Topical ointment formulations and methods of use thereof

Abstract

Described herein are ointment formulations for delivering active pharmaceutical agents to skin and particularly to hair follicles in skin. Methods of using the described ointment formulation for inhibiting the activity of epidermal growth factor receptor (EGFR) inhibitors, such as but not limited to treatments for EGFR-associated cancers, are also described.

Description

3417-1-2TOPICAL OINTMENT FORMULATIONS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] Benefit is claimed to US Provisional Patent Application No. 63 / 724,374, filed November 24, 2024, the contents of which are incorporated by reference herein in their entirety.FIELD

[0002] This disclosure relates to an ointment formulation for delivering active pharmaceutical agents to skin and particularly to hair follicles in skin. Methods of using the described ointment formulation for inhibiting the activity of epidermal growth factor receptor (EGFR) inhibitors, such as but not limited to treatments for EGFR-associated cancers, are also described.BACKGROUND

[0003] Systemically administered epidermal growth factor receptor (EGFR) inhibitors are often associated with dose-limiting skin-related side effects. Recently, a small molecule inhibitor of the interaction between EGFR and anti-neoplastic EGFR inhibitors, referred to as LW11, and which is identical to SDT-011 described herein, was described (see International Patent Publication No. WO 2021 / 028919) as a therapeutic agent to reduce toxic side effects of EGFR inhibitors. However, a continuing need exists for effective topical formulations to provide sufficiently high concentrations of SDT-011 to target areas of the skin, and particularly to hair follicles in the skin of a subject under systemic treatment with an EGFR inhibitor.

[0004] Dermal delivery of active ingredients to the hair follicular faces several significant challenges that impede its effectiveness. Firstly, hair follicles are complex structures with entrances often blocked by sebum and keratinocytes, forming a barrier that limits the diffusion of substances. Additionally, the natural protective mechanisms of the skin, such as the outflow of sebum, can prevent the penetration of applied formulations to the hair follicles. These challenges necessitate innovative formulation strategies to enhance follicular penetration and ensure that active ingredients retain their efficacy upon reaching the intended site of action within the follicles.3417-1-2SUMMARY

[0005] Described herein is an ointment formulation designed for delivering an active agent to the skin of a subject, and particularly to the hair follicles of a subject. The described formulation includes petrolatum or a non-petroleum-derived equivalent thereof; a hydrophobic solvent; an emulsifier; a moderately polar or non-polar solvent; and an active pharmaceutical ingredient (API), wherein particles of the API in the ointment have a mean diameter (D50) of about 1 pm to 5 pm, inclusive.

[0006] In particular embodiments, the petrolatum is white petrolatum or yellow petrolatum.

[0007] In other particular embodiments, the hydrophobic solvent is mineral oil, or a nonpetroleum derived equivalent thereof.

[0008] In some embodiments, the emulsifier is glyceryl monostearate.

[0009] In other embodiments, the moderately polar or non-polar solvent is dimethyl isosorbide, oleyl alcohol, or propylene carbonate.

[0010] In other further embodiments, the formulation includes 0.1%-10% w / w API.

[0011] In particular embodiments, the formulation includes about 50.0 to 95.0% w / w white petrolatum; about 0.1 to 25.0% w / w mineral oil; about 0.1 to 10% w / w glycerol monostearate; about 0.1 to 10.0% w / w oleyl alcohol or dimethyl isosorbide; and about 1.0 to 5.0% w / w API.

[0012] In some embodiments, the formulation includes about 4.9% w / w mineral oil; about 0.1 to 10% w / w glycerol monostearate; about 1 to 15% w / w oleyl alcohol or dimethyl isosorbide; about 0.1 to 10.0% w / w API; and the remainder of the formulation in % w / w, up to a total of 100%, of white petrolatum.

[0013] In other particular embodiments, the formulation includes about 83% w / w white petrolatum; about 4.9% w / w mineral oil; about 2% w / w glycerol monostearate; about 5% w / w oleyl alcohol or dimethyl isosorbide; and about 5.0% w / w API.

[0014] In certain embodiments, the formulation does not include one or more of PLGA (Poly(D,L-lactide-co-glycolide), water, propylene glycol, glycerol, isopropyl myristate, dimethyl sulfoxide, diethylene glycol monoethyl ether, gelling agents, or ionic surfactants.

[0015] As described, any suitable API for topical delivery can be used in the described ointment formulations. However, in particular embodiments, the API is a compound of formula I:3417-1-2

[0016] In other embodiments, the API is compound Cl:

[0017] Also provided herein is a composition for use in methods of providing an active pharmaceutical ingredient (API) to skin of a subject that includes any of the ointment formulations described herein.

[0018] Additionally described herein is a composition for use in methods of inhibiting toxic side effects of an epidermal growth factor receptor (EGFR) inhibitor in skin of a subject that includes any of the ointment formulations described herein.

[0019] In particular embodiments of the compositions for use in the described methods, the EGFR inhibitor is systemically administered to the subject.

[0020] In some embodiments, the ointment formulation is provided to the subject prior to, concurrently with, or following treatment with the EGFR inhibitor.

[0021] In other particular embodiments, the EGFR inhibitor is a small molecule, peptide, polypeptide, antibody or fragment thereof.

[0022] In further embodiments, the subject is receiving the EGFR inhibitor for treatment of an EGFR-associated cancer, such as but not limited to an EGFR-associated cancer selected from colon cancer, lung cancer, head and neck cancer, breast cancer or pancreatic cancer.

[0023] In the methods described herein, the ointment formulation is provided to the subject by topical administration of the ointment formulation to the subject, thereby inhibiting toxic side effects of the EGFR inhibitor, particularly in the skin of the subject, and more particularly in the hair follicles of the subject.3417-1-2

[0024] The formulations provided herein, in other particular embodiments, are useful in providing an API to a subject, such as in the methods of inhibiting toxicity of a systemically provided EGFR inhibitor, but with minimal to no systemic passage of the topically provided API.

[0025] The foregoing and other objects, features, and advantages will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS.

[0026] Fig. 1 is a chart showing the approximate concentration of SDT-011 recovered from skin, hair follicles, and receptor fluid (representing systemic penetration) in the IVPT assay comparing ointment, gel, cream, and PLGA formulations. Penetration of Ointment 2 containing 1%, 5%, and 10% of the API is also shown in the chart.

[0027] Fig. 2 is a chart comparing the concentration of SDT-011 recovered from skin, hair follicles and receptor fluid (representing systemic penetration) from the IVPT assay testing 1%, 5%, and 10% of SDT-011 in the "Ointment 2" formulation as described herein ("EMRIS 1%," "EMRIS 5%," and "EMRIS 10%)."

[0028] Fig. 3 is a chart comparing the concentration of SDT-011 recovered from skin, hair follicles and receptor fluid (representing systemic penetration) from the IVPT assay testing 5% of two lots of SDT-011 in the "Ointment 2" formulation as described herein ("EMRIS 5%-C" and "EMRIS 5%-W"), in comparison to a PLGA nanoparticle formulation loaded with SDT-011 ("POC-PLGA").DETAILED DESCRIPTION

[0029] Terms

[0030] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. It is further to be understood that all percentage amounts (e.g., % w / w in the case of the described formulations), and all molecular weight or molecular mass values are approximate, and are provided for description. Although3417-1-2 methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term "comprises" means "includes." The term "consists essentially of" or "consisting essentially of" indicates that the active ingredient or step of the described composition or method includes only the expressly recited ingredient or step, but that non-active ingredients or non-critical steps are included even if not expressly recited. This is in contrast to "consists" or "consisting" of which indicates that only the recited ingredients or steps are included in the claim. It is to be understood that compositions that "comprise" a given ingredient can also in other embodiments "consist essentially of" or "consist of" that ingredient. Similarly, methods that "comprise" a given set of steps can also in other embodiments "consist essentially of" or "consist of" the expressly indicated set of steps. The abbreviation, "e.g.," is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g.," is synonymous with the term "for example".

[0031] As used herein, "D50" refers to the median particle size diameter, where 50% of the particles in the distribution are smaller than the stated value.

[0032] In case of conflict, the present specification, including explanations of terms, will control. All materials, methods, and examples are illustrative and not intended to be limiting. References cited herein are incorporated by reference herein with respect to the technical aspects described (chemical structures, etc.).

[0033] Topical Formulations

[0034] SDT-011 is a small molecule inhibitor of the epidermal growth factor receptor (EGFR), which blocks the binding of antineoplastic EGFR inhibitors, such as anti-EGFR antibodies, to the EGFR (Friedman et al. Sc / . Transl. Med. 15, 2023, DOI:10.1126 / scitranslmed.abo0684). As previously described, subjects receiving systemically delivered antineoplastic EGFR receptor inhibitors will also often experience toxic side effects, particularly in the skin. By inhibiting the binding of EGFR inhibitors to the EGF receptor in the epidermis, and particularly in hair follicles, SDT-011 can reduce epidermal toxicity of systemically delivered antineoplastic EGFR receptor inhibitor drugs, allow for treatment with higher dosages of antineoplastic drug than would otherwise not be tolerated and avoid medication holiday and / or treatment discontinuation.3417-1-2

[0035] The current disclosure provides a topical ointment formulation that can effectively deliver an active pharmaceutical ingredient (API) such as SDT-011 to the skin, preferentially localize the API to hair follicles, and which does not allow for permeation of significant concentrations of the API through the skin and into the bloodstream where it could reduce the desired effect of systemically administered drugs, such as antineoplastic drugs.

[0036] It will be appreciated that although the formulations described herein were developed for topical administration of SDT-011, these formulations can also be used for topical administration of active pharmaceutical ingredients (APIs) with similar physical and chemical properties as SDT-011, such as but not limited to an API with low solubility in ointments in general, or an API with low solubility in hydrocarbons such as petrolatum and mineral oil or analogous non-petroleum based materials.

[0037] The described topical ointment formulations for delivering an API to the skin of a subject includes petrolatum or a non-petroleum-derived equivalent thereof; a hydrophobic solvent such as but not limited to mineral oil; an emulsifier; a moderately polar or non-polar solvent; and the API, wherein particles of the API in the ointment have a mean D50 diameter of about 1 pm to 5 pm, inclusive. In particular embodiments, the moderately polar or nonpolar solvent is not required. In particular embodiments, the hydrophobic solvent is not required. In particular embodiments, the formulation is anhydrous.

[0038] As used herein, "petrolatum," CAS No. 8009-03-8, refers to a petroleum derivative also commonly known as petroleum jelly or paraffin jelly. In particular embodiments, the petrolatum for use in the described formulation includes but is not limited to white petrolatum or yellow petrolatum. In other embodiments, the petrolatum component of the described formulation is a non-petroleum-derived equivalent of petrolatum, such as but not limited to plant or animal-derived natural oils and waxes and combinations thereof such as lanolin, beeswax and the like. In other embodiments, the petrolatum component is replaced by or supplemented with a hydrocarbon base or oleaginous base, such as Plastibase (Jelene), microcrystalline wax, paraffin wax, ozokerite, ceresin, or silicone gels / elastomers (e.g., dimethicone crosspolymer). In other embodiments, the formulation comprises a silicon elastomer component. In one or more embodiments, the silicon elastomer comprises one or more of cyclopentasiloxane (and) polysilicone-11 (Grant MGS-Elastomer 1100), dimethicone (and) polysilicone-11 (Gransil DMG-3), a cyclopentasiloxane (and) petrolatum (and)3417-1-2 polysilicone-11 (MGS-Elastomer 1148P), cyclopentasiloxane and dimethicone cross polymer (ST-Elastomer 10) and dimethicone (and) dimethicone crosspolymer (DOWSIL™ 9041).

[0039] Similarly, in particular embodiments, the hydrophobic solvent of the described formulations is mineral oil, however it will be appreciated that other hydrophobic solvents of similar properties to mineral oil can also be used. Such solvents include petroleum based oils and non-petroleum based oils such as but not limited to a mineral oil, a hydrocarbon oil, squalane, squalene, liquid paraffin, an ester oil (e.g., C12-15 alkyl benzoate, diisopropyl adipate, diethyl sebacate, isopropyl palmitate, isopropyl myristate), an ester of a dicarboxylic acid, a triglyceride oil (e.g., medium chain triglycerides, caprylic / capric triglyceride), an oil of plant origin (e.g., castor oil, soybean oil), an oil from animal origin, an unsaturated or polyunsaturated oil, a diglyceride, a fatty acid lactate (e.g., myristyl lactate, cetyl lactate, C12- 15 alkyl lactate), a PPG alkyl ether (e.g., PPG-15 stearyl ether), an essential oil, a silicone oil (e.g., dimethicone, cyclomethicone, phenyl trimethicone), an isoparaffin, a polyalphaolefin, a polyolefin, a synthetic isoalkane and the like.

[0040] In certain embodiments, the emulsifier can be glyceryl monostearate (including selfemulsifying grades) or magnesium stearate or analogous or equivalent substitutes thereof. In some embodiments, the emulsifier can be (i) a polyoxyethylene sorbitan ester (polysorbate), such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii) a sorbitan ester, such as sorbitan monolaurate and sorbitan monooleate; (iii) a polyoxyethylene fatty acid ester, such as PEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate, PEG- 150 distearate, PEG-8 laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8 oleate, PEG-9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate and PEG-20 oleate; (iv) a PEG-fatty acid diester; (v) a polyethylene glycol (PEG) ether of fatty alcohols; (vi) a glycerol ester, such as glyceryl monostearate, glyceryl monolaurate, glyceryl monopalmitate and glyceryl monooleate; (vii) a PEG-fatty acid mono- and di-ester mixture; (viii) a polyethylene glycol glycerol fatty acid ester; (ix) a propylene glycol fatty acid ester; (x) a mono- or di- glyceride; (xi) a sugar ester (mono-, di- and tri-esters of sucrose with fatty acids); (xii) sorbitan esters (SPANs) such as sorbitan oleate, sorbitan sesquioleate, or sorbitan stearate; (xiii) a PEG alkyl phenol; (xiv) polyglyceryl esters (e.g., polyglyceryl-3 diisostearate, polyglyceryl-3 polyricinoleate); and (xv) cholesterol or lanolin alcohols.3417-1-2

[0041] The described formulations can also include an API-compatible solvent. As described in the below examples, SDT-011 is insoluble in polar solvents and strongly hydrophilic environments. In contrast, SDT-011 has some degree of solubility in moderately polar to nonpolar, lipophilic environments. Surprisingly, it was observed that in the ointment formulations described herein, SDT-011 is mostly not solubilized. However, to effectively provide API to the skin, and particularly to be able to transmit API through sebum to the target epidermis and hair follicles, the described formulations can include an API-compatible solvent. In particular examples, the API compatible solvent can for example be selected from dimethyl isosorbide, oleyl alcohol, or propylene carbonate.

[0042] It will be appreciated that in view of the noted requirements, in some embodiments, the described formulations do not include polar and strongly hydrophilic solvents such as but not limited to PLGA (Poly(D,L-lactide-co-glycolide), CAS No. 26780-50-7), water, propylene glycol, glycerol, dimethyl sulfoxide or diethylene glycol monoethyl ether. In other embodiments, the formulation does not include isopropyl myristate, gelling agents, or ionic surfactants. In particular embodiments, the formulation further comprises an antioxidant to enhance the chemical stability of the API. Suitable antioxidants include but are not limited to Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Tocopherol (Vitamin E), Tocopheryl Acetate, Ascorbyl Palmitate, Propyl Gallate, or combinations thereof.

[0043] The described ointment formulations can deliver an API to the skin of a subject and particularly to the hair follicles in the skin. Although the formulations can include components that can solubilize the API, in the formulation the API remains suspended and is largely nonsolubilized. For example, in particular embodiments, more than 50% of the API remains nonsolubilized in the formulation such as at least 95%, at least 90%, at least 85%, at least 80%, at least 70%, at least 60% or at least 50% of the API remains suspended and non-solubilized in the described formulations. Accordingly, in general terms, an API for inclusion in the described formulations includes an API with low solubility in ointments, such as an API with low solubility in hydrocarbons such as petrolatum and mineral oil or their natural non-petroleum derived equivalents.

[0044] In particular embodiments, the API is the molecule known as SDT-011 (described in Friedman et al. Sc / . Transl. Med. 15, 2023, DOI:10.1126 / scitranslmed.abo0684 and as LW11 in3417-1-2International Patent Publication No. WO 2021 / 028919), and according to the followingFormula I:

[0045] It will be appreciated that among the APIs that can be used in the described formulations are SDT-011 derivatives that maintain the functional ability to bind to EGFR and prevent or inhibit the binding of EGFR inhibitors to the EGFR. Similar and derivative APIs are also described in International Patent Publication No. WO 2021 / 028919 and Friedman et al. Sc / '. Transl. Med. 15, 2023, DOI:10.1126 / scitranslmed.abo0684, the contents of both of which are incorporated by reference herein in their entirety. For example, an API similar to SDT-011 that can be used in the described formulations includes compound Cl (described in WO 2021 / 028919 as compound G4), l-[3-amino-4-(difluoromethyl)-6-(3-pyridinyl)thieno[2,3-b]pyridin-2-yl]ethanone:

[0046] APIs that are structurally similar and functionally equivalent to SDT-011 and Cl can be delivered in the formulations described herein.

[0047] In particular embodiments, the formulation contains an API in a % w / w of 0.1%-10%, inclusive, including 0.1%-l%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, and all increments in between.

[0048] The concentration of API in the described formulations is intended to provide a therapeutically effective amount. It will be appreciated that this amount will vary from application to application and API to API, however, in general terms, a "therapeutically effective amount" of an API includes a quantity of the API sufficient to achieve a desired therapeutic effect in a subject being treated. For example, an amount of SDT-011 necessary to inhibit binding of an EFGR inhibitor to the EGFR. The therapeutically effective amount of the3417-1-2 compound will be dependent on the compound applied, and in certain instances the subject being treated.

[0049] In particular embodiments, a therapeutically effective amount of SDT-011 is an amount which results in a concentration at the skin of 100-150 micromolar, and which is sufficient to, for example, block the binding of the EGFR inhibitory antibody cetuximab to the EGFR.

[0050] Delivery of an API to the skin in general and hair follicles in particular is thought to be in part dependent on the mean diameter of the API particles (D50) in the delivering formulation. In the previously described PLGA nanoparticle formulation (see Friedman et al.) the D50 of SDT-011 was in the low nanometer range (approximately 74 nm). Accordingly, it was thought that efficient administration of SDT-011 and its penetration to hair follicles required sub-micron sized particles. In contrast, and as demonstrated herein, the described formulation can effectively transmit SDT-011 to skin and hair follicles when the SDT-011 particles have a D50 in the low micrometer range. Accordingly, in particular embodiments, the D50 of the API of the described formulation can be from about 0.1 to 50 pm, and more particularly, from about 1 to 5 pm, such as 1 pm, 2 pm, 3 pm, 4 pm, or 5 pm, or any increment in between. In particular embodiments, the D50 of the API is not below 1 pm.

[0051] As noted, the described formulations provide an API to the skin surface (epidermis) and particularly the hair follicles of a subject, but without significant permeation of the API into the blood of the subject (i.e., without significant systemic permeation of the API). In particular embodiments less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than .05% or even less of the provided API permeates systemically.

[0052] In more particular embodiments, the formulation includes about 3-6%, such as about 4.9% w / w mineral oil; about 0.1 to 10% w / w glycerol monostearate; about 1 to 15% w / w oleyl alcohol or dimethyl isosorbide; about 0.1 to 10.0% w / w API; and the remainder, up to a total of 100%, of white petrolatum. In more particular embodiments the formulation includes about 50.0 to 95.0% w / w white petrolatum; about 0.1 to 25.0% w / w mineral oil; about 0.1 to 10% w / w glycerol monostearate; about 0.1 to 10.0% w / w oleyl alcohol or dimethyl isosorbide; and about 1.0 to 5.0% w / w API. In still more particular embodiments the formulation includes about 83% w / w white petrolatum; about 4.9% w / w mineral oil; about 2% w / w glycerol3417-1-2 monostearate; about 5% w / w oleyl alcohol or dimethyl isosorbide; and about 5.0% w / w API, wherein in particular embodiments, the API is SDT-011.

[0053] Also described herein are methods for administering an API on or in skin (e.g., to hair follicles) in a subject in need thereof by topically administering any of the formulations described herein to the subject.

[0054] More particularly, described herein are methods for inhibiting an EGFR inhibitor on or in skin (e.g., to hair follicles) in a subject in need thereof by topically administering any of the formulations described herein to the subject, who is undergoing treatment with an EGFR inhibitor. Through the provision of agent blocking binding of the EGFR inhibitor and EGFR, the described formulations reduce the incidence and / or severity of toxic side effects in skin related to systemic administration of an EGFR inhibitor.

[0055] In particular embodiments, the described formulation is administered to the subject prior to, concurrently with, or following treatment with the EGFR inhibitor. It will be appreciated that various dosing regimens of administering the formulation are encompassed herein. For example, in particular embodiments, a single administration of the formulation is sufficient to achieve the desired therapeutic effect, such as reducing or eliminating skin- related side effects of systemically administered EGFR inhibitor drugs. In other embodiments, the formulation is administered multiple times, whether simultaneously with repeated dosing of the EGFR inhibitor drug or one or more times after or between repeated dosing of the drug.

[0056] As used herein, an EGFR inhibitor is an active agent that blocks the activity of epidermal growth factor receptor (EGFR). EGFR inhibitors are used, inter alia, for treatment of EGFR-associated cancers. Non-limiting examples of such cancers include colon cancer, lung cancer, head and neck cancer, breast cancer and pancreatic cancer. Accordingly, a subject who may be in need of treatment with the described formulations includes a subject who is under treatment for a cancer, such as the noted cancers, with an EGFR inhibitor.

[0057] In particular embodiments the EGFR inhibitor is a small molecule, a peptide or polypeptide, or an antibody or fragment thereof, including but not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies, and bispecific antibodies. Specific non-limiting examples of anti-EGFR antibodies include cetuximab, panitumumab, pertuzumab, nimotuzumab, trastuzumab, rituximab, ofatumumab, veltuzumab, alemtuzumab, labetuzumab, adecatumumab, oregovomab, onartuzumab, dulanermin, apomab,mapatumumab, lexatumumab, conatumumab, necitumumab, zalutumumab, matuzumab, amivantamab, depatuxizumab, futuximab, duligotuzumab, modotuximab, petosemtamab, izalontamab, AFM24 and tigatuzumab.

[0058] EGFR-inhibitory antibody fragments include but are not limited to Fab fragments, scFv (single-chain variable fragment) fragments, VHH or nanobodies, and the like.

[0059] The following examples are provided to illustrate certain particular features and / or embodiments. These examples should not be construed to limit the disclosure to the particular features or embodiments described.EXAMPLES

[0060] Example 1: Formulation Development

[0061] This example describes the development of an ointment formulation for topical administration of SDT-011, and particularly assays of SDT-011 solubility and excipient compatibility.

[0062] Solubility Testing

[0063] Solubility testing for SDT-011 was performed to determine its compatibility with potentially solubilizing excipients. An excess amount of SDT-011 (15-20 mg) was added to 2 g of each test solvent in 20 mL glass vials. Each sample was stirred for 2 hours at 40°C. After stirring, the samples were centrifuged, and the clear portion of each solution was analyzed. Approximately 20 mg of each solution was transferred to a 10 mL volumetric flask, diluted with diluent (Acetonitrile 50:50), and injected for HPLC analysis. Aqueous samples were injected directly after centrifugation.

[0064] Among the materials tested for compatibility was a buffer solution of varying pH produced as follows. 1 mL of concentrated H3PO4was dissolved in 1 L of water. To achieve pH 4.0, 5% NaOH was added. For subsequent pH levels (5.0, 6.0, 7.0, and 8.0), the solution was titrated with NaOH to reach the desired pH levels. 20 mL of each buffer solution was used for the solubility test.

[0065] The solubility of SDT-011 was assessed in different excipients and aqueous buffers, with the results summarized in below Table 1.

[0066] Table 1: SDT-011 Solubility

[0067] Based on the results shown in Table 1, it can be concluded that SDT-011 is very slightly soluble to practically insoluble in moderately polar to non-polar, lipophilic environments. In contrast, SDT-011 is not soluble in polar solvents and strongly hydrophilic environments (see triphasepharmasolutions.com / Private / USP%20DESCRIPTION%20AND%20SOLUBILITY. pdf and biotium.com / faqs / where-can-i-find-out-how-to-dissolve-a-compound-2 / for discussion and definition of solubility, the contents of both of which are incorporated by reference herein in their entirety).

[0068] Excipient Compatibility

[0069] A comprehensive excipient compatibility study was conducted to evaluate potential interactions between SDT-011 and 29 excipients: xanthan gum, potassium sorbate, ceteareth- 20, sodium lauryl sulfate, cetostearyl alcohol, ceresin wax, natrosol 250 HHX, self-emulsifying glycerol monostearate, glycerol monostearate, carbopol 980, propylene glycol, glycerin, medium chain triglycerides, dimethyl isosorbide, polysorbate 80, mineral oil, isopropyl alcohol, ethanol, water, citrate buffer pH 4.0, citrate buffer pH 5.0, citrate buffer pH 6.0, citrate buffer pH 7.0, butylated hydroxytoluene, transcutol, PEG-40 stearate, white petrolatum, hydroxypropyl methylcellulose K100M, and a mixture of phenoxyethanol with methylparaben and propylparaben. Binary mixtures of each excipient with SDT-011 were3417-1-2 stored for 3 weeks at 5°C and 50°C and tested for stability and interaction. Most excipients tested were compatible with SDT-011, with no significant interactions that would compromise the stability of the API. The formulations described herein were prepared with excipients that showed no interaction with SDT-011.

[0070] Sample Formulations

[0071] Following the excipient compatibility results, several ointments, gels, and creams of different formulations, but all containing 0.1% SDT-011, were developed. Each formulation was tested for appearance, viscosity, phase separation, and microscopic analysis, and 3 of each underwent testing for stability, uniformity, degradation products, phase separation, and viscosity under accelerated conditions. It will be appreciated that formulations of equivalent ingredients to those used in the described formulations are encompassed by the current disclosure.

[0072] i. Ointments

[0073] ii. Gels3417-1-2

[0074] III. Creams3417-1-2

[0075] Formulation Testing

[0076] Using an in vitro permeation test (IVPT), the noted ointment, gel, and cream formulations were tested for the ability to deliver an active pharmaceutical ingredient (API, e.g., SDT-011) to hair follicles in skin (e.g., porcine or human), and whether the formulations also transmit the API through the skin and thus systemically. Formulations described herein were compared with a previously developed PLGA nanoparticle formulation loaded with SDT- 011 (described in Friedman et al. Sc / . Transl. Med. 15, 2023, DOI:10.1126 / scitranslmed.abo0684).

[0077] The IVPT was carried out using a standard Franz cell diffusion apparatus system (e.g., as shown and described at permegear.com / franz-cells / ). API-containing ointment, gel, or cream formulations were applied to the skin mounted in the Franz cell for a duration of 24 hours. Following this period, the skin was gently washed to remove any unabsorbed formulation. Fifteen tape strips were employed to remove the stratum corneum layer. Hair follicles were subsequently collected using cyanoacrylate glue, and SDT-011 was carefully extracted from these follicles using acetonitrile solvent. Following the removal of the hair follicles, SDT-011 was then extracted from the viable skin layers, which include the epidermis and dermis, utilizing acetonitrile as the extraction solvent. The receptor fluid, representing systemic transmission, was collected at the end of the 24-hour study duration and was directly injected into the liquid chromatography (LC) system for analysis.

[0078] An LC-MS method was developed to quantify SDT-011 in viable skin (epidermis and dermis), in hair follicles, and in the Franz cell receptor fluid. SDT-011 was detected from the precursor ion at 334.4 m / z, and the daughter ion at 317.0 m / z, and estimated amounts and concentration of SDT-011 were calculated. The SDT-011 hair follicles concentration wascalculated on a measured average of 9.6 hair follicles per Franz cell, and a measured average hair follicle weight of 0.14 mg. The receptor fluid volume in the Franz cell system was 5 mL for a skin area of 0.64 cm2. Accordingly, to determine the systemic exposure in humans, it was necessary to account for the larger blood volume corresponding to the same skin area. For humans, the comparable blood volume per 0.64 cm2skin area is approximately 115 mL, which is 23 times greater than the 5 mL receptor fluid volume. Accordingly, a factor of 23 was applied to the receptor fluid concentration to estimate the systemic exposure to SDT-011.

[0079] The approximate concentration of SDT-011 recovered from three assays is shown inTable 2 and illustrated in Fig. 1.

[0080] Table 2 - Formulation Comparison: SDT-011 concentration in skin and hair follicles

[0081] Table 2 and Fig. 1 demonstrate that, of the formulations tested, Ointments 1 and 2 demonstrated a superior ability to selectively deliver SDT-011 to hair follicles. Significantly, all of the newly developed formulations in general, and Ointments 1 and 2 in particular, demonstrate a significantly superior ability to deliver SDT-011 to hair follicles in comparison to the previously developed PLGA nanoparticles. Without being bound to any theory or mechanism, there can be several explanations for this superiority. The composition based on PLGA nanoparticles had a technical limitation on the amount of SDT-011 that can be encapsulated, hence resulting in a concentration of 0.024% SDT-011 in the formulation. In contrast, the ointment formulation has a much higher loading capacity. The use of SDT-011 as microcrystals suspended in the ointment (in contrast to PLGA encapsulation) enabled thisincreased drug loading capacity and favored the skin deposition and follicle concentration of SDT-011. Additionally, unlike formulations using polar PLGA nanoparticles, ointments are inherently lipophilic. This property allows them to interact with and liquefy the sebum around hair shafts, enhancing sebum fluidity and facilitating drug penetration into hair follicles.Moreover, the PLGA nanoparticles had an average particle size of 74 nm, versus 1-2 pm for the ointment formulation. Although previous teaching indicated that nanosized particles are favored for follicular delivery, the larger sized particle in the newly developed ointments demonstrated significantly more robust delivery.

[0082] The utilization of microparticles instead of the traditionally preferred nanoparticles for follicular delivery represents a departure from established practices and prevailing assumptions within the field. Contrary to the widely held belief that nanoparticles, due to their smaller size and presumed superior ability to penetrate hair follicles, are optimal for such applications, the unexpected discovery that microparticles suspended in a lipophilic ointment base not only match, but surpass, the follicular delivery efficacy of nanosized particles is particularly surprising. Therefore, the present disclosure provides a new and unexpected solution to enhancing drug delivery to hair follicles, thereby advancing the field of topical therapeutics.

[0083] Table 2 also shows the dose-dependent delivery of SDT-011 of increasing concentrations. This comparison of 1%, 5%, and 10% is also shown in Fig. 2, which includes the approximate amount of SDT-011 delivered systemically when applied to skin in the IVPT assay. As shown in Fig. 2, following the application of SDT-011 formulations at concentrations of 1%, 5%, and 10%, the recovery results across viable skin, hair follicles, and receptor fluid suggest a clear correlation between formulation strength and the delivered concentration of SDT-011.

[0084] In viable skin, the mean concentration values demonstrated an increase with higher concentrations of SDT-011. The 1% formulation yielded a mean concentration of 29.7 pM, whereas the 5% and 10% formulations resulted in notably higher concentration of 39.3 pM and 46.9 pM, respectively. These observations indicate enhanced penetration and retention within the viable skin as the formulation concentration increases.

[0085] A similar trend was observed in the hair follicles. The mean amount of SDT-011 recovered from hair follicles increased from 54.2 pM with the 1% formulation to 68.0 pM and3417-1-281.9 pM for the 5% and 10% formulations, respectively. This rise signifies that greater strengths of SDT-011 correspond to higher levels of deposition within hair follicles, potentially augmenting the compound's therapeutic effects localized to this area.

[0086] The receptor fluid, representing systemic transmission, demonstrated a significantly lower concentration of SDT-011 in comparison to the viable skin and hair follicles, with the highest recorded concentration at 1.7 pM for the 10% formulation. This suggests limited systemic absorption of SDT-011, as indicated by the estimated systemic exposure values, which were in the 0.05 to 0.07 pM range across the formulation strengths.

[0087] Taken together, these findings imply that the majority of SDT-011 remains localized within the skin and hair follicles, minimizing systemic exposure and potentially reducing the likelihood of systemic side effects.

[0088] Notably, in a separate study of Ointment 2 toxicity, it was determined that administration of SDT-011 Ointment (1%, 5% or 8%) at 2.5, 12.5 or 20.0 mg / kg / day by dermal application once daily for 23 days in a rodent model was well tolerated and did not result in any treatment-related mortality, and any adverse effects in clinical signs, body weight, food consumption, ophthalmology, clinical pathology, and pathology. Such lack of toxicity bears out the prediction from the IVPT study of limited systemic transmission of the API using the ointment formulation.

[0089] Example 2: Comparison of Ointment and PLGA Formulations

[0090] This example shows a comparison of the skin penetration and permeation of SDT-011 for different lots of the active ingredient in the Ointment 2 formulation with the previously described PLGA nanoparticle formulation of Friedman et al. (see Example 1).

[0091] IVPT methodology was generally the same as described in Example 1. Two lots of SDT- 011 were tested, produced by ChemBridge ("Ointment C") and WuXi CSU ("Ointment W"). The ointment formulations both included 5% SDT-011 w / w, whereas the PLGA nanoparticles included 0.024% SDT-011 w / w. The particle size distribution for the SDT-011 lot from ChemBridge had a D50 of 1.3 pm, compared to a D50 of 2.3 pm for the lot from WuXi CSU.

[0092] The average results of four replicates are shown in Table 3, and illustrated by Fig. 3.

[0093] Table 3: Estimated concentration (pM) of SDT-011 recovered3417-1-2

[0094] As noted above, the strengths of the SDT-011 formulations used in this study varied significantly, with the EMRIS formulations at 5% w / w and the POC PLGA formulation at 0.024% w / w. The lower concentration in the POC PLGA formulation corresponds to the solubility limit of the active pharmaceutical ingredient (API), which prevented a higher concentration from being achieved. In contrast, the 5% EMRIS formulations had the drug in a suspended state, enabling much higher concentrations of SDT-011 to be delivered.Consequently, each formulation displayed different skin penetration outcomes depending on its strength, solubility, and state of the API.

[0095] Both EMRIS 5%-C and EMRIS 5%-W demonstrated similar SDT-011 recovery trends, with concentrations of 27.2 pM and 28.2 pM in the viable skin, respectively, showing robust penetration. The different particle size distributions for the SDT-011 lots from ChemBridge (D50 =1.3 pm) and WuXi CSU (D50=2.3pm) resulted in similar skin penetration profiles. In stark contrast, the POC PLGA's soluble API formulation yielded a mean concentration of only 0.7 pM, indicating its limited penetration capability.

[0096] The hair follicle recovery results for EMRIS 5%-C and EMRIS 5%-W were comparable at 72.6 pM and 70.5 pM, whereas the POC PLGA formulation was substantially lower at 4.3 pM. This demonstrates that the higher API concentrations in the EMRIS formulations resulted in greater deposition within the hair follicles.

[0097] Regarding the estimated systemic exposure, both EMRIS formulations recorded a mean concentration of 0.05 pM. In comparison, the POC PLGA formulation displayed a lower mean concentration of 0.001 pM. This low systemic exposure across all formulations is beneficial for reducing potential systemic side effects as discussed above.

[0098] These results illustrate that while the POC PLGA formulation is constrained by the solubility limit of SDT-011, the higher concentration EMRIS 5% ointment formulations achieve superior localization and retention in the skin and hair follicles. The minimized systemic absorption across all formulations indicates potential for reduced systemic side effects.3417-1-2

[0099] Example 3: API Particle Size and Ointment Efficacy

[0100] This example compares the effects of particle size on the ability of the described ointment formulation to deliver SDT-011 to hair follicles.

[0101] Ointment efficacy was tested by the IVPT assay described in the previous examples, using the Ointment 2 formulation having 5% SDT-011 w / w. In the current assay, the penetration of the ointment with 5% API, API with mean particle sizes (D50) of D50=2.3pm (n=6 replicates) was compared with penetration of the ointment with D50= 5.0pm (n=6 replicates), on full porcine ear skin. The results are shown in Table 4.

[0102] Table 4: Effect of Particle Size on API Concentration in an IVPT study

[0103] As shown in Table 4, the penetration with the 5.0pm API is significantly lower than with the 2.3pm API. Previously, it was shown that API of D50 1.3pm and 2.3pm have similar skin penetration profiles.

[0104] Example 4: Pharmacokinetic Study of 5% SDT-011 Ointment in Sprague-Dawley Rats

[0105] This example shows the pharmacokinetic properties of a 5% SDT-011 ointment following repeated dermal administration to male Sprague-Dawley (SD) rats. The objective was to determine the systemic exposure to SDT-011 after topical application over a seven-day period.

[0106] Three male SD rats were administered the 5% SDT-011 ointment (Ointment 2 from the above formulations) once daily for seven consecutive days. The ointment was applied dermally at a dose of 0.25 g / kg, which corresponds to a 12.5 mg / kg dose of the active pharmaceutical ingredient (API), SDT-011. Blood samples were collected for plasma analysis at multiple time points (0.5, 1, 2, 4, 8, and 24 hours) after the first dose on Day 1 and the last dose on Day 7. Analysis of SDT-011 concentrations in plasma was conducted using a validated liquid chromatography with tandem mass spectrometry (LC-MS / MS) method as described above.3417-1-2

[0107] On Day 1, the plasma concentrations of SDT-011 were found to be mostly below the lower limit of quantitation (0.1 ng / mL) at all time points, indicating very low systemic absorption after a single topical application.

[0108] On Day 7, after seven consecutive daily applications, the systemic exposure to SDT-011 remained minimal. The mean peak plasma concentration (Cmax) was measured to be 0.472 ng / mL. The mean area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUCO-last) was 6.98 ng-h / mL.

[0109] The findings from this study indicate that the topical application of the 5% SDT-011 ointment results in very low systemic absorption, even after repeated administration. The very low plasma concentrations observed throughout the study suggest that the formulation primarily provides localized delivery of the API to the skin, thereby minimizing the potential for systemic side effects. The treatment was well-tolerated by all animals, with no adverse effects observed during the study.

[0110] Example 5: 23-Day Repeated Dose Dermal Toxicity Study in Rats

[0111] This example describes a study that was conducted to determine the maximum tolerated dose (MTD) and potential toxicity of the SDT-011 ointment upon repeated dermal application in Sprague-Dawley rats.

[0112] Twenty male Sprague-Dawley rats were divided into four groups of five. Group 1 received a vehicle control ointment, while Groups 2, 3, and 4 were treated with ointment formulations (described herein as "Ointment 2") containing 1%, 5%, and 8% SDT-011, respectively. The ointments were applied dermally once daily for 23 consecutive days. The respective doses for the treatment groups were 2.5, 12.5, and 20.0 mg / kg / day.

[0113] During and following the described treatments, there were no test article-related adverse effects observed in any of the treated groups with respect to clinical signs, body weight, food consumption, ophthalmic examinations, hematology, coagulation, serum chemistry, and urinalysis. Gross necropsy and organ weight analysis did not reveal any treatment-related abnormalities. Furthermore, histopathological evaluation of the dermal application sites showed no significant microscopic findings in any of the treatment groups.

[0114] As noted, the once-daily dermal administration of SDT-011 ointment at concentrations of 1%, 5%, and 8% for 23 days was well-tolerated by male Sprague-Dawley rats. This study3417-1-2 demonstrated a favorable local and systemic safety profile for the topical ointment formulation.

[0115] Example 6: Skin Sensitization Study in Guinea Pigs (Buehler Test)

[0116] This example describes a study that was conducted to evaluate the skin sensitization potential of the described SDT-011 Ointment in guinea pigs using the Buehler method, in accordance with OECD Guideline 406 (available online at oecd.org / en / publications / 2022 / 06 / test-no-406-skin-sensitisation_glgh292d.html). The study involved an induction phase and a challenge phase.

[0117] Induction Phase: On days 1, 8, and 15, the treatment group received a topical application of 0.5 g of a 5% SDT-011 ointment on a clipped area of their left flank. The placebo group was treated similarly with a placebo ointment. The application sites were covered with an occlusive dressing for 6 hours. Skin reactions were evaluated at 1 and 24 hours after patch removal.

[0118] Challenge Phase: On day 29, all groups were challenged with a topical application of the 5% SDT-011 ointment on a previously untreated area on the right flank. The challenge patch was also applied for 6 hours. Skin reactions, including erythema and edema, were evaluated at approximately 24 and 48 hours after patch removal according to the Magnusson and Kligman Scoring System.

[0119] During the induction phase, no skin reactions were observed in either the placebo control or the SDT-011 treatment groups. Following the challenge application, there were no observable skin reactions in any of the animals in the placebo control and SDT-011 treatment groups at both the 24-hour and 48-hour time points. No clinical signs of systemic toxicity or mortality were observed throughout the study.

[0120] The results of this assay demonstrate that the 5% SDT-011 Ointment did not trigger a skin sensitization reaction in guinea pigs and was classified as non-sensitizer.

[0121] Example 7: Bovine Corneal Opacity and Permeability (BCOP) Assay

[0122] The previous example demonstrated that the described 5% SDT-011 Ointment can be classified as a non-sensitizer under OECD Guideline 406. In this example, the potential for the 5% SDT-011 ointment to cause eye irritation was evaluated using the in vitro Bovine Corneal3417-1-2Opacity and Permeability (BCOP) assay, following the OECD Guideline 437 (available online at oecd.org / en / publications / 2023 / 07 / test-no-437-bovine-corneal-opacity-and-permeability-test- method-for-identifying-i-chemicals-inducing-serious-eye-damage-and-ii-chemicals-not- requiring-classification-for-eye-irritation-or-serious-eye-damage_glg34044.html).

[0123] Freshly isolated bovine corneas were mounted in holders, and a baseline opacity measurement was taken. The undiluted 5% SDT-011 ointment ("Ointment 2" in the above formulations) was then applied to the epithelial surface of the corneas and incubated for ten minutes. Following the exposure period, the substance was rinsed from the corneal surface, and the corneas were incubated for an additional two hours before a final opacity measurement was recorded. Subsequently, the permeability of each cornea was determined by measuring the passage of sodium fluorescein dye using a spectrophotometer.

[0124] The 5% SDT-011 ointment did not cause a significant increase in corneal opacity or permeability, resulting in a calculated In Vitro Irritancy Score (MS) well below the irritation threshold.

[0125] Accordingly, the 5% SDT-011 ointment is classified as a non-irritant under OECD Guideline 437, confirming that it is not expected to cause eye damage.

[0126] Example 8: In Vitro Skin Irritation Test (Reconstructed Human Epidermis Model)

[0127] In this example, the skin irritation potential of the SDT-011 ointment formulations was evaluated using a reconstructed human epidermis model (EpiDerm™) in a study compliant with OECD Test Guideline 439 (available online at oecd.org / en / publications / 2021 / 06 / test-no- 439-in-vitro-skin-irritation-reconstructed-human-epidermis-test-method_glg59b2f.html).

[0128] Three test articles were evaluated: the placebo ointment (vehicle), a 1% SDT-011 ointment, and a 5% SDT-011 ointment. Each test article was applied topically to triplicate reconstructed human epidermis tissues for a 60-minute exposure period. Following exposure, the tissues were rinsed and incubated for 42 hours. The potential for skin irritation was determined by measuring the relative viability of the tissues after exposure using the MTT assay, a colorimetric method that assesses mitochondrial dehydrogenase activity.

[0129] According to the test guideline's prediction model, a test article is classified as a nonirritant if the mean tissue viability is greater than 50%. The results showed mean tissue viabilities of 88% for the placebo ointment, 89% for the 1% SDT-011 ointment, and 83% for3417-1-2 the 5% SDT-011 ointment. As all test articles resulted in tissue viability well above the 50% threshold, they were all classified as non-irritants.

[0130] This study demonstrates that the topical ointment formulations, both with and without the active pharmaceutical ingredient SDT-011, are not irritating to the skin.

[0131] Example 9: Comparative In-Vitro Permeation Test Study in Human and Porcine Skin

[0132] This example shows an in vitro permeation test (IVPT) study that was performed to compare the skin penetration and follicular delivery of a 5% SDT-011 ointment using ex-vivo human and porcine skin.

[0133] The IVPT study was conducted as described in Example 1. Three skin models were used: full-thickness human abdominal skin, full-thickness porcine ear skin, and porcine ear skin dermatomed to about 700 pm. To differentiate between transepidermal and follicular absorption routes, dermatomed skin data was evaluated. Hair follicles extend from the epidermis deep into the dermis, often beyond 1000 pm. The preparation of a dermatomed skin sample to a thickness of approximately 700 pm physically transects the follicles, removing the lower, bulbous follicular structures that serve as the primary reservoir and pathway for drug delivery. A comparison of results from full-thickness skin (with intact follicles) and dermatomed skin (lacking deep follicular structures) allows for the isolation and quantification of the follicular pathway's contribution to delivery.

[0134] The results, presented in the table below, show that the ointment formulation delivers SDT-011, mainly through the follicular pathway. This was shown by a reduction of over 95% in the amount of SDT-011 recovered from the follicles of dermatomed porcine skin (133.2 ng) when compared to the amount recovered from full-thickness porcine skin (2752.9 ng). This result confirms that the follicular route is the primary delivery mechanism for the formulation, rather than transepidermal diffusion across the stratum corneum.

[0135] The study further showed that the ointment delivers meaningful concentrations of SDT-011 to hair follicles in human skin. In the human skin model, the mean follicular concentration reached 2208.4 pM. This concentration is approximately 44-fold higher than the 50 pM IC50 required for inhibition of EGFR inhibitor binding. This confirms the formulation can deliver the API to the target site at a concentration sufficient for therapeutic efficacy. Furthermore, the data validates the porcine skin model as a suitable surrogate for human skin3417-1-2 in this application, as the follicular recovery was comparable between species (2505.1 ng for human versus 2752.9 ng for pig).

[0136] Table 5: IVPT delivery of SDT-011

[0137] Concentrations of SDT-011 in the receptor fluid, representative of systemic exposure, were minimal. The measured value of 0.12 pM in the human full-thickness model is orders of magnitude lower than the high concentrations achieved within the follicles. This result indicates a low potential for systemic absorption of the API.

[0138] In conclusion, this study demonstrates that the ointment formulation uses the follicular pathway to deliver therapeutically significant concentrations of SDT-011 in a targeted manner to human hair follicles, with minimal potential for systemic exposure.

[0139] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

3417-1-2CLAIMS1. An ointment formulation comprising: petrolatum or a non-petroleum-derived equivalent thereof; a hydrophobic solvent; an emulsifier; a moderately polar or non-polar solvent; and an active pharmaceutical ingredient (API), wherein particles of the API in the ointment have a mean diameter (D50) of about 1 pm to 5 pm, inclusive.

2. The ointment formulation of claim 1, wherein the petrolatum is white petrolatum or yellow petrolatum.

3. The ointment formulation of claim 1 or claim 2, wherein the hydrophobic solvent is mineral oil, or a non-petroleum derived equivalent thereof.

4. The ointment formulation of any one of claims 1-3, wherein the emulsifier is glyceryl monostearate.

5. The ointment formulation of any one of claims 1-4, wherein the moderately polar or non-polar solvent is dimethyl isosorbide, oleyl alcohol, or propylene carbonate.

6. The ointment formulation of any one of claims 1-5, comprising 0.1%-10% w / w API.

7. The ointment formulation of any one of claims 1-6, comprising: about 50.0 to 95.0% w / w white petrolatum; about 0.1 to 25.0% w / w mineral oil; about 0.1 to 10% w / w glycerol monostearate; about 0.1 to 10.0% w / w oleyl alcohol or dimethyl isosorbide; and about 1.0 to 5.0% w / w API.3417-1-28. The ointment formulation of any one of claims 1-7, comprising: about 4.9% w / w mineral oil; about 0.1 to 10% w / w glycerol monostearate; about 1 to 15% w / w oleyl alcohol or dimethyl isosorbide; about 0.1 to 10.0% w / w API; and the remainder % w / w, up to a total of 100%, of white petrolatum.

9. The ointment formulation of any one of claims 1-8, comprising: about 83% w / w white petrolatum; about 4.9% w / w mineral oil; about 2% w / w glycerol monostearate; about 5% w / w oleyl alcohol or dimethyl isosorbide; and about 5.0% w / w API.

10. The ointment formulation of any one of claims 1-9, wherein the ointment formulation does not comprise one or more of PLGA, water, propylene glycol, glycerol, isopropyl myristate, dimethyl sulfoxide, diethylene glycol monoethyl ether, gelling agents, or ionic surfactants.

11. The ointment formulation of any one of claims 1-10, wherein the API comprises a compound of formula I:or when the API comprises compound Cl:3417-1-212. A composition for use in providing an active pharmaceutical ingredient (API) to skin of a subject, comprising the ointment formulation of any one of claims 1-11.

13. A composition for use in inhibiting toxic side effects of an epidermal growth factor receptor (EG FR) inhibitor in skin of a subject, comprising the ointment formulation of any one of claims 1-11.

14. The composition for use of claim 13, wherein the EGFR inhibitor is systemically administered to the subject.

15. The composition for use of claim 13, wherein the ointment formulation is provided to the subject prior to, concurrently with, or following treatment with the EGFR inhibitor.

16. The composition for use of claim 13, wherein the EGFR inhibitor is a small molecule, peptide, polypeptide, antibody or fragment thereof.

17. The composition for use of claim 13, wherein the subject is receiving the EGFR inhibitor for treatment of an EGFR-associated cancer.

18. The composition for use of claim 13, wherein the subject is receiving the EGFR inhibitor for treatment of an EGFR-associated cancer selected from colon cancer, lung cancer, head and neck cancer, breast cancer or pancreatic cancer.

19. A method for administering an API to skin of a subject, comprising topically administering a therapeutically effective amount of the ointment formulation of any one of claims 1-11 to a subject in need thereof, thereby administering the API.3417-1-220. A method for inhibiting toxic side effects of a epidermal growth factor receptor (EGFR) inhibitor in skin of a subject, comprising topically administering the ointment formulation of claim 11 to a subject receiving systemic treatment with an EGFR inhibitor, thereby inhibiting toxic side effects of the EGFR inhibitor.

21. The method of claim 20, wherein the ointment formulation is administered to the subject prior to, concurrently with, or following treatment with the EGFR inhibitor.

22. The method of claim 20, wherein the EGFR inhibitor is a small molecule, peptide, polypeptide, antibody or fragment thereof.

23. The method of claim 20, wherein the subject is receiving the EGFR inhibitor for treatment of an EGFR-associated cancer.

24. The method of claim 23, wherein the EGFR-associated cancer is colon cancer, lung cancer, head and neck cancer, breast cancer or pancreatic cancer.

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