Topical formulation comprising si-rna

Abstract

Aspects of the present disclosure provide a pharmaceutical composition comprising optionally a monovalent or bivalent, monospecific or bispecific siRNA, a plurality of micrometer or millimeter scale particles, and a pharmaceutical acceptable carrier.

Description

TOPICAL FORMULATION COMPRISING SI-RNACROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No.63 / 657,253 filed June 7, 2024, which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Inflammatory skin diseases are a large and heterogeneous group of skin conditions that can be chronic (long-lasting) and occur with a myriad of symptoms and signs, including erythema, papules, plaques, pustules, nodules, and alopecia. Atopic dermatitis, for example, is characterized by eczematous lesions with intense itch. Scratching may lead to further erythema, swelling, fissures, “weeping” clear fluid, crusting, and scaling. Other skin inflammatory diseases can lead to depigmentation (for example, vitiligo) with no visual sign of inflammation. Targeting the topical route to treat skin diseases is a preferred option for patients and has the advantage of decreasing systemic exposition to the drug. For this reason, superficial early-stage skin cancer and genetic skin disease favor the topical route for treatment. Large molecules like siRNA do not pass through the stratum corneum, limiting its use as a topical agent. Puncture through the stratum corneum is thus required for the delivery of siRNA. The use of particles in suspension in a formulation allows stratum corneum puncture, enabling thus a transepidermal delivery of the compounds. Yet, these particles are dense and the formulation thus needs to provide viscosity for the micrometer or millimeter scale particles (e.g. STAR particles) and stability for the drug substance.SUMMARY

[0003] Embodiments of the present disclosure provide a pharmaceutical composition comprising, optionally, a monovalent or bivalent, monospecific or bispecific siRNA, a plurality of micrometer or millimeter scale particles, and a pharmaceutical acceptable carrier. 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.

[0004] In some embodiments, the siRNA is present in an amount of between about 0.001 % w / w to about 0.01 % w / w, between about 0.01 % w / w to about 0.1 % w / w, between about 0.1 % w / w to about 1 % w / w, between about 1 % w / w to about 2% % w / w, between about 2 % 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, or between about 7 % w / w to about 8 % w / w, of the total weight of the composition.

[0005] 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 about10.4 % w / w, between about 10.4 % w / w to about 10.5 % w / w, between about 10.5 % w / w to about10.6 % w / w, between about 10.6 % w / w to about 10.7 % w / w, between about 10.7 % w / w to about10.8 % 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.

[0006] In some embodiments, the micrometer or millimeter scale-particles are present in an amount of between about 0.5 % w / w to about 1.5 % w / w, between about 1.5 % w / w to about 2.5 % w / w, between about 2.5 % w / w to about 3.5 % w / w, between about 3.5 % 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 6.5 % 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.

[0007] In some embodiments, the 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 15% w / w to about 40% w / w, 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. In some embodiments, the one or several of the solvent 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, betweenabout 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.

[0008] In some embodiments, the composition further comprises one or more gelling agents or thickening agents. In some embodiments, the one or more gelling, thickening agents comprise one or more of hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), Hydroxy ethyl 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 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% 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

[0009] In some embodiments, the composition 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.

[0010] In some embodiments, the composition 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 Hydroxy ethylidene 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.

[0011] In some embodiments, the composition 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 amount 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%.

[0012] In some embodiments, the composition 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, or 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.

[0013] In some embodiments, the composition 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.

[0014] In some embodiments, the composition 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.

[0015] In some embodiments, the composition 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, Propylenecarbonate, 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 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.

[0016] In some embodiments, the composition 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 mono laurate (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.

[0017] In some embodiments, the composition further comprises a suspending agent, and optionally an antioxidant. 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.

[0018] 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.

[0019] 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 pm to about 100 pm, about 100 pm to about500 pm, or about 500 m to about 1,000 pm. In some embodiments, each of the plurality of pointed structures has a tip having a radius of about 0.1 pm to about 30 pm. In some embodiments, the micrometer scale or millimeter scale particles have a largest dimension which is the largest of the following distances 1) 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 pm to about 1,000 pm. In some embodiments, the largest dimension is about 50 pm to about 2,000 pm.

[0020] In some embodiments, the micrometer scale or millimeter scale particles are substantially suspended in the formulation for 0 to 3 months, 3 months to 6 months, 6 months to 1 year, 1 year to 2 years, or 2 years to about 3 years when stored at 4 to 25°C.

[0100] In some embodiments, the pharmaceutical composition has one or more of viscosity properties 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.

[0021] In some embodiments, the siRNA is targeting a molecule or several molecules in a functional pathway, whether the target is a receptor, an intracellular or extracellular molecules, an enzyme, a transcription factor or a growth factors selected from the following pathways: an inflammatory pathway, a growth pathway, and / or endocrine and / or paracrine pathway, IL4 / 13 pathway, IL2 / 15 pathway, IL1 pathway, IL31 pathway, JAK / STAT pathways, IL17 pathway, IL23 pathway, TNF pathway, 0X40 pathway, TSLP pathway, retinoic pathway, INF-g pathway, IL22 pathway, IL-5 and / or 9 pathways. In some embodiments, the siRNA is a monovalent or bivalent or trivalent, monospecific or bispecific or bispecific siRNA In some embodiments, the siRNA is conjugated to a hydrophobic moiety comprising one or more of an alkyl chain, an ester linkage, an amide linkage, and / or a phosphate linkage.

[0022] 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 an inflammatory disease, skin cancer or genetic skin disease (e.g. but not restrictive to eczema, alopecia, vitiligo, psoriasis, atopic dermatitis, pyoderma gangrenosum, hidradenitis suppurativa, CTCL, EB).

[0023] In some embodiments, the method further comprises rubbing the pharmaceutical compositing on the skin of the subject, wherein the plurality of micrometer or millimeter particlestumble or move across the skin of the subject. In some embodiments, the plurality of micrometer or millimeter particles perforate the skin of the subject.

[0024] 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 up to 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.

[0025] 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. 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.

[0026] In some embodiments, the composition is a gel and remains in the gel state for at least 3 months when stored between 4°C and 25°C allowing for continuous suspension 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 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 5 mg / cm2to about 30 mg / cm2of formulation is applied on the skin of the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] 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.

[0028] Fig. 1 is an illustration showing mini-pig study dose site numbers.

[0029] Fig. 2 are bar graphs illustrating a silencing of the JAK1 target with C1-JAK1 4 days after a single application. The graph illustrate that STAR particles deliver functional siRNA to pig skin in vivo. The graphs show mRNA silencing of JAK1 siRNA following application of aformulated STAR+siRNA gel. About 3.5 mg (270 nmols) of siRNA, formulated with star particles, was rubbed for 60 seconds on a 3 x 3 cm zone for 4 days.

[0030] Figs. 3A and 3B are graphs showing the presence of the antisense strand 4 days after a single application in pig skin in vivo.

[0031] Figs. 4A and 4B illustrate STAR particle and siRNA application in ex vivo human skin. Fig. 4A show STAR particles formulated in a gel. Fig. 4B shows STAR particles applied to skin with a 40 kPa pressure.

[0032] Fig. 5 illustrates Star particle puncture depth following STAR particle application in ex vivo human skin.

[0033] Fig. 6 illustrates fluorescent siRNA diffusion into the dermis following STAR particle application in ex vivo human skin.

[0034] Fig. 7 are graphs showing the application of STAR particles formulated in the gel and applied at different pressures in human participant is well tolerated.

[0035] Fig. 8 is representative images showing single three-arm STAR particle (approximate size of 800pm from tip to tip).

[0036] Figs. 9 A, 9B and 9C show various a schematic representation of unconjugated and conjugated siRNAs. ALD102 & ALD105 contain a DCA conjugate (conjugate 1), ALD103 (seq22) & ADL106 contain a dendrimer conjugate (conjugate 2).

[0037] Fig. 10 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).

[0038] Fig. 11 is a half normal plot illustrating the statistically significance of parameters that have an effect on microscale particle performance.

[0039] Fig. 12 shows the results of different formulations tested on Gottingen minipig described in Example 12

[0040] Figs. 13A- 13D are microscopic images of various formulations. Fig. 13 A: AG44 ACT (5 mM ALD-102). Fig. 13B: AG45 ACT (5 mM ALD-102). Fig. 13C: AG46 ACT (5 mM ALD-102). Fig. 13D: AG47 ACT (5 mM ALD-102).

[0041] Figs. 14A- 14C are microscopic images of various formulations. Fig. 14A: AG48 ACT (5 mM ALD-102) . Fig. 14B: AG49 ACT (5 mM ALD-102). Fig. 14C: AG50 ACT (5 mM ALD-102).

[0042] Fig. 15 is a microscopic images of formulation AG63 ACT (5 mM ALD-102).

[0043] Figs. 16A- 16D are microscopic images of various formulations. Fig. 16A: AG65 ACT (5 mM ALD-102). Fig. 14B: AG67 ACT (5 mM AMP). Fig. 16C AG68 ACT (5 mM ALD-102).DETAILED DESCRIPTION

[0044] To deliver siRNA (e.g., and without limitation, ALD-102), 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 siRNA to enter into the living layers of the skin (e.g., to a depth of about 100 micrometer) to enable the delivery of water-soluble drugs and macromolecules that normally would not be able to enter the skin or be used for topical therapy. The micrometer or millimeter scale particles are not intended to be embedded in the skin and are to be brushed off by patient easily after application. The particles may be present in the formulation at various concentrations, e.g., and without limitation, about 10.45% w / w. Representative images of the micrometer or millimeter scale particles are presented in Fig. 8. Aspects of the present disclosure provide a pharmaceutical composition comprising siRNA (ALD-102), microparticles and a pharmaceutical acceptable carrier.STAR Particles

[0045] The micrometer or millimeter scale particles of the present invention can be, in some embodiments so-called STAR particles. To allow larger molecules to penetrate the stratum corneum and reach the 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 are denominated STAR particles. The STAR particles can be incorporated in the composition of the invention as micrometer or millimeter scale particles. By extension, STAR particles also encompass variants having various geometrical aspects, dimensions, 2D and 3D-structures and extensions (such as diamond-like, square-like or having microneedles or pointed structures).

[0046] 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.

[0047] In some embodiments, the STAR particles are structured to not become embedded in biological tissue after penetration.

[0048] 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 portions (or at least the tip end portion thereof) of the particles 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 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. In some embodiments, the micrometer or millimeter scale particles, or STAR particles, of the present invention include those disclosed in the co-pending patent applications US 63 / 689,218 and US 63 / 89,131.

[0049] 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.

[0050] 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 particles 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.

[0051] 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 someembodiments, 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 plurality 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.

[0052] In some embodiments, each of the plurality of pointed structures has a length of about 10 pm to about 100 pm. In certain embodiments, each of the plurality of pointed structures independently has a length of about 100 pm to about 2,000 pm. In certain embodiments, each of the plurality of pointed structures independently has a length of about 100 pm to about 500 pm. 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.

[0053] 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.

[0054] 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.

[0055] 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. Thesefeatures may include the core, the plurality of pointed structures, or the spatial relationship between / among the plurality of pointed structures or a subset of those plurality of pointed structures.

[0056] 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.

[0057] 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.

[0058] 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 pointed 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.

[0059] 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 pm to about 2,000 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 5 pm to about 2,000 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 50 pm to about 2,000 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 100 pm to about 1,000 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 250 pm to about 750 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 250 pm to about 500 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 500 pm to about 750 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 750 pm to about 1000 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1000 pm to about 1250 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1250 pm to about 1500 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1500 pm to about 1750 pm. In some embodiments, each of the plurality of pointed structures independently has a length of about 1750 pm to about 2000 pm. In yet another embodiment, each of the plurality of pointed structures independently has a length of about 100 pm to about 500 pm. In a still further embodiment, each of the plurality of pointed structures has a length of about 500 pm.

[0060] 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.

[0061] The plurality of pointed structures may have a tip having a radius of about 0.1 pm to about 30 pm. In some embodiments, the one or more pointed structures have a tip having a radius of about 0.1 pm to about 30 pm, about 0.1 pm to about 25 pm, about 0.1 pm to about 20 pm, about 0.1 pm to about 15 pm, about 0.1 pm to about 10 pm, about 0.1 pm to about 5 pm, about 1 pm to about 10 pm, about 1 pm to about 7 pm, about 1 pm to about 5 pm, about 1 pm to about 4 pm, or about 1 pm to about 3 pm. In some embodiments, each microneedle has a tip having a radius of about 0.1 pm to about 5 pm. The "tip" typically is the portion of the plurality of pointed structures that first penetrates a biological tissue.

[0062] 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.

[0063] 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 pm to about 2,000 pm, 100 pm to about 2,000 pm, about 250 pm to about 2,000 pm, about 500 to about 2,000 pm, or about 1,000 pm to about 2,000 pm. In some embodiments, the largest dimension of the STAR particles is about 1 mm to about 2 mm, about 2 mm to about 3 mm, 3 mm to about 4 mm, or about 4 mm to about 5 mm. The "largest dimension of the STAR particles" refers to the largest of the following distances: 1) 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.

[0064] 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 pointed 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.

[0065] 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,

[0066] STAR particles may have a thickness of about 1 pm to about 1,000 pm, about 5 pm to about 500 pm, about 10 pm to about 250 pm, 50 pm to about 250 pm, about 50 pm to about 200 pm, about 75 pm to about 200 pm, about 75 pm to about 150 pm, about 75 pm to about 125 pm, or about 80 pm to about 120 pm.

[0067] In some embodiments, the plurality of pointed structures includes 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 includes at least two planar pointed structures, and at least one pointed structure that is non-planar relative to the pair of planar pointed structures.

[0068] In some embodiments, the STAR particles are star-shaped millimeter-scale particles made of an aluminum oxide-based ceramic, e.g., Superstate® 996, that are intended to create transient microscopic pores across the stratum corneum.

[0069] In some embodiments, the STAR particles are made out of Superstate 996. Table 1 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.

[0070] Table 1. Analysis by ICP for the Superstrate 996 material

[0071] 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).

[0072] 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 studydemonstrates that topically applied STAR particles were well tolerated and acceptable after repeated application at various pressures and repeated daily use.Formulations

[0073] If the invention is generally understood and described herein as relating to a pharmaceutical composition and its use, in some embodiment the term “pharmaceutical composition” is to be understood as including medical and non medical indications, such non medical dermatological conditions and / or cosmetic use, for example for the enhancement of the skin health or aspect, In some embodiment the pharmaceutical composition of the invention is a cosmetic composition and / or the intended use is non medical and / or cosmetic. In some embodiments the cosmetic uses or purposes are cosmetic conditions or skin-health conditions linked to or due to or caused by life style factor or aging (such as. - but on restricted to wrinkles, skin volume loss or gain, skin texture changes, scares, hair loss). The cosmetic uses can be for treating or for preventing the symptoms or the skin conditions.

[0074] In some embodiment, the disease or health condition beneficially treated or prevented by the composition of the invention is an inflammatory disease, autoimmune skin disease, skin discoloration or skin cancer or, spontaneous or genetic skin disease, or an infectious disease such as but not limited to eczema, alopecia, vitiligo, psoriasis, atopic dermatitis, pyoderma gangrenosum, hidradenitis suppurativa, CTCL, EB, genodermatosis). The use of the composition of the invention can relate to the treatment or the prevention of such conditions.

[0075] Embodiments of the present disclosure provide a pharmaceutical composition comprising siRNA, microparticles and a pharmaceutical acceptable carrier. Embodiments of the present disclosure may provide a drug / device combination product consisting of a drug constituent part (e.g., siRNA 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. In some embodiments the siRNA used in the present invention is selected from any or a combination of those listed in Table 2 (Generally the Seq numbers and references in the present document are in reference to those listed in Table 2) .

[0076] siRNA is a small (approximately 21-23 nucleotides) double-stranded RNA, comprised of a passenger strand (sense strand) and an active, guide strand (antisense strand), which is complementary to the target mRNA (Alshaer et al,, siRNA: Mechanism of action, challenges, and therapeutic approaches (European Journal of Pharmacology, August, 15, 2121, 905(5): 174178).Upon internalization in the cells, the antisense strand of the siRNA is loaded into an RNA-induced silencing complex (RISC) capable of recognizing and cleaving complementary targeted mRNA, thus silencing the mRNA and aborting target protein translation. As the target specificity / selectivity is determined simply by the sequence of the antisense strand, siRNA sequences are selected among the transcriptome (full range of mRNA), representing a highly programable and specific / selective silencing-method. Unmodified siRNAs have a half-life of less than 5 minutes in circulation, without permeating intact cellular membranes. Chemical modifications are introduced at the level of the phosphate backbone, the ribose moiety or the base. Typically, these modifications are simultaneously introduced in siRNA. Overall, the precise chemical modifications of siRNAs increase their efficacy, specificity, and stability and reduce their toxicity and immunogenicity. In addition, siRNA-based drugs require addition of a conjugate to enable tissue targeting and efficient delivery.

[0077] 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.

[0078] The active ingredient, siRNA, e.g., ALD-102, is an oligonucleotide with a molecular weight of about 13,500 g / mol (as protonated form) and classified as a double-stranded small interfering RNA (siRNA). The siRNA of the present disclosure allows for the incorporation of lipid conjugation into the chemical structure of the sense strand with the aim of enhancing stability and increasing tissue-specific retention / half-life. The siRNA is intended to decrease skin inflammation and in particular decrease biomarkers and pathways linked to Th2 inflammation, allowing later reduction of symptoms.

[0079] In some embodiments the siRNA of the present invention is or comprises ALD-102 (sequence 16 of Table 2). ALD-102 drug substance is a chemically synthesized, ribonucleic acid (oligonucleotide) duplex composed of an 18-mer sense strand with a lipid conjugate (DCA, docosanoic acid [C22] with linker) linked to the 3' end, hybridized to a 21-mer antisense strand. The duplex is formed by 16 base pairs, through Watson-Crick hydrogen bonding. The various nucleotide modifications in the siRNA duplex design were developed and implemented to enhance siRNA functionality and improve other siRNA properties of ALD-102. Using a combination ofphosphorothioate and phosphodiester linkages allows for a balance between stability and functionality of the target siRNA. Introduction of alternating 2'-fluoro and 2 '-methoxy substitutions into both strands of siRNA does not block its interaction with RISC components and increases the duration of gene silencing. 5'-vinylphosphonate modification of the antisense strand was introduced to increase siRNA accumulation in tissues and to extend duration of silencing and to protect siRNAs from 5' exonucleases. To further optimize in vivo skin delivery, the hydrophobic conjugate, DCA, may be covalently linked to the sense strand of the duplex siRNA which supports local skin retention and productive delivery of ALD-102 to skin cells.

[0080] 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 for a period of time to enable 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 into the skin. In some embodiments, the formulation dries quickly enough to allow convenient removal of the STAR particles from the skin.

[0081] 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, this shear-thinning properties of the gel are sufficiently low at the shear levels experienced by the gel during normal transport and handling such that sedimentation or settling of the STAR particles does not occur 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.

[0082] 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 ormove 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.

[0083] 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 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).

[0084] In some embodiments, the siRNA is the active ingredient. In some embodiments, the siRNA is present in an amount of between about 0.1 % w / w to about 10 % w / w of the total weight of the composition. In some embodiments, the active is present in an amount of between about 0.01 % w / w to about 0.1 % w / w, 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 active 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. In some embodiments, the active is present in an amount of between 0.001 % w / w to about 0.01 % w / w, between about 0.01 % w / w to about 0.1 % w / w, between about 0.1 % w / w to about 1 % w / w, between about 1 % w / w to about 2% % w / w, between about 2 % 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, or between about 7 % w / w to about 8 % w / w of the total weight of the composition.

[0085] 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 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, 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.

[0086] 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.

[0087] 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 weight 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, betweenabout 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.

[0088] 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.

[0089] 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 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.

[0090] 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.

[0091] 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, Hydroxy ethyl ethylenediamine triacetic acid, or Hydroxy ethylidene 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.

[0092] 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 themolecule penetrates into the skin than without the skin penetration enhancer. In some embodiments, the skin 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.

[0093] 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, 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, or between about 0.9% w / w to about 1.0% w / w.

[0094] 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.

[0095] 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 / wof 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.

[0096] 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.

[0097] In some embodiments, the pharmaceutical composition further comprises an emulsifier. In some embodiments, the emulsifier is 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 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.

[0098] 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 inan 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.

[0099] In an embodiment, the pharmaceutical composition comprises siRNA in an amount of between about 0.001% w / w to about 8% 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, and water. In an embodiment, the pharmaceutical composition comprises siRNA in an amount of between about 0.1% w / w to about 5% w / w, micrometer scale or millmeter scale particles in an amount of between about 5% w / w to about 15% 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, and water.

[0100] 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 about100,000 cP to about 200,000 cP, between about 200,000 cP to about 300,000 cP, between about300,000 cP to about 400,000 cP, between about 500,000 cP to about 500,000 cP, between about600,000 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.

[0101] 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, theparticles 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 months, 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.

[0102] 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.

[0103] 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 an inflammatory skin disease. 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.

[0104] 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.

[0105] 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 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, the composition is a gel and remains in the gel state for atleast 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.

[0106] In some embodiments, from about 10 pg / cm2to about 100 pg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 100 pg / cm2to about 200 pg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 1 pg / cm2to about 10 pg / cm2, from about 10 pg / cm2to about 20 pg / cm2, from about 20 pg / cm2to about 30 pg / cm2, from about 30 pg / cm2to about 40 pg / cm2, from about 40 pg / cm2to about 50 pg / cm2, from about 50 pg / cm2to about 60 pg / cm2, from about 60 pg / cm2to about 70 pg / cm2, from about 70 pg / cm2to about 80 pg / cm2, from about 80 pg / cm2to about 90 pg / cm2, or from about 90 pg / cm2to about 100 pg / cm2of afamelanotide is delivered in the skin of the subject. In some embodiments, from about 100 pg / cm2to about 110 pg / cm2, from about 110 pg / cm2to about 120 pg / cm2, from about 120 pg / cm2to about 130 pg / cm2, from about 130 pg / cm2to about 140 pg / cm2, or from about 140 pg / cm2to about 150 pg / cm2of afamelanotide is delivered in the skin of the subject.

[0107] 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 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.

[0108] It is believed that the efficacy of the composition of the invention depends on many factors that all should play synergistically to induce the desired effect: The shape, size , geometry of the micrometer or millimeter size particles (or STAR particles), the polarity, density, viscosity, sequence of the siRNA, their suspension into the composition, their stability, the presence of an emollient or carrier are among the factors impacting the efficacy of the composition A proper balance between these factors have been studied and have led to the present invention.Table 2. siRNA Sequences

[0109] In embodiments, the siRNA comprises or has a nucleic acid sequence of any one of SEQ ID NO. 1 to SEQ ID NO. 27. In embodiments, the siRNA comprises or has a nucleic acid sequence having at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% sequence identity of any one of SEQ ID NO: 1 to SEQ ID NO: 27.

[0110] As used herein, “sequence identity” refers to the relatedness between or among polypeptides among nucleic acid molecules. Sequence identity can be assessed by aligning two sequences and counting the number of differences between the aligned portion and the sequence to which it is compared. Whether any two molecules have nucleotide sequences or amino acid sequences that are at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% “identical” or“homologous” can be determined using known computer algorithms such as the “FASTA” program, using for example, the default parameters as in Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA (Altschul, S. F., et al., J Mol Biol 215:403 (1990)); Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carrillo et al. (1988) SIAM J Applied Math 48: 1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include, DNAStar “MegAlign” program (Madison, WI) and the University of Wisconsin Genetics Computer Group (UWG) “Gap” program (Madison WI). Percent homology or identity of proteins and / or nucleic acid molecules can be determined, for example, by comparing sequence information using a GAP computer program (e.g., Needleman et al. (1970) J. Mol. Biol. 48:443, as revised by Smith and Waterman ((1981) Adv. Appl. Math. 2:482). Briefly, the GAP program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids), which are similar, divided by the total number of symbols in the shorter of the two sequences. Default parameters for the GAP program can include: (1) a unary comparison matrix (containing a value of 1 for identities and 0 for non identities) and the weighted comparison matrix of Gribskov et al. (1986) Nucl. Acids Res. 14:6745, as described by Schwartz and Dayhoff, eds., ATLAS OF PROTEIN SEQUENCE AND STRUCTURE, National Biomedical Research Foundation, pp. 353 358 (1979); (2) a penalty of 3.0 for each gap and an additional 0.10 penalty for each symbol in each gap; and (3) no penalty for end gaps.

[0111] Therefore, as used herein, the term “identity” or “homology” represents a comparison between a test and a reference polypeptide or polynucleotide.

[0112] As used herein, the term at least “90% identical to” refers to percent identities from 90 to 99.99 relative to the reference nucleic acid or amino acid sequence of the polypeptide. Identity at a level of 90% or more is indicative of the fact that, assuming for exemplification purposes a test and reference polypeptide length of 100 amino acids are compared. No more than 10% (i.e., 10 out of 100) of the amino acids in the test polypeptide differs from that of the reference polypeptide. Similar comparisons can be made between test and reference polynucleotides. Such differences can be represented as point mutations randomly distributed over the entire length of a polypeptide or they can be clustered in one or more locations of varying length up to the maximum allowable, e.g., 10 / 100 amino acid difference (approximately 90% identity). Differences are defined as nucleic acid or amino acid substitutions, insertions or deletions. At the level of homologies or identities aboveabout 85-90%, the result should be independent of the program and gap parameters set; such high levels of identity can be assessed readily, often by manual alignment without relying on software.

[0113] 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% (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.

[0114] 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. 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.EXAMPLESExample 1: Preparation of 12 grams of Star Particle Gel containing siRNAs ALD105, ALD106

[0115] Table 3. Star Particle Gel containing siRNAs

[0116] Weigh and add benzyl alcohol and purified water to a clean glass beaker. Mix until homogenous and clear.

[0117] Split Step 1 contents into two separate beakers. In one beaker, weigh and add the required amount of xanthan gum. Mix until hydrated with no lumps. In the other beaker containing benzyl alcohol and water, weigh and add the required amount of HPMC. Mix until hydrated with no lumps.

[0118] Add xanthan gum gel to the HPMC gel and mix until a homogenous gel phase is observed.

[0119] Weigh and add Cyclomethicone and dimethicone to gel phase and mix for 5-10 minutes.

[0120] Weigh and add STAR Particles. Mix until uniformly dispersed throughout the gel.

[0121] Weigh 4 gram of gel formulation.

[0122] Weigh 76.7 mg of ALD-105 (seq 26 of table 2) and resuspend in 1.0 mL of sterile water.

[0123] After ensuring that the ALD-105 is completely dissolved, add ~4.0g of gel formulation obtained from Step #5 into the ALD-105 solution from Step #7.

[0124] Mix the sample for minimum 15 minutes to ensure proper mixing of the sample to obtain 5g formulation.

[0125] Example 2: Single dose ALD105 / ALD106 (seq22 of table 2) Star particles Gel PK / PD in Gottingen minipigTable 4. Describes doses and application sites (see Fig 1A) :Dose LevelaD°seDose DoseGroup Test Material . Cone. Amount” Dose Site # ,, . RouteN / A N / A N / A Sham Site #1(Untreated Skin)AED-105A +STAR Particle 3.43 15.3 225 1 through 5 TopicalGelAED-106A + STAR Particle 3.89 17.3 225 6 through 10Gel1 n ia Dose DoseDose Level . , , DoseTest Material Cone. Volume Dose Site # ,( / t ) RouteCone. = Concentration; M = Male; N / A = Not applicable a Dose level corresponds to ALD-105A or ALD-106A (mg of Test Article) per site.bDoe amount corresponds to ALD-105A or ALD-106A + STAR particle gel (mg of total gel formulation) per site.

[0126] Dose sites will be clipped and cleaned with appropriate antiseptic at least 30 minutes prior to the first dose.

[0127] Topical dose administration is performed following predose transepidermal water loss (TEWL) measurements. Transepidermal dose formulations is administered to each demarcated area by topical application once on Dosing Phase Day 1.

[0128] ALD-105A is topically applied to Dose Sites #1 through #5 and ALD-106A is topically applied to Dose Sites #6 through #10. The chemical structures are schematized in Figs. 9A- 9C. Uniform application of transepidermal formulations s conducted using a gloved hand and two fingers. The dose amount is rubbed with strong force / pressure into each respective dose site using a clockwise motion for 15 seconds, STAR particles are re-grouped into the center of each respective dose site, then test material will be rubbed into each respective dose site using a counterclockwisemotion for 15 seconds. This procedure is repeated once (i.e., for a total of 60 seconds per dose site such that each 3 x 15 cm zone has a uniform application of test material). Note that overlap between sites for the same test article (i.e., overlap of Dose Sites #1 through #5 or Dose Sites #6 through #10) is allowed. Lateral and / or diagonal motion may be used to facilitate dose administration, if necessary.

[0129] Untreated zone for GV staining baseline comparison is designated as Sham Site #1 (or Control Site #1).

[0130] Intradermal dose administration will be performed following completion of GV staining, and associated photography. Intradermal dose formulations will be administered to each demarcated area by intradermal (ID) injection with a syringe once on Dosing Phase Day 1.

[0131] Placebo is intradermally injected to Dose Sites #11 through #16. ADD- 105 A will be intradermally injected to Dose Sites #17 through #20 and ALD-106A is intradermally injected to Dose Sites #21 through #24. The syringe needle is inserted into the animal’s skin (neck area / behind the ear) at an appropriate angle such that the tip of the needle is 2 mm below the skin surface. The dose volume is then injected into the dermal layer of skin.The dose formulations are allowed to equilibrate to ambient temperature for at least 15 minutes prior to and continuously throughout dose administration.Table 5. Assignment Scheme of Dose Site NumbersAssignment Scheme of Dose Site NumbersTreatmentsAnimal Sham STAR STAR PlaceboParticle Gel Particle Gel ALD-105A ALD-106A+ ALD-105A + ALD-106A1001 1 1, 2, 3, 4, 5 6, 7, 8, 9, 10 11, 12, 17, 18, 19, 21, 22, 23,13, 14, 20 2415, 16

[0132] Fig. 2 is a graph illustrating a silencing of the JAK1 target with C1-JAK1 4 days after a single application. The graph illustrates that STAR particles deliver functional siRNA to pig skin in vivo. The graph shows mRNA silencing of JAK1 siRNA following application of a formulated STAR+siRNA gel. About 3.5 mg (270 nmols) of siRNA, formulated with star particles, was rubbed for 60 seconds on a 3 x 3 cm zone for 4 days. Figs. 3A and 3B show the presence of the antisensestrand 4 days after a single application in pig skin in vivo, In saline refers to intradermal injection as a control.

[0133] Conclusions siRNA can be used to silence JAK1 in minipig in vivo. Conjugates on siRNA can be used to impact siRNA delivery to the skin. siRNAs can be delivered intradermally with minimal liver exposure. Transepidermal delivery offers a less invasive method for delivery of siRNAs to the skin.Example 3: Star particles gel on human skin

[0134] Figs. 4A, 4B illustrate STAR particle and siRNA application in ex vivo human skin. Fig. 4A show STAR particles formulated in a gel. Fig. 4B shows STAR particles applied to skin: 40 kPa pressure. Fig. 5 illustrates Star particle puncture depth following STAR particle application. Fig. 6 illustrates fluorescent siRNA diffusion into the dermis following STAR particle application. Fig. 2 shows graphs illustrating that STAR particles deliver functional siRNA to pig skin in vivo. The graphs show mRNA silencing of JAK1 siRNA following application of a formulated STAR+siRNA gel. About 3.5mg (270nmols) of siRNA, formulated with star particles, was rubbed for 60 seconds on a 3 x 3 cm zone for 4 days. Fig. 7 are graphs showing the application of STAR particles in human participant is well tolerated with this gel.

[0135] ConclusionsSTAR particle Gel can be used to silence JAK1 in human skin ex vivo when containing siRNA and the STAR gel is well tolerated in healthy volunteers.Example 4: Pre-Formulation Containing an siRNA (ALD-102 = Seq 16 of Table 2) For the Treatment Of Atopic Dermatitis

[0136] The aim of this study is to develop a single-phase gel formulation suitable for topical application containing the ALD-102 (seq 16 of table 2), for the treatment of atopic dermatitis. This is achieved by via the following objectives.• Analytical method implementation and forced degradation of ALD-102 in solution.• Pre-formulation experiments as chemical stability testing of ALD-102 in excipients / sy stems suitable for transdermal delivery.

[0137] Forced degradation studies were performed on ALD -102 drug substance. Accelerated forced degradation samples were generated to identify the drug’s potential impurities under certain conditions, to ensure that any impurity growth does not further reduce the resolution of the sense and anti-sense peaks and to determine the method’s mass balance. Samples of ALD-102 in 100% H2O were exposed to thermal degradation at 70°C and oxidative (3% H2O2) condition. The total ALD 102 content results are reported in

[0138] Table 66 and the major degradant peaks observed (that are more than 0.5% area due to the number of impurities present) are outlined in

[0139] Table 7 and Table 8.• Overall, ALD 102 is extremely sensitive to low oxidative conditions in a short amount of time. When exposed to oxidative conditions using 3% H2O2, after 2 hours there was ca. 65% degradation of ALD 102.• Compared to oxidation there was less degradation at 70 °C heat. After 3 days, overall, in terms of ALD 102 there was only 15% degradation observed.Table 6. Summary of forced degradation experiments performed on ALD 102 to demonstrate suitability for use in the detection of related substances.Table 7. Impurity peaks of ALDI 02 observed >0.5% area during ALDI 02 forced degradation experiments.• NP = not present in chromatogram, X = present above 0.5%• (*) Increased in size compared to t=0• (**) Decreased in size compared to t=0• (***) ]\[0change in peak size compared to t=0. Table 8. Impurity peaks of Sense observed >0.5% area during ALD102 forced degradation experiments.X = present above 0.5%(*) Increased in size compared to t=0(**) Decreased in size compared to t=0 •change in peak size compared to t=0.Example 5: Pre-formulation experiments: the chemical stability of ALD-102 in excipients and binary systems was performed.

[0140] The excipients / systems were loaded at 0.08%-0.1% w / w ALD-102 to assess the stability.

[0141] The percentage recovery compares the response of the drug peak to a standard of known concentration, whilst percentage area (% area) compares the area of the drug peak to the sum of the areas of all peaks in the chromatogram.

[0142] The % area and % recovery of ALD-102 in each excipient and system over the experimental period has been presented in Table 9 and

[0143] Table 10, respectively. The apparent pH of the aqueous-based systems over the duration of the study have also been presented in Table 111 to aid with the data interpretation.Table 9. Percentage purity (% peak area) of ALD-102 in excipients / binary / solvent systems (n=l)(*) All systems were diluted with 20% water such that the ALD-102 could be dissolved.(**) Repeated results reported.Table 10. Percentage recovery (% of the theoretical amount) of ALD-102 in excipients / binary / solvent systems (average of n=2 replicates, range in brackets).(*) All systems were diluted with 20% water such that the ALD-102 could be dissolved.(**) Repeated results reported.Table 11. Apparent pH of the aqueous chemical stability samples(*) All systems were diluted with 20% water such that the ALD-102 could be dissolved.(**) Not assessed in error.

[0144] Overall, the results indicated that ALD-102 was generally stable in most excipients assessed, although potential incompatibilities were identified. The main route of ALD-102 degradation in these excipients was identified as oxidative degradation. The inclusion of antioxidants (propyl gallate and methionine) in Transcutol P notably reduced the ALD-102 degradation. Propylene glycol was identified as a potential suitable alternative penetration enhancer to Transcutol P with good ALD-102 stability. Additionally, urea could be potentially considered during formulation development due to the stability of the drug in this excipient (no decrease at 40°C compared to 25 °C). ALD-102 had slightly better stability at an apparent pH of ca. 8 than 5 any notable degradation.Example 6: Anti-oxidant screening The stress condition (2 mL of ‘0.03% w / w H2O2 solution’ for 24 h) was applied to the selected formulations containing a range of different antioxidant systems.Table 12. Composition (% w / w) of the selected formulations for antioxidant screeningThe results have been presented in Table 13 (% purity) and Table 14 (% recovery).Table 13. Percentage purity (% peak area) of ALD-102 in formulation at t=0 and following subjected to 0.03% w / w H2O2 solution for 24h at ambient temperature (n=l replicate)Table 14. Percentage recovery (% of the theoretical amount) of ALD-102 in formulation at t=0 and following subjected to 0.03% w / w H2O2 solution for 24h at ambient temperature (n=2 replicates)Overall, increased level of EDTA, niacinamide, sodium metabisulphite and tert-butylhydroquinone were identified as potential suitable antioxidants. Among the antioxidants tested, ascorbic acid was noted to be the least effective antioxidant at preventing drug degradation. When the preservatives were compared, ALD-102 appeared to be more compatible with benzyl alcohol compared to phenoxyethanol.Example 7: Formulation stability with different shapes of STAR particlesDifferent designs of STAR particles, Shape 1, Shape 2 and Shape 3 have been tested in a short term stability assessment in 2 different formulations (AG27 and AG28). The STAR particles tested are according to publication WO2017 / 151745. U.S. Patent No. 11 ,291 ,816, and U.S. Patent Publication No.2022 / 0226626 (Shape 1) or according to co-pending patent applications US 63 / 689,218 and US 63 / 89,131 (Shape 2 and 3)Table 15. Composition of AG27 and AG28Table 16. Percentage purity (% peak area) of ALD-102 in formulation at t=0 and following up to 2 weeks storage at 25 and 40 °C (n=l replicate)Table 17. Percentage recovery (% of the theoretical amount) of ALD-102 in formulation at t=0 and following up to 2 weeks storage at 25 and 40 °C (n=3 replicates)Table 18. Macroscopic appearance of formulations at t=0 and following up to 2 weeks of storage at 25 and 40 °C.*Samples without STAR particlesTable 19. Microscopic appearance of formulations at t=0 and following up to 2 weeks of storage at 25 and 40 °C.* Samples without STAR particlesTable 202. Apparent pH of formulations at t=0 and following up to 2 weeks storage at 25 and 40 °C n=l replica)*Samples without STAR particlesTable 213. Homogeneity of STAR particles in formulation at t=0 and following up to 2 weeks storage at 25 and 40 °C (n=3 replicas)Table 22. Percentage recovery (% of the theoretical amount) of STAR particles in formulation at t=0 and following up to 2 weeks storage at 25 and 40 °C (n=3 replicates)The results of this testing indicated that the different shapes of STAR particles did not appear to be any notable difference in chemical or physical properties of the formulations containing the different STAR shapes. Example 8: Formulation stabilityThe formulations detailed in the table 23 below were placed on stability testing:Chemical and physical stability results are presented in table 24 to 31.Table 24. Percentage purity (% peak area) of ALD-102 in formulation at t=0 and following up to 4 or 14 weeks storage at 25 and 40 °C (n=l replicate)(*) Repeated results reported.Table 25. Percentage recovery (% of the theoretical amount) of ALD-102 in formulation at t=0 and following up to 4 or 14 weeks storage at 25 and 40 °C (n=3 replicates)(*) Repeated results reported.Table 26. Macroscopic appearance of formulations at t=0 and following up to 4 or 14 weeks of storage at 25 and 40 °C.Table 27. Microscopic appearance of formulations at t=0 and following up to 4 or 14 weeks of storage at 25 and 40 °C.Table 28. Apparent pH of formulations at t=0 and following up to 4 or 14 weeks storage at 25 and40 °C (n=l replica)Table 29. Viscosity of the formulations at t=0 and following up to 4 weeks storage at 25 and 40 °C n=l replica)Table 30. Homogeneity of STAR particles in formulation at t=0 and following up to 4 weeks storage at 25 and 40 °C (n=3 replicas)Table 31. Percentage recovery (% of the theoretical amount) of STAR particles in formulation at t=0 and following up to 4 weeks storage at 25 and 40 °C (n=3 replicates)Example 9: Further Formulation stabilityThree formulations (AG69, AG71 and AG73) at both 1 mM and 5 mM were selected for short-term formulation stability testing for up to 8 weeks storage at 2-8 and 25°C.Table 32. Percentage purity (% peak area) of ALD-102 in formulation at t=0 and following up to 8 weeks storage at 2-8 and 25 °C (n=l replicate)N.T. - Not testedTable 33. Percentage recovery (% of the theoretical amount) of ALD-102 in formulation at t=0 and following up to 8 weeks storage at 2-8 and 25 °C (n=3 replicates)N.T. - Not testedTable 34. Microscopic appearance of formulations at t=0 and following up to 2 weeks of storage at 2-8 and 25 °CN.T. - Not testedTable 35. Apparent pH of formulations at t=0 and following up to 8 weeks storage at 2-8 and 25 °C(n=l replica)N.T. - Not tested Table 36. Viscosity of the formulations at t=0 (n=l replica)Following 8 weeks storage at 2-8 and 25 C, there was no notable change in the stability of ALD- 102. The microscopic characteristics and the apparent pH of the formulations were observed to remain stable.Example 10: Formulation stability (physical stability at 5mM) The formulations detailed in the table below were placed on physical stability with the main objective to look at STAR sedimentation over time at room temperature.Tabel 37 Error! Reference source not found.Table 38 Error! Reference source not found.Table 39. Characterization of developed formulations during additional formulation development.N / T: Not tested(**) Although a layer without STAR particles in the vial containing AG50 was observed, and STARs did not continue to sediment. Table 40. Characterization of developed formulations during additional formulation developmentError! Reference source not found, (continued)Table 41. Error! Reference source not found, (continued)N / T: Not testedTable 42. Characterization of developed formulations during additional formulation development (continued).Example 11: The Effect of Load, Viscosity, and Concentration on Microscale Particle Performance

[0145] 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.

[0146] 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.

[0147] 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. 10), 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.

[0148] Also, the half normal plot (Fig. 11) 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 around 40kPa + / - 30kPa. These results demonstrate that the viscosity of the gel is one of the main parameters influencing the STAR particle application performance.Example 12 : Formulations tested on Gottingen minipig : tolerability and skin exposure mat D7 after topical application

[0149] The objective of this study is to determine the local tolerance and functional delivery of Tergus C, Tergus E2, AG77d E2, AG71 E2, AG69 E2, and AG75 E2, when given dermally as a single dose to minipig. The intended dose sites were be prepared by close clipping of the hair on Day -1. Dose sites were be wiped with gauze soaked in reverse osmosis (RO) water, followed by dry gauze. Following rinsing at least 30 minutes will pass prior to dose administration. Eleven test sites (4 x 4 cm) were marked on the skin. Sites of application needed to be as distant from one another as possible, with at least the minimum distance of 4 cm. Lateral and / or diagonal motion were used to facilitate dose administration, if necessary. Repeat application to ensure a minimum 56 second application time.

[0150] Excess STAR particles were then removed 10 to 25 minutes post the last dose administration by gently wiping each site with dry gauze. Special attention was be made to ensure surrounding sites are not contaminated with the debris of gel from the other application sites when removing the excess of gel or excess of dry gel with the gauze. Gloves were changed between each application site.

[0151] The first day of dosing was be designated as Day 1. On day 8, biopsies were collected following tape striping of the zone (20 times) to measure the quantity of the drug in the tissue

[0152] The Figure 12 shows the quantity of the drug (ALDI 02) in the skin of the 6 formulations tested at ImM (including a reference formulation) and the control at 0 mM. All formulas deliver the drug into the skin and can be quantified 7 days post-application. However, specific compositions more specifically the one with 1.5% guar gum, show superior efficacy at delivering the drug compound.The table 43 below shows an extract of the composition of the different formulations used.Table 43.REFERENCES1. Qi et al., “Rational design of a J AK1 -selective siRNA inhibitor for the modulation of autoimmunity in the skin.” Nature Communications, (2023) 14:7099

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical composition comprising: a monovalent or multivalent, monospecific or multispecific siRNA; a plurality of micrometer or millimeter scale particles; and a pharmaceutical acceptable carrier.

2. The pharmaceutical composition of claim 1 , wherein the micrometer or millimeter scaleparticles comprises one or more of micro-star particles, micro-diamond particles, microsquare particles, and / or microneedles.

3. The pharmaceutical composition of claim 1 or 2, wherein the multivalent siRNA is bivalent or trivalent.

4. The pharmaceutical composition of any of the preceding claims, wherein the multispecific siRNA is bispecific or trispecific.

5. The pharmaceutical composition of any of the preceding claims, wherein the siRNA is present in an amount of between about 0.001 % w / w to about 0.01 % w / w, between about 0.01 % w / w to about 0.1 % w / w, between about 0.1 % w / w to about 1 % w / w, between about 1 % w / w to about 2% % w / w, between about 2 % 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, between about 9 % w / w to about 10 % w / w, between about 10 % w / w to about 11 % w / w, between about 11 % w / w to about 12 % w / w, between about 12 % w / w to about 13 % w / w, between about 13 % w / w to about 14 % w / w, between about 14 % w / w to about 15 % w / w of the total weight of the composition.

6. 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 toabout 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.

7. The pharmaceutical composition of any of the preceding claims, wherein the micrometer or millimeter scale- particles are present in an amount of between about 0.5 % w / w to about 1.5 % w / w, between about 1.5 % w / w to about 2.5 % w / w, between about 2.5 % w / w to about 3.5 % w / w, between about 3.5 % 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 6.5 % 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.

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

9. The pharmaceutical composition of claim 8, wherein the solvent is purified water.

10. The pharmaceutical composition of claim 8 or 9, wherein the solvent is present in an amount of between about 15% w / w to about 40% w / w, 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.

11. The pharmaceutical composition of claim 8, wherein the solvent comprises one or more of mineral oil, propylene carbonate, dimethyl sulfoxide (DMSO), glycerin, propylene glycol, isopropyl alcohol, and / or hexylene glycol.

12. The pharmaceutical composition of claim 11, 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.

13. The pharmaceutical composition of any of the preceding claims further comprising one or more gelling agents or thickening agents.

14. The pharmaceutical composition of claim 13, 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, Carrageenan, Pectine, Guar Gum, PolyCarbophil, Carbopol 974 (Type B), Methyl cellulose, Magnesium aluminum silicate (Veegum), Sepineo 600, Sepineo PHD, Carbopol 971, Carbopol 980, Carbopol 981, Carbopol 2020, or Ultrez 10.

15. The pharmaceutical composition of claim 13 or 14, 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 toabout 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 / w16. The pharmaceutical composition of any of the preceding claims further comprising a viscosity modifier.

17. The pharmaceutical composition of claim 16, wherein the viscosity modifier comprises one or more of Cyclomethicone, Dimethicone, Cyclomethicone dimethicone copolyol, or PEG / PPG-18 Dimethicone.

18. The pharmaceutical composition of claim 16 or 17, 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 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.

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

20. The pharmaceutical composition of claim 19, wherein the chelating agent comprises one or more of Disodium EDTA, trisodium EDTA, Diethylenetriamine Pentaacetic Acid, Hydroxy ethyl ethylenediamine triacetic acid, or Hydroxyethylidene bisphosphonic acid.

21. The pharmaceutical composition of claim 19 or 20, 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, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w.

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

23. The pharmaceutical composition of claim 22, 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.

24. The pharmaceutical composition of claim 22 or 23, wherein the skin penetration enhancer is present in an amount between 1% w / w and 5% w / w, 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%.

25. The pharmaceutical composition of any of the preceding claims further comprising one or more antioxidants.

26. The pharmaceutical composition of claim 25, wherein the one or more antioxidants comprise one or more of Niacinamide, 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.

27. The pharmaceutical composition of claim 25 or 26, wherein 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, 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, or betweenabout 0.9% w / w to about 1.0% w / w, or between about 1.0% w / w to about 2.0% w / w, or between about 2.0% w / w to about 3.0% w / w.

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

29. The pharmaceutical composition claim 28, wherein the preservative comprises one or more of Benzyl alcohol, Phenoxyethanol, Benzoic acid, Sorbic acid, Methyl paraben, or Imidurea.

30. The pharmaceutical composition of claim 28 or 29, 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.

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

32. The pharmaceutical composition claim 31, wherein the humectant comprises one or more of Glycerin, PEG 3350, or Cyclomethicone.

33. The pharmaceutical composition of claim 31 or 32, 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.

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

35. The pharmaceutical composition of claim 34, 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.

36. The pharmaceutical composition of claim 34 or 35, 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.

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

38. The pharmaceutical composition of claim 37, 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, Ceteths (2-20), Steareths (2-20), PEG stearates (2-100), Tefose-1500 (source: Gattefosse), Tefose 63 (source: Gattefosse), or Polywax (source: Croda).

39. The pharmaceutical composition of claim 37 or 38, 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.

40. The pharmaceutical composition of any of the preceding claims further comprising a suspending agent, and optionally an antioxidant.

41. The pharmaceutical composition of claim 40, wherein the suspending agent comprises one or more of Xanthan Gum, Methyl cellulose, Carboxymethyl cellulose,Polycarbophil, or hydroxypropyl methylcellulose (“HPMC”), Carrageenan, Pectin, Guar Gum, PolyCarbophil, Carbopol 974 (Type B), Carbopol 971, Carbopol 980, Carbopol 981, Carbopol 2020, Ultrez 10, Calcium chloride, Magnesium aluminum silicate (Veegum), Sepineo 600, or Sepineo PHD.

42. The pharmaceutical composition of claim 40 or 41, 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.

43. 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.

44. 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.

45. The pharmaceutical composition of claim 44, wherein each of the plurality of pointed structures has a length of about 10 pm to about 100 pm, about 100 pm to about 500 pm, or about 500 pm to about 2,000 pm.

46. The pharmaceutical composition of claim 44, wherein each of the plurality of pointed structures has a tip having a radius of about 0.1 pm to about 30 pm.

47. The pharmaceutical composition of claim 44, wherein the micrometer scale or millimeter scale particles have a largest dimension which is the largest of the following distances:1) the distance between the tips of the two pointed structures that are the farthest apart, or2) 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.

48. The pharmaceutical composition of claim 47, wherein the largest dimension is about 50 pm to about 2,000 pm.

49. The pharmaceutical composition of any of the proceeding claims, wherein the micrometer scale or millimeter scale particles are substantially suspended in the formulation for 0 to 3 months, 3 months to 6 months, 6 months to 1 year, 1 year to 2 years, or 2 years to about 3 years when stored at 4 to 25°C.

50. 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 b. viscosity properties such that sedimentation or settling of the micrometer scale or millimeter scale particles does not occur during storage and transport.

51. The pharmaceutical composition of any of the proceeding claims, wherein the siRNA is targeting a molecule or several molecules in a functional pathway, whether the target is a receptor, an intracellular or extracellular molecules, a matrix molecules, an enzyme, a transcription factor, an hormone or a growth factors selected but not restricted to the following pathways: an inflammatory pathway, a growth pathway, and / or endocrine and / or paracrine pathway, and cell or tissue structural pathway, IL4 / 13 pathway, IL2 / 15 pathway, IL1 pathway, IL31 pathway, JAK / STAT pathways, IL7 pathway, IL17 pathway, IL23 pathway, TNF pathway, 0X40 pathway, TSLP pathway, retinoic pathway, INF-g pathway, IL22 pathway, IL- 5 and / or 9 pathways.

52. The pharmaceutical composition of any of the proceeding claims, wherein the formulation is preventing or treating disease or symptoms selected from the following conditions: inflammatory skin disease symptoms and conditions, skin cancers, skin dyspigmentation, skin infection, or several other conditions, like to genodermatosis whether they are spontaneous or genetically inherited diseases53. The pharmaceutical composition of any of the proceeding claims, wherein the siRNA is conjugated to a hydrophobic moiety comprising one or more of an alkyl chain, an ester linkage, an amide linkage, and / or a phosphate linkage.

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

55. The pharmaceutical composition of any of claims 1 to 54 for use as a medicament56. The pharmaceutical composition of any of the claims 1 to 54 for the treatment of inflammatory disease, autoimmune skin disease, skin discoloration or skin cancer or, spontaneous or genetic skin disease, or an infectious disease (such as eczema, alopecia, vitiligo, psoriasis, atopic dermatitis, pyoderma gangrenosum, hidradenitis suppurativa, CTCL, EB, genodermatosis) or a cosmetic condition especially due to life style factor or aging (such as wrinkles, skin volume loss or gain, skin texture changes, scares, hair loss).

57. The non-medical use of any of the compositions of claims 1 to 54 for enhancing the skin condition or the skin health or appearance or for cosmetic use.

58. 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.

59. The method of claim 58 wherein the disease or condition is an inflammatory disease, autoimmune skin disease, skin discoloration or skin cancer or, spontaneous or geneticskin disease, or an infectious disease (e.g. but not restrictive to eczema, alopecia, vitiligo, psoriasis, atopic dermatitis, pyoderma gangrenosum, hidradenitis suppurativa, CTCL, EB, genodermatosis) or a cosmetic condition due to life style factor or aging (e.g., but not restrictive to wrinkles, skin volume loss or gain, skin texture changes, scares, hair loss) and wherein the intervention strategy is preventing or treating the disease or the symptoms of the disease or the skin conditions.

60. The method of claim 58 or 59, further comprising rubbing the pharmaceutical composition on the skin of the subject, wherein the plurality of micrometer or millimeter particles tumble or move across the skin of the subject.

61. The method of any one of claims 58 to 60, wherein the plurality of micrometer or millimeter particles perforate the skin of the subject.

62. The method of any one of claims 58 to 61 further comprising rubbing the pharmaceutical composition 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.

63. The method of claim 62, wherein the pores are transient for a period of up to 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.

64. The method of claim 63, 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.

65. The method of any one of claims 58 to 64, 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.

66. The method of claim 65, 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.

67. The method of any one of claims 58 to 66, wherein the composition is a gel and remains in the gel state for at least 3 months when stored between 4°C and 25 °C allowing for continuous suspension of the micrometer or the millimeter scale particles.

68. The method of any one of claims 58 to 67, 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.

69. The method of any one of claims 58 to 68, wherein the siRNA comprises or has a nucleic acid sequence having at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% sequence identity of any one of SEQ ID NO: 1 to SEQ ID NO: 27.

70. The pharmaceutical composition of any of the claims 1 to 56, wherein the siRNA comprises or has a nucleic acid sequence having at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% sequence identity of any one of SEQ ID NO: 1 to SEQ ID NO: 27.

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