Methods & compositions for treating dermal atrophy

Abstract

The disclosure relates to methods of using locally administered formulations of a selective inhibitor of VEGFR2 and / or FGFR1, locally administered formulations of a PPAR-gamma agonist, or locally administered formulations of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor for reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject.

Description

[0001] METHODS & COMPOSITIONS FOR TREATING DERMAL ATROPHY

[0002] Field of the Embodiments

[0003]

[0001] The present disclosure relates to the use of an effective amount of a locally administered formulation of selective VEGFR2 and / or FGFR1 inhibitors, the use of an effective amount of a locally administered formulation of PPAR-gamma agonist, or the use of an effective amount of a locally administered formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor for reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject.

[0004] Background of the Embodiments

[0005]

[0002] GLP-1 receptor agonists can be used to treat Type 2 diabetes and treat obesity. A common side effect of GLP- 1 receptor agonist treatment is the atrophy of adipose tissue, including dermal adipose This atrophy of dermal adipose tissue also occurs in the face of a subject, which can result in a hollowed-out appearance and an increase in lines and wrinkles. The loss of adipose tissue can also cause thinning of the skin, especially thinning of facial skin. There is a lack of existing treatments for treating atrophy of facial dermal adipose, hence the need for the development of therapies that can aid subjects in reducing the rate of loss, preventing loss, and / or increasing the thickness of dermal adipose tissue, collectively enhancing dermal adipose tissue thickness, especially for facial dermal adipose tissue, and / or reducing the rate of or preventing the thinning of the skin, especially facial skin.

[0006]

[0003] Herein, described are methods for reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject using an effective amount of a locally administered formulation of selective inhibitors of VEGFR2 and / or FGFR 1.

[0007]

[0004] Herein, also described are methods for reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject using an effective amount of a locally administered formulation of a PPAR-gamma agonist.

[0008]

[0005] Herein, also described are methods reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject using an effective amount of a locally administered formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0009]

[0006] While PPAR-gamma agonists have been shown to play a role in follicle cycling via dermal adipocytes in obese mice (Zhang et al.), Zhang et al. is silent on the ability of PPAR- gamma agonists to reverse the atrophy of dermal adipose tissue under the circumstances described herein. These circumstances include the atrophy of dermal adipose as a result of exposure to GLP-1 agonists, normal aging, weight loss regimens, and other reasons (e.g., HIV-associated facial lipoatrophy, localized scleroderma, chronic treatment with corticosteroids, hormonal changes, yo-yo dieting, poor diet, excessive exercise, stress, excessive sun exposure, smoking, and lupus erythematosus profundus).

[0010] Summary

[0011]

[0007] In the present disclosure, we describe methods of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and / or fibroblast growth factor receptor 1 (FGFR1).

[0012]

[0008] Provided herein is a topical formulation comprising a selective inhibitor of VEGFR2 and FGFR1 and a delivery vehicle.

[0013]

[0009] In some embodiments, the delivery vehicle is selected from the group consisting of an ointment, a cream, a gel, a lotion, a solution, a foam, and a spray. In some embodiments, the delivery vehicle is a lotion.

[0014]

[0010] In some embodiments, the delivery vehicle comprises one or more of a humectant, an emollient, an occludent, or a secondary moisturizing ingredient.

[0015] [Oil] In some embodiments, the secondary moisturizing ingredient is selected from the group consisting of a ceramide, a free fatty acid, and a cholesterol.

[0016]

[0012] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor comprises 0.01%- 3% weight / weight (w / w ) of the topical formulation.

[0017]

[0013] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is brivanib alaninate or Su5402.

[0018]

[0014] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib.

[0019]

[0015] In some embodiments, the lotion comprises one or more of a liquid, a humectant, and a penetration enhancer.

[0020]

[0016] In some embodiments, the lotion further comprises one or more of an emulsifier or a solubilizer, a thickening or a gelling agent, an emollient, a secondary moisturizing ingredient, an emulsifier or a solubilizer, an excipient, a preservative, and an antioxidant.

[0017] In some embodiments, the lotion further comprises an emulsifier or a solubilizer, a thickening or a gelling agent, an emollient, a secondary moisturizing ingredient, an emulsifier or solubilizer, an excipient, a preservative, and an antioxidant.

[0021]

[0018] In some embodiments, the lotion comprises DMSO, ethanol or isopropyl myristate, propylene glycol, and glycerol and / or water.

[0022]

[0019] In some embodiments, the lotion comprises DMSO, ethanol, propylene glycol, glycerol, and water.

[0023]

[0020] In some embodiments, the lotion comprises diethylene glycol monoethyl ether, ethanol, propylene glycol, glycerol, water, and a thickening or a gelling agent.

[0024]

[0021] In some embodiments, the lotion comprises diethylene glycol monoethyl ether, ethanol, propylene glycol, glycerol, water, and hydroxypropyl cellulose.

[0025]

[0022] In some embodiments, the lotion comprises 45% wt / wt diethylene glycol monoethyl ether, 26.5% wt / wt ethanol, 11% wt / wt propylene glycol, 2% wt / wt glycerol, 12.5% wt / wt / water, 1.5% wt / wt hydroxypropyl cellulose, and 1.5% wt / wt the selective inhibitor of VEGFR2 and FGFR1.

[0026]

[0023] In some embodiments, the selective inhibitor of VEGFR2 and FGFR1 is nintedanib.

[0027]

[0024] Provided herein is a topical formulation comprising a PPAR-gamma agonist, a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, and a delivery vehicle.

[0028]

[0025] In some embodiments, the delivery vehicle is selected from the group consisting of an ointment, a cream, a gel, a lotion, a solution, a foam, and a spray. In some embodiments, the delivery vehicle is a lotion.

[0029]

[0026] In some embodiments, the delivery vehicle comprises one or more of a humectant, an emollient, an occludent, or a secondary moisturizing ingredient.

[0030]

[0027] In some embodiments, the secondary moisturizing ingredient is selected from the group consisting of a ceramide, a free fatty acid, and a cholesterol.

[0031]

[0028] In some embodiments, the PPAR-gamma agonist comprises 0.01 %-5% weight / weight (w / w) of the topical formulation.

[0032]

[0029] In some embodiments, the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T- 174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW-1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay- 54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR- 090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB- 900, DRF-4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

[0033]

[0030] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, the PPAR-gamma agonist is pioglitazone.

[0034]

[0031] In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib or nintedanib esylate. In some embodiments, nintedanib comprises 0.01 %-3% weight / weight (wt / wt) of the topical formulation.

[0035]

[0032] In some embodiments, the delivery vehicle comprises propylene glycol, cetyl alcohol, glycerin, and medium chain triglyceride oil.

[0036]

[0033] In some embodiments, the lotion comprises one or more of a liquid, a humectant, and a penetration enhancer.

[0037]

[0034] In some embodiments, the lotion further comprises an emulsifier or a solubilizer, a thickening or a gelling agent, an emollient, a secondary moisturizing ingredient, an emulsifier or a solubilizer, an excipient, a preservative, and an antioxidant.

[0038]

[0035] In some embodiments, the lotion comprises DMSO, ethanol or isopropyl myristate, propylene glycol, and glycerol and / or water.

[0039]

[0036] In some embodiments, the lotion comprises 45% wt / wt DMSO, 26.5% wt / wt ethanol, 11% wt / wt propylene glycol, 2% wt / wt glycerol, 11% wt / wt water, 1.5% wt / wt hydroxypropyl cellulose, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0040]

[0037] In some embodiments, the lotion comprises 45% wt / wt diethylene glycol monoethyl ether, 26.5% wt / wt ethanol, 11% wt / wt propylene glycol, 2% wt / wt glycerol, 11% wt / wt / water, 1.5% wt / wt hydroxypropyl cellulose, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0041]

[0038] In some embodiments, the lotion comprises 45% wt / wt DMSO, 24% wt / wt ethanol, 24% wt / wt propylene glycol; 2% wt / wt fatty alcohol, 2% levulinic acid, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0042]

[0039] In some embodiments, the fatty alcohol is Brij L4.

[0040] In some embodiments, the lotion comprises 32% wt / wt diethylene glycol monoethyl ether, 20% propylene glycol, 31.5% water, 3% Cetamacrogol 1000, 4% isopropyl myristate, 2% medium chain triglyceride oil, 4% polymer, 0.5% silicone, 0.1% methyl paraben, 0.3% butylated hydroxytoluene, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0043]

[0041] In some embodiments, the medium chain triglyceride oil is Crodamol GTCC, the polymer is Sepineo P600, and the silicone is cyclomethicone.

[0044]

[0042] In some embodiments, the lotion comprises 21% wt / wt diethylene glycol monoethyl ether, 15% propylene glycol, 44.5% water, 3% Cetamacrogol 1000, 4% isopropyl myristate, 2% medium chain triglyceride oil, 2% fatty alcohol, 4% polymer, 2% tefose 63, 0.5% silicone, 0.1% methyl paraben, 0.3% butylated hydro xytoluene, 1% wt / wt of the PPAR- gamma agonist, and 1% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0045]

[0043] In some embodiments, the medium chain triglyceride oil is Crodamol GTCC, the fatty alcohol is cetostearyl alcohol, the polymer is Sepineo P600, and the silicone is cyclomethicone.

[0046]

[0044] Provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a selective inhibitor of VEGFR2 and FGFR1.

[0047]

[0045] In some embodiments, the locally administered formulation is a topical formulation.

[0046] In some embodiments, the locally administered formulation is a local subcutaneous injection.

[0048]

[0047] In some embodiments, the subject is receiving a glucagon- like peptide- 1 (GLP-1) receptor agonist. In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide. In some embodiments, the GLP-1 receptor agonist is also a glucosedependent insulinotropic polypeptide (GIP) receptor agonist.

[0049]

[0048] In some embodiments, the dermal adipose and / or skin thickness is measured according to calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectancemode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, patient or clinician-reported rating scale, or a structured light 3D scanner.

[0049] In some embodiments, the topical formulation is as an ointment, a cream, a gel, a lotion, a solution, a foam, or a spray.

[0050]

[0050] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is selected from the group consisting of [4-(2,4-Difluoro-5-methoxycarbamoyl-phenylamino)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-6-yl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, Brivanib, Brivanib Alaninate, 2,4-Difluoro-5-[5-isopropyl-6-(5-trifluoromethyl-[l ,3,4]oxadiazol-2-yl)- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, 5-[(l-Ethylpiperidin-4- yl)amino]-3-[lH-imidazol-2-yl(phenyl)methylidene]-lH-indol-2-one, 2,4-Difluoro-5-[5- isopropyl-6-(5-methyl-4H-[l,2,4]triazol-3-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 5-[6-(5-Dimethylamino-[l,3,4]oxadiazol-2-yl)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N-methoxy-benzamide, 2,4-Difluoro-5- [5-isopropyl-6-(3-methyl-[l,2,4]oxadiazol-5-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 3-[(3-(2-Carboxyethyl)-4-methylpyrrol-2-YL)methylene]-2-indolinone (SU5402), 2,4-Difluoro-5-[5-isopropyl-6-(5-methyl-[l,3,4]oxadiazol-2-yl)-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, 5-[6-(5-Difluoromethyl- [l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N- methoxy-benzamidem, 3-[Benzimidazol-2-ylidene-(3-fluorophenyl)methyl]-5-[(l- ethylpiperidin-4-yl)amino]-lH-indol-2-ol, N-(Cyclopropylmethyl)-3-(l-methylpyrazol-4- yl)-N-phenylquinoxalin-6-amine, 2,4-Difluoro-5-(5-isopropyl-6-[l,3,4]oxadiazol-2-yl- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino)-N-methoxy-benzamide, 7-(4-Fluoroanilino)-l- [(lR,3R)-3-hydroxycyclopenty]]-3-(4-methoxyphenyl)-4H-pyrimido[4,5-d]pyrimidin-2-one, 5-[6-(5-Cyclopropyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4- ylamino]-2,4-difluoro-N-methoxy-benzamide, 6-(5-Methyl-l,3,4-oxadiazol-2-yl)-5-propan- 2-yl-N-(lH-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine, N- (Cyclopropylmethyl)-N-[3-methoxy-5-(trifluoromethyl)phenyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, 3-[Benzimidazol-2-ylidene-(3,5-difluorophenyl)methyl]-5-[(l- ethylpiperidin-4-yl)amino]-lH-indol-2-ol, 1,6-Naphthyridine 76, 2,4-Difluoro-5-{5- isopropyl-6-[5-(2,2,2-trifhioro-ethyl)-[l,3,4]oxadiazol-2-yl]-pyrrolo[2,l-f][l,2,4]triazin-4- ylamino}-N-methoxy-benzamide, (+)-(lR,3R)-l-(3-Hydroxy-cyclopentyl)-3-(4-methoxy- phenyl)-7-phenylamino-3,4-dihydro-lH-pyrimido[4,5-d]pyrimidin-2-one, 1,6-Naphthyridine 75, (-)-(lS,3S)-l-(3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4- dihydro-lH-pyrimido[4,5-d]pyrimidin-2-one, N-(Cyclopropylmethyl)-N-[3- [(dimethylamino)methyl]-5-methoxyphenyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-[3-(Aminomethyl)-5-methoxyphenyl]-N-(cyclopropylmethyl)-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine;hydrochloride, Chembl4573547, 1,6-Naphthyridine 77, 1,6- Naphthyridine 19, 1,6-Naphthyridine 26, N-(Cyclopropylmethyl)-N-[3- (difluoromethoxy)phenyl]-3-( 1 -methylpyrazol-4-yl)quinoxalin-6-amine, N'-(3,4-Difluoro-5- methoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- trifluoroethyl)propane-l,3-diamine;hydrochloride, 2,4-Difluoro-5-[5-isopropyl-6-(5- methanesulfonylmethyl-[l,3,4]oxadiazol-2-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 5-(2-Chlorophenyl)-7-fluoro- 1 ,2-dihydro-8-methoxy-3- methylpyrazolo(3,4-b)(l,4)benzodiazepine, [3-[Cyclopropylmethyl-[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]amino]-5-methoxyphenyl]-pyrrolidin- 1 -ylmethanone, 5- [( 1 - Ethylpiperidin-4-yl)amino]-3-[(2-fluorophenyl)-(5-methyl-lH-imidazol-2-yl)methylidene]- lH-indol-2-one, 5-[6-(5-Cyclopropylmethyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N-methoxy-benzamide, 3-[(3,5-Difluorophenyl)-(5- methyl-lH-imidazol-2-yl)methylidene]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-one, 5- [(1 -Ethylpiperidin-4-yl)amino]-3 - [(3-fluorophenyl)-( 1 H-imidazol-2-yl)methylidene] - 1 H- indol-2-one, Indolin-2-one deriv. 9c, Methyl (3Z)-2-oxo-3-[phenyl-[4-(piperidin-l- ylmethyl)anilino]methylidene]-lH-indole-6-carboxylate, N-(3,5-Dimethoxyphenyl)-N-[3-(3- methylimidazol-4-yl)prop-2-ynyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, (3z)-5-[( 1- Ethylpiperidin-4-Yl)amino]-3-[(5-Methoxy-lh-Benzimidazol-2-Yl)(Phenyl)methylidene]- l,3-Dihydro-2h-Indol-2-One, Chembl4449189, [5-Amino-l-(lH-indol-5-yl)pyrazol-4-yl]- (lH-indol-2-yl)methanone, 5-Isopropyl-6-(5-methyl-l,3,4-oxadiazol-2-yl)-N-(2-methyl-lH- pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine, 3-[Benzimidazol-2-ylidene- (4-methylphenyl)methyl]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-ol, 5-[6-(5-Ethyl- [l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N- methoxy-benzamide, 3-[Benzimidazol-2-ylidene(phenyl)methyl]-5-[(l-ethylpiperidin-4- yl)amino]-lH-indol-2-ol, 1,6-Naphthyridine 25, 2-(6-Fluoro-lH-indazol-3-yl)-5-(4- (piperidin-l-yl)piperidin-l-yl)-lH-benzo[d]imidazole, 3-[Benzimidazol-2-ylidene-(4- methoxyphenyl)methyl]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-ol, N-

[0051] (Cyclopropylmethyl)-N-[3-methoxy-5-[2-(methylamino)ethoxy]phenyl]-3-(l- methylpyrazol-4-yl)quinoxalin-6-amine, 3-Methoxy-N-methyl-5-[f3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]-[2-(propan-2-ylamino)ethyl]amino]benzamide, XL999;XL-999; XL 999, 3-N-(Cyclopropylmethyl)-l-N-methyl-3-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6- yl]benzene-l,3-diamine, 2,4-Difluoro-5-[6-(5-isobutyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, Methyl 2-hydroxy-3-[N-[4- [2-methyl-5-[(4-methylpiperazin-l-yl)methyl]pyrrol-l-yl]phenyl]-C-phenylcarbonimidoyl]- lH-indole-6-carboxylate, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[(2- pyridin-4-ylcyclopropyl)methyl]quinoxalin-6-amine, 3-(3,5-Dimethoxyphenyl)-7-N-[3-(4- methylpiperazm-l-yl)propyl]-l,6-naphthyridine-2,7-diamine, 9-Chloro-2-[3-[3- (dimethylamino)propyl]anilino]-5,7-dihydropyrimido[5,4-d][l]benzazepine-6-thione, Pyrido[2,3-d]pyrimidine 103, Pyrido[2,3-d]pyrimidine 105, 2,4-Difluoro-5-[5-isopropyl-6- (5-methyl-oxazol-2-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, N- (3,5-Dimethoxyphenyl)-N-[3-(2,5-dimethylimidazol-l-yl)propyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine;hydrochloride, N- [3- [2- [6-(2-Chlorophenyl)-2- [4- (diethylamino)butylamino]-7-oxopyrido[2,3-d]pyrimidin-8-yl]ethyl]phenyl]prop-2-enamide, N-(3,5-Dimethoxyphenyl)-3-(l -methylpyrazol-4-yl)-N-(2-piperazin- 1 -ylethyl)quinoxalin-6- amine;hydrochloride, Methyl (3Z)-3-[[4-[2-(dimethylamino)ethyl- methylsulfonylamino]anilino]-phenylmethylidene]-2-oxo-lH-indole-6-carboxylate, 4-[3- (3,5-Dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)prop-l-ynyl]pyridine- 3-carbonitrile, N-[(5-Chlorothiophen-2-yl)methyl]-N-(3,5-dimethoxyphenyl)-3-[l-(2- piperazin-l-ylethyl)pyrazol-4-yl]quinoxalin-6-amine;hydrochloride, N'-(3,5- Dichlorophenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- trifluoroethyl)propane-l,3-diamine, 2-[4-[7-[N-(Cyclopropylmethyl)anilino]quinoxalin-2- yl]pyrazol-l-yl]ethanol, Pyrido[2,3-d]pyrimidine 102, 7-N-[4-(Diethylamino)butyl]-3-(3,5- dimethoxyphenyl)-l,6-naphthyridine-2,7-diamine, N-(3,5-Dimethoxyphenyl)-N-[3-(4- methoxypyrimidin-2-yl)propyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, Methyl 3-[[4- [(dimethy]amino)methyl]anilino]-phenylmethylidene]-2-oxo-lH-indole-6-carboxylate, 3- Fluoro-N-methyl-5-[[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-[2-(propan-2- ylamino)ethyl]amino]benzamide, N-(Cyclopropylmethyl)-N-[3-(l,3-dioxolan-2-yl)-5- methoxyphenyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-[[(2S)-l-[3-(3,5- Dimethoxy-N- [3 -( 1 -methylpyrazol-4-yl)quinoxalin-6-y l]anilino)propyl]pyrrolidin-2- yl]methyl]- 1,1,1 -trifluoromethanesulfonamide, 3-Methoxy-N-methyl-5- [2-(propan-2- ylamino)ethyl-[3-(l-propan-2-ylpyrazol-4-yl)quinoxalin-6-yl]amino]benzamide, 5-{6-[5- (Difluoro-methanesulfonyl-methyl)-[l,3,4]oxadiazol-2-yl]-5-isopropyl-pyrrolo[2,l- f|[l,2,4]triazin-4-ylamino}-2,4-difluoro-N-methoxy-benzamide, N-[2-(3-Aminopiperidin-l- yl)ethyl]-N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5- Dimethoxyphenyl)-N-[(E)-3-(4-methoxypyrimidin-2-yl)prop-2-enyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, Methyl (3Z)-3-[[4-[acetyl-[2-(dimethylamino)ethyl]amino]anilino]- phenylmethylidene] -2-oxo- lH-indole-6-carboxylate, Methyl N-[4-[7-amino-3-(3,4- dimethoxyphenyl)-5-(l-methylpiperidin-4-yl)oxypyrazolo[l,5-a]pyrimidin-6- yl]phenyl]carbamate, Anilinoquinazoline deriv. 35, 1 ,6-Naphthyridine 17, Tert-butyl (lS,4S)-5-[2-(3,5-dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethyl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate, Lucitanib, 6-((7-((l -

[0052] Aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-N-methyl-l-naphthamide hydrochloride, Pyrido[2,3-d]pyrimidine 104, Nintedanib esylate, [(2S)-l-(3,5-Dimethoxy-N- [3-( 1 -methy lpyrazol-4-yl)quinoxalin-6-y 1] anilino)-3 -methoxypropan-2-yl] acetate, 3 - [2- Aminoethyl-f3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]amino]-5-methoxy-N- methylbenzamide, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[3-[4- (trifluoromethyl)piperidin-l-yl]propyl]quinoxalin-6-amine, 3-((4-Bromo-2,6- difluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide, N- (3,5-Dimethoxyphenyl)-N-[3-(2-methylimidazol-l-yl)propyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, 3-[3-(Morpholinomethyl)-4,5,6,7-tetrahydro-lH-indole-2- ylmethylene]-5-(ethylsulfonyl)-2,3-dihydro-lH-indole-2-one, 2-(3-Methoxy-N-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethanol, Epihematoxylol, N-[3-(5- Aminopyrazin-2-yl)prop-2-ynyl]-N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, 2-[3-[2-Aminoethyl-[7-(l-methylpyrazol-4-yl)quinoxalin-2- yl]amino]-5-fluorophenoxy]ethanol, N-[3-(3-Aminopyridin-2-yl)prop-2-ynyl]-N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5-Dimethoxyphenyl)- N-[3-(3-methoxypyridin-2-yl)propyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5- Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[(Z)-3-pyrimidin-2-ylprop-2- enyl]quinoxalin-6-amine, N'-(3,5-Dimethoxyphenyl)-N-methyl-N'-[3-[l -(oxan-4- ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]ethane-l,2-diamine;hydrochloride, [5-Amino-l-(2- chloro-5-hydroxyphenyl)pyrazol-4-yl]-[5-(morpholin-4-ylmethyl)-lH-indol-2-yl]methanone, 1,6-Naphthyridine 18, l-Tert-butyl-3-[3-(3,5-dimethoxyphenyl)-7-[4-(4-methylpiperazin-l- yl)butylamino]-l,6-naphthyridin-2-yl]urea, N'-(2-Chloro-3,5-dimethoxyphenyl)-N'-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane- 1 ,2-diamine;hydrochloride, N- (3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(3-piperazin-l-ylpropyl)quinoxalin-6- amine, Methyl (3Z)-3 - [ [4- [acetyl- [3-(dimethylamino)propyl] amino] anilino] - phenylmethylidene] -2-oxo- 1 H-indole-6-carboxylate, 3 - [4- [3 - [4- [7- [N-(Cyclopropylmethyl)- 3,5-dimethoxyanilino]quinoxalin-2-yl]pyrazol-l-yl]propyl]piperazin-l-yl]propan-l- ol;hydrochloride, 5-[(R)-l-(3,5-Dichloropyridine-4-yl)ethoxy]-3-[5-(4-methylpiperazine-l- yl)-lH-benzoimidazole-2-yl]-lH-indazole, 4-Amino-3-(lH-benzo[d]imidazol-2-yl)quinolin- 2( lH)-one, 3- [4- [3 - [4- [7- [3 ,5-Dimethoxy-N- [2-(propan-2-ylamino)ethyl]anilino]quinoxalin- 2-yl]pyrazol- 1 -yl]propyl]piperazin- 1 -yl]propan- 1 -ol;hydrochloride, 2-(2,6-Difluoro-3,5- dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethanol, [4-[7-[3,5- Dimethoxy-N-[2-(propan-2-ylamino)ethyl]anilino]quinoxalin-2-yl]-2-methylpyrazol-3- yl]methanol, 1,6-Naphthyridine deriv. 20, N-(2-Chloro-3,5-dimethoxyphenyl)-3-(l- methylpyrazol-4-yl)-N-(3-pyrrolidin- 1 -ylpropyl)quinoxalin-6-amine;hydrochloride, Methyl 3-[N-[4-[2-(dimethylamino)ethyl-methylcarbamoyl]phenyl]-C-phenylcarbonimidoyl]-2- hydroxy-lH-indole-6-carboxylate, N-[2-(l,4-Diazepan-l-yl)ethyl]-N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amme;oxalic acid, N'-(2,6- Difluoro-3,5-dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2- ylethane- 1 ,2-diamine, N-(3,5-Dimethoxyphenyl)-N-[(3-methyloxetan-3-yl)methyl]-3-(l- methylpyrazol-4-yl)quinoxalin-6-amine, Methyl (3Z)-3-[[4-[acetyl-[2-(dimethylamino)-2- oxoethyl]amino]anilino]-phenylmethylidene]-2-oxo-lH-indole-6-carboxylate, Chembl4213341, Anilinoquinazoline deriv. 36, [5-Amino-l-(lH-benzimidazol-6-yl)-lH- pyrazol-4-yl] - 1 H-indol-2-ylMethanone, Hematoxylone, N-Cyclopropyl-N'-(3 ,5 - dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine, N-(3,5- Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(3-pyrimidin-2-ylpropyl)quinoxalin-6- amine, N'-(3,5-Dimethoxyphenyl)-N'-[3-[5-[(dimethylamino)methyl]-l-methylpyrazol-4- yl]quinoxalin-6-yl]-N-propan-2-ylethane-l,2-diamine, N'-(2,6-Difluoro-3,5- dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- trifluoroethyl)propane-l,3-diamine, [5-Amino-l-(2-methyl-lH-indol-5-yl)pyrazol-4-yl]-(lH- indol-2-yl)methanone, Haematoxylin, N'-(3,5-Dimethoxyphenyl)-N'-[3-(5-ethyl-l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2-trifluoroethyl)ethane- 1 ,2-diamine, Methyl 3- [N-[4-[[dimethylcarbamoyl(methyl)amino]methyl]phenyl]-C-phenylcarbonimidoyl]-2- hydroxy-lH-indole-6-carboxylate, 3-Methoxy-N-methyl-5-[[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]-(3-pyrrolidin-l-ylpropyl)amino]benzamide, N-(3,5-Dimethoxyphenyl)- 3-(l-methylpyrazol-4-yl)-N-(3-pyridin-4-ylpropyl)quinoxalin-6-amine, l-[3-(3,5- Dimethoxy-N-[3-(l-propan-2-ylpyrazol-4-yl)quinoxalin-6-yl]anilino)propyl]pyrroli din-2- one, and Regorafenib.

[0053]

[0051] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is Brivanib Alaninate (Brivanib).

[0054]

[0052] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is selected from the group comprising of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib.

[0055]

[0053] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is nintedanib.

[0054] In some embodiments, the subject’s age is 30-39 years, 40-49 years, 50-59 years, 60- 69 years, 70-79 years, 80-89 years or 90-99 years.

[0056]

[0055] In some embodiments, the subject does not have acne.

[0057]

[0056] Provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist, wherein the subject is receiving a glucagon-like peptide- 1 (GLP-1) receptor agonist.

[0058]

[0057] Provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist, wherein the subject is receiving a corticosteroid.

[0059]

[0058] In some embodiments, the locally administered formulation is a topical formulation.

[0059] In some embodiments, the locally administered formulation is a local subcutaneous injection.

[0060]

[0060] In some embodiments, the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T- 174, UHC-1 , aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW-1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay- 54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR- 090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB- 900, DRF-4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

[0061]

[0061] In some embodiments, the PPAR-gamma agonist is rosiglitazone.

[0062]

[0062] In some embodiments, the PPAR-gamma agonist is selected from the group consisting of pioglitazone, CHS- 131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131 , KY- 903, MK-0533, pioglitazone hydrochloride, R-483, T-174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW-1929, GW- 409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB- 219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F- 707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

[0063]

[0063] In some embodiments, the PPAR-gamma agonist is pioglitazone.

[0064]

[0064] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide.

[0065]

[0065] In some embodiments, the GLP-1 receptor agonist is also a GIP-receptor agonist.

[0066] In some embodiments, the GLP-1 receptor agonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

[0066]

[0067] In some embodiments, the corticosteroid is selected from the group consisting of 11- Dehydrocorticosterone, 11 -Deoxycorticosterone, 11 -Deoxycortisol, 11 -Ketoprogesterone, 11 P-Hydroxypregnenolone, 11 P-Hydroxyprogesterone, 11 P, 17a, 21 - Trihydroxypregnenolone, 17a, 21 -Dihydroxypregnenolone, 17a-Hydroxypregnenolone, 17a- Hydroxyprogesterone, 18-Hydroxy- 11 -deoxycorticosterone, 18-Hydroxycorticosterone, 18- Hydroxyprogesterone, 21 -Deoxycortisol, 21 -Deoxycortisone, 21 -Hydroxypregnenolone, Aldosterone, Corticosterone, Cortisol, Cortisone, Pregnenolone, Progesterone, Flugestone, FluoromethoIone, Medrysone, Prebediolone acetate, Chloroprednisone, Cloprednol, Difluprednate, Fludrocortisone, Fluocinolone, Fluperolone, Fluprednisolone, Loteprednol, Methylprednisolone, Prednicarbate, Prednisolone, Prednisone, Tixocortol, Triamcinolone, Alclometasone, Beclometasone, Betamethasone, Clobetasol, Clobetasone, Clocortolone, Desoximetasone, Dexamethasone, Diflorasone, Difluocortolone, Fluclorolone, Flumetasone, Fluocortin, Fluocortolone, Fluprednidene, Fluticasone, Fluticasone furoate, Halometasone, Meprednisone, Mometasone, Mometasone furoate, Paramethasone, Prednylidene, Rimexolone, Ulobetasol, Amcinonide, Budesonide, Ciclesonide, Deflazacort, Desonide, Formocortal, Fluclorolone acetonide, Fludroxycortide, Flunisolide, Fluocinolone acetonide, Fluocinonide, Halcinonide, Triamcinolone acetonide, Cortivazol, and RU-28362.

[0068] In some embodiments, the corticosteroid is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

[0067]

[0069] In some embodiments, the dermal adipose and / or skin thickness is measured according to calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectancemode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, patient or clinician-reported rating scale, or a structured light 3D scanner.

[0068]

[0070] In some embodiments, topical formulation is as an ointment, cream, gel, lotion, solution, foam, or spray.

[0069]

[0071] In some embodiments, the subject’s age is 30-39 years, 40-49 years, 50-59 years, 60- 69 years, 70-79 years, 80-89 years or 90-99 years.

[0070]

[0072] Provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation comprising a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0071]

[0073] In some embodiments, the locally administered formulation is a topical formulation.

[0074] In some embodiments, the locally administered formulation is a local subcutaneous injection.

[0072]

[0075] In some embodiments, the subject is receiving a glucagon- like peptide- 1 (GLP-1) receptor agonist.

[0073]

[0076] In some embodiments, the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol, farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE- 0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW-1929, GW- 409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB- 219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F- 707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone. In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, the PPAR-gamma agonist is pioglitazone.

[0074]

[0077] In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of 5-Iodo-sunitinib, 5-Methoxy-sunitinib, Acrizanib, Agerafenib, Alectinib, Altiratinib, Amuvatinib, Amuvatinib hydrochloride, Apatinib, Apatinib Mesylate, Avapritinib, Axitinib, Bafetinib, Bemcentinib, Bosutinib, Brivanib, Brivanib alaninate, Brivanib metabolite M25, Cabozantinib, Cabozantinib oxidation B, Cabozantinib S-malate, Canertinib, Cediranib, Cerdulatinib hydrochloride, Ceritinib, Crenolanib, Dasatinib, Defactinib, Desmethyl nintedanib, Dovitinib, Entrectinib, Erdafitinib, Erlotinib, Famitinib, Fedratinib, Fisogatinib, Foretinib, Fostamatinib disodium, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, Golvatinib, Gunagratinib, Henatinib, Imatinib, Infigratinib, Infigratinib phosphate, Lapatinib, Lenvatinib, Lestaurtinib, Linifanib, Linsitinib, Lucitanib, Masitinib, Mivavotinib, Motesanib, N,N-Dimethyl Sunitinib, N-Desethyl Sunitinib, N-Desmethyl vandetanib, Neratinib, Nilotinib, Ningetinib, Nintedanib, Nintedanib esylate, Orantinib, Pacritinib, Pazopanib, Pelitinib, Pemigatinib, Pexidartinib, Pexmetinib, Ponatinib, Pralsetinib, Quizartinib, Quizartinib dihydrochloride, Ravoxertinib, Regorafenib, Ripretinib, Rogaratinib, Saracatinib, Selpercatinib, Semaxanib, Sitravatinib, Sorafenib, Sorafenib tosylate, Sunitinib, Tafetinib, Tamatinib, Tandutinib, Telatinib, Tesevatinib, Tivozanib, Toceranib, US10155768, Vandetanib, US9029401 , Sunitinib, Vandetanib, Vandetanib hydrochloride, Vatalanib, Vatalanib succinate, Vemurafenib, and Vimseltinib.

[0075]

[0078] In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib. In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib or nintedanib esylate.

[0076]

[0079] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide. In some embodiments, the GLP-1 receptor agonist is also a GIP-receptor agonist. In some embodiments, the GLP- 1 receptor agonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

[0077]

[0080] In some embodiments, the dermal adipose and / or skin thickness is measured according to calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectancemode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, patient or clinician-reported rating scale, or a structured light 3D scanner.

[0078]

[0081] In some embodiments, the topical formulation is as an ointment, a cream, a gel, a lotion, a solution, a foam, or a spray.

[0079]

[0082] In some embodiments, the subject’s age is 30-39 years, 40-49 years, 50-59 years, 60- 69 years, 70-79 years, 80-89 years or 90-99 years.

[0080]

[0083] Provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation comprising a means for activating PPAR- gamma and a means for inhibiting PDGFRA / B, VEGFR2 and / or FGFR1.

[0081]

[0084] In some embodiments, the means for activating PPAR-gamma is selected from the group consisting of rosiglitazone, pioglitazone, CHS-131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol, farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW- 1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN- 862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO- 52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF- 4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO- 5129, ZYH2, PN2034, and lobeglitazone.

[0082]

[0085] In some embodiments, the means for inhibiting PDGFRA / B, VEGFR2 and / or FGFR1 is selected from the group consisting of 5-Iodo-sunitinib, 5-Methoxy-sunitinib, Acrizanib, Agerafenib, Alectinib, Altiratinib, Amuvatinib, Amuvatinib hydrochloride, Apatinib, Apatinib Mesylate, Avapritinib, Axitinib, Bafetinib, Bemcentinib, Bosutinib, Brivanib, Brivanib alaninate, Brivanib metabolite M25, Cabozantinib, Cabozantinib oxidation B, Cabozantinib S-malate, Canertinib, Cediranib, Cerdulatinib hydrochloride, Ceritinib, Crenolanib, Dasatinib, Defactinib, Desmethyl nintedanib, Dovitinib, Entrectinib, Erdafitinib, Erlotinib, Famitinib, Fedratinib, Fisogatinib, Foretinib, Fostamatinib disodium, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, Golvatinib, Gunagratinib, Henatinib, Imatinib, Infigratinib, Infigratinib phosphate, Lapatinib, Lenvatinib, Lestaurtinib, Linifanib, Linsitinib, Lucitanib, Masitinib, Mivavotinib, Motesanib, N,N-Dimethyl Sunitinib, N-Desethyl Sunitinib, N-Desmethyl vandetanib, Neratinib, Nilotinib, Ningetinib, Nintedanib, Nintedanib esylate, Orantinib, Pacritinib, Pazopanib, Pelitinib, Pemigatinib, Pexidartinib, Pexmetinib, Ponatinib, Pralsetinib, Quizartinib, Quizartinib dihydrochloride, Ravoxertinib, Regorafenib, Ripretinib, Rogaratinib, Saracatinib, Selpercatinib, Semaxanib, Sitravatinib, Sorafenib, Sorafenib tosylate, Sunitinib, Tafetinib, Tamatinib, Tandutinib, Telatinib, Tesevatinib, Tivozanib, Toceranib, US10155768, Vandetanib, US9029401, Sunitinib, Vandetanib, Vandetanib hydrochloride, Vatalanib, Vatalanib succinate, Vemurafenib, and Vimseltinib.

[0083] Brief Description of the drawings

[0084]

[0086] FIGURE (FIG.) 1 A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at anterior location following treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0085]

[0087] FIG. IB. Dermis thickness, pm, of C57BL6 mice at anterior location following treatment with an IP injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0086]

[0088] FIG. 1C. Skin thickness, pm, of C57BL6 mice at anterior location following treatment with an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0087]

[0089] FIG. ID. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at posterior location following treatment with an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0088]

[0090] FIG. IE. Dermis thickness, pm, of C57BL6 mice at posterior location following treatment with an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0089]

[0091] FIG. IF. Skin thickness, pm, of C57BL6 mice at posterior location following treatment with an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0090]

[0092] FIG. 1G. Body weight of the C57BL6 mice treated with an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of vehicle alone plus a topical formulation of vehicle.

[0091]

[0093] FIG. 1H is an exemplary mouse labeled with an anterior site, where topical treatment is administered, and a posterior site, where topical treatment is not administered.

[0092]

[0094] FIG. 2A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0095] FIG. 2B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0093]

[0096] FIG. 2C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0094]

[0097] FIG. 2D. Dermal white adipose tissue thickness(dWAT), pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0098] FIG. 2E. Dermis thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0095]

[0099] FIG. 2F. Skin thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0096]

[0100] FIG. 2G. Body weight of the C57BL6 mice treated with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate.

[0097]

[0101] FIG. 3A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate, at the indicated weight / weight (w / w) percentage.

[0098]

[0102] FIG. 3B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate, at the indicated weigh / weight (w / w) percentage.

[0099]

[0103] FIG. 3C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate, at the indicated weigh / weight (w / w) percentage.

[0100]

[0104] FIG. 3D. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate, at the indicated weight / weight (w / w) percentage.

[0101]

[0105] FIG. 3E. Dermis thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate, at the indicated weigh / weight (w / w) percentage.

[0102]

[0106] FIG. 3F. Skin thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, brivanib alaninate, at the indicated weight / weight (w / w) percentage.

[0103]

[0107] FIG. 4A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402.

[0104]

[0108] FIG. 4B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402.

[0105]

[0109] FIG. 4C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402.

[0106] [HO] FIG. 4D. Dermal white adipose tissue thickness(dWAT), pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402. [Hl] FIG. 4E. Dermis thickness, m, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402.

[0107]

[0112] FIG. 4F. Skin thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a vehicle, or an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402.

[0108]

[0113] FIG 5. Body weight of the C57BL6 mice treated with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, an IP injection of semaglutide plus a topical formulation of an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402.

[0109]

[0114] FIG. 6A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0110]

[0115] FIG. 6B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0111]

[0116] FIG. 6C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0112]

[0117] FIG. 6D. Dermal white adipose tissue thickness (dWAT), pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0118] FIG. 6E. Dermis thickness, m, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0113]

[0119] FIG. 6F. Skin thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0114]

[0120] FIG. 6G. Body weight of the C57BL6 mice treated with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of rosiglitazone.

[0115]

[0121] FIG. 7A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0116]

[0122] FIG. 7B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0117]

[0123] FIG. 7C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0118]

[0124] FIG. 7D. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0119]

[0125] FIG. 7E. Dermis thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0126] FIG. 7F. Skin thickness, pm, of C57BL6 mice at the posterior location following treatment with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0120]

[0127] FIG. 7G. Body weight of the C57BL6 mice treated with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of semaglutide plus a topical formulation of pioglitazone.

[0121]

[0128] FIG. 7H is an exemplary mouse labeled with an anterior site, where topical treatment is administered, and a posterior site, where topical treatment is not administered, as well as the site of an IP injection.

[0122]

[0129] FIG. 8A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus a subcutaneous injection of vehicle, or an IP injection of semaglutide plus a subcutaneous injection of rosiglitazone.

[0123]

[0130] FIG. 8B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus a subcutaneous injection of vehicle, or an IP injection of semaglutide plus a subcutaneous injection of rosiglitazone.

[0124]

[0131] FIG. 8C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with an IP injection of vehicle plus a subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus a subcutaneous injection of vehicle, or an IP injection of semaglutide plus a subcutaneous injection of rosiglitazone.

[0125]

[0132] FIG. 8D. Body weight of the C57BL6 mice treated with an IP injection of vehicle plus a subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus a subcutaneous injection of vehicle, or an IP injection of semaglutide plus a subcutaneous injection of rosiglitazone.

[0126]

[0133] FIG. 8E is an exemplary mouse labeled with an anterior site, where a subcutaneous injection is administered as well as the site of an IP injection.

[0127]

[0134] FIG. 9A. Dermal white adipose tissue (dWAT) thickness, pm, of C57BL6 mice at the anterior location following treatment with topical formulation of vehicle, topical formulation of an exemplary corticosteroid, fluocinonide, or a topical formulation of a combination of an exemplary corticosteroid, fluocinonide, and pioglitazone.

[0128]

[0135] FIG. 9B. Dermis thickness, pm, of C57BL6 mice at the anterior location following treatment with topical formulation of vehicle, topical formulation of an exemplary corticosteroid, fluocinonide, or a topical formulation of a combination of an exemplary corticosteroid, fluocinonide, and pioglitazone.

[0129]

[0136] FIG. 9C. Skin thickness, pm, of C57BL6 mice at the anterior location following treatment with topical formulation of vehicle, topical formulation of an exemplary corticosteroid, fluocinonide, or a topical formulation of a combination of an exemplary corticosteroid, fluocinonide, and pioglitazone.

[0130]

[0137] FIG. 10A. Anterior dorsal dermal white adipose tissue (dWAT) thickness, pm, from female 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of vehicle (PBS) plus a topical formulation of vehicle (1:2 lotiomDMSO).

[0131]

[0138] FIG. 10B. Anterior dorsal dermis thickness, pm, from female 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of vehicle (PBS) plus a topical formulation of vehicle (1:2 lotiomDMSO).

[0132]

[0139] FIG. IOC. Anterior dorsal skin thickness, pm, from female 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle, or an IP injection of vehicle (PBS) plus a topical formulation of vehicle (1:2 lotiomDMSO).

[0133]

[0140] FIG. HA. Anterior dorsal dermal white adipose tissue (dWAT) thickness, pm, from female, 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle (1:2 lotiomDMSO), IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.02% weight / weight (w / w) in vehicle, IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle, or IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a combination of an exemplary PPAR gamma agonist, Pioglitazone, and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, both formulated at 0.02% w / w in vehicle.

[0141] FIG. 11B. Anterior dorsal dermis thickness, |im, from female, 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle (1:2 lotio DMSO), IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.02% w / w in vehicle, IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle, or IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a combination of an exemplary PPAR gamma agonist, Pioglitazone, and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, both formulated at 0.02% w / w in vehicle.

[0134]

[0142] FIG. 11C. Anterior dorsal skin thickness, m, from female, 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle (1:2 lotiomDMSO), IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.02% w / w in vehicle, IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle, or IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a combination of an exemplary PPAR gamma agonist, Pioglitazone, and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, both formulated at 0.02% w / w in vehicle.

[0135]

[0143] FIG. 12A. Anterior dorsal skin dermal white adipose tissue (dWAT) thickness, pm, from female, 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle (1:2 lotiomDMSO), IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.2% w / w in vehicle, IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle, or IP injection of an exemplary GLP- 1 receptor agonist, semaglutide, plus topical administration of a combination of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.2% w / w in vehicle, and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle.

[0144] FIG. 12B. Anterior dorsal dermis thickness, |im, from female 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle (1 :2 lotio DMSO), IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.2% w / w in vehicle, IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle, or IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a combination of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.2% w / w in vehicle, and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle.

[0136]

[0145] FIG. 12C. Anterior dorsal skin thickness, m, from female 7-9 month old C57BL6 mice following treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of vehicle (1 :2 lotiomDMSO), IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.2% w / w weight / weight (w / w) in vehicle, IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle, or IP injection of an exemplary GLP-1 receptor agonist, semaglutide, plus topical administration of a combination of an exemplary PPAR gamma agonist, Pioglitazone, formulated at 0.2% w / w in vehicle, and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.02% w / w in vehicle.

[0137]

[0146] FIG. 13 A. Anterior dorsal skin dermal white adipose tissue (dWAT) thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, tirzepatide or an IP injection of vehicle (PBS).

[0138]

[0147] FIG. 13B. Anterior dorsal dermis thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, tirzepatide or an IP injection of vehicle (PBS).

[0139]

[0148] FIG. 13C. Anterior dorsal skin thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, tirzepatide or an IP injection of vehicle (PBS).

[0149] FIG. 14A. Anterior dorsal skin dermal white adipose tissue (dWAT) thickness, m, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide.

[0140]

[0150] FIG. 14B. Anterior dorsal dermis thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide.

[0151] FIG. 14C. Anterior dorsal skin thickness, m, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide.

[0141]

[0152] FIG. 15A. Anterior dorsal skin dermal white adipose tissue (dWAT) thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.5% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide.

[0153] FIG. 15B. Anterior dorsal dermis thickness, |im, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.5% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide.

[0142]

[0154] FIG. 15C. Anterior dorsal skin thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.5% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide.

[0143]

[0155] FIG. 16 A. Anterior dorsal skin dermal white adipose tissue (dWAT) thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide.

[0144]

[0156] FIG. 16B. Anterior dorsal dermis thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide.

[0145]

[0157] FIG. 16C. Anterior dorsal skin thickness, pm, from female 7-9 month old C57BL6 mice following 4 days of treatment with an intraperitoneal (IP) injection of an exemplary GLP- 1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of vehicle (10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, 35% w / w medium chain triglyceride oil) and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and continued IP injection of tirzepatide, 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide, or 4 days of treatment with an IP injection of an exemplary GLP-1 receptor agonist, tirzepatide, then 8 days of treatment with topical administration of a combination of an exemplary PPAR gamma agonist, rosiglitazone, formulated at 0.05% w / w in vehicle and an exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, nintedanib, formulated at 0.5% w / w in vehicle and continued IP injection of tirzepatide

[0146] Detailed description of the embodiments

[0147] Definitions

[0148]

[0158] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0149]

[0159] As used herein, the terms “treat” or “treatment” are used interchangeably and are meant to indicate administering one or more compounds in accordance with the methods of the embodiments to enhance dermal adipose tissue thickness to obtain a desired therapeutic objective. The term “treatment” as used herein covers any treatment of a symptom or condition in a mammal, particularly a human, and includes: (a) inhibiting the symptom or condition, i.e., arresting its development; or (b) relieving the symptom or condition, i.e., causing regression of the symptoms or conditions. The treatment may be therapeutic in terms of a partial or complete cure of a condition, symptom, or adverse effect attributed to the symptom or condition.

[0150]

[0160] The term “prevention” as used herein, including the related terms such as “prevent” or “preventing,” is meant to refer to provide a subject not yet affected by the condition with a benefit that serves to avoid, delay, forestall, minimize, or reduce the recurrence / onset of the condition to be prevented and / or its attendant symptoms. Such preventive benefits include, for example, delaying development and / or recurrence of the condition, or reducing the duration, severity, or intensity of one or more unwanted features associated with the condition if it eventually develops. In some embodiments and as will be clear from context, the term “preventing” can indicate a prophylactic effect in terms of preventing or partially preventing a symptom or condition. The term “preventing” includes preventing the symptom or condition occurring in a subject who may be predisposed to the symptom or condition but has not yet been diagnosed.

[0151]

[0161] The term “effective amount” including related terms “prophylaxis-effective amount,” “treatment effective amount,” and “therapeutically effective amount,” refers to a concentration of a compound that is effective in reducing or reversing atrophy of dermal adipose and / or thinning of the skin (as will be clear from context in this specification) in a subject.

[0152]

[0162] As used herein, the term “small molecule” is meant to indicate a chemical compound having a molecular weight of less than about 500 Daltons. Small molecules do not include biologic polymers, such as polypeptides and polynucleotides.

[0153]

[0163] The term “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e. the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0154]

[0164] The term “physiological pH” or a “pH in the physiological range” is meant a pH in the range of approximately 7.2 to 8.0 inclusive, more typically in the range of approximately 7.2 to 7.6 inclusive.

[0155]

[0165] As used herein, the term “subject” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalia class: humans, non-human primates, such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. The term does not denote a particular age or gender.

[0156]

[0166] The term “about” is used when determinants or values do not need to be identical, i.e. 100% the same. Accordingly, “about” means, that a determinant or values may diverge by 0.1% to 20%, preferably by 0.1 % to 10%; in particular, by 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%. The skilled person will know that certain parameters or determinants may slightly vary based on the method how the parameter was determined.

[0157]

[0167] The terms “selective inhibitor of VEGFR2 and FGFR1” and “selective VEGFR2 and FGFR1 inhibitors” as used herein to mean a small molecule that targets VEGFR2 and FGFR1 with a reported ICso less than or equal to 10 pM for each target.

[0158]

[0168] The term “selective inhibitor of VEGFR2” as used herein means a small molecule that targets VEGRF2, and has a relative IC50 value below 1.

[0159]

[0169] The term “selective inhibitor of FGFR1” as used herein means a small molecule that targets FGFR1. and has a relative ICso value below 1.

[0160]

[0170] The term “relative ICso” is the calculation of the ratio of the reported ICso towards either VEGFR2 or FGFR1 to the next lower reported ICso to any gene target.

[0161]

[0171] The term “PPAR-gamma agonist” is used herein to mean a small molecule that binds to PPAR-gamma to promote the expression of several genetic networks.

[0162]

[0172] The term “locally administered” or “local administration” as used herein refers to a route of administration that is targeted to a specific location, such as the face of a subject, in contrast to systemic administration, which is an administration of a substance (e.g., medication or drug) that is intended for the substance to circulate the entire body of a subject. Local administration can encompass topical administration or local injection, e.g., sub-cutaneous injection at a treatment location such as, e.g., a portion of the face, e.g., the cheek area, of a subject.

[0163] Medical Significance

[0164]

[0173] Diabetes refers to a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes, is an acquired condition that accounts for more than 90% of diabetes cases. Typical onset of type 2 diabetes occurs in obese or otherwise sedentary adults when their body does not make enough insulin or they have insulin resistance. Though lifestyle changes can be useful in managing this disorder, patients with type 2 diabetes may be required to take anti-diabetic medications.

[0165]

[0174] Approximately 70% of American adults are obese or overweight. Being obese or overweight is a serious health issue associated with leading causes of death, including heart disease, stroke and diabetes, and is linked to an increased risk of certain types of cancer. Losing 5% to 10% of body weight through diet and exercise has been associated with a reduced risk of cardiovascular disease in adult patients with obesity or that are overweight.

[0175] Incretin metabolic hormones, including glucagon-like peptide- 1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP), function in the regulation of glucose homeostasis. Medicaments targeting this family of intestinal peptides, such as GLP-1 receptor agonists, have been shown to suppress glucagon production, decrease gastric motility, and increase satiety.

[0166]

[0176] GLP-1 receptor agonists are a class of medication used to treat diabetes, such as type 2 diabetes, as they help lower blood sugar levels. GLP-1 receptor agonists are also used to treat obesity. GLP-1 receptor agonists may also lower the risk of heart disease, such as heart failure, stroke, and kidney disease in a subject.

[0167]

[0177] GLP- 1 receptor agonists include exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide. GLP-1 receptor agonists include those listed in Table Al and Table A2.

[0168]

[0178] Exenatide (e.g., Bydureon, Byetta) is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Exenatide is administered at a dose 2 mg by subcutaneous injection once every 7 days (i.e., weekly). Exenatide is not administered to a subject who has a family history of medullary thyroid carcinoma or has Multiple Endocrine Neoplasia syndrome type 2.

[0169]

[0179] Exenatide may also be administered at 5 mcg per dose twice daily by subcutaneous injection within 60 minutes prior to morning and evening meals (or before the to main meals of the day, approximately 6 hours or more apart). The dose is increased to 10 mcg twice daily after 1 month based on clinical response.

[0170]

[0180] Liraglutide (e.g., Victoza, Saxenda) is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Liraglutide is administered once a day, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm. Liraglutide is administered at a dose of 0.6 mg per day for one week. After one week, the dose is increased to 1.2 mg per day. If the 1.2 mg dose per day does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. Liraglutide is not administered to a subject who has a family history of medullary thyroid carcinoma or has Multiple Endocrine Neoplasia syndrome type 2.

[0171]

[0181] Liraglutide is also indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia), and pediatric patients aged 12 years and older with body weight above 60 kg and an initial body mass index (BMI) of 30 kg / m2 for adults by international cut-offs. Liraglutide is administered once a day, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm. Liraglutide is administered at a dose of 0.6 mg per day for one week. In weekly intervals, the dose is increased until a dose of 3 mg is reached. If a dose is not tolerated, the dose can be lowered to a previous dose level, such as 2.4 mg per day.

[0172]

[0182] Albiglutide (e.g., Tanzeum) is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Albiglutide is administered, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm. Albiglutide is administered at a dose of 30 mg subcutaneously once weekly. The dose can be increased to 50 mg once per week in patients requiring additional glycemic control. Albiglutide is not administered to a subject who has a family history of medullary thyroid carcinoma or has Multiple Endocrine Neoplasia syndrome type 2.

[0173]

[0183] Dulaglutide (e.g., Trulicity) is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dulaglutide is administered, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm. Dulaglutide is administered at a dose of 0.75 mg subcutaneously once weekly. The dose can be increased to 1.5 mg once per week in patients requiring additional glycemic control. Dulaglutide is not administered to a subject who has a family history of medullary thyroid carcinoma or has Multiple Endocrine Neoplasia syndrome type 2.

[0174]

[0184] Lixisenatide (e.g., Adlyxin) is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

[0175] Lixisenatide is administered once a day within one hour before the first meal of the day by subcutaneous injection in the abdomen, thigh, or upper arm. Lixisenatide is administered at a dose of 10 mcg once daily for 14 days. On day 15, the dosage is increased to 20 mcg once daily.

[0176]

[0185] Semaglutide (e.g., Ozempic) is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Semaglutide is administered once weekly, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm. Semaglutide is administered at a dose of 0.25 mg once weekly for four weeks. After four weeks, the dose is increased to 0.5 mg once weekly. The dose can be increased to 1 mg once weekly if additional glycemic control is needed. Semaglutide is not administered to a subject who has a family history of medullary thyroid carcinoma or has Multiple Endocrine Neoplasia syndrome type 2.

[0186] Semaglutide is also indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Semaglutide is administered at a dose of 0.25 mg once weekly for four weeks. In four week intervals, the dose is increased until a dose of 2.4 mg is reached. Semaglutide is administered once weekly, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm.

[0177]

[0187] Tirzepatide (e.g., Mounjaro, Zepbound) is a glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Tirzepatide is administered once weekly, independent of meals, by subcutaneous injection in the abdomen, thigh, or upper arm. Tirzepatide is administered at a dose of 2.5 mg once weekly for four weeks. After four weeks, the dose is increased to 5 mg once weekly. The dose can be increased in 2.5 mg increments after at least four weeks on the current dose. The maximum dosage is 15 mg once weekly. The injection site is rotated with each dose. Tirzepatide is not administered to a subject who has a family history of medullary thyroid carcinoma or has Multiple Endocrine Neoplasia syndrome type 2.

[0178]

[0188] Tirzepatide is also indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMT) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dysplipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease). Tirzepatide is administered at a dose of 2.5 mg once weekly for four weeks. After four weeks, the dose is increase to 5 mg once weekly. The dose can be increase in 2.5 mg increments after at least four weeks on the current dose. The maximum dosage is 15 mg once weekly. The injection site is rotated with each dose.

[0179]

[0189] Additional GLP-1 receptor agonists are listed in Table Al and Table A2.

[0180]

[0190] GIP receptor agonists are also used to treat diabetes and obesity. Exemplary GIP receptor agonists are listed in Table Al . In some embodiments, a GLP-1 receptor agonist is also a GIP receptor agonist.

[0181]

[0191] Glucagon receptor agonists are also used to treat diabetes and obesity. Exemplary glucagon receptor agonists are listed in Table Al. In some embodiments, a GLP-1 receptor agonist is also a glucagon receptor agonist. In some embodiments, a GLP-1 receptor agonist is also a GIP receptor agonist and a glucagon receptor agonist.

[0182] Table Al. Exemplary compounds known to be GLP-1 receptor agonists, GIP receptor agonist, and / or glucagon receptor agonists

[0183] “X” in a cell notes that the listed compound is known to be an agonist to the corresponding receptor.

[0184] Table A2. Exemplary compounds known to be GLP-1 receptor agonists

[0185]

[0186]

[0192] While GLP- 1 receptor agonists and GIP receptor agonists have been successful in the treatment of diabetes and obesity, they are associated with certain side effects. One such side effect is the atrophy of dermal adipose, especially in the face, of a subject receiving a GLP- 1 receptor agonist or GIP receptor agonist. Subjects receiving GLP-1 receptor agonists or GIP receptor agonists can experience a hollowed-out appearance and an increase in lines and wrinkles as a result of the atrophy of adipose in the face. In some embodiments, a GLP-1 receptor agonist is also a GIP receptor agonist.

[0187]

[0193] Atrophy of dermal adipose in the face of a subject also can occur as a result of normal aging, other weight loss regimens, and additional reasons as well (e.g. HIV-associated facial lipoatrophy, localized scleroderma, chronic treatment with corticosteroids, hormonal changes, yo-yo dieting, poor diet, excessive exercise, stress, excessive sub exposure, smoking, and lupus erythematosus profundus).

[0188] Corticosteroids

[0189]

[0194] Corticosteroids are a class of drugs with a variety of medical uses. Long-term use of corticosteroids may be used to treat chronic illnesses and / or conditions including asthma, allergies, adrenocortical insufficiency, polymyalgia rheumatica, congenital adrenal hyperplasia (CAH), adrenal insufficiency, allergic rhinitis, atopic dermatitis, interstitial lung disease, systemic lupus erythematosus (SLE), vasculitis, vitiligo, uveitis, rheumatoid arthritis, myositis, IgG4-related diseases, chronic myelogenous leukemia (CML), lymphoma, leukemia, multiple sclerosis, chronic obstructive pulmonary disease (COPD), Graves’ ophthalmopathy, anterior uveitis, steroid-responsive dermatoses (SRD), tenosynovitis, and osteoarthritis or juvenile idiopathic arthritis, Addison’s disease, ulcerative colitis, Chom’s disease, autoimmune hepatitis, hemolytic anemia, idiopathic thrombocytopenic purpora, multiple myeloma, polymyositis, polyarteritis, vasculitis, uveitis, optic neuritis, keraconjunctivitis, prostate cancer, tendinosis, linchen planus, and / or organ transplantation. Long-term use of a corticosteroid include administration for more than 30 days. Atrophy of dermal adipose and / or thinning of the skin can occur as a result of chronic treatment with corticosteroids. Exemplary corticosteroids are listed in Table B.

[0190] Table B. Exemplary corticosteroids

[0191] Existing treatments and need for improved treatment

[0192]

[0195] Treatment options for the atrophy of facial dermal adipose are quite limited. Available treatments include synthetic dermal fillers and cosmetic surgery, such as fat pad transplants, which are administered by a medical professional. These current treatments have several drawbacks. Dermal fillers and cosmetic surgery are expensive, especially dermal fillers which may require routine administration, may cause bruising or allergic reactions in a subject due to the administration process, and cosmetic surgeries may involve medical complications. Therefore, there is a need in the art for treatments for reducing or reversing atrophy of facial dermal adipose tissue and / or thinning of the skin.

[0193] Description of Embodiments

[0194]

[0196] Herein, we describe method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1). We also describe topical formulations of a selective inhibitor of VEGFR2 and FGFR1 and a delivery vehicle.

[0195]

[0197] In some embodiments, the selective inhibitors comprise single agents that selectively inhibit both VEGFR2 and FGFR1. In some embodiments, the single agents that selectively inhibit both VEGFR2 and FGFR1 also inhibit platelet-derived growth factor receptor-alpha (PDGFRA) and / or platelet-derived growth factor receptor-beta (PDGFRB).VEGFR2, FGFR1, PDGFRA, and PDGFRA belong to the family of tyrosine kinases. In some embodiments, a selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB is a tyrosine kinase inhibitor (TKI).

[0196]

[0198] In some embodiments, the selective inhibitors comprise multiple agents each of which selectively inhibits either VEGFR2 and / or FGFR1.

[0197]

[0199] Brivanib alaninate is a selective inhibitor of VEGFR2 and FGFR1. We show that a topical formulation of this inhibitor was successful at enhancing dermal adipose tissue thickness in a subject.

[0200] Methods of measuring skin thickness include calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectance-mode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, and a structured light 3D scanner. Methods of evaluating skin thickness also include patient or clinician-reported rating scale and the methods known in the common technical knowledge.

[0198]

[0201] Herein, in another aspect, we describe a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of PPAR-gamma agonist, wherein the subject is receiving a glucagon-like peptide- 1 (GLP-1) receptor agonist. In another aspect, described herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of PPAR-gamma agonist, wherein the subject is receiving a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. In another aspect, described herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of PPAR-gamma agonist, wherein the subject is receiving a GLP-1 and GIP receptor agonist. In another aspect, described herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of PPAR-gamma agonist, wherein the subject is receiving a GIP receptor agonist. In some embodiments, the PPAR-gamma agonist is selected from the group consisting of rosiglitazone and pioglitazone.

[0199]

[0202] In some embodiments, the PPAR-gamma agonist is rosiglitazone. We show that a topical formulation of rosiglitazone was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. We show that a subcutaneous injection of rosiglitazone was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. In some embodiments, the subject was receiving an exemplary GLP- 1 receptor agonist, semaglutide.

[0200]

[0203] In some embodiments, the PPAR-gamma agonist is pioglitazone. We show that a topical formulation of pioglitazone was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. In some embodiments, the subject was receiving an exemplary GLP- 1 receptor agonist, semaglutide.

[0201]

[0204] Methods of measuring skin thickness include calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectance-mode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, and a structured light 3D scanner. Methods of evaluating skin thickness also include patient or clinician-reported rating scale and the methods known in the common technical knowledge.

[0202]

[0205] Herein, in other embodiments, we describe a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist and an inhibitor of PDGFRA / B, vascular endothelial growth factor receptor 2 (VEGFR2), and / or fibroblast growth factor receptor 1 (FGFR1). Herein we describe a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, wherein the subject is receiving a glucagon- like peptide- 1 (GLP-1) receptor agonist. In some embodiments, the GLP-1 receptor agonist is also a GIP receptor agonist. Herein, we describe a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, wherein the subject is receiving a GIP receptor agonist. We also describe topical formulations of a PPAR-gamma agonist, PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor 1 , and a delivery vehicle.

[0203]

[0206] In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor comprise single agents that inhibit PDGFRA / B, VEGFR2 and / or FGFR1. VEGFR2, FGFR1, PDGFRA, and PDGFRA belong to the family of tyrosine kinases. In some embodiments, a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is also a tyrosine kinase inhibitor (TKI). In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor inhibitors comprise multiple agents each of which inhibit PDGFRA / B, VEGFR2, and / or FGFR1.

[0204]

[0207] In some embodiments, the PPAR-gamma agonist is selected from the group consisting of rosiglitazone and pioglitazone. In some embodiments, the PPAR-gamma agonist is pioglitazone. We show that a topical formulation of pioglitazone was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. We show that a topical formulation of pioglitazone and nintedanib was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. In some embodiments, the subject was receiving an exemplary GLP-1 receptor agonist, semaglutide. In some embodiments, the subject was receiving an exemplary GLP-1 receptor agonist, tirzepatide.

[0205]

[0208] In some embodiments, the PPAR-gamma agonist is rosiglitazone. We show that a topical formulation of rosiglitazone was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. We show that a topical formulation of rosiglitazone and nintedanib was successful at reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject. In some embodiments, the subject was receiving an exemplary GLP-1 receptor agonist, semaglutide. In some embodiments, the subject was receiving an exemplary GLP-1 receptor agonist, tirzepatide.

[0206]

[0209] Methods of measuring skin thickness include calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectance-mode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, and a structured light 3D scanner. Methods of evaluating skin thickness also include patient or clinician-reported rating scale and the methods known in the common technical knowledge.

[0207] Selective inhibitors of VEGFR2 and FGFR1

[0208]

[0210] Selective inhibitors of VEGFR2 and FGFR1 were selected based on first identifying compounds that have reported target IC50 values toward VEGFR2 and FGFR1.

[0209]

[0211] Those results were then filtered for compounds that have a reported IC50 to VEGFR2 and FGFR1 less than or equal to 10 pM. The compounds were then narrowed to compounds that have fewer than 10 reported targets. The selected compounds are listed in Table 1.

[0210]

[0212] To identify compounds that selectively inhibit VEGFR2, compounds that have reported IC50 values toward VEGFR2 were first identified. For those compounds, all reported IC50 assay of that compound to any gene target were analyzed. To find selectivity, the ratio of the IC50 toward VEGFR2 to the next lowest reported IC50 to any gene target (relative IC o) was determined. Relative ICso values < 1 are considered as having selectivity of the compound toward VEGFR2. Relative IC50 values of 1 report that the compound has equal activity inhibiting VEGFR2 and another gene target. Compounds with relative IC50 > 1 are considered not to have selectivity to inhibiting VEGFR2. The selected compounds are listed in Table 3.

[0211]

[0213] To identify compounds that selectively inhibit FGFR1, compounds that have reported IC50 values toward FGFR1 were first identified. For those compounds, all reported IC50 assay of that compound to any gene target were analyzed. To find selectivity, the ratio of the IC50 toward FGFR1 to the next lowest reported IC50 to any gene target (relative IC50) was determined. Relative IC50 values < 1 are considered as having selectivity of the compound toward FGFR1. Relative IC50 values of 1 report that the compound has equal activity inhibiting FGFR1 and another gene target. Compounds with relative IC50 > 1 are considered not to have selectivity to inhibiting FGFR1. The selected compounds are listed in Table 2.

[0212]

[0214] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is brivanib alaninate. In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, or tivozanib.

[0213]

[0215] In some embodiments, selective inhibitors of VEGFR2 and FGFR1 also inhibit platelet-derived growth factor receptor-alpha (PDGFRA) and / or platelet-derived growth factor receptor-beta (PDGFRB).

[0214] PPAR-gamma agonists

[0215]

[0216] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily whose physiological functions are linked to metabolism, energy homeostasis, cellular development, and differentiation. Three members of PPARs have been identified, namely PPAR-alpha (PPARa), PPAR-gamma (PPARy), and PPAR-beta / gamma (PPARp / y).

[0216] In some embodiments, a PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS-131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921 , FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131, KY- 903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW- 1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN- 862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO- 52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF- 4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO- 5129, ZYH2, PN2034, and lobeglitazone. Table C provides the IUPAC names for PPAR- gamma agonists listed herein.

[0217] Table C. PPAR-gamma agonists

[0218]

[0217] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, the PPAR-gamma agonist is pioglitazone.

[0219] Inhibitors of PDGFRA / B, VEGFR2 and / or FGFR1

[0220]

[0218] Exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitors are listed in Table 1, comprising 5-Iodo-sunitinib, 5-Methoxy-sunitinib, Acrizanib, Agerafenib, Alectinib, Altiratinib, Amuvatinib, Amuvatinib hydrochloride, Apatinib, Apatinib Mesylate, Avapritinib, Axitinib, Bafetinib, Bemcentinib, Bosutinib, Brivanib, Brivanib alaninate, Brivanib metabolite M25, Cabozantinib, Cabozantinib oxidation B, Cabozantinib S-malate, Canertinib, Cediranib, Cerdulatinib hydrochloride, Ceritinib, Crenolanib, Dasatinib, Defactinib, Desmethyl nintedanib, Dovitinib, Entrectinib, Erdafitinib, Erlotinib, Famitinib, Fedratinib, Fisogatinib, Foretinib, Fostamatinib disodium, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, Golvatinib, Gunagratinib, Henatinib, Imatinib, Infigratinib, Infigratinib phosphate, Lapatinib, Lenvatinib, Lestaurtinib, Linifanib, Linsitinib, Lucitanib, Masitinib, Mivavotinib, Motesanib, N,N-Dimethyl Sunitinib, N-Desethyl Sunitinib, N-Desmethyl vandetanib, Neratinib, Nilotinib, Ningetinib, Nintedanib, Nintedanib esylate, Orantinib, Pacritinib, Pazopanib, Pelitinib, Pemigatinib, Pexidartinib, Pexmetinib, Ponatinib, Pralsetinib, Quizartinib, Quizartinib dihydrochloride , Ravoxertinib, Regorafenib, Ripretinib, Rogaratinib, Saracatinib, Selpercatinib, Semaxanib, Sitravatinib, Sorafenib, Sorafenib tosylate, Sunitinib, Tafetinib, Tamatinib, Tandutinib, Telatinib, Tesevatinib, Tivozanib, Toceranib, US 10155768, Vandetanib, US9029401, Sunitinib, Vandetanib, Vandetanib hydrochloride, Vatalanib, Vatalanib succinate, Vemurafenib, and Vimseltinib.

[0221]

[0219] Platelet-Derived Growth Factors (PDGFs) are a family of four cystine-knot-type growth factors (PDGF-A, -B, -C and -D) which control the growth of connective tissue cells such as fibroblasts and smooth muscle cells. By acting on these mesenchymal cells, PDGFs critically regulate embryonic development, especially the formation of vessels and organs. There are two types of receptors for PDGFs, PDGFRa and PDGFRp, which belong to the class III receptor tyrosine kinases (RTKs), and have different expression patterns and physiological roles. PDGFRa signaling controls gastrulation and the development of several organs such as lung, intestine, skin, testis, kidney, bones, and neuroprotective tissues. PDGFRP signaling is better recognized as an essential regulator of early hematopoiesis and blood vessel formation.

[0222]

[0220] , The human VEGF / VEGFR system is composed of VEGF-A (also VEGF), VEGF-B, VEGF-C, VEGF-D, and PGF (placental growth factor), three main VEGF receptors VEGFR- 1 (Fit- 1), VEGFR-2 (KDR), VEGFR-3 (Flt-4), and two non-protein kinase co-receptors neuropilin- 1 and neuropilin-2 (NRP-1 and -2). The VEGFR-1 and VEGFR-2 regulate angiogenesis and vascular permeability, and the VEGFR-3 mainly regulates lymphangiogenesis. Vascular endothelial growth factors are main regulators in vasculogenesis and angiogenesis and play their roles by binding to VEGFRs on cell surface and activating subsequently the signaling pathways of angiogenesis. The VEGFR-2 is the major receptor of VEGF, expresses in vascular endothelial cells, and plays a major role in angiogenesis.

[0223]

[0221] The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases consists of four transmembrane receptors, FGFR 1-4. When bonded to fibroblast growth factors (FGFs), these receptors form dimers with any one of the four other FGFRs and then cross-phosphorylate key tyrosine residues on their dimer partners. These newly phosphorylated sites bind cytosolic docking proteins such as FRS2, PRKCG and GRB2 which proceed to activate cell signaling pathways that lead to cellular differentiation, growth, proliferation, prolonged survival, migration, and other functions. Pharmaceutical formulations and routes of administration

[0224]

[0222] The methods described herein use pharmaceutical compositions comprising the molecules described above, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and / or prophylactic ingredients. Such excipients include liquids such as water, saline, glycerol, polyethyleneglycol, hyaluronic acid, ethanol, cyclodextrins, modified cyclodextrins (i.e., sufobutyl ether cyclodextrins), and related excipients known in the art. Suitable excipients for non-liquid formulations are also known to those of skill in the art.

[0225]

[0223] Pharmaceutically acceptable salts can be used in the compositions of the present embodiments and include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients, and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack Publishing Company, 1990).

[0226]

[0224] Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, may be present in such vehicles. A biological buffer can be virtually any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like. In some embodiments, a surfactant can include behen tri monium methosulfate or sodium lauroyl lactylate. In some embodiments, biological buffering substances can include potassium phosphate or dipotassium phosphate.

[0227]

[0225] In some embodiments, the mode of administration is a locally administered formulation. In some embodiments, the locally administered formulation is a topical formulation or a local subcutaneous injection. In some embodiments, the locally administered formulation is a local subcutaneous injection. In some embodiments, the local subcutaneous injection is administered to the face of a subject.

[0228]

[0226] In some embodiments, the locally administered formulation is a topical formulation. In some embodiments, a topical formulation can be an ointment, cream, gel, lotion, solution, foam, or spray.

[0229]

[0227] In some embodiments, a topical formulation includes one or more of a delivery vehicle. In some embodiments, the delivery vehicle includes one or more of a humectant, emollient, occludent, or a secondary moisturizing ingredient.

[0228] In some embodiments, a humectant can be glycerin, gelatin, propylene glycol, butylene glycol, panthenol, sorbitol, urea, hyaluronic acid, sodium hyaluronate, glycolic acid, lactic acid, phytosphingosine, ethylhexylglycerin, or sodium pyrrolidine carboxylic acid.

[0230]

[0229] In some embodiments, an emollient can be cholesterol, squalene, linoleic acid, stearic acid, oleic acid, or fatty alcohols. In some embodiments, a fatty alcohol is cetearyl alcohol, cetyl alcohol, or ceteareth-20.

[0231]

[0230] In some embodiments, an occludent can be white soft paraffin / petrolatum, beeswax, mineral oil, dimethicone, lanolin, carnuba wax, cetyl alcohol, caprylic / capric triglyceride.

[0232]

[0231] In some embodiments, secondary moisturizing ingredients include ceramides, free fatty acids, and cholesterol.

[0233]

[0232] In some embodiments, the delivery vehicle includes one or more of an excipient. In some embodiments an excipient can be a stiffening agent, thickening / gelling agent, silicone, humectant, emulsifier or solubilizer, solvent, penetration enhancer, chelating agents, acidifying, alkalizing or buffering agent, antioxidant, or preservative.

[0234]

[0233] In some embodiments, a stiffening agent includes white soft paraffin / petrolatum, liquid paraffin, lanolin, beeswax, carnauba wax, cetyl alcohol, and isohexadecane.

[0235]

[0234] In some embodiments, a thickening or gelling agent can include carbomer, cetyl alcohol, stearic acid, carnauba wax, hydroxyethyl cellulose, guar gum, xanthan gum, gelatin, magnesium aluminium silicate, silica, bentonite, cetyl palmitate, and ammonium acryloyldimethyltaurate.

[0236]

[0235] In some embodiments, a silicone can be dimethicone or cyclomethicone.

[0237]

[0236] In some embodiments, a humentant can be a polyol. In some embodiments, a polyol humectant can include glycerol, sorbitol, propylene glycol, polyethylene glycol, 1,2,6- hexanetriol, and triacetin.

[0238]

[0237] In some embodiments, an emulsifier or solubilizer includes glycerol monostearate, cetostearyl alcohol, cetyl palmitate, sorbitan monostearate, polysorbate 20, polysorbate 80, polysorbate 60, poloxamer, emulsifying wax, sorbitan monooleate, sodium lauryl sulfate, propylene glycol monostearate, xanthan gum, and diethylene glycol monoethyl ether.

[0239]

[0238] In some embodiments, a solvent includes water ( e.g., purified water), propylene glycol, hexylene glycol, oleyl alcohol, mineral oil / liquid paraffin, and propylene carbonate.

[0240]

[0239] In some embodiments, a penetration enhancer includes propylene glycol, oleic acid, isopropyl myristate, ethanol, and polyethylene glycol.

[0241]

[0240] In some embodiments, a chelating agent can be ethylene diamine tetraacetate.

[0241] In some embodiments, an acidifying, alkalizing or buffering agent can include citric acid, lactic acid, phosphoric acid, and sodium hydroxide.

[0242]

[0242] In some embodiments, an antioxidant includes butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, ascorbyl palmitate, and sodium ascorbyl phosphate.

[0243]

[0243] In some embodiments, a preservative includes benzoic acid, propyl paraben, methyl paraben, imidurea, sorbic acid, potassium sorbate, benzalkonium chloride, phenyl mercuric acetate, chlorobutanol, disodium edta, and phenoxyethanol.

[0244]

[0244] In some embodiments, the topical formulation is a lotion. In some embodiments, the lotion comprises water, glycerin, triglycerides, fatty alcohols, ceramides, sodium hyaluronate, cholesterol, and phenoxyethanol. In some embodiments, the lotion comprises water, glycerin, cetearyl alcohol, caprylic / capric triglyceride, cetyl alcohol, ceteareth-20, petrolatum, potassium phosphate, ceramide np, ceramide ap, ceramide eop, carbomer, dimethicone, behentrimonium methosulfate, sodium lauroyl lactylate, sodium hyaluronate, cholesterol, phenoxyethanol, disodium edta, dipotassium phosphate, tocopherol, phytosphingosine, xanthan gum, and ethylhexylglycerin.

[0245]

[0245] In some embodiments, a component of a delivery vehicle has more than one functionality. In some embodiments, an occludent may also be a thickening agent.

[0246]

[0246] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0247]

[0247] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in enhancement of dermal adipose tissue thickness in a subject. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer.

[0248]

[0248] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0249] Therapeutic or prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the subject, and the route of administration.

[0250] Dosing regimens

[0251]

[0249] In some embodiments, a pharmaceutically or therapeutically effective amount of a selective inhibitor of VEGFR2 and / or FGFR1 are delivered to the subject.

[0252]

[0250] In some embodiments, a pharmaceutically or therapeutically effective amount of a topical formulation of a selective inhibitor of VEGFR2 and / or FGFR1 is between about 0.01 %-3% weight / weight (w / w). In some embodiments, a topical formulation of a selective inhibitor of VEGFR2 and / or FGFR1 administered to a patient comprises between about 0.03 mg / cm2to about 0.3 mg / cm2of a selective inhibitor of VEGFR2 and / or FGFR1 administered, according to various embodiments, once, twice or three times per day.

[0253]

[0251] In some embodiments, a pharmaceutically or therapeutically effective amount of a local subcutaneous injection of a selective inhibitor of VEGFR2 and / or FGFR1 comprises between about 0.01 mg to about 3 mg of a selective inhibitor of VEGFR2 and / or FGFR1 administered, according to various embodiments, once, twice or three times per day. In some embodiments, the local subcutaneous injection comprises a selective inhibitor of VEGFR2 and / or FGFR1 at a concentration of about 0.01 mg / mL - 30 mg / mL in solution of an exemplary buffer, such as phosphate buffered saline (PBS) or DMSO in PBS.

[0254]

[0252] In some embodiments, the selective VEGFR2 and FGFR1 inhibitor is selected from the group consisting of [4-(2,4-Difluoro-5-methoxycarbamoyl-phenylamino)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-6-yl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, Brivanib, Brivanib Alaninate, 2,4-Difluoro-5-[5-isopropyl-6-(5-trifluoromethyl-[l ,3,4]oxadiazol-2-yl)- pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-ylamino]-N-methoxy-benzamide, 5-[(l -Ethylpiperidin-4- yl)amino]-3-[lH-imidazol-2-yl(phenyl)methylidene]-lH-indol-2-one, 2,4-Difluoro-5-[5- isopropyl-6-(5-methyl-4H-[l,2,4]triazol-3-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 5-[6-(5-Dimethylamino-[l,3,4]oxadiazol-2-yl)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-4-ylaminol-2,4-difluoro-N-methoxy-benzamide, 2,4-Difluoro-5- [5-isopropyl-6-(3-methyl-[l,2,4]oxadiazol-5-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 3-[(3-(2-Carboxyethyl)-4-methylpyrrol-2-YL)methylene]-2-indolinone (SU5402), 2,4-Difluoro-5-[5-isopropyl-6-(5-methyl-[l,3,4]oxadiazol-2-yl)-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, 5-[6-(5-Difluoromethyl- [l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N- methoxy-benzamidem, 3-[Benzimidazol-2-ylidene-(3-fluorophenyl)methyl]-5-[(l- ethylpiperidin-4-yl)amino]-lH-indol-2-ol, N-(Cyclopropylmethyl)-3-(l-methylpyrazol-4- yl)-N-phenylquinoxalin-6-amine, 2,4-Difluoro-5-(5-isopropyl-6-[l,3,4]oxadiazol-2-yl- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino)-N-methoxy-benzamide, 7-(4-Fluoroanilino)-l- [(lR,3R)-3-hydroxycyclopentyl]-3-(4-methoxyphenyl)-4H-pyrimido[4,5-d]pyrimidin-2-one, 5-[6-(5-Cyclopropyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4- ylamino]-2,4-difluoro-N-methoxy-benzamide, 6-(5-Methyl-l,3,4-oxadiazol-2-yl)-5-propan- 2-yl-N-(lH-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine, N- (Cyclopropylmethy])-N-[3-methoxy-5-(trifluoromethyl)pheny]]-3-(l-methy]pyrazol-4- yl)quinoxalin-6-amine, 3-[Benzimidazol-2-ylidene-(3,5-difluorophenyl)methyl]-5-[(l- ethylpiperidin-4-yl)amino]-lH-indol-2-ol, 1,6-Naphthyridine 76, 2,4-Difluoro-5-{5- isopropyl-6-[5-(2,2,2-trifluoro-ethyl)-[l,3,4]oxadiazol-2-yl]-pyrrolo[2,l-f][l,2,4]triazin-4- ylamino}-N-methoxy-benzamide, (+)-(lR,3R)-l-(3-Hydroxy-cyclopentyl)-3-(4-methoxy- phenyl)-7-phenylamino-3,4-dihydro-lH-pyrimido[4,5-d]pyrimidin-2-one, 1,6-Naphthyridine 75, (-)-(lS,3S)-l-(3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4- dihydro- lH-pyrimido[4,5-d]pyrimidin-2-one, N-(Cyclopropylmethyl)-N-[3- [(dimethylamino)methyl]-5-methoxyphenyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-[3-(Aminomethyl)-5-methoxyphenyl]-N-(cyclopropylmethyl)-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine;hydrochloride, Chembl4573547, 1,6-Naphthyridine 77, 1,6- Naphthyridine 19, 1,6-Naphthyridine 26, N-(Cyclopropylmethyl)-N-[3- (difluoromethoxy)phenyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N'-(3,4-Difluoro-5- methoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- tri lluoroethyl (propane- 1 ,3-diamine;hydrochloride, 2,4-Difluoro-5-[5-isopropyl-6-(5- methanesulfonylmethyl-[l,3,4]oxadiazol-2-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 5-(2-Chlorophenyl)-7-fluoro- 1 ,2-dihydro-8-methoxy-3- methylpyrazolo(3,4-b)(l,4)benzodiazepine, [3-[Cyclopropylmethyl-[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]amino]-5-methoxyphenyl]-pyrrolidin- 1 -ylmethanone, 5 - [( 1 - Ethylpiperidin-4-yl)amino]-3-[(2-fluorophenyl)-(5-methyl-lH-imidazol-2-yl)methylidene]- lH-indol-2-one, 5-[6-(5-Cyclopropylmethyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N-methoxy-benzamide, 3-[(3,5-Difluorophenyl)-(5- methyl-lH-imidazol-2-yl)methylidene]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-one, 5- [(1 -Ethylpiperidin-4-yl)amino]-3 - [(3-fluorophenyl)-( 1 H-imidazol-2-yl)methylidene] - 1 H- indol-2-one, Indolin-2-one deriv. 9c, Methyl (3Z)-2-oxo-3-[phenyl-[4-(piperidin-l- ylmethyl)anilino]methylidene]-lH-indole-6-carboxylate, N-(3,5-Dimethoxyphenyl)-N-[3-(3- methylimidazol-4-yl)prop-2-ynyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, (3z)-5-[(l- Ethylpiperidin-4-Yl)amino]-3-[(5-Methoxy-lh-Benzimidazol-2-Yl)(Phenyl)methylidene]- l,3-Dihydro-2h-Indol-2-One, Chembl4449189, [5-Amino-l-(lH-indol-5-yl)pyrazol-4-yl]- (lH-indol-2-yl)methanone, 5-Isopropyl-6-(5-methyl-l,3,4-oxadiazol-2-yl)-N-(2-methyl-lH- pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine, 3-[Benzimidazol-2-ylidene- (4-methylphenyl)methyl]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-ol, 5-[6-(5-Ethyl- [ 1 ,3 ,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2, 1 -f] [ 1 ,2,4] triazin-4-ylamino] -2,4-difluoro-N- methoxy-benzamide, 3-[Benzimidazol-2-ylidene(phenyl)methyl]-5-[(l-ethylpiperidin-4- yl)amino]-lH-indol-2-ol, 1 ,6-Naphthyridine 25, 2-(6-Fluoro-lH-indazol-3-yl)-5-(4- (piperidin-l-yl)piperidin-l-yl)-lH-benzo[d]imidazole, 3-[Benzimidazol-2-ylidene-(4- methoxyphenyl)methyl]-5-[(l-ethylpiperidin-4-yl)aniino]-lH-indol-2-ol, N- (Cyclopropylmethyl)-N-[3-methoxy-5-[2-(methylamino)ethoxy]phenyl]-3-(l- methylpyrazol-4-yl)quinoxalin-6-amine, 3-Methoxy-N-methyl-5-[[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]-[2-(propan-2-ylamino)ethyl]amino]benzamide, XL999;XL-999; XL 999, 3-N-(Cyclopropylmethyl)-l-N-methyl-3-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6- yl]benzene-l,3-diamine, 2,4-Difluoro-5-[6-(5-isobutyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, Methyl 2-hydroxy-3-[N-[4- [2-methyl-5-[(4-methylpiperazin-l-yl)methyl]pyrrol-l-yl]phenyl]-C-phenylcarbonimidoyl]- lH-indole-6-carboxylate, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[(2- pyridin-4-ylcyclopropyl)methyl]quinoxalin-6-amine, 3-(3,5-Dimethoxyphenyl)-7-N-[3-(4- methylpiperazin-l-yl)propyl]-l,6-naphthyridine-2,7-diamine, 9-Chloro-2-[3-[3- (dimethylamino)propyl]anilino]-5,7-dihydropyrimido[5,4-d][l]benzazepine-6-thione, Pyrido[2,3-d]pyrimidine 103, Pyrido[2,3-d]pyrimidine 105, 2,4-Difluoro-5-[5-isopropyl-6- (5-methyl-oxazol-2-yl)-pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-ylamino]-N-methoxy-benzamide, N- (3,5-Dimethoxyphenyl)-N-[3-(2,5-dimethylimidazol-l-yl)propyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine;hydrochloride, N-[3-[2-[6-(2-Chlorophenyl)-2-[4- (diethylamino)butylamino]-7-oxopyrido[2,3-d]pyrimidin-8-yl]ethyl]phenyl]prop-2-enamide, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(2-piperazin-l-ylethyl)quinoxalin-6- amine;hydrochloride, Methyl (3Z)-3-[[4-[2-(dimethylamino)ethyl- methylsulfonylamino]anilino]-phenylmethylidene]-2-oxo-lH-indole-6-carboxylate, 4-[3- (3,5-Dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)prop-l-ynyl]pyridine- 3-carbonitrile, N-[(5-Chlorothiophen-2-yl)methyl]-N-(3,5-dimethoxyphenyl)-3-[l-(2- piperazin-l-ylethyl)pyrazol-4-yl]quinoxalin-6-amine;hydrochloride, N'-(3,5- Dichlorophenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- trifluoroethyl)propane-l,3-diamine, 2-[4-[7-[N-(Cyclopropylmethyl)anilino]quinoxalin-2- yl]pyrazol-l-yl]ethanol, Pyrido[2,3-d]pyrimidine 102, 7-N-[4-(Diethylamino)butyl]-3-(3,5- dimethoxyphenyl)-l,6-naphthyridine-2,7-diamine, N-(3,5-Dimethoxyphenyl)-N-[3-(4- methoxypyrimidin-2-yl)propyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, Methyl 3- [ [4- [(dimethylamino)methyl] anilino] -phenylmethylidene] -2-oxo- 1 H-indole-6-carboxylate, 3 - Fluoro-N-methyl-5-[[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-[2-(propan-2- ylamino)ethyl]amino]benzamide, N-(Cyclopropylmethyl)-N-[3-(l,3-dioxolan-2-yl)-5- methoxyphenyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-[[(2S)-l-[3-(3,5- Dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]ani]ino)propyl]pyrrolidin-2- yl]methyl]- 1,1,1 -trifluoromethanesulfonamide, 3-Methoxy-N-methyl-5- [2-(propan-2- ylamino)ethyl-[3-(l-propan-2-ylpyrazol-4-yl)quinoxalin-6-yl]amino]benzamide, 5-{6-[5- (Difluoro-methanesulfonyl-methyl)-[ 1 ,3,4]oxadiazol-2-yl]-5-isopropyl-pyrrolo[2, 1 - f][l,2,4]triazin-4-ylamino}-2,4-difluoro-N-methoxy-benzamide, N-[2-(3-Aminopiperidin-l- yl)ethyl]-N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5- Dimethoxyphenyl)-N-[(E)-3-(4-methoxypyrimidin-2-yl)prop-2-enyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, Methyl (3Z)-3-[[4-[acetyl-[2-(dimethylamino)ethyl]amino]anilino]- phenylmethylidene]-2-oxo-lH-indole-6-carboxylate, Methyl N-|4-|7-amino-3-(3,4- dimethoxyphenyl)-5-(l-methylpiperidin-4-yl)oxypyrazolo[l,5-a]pyrimidin-6- yl]phenyl]carbamate, Anilinoquinazoline deriv. 35, 1 ,6-Naphthyridine 17, Tert-butyl (lS,4S)-5-[2-(3,5-dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethyl]-2,5- diazabicyclo[2.2.1 ]heptane-2-carboxylate, Lucitanib, 6-((7-(( 1 - Aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-N-methyl-l -naphthamide hydrochloride, Pyrido[2,3-d]pyrimidine 104, Nintedanib esylate, [(2S)-l-(3,5-Dimethoxy-N- [3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)-3-methoxypropan-2-yl] acetate, 3-[2- Aminoethyl-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]amino]-5-methoxy-N- methylbenzamide, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[3-[4- (trifluoromethyl)piperidin-l-yl]propyl]quinoxalin-6-amine, 3-((4-Bromo-2,6- difluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide, N- (3,5-Dimethoxyphenyl)-N-[3-(2-methylimidazol-l-yl)propyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, 3-[3-(Morpholinomethyl)-4,5,6,7-tetrahydro-lH-indole-2- ylmethylene]-5-(ethylsulfonyl)-2,3-dihydro-lH-indole-2-one, 2-(3-Methoxy-N-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethanol, Epihematoxylol, N-[3-(5- Aminopyrazin-2-yl)prop-2-ynyl]-N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, 2- [3- [2- Aminoethyl- [7-( 1 -methylpyrazol-4-yl)quinoxalin-2- yl]amino]-5-fluorophenoxy]ethanol, N-[3-(3-Aminopyridin-2-yl)prop-2-ynyl]-N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5-Dimethoxyphenyl)- N-[3-(3-methoxypyridin-2-yl)propyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5- Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[(Z)-3-pyrimidin-2-ylprop-2- enyl]quinoxalin-6-amine, N'-(3,5-Dimethoxyphenyl)-N-methyl-N'-[3-[l-(oxan-4- ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]ethane-l,2-diamine;hydrochloride, [5-Amino-l-(2- chloro-5-hydroxyphenyl)pyrazol-4-yl]-[5-(morpholin-4-ylmethyl)-lH-indol-2-yl]methanone, 1,6-Naphthyridine 18, l-Tert-butyl-3-[3-(3,5-dimethoxyphenyl)-7-[4-(4-methylpiperazin-l- yl)butylamino]-l ,6-naphthyridin-2-yl]urea, N'-(2-Chloro-3,5-dimethoxyphenyl)-N'-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane- 1 ,2-diamine;hydrochloride, N- (3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(3-piperazin-l-ylpropyl)quinoxalin-6- amine, Methyl (3Z)-3 - [ [4- [acetyl- [3-(dimethylamino)propyl] amino] anilino] - phenylmethylidene] -2-oxo- 1 H-indole-6-carboxylate, 3 - [4- [3 - [4- [7- [N-(Cyclopropylmethyl)- 3,5-dimethoxyanilino]quinoxalin-2-yl]pyrazol-l-yl]propyl]piperazin-l-yl]propan-l- ol;hydrochloride, 5-[(R)-l-(3,5-Dichloropyridine-4-yl)ethoxy]-3-[5-(4-methylpiperazine-l- yl)-lH-benzoimidazole-2-yl]-lH-indazole, 4-Amino-3-(lH-benzo[d]imidazol-2-yl)quinolin- 2(lH)-one, 3-[4-[3-[4-[7-[3,5-Dimethoxy-N-[2-(propan-2-ylamino)ethyl]anilino]quinoxalin- 2-yl]pyrazol- 1 -yl]propyl]piperazin- 1 -yl]propan- 1 -ol;hydrochloride, 2-(2,6-Difluoro-3,5- dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethanol, [4-[7- [3,5- Dimethoxy-N-[2-(propan-2-ylamino)ethyl]anilino]quinoxalin-2-yl]-2-methylpyrazol-3- yl]methanol, 1,6-Naphthyridine deriv. 20, N-(2-Chloro-3,5-dimethoxyphenyl)-3-(l- methylpyrazol-4-yl)-N-(3-pyrrolidin- 1 -ylpropyl)quinoxalin-6-amine;hydrochloride, Methyl 3-[N-[4-[2-(dimethylamino)ethyl-methylcarbamoyl]phenyl]-C-phenylcarbonimidoyl]-2- hydroxy-lH-indole-6-carboxylate, N-[2-(l,4-Diazepan-l-yl)ethyl]-N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine;oxalic acid, N'-(2,6- Difluoro-3,5-dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2- ylethane-l,2-diamine, N-(3,5-Dimethoxyphenyl)-N-[(3-methyloxetan-3-yl)methyl]-3-(l- methylpyrazol-4-yl)quinoxalin-6-amine, Methyl (3Z)-3-[[4-[acetyl-[2-(dimethylamino)-2- oxoethyl]amino]anilino]-phenyhnethylidene]-2-oxo-lH-indole-6-carboxylate, Chembl4213341, Anilinoquinazoline deriv. 36, [5-Amino-l-(lH-benzimidazol-6-yl)-lH- pyrazol-4-yl] - 1 H-indol-2-ylMethanone, Hematoxylone, N-Cyclopropyl-N’-(3 ,5 - dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine, N-(3,5- Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(3-pyrimidin-2-ylpropyl)quinoxalin-6- amine, N'-(3,5-Dimethoxyphenyl)-N'-[3-[5-[(dimethylamino)methyl]-l-methylpyrazol-4- yl]quinoxalin-6-yl]-N-propan-2-ylethane-l,2-diamine, N'-(2,6-Difluoro-3,5- dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- trifluoroethyl)propane-l,3-diamine, [5-Amino-l-(2-methyl-lH-indol-5-yl)pyrazol-4-yl]-(lH- indol-2-yl)methanone, Haematoxylin, N'-(3,5-Dimethoxyphenyl)-N'-[3-(5-ethyl-l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2-trifluoroethyl)ethane- 1 ,2-diamine, Methyl 3- [N-[4-[[dimethylcarbamoyl(methyl)amino]methyl]phenyl]-C-phenylcarbonimidoyl]-2- hydroxy-lH-indole-6-carboxylate, 3-Methoxy-N-methyl-5-[[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]-(3-pyrrolidin-l-ylpropyl)amino]benzamide, N- (3, 5 -Dimethoxyphenyl) - 3-(l-methylpyrazol-4-yl)-N-(3-pyridin-4-ylpropyl)quinoxalin-6-amine, l-[3-(3,5- Dimethoxy-N- [3 -( 1 -propan-2-ylpyrazol-4-yl)quinoxalin-6-yl] anilino)propyl]pyrrolidin-2- one, and Regorafenib.

[0255]

[0253] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is topically administered once a day. In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is administered twice a day.

[0256]

[0254] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is topically administered 3 times / day (e.g., every 8 hours). In some embodiments, the method comprises administering to the subject 3 times / day (e.g., every 8 hours) a dose between about 0.03 mg / cm2to 0.3 mg / cm2(e.g., between about 0.03 mg / cm2 and about 0.25 mg / cm2, between about 0.03 mg / cm2 and about 0.20 mg / cm2, or between 0.03 mg / cm2 and about 0.15 mg / cm2).

[0257]

[0255] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is topically administered 2 times / day (e.g., every 12 hours). In some embodiments, the method comprises administering to the subject 2 times / day (e.g., every 12 hours) a dose between about 0.03 mg / cm2to 0.3 mg / cm2e.g., between about 0.03 mg / cm2 and about 0.25 mg / cm2, between about 0.03 mg / cm2 and about 0.20 mg / cm2, or between 0.03 mg / cm2 and about 0.15 mg / cm2).

[0258]

[0256] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is topically administered 1 time / day (e.g., every 24 hours). In some embodiments, the method comprises administering to the subject 1 time / day (e.g., every 24 hours) a dose between about 0.03 mg / cm2to 0.3 mg / cm2(e.g., between about 0.03 mg / cm2 and about 0.25 mg / cm2, between about 0.03 mg / cm2 and about 0.20 mg / cm2, or between 0.03 mg / cm2 and about 0.15 mg / cm2).

[0259]

[0257] In some embodiments, the selective inhibitor of VEGFR2 and FGFR1 is brivanib alaninate. In some embodiments, brivanib alaninate is topically administered to a subject at a dose between about 0.03 mg / cm2to 0.3 mg / cm2per day.

[0260]

[0258] In some embodiments, the selective inhibitor of VEGFR2 and FGFR1 is Su5402. In some embodiments, Su5402 is topically administered to a subject at a dose between about 0.03 mg / cm2to 0.3 mg / cm2per day.

[0261]

[0259] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is administered by a local subcutaneous injection 3 times / day (e.g., every 8 hours). In some embodiments, the subject is administered a local subcutaneous injection 3 times / day (e.g., every 8 hours) a dose between about 0.01 mg to 3 mg (e.g., between about 0.01 mg and about 2.5 mg between about 0.01 mg and about 2 mg, or between 0.01 mg and about 1 .5 mg).

[0262]

[0260] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is topically administered 2 times / day (e.g., every 12 hours). In some embodiments, the subject is administered a local subcutaneous injection twice a day (e.g., every 12 hours) a dose between about 0.01 mg to 3 mg (e.g., between about 0.01 mg and about 2.5 mg between about 0.01 mg and about 2 mg, or between 0.01 mg and about 1.5 mg).

[0263]

[0261] In some embodiments, the selective inhibitor of VEGFR2 and / or FGFR1 is topically administered 1 time / day (e.g., every 24 hours). In some embodiments, the subject is administered a local subcutaneous injection 1 time / day (e.g., every 24 hours) a dose between about 0.01 mg to 3 mg (e.g., between about 0.01 mg and about 2.5 mg between about 0.01 mg and about 2 mg, or between 0.01 mg and about 1.5 mg).

[0262] In some embodiments, the selective inhibitor of VEGFR2 and FGFR1 is brivanib alaninate. In some embodiments, brivanib alaninate is administered by local subcutaneous injection to a subject at a dose between about 0.01 mg to 3 mg per day.

[0264]

[0263] In some embodiments, the selective inhibitor of VEGFR2 and FGFR1 is Su5402. In some embodiments, Su5402 is administered by local subcutaneous injection to a subject at a dose between about 0.01 mg to 3 mg per day. In some embodiments, the subcutaneous injection comprises brivanib alaninate or Su5402 at a concentration of 0.01 mg / mL - 30 mg / mL in solution of an exemplary buffer, such as phosphate buffered saline (PBS) or DMSO in PBS.

[0265]

[0264] In some embodiments, a pharmaceutically or therapeutically effective amount of a PPAR-gamma agonist are delivered to the subject.

[0266]

[0265] In some embodiments, a pharmaceutically or therapeutically effective amount of a topical formulation of a PPAR-gamma agonist is between about O.O5%-5% weight / weight (w / w). In some embodiments, a topical formulation of a PPAR-gamma agonist administered to a patient comprises between about 0.006 mg / cm2to about 0.5 mg / cm2of a PPAR-gamma agonist administered, according to various embodiments, once, twice, or three times per day.

[0267]

[0266] In some embodiments, a pharmaceutically or therapeutically effective amount of a local subcutaneous injection of a PPAR-gamma agonist comprises between about 0.05 mg to about 5 mg of a PPAR-gamma agonist administered, according to various embodiments, once, twice or three times per day. In some embodiments, the local subcutaneous injection comprises a PPAR-gamma agonist at a concentration of about 0.05 mg / mL - 50 mg / mL in solution of an exemplary buffer, such as phosphate buffered saline (PBS) or DMSO.

[0268]

[0267] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, the PPAR-gamma agonist is pioglitazone.

[0269]

[0268] In some embodiments, the PPAR-gamma agonist is topically administered once a day. In some embodiments, the PPAR-gamma agonist is administered twice a day.

[0270]

[0269] In some embodiments, the PPAR-gamma agonist is topically administered 3 times / day (e.g., every 8 hours). In some embodiments, the method comprises administering to the subject 3 times / day e.g., every 8 hours) a dose between about 0.006 mg / cm2to 0.5 mg / cm2(e.g., between about 0.006 mg / cm2and about 0.45 mg / cm2, between about 0.006 mg / cm2and about 0.40 mg / cm2, or between 0.006 mg / cm2and about 0.35 mg / cm2).

[0271]

[0270] In some embodiments, the PPAR-gamma agonist is topically administered 2 times / day (e.g., every 12 hours). In some embodiments, the method comprises administering to the subject 2 times / day (e.g., every 12 hours) a dose between about 0.006 mg / cm2to 0.5 mg / cm2(e.g., between about 0.006 mg / cm2and about 0.45 mg / cm2, between about 0.006 mg / cm2and about 0.40 mg / cm2, or between 0.006 mg / cm2and about 0.35 mg / cm2).

[0272]

[0271] In some embodiments, the PPAR-gamma agonist is topically administered 1 time / day (e.g., every 24 hours). In some embodiments, the method comprises administering to the subject 1 time / day (e.g., every 24 hours) a dose between about 0.006 mg / cm2to 0.5 mg / cm2(e.g., between about 0.006 mg / cm2and about 0.45 mg / cm2, between about 0.006 mg / cm2and about 0.40 mg / cm2, or between 0.006 mg / cm2and about 0.35 mg / cm2).

[0273]

[0272] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, rosiglitazone is topically administered to a subject at a dose between about 0.006 mg / cm2to 0.5 mg / cm2per day.

[0274]

[0273] In some embodiments, the PPAR-gamma agonist is pioglitazone. In some embodiments, pioglitazone is topically administered to a subject at a dose between about 0.006 mg / cm2to 0.5 mg / cm2per day.

[0275]

[0274] In some embodiments, the PPAR-gamma agonist is administered by a local subcutaneous injection 3 times / day (e.g., every 8 hours). In some embodiments, the subject is administered a local subcutaneous injection 3 times / day (e.g., every 8 hours) a dose between about 0.05 mg to 5 mg (e.g., between about 0.05 mg and about 4.5 mg between about 0.05 mg and about 4 mg, or between 0.05 mg and about 3.5 mg).

[0276]

[0275] In some embodiments, the PPAR-gamma agonist is topically administered 2 times / day (e.g., every 12 hours). In some embodiments, the subject is administered a local subcutaneous injection twice a day (e.g., every 12 hours) a dose between about 0.05 mg to 5 mg (e.g., between about 0.05 mg and about 4.5 mg between about 0.05 mg and about 4 mg, or between 0.05 mg and about 3.5 mg).

[0277]

[0276] In some embodiments, the PPAR-gamma agonist is topically administered 1 time / day (e.g., every 24 hours). In some embodiments, the subject is administered a local subcutaneous injection 1 time / day (e.g., every 24 hours) a dose between about 0.05 mg to 5 mg (e.g., between about 0.05 mg and about 4.5 mg between about 0.05 mg and about 4 mg, or between 0.05 mg and about 3.5 mg).

[0278]

[0277] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, rosiglitazone is administered by local subcutaneous injection to a subject at a dose between about 0.05 mg to 5 mg per day.

[0279]

[0278] In some embodiments, the PPAR-gamma agonist is pioglitazone. In some embodiments, pioglitazone is administered by local subcutaneous injection to a subject at a dose between about 0.01 mg to 3 mg per day. In some embodiments, the subcutaneous injection comprises rosiglitazone or pioglitazone at a concentration of 0.05 mg / mL - 50 mg / mL in solution of an exemplary buffer, such as phosphate buffered saline (PBS) or DMSO.

[0280]

[0279] In some embodiments, a pharmaceutically or therapeutically effective amount of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor are delivered to the subject.

[0281]

[0280] In some embodiments, a pharmaceutically or therapeutically effective amount of a topical formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor has between about 0.01 %-5% weight / weight (w / w) of a PPAR-gamma agonist and between about 0.01 %-3% weight / weight (w / w) of a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor. In some embodiments, a topical formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor administered to a patient comprises between about 0.003 mg / cm2to about 0.5 mg / cm2of a PPAR-gamma agonist and about 0.03 mg / cm2to about 0.3 mg / cm2of a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor administered, according to various embodiments, once, twice, or three times per day.

[0282]

[0281] In some embodiments, a pharmaceutically or therapeutically effective amount of a local subcutaneous injection of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor comprises between about 0.025 mg to about 5 mg of a PPAR-gamma agonist administered and between about 0.01 mg to about 3 mg of a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, according to various embodiments, once, twice or three times per day. In some embodiments, the local subcutaneous injection comprises a PPAR-gamma agonist at a concentration of about 0.025 mg / mL - 50 mg / mL and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor at a concentration of about 0.01 mg / mL - 30 mg / mL in solution of an exemplary buffer, such as phosphate buffered saline (PBS) or DMSO.

[0283]

[0282] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, the PPAR-gamma agonist is pioglitazone.

[0284]

[0283] In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1, consisting of lodo-sunitinib, 5-Methoxy-sunitinib, Acrizanib, Agerafenib, Alectinib, Altiratinib, Amuvatinib, Amuvatinib hydrochloride, Apatinib, Apatinib Mesylate, Avapritinib, Axitinib, Bafetinib, Bemcentinib, Bosutinib, Brivanib, Brivanib alaninate, Brivanib metabolite M25, Cabozantinib, Cabozantinib oxidation B, Cabozantinib S-malate, Canertinib, Cediranib, Cerdulatinib hydrochloride, Ceritinib, Crenolanib, Dasatinib, Defactinib, Desmethyl nintedanib, Dovitinib, Entrectinib, Erdafitinib, Erlotinib, Famitinib, Fedratinib, Fisogatinib, Foretinib, Fostamatinib disodium, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, Golvatinib, Gunagratinib, Henatinib, Imatinib, Infigratinib, Infigratinib phosphate, Lapatinib, Lenvatinib, Lestaurtinib, Linifanib, Linsitinib, Lucitanib, Masitinib, Mivavotinib, Motesanib, N,N-Dimethyl Sunitinib, N-Desethyl Sunitinib, N-Desmethyl vandetanib, Neratinib, Nilotinib, Ningetinib, Nintedanib, Nintedanib esylate, Orantinib, Pacritinib, Pazopanib, Pelitinib, Pemigatinib, Pexidartinib, Pexmetinib, Ponatinib, Pralsetinib, Quizartinib, Quizartinib dihydrochloride, Ravoxertinib, Regorafenib, Ripretinib, Rogaratinib, Saracatinib, Selpercatinib, Semaxanib, Sitravatinib, Sorafenib, Sorafenib tosylate, Sunitinib, Tafetinib, Tamatinib, Tandutinib, Telatinib, Tesevatinib, Tivozanib, Toceranib, US10155768, Vandetanib, US9029401, Sunitinib, Vandetanib, Vandetanib hydrochloride, Vatalanib, Vatalanib succinate, Vemurafenib, and Vimseltinib.

[0285]

[0284] In some embodiments, the PPAR-gamma agonist is 376501 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0286]

[0285] In some embodiments, the PPAR-gamma agonist is arhalofenate and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0287]

[0286] In some embodiments, the PPAR-gamma agonist is ATx-08-001 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0288]

[0287] In some embodiments, the PPAR-gamma agonist is balaglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0289]

[0288] In some embodiments, the PPAR-gamma agonist is cannabigerol and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1 .

[0290]

[0289] In some embodiments, the PPAR-gamma agonist is ciglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0291]

[0290] In some embodiments, the PPAR-gamma agonist is CLX-0921 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0292]

[0291] In some embodiments, the PPAR-gamma agonist is DS-6930 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0293]

[0292] In some embodiments, the PPAR-gamma agonist is efatutazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0294]

[0293] In some embodiments, the PPAR-gamma agonist is farglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0295]

[0294] In some embodiments, the PPAR-gamma agonist is FX-909 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0295] In some embodiments, the PPAR-gamma agonist is GED-0507 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0296]

[0296] In some embodiments, the PPAR-gamma agonist is INT-131 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0297]

[0297] In some embodiments, the PPAR-gamma agonist is KY-903 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0298]

[0298] In some embodiments, the PPAR-gamma agonist is MK-0533 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0299]

[0299] In some embodiments, the PPAR-gamma agonist is pioglitazone hydrochloride and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0300]

[0300] In some embodiments, the PPAR-gamma agonist is R-483 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0301]

[0301] In some embodiments, the PPAR-gamma agonist is rivoglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0302]

[0302] In some embodiments, the PPAR-gamma agonist is rosiglitazone maleate and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0303]

[0303] In some embodiments, the PPAR-gamma agonist is T-174 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1 .

[0304]

[0304] In some embodiments, the PPAR-gamma agonist is UHC-1 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0305]

[0305] In some embodiments, the PPAR-gamma agonist is aleglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0306]

[0306] In some embodiments, the PPAR-gamma agonist is AVE-0897 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0307]

[0307] In some embodiments, the PPAR-gamma agonist is AZD-6610 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0308]

[0308] In some embodiments, the PPAR-gamma agonist is cevoglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0309]

[0309] In some embodiments, the PPAR-gamma agonist is chiglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0310] In some embodiments, the PPAR-gamma agonist is E-3030 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0310]

[0311] In some embodiments, the PPAR-gamma agonist is etalocib and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0311]

[0312] In some embodiments, the PPAR-gamma agonist is etrinabdione and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0312]

[0313] In some embodiments, the PPAR-gamma agonist is GW-1929 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0313]

[0314] In some embodiments, the PPAR-gamma agonist is GW-409544 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0314]

[0315] In some embodiments, the PPAR-gamma agonist is indeglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0315]

[0316] In some embodiments, the PPAR-gamma agonist is KRP-297 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0316]

[0317] In some embodiments, the PPAR-gamma agonist is lanifibranor and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0317]

[0318] In some embodiments, the PPAR-gamma agonist is lobeglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0318]

[0319] In some embodiments, the PPAR-gamma agonist is LR-90 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1 .

[0319]

[0320] In some embodiments, the PPAR-gamma agonist is LSN-862 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0320]

[0321] In some embodiments, the PPAR-gamma agonist is LY-929 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0321]

[0322] In some embodiments, the PPAR-gamma agonist is muraglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0322]

[0323] In some embodiments, the PPAR-gamma agonist is naveglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0323]

[0324] In some embodiments, the PPAR-gamma agonist is NC-2100 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0324]

[0325] In some embodiments, the PPAR-gamma agonist is netoglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0326] In some embodiments, the PPAR-gamma agonist is oxeglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0325]

[0327] In some embodiments, the PPAR-gamma agonist is peliglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0326]

[0328] In some embodiments, the PPAR-gamma agonist is ragaglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0327]

[0329] In some embodiments, the PPAR-gamma agonist is reglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0328]

[0330] In some embodiments, the PPAR-gamma agonist is saroglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0329]

[0331] In some embodiments, the PPAR-gamma agonist is SB-219994 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0330]

[0332] In some embodiments, the PPAR-gamma agonist is sodelglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0331]

[0333] In some embodiments, the PPAR-gamma agonist is T3D-959 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0332]

[0334] In some embodiments, the PPAR-gamma agonist is tesaglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0333]

[0335] In some embodiments, the PPAR-gamma agonist is troglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of Table 1.

[0334]

[0336] In some embodiments, the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW- 1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN- 862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DI5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL- 17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone, and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib.

[0335]

[0337] In some embodiments, the PPAR-gamma agonist is 376501 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0336]

[0338] In some embodiments, the PPAR-gamma agonist is arhalofenate and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0337]

[0339] In some embodiments, the PPAR-gamma agonist is ATx-08-001 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0338]

[0340] In some embodiments, the PPAR-gamma agonist is balaglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0339]

[0341] In some embodiments, the PPAR-gamma agonist is cannabigerol and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0340]

[0342] In some embodiments, the PPAR-gamma agonist is ciglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0341]

[0343] In some embodiments, the PPAR-gamma agonist is CLX-0921 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0342]

[0344] In some embodiments, the PPAR-gamma agonist is DS-6930 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0343]

[0345] In some embodiments, the PPAR-gamma agonist is efatutazone and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0344]

[0346] In some embodiments, the PPAR-gamma agonist is farglitazar and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0345]

[0347] In some embodiments, the PPAR-gamma agonist is FX-909 and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0346]

[0348] In some embodiments, the PPAR-gamma agonist is GED-0507 and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0347]

[0349] In some embodiments, the PPAR-gamma agonist is INT-131 and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0348]

[0350] In some embodiments, the PPAR-gamma agonist is KY-903 and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0349]

[0351] In some embodiments, the PPAR-gamma agonist is MK-0533 and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is nintedanib esylate or nintedanib.

[0350]

[0352] In some embodiments, the PPAR-gamma agonist is pioglitazone hydrochloride and the PDGFRA / B, VEGFR2 and / or FGFRI inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib. In some embodiments, the PPAR-gamma agonist is pioglitazone hydrochloride and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0351]

[0353] In some embodiments, the PPAR-gamma agonist is R-483 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0352]

[0354] In some embodiments, the PPAR-gamma agonist is rivoglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0353]

[0355] In some embodiments, the PPAR-gamma agonist is rosiglitazone maleate and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib. In some embodiments, the PPAR-gamma agonist is rosiglitazone maleate and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0354]

[0356] In some embodiments, the PPAR-gamma agonist is T-174 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0355]

[0357] In some embodiments, the PPAR-gamma agonist is UHC-1 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0356]

[0358] In some embodiments, the PPAR-gamma agonist is aleglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0357]

[0359] In some embodiments, the PPAR-gamma agonist is AVE-0897 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0358]

[0360] In some embodiments, the PPAR-gamma agonist is AZD-6610 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0359]

[0361] In some embodiments, the PPAR-gamma agonist is cevoglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0360]

[0362] In some embodiments, the PPAR-gamma agonist is chiglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0361]

[0363] In some embodiments, the PPAR-gamma agonist is E-3030 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0362]

[0364] In some embodiments, the PPAR-gamma agonist is etalocib and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0363]

[0365] In some embodiments, the PPAR-gamma agonist is etrinabdione and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0364]

[0366] In some embodiments, the PPAR-gamma agonist is GW-1929 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0367] In some embodiments, the PPAR-gamma agonist is GW-409544 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib

[0365]

[0368] In some embodiments, the PPAR-gamma agonist is indeglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0366]

[0369] In some embodiments, the PPAR-gamma agonist is KRP-297 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0367]

[0370] In some embodiments, the PPAR-gamma agonist is lanifibranor and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0368]

[0371] In some embodiments, the PPAR-gamma agonist is lobeglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0369]

[0372] In some embodiments, the PPAR-gamma agonist is LR-90 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0370]

[0373] In some embodiments, the PPAR-gamma agonist is LSN-862 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0371]

[0374] In some embodiments, the PPAR-gamma agonist is LY-929 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0372]

[0375] In some embodiments, the PPAR-gamma agonist is muraglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0373]

[0376] In some embodiments, the PPAR-gamma agonist is naveglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0374]

[0377] In some embodiments, the PPAR-gamma agonist is NC-2100 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0375]

[0378] In some embodiments, the PPAR-gamma agonist is netoglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0376]

[0379] In some embodiments, the PPAR-gamma agonist is oxeglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0377]

[0380] In some embodiments, the PPAR-gamma agonist is peliglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0378]

[0381] In some embodiments, the PPAR-gamma agonist is ragaglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0379]

[0382] In some embodiments, the PPAR-gamma agonist is reglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0380]

[0383] In some embodiments, the PPAR-gamma agonist is saroglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0384] In some embodiments, the PPAR-gamma agonist is SB-219994 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0381]

[0385] In some embodiments, the PPAR-gamma agonist is sodelglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0382]

[0386] In some embodiments, the PPAR-gamma agonist is T3D-959 and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0383]

[0387] In some embodiments, the PPAR-gamma agonist is tesaglitazar and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0384]

[0388] In some embodiments, the PPAR-gamma agonist is troglitazone and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib esylate or nintedanib.

[0385]

[0389] In some embodiments, the PPAR-gamma agonist and PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is topically administered once a day. In some embodiments, the PPAR- gamma agonist and PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is administered twice a day.

[0386]

[0390] In some embodiments, the PPAR-gamma agonist and PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is topically administered 3 times / day (e.g., every 8 hours). In some embodiments, the method comprises administering to the subject 3 times / day e.g., every 8 hours) a dose between about 0.001 mg / cm2to 0.5 mg / cm2(e.g., between about 0.001 mg / cm2and about 0.45 mg / cm2, between about 0.001 mg / cm2and about 0.40 mg / cm2, or between 0.001 mg / cm2and about 0.35 mg / cm2) of the PPAR-gamma agonist and a dose between about 0.001 mg / cm2to 0.5 mg / cm2(e.g., between about 0.001 mg / cm2 and about 0.25 mg / cm2, between about 0.001 mg / cm2 and about 0.20 mg / cm2, or between 0.001 mg / cm2 and about 0.15 mg / cm2) of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor .

[0387]

[0391] In some embodiments, the PPAR-gamma agonist is topically administered 2 times / day (e.g., every 12 hours). In some embodiments, the method comprises administering to the subject 2 times / day (e.g., every 12 hours) a dose between about 0.001 mg / cm2to 0.5 mg / cm2(e.g., between about 0.001 mg / cm2and about 0.45 mg / cm2, between about 0.001 mg / cm2and about 0.40 mg / cm2, or between 0.001 mg / cm2and about 0.35 mg / cm2) of the PPAR-gamma agonist and a dose between about 0.001 mg / cm2to 0.5 mg / cm2(e.g., between about 0.001 mg / cm2 and about 0.25 mg / cm2, between about 0.001 mg / cm2 and about 0.20 mg / cm2, or between 0.001 mg / cm2 and about 0.15 mg / cm2) of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor .

[0388]

[0392] In some embodiments, the PPAR-gamma agonist is topically administered 1 time / day (e.g., every 24 hours). In some embodiments, the method comprises administering to the subject 1 time / day (e.g., every 24 hours) a dose between about 0.001 mg / cm2to 0.5 mg / cm2(e.g., between about 0.001 mg / cm2and about 0.45 mg / cm2, between about 0.001 mg / cm2and about 0.40 mg / cm2, or between 0.001 mg / cm2and about 0.35 mg / cm2) of the PPAR- gamma agonist and a dose between about 0.001 mg / cm2to 0.5 mg / cm2(e.g., between about 0.001 mg / cm2 and about 0.25 mg / cm2, between about 0.001 mg / cm2 and about 0.20 mg / cm2, or between 0.001 mg / cm2 and about 0.15 mg / cm2) of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor .

[0389]

[0393] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, rosiglitazone is topically administered to a subject at a dose between about 0.006 mg / cm2to 0.5 mg / cm2per day.

[0390]

[0394] In some embodiments, the PPAR-gamma agonist is pioglitazone. In some embodiments, pioglitazone is topically administered to a subject at a dose between about 0.006 mg / cm2to 0.5 mg / cm2per day.

[0391]

[0395] In some embodiments, the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib. In some embodiments, nintedanib is topically administered to a subject at a dose between about 0.03 mg / cm2to 0.3 mg / cm2per day.

[0392]

[0396] In some embodiments, the PPAR-gamma agonist and the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is administered by a local subcutaneous injection 3 times / day (e.g., every 8 hours). In some embodiments, the subject is administered a local subcutaneous injection 3 times / day (e.g., every 8 hours) a dose between about 0.025 mg to 5 mg (e.g., between about 0.025 mg and about 4.5 mg between about 0.025 mg and about 4 mg, or between 0.025 mg and about 3.5 mg) of the PPAR-gamma agonist and a dose between about 0.01 mg to 3 mg (e.g., between about 0.01 mg and about 2.5 mg between about 0.01 mg and about 2 mg, or between 0.01 mg and about 1.5 mg) of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0393]

[0397] In some embodiments, the PPAR-gamma agonist is topically administered 2 times / day (e.g., every 12 hours). In some embodiments, the subject is administered a local subcutaneous injection twice a day (e.g., every 12 hours) a dose between about 0.025 mg to 5 mg (e.g., between about 0.025 mg and about 4.5 mg between about 0.025 mg and about 4 mg, or between 0.025 mg and about 3.5 mg) of the PPAR-gamma agonist and a dose between about 0.01 mg to 3 mg (e.g., between about 0.01 mg and about 2.5 mg between about 0.01 mg and about 2 mg, or between 0.01 mg and about 1.5 mg) of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0398] In some embodiments, the PPAR-gamma agonist is topically administered 1 time / day (e.g., every 24 hours). In some embodiments, the subject is administered a local subcutaneous injection 1 time / day (e.g., every 24 hours) a dose between about 0.025 mg to 5 mg e.g., between about 0.025 mg and about 4.5 mg between about 0.025 mg and about 4 mg, or between 0.025 mg and about 3.5 mg) of the PPAR-gamma agonist and a dose between about 0.01 mg to 3 mg (e.g., between about 0.01 mg and about 2.5 mg between about 0.01 mg and about 2 mg, or between 0.01 mg and about 1.5 mg) of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0394]

[0399] In some embodiments, the PPAR-gamma agonist is rosiglitazone. In some embodiments, rosiglitazone is administered by local subcutaneous injection to a subject at a dose between about 0.05 mg to 5 mg per day.

[0395]

[0400] In some embodiments, the PPAR-gamma agonist is pioglitazone. In some embodiments, pioglitazone is administered by local subcutaneous injection to a subject at a dose between about 0.01 mg to 3 mg per day. In some embodiments, the subcutaneous injection comprises rosiglitazone or pioglitazone at a concentration of 0.05 mg / mL - 50 mg / mL in solution of an exemplary buffer, such as phosphate buffered saline (PBS) or DMSO.

[0396] Methods of Treatment

[0397]

[0401] Provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to a subject an effective amount of a topical formulation of a selective inhibitor of VEGFR2 and FGFR1.

[0398]

[0402] Also provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to a subject an effective amount of a topical formulation of a PPAR-gamma agonist.

[0399]

[0403] Also provided herein is a method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to a subject an effective amount of a topical formulation of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0400]

[0404] In some embodiments, the subject is receiving a glucagon-like peptide- 1 (GLP-1) receptor agonist. In some embodiments, the subject has received a GLP-1 receptor agonist. In some embodiments, the subject will receive a GLP-1 receptor agonist. In some embodiments, the subject is receiving a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. In some embodiments, the subject has received a GIP receptor agonist. In some embodiments, the subject will receive a GIF receptor agonist. In some embodiments, a GLP-1 receptor agonist is also a GIP receptor agonist and a glucagon receptor agonist. In some embodiments, a GLP-1 receptor agonist or a GIP receptor agonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

[0401]

[0405] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide.

[0402]

[0406] In some embodiments, the subject receiving a GLP-1 agonist has lost or is at a risk of losing facial dermal adipose tissue. In some embodiments, the loss of facial dermal adipose leads to a hollowed-out appearance and an increase in lines and wrinkles.

[0403]

[0407] In some embodiments, the GIP receptor agonist is tirzepatide. In some embodiments, the subject receiving a GIP receptor agonist has lost or is at a risk of losing facial dermal adipose tissue. In some embodiments, the loss of facial dermal adipose leads to a hollowed- out appearance and an increase in lines and wrinkles

[0404]

[0408] In some embodiments, the subject is a human. In some embodiments, the human is older than 30 years in age. In some embodiments, the subject’s age is 30-39 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, 80-89 years or 90-99 years.

[0405]

[0409] In some embodiments, the loss of facial dermal adipose tissue is a result of normal aging. In some embodiments, the loss of facial dermal adipose tissue is a result of other weight loss regimens or additional reasons, such as HIV-associated facial lipoatrophy, localized scleroderma, chronic treatment with corticosteroids, hormonal changes, yo-yo dieting, poor diet, excessive exercise, stress, excessive sub exposure, smoking, and lupus erythematosus profundus.

[0406]

[0410] In some embodiments, the atrophy of facial dermal adipose tissue is a result of normal aging. In some embodiments, the atrophy of facial dermal adipose tissue is a result of other weight loss regimens or additional reasons, such as HIV-associated facial lipoatrophy, localized scleroderma, chronic treatment with corticosteroids, hormonal changes, yo-yo dieting, poor diet, excessive exercise, stress, excessive sun exposure, smoking, and lupus erythematosus profundus.

[0407]

[0411] In some embodiments, the subject does not have acne. In some embodiments, the subject does not have a skin infection due to bacteria on their face. In some embodiments, acne includes simple acne, comedogenic acne, papulopustular acne, papulocomedonic acne, nodulocystic acne, acne conglobata, cheloid acne of the nape of the neck, recurrent miliary acne, necrotic acne, neonatal acne, occupational acne, acne rosacea, senile acne, solar acne, medication-related acne and acne vulgaris.

[0408]

[0412] Also provided herein are topical formulations comprising a selective inhibitor of VEGFR2 and FGFR1 and a delivery vehicle.

[0409]

[0413] Also provided herein are topical formulations comprising a PPAR-gamma agonist and a delivery vehicle.

[0410]

[0414] Also provided herein are topical formulations comprising a PPAR-gamma agonist, a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, and a delivery vehicle.

[0411]

[0415] In some embodiments, the subject is administered a facial fat transplant. Facial fat transplants are also known as an autologous fat transfer, fat grafting, fat injections, and lipofilling. In some embodiments, the facial fat transplant is administered before the administration of an effective amount of a locally administered formulation of a selective inhibitor of VEGFR2 and FGFR1. In some embodiments, the facial fat transplant is administered before the administration of an effective amount of a locally administered formulation of a PPAR-gamma agonist, wherein the subject is receiving a glucagon-like peptide- 1 (GLP-1) receptor agonist. In some embodiments, the facial fat transplant is administered before the administration of an effective amount of a locally administered formulation of a PPAR-gamma agonist, wherein the subject is receiving a corticosteroid. In some embodiments, the facial fat transplant is administered before the administration of an effective amount of a locally administered formulation comprising a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

[0412]

[0416] In some embodiments, the facial fat transplant is administered after the administration of an effective amount of a locally administered formulation of a selective inhibitor of VEGFR2 and FGFR1. In some embodiments, the facial fat transplant is administered after the administration of an effective amount of a locally administered formulation of a PPAR- gamma agonist, wherein the subject is receiving a glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, the facial fat transplant is administered after the administration of an effective amount of a locally administered formulation of a PPAR- gamma agonist, wherein the subject is receiving a corticosteroid. In some embodiments, the facial fat transplant is administered after the administration of an effective amount of a locally administered formulation comprising a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor. EXAMPLES

[0413] Example 1. Semaglutide causes the loss of dermal adipose tissue in mice

[0414]

[0417] C57BL6 mice were dosed with an intraperitoneal (IP) injection, 10 nmol / kg per day, of an exemplary GLP-1 agonist, semaglutide, plus a topical formulation of vehicle, or an IP injection of vehicle plus a topical formulation of vehicle. The IP injection of vehicle comprised phosphate buffered saline (PBS). The topical formulation comprised a 1:2 lotion to DMSO solution. The exemplary lotion that was used (e.g., CeraVe™ ) comprised water, glycerin, cetearyl alcohol, caprylic / capric triglyceride, cetyl alcohol, ceteareth-20, petrolatum, potassium phosphate, ceramide np, ceramide ap, ceramide eop, carbomer, dimethicone, behentrimonium methosulfate, sodium lauroyl lactylate, sodium hyaluronate, cholesterol, phenoxyethanol, disodium edta, dipotassium phosphate, tocopherol, phytosphingosine, xanthan gum, and ethylhexylglycerin. The location of the topical administration was labeled the anterior site. A site on the opposite end of the mice was used as the untreated site, which was labeled the posterior site for the purposes of the experiments. The mice received daily treatment for 9 days. All recited percentages are weight / weight (w / w).

[0415]

[0418] The thickness of dWAT, dermis, and skin was measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0416]

[0419] The mice that were treated with semaglutide showed a statistically significant decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 1A, FIG. IB, and FIG. 1C).

[0417]

[0420] The mice that were treated with semaglutide also showed a statistically significant decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with vehicle (FIG. ID, FIG. IE, and FIG. IF).

[0418]

[0421] The body weight of the mice was measured throughout the treatment (FIG. 1G). The mice treated with semaglutide showed a decrease in body weight over the course of treatment compared to the mice treated with vehicle.

[0419] Example 2. Brivanib alaninate preserves dermal adipose tissue in mice

[0420]

[0422] C57BL6 mice were dosed with an IP injection of vehicle plus a topical formulation of vehicle, an IP injection of 10 nmol / kg per day of semaglutide plus a topical formulation of vehicle, or an IP injection of semaglutide plus a topical formulation of 1% w / w of an exemplary selective VEGFR2 and FGFR 1 inhibitor, brivanib alaninate. The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and the exemplary lotion is described in Example 1. The location of the topical administration was labeled the anterior site. A site on the opposite end of the mice was used as the untreated site, which was labeled the posterior site for the purposes of the experiments. The mice received daily treatment for 9 days. All recited percentages are weight / weight (w / w).

[0421]

[0423] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0422]

[0424] The mice that were treated with semaglutide showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 2A, FIG. 2B, and FIG. 2C). The mice that were treated with semaglutide and brivanib alaninate did not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 2 A, FIG. 2B, and FIG. 2C). The statistical significance shown in FIG. 2A and FIG. 2C is in comparison to the semaglutide treatment.

[0423]

[0425] The mice that were treated with semaglutide also showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with vehicle (FIG. 2D, FIG. 2E, and FIG. 2F). The mice that were treated with semaglutide and brivanib alaninate also showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with vehicle (FIG. 2D, FIG. 2E, and FIG. 2F).

[0424]

[0426] The body weight of the mice was measured throughout the treatment (FIG. 2G). The mice treated with semaglutide or semaglutide and brivanib alaninate showed a decrease in body weight over the course of treatment compared to the mice treated with vehicle.

[0425]

[0427] Further, C57BL6 mice were dosed with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of 10 nmol / kg per day of semaglutide plus a topical formulation of vehicle, or an IP injection of semaglutide plus a topical formulation of either 0.3% w / w brivanib alaninate or 1.5% w / w brivanib alaninate for 8 days.

[0426]

[0428] The mice that were treated with semaglutide showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 3A, FIG. 3B, and FIG. 3C). The mice that were treated with semaglutide and either 0.3% or 1.5% brivanib alaninate did not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 3A, FIG. 3B, and FIG. 3C). The statistical significance shown in FIG. 3A and FIG. 3C is in comparison to the semaglutide treatment.

[0427]

[0429] The mice that were treated with semaglutide also showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the posterior site compared to mice treated with vehicle (FIG. 3D, FIG. 3E, and FIG. 3F). The mice that were treated with semaglutide and either 0.3% or 1.5% brivanib alaninate also showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the posterior site compared to the mice treated with vehicle (FIG. 3D, FIG. 3E, and FIG. 3F).

[0428] Example 3. SU5402 preserves dermal adipose tissue in mice

[0429]

[0430] C57BL6 mice were dosed with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of 10 nmol / kg per day of semaglutide, plus a topical formulation of a vehicle, or an IP injection of semaglutide plus a topical formulation of 1% an exemplary selective VEGFR2 and FGFR1 inhibitor, SU5402. The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and the exemplary lotion is described in Example 1. The location of the topical administration was labeled the anterior site. A site on the opposite end of the mice was used as the untreated site, which was labeled the posterior site for the purposes of the experiments. The mice received daily treatment for 8 days. All recited percentages are weight / weight (w / w).

[0430]

[0431] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0431]

[0432] The mice that were treated with semaglutide showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 4A, FIG. 4B, and FIG. 4C). The mice that were treated with semaglutide and Su5402 did not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 4A, FIG. 4B, and FIG. 4C). The statistical significance shown in FIG. 4A and FIG. 4C is in comparison to the semaglutide treatment.

[0432]

[0433] The mice that were treated with semaglutide also showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the posterior site compared to mice treated with vehicle (FIG. 4D, FIG. 4E, and FIG. 4F). The mice that were treated with semaglutide and Su5402 also showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the posterior site compared to the mice treated with vehicle (FIG. 4D, FIG. 4E, and FIG. 4F).

[0433]

[0434] The body weight of the mice was measured at the end of the treatment (FIG. 5). The mice treated with semaglutide or semaglutide and 1 % Su5402 showed a decrease in body weight at the end of treatment compared to the mice treated with vehicle only.

[0434] Example 4. A selective VEGFR2 and FGFR1 inhibitor preserves dermal adipose tissue in mice

[0435]

[0435] C57BL6 mice are dosed with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of semaglutide plus a topical formulation of vehicle, or an IP injection of semaglutide plus a topical formulation of 0.01% -3% w / w (between about 0.03 mg / cm2to about 0.3 mg / cm2) cabozantinib, axinitib, lenvatinib, nintedanib, or pazopanib. The topical formulation comprises a 1 :2 lotion (the exemplary lotion used in Examples 1-3) to DMSO solution. The IP injection of vehicle comprises phosphate buffered saline (PBS). The location of the topical administration is labeled the anterior site. A site on the opposite end of the mice is used as the untreated site, which is labeled the posterior site for the purposes of the experiments. The mice receive daily treatment for 3 days, 4, days, 5, days, 6, days, 7, days, 8 days, 9 days, or 10 days. All recited percentages are weight / weight (w / w).

[0436]

[0436] The thickness of dWAT, dermis, and skin is measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that are sectioned and stained with hematoxylin and eosin.

[0437]

[0437] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle. The mice that are treated with semaglutide and cabozantinib, axinitib, lenvatinib, nintedanib, or pazopanib do not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide plus topical vehicle. The mice that are treated with semaglutide and cabozantinib, axinitib, lenvatinib, nintedanib, or pazopanib show a statistically significant thicker measurement of white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide plus topical vehicle.

[0438]

[0438] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with vehicle. The mice that are treated with semaglutide and cabozantinib, axinitib, lenvatinib,nintedanib, or pazopanib also show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with a topical vehicle.

[0439]

[0439] The body weight of the mice is measured throughout the treatment. The mice treated with semaglutide or semaglutide and cabozantinib, axinitib, lenvatinib,nintedanib, or pazopanib show a decrease in body weight over the course of treatment compared to the mice treated with a topical vehicle.

[0440] Example 5. A selective VEGFR2 and FGFR1 inhibitor preserves dermal adipose tissue in mice

[0441]

[0440] C57BL6 mice are dosed with an IP injection of vehicle alone plus a local subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 agonist, such as 10 nmol / kg per day semaglutide, plus a local subcutaneous injection of vehicle, or an IP injection of semaglutide plus a local subcutaneous injection of a selective VEGFR2 and FGFR1 inhibitor chosen from Table 1. The vehicle comprises phosphate buffered saline (PBS). The location of the local subcutaneous injection is labeled the anterior site. The mice receive daily treatment for 3 days, 4, days, 5, days, 6, days, 7, days, 8 days, 9 days, or 10 days.

[0442]

[0441] The thickness of dWAT, dermis, and skin is measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that are sectioned and stained with hematoxylin and eosin.

[0443]

[0442] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle. The mice that are treated with semaglutide and a selective VEGFR2 and FGFR1 inhibitor chosen from Table 1 do not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide.

[0444]

[0443] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with vehicle. The mice that are treated with semaglutide and a selective VEGFR2 and FGFR1 inhibitor chosen from Table 1 also show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with vehicle. The mice that are treated with semaglutide and a selective VEGFR2 and FGFR1 inhibitor chosen from Table 1 show a statistically significant thicker measurement of white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide and vehicle.

[0445]

[0444] The body weight of the mice is measured throughout the treatment. The mice treated with semaglutide or semaglutide and a selective VEGFR2 and FGFR1 inhibitor chosen from Table 1 show a decrease in body weight over the course of treatment compared to the mice treated with vehicle.

[0446] Example 6. A selective inhibitor of VEGFR2 and a selective inhibitor of FGFR1 recapitulate the effects of a selective inhibitor of VEGFR2 and FGFR1

[0447]

[0445] C57BL6 mice are dosed with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of semaglutide plus a topical formulation of vehicle, or an IP injection of semaglutide plus a 0.01 %-3% w / w (between about 0.03 mg / cnr to about 0.3 mg / cm2) topical formulation of a selective inhibitor of VEGFR2 chosen from Table 3 and a selective inhibitor of FGFR1 chosen from Table 2 or topical vehicle alone.

[0448] The topical formulation comprises a 1 :2 lotion to DMSO solution (the exemplary lotion used in Examples 1-3). The IP injection of vehicle comprises phosphate buffered saline (PBS). The location of the topical administration is labeled the anterior site. A site on the opposite end of the mice is used as the untreated site, which is labeled the posterior site for the purposes of the experiments. The mice receive daily treatment for 3 days, 4, days, 5, days, 6, days, 7, days, 8 days, 9 days, or 10 days. All recited percentages are weight / weight (w / w).

[0449]

[0446] The thickness of dWAT, dermis, and skin is measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that are sectioned and stained with hematoxylin and eosin.

[0450]

[0447] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle. The mice that were treated with semaglutide, a selective inhibitor of VEGFR2, and a selective inhibitor of FGFR1 do not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide. The mice that are treated with semaglutide, a selective inhibitor of VEGFR2, and a selective inhibitor of FGFR1 show a statistically significant thicker measurement of white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide.

[0451]

[0448] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with a topical vehicle. The mice that are treated with semaglutide, a selective inhibitor of VEGFR2, and a selective inhibitor of FGFR1 also show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with a topical vehicle.

[0452]

[0449] The body weight of the mice is measured throughout the treatment. The mice treated with semaglutide or semaglutide, a selective inhibitor of VEGFR2, and a selective inhibitor of FGFR1 show a decrease in body weight over the course of treatment compared to the mice treated with a topical vehicle.

[0453] Example 7. A selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB preserves dermal adipose tissue in mice

[0454]

[0450] C57BL6 mice are dosed with an IP injection of vehicle alone plus a topical formulation of vehicle, an IP injection of semaglutide plus a topical formulation of vehicle, or an IP injection of semaglutide plus a 0.01 %-3% w / w (between about 0.03 mg / cm2to about 0.3 mg / cm2) topical formulation of a selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB chosen from Table 5 or topical vehicle alone. The topical formulation comprises a 1 :2 lotion to DMSO solution (the exemplary lotion used in Examples 1-3). The IP injection of vehicle comprises phosphate buffered saline (PBS). The location of the topical administration is labeled the anterior site. A site on the opposite end of the mice is used as the untreated site, which is labeled the posterior site for the purposes of the experiments. The mice receive daily treatment for 3 days, 4, days, 5, days, 6, days, 7, days, 8 days, 9 days, or 10 days. All recited percentages are weight / weight (w / w).

[0455]

[0451] The thickness of dWAT, dermis, and skin is measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that are sectioned and stained with hematoxylin and eosin.

[0456]

[0452] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle. The mice that were treated with semaglutide, a selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB do not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide. The mice that are treated with semaglutide, a selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB show a statistically significant thicker measurement of white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide.

[0453] The mice that are treated with semaglutide show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with a topical vehicle. The mice that are treated with semaglutide, a selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB also show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with a topical vehicle.

[0457] The body weight of the mice is measured throughout the treatment. The mice treated with semaglutide or semaglutide, a selective inhibitor of VEGFR2 and FGFR1 that also inhibits PDGFRA and / or PDGFRB show a decrease in body weight over the course of treatment compared to the mice treated with a topical vehicle.

[0458] Example 8. Semaglutide causes the loss of dermal adipose tissue in mice

[0459]

[0454] C57BL6 mice were dosed with an intraperitoneal (IP) injection, 10 nmol / kg per day, of an exemplary GLP-1 agonist, semaglutide, plus a topical formulation of vehicle, or an IP injection of vehicle (100 pL) plus a topical formulation of vehicle (50 pL). The IP injection of vehicle comprised phosphate buffered saline (PBS). The topical formulation comprised a 1:2 lotion to DMSO solution. The exemplary lotion that was used (e.g., CeraVe™) comprised of water, glycerin, cetearyl alcohol, caprylic / capric triglyceride, cetyl alcohol, ceteareth-20, petrolatum, potassium phosphate, ceramide np, ceramide ap, ceramide eop, carbomer, dimethicone, behentrimonium methosulfate, sodium lauroyl lactylate, sodium hyaluronate, cholesterol, phenoxyethanol, disodium EDTA, dipotassium phosphate, tocopherol, phytosphingosine, xanthan gum, and ethylhexylglycerin. The location of the topical administration was labeled the anterior site. A site on the opposite end of the mice was used as the untreated site, which was labeled the posterior site for the purposes of the experiments (FIG. 1H). The mice received daily IP and topical dosing treatment for 9 days. All recited percentages are weight / weight (w / w).

[0460]

[0455] The thickness of dWAT, dermis, and skin was measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0461]

[0456] The mice that were treated with semaglutide showed a statistically significant decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 1A, FIG. IB, and FIG. 1C).

[0462]

[0457] The mice that were treated with semaglutide also showed a statistically significant decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with vehicle (FIG. ID, FIG. IE, and FIG. IF).

[0458] The body weight of the mice was measured throughout the treatment (FIG. 1G). The mice treated with semaglutide showed a decrease in body weight over the course of treatment compared to the mice treated with vehicle.

[0463] Example 9. Rosiglitazone preserves dermal adipose tissue in mice

[0464]

[0459] C57BL6 mice were dosed with an IP injection of vehicle (100 pL) plus a topical formulation of vehicle (50 pL), an IP injection of 10 nmol / kg per day of semaglutide plus a topical formulation of vehicle, or an IP injection of semaglutide plus a topical formulation of 1% w / w of rosiglitazone (50 pL). The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and the exemplary lotion is described in Example 1. The location of the topical administration was labeled the anterior site. A site on the opposite end of the mice was used as the untreated site, which was labeled the posterior site for the purposes of the experiments (FIG. 7H). The mice received daily IP and topical dosing treatment for 9 days. All recited percentages are weight / weight (w / w).

[0465]

[0460] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0466]

[0461] The mice that were treated with semaglutide showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with IP vehicle and topical vehicle (FIG. 6A, FIG. 6B, and FIG. 6C). The mice that were treated with semaglutide and rosiglitazone did not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 6 A, FIG. 6B, and FIG. 6C). The statistical significance shown in FIG. 6A and FIG. 6C is in comparison to the semaglutide with a vehicle topical treatment.

[0467]

[0462] The mice that were treated with semaglutide also showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with IP vehicle and topical vehicle (FIG. 6D, FIG. 6E, and FIG. 6F). The mice that were treated with semaglutide and rosiglitazone showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with IP vehicle (FIG. 6D, FIG. 6E, and FIG. 6F).

[0468]

[0463] The body weight of the mice was measured throughout the treatment (FIG. 6G). The mice treated with semaglutide or semaglutide and 1 % rosiglitazone showed a decrease in body weight over the course of treatment compared to the mice treated with vehicle. Example 10. Pioglitazone preserves dermal adipose tissue in mice

[0469]

[0464] C57BL6 mice were dosed with an IP injection of vehicle (100 pL) alone plus a topical formulation of vehicle (50 pL), an IP injection of 10 nmol / kg per day of semaglutide, plus a topical formulation of vehicle, or an IP injection of semaglutide plus a topical formulation of 2% of pioglitazone (50 pL). The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and the exemplary lotion is described in Example 1. The location of the topical administration was labeled the anterior site. A site on the opposite end of the mice was used as the untreated site, which was labeled the posterior site for the purposes of the experiments (FIG. 7H). The mice received daily IP and topical dosing treatment for 8 days. All recited percentages are weight / weight (w / w).

[0470]

[0465] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0471]

[0466] The mice that were treated with semaglutide showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 7A, FIG. 7B, and FIG. 7C). The mice that were treated with semaglutide and pioglitazone did not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 7A, FIG. 7B, and FIG. 7C). The statistical significance shown in FIG. 7A and FIG. 7C is in comparison to the semaglutide with a topical vehicle treatment.

[0472]

[0467] The mice that were treated with semaglutide also showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the posterior site compared to mice treated with vehicle (FIG. 7D, FIG. 7E, and FIG. 7F). The mice that were treated with semaglutide and pioglitazone also showed a decrease in white dermal adipose tissue (dWAT) and skin thickness at the posterior site compared to the mice treated with IP vehicle (FIG. 7D, FIG. 7E, and FIG. 7F).

[0473]

[0468] The body weight of the mice was measured at the end of the treatment (FIG. 7G). The mice treated with semaglutide or semaglutide and 2% pioglitazone showed a decrease in body weight at the end of treatment compared to the mice treated with vehicle only.

[0474] Example 11. Rosiglitazone preserves dermal adipose tissue in mice

[0469] C57BL6 mice were dosed with an IP injection of vehicle (100 pL) plus a subcutaneous injection of vehicle (25 pL), an IP injection of 10 nmol / kg per day of semaglutide, plus a subcutaneous injection of vehicle, or an IP injection of semaglutide plus a subcutaneous injection of 100 pg rosiglitazone dissolved in 25 pL of DMSO. The IP injection of vehicle comprised phosphate buffered saline (PBS). The subcutaneous injection comprised DMSO. The location of administration on the mice was labeled the anterior site (FIG. 8E). The mice received daily IP and subcutaneous injection treatment for 8 days. All recited percentages are weight / weight (w / w).

[0475]

[0470] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0476]

[0471] The mice that were treated with semaglutide showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 8A, FIG. 8B, and FIG. 8C). The mice that were treated with semaglutide and rosiglitazone did not show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 8A, FIG. 8B, and FIG. 8C). The statistical significance shown in FIG. 8A, FIG. 8B, and 8C is in comparison to the semaglutide with a vehicle subcutaneous injection treatment.

[0477]

[0472] The body weight of the mice was measured at the end of the treatment (FIG. 8D). The mice treated with semaglutide or semaglutide and rosiglitazone showed a decrease in body weight at the end of treatment compared to the mice treated with vehicle only.

[0478]

[0473] Example 5. Pioglitazone preserves dermal adipose tissue in mice.

[0479]

[0474] C57BL6 mice were dosed with topical formulation of vehicle (50 pL), a topical formulation of 0.05% fluocinonide (50 pL), or topical formulation of a combination of 0.05% fluocinonide and 2% of pioglitazone (50 pL). The topical formulation comprised a 1:2 lotion to DMSO solution. The location of the topical administration was the anterior site(FIG. 7H). The mice received daily topical dosing treatment for 9 days. All recited percentages are weight / weight (w / w).

[0480]

[0475] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0476] The mice that were treated with the topical formulation of 0.05% fhiocinonide showed a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 9A, FIG. 9B, and FIG. 9C).

[0481] The mice that were treated a topical formulation of a combination of 0.05% fluocinonide and 2% pioglitazone showed an increase in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with 0.05% fluocinonide (FIG.

[0482] 9A, FIG. 9B, and FIG. 9C). The statistical significance shown in FIG. 9A, FIG. 9B, and FIG. 9C is in comparison to the box plots that are below the horizontal line with the indicated P value.

[0483] Example 12. A PPAR-gamma agonist preserves dermal adipose tissue in mice

[0484]

[0477] C57BL6 mice are dosed with an IP injection of vehicle plus a local subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 agonist, such as 10 nmol / kg per day semaglutide, or an exemplary GIP agonist, plus a local subcutaneous injection of vehicle, or an IP injection of a GLP-1 agonist or GIP agonist plus a local subcutaneous injection of a PPAR-gamma agonist. The vehicle comprises phosphate buffered saline (PBS). The subcutaneous injection comprises DMSO. The location of the local subcutaneous injection is labeled the anterior site. The mice receive daily treatment for 3 days, 4, days, 5, days, 6, days, 7, days, 8 days, 9 days, or 10 days.

[0485]

[0478] The thickness of dWAT, dermis, and skin is measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that are sectioned and stained with hematoxylin and eosin.

[0486]

[0479] The mice that are treated with a GLP- 1 agonist or GIP agonist show a decrease in white dermal adipose tissue (dWAT), and skin thickness at the anterior site compared to the mice treated with vehicle. The mice that are treated with a GLP- 1 agonist or GIP agonist and a PPAR-gamma agonist do not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with a GLP- 1 agonist or GIP agonist with a vehicle subcutaneous injection treatment.

[0487]

[0480] The mice that are treated with a GLP- 1 agonist or GIP agonist show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with vehicle. The mice that are treated with a GLP- 1 agonist or GIP agonist and a PPAR-gamma agonist also show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to the mice treated with vehicle. The mice that are treated with a GLP-1 agonist or GIP agonist and a PPAR-gamma agonist show a statistically significant thicker measurement of white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with a GLP-1 agonist or GIP agonist and vehicle subcutaneous injection treatment.

[0488]

[0481] The body weight of the mice is measured throughout the treatment. The mice treated with a GLP-1 agonist or GIP agonist or a GLP-1 agonist or GIP agonist and a PPAR-gamma agonist show a decrease in body weight over the course of treatment compared to the mice treated with vehicle.

[0489] Example 13. Semaglutide causes the loss of dermal adipose tissue in mice

[0490]

[0482] Female, 7-9 month old C57BL6 mice were dosed with an intraperitoneal (IP) injection, 10 nmol / kg per day, of an exemplary GLP-1 agonist, semaglutide, plus a topical formulation of vehicle, or an IP injection of vehicle (100 pL) plus a topical formulation of vehicle (50 pL). The IP injection of vehicle comprised phosphate buffered saline (PBS). The topical formulation comprised a 1:2 lotion to DMSO solution. The exemplary lotion that was used (e.g., CeraVe™) comprised water, glycerin, cetearyl alcohol, caprylic / capric triglyceride, cetyl alcohol, ceteareth-20, petrolatum, potassium phosphate, ceramide np, ceramide ap, ceramide eop, carbomer, dimethicone, behentrimonium methosulfate, sodium lauroyl lactylate, sodium hyaluronate, cholesterol, phenoxyethanol, disodium EDTA, dipotassium phosphate, tocopherol, phytosphingosine, xanthan gum, and ethylhexylglycerin. The location of the topical administration was labeled the anterior site. The mice received daily IP and topical dosing treatment for 9 days. AU recited percentages are weight / weight (w / w).

[0491]

[0483] The thickness of dWAT, dermis, and skin was measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0492]

[0484] The mice that were treated with semaglutide showed a statistically significant decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with vehicle (FIG. 10A, FIG. 10B, and FIG. 10C).

[0493] Example 14. Pioglitazone and a combination of pioglitazone and nintedanib preserve dermal adipose tissue in mice

[0494]

[0485] C57BL6 mice were dosed with an IP injection of 10 nmol / kg per day of semaglutide plus a topical formulation of vehicle; an IP injection of semaglutide plus a topical formulation of 0.02% w / w of Pioglitazone (50 pL); an IP injection of semaglutide plus a topical formulation of 0.02% w / w of nintedanib (50 pL); or an IP injection of semaglutide plus a topical formulation of 0.02% w / w of Pioglitazone and 0.02% w / w of nintedanib (50 pL). The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and the exemplary lotion is described in Example 13. The location of the topical administration was labeled the anterior site. The mice received daily IP and topical dosing treatment for 9 days. All recited percentages are weight / weight (w / w).

[0495]

[0486] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0496]

[0487] The mice that were treated with semaglutide had the thinnest (dWAT), dermis, and skin thickness. The mice that were treated with semaglutide and pioglitazine showed a statistically significant increase in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 11 A, FIG. 1 IB, and FIG. 11C). The mice that were treated with semaglutide and a combination of pioglitazine and nintedamib showed the greatest statistically significant increase in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with semaglutide, semaglutide and pioglitazone, or semaglutide and nintedanib (FIG. 11 A, FIG. 1 IB, and FIG. 11C).

[0497] Example 15. Pioglitazone and a combination of pioglitazone and nintedanib preserve dermal adipose tissue in mice

[0498]

[0488] C57BL6 mice were dosed with an IP injection of 10 nmol / kg per day of semaglutide plus a topical formulation of vehicle; an IP injection of semaglutide plus a topical formulation of 0.2% w / w of Pioglitazone (50 pL); an IP injection of semaglutide plus a topical formulation of 0.02% w / w of nintedanib (50 pL); or an IP injection of semaglutide plus a topical formulation of 0.2% w / w of Pioglitazone and 0.02% w / w of nintedanib (50 pL). The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and the exemplary lotion is described in Example 13. The location of the topical administration was labeled the anterior site. The mice received daily IP and topical dosing treatment for 9 days. All recited percentages are weight / weight (w / w).

[0489] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0499]

[0490] The mice that were treated with only semaglutide had the thinnest (dWAT), dermis, and skin thickness. The mice that were treated with semaglutide and pioglitazine showed a statistically significant increase in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide (FIG. 12A, FIG. 12B, and FIG. 12C). The mice that were treated with semaglutide and a combination of pioglitazine and nintedamib showed the greatest statistically significant increase in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with semaglutide, semaglutide and pioglitazone, or semaglutide and nintedanib (FIG. 12 A, FIG. 12B, and FIG. 12C).

[0500] Example 16. Tirzepatide causes the loss of dermal adipose tissue in mice

[0501]

[0491] Female, 7-9 month old C57BL6 mice were dosed with an intraperitoneal (IP) injection, 3 nmol / kg per day, of an exemplary GLP-1 agonist, tirzepatide, or an IP injection of vehicle (100 pL). The IP injection of vehicle comprised phosphate buffered saline (PBS). The mice received daily IP dosing treatment for 4 days. All recited percentages are weight / weight (w / w).

[0502]

[0492] The thickness of dWAT, dermis, and skin was measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0503]

[0493] The mice that were treated with tirzepatide showed a statistically significant decrease in white dermal adipose tissue (dWAT) and skin thickness compared to the mice treated with vehicle (FIG. 13A, FIG. 13B, and FIG. 13C).

[0504] Example 17. Rosiglitazone and a combination of rosiglitazone and nintedanib preserve dermal adipose tissue in mice

[0505]

[0494] Female 7-9 month old C57BL6 were dosed with an IP injection of 3 nmol / kg per day of tirzepatide for four days. C57BL6 mice were then dosed with an IP injection of 3 nmol / kg per day of tirzepatide plus a topical formulation of vehicle; an IP injection of semaglutide plus a topical formulation of 0.05% w / w of Rosiglitazone (50 pL); an IP injection of semaglutide plus a topical formulation of 0.05% w / w of nintedanib (50 pL); or an IP injection of semaglutide plus a topical formulation of 0.05% w / w of Rosiglitazone and 0.05% w / w of nintedanib (50 pL). The topical formulation comprised a 1 :2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and an exemplary lotion. The exemplary lotion comprised 10% DMSO, 10% propylene glycol, 10% cetyl alcohol, 35% glycerin, and 35% medium chain triglyceride oil. The location of the topical administration was labeled the anterior site. The mice received daily IP and topical dosing treatment for 8 days. All recited percentages are weight / weight (w / w).

[0506]

[0495] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0507]

[0496] The mice that were treated with only tirzepatide had the thinnest (dWAT), dermis, and skin thickness. The mice that were treated with tirzepatide and rosiglitazone showed a statistically significant increase in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with tirzepatide (FIG. 14 A, FIG. 14B, and FIG. 14C). The mice that were treated with tirzepatide and a combination of rosiglitazone and nintedanib showed the greatest statistically significant increase in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with tirzepatide, tirzepatide and rosiglitazone, or tirzepatide and nintedanib (FIG. 14 A, FIG. 14B, and FIG. 14C).

[0508] Example 18. Rosiglitazone and a combination of rosiglitazone and nintedanib preserve dermal adipose tissue in mice

[0509]

[0497] Female 7-9 month old C57BL6 were dosed with an IP injection of 3 nmol / kg per day of tirzepatide for four days. C57BL6 mice were then dosed with an IP injection of 3 nmol / kg per day of tirzepatide plus a topical formulation of vehicle; an IP injection of semaglutide plus a topical formulation of 0.5% w / w of Rosiglitazone (50 pL); an IP injection of semaglutide plus a topical formulation of 0.05% w / w of nintedanib (50 pL); or an IP injection of semaglutide plus a topical formulation of 0.5% w / w of Rosiglitazone and 0.05% w / w of nintedanib (50 pL). The topical formulation comprised a 1 :2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and an exemplary lotion. The exemplary lotion comprised 10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, and 35% w / w medium chain triglyceride oil. The location of the topical administration was labeled the anterior site. The mice received daily IP and topical dosing treatment for 8 days. All recited percentages are weight / weight (w / w).

[0498] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0510]

[0499] The mice that were treated with only tirzepatide had the thinnest (dWAT), dermis, and skin thickness. The mice that were treated with tirzepatide and rosiglitazone showed a statistically significant increase in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with tirzepatide (FIG. 15A, FIG. 15B, and FIG.l 6C). The mice that were treated with tirzepatide and a combination of rosiglitazone and nintedanib showed the greatest statistically significant increase in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with tirzepatide, tirzepatide and rosiglitazone, or tirzepatide and nintedanib (FIG. 15A, FIG. 15B, and FIG. 15C).

[0511] Example 19. Rosiglitazone and a combination of rosiglitazone and nintedanib preserve dermal adipose tissue in mice

[0512]

[0500] Female 7-9 month old C57BL6 were dosed with an IP injection of 3 nmol / kg per day of tirzepatide for four days. C57BL6 mice were then dosed with an IP injection of 3 nmol / kg per day of tirzepatide plus a topical formulation of vehicle; an IP injection of semaglutide plus a topical formulation of 0.05% w / w of Rosiglitazone (50 pL); an IP injection of semaglutide plus a topical formulation of 0.5% w / w of nintedanib (50 pL); or an IP injection of semaglutide plus a topical formulation of 0.05% w / w of Rosiglitazone and 0.5% w / w of nintedanib (50 pL). The topical formulation comprised a 1:2 lotion to DMSO solution. The IP injection of vehicle comprised phosphate buffered saline (PBS) and an exemplary lotion. The exemplary lotion comprised 10% w / w DMSO, 10% w / w propylene glycol, 10% w / w cetyl alcohol, 35% w / w glycerin, and 35% w / w medium chain triglyceride oil. The location of the topical administration was labeled the anterior site. The mice received daily IP and topical dosing treatment for 8 days. All recited percentages are weight / weight (w / w).

[0513]

[0501] The thickness of dWAT, dermis, and skin were measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that were sectioned and stained with hematoxylin and eosin.

[0514]

[0502] The mice that were treated with only tirzepatide had the thinnest (dWAT), dermis, and skin thickness. The mice that were treated with tirzepatide and rosiglitazone showed a statistically significant increase in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with tirzepatide (FIG. 16A, FIG. 16B, and FIG. 16C). The mice that were treated with tirzepatide and a combination of rosiglitazone and nintedanib showed the greatest statistically significant increase in white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with tirzepatide, tirzepatide and rosiglitazone, or tirzepatide and nintedanib (FIG. 16 A, FIG. 16B, and FIG. 16C).

[0515] Example 20. A combination of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor preserve dermal adipose tissue in mice

[0516]

[0503] C57BL6 mice are dosed with an IP injection of vehicle plus a local subcutaneous injection of vehicle, an IP injection of an exemplary GLP-1 agonist or GIP agonist, such as 10 nmol / kg per day semaglutide, 3 nmol / kg per day of tirzepatide, or an exemplary GIP agonist or GIP agonist, plus a local subcutaneous injection of vehicle, or an IP injection of a GLP-1 agonist or GIP agonist plus a local subcutaneous injection of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor. The vehicle comprises phosphate buffered saline (PBS). The subcutaneous injection comprises DMSO. The location of the local subcutaneous injection is labeled the anterior site. The mice receive daily treatment for 3 days, 4, days, 5, days, 6, days, 7, days, 8 days, 9 days, or 10 days.

[0517]

[0504] The thickness of dWAT, dermis, and skin is measured by morphometric histologic analyses of formalin fixed, paraffin embedded, skin samples that are sectioned and stained with hematoxylin and eosin.

[0518]

[0505] The mice that are treated with a GLP-1 agonist or GIP agonist show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with vehicle. The mice that are treated with a GLP- 1 agonist or GIP agonist and a combination of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor do not show a decrease in white dermal adipose tissue (dWAT) and skin thickness at the anterior site compared to the mice treated with a GLP- 1 agonist or GIP agonist with a vehicle subcutaneous injection treatment.

[0519]

[0506] The mice that are treated with a GLP- 1 agonist or GIP agonist show a decrease in white dermal adipose tissue (dWAT), dermis, and skin thickness at the posterior site compared to mice treated with vehicle. The mice that are treated with a GLP- 1 agonist or GIP agonist and a combination of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor show a statistically significant thicker measurement of white dermal adipose tissue (dWAT), dermis, and skin thickness at the anterior site compared to the mice treated with a GLP-1 agonist or GIP agonist and vehicle subcutaneous injection treatment.

[0507] The body weight of the mice is measured throughout the treatment. The mice treated with a GLP- 1 agonist, GIP agonist, a GLP- 1 agonist and a combination of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, or GIP agonist and a combination of a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor show a decrease in body weight over the course of treatment compared to the mice treated with vehicle.

[0520] Example 21. Topical formulations for the delivery of a selective VEGFR2 and / or FGFR1 inhibitor, a PPAR-gamma agonist, or a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor

[0521]

[0508] This Example compares the ability of lotion formulations to deliver a selective VEGFR2 and / or FGFR1 inhibitor or a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor and / or a PPAR-gamma agonist compared to a standard lotion.

[0522]

[0509] The lotion formulations are detailed in Table D below.

[0523] Table D. Components of Formulations 1-8 in wt / wt %

[0524]

[0510] The lotion formulations were tested for their ability to deliver an exemplary selective VEGFR2 and FGFR1 inhibitor, nintedanib, and / or a PPAR gamma agonist, Pioglitazone, in human skin using a Franz Cell Permeation Assay, an assay that measures the penetration of a drug in and through human skin explants. The results are summarized in Table E below.

[0525] Table E. Delivered dose of nintedanib by lotion formulations

[0526]

[0511] Liquid-chromatography-Mass Spectrometry (LC-MS) quantified amounts of nintedanib in epidermal, dermal, and Franz cell receptor fluid (transdermal) compartments 6 or 24 hours after topical application of 5 pL of indicated formulation over a 0.55 cm2area of explanted human skin. Lotion 8 was the exemplary lotion used in the Examples disclosed herein. Therefore, at minimum, a desired lotion formulation should deliver at least the same amount of nintedanib as lotion 8. As shown in Table E, lotion formulations 1 and 3 delivered about 49X and 200X more nintedanib, respectively, into transdermal skin after 24 hrs compared to lotion 8 (standard lotion comprising DMSO and Cerave™). Lotion formulations 2, 5, and 7 delivered about 2X-8X more nintedanib into transdermal skin after 24 hrs compared to lotion 8. Lotion formulations 1, 2, 3, and 5 delivered about 4X-13X more nintedanib into the epidermis after 24 hrs compared to lotion 8. Lotion formulations 1, 3, 5, 6, and 7 delivered about 2.9X -4X more nintedanib into the dermis after 24 hrs compared to lotion 8. The indicated lotions delivered greater amounts of nintedanib than lotion 8.

[0527]

[0512] The lotion formulations were also tested for their ability to deliver an exemplary PPAR-gamma agonist, pioglitazone, in human skin using a Franz Cell Permeation Assay. The results are summarized in Table F below.

[0528] Table F. Delivered dose of pioglitazone by lotion formulations

[0529] 513] Liquid-chromatography-Mass Spectrometry (LC-MS) quantified amounts of pioglitazone in epidermal, dermal, and Franz cell receptor fluid (transdermal) compartments 6 or 24 hours after topical application of 5 pL of indicated formulation over a 0.55 cm2area of explanted human skin. Lotion 8 was the exemplary lotion used in the Examples disclosed herein. Therefore, at minimum, a desired lotion formulation should deliver at least the same amount of pioglitazone as lotion 8. As shown in Table F, lotion formulations 1 , 2, 3, 4, and 6 delivered about 2.4X-13X more pioglitazone into transdermal skin after 24 hrs compared to lotion 8 (standard lotion comprising DMSO and Cerave™). Lotion formulations 1, 2, 3, and 4 delivered about 3.5X-5.4X more pioglitazone into the epidermis after 24 hrs compared to lotion 8. Lotion formulation 4 delivered about 2X more pioglitazone into the dermis after 24 hrs compared to lotion 8. The indicated lotions delivered greater amounts of pioglitazone than lotion 8.

[0530]

[0514] The ability of the lotions to maintain the initial concentration of nintedanib and / or pioglitazone over 2 weeks was tested. The results are summarized in Table G below.

[0531] Table G. Stability of nintedanib and pioglitazone concentrations in lotion formulations

[0532]

[0515] As summarized in Table G, all of the tested lotions all maintained 94% or higher of the initial concentration of nintedanib and / or pioglitazone over two weeks at the two tested temperatures.

[0533] Example 22. The combination of Nintedanib and Pioglitazone show a synergistic effect in promoting adipogenesis in human dermis.

[0534]

[0516] This Example shows a lotion comprising Nintedanib and Pioglitazone will have a synergistic effect in promoting adipogenesis in primary human preadipocytes and in human full thickness skin explants.

[0535]

[0517] Primary human preadipocytes are treated with a lotion comprising Nintedanib, a lotion comprising Pioglitazone, or a lotion comprising Nintedanib and Pioglitazone. Quantification of adipogenesis by oil red o staining and gene expression of adipogenesis markers (FABP4, PPARG, ADIPOQ, KLF4) by quantitative real time PCR (Q-RT-PCR) of the gene expression markers will show the lotion comprising Nintedanib and Pioglitazone has a synergistic effect in promoting adipogenesis in human dermis compared to a lotion the comprises only Nintedanib or only Pioglitazone. The lotion comprising Nintedanib and Pioglitazone may have a lower amount of either drug compared to the amount in the lotion comprising only one of the two drugs and still show a synergistic effect in promoting adipogenesis in human dermis.

[0536]

[0518] The experiment is conducted in human skin explants and the same results are shown, the combination of a lotion comprising Nintedanib and Pioglitazone induces more adipogenesis than a lotion comprising Nintedanib or a lotion comprising Pioglitazone.

[0537] Table 1. List of selective inhibitors of VEGFR2 and FGFR1

[0538] Ill Table 2. List of selective inhibitors of FGFR1

[0539]

[0540] Column Key

[0541] FGFR1 IC50 um: reported IC50 to FGFR1 in uM.

[0542] Min IC50 um: next lowest IC50 value to any gene target in uM.

[0543] Rel. 1C50: IC50 of target of interest divided by next lowest IC50

[0544] Num IC50 Targets: the number of gene targets that have a reported IC50 within 10-fold of the IC50 to the target of interest (VEGFR2 or FGFR1).

[0545] Pubchem_cid: Pubchem chemical ID

[0546] Compound name: Name of compound

[0547] Table 3. List of selective inhibitors of VEGFR2

[0548] Column Key

[0549] VEGFR2 IC50 um: reported IC50 to VEGFR2 in uM.

[0550] Min IC50 um: next lowest IC50 value to any gene target in uM.

[0551] Rel 1C50: IC50 of target of interest divided by next lowest 1C50

[0552] Num IC50 Targets: the number of gene targets that have a reported IC50 within 10-fold of the IC50 to the target of interest (VEGFR2 or FGFR1).

[0553] Pubchem_cid: Pubchem chemical ID

[0554] Compound name: Name of compound

[0555] Table 4. Structures of exemplary selective inhibitors of VEGFR2 and FGFR1

[0556] Table 5. List of exemplary PDGFR inhibitors which are also exemplary selective inhibitors of VEGFR2 and FGFR1

[0557] Table 6. List of exemplary PDGFRA / B, VEGFR2 and / or FGFR1 inhibitors

[0558] Incorporation by reference

[0559]

[0519] The entire disclosure of each of the patent documents and scientific articles cited herein is incorporated by reference for all purposes.

Claims

ClaimsWe claim:

1. A topical formulation comprising a selective inhibitor of VEGFR2 and FGFR1 and a delivery vehicle.

2. The topical formulation of claim 1 , wherein the delivery vehicle is selected from the group consisting of an ointment, a cream, a gel, a lotion, a solution, a foam, and a spray.

3. The topical formulation of claim 1 or 2, wherein the delivery vehicle is a lotion.

4. The topical formulation of claim 1 or 2, wherein the delivery vehicle comprises one or more of a humectant, an emollient, an occludent, or a secondary moisturizing ingredient.

5. The topical formulation of claim 4, wherein the secondary moisturizing ingredient is selected from the group consisting of a ceramide, a free fatty acid, and a cholesterol.

6. The topical formulation of claim 1, wherein the selective VEGFR2 and FGFR1 inhibitor comprises 0.01%-3% weight / weight (w / w ) of the topical formulation.

7. The topical formulation of any one of claims 1- 6, wherein the selective VEGFR2 and FGFR1 inhibitor is brivanib alaninate or Su5402.

8. The topical formulation of any one of claims 1- 6, wherein the selective VEGFR2 and FGFR1 inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib.

9. The topical formulation of claim 3, wherein the lotion comprises one or more of a liquid, a humectant, and a penetration enhancer.

10. The topical formulation of claim 9, wherein the lotion further comprises one or more of an emulsifier or a solubilizer, a thickening or a gelling agent, an emollient, a secondary moisturizing ingredient, an emulsifier or a solubilizer, an excipient, a preservative, and an antioxidant.

11. The topical formulation of claim 9, wherein the lotion further comprises an emulsifier or a solubilizer, a thickening or a gelling agent, an emollient, a secondary moisturizing ingredient, an emulsifier or solubilizer, an excipient, a preservative, and an antioxidant.

12. The topical formulation of any one of claims 1 or 9, wherein the lotion comprises DMSO, ethanol or isopropyl myristate, propylene glycol, and glycerol and / or water.

13. The topical formulation of any one of claims 1 or 9, wherein the lotion comprises DMSO, ethanol, propylene glycol, glycerol, and water.

14. The topical formulation of any one of claims 1 or 9, wherein the lotion comprises diethylene glycol monoethyl ether, ethanol, propylene glycol, glycerol, water, and a thickening or a gelling agent.

15. The topical formulation of claim 14, wherein the lotion comprises diethylene glycol monoethyl ether, ethanol, propylene glycol, glycerol, water, and hydroxypropyl cellulose.

16. The topical formulation of claim 15, wherein the lotion comprises 45% wt / wt diethylene glycol monoethyl ether, 26.5% wt / wt ethanol, 11% wt / wt propylene glycol, 2% wt / wt glycerol, 12.5% wt / wt / water, 1.5% wt / wt hydroxypropyl cellulose, and 1.5% wt / wt the selective inhibitor of VEGFR2 and FGFR1.

17. The topical formulation of claim 15, wherein the selective inhibitor of VEGFR2 and FGFR1 is nintedanib.

18. A topical formulation comprising a PPAR-gamma agonist, a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor, and a delivery vehicle.

19. The topical formulation of claim 18, wherein the delivery vehicle is selected from the group consisting of an ointment, a cream, a gel, a lotion, a solution, a foam, and a spray.

20. The topical formulation of claim 19, wherein the delivery vehicle is a lotion.

21. The topical formulation of claim 18 or 19, wherein the delivery vehicle comprises one or more of a humectant, an emollient, an occludent, or a secondary moisturizing ingredient.

22. The topical formulation of claim 21 , wherein the secondary moisturizing ingredient is selected from the group consisting of a ceramide, a free fatty acid, and a cholesterol.

23. The topical formulation of any one of claims 18-22, wherein the PPAR-gamma agonist comprises 0.01%-5% weight / weight (w / w) of the topical formulation.

24. The topical formulation of any one of claims 18-23, wherein the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE-0897, AZD- 6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW-1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY- 554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847,AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL-17564,DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

25. The topical formulation of any one of claims 18-24, wherein the PPAR-gamma agonist is rosiglitazone.

26. The topical formulation of any one of claims 18-24, wherein the PPAR-gamma agonist is pioglitazone.

27. The topical formulation of any one of claims 18-24, wherein the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib or nintedanib esylate.

28. The topical formulation of claim 27, wherein nintedanib comprises 0.01%-3% weight / weight (wt / wt) of the topical formulation.

29. The topical formulation of claim 21 , wherein the delivery vehicle comprises propylene glycol, cetyl alcohol, glycerin, and medium chain triglyceride oil.

30. The topical formulation of claim 20, wherein the lotion comprises one or more of a liquid, a humectant, and a penetration enhancer.

31. The topical formulation of claim 30, wherein the lotion further comprises an emulsifier or a solubilizer, a thickening or a gelling agent, an emollient, a secondary moisturizing ingredient, an emulsifier or a solubilizer, an excipient, a preservative, and an antioxidant.

32. The topical formulation of claim 30, wherein the lotion comprises DMSO, ethanol or isopropyl myristate, propylene glycol, and glycerol and / or water.

33. The topical formulation of claim 30, wherein the lotion comprises 45% wt / wt DMSO, 26.5% wt / wt ethanol, 11% wt / wt propylene glycol, 2% wt / wt glycerol, 11% wt / wt water, 1.5% wt / wt hydroxypropyl cellulose, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

34. The topical formulation of claim 30, wherein the lotion comprises 45% wt / wt diethylene glycol monoethyl ether, 26.5% wt / wt ethanol, 11% wt / wt propylene glycol, 2% wt / wt glycerol, 11% wt / wt / water, 1.5% wt / wt hydroxypropyl cellulose, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

35. The topical formulation of claim 30, wherein the lotion comprises 45% wt / wt DMSO, 24% wt / wt ethanol, 24% wt / wt propylene glycol; 2% wt / wt fatty alcohol, 2% levulinic acid, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

36. The topical formulation of claim 35, wherein the fatty alcohol is Brij L4.

37. The topical formulation of claim 30, wherein the lotion comprises 32% wt / wt diethylene glycol monoethyl ether, 20% propylene glycol, 31.5% water, 3% Cetamacrogol 1000, 4% isopropyl myristate, 2% medium chain triglyceride oil, 4% polymer, 0.5% silicone, 0.1% methyl paraben, 0.3% butylated hydroxy toluene, 1.5% wt / wt of the PPAR-gamma agonist, and 1.5% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

38. The topical formulation of claim 37, wherein the medium chain triglyceride oil is Crodamol GTCC, the polymer is Sepineo P600, and the silicone is cyclomethicone.

39. The topical formulation of claim 30, wherein the lotion comprises 21 % wt / wt diethylene glycol monoethyl ether, 15% propylene glycol, 44.5% water, 3% Cetamacrogol 1000, 4% isopropyl myristate, 2% medium chain triglyceride oil, 2% fatty alcohol, 4% polymer, 2% tefose 63, 0.5% silicone, 0.1% methyl paraben, 0.3% butylated hydroxytoluene, 1% wt / wt of the PPAR-gamma agonist, and 1% wt / wt of the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

40. The topical formulation of claim 39, wherein the medium chain triglyceride oil is Crodamol GTCC, the fatty alcohol is cetostearyl alcohol, the polymer is Sepineo P600, and the silicone is cyclomethicone.

41. A method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a selective inhibitor of VEGFR2 and FGFR1.

42. The method of claim 41 , wherein the locally administered formulation is a topical formulation.

43. The method of claim 41 , wherein the locally administered formulation is a local subcutaneous injection.

44. The method of any one of claims 41-43, wherein the subject is receiving a glucagon- like peptide- 1 (GLP-1) receptor agonist.

45. The method of claim 44, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide.

46. The method of claim 44, wherein the GLP-1 receptor agonist is also a glucosedependent insulinotropic polypeptide (GIP) receptor agonist.

47. The method of any one of claims 41-46, wherein the dermal adipose and / or skin thickness is measured according to calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photonor multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectance-mode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, patient or clinician- reported rating scale, or a structured light 3D scanner.

48. The method of claim 41 , wherein the topical formulation is as an ointment, a cream, a gel, a lotion, a solution, a foam, or a spray.

49. The method of claim 41, wherein the selective VEGFR2 and FGFR1 inhibitor is selected from the group consisting of [4-(2,4-Difluoro-5-methoxycarbamoyl-phenylamino)-5- isopropyl-pyrrolo[2,l-f][l,2,4]triazin-6-yl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, Brivanib, Brivanib Alaninate, 2,4-Difhioro-5-[5-isopropyl-6-(5-trifluoromethyl-[1.3.4]oxadiazol-2-yl)-pyrrolo[2,l-f][ 1,2, 4]triazin-4-ylamino]-N-methoxy -benzamide, 5-[(l - Ethylpiperidin-4-yl)amino]-3-[lH-imidazol-2-yl(phenyl)methylidene]-lH-indol-2-one, 2,4- Difluoro-5-[5-isopropyl-6-(5-methyl-4H-[l,2,4]triazol-3-yl)-pyrrolo[2,l-f][l,2,4]triazin-4- ylamino]-N-methoxy-benzamide, 5-[6-(5-Dimethylamino-[l,3,4]oxadiazol-2-yl)-5-isopropyl- pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N-methoxy-benzamide, 2,4-Difluoro-5- [5-isopropyl-6-(3-methyl-[l,2,4]oxadiazol-5-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N- methoxy-benzamide, 3-[(3-(2-Carboxyethyl)-4-methylpyrrol-2-YL)methylene]-2-indolinone (SU5402), 2,4-Difluoro-5-[5-isopropyl-6-(5-methyl-[l,3,4]oxadiazol-2-yl)-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, 5-[6-(5-DiHuoromethyl-[l,3,4]oxadiazol- 2-yl)-5-isopropyl-pyrrolo[2, 1 -f] [ 1 ,2,4] triazin-4-ylamino]-2,4-difluoro-N-methoxy- benzamidem, 3-[Benzimidazol-2-ylidene-(3-fluorophenyl)methyl]-5-[(l-ethylpiperidin-4- yl)amino]-lH-indol-2-ol, N-(Cyclopropylmethyl)-3-(l-methylpyrazol-4-yl)-N- phenylquinoxalin-6-amine, 2,4-Difluoro-5-(5-isopropyl-6-[l,3,4]oxadiazol-2-yl-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino)-N-methoxy-benzamide, 7-(4-Fluoroanilino)-l-[(lR,3R)-3- hydroxycyclopentyl]-3-(4-methoxyphenyl)-4H-pyrimido[4,5-d]pyrimidin-2-one, 5-[6-(5- Cyclopropyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4- difluoro-N-methoxy-benzamide, 6-(5-Methyl-l,3,4-oxadiazol-2-yl)-5-propan-2-yl-N-(lH- pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine, N-(Cyclopropylmethyl)-N- f3-methoxy-5-(trifluoromethyl)phenyll-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, 3- [Benzimidazol-2-ylidene-(3,5-difluorophenyl)methyl]-5-[(l-ethylpiperidin-4-yl)amino]-lH- indol-2-ol, 1,6-Naphthyridine 76, 2,4-Difluoro-5-{5-isopropyl-6-[5-(2,2,2-trifluoro-ethyl)-[1.3.4]oxadiazol-2-yl]-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino}-N-methoxy-benzamide, (+)- (lR,3R)-l-(3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-lH- pyrimido[4,5-d]pyrimidin-2-one, 1,6-Naphthyridine 75, (-)-(lS,3S)-l-(3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-lH-pyrimido[4,5- d]pyrimidin-2-one, N-(Cyclopropylmethyl)-N-[3-[(dimethylamino)methyl]-5- methoxyphenyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-[3-(Aminomethyl)-5- methoxyphenyl] -N-(cyclopropylmethy 1) - 3 - ( 1 -methy lpyrazol-4-yl)quinoxalin- 6- amine;hydrochloride, Chembl4573547, 1,6-Naphthyridine 77, 1,6-Naphthyridine 19, 1,6- Naphthyridine 26, N-(Cyclopropylmethyl)-N-[3-(difluoromethoxy)phenyl]-3-( 1 - methylpyrazol-4-yl)quinoxalin-6-amine, N'-(3,4-Difluoro-5-methoxyphenyl)-N'-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2-trifluoroethyl)propane-l,3- diamine;hydrochloride, 2,4-Difluoro-5-[5-isopropyl-6-(5-methanesulfonylmethyl-[1.3.4]oxadiazol-2-yl)-pyrrolo[2,l-f][l, 2, 4]triazin-4-ylamino]-N-methoxy -benzamide, 5-(2- Chlorophenyl)-7-fluoro-l,2-dihydro-8-methoxy-3-methylpyrazolo(3,4- b)(l,4)benzodiazepine, [3-[Cyclopropylmethyl-[3-(l-methylpyrazol-4-yl)quinoxalin-6- yl]amino]-5-methoxyphenyl]-pyrrolidin-l-ylmethanone, 5-[(l-Ethylpiperidin-4-yl)amino]-3- [(2-fluorophenyl)-(5 -methyl- 1 H-imidazol-2-y l)methylidene] - 1 H-indol-2-one, 5 - [6 - ( 5 - Cyclopropylmethyl- [ 1 ,3 ,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4- ylamino]-2,4-difluoro-N-methoxy-benzamide, 3-[(3,5-Difluorophenyl)-(5-methyl-lH- imidazol-2-yl)methylidene]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-one, 5-[( 1 - Ethylpiperidin-4-yl)amino] -3 - [(3 -fluorophenyl) -( 1 H-imidazol-2-yl)methylidene] - 1 H-indol-2- one, Indolin-2-one deriv. 9c, Methyl (3Z)-2-oxo-3-[phenyl-[4-(piperidin-l- ylmethyl)anilino]methylidene]-lH-indole-6-carboxylate, N-(3,5-Dimethoxyphenyl)-N-[3-(3- methylimidazol-4-yl)prop-2-ynyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, (3z)-5-[(l - Ethylpiperidin-4-Yl)amino]-3-[(5-Methoxy-lh-Benzimidazol-2-Yl)(Phenyl)methylidene]- l,3-Dihydro-2h-Indol-2-One, Chembl4449189, [5-Amino-l-(lH-indol-5-yl)pyrazol-4-yl]- (lH-indol-2-yl)methanone, 5-Isopropyl-6-(5-methyl-l,3,4-oxadiazol-2-yl)-N-(2-methyl-lH- pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine, 3-[Benzimidazol-2-ylidene- (4-methylphenyl)methyl]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-ol, 5-[6-(5-Ethyl-[1.3.4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-2,4-difluoro-N- methoxy-benzamide, 3-[Benzimidazol-2-ylidene(phenyl)methyl]-5-[(l-ethylpiperidin-4- yl)amino]-lH-indol-2-ol, 1,6-Naphthyridine 25, 2-(6-Fluoro-lH-indazol-3-yl)-5-(4- (piperidin-l-yl)piperidin-l-yl)-lH-benzo[d]imidazole, 3-[Benzimidazol-2-ylidene-(4- methoxyphenyl)methyl]-5-[(l-ethylpiperidin-4-yl)amino]-lH-indol-2-ol, N- (Cyclopropylmethyl)-N-[3-methoxy-5-[2-(methylamino)ethoxy]phenyl]-3-(l-methylpyrazol- 4-yl)quinoxalin-6-amine, 3-Methoxy-N-methyl-5-[[3-(l-methylpyrazol-4-yl)quinoxalin-6- yl]-[2-(propan-2-ylamino)ethyl]amino]benzamide, XL999;XL-999; XL 999, 3-N-(Cyclopropylmethyl)-l-N-methyl-3-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]benzene- 1,3-diamine, 2,4-Difluoro-5-[6-(5-isobutyl-[l,3,4]oxadiazol-2-yl)-5-isopropyl-pyrrolo[2,l- f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, Methyl 2-hydroxy-3-[N-[4-[2-methyl-5- [(4-methylpiperazin- 1 -yl)methyl]pyrrol- 1 -yl]phenyl] -C-phenylcarbonimidoyl] - 1 H-indole-6- carboxylate, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-[(2-pyridin-4- ylcyclopropyl)methyl]quinoxalin-6-amine, 3-(3,5-Dimethoxyphenyl)-7-N-[3-(4- methylpiperazin- 1 -yl)propyll - 1 ,6-naphthyridine-2,7-diamine, 9-Chloro-2-[3-[3- (dimethylamino)propyl]anilino]-5,7-dihydropyrimido[5,4-d][l]benzazepine-6-thione, Pyrido[2,3-d]pyrimidine 103, Pyrido[2,3-d]pyrimidine 105, 2,4-Difluoro-5-[5-isopropyl-6-(5- methyl-oxazol-2-yl)-pyrrolo[2,l-f][l,2,4]triazin-4-ylamino]-N-methoxy-benzamide, N-(3,5- Dimethoxyphenyl)-N-[3-(2,5-dimethylimidazol-l-yl)propyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine;hydrochloride, N-[3-[2-[6-(2-Chlorophenyl)-2-[4- (diethylamino)butylamino]-7-oxopyrido[2,3-d]pyrimidin-8-yl]ethyl]phenyl]prop-2-enamide, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(2-piperazin-l-ylethyl)quinoxalin-6- amine;hydrochloride, Methyl (3Z)-3-[[4-[2-(dimethylamino)ethyl- methylsulfonylamino]anilino]-phenylmethylidene]-2-oxo- 1 H-indole-6-carboxylate, 4- [3- (3 ,5 -Dimethoxy-N- [3 -( 1 -methylpyrazol-4-yl)quinoxalin-6-yl] anilino)prop- 1 -ynyl]pyridine-3 - carbonitrile, N-[(5-Chlorothiophen-2-yl)methyl]-N-(3,5-dimethoxyphenyl)-3-[l-(2-piperazin- l-ylethyl)pyrazol-4-yl]quinoxalin-6-amine;hydrochloride, N'-(3,5-Dichlorophenyl)-N'-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2-trifluoroethyl)propane-l,3-diamine, 2- [4- [7- [N-(Cyclopropylmethyl)anilino]quinoxalin-2-y]]pyrazol-l-yl]ethano], Pyrido[2,3- d]pyrimidine 102, 7-N-[4-(Diethylamino)butyl]-3-(3,5-dimethoxyphenyl)-l ,6-naphthyridine- 2,7-diamine, N-(3,5-Dimethoxyphenyl)-N-[3-(4-methoxypyrimidin-2-yl)propyl]-3-(l- methylpyrazol-4-yl)quinoxalin-6-amine, Methyl 3-[[4-[(dimethylamino)methyl]anilino]- phenylmethylidene] -2-oxo- lH-indole-6-carboxylate, 3-Fluoro-N-methyl-5-[[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]-[2-(propan-2-ylamino)ethyl]amino]benzamide, N- (Cyclopropylmethyl)-N-[3-(l,3-dioxolan-2-yl)-5-methoxyphenyl]-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, N-[[(2S)-l-[3-(3,5-Dimethoxy-N-[3-(l-methylpyrazol-4- yl)qumoxalin-6-yl]anilmo)propyl]pyrrolidin-2-yl]methyl]- 1,1,1- trifluoromethanesulfonamide, 3-Methoxy-N-methyl-5-[2-(propan-2-ylamino)ethyl-[3-(l- propan-2-ylpyrazol-4-yl)quinoxalin-6-yl]amino]benzamide, 5-{6-[5-(Difluoro- methanesulfonyl-methyl)-[l,3,4]oxadiazol-2-yl]-5-isopropyl-pyrrolo[2,l-f][l,2,4]triazin-4- ylamino }-2,4-difluoro-N-methoxy-benzamide, N-[2-(3-Aminopiperidin- 1 -yl)ethyl]-N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5-Dimethoxyphenyl)-N-[(E)-3-(4-methoxypyrimidin-2-yl)prop-2-enyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6- amine, Methyl (3Z)-3-[[4-[acetyl-[2-(dimethylamino)ethyl]amino]anilino]- phenylmethylidene] -2-oxo- lH-indole-6-carboxylate, Methyl N-[4-[7-amino-3-(3,4- dimethoxyphenyl)-5-(l-methylpiperidin-4-yl)oxypyrazolo[l,5-a]pyrimidin-6- yl]phenyl]carbamate, Anilinoquinazoline deriv. 35, 1,6-Naphthyridine 17, Tert-butyl (1S,4S)-5-[2-(3,5-dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]anilino)ethyl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate, Lucitanib, 6-((7-((l-Aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-N-methyl- 1 -naphthamide hydrochloride, Pyrido[2,3- d]pyrimidine 104, Nintedanib esylate, [(2S)-l-(3,5-Dimethoxy-N-[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]anilino)-3-methoxypropan-2-yl] acetate, 3-[2-Aminoethyl-[3-(l- methylpyrazol-4-yl)quinoxalin-6-yl]amino]-5-methoxy-N-methylbenzamide, N-(3,5- Dimethoxyphenyl)-3-( 1 -methylpyrazol-4-yl)-N- [3- [4-(trifluoromethyl)piperidin- 1 - yl]propyl]quinoxalin-6-amine, 3-((4-Bromo-2,6-difluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-l- yl)butyl)ureido)isothiazole-4-carboxamide, N-(3,5-Dimethoxyphenyl)-N-[3-(2- methylimidazol-l-yl)propyl]-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, 3-[3- (Morpholinomethyl)-4,5,6,7-tetrahydro-lH-indole-2-ylmethylene]-5-(ethylsulfonyl)-2,3- dihydro-lH-indole-2-one, 2-(3-Methoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6- yl]anilino)ethanol, Epihematoxylol, N-[3-(5-Aminopyrazin-2-yl)prop-2-ynyl]-N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine, 2-[3-[2-Aminoethyl-[7-(l- methylpyrazol-4-yl)quinoxalin-2-yl]amino] -5-fluorophenoxy Jethanol, N- [3 -(3 - Aminopyridin-2-y])prop-2-ynyl]-N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4- yl)quinoxalin-6-amine, N-(3,5-Dimethoxyphenyl)-N-[3-(3-methoxypyridin-2-yl)propyl]-3- (l-methylpyrazol-4-yl)quinoxalin-6-amine, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4- yl)-N-[(Z)-3-pyrimidin-2-ylprop-2-enyl]quinoxalin-6-amine, N'-(3,5-Dimethoxyphenyl)-N- methyl-N'-[3-[l-(oxan-4-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]ethane-l,2- diamine;hydrochloride, [5-Amino-l-(2-chloro-5-hydroxyphenyl)pyrazol-4-yl]-[5-(morpholin- 4-ylmethyl)-lH-indol-2-yl]rnethanone, 1,6-Naphthyridine 18, l-Tert-butyl-3-[3-(3,5- dimethoxyphenyl)-7-[4-(4-methylpiperazin-l-yl)butylamino]-l,6-naphthyridin-2-yl]urea, N’- (2-Chloro-3,5-dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2- ylethane-l,2-diamine;hydrochloride, N-(3,5-Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N- (3 -piperazin- 1 -ylpropyl)quinoxalin-6-amine, Methyl (3Z)-3- [[4- [acetyl- [3- (dimethylamino)propyl]amino]anilino]-phenylmethylidene]-2-oxo-lH-indole-6-carboxylate, 3-[4-[3-[4-[7-[N-(Cyclopropylmethyl)-3,5-dimethoxyanilino]quinoxalin-2-yl]pyrazol-l- yl]propyl]piperazin-l-yl]propan-l-ol;hydrochloride, 5-[(R)-l-(3,5-Dichloropyridine-4-yl)ethoxy ] -3 - [5 -(4-methylpiperazine- 1 -yl)- 1 H-benzoimidazole-2-y 1] - 1 H-indazole, 4-Amino- 3-(lH-benzo[d]imidazol-2-yl)quinolin-2(lH)-one, 3-[4-[3-[4-[7-[3,5-Dimethoxy-N-[2- (propan-2-ylamino)ethyl]anilino]quinoxalin-2-yl]pyrazol- 1 -yl]propyl]piperazin- 1 -yl]propan-1-ol;hydrochloride, 2-(2,6-Difluoro-3,5-dimethoxy-N-[3-(l-methylpyrazol-4-yl)quinoxalin-6- yl]anilino)ethanol, [4-[7-[3,5-Dimethoxy-N-[2-(propan-2-ylamino)ethyl]anilino]quinoxalin-2-yl]-2-methylpyrazol-3-yl]methanol, 1,6-Naphthyridine deriv. 20, N-(2-Chloro-3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(3-pyrrolidin-l-ylpropyl)quinoxalin-6- amine;hydrochloride, Methyl 3-[N-[4-[2-(dimethylamino)ethyl-methylcarbamoyl]phenyl]-C- phenylcarbonimidoyl]-2-hydroxy-lH-indole-6-carboxylate, N-[2-(l,4-Diazepan-l-yl)ethyl]- N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxalin-6-amine;oxalic acid, N’-(2,6- Difluoro-3,5-dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2- ylethane- 1 ,2-diamine, N-(3,5-Dimethoxyphenyl)-N-[(3-methyloxetan-3-yl)methyl]-3-(l- methylpyrazol-4-yl)quinoxalin-6-amine, Methyl (3Z)-3-[[4-[acetyl-[2-(dimethylamino)-2- oxoethyl]amino]anilino]-phenylmethylidene]-2-oxo-lH-indole-6-carboxylate,Chembl4213341, Anilinoquinazoline deriv. 36, [5-Amino-l-(lH-benzimidazol-6-yl)-lH- pyrazol-4-yl]-lH-indol-2-ylMethanone, Hematoxylone, N-Cyclopropyl-N'-(3,5- dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine, N-(3,5- Dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)-N-(3-pyrimidin-2-ylpropyl)quinoxalin-6-amine, N'-(3,5-Dimethoxyphenyl)-N'-[3-[5-[(dimethylamino)methyl]-l-methylpyrazol-4- yl]quinoxalin-6-yl]-N-propan-2-ylethane-l,2-diamine, N'-(2,6-Difhioro-3,5- dimethoxyphenyl)-N'-[3-(l-methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2- tri IT uoroethyl Jpropane- 1 ,3-diamine, [5-Amino- 1 -(2-methyl- 1 H-indol-5-yl)pyrazol-4-yl]-( 1 H- indol-2-yl)methanone, Haematoxylin, N'-(3,5-Dimethoxyphenyl)-N'-[3-(5-ethyl-l- methylpyrazol-4-yl)quinoxalin-6-yl]-N-(2,2,2-trifluoroethyl)ethane- 1 ,2-diamine, Methyl 3- [N-[4-[[dimethylcarbamoyl(methyl)amino]methyl]phenyl]-C-phenylcarbonimidoyl]-2- hydroxy-lH-indole-6-carboxylate, 3-Methoxy-N-methyl-5-[[3-(l-methylpyrazol-4- yl)quinoxalin-6-yl]-(3-pyrrolidin-l-ylpropyl)amino]benzamide, N-(3,5-Dimethoxyphenyl)-3- (l-methylpyrazol-4-yl)-N-(3-pyridin-4-ylpropyl)quinoxalin-6-amine, l-[3-(3,5-Dimethoxy- N-[3-(l-propan-2-ylpyrazol-4-yl)quinoxalin-6-yl]anilino)propyl]pyrrolidin-2-one, and Regorafenib.

50. The method of claim 49, wherein the selective VEGFR2 and FGFR1 inhibitor isBrivanib Alaninate (Brivanib).

51. The method of claim 49, wherein the selective VEGFR2 and FGFR1 inhibitor is selected from the group comprising of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib.

52. The method of claim 49 or 51, wherein the selective VEGFR2 and FGFR1 inhibitor is nintedanib.

53. The method of any one of claims 41-52, wherein the subject’s age is 30-39 years, 40- 49 years, 50-59 years, 60-69 years, 70-79 years, 80-89 years or 90-99 years.

54. The method of any one of claims 41-52, wherein the subject does not have acne.

55. The method of any one of claims 41-54, wherein the subject is administered a facial fat transplant.

56. The method of claim 55, wherein the subject is administered a facial fat transplant before or after administering the effective amount of a locally administered formulation of a selective inhibitor of VEGFR2 and FGFR1.

57. A method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist, wherein the subject is receiving a glucagon-like peptide- 1 (GLP-1) receptor agonist.

58. A method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation of a PPAR-gamma agonist, wherein the subject is receiving a corticosteroid.

59. The method of claim 57 or 58, wherein the locally administered formulation is a topical formulation.

60. The method of claim 57 or 58, wherein the locally administered formulation is a local subcutaneous injection.

61. The method of any one of claims 57-60, wherein the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507- 34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX- 909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW- 1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100,netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010- 198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

62. The method of any one of claims 57-61, wherein the PPAR-gamma agonist is rosiglitazone.

63. The method of any one of claims 57-60, wherein the PPAR-gamma agonist is selected from the group consisting of pioglitazone, CHS-131, efatutazone, GED 0507-34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol (VivaCell Biotechnology), farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, T-174, UHC-1, aleglitazar, AVE-0897, AZD- 6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW-1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN-862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY- 554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL-17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

64. The method of any one of claims 57-63, wherein the PPAR-gamma agonist is pioglitazone.

65. The method of any one of claims 57 or 59-64, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide.

66. The method of claim 57, wherein the GLP-1 receptor agonist is also a GIP-receptor agonist.

67. The method of any one of claims 57 or 59-66, wherein the GLP-1 receptor agonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

68. The method of any one of claims 58-64, wherein the corticosteroid is selected from the group consisting of 11 -Dehydrocorticosterone, 11 -Deoxycorticosterone, 11- Deoxycortisol, 11 -Ketoprogesterone, l ip-Hydroxypregnenolone, 110-Hydroxyprogesterone,1 ip,17a,21-Trihydroxypregnenolone, 17 a, 21 -Dihydroxypregnenolone, 17a- Hydroxypregnenolone, 17a- Hydroxyprogesterone, 18-Hydroxy- 11 -deoxycorticosterone, 18- Hydroxycorticosterone, 18-Hydroxyprogesterone, 21 -Deoxycortisol, 21 -Deoxycortisone, 21- Hydroxypregnenolone, Aldosterone, Corticosterone, Cortisol, Cortisone, Pregnenolone, Progesterone, Flugestone, FluoromethoIone, Medrysone, Prebediolone acetate, Chloroprednisone, Cloprednol, Difhiprednate, Fludrocortisone, Fluocinolone, Fluperolone, Fluprednisolone, Loteprednol, Methylprednisolone, Prednicarbate, Prednisolone, Prednisone, Tixocortol, Triamcinolone, Alclometasone, Beclometasone, Betamethasone, Clobetasol, Clobetasone, Clocortolone, Desoximetasone, Dexamethasone, Diflorasone, Difluocortolone, Fluclorolone, Flumetasone, Fluocortin, Fluocortolone, Fluprednidene, Fluticasone, Fluticasone furoate, Halometasone, Meprednisone, Mometasone, Mometasone furoate, Paramethasone, Prednylidene, Rimexolone, Ulobetasol, Amcinonide, Budesonide, Ciclesonide, Deflazacort, Desonide, Formocortal, Fluclorolone acetonide, Fludroxycortide, Flunisolide, Fluocinolone acetonide, Fluocinonide, Halcinonide, Triamcinolone acetonide, Cortivazol, and RU-28362.

69. The method of any one of claims 58-64 or 68, wherein the corticosteroid is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

70. The method of any one of claims 57-69, wherein the dermal adipose and / or skin thickness is measured according to calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectance-mode confocal microscopy, computerized tomography, diffuse reflectance, digital micrometers, radiography, shear wave elastography, patient or clinician- reported rating scale, or a structured light 3D scanner.

71. The method of any one of claims 57-70, wherein the topical formulation is as an ointment, cream, gel, lotion, solution, foam, or spray.

72. The method of any one of claims 57-71, wherein the subject’s age is 30-39 years, 40- 49 years, 50-59 years, 60-69 years, 70-79 years, 80-89 years or 90-99 years.

73. The method of any one of claims 57-72, wherein the subject is administered a facial fat transplant.

74. The method of claim 73, wherein the subject is administered a facial fat transplant before or after administering the effective amount of a locally administered formulation of aPPAR-gamma agonist, wherein the subject is receiving a glucagon-like peptide- 1 (GLP-1) receptor agonist or corticosteroid.

75. A method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation comprising a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

76. The method of claim 75, wherein the locally administered formulation is a topical formulation.

77. The method of claim 75, wherein the locally administered formulation is a local subcutaneous injection.

78. The method of any one of claims 75-77, wherein the subject is receiving a glucagon- like peptide- 1 (GLP-1) receptor agonist.

79. The method of any one of claims 75-78, wherein the PPAR-gamma agonist is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507- 34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol, farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC-1, aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW- 1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN- 862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL- 17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

80. The method of any one of claims 75-79, wherein the PPAR-gamma agonist is rosiglitazone.

81. The method of any one of claims 75-79, wherein the PPAR-gamma agonist is pioglitazone.

82. The method of any one of claims 75-81, wherein the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of 5-Iodo-sunitinib, 5-Methoxy- sunitinib, Acrizanib, Agerafenib, Alectinib, Altiratinib, Amuvatinib, Amuvatinib hydrochloride, Apatinib, Apatinib Mesylate, Avapritinib, Axitinib, Bafetinib, Bemcentinib,Bosutinib, Brivanib, Brivanib alaninate, Brivanib metabolite M25, Cabozantinib, Cabozantinib oxidation B, Cabozantinib S-malate, Canertinib, Cediranib, Cerdulatinib hydrochloride, Ceritinib, Crenolanib, Dasatinib, Defactinib, Desmethyl nintedanib, Dovitinib, Entrectinib, Erdafitinib, Erlotinib, Famitinib, Fedratinib, Fisogatinib, Foretinib, Fostamatinib disodium, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, Golvatinib, Gunagratinib, Henatinib, Imatinib, Infigratinib, Infigratinib phosphate, Lapatinib, Lenvatinib, Lestaurtinib, Linifanib, Linsitinib, Lucitanib, Masitinib, Mivavotinib, Motesanib, N,N-Dimethyl Sunitinib, N- Desethyl Sunitinib, N-Desmethyl vandetanib, Neratinib, Nilotinib, Ningetinib, Nintedanib, Nintedanib esylate, Orantinib, Pacritinib, Pazopanib, Pelitinib, Pemigatinib, Pexidartinib, Pexmetinib, Ponatinib, Pralsetinib, Quizartinib, Quizartinib dihydrochloride, Ravoxertinib, Regorafenib, Ripretinib, Rogaratinib, Saracatinib, Selpercatinib, Semaxanib, Sitravatinib, Sorafenib, Sorafenib tosylate, Sunitinib, Tafetinib, Tamatinib, Tandutinib, Telatinib, Tesevatinib, Tivozanib, Toceranib, US10155768, Vandetanib, US9029401, Sunitinib, Vandetanib, Vandetanib hydrochloride, Vatalanib, Vatalanib succinate, Vemurafenib, and Vimseltinib.

83. The method of any one of claims 75-81, wherein the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is selected from the group consisting of axitinib, cabozantanib, lenvatinib, nintedanib, ponatinib, pazopanib, and tivozanib.

84. The method of any one of claims 75-81 , wherein the PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor is nintedanib or nintedanib esylate.

85. The method of any one of claims 75-84, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide.

86. The method of any one of claims 75-84, wherein the GLP-1 receptor agonist is also a GIP-receptor agonist.

87. The method of any one of claims 75-86, wherein the GLP-1 receptor agonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, by implantation, intrathecally, intraventricularly, or intranasally.

88. The method of any one of claims 75-87, wherein the dermal adipose and / or skin thickness is measured according to calipers, ultrasound (e.g., dermascan), optical coherence tomography, histology or pathology with light microscopy, dual x-ray absorption, 2-photon or multiphoton microscopy, magnetic resonance imaging, confocal laser scanning microscopy, reflectance-mode confocal microscopy, computerized tomography, diffusereflectance, digital micrometers, radiography, shear wave elastography, patient or clinician- reported rating scale, or a structured light 3D scanner.

89. The method of any one of claims 76 or 78-88, wherein the topical formulation is as an ointment, a cream, a gel, a lotion, a solution, a foam, or a spray.

90. The method of any one of claims 75-89, wherein the subject’s age is 30-39 years, 40- 49 years, 50-59 years, 60-69 years, 70-79 years, 80-89 years or 90-99 years.

91. The method of any one of claims 75-90, wherein the subject is administered a facial fat transplant.

92. The method of claim 91 , wherein the subject is administered a facial fat transplant before or after administering the effective amount of a locally administered formulation comprising a PPAR-gamma agonist and a PDGFRA / B, VEGFR2 and / or FGFR1 inhibitor.

93. A method of reducing or reversing atrophy of dermal adipose and / or thinning of the skin in a subject, comprising: administering to the subject an effective amount of a locally administered formulation comprising a means for activating PPAR-gamma and a means for inhibiting PDGFRA / B, VEGFR2 and / or FGFR1.

94. The method of claim 93, wherein the means for activating PPAR-gamma is selected from the group consisting of rosiglitazone, pioglitazone, CHS- 131, efatutazone, GED 0507- 34-Levo, OMS 405, balaglitazone, troglitazone, ciglitazome, CLX0921, FK-614, MK-0533, netoglitzone, DS 6930, rivoglitazone, edaglitazome, T3D 959, oxeglitazar, saroglitazar, 376501, arhalofenate, ATx-08-001, cannabigerol, farglitazar, FX-909, INT-131, KY-903, MK-0533, pioglitazone hydrochloride, R-483, rosiglitazone maleate, T-174, UHC- 1 , aleglitazar, AVE-0897, AZD-6610, cevoglitazar, chiglitazar, E-3030, etalocib, etrinabdione, GW- 1929, GW-409544, indeglitazar, ,KRP-297, lanifibranor, lobeglitazone, LR-90, LSN- 862, LY-929, muraglitazar, naveglitazar, NC-2100, netoglitazone, peliglitazar, ragaglitazar, reglitazar, SB-219994, sodelglitazar, tesaglitazar, ADC-3277, ADC-8316, Bay-54-9801, DJ5, ENERGI-F-707, LY-554862, S-010-188, S-010-198, SCD-DKY, THR-090717, VDO-52, AK-109, AVE-0847, AVE-5376, BMS-759509, CLX-0940, CS-204, DB-900, DRF-4158, DRF-4832, DRL- 17564, DSP-8658, GFT-930, KT6-207, MC-3002, NovAQ, ONO-5129, ZYH2, PN2034, and lobeglitazone.

95. The method of claim 93, wherein the means for inhibiting PDGFRA / B, VEGFR2 and / or FGFR1 is selected from the group consisting of 5-Iodo-sunitinib, 5-Methoxy-sunitinib, Acrizanib, Agerafenib, Alectinib, Altiratinib, Amuvatinib, Amuvatinib hydrochloride, Apatinib, Apatinib Mesylate, Avapritinib, Axitinib, Bafetinib, Bemcentinib, Bosutinib, Brivanib, Brivanib alaninate, Brivanib metabolite M25, Cabozantinib, Cabozantiniboxidation B, Cabozantinib S-malate, Canertinib, Cediranib, Cerdulatinib hydrochloride, Ceritinib, Crenolanib, Dasatinib, Defactinib, Desmethyl nintedanib, Dovitinib, Entrectinib, Erdafitinib, Erlotinib, Famitinib, Fedratinib, Fisogatinib, Foretinib, Fostamatinib disodium, Futibatinib, Gefitinib, Gilteritinib, Glesatinib, Golvatinib, Gunagratinib, Henatinib, Imatinib, Infigratinib, Infigratinib phosphate, Lapatinib, Lenvatinib, Lestaurtinib, Linifanib, Linsitinib, Lucitanib, Masitinib, Mivavotinib, Motesanib, N,N-Dimethyl Sunitinib, N-Desethyl Sunitinib, N-Desmethyl vandetanib, Neratinib, Nilotinib, Ningetinib, Nintedanib, Nintedanib esylate, Orantinib, Pacritinib, Pazopanib, Pelitinib, Pemigatinib, Pexidartinib, Pexmetinib, Ponatinib, Pralsetinib, Quizartinib, Quizartinib dihydrochloride, Ravoxertinib, Regorafenib, Ripretinib, Rogaratinib, Saracatinib, Selpercatinib, Semaxanib, Sitravatinib, Sorafenib, Sorafenib tosylate, Sunitinib, Tafetinib, Tamatinib, Tandutinib, Telatinib, Tesevatinib, Tivozanib, Toceranib, US10155768, Vandetanib, US9029401, Sunitinib, Vandetanib, Vandetanib hydrochloride, Vatalanib, Vatalanib succinate, Vemurafenib, and Vimseltinib.

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