Topical delivery of melanocortin-1 receptor agonists formulations

Abstract

The disclosure relates to pharmaceutical compositions comprising a melanocortin-1 receptor (MC1R) agonist; a plurality of micrometer or millimeter scale particles; and a pharmaceutically acceptable carrier, and use thereof for the treatment of disease.

Description

TOPICAL DELIVERY OF MELANOCORTIN-1 RECEPTOR AGONISTS FORMULATIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No.63 / 657,251 filed June 7, 2024 and U.S. Provisional Patent Application No.63 / 760,961 filed February 20, 2025, each of which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Vitiligo is a chronic autoimmune skin disease in which CD8+ T cells destroy melanocytes, leading to the formation of depigmented white spots or patches on the skin. It is a common condition, affecting 1.3% of the population worldwide, including approximately 4.6 million people in the United States. The average age of onset of vitiligo is in the mid-twenties, although it can occur at any age, and it progresses for life, resulting in a heavy burden of disease. Vitiligo has a profound impact on a patient’s quality of life. It is associated with significant impairments in routine activities, employment, and psychological well-being. Numerous studies have revealed the association of stigmatization, distress, depression, anxiety, low self-esteem, social isolation, and impact on sexual life with vitiligo. Studies have shown that vitiligo lesions located on visible areas (e.g., face, hands) or sensitive areas (e.g., genitalia) impact patient quality of life more severely.

[0003] Opzelura® (ruxolitinib) Cream, a topical Janus kinase inhibitor, became the first and only FDA-approved treatment for vitiligo repigmentation in July 2022. Opzelura® Cream is effective at returning pigment to the skin and its use is limited to treatment of affected areas of up to 10% body surface area. Other non-approved treatment options for vitiligo repigmentation include off-label use of topical corticosteroids and calcineurin inhibitors, psoralen and ultraviolet (UV) A, narrowband (NB)-UVB, and other light therapies such as excimer laser.

[0004] Scenesse® (afamelanotide) Implant, is a melanocortin 1 receptor (MC1R) agonist with FDA and EMA approval, indicated to increase pain-free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria (EPP). Scenesse® Implant, delivered as a biodegradable subcutaneous implant (afamelanotide is not bioavailable following oral or topical administration), has been evaluated in vitiligo patients for DB1 / 159304575.3 1repigmentation. In one study, fifty-five vitiligo patients with Fitzpatrick skin phototypes (SPTs) III to VI were randomized to NB-UVB phototherapy or a combination of afamelanotide implant and NB-UVB. Patients who received the combination therapy showed clinically apparent, statistically significant superior and faster repigmentation compared to NB-UVB monotherapy. There was an increased rate of report of nausea and fatigue in the combination therapy group, attributed to the systemic exposure. Hyperpigmentation of unaffected skin was subjectively experienced by all subjects in the combination therapy group and led to withdrawal of two subjects out of 28 (7%). SUMMARY

[0005] Embodiments of the present disclosure provide a pharmaceutical composition comprising a melanocortin-1 receptor (MC1R) agonist, a plurality of micrometer or millimeter scale particles, and a pharmaceutically acceptable carrier.

[0006] In some embodiments, the MC1R agonist is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: Ra-(CH2)m-C(O)-[Ser-Tyr-Ser]n-Nle-Glu-His-D-Phe-X-Trp-[Gly-Lys-Pro-Val]p-NH2 Formula (I) wherein in Formula (I): Rais selected from -CH3and -N+R1R2R3; R1, R2, and R3are each independently selected from -CH3, -CH2CH3, and -CH2CH2CH3; X is selected from Arg, homoArg, and norArg; m is selected from 0, 1, 2, 3, and 4; and n and p are each independently selected from 0 and 1.

[0007] In some embodiments, in Formula (I), Rais -CH3 when m is 0. In some embodiments, in Formula (I), Rais -N+R1R2R3. In some embodiments, in Formula (I), n and p are both 0.

[0008] In some embodiments, the MC1R agonist is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof: Ra-(CH2)m-C(O)-Nle-Glu-His-D-Phe-X-Trp-NH2 Formula (Ia) wherein in Formula (Ia): Rais selected from -CH3 and -N+R1R2R3; R1, R2, and R3 are each independently selected from -CH3, -CH2CH3, and -CH2CH2CH3; X is selected from Arg, homoArg, and norArg; and m is selected from 0, 1, 2, 3, and 4, wherein Rais -CH3when m is 0. DB1 / 159304575.3 2

[0009] In some embodiments, in Formula (I) and / or Formula (Ia), X is Arg. In some embodiments, in Formula (I) and / or Formula (Ia), X is homoArg. In some embodiments, in Formula (I) and / or Formula (Ia), X is norArg. In some embodiments, in Formula (I), n and p are both 1.

[0010] In some embodiments, the MC1R agonist is CH3-C(O)-Ser-Tyr-Ser-Nle-Glu-His-D- Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2or a pharmaceutically acceptable salt thereof. In some embodiments, the MC1R agonist is afamelanotide or a pharmaceutically acceptable salt thereof. In some embodiments, the MC1R agonist is afamelanotide acetate salt.

[0011] In some embodiments, the MC1R agonist is CH3-C(O)-Nle-Glu-His-D-Phe- homoArg-Trp-NH2or a pharmaceutically acceptable salt thereof. In some embodiments, the MC1R agonist is a compound, or pharmaceutically acceptable salt thereof, selected from: (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-Arg-Trp-NH2, (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D- Phe-Arg-Trp-NH2, (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-homoArg-Trp-NH2, (CH3)3N+- (CH2)3-CO-Nle-Glu-His-D-Phe-homoArg-Trp-NH2, (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe- norArg-Trp-NH2, and (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-norArg-Trp-NH2.

[0012] In some embodiments, the micrometer or millimeter scale-particles comprises one or more of micro-STAR particles, micro-diamond particles, micro-square particles, and / or microneedles.

[0013] In some embodiments, the afamelanotide or pharmaceutically acceptable salt thereof is present in an amount of between about 0.1 % w / w to about 0.15 % w / w, between about 0.15 % w / w to about 0.20 % w / w, between about 0.20 % w / w to about 0.25 % w / w, between about 0.25 % w / w to about 0.30 % w / w, between about 0.30 % w / w to about 0.35 % w / w, or between about 0.35 % w / w to about 0.40 % w / w of the total weight of the composition.

[0014] In some embodiments, the micrometer or millimeter scale-particles are present in an amount of between about 10.0 % w / w to about 10.1 % w / w, between about 10.1 % w / w to about 10.2 % w / w, between about 10.2 % w / w to about 10.3 % w / w, between about 10.3 % w / w to about 10.4 % w / w, between about 10.4 % w / w to about 10.5 % w / w, between about 10.5 % w / w to about 10.6 % w / w, between about 10.6 % w / w to about 10.7 % w / w, between about 10.7 % w / w to about 10.8 % w / w, between about 10.8 % w / w to about 10.9 % w / w, or between about 10.9 % w / w to about 11.0 % w / w of the total weight of the composition. In some embodiments, the micrometer or millimeter scale-particles are present in an amount of between about 5 % w / w DB1 / 159304575.3 3to about 5.5 % w / w, between about 5.5 % w / w to about 6 % w / w, between about 6.5 % w / w to about 7 % w / w, between about 7.5 % w / w to about 8 % w / w, between about 8.5 % w / w to about 9 % w / w, between about 9.5 % w / w to about 10 % w / w, between about 10.0 % w / w to about 11.0 % w / w, between about 11.0 % w / w to about 12.0 % w / w, between about 12.0 % w / w to about 13.0 % w / w, between about 13.0 % w / w to about 14.0 % w / w, or between about 14.0 % w / w to about 15.0 % w / w, of the total weight of the composition.

[0015] In some embodiments, the pharmaceutical composition further comprises a solvent. In some embodiments, the solvent is purified water. In some embodiments, the solvent is present in an amount of between about 40% w / w to about 45% w / w, between about 45% w / w to about 50% w / w, between about 50% w / w to about 55% w / w, between about 55% w / w to about 60% w / w, between about 60% w / w to about 65% w / w, between about 65% w / w to about 70% w / w, between about 70% w / w to about 75% w / w, between about 75% w / w to about 80% w / w, between about 80% w / w to about 85% w / w, between about 85% w / w to about 90% w / w, between about 90% w / w to about 95% w / w. In some embodiments, the solvent comprises one or more of mineral oil, propylene carbonate, dimethyl sulfoxide (DMSO), glycerin, propylene glycol, isopropyl alcohol, and / or hexylene glycol.

[0016] In some embodiments, the one or several of the solvents are present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, between about 4% w / w to about 4.5% w / w, between about 4.5% w / w to about 5.0% w / w, between about 5% w / w to about 5.5% w / w, between about 5.5% w / w to about 6% w / w, between about 6% w / w to about 6.5% w / w, between about 6.5% w / w to about 7% w / w, between about 7% w / w to about 7.5% w / w, between about 7.5% w / w to about 8% w / w, between about 8% w / w to about 8.5% w / w, between about 8.5% w / w to about 9% w / w, between about 9% w / w to about 9.5% w / w, between about 9.5% w / w to about 10% w / w.

[0017] In some embodiments, the pharmaceutical formulation further comprises one or more gelling agents. In some embodiments, the one or more gelling, thickening agents comprise one or more of hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), Hydroxyethyl cellulose (HEC), Carboxy methyl cellulose sodium (CMC sodium), Xanthan Gum, DB1 / 159304575.3 4PolyCarbophil, Carbopol 974 (Type B), Methyl cellulose, Magnesium aluminum silicate (Veegum), Sepineo 600, Carbopol 971, Carbopol 980, Carbopol 981, Carbopol 2020, or Ultrez 10. In some embodiments, the one or more gelling, thickening agents are present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, between about 4.0% w / w to about 4.5% w / w, between about 4.5% w / w to about 5.0% w / w, between about 5.0% w / w to about 5.5% w / w, or between about 5.5% w / w to about 6.0% w / w.

[0018] In some embodiments, the pharmaceutical formulation further comprises a viscosity modifier. In some embodiments, the viscosity modifier comprises one or more of Cyclomethicone, Dimethicone, Cyclomethicone dimethicone copolyol, or PEG / PPG-18 Dimethicone. In some embodiments, the viscosity modifier is present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w.

[0019] In some embodiments, the pharmaceutical formulation further comprises a chelating agent. In some embodiments, the chelating agent comprises one or more of Disodium EDTA, trisodium EDTA, Diethylenetriamine Pentaacetic Acid, Hydroxyethyl ethylenediamine triacetic acid, or Hydroxyethylidene bisphosphonic acid. In some embodiments, the chelating agent is present in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, or about 0.5% w / w.

[0020] In some embodiments, the pharmaceutical formulation further comprises a skin penetration enhancer. In some embodiments, the skin penetration enhancer comprises one or more of HP, Diethylene glycol monoethyl ether (Transcutol P), Dimethyl sulfoxide (DMSO), lipid nano-particles, micelles, activated plasma, ionic layers, liposomes, Oleyl alcohol, Dimethyl isosorbide (Arlasolve DMI), Propylene glycol, Isopropyl alcohol, Propylene Glycol, Medium chain triglycerides other glycerides including mono-, di-, and mixed-glycerides, Isopropyl myristate or Oleic acid. In some embodiments, the skin penetration enhancer is present in an DB1 / 159304575.3 5amount of between 5% w / w and 10% w / w, between 10 and about 14%, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, or between 24 and 27%, between 27% and 30%, or between 30% and 35% w / w., between 35% and 40%.

[0021] In some embodiments, the pharmaceutical formulation further comprises one or more antioxidants. In some embodiments, the one or more antioxidants comprise one or more of Propyl Gallate, Methionine, Ascorbic acid, Propyl gallate, T-BHQ, EDTA disodium, BHT, Sodium Sulfite, Cysteine HCL, Monothioglycerol, Gluconolactone, L-Histidine, Butylated hydroxyanisole (BHA) or Tocopherol. In some embodiments, the one or more antioxidants are present in an amount of between about 0% w / w to about 0.1% w / w, between about 0.1% w / w to about 0.2% w / w, between about 0.2% w / w to about 0.3% w / w, between about 0.3% w / w to about 0.4% w / w, between about 0.4% w / w to about 0.5% w / w, between about 0.5% w / w to about 0.6% w / w, between about 0.6% w / w to about 0.7% w / w, between about 0.7% w / w to about 0.8% w / w, between about 0.8% w / w to about 0.9% w / w, between about 0.9% w / w to about 1.0% w / w,, or between about 1.0% w / w to about 3.0% w / w.

[0022] In some embodiments, the pharmaceutical formulation further comprises a preservative. In some embodiments, the preservative comprises one or more of Benzyl alcohol, Phenoxyethanol, Benzoic acid, Sorbic acid, Methyl paraben, or Imidurea. In some embodiments, the preservative is present in an amount of between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, or between about 2.0% w / w to about 2.5% w / w.

[0023] In some embodiments, the pharmaceutical formulation further comprises a humectant. In some embodiments, the humectant comprises one or more of Glycerin, PEG 3350, or Cyclomethicone. In some embodiments, the humectant is present in an amount of about 0% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w.

[0024] In some embodiments, the pharmaceutical formulation further comprises an emollient. In some embodiments, the emollient comprises one or more of Isopropyl myristate, Crodamol CAP (Cetearyl ethylhexanoate and Isopropyl Myristate), Crodamol DA (Di-isopropyl adipate), Glycerin, Propylene carbonate, Propylene glycol, Isopropyl alcohol, Hexylene glycol, DB1 / 159304575.3 6Hyaluronic acid, Sorbitol, Urea, Butylene glycol, Mineral Oil, white petrolatum, Medium Chain Triglycerides, Cyclomethicone, or Dimethicone. In some embodiments, the emollient is present in an amount of between about 0% w / w to about 5% w / w, between about 5% w / w to about 10% w / w, between about 10% w / w to about 15% w / w, between about 15% w / w to about 20% w / w, between about 20% w / w to about 25% w / w, or between about 25% w / w to about 30% w / w.

[0025] In some embodiments, the pharmaceutical formulation further comprises an emulsifier. In some embodiments, the emulsifier comprises one or more of Glyceryl Monostearates, Cetyl Alcohol, Stearyl Alcohol, Glyceryl Monostearates, Cetyl Alcohol, Stearyl Alcohol, Sorbitan monooleate (Span 80), Tween 80 (polysorbate-80), Gylceryl monotearates, Oleic acid, Sorbitane monostearate (Span 60), Polysorbate 60, Sorbitan Monopalmitate (Span 40), Polysorbate 40, Sorbitan monolaurate (Span 20), Polysorbate 20, Ceteths (2-20), Steareths (2-20), PEG stearates (2-100), Tefose-1500 (source: Gattefosse), Tefose 63 (source: Gattefosse), or Polywax (source: Croda). In some embodiments, the emulsifier is present in an amount of between about 0% w / w to about 1% w / w, between about 1% w / w to about 2% w / w, between about 2% w / w to about 3% w / w, between about 3% w / w to about 4% w / w, between about 4% w / w to about 5% w / w, between about 5% w / w to about 6% w / w, between about 6% w / w to about 7% w / w, between about 7% w / w to about 8% w / w, between about 8% w / w to about 9% w / w, or between about 9% w / w to about 10% w / w.

[0026] In some embodiments, the pharmaceutical formulation further comprises a suspending agent. In some embodiments, the suspending agent comprises one or more of Xanthan Gum, Methyl cellulose, Carboxymethyl cellulose, Polycarbophil, or hydroxypropyl methylcellulose (“HPMC”). In some embodiments, the suspending agent is present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w, or between about 4.5 % w / w to about 5 % w / w of the total weight of the composition.

[0027] In some embodiments, the apparent viscosity of the composition is about 20,000 cP to about 800,000 cP throughout the shelf life of the composition as measured by a viscometer. DB1 / 159304575.3 7

[0028] In some embodiments, the micrometer or millimeter scale particles comprise a core and a plurality of pointed structures extending outwards from the core. In some embodiments, each of the plurality of pointed structures has a length of about 10 μm to about 100 μm, about 100 μm to about 500 μm, or about 500 μm to about 1,000 μm. In some embodiments, each of the plurality of pointed structures independently has a tip having a radius of about 0.1 μm to about 30 μm.

[0029] In some embodiments, the micrometer scale or millimeter scale particles have a largest dimension which is the largest of the following distances l) the distance between the tips of the two pointed structures that are the farthest apart, or 2) the farther possible distance between a tip of a pointed structures and the side of the core that is opposite the side from which the measured pointed structures extends. In some embodiments, the largest dimension is about 50 μm to about 1,000 μm. In some embodiments, the largest dimension is about 1,000 μm to about 2,000 μm. In some embodiments, the micrometer scale or millimeter scale particles are substantially suspended in the formulation for up to 3 years.

[0030] In some embodiments, the pharmaceutical composition has one or more of viscosity properties of suitable for easily spreading the pharmaceutical composition manually, and viscosity properties such that sedimentation or settling of the micrometer scale or millimeter scale particles does not occur during storage and transport.

[0031] Embodiments of the present disclosure provide a method of treating a disease or condition, the method comprising topically applying the pharmaceutical composition of any of the proceeding claims to the skin of a subject in need thereof. In some embodiments, the disease or condition is vitiligo.

[0032] In some embodiments, the method further comprises rubbing the pharmaceutical compositing on the skin of the subject, wherein the plurality of micrometer or millimeter particles tumble or move across the skin of the subject. In some embodiments, the plurality of micrometer or millimeter particles perforate the skin of the subject. In some embodiments, the method further comprises rubbing the pharmaceutical compositing on the skin of the subject, wherein the plurality of micrometer or millimeter particles perforate the skin of the subject creating microscopic pores across the stratum corneum. In some embodiments, the pores are transient for a period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 DB1 / 159304575.3 8hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the pores are transient for a period of about 1 day, about 2 days, about 3 days, about 4 days, or about 7 days.

[0033] In some embodiments, a substantial portion of the composition is absorbed into the subject’s skin, and wherein the plurality of micrometer or millimeter scale particles do not fully penetrate into the skin the skin. In some embodiments, after the substantial portion of the composition is absorbed into the subject’s skin, the plurality of micrometer or millimeter scale particles are removable from the surface of the skin. In some embodiments, the composition is a gel and remains in the gel state for at least at least 0.5 minutes to 1 minute upon manual application and then dries in not more than 5 minutes to 30 minutes, , allowing for removal of the micrometer or the millimeter scale particles. In some embodiments, from about 10 µg / cm2to about 100 µg / cm2or from about 100 µg / cm2to about 500 µg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 5 mg / cm2to about 30 mg / cm2or from about 30 mg / cm2to about 100 mg / cm2of formulation is applied on the skin of the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The presently disclosed embodiments will be further explained with reference to the attached drawings. The drawings shown are not necessarily to scale, with emphasis instead generally being placed upon illustrating the principles of the presently disclosed embodiments.

[0035] Figs.1A- 1E are photographs illustrating the STAR particles in cellulose / xantham gum gels. Fig.1A shows STAR particles settled to bottom of the jar in Gel-1 (overnight / Day-1). Fig 1B shows STAR particles suspended sparsely throughout the Gel and a layer was settled to bottom of the jar in Gel-2 (overnight / Day-2). Fig 1C shows STAR particles settled to bottom of the jar in Gel-4 (overnight / Day-1). Fig 1D shows STAR particles settled to bottom of the jar in Gel-5 (Day-3). Fig 1E shows STAR particles homogeneously suspended in Gel-3 + afamelanotide (Day-3).

[0036] Figs.2A- 2C are photographs illustrating initial prototype Carbopol / Polycarbophil gels. Figs.2A shows homogenously suspended STAR particles in Gel-6 (Day-6). Fig 2B shows homogenously suspended STAR particles in Gel-7 (Day-6). Fig 2C shows homogenously suspended STAR particles in Gel-7 with afamelanotide. DB1 / 159304575.3 9

[0037] Figs.3A- 3D are photographs illustrating the STAR particles in cream. Fig.3A shows a thin, white cream with no lumps or separation formed in Cream-1. Fig 3B shows milky, white liquid with lumps of cetyl and stearyl alcohol that were observed in Cream- 2. This Prototype was not stable. Fig 3C shows a thick, white cream with no lumps or separation was formed in Cream-3. Fig 3D shows an off-white, glossy and opaque cream with no separation was observed. STAR particles were suspended throughout the cream-4.

[0038] Figs.4A- 4B are photographs showing water based low viscosity hydroxy ethyl cellulose (HEC) gels Gel-11 and Gel-11 before and after shaking. Fig.4A shows the formulation before shaking and Fig.4B shows the formulation after shaking.

[0039] Figs.5A- 5C are photographs illustrating the STAR particles in cellulose / veegum gels. Fig.5A Gel-8 (Day-1), Fig.5B Gel-9 (Day-1), Fig.5C Gel-10 (Day-2), and Fig.5D-5E are photographs illustrating the STAR particles in water based low viscosity hydroxy ethyl cellulose (HEC) gels Gel-11 (after shaking), and Fig.5E Gel-12 (40 min after shaking).

[0040] Fig.6 is a chromatogram showing the results of Standard Injection- T2M.

[0041] Fig.7 is a chromatogram showing the stability results of Gel-15 at 5°C- T2M.

[0042] Fig.8 is a chromatogram showing the stability results of Gel-15 at 25°C- T2M.

[0043] Fig.9 is a chromatogram showing the stability results of Standard Injection- T3M.

[0044] Fig.10 is a chromatogram showing the stability results of Gel-15 at 5°C- T3M.

[0045] Fig.11 is a chromatogram showing the stability results of Gel-15 at 25°C- T3M.

[0046] Fig.12 is a graph illustrating concentration-dependent permeation of afamelanotide in human ex vivo skin with and without pre-treatment with 10% STAR particles.

[0047] Fig.13 is a graph illustrating the comparison of cumulative amounts of afamelanotide released from afamelanotide gel, 0.32% w / w formulations with and without 10% STAR particles (IVRT study).

[0048] Fig.14 is a graph illustrating human ex vivo skin permeation of afamelanotide (2mM afamelanotide) co-formulated with and without 10% STAR particles in a gel or a cream.

[0049] Fig.15 is a graph illustrating afamelanotide average amount in the dermis at 24 hours in human ex vivo skin using STAR particles co-formulated in a gel with and without 20% Transcutol. DB1 / 159304575.3 10

[0050] Fig.16 is a graph illustrating potency of afamelanotide drug substance batch 1 (AFA1) in a cAMP production cell-based assay (CHO cell line stably expressing human MC1R) as compared to a reference compound.

[0051] Fig.17 is a graph illustrating potency of afamelanotide drug substance batch 2 and batch 3 (AFA21X1 / 1 and AFA2301, respectively) as compared to the reference compound.

[0052] Fig.18 is a graph illustrating concentration-dependent induction of key markers of melanogenesis by afamelanotide (AFA21X1 / 1) ex vivo in fresh human skin treated for 14 days (basolateral dosing).

[0053] Fig.19 is a representative picture of a puncture of human ex vivo skin by STAR particle.

[0054] Fig.20 illustrates a gel manufacturing schematic.

[0055] Fig.21 is flow chart illustrating the STAR particle manufacturing process

[0056] Fig.22 illustrates the Gel Process Flow Diagram.

[0057] Fig.23 is a graph illustrating in the epidermis of minipig treated topically with a gel that contains afamelanotide and STAR particles daily for 7 days. Mean afamelanotide concentrations + / - SEM measured 2h post-dose at study day (SD)1 and, 2h and 24h post-dose at SD7.

[0058] Fig.24 is a graph illustrating concentrations of afamelanotide in the dermis of minipig treated topically with a gel that contains afamelanotide and STAR particles daily for 7 days. Mean afamelanotide concentrations + / - SEM measured 2h post-dose at study day (SD)1 and, 2h and 24h post-dose at SD7.

[0059] Fig. 25 is a graph illustrating concentrations of afamelanotide in the epidermis of minipig treated topically with a gel that contains afamelanotide and STAR particles daily for 90 days. Mean afamelanotide concentrations + / - SEM measured between 2 and 3h post-dose at study days 1, 42 or 90.

[0060] Fig.26 is a graph illustrating concentrations of afamelanotide in the dermis of minipig treated topically with a gel that contains afamelanotide and STAR particles daily for 90 days. Mean afamelanotide concentrations + / - SEM measured between 2 and 3h post-dose at study days 1, 42 or 90. DB1 / 159304575.3 11

[0061] Fig. 27 is a bar graph illustrating various parameters’ effects on microscale particle performance. The parameters tested were load (L), the viscosity of the gel (V), and the weight concentration of microscale particles in the gel (C).

[0062] Fig.28 is a half normal plot illustrating the statistically significance of parameters that have an effect on microscale particle performance.

[0063] Fig.29 is a chromatogram showing the stability results of the formulations of Example 6 (Gel- 15, Gel-19, and Gel-20)- T=0.

[0064] Fig.30 is a chromatogram showing the stability results of the formulations of Example 6 (Gel- 15, Gel-19, and Gel-20)- T1M.

[0065] Fig.31 is a chromatogram showing the stability results of the formulations of Example 6 (Gel- 15, Gel-19, and Gel-20)- T1M.

[0066] Fig.32 is a chromatogram showing the stability results of of the formulations of Example 6 (Gel- 15, Gel-19, and Gel-20)- T2M.

[0067] Fig.33 is a chromatogram showing the stability results of of the formulations of Example 6 (Gel- 15, Gel-19, and Gel-20)- T2M. DETAILED DESCRIPTION

[0068] To deliver a melanocortin-1 receptor (MC1R) agonist, such as afamelanotide, a stable topical vehicle is combined with micrometer or millimeter-scale particles that are intended to create transient micropores across the stratum corneum and thus allow the MC1R agonist to enter into the living layers of the skin (epidermis and dermis). The target cells of MC1R agonists such as afamelanotide are MC1R positive melanocytes localized in the deep epidermis and melanocyte stem cells, localized deeper in the skin, that express MC1R after UVB exposure and subsequently migrate from dermis to epidermis in a MC1R-dependent manner.

[0069] Aspects of the present disclosure provide a pharmaceutical composition comprising a melanocortin-1 receptor (MC1R) agonist; micrometer or millimeter scale particles; and a pharmaceutically acceptable carrier.

[0070] “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, DB1 / 159304575.3 12allergic response, or other adverse complications commensurate with a reasonable benefit / risk ratio.

[0071] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts are formed with inorganic acids and organic acids. Preferred inorganic acids from which salts are derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts are derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts are formed with inorganic and organic bases. Inorganic bases from which salts are derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts are derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines and cyclic amines.

[0072] “Pharmaceutically acceptable carrier” or “excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients (e.g., gelling agents, thickening agents, viscosity modifiers, chelating agents, skin penetration enhancers, antioxidants, preservatives, humectants, emollients, emulsifiers, suspending agents, etc.). The use of such pharmaceutically acceptable carriers or excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or excipient is incompatible with the active pharmaceutical ingredient(s), its use in the compositions of the disclosure is contemplated.

[0073] “Ac” refers to acetyl or CH3-C(O)-.

[0074] The use of any melanocortin-1 receptor (MC1R) agonist (or alpha-MSH analogue) is contemplated in the pharmaceutical compositions described herein. Several derivatives of MC1R agonists have been synthesized. In one aspect, the MC1R agonists described in U.S. Pat. Nos. 4,457,864, 4,485,039, 4,866,038, 4,918,055, 5,049,547, 5,674,839, 5,714,576, 9,345,911, 10,076,555, 10,508,142, and 11,286,288, and U.S. Pat. Appl. Pub. No.2018 / 0086789, which are DB1 / 159304575.3 13herein incorporated by reference for their teachings with respect to MC1R agonists and their synthesis thereof, can be used herein.

[0075] In some embodiments, the MC1R agonist is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: Ra-(CH2)m-C(O)-[Ser-Tyr-Ser]n-Nle-Glu-His-D-Phe-X-Trp-[Gly-Lys-Pro-Val]p-NH2 Formula (I) wherein in Formula (I): Rais selected from -CH3 and -N+R1R2R3; R1, R2, and R3are each independently selected from -CH3, -CH2CH3, and -CH2CH2CH3; X is selected from Arg, homoArg, and norArg; m is selected from 0, 1, 2, 3, and 4; and n and p are each independently selected from 0 and 1.

[0076] In some embodiments, in Formula (I), Rais -CH3when m is 0.

[0077] In some embodiments, in Formula (I), Rais -N+R1R2R3.

[0078] In some embodiments, in Formula (I), n and p are both 0.

[0079] In some embodiments, the MC1R agonist is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof: Ra-(CH2)m-C(O)-Nle-Glu-His-D-Phe-X-Trp-NH2 Formula (Ia) wherein in Formula (Ia): Rais selected from -CH3 and -N+R1R2R3; R1, R2, and R3are each independently selected from -CH3, -CH2CH3, and -CH2CH2CH3; X is selected from Arg, homoArg, and norArg; and m is selected from 0, 1, 2, 3, and 4, wherein Rais -CH3 when m is 0.

[0080] In some embodiments, in Formula (I) and / or Formula (Ia), X is Arg.

[0081] In some embodiments, in Formula (I) and / or Formula (Ia), X is homoArg.

[0082] In some embodiments, in Formula (I) and / or Formula (Ia), X is norArg.

[0083] In some embodiments, in Formula (I), n and p are both 1.

[0084] In some embodiments, the MC1R agonist is CH3-C(O)-Ser-Tyr-Ser-Nle-Glu-His-D- Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2or a pharmaceutically acceptable salt thereof. DB1 / 159304575.3 14

[0085] In some embodiments, the MC1R agonist is afamelanotide or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the MC1R agonist is afamelanotide acetate salt.

[0087] In some embodiments, the MC1R agonist is CH3-C(O)-Nle-Glu-His-D-Phe- homoArg-Trp-NH2 or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the MC1R agonist is a compound, or pharmaceutically acceptable salt thereof, selected from: (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-Arg-Trp-NH2, (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-Arg-Trp-NH2, (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-homoArg-Trp-NH2, (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-homoArg-Trp-NH2, (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-norArg-Trp-NH2, and (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-norArg-Trp-NH2.

[0089] Topical administration of a gel that contains a MC1R agonist of Formula (I) or Formula (Ia), as described herein, and micrometer or millimeter scale particles by direct application to the vitiligo lesions will allow control of the anatomical areas that re-pigment, rather than the unwanted side effect of full body hyperpigmentation and will minimize or eliminate the adverse effects from systemic exposure of the MC1R agonists that result from subcutaneous delivery. The MC1R agonists of Formula (I) and Formula (Ia), such as, afamelanotide, are believed to stimulate both the proliferation and migration of melanocytes.

[0090] For example, as described in U.S. Pat. Appl. Pub. No.2018 / 0086789, an MC1R agonist Ac-Nle-Glu-His-D-Phe-homoArg-Trp-NH2(“compound A”) and reference NDP-MSH were tested on melanocytes 1753 and cAMP was measured using a radioimmunoassay. Compound A outperformed reference compound NDP-MSH by achieving highest efficacy (216% at 10−7M vs 202% at 10−7M), and the results were statistically different compared to the control (p<0.05) at concentrations from 10−10M to 10−7M.

[0091] As described in U.S. Pat. Nos.10,508,142 and 11,286,288, MC1R agonists (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-Arg-Trp-NH2 (“compound B”), (CH3)3N+-(CH2)3-CO- Nle-Glu-His-D-Phe-Arg-Trp-NH2(“compound C”), and (C2H5)3N+-CH2-CO-Nle-Glu-His-D- Phe-homoArg-Trp-NH2(“compound D”) were tested on melanocytes 1753 and cAMP was determined using a radioimmunoassay. It was found that compound B achieved highest overall DB1 / 159304575.3 15efficacy value of 431% at 10−7M vs. control (no compound), compound C achieved maximum effect at the lowest dose of 10−11M, and compound D achieved maximum effect at the lowest dose of 10−9M vs. control (no compound), in which the results were statistically different compared to the control at p<0.05. Compound C and compound D were also tested on melanocytes 1750 and cAMP was measured, where compound C achieved maximum effect (vs. control) at the lowest dose of 10−8M, and compound D achieved highest overall efficacy value of 327% at 10−7M vs. control (no compound) (both results were statistically different compared to the control at p<0.05). Another MC1R agonist, (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe- homoArg-Trp-NH2(“compound E”), and reference compound NDP-MSH were tested on melanocytes 1753 to determine cAMP using the radioimmunoassay. The results showed that Compound E outperformed reference compound NDP-MSH by achieving highest efficacy (253% at 10−7M vs 202% at 10−7M), which was statistically different compared to the control at p<0.05.

[0092] Therefore, pharmaceutical formulations of present disclosure provide the potential to address a significant unmet need in treating vitiligo lesions that are refractory to other treatment options. Compositions of the present disclosure may also be used for protection while sun tanning.

[0093] In some embodiments, the present disclosure provides a pharmaceutical composition comprising afamelanotide or a pharmaceutically acceptable salt thereof; micrometer or millimeter scale particles; and a pharmaceutically acceptable carrier.

[0094] Typically, molecules of less than 450 Daltons are desired in drug substance selection to penetrate the stratum corneum and reach epidermis and dermis. Afamelanotide has a MW of 1647 Daltons. Afamelanotide and its Biology

[0095] Table 1. Properties of Afamelanotide Drug Substance Afamelanotide [NIe4, D-Phe7]-α-melanocyte stimulating hormone Synonyms (NDP-MSH), Melanotan-1, EPT1647, Afamelanotide, CUV-1647 Drug class Peptide Mechanism of action Agonist of melanocortin-1 receptor (MC1-R), thatincreases synthesis, release, and transfer of eumelanin.Molecular Formula – free base C78H111N21O19DB1 / 159304575.3 16Molecular weight – free base 1,647 g / mol Molecular Formula – acetate salt C78H111N21O19.xCH3COOH Structure Physical Form white to off white hygroscopic amorphous powder FDA UNII QW68W3J66U Freely soluble in water, 1% acetic acid and methanol Solubility Slightly to very slightly soluble in ethanol Practically insoluble in acetonitrile and 1-octanol pKa (Strongest Acidic) 3.46 pKa (Strongest Basic) 11.58 Log P -1.4, -8.2 CAS No 75921-69-6

[0096] Afamelanotide is a synthetic, 13-amino acid peptide analogue of the endogenous alpha-melanocyte-stimulating hormone (α-MSH) where the amino acids at positions 4 and 7 have been replaced with norleucine and D-phenylalanine, respectively. These structural differences improve biological efficacy by imparting a greater affinity for its target MC1R and a longer biological half-life. The sequence is the following: Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2.

[0097] After its agonistic binding to its receptor, MC1R, α-MSH (or afamelanotide) activates the synthesis of (eu)melanin by increasing the expression of the rate limiting enzyme tyrosinase, as well as tyrosinase-related proteins 1 and 2. The latter two induce a shift from yellow-red pheomelanin to brown–black eumelanin production, with eumelanin being more protective against ultraviolet radiation (UVR) than pheomelanin. MC1R signaling also stimulates the transcription and folding of tyrosinase within the Golgi network and ensures that the newly produced melanin is incorporated into small vesicles (melanosomes) and then distributed by the DB1 / 159304575.3 17dendrites of the melanocytes to the surrounding keratinocytes. Keratinocytes concentrate the melanosomes above their cell nucleus, and these form a cap to protect the organelle most sensitive to UVR insult. MC1R signaling and potency of afamelanotide

[0098] The melanocortin 1 receptor, MC1R, is a receptor that forms a complex with heterotrimeric G proteins. When agonistic ligands bind to MC1R, the Gαs protein is separated, and MC1R activates adenylyl cyclase, which leads to the production of cyclic adenosine monophosphate (cAMP), a crucial second messenger that regulates many cellular processes. In melanocytes, cAMP activates protein kinase A (PKA) and triggers downstream signaling pathways that activate different effector pathways, including the C-AMP Response Element- binding protein (CREB) and Microphthalmia-associated transcription factor (MITF) networks. These pathways lead to the increased expression of tyrosinase and dopachrome tautomerase (DCT), two enzymes that are involved in melanin synthesis, resulting in the production of melanin. The melanin produced is then transmitted to nearby keratinocytes, creating a protective layer that improves the ability of the skin to prevent further UV damage. Moreover, the increase in cAMP levels in melanocytes enhances antioxidant defenses and accelerates nucleotide excision repair (NER), which is vital for safeguarding the skin from UV damage. Upon binding to the MC1R at melanocytes, transcription, translation, proper folding, and transport into melanosomes of tyrosinase and tyrosinase-related proteins is stimulated, the outgrowth of dendrites propagated, and melanosomes are distributed to adjacent keratinocytes. In addition, MC1R signaling promotes DNA repair and synthesis of antioxidant enzymes.

[0099] The binding potency and agonistic activity of afamelanotide at MC1R are sub nanomolar (nM), and several orders of magnitude more than α-MSH. The EC50values of cAMP production by 3 different batches of afamelanotide drug substance were compared to a reference standard in a cell-based assay using a CHO cell line stably expressing human MC1R. The first batch, AFA1, had an EC50 = 0.026 nM, comparable to that of the reference (EC50 = 0.044 nM, historical mean EC50 = 0.041 nM) (Figure 16). Batch 2, AFA21X1 / 1 (EC50 = 0.036 nM) and batch 3, AFA2301 (EC50 = 0.060 nM), were also comparable to the afamelanotide reference compound (Figure 17). Subsequently, the primary pharmacology of afamelanotide (AFA21X1 / 1), was confirmed in an ex vivo human skin model. The human skin, which was obtained from abdominoplasties, was dermatomed to an approximate thickness of 750 ± 100 μm DB1 / 159304575.3 18using an Integra® dermatome. The dermatomed skin was then further sectioned into ~1 cm2sections and the explants were mounted onto 0.6 cm2static cells in a high throughput device for basolateral dosing. Afamelanotide (AFA21X1 / 1) induced gene expression of the rate-limiting enzyme in melanogenesis, tyrosinase (TYR), as well as the tyrosinase-related protein 1 (TYRP1), which is known to convert 5,6-dihydroxyindole-2-carboxylic acid into eumelanin, and the premelanosone protein (PMEL), a key protein involved in melanogenesis, melanosome maturation and melanin polymerization.

[0100] The primary target cells of afamelanotide are melanocytes, which express MC1R. Melanocytes are located in hair follicles and the basal layer of the interfollicular epidermis, where they produce and distribute melanin, which absorbs ultraviolet (UV) light and protects the skin from UV radiation-induced damage.

[0101] During embryogenesis, neural crest cells, a transient population of cells arising from the dorsal part of the neural tube, give rise to melanocyte precursors, the melanoblasts, which migrate to and colonize the dermis. Some melanoblasts differentiate directly in melanocytes that start melanin production and participate in the initial hair cycle. Other melanoblasts become melanocyte stem cells (MSCs), which have the capacity of self-renewal. MSCs remain quiescent until activated in the next hair cycles, resulting in transient amplifying cells and their subsequent differentiation into functional melanocytes.

[0102] In adults, in response to wounding or UV irradiation, follicular MSCs can exit the stem cell niche, migrate toward the basal layer of the epidermis in a MC1R-dependent manner, and differentiate into functional epidermal melanocytes. This MC1R-dependent migration behavior of MSCs in hair follicles triggered by environmental stimuli such as UV provides a mechanistic rationale for developing therapeutic approaches to treat skin hypopigmentation disorders such as vitiligo with a combination of afamelanotide and NB-UVB. STAR particles

[0103] In some embodiments, the micrometer or millimeter scale particules are so-called “STAR particles”. To allow larger molecules to penetrate the stratum corneum and reach epidermis and dermis, a device resembling a star has been fabricated as a medical device to assist in the penetration permeation of the large molecules. Such devices scan the micrometer or millimeter scale particle use in the present invention and are referred as “STAR particles“. DB1 / 159304575.3 19

[0104] Without being bound by the theory, the inventors have observed and believe that the STAR particles enhance the penetration of the active compound(s) present in the composition of the invention. It is believed that that the STAR particles induce microperforations of the skin that in turn enhance the passage of the active compound(s) through the skin. It is believed that the 2D-geometry, the 3D-geometry, the size, the rigidity / flexibility, the material the presence of sharp edges or sharp tips or pointed structures all play a synergistic role in the mechanism of action of the STAR particles. It is believed that a synergy exists between the characteristics of the active compounds (such as viscosity, stability, polarity, etc...) and the STAR particles to induce an optimal effect of the composition of the invention

[0105] In some embodiments, the STAR particles are rigid enough to at least partially penetrate a biological tissue (e.g., skin). In some embodiments, the geometry of the STAR particle prevents the entire STAR particle from penetrating biological tissue. In some embodiments, the STAR particles create a microscale hole in biological tissue when the STAR particle penetrates biological tissue. In some embodiments, after the STAR particle penetrates biological tissue, the STAR particles can be wiped away or washed away from the biological tissue.

[0106] In some embodiments, the STAR particles are structured to not become embedded in biological tissue after application.

[0107] The STAR particles are structured to at least partially penetrate a biological tissue, such as the stratum corneum of human skin. That is, the STAR particles (or at least the tip end portion thereof) are dimensioned and possess the mechanical rigidity to enable them to be pressed into and penetrate the biological tissue, forming a microscale hole or channel therein, and the STAR particles each have an overall geometric shape or other design feature that generally prevents the particle as a whole from penetrating into the biological tissue. Mere elastic deformation of the biological tissue is not penetration. In some embodiments, penetration may include elastic deformation, but further includes penetration into the tissue. In some embodiments, the microparticles described herein or the STAR particles include the microparticles described in International Publication WO 2017 / 151745, U.S. Patent No. 11,291,816, U.S. Patent Publication No.2022 / 0226626, each of which is incorporated by reference in its entirety. DB1 / 159304575.3 20

[0108] Here and throughout this disclosure, when used to refer to the interaction between STAR particles and a tissue such as the skin, the terms penetrate and perforate, or penetration and perforation, are meant equivalently to mean the physical ingress of a part of the STAR particle into the tissue to create a gap or hole or break or tear in the tissue. In contrast, when used in the context of the interaction between a molecule (e.g., a drug) and a tissue such as the skin, the term penetrate or penetration refers to the movement of the molecule into the tissue, but does not involve the creation of a gap or hole or break or tear in the tissue.

[0109] In some embodiments, the STAR particles comprise a core and a plurality of pointed structures extending outwards from the core. In some embodiments, the plurality of pointed structures may extend independently in any direction from the core. In one embodiment, the plurality of pointed structures are structured to at least partially penetrate a first type of biological tissue, and prevent or decrease the likelihood that the plurality of pointed structures can penetrate a second type of biological tissue. The second type of biological tissue, for example, may include the skin of the fingers, while the first type of biological tissue may include a tissue to be treated, for example, an area of the skin having a relatively thinner stratum corneum or a mucosal tissue.

[0110] In some embodiments, at least one of (i) the core, (ii) the one or more pointed structures, and (iii) a spatial relationship between / among two or more of the pointed structures is configured to prevent the entire STAR particle from penetrating the biological tissue. In some embodiments, the plurality of pointed structures comprises three pointed structures, four pointed structures, five pointed structures, six pointed structures, seven pointed structures, eight pointed structures, or ten pointed structures extending from the core.

[0111] In some embodiments, the plurality of pointed structures are coplanar. In some embodiments, the plurality of pointed structures are noncoplanar. In some embodiments, the plurality of pointed structures comprises three or more microneedles, and at least one of the three or more plurality of pointed structures is a non-planar plurality of pointed structures. In some embodiments, the core is solid. In some embodiments, the plurality of pointed structures comprises two or more pointed structures. In some embodiments, the plurality of pointed structures comprises three or more pointed structures. In some embodiments, the plurality of pointed structures comprises four or more pointed structures. In some embodiments, the plurality of pointed structures comprises an odd number of pointed structures. In some embodiments, the DB1 / 159304575.3 21plurality of pointed structures comprises an even number of pointed structures. In some embodiments, the plurality of pointed structures have the same dimensions. In some embodiments, the plurality of pointed structures comprises 1 pointed structure, 2 pointed structures, 3 pointed structures, 4 pointed structures, 5 pointed structures, 6 pointed structures, 7 pointed structures, 8 pointed structures, 9 pointed structures, or 10 pointed structures. In some embodiments, the plurality of pointed structures comprises 2 to 50 pointed structures, 2 to 100 pointed structures, 2 to 200 pointed structures, or 2 to 300 pointed structures.

[0112] In some embodiments, each of the plurality of pointed structures has a length defined as the distance from the core of the STAR particle to the tip of the pointed structure. In some embodiments, each of the plurality of pointed structures in the plurality of pointed structures has a length of about 10 μm to about 100 μm. In certain embodiments, each of the plurality of pointed structures independently has a length of about 100 μm to about 2,000 μm. In certain embodiments, each of the plurality of pointed structures independently has a length of about 100 μm to about 500 μm. In certain embodiments, each of the plurality of pointed structures independently has a length of up to 1 mm. In certain embodiments, each of the plurality of pointed structures independently has a length of up to 1.5 mm. In certain embodiments, each of the plurality of pointed structures independently has a length of up to 2 mm.

[0113] In some embodiments, the core is the interface that connects the plurality of pointed structures. In embodiments when a microneedle particle has only one microneedle, the core structure can include a non-penetrating portion of the STAR particle. Such a non-penetrating portion is provided at the base of the pointed structure (distal to the tip) and would include a laterally extending portion (lateral with respect to the longitudinal axis of the pointed structure) that is effective to function as a penetration stop. In some embodiments, the core may be shaped as a ball or a flange.

[0114] In some embodiments, the core may be a solid structure, or a hollow structure having one or more internal cavities. When the core has a hollow structure, the core may be filled with a material, which may be delivered to a biological tissue. The material, which may be a solid or liquid, may be or include a bioactive agent and / or other substance of interest.

[0115] In some embodiments, the STAR particles may be designed to impart the particles with the functionality preventing the entire STAR particle from penetrating a biological tissue. These features may include the core, the plurality of pointed structures, or the spatial relationship DB1 / 159304575.3 22between / among the plurality of pointed structures or a subset of those plurality of pointed structures.

[0116] In some embodiments, upon penetrating the biological tissue at least once, at least one of the plurality of pointed structures is configured to fail mechanically, preventing the at least one of the plurality of pointed structures from re-penetrating the biological tissue. In some embodiments, upon penetrating the biological tissue at least once, at least one of the plurality of pointed structures is configured to fail chemically, thereby preventing the at least one of the plurality of pointed structures from re-penetrating the biological tissue.

[0117] In some embodiments, the core may have a size, shape, and / or a lack of sharp edges that permits the plurality of pointed structures extending from the core to penetrate a biological tissue, but that inhibits all or substantially all of the core from penetrating into the biological tissue. In some embodiments, the plurality of pointed structures may have a structural feature, such as tapering, that permits only a portion of the plurality of pointed structures to penetrate a biological tissue. In some embodiments, a microneedle may have a shoulder or plateau that permits only the portion of the microneedle below the shoulder or plateau to penetrate the biological tissue. In some embodiments, this configuration may prevent the core structure from contacting the biological tissue. In some embodiments, two or more pointed structures may be spatially arranged with respect to one another so that as one of the pointed structures penetrates a biological tissue, the other pointed structure(s) is / are fixed in an orientation that impart(s) resistance to further penetration by the particle, preventing the entire STAR particle from penetrating the biological tissue. For example, one pointed structure may be oriented toward and into the biological tissue, while one or more other microneedles of the particle extend in a lateral orientation, so that the flat sidewall of at least one of the other pointed structures faces the biological tissue. The resistance may be provided when any part of the other pointed structure(s) contact(s) the biological tissue.

[0118] In some embodiments, the plurality of pointed structures extend from the core in a symmetrical manner. In some embodiments, the plurality of pointed structures extend from the core in an asymmetrical manner. In some embodiments, each of the plurality of pointed structures has the same dimension. In some embodiments, each of the plurality of pointed structures has substantially the same dimension. In some embodiments, each of the plurality of DB1 / 159304575.3 23pointed structures has a different dimension. For example, a STAR particle may have three pointed structures, and all three microneedles may have the same dimensions. In some embodiments, all three pointed structures may have different dimensions. In some embodiments, a subset of the three pointed structures may have the same dimensions, and those dimensions may differ from the rest of the pointed structures.

[0119] In embodiments, the plurality of pointed structures are high- aspect ratio structures having a length at least two times greater than a width. The length of a pointed structure is the distance from the core to the tip of the pointed structure. In some embodiments, each of the pointed structures independently has a length of about 1 μm to about 2,000 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 5 μm to about 2,000 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 50 μm to about 2,000 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 100 μm to about 1,000 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 250 μm to about 750 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 250 μm to about 500 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 500 μm to about 750 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 750 μm to about 1000 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1000 μm to about 1250 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1250 μm to about 1500 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1500 μm to about 1750 μm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1750 μm to about 2000 μm. In yet another embodiment, each of the plurality of pointed structures independently has a length of about 100 μm to about 500 μm. In a still further embodiment, each of the plurality of pointed structures has a length of about 500 μm.

[0120] In some embodiments, at least one dimension of the plurality of pointed structures may be tapered. For example, one or more dimensions of the plurality of pointed structures, such as the width and / or height of the one or more plurality of pointed structures may be greatest at a particular position, such as a position adjacent to the core. DB1 / 159304575.3 24

[0121] The plurality of pointed structures may have a tip having a radius of about 0.1 μm to about 30 μm. In some embodiments, the one or more pointed structures have a tip having a radius of about 0.1 μm to about 30 μm, about 0.1 μm to about 25 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 15 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 5 μm, about 1 μm to about 10 μm, about 1 μm to about 7 μm, about 1 μm to about 5 μm, about 1 μm to about 4 μm, or about 1 μm to about 3 μm. In some embodiments, each microneedle has a tip having a radius of about 0.1 μm to about 5 μm. The "tip" typically is the portion of the plurality of pointed structures that first penetrates a biological tissue.

[0122] The plurality of pointed structures may have a tip having a radius of about 0.01 mm to about 0.02 mm. In some embodiments, the one or more pointed structures have a tip having a radius of about 0.02 mm to about 0.03 mm, about 0.03 mm to about 0.04 mm, or about 0.04 mm to about 0.05 mm.

[0123] In some embodiments, the pointed structure is a size that prevents or reduces the likelihood of the STAR particle becoming completely or irremovably embedded in the biological tissue. In some embodiments, the largest dimension of the STAR particles is about 10 μm to about 2,000 μm, 100 μm to about 2,000 μm, about 250 μm to about 2,000 μm, about 500 to about 2,000 μm, or about 1,000 μm to about 2,000 µm. In some embodiments, the largest dimension of the STAR particles is about 1 mm to about 2 mm. The "largest dimension of the STAR particles" refers to the largest of the following distances: l) the distance between the tips of the two pointed structures that are the farthest apart (if the STAR particle includes two or more pointed structures), or 2) the farther possible distance between a tip of a pointed structures and the side of the core that is opposite the side from which the measured pointed structures extends.

[0124] In some embodiments, the one or more pointed structures are planar pointed structures. In some embodiments, planar pointed structures refer to two or more pointed structures, each having either a central axis that extends from the core in at least substantially the same plane, or a tip that exists in substantially the same plane. The planar pointed structures may include pointed structures that extend from the core structure in the same direction, different directions, or a combination thereof. The planar pointed structures also may include co-linear planar pointed structures, which extend from opposite sides of the core in a manner that permits the central axis of each pointed structures to at least substantially correspond with a single line. In some embodiments, the STAR particles have two planar pointed structures, three planar DB1 / 159304575.3 25pointed structures, four planar pointed structures, five planar pointed structures, six planar pointed structures, seven planar pointed structures, eight planar pointed structures, nine planar pointed structures, or ten planar pointed structures.

[0125] When the one or more pointed structures are planar pointed structures, the pointed structures may have a substantially planar or flat, structure. The substantially planar or flat,

[0126] STAR particles may have a thickness of about 1 μm to about 1,000 μm, about 5 μm to about 500 μm, about 10 μm to about 250 μm, 50 μm to about 250 μm, about 50 μm to about 200 μm, about 75 μm to about 200 μm, about 75 μm to about 150 μm, about 75 μm to about 125 μm, or about 80 μm to about 120 μm.

[0127] In some embodiments, the plurality of pointed structures include non-planar pointed structures. Non-planar pointed structures, refers to pointed structures each independently having a central axis that extends from the core in different planes. In one embodiment, the plurality of pointed structures of the STAR particle are non-planar pointed structures. In another embodiment, the plurality of pointed structures include at least two planar pointed structures, and at least one pointed structure that is non-planar relative to the pair of planar pointed structures.

[0128] In some embodiments, the STAR particles are star-shaped millimeter-scale particles made of an aluminum oxide-based ceramic, e.g., Superstrate® 996, that are intended to create transient microscopic pores across the stratum corneum.

[0129] In some embodiments, the STAR particles are made out of Superstrate 996. Table 2 shows a typical analysis by ICP (Inductively Coupled Plasma) for the Superstrate® 996 material. Alumina percentages vary from approximately 98.5% to 99.6% across batches.

[0130] Table 2. Analysis by ICP for the Superstrate 996 material Alumina SuperStrate S18-1 Al2O398.69 SiO20.705 Fe2O3 0.0310 MgO 0.329 CaO 0.124 BaO 0.0540 TiO20.0092 ZrO2 0.0034 Na2O 0.051 K2O <0.01 DB1 / 159304575.3 26MnO20.0006 B2O30.0025

[0131] Testing of the device constituent in human subject was conducted to assess STAR particle safety, tolerability, efficacy, and acceptability in human participants. Application of STAR particles was repeated on human subjects for 10 consecutive days at 80 kPa pressure during application. The Results showed that skin microporation (approximatively 0.5% of skin area stained with gentian violet staining), erythema (low-to-moderate), and comfort with self- administration (75%) were similar over the course of the study (Kim et al 2023).

[0132] Comfort of sensations associated with STAR particles increased from 58% to 71% during the study, and familiarity with STAR particles increased from 12.5% to 50% of subjects reporting STAR particle application not feeling different from other skin products. This study demonstrates that topically applied STAR particles were well tolerated and acceptable after repeated application at various pressures and repeated daily use. Manufacturing Process

[0133] Figure 20 schematically describes the manufacturing process of a formulation that contains afamelanotide and STAR particles from the device constituent part perspective. The process steps involved in the manufacturing of the device constituent part (STAR particles) are listed in Figure 25. The process steps for the manufacturing of the combination product, e.g., mixing the excipients, drug substance and STAR particles is covered in Figure 22.

[0134] The manufacturing process of the topical formulation must not damage STAR particles to such an extent that the functional behavior of penetrating the stratum corneum is impaired. This is achieved through optimization of the order of addition of the components (excipients, active substance and STAR particles) during manufacturing and through minimization of the duration and velocity of mixing to incorporate the STAR particles. Formulations

[0135] Embodiments of the present disclosure provide a pharmaceutical composition comprising a melanocortin-1 receptor (MC1R) agonist according to Formula (I) or Formula (Ia), as described herein; a plurality of micrometer or millimeter scale particles; and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition DB1 / 159304575.3 27comprises afamelanotide or a pharmaceutically acceptable salt thereof; a plurality of micrometer or millimeter scale particles; and a pharmaceutically acceptable carrier. Embodiments of the present disclosure may provide a drug / device combination product consisting of a drug constituent part (e.g., afamelanotide and excipients) and a device constituent part (e.g., STAR particles). Embodiments of the present disclosure may provide a drug / device combination product that has sufficient chemical and physical stability. Embodiments of the present disclosure may provide a drug product that does not have a device component because the STAR particles are not considered a device in some contexts.

[0136] The STAR particles must be adequately suspended throughout the life of the product to provide uniform distribution to deliver intended amount of drug to targets. This includes both storage (at various conditions) and during transportation. In some embodiments, the formulation must break down reasonably quickly and sufficiently to allow the STAR particles to be easily brushed off after application, without creating a film or limiting rate of delivery. The active ingredient is an MC1R agonist according to Formula (I) or Formula (Ia). In some embodiments, the active ingredient is afamelanotide or a pharmaceutically acceptable salt thereof, which is a synthetic, 13-amino acid peptide analogue of the endogenous alpha-melanocyte stimulating hormone (aMSH). Afamelanotide has 2 amino acid modifications as compared to aMSH to improve biological efficacy by imparting a greater affinity for its target melanocortin-1 receptor (MC1R) and a longer biological half-life. Afamelanotide achieves its primary intended purposes (treatment of vitiligo) through activation of MC1R, to trigger the synthesis of melanin in melanocytes, which leads to skin pigmentation. In some embodiments, the STAR particles (device constituent part) create, via the projections of the particles, micrometer scale openings in the stratum corneum to increase skin permeability which improves the performance of the drug constituent part when applied to the skin. In some embodiments, the formulation is a water-based gel that enables the STAR particles to be dispensed conveniently from a container. In some embodiments, the formulation exists as a gel for a sufficient amount of time for the gel to deliver the drug. The formulation must have a liquid phase for diffusion of drug through the formulation and into the skin. The liquid phase may be the liquid domain within a gel-based formulation, such as for a gel comprised of a polymer network infused with a liquid filling the spaces between polymer network molecular strands. In some embodiments, the formulation dries quickly enough to allow convenient removal of the STAR particles from the skin. DB1 / 159304575.3 28

[0137] In some embodiments, the formulation is a gel that has sufficient stability to maintain the STAR particles in suspension for significant amounts of time. This means that the viscosity of the gel is sufficient to maintain the STAR particles during storage. Further, the gel may have shear-thinning properties that do not excessively reduce viscosity at the shear levels experienced by the gel during normal transport and handling and thereby avoid sedimentation or settling of the STAR particles during shelf life. The viscosity of the gel or drug product is such that under the shear forces of application to the skin, the product is easily spread by manual application.

[0138] In some embodiments, the STAR particles may also be referred to as microparticles, micro-scale particles, milli-scale particles, or penetration devices. In some embodiments, the microparticles are micro-STAR particles, micro-diamond particles, micro-square particles or microneedles. In some embodiments, the microparticles are a penetration device or a device capable of piercing the skin based on mechanical action of rubbing the microparticles on the skin. In some embodiments, the microparticles are a sub-millimeter scale sharp device that can create pores in the skin or perforate the skin when a user rubs the microparticles of the penetration device on the skin. In some embodiments, the microparticles of the penetration device are capable of perforating the stratum corneum. In some embodiments, as a user rubs the microparticles on the skin, the microparticles tumble or move along the skin. In some embodiments, the microparticles tumble or move along the skin based on lateral and perpendicular mechanical action. This allows the penetration device to create perforations into the skin, rather than scratches along the surface of the skin. In some embodiments, the microparticles are two dimensional in shape. In some embodiments, the microparticles are three dimensional in shape. In some embodiments, the penetration device of the present disclosure allows a user to apply the formulation in small contours on the skin. In some embodiments, the penetration device of the present disclosure allows a user to apply the formulation in any area of the body with any geometry.

[0139] In some embodiments, the formulation is viscous enough to uniformly suspend the penetration device in the formulation, yet spreadable on the skin. In some embodiments, the formulation dries after it is applied onto the skin, such that the penetration device could be wiped or brushed off. In some embodiments, the formulation is a non-Newtonian fluid. In some embodiments, the formulation thins (e.g., shear thinning) as stress is applied (e.g., as the formulation is applied to the skin). DB1 / 159304575.3 29

[0140] In some embodiments, the pharmaceutical compositions described herein contain a melanocortin-1 receptor (MC1R) agonist according to Formula (I) or Formula (Ia), as described herein. In some embodiments, the MC1R agonist of Formula (I) or Formula (Ia) is present in an amount of between about 10 % w / w to about 0.15 % w / w of the total weight of the composition. In some embodiments, the MC1R agonist of Formula (I) or Formula (Ia) is present in an amount of between about 0.1 % w / w to about 0.15 % w / w, between about 0.15 % w / w to about 0.20 % w / w, between about 0.20 % w / w to about 0.25 % w / w, between about 0.25 % w / w to about 0.30 % w / w, between about 0.30 % w / w to about 0.35 % w / w, or between about 0.35 % w / w to about 0.40 % w / w of the total weight of the composition. In some embodiments, the MC1R agonist of Formula (I) or Formula (Ia) is present in an amount of between about 0 % w / w to about 1 % w / w, between about 1 % w / w to about 2 % w / w, between about 2 % w / w to about 3 % w / w, between about 3 % w / w to about 4 % w / w, or between about 4 % w / w to about 5 % w / w of the total weight of the composition.

[0141] In some embodiments, the MC1R agonist is afamelanotide or a pharmaceutically acceptable salt therof. In some embodiments, the MC1R agonist is afamelanotide acetate salt. In some embodiments, afamelanotide or pharmaceutically acceptable salt thereof is present in an amount of between about 10 % w / w to about 0.15 % w / w of the total weight of the composition. In some embodiments, afamelanotide or pharmaceutically acceptable salt thereof is present in an amount of between about 0.1 % w / w to about 0.15 % w / w, between about 0.15 % w / w to about 0.20 % w / w, between about 0.20 % w / w to about 0.25 % w / w, between about 0.25 % w / w to about 0.30 % w / w, between about 0.30 % w / w to about 0.35 % w / w, or between about 0.35 % w / w to about 0.40 % w / w of the total weight of the composition. In some embodiments, afamelanotide or pharmaceutically acceptable salt thereof is present in an amount of between about 0 % w / w to about 1 % w / w, between about 1 % w / w to about 2 % w / w, between about 2 % w / w to about 3 % w / w, between about 3 % w / w to about 4 % w / w, or between about 4 % w / w to about 5 % w / w of the total weight of the composition.

[0142] In some embodiments, the plurality of microparticles are present in an amount of between about 4.5 % w / w to about 30 % w / w of the total weight of the composition. In some embodiments, the plurality of microparticles are present in an amount of between about 4.5 % w / w to about 5 % w / w, between about 5% w / w to about 5.5 % w / w, between about 5.5 % w / w to about 6 % w / w, between about 6 % w / w to about 6.5 % w / w, between about 6.5 % w / w to about DB1 / 159304575.3 307 % w / w, between about 7 % w / w to about 7.5 % w / w, between about 7.5 % w / w to about 8 % w / w, between about 8 % w / w to about 8.5 % w / w, between about 8.5 % w / w to about 9 % w / w, between about 9 % w / w to about 9.5 % w / w, between about 9.5 % w / w to about 10 % w / w, between about 10 % w / w to about 10.5 % w / w, between about 10.5 % w / w to about 11 % w / w, between about 11 % w / w to about 11.5 % w / w, between about 11.5 % w / w to about 12 % w / w, between about 12 % w / w to about 12.5 % w / w, between about 12.5 % w / w to about 13 % w / w, between about 13 % w / w to about 13.5 % w / w, between about 13.5 % w / w to about 14 % w / w, between about 14 % w / w to about 14.5 % w / w, between about 14.5 % w / w to about 15 % w / w, between about 15% w / w to about 15.5 % w / w, between about 15.5 % w / w to about 16 % w / w, between about 16 % w / w to about 16.5 % w / w, between about 16.5 % w / w to about 17 % w / w, between about 17 % w / w to about 17.5 % w / w, between about 17.5 % w / w to about 18 % w / w, between about 18 % w / w to about 18.5 % w / w, between about 18.5 % w / w to about 19 % w / w, between about 19 % w / w to about 19.5 % w / w, or between about 19.5 % w / w to about 20 % w / w of the total weight of the composition. In some embodiments, the microparticles are present in an amount of between about 5 % w / w to about 10 % w / w, between about 10 % w / w to about 15 % w / w, between about 15 % w / w to about 20 % w / w, or between about 20 % w / w to about 25 % w / w of the total weight of the composition.

[0143] In some embodiments, the composition further comprises purified water. In some embodiments, the purified water is present in an amount of between about 40% w / w to about 100% w / w of the total weight of the composition. In some embodiments, the purified water is present in an amount of between about 40% w / w to about 45% w / w, between about 45% w / w to about 50% w / w, between about 50% w / w to about 55% w / w, between about 55% w / w to about 60% w / w, between about 60% w / w to about 65% w / w, between about 65% w / w to about 70% w / w, between about 70% w / w to about 75% w / w, between about 75% w / w to about 80% w / w, between about 80% w / w to about 85% w / w, between about 85% w / w to about 90% w / w, between about 90% w / w to about 95% w / w, or between about 95% w / w to about 100% w / w of the total weight of the composition.

[0144] In some embodiments, the composition further comprising a solvent. In some embodiments, the solvent is mineral oil, propylene carbonate, dimethyl sulfoxide (DMSO), glycerin, propylene glycol, isopropyl alcohol, or hexylene glycol. In some embodiments, the solvent is present in an amount of between about 40% w / w to about 100% w / w of the total DB1 / 159304575.3 31weight of the composition. In some embodiments, the solvent is present in an amount of between about 40% w / w to about 45% w / w, between about 45% w / w to about 50% w / w, between about 50% w / w to about 55% w / w, between about 55% w / w to about 60% w / w, between about 60% w / w to about 65% w / w, between about 65% w / w to about 70% w / w, between about 70% w / w to about 75% w / w, between about 75% w / w to about 80% w / w, between about 80% w / w to about 85% w / w, between about 85% w / w to about 90% w / w, between about 90% w / w to about 95% w / w, or between about 95% w / w to about 100% w / w of the total weight of the composition.

[0145] In some embodiments, the composition further comprises one or more gelling or thickening agents. In some embodiments, the one or more gelling agents or thickening agents are one or more of hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), Hydroxyethyl cellulose (HEC), Carboxy methyl cellulose sodium (CMC sodium), Xanthan Gum, PolyCarbophil, Carbopol 974 (Type B), Methyl cellulose, Magnesium aluminum silicate (Veegum), Sepineo 600, Carbopol 971, Carbopol 980, Carbopol 981, Carbopol 2020, or Ultrez 10. In some embodiments, the gelling or thickening agents are present in an amount of between about 0% w / w to about 15% w / w of the total weight of the composition. In some embodiments, the one or more gelling agents are present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, between about 4.0% w / w to about 4.5% w / w, between about 4.5 % w / w to about 5 % w / w, between about 5% w / w to about 5.5 % w / w, between about 5.5 % w / w to about 6 % w / w, between about 6 % w / w to about 6.5 % w / w, between about 6.5 % w / w to about 7 % w / w, between about 7 % w / w to about 7.5 % w / w, between about 7.5 % w / w to about 8 % w / w, between about 8 % w / w to about 8.5 % w / w, between about 8.5 % w / w to about 9 % w / w, between about 9 % w / w to about 9.5 % w / w, or between about 9.5 % w / w to about 10 % w / w of the total weight of the composition.

[0146] In some embodiments, the composition further comprises a viscosity modifier. In some embodiments, the viscosity modifier is Cyclomethicone, Dimethicone, Cyclomethicone dimethicone copolyol, or PEG / PPG-18 Dimethicone. In some embodiments, the viscosity modifier is present in an amount of between about 0% w / w to about 15% w / w of the total weight of the composition. In some embodiments, the viscosity modifier is present in an amount of DB1 / 159304575.3 32between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w, between about 4.5 % w / w to about 5 % w / w, between about 5% w / w to about 5.5 % w / w, between about 5.5 % w / w to about 6 % w / w, between about 6 % w / w to about 6.5 % w / w, between about 6.5 % w / w to about 7 % w / w, between about 7 % w / w to about 7.5 % w / w, between about 7.5 % w / w to about 8 % w / w, between about 8 % w / w to about 8.5 % w / w, between about 8.5 % w / w to about 9 % w / w, between about 9 % w / w to about 9.5 % w / w, between about 9.5 % w / w to about 10 % w / w, between about 10 % w / w to about 10.5 % w / w, between about 10.5 % w / w to about 11 % w / w, between about 11 % w / w to about 11.5 % w / w, or between about 11.5 % w / w to about 12 % w / w of the total weight of the composition.

[0147] In some embodiments, the composition further comprises a de-tackifier. In some embodiments, the de-tackifier is Cyclomethicone, Dimethicone, Cyclomethicone dimethicone copolyol, PEG / PPG-18 Dimethicone or silicon dioxide. In some embodiments, the de-tackifier is present in an amount of between about 0% w / w to about 15% w / w of the total weight of the composition. In some embodiments, the de-tackifier is present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w, between about 4.5 % w / w to about 5 % w / w, between about 5% w / w to about 5.5 % w / w, between about 5.5 % w / w to about 6 % w / w, between about 6 % w / w to about 6.5 % w / w, between about 6.5 % w / w to about 7 % w / w, between about 7 % w / w to about 7.5 % w / w, between about 7.5 % w / w to about 8 % w / w, between about 8 % w / w to about 8.5 % w / w, between about 8.5 % w / w to about 9 % w / w, between about 9 % w / w to about 9.5 % w / w, between about 9.5 % w / w to about 10 % w / w, between about 10 % w / w to about 10.5 % w / w, between about 10.5 % w / w to about 11 % w / w, between about 11 % w / w to about 11.5 % w / w, or between about 11.5 % w / w to about 12 % w / w of the total weight of the composition. DB1 / 159304575.3 33

[0148] In some embodiments, the pharmaceutical composition further comprises a chelating agent. In some embodiments, the chelating agent is Disodium EDTA, trisodium EDTA, Diethylenetriamine Pentaacetic Acid, Hydroxyethyl ethylenediamine triacetic acid, or Hydroxyethylidene bisphosphonic acid. In some embodiments, the chelating agent is present in an amount of between about 0% w / w to about 1% w / w of the total weight of the composition. In some embodiments, the chelating agent is present in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, or about 0.5% w / w.

[0149] In some embodiments, the pharmaceutical composition further comprises a skin penetration enhancer. A skin penetration enhancer is a chemical compound that interacts with the skin and / or the molecules whose penetration is being enhanced in such a way that more of the molecule penetrates into the skin than without the skin penetration enhancer. In some embodiments, the penetration enhancer is Diethylene glycol monoethyl ether (Transcutol), Dimethyl sulfoxide (DMSO), Oleyl alcohol, Dimethyl isosorbide (Arlasolve DMI), Propylene glycol, Isopropyl alcohol, Propylene Glycol, Isopropyl myristate, Medium Chain Triglycerides (MCT), other glycerides including mono-, di-, and mixed-glycerides or Oleic acid. In some embodiments, the skin penetration enhancer is present in an amount of between about 1% w / w to about 30% w / w of the total weight of the composition. In some embodiments, the skin penetration enhancer is present in an amount of about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, or about 25% w / w.

[0150] In some embodiments, the pharmaceutical composition further comprises one or more antioxidants. In some embodiments, the one or more antioxidants are one or more of Propyl Gallate, Methionine, Ascorbic acid, Propyl gallate, T-BHQ, EDTA disodium, BHT, Sodium Sulfite, Cysteine HCL, Monothioglycerol, Gluconolactone, L-Histidine, Butylated hydroxyanisole (BHA) or Tocopherol. In some embodiments, the antioxidant is present in an amount of between about 0% w / w to about 2% w / w of the total weight of the composition. In some embodiments, the antioxidant is present in an amount of between about 0% w / w to about 0.1% w / w, between about 0.1% w / w to about 0.2% w / w, between about 0.2% w / w to about 0.3% w / w, between about 0.3% w / w to about 0.4% w / w, between about 0.4% w / w to about 0.5% w / w, DB1 / 159304575.3 34between about 0.5% w / w to about 0.6% w / w, between about 0.6% w / w to about 0.7% w / w, between about 0.7% w / w to about 0.8% w / w, between about 0.8% w / w to about 0.9% w / w, or between about 0.9% w / w to about 1.0% w / w.

[0151] In some embodiments, the pharmaceutical composition further comprises a preservative. In some embodiments, the preservative is Benzyl alcohol, Phenoxyethanol, Benzoic acid, Sorbic acid, Methyl paraben, or Imidurea. In some embodiments, the preservative is present in an amount of between about 0% w / w to about 3 % w / w of the total weight of the composition. In some embodiments, the preservative is present in an amount of between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, or between about 2.0% w / w to about 2.5% w / w.

[0152] In some embodiments, the pharmaceutical composition further comprises a humectant. In some embodiments, the humectant is Glycerin, PEG 3350, or Cyclomethicone. In some embodiments, the humectant is present in an amount of between about 1% w / w to about 20% w / w of the total weight of the composition. In some embodiments, the humectant is present in an amount of about 2% w / w to about 3% w / w, 3% w / w to about 4% w / w, about 4% w / w to about 5% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w.

[0153] In some embodiments, the pharmaceutical composition further comprises an emollient. In some embodiments, the emollient is Isopropyl myristate, Crodamol CAP (Cetearyl ethylhexanoate and Isopropyl Myristate), Crodamol DA (Di-isopropyl adipate), Glycerin, Propylene carbonate, Propylene glycol, Isopropyl alcohol, Hexylene glycol, Hyaluronic acid, Sorbitol, Urea, Butylene glycol, Mineral Oil, white petrolatum, Medium Chain Triglycerides, Cyclomethicone, or Dimethicone. In some embodiments, the emollient is present in an amount of between about 0% w / w to about 30% w / w of the total weight of the composition. In some embodiments, the emollient is present in an amount of between about 0% w / w to about 5% w / w, between about 5% w / w to about 10% w / w, between about 10% w / w to about 15% w / w, between about 15% w / w to about 20% w / w, between about 20% w / w to about 25% w / w, or between about 25% w / w to about 30% w / w.

[0154] In some embodiments, the pharmaceutical composition further comprises an emulsifier. In some embodiments, the emulsifier is Glyceryl Monostearates, Cetyl Alcohol, DB1 / 159304575.3 35Stearyl Alcohol, Glyceryl Monostearates, Cetyl Alcohol, Stearyl Alcohol, Sorbitan monooleate (Span 80), Tween 80 (polysorbate-80), Gylceryl monotearates, Oleic acid, Sorbitane monostearate (Span 60), Polysorbate 60, Sorbitan Monopalmitate (Span 40), Polysorbate 40, Sorbitan monolaurate (Span 20), Polysorbate 20, Ceteths (2-20), Steareths (2-20), PEG stearates (2-100), Tefose-1500 (source: Gattefosse), Tefose 63 (source: Gattefosse), or Polywax (source: Croda). In some embodiments, the emulsifier is present in an amount of between about 0% w / w to about 15% w / w of the total weight of the composition. In some embodiments, the emulsifier is present in an amount of between about 0% w / w to about 1% w / w, between about 1% w / w to about 2% w / w, between about 2% w / w to about 3% w / w, between about 3% w / w to about 4% w / w, between about 4% w / w to about 5% w / w, between about 5% w / w to about 6% w / w, between about 6% w / w to about 7% w / w, between about 7% w / w to about 8% w / w, between about 8% w / w to about 9% w / w, or between about 9% w / w to about 10% w / w.

[0155] In some embodiments, the pharmaceutical composition further comprises a suspending agent. In some embodiments, the suspending agent is Xanthan Gum, Methyl cellulose, Carboxymethyl cellulose, Polycarbophil, or hydroxypropyl methylcellulose (“HPMC”). In some embodiments, the suspending agent is present in an amount of between about 0% w / w to about 5% w / w of the total weight of the composition. In some embodiments, the suspending agent is present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w, or between about 4.5 % w / w to about 5 % w / w of the total weight of the composition.

[0156] In an embodiment, the pharmaceutical composition comprises a melanocortin-1 receptor (MC1R) agonist according to Formula (I) or Formula (Ia), as described herein, in an amount of between about 0.1% w / w to about 0.4% w / w, microscale or milliscale particles in an amount of between about 10% w / w to about 11% w / w, hydroxypropyl methyl cellulose in an amount of between about 2% w / w to about 3% w / w, xanthan gum in an amount of between about 0.5% w / w to about 1% w / w, benzyl alcohol in an amount of between about 0.5% w / w to about 1% w / w, cyclomethicone in an amount of between about 3.5% w / w to about 4.5% w / w, dimethicone in an amount of between about 0.5% w / w to about 1.5% w / w, propyl gallate in an DB1 / 159304575.3 36amount of between about 0% w / w to about 0.1% w / w, disodium EDTA in an amount of between about 0% w / w to about 0.1% w / w, Transcutol-HP in an amount of between about 15% w / w to about 25% w / w, methionine in an amount of between about 0% w / w to about 0.5% w / w, and water.

[0157] In an embodiment, the pharmaceutical composition comprises afamelanotide or pharmaceutically acceptable salt thereof in an amount of between about 0.1% w / w to about 0.4% w / w, microscale or milliscale particles in an amount of between about 10% w / w to about 11% w / w, hydroxypropyl methyl cellulose in an amount of between about 2% w / w to about 3% w / w, xanthan gum in an amount of between about 0.5% w / w to about 1% w / w, benzyl alcohol in an amount of between about 0.5% w / w to about 1% w / w, cyclomethicone in an amount of between about 3.5% w / w to about 4.5% w / w, dimethicone in an amount of between about 0.5% w / w to about 1.5% w / w, propyl gallate in an amount of between about 0% w / w to about 0.1% w / w, disodium EDTA in an amount of between about 0% w / w to about 0.1% w / w, Transcutol-HP in an amount of between about 15% w / w to about 25% w / w, methionine in an amount of between about 0% w / w to about 0.5% w / w, and water.

[0158] In some embodiments, the apparent viscosity of the composition is about 100,000 cP throughout the shelf life of the composition as measured by a viscometer. In some embodiments, the viscosity of the composition is between about 20,000 cP to about 100,000 cP, between about 100,000 cP to about 200,000 cP, between about 200,000 cP to about 300,000 cP, between about 300,000 cP to about 400,000 cP, between about 500,000 cP to about 500,000 cP, between about 600,000 cP to about 700,000 cP, between about 700,000 cP to about 800,000 cP, and / or throughout the shelf life of the composition as measured by a viscometer.

[0159] In some embodiments, the composition is viscous enough to adequately suspend the micrometer-scale or millimeter-scale particles in the composition for the shelf life of the composition. In some embodiments, the particles are substantially suspended in the composition for the entire shelf life of the composition. In some embodiments, a user needs to shake the composition to re-suspend the micrometer-scale or millimeter-scale particles. In some embodiments, the particles are substantially suspended in the composition for 3 years. In some embodiments, the particles are substantially suspended in the composition for 2 years. In some embodiments, the particles are substantially suspended in the composition for at least 2 years. In some embodiments, the particles are substantially suspended in the composition for at least 3 DB1 / 159304575.3 37months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 24 months. In some embodiments, the STAR particles are adequately suspended throughout the life of the composition to provide content uniformity and deliver intended amount of drug to targets. This includes both storage (at various conditions) and during transportation.

[0160] In some embodiments, the uniformity of the penetration device is measured from container to container. In some embodiments, the uniformity of the penetration device is measured for each dispensation from the same container.

[0161] Embodiments of the present disclosure provide a method of treating a disease or condition, the method comprising applying the pharmaceutical composition as described above to a subject in need thereof. In some embodiments, the disease or condition is vitiligo. In some embodiments, the composition is used for protection while sun tanning. In some embodiments, the method further comprises rubbing the pharmaceutical compositing on the skin of the subject, causing the micrometer- scale or millimeter-scale particles to create transient microscopic pores across the stratum corneum to deliver the drug. In some embodiments, the plurality of micrometer or millimeter particles perforate the skin of the subject.

[0162] In some embodiments, the pores are transient for a period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the pores are transient for a period of about 1 day, about 2 days, about 3 days, about 4 days, or about 7 days. In some embodiments, a substantial portion of the composition is absorbed into the subject’s skin, and wherein the plurality of micrometer or millimeter scale particles do not fully penetrate into the skin the skin. In some embodiments, after the substantial portion of the composition is absorbed into the subject’s skin, the plurality of micrometer or millimeter scale particles are removable from the surface of the skin.

[0163] In some embodiments, the composition is a gel and remains in the gel state for at least 10 seconds upon manual application and then dries in not more than 5 minutes, allowing for removal of the micrometer or the millimeter scale particles. In some embodiments, the composition is a gel and remains in the gel state for at least 0.5 minutes to 1 minute upon manual DB1 / 159304575.3 38application and then dries in not more than 5 minutes to 30 minutes, allowing for removal of the micrometer or the millimeter scale particles. In some embodiments, the composition is a gel and remains in the gel state for at least 10 seconds to 1 minute upon manual application and then dries in not more than 5 minutes to 30 minutes, allowing for removal of the micrometer or the millimeter scale particles.

[0164] In some embodiments, from about 10 µg / cm2to about 100 µg / cm2of a melanocortin- 1 receptor (MC1R) agonist according to Formula (I) or Formula (Ia), as described herein, is delivered in the skin of the subject. In some embodiments, from about 100 µg / cm2to about 200 µg / cm2of MC1R agonist according to Formula (I) or Formula (Ia) is delivered in the skin of the subject. In some embodiments, from about 1 µg / cm2to about 10 µg / cm2, from about 10 µg / cm2to about 20 µg / cm2, from about 20 µg / cm2to about 30 µg / cm2, from about 30 µg / cm2to about 40 µg / cm2, from about 40 µg / cm2to about 50 µg / cm2, from about 50 µg / cm2to about 60 µg / cm2, from about 60 µg / cm2to about 70 µg / cm2, from about 70 µg / cm2to about 80 µg / cm2, from about 80 µg / cm2to about 90 µg / cm2, or from about 90 µg / cm2to about 100 µg / cm2of MC1R agonist according to Formula (I) or Formula (Ia) is delivered in the skin of the subject. In some embodiments, from about 100 µg / cm2to about 110 µg / cm2, from about 110 µg / cm2to about 120 µg / cm2, from about 120 µg / cm2to about 130 µg / cm2, from about 130 µg / cm2to about 140 µg / cm2, or from about 140 µg / cm2to about 150 µg / cm2of MC1R agonist according to Formula (I) or Formula (Ia) is delivered in the skin of the subject. In some embodiments, from about 100 µg / cm2to about 200 µg / cm2, from about 200 µg / cm2to about 300 µg / cm2, from about 300 µg / cm2to about 400 µg / cm2, or from about 400 µg / cm2to about 500 µg / cm2of MC1R agonist according to Formula (I) or Formula (Ia) is delivered in the skin of the subject.

[0165] In some embodiments, from about 10 µg / cm2to about 100 µg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 100 µg / cm2to about 200 µg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 1 µg / cm2to about 10 µg / cm2, from about 10 µg / cm2to about 20 µg / cm2, from about 20 µg / cm2to about 30 µg / cm2, from about 30 µg / cm2to about 40 µg / cm2, from about 40 µg / cm2to about 50 µg / cm2, from about 50 µg / cm2to about 60 µg / cm2, from about 60 µg / cm2to about 70 µg / cm2, from about 70 µg / cm2to about 80 µg / cm2, from about 80 µg / cm2to about 90 µg / cm2, or from about 90 µg / cm2to about 100 µg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 100 µg / cm2to about 110 µg / cm2, from about 110 DB1 / 159304575.3 39µg / cm2to about 120 µg / cm2, from about 120 µg / cm2to about 130 µg / cm2, from about 130 µg / cm2to about 140 µg / cm2, or from about 140 µg / cm2to about 150 µg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 100 µg / cm2to about 200 µg / cm2, from about 200 µg / cm2to about 300 µg / cm2, from about 300 µg / cm2to about 400 µg / cm2, or from about 400 µg / cm2to about 500 µg / cm2of afamelanotide is delivered in the skin of the subject.

[0166] In some embodiments, from about 5 mg / cm2to about 30 mg / cm2of formulation is applied on the skin of the subject. In some embodiments, from about 30 mg / cm2to about 100 mg / cm2of formulation is applied on the skin of the subject. In some embodiments, from about 1 mg / cm2to about 50 mg / cm2of formulation is applied on the skin of the subject. In some embodiments, from about 5 mg / cm2to about 10 mg / cm2, from about 10 mg / cm2to about 15 mg / cm2, from about 15 mg / cm2to about 20 mg / cm2, from about 20 mg / cm2to about 25 mg / cm2, from about 25 mg / cm2to about 30 mg / cm2, from about 30 mg / cm2to about 35 mg / cm2, from about 35 mg / cm2to about 40 mg / cm2, from about 40 mg / cm2to about 45 mg / cm2, or from about 45 mg / cm2to about 50 mg / cm2of formulation is applied on the skin of the subject. In some embodiments, from about 30 mg / cm2to about 40 mg / cm2, from about 40 mg / cm2to about 50 mg / cm2, from about 50 mg / cm2to about 60 mg / cm2, from about 60 mg / cm2to about 70 mg / cm2, from about 70 mg / cm2to about 80 mg / cm2, from about 80 mg / cm2to about 90 mg / cm2, or from about 90 mg / cm2to about 100 mg / cm2of formulation is applied on the skin of the subject.

[0167] The term “about” or “approximately” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number, which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. It should be appreciated that all numerical values and ranges disclosed herein are approximate values and ranges, whether “about” is used in conjunction therewith. It should also be appreciated that the term “about,” as used herein, in conjunction with a numeral refers to a value that may be ±0.01% (inclusive), ±0.1% (inclusive), ±0.5% (inclusive), ±1% (inclusive) of that numeral, ±2% (inclusive) of that numeral, ±3% (inclusive) of that numeral, ±5% (inclusive) of that numeral, ±10% (inclusive) of that numeral, or ±15% DB1 / 159304575.3 40(inclusive) of that numeral. It should further be appreciated that when a numerical range is disclosed herein, any numerical value falling within the range is also specifically disclosed.

[0168] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concepts thereof. It is to be understood that the embodiments and claims disclosed herein are not limited in their application to the details of construction and arrangement of the components set forth in the description and illustrated in the drawings. Rather, the description and the drawings provide examples of the embodiments envisioned. The embodiments and claims disclosed herein are further capable of other embodiments and of being practiced and carried out in various ways.

[0169] Specific features of the exemplary embodiments may or may not be part of the claimed invention and various features of the disclosed embodiments may be combined. Unless specifically set forth herein, the terms “a”, “an” and “the” are not limited to one element but instead should be read as meaning “at least one”. Finally, unless specifically set forth herein, a disclosed or claimed method should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be performed in any practical order. EXAMPLES Example 1: Overview of Development Program

[0170] In the development program, various structure-forming excipients (i.e., the materials that form the gel structure, such as entangled or cross-linked (covalently or noncovalently) polymers in a liquid matrix) were evaluated to determine the best type of formulation to have both chemical / physical stability as well as sufficient structure to adequately suspend the STAR particles uniformly while not impeding drug delivery.

[0171] Additionally, the formulation needed to be chemically as well as physically stable requiring careful selection of functional excipients and screening for effective antioxidants.

[0172] The data below demonstrates that the gel forming excipients, hydroxy propyl methyl cellulose and xanthan gum, have suitable properties to allow for stable suspension of the STAR particles and achieving even distribution throughout the product without causing damage to the STAR particles. The structure forming excipients also have acceptable rub-in properties to allow DB1 / 159304575.3 41the STAR particles to be easily brushed off after sufficient application time has lapsed to perforate the stratum corneum to allow the drug to penetrate into the living layers of the skin (epidermis and dermis).

[0173] To ensure the development of a physically and chemically stable formulation, a topical formulation development program was conducted that included but was not limited to: • Drug-excipient compatibility studies • Forced degradation studies • Drug substance-solvent solubility studies • Formulation development with informal stability using Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines • In vitro permeation tests (“IVPT”) to ensure drug is being released from the formulation and reaching desired skin compartments • Manufacturing process development / scale-up • Primary packaging compatibility assessment • Required stability studies for toxicology batches • Long-term stability studies for clinical batches

[0174] The gel forming excipients, hydroxy propyl methyl cellulose and xanthan gum, have suitable properties to allow for incorporation of the STAR particles and for achieving even distribution of the STAR particles throughout the product without causing damage to the STAR particles. The structure forming excipients also have acceptable rub-in properties to allow the STAR particles to cause perforation of the stratum corneum to facilitate the penetration of the drug into the lower layer of the skin, and then after a short period of time, the gel has acceptable properties to dry and allow the STAR particles to be easily brushed off.

[0175] The top and bottom portions of packaged drug product are evaluated by microscopy to ensure that the geometry of the STAR particles is intact after manufacturing and filling operations. Cyclomethicone and dimethicone are being used at levels that are stable and in sufficient quantity to act as viscosity-enhancing and de-tackifier agents for cellulose gel formulation. These excipients also provide the formula with some emollient characteristics to improve tolerability.

[0176] In order to stabilize the formulation against oxidative degradation, a series of antioxidants were screened for compatibility with the drug substance and effectiveness to DB1 / 159304575.3 42determine the most suitable antioxidant. Based on the results of these studies, propyl gallate and methionine were selected to protect the formulation from oxidative degradation. They are being used in the formula at a level of 0.05% w / w and 0.1% w / w respectively which is within the current Inactive Ingredient Database (“IID”) listing. This listing describes the Food and Drug Administration's (FDA's) IID and provides recommendations for how to use the IID in the development of drug products. Additionally, disodium EDTA will be added to the formulation as a chelating agent and to enhance the preservative system at a level that complies with the current IID listing for a gel.

[0177] Comparative batches of a formulation without the STAR particle were compared (using IVRT, see Figure 13) to a formulation with STAR particles to ensure that the STAR particles are not interfering with the release of the drug substance via surface adsorption of the drug substance.

[0178] IVPT in human skin have been used to evaluate various formulations and lead formulation to ensure that the formulation is capable of delivering drug in the desired skin compartment.

[0179] On Figure 15, example of lead formulations tested in IVPT are shown. The two gels (0.33% w / w (net peptide content) afamelanotide) with and without Transcutol deliver afamelanotide to the dermis resulting in at least 1000-fold increase over EC50 in vitro (0.3 nM). The gel with Transcutol delivers 3-fold more in the dermis than the similar gel without Transcutol. Manufacture Key parameters for the manufacturing process are: • Complete dissolution of the preservative, antioxidant and EDTA in the aqueous phase • Adequate mixing of the xanthan gum and hydroxy propyl methyl cellulose (HPMC) to insure hydration of the gel • Adequate mixing of the dimethicone and cyclomethicone to insure even distribution of droplets throughout the formulation • Complete dissolution of the drug substance • Adequate mixing of the STAR particles to insure even distribution of STAR particles throughout the formulation • Mixing parameters (geometry, speed) to avoid damage to STAR particles.

[0180] Fig.22 illustrates the Gel Process Flow Diagram. DB1 / 159304575.3 43

[0181] Specifications

[0182] Specifications were developed for description, identification (ID) testing, assay / degradation products, and microscopy to ensure the quality of the combination product at release and throughout the shelf life. The High-performance liquid chromatography (“HPLC”) method (identification, assay, content uniformity, related substances and degradation products) uses a Trifluoroacetic acid (“TFA”)- modified acetonitrile: water gradient on a reversed phase column with UV detection.

[0183] The gravimetric method for STAR particle content (batch content, content uniformity and container uniformity) uses repeated aqueous washing and centrifugation to separate the gel- phase (active and excipients) from the STAR particles. A final methanol wash is followed by drying and weighing to determine the net STAR particle content of the sample.

[0184] Other release and stability tests for the combination product use either compendial methods or visual (or microscopic) examination. Example 2: Preformulation studies

[0185] Solubility studies

[0186] To determine the saturation solubility of Afamelanotide in a series of excipients, solubility studies were conducted. In this study, the evaluation of solubility and selection of solvents and cosolvents was performed by visual observation. Table 5. Excipients Chosen for Solubility Screening No. Excipients Functional Category 1 Isopropyl alcohol Penetration enhancer 2 Propylene Glycol Solvent, Penetration enhancer 3 Glycerin Solvent, humectant 4 Hexylene Glycol Solvent 5 Polyethylene Glycol 400 Solvent 6 Oleyl alcohol Penetration enhancer 7 Benzyl alcohol Solvent, preservative 8 Medium chain triglycerides Penetration enhancer, solubilizer 9Polysorbate 80 / Tween 80 (Polyoxyethylenesorbitan monooleate) Surfactant10 Mineral oil Solvent 11 Purified water Solvent DB1 / 159304575.3 4412 Propylene carbonate Solvent 13 DMSO (Dimethyl sulfoxide) Solvent, Penetration enhancer 14 Isopropyl myristate Penetration enhancer, solubilizer, emollient 15 Oleic acid Penetration enhancer 16Crodamol CAP (Cetearyl ethylhexanoate andIsopropyl Myristate) Emollient17 Crodamol DA (Di-isopropyl adipate) Emollient 18 Transcutol P (Diethylene glycol monoethyl ether) Solubilizer, Penetration enhancer 19 Dimethyl Isosorbide Solubilizer 20 Dimethicone 350 Moisturizing agent 21 Cyclomethicone Solvent 22 Phenoxy ethanol Preservative 23 Span 80 (Sorbitan monooleate) Surfactant * All the above listed excipients were approved under FDA IID for Topical dosage forms -Creams, lotions, Ointments, Gels, etc. The study was performed on the excipients available on the day of study Table 6. Total solubility of Afamelanotide (API) from Visual Observations Total amount of Observation at end Observation at t APIVial#Excipient / Qty ofhe (A Wt. of excipient Excipient (g)of the day end of 24 Hours famelanotide)%w / w(g)solubilized in(g)2g excipient Cloudy white Cloudy white solution 1 Isopropyl alcohol solution with visible with visible API 0.0049 2.0236 0.24 API particles particles 2 Propylene glycol Clear solution Clear solution 0.0408 2.0077 2.03(12.0mM) 3GlycerinInsoluble APIparticles Insoluble API particles 0.0106 2.0097 0.534 Hexylene GlycolCloudy solution withCloudy solution with API particles API particles0.0052 2.0088 0.26Cloudy solution with Cloudy solu 5Polyethylenetion with Glycol 400large chunks of API large chunks of API 0.005 2.0122 0.25 particles particles 6Oleyl AlcoholCloudy solution withCloudy solution with API particles API particles0.0054 2.0135 0.277 Benzyl alcohol Clear solution Clear solution 0.0544 2.0148 2.70(16 mM) 8Medium chainCloudy solution with Cloudy solution with TriglyceridesAPI particlesAPI particles0.0053 2.0056 0.269Polysorbate 80 / Cloudy solution with Cloudy solution with Tween 80API particlesAPI particles0.0072 2.0099 0.3610 Mineral oilCloudy solution withCloudy solution with API particles API particles0.0053 2.0124 0.2611 Purified water Clear solution Clear solution 0.1512 2.0965 7.21(45 mM) 12PropyleneCloudy solution with Cloudy solution with carbonateAPI particlesAPI particles0.0054 2.0098 0.2713 DMSO Clear solution Clear solution 0.1002 2.0154 4.97(31 mM) 14IsopropylCloudy solution with Cloudy solution with myristateAPI particlesAPI particles0.0053 2.0183 0.2615 Oleic acidCloudy solution withCloudy solution with API particles API particles0.0069 2.0076 0.3416 Crodamol CAPCloudy solution withCloudy solution with API particles API particles0.006 2.0159 0.3017 Crodamol DACloudy solution withCloudy solution with API particles API particles0.0049 2.0021 0.24DB1 / 159304575.3 45Transcutol P Cloudy SolutionCloudy Solution with with API particles API particles0.0108 2.0101 0.54DimethylCloudy solution with Cloudy solution with IsosorbideAPI particlesAPI particles0.0056 2.0044 0.28

[0187] Drug Excipient Compatibility studies (DEC) (Ingredients / excipients) were evaluated during formulation development. Each excipient was combined with a stock solution of afamelanotide at 0.329 % w / w (net peptide content), stored at 25 °C and tested at 2-weeks and 4- weeks. The 4-weeks data are reported. Table 7. DEC-Round 1 (Initial evaluation of various excipients to decide dosage form) Ingredient Function / class Total impurities- as % related substances 4wk at 25 °C Water Solvent 1.2 Glycerin Solvent / humectant 2.9 PEG 3350 Ointment component 1.6 Benzyl Alcohol Preservative 0.9 HPMC Gelling agent 1.5 Xanthan Gum Gelling agent 1.3 PolyCarbophil Gelling agent 3.5 Carbopol 974 (Type B) Gelling agent 3.1 Cetyl Alcohol Co-Emulsifier / oil phase component 1.6 Stearyl Alcohol Co-Emulsifier / oil phase component 0.9 White petrolatum Ointment component 1.6 Span80 Emulsifier 0.9 Tween 80 (polysorbate-80) Emulsifier 1.8 Table 8. DEC-Round 2 (Screening of additional functional excipients) Ingredient Function / classTotal impurities-as % related substances 4wk@25°C Ascorbic acid Anti-oxidant 20.62 Propyl gallate Anti-oxidant 1.76 T-BHQ Anti-oxidant 17.60 EDTA disodium Chelating agent / Anti-oxidant 1.6 Transcutol-P Penetration enhancer 2.09 Phosphate BS 7.4 pH Buffering agent 1.65 Hydroxy ethyl cellulose Gelling agent 1.69 Cyclomethicone Viscosity-enhancing agent 1.69 Dimethicone De-tackifier 1.82 DB1 / 159304575.3 46Table 9. DEC-Round 3 (Anti-oxidant selection) Ingredient(s) Function / classTotalimpurities- as % related substances 4wk@25 °C Propyl Gallate:EDTA Anti-oxidant: chelating agent 2.0 BHT: Benzyl Alcohol: Anti-oxidant: preservative: chelating 2.2 EDTA agent Propyl Gallate: BHT: Anti-oxidant: anti-oxidant: 2.0 Benzyl Alcohol: EDTA preservative: chelating agent Sodium Sulfite: EDTA Anti-oxidant: chelating agent 61.0* Sodium Sulfite Anti-oxidant 51.3* Cysteine HCL: EDTA Anti-oxidant: chelating agent 6.9 Monothioglycerol: Anti-oxidant: chelating agent 4.4 EDTA Methionine: EDTA Anti-oxidant: chelating agent 1.8 Gluconolactone: EDTA Anti-oxidant: chelating agent 2.5 L-Histidine: EDTA Anti-oxidant: chelating agent 2.5 DMSO Penetration enhancer 2.1 *T-0 Immediately degraded Example 3: High level summary of Formulation Development

[0188] In the development program, various structure-forming excipients were evaluated to determine the best type of formulation to have both chemical / physical stability as well as sufficient structure to adequately suspend the STAR particles uniformly while not impeding drug delivery. Without wishing to be bound by any particular theory, formulations were also developed to have a pleasant application feeling, as opposed to a formulation that is greasy or tacky which is generally not desired. The formulation was also developed, without limitation, to not have an unpleasant scent. Initial DEC studies guided the selection of excipients. A summary of the early development prototype formulations follows below. The prototypes can be divided into four groups: o Prototype Cellulose / Gels o Prototype Carbopol / Gels o Prototype Creams o Additional Prototype Development

[0189] Initial Prototype Development DB1 / 159304575.3 47Table 10. Initial Cellulose Gels Prototypes Prototype Cellulose Gels % w / w Ingredient Function Gel-1 Gel-2 Gel-3 Gel-4 Gel-5 Afamelanotide Drug Substance - STAR particles Device 10.0 10.0 10.0 10.0 10.0 Water Solvent 76.5 76.3 76.15 75.5 Benzyl alcohol Preservative 1.0 1.0 1.0 1.0 1.0 Glycerin Humectant 10.0 10.0 10.0 10.0 10.0 Hydroxy propyl Gelling agent methyl cellulose 2.5 2.5 2.5 2.5 2.5 (HPMC) / Hypromellose Xanthan Gum suspending0.2 0.35 agent / stabilizerMethyl cellulose suspending1.0 agent / stabilizerCarboxymethyl suspending 1.0 celluloseagent / stabilizerTotal 100.0 100.0 100.0 100.0 100.0 Homogeno STAR STAR STAR usly particles particles particles suspended settled to settled to s STAR bottom of the bottom of the STAR uspended particles -3 sparsely jar jar (over the particles days. settled to throughout (overnight / weekend Eventually the Gel and Day-1) Day 3) Physicalbottom of settled to a layer was observationthe jar bottom of Fig.1C Fig.1D (overnight / settled to jar Day-1) bottom of the jar Fig.1E Fig.1A (overnight / illustrates Day-2) Gel-3 + Afamelanot Fig.1B ide on day- 3 DB1 / 159304575.3 48Table 11. Initial Prototype Carbopol Gels Prototype Carbopol Gels % w / w Ingredient Function Gel-6 Gel-7 Gel-7 AfamelanotideDrug Substance-0.329 (net peptidecontent)STAR particles Device 10.0 10.0 10.0 Water Solvent 76.5 76.0 75.68 Benzyl alcohol Preservative 1.0 1.0 1.0 Glycerin Humectant 10.0 10.0 10.0 Polycarbophilsuspending agent / stabilizer 1.5 2.0 2.0Carbopol 974 (Carbomer Gelling agent 1.0 1.0 1.0 homopolymer type B) Total 100.0 100.0 100.0 Physical observationHomogenouslyHomogenou Homogenously suspended sly sus cles suspende pended STAR parti d STAR (Day 6) particles (Day 6) STAR particles Fig.2A Fig.2B Fig.2C Table 12. Initial Prototype Cream formulations and later stage cream prototype with STAR particles Early Prototype Creams and later % w / w stage prototype w / STAREarly proCream-3Ingredient Function Cream-1 Cream-2 Cream-3w / STARAfamelanotide Drug Substance STAR particles Device 10.0 Purified Water Diluent 58.6 72.6 44.4 44.4 Glycerin humectant 10.0 Benzyl Alcohol preservative 1.0 1.0 1.0 Oleyl Alcohol oil 10.0 DB1 / 159304575.3 49Cetyl Alcohol oil / co-emulsifier 1.0 4.0 4.0 Stearyl Alcohol oil / co-emulsifier 1.0 4.0 4.0 Mineral Oil oil / emollient 9.0 White Petrolatum oil / emollient 18.0 26.0 26.0 Medium Chain Triglyceridesoil / emollient 10.0Glyceryl Monostearatesemulsifier 0.8Xanthan Gum suspendingagent / stabilizer1.5suspending HPMC agent / viscosity 0.1 agent Span 80 surfactant 3.5 3.5 3.5 Tween 80 surfactant 2.5 2.5 2.5 PEG 3350 humectant 0.4 4.6 4.6 Total 100.0 100.0 100.0 100.0 A thick, An off-white, white cream glossy and with no opaque lumps or cream with Milky, white A thin, white separation no separation liquid with cream with was formed. was lumps of no lumps or When observed. cetyl and separation spread, STAR stearyl Physicalwas formed. cream has a particles alcohol was observationWhen greasy were observed. spread, feeling. suspended Prototype 2 cream has a Suspending throughout was not tacky feeling. agent will be the cream stable added for prototype. Fig.3A Fig.3B suspending Fig.3D the STAR particles Fig.3C DB1 / 159304575.3 50Example 4: Summary of Short-Term Stability for Formulation Development

[0190] First round of Stability Studies: Short Term Stability-I on cellulose gel (Gel-3), Cream (Cream-3), Carbopol gel (Gel-7) with Afamelanotide 0.329% (net peptide content) and 10% (w / w) of STAR Particles. T0 T1M T2M T3M Gel-3NA 5°C, 25°C / 60% 5°C, 25°C / 60% 5°C, 25°C / 60% RH RH RH Cream-3NA 5°C, 25°C / 60%5°C, 25°C / 60% 5°C, 25°C / 60% RH RH RH Gel-7NA 5°C, 25°C / 60%5°C, 25°C / 60% 5°C, 25°C / 60% RH RH RH Table 13. High level summary of Short-Term Stability for Formulation Development Sample name Physical Stability Chemical stability Gel-3: Afamelanotide Clear gel with STAR Assay @3M Gel 0.329% (net Particles settled at the 25°C=99.8%LC peptide content) with bottom within 1M at STAR Particles HPMC all conditions and Xanthan Gum UNACCEPTABLE Impurities @3M 25°C=6.7 %LC ACCEPTABLE Cream-3: Phase separation @2M Assay @3M Afamelanotide Cream all conditions 25°C=79.9%LC 0.329% (net peptide (5C,25°C) content), STAR Particles UNACCEPTABLE Impurities @3M 25°C=4.5 %LC UNACCEPTABLE Gel-7: Afamelanotide Clear gel with STAR Assay @3M Gel 0.329% (net particles uniformly 25°C=7.2%LC peptide content), distributed STAR Particles with carbopol 1.25% ACCEPTABLE Impurities @3M 25°C=13.5 %LC UNACCEPTABLE

[0191] In conclusion, both Carbopol gel (Gel-7) and Cream (Cream-3) had physical and / or chemical stability less than that of Gel-3. DB1 / 159304575.3 51137369-5001-PR Table 14. Stability Testing Results Test Sample Name Condition Appearance Microscopy Time point API T0 Clear gel with ) STAR No birefringence T0 (Initial particles uniformly Observed in suspended matrix. Clear gel with STAR Particles No birefringence 5℃±3℃ settled at Observed in thebottom. matrix. T1M Clear gel with STAR Pa No birefringence 25C℃ / 60%RH rticles settled at Observed in thebottom. matrix. Gel 3, Afamelatonide Gel Clear gel with STAR Particles No birefringence 0.32% with Star Particles 5℃±3℃ se Observed in HPMC and Xanthan Gum ttled at thebottom. matrix. T2M Clear gel with STAR P No birefringence 25C℃ / 60%RH articles settled at Observed in thebottom. matrix. Clear gel with No birefring ±3℃ STAR P ence 5℃ articles settled at Observed in thebottom. matrix. T3M Clear gel with STAR Par No birefringence 25C℃ / 60%RH ticles settled at Observed in thebottom. matrix. No bire Initial) white-to offringence T0 ( fwhitehomogenous creamObserved in matrix. white-to offwNo birefringence 5℃±3℃ hitehomogenous creamObserved in T1M matrix. No birefringence Cream 3, Afamelatonide 25C℃ / 60%RH Ter Observed in Cream 0.32% Star matrix. ParticlesSeparaNo birefringence 5℃±3℃tion of liquidphase observedObserved in T2M matrix. Separation ofNo birefringence 25C℃ / 60%RHliquidphase observedObserved in matrix. Separation of liqNo birefringence T3M 5℃±3℃uidphase observedObserved in matrix. 52DB1 / 159304575.3SeparatiNo birefringence 25C℃ / 60%RHon of liquidphase observedObserved in matrix. Clear gel with No birefri nitial) (%Adusted Area for RS) STAR p ngence T0 (I articles uniformly Observed in distributed matrix. Clear gel with 5℃±3℃(%Adusted Area STAR particles No birefringence for RS) uniformly Observed in distributed matrix. T1M Clear gel with 25C℃ / 60%RH(%Adusted STAR particles No birefringence Area for RS) uniformly Observed in distributed matrix. Gel 7, Afamelatonide Gel Clear gel with No birefringence 0.32% Star Particles with 5℃±3℃ STAR particles Observed in carbopol 1.25% uniformly distributed matrix. T2M Clear gel with STAR particl No birefringence 25C℃ / 60%RH es uniformly Observed in distributed matrix. Clear gel with STAR par No birefringence 5℃±3℃ ticles uniformly Observed in distributed matrix. T3M Clear gel with STAR p No birefringence 25C℃ / 60%RH articles uniformly Observed in distributed matrix.

[0192] Conclusions: • T0 testing: Pure API (Afamelanotide) alone was analyzed and the recovery was 99.6% with total impurities of ~1.02%

[0193] Gel-3: Afamelanotide Gel 0.32% with STAR Particles HPMC and Xanthan Gum (cellulose): • Gel prototype with HPMC and Xanthan gum showed a recovery of 102.3% with total impurities of 1%.

[0194] Cream-3: Afamelanotide Cream 0.32% with STAR Particles: • Cream prototype had a recovery of 103.5% with total impurities of 1.9%.

[0195] Gel-7: Afamelanotide Gel 0.32% with STAR Particles and Carbopol: • Gel prototype with 1.25% of Carbopol showed a recovery of 98.3%. Assay and related substances were analyzed using different methods. % areas were reported for related substances as recoveries were very low for Related substances. Total impurities % area for Carbopol prototype was found to be 2.4%. DB1 / 159304575.3 53

[0196] T1M testing: Gel-3: Afamelanotide Gel 0.32% with STAR Particles HPMC and Xanthan Gum (cellulose): • Recoveries were 101.9% at 5°C and 96.8% at 25°C. slightly lower at 25°C. Impurities increased slightly from previous timepoint T0 for 5°C sample from 1% to 1.9% and for 25°C sample impurities increased to 3%.

[0197] Cream-3: Afamelanotide Cream 0.32% STAR Particles: • Recoveries were 102.6% at 5°C and 93.1% at 25°C. lower at 25°C. Impurities increased from previous timepoint T0 for 5°C sample from 3% to 4% and for 25C sample impurities increased to 4.6%.

[0198] Gel-7: Afamelanotide Gel 0.32% with STAR Particles and Carbopol: • Recoveries were less compared to T0, 93% at 5°C and 86% at 25°C. lower at 25°C. Impurities increased from previous timepoint T0 for 25°C sample from 2.6% to 4.6% and for 5°C sample impurities are at 1.7%.

[0199] Assay loss was observed with all formulations at T1M but only about 2% impurity increase was observed in all prototypes. From the forced degradation studies, degradation was seen with light and oxidation pathways where sufficient mass balance was not achieved. This could be a possible reason to why the assay recovery was low at T1M. Addition of antioxidant and protection from light in the formulation could help with decreasing impurity generation. For Carbopol formulation, % adjusted areas were filled out for Related substances as % recoveries were low.

[0200] T2M testing: Gel-3: Afamelanotide Gel 0.32% with STAR Particles HPMC and Xanthan Gum (cellulose): • Recoveries were 110% at 5°C and 96.2% at 25°C, slightly lower at 25°C. Repeat test of 5°C sample gave ~111% assay confirming the result. Impurities increased by ~1% at 5°C and ~2% at 25°C compared to the previous timepoint to ~3% and ~5% respectively.

[0201] Cream-3: Afamelanotide Cream 0.32% STAR Particles: • Recoveries were 100% at 5°C and 89% at 25°C, lower at 25°C. Repeat test of 25°C sample gave ~88% assay confirming the result. Impurities increased by ~1% at both conditions to ~4.5%.

[0202] Gel-7: Afamelanotide Gel 0.32% with STAR Particles and Carbopol: DB1 / 159304575.3 54• Recoveries were less compared to T1M at 25°C, 92% recovery was observed at 5°C and 82% at 25°C. Impurities increased by ~2% at 5°C and ~4% at 25°C compared to the previous timepoint to ~3.5% and ~9% respectively.

[0203] T3M testing: Gel-3: Afamelanotide Gel 0.32% with STAR Particles HPMC and Xanthan Gum (cellulose): • Assay values were variable compared to the previous timepoint. This is due to the sedimentation of STAR particles and therefore when sample is taken, there are irregular number of STAR particles in collected samples occupying variable mass. Recovery of 5°C sample was lower and 25°C was higher than previous timepoints. Repeat testing also gave variable assay values. • However, similar RS data compared to previous timepoint indicates that the product did not degrade further from previous timepoint.

[0204] Cream-3: Afamelanotide Cream 0.32% STAR Particles: • Recoveries were ~10% lower compared to previous timepoint. This may also be attributed significantly to sedimentation. Impurities increased by ~1% compared to previous timepoint at 25 °C.

[0205] Gel-7: Afamelanotide Gel 0.32% with STAR Particles and Carbopol: • No significant change in assay or RS at 5 °C compared to previous timepoint. At 25 °C, assay decreased by ~5% with similar increase in impurities showing that the product degraded significantly compared to previous timepoint. Example 5: Additional Prototype Development

[0206] Since xanthan gum was found to be compatible with the API (Afamelanotide) from the DEC study, a new prototype was made with doubled the amount compared to previous formulation in order to increase the viscosity and enhance the overall activity as a suspending agent. Glycerin was not used in these formulations due to the impurities it creates in reaction with the API. Additionally, low viscosity silicones like cyclomethicone and dimethicone were used in this prototype as a replacement for glycerin as a way to decrease the tack level of the formulation.

[0207] Additionally, a formulation with the ability to re-suspend after shaking was developed as an alternative strategy to a consistently uniform suspension. These formulations are referred to as Gel-11 and Gel-12. Approximately 5 minutes after shaking the suspension and observing dispersed STAR Particles, all particles had completely settled back to the bottom of the product. Fig.4A DB1 / 159304575.3 55shows the formulation before shaking and Fig.4B / 5D shows the formulation after shaking. Before shaking, STAR particles were settled at the bottom of the clear, colorless suspension. After shaking, STAR particles were dispersed uniformly throughout the clear, colorless suspension. Table 15. Formulation composition for Additional Prototype Development Additional Prototype Development % w / w Ingredient Function Gel-8 Gel-9 Gel-10* Gel-11 Gel-12 Afamelanotide Drug Substance STAR particles Device 10.0 10.0 10.0 10.0 10.0 Water Solvent 80.8 85.8 85.0 88.31 88.0 HPMC Gelling agent 2.5 2.5 2.5 Xanthan Gum Suspending agent 0.7 Benzyl Alcohol Preservative 1.0 1.0 1.0 1.0 1.0 Cyclomethicone Viscosity increasing agent4.0Dimethicone De-tackifier 1.0 Veegum HV Suspending agent 0.7 1.5 (Magnesium Aluminum Silicate) Hydroxy ethylSuspending agent 0.69 1.0cellulose (HEC) Total 100.0 100.0 100.0 100.0 100.0 Day 48 – After 40 minutes STAR Shaking – after shaking STAR particles STAR – Some STAR particles were particles were Particles could All STAR were suspended dispersed be seen particles suspended homogeno uniformly throughout the settled to the Physicalhomogenous usly throughout the suspension; bottom of observationly throughout clear, colorless however, most the beige, throughout the beige, suspension. STAR opaque gel. the white, opaque particles had opaque gel. Fig.5B gel. Fig.5D settled to the bottom of the Fig.5A Fig.5C formulation. Fig.5E 5 *with heating DB1 / 159304575.3 56

[0208] Second Round of Stability Studies: Short Term Stability-II on HPMC / Xanthan gum (cellulose) gel:

[0209] Since Gel 8 showed good physical stability and did not require heating for processing, it was used as the starting point for further optimization. Short Term Stability-II evaluated various antioxidants and disodium EDTA, as well as Transcutol. Table 16. Formulation composition for Short Term Stability-II %w / w Gel- Gel- Gel - Gel- Gel- Ingredient 13 14 15 1617Gel-18Afamelanotide acetate0.37* 0.37* 0.37* 0.37* 0.37STAR particles 10.45 10.45 10.45 10.45 10.45 10.45 Waterqs qs qs qs qs 87.47Xanthan Gum0.7 0.7 0.7 0.7 1Benzyl alcohol1 1 1 1 1 1Hydroxy propyl methyl cellulose (HPMC) / Hypromellose2.5 2.5 2.5 2.5 2.5HEC0.69Cyclomethicone4 4 4 4 4Dimethicone1 1 1 1 1Ascorbic acid (Vitamin C) 0.05 0.05 0.05 Propyl Gallate 0.05 T-Butyl Hydroquinone0.01 0.02Disodium EDTA0.1 0.1 0.1 0.1 0.1Transcutol-HP10Table 17. Short Term Stability-II on HPMC / XG (cellulose) gel summary Sample name Physical Stability Chemical stability Gel-13 Acceptable while on stability Unacceptable after 2W Gel-14 Acceptable while on stability Unacceptable after 2W Gel-15 Acceptable while on stability Assay @5M 25C=96.8%LC Impurities @5M 25C=3.37 %LC Gel-16 Acceptable while on stability Unacceptable after 4W Gel-17 Acceptable while on stability Unacceptable after 2W Gel-18 Not Tested Unacceptable after 4W DB1 / 159304575.3 57137369-5001-PR Table 18. Stability testing Gel-15 Sample Test Condition Appearance MicrosViscosityNameTime copy pHpoint(cP)API 5℃±3℃ API+2 w5℃±3℃ Not ApplicableWatereeks40°C / 75%RH Colorless gel with Clear matrix with Star Particles T0 (Initial) Star Particles present and no birefringence 5.25 18365.0 uniformly suspended. observed under polarized light. 5℃±3℃ T2 week 25°C / 60%RH Not Applicable 40°C / 75%RH Colorless gel with Clear matrix with Star Particles Gel 15 5℃±3℃ Star Particles present and no birefringence 5.13 21150 uniformly suspended. observed under polarized light. Colorless gel with Clear matrix with Star Particles T1M 25°C / 60%RH Star Particles present and no birefringence 5.15 18352.5 uniformly suspended. observed under polarized light. Colorless gel with Clear matrix with Star Particles 40°C / 75%RH Star Particles present and no birefringence 5.09 19107.5 uniformly suspended. observed under polarized light. Table 19. Stability testing Gel-16 Sample Test TimeCondition Appearance MicroscViscosityNameopy pHpoint(cP)Colorless gel with Star Clear matrix with Star Particles T0 (Initial) Particles uniformly present and no birefringence 5.23 16782.5 suspended. observed under polarized light. 5℃±3℃ T2 week 25°C / 60%RH Not Applicable 40°C / 75%RH Gel-16 Colorless gel with Star Clear matrix with Star Particles 5℃±3℃ Particles uniformly present and no birefringence 5.13 17002.5 suspended. observed under polarized light. T1M Colorless gel with Star Clear matrix with Star Particles 25°C / 60%RH Particles uniformly present and no birefringence 5.10 14730.0 suspended. observed under polarized light. 58DB1 / 159304575.3Beige gel with Star Clear matrix with Star Particles 40°C / 75%RH Particles uniformly present and no birefringence 4.98 11025.0 suspended. observed under polarized light.

[0210] Conclusions

[0211] T0: 1. It appears that API (Afamelanotide) alone has impurities at ~1.8%. 2. Compared to the API alone, it appears that the Gel-15 and Gel-16 prototypes have less impurities at T0 indicating that potentially Propyl gallate and TBHQ may be helping in reduction of impurities. 3. Gel-13 and Gel-14 formulations containing Ascorbic Acid appears to be causing further degradation of API and the impurities are ~0.5-1% higher in these samples compared to API alone. 4. Assay values are >95% in all formulations except Gel-16 where the assay is ~93%.

[0212] T2 week: API in Water when stored at 40 °C for 2 weeks, showed ~4.3% total impurities. At 5 °C, the impurities was ~2.1%. 1. At 5 °C, ~1% increase in impurities was observed in all formulations containing Ascorbic Acid and TBHQ. The propyl gallate formulation had ~0.7% increase in impurities. 2. At 25 °C, ~4-5% increase in impurities was observed in formulations containing Ascorbic Acid while ~1.8% increase in TBHQ and ~1.5% increase in propyl gallate formulation. 3. At 40 °C, ~6-8% increase in impurities was observed in formulations containing Ascorbic Acid and TBHQ while ~3.5% increase is observed in propyl gallate formulation. 4. No significant assay drop was observed in Propyl gallate formulation (Gel-13). 5.4% and 12% assay drop was seen respectively at 25 °C and 40 °C in Gel-13 and Gel-16 formulations. 6. Propyl gallate formulation (Gel-15) has only one significantly growing impurity compared to API alone at RRT 0.883. This was observed in DEC at ~2.7%. Remaining data is similar to pure API alone. 7. Several new impurities are observed in Ascorbic acid and TBHQ formulations specially at 40 °C.

[0213] T4 week: Gel-13 and Gel-14 formulations were discontinued based on the degradation rate. DB1 / 159304575.3 591. All assay values for Gel-15 formulation decreased by ~4% from previous timepoint to ~92%. For Gel-16, severe assay loss of ~10%, 18% and ~20% was observed at 5 °C, 25 °C, and 40 °C respectively when compared to the previous timepoint. 2. In Gel-16, Impurity profile did not grow at the same rate indicating a mass balance issue upon severe degradation. 3. The total impurities in Gel-15 formulation at 4 weeks is similar to API at 2 weeks. This indicates a potential benefit of using Propyl gallate but impurities are still growing at a steady rate. 4. The impurity at RRT 0.883 which was reported as an impurity in Gel-13 formulation was confirmed a s a placebo peak and has been removed from the total impurities. 5. Severe degradation was observed in Gel-16 formulation due to TBHQ in the formulation. The degradation is consistent with the DEC profile of TBHQ. >10% degradation was observed at 40 °C. 6. HEC gel formula also showed significant degradation due to the presence of TBHQ in the formulation at higher concentration. >10% degradation was observed a 25 °C in this formulation probably due to 2x concentration of TBHQ. Table 20. Stability testing Gel-15 Sample Batch Test CondViscosityName NumberTime ition Appearance Microscopy pH (cP)point API AFA21X1 / 1 5℃±3℃ Not Applicable Colorless gel Clear matrix with with Star Star Particles present T0 (Initial) Particles and no birefringence 5.25 18365 uniformly observed under suspended. polarized light. 5℃±3℃ T2 week 25°C / 60%RH Not tested 40°C / 75%RH Gel 15 VMA-01-1715-151Colorless gel Clear matrix with with Star Star Particles present 5℃±3℃ Particles and no birefringence 5.13 21150 uniformly observed under T1M suspended. polarized light. Colorless gel Clear matrix with with Star Star Particles present 25°C / 60%RH Particles and no birefringence 5.15 18353 uniformly observed under suspended. polarized light. DB1 / 159304575.3 60Colorless gel Clear matrix with with Star Star Particles present 40°C / 75%RH Particles and no birefringence 5.09 19108 uniformly observed under suspended. polarized light. 5℃±3℃ T2M Not tested 25°C / 60%RH Colorless gel Clear matrix with with Star Star Particles present 5℃±3℃ Particles and no birefringence5.17 19823uniformly observed under T3M suspended. polarized light. Colorless gel Clear matrix with with Star Star Particles present 25°C / 60%RH Particles and no birefringence 5.06 18000 uniformly observed under suspended. polarized light. Colorless gel Clear matrix with with Star Star Particles present 5℃±3℃ Particles and no birefringence5.12 20557.5uniformly observed under suspended. polarized light. T5M Colorless gel Clear matrix with with Star Star Particles present 25°C / 60%RH Particles and no birefringence5.08 19030.0uniformly observed under suspended. polarized light. 40°C / 75%RH NA NA NA NA

[0214] T2 Months: Gel-16 and Gel-18 formulations were discontinued based on the degradation rate. Only Gel-15 was tested. 1. Assay values for Gel-15 formulation decreased by ~5% from previous timepoint to ~87% at both 5 °C and 25 °C. 2. Impurity profile did not grow at the same rate indicating a mass balance issue upon severe degradation. 3. The total impurities in Gel-15 formulation at 2 Months is similar to T4 weeks. No further degradation observed.

[0215] T3 Months: Note: Two samples were prepared using new centrifuge method. One sample was prepared using volumetric flask procedure. 1. Assay values are consistently ~96% for all three preparations at 5°C. Impurities appear to have grown by ~0.2% and average at ~2.3% 2. Assay values are variable with centrifuge tube preparations but at ~96% with V.F. Analyst observed some matrix when cleaning the sample for collecting star particles in the preparation with 89% assay. DB1 / 159304575.3 613. Impurities appear to have increased by ~0.4% from previous timepoint to ~2.8%. 4. Impurities in pure API alone within the same sample set is ~2.3%. This indicates that 5 °C had no significant impurities in drug product compared to API and 25 °C has ~0.5% additional impurity growth compared to API.

[0216] Conclusions: Gel-15 formulation with Propyl Gallate and dimethicone / cyclomethicone is the only gel that has acceptable stability at 25 °C and 5 °C. Unacceptable at 40 °C. Example 6: Third Round of Stability Studies: Short Term Stability-II on HPMC / Xantham Gum (cellulose) Gel

[0217] Solubility studies with the Gel-15 formulation system were carried out to evaluate the success of incorporating BHT into the formulation at a level of 0.02% w / w. BHT was not able to be solubilized into the formulation. Another antioxidant of interest was Methionine. This round of short-term stability studies evaluated the following formulations. Table 21. Formulations for Short Term Stability Studies IID ient Function Limits Gel-19: Gel-20: Ingred Gel- Worst %w / w Gel-15 Gel-15+ Case 15 + Methionine + Methionine Placebo Transcutol Active Afamelanotide acetate Pharmaceutical NA 0.38* 0.38* 0.38* - Ingredient (API) STAR particles Penetration Aid NA 10.4510.45 10.45 10.45 Water Solvent NA Q.S. Q.S. Q.S. Q.S. Xanthan Gum Thickening agent 2.85 0.70 0.70 0.70 0.70 Benzyl alcohol Preservative 2 1.00 1.00 1.00 1.00 Hydroxy propyl methyl cellulose (HPMC) / Thickening agent NA 2.50 2.50 2.50 2.50 Hypromellose CyclomethiconeEmollient,humectant 11.57 4.00 4.00 4.00 4.00Dimethicone Emollient, occlusive 1.00 1.00 1.00 1.00 1.00 DB1 / 159304575.3 62Propyl Gallate Antioxidant 0.05 0.05 0.05 0.05 0.05 Methionine Antioxidant 0.15 0.10 0.10 0.10 Disodium EDTA Chelating agent 0.1 0.10 0.10 0.10 0.10 Transcutol-HP Penetration enhancer 49 20.00 20.00 * Afamelanotide acetate salt %w / w overage will be calculated and weighed according to COA at time of manufacturing and overage weight will be compensated with %w / w of water. Short term stability studies were done with Afamelanotide 2 mM gels at timepoints T0, T2 wk, T1M, T2M and T3M at 2-8℃; 25°C / 60% RH, 40°C / 75% RH. Table 22. Short Term Stability-III on HPMC / Xanthan Gum gel, with Propyl Gallate, Methionine and Transcutol summary table Sample name Physical Chemical stability Stability Gel-15 Acceptable while Assay @1M, 25 °C: 99.96%; 40 °C: 97.61% on stability Assay @2M, 5°C: 98.82%, 25°C: 100.49% Assay @3M, 5°C: 99.92%, 25°C: 98.01%, 40°C: 86.61% Gel-19 Acceptable while Assay @1M, 25 °C: 102.69%; 40 °C: 101.59% on stability Assay @2M, 5°C: 98.56%, 25°C: 99.75% Assay @3M, 5°C: 99.03%, 25°C: 100.01%, 40°C: 95.17% Gel-20 Acceptable while Assay @1M, 25 °C: 101.77%; 40 °C: 100.60% on stability Assay @2M, 5°C: 102.77%, 25°C: 100.02% Assay @3M, 5°C: 99.99%, 25°C: 98.42%, 40°C: 98.69% Assay @6M*, 5°C: 108.7%, 25°C: 95.3% Worst Case NA Placebo *new batch Gel-20 (batch size 7kg) DB1 / 159304575.3 63Table 23. Short Term Stability-III Conditions Test Star Particles CU SampleCondition Appearance MicroscoViscosityName Timepy pH (cP)Position% pointw / w TOP 10.30 Colorless gel with Uniform MIDDLE 10.05 ial) Star Par matrix T0 (Init ticles uniformly with Star Particles 5.12 19070 BOTTOM 11.53 suspended. present throughout. Average 10.63 % RSD 7.46 Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.16 20627.5 T 2 suspended. present throughout. week NA Colorless gel with 40°C / 75% Star Particles Uniform matrix RH uniformly with Star Particles 5.14 18867.5 suspended. present throughout. Colorless gel with Star Parti Uniform matrix 5±3 °C cles uniformly with Star Particles 5.13 48562.5 11.6 suspended. present throughout. T1M Colorless gel with 25°C / 60% Star Particles Uniform matrix Gel- 15 RH uniformly with Star Particles 5.13 49312.5 11.1 suspended. present throughout. 40°C / 75% RHNot TestedColorless gel with Star Parti Uniform matrix 5±3 °C cles uniformly with Star Particles 5.12 55595.0 present throughout. T 2 M suspended. Colorless gel with NA 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.11 46380.0 suspended. present throughout. Colorless gel with Uni 3 °C St form matrix 5± ar Particles uniformly with Star Particles 5.12 54130.0 10.17 suspended. present throughout. T3M Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.09 46752.5 9.52 suspended. present throughout. 40°C / 75% RHNot Tested NATOP 9.58 Colorless gel with Un MIDDLE 9.74 0 (Initial) S iform matrix T tar Particles uniformly with Star Particles 5.14 18845 BOTTOM 12.21 suspended. present throughout. Average 10.51 Gel- 19 % RSD 14.03 Colorless gel with T 2 25°C / 60% Star Particles Uniform matrix week RH uniformly with Star Particles 5.19 21147.5 NA suspended. present throughout. DB1 / 159304575.3 64Colorless gel with 40°C / 75% Star Particles Uniform matrix RH uniformly with Star Particles 5.16 20547.5 suspended. present throughout. Colorless gel with Star Particl Uniform matrix 5±3 °C es uniformly with Star Particles 5.11 52845.0 12.12 suspended. present throughout. T1M Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.13 53190.0 10.95 suspended. present throughout. 40°C / 75% RHNot TestedColorless gel with Star P Uniform matrix 5±3 °C articles uniformly with Star Particles 5.09 50845.0 suspe present throughout. T2M nded. Colorless gel with NA 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.11 50407.5 suspended. present throughout. Colorless gel with Star Particles Uniform matrix 5±3 °C uniformly with Star Particles 5.14 55942.5 9.81 suspended. present throughout. T3M Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.12 51970.0 9.91 suspended. present throughout. 40°C / 75% RHNot Tested NATOP Colorless gel with Uniform m MIDDLE 9.74 Star Par atrix T0 (Initial) ticles uniformly with Star Particles 5.46 28968 BOTTOM 11.26 suspended. present throughout. Average 10.50 % RSD 10.24 Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.51 29830 T 2 suspended. present throughout. week Colorles NA Gel- 20 s gel with 40°C / 75% Star Particles Uniform matrix RH uniformly with Star Particles 5.50 30235 suspended. present throughout. Colorless gel with Sta Uniform matrix 5±3 °C r Particles uniformly with Star Particles 5.42 75192.5 11.7 suspended. present throughout. T1M Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.48 80750.0 11.5 suspended. present throughout. 40°C / 75% RHNot TestedDB1 / 159304575.3 65Colorless gel with Star Particl Uniform matrix 5±3 °C es uniformly with Star Particles 5.46 83940.0 suspended. present throughout. T 2 M NA Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.42 76345.0 suspended. present throughout. Colorless gel with Star Parti Uniform matrix 5±3 °C cles uniformly with Star Particles 5.47 82035.0 9.96 suspended. present throughout. T3M Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.49 83910.0 9.93 suspended. present throughout. 40°C / 75% RHNot Tested NATOP 10.15 Colorless gel with Uni MIDDLE 9.70 Star form matrix T0 (Initial) Particles uniformly with Star Particles 5.64 28555 BOTTOM 12.30 suspended. present throughout. Average 10.72 % RSD 12.97 Colorless gel with 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.70 28915 T 2 suspended. present throughout. week Colorless gel with NA 40°C / 75% Star Particles Uniform matrix RH uniformly with Star Particles 5.73 29532.5 suspended. present throughout. Colorless gel with Star Particl Uniform matrix 5±3 °C es uniformly with Star Particles 5.74 74565.0 11.68 suspended. present throughout. Colorless gel with Worst 25°C / 60% Star Uniform matrix Case T1M Particles RH uniformly with Star Particles 5.70 72065.0 11.77 Placebo suspended. present throughout. Colorless gel with 40°C / 75% Star Particles Uniform matrix RH uniformly with Star Particles 5.72 72157.5 NA suspended. present throughout. Colorless gel with Star Uniform matrix 5±3 °C Particles uniformly with Star Particles 5.64 74285.0 pre M suspe sent throughout. T 2 nded. Colorless gel with NA 25°C / 60% Star Particles Uniform matrix RH uniformly with Star Particles 5.66 76502.5 suspended. present throughout. Colorless gel with Un °C St iform matrix 5±3 ar Particles uniformly with Star Particles 5.57 77347.5 9.8 suspende present throughout. T3M d. 25°C / 60% Colorless gel with Uniform matrix RH Star Particles with Star Particles 5.76 80222.5 10.2 present throughout. DB1 / 159304575.3 66uniformly suspended. Colorless gel with 40°C / 75% Star Particles Uniform matrix RH uniformly with Star Particles 5.84 74312.5 NA suspended. present throughout.

[0218] T0 Assay: The assay values for the prototypes were about 100%. The Gel-13 (original) was ~103 and the optimized prototypes were ~101%.

[0219] Impurities: The impurities were ~1.5-1.6%. similar to API materials.

[0220] STAR Particle CU: The average CU of STAR Particles were ~10.5-10.9% on average.

[0221] T=1 Month: Gel-15, Gel-19, and Gel-20 were evaluated after one month at 5°C, 25°C and 40°C storage conditions.

[0100] 1. Assay values for Gel-15, Gel-19 and Gel-20 showed minimal change at all storage conditions.

[1000] 2. The impurity profiles showed similar performance at 1 month for the 5°C and 25°C conditions, with an increase of about 2% in total impurities noted at 40°C.

[0222] T2 Months: Gel-15, Gel-19 and Gel-20 were evaluated at two months at the 5°C and 25°C conditions only.

[0223] 1. Assay values for Gel-19 and Gel-20 formulations remained within about 2% of the T0 value, while the assay value for Gel-15 appeared to decrease about 4% from the T0 value.

[0224] 2. Total impurities for the Gel-19 and Gel-20 formulations remained similar to the T0 values, although Gel-19 increased slightly, by 0.5% area. For the Gel-15 formulation, total impurities at 2 months were unchanged from T0 at 5°C, and increased by about 0.9% at 25°C versus the T0 value.

[0225] T3 Months: Gel-15, Gel-19 and Gel-20 were evaluated at all 5°C, 25°C and 40°C after three months. 1. Assay values at 5°C were consistent with the T0 values; at 25°C the Gel-15 assay appeared to have decreased by about 5%, while the Gel-19 and Gel-20 values were DB1 / 159304575.3 67within 3% of the T0 value; at 40°C the Gel-20 value was about 2% lower than T0, the Gel-19 value about 6% lower than T0, and the Gel-15 value more than 15% below T0. 2. Total impurity values at 5°C were within 0.4% of T0 for the Gel-19 and Gel-20 formulations, and showed about a slight (0.5%) increase; at 25°C the Gel-20 formulation had no apparent increase while the Gel-19 and Gel-15 formulations showed increases of about 0.6% and 2%, respectively; at 40°C the Gel-20 formulation saw an increase of about 2.4% over T0, the Gel-19 formulation saw an increase of about 6.5%, and the Gel- 15 formulation an increase of about 10.5%. Conclusions: The Gel-20 formulation, which combined Transcutol and methionine appeared to have superior chemical stability performance over the Gel-15 and Gel-19 formulations. Example 7: Summary of Non-Obvious Results and Synergies Transcutol enhances delivery while not decreasing viscosity of the HPMC / Xanthan Gum (cellulose) gel. Transcutol increases the viscosity of the blend of gelling agents. HEC and HPMC alone have an inverse relationship with Transcutol regarding the viscosity of the product.

[0226] Typically, cellulose gels loose about 10% viscosity over a period of 2 years shelf life. Given the critical role that the gel plays in uniformly suspending the STAR particles, this is a very significant property of the excipient.

[0227] In Vitro Permeation Testing (“IVPT”)

[0228] IVPT with Ex vivo human surgical abdominal skin (frozen, dermatomed) has been used to evaluate various formulations and lead formulation to ensure that the formulation is capable of delivering drug in the desired skin compartment.

[0229] In Figure 15, examples of lead formulations tested in IVPT are shown. The two gels with and without Transcutol deliver afamelanotide to the dermis resulting in at least 1000-fold increase over EC50 in vitro (0.3nM). The gel with Transcutol delivers 3-fold more in the dermis than the similar gel without Transcutol. DB1 / 159304575.3 68Example 8: Human Skin Ex Vivo Testing of The Device Constituent

[0230] In a human skin ex vivo experiment, the ex vivo skin tissue was subjected to histological analysis to identify the depth of the puncture. Quantitative measurement revealed a depth of puncture of 80 µm in average. Figure 19 is a representative picture of a puncture observed. Example 9: Nonclinical Testing

[0231] The primary pharmacology of afamelanotide was confirmed in an ex vivo human skin model in which key proteins involved in melanogenesis were induced in a concentration dependent manner.

[0232] In vitro permeation studies conducted with STAR particles administered to ex vivo human skin demonstrate that afamelanotide is successfully delivered with a gel-based formulation containing the STAR particles (see example 7-IVPT).

[0233] Data from these studies suggest that a gel that contains Afamelanotide and STAR particles has the potential for clinical benefit in vitiligo through potent agonism of the MC1R. A Gottingen minipig study was conducted to determine the dose feasibility, tolerability, and toxicokinetics of a gel with similar composition as gel-20. The study was conducted in two phases: a maximum feasible application volume phase (Phase 1, single application phase) and a 7-day fixed dose phase (Phase 2, one daily application for 7 consecutive days phase). In Phase 1, minipigs were dosed at 10, 15, 20 and 25 mg / cm2and the maximum feasible application volume was established at 20 mg / cm2.

[0234] In Phase 2, two treatment groups of minipigs (2 males / 2 females each group) and a placebo group (1 male / 1 female) received 0, 0.11, and 0.27% w / w (net peptide content) gel at 20 mg / cm2once daily over 10% BSA for 7-days. The impact of the test article on body weight, food consumption, clinical observations, Draize scores, clinical pathology (hematology, clinical chemistry, coagulation), plasma and skin toxicokinetics, macroscopic observations, organ weights, microscopic evaluation were evaluated as part of this study. Blood samples for toxicokinetics were obtained on Day 1 and Day 7 (pre-dose, 0.5, 1, 2, 4, 6, 8, 24-hour post dose administration) and analyzed using a qualified bioanalytical method with a lower limit of quantitation (LLOQ) of 0.5 ng / mL. Skin biopsies were collected on Day 1 (2 hour) and Day 7 (2 and 24 hour) for bioanalysis to determine levels in the epidermis and dermis. DB1 / 159304575.3 69

[0235] Local tolerance was assessed using a classical Draize scoring method. No significant erythema or edema were observed at the application sites.

[0236] There were no test-article related effects on any of the evaluated parameters including clinical observations, body weights, clinical pathology for the gel administered daily for 7 consecutive days. Minimal Draize scores up to Grade 2 were observed in the animals up to 2 hours post dose. Histopathology is pending.

[0237] There was no measurable test article concentrations in the plasma from animals treated with 0.11% or 0.27% Afamelanotide gel. However, at the 0.11% dose level afamelanotide was detected in the epidermis and at the higher dose of 0.27%, the mean skin concentration levels were biologically relevant in both the epidermis and the dermis (Fig.23 and 24).

[0238] Another Gottingen minipig study was conducted to determine the toxicity, tolerability and toxicokinetics of Afamelanotide in a gel with similar composition as gel-20. In this study, groups of 3 / sex Gottingen minipigs received 0 (placebo), 0.11% or 0.33% w / w (net peptide content) gel at 20 mg / cm2once daily over 5% BSA for up to 90 days equivalent to 0, 0.022 or 0.066 mg / cm2 / day, respectively.

[0239] The impact of the test article on body weight, food consumption, clinical observations, Draize scores, ophthalmology, ECGs, clinical pathology (hematology, clinical chemistry, coagulation), plasma and skin toxicokinetics, macroscopic observations, organ weights, microscopic evaluation were evaluated as part of this study. Trans epidermal water loss (TEWL) measurements were performed for each dose site using Delfin equipment to determine the change in water vapor density at the skin surface on Days 1, 42, 64, and 90. Blood samples for toxicokinetics were obtained on Day 1, 42 and 90 (pre-dose, 0.5, 1, 2, 4, 6, 8, 24-hour post dose administration) and analyzed using a qualified bioanalytical method with a lower limit of quantitation (LLOQ) of 0.5 ng / mL. Skin biopsies were collected on Day 1, 42, and 90 (2-3 hours post first dose administration) for bioanalysis to determine levels of afamelanotide concentration in the epidermis and dermis.

[0240] There were no unscheduled deaths. There were no Afamelanotide Gel-related clinical observations, Draize scores or ophthalmic findings, and no Afamelanotide Gel-related effects on body weight, food consumption, ECG and clinical pathology parameters. Scheduled necropsies were conducted and organ weights, and macroscopic and microscopic (including skin biopsies) findings were evaluated. DB1 / 159304575.3 70

[0241] No macroscopic, microscopic or organ weight changes were associated with the topical application of Afamelanotide Gel at any dose. In conclusion, Afamelanotide Gel applied dermally to Gottingen minipigs at 0.022 and 0.066 mg / cm2 / day for up to 90 days was well tolerated and resulted in no adverse findings. Based on the absence of adverse Afamelanotide Gel related findings, the no-observed-adverse-effect-level (NOAEL) was considered to be 0.066 mg / cm2 / day, the highest dose tested. Concentrations of afamelanotide were not quantifiable in all plasma samples from low (0.022 mg / cm2) and high (0.066 mg / cm2) dose groups; indicating no systemic exposure of afamelanotide above 0.500 ng / mL following once daily topical administration of Afamelanotide Gel to female and male miniature swine for 90 days. Mean epidermal afamelanotide concentrations were notably higher than dermis corroborating with higher mean % absorption in epidermis over dermis. Mean afamelanotide concentration accumulation ratios were generally higher (>2-fold) in both matrices in low and high dose levels on Days^42 and 90 compared to Day 1 at 2.5 hours post dose (Fig.25 and 26). Example 10: The Effect of Load, Viscosity, and Concentration on Microscale Particle Performance

[0242] The tests have been conducted with a Martindale machine. With this machine, the rubbed area was a square of 6 cm x 6 cm, 36 cm2, for a duration of 2 minutes (100 cycles), with up to 1 g of gel.

[0243] The parameters studied were the load (L), the viscosity of the gel (V), and the weight concentration of STAR particles in the gel (C). They were studied in the respective ranges of 328-944 g of gel (i.e.9 mg / cm2to 26 mg / cm2of gel), 16-312 Pa.s, 4%-10% w / w, following a central composite faced Design of Experiment.

[0244] The analysis of results gives the influence of each parameter, its square power, as well as the interaction between them. On the bar plot (Fig.25), the longer the bar, the more influent the term is. If the sign of the value is positive (resp. negative), the stinging of the skin has the same variation (resp. opposite variation) as the parameter.

[0245] Also, the half normal plot (Fig.26) helps determine the most relevant parameters by highlighting the most statistically significant ones which appear to deviate from the straight line. The statistically insignificant parameters are the closest to the straight line. The pressure varying DB1 / 159304575.3 71around 40kPa + / - 30kPa. These results demonstrate that the viscosity of the gel is one of the main parameters influencing the STAR particle application performance. Example 11: The Effects on cAMP

[0246] MC1R agonists having a structure of Formula (I) and Formula (Ia) are tested using human melanocyte cultures that can be derived from 1 or more different donors expressing functional MC1R. The melanocytes are plated at a given density of cells per well, and after a period of time, e.g., 48 hours, the melanocytes are treated with different concentrations of MC1R agonist for a period of time, e.g., 1 hour. A control without the MC1R agonist can be included in the experiments, and some experiments will include reference compound NDP-MSH. Reactions are stopped by addition of diluted HCl, and the supernatant in each well is collected for measuring cAMP therein using a radioimmunoassay as described by Suzuki 1996 (Suzuki I, Cone R D, Im S, Nordlund J J, Abdel-Malek Z: “Binding of melanotropic hormones to the MC1 receptor on human melanocytes stimulates proliferation and melanogenesis.” Endocrinology 137: 1627-1633, 1996). Duplicate samples from each well are assayed with multiplicate wells included in each MC1R agonist group. The mean of measurements per group is expressed as % of the control group. Statistical analysis can be carried out using ANOVA followed by Newman Kuels test. In some cases, unpaired t-test can be used. REFERENCES

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Claims

CLAIMS 1. A pharmaceutical composition comprising: a melanocortin-1 receptor (MC1R) agonist; a plurality of micrometer or millimeter scale particles; and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein the MC1R agonist is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: Ra-(CH2)m-C(O)-[Ser-Tyr-Ser]n-Nle-Glu-His-D-Phe-X-Trp-[Gly-Lys-Pro-Val]p-NH2Formula (I) wherein in Formula (I): Rais selected from -CH3and -N+R1R2R3; R1, R2, and R3 are each independently selected from -CH3, -CH2CH3, and -CH2CH2CH3; X is selected from Arg, homoArg, and norArg; m is selected from 0, 1, 2, 3, and 4; and n and p are each independently selected from 0 and 1.

3. The pharmaceutical composition of claim 2, wherein Rais -CH3when m is 0.

4. The pharmaceutical composition of claim 2, wherein Rais -N+R1R2R3.

5. The pharmaceutical composition of any one of claims 2 to 4, wherein n and p are both 0.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the MC1R agonist is a compound Formula (Ia) or a pharmaceutically acceptable salt thereof: Ra-(CH2)m-C(O)-Nle-Glu-His-D-Phe-X-Trp-NH2 Formula (Ia) wherein in Formula (Ia): Rais selected from -CH3and -N+R1R2R3; DB1 / 159304575.3 76R1, R2, and R3 are each independently selected from -CH3, -CH2CH3, and -CH2CH2CH3; X is selected from Arg, homoArg, and norArg; and m is selected from 0, 1, 2, 3, and 4, wherein Rais -CH3when m is 0.

7. The pharmaceutical composition of any one of claims 2 to 6, wherein X is Arg.

8. The pharmaceutical composition of any one of claims 2 to 6, wherein X is homoArg.

9. The pharmaceutical composition of any one of claims 2 to 6, wherein X is norArg.

10. The pharmaceutical composition of any one of claims 2, 3, and 7, wherein n and p are both 1.

11. The pharmaceutical composition of any one of claims 1-3, 7, and 10, wherein the MC1R agonist is CH3-C(O)-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of any one of claims 1-3, 7, and 10, wherein the MC1R agonist is afamelanotide or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 12, wherein the MC1R agonist is afamelanotide acetate salt.

14. The pharmaceutical composition of any one of claims 1-3, 5-6, and 8, wherein the MC1R agonist is CH3-C(O)-Nle-Glu-His-D-Phe-homoArg-Trp-NH2 or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of any one of claims 1-2 and 4-9, wherein the MC1R agonist is a compound, or pharmaceutically acceptable salt thereof, selected from: (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-Arg-Trp-NH2, (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-Arg-Trp-NH2, DB1 / 159304575.3 77(C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-homoArg-Trp-NH2, (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-homoArg-Trp-NH2, (C2H5)3N+-CH2-CO-Nle-Glu-His-D-Phe-norArg-Trp-NH2, and (CH3)3N+-(CH2)3-CO-Nle-Glu-His-D-Phe-norArg-Trp-NH2.

16. The pharmaceutical composition of any of the preceding claims, wherein the micrometer or millimeter scale-particles comprises one or more of micro-STAR particles, micro-diamond particles, micro-square particles, and / or microneedles.

17. The pharmaceutical composition of any of the preceding claims, wherein afamelanotide or pharmaceutically acceptable salt thereof is present in an amount of between about 0.1 % w / w to about 0.15 % w / w, between about 0.15 % w / w to about 0.20 % w / w, between about 0.20 % w / w to about 0.25 % w / w, between about 0.25 % w / w to about 0.30 % w / w, between about 0.30 % w / w to about 0.35 % w / w, or between about 0.35 % w / w to about 0.40 % w / w of the total weight of the composition.

18. The pharmaceutical composition of any of the preceding claims, wherein the micrometer or millimeter scale-particles are present in an amount of between about 10.0 % w / w to about 10.1 % w / w, between about 10.1 % w / w to about 10.2 % w / w, between about 10.2 % w / w to about 10.3 % w / w, between about 10.3 % w / w to about 10.4 % w / w, between about 10.4 % w / w to about 10.5 % w / w, between about 10.5 % w / w to about 10.6 % w / w, between about 10.6 % w / w to about 10.7 % w / w, between about 10.7 % w / w to about 10.8 % w / w, between about 10.8 % w / w to about 10.9 % w / w, or between about 10.9 % w / w to about 11.0 % w / w of the total weight of the composition.

19. The pharmaceutical composition of any of the preceding claims, wherein the micrometer or millimeter scale-particles are present in an amount of between about 5 % w / w to about 5.5 % w / w, between about 5.5 % w / w to about 6 % w / w, between about 6.5 % w / w to about 7 % w / w, between about 7.5 % w / w to about 8 % w / w, between about 8.5 % w / w to about 9 % w / w, between about 9.5 % w / w to about 10 % w / w, between about 10.0 % w / w to about 11.0 % w / w, between about 11.0 % w / w to about 12.0 % w / w, between about 12.0 % w / w to about 13.0 % DB1 / 159304575.3 78w / w, between about 13.0 % w / w to about 14.0 % w / w, or between about 14.0 % w / w to about 15.0 % w / w, of the total weight of the composition.

20. The pharmaceutical composition of any of the preceding claims further comprising a solvent.

21. The pharmaceutical composition of claim 20, wherein the solvent is purified water.

22. The pharmaceutical composition of claim 20 or 21, wherein the solvent is present in an amount of between about 40% w / w to about 45% w / w, between about 45% w / w to about 50% w / w, between about 50% w / w to about 55% w / w, between about 55% w / w to about 60% w / w, between about 60% w / w to about 65% w / w, between about 65% w / w to about 70% w / w, between about 70% w / w to about 75% w / w, between about 75% w / w to about 80% w / w, between about 80% w / w to about 85% w / w, between about 85% w / w to about 90% w / w, between about 90% w / w to about 95% w / w.

23. The pharmaceutical composition of claim 20, wherein the solvent comprises one or more of mineral oil, propylene carbonate, dimethyl sulfoxide (DMSO), glycerin, propylene glycol, isopropyl alcohol, and / or hexylene glycol.

24. The pharmaceutical composition of claim 23, wherein the one or several of the solvents are present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, between about 4% w / w to about 4.5% w / w, between about 4.5% w / w to about 5.0% w / w, between about 5% w / w to about 5.5% w / w, between about 5.5% w / w to about 6% w / w, between about 6% w / w to about 6.5% w / w, between about 6.5% w / w to about 7% w / w, between about 7% w / w to about 7.5% w / w, between about 7.5% w / w to about 8% w / w, between about 8% w / w to about 8.5% w / w, between about 8.5% w / w to about 9% w / w, between about 9% w / w to about 9.5% w / w, between about 9.5% w / w to about 10% w / w. DB1 / 159304575.3 7925. The pharmaceutical composition of any of the preceding claims further comprising one or more gelling agents.

26. The pharmaceutical composition of claim 25, wherein the one or more gelling, thickening agents comprise one or more of hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), Hydroxyethyl cellulose (HEC), Carboxy methyl cellulose sodium (CMC sodium), Xanthan Gum, PolyCarbophil, Carbopol 974 (Type B), Methyl cellulose, Magnesium aluminum silicate (Veegum), Sepineo 600, Carbopol 971, Carbopol 980, Carbopol 981, Carbopol 2020, or Ultrez 10.

27. The pharmaceutical composition of claim 25 or 26, wherein the one or more gelling, thickening agents are present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, between about 4.0% w / w to about 4.5% w / w, between about 4.5% w / w to about 5.0% w / w, between about 5.0% w / w to about 5.5% w / w, or between about 5.5% w / w to about 6.0% w / w.

28. The pharmaceutical composition of any of the preceding claims further comprising a viscosity modifier.

29. The pharmaceutical composition of claim 28, wherein the viscosity modifier comprises one or more of Cyclomethicone, Dimethicone, Cyclomethicone dimethicone copolyol, or PEG / PPG-18 Dimethicone.

30. The pharmaceutical composition of claim 28 or 29, wherein the viscosity modifier is present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to DB1 / 159304575.3 80about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w.

31. The pharmaceutical composition of any of the preceding claims further comprising a chelating agent.

32. The pharmaceutical composition of claim 31, wherein the chelating agent comprises one or more of Disodium EDTA, trisodium EDTA, Diethylenetriamine Pentaacetic Acid, Hydroxyethyl ethylenediamine triacetic acid, or Hydroxyethylidene bisphosphonic acid.

33. The pharmaceutical composition of claim 31 or 32, wherein the chelating agent is present in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, or about 0.5% w / w.

34. The pharmaceutical composition of any of the preceding claims further comprising a skin penetration enhancer.

35. The pharmaceutical composition of claim 34, wherein the skin penetration enhancer comprises one or more of HP, Diethylene glycol monoethyl ether (Transcutol P), Dimethyl sulfoxide (DMSO), lipid nano-particles, micelles, activated plasma, ionic layers, liposomes, Oleyl alcohol, Dimethyl isosorbide (Arlasolve DMI), Propylene glycol, Isopropyl alcohol, Propylene Glycol, Medium chain triglycerides other glycerides including mono-, di-, and mixed- glycerides, Isopropyl myristate or Oleic acid.

36. The pharmaceutical composition of claim 34 or 35, wherein the skin penetration enhancer is present in an amount of between 5% w / w and 10% w / w, between 10 and about 14%, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, or between 24 and 27%, between 27% and 30%, or between 30% and 35% w / w., between 35% and 40%. DB1 / 159304575.3 8137. The pharmaceutical composition of any of the preceding claims further comprising one or more antioxidants.

38. The pharmaceutical composition of claim 37, wherein the one or more antioxidants comprise one or more of Propyl Gallate, Methionine, Ascorbic acid, Propyl gallate, T-BHQ, EDTA disodium, BHT, Sodium Sulfite, Cysteine HCL, Monothioglycerol, Gluconolactone, L- Histidine, Butylated hydroxyanisole (BHA) or Tocopherol.

39. The pharmaceutical composition of claim 37 or 38, wherein the one or more antioxidants are present in an amount of between about 0% w / w to about 0.1% w / w, between about 0.1% w / w to about 0.2% w / w, between about 0.2% w / w to about 0.3% w / w, between about 0.3% w / w to about 0.4% w / w, between about 0.4% w / w to about 0.5% w / w, between about 0.5% w / w to about 0.6% w / w, between about 0.6% w / w to about 0.7% w / w, between about 0.7% w / w to about 0.8% w / w, between about 0.8% w / w to about 0.9% w / w, between about 0.9% w / w to about 1.0% w / w,, or between about 1.0% w / w to about 3.0% w / w.

40. The pharmaceutical composition of any of the preceding claims further comprising a preservative.

41. The pharmaceutical composition of claim 40, wherein the preservative comprises one or more of Benzyl alcohol, Phenoxyethanol, Benzoic acid, Sorbic acid, Methyl paraben, or Imidurea.

42. The pharmaceutical composition of claim 40 or 41, wherein the preservative is present in an amount of between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, or between about 2.0% w / w to about 2.5% w / w.

43. The pharmaceutical composition of any of the preceding claims further comprising a humectant. DB1 / 159304575.3 8244. The pharmaceutical composition of claim 43, wherein the humectant comprises one or more of Glycerin, PEG 3350, or Cyclomethicone.

45. The pharmaceutical composition of claim 43 or 44, wherein the humectant is present in an amount of about 0% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w.

46. The pharmaceutical composition of any of the preceding claims further comprising an emollient.

47. The pharmaceutical composition of claim 46, wherein the emollient comprises one or more of Isopropyl myristate, Crodamol CAP (Cetearyl ethylhexanoate and Isopropyl Myristate), Crodamol DA (Di-isopropyl adipate), Glycerin, Propylene carbonate, Propylene glycol, Isopropyl alcohol, Hexylene glycol, Hyaluronic acid, Sorbitol, Urea, Butylene glycol, Mineral Oil, white petrolatum, Medium Chain Triglycerides, Cyclomethicone, or Dimethicone.

48. The pharmaceutical composition of claim 46 or 47, wherein the emollient is present in an amount of between about 0% w / w to about 5% w / w, between about 5% w / w to about 10% w / w, between about 10% w / w to about 15% w / w, between about 15% w / w to about 20% w / w, between about 20% w / w to about 25% w / w, or between about 25% w / w to about 30% w / w.

49. The pharmaceutical composition of any of the preceding claims further comprising an emulsifier.

50. The pharmaceutical composition of claim 49, wherein the emulsifier comprises one or more of Glyceryl Monostearates, Cetyl Alcohol, Stearyl Alcohol, Glyceryl Monostearates, Cetyl Alcohol, Stearyl Alcohol, Sorbitan monooleate (Span 80), Tween 80 (polysorbate-80), Gylceryl monotearates, Oleic acid, Sorbitane monostearate (Span 60), Polysorbate 60, Sorbitan Monopalmitate (Span 40), Polysorbate 40, Sorbitan monolaurate (Span 20), Polysorbate 20, DB1 / 159304575.3 83Ceteths (2-20), Steareths (2-20), PEG stearates (2-100), Tefose-1500 (source: Gattefosse), Tefose 63 (source: Gattefosse), or Polywax (source: Croda).

51. The pharmaceutical composition of claim 49 or 50, wherein the emulsifier is present in an amount of between about 0% w / w to about 1% w / w, between about 1% w / w to about 2% w / w, between about 2% w / w to about 3% w / w, between about 3% w / w to about 4% w / w, between about 4% w / w to about 5% w / w, between about 5% w / w to about 6% w / w, between about 6% w / w to about 7% w / w, between about 7% w / w to about 8% w / w, between about 8% w / w to about 9% w / w, or between about 9% w / w to about 10% w / w.

52. The pharmaceutical composition of any of the preceding claims further comprising a suspending agent.

53. The pharmaceutical composition of claim 52, wherein the suspending agent comprises one or more of Xanthan Gum, Methyl cellulose, Carboxymethyl cellulose, Polycarbophil, or hydroxypropyl methylcellulose (“HPMC”).

54. The pharmaceutical composition of claim 52 or 53, wherein the suspending agent is present in an amount of between about 0% w / w to about 0.5% w / w, between about 0.5% w / w to about 1.0% w / w, between about 1.0% w / w to about 1.5% w / w, between about 1.5% w / w to about 2.0% w / w, between about 2.0% w / w to about 2.5% w / w, between about 2.5% w / w to about 3.0% w / w, between about 3.0% w / w to about 3.5% w / w, between about 3.5% w / w to about 4.0% w / w, or between about 4.0% w / w to about 4.5% w / w, or between about 4.5 % w / w to about 5 % w / w of the total weight of the composition.

55. The pharmaceutical composition of any of the preceding claims, wherein the apparent viscosity of the composition is about 20,000 cP to about 800,000 cP throughout the shelf life of the composition as measured by a viscometer. DB1 / 159304575.3 8456. The pharmaceutical composition of any of the preceding claims, wherein the micrometer or millimeter scale particles comprise a core and a plurality of pointed structures extending outwards from the core.

57. The pharmaceutical composition of claim 56, wherein each of the plurality of pointed structures has a length of about 10 μm to about 100 μm, about 100 μm to about 500 μm, or about 500 μm to about 1,000 μm.

58. The pharmaceutical composition of claim 56, wherein each of the plurality of pointed structures independently has a tip having a radius of about 0.1 μm to about 30 μm.

59. The pharmaceutical composition of claim 56, wherein the micrometer scale or millimeter scale particles have a largest dimension which is the largest of the following distances: l) the distance between the tips of the two pointed structures that are the farthest apart, or 2) the farther possible distance between a tip of a pointed structures and the side of the core that is opposite the side from which the measured pointed structures extends.

60. The pharmaceutical composition of claim 59, wherein the largest dimension is about 50 μm to about 2,000 μm.

61. The pharmaceutical composition of any of the proceeding claims, wherein the micrometer scale or millimeter scale particles are substantially suspended in the formulation for up to 3 years.

62. The pharmaceutical composition of any of the proceeding claims, wherein the pharmaceutical composition has one or more of: a. viscosity properties suitable for easily spreading the pharmaceutical composition manually, and DB1 / 159304575.3 85b. viscosity properties such that sedimentation or settling of the micrometer scale or millimeter scale particles does not occur during storage and transport.

63. A method of treating a disease or condition, the method comprising topically applying the pharmaceutical composition of any of the proceeding claims to the skin of a subject in need thereof.

64. The method of claim 63, wherein the disease or condition is vitiligo.

65. The method of claim 63 or 64, further comprising rubbing the pharmaceutical compositing on the skin of the subject, wherein the plurality of micrometer or millimeter particles tumble or move across the skin of the subject.

66. The method of any one of claims 63 to 65, wherein the plurality of micrometer or millimeter particles perforate the skin of the subject.

67. The method of any one of claims 63 to 66, further comprising rubbing the pharmaceutical compositing on the skin of the subject, wherein the plurality of micrometer or millimeter particles perforate the skin of the subject creating microscopic pores across the stratum corneum.

68. The method of claim 67, wherein the pores are transient for a period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours.

69. The method of claim 67, wherein the pores are transient for a period of about 1 day, about 2 days, about 3 days, about 4 days, or about 7 days. DB1 / 159304575.3 8670. The method of any one of claims 63 to 68, wherein a substantial portion of the composition is absorbed into the subject’s skin, and wherein the plurality of micrometer or millimeter scale particles do not fully penetrate into the skin.

71. The method of claim 70, wherein after the substantial portion of the composition is absorbed into the subject’s skin, the plurality of micrometer or millimeter scale particles are removable from the surface of the skin.

72. The method of any one of claims 63 to 71, wherein the composition is a gel and remains in the gel state for at least 0.5 minutes to 1 minute upon manual application and then dries in not more than 5 minutes to 30 minutes, allowing for removal of the micrometer or the millimeter scale particles.

73. The pharmaceutical composition of any of the proceeding claims, wherein from about 10 µg / cm2to about 100 µg / cm2or from about 100 µg / cm2to about 500 µg / cm2of afamelanotide is delivered in the skin of the subject.

74. The pharmaceutical composition of any of the proceeding claims, wherein from about 5 mg / cm2to about 30 mg / cm2or from about 30 mg / cm2to about 100 mg / cm2of formulation is applied on the skin of the subject.

75. A pharmaceutical composition of any of claims 1 to 62 for use as a medicament.

76. A pharmaceutical composition for any of claims 1 to 62 for use in the treatment of an adverse skin condition or vitiligo. DB1 / 159304575.3 87

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