Topical compositions of glp-1 agonists and uses of glp-1 agonists and compositions thereof in the treatment of vitiligo

Abstract

The disclosed subject matter provides topical compositions comprising GLP-1 agonists, kits comprising such compositions, and methods of treating or preventing vitiligo using GLP-1 agonists or compositions thereof.

Description

Background Technology

[0001] Vitiligo is a chronic autoimmune disease in which the skin loses its natural color due to pigment loss. Normally, the immune system works throughout the body to fight infections, such as those caused by viruses and bacteria. However, in vitiligo patients, it is believed that the immune system attacks and destroys melanocytes—the cells that produce pigment that determines skin color. This causes irregularly shaped white patches to appear on any part of the skin's surface. Vitiligo can alter the color of a person's hair and eyes, especially the iris and retina. Over time, these white patches may enlarge and / or spread to other parts of the body. People with vitiligo are prone to sunburn, skin cancer, eye problems, and psychological distress.

[0002] Current treatments for vitiligo aim to restore color to the white, depigmented patches of skin. Medications or topical medicated creams (such as corticosteroids or calcineurin inhibitors) may be able to restore color to these white patches, likely by inhibiting the local autoimmune processes that cause depigmentation. (Lee et al., “Treatment Outcomes of Topical Calcineurin Inhibitor Therapy for Patients With Vitiligo”, JAMADermatol. [JAMA Dermatology] 2019 Aug; 155(8): 929–938). Topical ruxolitinib (a selective JAK1 / 2 inhibitor) has also recently been approved for the treatment of non-segmental vitiligo in children aged 12 years and older. Ruxolitinib modulates IFN-γ-mediated JAK-STAT signaling, which is thought to inhibit CD8+ T cells from destroying melanocytes or pigment-producing cells in the skin. (Sheikh et al., “FDA approves Ruxolitinib (Opzelura) for Vitiligo Therapy: A breakthrough in the field of dermatology”, Ann Med Surg (Lond). [Annals of Medicine and Surgery (London)] Sep 2022; 81: 104499). Phototherapy in the form of narrow-band ultraviolet radiation B (nbUVB) can also be used to help restore skin color by locally suppressing autoimmunity. For best results, topical medications can be used in conjunction with phototherapy.

[0003] Another treatment for vitiligo is depigmentation therapy. In depigmentation therapy, the color is removed from the darker areas of the skin to match the white patches. The depigmentation process can take more than a year to complete.

[0004] None of these treatments for vitiligo are very effective in the long run.

[0005] Smegglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and mimics the hormone GLP-1. See, for example, U.S. Patent Nos. 8,129,343; 8,536,122; 9,278,123; 9,764,003; 10,086,047; 10,335,462; and 10,888,605. GLP-1 functions in the body in various ways. For example, during eating, GLP-1 is released into the gastrointestinal tract, prompting the body to produce more insulin, which in turn lowers blood sugar levels. At higher levels, GLP-1 interacts with portions of the brain responsible for reducing appetite and sending satiety signals. Therefore, by mimicking GLP-1, GLP-1 receptor agonists such as smegglutide can be used to help the body produce more insulin and reduce appetite. Currently, there are three FDA-approved semaglutide formulations: OZEMPIC®, WEGOVY®, and RYBELSUS®, all developed by Novo Nordisk. (The information on "Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss" is available at fda.gov / drugs / postmarket-drug-safety-information-patients-and-providers / medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss".)

[0006] WO2006 / 097537 (“Published Text 537”) discloses acylated GLP-1 analogues, which are claimed to be used to treat hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers. Example 4 of “Published Text 537” describes the synthesis of smegglutinin, also known as N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetamido)ethoxy]ethoxy)-acetyl][Aib8,Arg34]GLP-1-(7-37) peptide.

[0007] Any reference cited in Section 1 of this application shall not be construed as an admission that such reference is prior art of this disclosure. Summary of the Invention

[0008] This disclosure relates to the finding that GLP-1 agonists (such as smegglutide) may be very effective in treating vitiligo.

[0009] In one aspect, this disclosure provides topical compositions comprising a GLP-1 agonist (such as smegglutinin) or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0010] In another aspect, this disclosure provides a method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a GLP-1 agonist (such as smegglutinin) or a pharmaceutically acceptable salt thereof, or a composition comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof.

[0011] On the one hand, GLP-1 agonists (such as smegglutide) or their pharmaceutically acceptable salts can be administered orally.

[0012] On the other hand, compositions containing GLP-1 agonists (such as smegglutinin) or pharmaceutically acceptable salts thereof can be administered orally or topically. Detailed Implementation

[0013] This invention includes the following:

[0014] 1. A topical composition comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0015] 2. A topical composition comprising smegglutinin or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0016] 3. The topical composition as described in 1 or 2 above, wherein the composition is formulated as a transdermal patch, gel, cream, ointment, lotion, or foam.

[0017] 4. The topical composition as described in any one of 1 to 3 above, wherein the at least one dermatologically acceptable excipient is mineral oil, paraffin, propylene carbonate, white petrolatum, beeswax, or any combination thereof.

[0018] 5. The topical composition as described in any one of 1 to 4 above, wherein the topical composition further comprises an additional therapeutic agent.

[0019] 6. The topical composition as described in 5 above, wherein the additional therapeutic agent is a corticosteroid, an immunomodulator, a calcineurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or an analogue thereof, a dietary supplement, or any combination thereof.

[0020] 7. The topical composition as described in 5 above, wherein the additional therapeutic agent is aclomethasone, ancinonide, betamethasone, clobetasol, clocotropin, desonide, desoxymethasone, difluralasone, fluocinolone acetonide, fludrocinolone acetonide, fluticasone, halcinonide, halometasol, hydrocortisone, mometasone, prednisolone, triamcinolone, tacrolimus, pimecrolimus, ruxolitinib, tofacitinib, calcipotriene, beta-carotene, alpha-carotene, retinoic acid, vitamin A, vitamin C, vitamin E, vitamin B12, vitamin D, folic acid, carotenoids (such as lycopene), or any combination thereof.

[0021] 8. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a GLP-1 agonist or a pharmaceutically acceptable salt thereof.

[0022] 9. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of smegglutinin or a pharmaceutically acceptable salt thereof.

[0023] 10. The method as described in 8 or 9 above, wherein the GLP-1 agonist or smegglutinin or a pharmaceutically acceptable salt thereof is administered orally.

[0024] 11. The method as described in any one of 8 to 10 above, the method further comprising exposing the vitiligo-affected skin to phototherapy.

[0025] 12. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a composition comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof.

[0026] 13. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a composition comprising smegglutinin or a pharmaceutically acceptable salt thereof.

[0027] 14. The method as described in 12 or 13 above, wherein the composition is administered orally.

[0028] 15. The method as described in 12 or 13 above, wherein the composition is applied topically.

[0029] 16. The method as described in any one of 12 to 15 above, the method further comprising exposing the vitiligo-affected skin to phototherapy.

[0030] 17. A kit comprising a topical preparation as described in any one of 1 to 7 above.

[0031] 18. Use of GLP-1 agonists in the preparation of drugs for the treatment of vitiligo.

[0032] 19. Use of smegglutinin in the preparation of drugs for the treatment of vitiligo.

[0033] 20. Use of the topical composition as described in any one of 1 to 7 above in the preparation of a medicament for treating vitiligo.

[0034] 21. A GLP-1 agonist for use in the treatment of vitiligo.

[0035] 22. Smegglutinin, which is used in the treatment of vitiligo.

[0036] 23. The topical composition as described in any one of 1 to 7 above, for use in the treatment of vitiligo.

[0037] 3.1 Definition

[0038] Unless otherwise expressly indicated, the following terms as used herein have the meanings indicated below.

[0039] Throughout this specification, the word “comprise” or its variations such as “comprises” or “comprising” should be understood to imply inclusion of the stated integers or groups of integers, but not to exclude any other integers or groups of integers. At any point in this document, any of the terms “comprise,” “basically composed of,” and “composed of” may be replaced by any of the other two terms.

[0040] The term "a or an" can refer to more than one item.

[0041] The terms “and” and “or” can refer to both a connection and a choice, and mean “and / or”.

[0042] The term “about” means within plus or minus 10% of the stated value. For example, “about 100” means any number between 90 and 110.

[0043] The term "topical composition" (which contains a GLP-1 agonist or smegglutinin) refers to a formulation consisting of a GLP-1 agonist or smegglutinin and a medium known or recognized in the art for delivering a pharmacologically active compound to the skin (e.g., mammalian skin).

[0044] The term "GLP-1" refers to glucagon-like peptide-1.

[0045] The term "GLP-1 agonist" refers to an agonist of the glucagon-like peptide-1 receptor. GLP-1 agonists may be referred to as GLP-1 receptor agonists, incretin mimics, GLP-1 analogs, and GLP-1 derivatives. Exemplary GLP-1 agonists include, but are not limited to, GLP-1, abiglutide, dulaglutide (LY2189265), iperagnatide, exenatide (Exendin-4), liraglutide (NN2211), liximabide, semaglutide, telpoxetine, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, other GLP-1 agonists described in the following patents: U.S. Patent Nos. 11,357,820; 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 8,536,122; 8,501,698; 8,129,343; 8,114,833; 7,452,966; 7,141,547; and RE45313.

[0046] "Pharmaceutically acceptable salt" means any salt of a therapeutic agent disclosed herein, which may include any of a variety of organic and inorganic counterions known in the art, and which is pharmaceutically acceptable.

[0047] "Dermatologically acceptable excipients" means any substance that is not itself a therapeutic agent and is used as a carrier, diluent, adjuvant, excipient, filler, binder, flow aid, preservative, dye / colorant, surfactant, wetting agent, dispersant, suspending agent, buffer, solubilizer, viscosity enhancer, pH adjuster, stabilizer, antioxidant, free radical scavenger, isotonic agent, solvent, thickener, lubricant, emulsifier, absorbent, penetration enhancer, humectant, adhesive, fragrance, emollient, chelating agent, and / or a medium for delivering a therapeutic agent to a subject, or added to a composition to improve the administration and / or absorption of the therapeutic agent, or added to a composition to improve its handling or storage properties, or allows or promotes the formation of a dosage form suitable for administration.

[0048] Dermatologically acceptable excipients are well known in the art, and examples include gelatin; starch; pullulan; gum arabic; astragalus gum; dextran; cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polymers such as carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone; lecithin; collagen; alcohols such as alkanols having one to twenty carbons, such as ethanol, propanol, propylene glycol, 1,3-butanediol, phenol, oleyl alcohol, cetyl alcohol, octyldodecyl alcohol, cetearyl alcohol, stearyl alcohol, benzyl alcohol, butanediol, diethylene glycol, tetrahydrofuran polyethylene glycol ether (glycofurol), glycerides, glycerin, glycerol, glyceryl glycerol, phenethyl alcohol, and phenoxyethanol; amino acids such as L-α-amino acids and water-soluble... Proteins; oils, such as vegetable oils, almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, castor oil, 1-carvone, coconut oil, corn oil, cottonseed oil, clove oil, menthol, fennel oil, orange oil, olive oil, peanut oil, peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil (squalene), soybean oil, sunflower oil, and walnut oil; vitamins and herbs, such as aloe vera, allantoin, black walnut extract, chamomile extract, panthenol, papain, tocopherol, and vitamin A palmitate; waxes, such as white wax, candelilla wax, carnauba wax, ceresin, beeswax, lanolin wax, jojoba oil, paraffin wax, hydrophilic petrolatum, and petrolatum; animal fats or animal-derived ingredients, such as beef tallow, lanolin, collagen, lard, and butter; lanolin derivatives, such as lanolin alcohol, PEG 16 lanolin, and acetylated lanolin; oxazoline; oxazolidinone; proline esters;Surfactants, including cationic, anionic, or nonionic surfactants, such as nonoxynol ether, polysorbate (e.g., polysorbate 80), glycerol fatty acid esters, polyoxyethylene alcohol, polyoxyethylene fatty acid esters, sodium lauryl sulfate and sorbitan monostearate, saturated or unsaturated fatty acid esters, polyoxyethylene fatty ethers, polyoxyethylene fatty acid esters, diethylene glycol monoethyl ether, 1,3-dimethyl-2-imidazolidineone and / or dimethyl isosorbide, polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene glycol 1500 (PEG 1500), polyethylene glycol 1600 (PEG 1600), polyethylene glycol 4000 (PEG 4000), polyethylene glycol 6000 (PEG 6000), glycerol, Transcutol P (diethylene glycol monoethyl ether), propylene glycol, propylene carbonate, 1,3-dimethyl-2-imidazolium ketone (DMI), sodium metabisulfite, butylated hydroxytoluene (BHT), benzyl alcohol, sodium benzoate, isopropyl myristate, diisopropyl adipate, crodamol OHS (ethylhexyl hydroxystearate), mineral oil, β-cyclodextrin, polysorbate 20 (TWEEN 20), (polyoxyethylene (20) stearyl ether), silicone (e.g., polydimethylsiloxane, cyclodimethylsiloxane, etc.), stearyl alcohol polyether-2 (Brij S2), stearyl alcohol polyether-20 (Brij S20), glyceryl stearate, stearic acid, magnesium stearate, diethylene glycol monoethyl ether, 1,3-dimethyl-2-imidazolium ketone; ethylenediaminetetraacetic acid (EDTA); methylparaben and propylparaben.

[0049] The term "subject" refers to an animal, such as a mammal, including but not limited to humans. In certain embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0050] "Effective amount" means an amount of a therapeutic agent or its pharmaceutically acceptable salt that is sufficient to achieve the desired result but generally not sufficient to cause adverse side effects. As understood in the art, an effective amount may be administered in one or more doses.

[0051] "Treatment" refers to methods used to obtain beneficial or desired outcomes (including clinical outcomes). For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to: suppressing and / or halting the onset and / or development of a condition, or reducing the severity of such a condition, such as reducing the number and / or severity of symptoms associated with the condition, improving the quality of life of patients with the condition, reducing the dosage of other medications required to treat the condition, enhancing the effect of another medication taken by the patient for the condition, and / or prolonging the survival of patients with the condition.

[0052] "Prevention" refers to reducing the likelihood of developing the disease in patients who do not yet have the disease but are at risk of developing it. Patients "at risk" may or may not have a detectable disease and may have exhibited or not exhibited a detectable disease prior to the treatments disclosed herein. "At risk" means that a patient has one or more so-called risk factors, which are measurable parameters associated with the development of the disease and are known in the art. Patients with one or more of these risk factors are more likely to develop the disease compared to patients without such risk factors.

[0053] When a range of values ​​is provided, it should be understood that the range includes every intermediate integer value between the upper and lower limits of the range. For example, if a range of 1 to 10 is stated, it should be understood to explicitly include subranges such as 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 2 to 4, 2 to 6, 2 to 8, etc., as well as individual values ​​within the range such as 1.1, 2, 2.6, 3, 3.9, 4, 4.2, 5, 5.7, 6, 6.5, 7, 7.4, 8, 8.8, 9, 9.1, and 10.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials may be used in carrying out or testing this invention, suitable methods and materials are described below. These materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patents, and other documents mentioned herein are incorporated herein by reference in their entirety.

[0055] 3.2 Topical Composition

[0056] This disclosure provides a topical formulation comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0057] In various embodiments, the GLP-1 agonist may be GLP-1, abiglutide, dulaglutide (LY2189265), iperagnatide, exenatide (Exendin-4), liraglutide (NN2211), liximabide, smegglutide, telpoglycinide, ZP2929, NNC0113-0987, BPI-3016, and TT401. GLP-1 agonists can also be agonists described in the following patents: U.S. Patent Nos. 11,357,820; 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 8,536,122; 8,501,698; 8,129,343; 8,114,833; 7,452,966; 7,141,547; and RE45313.

[0058] In one embodiment, this disclosure provides a topical formulation comprising semaglutide or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0059] Examples of dermatologically acceptable excipients include those listed above, such as carriers, flow aids, preservatives, dyes / colorants, surfactants, wetting agents, dispersants, suspending agents, buffers, solubilizers, viscosity enhancers, pH adjusters, stabilizers, antioxidants, free radical scavengers, isotonic agents, solvents, lubricants, emulsifiers, absorbents, absorption enhancers, penetration enhancers, humectants, adhesives, fragrances, emollients, lubricants, hardening agents, and any combination thereof. It should be understood that a dermatologically acceptable excipient can perform more than one function. For example, paraffin can be used as both a lubricant and a humectant.

[0060] In various embodiments, the topical formulation comprises at least one dermatologically acceptable excipient. In one aspect, the topical formulation comprises at least two dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least three dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least four dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least five dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least six dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least seven dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least eight dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least nine dermatologically acceptable excipients. In another aspect, the topical formulation comprises at least ten dermatologically acceptable excipients.

[0061] The amount of GLP-1 agonist (e.g., smegglutide) present in the topical composition is the amount that is effective in treating or preventing vitiligo after the topical composition is applied to the affected area. In some embodiments, a GLP-1 agonist (e.g., semaglutide) is present in the following amounts: about 0.001% w / w to about 25% w / w, about 0.001% w / w to about 20% w / w, about 0.001% w / w to about 15% w / w, about 0.001% w / w to about 10% w / w, about 0.001% w / w to about 5% w / w, about 0.001% w / w to about 4% w / w, about 0.001% w / w to about 3% w / w, about 0.001% w / w to about 2% w / w, about 0.001% w / w to about 1% w / w, about 0.01% w / w to about 25% w / w, about 0.01% w / w to about 20% w / w, about 0.01% w / w to about 15% w / w, and about 0.01% w / w to about 10%. w / w, about 0.01% w / w to about 5% w / w, about 0.01% w / w to about 4% w / w, about 0.01% w / w to about 3% w / w, about 0.01% w / w to about 2% w / w, about 0.01% w / w to about 1% w / w, about 0.1% w / w to about 25% w / w, about 0.1% w / w to about 20% w / w, about 0.1% w / w to about 15% w / w, about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 4% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 25% w / w, about 0.5% w / w to about 20% w / w, about 0.5% w / w to about 15% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 4% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 25% w / w, about 1% w / w to about 20% w / w, about 1% w / w to about 15% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 1% w / w to about 1.5% w / w.

[0062] In various embodiments, a GLP-1 agonist (e.g., semaglutide) is present in the topical formulation in the following amounts: about 0.001% w / w, about 0.01% w / w, about 0.05% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, and about 2.1%. w / w, approximately 2.2% w / w, approximately 2.3% w / w, approximately 2.4% w / w, approximately 2.5% w / w, approximately 2.6% w / w, approximately 2.7% w / w, approximately 2.8% w / w, approximately 2.9% w / w, approximately 3% w / w, approximately 3.1% w / w, approximately 3.2% w / w, approximately 3.3% w / w, approximately 3.4% w / w, approximately 3.5% w / w, approximately 3.6% w / w, approximately 3.7% w / w, approximately 3.8% w / w, approximately 3.9% w / w, approximately 4% w / w, approximately 4.1% w / w, approximately 4.2% w / w, approximately 4.3% w / w, approximately 4.4% w / w, approximately 4.5% w / w, approximately 4.6% w / w, approximately 4.7% w / w, approximately 4.8% w / w, approximately 4.9% w / w, approximately 5% w / w, approximately 6% w / w, approximately 7% w / w, approximately 8% w / w, approximately 9% w / w, approximately 10% w / w, approximately 11% w / w, approximately 12% w / w, approximately 13% w / w, approximately 14% w / w, approximately 15% w / w, approximately 16% w / w, approximately 17% w / w, approximately 18% w / w, approximately 19% w / w, approximately 20% w / w, approximately 21% w / w, approximately 22% w / w, approximately 23% w / w, approximately 24% w / w, or approximately 25% w / w.

[0063] Topical compositions can be formulated as transdermal patches, gels (aqueous or non-aqueous), creams, ointments, lotions, foams, solutions, suspensions, emulsions, drops, sprayable liquids, dispersions, ointments, pastes, liposomes, micelles, or giant micelles.

[0064] In various embodiments, the topical formulation is a transdermal patch in the first embodiment, a gel in the second embodiment, a cream in the third embodiment, an ointment in the fourth embodiment, a lotion in the sixth embodiment, and a foaming agent in the seventh embodiment.

[0065] The topical compositions disclosed herein can be prepared according to procedures known in the field of dermatological composition formulation. Typically, a base formulation is prepared first, followed by the addition of a GLP-1 agonist (e.g., smegglutinin) or a pharmaceutically acceptable salt thereof, and thorough mixing is performed. If necessary, the pH of the topical composition can be adjusted.

[0066] In one embodiment, the topical composition further comprises an additional therapeutic agent. The additional therapeutic agent may be a corticosteroid, an immunomodulator, a calcineurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or its analogue, a dietary supplement, and any combination thereof. Examples of the additional therapeutic agents that may be used include, but are not limited to, aclomethasone, ancinonide, betamethasone, clobetasol, clotropone, desonide, desoxymethasone, diflubenzuron, fluocinolone acetonide, fludrocinolone acetonide, fluticasone, halcinonide, halometasol, hydrocortisone, mometasone, prednisolone, triamcinolone, tacrolimus, pimecrolimus, ruxolitinib (marketed as OPZELURA™), tofacitinib, calcipotriene, beta-carotene, alpha-carotene, retinoic acid, vitamin A, vitamin C, vitamin E, vitamin B12, vitamin D, folic acid, carotenoids (such as lycopene), and any combination thereof.

[0067] 3.3 Methods of using GLP-1 agonists and their compositions

[0068] This disclosure provides methods for treating or preventing vitiligo. In one embodiment, the method includes administering to a subject in need a GLP-1 agonist or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof. In one aspect, the method is used to treat vitiligo in a subject in need, and in a second aspect, the method is used to prevent vitiligo in a subject in need. The GLP-1 agonist may be any agonist described in Section 3.2.

[0069] In another embodiment, the method includes administering smegglutinin or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising smegglutinin or a pharmaceutically acceptable salt thereof, to a subject in need. In one aspect, the method is used to treat vitiligo in a subject in need, and in a second aspect, the method is used to prevent vitiligo in a subject in need.

[0070] The GLP-1 agonist (e.g., semaglutide) used in the methods disclosed herein can be formulated for oral or topical administration. Oral formulations of semaglutide are known and can be prepared as described in U.S. Patent Nos. 9,278,123 and 10,086,047. Topical compositions of GLP-1 agonists are described in Section 3.2, and any of them can be used in the methods disclosed herein.

[0071] When treating vitiligo topically, the topical composition disclosed herein is applied directly to the vitiligo-affected areas (i.e., white patches of skin) of the skin of the subject in need.

[0072] Prior to topical application of the GLP-1 agonist composition to the subject, the affected vitiligo skin may optionally be pretreated, for example by cleaning the skin with soap and water or an alcohol-based cleanser.

[0073] The compositions disclosed herein can be administered before, substantially simultaneously with, or after the administration of additional therapeutic agents. Administration regimens may include pretreatment and / or co-administration with additional therapeutic agents. In this case, the GLP-1 agonist composition and the additional therapeutic agent may be administered simultaneously, separately, or sequentially.

[0074] Examples of administration regimens include, but are not limited to: sequential administration of each GLP-1 agonist composition and therapeutic agent; and co-administration of the GLP-1 agonist composition and therapeutic agent in a substantially simultaneous manner (e.g., in a single unit dosage form) or in multiple separate unit dosage forms of the GLP-1 agonist composition and therapeutic agent.

[0075] Other therapeutic agents may be corticosteroids, immunomodulators, calcineurin inhibitors, JAK inhibitors, retinoids, vitamins or their analogues, antioxidants, and any combination thereof. Examples of other therapeutic agents that may be used include, but are not limited to, aclomethasone, ancinonide, betamethasone, clobetasol, clotropone, desonide, desoxymethasone, difluralasone, fluocinolone acetonide, fluticasone propionate, fluticasone, halcinonide, halometasol, hydrocortisone, mometasone, prednisolone, triamcinolone, tacrolimus, pimecrolimus, ruxolitinib (marketed as OPZELURA™), tofacitinib, calcipotriene, beta-carotene, alpha-carotene, retinoic acid, vitamin A, vitamin C, vitamin E, vitamin B12, vitamin D, folic acid, carotenoids (such as lycopene), and any combination thereof.

[0076] In various embodiments, the method disclosed herein further includes exposing vitiligo-affected skin to phototherapy. Phototherapy includes exposure to sunlight or radiation of a specific wavelength, such as UV radiation, including UVA and UVB radiation.

[0077] 3.4 Administration regimen and dosage level

[0078] As described in Section 3.3, GLP-1 agonists and their combinations can be administered orally or topically.

[0079] The amount of GLP-1 agonists or combinations thereof used to treat or prevent vitiligo will vary depending on the severity and progression of vitiligo, the specific formulation used, the route of administration, the age and weight of the subject, the subject's sex and overall health status, and the judgment of the attending physician.

[0080] When a composition containing a GLP-1 agonist is administered, the dosage is expressed based on the amount of GLP-1 agonist.

[0081] In an embodiment of topical application of a GLP-1 agonist, the topical GLP-1 agonist composition is applied topically to the skin affected by vitiligo. Preferably, the topical formulation is applied in a thin layer.

[0082] Topical GLP-1 agonist compositions may be administered topically in the following ranges: about 0.001 mg / day to about 2000 mg / day, about 0.01 mg / day to about 2000 mg / day, about 0.1 mg / day to about 2000 mg / day, about 1.0 mg / day to about 2000 mg / day, about 10 mg / day to about 2000 mg / day, about 100 mg / day to about 2000 mg / day, about 1100 mg / day to about 2000 mg / day, about 1200 mg / day to about 2000 mg / day, about 1300 mg / day to about 2000 mg / day, about 1400 mg / day to about 2000 mg / day, about 1500 mg / day to about 2000 mg / day, about 1600 mg / day to about 2000 mg / day, about 1700 mg / day to about 2000 mg / day. mg / day, approximately 1800 mg / day to approximately 2000 mg / day, approximately 1900 mg / day to approximately 2000 mg / day, approximately 0.001 mg / day to approximately 1900 mg / day, approximately 0.001 mg / day to approximately 1800 mg / day, approximately 0.001 mg / day to approximately 1700 mg / day, approximately 0.001 mg / day to approximately 1600 mg / day, approximately 0.001 mg / day to approximately 1500 mg / day, approximately 0.001 mg / day to approximately 1400 mg / day, approximately 0.001 mg / day to approximately 1300 mg / day, approximately 0.001 mg / day to approximately 1200 mg / day, approximately 0.001 mg / day to approximately 1100 mg / day, approximately 0.001 mg / day to approximately 1000 mg / day, approximately 0.001 mg / day to approximately 900 mg / day, approximately 0.001 mg / day mg / day to about 800 mg / day, about 0.001 mg / day to about 700 mg / day, about 0.001 mg / day to about 600 mg / day, about 0.001 mg / day to about 500 mg / day, about 0.001 mg / day to about 400 mg / day, about 0.001 mg / day to about 300 mg / day, about 0.001 mg / day to about 200 mg / day, about 0.001 mg / day to about 100 mg / day, about 0.001 mg / day to about 10 mg / day, about 0.001 mg / day to about 1 mg / day, about 0.001 mg / day to about 0.10 mg / day, or about 0.001 mg / day to about 0.010 mg / day.

[0083] In various embodiments, the topical GLP-1 agonist composition was administered topically in the following amounts: about 0.001 mg / day, about 0.01 mg / day, about 0.1 mg / day, about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 200 mg / day, about 300 mg / day, about 400 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day. mg / day, approximately 1100 mg / day, approximately 1200 mg / day, approximately 1300 mg / day, approximately 1400 mg / day, approximately 1500 mg / day, approximately 1600 mg / day, approximately 1700 mg / day, approximately 1800 mg / day, approximately 1900 mg / day, or approximately 2000 mg / day.

[0084] Topical GLP-1 agonist compositions can be applied once or more daily, for example, once to six times daily. The duration of treatment will depend on the severity of vitiligo symptoms and the disease state, and can be easily adjusted by the attending physician. Typically, treatment can last for weeks, months, or longer.

[0085] In examples of oral administration of GLP-1 agonists, the GLP-1 agonist or combinations thereof is administered in the following ranges: about 0.1 mg / kg / week to about 3 mg / kg / week, about 0.1 mg / kg / week to about 2.5 mg / kg / week, about 0.1 mg / kg / week to about 2 mg / kg / week, about 0.1 mg / kg / week to about 1.5 mg / kg / week, about 0.1 mg / kg / week to about 1 mg / kg / week, about 0.1 mg / kg / week to about 0.5 mg / kg / week, about 0.1 mg / kg / week to about 0.25 mg / kg / week, about 0.1 mg / kg / week to about 0.2 mg / kg / week, about 0.2 mg / kg / week to about 3 mg / kg / week, about 0.25 mg / kg / week to about 3 mg / kg / week, about 0.5 mg / kg / week to about 3 mg / kg / week, about 1 mg / kg / week to about 3 mg / kg / week, about 1.5 mg / kg / week. mg / kg / week to about 3 mg / kg / week, about 2 mg / kg / week to about 3 mg / kg / week, or about 2.5 mg / kg / week to about 3 mg / kg / week.

[0086] In various embodiments, oral GLP-1 agonists or combinations thereof were administered in the following amounts: about 0.1 mg / kg / week, about 0.15 mg / kg / week, about 0.2 mg / kg / week, about 0.25 mg / kg / week, about 0.3 mg / kg / week, about 0.35 mg / kg / week, about 0.4 mg / kg / week, about 0.45 mg / kg / week, about 0.5 mg / kg / week, about 0.55 mg / kg / week, about 0.6 mg / kg / week, about 0.65 mg / kg / week, about 0.7 mg / kg / week, about 0.75 mg / kg / week, about 0.8 mg / kg / week, about 0.85 mg / kg / week, about 0.9 mg / kg / week, about 0.95 mg / kg / week, about 1.0 mg / kg / week, about 1.1 mg / kg / week, about 1.2 mg / kg / week, about 1.3 mg / kg / week. mg / kg / week, approximately 1.4 mg / kg / week, approximately 1.5 mg / kg / week, approximately 1.6 mg / kg / week, approximately 1.7 mg / kg / week, approximately 1.8 mg / kg / week, approximately 1.9 mg / kg / week, approximately 2.0 mg / kg / week, approximately 2.1 mg / kg / week, approximately 2.2 mg / kg / week, approximately 2.3 mg / kg / week, approximately 2.4 mg / kg / week, approximately 2.5 mg / kg / week, approximately 2.6 mg / kg / week, approximately 2.7 mg / kg / week, approximately 2.8 mg / kg / week, approximately 2.9 mg / kg / week, or approximately 3 mg / kg / week.

[0087] Oral GLP-1 agonist compositions can be administered once or more weekly, for example, once to six times a week. The duration of oral treatment will depend on the severity of vitiligo symptoms and the disease state, and can be easily adjusted by the attending physician. Typically, treatment can last for weeks, months, or longer.

[0088] 3.5 Kits containing pharmaceutical compositions

[0089] This disclosure provides kits comprising the compositions disclosed herein. The topical compositions disclosed herein may be available in the form of packages, dispenser devices, patches, bottles, jars, tubes, or pouches. When the topical composition is provided as a patch, it is on the side of the patch that directly contacts the skin. The patch can be adhered to the skin using a dermatologically acceptable adhesive for the desired duration.

[0090] In various embodiments, the kit further comprises additional therapeutic agents as described in Section 3.2.

[0091] In one embodiment, the kit further includes instructions for use according to any of the methods described herein. The instructions may contain instructions for administration of the composition for the treatment or prevention of vitiligo as described herein. The instructions may include information regarding dosage and dosing schedule.

[0092] The instructions included in the kit may be in any suitable form, such as written instructions on a label or packaging insert, or electronic storage media (e.g., disk or optical disc).

[0093] To provide a fuller understanding of the invention, the following examples are set forth. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

[0094] 4. Examples

[0095] 4.1 Example 1 - Preparation of the composition disclosed herein

[0096] Topical ointments (or lotions, gels, etc.) are prepared by mixing smegglutinin (as described in Example 4 of WO2006 / 097537) with at least one dermatologically acceptable excipient, such as mineral oil, paraffin, propylene carbonate, white petrolatum or beeswax, optionally with buffers, stabilizers, fragrance ingredients, emulsifiers, oils, alcohols or other excipients.

[0097] 4.2 Example 2 - Preparation of the composition disclosed herein

[0098] A 0.5% smegglutinin topical ointment was prepared by mixing smegglutinin powder (obtained from Facron, Inc.) with 200% standard alcohol ethanol (129 ml / 100 gm), polysorbate 80 NF liquid, and a hydrophilic anhydrous matrix (ointment).

[0099] 4.3 Example 3 - Treatment of vitiligo with oral smegglutinin combination

[0100] Case 1: A 42-year-old woman with a history of type 2 diabetes and long-term stable but untreated vitiligo began treatment with Ozempic® (semaglutide) at a dose of 0.25 mg once weekly. Within one month of treatment initiation, perifolliculitis was observed in the vitiligo patches. As with empirical and FDA-approved treatments for vitiligo, perifolliculitis is a primary sign of treatment response.

[0101] Case 2: A 37-year-old male with a history of type 2 diabetes and long-term stable but untreated vitiligo was initiated with Ozempic® (semaglutide) at a dose of 0.25 mg once weekly. Within one month of starting treatment, perifollicular repigmentation was observed in the vitiligo patches.

[0102] 4.4 Example 4 - Treatment of vitiligo with topical smegglutinin composition

[0103] Case 3: An 82-year-old male with a history of untreated, stable vitiligo for more than 6 months was started with Smegglutinin ointment (as described in Case 2), applied twice daily to the vitiligo patches on his face. After 5 months of treatment, detectable improvement was observed in the patient.

[0104] Case 4: A 53-year-old woman with a history of untreated, stable vitiligo for more than 6 months was treated with Smegglutinin ointment (as described in Case 2), applied twice daily to the vitiligo patches on her face. After 6 months of treatment, several new perifollicular macules appeared in the vitiligo area.

[0105] Case 5: A 73-year-old woman with a history of untreated, stable vitiligo for more than 6 months was treated with Smegglutinin ointment (as described in Case 2), applied twice daily to the vitiligo patches on her face. After two months of treatment, several new perifollicular macules appeared in the vitiligo area.

[0106] 4.5 Example 5 - Treatment of vitiligo with topical smegglutinin composition

[0107] An open-label, non-randomized study enrolled patients with a history of vitiligo who received once-daily treatment of vitiligo patches (excluding the perioral and periocular areas) with the topical composition disclosed herein for 20 weeks. Participants had at least 1% of their body surface area (BSA) affected by vitiligo.

[0108] The primary outcome was determined by improvement in the Vitiligo Area Score Index (VASI) at week 20. The VASI score (range 0-100) was calculated by multiplying the affected BSA (estimated per palmar unit) by the degree of depigmentation within each palmar unit (0-100%).

[0109] Secondary outcomes were determined based on improvements in the Vitiligo European Task Force (VETF) score, physician's overall vitiligo assessment, BSA, and Dermatology Quality of Life Index. The VETF is a validated tool for classifying vitiligo based on disease extent, stage, and spread. Disease extent was calculated using a nine-point scale to estimate BSA; stage was assessed using a scale of 0 (no depigmentation) to 4 (complete depigmentation); and spread was scored using a simple rating scale (+1: progression; 0: stable; -1: regression). Physician's overall vitiligo assessment was determined using a five-point scale ranging from 0 (elimination) to 4 (severe disease). A fingerprint (palm and fingertips palmar surface) was used to calculate the total BSA to estimate 1% BSA.

[0110] While specific materials, formulations, sequences of operations, process parameters, and end products have been described and illustrated to illustrate the invention, they are not intended to be limiting. Rather, those skilled in the art should note that the written disclosure is exemplary only and various other alternatives, adjustments, and modifications can be made within the scope of this disclosure.

Claims

1. A topical composition comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

2. A topical composition comprising smegglutinin or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

3. The topical composition of claim 1 or claim 2, wherein the composition is formulated as a transdermal patch, gel, cream, ointment, lotion, or foam.

4. The topical composition according to any one of claims 1 to 3, wherein the at least one dermatologically acceptable excipient is mineral oil, paraffin, propylene carbonate, white petrolatum, beeswax, hydrophilic petrolatum, or any combination thereof.

5. The topical composition according to any one of claims 1 to 4, wherein the topical composition further comprises an additional therapeutic agent.

6. The topical composition of claim 5, wherein the additional therapeutic agent is a corticosteroid, an immunomodulator, a calcineurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or an analogue thereof, a dietary supplement, or any combination thereof.

7. The topical composition of claim 5, wherein the additional therapeutic agent is aclomethasone, ancinonide, betamethasone, clobetasol, clocotropin, desonide, desoxymethasone, difluralasone, fluocinolone acetonide, fluticasone propionate, fluticasone, halcinonide, halometasol, hydrocortisone, mometasone, prednisolone, triamcinolone, tacrolimus, pimecrolimus, ruxolitinib, tofacitinib, calcipotriene, beta-carotene, alpha-carotene, retinoic acid, vitamin A, vitamin C, vitamin E, vitamin B12, vitamin D, folic acid, carotenoids (such as lycopene), or any combination thereof.

8. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a GLP-1 agonist or a pharmaceutically acceptable salt thereof.

9. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of smegglutinin or a pharmaceutically acceptable salt thereof.

10. The method of claim 8 or 9, wherein the GLP-1 agonist or smegglutinin or a pharmaceutically acceptable salt thereof is administered orally.

11. The method of any one of claims 8 to 10, the method further comprising exposing vitiligo-affected skin to phototherapy.

12. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a composition comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof.

13. A method for treating or preventing vitiligo, the method comprising administering to a subject in need an effective amount of a composition comprising smegglutinin or a pharmaceutically acceptable salt thereof.

14. The method of claim 12 or claim 13, wherein the composition is administered orally.

15. The method of claim 12 or claim 13, wherein the composition is applied topically.

16. The method of any one of claims 12 to 15, the method further comprising exposing vitiligo-affected skin to phototherapy.

17. A kit comprising a topical formulation as described in any one of claims 1 to 7.

18. Use of GLP-1 agonists in the preparation of drugs for the treatment of vitiligo.

19. Use of smegglutinin in the preparation of drugs for the treatment of vitiligo.

20. Use of the topical composition according to any one of claims 1-7 in the preparation of a medicament for treating vitiligo.

21. A GLP-1 agonist for use in the treatment of vitiligo.

22. Smegglutinin, which is used in the treatment of vitiligo.

23. The topical composition according to any one of claims 1 to 7, for use in the treatment of vitiligo.