Topical aprepitant formulation

Abstract

Topical aprepitant formulations and methods of treating epidermal growth factor receptor inhibitor-associated skin toxicities. In some embodiments, the present disclosure pertains to a topical composition comprising a neurokinin-1 receptor antagonist selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof, and at least one excipient, wherein the composition is a non-aqueous emulsion.

Description

148540.615689TOPICAL APREPITANT FORMULATIONCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 685,456, filed August 21, 2024, and 63 / 750,577, filed January 28, 2025, the disclosures of which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION

[0002] The disclosure relates to topical aprepitant formulations and methods of treating epidermal growth factor receptor inhibitor-associated skin toxicities.BACKGROUND

[0003] Epidermal growth factor receptor inhibitors (EGFRIs) are utilized to treat many cancers of epithelial origin. However, it has been reported that many EGFRIs can cause numerous side effects, including cutaneous toxicities such as rash (e.g., acneiform rash), pruritus, and alopecia. In severe cases, such cutaneous side effects may profoundly diminish patients’ quality of life and may reduce patient adherence to the cancer therapy. Papulopustular eruptions (PPEs) (e.g., acneiform rash) are the most common cutaneous complication of EGFRIs, occurring in up to 90% of patients. (Hirotsu et al., 2019 JAMA Dermatol. 155(7):848-850). Cutaneous complications arise due to high EGFR levels in the basal cells of the epidermis, hair shaft, sebaceous glands, and outer root sheath. (Guggina et al., 2017 Oncology and Therapy. 5(2): 135-148). EGFRs play a crucial role in the normal development and homeostasis of the skin as well as in the inflammatory functions of the epidermis. (Pastore et al. 2008 J Invest Dermatol.128(6): 1365-1374). EGFR signaling has been implicated in innate immunity and chronic inflammation. While the exact pathophysiology has not been fully elucidated and without wishing to be bound by theory, EGFRI-associated skin toxicities including PPEs are postulated to result from disrupted homeostatic and innate immune mechanisms of the epidermis, leading to skin inflammation. Id. Skin toxicities including PPEs generally arise a few weeks after EGFRI initiation and often cause significant pruritus and pain or burning. (Farahnik et al., 2016 J Am Acad Dermatol. 75(5):el91).165742325-vl148540.615689

[0004] Although PPEs are an indicator of drug efficacy, the symptoms can significantly affect patients’ quality of life and lead to reduction, interruption, and even discontinuation of anti-cancer therapies. (Lacouture et al., 2011 Support Care Cancerl9(8): 1079-1095). Untreated skin toxicities due to EGFRI treatment have been documented to result in dose adjustment and / or discontinuation of EGFRI treatment. For example, one study of found that 76% of surveyed oncology practitioners reported temporarily halting EGFRI therapy due to EGFRI-induced skin toxicities, 60% of the practitioners reported reducing the EGFRI dose to their patients, and 32% reported completely discontinuing all EGFRI treatment. (Boone et al., 2007 Survey results, Oncology 72, 152-159).

[0005] Given that EGFRIs are essential to survival, appropriate management of PPEs without compromising anti-cancer therapy is critical. Topical corticosteroids and oral tetracyclines used prophylactically and reactively have been the mainstay of management for these eruptions, though are limited by their adverse effects. (Guggina et al., 2004; Lacouture et al., 2011). Thus, there remains a need for alternative, effective, and safe treatment options for EGFRI-induced skin toxicities, including PPEs. Embodiments of the present disclosure fulfill this need and provide further related advantages.SUMMARY OF THE DISCLOSURE

[0006] One aspect of the present disclosure pertains to a topical composition comprising a neurokinin-1 receptor antagonist selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof, and at least one excipient, wherein the composition is a non-aqueous emulsion.

[0007] Another aspect of the present disclosure pertains to a topical composition comprising:(a) aprepitant or a pharmaceutically acceptable salt thereof,(b) at least one solvent,(c) at least one humectant, and(d) at least one gelling agent.

[0008] Another aspect of the present disclosure pertains to a topical composition comprising:(a) aprepitant or a pharmaceutically acceptable salt thereof,(b) diethylene glycol monoethyl ether,265742325-vl148540.615689(c) benzyl alcohol, and(d) polyethylene glycol.

[0009] Another aspect of the present disclosure pertains to a method of treating a skin toxicity in a subject in need thereof, comprising topically administering to the subject in need thereof a composition comprising a neurokinin- 1 receptor antagonist and at least one excipient, wherein the neurokinin-1 receptor antagonist is selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof, wherein the skin toxicity is induced by an epidermal growth factor receptor inhibitor (EGFRI).BRIEF DESCRIPTION OF THE FIGURES

[0010] Figure 1 shows comparison of facial dermatitis and hair loss at week 12 treatment with erlotinib (10 mg / kg / day) and oral aprepitant (2 mg / kg / day) or topical aprepitant (0.7 mg / kg / day). N= 5 rats per group.

[0011] Figure 2 shows % changes in treatment groups compared to control (Ctl = 100%) with respect to immunohistochemical staining for CD1 lb positive inflammatory cells in the paraffin imbedded 5 pm cross sections of facial skin from control, oral erlotinib [Erl(O), 10 mg / kg / day], oral erlotinib + oral aprepitant at 2 mg / kg / day [Erl+A(O)], and oral erlotinib + topical aprepitant [Erl+A(T)] at 0.7 mg / kg / day in Vehicle A - treated rats at 12 weeks. Values are means ± of 4 rats per group. * p<0.05 vs Ctl; # p<0.05 vs Erl.

[0012] Figure 3 shows comparison of facial dermatitis and hair loss at week 12 treatment with erlotinib (10 mg / kg / day) and two doses of topical aprepitant (1 mg / kg / day (high) and 0.333mg / kg / day (low)). N= 5 rats per group.

[0013] Figure 4 shows the dose-dependent impact of topical aprepitant in Vehicle C on basal superoxide generation by freshly isolated neutrophil of 12 week oral erlotinib (Erl) with or without Vehicle C. Erl+Hi A: oral erlotinib plus topical aprepitant 1 mg / kg / day; Erl+Lo A: oral erlotinib plus topical aprepitant 0.33 mg / kg / day. Values are means ± SE of 4-5 rats per group. # p<0.001 vs Ctl; ++ p<0.01 vs Erl and Erl + Veh; * p<0.05 vs Erl+Veh, and ** p <0.01 vs Erl+Hi A.

[0014] Figure 5 shows representative micrographs of immunohistochemical staining for CD1 lb positive, inflammatory cells (brown) in the facial skin from rats on MgS (25mmol MgO / kg food) +365742325-vl148540.615689 erlotinib (10 mg / kg / day, oral) diet at 12 weeks treated topically with aprepitant high (1 mg / kg / day) or low (0.33 mg / kg / day) doses. Mouse anti-rat CD1 lb antibody (Millipore, Billerica, MA) at the dilution 1 :250 was used to process the fresh frozen 5 pm cross sections and Vector Labs ABC and Vector Labs for HRP DAB kits to label and visualize the membrane bound CD1 lb antigen (Burlingame, CA). CD1 lb positive cells were scattered within the epidermis and dermis. Scale bar = 100 pm.

[0015] Figure 6 shows week 12 treatment with afatinib (afa) & topical aprepitant (aprep: 1 mg / kg / day) initiated at exposure week 1. N= 5 rats per group.

[0016] Figure 7 shows mean values of aprepitant in ng / cm2in stratum comeum, epidermis, dermis, absorbed dose total skin and total penetrated with corresponding statistical analysis. Each of Figures 7A-7F shows data for the following formulations of Table 7 in order from left to right: A, E, G, H, B, K.

[0017] Figure 8 shows clinical images of the face and posterior scalp (A and C) before initiation of aprepitant 2% emulsion gel and (B and D) 1 month later (after 1 week of twice-daily treatment with topical aprepitant followed by three weeks of no therapy).DETAILED DESCRIPTION

[0018] Managing the distressing skin toxicities of EGFRIs is essential to preventing disruptions of critical anti -cancer therapy. EGFRLinduced skin toxicities may lead to an interruption, reduction or cessation of therapy. However, there is some evidence that an EGFRLinduced rash better correlates to overall survival and progression-free survival and, therefore, the presence of these skin toxicities may be predictive of a positive tumor response to the therapy. (Guggina et al., 2017). As such, EGFRI therapy is ideally continued despite the skin toxicities. However, as described above, untreated skin toxicities due to EGFRI treatment have been documented to result in dose adjustment and / or discontinuation of EGFRI treatment.

[0019] Despite the important need of continued use of EGFRIs, there are currently no FDA- approved treatments specifically for EGFRLinduced skin toxicities, including PPEs. Some guidelines recommend prophylactic management of EGFRI-associated PPE in patients with no contraindications to treatment, given the frequency of occurrence. (Lacouture et al., 2011). Prophylactic management regimens with the highest level of evidence include topical emollients,465742325-vl148540.615689 sunscreen, low potency topical steroids, and oral tetracyclines. (Guggina et al., 2004; Lacouture et al., 2011). Guidelines for reactive management are similar and include higher potency topical steroids, oral tetracyclines, and low-dose isotretinoin for refractory cases. Oral tetracyclines are among the most frequently prescribed therapy for the management of PPEs. (Oliel et al., 2024 J Cutan Med Surg. 28(1): 79-81). Given their high risk of antibiotic resistance and inability to achieve complete PPE resolution, it is important to explore alternative, safer, treatment strategies. (Hirotsu et al., 2019). Moreover, while there is an established standard of care (SOC) regimen used to mitigate dermatological adverse effects associated with EGFRI therapy, patients continue to rate “my dermatology treatment for my skin, hair, or nails has made it easier to stick to my cancer treatment plan” the lowest satisfaction score (Aizman et al., 2020).

[0020] Aprepitant is a neurokinin 1 receptor (NK1R) antagonist, the oral formulation of which was approved for the treatment of chemotherapy-associated nausea and vomiting in 2003. Notably, the oral formulation may be used off-label for chronic refractory pruritus. (He et al., 2017 Biomed Res Int. 4790810). Substance P (SP) is the natural ligand of NK1R, and the SP-NK1R signaling pathway has an established role in immune cell regulation and response to microbial infection. (Suvas 2017 J Immunol. 199(5): 1543-1552). Across several studies, SP has been shown to have largely pro- inflammatory effects such as inducing mast cell degranulation as well as enhancing the phagocytic activity and promoting the influx of neutrophils in inflamed tissue.

[0021] Given that induction of inflammation underlies the dermatologic manifestations of EGFRIs, aprepitant has the potential to provide therapeutic benefit by blocking the pro-inflammatory effects of the SP-NK1R signaling pathway. A study conducted in a rat model investigated the role of SP and oral aprepitant during therapy with the EGFRI: erlotinib. Compared with controls, erlotinib-treated rats were found to have an increased SP level and upregulation of NKIRs in epidermal cells and hair follicles at 12 weeks. (Chmielinska et al., 2020 Mol Cell Biochem. 465(1-2): 175-185). In rats cotreated with erlotinib and oral aprepitant, both of these findings were diminished, and a reduction in dermatitis and hair loss was observed. Id. As described in the Oral and Topical Aprepitant Study section below, and in part in Example 1, evaluating topical aprepitant’ s effect on dermatologic symptoms in erlotinib-treated rats, emerging evidence from preclinical studies supports the use of topical aprepitant in the treatment of EGFRI-associated skin toxicities, including PPEs. The data demonstrated that topical aprepitant reduced the dermatologic symptoms to a greater extent than oral565742325-vl148540.615689 aprepitant, specifically suggesting a role for topical aprepitant in the management of EGFRI-induced skin toxicities. Finally, the role of aprepitant on human keratinocytes has been explored through a phosphoproteomic approach which found that aprepitant activates EGFR, and this is believed to underlie aprepitant’s antipruritic effects. (Kwatra et al. 2019 Medicines (Basel). 6(4): 114)

[0022] While the use of oral aprepitant is known, there are no approved topical aprepitant formulations to date. Topical administration may provide several benefits including potentially lower systemic effects, lower relevant dose, higher compliance (including in patients that may have difficulty with oral dosage forms and associated side effects), and localized drug delivery that can bypass the GI tract. However, it is known that topical formulation can be particularly challenging due to issues with penetration, stability, irritation, viscosity, and possibly even appearance and smell of a topical dosage form that may reduce patient compliance.

[0023] A novel topical composition comprising aprepitant or a pharmaceutically acceptable salt thereof, which can be a safe and effective for the treatment of EGFRI-associated (i.e., EGFRI- induced) skin toxicities including papulopustular eruption has now been formulated, as described throughout this disclosure, including in the Examples. It has now been discovered that topical aprepitant not only can lead to the rapid resolution of skin toxicities but also may alleviate symptoms such as pruritus and burning. Notably, it has also now been discovered that the novel topical compositions may be protective against development of new, symptomatic skin toxicities for a period following the discontinuation of therapy. The topical aprepitant compositions of the disclosure can provide a safe and effective treatment of EGFRI-induced skin toxicities while providing certain benefits over an oral aprepitant dosage form, including lower systemic exposure, increased compliance, and / or fewer side effects, as well as benefits over current standard of care treatment (e.g., steroids), including reduced side effects, longer term reduction of skin-toxicities, and / or the potential to treat the underlying inflammatory mechanism. This fills a significant gap in supportive care for patients, reducing the impact of dermatological toxicities on patient quality of life, and can support improved EGFRI treatment outcomes by reducing the need for dose reductions or discontinuations of EGFRI therapy.

[0024] As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise.665742325-vl148540.615689

[0025] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0026] Except where otherwise indicated, all numbers expressing quantities of ingredients, time periods, and so forth used in the disclosure and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not to be considered as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding conventions.

[0027] Additionally, the disclosure of numerical ranges within this specification is considered to be a disclosure of all numerical values and ranges within that range. For example, if a range is from about 1 to about 50, it is deemed to include, for example, 1, 7, 34, 46.1, 23.7, 50 or any other value or range within the range. Moreover, as used herein, the term “at least” includes the stated number, e.g., “at least 50” includes 50.

[0028] All references cited herein, including patent applications and publications, are incorporated by reference in their entirety for any purpose.

[0029] As used herein, “subject” or “patient” refers to an animal, preferably a mammal, including a human or a non-human animal including livestock animals and domestic animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals in need of treatment. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human (i.e., > 18 years of age). In some embodiments, the subject is less than 18 years old.

[0030] As used herein, a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0031] As used herein, the term “administration” and variants thereof (e.g., “administering”) in reference to a composition of the disclosure means providing the composition to a subject in need of treatment. Administering of a composition of the disclosure to the subject includes both selfadministration and administration to the subject by another, including a medical professional.765742325-vl148540.615689

[0032] “ Treat,” “treatment,” or “treating,” as used herein refers to administering a therapeutic agent or pharmaceutical composition to a subject for preventative (i.e., prophylactic) and / or therapeutic purposes. The terms “treat,” “treating,” and “treatment” and variants thereof are meant to include preventing, alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or preventing, alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0033] For example, with respect to treating a skin toxicity of the disclosure, such treatment includes, for example, alleviation of at least one of the symptoms associated therewith, including, but not limited to, reduction in papulopustular eruptions (e.g., acneiform rash), pruritus, pain, xerosis, and nail paronychia. Treatment will also be understood to include the prophylactic administration of a composition of the disclosure, including for example to a patient who has not yet received an EGFRI but will receive at least one dose of an EGFRI, a patient who has been diagnosed with a condition or disease for which EGFRI therapy may be or has been prescribed, or a patient who has already received at least one dose of an EGFRI but has not yet experienced skin toxicity symptoms.

[0034] As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.

[0035] As used herein, the term “alleviate” is meant to describe a process by which the severity of a sign or symptom of a disease or disorder is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. In some embodiments, the administration of a composition disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required.

[0036] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of an active agent that is substantially non-toxic to living organisms, e.g., subjects in need of methods of treatment. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the one or more active components of the disclosure with an inorganic or organic acid, or an organic base, depending on the substituents present on the one or more active components of the disclosure.

[0037] Inorganic acids which may be used to prepare pharmaceutically acceptable salts of the active components include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like. Organic acids which may be used865742325-vl148540.615689 to prepare pharmaceutically acceptable salts include, without limitation, aliphatic mono- and dicarboxylic acids, such as oxalic acid, carbonic acid, citric acid, succinic acid, phenyl-heteroatom- substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the like. Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include, but are not limited to, hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate, p-toluenesulfonate, methanesulfonate, and maleate. Suitable pharmaceutically acceptable salts may also be formed by reacting the active components with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like. Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate groups that may be found on some of the active components and inorganic cations, such as sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium.

[0038] The term “non-aqueous” as used herein in relation to a topical composition or excipient of the disclosure refers to a composition or excipient that is free of water or contains only trace amounts of water. For example, in an embodiment, the water content is less than about 1%. In an embodiment, the water content is less than about 0.6%. In an embodiment, the water content is less than about 0.55%. In an embodiment, the water content is less than about 0.5%. In an embodiment, the water content is less than about 0.4%. In an embodiment, the water content is less than about 0.3%. In an embodiment, the water content is less than about 0.2%. In an embodiment, the water content is less than about 0.1%. In an embodiment, the water content is less than about 0.01%. In an embodiment, the water content is less than about 0.001%. In an embodiment, the water content is less than about 0.0001%. A non-aqueous composition includes a lipophilic composition, for example, which refers to having a tendency to be to dissolve in substances such as fats, oils, and lipids. The term “anhydrous” may also be used to describe non-aqueous compositions and excipients.

[0039] As used herein, and unless indicated otherwise, the term “w / w” refers to percent by weight of the total weight of a composition. For example, the term “5% w / w / ” refers to 5 percent by weight965742325-vl148540.615689 of the total weight of a composition. Where a range is provided, such as “0.5-5% w / w”, the term is intended to refer to a range of 0.5% w / w to 5% w / w.

[0040] As used herein, “stable” in reference to a composition refers to a composition whose chemical and / or physical properties remain or can be caused to remain essentially (or substantially) unchanged for a period of time.

[0041] The present disclosure provides a topical composition comprising a neurokinin- 1 receptor antagonist and at least one excipient.

[0042] A neurokinin- 1 receptor antagonist (or “NK-1 receptor antagonist”) is a small molecule therapeutic. Examples of the NK-1 receptor antagonists include aprepitant, fosaprepitant, serlopitant, vestipitant, tradipitant, orvepitant, casopitant, and pharmaceutically acceptable salts thereof. It will be understood that the disclosure encompasses the NK-1 receptor antagonist in any form. For example, the NK-1 receptor antagonist may be in a solid form, which may be crystalline or amorphous, and includes solvates and hydrates thereof, all of which are encompassed within the scope of the disclosure. Any pharmaceutically acceptable pro-drug modification of an NK-1 receptor antagonist disclosed herein which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0043] In some embodiments, the NK-1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the NK-1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, provided herein is a topical composition comprising a neurokinin- 1 receptor antagonist selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof, and at least one excipient.

[0045] In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant.

[0047] In some embodiments, the composition comprises about 0.1-5% w / w or any sub-range thereof of the neurokinin- 1 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the composition comprises about 0.1-5% w / w, or1065742325-vl148540.615689 about 0.1-3%, or about 0.2-5% w / w, or about 0.2-4.5% w / w, or about 0.2-4% w / w, or about 0.2- 3.5% w / w, or about 0.2-3% w / w, or about 0.2-2.5% w / w, or about 0.2-2% w / w, or about 0.2-1.5% w / w, or about 0.2-1% w / w, or about 0.2-0.5% w / w, or about 0.3-5% w / w, about 0.3-4.5% w / w, or about 0.3-4% w / w, or about 0.3-3.5% w / w, or about 0.3-3% w / w, or about 0.3-2.5% w / w, or about 0.3-2% w / w, or about 0.3-1.5% w / w, or about 0.3-1% w / w, or about 0.3-0.5% w / w, or about 0.4-5% w / w, about 0.4-4.5% w / w, or about 0.4-4% w / w, or about 0.4-3.5% w / w, or about 0.4-3% w / w, or about 0.4-2.5% w / w, or about 0.4-2% w / w, or about 0.4-1.5% w / w, or about 0.4-1% w / w, or about 0.4-0.5% w / w, or about 0.5-1% w / w, or about 0.5- 1.5% w / w, or about 0.5- 1.7% w / w, or about 0.5- 2% w / w, or about 0.5-2.5% w / w, or about 0.5-3% w / w, or about 1-1.5% w / w, or about 1-2% w / w, or about 1.5-2% w / w, or about 2-2.5% w / w of the neurokinin- 1 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant. In some embodiments, the composition comprises about 0.1-3% w / w, or about 0.5-3% w / w, or any sub-range thereof of aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 0.1-3% w / w, or about 0.5-3% w / w, or any sub-range thereof of aprepitant.

[0048] In some embodiments, the composition comprises about 0.1% w / w, or about 0.2% w / w, or about 0.3% w / w, or about 0.4% w / w, or about 0.5% w / w, or about 0.6% w / w, or about 0.7% w / w, or about 0.8% w / w, or about 0.9% w / w, or about 1 % w / w, or about 1.1% w / w, or about 1 .2% w / w, or about 1.3% w / w, or about 1.4% w / w, or about 1.5% w / w, or about 1.6% w / w, or about 1.7% w / w, or about 1.8% w / w, or about 1.9% w / w, or about 2% w / w, or about 2.1% w / w, or about 2.2% w / w, or about 2.3% w / w, or about 2.4% w / w, or about 2.5% w / w, or about 2.6% w / w, or about 2.7% w / w, or about 2.8% w / w, or about 2.9% w / w, or about 3% w / w of the neurokinin- 1 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 0.5% w / w, about 1% w / w, or about 2% w / w of the neurokinin-1 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 0.5% w / w of the neurokinin- 1 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 1% w / w of the neurokinin- 1 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 2% w / w of the neurokinin- 11165742325-vl148540.615689 receptor antagonist of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant.

[0049] The compositions disclosed herein may comprise any form suitable for topical administration. Topical administration will be understood herein to refer to local or dermatological application to the skin surface or the mucous membranes, and includes application to the skin, nails and / or scalp. Suitable forms for topical administration include, but are not limited to, a lotion, emulsion, cream, gel, emulsion gel, ointment, foam, liquid, paste, solution, suspension, spray, patch, or any other topically administrable form.

[0050] Additionally, the compositions disclosed herein may comprise a form suitable for transdemial administration, including a transdermal patch, transdermal lotion, transdemial cream, transdermal gel, transdermal ointment, transdermal foam, transdermal liquid, transdermal paste or other transdermally-administrable form.

[0051] In some embodiments, the topical compositions disclosed herein are in the form of a lotion, emulsion, cream, gel, emulsion gel, ointment, foam, liquid, paste, solution, or suspension. In some embodiments, the composition is a lotion. In some embodiments, the composition is an emulsion. In some embodiments, the composition is a gel. In some embodiments, the composition is an emulsion gel. In some embodiments, the composition is an ointment. In some embodiments, the composition is a foam. In some embodiments, the composition is a liquid. In some embodiments, the composition is a paste. In some embodiments, the composition is a solution. In some embodiments, the composition is a suspension.

[0052] In some embodiments, the composition is an emulsion. The emulsion can be in a form of a macro-emulsion, micro-emulsion or nano-emulsion. An emulsion may be aqueous or non-aqueous in nature (e.g., water-in-oil, oil-in-water, oil-in-oil, silicone-in-water, water-in-oil-in-water, oil-in- water-in-silicone, etc.).

[0053] In some embodiments, the composition is a non-aqueous emulsion. In some embodiments, the composition has a water content equal to or less than about 1% w / w, equal to or less than about 0.9% w / w, equal to or less than about 0.8% w / w, equal to or less than about 0.7% w / w, equal to or less than about 0.6% w / w, equal to or less than about 0.55% w / w, equal to or less than about 0.5% w / w, equal to or less than about 0.4% w / w, equal to or less than about 0.3% w / w, equal to or less1265742325-vl148540.615689 than about 0.2% w / w, equal to or less than about 0.1% w / w, equal to or less than about 0.01% w / w, equal to or less than about 0.001% w / w, equal to or less than about 0.0001% w / w, equal to or less than about 0.00001% w / w, or equal to or less than about 0.000001% w / w of the topical composition, or any concentration therebetween.

[0054] In some embodiments, the composition is an emulsion gel. An “emulsion gel” refers to an emulsion in a gel form. In some embodiments, the aprepitant is fully dissolved in the emulsion gel such that the emulsion gel composition is free of or substantially free of identifiable aprepitant crystals. In this context, the term “substantially free” means that the aprepitant is not added to the composition in crystal form and that the composition comprises essentially no identifiable aprepitant crystals (e.g., aprepitant crystals cannot be present in any concentration greater than about 0.1% w / w, or about 0.01% w / w, or about 0.001% w / w, or about 0.0001% w / w, or about 0.00001% w / w). This may also refer to the stability of the composition for a certain amount of time as described herein. For example, a composition of the disclosure may be free of or substantially free of identifiable crystals for a particular length of time under certain storage conditions (e.g., for one month at room temperature).

[0055] The topical compositions of the disclosure comprise at least one excipient. In the present disclosure, the one or more excipients include standard pharmaceutical excipients and generally recognized as safe (“GRAS”) excipients used for topical products. Any type of excipient suitable for topical administration may be used in the topical compositions of the disclosure, including, but not limited to, a solvent, an emollient, a humectant, a gelling agent, a stabilizing agent (e.g., an antioxidant), a viscosity modifier, a surfactant, an emulsifier, a preservative, a buffering agent, a penetration enhancer, a skin protectant, a chelating agent, a fragrance, and a colorant or pigment.

[0056] It would be understood by a person of skill in the art that certain excipients may have more than one function and can be classified in more than one of the above categories of excipients. For example, a particular excipient may be both a solvent and an antioxidant. This may depend, for example, on the type of composition, the amount of excipient used, and / or the other excipients present. In such cases where an excipient can be classified in more than one category (“overlapping excipient”) and the composition includes such categories of excipients, the overlapping excipient does not represent more than one category in said composition. For example, where an excipient could be classified as both a solvent and an antioxidant, and a specific composition is said to have1365742325-vl148540.615689 both a solvent and an antioxidant, the overlapping excipient will not serve as both the solvent and the antioxidant in the composition.

[0057] As will be appreciated by the ordinarily skilled artisan, an excipient includes any constituent which adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect. In general, compositions comprise more than one excipient, and the excipient(s) is selected based on the form of the dosage form. Examples of pharmaceutically acceptable excipients and methods of manufacture of topical dosage forms such as those mentioned above may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD. Except insofar as any conventional carrier or excipient is incompatible with the active ingredient, the disclosure encompasses the use of all conventional carriers and excipients in topical compositions containing a composition of the disclosure.

[0058] The compositions of the disclosure may comprise a non-aqueous (or anhydrous) solvent (i.e., a solvent other than water). Non-limiting examples of non-aqueous solvents include, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethyl isosorbide (DMI), ethanol, isopropanol, t- butyl alcohol, amyl alcohol, benzyl alcohol, oleyl alcohol, cyclohexanedimethanol, acetone, diacetone alcohol, hexyl alcohol, tetrahydrofurfuryl alcohol, diethylene glycol monoethyl ether (also referred to as ethoxy diglycol, and sold under the tradename Transcutol), carboxylic acids such as acetic acid or multi carboxylic acid; glycol ether (e.g., phenoxyethanol), 1 ,2-hexanediol, butylene glycol, diethylene glycol, dipropylene glycol, ethyl hexanediol, ethylene glycol, hexylene glycol, pentylene glycol, propylene glycol, propylene glycol monolaurate, tetraethylene glycol, triethylene glycol, tripropylene glycol, polyethylene glycol, butanetriol, glycerol, 1,2,6-hexanetriol, butyl stearate, C12-15 alkyl benzoate, C12-15 alkyl lactate, caprylic / capric triglyceride, cetearyl ethylhexanoate, cetearyl isononanoate, cetyl octanoate, cetyl palmitate, coco-caprylate / caprate, cocoglycerides, decyl oleate, dibutyl adipate, dicaprylyl carbonate, diethylhexyl adipate, di- ethylhexyl succinate, diisopropyl adipate, dioctyl malate, di-PPG-2 myreth-10 adipate, di-PPG-3 myristyl ether adipate, ethyl oleate, ethylhexyl cocoate, ethylhexyl hydroxystearate, ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, hexyl laurate, hexyldecyl laurate, hexyldecyl stearate, isocetyl stearate, isocetyl stearoyl stearate, isodecyl oleate, isopropyl myristate, isopropyl palmitate, isostearyl neopentanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate,1465742325-vl148540.615689 myristyl myristate, octyldodecyl stearoyl stearate, oleyl erucate, oleyl oleate, pentaerythrityl tetracaprylate / caprate, pentaerythrityl tetraisostearate, PPG-2 myristyl ether propionate, propylene glycol dicaprylate / dicaprate, propylene glycol isostearate, propyl heptyl caprylate, stearyl octanoate dimethyl isosorbide and propylene carbonate, macrogol- 15 -hydroxystearate, oleyl macrogol 6 glycerides, octyldodecanol, N-methyl-2 -pyrrolidone, and mixtures thereof.

[0059] In some embodiments, the topical composition comprises at least one solvent. In some embodiments, the topical composition comprises at least two solvents (co-solvents). In some embodiments, the topical composition comprises at least three solvents (co-solvents). In some embodiments, any pharmaceutically acceptable non-aqueous solvent can be used. In some embodiments, the solvent comprises diethylenc glycol monoethyl ether. In some embodiments, the solvent comprises benzyl alcohol. In some embodiments, the solvent comprises polyethylene glycol. In some embodiments, the solvent comprises phenoxyethanol. In some embodiments, the solvent comprises propylene glycol. In some embodiments, the solvent comprises hexylene glycol.

[0060] In some embodiments, the solvent is free of or substantially free of phenoxyethanol, propylene glycol, hexylene glycol, acetone, DMSO, and / or DMI. The term “substantially free” as used herein, is used to indicate that a component is not added to a composition and the composition comprises essentially none of that component (e.g., the component cannot be present in any concentration greater than about 0.001% w / w, or about 0.0001% w / w, or about 0.00001% w / w). The term “free of’, as used here in, indicates that a component is not added to a composition and the composition contains none (i.e., 0% w / w) of that component.

[0061] In some embodiments, the solvent is free of or substantially free of phenoxyethanol, propylene glycol, hexylene glycol, and DMSO. In some embodiments, the solvent is free of or substantially free of phenoxyethanol, propylene glycol, hexylene glycol, DMSO, and DMI. In some embodiments, the solvent is free of or substantially free of phenoxyethanol. In some embodiments, the solvent is free of or substantially free of propylene glycol. In some embodiments, the solvent is free of or substantially free of hexylene glycol. In some embodiments, the solvent is free of or substantially free of DMSO. In some embodiments, the solvent is free of or substantially free of DMI.

[0100] In some embodiments, the solvent comprises diethylene glycol monoethyl ether and benzyl alcohol. In some embodiments, the solvent comprises diethylene glycol monoethyl ether and1565742325-vl148540.615689 polyethylene glycol. In some embodiments, the solvent comprises benzyl alcohol and polyethylene glycol. In some embodiments, the solvent comprises diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol. In some embodiments, the solvent is diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, phenoxyethanol, propylene glycol, and / or hexylene glycol. In some embodiments, the solvent is diethylene glycol monoethyl ether, benzyl alcohol, and / or polyethylene glycol. In some embodiments, the solvent is diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol.

[0062] In some embodiments, the polyethylene glycol has a molecular weight range of about 200 to about 2,000. In some embodiments, the polyethylene glycol is PEG 200, PEG 300, PEG 400 or PEG 600. In some embodiments, the polyethylene glycol is PEG 400. In some embodiments, the polyethylene glycol is PEG 400 super refined.

[0063] In some embodiments, the composition comprises about 40-95% w / w or any sub-range thereof of at least one solvent. The %w / w of at least one solvent herein is understood to mean the total amount of solvent in the composition whether the composition comprises one solvent or more than one solvent. For example, if the composition comprises one solvent, the composition may comprise any solvent concentration range disclosed (e.g., 40-95% w / w) of that one solvent. For example, if the composition comprises three solvents, the combined (e.g., total) concentration of the three solvents would be within any solvent concentration range disclosed (e.g., 40-95% w / w), such that the total solvent concentration range would represent the %w / w of the first solvent plus the %w / w of the second solvent plus the %w / w of the third solvent. For example, a topical composition of the disclosure may comprise three solvents with 40% of diethylene glycol monoethyl ether, 2% of benzyl alcohol and 47.4% polyethylene glycol, such that combined solvent concentration is about 89.4%.

[0064] In some embodiments, the composition comprises about 40-95% w / w, or about 50-95% w / w, or about 60-95% w / w, or about 65-95% w / w, or about 70-95% w / w, or about 75-95% w / w, or about 80-95% w / w, or about 85-95% w / w, or about 50-90% w / w, or about 60-90% w / w, or about 65-90% w / w, or about 70-90% w / w, or about 75-90% w / w, or about 80-90% w / w, or about 85-90% w / w, or about 85-92% w / w, or about 87% to 92% w / w, or any sub-range thereof of at least one solvent. In some embodiments, the solvent is diethylene glycol monoethyl ether, benzyl alcohol,1665742325-vl148540.615689 and / or polyethylene glycol. In some embodiments, the solvent is diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol.

[0065] In some embodiments, the composition comprises about 35-60% w / w or 35-55% w / w or any subrange thereof of diethylene glycol monoethyl ether. For example, in some embodiments, the composition comprises about 35-60% w / w, or about 35-55% w / w, or about 37-55% w / w, or about 38-55% w / w, or about 39-55% w / w, or about 40-55% w / w, or about 38-50% w / w, or about 39-50% w / w, or about 40-50% w / w, or about 37-45% w / w, or about 38-45% w / w, or about 39-45% w / w, or about 40-45% w / w, or any subrange thereof of di ethylene glycol monoethyl ether.

[0066] In some embodiments, the composition comprises about 35% w / w, or about 36% w / w, or about 37% w / w, or about 38% w / w, or about 39% w / w, or about 40% w / w, or about 41% w / w, or about 42% w / w, or about 43% w / w, or about 44% w / w, or about 45% w / w, or about 46% w / w, or about 47% w / w, or about 48% w / w, or about 49% w / w, or about 50% w / w, or about 51% w / w, or about 52% w / w, or about 53% w / w, or about 54% w / w, or about 55% w / w, of the diethylene glycol monoethyl ether. In some embodiments, the composition comprises about 40% w / w, about 45% w / w, or about 50% w / w of the diethylene glycol monoethyl ether. In some embodiments, the composition comprises about 40% w / w of the diethylene glycol monoethyl ether.

[0067] In some embodiments, the composition comprises about 0.5-5% w / w or any subrange thereof of benzyl alcohol. For example, in some embodiments, the composition comprises about 0.5- 5% w / w, or about 0.5-4%w / w, or about 0.5-3%w / w, or about 0.5-2.5%w / w, or about 0.5-2%w / w, 1- 5% w / w, or about l-4%w / w, or about l-3%w / w, or about l-2.5%w / w, or about l-2%w / w, or about 1.5-4%w / w, or about 1.5-3%w / w, or about 1.5-2.5%w / w, or about 1.5-2%w / w, or about 1.8-2.5% w / w, or about 1.9-2.5% w / w, or about 2-2.5% w / w, or about 2-3% w / w, or about 2-2.2% w / w, or any subrange thereof of benzyl alcohol.

[0068] In some embodiments, the composition comprises about 0.5% w / w, or about 0.6% w / w, or about 0.7% w / w, or about 0.8% w / w, or about 0.9% w / w, or about 1% w / w, or about 1.1% w / w, or about 1.2% w / w, or about 1.3% w / w, or about 1.4% w / w, or about 1.5% w / w, or about 1.6% w / w, or about 1 .7% w / w, or about 1 .8% w / w, or about 1 .9% w / w, or about 2% w / w, or about 2.1 % w / w, or about 2.2% w / w, or about 2.3% w / w, or about 2.4% w / w, or about 2.5% w / w of benzyl alcohol. In some embodiments, the composition comprises about 2% w / w or about 2.2% w / w of benzyl alcohol. In some embodiments, the composition comprises about 2% w / w of benzyl alcohol.1765742325-vl148540.615689

[0069] In some embodiments, the composition comprises about 30-60% w / w or 30-55% w / w or any subrange thereof of polyethylene glycol. For example, in some embodiments, the composition comprises about 30-60% w / w, or about 30-55% w / w, or about 33-55% w / w, or about 35-55% w / w, or about 38-55% w / w, or about 40-55% w / w, or about 45-55% w / w, or about 47-55% w / w, or about 30-50% w / w, or about 31-50% w / w, or about 32-50% w / w, or about 33-50% w / w, or about 34-50% w / w, or about 35-50% w / w, or about 36-50% w / w, or about 37-50% w / w, or about 38-50% w / w, or about 39-50% w / w, or about 40-50% w / w, or about 34-48% w / w, or about 35-48% w / w, or about 38-48% w / w, or about 40-48% w / w, or about 45-48% w / w, or about 46-49% w / w, or any subrange thereof of polyethylene glycol.

[0070] In some embodiments, the composition comprises about 30% w / w, or about 31% w / w, or about 32% w / w, or about 33% w / w, or about 34% w / w, or about 35% w / w, or about 36% w / w, or about 37% w / w, or about 38% w / w, or about 39% w / w, or about 40% w / w, or about 41% w / w, or about 42% w / w, or about 43% w / w, or about 44% w / w, or about 45% w / w, or about 46% w / w, or about 47% w / w, or about 48% w / w, or about 49% w / w, or about 50% w / w, or about 51% w / w, or about 52% w / w, or about 53% w / w, or about 54% w / w, or about 55% w / w of the polyethylene glycol. In some embodiments, the composition comprises about 34% w / w, or about 34.05% w / w, or about 34.1% w / w, or about 34.25% w / w, or about 34.95% w / w, or about 40% w / w, or about 45% w / w, or about 45.25% w / w, or about 47.4% w / w of the polyethylene glycol.

[0071] Emollients are typically materials used for moisturizing and lubricating the skin, such as for the prevention or relief of dryness. A number of suitable emollients are known and may be used in the present disclosure. For example, Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972) and the International Cosmetic Ingredient Dictionary and Handbook, eds. Wenninger and McEwen, pp. 1656-61, 1626, and 1654-55 (The Cosmetic, Toiletry, and Fragrance Assoc., Washington, D.C., 7th Edition, 1997) (hereinafter “ICI Handbook”) contains numerous examples of suitable materials. Non-limiting examples of emollients include medium chain triglycerides (e.g., Miglyol® 812N), isopropyl isostearate, petrolatum, dimethicone, dimethiconoL sopropyl myristate, isopropyl palmitate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, lanolin, mineral oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, cetyl acetate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol1865742325-vl148540.615689 dicaprylate / dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, octyl dodecanol, sucrose esters of fatty acids and octyl hydroxystearate.

[0072] In some embodiments, the topical composition comprises at least one emollient. In some embodiments, any pharmaceutically acceptable emollient can be used. In some embodiments, the emollient comprises a medium chain triglyceride. In some embodiments, the emollient is a medium chain triglyceride. In some embodiments, the emollient comprises dimethicone. In some embodiments, the emollient does not comprise dimethicone.

[0073] In some embodiments, the composition comprises about 0.5-10% w / w or any sub-range thereof of at least one emollient. The %w / w of at least one emollient herein is understood to mean the total amount of emollient in the composition whether the composition comprises one emollient or more than one emollient.

[0074] In some embodiments, the composition comprises about 0.5-10% w / w, 0.5-9% w / w, or about 0.5-8% w / w, or about 0.5-7% w / w, or about 0.5-6% w / w, or about 0.5-5% w / w, or about 0.5- 4% w / w, or about 0.5-3% w / w, or about 0.5-2% w / w, or about 1-10% w / w, or about 1-9% w / w, or about 1-8% w / w, or about 1-7% w / w, or about 1-6% w / w, or about 1-5% w / w, or about 1-4% w / w, or about 1-3% w / w, or about 1-2% w / w, or about 1.5-10% w / w, or about 1.5-9% w / w, or about 1.5- 8% w / w, or about 1.5-7% w / w, or about 1.5-6% w / w, or about 1.5-6% w / w, or about 1.5-5% w / w, or about 1.5-4% w / w, or about 1.5-3% w / w, or about 1.5-2.5% w / w, or about 1.5-2% w / w, or any subrange thereof of at least one emollient.

[0075] In some embodiments, the composition comprises about 0.5-10% w / w or any sub-range thereof of a medium chain triglyceride. In some embodiments, the composition comprises about 0.5- 10% w / w, 0.5-9% w / w, or about 0.5-8% w / w, or about 0.5-7% w / w, or about 0.5-6% w / w, or about 0.5-5% w / w, or about 0.5-4% w / w, or about 0.5-3% w / w, or about 0.5-2% w / w, or about 1-10% w / w, or about 1-9% w / w, or about 1-8% w / w, or about 1-7% w / w, or about 1-6% w / w, or about 1- 5% w / w, or about 1-4% w / w, or about 1-3% w / w, or about 1-2% w / w, or about 1.5-10% w / w, or about 1.5-9% w / w, or about 1.5-8% w / w, or about 1.5-7% w / w, or about 1.5-6% w / w, or about 1.5- 5% w / w, or about 1.5-4% w / w, or about 1.5-3% w / w, or about 1.5-2.5% w / w, or about 1.5-2% w / w, or any sub-range thereof of a medium chain triglyceride.

[0076] In some embodiments, the composition comprises about 0.5% w / w, or about 0.6% w / w, or about 0.7% w / w, or about 0.9% w / w, or about 0.9% w / w, or about 1% w / w, or about 1.1% w / w, or1965742325-vl148540.615689 about 1.2% w / w, or about 1.3% w / w, or about 1.4% w / w, or about 1.5% w / w, or about 1.6% w / w, or about 1.7% w / w, or about 1.8% w / w, or about 1.9% w / w, or about 2% w / w, or about 2.5% w / w, or about 3% w / w, or about 3.5% w / w, or about 4% w / w, or about 4.5% w / w, or about 5% w / w, or about 5.5% w / w, or about 6% w / w of a medium chain triglyceride. In some embodiments, the composition comprises about 1.5% w / w a medium chain triglyceride. In some embodiments, the composition comprises about 2.5% w / w a medium chain triglyceride. In some embodiments, the composition comprises about 5% w / w a medium chain triglyceride.

[0077] Humectants are typically substances which provide the skin with water-retention benefits. Non-limiting examples of humectants include polyhydric alcohols, amino acids and derivatives thereof such as proline and arginine aspartate, 1,3-butylene glycol, propylene glycol and water and codium tomentosum extract, collagen amino acids or peptides, creatinine, diglycerol, biosaccharide gum-1, glucamine salts, glucuronic acid salts, glutamic acid salts, polyethylene glycol ethers of glycerin (e.g., glycereth 20), glycerin, glycerol monopropoxy late, glycogen, hexylene glycol, honey, and extracts or derivatives thereof, hydrogenated starch hydrolysates, hydrolyzed mucopolysaccharides, inositol, keratin amino acids, glycosaminoglycans, methoxy PEG- 10, methyl gluceth-10, methyl gluceth-20, methyl glucose, 3-methyl-l,3-butanediol, N-acetyl glucosamine salts, polyethylene glycol and derivatives thereof (such as PEG- 15 butanediol, PEG-4, PEG-5 pentaerythitol, PEG-6, PEG-8, PEG-9), pentaerythitol, 1,2 pentanediol, PPG-1 glyceryl ether, PPG- 9,2-pyrrolidone-5-carboxylic acid and its salts such as glyceryl pea, saccharide isomerate, sericin, silk amino acids, sodium acetylhyaluronate, sodium hyaluronate, sodium poly-aspartate, sodium polyglutamate, sorbeth 20, sorbeth 6, sugar and sugar alcohols and derivatives thereof such as glucose, mannose and polyglycerol sorbitol, trehalose, triglycerol, trimethyolpropane, tris (hydroxymethyl) amino methane salts, lactic acid, urea, hyaluronic acid, and yeast extract, and mixtures thereof. Nonlimiting examples of polyhydric alcohols may include glycerin, diglycerin, glycerol, erythritol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, maltitol, mannose, inositol, triethyleneglycol, sodium pyrrolidone carboxylic acid (PCA), zinc PCA and derivatives and mixtures thereof.

[0078] In some embodiments, the topical composition comprises at least one humectant. In some embodiments, any pharmaceutically acceptable humectant can be used. In some embodiments, the humectant comprises glycerin. In some embodiments, the humectant is glycerin.2065742325-vl148540.615689

[0079] In some embodiments, the composition comprises about 1-10% w / w or about 1-15% w / w or any sub-range thereof of at least one humectant. The %w / w of at least one humectant herein is understood to mean the total amount of humectant in the composition whether the composition comprises one humectant or more than one humectant.

[0080] In some embodiments, the composition comprises about 1-15% w / w, or about 1-12% w / w, or about 1-10% w / w, or about 1-9% w / w, or about 1-8% w / w, or about 1-7% w / w, or about 1-6% w / w, or about 1-5% w / w, or about 1-4% w / w, or about 1-3% w / w, or about 2-10% w / w, or about 2- 9% w / w, or about 2-8% w / w, or about 2-7% w / w, or about 2-6% w / w, or about 2-5% w / w, or about 3-10% w / w, or about 3-9% w / w, or about 3-8% w / w, or about 3-7% w / w, or about 3-6% w / w, or about 3-5% w / w, or about 4-10% w / w, or about 4-9% w / w, or about 4-8% w / w, or about 4-7% w / w, or about 4-6% w / w, or about 4-5% w / w, or about 5-10% w / w, or about 5-9% w / w, or about 5-8% w / w, or about 5-7% w / w, or about 5-6% w / w or any sub-range thereof of at least one humectant.

[0081] In some embodiments, the composition comprises about 1-10% w / w or about 1-15% w / w or any sub-range thereof of glycerin. In some embodiments, the composition comprises about 1-15% w / w, or about 1-12% w / w, or about 1-10% w / w, or about 1-9% w / w, or about 1-8% w / w, or about 1- 7% w / w, or about 1-6% w / w, or about 1-5% w / w, or about 1-4% w / w, or about 1-3% w / w, or about 2-10% w / w, or about 2-9% w / w, or about 2-8% w / w, or about 2-7% w / w, or about 2-6% w / w, or about 2-5% w / w, or about 3-10% w / w, or about 3-9% w / w, or about 3-8% w / w, or about 3-7% w / w, or about 3-6% w / w, or about 3-5% w / w, or about 4-10% w / w, or about 4-9% w / w, or about 4-8% w / w, or about 4-7% w / w, or about 4-6% w / w, or about 4-5% w / w, or about 5-10% w / w, or about 5- 9% w / w, or about 5-8% w / w, or about 5-7% w / w, or about 5-6% w / w or any sub-range thereof of glycerin.

[0082] In some embodiments, the composition comprises about 1% w / w, or about 2% w / w, or about 3% w / w, or about 4% w / w, or about 4.5% w / w, or about 5% w / w, or about 5.5% w / w, or about 6% w / w, or about 6.5% w / w, or about 7% w / w, or about 7.5% w / w, or about 8% w / w, or about 8.5% w / w, or about 9% w / w, or about 9.5% w / w, or about 10% w / w of glycerin. In some embodiments, the composition comprises about 6% w / w of glycerin. In some embodiments, the composition comprises about 7% w / w of glycerin.

[0083] Non-limiting examples of gelling agents include agar, alginate, arabinoxylan, carrageenan, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl2165742325-vl148540.615689 methylcellulose, cellulose, curdlan, gelatin, gellan, P-glucan, tragacanth gum, guar gum, gum arabic, locust bean gum, pectin, starch, a carbomer, acrylate copolymers, silica, xanthan gum, salts thereof, or a combination or mixture thereof.

[0084] In some embodiments, the topical composition comprises at least one gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the gelling agent is hydroxypropyl cellulose.

[0085] In some embodiments, the composition comprises about 0.2-5% w / w or about 0.5-5% w / w or any sub-range thereof of at least one gelling agent. The %w / w of at least one gelling agent herein is understood to mean the total amount of gelling agent in the composition whether the composition comprises one gelling agent or more than one gelling agent.

[0086] In some embodiments, the composition comprises about 0.2-5% w / w, or about 0.3-5% w / w, or about 0.4-5% w / w, or about 0.5-5% w / w, or about 0.6-5% w / w, or about 0.7-5% w / w, or about 0.75-5% w / w, or about 0.8-5% w / w, or about 0.9-5% w / w, or about 1-5% w / w, or about .2-4% w / w, or about 0.5-4% w / w, or about 0.6-4% w / w, or about 0.7-4% w / w, or about 0.75-4% w / w, or about 0.8-4% w / w, or about 0.9-4% w / w, or about 1-4% w / w, or about 0.5-3% w / w, or about 0.6-3% w / w, or about 0.7-3% w / w, or about 0.8-3% w / w, or about 0.9-3% w / w, or about 1-3% w / w, or about 0.5- 2% w / w, or about 0.6-2% w / w, or about 0.7-2% w / w, or about 0.8-2% w / w, or about 0.9-2% w / w, or about 1-2% w / w, or about 0.5-1.5% w / w, or about 0.6-1.5% w / w, or about 0.7-1.5% w / w, or about 0.8-1 .5% w / w, or about 0.9-1 .5% w / w, or about 1-1.5% w / w, or about 0.7-1 .4% w / w, or about 0.7- 1.3% w / w, or about 0.7-1.2% w / w, or about 0.7-1.1% w / w, or about 0.75-1% w / w, or about 0.8- 1.2% w / w or any sub-range thereof of at least one gelling agent.

[0087] In some embodiments, the composition comprises about 0.2-5% w / w, or about 0.3-5% w / w, or about 0.4-5% w / w, or about 0.5-5% w / w, or about 0.6-5% w / w, or about 0.7-5% w / w, or about 0.75-5% w / w, or about 0.8-5% w / w, or about 0.9-5% w / w, or about 1-5% w / w, or about .2-4% w / w, or about 0.5-4% w / w, or about 0.6-4% w / w, or about 0.7-4% w / w, or about 0.75-4% w / w, or about 0.8-4% w / w, or about 0.9-4% w / w, or about 1-4% w / w, or about 0.5-3% w / w, or about 0.6-3% w / w, or about 0.7-3% w / w, or about 0.8-3% w / w, or about 0.9-3% w / w, or about 1-3% w / w, or about 0.5- 2% w / w, or about 0.6-2% w / w, or about 0.7-2% w / w, or about 0.8-2% w / w, or about 0.9-2% w / w, or about 1-2% w / w, or about 0.5-1.5% w / w, or about 0 6-1.5% w / w, or about 0.7-1.5% w / w, or about 0.8-1.5% w / w, or about 0.9-1.5% w / w, or about 1-1.5% w / w, or about 0.7-1.4% w / w, or about 0.7-2265742325-vl148540.6156891.3% w / w, or about 0.7-1.2% w / w, or about 0.7-1.1% w / w, or about 0.75-1% w / w, or about 0.8- 1.2% w / w or any sub-range thereof of hydroxypropyl cellulose.

[0088] In some embodiments, the composition comprises about 0.2% w / w, or about 0.3% w / w, or about 0.4% w / w, or about 0.5% w / w, or about 0.6% w / w, or about 0.7% w / w, or about 0.75% w / w, or about 0.8% w / w, or about 0.9% w / w, or about 1% w / w, or about 1.1% w / w, or about 1.2% w / w, or about 1.3% w / w, or about 1.4% w / w, or about 1.5% w / w, or about 1.6% w / w, or about 1.7% w / w, or about 1.8% w / w, or about 1.9% w / w, or about 2% w / w of hydroxypropyl cellulose. In some embodiments, the composition comprises about 1% w / w of hydroxypropyl cellulose. In some embodiments, the composition comprises about .75% w / w of hydroxypropyl cellulose.

[0089] Non-limiting examples of antioxidants include tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), dodecyl gallate, octyl gallate, propyl gallate, ascorbyl palmitate, sodium ascorbate, thymol and combinations thereof. Any GRAS (“generally recognized as safe” by the U.S. Food & Drug Administration) antioxidant is suitable for use in the present disclosure.

[0090] In some embodiments, the topical composition comprises at least one antioxidant. In some embodiments, the antioxidant comprises butylated hydroxytoluene. In some embodiments, the antioxidant comprises butylated hydroxyanisole. In some embodiments, the antioxidant comprises propyl gallate. In some embodiments, the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, and / or propyl gallate. In some embodiments, the antioxidant is butylated hydroxytoluene and / or butylated hydroxyanisole. In some embodiments, the antioxidant is propyl gallate. In some embodiments, the antioxidant is butylated hydroxy toluene. In some embodiments, the antioxidant is butylated hydroxyanisole. In some embodiments, the antioxidant is butylated hydroxytoluene and the topical composition does not contain an additional antioxidant. In some embodiments, the composition does not comprise an antioxidant. In some embodiments, the composition does not comprise propyl gallate. In some embodiments, the composition does not comprise any of propyl gallate, dodecyl gallate, and octyl gallate.

[0091] In some embodiments, the composition comprises about 0.01-1% w / w or any sub-range thereof of at least one antioxidant. The %w / w of at least one antioxidant herein is understood to mean the total amount of antioxidant in the composition whether the composition comprises one antioxidant or more than one antioxidant.2365742325-vl148540.615689

[0092] In some embodiments, the composition comprises about 0.01-1% w / w, or about 0.01-0.5% w / w, or about 0.01-0.4% w / w, or about 0.01-0.3% w / w, or about 0.01-0.2% w / w, 0.03-1% w / w, or about 0.03-0.5% w / w, or about 0.03-0.4% w / w, or about 0.03-0.3% w / w, or about 0.03-0.2% w / w, 0.04-1% w / w, or about 0.04-0.5% w / w, or about 0.04-0.4% w / w, or about 0.04-0.3% w / w, or about 0.04-0.2% w / w, 0.05-1% w / w, or about 0.05-0.5% w / w, or about 0.05-0.4% w / w, or about 0.05- 0.3% w / w, or about 0.05-0.2% w / w, 0.06-0.2% w / w, 0.07-0.2% w / w, 0.08-0.2% w / w, 0.09-0.2% w / w, 0.1-0.2% w / w, 0.09-0.15% w / w, or any sub-range thereof of at least one antioxidant.

[0093] In some embodiments, the composition comprises about 0.01-1% w / w, or about 0.01-0.5% w / w, or about 0.01-0.4% w / w, or about 0.01-0.3% w / w, or about 0.01-0.2% w / w, 0.03-1% w / w, or about 0.03-0.5% w / w, or about 0.03-0.4% w / w, or about 0.03-0.3% w / w, or about 0.03-0.2% w / w, 0.04-1% w / w, or about 0.04-0.5% w / w, or about 0.04-0.4% w / w, or about 0.04-0.3% w / w, or about 0.04-0.2% w / w, 0.05-1% w / w, or about 0.05-0.5% w / w, or about 0.05-0.4% w / w, or about 0.05- 0.3% w / w, or about 0.05-0.2% w / w, 0.06-0.2% w / w, 0.07-0.2% w / w, 0.08-0.2% w / w, 0.09-0.2% w / w, 0.1-0.2% w / w, 0.09-0.15% w / w, or any sub-range thereof of any of butylated hydroxytoluene, butylated hydroxyanisole, and / or propyl gallate.

[0094] In some embodiments, the composition comprises about 0.01-1% w / w, or about 0.01-0.5% w / w, or about 0.01-0.4% w / w, or about 0.01-0.3% w / w, or about 0.01-0.2% w / w, 0.03-1% w / w, or about 0.03-0.5% w / w, or about 0.03-0.4% w / w, or about 0.03-0.3% w / w, or about 0.03-0.2% w / w, 0.04-1% w / w, or about 0.04-0.5% w / w, or about 0.04-0.4% w / w, or about 0.04-0.3% w / w, or about 0.04-0.2% w / w, 0.05-1% w / w, or about 0.05-0.5% w / w, or about 0.05-0.4% w / w, or about 0.05- 0.3% w / w, or about 0.05-0.2% w / w, or about 0.05-0.15% w / w, or about 0.05-0.1% w / w, 0.06-0.2% w / w, 0.07-0.2% w / w, 0.08-0.2% w / w, 0.09-0.2% w / w, 0.1-0.2% w / w, 0.09-0.15% w / w, or any subrange thereof of any of butylated hydroxytoluene and / or butylated hydroxyanisole.

[0095] In some embodiments, the composition comprises about 0.01-1% w / w, or about 0.01-0.5% w / w, or about 0.01-0.4% w / w, or about 0.01-0.3% w / w, or about 0.01-0.2% w / w, 0.03-1% w / w, or about 0.03-0.5% w / w, or about 0.03-0.4% w / w, or about 0.03-0.3% w / w, or about 0.03-0.2% w / w, 0.04-1% w / w, or about 0.04-0.5% w / w, or about 0.04-0.4% w / w, or about 0.04-0.3% w / w, or about 0.04-0.2% w / w, 0.05-1% w / w, or about 0.05-0.5% w / w, or about 0.05-0.4% w / w, or about 0.05- 0.3% w / w, or about 0.05-0.2% w / w, or about 0.05-0.15% w / w, or about 0.05-0.1% w / w, 0.06-0.2%2465742325-vl148540.615689 w / w, 0.07-0.2% w / w, 0.08-0.2% w / w, 0.09-0.2% w / w, 0.1 -0.2% w / w, 0.09-0.15% w / w, or any subrange thereof of butylated hydroxytoluene.

[0096] In some embodiments, the composition comprises about 0.01-1% w / w, or about 0.01-0.5% w / w, or about 0.01-0.4% w / w, or about 0.01-0.3% w / w, or about 0.01-0.2% w / w, 0.03-1% w / w, or about 0.03-0.5% w / w, or about 0.03-0.4% w / w, or about 0.03-0.3% w / w, or about 0.03-0.2% w / w, 0.04-1% w / w, or about 0.04-0.5% w / w, or about 0.04-0.4% w / w, or about 0.04-0.3% w / w, or about 0.04-0.2% w / w, 0.05-1% w / w, or about 0.05-0.5% w / w, or about 0.05-0.4% w / w, or about 0.05- 0.3% w / w, or about 0.05-0.2% w / w, or about 0.05-0.15% w / w, or about 0.05-0.1% w / w, 0.06-0.2% w / w, 0.07-0.2% w / w, 0.08-0.2% w / w, 0.09-0.2% w / w, 0.1-0.2% w / w, 0.09-0.15% w / w, or any subrange thereof of butylated hydroxyanisole.

[0097] In some embodiments, the composition comprises about 0.02%w / w, or about 0.03%w / w, or about 0.04%w / w, or about 0.05%w / w, or about 0.06%w / w, or about 0.07%w / w, or about 0.08%w / w, or about 0.09%w / w, or about 0.1%w / w, or about 0.15%w / w, or about 0.2%w / w, or about 0.25%w / w, or about 0.3%w / w, or about 0.4%w / w, or about 0.5%w / w of any of butylated hydroxytoluene, butylated hydroxyanisole, and / or propyl gallate.

[0098] In some embodiments, the composition comprises about 0.02%w / w, or about 0.03%w / w, or about 0.04%w / w, or about 0.05%w / w, or about 0.06%w / w, or about 0.07%w / w, or about 0.08%w / w, or about 0.09%w / w, or about 0.1%w / w, or about 0.15%w / w, or about 0.2%w / w, or about 0.25%w / w, or about 0.3%w / w, or about 0.4%w / w, or about 0.5%w / w of any of butylated hydroxytoluene and / or butylated hydroxyanisole. In some embodiments, the composition comprises about 0.1% w / w of butylated hydroxytoluene. In some embodiments, the composition comprises about 0.05% w / w of butylated hydroxy anisole.

[0099] In some embodiments, the composition comprises a surfactant or emulsifier. As used herein, a surfactant is a compound that lowers the surface tension between two liquids or between a liquid and a solid. Surfactants may also act as detergents, wetting agents, emulsifiers, foaming agents, and dispersants As further used herein, an emulsifier is equivalent to a surfactant and the terms are used interchangeably herein.

[0100] Surfactants and emulsifiers may be nonionic, anionic or cationic. Examples of surfactants and emulsifiers are disclosed in, for example, in McCutcheon’s Detergents and Emulsifiers, North American Edition, pp. 317-324 (1986), and the ICI Handbook, pp. 1673-1686. Non-limiting2565742325-vl148540.615689 examples of surfactants and emulsifiers include polysorbate (e.g., Tween 80), sorbitan monooleate (e.g., Span 80), poly lycolized glycerides, fatty acid macrogol-32 glycerides, fatty acid macrogol-6 glycerides, ethoxylated fatty alcohol ethers, PEG castor oils, PEG esters, propylene glycol esters, glyceryl esters and derivatives, polymeric ethers, sorbitan derivatives, fatty alcohols, emulsifying waxes, and mixtures thereof.

[0101] In some embodiments, the composition comprises an emulsifier or surfactant. In some embodiments, the emulsifier or surfactant is polysorbate (e.g., Tween 80) and / or sorbitan monooleate (e.g., Span 80). In some embodiments, the emulsifier or surfactant is polysorbate (e.g., Tween 80) and sorbitan monooleate (e.g., Span 80). In some embodiments, the composition does not comprise an emulsifier or a surfactant. In some embodiments, the composition does not comprise polysorbate (e.g., Tween 80). In some embodiments, the composition does not comprise sorbitan monooleate (e.g., Span 80).

[0102] Preservatives include compounds that increase the usable shelf life of the pharmaceutical composition. For example, some preservatives are antioxidants, some preservatives are antifungal agents, and some preservatives are antibacterial agents. Non-limiting examples of preservatives include phenol, parabens and parabens esters, phenoxyethanol, benzalkonium chloride, benzoic acid and salts thereof, benzyl alcohol, benzylhemiformal, benzylparaben, 5-bromo-5-nitro-l,3-dioxane, 2- bromo-2-nitropropane-l,3-diol, butyl paraben, methyl paraben, propyl paraben, diazolidinyl urea, sodium benzoate, calcium benzoate, calcium propionate, caprylyl glycol, biguanide derivatives, captan, chlorhexidine diacetate, chlorhexidine digluconate, chlorhexidine dihydrochloride, chloroacetamide, chlorobutanol, p-chloro-m-cresol, chlorophene, chlorothymol, chloroxylenol, m- cresol, o-cresol, DEDM hydantoin, DEDM hydantoin dilaurate, dehydroacetic acid, diazolidinyl urea, dibromopropamidine diisethionate, DMDM hydantoin, glyceryl caprylate, potassium sorbate, salicylic acid, hexamidine, capryloyl glycine, 1,2-hexanediol, undecylenoyl glycine, ethylhexylglycerin, caprylhydroxamic acid, methylpropanediol, hinokitiol, sodium hinokitiol, phenylethyl alcohol, levulinic acid, acid, p-anisic acid, 2-bromo-2-nitropipane- 1,3 -diol, sodium hydroxymethylglycinate, iodopropynyl bulylcarbamatc, methylchloroisothiazolinone, methylisothiazolinone, piroclone olamine, cinnamon oil, rosemary extract, and combinations thereof. Preservatives are often added to topical compositions to prevent or retard the formation of yeast, bacteria, and / or mold.2665742325-vl148540.615689

[0103] Buffers include combinations of acids and bases that have a pH buffering capacity. Some buffers include, for example, citrate, phosphate, acetate, borate, ethylenediaminetetraacetate (EDTA), conjugate acids thereof, and combinations thereof.

[0104] Coloring agents can be added to improve the visual appearance of the composition and include, for example, 2-(2-Quinolyl)-l,3-indandione disulfonic acid disodium salt (D&C Yellow #10).

[0105] Other non-limiting examples of suitable excipients, some of which may fit within one or more of the excipient categories above, include glycerol trioleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene (1) monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol (50) monostearate, octylphenoxypoly (ethyleneoxy) ethanol, decaglycerin pentaisostearate, sorbitan sesquioleate, hydroxylated lanolin, lanolin, triglyceryl diisostearate, polyoxyethylene (2) oleyl ether, calcium stearoyl-2-lactylate, methyl glucoside sesqui stearate, sorbitan monopalmitate, methoxy polyethylene glycol-22 / dodecyl glycol copolymer (Elfacos E200), polyethylene glycol-45 / dodecyl glycol copolymer (Elfacos ST9), polyethylene glycol 400 distearate, and lanolin derived sterol extracts, glycol stearate and glycerol stearate; alcohols, such as cetyl alcohol and lanolin alcohol; cholesterol; stearic acid; hydroxypropyl p cyclodextrin; and the like.

[0106] In some embodiments, the at least one excipient comprises a solvent, an emollient, a humectant, a gelling agent, a stabilizing agent (e.g., an antioxidant), a viscosity modifier, a surfactant, an emulsifier, a preservative, a buffering agent, a penetration enhancer, a skin protectant, a chelating agent, a fragrance and / or a colorant. In an embodiment, the at least one excipient comprises a solvent, an emollient, a humectant, a gelling agent, and / or an antioxidant.

[0107] In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one solvent, and at least one humectant. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one solvent, and at least one gelling agent. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one humectant, and at least one gelling agent. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one solvent, at least one humectant, and at least one gelling agent. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one solvent, at least one humectant, at least one gelling agent, and at least one emollient. In2765742325-vl148540.615689 some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one solvent, at least one humectant, at least one gelling agent, at least one emollient, and at least one antioxidant. In some embodiments, the composition comprises aprepitant, at least one solvent, at least one humectant, at least one gelling agent, at least one emollient, and at least one antioxidant. In some embodiments, the composition comprises aprepitant and at least two solvents. In some embodiments, the composition comprises aprepitant and at least three solvents.

[0108] In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least two solvents, at least one humectant, and at least one gelling agent. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least two solvents, at least one humectant, at least one gelling agent, and at least one emollient. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least two solvents, at least one humectant, at least one gelling agent, at least one emollient, and at least one antioxidant.

[0109] In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least three solvents, at least one humectant, and at least one gelling agent. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least three solvents, at least one humectant, at least one gelling agent, and at least one emollient. In some embodiments, the composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least three solvents, at least one humectant, at least one gelling agent, at least one emollient, and at least one antioxidant.

[0110] In some embodiments, the topical composition comprises about 0.1 - 5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 50 - 95% w / w of at least one solvent, about 1 - 10% w / w of at least one humectant, and about 0.5 - 5% w / w of at least one gelling agent. In some embodiments, the topical composition comprises about 0.1 - 5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 50 - 95% w / w of at least one solvent, about 1 - 10% w / w of at least one humectant, about 0.5 - 5% w / w of at least one gelling agent, and about 0.5 - 10% w / w of at least one emollient. In some embodiments, the topical composition comprises about 0.1 - 5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 50 - 95% w / w of at least one solvent, about 1 - 10% w / w of at least one humectant, about 0.5 - 5% w / w of at least one gelling2865742325-vl148540.615689 agent, about 0.5 - 10% w / w of at least one emollient, and about 0.01-1% w / w of at least one antioxidant.

[0111] In some embodiments, the topical composition comprises about 0.1-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 35-55% w / w of diethylene glycol monoethyl ether, about 0.5-5% w / w of benzyl alcohol, about 30-55% w / w of polyethylene glycol, about 1-10% w / w of glycerin, and about 0.5-5% w / w of hydroxypropyl cellulose.

[0112] In some embodiments, the topical composition comprises about 0.1-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 35-55% w / w of diethylene glycol monoethyl ether, about 0.5-5% w / w of benzyl alcohol, about 30-55% w / w of polyethylene glycol, about 1-10% w / w of glycerin, about 0.5-5% w / w of hydroxypropyl cellulose, and about 0.5-10% w / w of medium chain triglyceride.

[0113] In some embodiments, the topical composition comprises about 0.2-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 35-55% w / w of diethylene glycol monoethyl ether, about 0.5-5% w / w of benzyl alcohol, about 30-55% w / w of polyethylene glycol, about 1-10% w / w of glycerin, about 0.5-5% w / w of hydroxypropyl cellulose, about 0.5-10% w / w of medium chain triglyceride, and about 0.01-1% w / w of at least one antioxidant.

[0114] In some embodiments, the topical composition comprises about 0.1-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 35-55% w / w of diethylene glycol monoethyl ether, about 0.5-5% w / w of benzyl alcohol, about 30-55% w / w of polyethylene glycol, about 1-10% w / w of glycerin, about 0.5-5% w / w of hydroxypropyl cellulose, about 0.5-10% w / w of medium chain triglyceride, and about 0.01-1% w / w of BHT (butylated hydroxytoluene).

[0115] In some embodiments, the topical composition comprises about 0.1-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 35-55% w / w of diethylene glycol monoethyl ether, about 0.5-5% w / w of benzyl alcohol, about 30-55% w / w of polyethylene glycol, about 1-10% w / w of glycerin, about 0.5-5% w / w of hydroxypropyl cellulose, about 0.5-10% w / w of medium chain triglyceride, and about 0.01-1% w / w of BHA (butylated hydroxyanisole).

[0116] In some embodiments, the topical composition comprises about 0.5-2% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 38-50% w / w of diethylene glycol monoethyl ether, about 1-2.5% w / w of benzyl alcohol, about 34-50% w / w of polyethylene glycol, about 1-5%2965742325-vl148540.615689 w / w of medium chain triglyceride, about 5-7% w / w of glycerin, about 0.5-1.5% w / w of hydroxypropyl cellulose, and about 0.05-.2% w / w of BHT (butylated hydroxytoluene).

[0117] In some embodiments, the topical composition comprises about 0.5-2% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 38-50% w / w of diethylene glycol monoethyl ether, about 1-2.5% w / w of benzyl alcohol, about 34-50% w / w of polyethylene glycol, about 1-5% w / w of medium chain triglyceride, about 5-7% w / w of glycerin, about 0.5-1.5% w / w of hydroxypropyl cellulose, and about 0.05-.2% w / w of BHA (butylated hydroxyanisole).

[0118] In some embodiments, the topical composition comprises about 0.1 - 5% w / w of aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the topical composition comprises 0.5%, 1%, or 2% w / w of aprepitant or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the topical composition comprises aprepitant or a pharmaceutically acceptable salt thereof, at least one solvent, at least one humectant, and at least one gelling agent. In some embodiments, the topical composition further comprises at least one emollient. In some embodiments, the topical composition further comprises at least one antioxidant. In some embodiments, the solvent comprises diethylene glycol monoethyl ether, benzyl alcohol, and / or polyethylene glycol. In some embodiments, the solvent comprises di ethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol. In some embodiments, the humectant comprises glycerin. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the emollient comprises medium chain triglyceride. In some embodiments, the antioxidant is BHA (butylated hydroxyanisole) and / or BHT (butylated hydroxytoluene). In some embodiments, the antioxidant is BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene). In some embodiments, the antioxidant is BHT (butylated hydroxytoluene). In some embodiments, the antioxidant is BHA (butylated hydroxyanisole).

[0120] In some embodiments, the topical composition comprises about 0.1-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the topical composition comprises about 0.1-2% w / w of aprepitant. In some embodiments, the topical composition comprises about 35-55% w / w of diethylene glycol monoethyl ether. In some embodiments, the topical composition comprises about 0.5-5% w / w of benzyl alcohol. In some embodiments, the topical composition comprises 30-55% w / w of polyethylene glycol. In some embodiments, the topical composition comprises about 1-10% w / w of glycerin. In some embodiments, the topical3065742325-vl148540.615689 composition comprises about 0.5-5% w / w of hydroxypropyl cellulose. In some embodiments, the topical composition comprises about 0.5-10% w / w of medium chain triglyceride. In some embodiments, the topical composition comprises about 0.01-1% w / w of BHT (butylated hydroxytoluene). In some embodiments, the topical composition comprises about 0.01-1% w / w of BHA (butylated hydroxyanisole).

[0121] In some embodiments, the topical composition comprises about 0.2-2% w / w of aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the topical composition comprises about 38-50% w / w of diethylene glycol monoethyl ether. In some embodiments, the topical composition comprises about 1-2.5% w / w of benzyl alcohol. In some embodiments, the topical composition comprises 34-50% w / w of polyethylene glycol. In some embodiments, the topical composition comprises about 5-7% w / w of glycerin. In some embodiments, the topical composition comprises about 0.5-1.5% w / w of hydroxypropyl cellulose. In some embodiments, the topical composition comprises about 1-5% w / w of medium chain triglyceride. In some embodiments, the topical composition comprises about 0.05-2% w / w of BHT (butylated hydroxytoluene). In some embodiments, the topical composition comprises about 0.05-2% w / w of BHA (butylated hydroxyanisole).

[0122] In some embodiments, the topical composition comprises about 0.2-5% w / w of aprepitant or a pharmaceutically acceptable salt thereof, about 35-55% w / w of diethylene glycol monoethyl ether, about 0.5-5% w / w of benzyl alcohol, about 30-55% w / w of polyethylene glycol, about 0.5- 10% w / w of medium chain triglyceride, about 1-10% w / w of glycerin, about 0.5-5% w / w of hydroxypropyl cellulose, and about 0.01-1% w / w of BHT (butylated hydroxytoluene).

[0123] In some embodiments, the topical composition comprises about 0.5-2% w / w of the aprepitant or a pharmaceutically acceptable salt thereof, about 38-50% w / w of the diethylene glycol monoethyl ether, about 1-2.5% w / w of the benzyl alcohol, about 34-50% w / w of the polyethylene glycol, about 1-5% w / w of the medium chain triglyceride, about 5-7% w / w of the glycerin, about 0.5-1.5% w / w of the hydroxypropyl cellulose, and about 0.05-0.2% w / w of the BHT (butylated hydroxy toluene).

[0124] In some embodiments, the topical composition comprises about 0.5-2% w / w of the aprepitant or a pharmaceutically acceptable salt thereof, about 38-42% w / w of the di ethylene glycol monoethyl ether, about 1.5-2.5% w / w of the benzyl alcohol, about 34-50% w / w of the polyethylene3165742325-vl148540.615689 glycol, about 1-5% w / w of the medium chain triglyceride, about 5-7% w / w of the glycerin, about 0.5-1.5% w / w of the hydroxypropyl cellulose, and about 0.05-0.2% w / w of the BHT (butylated hydroxytoluene).

[0125] In some embodiments, the topical composition comprises any of formulations A-K disclosed herein in Table 7 below. In some embodiments, the topical composition comprises any of formulations B-K. In some embodiments, the topical composition is formulation A, or formulation B, or formulation C, or formulation D, or formulation E, or formulation F, or formulation G, or formulation H, or formulation I, or formulation J, or formulation K.

[0126] In some embodiments, the topical composition comprises aprepitant or a pharmaceutically acceptable salt thereof, di ethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol. In some embodiments, the topical composition further comprises glycerin, hydroxypropyl cellulose, a medium chain triglyceride, and / or at least one antioxidant. In some embodiments, the topical composition further comprises glycerin, hydroxypropyl cellulose, a medium chain triglyceride, and at least one antioxidant.

[0127] In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, and glycerin. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, and hydroxypropyl cellulose. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, and a medium chain triglyceride. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, and at least one antioxidant. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, glycerin, and hydroxypropyl cellulose. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, glycerin, and a medium chain triglyceride. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, glycerin, and at least one antioxidant. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, hydroxypropyl cellulose, and a medium chain triglyceride. In some3265742325-vl148540.615689 embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, hydroxypropyl cellulose, and at least one antioxidant. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, glycerin, hydroxypropyl cellulose, and a medium chain triglyceride. In some embodiments, the topical composition comprises aprepitant, diethylene glycol monoethyl ether, benzyl alcohol, polyethylene glycol, glycerin, hydroxypropyl cellulose, a medium chain triglyceride, and at least one antioxidant.

[0128] It will be understood that while particular embodiments disclosed herein can include each of the components discussed above, other particular embodiments can be required to be “free of’ or “substantially free of’ one or more of these components in various combinations. The term “substantially free” as used herein, is used to indicate that a component is not added to a composition and the composition comprises essentially none of that component (e.g., the component cannot be present in any concentration greater than about 0.001% w / w, or about 0.0001% w / w, or about 0.00001% w / w). The term “free of’, as used here in, indicates that a component is not added to a composition and the composition contains none (i.e., 0% w / w) of that component. In some embodiments, a composition may be substantially free of a particular excipient. In some embodiments, a composition may be free of a particular excipient.

[0129] For example, particular embodiments disclosed herein can be free of or substantially free of a surfactant and / or emulsifier. In some embodiments, the topical compositions are free of a surfactant. In some embodiments, the topical compositions are free of an emulsifier. In some embodiments, the topical compositions are free of a surfactant and emulsifier. In some embodiments, the topical compositions comprise less than about 0.001% of a surfactant or emulsifier. In some embodiments, the topical compositions comprise less than about 0.0001% of a surfactant or emulsifier.

[0130] For example, particular embodiments disclosed herein can be free of or substantially free of one or more of propyl gallate, polysorbate, sorbitan monooleate, stearyl alcohol, and / or dimethicone. In some embodiments, the topical compositions are substantially free of one or more of propyl gallate, polysorbate, sorbitan monooleate, stearyl alcohol, and / or dimethicone. In some embodiments, the topical compositions are substantially free of any of propyl gallate, polysorbate, sorbitan monooleate, stearyl alcohol, and dimethicone. In some embodiments, the topical3365742325-vl148540.615689 compositions are free of one or more of propyl gallate, polysorbate, sorbitan monooleate, stearyl alcohol, and / or dimethicone. In some embodiments, the topical compositions are substantially free of propyl gallate. In some embodiments, the topical compositions are free of propyl gallate. In some embodiments, the topical compositions are substantially free of polysorbate. In some embodiments, the topical compositions are free of polysorbate. In some embodiments, the topical compositions are substantially free of sorbitan monooleate. In some embodiments, the topical compositions are free of sorbitan monooleate. In some embodiments, the topical compositions are substantially free of sorbitan stearyl alcohol. In some embodiments, the topical compositions are free of sorbitan stearyl alcohol. In some embodiments, the topical compositions are substantially free of dimethicone. In some embodiments, the topical compositions are free of dimethicone.

[0131] The topical compositions of the present disclosure may be generally prepared by conventional methods such as are known in the art of making topical compositions. Such methods typically involve mixing of the ingredients in one or more steps to a relatively uniform state, with or without heating, cooling, application of vacuum, and the like. The compositions may be prepared such as to optimize stability (e.g., physical stability, chemical stability), delivery of the active materials, and / or to minimize toxicity.

[0132] In some embodiments, the topical composition is physically stable. As used herein, “physical stability” can refer to the appearance or other physical characteristics of the composition such as macroscopic appearance, viscosity, microscopic appearance (e.g., presence of crystals), and / or color. For example, color formation may be indicative of physical instability. Additionally, a change in a physical property (i.e., a change in macroscopic appearance, viscosity, microscopy, and / or color) may be an indication of reduction in physical stability or an indication of physical instability. With respect to an emulsion, physical stability may also refer to the composition being in the form of a single-phase mixture. For example, with respect to an emulsion, turbidity or phase separation may indicate physical instability. Physical stability may be measured at zero time (TO) and at appropriate intervals thereafter. Physical stability can be measured under various storage conditions.

[0133] In some embodiments, the topical composition is physically stable for about one month (i.e., about 4 weeks or 30 days), or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about3465742325-vl148540.615689 nine months, or about ten months, or about eleven months, or about one year, or about 1.5 years, or about 2 years when stored at 5°C, room temperature (i.e., about 20°C to about 25°C, e.g., about 21.53 ± 0.93 °C), and / or 40°C. In some embodiments, the topical composition is physically stable for about one month, or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about eleven months, or about one year, or about 1.5 years, or about 2 years when stored at 5°C. In some embodiments, the topical composition is physically stable for about one month, or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about eleven months, or about one year, or about 1.5 years, or about 2 years when stored at room temperature. In some embodiments, the topical composition is physically stable for about one month, or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about eleven months, or about one year, or about 1.5 years, or about 2 years when stored at 40°C. In some embodiments, the topical composition is physically stable for about three months when stored at 5°C, room temperature and / or 40°C. In some embodiments, the topical composition is physically stable for about 2 years when stored at 5°C, room temperature and / or 40°C. In some embodiments, the topical composition is physically stable for about three months when stored at 40°C.

[0134] In some embodiments, the topical composition shows no change in physical appearance when stored for about three months at 5°C, room temperature and / or 40°C. In some embodiments, the topical composition shows substantially no change in color when stored for about three months at 5°C, room temperature and / or 40°C. In some embodiments, the topical composition shows substantially no change in viscosity when stored for about three months at 5°C, room temperature and / or 40°C. In some embodiments, the topical composition shows substantially no change in macroscopic appearance when stored for about three months at 5°C, room temperature and / or 40°C. In some embodiments, the topical composition shows substantially no change in microscopic appearance when stored for about three months at 5°C, room temperature and / or 40°C.

[0135] In some embodiments, the topical composition is chemically stable. In some embodiments, the topical composition is physically stable. “Chemical stability”, as used herein, can refer to a low3565742325-vl148540.615689 level of degradation of the API (i.e., active ingredient). For example, chemical stability may be measured by conducting an HPLC assay for aprepitant at zero time (TO) and at appropriate intervals thereafter. Chemical stability can be measured under various storage conditions.

[0136] In some embodiments, the topical composition is chemically stable for about one month, or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about eleven months, or about one year, or about 1.5 years, or about 2 years when stored at room temperature. In some embodiments, the topical composition is chemically stable for about one month, or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about eleven months, or about one year, or about 1.5 years, or about 2 years when stored at 40°C.

[0137] In some embodiments, the topical composition is physically stable and chemically stable. In some embodiments, the topical composition is physically stable and chemically stable for one month, or two months, or three months, or four months, or five months, or six months, or seven months, or eight months, or nine months, or ten months, or eleven months, or one year, or 1.5 years, or 2 years when stored at 40°C. In some embodiment, the topical composition non-irritating or essentially non-irritating. In some embodiments, the topical composition is physically stable, chemically stable, and non-irritating or essentially non-irritating. In some embodiments, the topical composition is chemically and physically stable for about 3 months when stored at 40°C. In some embodiments, the topical composition is chemically and physically stable for about 6 months when stored at 40°C. In some embodiments, the topical composition is chemically and physically stable for about 6 months, or about one year, or about two years when stored at room temperature.

[0138] In some embodiments, the topical composition has a relative viscosity or Brookfield viscosity from about 2,000 cP (centipoise) to about 50,000 cP or any sub-range thereof as measured at about room temperature (e.g., about 21.53 ± 0.93 °C), or about 25°C, or about 40°C. For example, in some embodiments, the topical composition has a relative viscosity or Brookfield viscosity from about 2,000 cP to about 50,000 cP, from about 5,000 cP to about 40,000 cP, from about 5,000 cP to about 30,000 cP, from about 5,000 cP to about 20,000 cP, from about 6,000 cP to about 20,000 cP, from about 7,000 cP to about 15,000 cP, from about 8,000 cP to about 15,000 cP, from about 9,0003665742325-vl148540.615689 cP to about 15,000 cP, from about 10,000 cP to about 15,000 cP, from about 11,000 cP to about 15,000 cP, from about 12,000 cP to about 15,000 cP, or from about 13,000 cP to about 15,000 cP. The viscosity of the topical composition may be determined by any known method, including for example the Brookfield method and using a commercial viscometer, such as a Brookfield viscometer. The following example conditions can be implemented when using the commercial viscometer: Brookfield RV, CP spindle 27, 10 rpm, 2 min, room temperature (e.g., about 21.53 ± 0.93 °C) or 40°C.Methods of Using Topical Compositions

[0139] The topical compositions of the disclosure may be used in methods of treating a skin toxicity. For example, the present disclosure pertains to methods of treating a skin toxicity in a subject in need thereof, comprising topically administering to the subject in need thereof any composition disclosed herein. The present disclosure also pertains to methods of treating a skin toxicity in a subject in need thereof, comprising topically administering to the subject in need thereof any composition disclosed herein, wherein the skin toxicity is induced by the epidermal growth factor receptor inhibitor (EGFRI).

[0140] In some embodiments, a method for treating a skin toxicity in a subject in need thereof, comprises topically administering to the subject in need thereof a composition comprising a neurokinin- 1 receptor antagonist and at least one excipient, wherein the neurokinin- 1 receptor antagonist is selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof. In some embodiments, the neurokinin- 1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the skin toxicity is induced by an epidermal growth factor receptor inhibitor (EGFRI).

[0141] The epidermal growth factor receptor (EGFR) is a tyrosine kinase transmembrane receptor that is stimulated by ligands including amphiregulin, epiregulin and transforming growth factor-a, leading to homo- or heterodimerization with ErbB family members and subsequent signaling of the Ras-Raf-MAP, PI3K and Akt pathways (Garrett and Eng, Expert Opin Biol Ther 2011; 11 : 937- 949). These pathways are important for the regulation of cell proliferation and inhibition of apoptosis and can be activated in colorectal cancer (Lockhart and Berlin, Semin Oncol 2005; 32: 52- 3765742325-vl148540.61568960). Other cancers driven by deregulated EGFR include non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, and hepatocellular cancer, including metastatic forms thereof.[00142J An EGFR inhibitor can be a monoclonal antibody or a small molecule inhibitor. EGFR directed monoclonal antibodies in clinical use include cetuximab and panitumumab. Cetuximab is a humanized monoclonal antibody that binds to an extracellular epitope on EGFR and blocks activation of the receptor by preventing both ligand binding and receptor dimerization. Cetuximab in combination with chemotherapy has been approved by health authorities for the treatment of metastatic colorectal cancer and for the treatment of locally advanced and metastatic head and neck cancer. Panitumumab is a human IgG2 mAB against EGFR and approved for treatment of metastatic colorectal cancer. Other monoclonals in clinical development are zalutumumab, nimotuzumab, matuzumab and necitumumab.

[0143] Small molecule inhibitors that target EGFR include erlotinib and gefitinib, both binding reversibly to the EGFR. Erlotinib is indicated as treatment of advanced NSCLC after prior chemotherapy, but is in development for all lines of EGFR mutation positive NSCLC. Gefitinib is indicated in all lines of treatment of advanced NSCLC harboring EGFR mutations in the tumor. Other small molecule inhibitors of EGFR include afatinib, brigatinib, icotinib, lapatinib, osimertinib, dacomitinib, neratinib, and vandetanib. In one embodiment, a small molecule inhibitor can be a pharmaceutically acceptable salt of the above-described small molecule inhibitors.

[0144] It is known that skin toxicities are frequently observed during EGFR inhibitor therapy. The prevalence of EGFRI-induced skin toxicities is thought to be related to the fact that EGFR is constitutively expressed in epithelial tissues, such as skin and hair follicles, where it is critical for normal tissue homeostasis and repair.

[0145] As used herein, the terms “EGFRLassociated skin toxicity” or “EGFRI-related skin toxicity” or “EGFRI-induced skin toxicity” refer to the skin toxicities that are related to or induced by or frequently observed with the use of EGFR inhibitors. EGFRI-induced skin toxicities may occur at any time after treatment with an EGFRI has begun (i.e., any time after a subject has received at least one dose of an EGFRI). For example, EGFRI-skin toxicities may occur after one dose or more of an EGFRI, or after the EGFRI has been administered to the subject (i.e., the subject 3865742325-vl148540.615689 has received an EGFRI) for at least one day or at least one week or more. For example, EGFRI-skin toxi cities may occur after the EGFRI has been administered to the subject for at least one day, or at least two days, or at least three days, or at least four days, or at least five days, or at least six days, or at least seven days (i.e., one week), or at least two weeks, or at least three weeks, or at least four weeks (i.e., about a month), or at least five weeks, or at least six weeks, or at least seven weeks, or at least two months, or at least three months, or at least six months.

[0146] As used herein, the term “skin toxicity” includes various dermatologic conditions including, but not limited to rash (e.g., papulopustular eruptions (e.g., acneiform rash or acneiform dermatitis)), acne, folliculitis, erythema, skin fissures, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, pruritic rash, eczema, psoriasiform rash, lichenified rash, and follicular rash), skin ulcer, dry skin (xerosis), pruritus, nail disorders (e.g., paronychia, nail bed disorder, nail bed inflammation, nail discoloration, nail pigmentation, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, and onychomalacia), and alopecia (hair loss).[00147J In some embodiments, a method for treating a skin toxicity in a subject in need thereof, comprises topically administering to the subject a composition comprising aprepitant or a pharmaceutically acceptable salt thereof and at least one excipient, wherein the skin toxicity is induced by an epidermal growth factor receptor inhibitor (EGFRI).

[0148] In some embodiments, the EGFR inhibitor is a monoclonal antibody or a small molecule inhibitor. In some embodiments, the EGFR inhibitor is a monoclonal antibody. In some embodiments, the EGFR inhibitor is a small molecule inhibitor. In some embodiments, the EGFR inhibitor is selected from cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, necitumumab, erlotinib, gefitinib, afatinib, brigatinib, icotinib, lapatinib, osimertinib, dacomitinib, neratinib, or vandetanib. In some embodiments, the EGFR inhibitor is selected from cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, or necitumumab. In some embodiments, the EGFR inhibitor is selected from erlotinib, gefitinib, afatinib, brigatinib, icotinib, lapatinib, osimertinib, dacomitinib, neratinib, and vandetanib. In some embodiments, the EGFR inhibitor is selected from erlotinib or afatinib. In some embodiments the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is afatinib.3965742325-vl148540.615689

[0149] It is possible that the subject receiving an EGFRI may be receiving two or more EGFR inhibitors. For example, the subject may be receiving cetuximab and erlotinib or other combinations of EGFRI drugs.

[0150] In some embodiments, the subject is receiving, has previously received, or will receive an epidermal growth factor receptor inhibitor (EGFRI). As used herein, “is receiving”, “has received” or “will receive” with respect to receiving an EGFRI refers to current, prior, or future (respectively) administration of an EGFRI to a subject. The term “will receive” with respect to receiving an EGFRI may also refer to the prescription by a medical professional of an EGFRI to a subject where the subject has not yet started the EGFRI treatment. The administration of the EGFRI can be by any known method of administering an EGFRI in any known dose and with any known dosing regimen as would be understood by a person of skill in the art. A person of skill in the art would understand that each EGFRI may be administered in accordance with its specific dosing regimen and that dosing amounts, concentrations, and / or dosing regiments may vary, as a person of ordinary skill in the art will appreciate, according to various factors, including but not limited to the disease type and state, age, sex, and weight of the individual, the particular compound, the route of administration, and the frequency and / or duration of dosing.

[0151] In some embodiments, the subject in need is receiving or has previously received an epidermal growth factor receptor inhibitor (EGFRI). In some embodiments, the subject in need is receiving an epidermal growth factor receptor inhibitor (EGFRI). In some embodiments, the subject in need has previously received an epidermal growth factor receptor inhibitor (EGFRI).

[0152] In some embodiments, the topical composition is administered after the subject has received at least one dose of an EGFRI. In some embodiments, the topical composition is administered after the subject has received at least one, or at least two, or at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve, or at least thirteen, or at least fourteen, or at least fifteen, or at least sixteen, or at least seventeen, or at least eighteen, or at least nineteen, or at least twenty or more doses of an EGFRI.

[0153] In some embodiments, the topical composition is administered at least one day after the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least seven (7) days after the first day that the subject has 4065742325-vl148540.615689 received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least one, or at least two, or at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve, or at least thirteen, or at least fourteen, or at least fifteen, or at least sixteen, or at least seventeen, or at least eighteen, or at least nineteen, or at least twenty or more days after the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 weeks or more after the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 weeks or more after the first day that the subject has received at least one dose of the EGFRI.

[0154] As used herein, a “week” means seven consecutive days. As used herein, a “month” means 28-31 consecutive days or about four weeks.

[0155] In some embodiments, the topical composition is administered at least one day before the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least one day before the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least one, or at least two, or at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve, or at least thirteen, or at least fourteen, or at least fifteen, or at least sixteen, or at least seventeen, or at least eighteen, or at least nineteen, or at least twenty or more days before the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 weeks or more before the first day that the subject has received at least one dose of the EGFRI. In some embodiments, the topical composition is administered at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 weeks or more before the first day that the subject has received at least one dose of the EGFRI.

[0156] In some embodiments, the topical composition is administered three times a day, or twice a day (i.e., twice daily), or daily, or every other day, or twice a week, or three times a week, or four times a week, or five times a week, or six times a week, or weekly, or bi-weekly, or three times a4165742325-vl148540.615689 month, or once a month (i.e., monthly), or once every other month, or once every three months, or once every four months. In some embodiments, the topical composition is administered daily. In some embodiments, the topical composition is administered twice daily. In some embodiments, the topical composition is administered daily for six weeks. In some embodiments, the topical composition is administered daily for up to six weeks. In some embodiments, the topical composition is administered twice daily for six weeks. In some embodiments, the topical composition is administered twice daily for less than six weeks. In some embodiments, the topical composition is administered twice daily for at least one week. In some embodiments, the topical composition is administered three times a week.

[0157] In some embodiments, the topical composition is administered for 1-365 days, or 1-182 days, or 1-140 days, or 1-112 days, or 1-84 days, or 1-77 days, or 1-63 days, or 1-56 days, or 1-42 days, or 1-35 days, or 1-28 days, or 1-14 days, or 1-7 days, or 7-14 days, or 7-28 days, or 7-35 days, or 7-42 days, or 7-56 days, or 7-63 days, or 7-77 days, or 7-84 day, or 7-112, or 7-140, or 7-182, or 7-365 days, or any range therebetween.

[0158] In some embodiments, the topical composition is administered for at least one day, or at least two days, or at least three days, or at least four days, or at least five days, or at least six days, or one week, or at least two weeks, or at least three weeks, or at least four weeks, or at least five weeks, or at least six weeks, or at least seven weeks, or at least eight weeks, or at least three months, or at least four months, or at least five months, or at least six months, or at least seven months, or at least eight months, or at least nine months, or at least ten months, or at least eleven months, or at least one year, or at least one year and six months, or at least two years, or at least two years and six months, or at least three years, or at least four years, or at least five years, or at least six years, or at least seven years, or at least eight years, or at least nine years or at least ten years.

[0159] In some embodiments, the topical composition is administered for one day, or two days, or three days, or four days, or five days, or six days, or one week, or two weeks, or three weeks, or four weeks, or five weeks, or six weeks, or seven weeks, or eight weeks, or three months, or four months, or five months, or six months, or seven months, or eight months, or nine months, or ten months, or eleven months, or one year, or one year and six months, or two years, or two years and six months, or three years, or four years, or five years.4265742325-vl148540.615689

[0160] In some embodiments, the topical composition is administered for the remaining lifetime of the subject. In some embodiments, the topical composition is administered for the duration or remaining duration of co-pending EFGRI treatment.

[0161] In some embodiments, the topical composition is administered for less than six months, or less than five months, or less than four months, or less than three months, or less than two months, or less than seven weeks, or less than six weeks, or less than five weeks, or less than one month, or less than three weeks, or less than two weeks. In some embodiments, the topical composition is administered for one week. In some embodiments, the topical composition is administered for six weeks.

[0162] In some embodiments, the topical composition is administered continuously according to a dosing regimen. In some embodiments, administration is discontinued after the alleviation or reduction of an EGFRI-induced skin toxicity or at least one symptom thereof. In some embodiments, the topical composition is administered intermittently. For example, in some embodiments, the administration may be discontinued temporarily and then the administration may be started again at a later time. In some embodiments, the topical composition is administered according to a variable dosing regimen (e.g., the composition may be administered twice daily for 1 or more weeks and then once daily or less for the duration of treatment). In some embodiments, the frequency of administration may be reduced. In some embodiments, the frequency of administration may be increased. In some embodiments, the topical composition may be administered as needed (e.g., the composition may be applied when at least one symptom develop or worsens and use may be discontinued when at least one symptom is alleviated).

[0163] In some embodiments, the topical composition is administered in any amount needed to treat an EGFRI-induced skin toxicity or at least one symptom thereof. In some embodiments, the topical composition is administered in any safe amount.

[0164] In some embodiments, the topical composition is administered in any amount needed to prevent an EGFRI-induced skin toxicity or at least one symptom thereof. In some embodiments, the topical composition is administered in any safe amount needed to prevent an EGFRI-induced skin toxicity or at least one symptom thereof. An amount needed for prevention is intended to mean the amount that will prevent or reduce the risk of occurrence of the biological or medical event that is4365742325-vl148540.615689 sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.

[0165] ‘ ‘Amounts” and “concentrations” may vary, as a person of ordinary skill in the art will appreciate, according to various factors, including but not limited to the disease type and state, age, sex, and weight of the individual, the particular compound, the route of administration, and the frequency and / or duration of dosing. The response may be measured by one or more recognized techniques, for example, by in vivo non-human animal studies and / or further supported from clinical trials. It is understood that a specific dosage amount or concentration can simultaneously be sufficient for providing a therapeutic effect (e.g., to alleviate a skin toxicity or a symptom thereof) and a prophylactically effective (e.g., for the prevention of a skin toxicity or a symptom thereof). In relation to topical administration, it will be understood by a person of skill in the art that “concentration” rather than total dosage amount is often referenced with respect to the composition components and the total amount on a component administered is dependent on the amount of the topical composition applied.

[0166] In some embodiments, the average amount of aprepitant administered per dose is about 1 mg, or about 1.5 mg, or about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg, or about 5.5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg, or about 10 mg, or about 11 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg, or about 16 mg, or about 17 mg, or about 18 mg, or about 19 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 55 mg, or about 60 mg, or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 85 mg, or about 90 mg, or about 95 mg, or about 100 mg, of about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg.

[0167] In some embodiments, the total amount of aprepitant administered per dose is about 1 mg, or about 1.5 mg, or about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg, or about 5.5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg, or about 10 mg, or about 11 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg, or about 16 mg, or about 17 mg, or about 18 mg, or about 19 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 55 mg, or about 60 mg, or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 854465742325-vl148540.615689 mg, or about 90 mg, or about 95 mg, or about 100 mg, of about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg.

[0168] In some embodiments, the maximum amount of aprepitant administered per dose is about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 55 mg, or about 60 mg, or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 85 mg, or about 90 mg, or about 95 mg, or about 100 mg, of about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg.

[0169] In some embodiments, the maximum daily amount of aprepitant administered is about 500 mg / m2, or about 400 mg / m2, or about 300 mg / m2, or about 275 mg / m2, or about 260 mg / m2, or about 250 mg / m2, or about 200 mg / m2, or about 150 mg / m2, or about 130 mg / m2, or about 100 mg / m2, or about 75 mg / m2, or about 65 mg / m2, or about 50 mg / m2. In some embodiments, the maximum daily amount of aprepitant administered is about 263 mg / m2, or about 132 mg / m2, or about 66 mg / m2with reference to body surface area.

[0170] Topical administration as used within the present disclosure refers to application to the skin, nails, and scalp of the subject by any known method for topical administration including, for example, by use of an applicator, a cotton gauze, a patch, or by hand. The topical composition may be stored and / or provided in any known container or vessel, including but not limited to tubes, vials, or pumps. In some embodiments, the topical composition is in a pump container (e.g., airless pump). The topical compositions of the disclosure may be applied to any area affected by the EGFRI- induced skin toxicity.

[0171] In some embodiments, the topical composition is administered to the skin of a subject in need thereof. In some embodiments, the topical composition is administered to the face, chest, abdomen, back, arms, and / or legs of the subject. .In some embodiments, the topical composition is administered to the nails of a subject in need thereof. In some embodiments, the topical composition is administered to the scalp of a subject in need thereof. In some embodiments, the topical composition is administered to the affected area of the subject.

[0172] In some embodiments, the topical composition is administered to less than about 50%, or 40%, or 35%, or 30%, or 25%, or 20%, or 15%, or 10%, or 5%, or 4%, or 3%, or 2%, or 1% of the total body surface area (BSA). In some embodiments, the topical composition is administered to less 4565742325-vl148540.615689 than about 50%, or 40%, or 35%, or 30%, or 25%, or 20%, or 15%, or 10%, or 5%, or 4%, or 3%, or 2%, or 1% of the total surface area of the skin. In some embodiments, the topical composition is administered to less than about 50%, or 40%, or 35%, or 30%, or 25%, or 20%, or 15%, or 10%, or 5%, or 4%, or 3%, or 2%, or 1% of the total surface area of the nails. In some embodiments, the topical composition is administered to less than about 50%, or 40%, or 35%, or 30%, or 25%, or 20%, or 15%, or 10%, or 5%, or 4%, or 3%, or 2% of the total surface area of the scalp.

[0173] In some embodiments, the skin toxicity is a papulopustular eruption (e.g., acneiform rash), pruritus, xerosis, and / or nail paronychia. In some embodiments, the skin toxicity is a papulopustular eruption and / or pruritus. In some embodiments, the skin toxicity is a papulopustular eruption, pruritus, and / or xerosis. In some embodiments, the skin toxicity is a papulopustular eruption, pruritus, and / or nail paronychia. In some embodiments, the skin toxicity is pruritus and / or nail paronychia. In some embodiments, the skin toxicity is pruritus and / or xerosis. In some embodiments, the skin toxicity is nail paronychia and / or xerosis. In some embodiments, the skin toxicity is a papulopustular eruption. In some embodiments, the skin toxicity is pruritus. In some embodiments, the skin toxicity is xerosis. In some embodiments, the skin toxicity is nail paronychia. In some embodiments, the papulopustular eruption is an acneiform rash.

[0174] In some embodiments, the methods comprise topically administering to the subject in need thereof a composition of the disclosure, thereby treating the skin toxicity or at least one symptom thereof. In some embodiments, the methods comprise topically administering to the subject in need thereof a composition of the disclosure, thereby treating the papulopustular eruption, pruritus, xerosis, and / or nail paronychia or at least one symptom thereof.

[0175] In some embodiments, the topical composition is non- irritating or substantially (or essentially) non-irritating. In some embodiments, the disclosed methods of administering the topical compositions of the disclosure do not cause additional irritation to skin, nails, and / or scalp. As used herein, the term “irritation” or “irritating” may refer, for example, to skin redness, erythema, pruritis, and / or edema.

[0176] In some embodiments, the subject receiving an EGFR inhibitor may also be receiving a second non-EGFR blocking chemotherapeutic agent. For instance, an EGFR blocking drug, erlotinib, is often combined with cisplatin for the treatment of lung cancer. Accordingly, the4665742325-vl148540.615689 disclosure provides methods for treating skin toxicities in a subject in need, wherein the subject is receiving an EGFRI and a second (non-EGFRI) chemotherapeutic agent.

[0177] In some embodiments, one or more additional therapeutic agents may be administered in combination with an NK-1 receptor antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt thereof. As used herein, an “additional therapeutic agent(s)” is intended to mean a pharmaceutically active agent(s) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compounds of the disclosure, and also includes pharmaceutically acceptable salts of the additional active agents. As used herein, an “additional therapeutic agent(s)” may also refer to an additional NK-1 receptor antagonist (e.g., if aprepitant is used in a composition then the additional therapeutic agent may be an NK-1 receptor antagonist other than aprepitant). Where topical aprepitant is used in a composition of the disclosure, non-topical aprepitant (e.g., oral aprepitant) is also included in the term “additional therapeutic agent”. Generally, any suitable additional therapeutic agent(s) may be used in any combination with the compositions of the disclosure in a single dosage form (a fixed dose drug combination) or may be administered to the subject in one or more separate dosage formulations, which allows for concurrent or sequential administration of the compositions of the disclosure and the additional therapeutic agent(s) (co-administration of the separate active agents). The sequence in which the therapeutic agents are administered can vary. Therapeutic agents may also be administered in alternation.

[0178] In some embodiments, the method can comprise administering to the subject in need thereof one or more additional therapeutic agent(s) for the treatment of EGFRI-induced skin toxicities. In some embodiments, the additional therapeutic agent(s) can be co-administered to the subject with an NK-1 receptor antagonist (e.g., aprepitant). In some embodiments, the additional therapeutic agent(s) can be administered to the subject before and / or after the administration of an NK-1 receptor antagonist (e.g., aprepitant). In some embodiments, the additional therapeutic agent(s) can be concurrently administered to the subject with an NK-1 receptor antagonist (e.g., aprepitant).

[0179] In some embodiments, the additional therapeutic agent(s) is a topical steroid, an oral tetracycline, and / or isotretinoin.

[0180] In some embodiments, the additional therapeutic agent(s) is an oral aprepitant dosage form.4765742325-vl148540.615689

[0181] In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof a topical composition comprising an NK-1 receptor antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt thereof, as the sole therapeutic agent for the treatment of EGFRI- induced skin toxicities. In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof a topical composition comprising an NK-1 receptor antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt thereof, wherein no additional therapeutic agents are co-administered for the treatment of EGFRI-induced skin toxicities.

[0182] In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof a topical composition comprising aprepitant or a pharmaceutically acceptable salt thereof, wherein the subject is receiving or has received an oral aprepitant dosage form. In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof, wherein the topical composition is co-administered with an oral aprepitant dosage form. The coadministration may be sequential or concurrent. In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof a topical composition comprising aprepitant or a pharmaceutically acceptable salt thereof, wherein the subject has not received an oral aprepitant dosage form. In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof, wherein the topical composition is not co-administered with an oral aprepitant dosage form. In some embodiments, the methods of the disclosure comprise administering to the subject in need thereof a topical composition comprising aprepitant or a pharmaceutically acceptable salt thereof, wherein the subject has not received an oral aprepitant dosage form in at least the last week, month, six months, or year.

[0183] Also provided herein is a kit comprising a container including the topical composition. In some embodiments, the kit comprises a container including the topical composition in a ready-to-use form. The container may be any conventional container used in the art for topical compositions. In some embodiments, the container is a pump container (e.g., airless pump). In some embodiments, the pump container comprises about lOmL, or 20 mL, or 30 mL, or 40 mL, or 50 mL, or 60 mL, or 70 mL, or 80 mL, or 90 mL, or lOOmL, or 110 mL, or 120 mL, or 130 mL, or 140 mL, or 150 mL, or 175 mL, or 200 mL of the topical composition. In some embodiments, the pump container comprises about 1 OOmL of the topical composition.4865742325-vl148540.615689

[0184] In some embodiments, the methods of the disclosure comprise administering about 0.5 pumps, or 1 pump, or 1.5 pumps, or 2 pumps, or 2.5 pumps, or 3 pumps, or 3.5 pump, or 4 pumps, or 4.5 pumps, or 5 pumps, or 5.5 pumps, or 6 pumps, or 6.5 pumps, or 7 pumps, or 7.5 pumps, or 8 pumps, or 9 pumps, or 10 pumps of the composition. In some embodiments, the methods of the disclosure comprise administering about 0.5 pumps, or 1 pump, or 1.5 pumps, or 2 pumps, or 2.5 pumps, or 3 pumps, or 3.5 pump, or 4 pumps, or 4.5 pumps, or 5 pumps, or 5.5 pumps, or 6 pumps, or 6.5 pumps, or 7 pumps, or 7.5 pumps, or 8 pumps, or 9 pumps, or 10 pumps of the composition per dose. In some embodiments, the methods of the disclosure comprise administering about 0.5 pumps, or 1 pump, or 1.5 pumps, or 2 pumps, or 2.5 pumps, or 3 pumps, or 3.5 pump, or 4 pumps, or 4.5 pumps, or 5 pumps, or 5.5 pumps, or 6 pumps, or 6.5 pumps, or 7 pumps, or 7.5 pumps, or 8 pumps, or 9 pumps, or 10 pumps, or 11 pumps, or 12 pumps, or 13 pumps, or 14 pumps, or 15 pumps, or 16 pumps of the composition per day. In some embodiments, the methods of the disclosure comprise administering about 0.5 pumps, or 1 pump, or 1.5 pumps, or 2 pumps, or 2.5 pumps, or 3 pumps, or 3.5 pump, or 4 pumps, or 4.5 pumps, or 5 pumps, or 5.5 pumps, or 6 pumps, or 6.5 pumps, or 7 pumps, or 7.5 pumps, or 8 pumps, or 9 pumps, or 10 pumps per dose of the composition per day. In some embodiments, the methods of the disclosure comprise administering a maximum of 4 pumps, or 4.5 pumps, or 5 pumps, or 5.5 pumps, or 6 pumps, or 6.5 pumps, or 7 pumps, or 7.5 pumps, or 8 pumps, or 9 pumps, or 10 pumps, or 11 pumps, or 12 pumps, or 13 pumps, or 14 pumps, or 15 pumps, or 16 pumps of the composition per day. In some embodiments, the methods of the disclosure comprise administering a maximum of 4 pumps, or 4.5 pumps, or 5 pumps, or 5.5 pumps, or 6 pumps, or 6.5 pumps, or 7 pumps, or 7.5 pumps, or 8 pumps, or 9 pumps, or 10 pumps per dose of the composition per day. In some embodiments, the methods of the disclosure comprise administering a maximum of 7 pumps per dose of the composition per day. In some embodiments, the methods of the disclosure comprise administering a maximum of 7.5 pumps per dose of the composition per day.

[0185] Also provided herein is the use of any topical composition described herein for the treatment of a skin toxicity in a subject in need, comprising topically administering the composition to the subject, wherein the skin toxicity is induced by an EGFRI.4965742325-vl148540.615689

[0186] Also provided herein is a topical composition as disclosed herein for use in the treatment of a skin toxicity in a subject in need, comprising topically administering the composition to the subject, wherein the skin toxicity is induced by an EGFRI.Oral and Topical Aprepitant Study

[0187] In a study to compare oral and topical aprepitant, young (age-matched) male Sprague- Dawley (SD) rats (n = 4 to 5 per group) were administered oral erlotinib (10 mg / kg / day) alone or in combination with aprepitant (oral or topical for up to 12 weeks. Rat groups included: control (Ctl) (untreated), erlotinib-treated [Erl(O)], erlotinib + oral aprepitant-treated [Erl(O)+Apre(O)] and oral aprepitant-treated [Apre(O)]. The oral control group consisted of a normal diet without erlotinib.

[0188] Oral aprepitant (2 mg / kg / day) was initiated on day 1 with erlotinib while topical aprepitant application was initiated 1 week after starting oral erlotinib intake in the diet.

[0189] Topical application was initiated one week after starting oral erlotinib intake in the diet (prior to development of skin toxicities). For topical aprepitant, a dose of 0.7 mg / kg / day aprepitant in Vehicle A (70% w / w Transcutol + 10% w / w DMSO + 20% w / w acetone) was used. Using a volume of about 105 pL, topical treatment was applied 3 times / week and covered a total area of application of about 4-5 cm2encompassing a rat’s unshaven face near the nose, between and beneath the eyes, forehead, and upper back near the head and ears.

[0190] Facial rash and hair loss began to develop in the erlotinib alone group by 3-5 weeks after initiating erlotinib treatment, which progressed in severity by weeks 8-12.

[0191] Severity of facial dermatitis was scored on a 0 (none) to 4 (severe) scale based on macular or papular eruption or erythema, and hair loss (alopecia) was similarly scored 0 (none) to 4 (severe, loss from >50% facial surface area). Dermatitis and hair loss values were averaged for each group, and then combined scores (skin + hair loss changes) were obtained for each group.

[0192] The results are shown in Table 1 and Figures 1 and 2.

[0193] Table 1: Effects of erlotinib (O) ± oral (O) or topical (T) aprepitant in Vehicle A (intermediate dose) on combined development of facial skin dermatitis and hair loss in young SD rats after 12 weeks.5065742325-vl148540.615689

[0194] The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosure.EXAMPLESExample 1

[0195] Effect of Aprepitant on CD1 lb Positive Cells in Skin of Rats Treated with Erlotinib

[0196] Male SD (Sprague-Dawley) rats were used for studies with topical aprepitant. Following quarantine, all age-matched rats (125-175 g) (N= 4 to 5 per group) received an ad libitum Mg normal diet (25 mmole magnesium oxide / kg food considered 100% recommended daily allowance for rodents, TD 93104) obtained from Envigo-Teklad Laboratory (Madison, WI) containing extracted casein as the diet base and essential vitamins and nutrients. The rats received 10 mg / kg / day oral erlotinib (obtained from Cayman Chem. MI).5165742325-vl148540.615689

[0197] The efficacies of two doses of topical aprepitant in erlotinib (initial lOmg / kg / day, oral) treated SD (Sprague-Dawley) male rats (N=5) over 12 weeks: a low dose (0.33 mg / kg / day) in Vehicle C (40% w / w Transcutol P, 2%, w / w benzyl alcohol, 58% w / w propylene glycol), and a higher dose in Vehicle C (1.0 mg / kg / day). Treatment groups were compared to untreated control (Ctl).

[0198] Topical application was initiated one week after starting oral erlotinib intake in the diet (prior to development of skin toxicities). When under anesthesia (2% isoflurane, EZ Anesthesia System plus nose cone, Palmer, PA), the aprepitant (in Vehicle C) was delivered through micropipette tips on the rat’s unshaven face near the nose, in between and beneath eyes, forehead, and the upper back near the head and ears. Total area of application was about 4-5 cm2. Topical aprepitant was applied 3 times a week (Monday, Wednesday, Friday). Each time a total volume of 105pl aprepitant solution containing 0.667% w / v aprepitant for the high dose and 0.222% w / v aprepitant for the low dose was applied by one investigator for consistency. The total aprepitant dose for the 0.222% w / v formulation was about 0.231 mg / rat per application or 0.693 mg / week; or roughly 2.31 mg / kg / week or about 0.33 mg / kg / rat / day. The total rat body surface area (BSA) is 0.025 m2(assume 30% BSA, 0.0075 m2), providing a dose of 93.3 mg / m2per dose (280.0 mg / m2per week) or 30.8 mg / m2per dose (92.4 mg / m2per week) for the 0.667% and 0.222% formulations, respectively.

[0199] During treatment weeks 8 and 12, anesthetized rats from each group were place ventral side down upon toweling and a photographic image was taken primarily of the facial / head region at an approximate distance of 6 inches from the subject. Afterward, animals were placed in their holding cages until fully recovered. The camera feature of the iPhone 6s Plus was used with high dynamic range (HDR to blend the best of 3 separate exposures into a single picture). The rear camera has a 12 mega-pixel sensor, 1.22 pm pixels, an f / 2.2 aperture, and includes optical image stabilization. Stored digital photographic images of all rats were evaluated by two blinded investigators and average scores for visual skin / hair loss changes were graded using the National Cancer Institute Common Toxicity Criteria (5, NCI, Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Publish Date: November 27, 2017). Severity of facial dermatitis was scored on a 0 (none) to 4 (severe) scale based on macular or papular eruption or erythema, and hair loss (alopecia) was similarly scored 0 (none) to 4 (severe, loss from >50% facial surface area). Dermatitis and hair loss values were averaged for each group, and then combined scores (skin + hair5265742325-vl148540.615689 loss changes) were obtained for each group. Representative images of the rats in each group are provided in Figure 3.

[0200] Blood samples were collected at sacrifice (~ 8- 10ml collected in heparin plus aprotinin [10.74 units / ml and 0.016 units / ml, respectively] containing BD vacutainer SST tubes) were taken from 2-5 % isoflurane anaesthetized, heparinized rats (0.3-0.4 ml 358 units / ml heparin in 0.9% NaCl, i.p.) by cardiac puncture, and were centrifuged (3,500 rpm, 10 min, RT). Sacrifice plasma samples were stored at -80°C for biochemical assays later, whereas whole blood samples were processed for neutrophil isolation and assessment of superoxide anion production. The results are shown in Figure 4, which shows the dose-dependent impact of topical aprepitant in Vehicle C on basal superoxide generation by freshly isolated neutrophil of 12 week oral erlotinib (Erl) with or without Vehicle C.

[0201] Immediately following sacrifice, the facial area was shaved with an electric razor and treated with depilatory cream (< 2 min exposure), then cleaned. The skin was removed with a scalpel from the facial area from above the nose between the eyes and towards the forehead. The triangularshaped tissue sample had an approximate area of 4.5 cm2. The skin samples were quickly rinsed in PBS, embedded in OCT, wrapped in aluminum foil, frozen by immersing in 2-methyl butane on dry ice and kept at -80°C until used. Cryosections, 5 pm thick, from erlotinib treated rats (E = 1 Omg / kgBW / day) and from groups treated with topical application of aprepitant (A) at 1 mg / kgBW / day (high dose) and with the low dose (A Low D) at 0.33 mg / kgBW / day after 12 weeks were stained immunohistochemically using rabbit anti-Substance P receptor (NK1R) polyclonal antibody at 1 :200 dilution (EMD Millipore, Tamecula, CA). Sections were blocked for non-specific binding with Blocking Buffer (10% horse serum, 1% BSA and 0.05% Triton 100X in TBS) for 30 min. After blocking endogenous horseradish peroxidase with 0.03% hydrogen peroxide in TBS, the sections were incubated with the primary antibody (Millipore mouse anti rat CD1 lb 1: 250 in Blocking Buffer) overnight at 4°C in humidity chamber. After multiple washes in TBS, Vector ABC Kit for mouse IgG antibody (2°Ab) and Vector Kit for HRP DAB were used to label and visualize the antigen of interest (brown color). For counterstaining hematoxylin was used (blue nuclei). The sections were dehydrated in graded alcohols and in 3 changes of xylenes, mounted with mounting medium and let dry before observing under the microscope.5365742325-vl148540.615689

[0202] Samples were examined under Nikon Eclipse Ti microscope at 10 x magnification (scale bar = 100 um) and multiple images were taken with a digital camera (Nikon Digital Sight DS-U3). The areas (number of pixels) of positively stained skin sections were measured using ImageJ (10 different microscopic fields / section for 5 rats / group). The individual cells and small clusters were observed scattered within the epidermis and dermis. The number of pixels in the brown stained areas was normalized according to the total number of pixels in the tissue in the field and reported as percent of positive staining in the observed tissue. The results were analyzed using paired Student t- test.

[0203] The results are shown in Table 2 and Figures 3-5.

[0204] Exposure to erlotinib (12 weeks) leads to significant activation of neutrophil superoxide production from the blood, and at the facial skin level, a significant CD1 Ib-positive WBC infiltration. There was a significant (43% vs E, 41% vs E+V) decrease of positive staining in the aprepitant treated with 1 mg / kgBW / day group compared to the group receiving only erlotinib [*** E v E+A; p<0.05 (p=0.00035)]. The lower dose of aprepitant (0.33 mg / kgBW / day) produced similar results of (39% vs E, 36% vs E+V) decrease in the presence of the inflammatory cells in the skin [***: E vs E+ALowD; p<0.05 (p= 2.250E-11)]. There was no significant difference between average positive staining for CD1 lb in samples from the group treated with higher dose of aprepitant and group receiving lower dose [NS: E+A vs E+ALowD; p>0.05 (p=0.679)]. Also, there was no significant difference between the average positive staining for group treated with erlotinib only and the erlotinib group treated topically with vehicle C [NS E vs E+V; p>0.05 (p=0.338)].

[0205] The results demonstrate changes in the presence of positive staining for CD1 lb inflammatory cells in facial skin caused by topically applied aprepitant in rats treated with erlotinib compared to those only treated with erlotinib or erlotinib + vehicle.

[0206] The treatment with aprepitant significantly decreased the presence of the inflammatory cells expressing CD1 lb membrane marker in the skin of rats receiving erlotinib therapy. The Vehicle C used to deliver aprepitant topically did not have any significant effect by itself on the CD1 lb cell levels in the skin of erlotinib treated animals.

[0207] Topical application of aprepitant in Vehicle C on the facial area 3 times / week, provided dose-dependent protection against facial dermatitis and hair loss in rats exposed to oral erlotinib for5465742325-vl148540.615689 up to 12 weeks. Topical application with the high dose of aprepitant (1 mg / kg / day) achieved >70% protection, while the low dose (0.33 mg / kg / day) provided about 20% attenuation.

[0208] Table 2: Effects of erlotinib (O) ± topical (T) aprepitant in Vehicle C on combined development of facial skin dermatitis and hair loss in young SD rats after 12 weeks.

[0209] In a follow-on study, topical aprepitant was applied to SD rats (N=5) three times a week at a dose of 1.5 mg / kg / day aprepitant in Vehicle C was applied either 1 week after initial 10 mg / kg / day oral erlotinib dose (before cutaneous toxicities developed) or 6 weeks after initial 10 mg / kg / day oral5565742325-vl148540.615689 erlotinib dose (after cutaneous toxi cities developed). The 1.5 mg / kg / day aprepitant dose is equivalent to 200 mg / m2 / day or 600 mg / m week (applied 3 times per week).

[0210] A comparison of preventative (after 1 week of erlotinib) and proactive (after 6 weeks of erlotinib) topical aprepitant treatment is shown in Tables 3 and 4. Overall, after 12 weeks of erlotinib exposure, both groups receiving topical aprepitant (either 1 week or 6 weeks after commencing erlotinib treatment) demonstrated a significant reduction in the overall facial lesions (p < 0.001 vs erlotinib for preventative aprepitant treatment; p < 0.02 vs erlotinib for proactive treatment) and hair loss (p < 0.001 vs erlotinib for both preventative and proactive treatment groups). In addition, early topical aprepitant treatment (1 week after starting erlotinib) significantly decreased (67%) erlotinib- induced superoxide production (p < 0.01; vs erlotinib alone).

[0211] Table 3 : Topical Aprepitant Applied after 1 Week or 6 Weeks of ErlotinibMeans ± SE of 5 SD male rats per group. § p < 0.01 vs Ctl: * p < 0.001 vs Ctl: ip < 0.02 vs Erl; rp < 0.001 vs Erl

[0212] Table 4: Topical Aprepitant Applied after 1 Week or 6 Weeks of Erlotinib

[0213] 65742325-vl148540.615689p-values are compared to erlotinib + topical vehicle control.Example 2

[0214] Effect of Aprepitant on CD1 lb Positive Cells in Skin of Rats treated with afatanib

[0215] In a study similar to Example 1, the effect of topical aprepitant treatment on oral afatinib- treated rats was observed.

[0216] Rats received either 5 mg / kg / day or 2 mg / kg / day of oral afatinib with or without topical aprepitant in Vehicle C (1 mg / kg / day) for 12 weeks (n=5 in each group, 4 total groups. Topical aprepitant administration was initiated after 1 week of afatinib exposure.

[0217] Fig. 6 contains representative digital images of the facial region of afatinib-treated rats with or without topical aprepitant application at week 12. All animals (n=5) in the 5 mg / kg / day afatinib group had skin lesions and / or hair loss ranging from mild to moderate, and topical aprepitant (n=5) was protective. None of the animals receiving the lower dose (2 mg / kg / day) of afatinib with or without aprepitant exhibited notable skin lesions or hair loss. Facial lesion and hair loss at 12 weeks was not as severe as it was during exposure week 10, indicating that some restoration (healing) was occurring.

[0218] The influence of afatinib (2 or 5mg / kg / day, oral) with or without facial topical aprepitant (1 mg / kg / day) on basal neutrophil activation (measured as basal superoxide production) and plasma isoprostane levels after exposure week 12 are summarized in Table 5. Afatinib at low and high doses respectively, elevated basal neutrophil superoxide production 1.92- and 2.75-fold versus control, and increased plasma 8-isoprostane 29% and 75% versus control. Aprepitant treatment lessened oxidative stress by reducing basal neutrophil superoxide production and plasma isoprostane towards control levels at both afatinib doses.65742325-vl148540.615689

[0219] Table 5. The Impact of Afatinib (2 mg / kg / day or 5 mg / kg / day, oral) with or without facial topical aprepitant (1 mg / kg / day) in Vehicle C on basal neutrophil superoxide production and plasma isoprostane levels after exposure week 12.Example 3

[0220] A saturated solubility study of aprepitant in various solvents was conducted as shown in Table 6 below.Table 6Example 4

[0221] Examples of topical aprepitant compositions

[0222] Table ?65742325-vl148540.61568965742325-vl148540.6156896065742325-vl148540.615689a Super Refined PEG 400Example 5

[0223] An exemplary process for preparing a composition of Formulation B of Table 7 is provided below:

[0224] Active Phase: PEG 400, Transcutol, aprepitant, benzyl alcohol, and BHT were combined and then stirred under vacuum. The combination was homogenized for at least for 60 minutes until complete dissolution. While stirring, the Medium chain triglyceride (Miglyol® 812N) was added6165742325-vl148540.615689 and then stirred under vacuum. The temperature was kept at about 25±5°C. The combination was homogenized at least for 20 minutes until obtention of a homogeneous phase.

[0225] Gel Phase: In a 5L stainless-steal beaker, glycerin was mixed at 600±100 rpm using the defloculator blade to obtain a vortex. Hydroxypropyl cellulose (Klucel® HXF) was added and the combination was mixed for at least 10 minutes until obtention of a homogeneous phase free of lumps.

[0226] The Gel Phase was then added to the Active Phase and stirred under vacuum at 25±5°C, for at least for 1 hour until obtention of a homogeneous gel.

[0227] The formulation was placed in a lOOmL pump container where one pump is equal to approximately 1 mb where 1 mb contains about 20mg of aprepitant.Example 6

[0228] Dermal Toxicity Study in minipigs

[0229] In a repeat-dose study in Gottingen minipigs, the toxicity and toxicokinetic profiles of a topical aprepitant or placebo following daily dermal applications for 42 days was evaluated in addition to the persistence, delayed onset, or reversibility of any changes following a 20-day recovery period. Study groups consisted of: sham dose, placebo, 0.5% aprepitant, 1% aprepitant, and 2% aprepitant (Formulation A. The aprepitant groups received 0.75 mL / kg at a dose level of 0, 3.87 mg / kg / day (0.5% group), 7.75 mg / kg / day (1% group), and 15.50 mg / kg / day (2% group), respectively. Each group contained 8 animals total (4 male / 4 female) for the terminal phase; 4 animals (2 males / 2 females) were included in the sham, placebo, and aprepitant (Formulation A) groups for the recovery phase. The study design is shown in Table 8.

[0230] Table 865742325-vl148540.615689- : Not applicable. a Based on the most recent body weight measurement. b Dose levels were calculated based on the density of the formulations, 1.033 g / mL.

[0231] There were no mortalities or clinical observations of systemic toxicity. Clinical observations were local in nature. There were no aprepitant-related body weight effects, ophthalmoscopic findings, electrocardiogram (ECG) findings, effects on any clinical pathology parameter, and no notable macroscopic observations or microscopic evidence of systemic toxicity.

[0232] Aprepitant plasma concentrations obtained from control animals (Groups 1 and 2) on Days 1 and 42 and in all pre-dose plasma samples obtained from aprepitant-treated animals on Day 1 were below the lower limit of quantitation (LLOQ = 1.00 ng / mL).

[0233] Toxicokinetic results post-dose are provided for Day 1 and Day 42 in Tables 9 and 10 below.

[0234] Table 9: Mean (±SD) and CV% Toxicokinetic Parameters on Days 1 and 42 Following Daily Dermal Administration Topical Aprepitant (0.5% at 3.87 mg / kg, 1% at 7.75 mg / kg, and 2% at 15.50 mg / kg) to Minipigs (Males and Females Combined)6365742325-vl148540.61568965742325-vl148540.61568965742325-vl148540.615689

[0235] Table 10: Mean TK Parameters on Days 1 and 42 (Males and Females Combined)

[0236] Systemic exposure to aprepitant did not appear to be sex-dependent. Mean Cmax and AUCO-24 aprepitant values did not generally increase in a dose proportional matter from 3.87 to 15.50 mg / kg / day on Days 1 and 42. Systemic exposure of aprepitant (based on AUCO-24) increased following repeated daily dermal application of topical aprepitant at 3.87, 7.75, and 15.50 mg / kg / day (when comparing Day 42 / Day 1 AUCO-24).

[0237] Very slight (score of 1) to moderate-to-severe (score of 3) erythema was noted in the placebo and aprepitant treated animals, generally at a similar incidence, beginning within the first week (by Day 4) of the study. These findings correlated with local clinical observations of red discolored skin at the application sites with occasional scabbing noted. By the end of the dosing period, the scores generally improved to only very slight to well-defined (score of 2) erythema (and all scabbing had resolved) and all Draize scorings (and red discolored skin) resolved (back to 0) following the first week of the recovery period. Edema was periodically noted (generally very slight, score of 1, to slight, score of 2) with a few instances of moderate edema (score of 3) noted in the placebo group only and on Days 21-28 only. Edema observed in the placebo group was no longer evident during the recovery period. These observations were not considered adverse; although they progressed to moderate-to-severe in some animals, they generally improved (to very slight to well-defined erythema) with continued treatment and completely resolved within a week of recovery, as evidenced by the lack of effects at the end of the first week of the recovery period.6665742325-vl148540.615689

[0238] Erythema and edema (with associated clinical findings) as well as non-adverse microscopic findings at the application sites were noted in the placebo and aprepitant treated groups in a similar incidence and were therefore considered vehicle-related and not attributed to administration of aprepitant. The NOAEL for both systemic and local toxicity was established at 15.50 mg / kg / day (2% aprepitant). On Day 42, the combined sex AUCO-24 and Cmax values at the NOAEL were 2130 h*ng / mL and 162 ng / mL, respectively.Example 7

[0239] Dermal Toxicity Study in Minipigs

[0240] Male (n=6) and female (n=6) Gottingen Minipigs were administered daily dermal doses of either placebo or an aprepitant emulsion gel (Formulation B of Table 6) at 0.75 mL / kg for 7 consecutive days. The placebo was the same as Formulation B except that there was 0% of aprepitant and 49.4% of PEG 400. All animals were euthanized and necropsied on Day 8. The first day of dose administration was referred to as Day 1. Animals were dosed once daily on both sides of the back (avoiding the spine area) at 10% of BSA total at 2 sites (Body surface area, cm2). Individual administered doses were based on the most recent body weight. Half of the test article or placebo gel was applied with a syringe and distributed over each of the prescribed areas (Dose Sites 1 and 2) using a gloved finger. The test article or placebo gel was applied evenly with a thin, uniform film of the appropriate dosing material over the test sites. No bandaging or occlusion was required.

[0241] Parameters evaluated were clinical observations (AM and PM and detailed clinical observations), dermal scoring, body weight, food consumption, ophthalmologic examinations, electrocardiographic examinations (ECG), and clinical pathology (hematology, coagulation, serum chemistry, and urinalysis). Following the last dosing, the animals were euthanized and subjected to a necropsy examination on Day 8, macroscopic and microscopic examination was performed on all animals at necropsy. Blood samples, for toxicokinetic evaluation, were collected on Days 1 and 7 at predose (on Day 1 and at 24 hours post last administration for Day 6) and at 2, 4, 8, and 24 hours postdose and were analyzed for aprepitant using a validated LC- MS / MS method to quantitate levels in plasma.6765742325-vl148540.615689

[0242] There were no aprepitant-related changes in mortality / morbidity, body weights, clinical observations, dermal irritations, food consumption, ECG’s, ophthalmology examinations, clinical pathology parameters (hematology, coagulation, serum chemistry, and urinalysis), or macroscopic and microscopic pathology. Aprepitant was not detected in any of the samples collected from the Placebo (Group 1) animals on Days 1 and 7. In treated animals (Group 2), quantifiable levels of aprepitant were detected in the majority of the samples collected postdose of exposure (up to 24 hours postdose) on Days 1 and 7.

[0243] On Day 1, the mean maximal concentration of aprepitant was 17.4 ng / mL in males at 4 hours postdose and 47.7 ng / mL in females at 24 hours postdose. On Day 7, mean maximal concentration of 144.1 ng / ml was reach at 2 hours postdose in males and 216 ng / mL at 4 hours postdose in females. Samples were collected from all three animals / group / sex. While no pharmacokinetic analysis was performed, predose samples collected on Day 7, from the Group 2 animals, tend to show a possible aprepitant accumulation as predose mean values were 90.4 ng / mL for males and 140.3 ng / mL for females.

[0244] Formulation B administered as a once daily dermal administration for 7 consecutive days to male and female Gottingen Minipigs was considered well tolerated at 0.75 mL / kg using the ready-to-use emulsion gel formulation. Formulation B did not produce any dermal related irritation.

[0245] Bioanalytical plasma analysis for the aprepitant treated group exhibited low levels of exposure on Day 1, with postdose male plasma averages of 10.3, 17.4, 6.6, and 14.5 ng / mL, and for females 1.7, 7.9, 24.6, and 47.7 ng / mL for 2, 4, 8 and 24 hour timepoints, respectively. Exposures on Day 7 resulted in higher ng / mL, with exposures for male averages of 90.4, 144.1, 85.5, 126.1 and 64.8, ng / mL, and for females 140.3, 131.3, 216.0, 90.6, 100.2 ng / mL for predose, 2, 4, 8 and 24 hour timepoints, respectively. Results are shown in Tables 11 and 12 below.

[0246] Based on the results from this study, the NOAEL (No-Observed-adverse-effect-level) was determined to be 0.75 mL / kg, the highest dose administered in this study.6865742325-vl148540.615689

[0247] Table 11 : Plasma Concentrations ng / mL (Day 1)

[0248] Table 12: Plasma Concentrations ng / mL (Day 7)6965742325-vl148540.615689Example 8

[0249] Dermal Toxicity Study in Rabbits

[0250] AlO-day non-GLP study was conducted in New Zealand white rabbits.

[0251] Test article was applied to the skin of rabbits once per day with a saturated cotton gauze (24-hour exposure). Each application site was scored for erythema and edema formation using a 0 to 4 severity scale. The placebo formulations listed in Table 13 were evaluated using a matrixed approach removing groups of excipients by type: 1) Placebo 1 : Formulation A Placebo - same excipients as Formulation A but without aprepitant (positive control for erythema); 2) Placebo 2: “solvent blend” only Placebo (negative control for erythema); 3) Placebo 3: Formulation A Placebo without dimethicone; 4) Placebo 4: Formulation A Placebo without PEG 400; 5) Placebo 5: Formulation A Placebo without surfactants; 6) Placebo 6: Formulation A Placebo without PEG / surf actants.

[0252] Table 13: Placebo Formulations7065742325-vl148540.615689

[0253] Overall, a higher frequency and severity of irritation (Formulation A Placebo [positive control]) was observed on sites treated with the Formulation A Placebo with no dimethicone and the Formulation A Placebo with no PEG 400. The lowest severity / frequency of irritation was observed with the Formulation A Placebo with no surfactants and the Formulation A Placebo with no PEG / surf actants. No edema was observed in any of the animals 24 hours after dose 10.Example 9

[0254] A stability study was performed using certain formulations of Table 7 above. The emulsion gels were characterized at TO, 24 hours after manufacturing. All analyzed formulations has similar appearance and viscosity, except for the lower viscosity of Formulation G.

[0255] The formulations were then analyzed after storage for 1 month at 5°C, Room Temperature (RT), and 40°C. All tested formulations were chemically stable at RT and 40°C. All formulations showed no change in physical appearance (e g., no discoloration or browning) with the exception of Formulations C and J. For Formulations C and J, comprising 0.05% propyl gallate, browning coloration was observed after storage for 1 month.

[0256] An additional assay of aprepitant was performed at T11 weeks at 40°C storage for Formulation B and I. Formulations B and I were both chemically and physically stable for at least 3 months at 40°C (Formulation B %LC= 97.6% (99.3% Rec / TO) and Formulation I % LC =97.1% (98.3% Rec / T0)). Further studies showed stability for Formulation B and I for 24 months at about 25°C.7165742325-vl148540.615689

[0257] Physical instability (browning / color formation) in PEG 400 alone and in Transcutol HP with propyl gallate was observed. Chemical degradation in pure standard grade and Super Refined PEG 400 was observed after 4 weeks at 40°C. This degradation was confirmed after 3 months at 40°C in PEG400SR* at 0.3% [*Chemical stability %LC 3M 40°C = 88.9% (RDS1.5)].

[0258] The results at TO and T 1 month are provided in Tables 13 and 14 below.

[0259] Table 14: Characterization of Formulations B-K at TO65742325-vl148540.6156897365742325-vl148540.615689Table 15: Stability results of Formulations B-K at TIM65742325-vl148540.61568965742325-vl148540.615689Example 10

[0260] An in vitro permeation study was conducted using 6 example formulations of Table 7 above.

[0261] Permeation experiments were performed as finite dose application of 5 mg / cm2of formulation to mimic realistic exposure. Formulations were applied using a positive displacement micropipette and the exact amount applied recorded gravimetric measurements. The experimental design is provided in Table 16 below.

[0262] Table 16: Study design summary

[0263] The results are provided in Table 17 and Figures 7A-7F, which compile averages of values (N=12 for all and N=11 for Formulation H) obtained for each compartment analyzed. Results are expressed in ng / cm2and in percentage of applied dose. All mass balances fulfilled criteria of acceptance of 100 ± 20 % of the applied dose. Each of Figures 7A-7F shows data for the following formulations of Table 7 in order from left to right: A, E, G, H, B, K.7665742325-vl148540.615689Table 17:65742325-vl148540.615689Example 11Case History

[0264] A 59-year-old female with a history of metastatic breast cancer with bilateral lung nodules managed with THP (Taxol, Herceptin (trastuzumab), and Perjeta (pertuzumab) and weekly Abraxane presented to our clinic with pruritic, burning ery thematous papules on her face, scalp, and upper back which began roughly two weeks after treatment initiation (Figure 8). Per her oncologist’s recommendation, the patient had tried Selsun Blue shampoo, which offered minimal relief On exam, there were 19 inflammatory papules scattered across the parietal scalp bilaterally and posterior scalp, 4 eroded papules on the posterior neck and upper back, prominent facial erythema, and minuscule papules on the cheeks bilaterally.

[0265] The patient was only interested in topical therapies and a trial of aprepitant 2% emulsion gel (Formulation B of Table 7 above) was initiated. The patient was instructed to use the gel twice daily for one month. However, at her one-month follow-up, the patient reported that she self-discontinued aprepitant after only one week of twice-daily use due to rapid improvement in symptoms and lesion resolution. She denied the development of any new lesions in the three weeks after discontinuation. At her follow-up, a physical exam revealed two papules on the right parietal scalp but predominantly hyperpigmented macules on the scalp and upper back. Facial erythema subjectively improved from the previous visit.Example 12

[0266] A Randomized, Placebo-controlled, Parallel Phase 2a Dose-ranging Study to Investigate the Efficacy, Safety7, and Tolerability7of Topical Aprepitant Gel for the Treatment of Skin Toxicities Associated With Epidermal Growth Factor Receptor Inhibitors

[0267] STUDY OVERVIEW

[0268] The goal of this clinical trial is to learn about Aprepitant Topical Emulsion Gel for treatment of EGFR inhibitor-induced skin toxicities. The main questions it aims to answer are:• Determine the therapeutic effect of aprepitant gel for treatment of patients who develop acneiform rash undergoing Epidermal Grow th Factor inhibitor (EGFRI) therapy using the acneiform rash investigator’s global assessment scale [ARI GA]• Evaluate the safety of aprepitant gel during treatment7865742325-vl148540.615689

[0269] Participants apply aprepitant emulsion gel once per day for 6 weeks, during which the effect on treating acneiform rash or other skin disorders induced by EGFRI therapy is evaluated using different assessment tools to measure severity of rash, pain, and itching (pruritus), as well as the change in quality of life.

[0270] This is a randomized, double-blind, placebo-controlled, multi-center Phase 2a dose-ranging study to evaluate the efficacy, safety, and tolerability of aprepitant emulsion gel for treatment of EGFRI-induced skin toxicity. The study includes adult patients (> 18 years of age) scheduled to receive initial or repeat EGFRI therapy.

[0271] The study is conducted in 2 cohorts: Part 1, an open-label (unblinded) cohort consisting of 12 patients to measure pharmacokinetics of topical aprepitant emulsion gel, and Part 2, a blinded randomized, parallel arm study comparing 3 dose strengths of aprepitant emulsion gel (0.5%, 1%, or 2% aprepitant ) to placebo (vehicle). Patients (140) in the randomized cohorts are randomly assigned to 1 of the 4 treatment arms in a 2:2:2: 1 ratio (active groups = 2: placebo = 1). Tables 18 and 19 provide below for more information on the study drug.

[0272] Patients consenting to PK sampling are not randomized. Rather, these patients remain in a separate open-label cohort (n = 12) and only receive aprepitant emulsion gel with 2% aprepitant. These patients are not assigned a randomization number.

[0273] Researchers compare aprepitant emulsion gel to the placebo in the second period to see if aprepitant emulsion gel provides a significant treatment effect.

[0274] The goal of the study is to determine the minimum efficacious dose strength(s) for further investigation. The dose effect, together with the application site safety assessments, and therapeutic effects based on the primary and secondary endpoints is evaluated.

[0275] Patients initiating EGFRI therapy are monitored by their oncologist for development of cutaneous toxicities and referred for Screening / Baseline (Visit 1), at which point they are enrolled in the open-label cohort (Part 1) for application of aprepitant emulsion gel (2% aprepitant) for 6 weeks or randomized to aprepitant emulsion gel (0.5%, 1.0%, or 2.0% aprepitant) or placebo (vehicle) for 6 weeks (Part 2). Patients in the randomized, double-blind cohort (Part 2 only) are stratified across severity scores of acneiform rash to allow for subgroup analysis for safety and efficacy per severity. All affected BSA with EGFRI-related cutaneous toxicity disorders are treated. Patients from each arm are monitored for treatment failures requiring rescue medication. BSA for each patient is recorded at each visit and when dosing areas change, as well as total dose applied, and any changes to application area will be monitored.7965742325-vl148540.615689

[0276] In Part 1, the open-label cohort (n = 12) patients receive aprepitant emulsion gel (2% aprepitant) for a 6-week duration of treatment. During this treatment period, PK samples are collected at treatment Day 1 (pre-dose, 1, 2. 3, 4, 6. 8. and 24 hours [Day 2]), as well as on Day 7 (pre-dose), Day 21, (pre dose). Day 41 (pre-dose), and Day 42 (pre-dose, 1, 2, 3, 4, 6, 8, and 24 hours [Day 43]).

[0277] The study includes a Screening / Basehne Visit with a 6-week double-blind treatment period, and a 2-week follow-up period following last dose of study drug. Total duration: up to 60 days. The Screening / Baseline visit is to occur after start of EGFRI therapy and development of rash.

[0278] Table 18: Arms and Interventions

[0279] Topical aprepitant is formulated as a gel and provided in an airless pump. The study includes aprepitant emulsion gel formulated at 3 dose strengths of aprepitant: 0.5%, 1%, and 2%8065742325-vl148540.615689 aprepitant. The corresponding placebo is formulated using the same excipients and is identical in color and physical appearance. Information about the study drugs is provided in Table 19 below.

[0280] The study drugs are supplied ready to use with no preparation required. One pump actuation is equivalent to approximately 1 mL.

[0281] Table 19: Clinical Study Drug Formulation CompositionsAPI = active pharmaceutical ingredient; w / w = weight by weight

[0282] A patient is considered to have completed the study treatment phase when he or she completes the Day 43 visit (PK cohort only. V8) or the Day 42 visit (randomized study, V5). A patient will be considered to have completed the study when he or she completes the 2-week followup visit.

[0283] All patients in both open-label and blinded cohorts apply the study drug in an even, thin layer once a day to each area affected with cutaneous toxicity up to 30% body surface area (BSA) involvement, inclusive of:• Skin (face, chest / abdomen, back, arms / legs)8165742325-vl148540.615689 o For rash present on the face, study drug is applied to the entire face. For other areas, study drug is only applied to the affected area, ensuring to cover the entire area to the surrounding healthy skin.• Scalp (for treatment of acneiform rash, not inclusive of treatment of alopecia)• The following conditions may also be treated as long as the 30% BSA maximum has not been exceeded: o Nails (paronychia only) o Areas with xerosis (outside of areas already being treated for acneiform rash)

[0284] The amount of study drug to be applied per body area is determined based on the BSA as described in the Table 20 below as an example.

[0285] The general guideline that 2% BSA = 0.5 pump (0.5 mL) gel or 4% BSA = 1 pump (1 mL gel) is used. If the affected area is less than the body site, the affected area is covered and the remainder is discarded or used on an alternate site per the dosing chart. To apply units of ! pump, a complete full pump is used and divided in approximately one half discarding the remainder. A maximum of 7.5 mL (equivalent to 7.5 pumps) is to be applied per day; note that the amount of gel applied to the nails is not included in this total since a partial amount is applied only to the affected area and the remainder is discarded.

[0286] New areas of acneiform rash that present after the Day 1 dosing are treated per protocol as long as the maximum daily dose of 7.5 mL is not exceeded (or staying within the 30% BSA involvement maximum). The study Investigator should evaluate the prescribed dose at each study visit to determine if additional rash areas are present. Existing areas should continue study drug application through the entire study, even if a score of clear or almost clear (0 or 1) on the ARI GA scale is achieved.

[0287] In the event of mild to moderate treatment-related AEs, the application frequency can be reduced to every other day using the same prescribed dose volume per affected body surface area.

[0288] Areas where study drug has been applied (excluding the face) should be covered with loosefitting clothing post-application. Patients are e instructed to not swim, bathe, perform strenuous exercise (resulting in sweating / elevated heart rate), or wash the treated areas for at least 6 hours after application.

[0289] One filled pump container of study drug supplies daily application for up to 2-3 weeks, depending on the total dose.8265742325-vl148540.615689

[0290] Table 20: Example Dosing Chart*Note that the 1 pump used to apply across all nail areas affected is not included in the 7.5 mL total because the gel is only applied to affected areas and the remainder is discarded.

[0291] PARTICIPATION CRITERIA

[0292] Inclusion Criteria:1. Adult participant (i.e , > 18 years of age at Screening / Baseline [VI]) prescribed an approved EGFRI to treat cancer (indication within the approved labeling for the EGFRI and / or on National Comprehensive Cancer Network guidelines or equivalent local standards). a. Approved EGFRIs include, but are not limited to: gefitinib, erlotinib, osimertinib, lapatinib, afatinib, dacomitinib, neratinib, vandetanib, lazertinib, cetuximab, panitumumab, necitumumab, pertuzumab. and amivantamab-vmj w.8365742325-vl148540.615689 b. Administration of an EGFRI, in combination with other drugs, for treatment of cancer is acceptable as long as the other drug is identified in the approved label of the EGFRI (e.g., erlotinib with gemcitabine) or part of the NCCN guidelines or equivalent local standards.2. Participant has developed a rash or symptoms of a rash (papular and / or pustular eruptions or cutaneous burning), as assessed by both Common Terminology Criteria for Adverse Events (CTCAE) grading and ARIGA scales (severity < 3) with overall involvement < 30% BSA.3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.4. Predicted life expectancy > 3 months.5. Participant is able and willing to comply with contraceptive requirements: a. All sexually active female participants of childbearing potential (hereafter WOCBP) must use highly effective contraception during the study and for 3 months after the last dose of study drug (whichever is longer). A WOCBP is defined as a woman who has not undergone surgical sterilization (hysterectomy, bilateral oophorectomy, and / or bilateral salpingectomy) and who is not postmenopausal (no menses for > 12 months without an alternative medical cause with confirmed serum follicle-stimulating hormone [FSH] concentration > 40 International Units [IU] / L). Highly effective birth control methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; or vasectomized partner. Note that birth control containing hormonal contraception may not be effective during concomitant use with HT-001 topical gel. An effective alternative or back-up method of contraception (such as condoms and spermicides) should be used during the study and for 28 days after administration of the last dose of HT-001.8465742325-vl148540.615689 b. All sexually active male participants with WOCBP partners must use a condom with or without spermicide in addition to the birth control used by their partners from Screening / Baseline (VI) and for 3 months after the last dose of study drug.Sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the study and for 3 months after the last dose of study drug (whichever is longer). The reliability of sexual abstinence needs to be evaluated by the Investigator in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant.WOCBP must have a negative pregnancy test at Screening / Baseline (VI) and be willing to have additional pregnancy tests as required throughout the study.6. Participant must have the ability and willingness to attend the necessary visits (telehealth and in person).7. Participant must be willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.

[0293] Exclusion Criteria:1. Participant has severe cutaneous toxicity (severity = 4 on the CTCAE grading and ARIGA scales) or cutaneous toxicity involvement that is > 30% BSA, or other severe systemic toxicity7(severity > 3 on the CTCAE v5.0 scale) as a result of EGFRI therapy.2. Participant has any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the participant would comply with the protocol or complete the study per protocol.3. Participant has a history of other skin disorders (e.g., atopic dermatitis, psoriasis, recurrent skin infections), or history7of illness that, in the opinion of the8565742325-vl148540.615689Investigator, would confound results of the study or pose unwarranted risk in administering study drug to the participant.4. Participant has abnormal laboratory values at Screening / Baseline (VI): a. Absolute neutrophil count < 1000 / mm3and WBC count < 3000 / mm3b. Platelet count < 50,000 / mm3c. Aspartate transaminase (AST) > 2.5 x upper limit of normal (ULN) d. Alanine transaminase (ALT) > 2.5 x ULN e. Bilirubin > 1.5 x ULN f. Creatinine > 1.5 x ULN5. Participant has a known history of QT interval prolongation.6. Participant has a prescribed cancer treatment plan that requires radiation treatment to the head, neck, or upper trunk concurrent with EGFRI therapy or has previously received radiation therapy within 4 weeks prior to Screening / Baseline (VI).7. Participant has received aprepitant or other neurokinin- 1 receptor antagonist within 4 weeks prior to Screening / Baseline (VI).8. Participant has had prior treatment with an investigational drug within 4 weeks prior to Screening / Baseline (VI), or at least 8 half-lives of the drug, whichever is longer.9. Participant has an active infection (e.g., pneumonia or pneumonitis) or any uncontrolled disease except for the malignancy that, in the opinion of the Investigator, might confound the result or the study or pose unwarranted risk in administering the study drug to the participant.10. Participant has received non-stable escalating doses of topical antibiotics, topical steroids, or other topical treatments within 14 days prior to Screening / Baseline (VI). Participants who have been on stable doses of topical antibiotics, topical steroids, or other topical treatments for 14 days or more are allowed to be enrolled and to stay on their current prescription. Reduction in dose due to improvement in EGFRI-related toxicities is allowed.8665742325-vl148540.61568911. Participant has used non-stable escalating doses of systemic steroids within 14 days prior to Screening / Baseline (VI) excluding low-dose systemic corticosteroids as part of standard of care for prevention or treatment of chemotherapy -induced nausea and vomiting; acceptability of the steroid and dose is to be determined by the Investigator. Participants who have been on a stable dose of systemic steroids for 14 days or more are allowed to be enrolled and to stay on their current prescription. Reduction in dose due to improvement in EGFRI-related toxicities is allowed. Use of steroid inhalers and nasal corticosteroids is allowed.12. Participant has received non-stable escalating dose treatment with a systemic antibiotic within 14 days prior to Screening / Baseline (VI). Participants who have been on stable doses of systemic antibiotics for 14 days or more are allowed to be enrolled and to stay on their current prescription. Reduction in dose due to improvement in EGFRI-related toxicities is allowed.13. Participant has received concomitant treatment with pimozide, moderate to strong cytochrome p450 (CYP) 3A4 inhibitors (diltiazem, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfmavir). or strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin) within 30 days of Screening / Baseline (VI).14. Participant has a history of hypersensitivity to aprepitant or any component of HT- 001.15. Participant is pregnant or lactating at Screening / Baseline (VI) or planning to become pregnant (self or partner) at any time during the study, including the follow-up period.

[0294] Primary Endpoints

[0295] Part 1 (open-label, PK cohort) - The primary endpoint of the Part 1 study is:• Investigating PK parameters including: measured drug concentrations above the lower limit of quantitation, number of patients with measurable systemic exposure; if data allow - area under the curve (AUC), maximum (or peak) concentration (Cmax), and time of peak concentration (Tmax)

[0296] Part 2 (randomized double-blind cohort) - The primary endpoint of the Part 2 study is:8765742325-vl148540.615689• Proportion of patients with a grade < 1 based on the ARIGA scale after 6 weeks of aprepitant emulsion gel treatment

[0297] Secondary Endpoints (all study cohorts)

[0298] The secondary endpoints of this study are:• Change from Baseline in pruritus NRS (average itch and worst itch) after 3 weeks and 6 weeks of aprepitant emulsion gel treatment compared to placebo• Change from Baseline in pain based on an NRS after 3 weeks and 6 weeks of aprepitant emulsion gel treatment compared to placebo• Change from Baseline in acneiform rash grade based on the ARIGA scale at 3 weeks and 6 weeks of aprepitant emulsion gel treatment compared to placebo• Time to improvement by at least 1 grade using the ARIGA scale for acneiform rash for aprepitant emulsion gel treatment compared to placebo• Time to topical rescue therapy treatment after initiation of aprepitant emulsion gel treatment compared to placebo• Proportion of patients with EGFRI dose reduction or discontinuation due to EGFRI skin toxicities after 6 weeks of aprepitant emulsion gel treatment compared to placebo• Safety and tolerability of aprepitant emulsion gel as measured by: o Incidence of treatment-emergent adverse events (TEAEs) and treatment- emergent SAEs o Skin irritation, as assessed using the modified Draize Scale to evaluate cutaneous signs of erythema and edema o Physical examinations o Vital signs o 12-lead ECG8865742325-vl148540.615689 o Clinical laboratory values (hematology, chemistry, urinalysis), including transaminase and bilirubin levels o Additional secondary' endpoint for Part 1 open-label PK cohort: The proportion of patients with acneiform rash of grade < 1 based on the ARIGA scale after 6 weeks of treatment.

[0299] Exploratory Endpoints (all study cohorts)

[0300] The exploratory endpoints of this study are: o Proportion of patients with improvement in paronychia based on the scoring system for paronychia related to oncologic treatments (SPOT) scale after 6 weeks of aprepitant emulsion gel treatment compared to placebo o Proportion of patients with improvement in xerosis based on the Xerosis Severity- Scale after 6 weeks of aprepitant emulsion gel treatment compared to placebo o Change in quality' of life (QoL) after 6 weeks of aprepitant emulsion gel treatment based on Dermatology -related Quality of Life Assessment in Patients Treated with Epidermal Growth Factor Receptor Inhibitors (FACT-EGFR-18)

[0301] Efficacy Assessments

[0302] The primary efficacy analysis compares the proportions of participants achieving a toxicity' grade < 1 based on the ARIGA scale after 6 weeks using the intent-to-treat (ITT) analysis set, defined as all randomized participants in the double-blind cohort. Each treatment group is compared to placebo using Fisher’s exact test. In addition, 95% confidence intervals for the proportion in each treatment group are provided using exact (Clopper-Pearson) estimates.

[0303] The change from Baseline to Weeks 3 and 6 in pruritus NRS (average itch and worst itch), pain NRS, and the investigator’s global assessment (IGA) for acneiform rash (ARIGA) scale are analyzed using an analysis of co-variance model (ANCOVA) including treatment and baseline acneiform rash severity as factors.

[0304] Acneiform Rash Investigator Global Assessment (ARIGA)

[0305] The overall extent of acneiform rash is graded according to the scale in Table 21 below. Each of the primary areas for acneiform rash development (face, scalp, chest, and back) are assessed by morphological description and the total BSA of involvement. Secondary' areas (e.g., abdomen,8965742325-vl148540.615689 arms, legs, etc.) are also considered for overall area of involvement after confirming the diagnosis of acneiform rash in these regions.

[0306] The Common Terminology Criteria for Adverse Events (CTCAE) scale is often used in cancer-related clinical trials to report a broad range of AEs. Many agents such as EGFRIs generate a constellation of AEs that are not adequately characterized by the nosology of CTCAE, particularly skin toxicities (e.g., dermatologic AEs uncommonly reach grade 3 and beyond in severity on the CTCAE)

[0307] To address limitations of the CTCAE scale, a novel IGA for acneiform rash has been developed as a measure for the primary study endpoint, the ARI GA The ARIGA focuses on the most critical elements influencing clinical severity of acneiform rash, which is the overall area of involvement (BSA) impacted. Unlike other dermatological disorders, acneiform rash generally presents in a single morphology that does not change with disease progression or severity. Acneiform rash presents with papules or pustules that may also have a scale or crust. Patients with acneiform rash that progresses in severity usually have a higher area of involvement. Acneiform rash usually presents initially on the face and / scalp, and then progresses to papules / pustules on the chest and back. Presence of acneiform rash on other areas of the body (eg, arms, legs, abdomen) is an indication of severe disease. Development of nodules in the primary areas is the only morphological change indicating severe (grade 4 disease).

[0308] Assessments using CTCAE are used during the study to show correlation with the ARIGA scale.

[0309] Table 21: Acneiform Rash Investigator Global Assessment (ARIGA)65742325-vl148540.615689ARIGA = acneiform rash investigator global assessment; IGA = investigator global assessment

[0310] Numeric Rating Scale for Pruritus

[0311] The NRS is comprised of 2 scales, one that measures the average itch severity over the last 24 hours and one that measures the worst itch severity over the last 24 hours. The numerical scale is ranked from 0 (“no itch”) to 10 (“worst imaginable itch”). Patients are asked to rate the intensity of their itch over the last 24 hours using this scale (average and worst itch). It features high reliability and concurrent validity and is a popular choice for all patients due to its simple form. It can be interpreted as follows: NRS = 0 (no pruritus), NRS < 3 (mild pruritus), > 3 to < 7 (moderate pruritus), NRS > 7 to < 9 (severe pruritus), NRS > 9 (very' severe pruritus).

[0312] Pain Numerical Rating Scale

[0313] The NRS is comprised of 2 scales, one that measures the average pain over the last 24 hours and one that measures the worst pain over the last 24 hours. The 11 -point NRS (where “0” indicates “no pain"’, “5” indicates “moderate pain” and “10” indicates “worst pain imaginable”) is a commonly used and validated measure for pain. Patients are asked to rate the severity of their pain over the last 24 hours using this scale (average and worst pain) as noted in the SoA to assess the patient’s level of pain at various time points.

[0314] Xerosis Assessment

[0315] Xerosis will be assessed using the Xerosis Severity Scale adapted from Guenther et al. 2012. The assessment uses signs and symptoms of xerosis (such as rough / scaling skin, itching, pain, erythema, and fissures) as a composite score to determine the severity classification. Itching is defined as moderate if it is present up to 10% of the time and interferes with the activity of dailyliving. It is defined as severe if it is present most of the time and makes the individual wake up at night. If fissures are present, the score is moderate or severe.

[0316] Table 22: Xerosis Severity Scale9165742325-vl148540.615689- = not present; + = mild; ++ = moderate; +++ = severe.

[0317] Common Terminology Criteria for Adverse Event

[0318] The overall acneiform rash and other cutaneous toxicity severities will be rated at screening and during the study according to the CTCAE v5.0 or the most cunent released version. The National Cancer Institute CTCAE is a descriptive terminology that can be utilized for AE reporting. A grading (severity) scale is provided for each AE term.

[0319] CTCAE v5.0 defines acneiform rash as "a disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.”

[0320] Table 23: Common Terminology Criteria for Adverse Event Grades: Rash Acneiform9265742325-vl148540.615689ADL = activity of daily living; BSA = body surface area

[0321] Paronychia Assessment

[0322] Paronychia is assessed using the scoring system for paronychia related to oncologic treatments (SPOT scale). The SPOT scoring system was designed for assessing the severity of paronychia. In the scoring system, each parameter of paronychia, such as redness (R), edema (E), discharge (D) and granulation tissue (G), is evaluated on a 4-point scale from 0 to 3. Upon examination, the severity of each parameter for each finger (or toe) is noted. The highest score for each R-E-D-G parameter among all involved fingers (or toes) of the respective hand (or foot) represents the overall score for that parameter on that hand (or foot) - note, the highest scores for the different parameters could originate from different fingers (or toes). For each hand or foot, the highest possible summed score is 12, so the highest possible total composite score for all 4 limbs of a single patient is 48.

[0323] Table 24: Definition of Each Component of the SPOT Scoring System65742325-vl148540.615689SPOT = scoring system for paronychia-related to oncologic treatments

[0324] Modified Draize Scale Scoring

[0325] A modified Draize Scale is utilized to assess erythema and edema at the site of aprepitant emulsion gel application to determine if a sensitization reaction has occurred. Modified Draize assessment is performed in the areas where study drug has been applied for each assessment. The supplemental scores are added to the basic score if the reactions include described symptoms. The final score is the sum of basic and supplemental score values. Observations of papules, vesicles, or bullae should be considered for involvement from acneiform rash or other cutaneous toxicities from EGFR1 therapy and scored using the AR1GA or CTCAE scale as appropriate.

[0326] Table 25: Modified Draize Scale Scoring

[0327] Table 26: Primary' Outcome Measures65742325-vl148540.615689

[0328] Table 27: Secondary Outcome Measures65742325-vl148540.6156899665742325-vl148540.615689

[0329] Table 28: Other Outcome Measures9765742325-vl148540.615689

[0330] Data for three patients from the open label cohort (PK cohort) is provided in Table 29 below.

[0331] Table 299865742325-vl148540.615689* At screening / baseline (pre-dose)

[0332] While the disclosure has been described above with reference to specific embodiments thereof, it is apparent that many changes, modification, and variations can be made without departing from the concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims.65742325-vl

Claims

1. 148540.615689WHAT IS CLAIMED IS:

1. A topical composition comprising a neurokinin- 1 receptor antagonist selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof, and at least one excipient, wherein the composition is a non-aqueous emulsion.

2. The topical composition of claim 1, wherein the neurokinin- 1 receptor antagonist is aprepitant or a pharmaceutically acceptable salt thereof.

3. The topical composition of claim 1 or 2, wherein the neurokinin- 1 receptor antagonist is aprepitant.

4. The topical composition of any of claims 1-3, wherein the composition is an emulsion gel.

5. The topical composition of any of claims 1-4, wherein the at least one excipient comprises a solvent, an emollient, a humectant, and / or a gelling agent.

6. The topical composition of any of claims 1-5, wherein the composition comprises:(a) aprepitant or the pharmaceutically acceptable salt thereof,(b) at least one solvent,(c) at least one humectant, and(d) at least one gelling agent.

7. The topical composition of claims 5 or 6, wherein the solvent comprises diethylene glycol monoethyl ether, benzyl alcohol, and / or polyethylene glycol.

8. The topical composition of any of claims 5-7, wherein the solvent comprises diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol.

9. The topical composition of any of claims 5-8, wherein the humectant comprises glycerin.

10. The topical composition of any of claims 5-9, wherein the gelling agent comprises hydroxypropyl cellulose.1 1 . The topical composition of any of claims 5-10, comprising an emollient.

12. The topical composition of claim 11, wherein the emollient comprises a medium chain triglyceride.

13. The topical composition of any of claims 5-12, further comprising an antioxidant.

14. The topical composition of claim 13, wherein the antioxidant comprises propyl gallate, BHA (butj dated hydroxyanisole), and / or BHT (butj dated hydroxytoluene).10065742325-vl148540.61568915. The topical composition of claim 14, wherein the antioxidant comprises BHA or BHT.

16. The topical composition of claim 15, wherein the antioxidant is BHT.

17. The topical composition of any of claims 5-16, comprising:(a) about 0.1 - 5% w / w of aprepitant or the pharmaceutically acceptable salt thereof,(b) about 50 - 95% w / w of the solvent,(c) about 1 - 10% w / w of the humectant, and(d) about 0.5 - 5% w / w of the gelling agent.

18. The topical composition of any of claims 11-17, comprising about 0.5 - 10% w / w of emollient.

19. The topical composition of any of claims 2-18, wherein the composition comprises 0.5% w / w, 1% w / w, or 2% w / w of the aprepitant or the pharmaceutically acceptable salt thereof.

20. The topical composition of any of claims 1-19, wherein the composition is free of or substantially free of propyl gallate.

21. The topical composition of any of claims 1-20, wherein the composition is free of or substantially free of a surfactant or emulsifier.

22. The topical composition of any of claims 1-21, comprising:(a) about 0.1-5% w / w of aprepitant or the pharmaceutically acceptable salt thereof,(b) about 35-55% w / w of diethylene glycol monoethyl ether,(c) about 0.5-5% w / w of benzyl alcohol,(d) about 30-55% w / w of polyethylene glycol,(e) about 1-10% w / w of glycerin, and(1) about 0.5-5% w / w of hydroxy propyl cellulose.

23. The topical composition of claim 22, further comprising about 0.5-10% w / w of medium chain triglyceride and about 0.01-1% w / w of BHT (butylated hydroxy toluene).

24. The topical composition of claim 23, comprising:(a) about 0.5-2% w / w of the aprepitant or the pharmaceutically acceptable salt thereof.(b) about 38-50% w / w of the diethylene glycol monoethyl ether,(c) about 1-2.5% w / w of the benzyl alcohol.(d) about 34-50% w / w of the polyethylene glycol,10165742325-vl148540.615689(e) about 1-5% w / w of the medium chain triglyceride,(f) about 5-7% w / w of the glycerin,(g) about 0 5-1.5% w / w of the hydroxypropyl cellulose, and(h) about 0.05-0.2% w / w of the BHT (butylated hydroxytoluene).

25. The topical composition of any of claims 1-24, wherein the composition is chemically and physically stable for 3 months when stored at 40°C.

26. A topical composition comprising:(a) aprepitant or a pharmaceutically acceptable salt thereof,(b) at least one solvent,(c) at least one humectant, and(d) at least one gelling agent.

27. The topical composition of claim 26, further comprising at least one emollient,28. The topical composition of claim 26 or 27, further comprising at least one antioxidant.

29. The topical composition of any of claim 26-28, wherein the solvent comprises diethylene glycol monoethyl ether, benzyl alcohol, and / or polyethylene glycol.

30. The topical composition of any of claims 26-29, comprising diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol.

31. The topical composition of any of claims 26-30. wherein the humectant comprises glycerin.

32. The topical composition of any of claims 26-31, wherein the gelling agent comprises hydroxypropyl cellulose.

33. The topical composition of any of claims 26-32, wherein the emollient comprises medium chain triglyceride.

34. The topical composition of any of claims 28-33. wherein the antioxidant is BHA (butylated hydroxyanisole) and / or BHT (butylated hydroxytoluene).

35. The topical composition of any of claims 26-34. comprising about 0.1-5% w / w of aprepitant or the pharmaceutically acceptable salt thereof.

36. The topical composition of any of claims 29-35, comprising about 35-55% w / w of diethylene glycol monoethyl ether.

37. The topical composition of any of claims 29-36, comprising about 0.5-5% w / w of benzyl alcohol.10265742325-vl148540.61568938. The topical composition of any of claims 29-37, comprising about 30-55% w / w of polyethylene glycol.

39. The topical composition of any of claims 31-38, comprising about 1-10% w / w of glycerin.

40. The topical composition of any of claims 32-39. comprising about 0.5-5% w / w of hydroxypropyl cellulose.

41. The topical composition of any of claims 33-40, comprising about 0.5-10% w / w of medium chain triglyceride.

42. The topical composition of any of claims 34-41, comprising about 0.01-1% w / w of BHT (butylated hydroxytoluene).

43. The topical composition of any of claims 26-42, comprising:(a) about 0.1-5% w / w of aprepitant or the pharmaceutically acceptable salt thereof,(b) about 35-55% w / w of diethylene glycol monoethyl ether,(c) about 0.5-5% w / w of benzyl alcohol,(d) about 30-55% w / w of polyethylene glycol,(e) about 0.5-10% w / w of medium chain triglyceride.(f) about 1-10% w / w of glycerin,(g) about 0.5-5% w / w of hydroxypropyl cellulose, and(h) about 0.01-1% w / w of BHT (butylated hydroxytoluene).

44. The topical composition of claim 43, comprising:(a) about 0.5-2% w / w of the aprepitant or the pharmaceutically acceptable salt thereof.(b) about 38-50% w / w of the diethylene glycol monoethyl ether,(c) about 1-2.5% w / w of the benzyl alcohol.(d) about 34-50% w / w of the polyethylene glycol,(e) about 1-5% w / w of the medium chain triglyceride,(f) about 5-7% w / w of the glycerin,(g) about 0.5-1.5% w / w of the hydroxypropyl cellulose, and(h) about 0.05-0.2% w / w of the BHT (butylated hydroxytoluene).

45. A topical composition comprising:(a) aprepitant or a pharmaceutically acceptable salt thereof,10365742325-vl148540.615689(b) diethylene glycol monoethyl ether,(c) benzyl alcohol, and(d) polyethylene glycol.

46. The topical composition of claim 45, further comprising glycerin.

47. The topical composition of any of claim 45 or 46, further comprising hydroxypropyl cellulose.

48. The topical composition of any of claims 45-47, further comprising medium chain triglyceride.

49. The topical composition of any of claims 45-48, further comprising at least one antioxidant.

50. The topical composition of any of claims 45-49. comprising hydroxypropyl cellulose, glycerin, medium chain triglyceride, and at least one antioxidant.

51. The topical composition of claim 49 or 50, wherein the antioxidant is BHA (butylated hydroxyanisole) and / or BHT (butylated hydroxy toluene).

52. The topical composition of any of claims 49-51, comprising:(a) about 0. 1-5% w / w of aprepitant or the pharmaceutically acceptable salt thereof,(b) about 35-55% w / w of diethylene glycol monoethyl ether,(c) about 0.5-5% w / w of benzyl alcohol,(d) about 30-55% w / w of polyethylene glycol,(e) about 0.5-10% w / w of medium chain triglyceride,(!) about 1-10% w / w of glycerin,(g) about 0.5-5% w / w of hydroxy propyl cellulose, and(h) about 0.01-1% w / w of BHT (butylated hydroxytoluene).

53. The topical composition of claim 52, comprising:(a) about 0.5-2% w / w of the aprepitant or the pharmaceutically acceptable salt thereof.(b) about 38-50% w / w of the diethylene glycol monoethyl ether,(c) about 1-2.5% w / w of the benzyl alcohol.(d) about 34-50% w / w of the polyethylene glycol,(e) about 1-5% w / w of the medium chain triglyceride,(f) about 5-7% w / w of the glycerin,10465742325-vl148540.615689(g) about 0.5-1.5% w / w of the hydroxypropyl cellulose, and(h) about 0.05-0.2% w / w of the BHT (butylated hydroxytoluene).

54. A method of treating a skin toxicity in a subject in need thereof, comprising topically administering to the subject in need thereof a composition according to any of claims 1-53, wherein the skin toxicity is induced by an epidermal growth factor receptor inhibitor (EGFRI).

55. A method of treating a skin toxicity in a subject in need thereof, comprising topically administering to the subject in need thereof a composition comprising a neurokinin- 1 receptor antagonist and at least one excipient, wherein the neurokinin- 1 receptor antagonist is selected from aprepitant or a pharmaceutically acceptable salt thereof or fosaprepitant or a pharmaceutically acceptable salt thereof, wherein the skin toxicity is induced by an epidermal grow th factor receptor inhibitor (EGFRI).

56. The method of claim 55, wherein the neurokinin-1 receptor antagonist is aprepitant or the pharmaceutically acceptable salt thereof.

57. The method of any of claims 54-56, wherein the subject is receiving, has previously received, or will receive the EGFRI.

58. The method of claim 57. wherein the subject is receiving or has previously received the EGFRI.

59. The method of any of claims 54-58, wherein the EGFRI is cetuximab, panitumumab. zalutumumab, nimotuzumab, matuzumab. necitumumab, erlotinib, gefitinib, afatinib, brigatinib. icotinib, lapatinib, osimertinib, dacomitinib, neratinib, and / or vandetanib.

60. The method of claim 59, wherein the EGFR inhibitor is erlotinib and / or afatinib.

61. The method of claim 60, w herein the EGFR inhibitor is erlotinib.

62. The method of any of claims 54-61, wherein the subject is a human.

63. The method of any of claims 55-62, wherein the composition comprises:(a) aprepitant or the pharmaceutically acceptable salt thereof.(b) at least one solvent,(c) at least one emollient,(d) at least one humectant, and(e) at least one gelling agent.10565742325-vl148540.61568964. The method of claim 63, wherein the solvent comprises diethylene glycol monoethyl ether, benzyl alcohol, and / or polyethylene glycol.

65. The method of claim 64, comprising diethylene glycol monoethyl ether, benzyl alcohol, and polyethylene glycol.

66. The method of any of claims 63-65, wherein the emollient comprises medium chain triglyceride.

67. The method of any of claims 63-66, wherein the humectant comprises glycerin.

68. The method of any of claims 63-67, wherein the gelling agent comprises hydroxypropyl cellulose.

69. The method of any of claims 63-68, wherein the composition further comprises at least one antioxidant.

70. The method claim 69, wherein the antioxidant is BHA (butylated hydroxyanisole) and / or BHT (butylated hydroxytoluene).

71. The method of any of claims 55-70, wherein the composition comprises about 0.1-5% w / w of aprepitant or the pharmaceutically acceptable salt thereof.

72. The method of any of claims 55-71, wherein the composition comprises about 35-55% w / w of diethylene glycol monoethyl ether.

73. The method of any of claims 55-72, wherein the composition comprises about 0.5-5% w / w of benzxd alcohol.

74. The method of any of claims 55-73, wherein the composition comprises about 30-55% w / w of polyethylene glycol.

75. The method of any of claims 55-74, wherein the composition comprises about 0.5-10% w / w of medium chain triglyceride.

76. The method of any of claims 55-75, wherein the composition comprises about 1-10% w / w of glycerin.

77. The method of any of claims 55-76, wherein the composition comprises about 0.5-5% w / w of hydroxypropyl cellulose.

78. The method of any of claims 55-77, wherein the composition comprises about 0.01-1% w / w of BHT (butylated hydroxytoluene).

79. The method of any of claims 55-78, wherein the composition comprises:10665742325-vl148540.615689(a) about 0.1-5% w / w of aprepitant or the pharmaceutically acceptable salt thereof(b) about 35-55% w / w of diethylene glycol monoethyl ether,(c) about 0.5-5% w / w of benzy l alcohol,(d) about 30-55% w / w of polyethylene glycol,(e) about 0.5-10% w / w of medium chain triglyceride,(f) about 1-10% w / w of glycerin,(g) about 0.5-5% w / w of hydroxy propyl cellulose, and(h) about 0.01-1% w / w of BHT (butyl ated hydroxytoluene).

80. The method of any of claims 55-79, wherein the composition comprises:(a) about 0.5-2% w / w of the aprepitant or the pharmaceutically acceptable salt thereof,(b) about 38-50% w / w of the diethylene glycol monoethyl ether,(c) about 1-2.5% w / w of the benzy l alcohol,(d) about 34-50% w / w of the polyethylene glycol,(e) about 1-5% w / w of the medium chain triglyceride,(f) about 5-7% w / w of the glycerin,(g) about 0 5-1.5% w / w of the hydroxypropyl cellulose, and(h) about 0.05-.2% w / w of the BHT (butylated hydroxytoluene).

81. The method of any of claims 57-80 wherein the composition is administered on the first day that the subject received the EGFRI.

82. The method of any of claims 57-80, wherein the composition is administered at least one day after the first day that the subject has received at least one dose of the EGFRI.

83. The method of any of claims 57 or 59-80, wherein the composition is administered before the subject has received at least one dose of the EGFRI.

84. The method of claim 82, wherein the composition is administered at least 7 days after the subject has received an EGFRI.

85. The method of any of claims 54-84, wherein the composition is administered twice a day, daily, every other day, twice a week, weekly, twice a month, or monthly.

86. The method of any of claims 85. wherein the composition is administered daily.10765742325-vl148540.61568987. The method of any of claims 54-86, wherein the skin toxicity is a papulopustular eruption, pruritus, xerosis, and / or nail paronychia.

88. The method of claim 87, wherein the skin toxicity is a papulopustular eruption and / or pruritus.

89. The method of claim 88, wherein the skin toxicity is a papulopustular eruption.

90. The method of claim 89, wherein the papulopustular eruption is an acneiform rash.

91. The method of any of claims 54-90, wherein the composition is administered to the skin, scalp, and / or nails.

92. Use of the composition of any of claims 1-53 for the treatment of a skin toxicity in a subject in need, comprising topically administering the composition to the subject, wherein the skin toxicity is induced by an EGFRI.

93. The composition of any of claims 1-53 for use in the treatment of a skin toxicity in a subject in need, comprising topically administering the composition to the subject, wherein the skin toxicity is induced by an EGFRI.10865742325-vl

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