group consisting of kynurenine and kynurenic acid for use in the treatment of atrophic scars.

15. 15. A small molecule compound for use according to claim 14, wherein the atrophic scar is an atrophic acne scar.

16. A small molecule compound for use according to claim 14, selected from the group consisting of DL-kynurenine, L-kynurenine, D-kynurenine, 3-hydroxy-DL-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxy-D-kynurenine, 5-hydroxy-DL-kynurenine, 5-hydroxy-L-kynurenine, 5-hydroxy-D-kynurenine, N'-formyl-kynurenine, N-acetyl-3-OH-kynurenine, 4-chloro-DL-kynurenine, xanthurenic acid and kynurenic acid.

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