Use of aprepitant for treatment and prevention of hair loss

Abstract

Disclosed herein include methods, compositions, and kits suitable for use in treating and preventing hair loss. The composition includes a neurokinin 1 receptor (NK1R) antagonist (e.g., aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof). The composition can be formulated in form of ointment, gel, lotion, cream, paste, powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, solution, suspension, emulsion, aerosols, or nanoparticles. The method of treating or preventing hair loss, comprises administering to a subject a therapeutically or prophylactically effective amount of a composition herein described, for example, by topical application.

Description

USE OF APREPITANT FOR TREATMENT AND PREVENTION OF HAIR LOSSRELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 63 / 575,546, filed April 5, 2024, the content of which is incorporated herein by reference in its entirety for all purposes.BACKGROUNDField

[0002] The present disclosure relates generally to the fields of medicine. One aspect relates to the treatment and prevention of hair loss using a neurokinin 1 receptor (NK1R) antagonist (e.g., aprepitant).Description of the Related Art

[0003] Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. The severity of hair loss can vary from a small area to the entire body. Hair loss is a common problem that affects millions of males and females of all ages.

[0004] People have between 100,000 and 150,000 hairs on their head. The number of strands of hairs normally lost in a day varies but on average is about 100. In order to maintain a normal volume, hair must be replaced at the same rate at which it is lost. A hair loss thus occurs when the number of hair replacement is less than that of the hair lost.

[0005] Hair is considered an essential part of overall physical appearance for males and females. There is a financial and psychological cost due to hair loss. One of the challenges with identifying effective treatment for hair loss is the multiplicity of causes for hair loss. Known causes for hair loss include hormonal changes, heredity, disease, stress, medications, infections, genetic disorders, toxic agents, and / or food deficiencies.

[0006] Therefore, compositions and methods for treating and preventing hair loss remain an unmet medical need.SUMMARY

[0007] Disclosed herein include methods of treating and preventing hair loss. In some embodiments, the method comprises administering to a subject a therapeutically or prophylactically effective amount of a composition comprising aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof; thereby treating or preventing hair loss in the subject. The composition can, e.g., comprise a therapeutically or prophylactically effective amount of NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof. In some embodiments, the subject is a mammal, e.g., a human.

[0008] In some embodiments, the composition is a pharmaceutical composition comprising NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is in a formulation for topical application. In some embodiments, the composition is administered to the subject by intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, or nebulization. In some embodiments, the composition is administered to the subject by oral or intravenous administration. In some embodiments, the composition is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, solution, suspension, emulsion, aerosols, or nanoparticles. In some embodiments, the composition is administered to the subject once, twice, or three times a day. In some embodiments, the composition is administered to the subject once every day, every two days, or every three days. In some embodiments, the composition is administered to the subject at an effective daily dose of NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof at from 10 mg to 250 mg. In some embodiments, the composition comprises one or more additional therapeutic agents.

[0009] In some embodiments, administering the composition reduces the hair loss by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0010] In some embodiments, the subject is administered with a composition comprising fosaprepitant.

[0011] Disclosed herein include kit for treating and preventing hair loss. In some embodiments, the kit comprises: NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof; and a label indicating that the kit is for treating and preventing hair loss.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 illustrates a scalp (10) of a male subject with alopecia (102) in which a composition as described herein was administered to treatment portion (101) while control portion (103) was untreated or treated with a vehicle.

[0013] FIG. 2 shows digital facial images after 8 weeks: Control (Panel A); Erlotinib- treated (oral) without vehicle C (Panel B); Erlotinib (oral) + topical Aprepitant treatment initiated Week 1 after starting Erlotinib (Panel C); and Erlotinib (oral) + topical Aprepitant treatment initiated Week 6 after starting Erlotinib (oral) (Panel D). N = 5 rats per group. Erlotinib = initial 10 mg / kg / day, oral; Aprepitant = 1.5 mg / kg / day in vehicle C. Facial treatment area = 4 - 5 cm2.

[0014] FIG. 3 shows digital facial images after 12 weeks: Control (Panel A); Erlotinib- treated (oral) without vehicle C (Panel B); Erlotinib (oral) + topical Aprepitant treatment initiated Week 1 after starting Erlotinib(Panel C); and Erlotinib (oral) + topical Aprepitant treatment initiated Week 6 after starting Erlotinib (oral) (Panel D). N = 5 rats per group. Erlotinib = initial 10 mg / kg / day, oral; Aprepitant = 1.5 mg / kg / day in vehicle C. Facial treatment area = 4 - 5 cm2.

[0015] Throughout the drawings, reference numbers may be re-used to indicate correspondence between referenced elements. The drawings are provided to illustrate example embodiments described herein and are not intended to limit the scope of the disclosure.DETAILED DESCRIPTION

[0016] The illustrative embodiments described in the detailed description, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein and made part of the disclosure herein.

[0017] All patents, published patent applications, other publications, and sequences from GenBank, and other databases referred to herein are incorporated by reference in their entirety with respect to the related technology.

[0018] Alopecia is a common condition. According to the National Alopecia Areata Foundation, Alopecia Areata itself affects approximately 2.1 percent of the population worldwide, including more than 6.8 million people in the United States.

[0019] The severity of hair loss can vary from a small area to the entire body. Common types include male- or female-pattern hair loss, alopecia areata, and a thinning of hair known as telogen effluvium. The cause of male-pattern hair loss is a combination of genetics and male hormones; the cause of female pattern hair loss is unclear; the cause of alopecia areata is autoimmune; and the cause of telogen effluvium is typically a physically or psychologically stressful event. Telogen effluvium is very common following pregnancy. Baldness is the partial or complete lack of hair growth, and part of the wider topic of "hair thinning". The degree and pattern of baldness varies, but its most common cause is androgenic hair loss, alopecia androgenetica, or alopecia seborrheica, with the last term primarily used in Europe.

[0020] Symptoms of hair loss include hair loss in patches usually in circular patterns, dandruff, skin lesions, and scarring. Alopecia areata (mild - medium level) usually shows in unusual hair loss areas, e.g., eyebrows, backside of the head or above the ears, areas the male pattern baldness usually does not affect. In male-pattern hair loss, loss and thinning begin at thetemples and the crown and hair either thins out or falls out. Female-pattern hair loss occurs at the frontal and parietal.

[0021] Disclosed herein include methods for treating or preventing hair loss. In some embodiments, the subject suffers from or is at the risk of suffering from alopecia selected from the group consisting of androgenic alopecia, traction alopecia, alopecia barbae, alopecia mucinosa, alopecia neoplastica, cicatricial alopecia, scarring alopecia, anagen effluvium, telogen effluvium, anagen alopecia, telogen alopecia, and alopecia areata.

[0022] In some embodiments, the subject suffers from or is at risk of suffering from an alopecia condition selected from anagen alopecia, telogen alopecia, and alopecia areata. In some embodiments, the alopecia areata is alopecia totalis. In some embodiments, the alopecia areata is alopecia universalis. In some embodiments, the alopecia areata is in a plurality of patches.

[0023] In some embodiments, the hair loss is not associated with a cancer treatment; optionally the hair loss is not associated with radiotherapy, a chemotherapy agent, or both; and further optionally the hair loss is not associated with Erlotinib. In some embodiments, the hair loss is not induced or caused by a cancer treatment, e.g., the hair loss is not induced or caused by radiotherapy, a chemotherapy agent, or both (e.g., the hair loss is not associated with Erlotinib).

[0024] In some embodiments, the composition comprising aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof is topically administered to the subject undergoing cancer treatment. In some embodiments, the topical administration of the composition is delayed relative to the initiation of cancer treatment by 0, 1, 2, 3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9 10, or 11 months, 1, 2, 3 4, or 5 years, or any value between any two numbers thereof.

[0025] The composition can be, for example, administered to the subject by topical administration, intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, nebulization, or a combination thereof. In some embodiments, the composition is administered to the subject by oral or intravenous administration.

[0026] The composition can be, for example, formulated in form of ointment, gel, lotion, cream, paste, powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, solution, suspension, emulsion, aerosols, or nanoparticles. In some embodiments, the composition is formulated in the form of ointment, gel, lotion, cream, or paste.

[0027] In some embodiments, the composition is administered to the subject once every day, every two days, or every three days. In some embodiments, the composition is administered to the subject at an effective daily dose of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof at from 10 mg to 250 mg.

[0028] In some embodiments, the composition comprises one or more additionaltherapeutic agents (e.g., a hair growth stimulating agent). Non-limiting examples of the hair growth stimulating agent include minoxidil, diazoxide, pinacidil, bimatoprost, finasteride, dutasteride, bicalutamide, spironolactone, vitamin D, vitamin D3, (-)-epigallocatechin-3 -gallate (EGCG), prostaglandin El, prostaglandin E2, prostaglandin F2a and any combination thereof.

[0029] The composition can comprise at least one excipient selected from propylene glycol, benzyl alcohol, DMSO, ethanol, diethylene glycol monoethyl ether, vitamin E, glycerol monooleate, glyceryl monostearate, ethyl ester of linoleic acid, glyceryl monolinoleate, polyoxyl castor oil or any combination thereof. In some embodiments, the composition comprises at least one excipient selected from diluting agent, binding agent, lubricating agent, disintegrating agent, absorption accelerating agents, wetting agents, absorbents, coloring agent, flavoring agent, sweetening agent, and any combination thereof. The composition can further comprise at least one surfactant. The composition can be formulated in form of solution, suspension, or emulsion.

[0030] In some embodiments, the administering the composition reduces hair loss by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0031] In some embodiments, a composition is described, the composition comprising aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof for use in treating and preventing hair loss. In some embodiments, the prodrug for aprepitant comprises fosaprepitant. In some embodiments, the subject is administered with fosaprepitant.

[0032] In some embodiments, the composition is formulated in form of ointment, gel, lotion, cream, paste, powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, liquid, aerosols, or nanoparticles. In some embodiments, the composition is formulated in a dosage of 10 mg to 250 mg of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof.

[0033] In some embodiments, the composition was applied topically to the skin based on the basis of per skin area. In some embodiments, the composition was applied to the affected skin area a dosage of 0.001 mg / cm2to 2.50 mg / cm2of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof. In some embodiments, the composition was applied to the affected skin area a dosage of 0.01 mg / cm2to 0.250 mg / cm2of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof.

[0034] The composition can comprise one or more additional therapeutic agents (e.g., a hair growth stimulating agent). In some embodiments, the hair growth stimulating agent is selected from the group consisting of minoxidil, diazoxide, pinacidil, bimatoprost, finasteride,dutasteride, bicalutamide, spironolactone, vitamin D, vitamin D3, (-)-epigallocatechin-3 -gallate (EGCG), prostaglandin El, prostaglandin E2, prostaglandin F2a and any combination thereof.

[0035] The composition can be formulated in form of ointment, gel, lotion, cream, or paste. In some embodiments, the composition is formulated in form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, or nanoparticles.

[0036] The composition can further comprise at least one excipient selected from propylene glycol, benzyl alcohol, DMSO, ethanol, diethylene glycol monoethyl ether, vitamin E, glycerol monooleate, glyceryl monostearate, ethyl ester of linoleic acid, glyceryl monolinoleate, polyoxyl castor oil or any combination thereof.

[0037] In some embodiments, the composition as described herein comprises aprepitant (about 0.1-2% w / v) in benzyl alcohol (1-5% w / v) and propylene glycol (50-60% w / v), and diethylene glycol monoethyl ether (transcutol) (30-50% w / v). In some embodiments, the composition as described herein comprises aprepitant (about 0.2-1% w / v) in benzyl alcohol (about 2% w / v) and propylene glycol (about 56-57% w / v), and diethylene glycol monoethyl ether (transcutol) (about 40-45% w / v).

[0038] The composition can comprise at least one excipient selected from diluting agent, binding agent, lubricating agent, disintegrating agent, absorption accelerating agents, wetting agents, absorbents, coloring agent, flavoring agent, sweetening agent, and any combination thereof.

[0039] In some embodiments, a kit comprises aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof; and a label indicating that the kit is for treating and preventing hair loss.

[0040] In the method, composition or kit as described herein, the composition can comprise fosaprepitant.Definitions

[0041] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. See, e.g., Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press (Cold Spring Harbor, NY 1989). For purposes of the present disclosure, the following terms are defined below.

[0042] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animals" include cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses;primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.

[0043] As used herein, a "patient" refers to a subject that is being treated by a medical professional, such as a Medical Doctor (i.e. Doctor of Allopathic medicine or Doctor of Osteopathic medicine) or a Doctor of Veterinary Medicine, to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.

[0044] As used herein, a hair loss and alopecia are used interchangeably, both of which refer to a partial or complete disappearance of hair from part of a head or body of a mammal.

[0045] As used herein, "administration" or "administering" refers to a method of giving a dosage of a pharmaceutically active ingredient to a vertebrate.

[0046] As used herein, a "dosage" refers to the combined amount of the active ingredients (e.g., NK1R antagonist).

[0047] As used herein, a "unit dosage" refers to an amount of therapeutic agent administered to a patient in a single dose.

[0048] As used herein, a "daily dosage" refers to the total amount of therapeutic agent administered to a patient in a day,

[0049] As used herein, "therapeutically effective amount" or "pharmaceutically effective amount" is meant an amount of therapeutic agent, which has a therapeutic effect. The dosages of a pharmaceutically active ingredient which are useful in treatment are therapeutically effective amounts. Thus, as used herein, a therapeutically effective amount means an amount of therapeutic agent which produces the desired therapeutic effect as judged by clinical trial results and / or model animal studies.

[0050] As used herein, a "therapeutic effect" relieves, to some extent, one or more of the symptoms of a disease or disorder. For example, a therapeutic effect may be observed by a reduction of the subjective discomfort that is communicated by a subject (e.g., reduced discomfort noted in self-administered patient questionnaire). "Treat," "treatment," or "treating," as used herein refers to administering a therapeutic agent or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease or condition.

[0051] As used herein, a placebo is a substance that is designed to look and feel like the composition being tested, but is actually an inactive or inert substance. The use of a placebo is intended to control for the placebo effect, which is a psychological effect where patientsexperience an improvement in symptoms simply because they believe they are receiving an effective treatment.Methods of treating and preventing hair loss

[0052] Aprepitant is a highly selective antagonist of the G-protein coupled neurokinin-1 receptor. It is also commercially available in form of a prodrug as fosaprepitant.

[0053] The neurokinin 1 receptor (NK1R) is a member of the tachykinin receptor family that preferentially binds the tachykinin substance P (SP) (Ubaldi et al. "Emerging targets for addiction neuropharmacology: from mechanisms to therapeutics." Progress in brain research. Vol. 224. Elsevier, 2016. 251-284; incorporated herein by reference in its entirety). NK1 receptors are widely distributed on human pulmonary arterial blood vessels, on circular and longitudinal smooth muscle throughout the human gastrointestinal tract, and over ganglia of the myenteric plexus (Munoz & Covenas). These receptors have been also located in the placenta, thyroid gland, endothelial cells, immune cells (e.g., dendritic cells, macrophages, monocytes, and lymphocytes) and in platelets (Munoz & Covenas). The occurrence of NK1 receptors in spleen, in thymus, on arterioles and venules of the lymph nodes, and on T lymphocytes provides evidence for an involvement of Substance P (SP) in immunoregulation (Munoz & Covenas). SP is the most abundant NK and is involved in many physiological processes, such as in the gastrointestinal, bronchial, and vascular systems. For example, the potent vasodilator action of SP is mediated primarily by binding to NK1 receptors on the endothelium of peripheral arterial blood vessels (Munoz & Covenas).

[0054] The glycosylation / phosphorylation of the NK1 receptor influences the NK1 receptor signaling (Munoz & Covenas). SP generates second messengers and affects many signaling pathways controlling the cell function: activation of phospholipases A2 / C, protein kinases A / C and adenylyl cyclase, synthesis of diacylglicerol / inositol triphosphate / arachidonic acid, mobilization of intracellular Ca2+generation of thromboxane / leukotrienes, phosphorylation of myosin regulatory light chain, and activation of Rho-associated protein-kinase (ROCK) (Munoz & Covenas). SP, via the NK1 receptor, transactivates the epidermal growth factor receptor (EGFR) leading to the activation of mitogen-activated protein kinases (MAPK), extracellular signal -regulated kinases (ERK) 1 and 2, DNA synthesis and proliferation (Munoz & Covenas). SP exerts an antiapoptotic effect involving the Janus kinase 2 (JAK-2) and phosphoinositide 3- kinase (PI3K)-mediated activation of the antiapoptotic molecule Akt (protein kinase B) (Munoz & Covenas). SP activates p38, promotes the synthesis of proinflammatory cytokines (e.g., interleukin-6, interleukin-8) and activates proinflammatory transcription factors (e.g., nuclear factor kappa B (NF-KB) by mechanisms in which the activation of the Rho family kinases is involved) (Munoz & Covenas).

[0055] The NK-1 receptor has been a therapeutic target for the treatment of functional gastrointestinal disorders (FGIDs), such as dyspepsia and irritable bowel syndrome (IBS). FGIDs are diagnosed by the presence of recurrent symptoms of abdominal pain or discomfort, and often subjects with IBS generally present with diarrhea or constipation. Evidence for the role of neurokinins in abdominal pain has been observed in a double-blind study in which the NK-1 antagonist (CJ-11,974) alleviated the discomfort associated with rectosigmoidal distension in patients with IBS. Both NK-1 and NK-2 receptor antagonists have been investigated for their potential use in alleviating symptoms of food allergy and IBS. The NK-2 receptor antagonist nepadutant (MEN 11420) effectively antagonized the motility-stimulating effect of neurokinin A without affecting basal gastrointestinal motility.

[0056] Newer antiemetic agents such as NK1 receptor antagonists have also been shown to be effective for vomiting. However, it is described herein that NK1 receptor antagonists, for example, aprepitant shows unexpected result for treating and preventing hair loss.

[0057] There are provided, in some embodiments, methods and compositions for treating and preventing hair loss. In some embodiments, the method comprises: administering to a subject a composition comprising an NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, thereby retreating or preventing hair loss in the subject. Disclosed herein include methods and compositions for treating or reducing the likelihood of hair loss. In some embodiments, the method comprises: administering to a subject a composition comprising a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptablesalt, solvate, stereoisomer, prodrug thereof, thereby treating or reducing the likelihood of onset of hair loss in the subject.

[0058] In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human and the administering is performed by topical application of the composition on an area of the skin of the subjection.

[0059] There are provided, in some embodiments, methods of treating and preventing hair loss. In some embodiments, the method comprises: administering to a subject a composition comprising a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, thereby treating and preventing hair loss in the subject. In some embodiments, the hair loss is prevented from occurring. In some embodiments, the likelihood of onset of hair loss is reduced. Administering the composition can result in an at least, or at least about, 2% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, or a number or a range between any two of these values) reduction of hair loss. In some embodiments, the reduction of likelihood of hair loss is reduced by at least, or at least about, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, or a number or a range between any two of these values.

[0060] The method can comprise measuring hair loss in the subject before administering the composition to the subject, after administering the composition to the subject, or both.Therapeutic Agents

[0061] The NK1R antagonist can be or can include a selective NK1R antagonist. Nonlimiting examples of NK1R antagonists include aprepitant (L-754030 or MK-(0)869), fosaprepitant (L-758298), befetupitant, casopitant (GW-679769), dapitant (RPR-100893),ezlopitant (CJ-11974), lanepitant (LY-303870), maropitant (CJ-11972), netupitant, nolpitantium (SR-140333), orvepitant (GW-823296), rolapitant (SCH-619734), SCH-720881 (active metabolite of rolapitant), serlopitant (MK-(0)594 or VPD-737), tradipitant (VLY-686 or LY- 686017), vestipitant (GW-597599), vofopitant (GR-205171), hydroxyphenyl propamidobenzoic acid, maltooligosaccharides (e.g., maltotetraose and maltopentaose), spantides (e.g., spantide I and II), AV-608, AV-818, AZD-2624, BIIF 1149 CL, CGP-49823, CJ-17493, CP-96345, CP- 99994, CP- 122721, DNK-333, FK-224, FK-888, GR-82334, GR-205171, GSK-424887, HSP- 117, KRP-103, L-703606, L-733060, L-736281, L-759274, L-760735, LY-686017, M516102, MDL-105212, MK-0303 (L-001182885), MK- 8478 (L-001983867), NKP-608, R-l 16031, R-l 16301, RP-67580, S-41744, SCH-206272, SCH-388714, SCH-900978, SLV-317, SSR-240600, T-2328, TA-5538, TAK-637, TKA-731, WIN-51708, ZD-4974, ZD-6021, cycloalkyl (including, but not limited to, cyclopentyl, cyclohexyl and cycloheptyl) tachykinin receptor antagonists disclosed in U.S. PatentNo. 5,750,549, hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists disclosed in U.S. Patent No. 8,124,633, and analogs, derivatives, prodrugs, metabolites and salts thereof. Non-limiting examples of NK1R antagonists also include Casopitant, CGP49823, CP-122,721, CP-96,345, CP-99,994, FK 888, GR 82334, GR 94800, GR203040, GR-205171, GSK1144814, GSK206136, GSK424887, GW679769, HSP-117, L 703,606, L 732,138, L 733,060, L 742,694, L668,169, LY 303241, LY 303870, LY 306740, Maropitant, MEN 11149, Orvepitant, PD 154075, R-544, RP-67580, RPR 100893, SCH619734, Spantide II, Spantide III, Spendide, SR140333, Vestipitant, WIN-41,708, WIN-62,577, and analogs, derivatives, prodrugs, metabolites and salts thereof. Non-limiting examples of NK1R antagonists also include FK 888 (Fujisawa); GR 205171 (Glaxo Wellcome); LY 303870 (Lilly); MK 869 (Merck); GR82334 (Glaxo Wellcome); L758298 (Merck); L 733060 (Merck); L 741671 (Merck); L 742694 (Merck); PD 154075 (Parke-Davis); SI 8523 (Servier); SI 9752 (Servier); OT 7100 (Otsuka); WIN 51708 (Sterling Winthrop); NKP-608A; TKA457; DNK333; CP-96345; CP- 99994; CP122721; L-733060; L-741671; L742694; L-758298; L-754030; GR-203040; GR- 205171; RP-67580; RPR-100893 (dapitant); RPR-107880; RPR-111905; FK-888; SDZ-NKT- 343; MEN-10930; MEN-11149; S-18523; S-19752; PD-154075 (CAM-4261); SR-140333; LY- 303870 (lanepitant); EP-00652218; EP00585913; L-737488; CGP-49823; WIN-51708; SR- 48968 (saredutant); SR-144190; YM383336; ZD-7944; MEN-10627; GR-159897; RPR-106145; PD-147714 (CAM-2291); ZM253270; FK-224; MDL-1 05212A; MDL-105172A; L-743986; L- 743986 analogs; S-16474; SR-1 42801 (osanetant); PD-161182; SB-223412; SB-222200; and analogs, derivatives, prodrugs, metabolites and salts thereof.

[0062] In some embodiments, the method can comprise administering to the subject one or more additional therapeutic agents (e.g., hair growth stimulating agents).

[0063] As disclosed herein, co-administration of particular ratios and / or amounts of an NK1R antagonist (e.g., aprepitant) and one or more additional therapeutic agents (e.g., hair growth stimulating agents) can result in synergistic effects in treating or preventing the hair loss. These synergistic effects can be such that the one or more effects of the combination compositions are greater than the one or more effects of each component alone at a comparable dosing level, or they can be greater than the predicted sum of the effects of all of the components at a comparable dosing level, assuming that each component acts independently. The synergistic effect can be, be about, be greater than, or be greater than about, 5%, 10%, 20%, 30%, 50%, 75%, 100%, 110%, 120%, 150%, 200%, 250%, 350%, or 500% better than the effect of relieving a subject with one of the components alone, or the additive effects of each of the components when administered individually. The effect can be any of the measurable effects described herein. The composition comprising a plurality of components can be such that the synergistic effect is a reduction in occurrence of hair loss that is reduced to a greater degree as compared to the sum of the effects of administering each component, determined as if each component exerted its effect independently, also referred to as the predicted additive effect herein. For example, if a composition comprising component (a) yields an effect of a 20% reduction in the occurrence of the hair loss and a composition comprising component (b) yields an effect of 50% reduction in the occurrence of hair loss, then a composition comprising both component (a) and component (b) would have a synergistic effect if the combination composition's effect on the occurrence of hair loss was greater than 70%.

[0064] A synergistic combination composition can have an effect that is greater than the predicted additive effect of administering each component of the combination composition alone as if each component exerted its effect independently. For example, if the predicted additive effect is 70%, an actual effect of 140% is 70% greater than the predicted additive effect or is 1- fold greater than the predicted additive effect. The synergistic effect can be at least, or at least about, 20%, 50%, 75%, 90%, 100%, 150%, 200% or 300% greater than the predicted additive effect. In some embodiments, the synergistic effect can be at least, or at least about, 0.2-, 0.5-, 0.9- , 1.1-, 1.5-, 1.7-, 2-, or 3-fold greater than the predicted additive effect.

[0065] In some embodiments, the synergistic effect of the combination compositions can also allow for reduced dosing amounts, leading to reduced side effects to the subject and reduced cost of treatment. Furthermore, the synergistic effect can allow for results that are not achievable through any other treatments. Therefore, proper identification, specification, and use of combination compositions can allow for significant improvements in the treatment and prevention of hair loss.Compositions and Methods of Administration

[0066] There are provided, in some embodiments, kits. The kit can comprise: a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and a label indicating: the kit is for treating or preventing hair loss. There are provided, in some embodiments, compositions for treating or preventing hair loss. The composition can comprise: a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof for use in treating or preventing hair loss.

[0067] The composition can be a pharmaceutical composition comprising a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is administered to the subject by intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, or nebulization. In some embodiments, the composition is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, liquid, aerosols, or nanoparticles. In some embodiments, the composition is administered to the subject once, twice, or three times a day. In some embodiments, the composition is administered to the subject once every day, every two days, or every three days. In some embodiments, the composition is administered to the subject over the course of at least two weeks, at least three weeks, at least four weeks, or at least five weeks. In some embodiments, the composition is administered to the subject at an effective daily dose of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof at from 10 mg to 250 mg.

[0068] The therapeutically effective amount and the frequency of administration of, and the length of treatment with, the NK1R antagonist (e.g., aprepitant) may depend on various factors, including the nature and the severity of the hair loss, the potency of the NK1R antagonist, the mode of administration, the age, the body weight, the general health, the gender and the diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician. In some embodiments, a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant) for treating or preventing hair loss as described herein is about 0.1- 200 mg, 0.1-150 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.5-20 mg, 0.5-10 mg or 1-10 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In some embodiments, the therapeutically effective dose (e.g., per day or per dose) of the NK1R antagonist (e.g., aprepitant) for treating or preventing hair loss as described herein is about 0.1-1 mg (e.g., about 0.1 mg, 0.5 mg or 1 mg), about 1-5 mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5-10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10-20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20-30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30-40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40-50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50-100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100-150 mg (e.g., about 100 mg, 125 mg or 150 mg), or about 150-200 mg (e.g., about 150 mg, 175 mg or 200 mg). In some embodiments, the therapeutically effective dose of the NK1R antagonist (e.g., aprepitant) is administered one or more (e.g., two, three or more) times a day, or once every two or three days, or once, twice or thrice a week, or as deemed appropriate by the treating physician. In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof.

[0069] The NK1R antagonist (e.g., aprepitant) can also be dosed in an irregular manner. For example, the NK1R antagonist can be administered once, twice or thrice in a period of two weeks, three weeks or a month in an irregular manner. Furthermore, the NK1R antagonist (e.g., aprepitant) can be taken pro re rata (as needed). For instance, the NK1R antagonist can be administered 1, 2, 3, 4, 5 or more times, whether in a regular or irregular manner, until symptoms of hair loss improves. Once relief from the hair loss is achieved, dosing of the NK1R antagonist can optionally be discontinued. If the hair loss returns, administration of the NK1R antagonist, whether in a regular or irregular manner, can be resumed. The appropriate dosage of, frequency of dosing of and length of treatment with the NK1R antagonist can be determined by the treating physician.

[0070] In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered under a chronic dosing regimen. In some embodiments, a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant) is administered over a period of at least about 6 weeks, 2 months, 10 weeks, 3 months, 4 months, 5 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months).

[0071] The NK1R antagonist (e.g., aprepitant) can also be used prophylactically to prevent hair loss. The prophylactically effective amount of an NK1R antagonist (e.g., aprepitant) can be any therapeutically effective amount of the NK1R antagonist described herein.

[0072] The NK1R antagonist (e.g., aprepitant) can be administered via any suitable route. Potential routes of administration of the NK1R antagonist include without limitation oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intramedullary and intrathecal), intracavitary, intraperitoneal, and topical (including dermal / epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal and vaginal). In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered orally (e.g., as a capsule or tablet, optionally with an enteric coating). In otherembodiments, the NK1R antagonist (e.g., aprepitant) is administered parenterally (e.g., intravenously, subcutaneously or intradermally). In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered topically (e.g., dermally / epicutaneously, transdermally, mucosally, transmucosally, buccally or sublingually).

[0073] The NK1R antagonist (e.g., aprepitant) can be administered without food. For example, the NK1R antagonist (e.g., aprepitant) can be administered at least about 1 or 2 hours before or after a meal. In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered at least about 2 hours after an evening meal. The NK1R antagonist can also be taken substantially concurrently with food (e.g., within about 0.5, 1 or 2 hours before or after a meal, or with a meal).

[0074] In some embodiments where a more rapid establishment of a therapeutic level of the NK1R antagonist (e.g., aprepitant) is desired, the NK1R antagonist is administered under a dosing schedule in which a loading dose is administered, followed by (i) one or more additional loading doses and then one or more therapeutically effective maintenance doses, or (ii) one or more therapeutically effective maintenance doses without an additional loading dose, as deemed appropriate by the treating physician. A loading dose of a drug is typically larger (e.g., about 1.5, 2, 3, 4 or 5 times larger) than a subsequent maintenance dose and is designed to establish a therapeutic level of the drug more quickly. The one or more therapeutically effective maintenance doses can be any therapeutically effective dose described herein. In some embodiments, the loading dose is about three times greater than the maintenance dose. In some embodiments, a loading dose of the NK1R antagonist (e.g., aprepitant) is administered, followed by administration of a maintenance dose of the NK1R antagonist after an appropriate time (e.g., after about 12 or 24 hours) and thereafter for the duration of therapy. For example, a loading dose of the NK1R antagonist is administered on day 1 and a maintenance dose is administered on day 2 and thereafter for the duration of therapy. In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered in a loading, dose of about 1.5, 3, 15 or 30 mg (e.g., 3*about 0.5, 1, 5 or 10 mg) orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 0.5, 1, 5 or 10 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 2 weeks, 1 month (4 weeks), 6 weeks, 2 months, 10 weeks, 3 months, 4 months, 5 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months). In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered in a loading dose of about 15 mg (e.g., 3 x about 5 mg) orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 5 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months).

[0075] In some embodiments, a first loading dose of the NK1R antagonist (e.g., aprepitant) is administered on day 1, a second loading dose is administered on day 2, and a maintenance dose is administered on day 3 and thereafter for the duration of therapy. In some embodiment, the first loading dose is about three times greater than the maintenance dose, and the second loading dose is about two times greater than the maintenance dose.

[0076] As disclosed herein, the therapeutic agent (e.g., NK1R antagonist) can be formulated for administration in a pharmaceutical composition comprising a physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, coating assistants, or a combination thereof. In some embodiments, the therapeutic agent (e.g., NK1R antagonist) are formulated for administration with a pharmaceutically acceptable carrier or diluent. The therapeutic agent (e.g., NK1R antagonist) can be formulated as a medicament with a standard pharmaceutically acceptable carrier(s) and / or excipient(s) as is routine in the pharmaceutical art. The exact nature of the formulation will depend upon several factors including the desired route of administration. In some embodiments, the NK1R antagonist is formulated for oral, intravenous, intragastric, intravascular or intraperitoneal administration. Standard pharmaceutical formulation techniques may be used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety.

[0077] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0078] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose: starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil and oil of Theobroma; polyols such as propylene glycol, benzyl alcohol, DMSO, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers,such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0079] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject therapeutic agent is basically determined by the way the composition is to be administered.

[0080] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a therapeutic agent (e.g., NK1R antagonist) that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0081] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically- active materials may be included, which do not substantially interfere with the inhibitory activity of the therapeutic agent (e.g., NK1R antagonist). The amount of carrier employed in conjunction with the therapeutic agent (e.g., NK1R antagonist) is sufficient to provide a practical quantity of material for administration per unit dose of the therapeutic agent (e.g., NK1R antagonist). Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, ail incorporated by reference herein: Modem Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989), and Ansel, Introduction to Pharmaceutical DosageForms 8th Edition (2004).

[0082] Various oral dosage forms can be used, including such solid forms as tablets, capsules, and granules. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0083] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0084] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polvsorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0085] Other compositions useful for attaining systemic delivery of the subject therapeutic agents include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0086] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the therapeutic agent (e.g., NK1R antagonist) disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0087] For intravenous administration, the therapeutic agent (e.g., NK1R antagonist) and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-31 1 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenyl mercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0088] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a therapeutic agent (e.g., NK1R antagonist) described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0089] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be between about 0.1mg / kg and 4000 mg / kg body weight, preferably between about 80 mg / kg and 1600 mg / kg body weight. Alternatively, dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.

[0090] Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow-release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered is dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician. The therapeutic agent (e.g., NK1R antagonist) or combination of therapeutic agents disclosed herein may be administered orally or via injection at a dose from 0, 1 mg / kg to 4000 mg / kg of the patient's body weight per day. The dose range for adult humans is generally from 1 g to 100 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the therapeutic agent (e.g., NK1R antagonist) or combination of therapeutic agents disclosed herein which is effective at such dosage or as a multiple of the same, for instance, units containing 1 g to 60 g (for example, from about 5 g to 20 g, from about 10 g to 50 g, from about 20 g to 40 g, or from about 25 g to 35 g). The precise amount of therapeutic agent administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Additionally, the route of administration may vary depending on the condition and its severity. A typical dose of the therapeutic agent (e.g., NK1R antagonist) can be from 0.02 g to 1.25 g per kg of body weight, for example from 0.1 g to 0.5 g per kg of body weight, depending on such parameters. In some embodiments, a dosage of the therapeutic agent (e.g., NK1R antagonist) can be from 1 g to 100 g, for example, from 10 g to 80 g, from 15 g to 60 g, from 20 g to 40 g, or from 25 g to 35 g. In A physician will be able to determine the required dosage of the therapeutic agent (e.g., NK1R antagonist) for any particular subject.

[0091] The exact formulation, route of administration and dosage for the pharmaceutical compositions of the therapeutic agent (e.g., NK1R antagonist) or combination of therapeutic agents disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics," which is hereby incorporated herein by reference, with particular reference to Ch. 1). Typically, the dose range of the composition administered to the patient can be from about 0.1 to about 4000 mg / kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for therapeutic agents have been established for at least some condition, the presentdisclosure will use those same dosages, or dosages that are between about 0.1 % and about 5000%, more preferably between about 25% and about 1000% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from EDso or IDso values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0092] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0093] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the compositions disclosed herein may be administered by continuous intravenous infusion, e.g., at a dose of each active ingredient up to 100 g per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compositions disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the therapeutic agent (e.g., NK1R antagonist) or combination of therapeutic agents disclosed herein will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0094] In some embodiments, the dosing regimen of the therapeutic agent (e.g., NK1R antagonist) or combination of therapeutic agents disclosed herein is administered for a period of time, which time period can be, for example, from at least about 1 week to at least about 4 weeks, from at least about 4 weeks to at least about 8 weeks, from at least about 4 weeks to at least about 12 weeks, from at least about 4 weeks to at least about 16 weeks, or longer. The dosing regimen of the therapeutic agent (e.g., NK1R antagonist) or combination of therapeutic agents disclosed herein can be administered three times a day, twice a day, daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously orcontinuously.

[0095] The NK1R antagonist (e.g., aprepitant) can be administered alone or in the form of a composition (e.g., a pharmaceutical composition). In some embodiments, a pharmaceutical composition comprises an NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug or metabolite thereof, and one or more pharmaceutically acceptable carriers or excipients. The composition can optionally contain one or more additional therapeutic agents as described herein. A pharmaceutical composition contains a therapeutically effective amount of a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant) and one or more pharmaceutically acceptable carriers or excipients, and is formulated for administration to a subject for therapeutic use. For purposes of the content of a pharmaceutical composition, the terms "therapeutic agent", "active ingredient", "active agent" and "drug" encompass prodrugs.

[0096] A pharmaceutical composition contains a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant) in substantially pure form. In some embodiments, the purity of the therapeutic agent is at least about 95%, 96%, 97%, 98% or 99%. In some embodiments, the purity of the therapeutic agent is at least about 98% or 99%. In addition, a pharmaceutical composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inactive ingredients. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 2% or 1% relative to the combined weight of the intended active and inactive ingredients. Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act §501 (a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.

[0097] Pharmaceutically acceptable carriers and excipients include pharmaceutically acceptable materials, vehicles and substances. A vehicle is a substance used as a carrier or solvent for a pharmaceutically active ingredient (e.g., aprepitant) that is being tested, e.g. a mixture of benzyl alcohol (1-5% w / v) and propylene glycol (50-60% w / v), and diethylene glycol monoethyl ether (transcutol) (30-50% w / v) as carrier for aprepitant. It is intended to be inert and not have any therapeutic effect of its own. A vehicle can be used as a control in studies to ensure that any effects observed are due to the pharmaceutically active ingredient being tested and not the carrier substance. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, solubilizers, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pHadjusters, stabilizers, preservatives, antioxidants, antimicrobial agents, antibacterial agents, antifungal agents, absorption- delaying agents, sweetening agents, flavoring agents, coloring agents, adjuvants, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils, such as sesame oil), aqueous solvents (e.g., saline, phosphate-buffered saline [PBS] and isotonic solutions [e.g., Ringer's solution]), and solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional carrier or excipient is incompatible with the active ingredient, the disclosure encompasses the use of conventional carriers and excipients in formulations containing a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant). See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania

[2005] ); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida, 2004).

[0098] Proper formulation can depend on various factors, such as the mode of administration chosen. Potential modes of administration of pharmaceutical compositions comprising an NK1R antagonist (e.g., aprepitant) include without limitation oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary, intrathecal and topical), intracavitary, and topical (including dermal / epicutaneous, transdermal, mucosal, transmucosal, intranasal e.g., by nasal spray or drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]).

[0099] As an example, formulations of an NK1R antagonist (e.g., aprepitant) suitable for oral administration can be presented as, e.g., boluses; tablets, capsules, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or / and a non-aqueous liquid; or as oil-in-water liquid emulsions or water- in-oil liquid emulsions.

[0100] Tablets can contain an NK1R antagonist (e.g., aprepitant) in admixture with, e.g., a filler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate). The tablets can beuncoated or can be coated with, e.g., an enteric coating that protects the active ingredient from the acidic environment of the stomach, or with a material that delays disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby provides a sustained action over a longer time period. In some embodiments, a tablet comprises an NK1R antagonist (e.g., aprepitant), mannitol, microcrystalline cellulose, magnesium stearate, silicon dioxide, croscarmellose sodium and sodium lauryl sulfate, and optionally lactose monohydrate, and the tablet is optionally film-coated (e.g., with Opadry®).

[0101] Push-fit capsules or two-piece hard gelatin capsules can contain an NK1R antagonist (e.g., aprepitant) in admixture with, e.g., a filler or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or / and a preservative. For soft capsules or single-piece gelatin capsules, an NK1R antagonist (e.g., aprepitant) can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or more other liquid excipients or / and semi- solid excipients, such as a stabilizer or / and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol).

[0102] Compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid or / and a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. Dispersible powder or granules of an NK1R antagonist (e.g., aprepitant) can be mixed with any suitable combination of an aqueous liquid, an organic solvent or / and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or / and a preservative) to form a solution, suspension or emulsion.

[0103] In some embodiments, an NK1R antagonist (e.g., aprepitant) is contained in an amphiphilic vehicle of a liquid or semi-solid formulation for oral administration which provides improved solubility, stability and bioavailability of the NK1R antagonist, as described in US 2010 / 0209496. The amphiphilic vehicle contains a solution, suspension, emulsion (e.g., oil-in- water emulsion) or semi-solid mixture of the NK1R antagonist (e.g., aprepitant) admixed with liquid or / and semi-solid excipients which fills an encapsulated dosage form (e.g., a hard gelatin capsule or a soft gelatin capsule containing a plasticizer [e.g., glycerol or / and sorbitol]). In some embodiments, the amphiphilic vehicle comprises an amphiphilic agent selected from fatty acid esters of glycerol (glycerin), propylene glycol and sorbitol. In some embodiments, the amphiphilic agent is selected from mono- and di-glycerides of Cs-Cn saturated fatty acids. In some embodiments, the amphiphilic agent is selected from CAPMUL® MCM, CAPMUL® MCM 8,CAPMUL® MCM 10, IMWITOR® 308, IMWITOR® 624, IMWITOR® 742, IMWITOR® 988, CAPRYOL™ PGMC, CAPRYOL™ 90, L AUROGLYCOL™ 90, CAPTEX® 200, CRILL™ 1, CRILL™ 4, PECEOL® and MAIS INE™ 35-1. In some embodiments, the amphiphilic vehicle further comprises propylene glycol, a propylene glycol- sparing agent (e.g., ethanol or / and glycerol), or an antioxidant (e.g., butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate or / and sodium sulfite), or any combination thereof. In additional embodiments, the amphiphilic vehicle contains on a weight basis about 0.1-5% of the NK1R antagonist (e.g., aprepitant), about 50-90% of the amphiphilic agent, about 5-40% of propylene glycol, about 5- 20% of the propylene glycol- sparing agent, and about 0.01-0.5% of the antioxidant.

[0104] An NK1R antagonist (e.g., aprepitant) can also be formulated for parenteral administration by injection or infusion to circumvent gastrointestinal absorption and first-pass metabolism. A representative parenteral route is intravenous.

[0105] Additional advantages of intravenous administration include direct administration of a therapeutic agent into systemic circulation to achieve a rapid systemic effect, and the ability to administer the agent continuously or / and in a large volume if desired. Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or / and stabilizing agents. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain an NK1R antagonist (e.g., aprepitant) along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject. Aqueous or non-aqueous sterile suspensions can contain an NK1R antagonist (e.g., aprepitant) along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the NK1R antagonist to allow for the preparation of a more concentrated solution or suspension. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneously or intravenously) can contain an NK1R antagonist (e.g., aprepitant), NaCl, a buffering agent (e.g., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or / and an acid (e.g., HC1) to adjust pH.

[0106] For topical administration, an NK1R antagonist (e.g., aprepitant) can be formulated as, e.g., a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of first-pass metabolism and circumvention of gastrointestinal absorption. A buccal or sublingual tablet or pill can also be designed to provide faster release of the NK- 1 antagonist for more rapid uptake of it into systemic circulation. In addition to a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant), the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation anycombination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

[0107] For topical administration, an NK1R antagonist (e.g., aprepitant) can also be formulated for intranasal administration. The nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability. Moreover, intranasal administration avoids first-pass metabolism and can introduce a significant concentration of the NK1R antagonist to the central nervous system, allowing the NK1R antagonist to block the central cough reflex via the nucleus tractus solitarius in the cough center in the medulla oblongata, where vagal afferent nerves terminate. An intranasal solution or suspension formulation can comprise an NK1R antagonist (e.g., aprepitant) along with excipients such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethylcellulose) or / and a penetration enhancer. In some embodiments, a nasal spray formulation comprises an NK1R antagonist (e.g., aprepitant), microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and water, and optionally an acid (e.g., HC1) to adjust pH. An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or spray using, e.g., a metering atomizing spray pump.

[0108] An additional mode of topical administration is pulmonary, including by oral inhalation and nasal inhalation, which is described in detail below.

[0109] Other suitable topical formulations and dosage forms include without limitation ointments, creams, gels, lotions, pastes and the like, as described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania, 2005).

[0110] Ointments are semi-solid preparations that are typically based on petrolatum or a petroleum derivative. Creams are viscous liquids or semi-solid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, generally comprises petrolatum and a fatty alcohol (e.g., cetyl or stearyl alcohol). The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and usually contains a humectant. The emulsifier in a cream formulation is generally a non-ionic, anionic, cationic or amphoteric surfactant. Gels are semi-solid, suspension-type systems. Single-phase gels contain organic macromolecules(polymers) distributed substantially uniformly throughout the carrier liquid, which is typically aqueous but can also contain an alcohol (e.g., ethanol or isopropanol) and optionally an oil. Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semi-liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of finely divided solids and typically contain suspending agents to produce better dispersion as well as compounds useful for localizing and holding the active agent in contact with the skin. Pastes are semi-solid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels.

[0111] Various excipients can be included in a topical formulation. For example, solvents, including a suitable amount of an alcohol, can be used to solubilize the active agent. Other optional excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, stabilizers, buffers, antioxidants, preservatives, cooling agents (e.g., menthol), opacifiers, fragrances and colorants. For an active agent having a low rate of permeation through the skin or mucosal tissue, a topical formulation can contain a permeation enhancer to increase the permeation of the active agent through the skin or mucosal tissue. A topical formulation can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the active agent, the permeation enhancer or any other component of the formulation.

[0112] In some embodiments, an NKIR antagonist (e.g., aprepitant) is delivered from a sustained-release composition. As used herein, the term "sustained-release composition" encompasses sustained-release, prolonged-release, extended-release, slow-release and controlled- release compositions, systems and devices. Use of a sustained- release composition can have benefits, such as an improved profile of the amount of the drug or an active metabolite thereof delivered to the target site(s) over a time period, including delivery of a therapeutically effective amount of the drug or an active metabolite thereof over a prolonged time period. In some embodiments, the sustained-release composition delivers the NK1R antagonist over a period of at least about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer. In some embodiments, the sustained-release composition is a drug-encapsulation system, such as nanoparticles, microparticles or a capsule made of, e.g., a biodegradable polymer or / and a hydrogel. In some embodiments, the sustained-release composition comprises a hydrogel. Nonlimiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium poly acrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or / and carboxylate groups). In other embodiments, the sustained-release drug-encapsulation system comprises a membrane- enclosed reservoir, wherein the reservoir contains a drug and the membrane is permeable to thedrug. Such a drug-delivery system can be in the form of, e.g., a transdermal patch.

[0113] In some embodiments, the sustained-release composition is an oral dosage form, such as a tablet or capsule. For example, a drug can be embedded in an insoluble porous matrix such that the dissolving drag must make its way out of the matrix before it can be absorbed through the gastrointestinal tract. Alternatively, a drug can be embedded in a matrix that swells to form a gel through which the drug exits. Sustained release can also be achieved by way of a singlelayer or multi-layer osmotic controlled-release oral delivery system (OROS). An OROS is a tablet with a semi-permeable outer membrane and one or more small laser- drilled holes in it. As the tablet passes through the body, water is absorbed through the semipermeable membrane via osmosis, and the resulting osmotic pressure pushes the drug out through the hole(s) in the tablet and into the gastrointestinal tract where it can be absorbed.

[0114] In some embodiments, the sustained-release composition is formulated as polymeric nanoparticles or microparticles, wherein the polymeric particles can be delivered, e.g., by inhalation or injection or from an implant. In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of a biodegradable polymer. In some embodiments, the biodegradable polymer comprises lactic acid or / and glycolic acid [e.g., an L- lactic acid-based copolymer, such as poly(L-lactide-co-glycolide) or poly(L-lactic acid-co-D,L- 2-hydroxyoctanoic acid)]. For example, biodegradable polymeric microspheres composed of polylactic acid or / and polyglycolic acid can serve as sustained-release pulmonary drug-delivery systems. The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer's degradation, like the polymer, are biocompatible.

[0115] For a delayed or sustained release of an NK1R antagonist (e.g., aprepitant), a composition can also be formulated as a depot that can be implanted in or injected into a subject, e.g., intramuscularly or subcutaneously. A depot formulation can be designed to deliver the NK1R antagonist over a longer period of time, e.g., over a period of at least about 1 week, 2 weeks, 3 weeks, 1 month, 6 weeks, 2 months, 3 months or longer. For example, the NK1R antagonist can be formulated with a polymeric material (e.g., polyethylene glycol (PEG), polylactic acid (PLA) or polyglycolic acid (PGA), or a copolymer thereof (e.g., PLGA)), a hydrophobic material (e.g., as an emulsion in an oil) or / and an ion-exchange resin, or as a sparingly soluble derivative (e.g., a sparingly soluble salt). As an illustrative example, an NK1R antagonist (e.g., aprepitant) can be incorporated or embedded in sustained-release microparticles composed of PLGA and formulated as a monthly depot.

[0116] An NK1R antagonist (e.g., aprepitant) can also be contained or dispersed in amatrix material. The matrix material can comprise a polymer (e.g., ethylene-vinyl acetate) and controls the release of the compound by controlling dissolution or / and diffusion of the compound from, e.g., a reservoir, and can enhance the stability of the compound while contained in the reservoir. Such a release system can be designed as a sustained-release system, can be configured as, e.g., a transdermal or transmucosal patch, and can contain an excipient that can accelerate the compound's release, such as a water-swellable material (e.g., a hydrogel) that aids in expelling the compound out of the reservoir. For example, U.S. Patent Nos. 4,144,317 and 5,797,898 describe examples of such a release system.

[0117] The release system can provide a temporally modulated release profile (e.g., pulsatile release) when time variation in plasma levels is desired, or a more continuous or consistent release profile when a constant plasma level is desired. Pulsatile release can be achieved from an individual reservoir or from a plurality of reservoirs. For example, where each reservoir provides a single pulse, multiple pulses ("pulsatile" release) are achieved by temporally staggering the single pulse release from each of multiple reservoirs.

[0118] Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of a compound through it over an extended time period. In addition, continuous release can be approximated by releasing several pulses of a compound in rapid succession ("digital" release). An active release system can be used alone or in conjunction with a passive release system, as described in U.S. Patent No. 5,797,898.

[0119] In addition, pharmaceutical compositions comprising an NK1R antagonist (e.g., aprepitant) can be formulated as, e.g., liposomes, micelles (e.g., those composed of biodegradable natural or / and synthetic polymers, such as lactosomes), microspheres, microparticles or nanoparticles, whether or not designed for sustained release. For example, liposomes can be used as sustained release pulmonary drug-delivery systems that deliver drugs to the alveolar surface for treatment of systemic diseases.

[0120] The pharmaceutical compositions can be manufactured in any suitable manner known in the art, e.g., by means of conventional mixing, dissolving, suspending, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

[0121] A pharmaceutical composition can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. The unit dosage form can contain an effective dose, or an appropriate fraction thereof, of a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant). Representative examples of a unit dosage form includea tablet, capsule or pill for oral administration, and powder in a vial or ampoule for oral or nasal inhalation.

[0122] Alternatively, a pharmaceutical composition can be presented as a kit, wherein the active ingredient, excipients and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected intravenously).

[0123] A kit can contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers, and can contain instructions for using the pharmaceutical composition.

[0124] In some embodiments, a kit contains an NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug or metabolite thereof, and instructions for administering the compound. In some embodiments, the compound is contained or incorporated in, or provided by, a device or system configured for pulmonary delivery of the compound by oral inhalation, such as a metered-dose inhaler, a dry powder inhaler or a nebulizer.

[0125] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a transparent plastic material.

[0126] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

[0127] In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. For example, the dispenser is equipped with a memory aid, so as to further facilitate compliance with the regimen. An example of such a memory aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory aid is a battery- powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signalwhich, for example, reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken.

[0128] Oral or nasal inhalation can be achieved by means of, e.g., a metered-dose inhaler (MDI), a nebulizer or a dry powder inhaler (DPI). For example, an NK1R antagonist (e.g., aprepitant) can be formulated for aerosol administration to the respiratory tract by oral or nasal inhalation. The drug is delivered in a small particle size (e.g., between about 0.5 micron and about 5 microns), which can be obtained by micronization, to improve, e.g., drug deposition in the lungs and drug suspension stability. The drug can be provided in a pressurized pack with a suitable propellant, such as a hydrofluoroalkane (HFA, e.g., 1,1,1,2-tetrafluoroethane [HFA-134a]), a chlorofluorocarbon (CFC, e.g., dichlorodifluoromethane, tri chlorofluoromethane or dichlorotetrafluoroethane), or a suitable gas (e.g., oxygen, compressed air or carbon dioxide). The drug in the aerosol formulation is dissolved, or more often suspended, in the propellant for delivery to the lungs. The aerosol can contain excipients such as a surfactant (which enhances penetration into the lungs by reducing the high surface tension forces at the air-water interface within the alveoli, may also emulsify, solubilize or / and stabilize the drug, and can be, e.g., a phospholipid such as lecithin) or / and a stabilizer. For example, an MDI formulation can comprise an NK1R antagonist (e.g., aprepitant), a propellant (e.g., an HFA such as 1,1,1,2-tetrafluoroethane), a surfactant (e.g., a fatty acid such as oleic acid), and a co-solvent (e.g., an alcohol such as ethanol). The MDI formulation can optionally contain a dissolved gas (e.g., CO2). After device actuation, the bursting of CO2 bubbles within the emitted aerosol droplets breaks up the droplets into smaller droplets, thereby increasing the respirable fraction of drug. As another example, a nebulizer formulation can comprise an NK1R antagonist (e.g., aprepitant), a surfactant (e.g., a Tween® such as polysorbate 80), a chelator or preservative (e.g., edetate disodium), an isotonicity agent (e.g., sodium chloride), pH buffering agents (e.g., citric acid / sodium citrate), and water. The drug can be delivered by means of, e.g., a nebulizer or an MDI with or without a spacer, and the drug dose delivered can be controlled by a metering chamber (nebulizer) or a metering valve (MDI).

[0129] For oral or nasal inhalation using a dry powder inhaler (DPI), an NK1R antagonist (e.g., aprepitant) can be provided in the form of a dry micronized powder, where the drug particles are of a certain small size (e.g., between about 0.5 micron and about 5 microns) to improve, e.g., aerodynamic properties of the dispersed powder and drug deposition in the lungs. Particles between about 0.5 micron and about 5 microns deposit by sedimentation in the terminal bronchioles and the alveolar regions. By contrast, the majority of larger particles (> 5 microns) do not follow the stream of air into the many bifurcations of the airways, but rather deposit by impaction in the upper airways, including the oropharyngeal region of the throat. A DPI formulation can contain the drug particles alone or blended with a powder of a suitable largerbase / carrier, such as lactose, starch, a starch derivative (e.g., hydroxypropylmethyl cellulose) or polyvinylpyrrolidine. The carrier particles enhance flow, reduce aggregation, improve dose uniformity and aid in dispersion of the drug particles. A DPI formulation can optionally contain an excipient such as magnesium stearate or / and leucine that improves the performance of the formulation by interfering with inter-particle bonding (by anti-adherent action). The powder formulation can be provided in unit dose form, such as a capsule (e.g., a gelatin capsule) or a cartridge in a blister pack, which can be manually loaded or pre-loaded in an inhaler. The drug particles can be drawn into the lungs by placing the mouthpiece or nosepiece of the inhaler into the mouth or nose, taking a sharp, deep inhalation to create turbulent airflow, and holding the breath for a period of time (e.g., about 5-10 seconds) to allow the drug particles to settle down in the bronchioles and the alveolar regions.

[0130] Lactose (e.g., alpha-lactose monohydrate) is the most commonly used carrier in DPI formulations. Other carriers for DPI formulations include without limitation glucose, mannitol (e.g., crystallized mannitol [Pearlitol 110 C] and spray-dried mannitol [Pearlitol 100 SD]), maltitol (e.g., crystallized maltitol [Maltisorb P90]), sorbitol and xylitol.

[0131] Dry powder inhalers can be classified by dose type into single-unit dose (including disposable and reusable) and multi-dose (including multi-dose reservoirs and multiunit dose). In a single-unit dose DPI, the formulation can be a powder mix of a micronized drug powder and a carrier and can be supplied in individual capsules, which are inserted into the inhaler for a single dose and are removed and discarded after use. The capsule body containing the dose falls into the device, while the cap is retained in the entry port for subsequent disposal. As the user inhales, the portion of the capsule containing the drug experiences erratic motion in the airstream, causing dislodged particles to be entrained and subsequently inhaled. Particle de-aggregation is caused mainly by turbulence promoted by the grid upstream of the mouthpiece or nosepiece. Examples of single-unit dose DPIs include without limitation Aerolizer®, AIR®, Conix One® (foil seal), Diskhaler®, Diskus®, Handihaler®, Microhaler®, Rotahaler® and Turbo spin®.EXAMPLES

[0132] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure.Example 1 : Materials and MethodsAnimal treatment model procedure

[0133] All animal studies were performed according to the principles in the US Department of Health and Human Services Guide for the Care and Use of Laboratory Animals, and received approval (IACUC # A391 approved January 8th, 2018) from The GeorgeWashington University (GWU) Institutional Animal Care and Use Committee. Male Sprague- Dawley (SD) rats were procured from Hilltop Lab Animals, Inc. (Scottdale, PA) through the GWU Animal Research Facility (ARF). Following quarantine, all age-matched rats (325-375 g) received an ad libitum Mg -normal diet (25 mol magnesium oxide / kg food considered 100% recommended daily allowance for rodents, TD 93104) obtained from Envigo-Teklad Laboratory (Somerset, NJ, USA) containing extracted casein as the diet base and essential vitamins and nutrients; or this diet supplemented with erlotinib (Tarceva®: OSI Pharmaceuticals, LLC, Northbrook, IL 60062, USA) to reach a starting dose of 10 mg / kg / day, aprepitant (Emend®: Merck & Co., Inc., USA) for a starting dose of 2 mg / kg / day, or both at these doses. Rats in four groups included: [1] control (n = 5) + vehicle C, [2] erlotinib (10 mg / kg / day, oral)-treated (n = 5) alone, [3] erlotinib oral + topical aprepitant (1.5 mg / kg / day) in vehicle C-treated (n = 5) starting at week 1, and [4] erlotinib oral + topical aprepitant (1.5 mg / kg / day) in vehicle C-treated (n = 5) starting at week 6. Rats were housed individually, and body weight and food consumption recorded daily to determine actual drug dosage during 12 weeks of treatment. Free access to distilled deionized drinking water, and a 12- h light / dark cycle for up to 12 weeks was provided. As used herein, vehicle C refers to a solvent consisting of transcutol (about 42% v / v) benzyl alcohol (about 2% v / v) and propylene glycol (about 56 % v / v). Aprepitant can be dissolved in vehicle C to make a solution at a concentration of up to 2% (w / v).Blood collection / preparation

[0134] Tail blood was collected (- 0.5 ml) aseptically from anesthetized rats (2% isoflurane, EZ Anesthesia Chamber plus nose cone) at periodic intervals in sterile microtainer, with the plasma separator tubes containing heparin and aprotinin (protease inhibitor, Sigma Chemicals, St. Louis, MO) to give blood concentrations of 10.74 U / ml and 0.016 U / ml, respectively. After centrifugation (12,000 rpm, 2 min, RT, IDEXX StatSpin VT, Iris International, Inc., Westwood, MA), plasma samples were used to assess Mg and substance P levels. Blood samples collected at sacrifice (- 8 ml collected in heparin plus aprotinin containing BD vacutainer SST tubes) were taken from anesthetized, heparinized rats (0.3-0.4 ml 358 U / ml heparin in 0.9o / c NaCl, i.p.) by cardiac puncture, and were centrifuged (3500 rpm, 10 min, RT). Sacrifice plasma samples were assayed for 8-isoprostane levels, whereas whole blood samples were processed for neutrophil isolation and assessment of superoxide anion production.Plasma magnesium

[0135] Plasma samples were acidified and diluted 1 :50 fold in 2% nitric acid. The Mg levels were determined by atomic absorption flame emission spectroscopy (wavelength = 285.2 nm) using an AA-6200 Shimadzu spectrophotometer (Columbia, MD). Values obtained were estimated from a standard curve and reported as % of control.Plasma substance P

[0136] An ELISA kit from R&D Systems (Minneapolis, MN) is a competitive binding assay used to assess plasma SP levels. SP within diluted plasma samples (50 pl of 1 : 1) competes with a fixed amount of horseradish peroxidase-labeled SP for murine monoclonal antibody sites. SP concentration was inversely proportional to color development and absorbance was read at 450 nm with background subtraction at 540 nm using a VersaMax microplate reader (Molecular Devices, Sunnyvale, CA). Values are mean± SE for each group of 5 rats and represent % changes in plasma SP levels compared to time-paired controls (100%). Overall average (n = 15) of control rat plasma SP levels at 4, 8, and 12 weeks was 510.5 ± 22.8 pg / ml.Plasma 8-isoprostane

[0137] Plasma samples were diluted 5- and 10-fold (by ELISA assay buffer from Cayman Chemical). Free 8-isoprostane levels in samples were determined by an 8-isoprostane ELISA kit (Cayman Chemical. Ann Arbor, MI, item no. 516351) and estimated according to standard curves.Neutrophil basal and stimulated superoxide generating activity

[0138] At sacrifice, neutrophils from 3 ml of whole blood from each rat were obtained by a step-gradient centrifugation method. Superoxide anion production from the neutrophils (0.7- 1 X 106 / ml) without (basal) or with (stimulated) phorbol myristate acetate (PMA, 100 ng / ml) was determined in a Na-phosphate buffer (pH 7.6) containing 5 mM glucose, 1 mM MgC12, 1 mM CaCl2, and 75 μM cytochrome c ± 50 μg SOD. Superoxide generating activity was estimated as SOD-inhibitable reduction of cytochrome c using the extinction coefficient: E550=2.1 x 104 M'1cm'1.Thoracic non-invasive echocardiography

[0139] Anesthetized rats (2% isoflurane, EZ Anesthesia Chamber plus nose cone) received periodic echocardiography during treatment using a GE VingMed System Five Echocardiogram System. Rectal temperature (35.9-37.5 °C) and heart rate were monitored with placement of animals on a warming platform with paws taped down to limit motion during imaging. To prevent eye drying during the procedure, a sterile eye lubricant was applied. An electric clipper was first used to remove hair over the thorax, followed by a depilatory cream (< 2 min exposure). Animals were imaged (10 MHz probe) for 20 min at a 3-cm image depth, allowing for both cardiac structural and functional evaluation. Left ventricular systolic function was measured as % fractional shortening (% FS) using M-mode imaging, and left ventricular ejection fraction (LVEF) was calculated from M-mode measurements. Anatomical parameters of interest (LY posterior wall thickness in diastole or systole = LVPWd ors; interventricular septum wall dimension in diastole or systole=IVSs or s; LV chamber diameter in diastole or systole= LVDdor s) were measured to evaluate the presence of dilated cardiomyopathy and reduced cardiac function. Aortic and pulmonary artery diameter measurements were used to calculate stroke volumes; aortic pressure max (AoPmax) was assessed; and measurements of spectral Doppler velocities were used for pulmonic and aortic outflows to calculate cardiac output (CO); and for mitral valve inflows to evaluate ventricular diastolic function (obtain mitral valve E and A wave velocities and the EIA ratio). Following echocardiography, rats were placed in room air until awake, and observed until fully recovered.Facial / head digital images and grading skin / hair loss changes

[0140] Immediately following echocardiography during treatment weeks 4, 8, and 12, anesthetized rats from each group (1 l=5 / grp) were placed ventral side down upon toweling and a photographic image was taken primarily of the facial / head region at an approximate distance of 6 in. from the subject. Afterward, animals were placed in their holding cages until fully recovered. The camera feature of the iPhone 6 s Plus was used with high dynamic range (HOR to blend the best of 3 separate exposures into a single picture). The rear camera has a 12 mega-pixel sensor, 1.22 μm 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. Severity of facial dermatitis was scored separately on a O (none) to 4 (worse) scale based on macular or papular eruption or erythema; hair loss was similarly scored O (none) to 4 (loss from> 50% facial surface area).Skin sampling and substance P receptor assessment

[0141] 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 triangular shaped tissue sample had an approximate area of 4.5 cm2. The skin samples were quickly rinsed in PBS, embedded in OCT compound, frozen immersed in 2-methylbutane on dry ice, and kept at - 80 °C until used. Cryosections, 5 μm thick, were stained immunohistochemically using rabbit anti-substance Preceptor (NKIR) polyclonal antibody at 1 : 200 dilution (EMD Millipore, Tamecula, CA). VectaStain Elite ABC Kit Immunoperoxidase System using 3', 3'- diaminobenzidine as the substrate (DAB) from Vector Laboratories, Burlingame, CA for bright- field microscopy and Alexa Fluor 488-conjugated donkey anti -rabbit secondary antibody (Jackson ImmunoResearch Laboratories Inc., West Grove, PA) for immunofluorescence were used. Samples were examined under the Olympus BX60 microscope at x 20 and x 10 magnification, and multiple images were taken with a digital camera (Evolution Color MP; Media Cybernetics, Silver Spring, MD). Both techniques produced similar staining patterns for each of theexperimental groups. However, obtaining multiple micrographs of the skin sections from many groups of animals proved to be a more expedient procedure for slides stained with Vecta-Stain Elite ABC kit rather than the ones stained with fluorophores. Secondary antibody conjugated to DAB produces a stable brown staining of the tissue; thus, for the quantification protocol, the tissues stained with DAB and observed under bright-field microscope were photographed at ten different areas per slide and the micrographs were used in ImageJ analysis. Image processing and analysis in Java, imagej.nih.gov (ImageJ) is a reliable program for computer-assisted analysis of microscopic micrographs. Selecting the "Image / Adjust / Color Threshold" function allows one to manually filter and mark positively stained areas of interest in the tissue section. When satisfied with the color threshold levels, the function "Analyze / Measure" calculates the number of pixels in the area of interest. Ratio of# pixels in area of interest / # pixels in entire tissue area x 100 results in% positive stained area. Data from analysis of ten fields in each micrograph from five animals per group were used for quantification.Statistical analyses

[0142] Data are the mean± SEM of five rats per group, and were checked by F test for equality of groups' variation. Statistical differences were evaluated by two-tailed Student's / -test, and selected data were analyzed by one-way ANOVA and then by a Tukey's test. Significance was obtained at p < 0.05.Example 2: Topical application of aprepitant in rats reduced hair loss

[0143] Topical application of aprepitant (1.5 mg / kg / day) in vehicle C on the facial area (4 - 5 cm2) three times / week, provided protection against facial dermatitis and hair loss in rats exposed to oral erlotinib for up to 12 weeks (FIG. 3 Panel C and D). Topical application with aprepitant applied after week 1 of erlotinib exposure (FIG. 2 Panel C) appeared to be more protective against skin lesions and hair loss by week 8 compared to rats receiving aprepitant only after week 6 of erlotinib exposure (FIG. 2 Panel D).

[0144] However, after 12 weeks of erlotinib exposure, both topical applications with aprepitant given after week 1 or week 6 of erlotinib exposure appeared to be protective against skin lesions and hair loss (Tables 1-2 and FIG. 3), yet the early topical treatment with aprepitant (1.5 mg / kg / day) in vehicle C was shown to be more beneficial than delayed application (FIG. 2 Panel C and D; FIG. 3 Panel C and D)

[0145] Topical application of vehicle C alone to control rats for 12 weeks did not provide any effects related to skin dermatitis or hair loss (Table 1). Table 1 contains raw data for facial cutaneous scoring of rats for up to 12 weeks. Table 1 therefore shows greater protection against erlotinib-induced dermatitis and hair loss was seen after 12 weeks with early aprepitanttopical application (week 1) compared to the delayed application (week 6), but both protocols provided significant benefits, even after only 8 weeks of erlotinib treatment. Table 2 contains raw data for facial hair weight and heart weight of rats for up to 12 weeks. Table 2 demonstrates significant changes in heart wet wt. was observed among groups vs control; however, we showed that prevention of hair loss was substantially improved by early (Apre(T-l) topical aprepitant application compared to delayed application Apre(T-6)).| | | | | | | | | |Example 3: Topical application of aprepitant in rats suppressed the neutrophil activation

[0146] Exposure to erlotinib (12 weeks) led to significant activation of neutrophilsuperoxide production from the blood: Erl alone resulted in about 7-fold activation of the basal superoxide activity compared to Ctl. Topical facial application of aprepitant suppressed the neutrophil activation (superoxide), but was somewhat more protective with early application versus delayed application (Table 5 in FIG. 8). Aprepitant application starting at week 1 provided 67% inhibition (p<0.01 vs Erl alone), whereas aprepitant applied after week 6 provided only 23% protection (N.S. vs Erl alone) (Table 5 in FIG. 8). These findings also suggest that topical treatment with 1.5 mg / kg / day aprepitant may have reached a systemic concentration capable of suppressing neutrophil-mediated oxidative stress.

[0147] This example demonstrates that the therapeutic beneficial mechanism(s) of aprepitant may involve suppression of systemic and local (skin) neurogenic inflammation (through substance P-receptor blockade) as well as reduction of oxy-radical production derived from tissue infiltrating white blood cells (WBCs).Example 4: Body weight food consumption and PMN superoxide of rats

[0148] This examples shows the body weight changes and food consumption for the four groups of rats in FIG. 1 and FIG. 2. Table 3 contains raw data for body weight gain of rats for up to 12 weeks. As depicted in Table 3, weight gain of rats was not significantly different vs time-matched Ctl at any week. Table 4 contains raw data for food consumed by rats up to 12 weeks. Also depicted in Table 4, food consumption (custom-prepared by Envigo-Teklad Lab) was mildly higher in experimental groups vs time-matched Ctl at all weeks. Conclusion: Food was mildly higher in experimental groups vs time-matched Ctl at all weeks. Table 5 contains raw data for PMN superoxide of rats for up to 12 weeks.Example 5: test of a composition formulated in form of solution

[0149] A composition is formulated in form of solution comprising aprepitant in benzyl alcohol (1-5% w / v) and propylene glycol (50-60% w / v), and transcutol (30-50% w / v). Benzyl alcohol (a topical anesthetic with anti-parasitic properties) is FDA approved for clinical use up to 5%. Propylene glycol is also FDA approved and it has been used in preparations of cosmetics and even used as a food additive. The solution can dissolve aprepitant with an upper limit of 2% (w / v). For the main series of study, two different concentrations (0.22% w / v and 0.67% w / v aprepitant solutions) are used to provide the selected low and high doses of aprepitant.

[0150] A male human subject with alopecia areata is selected for application of the solution in a treated area of the scalp as shown in FIG. 1 comprising the aprepitant solution twice a day, once in the morning and once at night, 12 hours apart, for a period of 90 days. The solution is applied to area 101 of FIG. 1. After 90 days of application of the ointment, an increase in hair growth is measured by length, weight and number of strands of hair as compared to the untreatedarea 103.Example 6: A composition of aprepitant formulated in form of a tablet

[0151] A composition is formulated in form of tablet comprising 40 mg, 80 mg, or 125 mg of aprepitant and excipients including lactose monohydrate, cellulose microcrystalline (E460), starch pregelatinised, sodium starch glycolate (Type A), magnesium stearate (E470b), docusate sodium.Example 7: A composition of aprepitant with finasteride formulated in form of a tablet

[0152] A composition is formulated in form of tablet comprising 40 mg, 80 mg, or 125 mg of aprepitant, 5 mg of finasteride and excipients including lactose monohydrate, starch pregelatinised, sodium starch glycolate (Type A), magnesium stearate (E470b), docusate sodium, sucrose, microcrystalline cellulose microcrystalline (E460), hydroxypropyl cellulose and sodium lauryl sulfate.

[0153] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0154] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Any reference to “or” herein is intended to encompass “and / or” unless otherwise stated.

[0155] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, theuse of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms.

[0156] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0157] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articlesrefers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0158] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing hair loss, comprising administering to a subj ect a therapeutically or prophylactically effective amount of a composition comprising aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof; thereby treating or preventing hair loss in the subject.

2. The method of claim 1, wherein the subject is a mammal.

3. The method of any one of claims 1-2, wherein the subject is a human and the administering is performed by topical application of the composition on an area of the skin of the subjection.

4. The method of any one of claims 1-3, wherein the subject suffers from or is at the risk of suffering from alopecia selected from the group consisting of androgenic alopecia, traction alopecia, alopecia barbae, alopecia mucinosa, alopecia neoplastica, cicatricial alopecia, scarring alopecia, anagen effluvium, telogen effluvium, anagen alopecia, telogen alopecia, and alopecia areata.

5. The method of any one of claims 1-4, wherein the subject suffers from or is at risk of suffering from an alopecia condition selected from the group consisting of anagen alopecia, telogen alopecia, and alopecia areata.

6. The method of claim 5, wherein the alopecia areata is alopecia totalis.

7. The method of claim 5, wherein the alopecia areata is alopecia universalis.

8. The method of any one of claims 4-7, wherein the alopecia areata is in a plurality of patches.

9. The method of any one of claims 1-8, wherein the hair loss is not associated with a cancer treatment; optionally the hair loss is not associated with radiotherapy, a chemotherapy agent, or both; and further optionally the hair loss is not associated with Erlotinib.

10. The method of any one of claims 1-8, wherein the hair loss is not induced or caused by a cancer treatment; optionally the hair loss is not induced or caused by radiotherapy, a chemotherapy agent, or both; and further optionally the hair loss is not associated with Erlotinib.

11. The method of any one of claims 1-8, wherein the composition is administered to the subject by topical administration, intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, nebulization, or a combination thereof.

12. The method of any one of claims 1-11, wherein the composition is administered to the subject by oral or intravenous administration.

13. The method of any one of claims 1-12, wherein the composition is formulated in form of ointment, gel, lotion, cream, paste, powder, pill, tablet, microtablet, pellet, micropellet,capsule, capsule containing microtablets, solution, suspension, emulsion, aerosols, or nanoparticles.

14. The method of claim 13, wherein composition is formulated in the form of ointment, gel, lotion, cream, or paste.

15. The method of any one of claims 1-14, wherein the composition is administered to the subject once, twice, or three times a day.

16. The method of any one of claims 1-15, wherein the composition is administered to the subject once every day, every two days, or every three days.

17. The method of any one of claims 1-16, wherein the composition is administered to the subject at an effective daily dose of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof at from 10 mg to 250 mg.

18. The method of any one of claims 1-17, wherein the composition comprises one or more additional therapeutic agents.

19. The method of claim 18, wherein the one or more additional therapeutic agents comprises a hair growth stimulating agent.

20. The method of claim 19, wherein the hair growth stimulating agent is selected from the group consisting of minoxidil, diazoxide, pinacidil, bimatoprost, finasteride, dutasteride, bicalutamide, spironolactone, vitamin D, vitamin D3, (-)-epigallocatechin-3 -gallate (EGCG), prostaglandin El, prostaglandin E2, prostaglandin F2a and any combination thereof.

21. The method of any one of claims 1-20, wherein the composition is formulated in form of ointment, gel, lotion, cream, or paste.

22. The method of claim 21, wherein the composition further comprises at least one excipient selected from the group consisting of propylene glycol, benzyl alcohol, DMSO, ethanol, diethylene glycol monoethyl ether, vitamin E, glycerol monooleate, glyceryl monostearate, ethyl ester of linoleic acid, glyceryl monolinoleate, polyoxyl castor oil or any combination thereof.

23. The method of any one of claims 1-20, wherein the composition is formulated in form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, aerosols, or nanoparticles.

24. The method of claim 23, wherein the composition further comprises at least one excipient selected from the group consisting of diluting agent, binding agent, lubricating agent, disintegrating agent, absorption accelerating agents, wetting agents, absorbents, coloring agent, flavoring agent, sweetening agent or any combination thereof.

25. The method of any one of claims 1-20, wherein the composition is formulated in form of solution, suspension, or emulsion.

26. The method of claim 25, wherein the composition further comprises at least onesurfactant.

27. The method of any one of claims 1-26, wherein administering the composition reduces hair loss by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

28. The method of any one of claims 1-27, wherein the subject is administered with fosaprepitant.

29. A composition comprising aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof for use in treating and preventing hair loss.

30. The composition of claim 29, wherein the composition is formulated in form of ointment, gel, lotion, cream, paste, powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, liquid, aerosols, or nanoparticles.

31. The composition of any one of claims 29-30 wherein the composition is formulated in a dosage of 10 mg to 250 mg.

32. The composition of any one of claims 29-31, wherein the composition comprises one or more additional therapeutic agents.

33. The composition of claim 32, wherein the one or more additional therapeutic agents comprises a hair growth stimulating agent.

34. The composition of claim 33, wherein the hair growth stimulating agent is selected from the group consisting of minoxidil, diazoxide, pinacidil, bimatoprost, finasteride, dutasteride, bicalutamide, spironolactone, vitamin D, vitamin D3, (-)-epigallocatechin-3 -gallate (EGCG), prostaglandin El, prostaglandin E2, prostaglandin F2a and any combination thereof.

35. The composition of any one of claims 29-34, wherein the composition is formulated in form of ointment, gel, lotion, cream, or paste.

36. The composition of claim 35, wherein the composition further comprises at least one excipient selected from the group consisting of propylene glycol, benzyl alcohol, DMSO, ethanol, diethylene glycol monoethyl ether, vitamin E, glycerol monooleate, glyceryl monostearate, ethyl ester of linoleic acid, glyceryl monolinoleate, polyoxyl castor oil or any combination thereof.

37. The composition of claim 36, wherein the composition comprises aprepitant (about 0.1-2% w / v) in benzyl alcohol (1-5% w / v) and propylene glycol (50-60% w / v), and di ethylene glycol monoethyl ether (transcutol) (30-50% w / v).

38. The composition of claim 36, wherein the composition comprises aprepitant (about0.2-1% w / v) in benzyl alcohol (about 2% w / v) and propylene glycol (about 56-57% w / v), and diethylene glycol monoethyl ether (transcutol) (about 40-45% w / v).

39. The composition of any one of claims 29-34, wherein the composition is formulated in form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, or nanoparticles.

40. The composition of claim 39, wherein the composition further comprise at least one excipient selected from the group consisting of diluting agent, binding agent, lubricating agent, disintegrating agent, absorption accelerating agents, wetting agents, absorbents, coloring agent, flavoring agent, sweetening agent or any combination thereof.

41. A kit, comprising aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, optionally formulated for topical application; and a label indicating: the kit is for treating and preventing hair loss.

42. The method, composition or kit of any one of claims 1-41, wherein the composition comprises fosaprepitant.

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