Dexmecamylamine and its uses

Abstract

The disclosure features a method of treating a subject having acne, enlarged pores, hidradenitis, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous gland carcinoma, sebaceous cyst, wrinkles, or oily skin suppuration by administering to the subject dexmecamylamine, or a pharma- ceutically acceptable salt thereof, which is substantially free of exo-R-mecamylamine.

Description

Summary of the Invention

[0001] The disclosure provides methods, such as administering a compound (e.g., dexmecamylamine substantially free of exo-R-mecamylamine), for treating a disease in a patient.

[0002] In one aspect, the disclosure features administering to a subject in need thereof a therapeutically effective amount of dexmecamylamine, or a pharmacologic agent, substantially free of exo-R-mecamylamine, to the subject, the ...

[0003] In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject having acne (e.g., not having enlarged pores). In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject having enlarged pores. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject having hidradenitis suppurativa. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject having seborrhea. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject with sebaceous gland hyperplasia. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject with seborrheic dermatitis. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject with sebaceous adenoma. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject with sebaceous gland carcinoma. In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject having a sebaceous cyst.In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject having a wrinkle.In some embodiments, the method comprises administering a therapeutically effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, to a subject with oily skin.

[0004] In some embodiments, the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine is administered orally, by inhalation, intranasally, or topically. In some embodiments, when the subject has enlarged pores, the dexmecamylamine, that is substantially free of exo-R-mecamylamine, is administered orally.

[0005] In some embodiments, the subject is administered 0.1 mg to 16 mg (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 mg) of the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine.

[0006] In some embodiments, the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, is administered to the subject at a dose of about 1, 2, 4, or 8 mg. In some embodiments, the subject is administered 2 mg of the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine. In some embodiments, the subject is administered 4 mg of the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine.

[0007] In some embodiments, the dexmecamylamine that is substantially free of exo-R-mecamylamine is in the form of a salt, e.g., the hydrochloride salt.

[0008] In some embodiments, the analyte is at least 100 μg / cm 2 or 100 μg / cm2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 In some embodiments, after the treatment with dexmecamylamine, or a pharma- ceutical acceptable salt thereof, substantially free of exo-R-mecamylamine, the subject exhibits sebum production that is at least 20% (e.g., at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or greater) less than the subject's sebum production prior to the treatment with the dexmecamylamine, or a pharma- ceutical acceptable salt thereof, substantially free of exo-R-mecamylamine. In some embodiments, the sebum production is facial sebum production.

[0009] In some embodiments, the subject is a human.

[0010] In some embodiments, the treatment is for at least 1 week, such as at least 2, 3, or 4 weeks, or for at least 2, 3, 6, or 12 months.

[0011] definition As used herein, the terms "about" and "approximately" refer to values ​​within 10% above or below the stated value. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0012] As used herein, the term "administration" refers to administration of a composition (e.g., a compound described herein or a preparation comprising a compound) to a subject or system. Administration to an animal subject (e.g., a human) may be by any suitable route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal by inhalation, intestinal, transdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal), transdermal, intravaginal, or intravitreal.

[0013] For reference, as used herein, "dexmecamylamine substantially free of exo-R-mecamylamine" comprises greater than or equal to 95% by weight dexmecamylamine and less than or equal to 5% by weight exo-R-mecamylamine. More preferably, "dexmecamylamine substantially free of exo-R-mecamylamine" comprises greater than or equal to 98% by weight dexmecamylamine and less than or equal to 2% by weight exo-R-mecamylamine. More preferably, "dexmecamylamine substantially free of exo-R-mecamylamine" comprises greater than or equal to 99% by weight dexmecamylamine and less than or equal to 1% by weight exo-R-mecamylamine. More preferably, "dexmecamylamine substantially free of exo-R-mecamylamine" comprises greater than or equal to 99.5% by weight dexmecamylamine and less than or equal to 0.5% by weight exo-R-mecamylamine. Most preferably, "dexmecamylamine substantially free of exo-R-mecamylamine" comprises greater than or equal to 99.7% by weight dexmecamylamine and less than or equal to 0.3% by weight exo-R-mecamylamine.

[0014] The term "pharmaceutical composition" as used herein refers to a composition that contains the compound described herein, which is formulated with pharmaceutically acceptable excipients.The pharmaceutical composition can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gelatin capsule, buccal, or syrup); for topical administration (e.g., cream, gel, lotion, skin patch, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system that is free of particulate emboli and suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0015] "Pharmaceutically acceptable excipient" as used herein refers to any component other than the compounds described herein (e.g., a vehicle that can suspend or dissolve active compounds) that has the characteristics of being substantially non-toxic and non-inflammatory in patients.Excipients include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, lubricants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending agents or dispersing agents, sweeteners, and hydration water. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0016] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of the compounds described herein. For example, pharmaceutically acceptable salts of any compounds described herein include salts that are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic reaction, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J.Pharmaceutical Sciences 66:1-19, 1977, and Pharmaceutical Salts:Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting the free base group with a suitable organic acid.

[0017] The compounds of the present disclosure may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts.These salts may be acid addition salts, including inorganic or organic acids.Often, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids.The methods of preparing suitable pharmaceutically acceptable acids and suitable salts are well known in the art.Salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.

[0018] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfonate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts in the form of tert-butyl ether, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts.

[0019] As used herein, the term "subject" refers to any organism to which a composition according to the present disclosure may be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal seeking or in need of treatment, in need of treatment, undergoing treatment, will undergo treatment in the future, or being treated by a trained professional for a particular disease or condition.

[0020] As used herein, the terms "treat", "treated" or "treating" refer to both therapeutic and prophylactic or preventative treatments, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent of a condition, disorder, or disease; stabilization (i.e., not worsening) of a condition, disorder, or disease; delay in onset or slowing of progression of a condition, disorder, or disease; detectable or undetectable improvement or remission (whether partial or total) of the condition, disorder, or disease state; improvement of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without undue side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment.

[0021] The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will become apparent from the specification and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present disclosure provides methods of treating various diseases or disorders in patients (e.g., acne, enlarged pores, hidradenitis suppurativa, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous carcinoma, sebaceous gland cyst, wrinkles, and oily skin) with dexmecamylamine, or a pharma- ceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine. Subjects having acne, enlarged pores, hidradenitis suppurativa, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous adenoma, sebaceous gland carcinoma, sebaceous gland cyst, wrinkles, or oily skin may be treated according to the methods of the present disclosure by administering to the subject an effective amount of dexmecamylamine, or a pharma- ceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine, by any route described herein.

[0023] Pharmaceutical Compositions The compounds of the present disclosure are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0024] The compounds of the present disclosure may be used in free base form or in salt form. All forms are within the scope of the present disclosure. According to the method of the present disclosure, the described compounds or their pharma- ceutically acceptable salts may be administered to a patient in various forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the present disclosure may be administered, for example, orally, parenterally, bucally, topically, sublingually, nasally, by inhalation (e.g., by nebulizer), rectally, by patch, by pump, or by transdermal administration, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical administration. Parenteral administration may be performed by continuous infusion over a selected period of time.

[0025] The present disclosure includes salts or solvates of the compounds described herein, including combinations thereof, such as solvates of salts. The compounds may exist in solvated and non-solvated forms, such as hydrates, and the present disclosure includes all such forms. Typically, but not necessarily, the salts of the present disclosure are pharmaceutically acceptable salts. The salts encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present disclosure. Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; and salts with acidic amino acids such as aspartate and glutamate. The salts may optionally be hydrates or ethanol solvates. In certain embodiments, dexmecamylamine hydrochloride is the preferred salt form.

[0026] Although it is possible to administer the compound of the present disclosure in the form of bulk active chemicals, it is preferable to administer the compound in the form of a pharmaceutical composition or formulation.Accordingly, one aspect of the present disclosure includes a pharmaceutical composition comprising a compound (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) and / or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.Another aspect of the present disclosure provides a process for the preparation of a pharmaceutical composition, comprising mixing a compound of the present disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) and / or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0027] The compounds of the present disclosure may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or may be enclosed in hard or soft shell gelatin capsules, or may be compressed into tablets, or may be incorporated directly into the diet. For oral therapeutic administration, the compounds of the present disclosure may be combined with excipients and used in the form of oral, buccal or sublingual films, digestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.

[0028] The compounds of the present disclosure may also be administered parenterally. Solutions of the compounds of the present disclosure may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under normal conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Usual procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2020, 23 rd ed.), and The United States Pharmacopeia: The National Formulary (USP43-NF38). For example, dexmecamylamine, which is substantially free of exo-R-mecamylamine, can be administered topically. Topical formulations of the compound can include 0.05% to 1% (w / w) of the compound, for example about 0.1% (w / w) of the compound.

[0029] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy administration via syringe is possible.

[0030] Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels and powders. Aerosol formulations generally comprise a solution or fine suspension of active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sealed container under sterile conditions, which can take the form of a cartridge or refill for use with a nebulizer. Alternatively, the sealed container can be an integrated dispensing device, such as a single-dose nasal inhaler, or an aerosol dispenser with a metering valve intended for disposal after use. When the dosage form comprises an aerosol dispenser, it contains a propellant, which can be a compressed gas, such as compressed air, or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage form can also take the form of a pump atomizer.

[0031] The pharmaceutical composition may be formulated in the form of a unit dose, or in the form of a multiple or sub-unit dose.The pharmaceutical composition may be administered to a patient or subject, such as a mammal, such as a mouse, a rat, a cat, a rabbit, a dog, a pig, a cow, or a monkey, but is preferably administered to a human.Furthermore, the time of day (e.g., morning, evening, before going to bed) and the number of times per day (e.g., once a day, twice a day) that the pharmaceutical composition is administered may vary.

[0032] In some embodiments, the unit dose is about 1 to 8 mg, e.g., about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, or 8 mg. For example, an oral dosage form may contain 2 mg, 4 mg, or 8 mg of dexmecamylamine substantially free of exo-R-mecamylamine.

[0033] Treatment method The inventors have discovered that dexmecamylamine reduces sebum production, indicating that dexmecamylamine can be used to treat diseases and disorders caused or exacerbated by oily skin, including acne, enlarged pores, hidradenitis suppurativa, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous carcinoma, sebaceous cyst, wrinkles, and oily skin.

[0034] For example, compounds of the present disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine, or a pharma- ceutically acceptable salt thereof) are effective in treating acne. Acne, also known as acne vulgaris, is a chronic disease affecting the hair and pilosebaceous glands, causing dilation and occlusion of hair follicles, resulting in inflammation. Acne is characterized by blackheads and whiteheads, pimples, oily skin, and potential scarring. There are several types of acne, including comedonal acne and nodular acne. Enlarged pores, which may be associated with acne as well as other conditions such as rosacea, are generally associated with sebum production, aging and photodamage of the skin, and size of hair follicles.

[0035] The compounds of the present disclosure (e.g., dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine) may also be administered to a subject to treat any one of the symptoms of the diseases or disorders described herein. In some embodiments, the subject does not have hyperhidrosis, overactive bladder (OAB), substance addiction (e.g., nicotine, cocaine, alcohol, amphetamines, opiates, other psychostimulants, and combinations thereof), hypertension, hypertensive crisis, herpes types I and II, Tourette's syndrome or other tremors, cancer (such as small cell lung cancer), atheromatous profile, neuropsychiatric disorders (such as bipolar disorder, depression, anxiety disorder, panic disorder, schizophrenia, seizure disorder, Parkinson's disease, and attention deficit hyperactivity disorder), chronic fatigue syndrome, Crohn's disease, dysautonomia, or spastic bowel disease, and / or does not smoke.

[0036] To treat any of the conditions described herein, the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, can be administered to the patient once daily. Alternatively, the dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, can be administered two, three, four, five, or more times daily as needed for effective treatment of the condition.

[0037] Treatment may be performed for as long as necessary to achieve or maintain desired therapeutic results.For example, treatment may be performed for at least 1 week, for example at least 2, 3, or 4 weeks, or for 2, 3, 4, 5, or 6 months, or for 1 year or longer.Treatment may be performed once or more than once daily, for example 2 or 3 times daily.

[0038] In some embodiments, the subject is diagnosed with acne, enlarged pores, hidradenitis suppurativa, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous gland carcinoma, sebaceous cyst, wrinkles, or oily skin prior to treatment.

[0039] Dosage The dosage of the compound of the present disclosure or the composition containing the compound may vary depending on several factors, such as, for example, the pharmacodynamic properties of the compound, the mode of administration, the age, health condition, or weight of the recipient, the nature and extent of symptoms, the frequency of treatment, the type of concurrent treatment, if any, and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present disclosure may be initially administered at an appropriate dose, which may be adjusted as necessary depending on the clinical response. Typically, the compound of the present disclosure may be administered to humans at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as solid form), and may provide satisfactory results. The dose range may be, for example, 0.1 to 1000 mg (e.g., 0.2 to 950, 0.4 to 900, 0.6 to 850, 0.8 to 800, 1 to 750, 1 to 20, 2 to 16, 2 to 700, 4 to 650, 6 to 600, 8 to 550, 10 to 500, 15 to 450, 20 to 400, 30 to 350, 40 to 300, 50 to 250, 75 to 200, or 100 to 150 mg). In some embodiments, about 1, 2, 2.5, 4, 5, 8, 10, 15, or 20 mg of the dexmecamylamine or a pharma- ceutically acceptable salt thereof substantially free of exo-R-mecamylamine is administered per day, for example. Single or multiple administrations may be performed in a 24-hour cycle. For example, in certain embodiments, 0.5 to 8 mg (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 mg) of the compound is administered to the subject once or more than once, e.g., twice, per day.

[0040] Alternatively, the dosage can be calculated using the patient's body weight. For example, the dosage of the compound or its pharmaceutical composition administered to the patient is 0.005-5 (0.01-4.8, 0.02-4.6, 0.04-4.4, 0.06-4.2, 0.08-4.0, 0.1-3.8, 0.2-3.6, 0.3-3.4, 0.4-3.2, 0.5-3.0, 0.6, 2.8, 0.7-2.6, 0.8-2.4, 0.9-2.2, 1-2, 1.1-1.9, 1.2-1.8, 1.3-1.7, or 1.4-1.6) mg / kg. In exemplary, non-limiting embodiments, the dose may be in the range of 0.005 to 1 mg / kg (e.g., 0.01 to 0.5, 0.01 to 0.2, or 0.01 to 0.1 mg / kg). EXAMPLES

[0041] The following examples are put forth to provide one of ordinary skill in the art with an illustration of how the compositions and methods described herein can be used, made, and evaluated, and are intended to be merely illustrative of the disclosure and are not intended to limit the scope of what the inventors regard as their invention.

[0042] Example 1. Phase II Clinical Trial in Subjects Treated with Dexmecamylamine Acne vulgaris is a skin condition characterized by enhanced sebum production, which is in part caused by cholinergic signaling within the sympathetic nervous system. Activation of nicotinic receptors on human sebaceous glands is known to enhance sebum production and secretion. Dexmecamylamine acts on nicotinic acetylcholine receptors and reduces sympathetic tone by selectively inhibiting presynaptic nicotinic receptors in sympathetic ganglia. To clarify the therapeutic effect of dexmecamylamine in the treatment of acne and its related conditions, the inventors conducted a clinical study of hyperhidrotic and oily skin (i.e., 100 μg / cm2) treated with dexmecamylamine hydrochloride. 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2A Phase II clinical trial was conducted in 15 human subjects with sebum production of 0.01 mg or greater on their face. Subjects treated with dexmecamylamine 2 mg or 4 mg BID demonstrated a decrease in facial sebum production after 4 weeks of treatment with dexmecamylamine, as shown in Table 1 below.

[0043] [Table 1] *Response is measured as the percentage change in mean facial sebum production at the end of a two-week treatment regimen compared to baseline sebum production. **Response is defined as the percentage change in mean facial sebum production at the end of a 4-week treatment regimen compared to baseline sebum production. ***Responders are defined as subjects who showed a 20% or greater reduction in sebum volume after treatment with dexmecamylamine. †Less than 20% reduction in sebum production. ††Between 20% and 35% reduction in sebum production. †††Over 35% reduction in sebum production.

[0044] These results indicate that dexmecamylamine may be advantageously used as a therapeutic agent for the treatment of conditions associated with excess sebum production including, for example, acne, enlarged pores, hidradenitis suppurativa, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous carcinoma, sebaceous cyst, wrinkles, or oily skin, especially for treatment periods greater than two weeks.

[0045] Example 2. Treatment of Acne A compound of the disclosure (e.g., dexmecamylamine or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine) is administered to an acne patient. Patients administered the compound exhibit improved symptoms, and signs of acne, including white spots, blackheads, papules, pimples, nodules, and cysts, are reduced or eliminated as a result of administration of the compound. In some embodiments, the compound is dexmecamylamine, or a pharma- ceutically acceptable salt thereof, substantially free of exo-R-mecamylamine. In some embodiments, the subject is administered 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 or greater) in the amount of sebum produced by the cutaneous sebum.

[0046] In particular, dexmecamylamine hydrochloride 4 mg is administered orally twice daily to subjects. Subjects are classified as having oily skin (>100 μg / cm2) as measured by a Sebumeter® grease spot photometer at three locations on the face. 2 ) with facial acne vulgaris (including the nose). Efficacy is determined by comparison of sebum as absolute change from baseline at 12 weeks. Other measures of efficacy include absolute change from baseline in inflammatory and non-inflammatory lesion counts at 8 weeks, and percent change from baseline in lesion counts (inflammatory and non-inflammatory) at 8 and 12 weeks. A further indicator of efficacy is a qualitative assessment on a 5-point scale (0-4) of change from baseline at 12 weeks. Success can be defined as a grade of 0 or 1 and an improvement of at least 2 grades. The assessment may include lesion volume, lesion size, inflammation intensity, and lesion location to take into account the quality and quantity of lesions.

[0047] Example 3. Treatment of enlarged pores A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient having enlarged pores. Patients administered the compound exhibit improved symptoms and a reduction or disappearance of enlarged pores as a result of administration of the compound. In some embodiments, the compound is dexmecamylamine substantially free of exo-R-mecamylamine, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is administered 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0048] Example 4. Treatment of hidradenitis suppurativa A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with hidradenitis suppurativa. Patients administered the compound exhibit improved symptoms, and hidradenitis suppurativa is reduced or eliminated as a result of administration of the compound. In some embodiments, the subject receives a dose of 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater).

[0049] In particular, dexmecamylamine hydrochloride 4 mg is administered orally twice daily to subjects with hidradenitis suppurativa. Efficacy will be measured by change in pain from baseline to 12 weeks using a 10-point numerical rating scale from 1 to 10, with 10 being the worst; change in quality of life from baseline to 12 weeks using the Dermatology Life Quality Index (DLQI); change in clinical status from baseline to 12 weeks using the Hurley Staging; change in clinical status from baseline to 12 weeks using the International Hidradenitis Suppurative Severity Score System (IHS4); change in clinical status from baseline to 12 weeks using the Hidradenitis Suppurative Clinical Response (HiSCR); change in clinical status from baseline to 12 weeks using the Hidradenitis Suppurative Physician Global Assessment (HS-PGA); change in clinical status from baseline to 12 weeks using the Hidradenitis Suppurative Area and Severity Index-Revised (HASI-R); and / or change in absolute number of abscesses or inflammatory nodules.

[0050] Example 5. Treatment of seborrhea A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with seborrhea. Patients administered the compound exhibit improved symptoms and seborrhea is reduced or eliminated as a result of administration of the compound. In some embodiments, the subject receives a dose of 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0051] Example 6. Treatment of sebaceous hyperplasia A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with sebaceous gland hyperplasia. Patients administered the compound exhibit improved symptoms and sebaceous gland hyperplasia is reduced or eliminated as a result of administration of the compound. In some embodiments, the subject is administered 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0052] Example 7. Treatment of seborrheic dermatitis A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with seborrheic dermatitis. Patients administered the compound exhibit improved symptoms, and seborrheic dermatitis is reduced or eliminated as a result of administration of the compound. In some embodiments, the subject is administered 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0053] Example 8. Treatment of sebaceous adenoma A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with sebaceous adenoma. Patients administered the compound exhibit improved symptoms and sebaceous adenomas are reduced or eliminated as a result of administration of the compound. In some embodiments, the subject receives a dose of 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0054] Example 9. Treatment of sebaceous carcinoma A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with sebaceous gland carcinoma. Patients administered the compound exhibit improved symptoms and sebaceous carcinomas are reduced or eliminated as a result of administration of the compound. In some embodiments, the subject is administered 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0055] Example 10. Treatment of sebaceous cyst A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with a sebaceous cyst. Patients administered the compound exhibit improved symptoms and the sebaceous cyst is reduced or eliminated as a result of administration of the compound. In some embodiments, the subject receives a dose of 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0056] Example 10. Treatment of sebum-induced wrinkles A compound of the present disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient having wrinkles. Patients administered the compound exhibit improved symptoms and wrinkles are reduced or eliminated as a result of administration of the compound. In some embodiments, the subject receives a dose of 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0057] Example 11. Treatment of oily skin A compound of the disclosure (e.g., dexmecamylamine substantially free of exo-R-mecamylamine) is administered to a patient with oily skin. Patients administered the compound exhibit improved symptoms, and sebum production by the skin is reduced or eliminated as a result of administration of the compound. In some embodiments, the subject is administered 100 μg / cm 2 or 100 μg / cm 2 Greater (e.g., 125, 135, 150, 175, 200 μg / cm 2 , or greater) in amounts of sebum.

[0058] Other embodiments Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention. Other embodiments are within the scope of the claims.

Claims

1. A pharmaceutical composition comprising dexmecamylamine or a pharmaceutically acceptable salt thereof for use in the treatment of acne, enlarged pores, hidradenitis suppurativa, seborrhea, sebaceous gland hyperplasia, seborrheic dermatitis, sebaceous adenoma, sebaceous gland carcinoma, sebaceous cyst, wrinkles, or oily skin in a subject in need thereof, wherein the dexmecamylamine is substantially free of exo-R-mecamylamine.

2. 10. The pharmaceutical composition for use according to claim 1, wherein the subject has acne.

3. 10. The pharmaceutical composition for use according to claim 1, wherein the subject has enlarged pores.

4. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has hidradenitis suppurativa.

5. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has seborrhea.

6. The pharmaceutical composition for use according to claim 1, wherein the subject has sebaceous gland hyperplasia.

7. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has seborrheic dermatitis.

8. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a sebaceous adenoma.

9. The pharmaceutical composition for use according to claim 1, wherein the subject has sebaceous gland carcinoma.

10. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a sebaceous cyst.

11. The pharmaceutical composition for use according to claim 1, wherein the subject has wrinkles.

12. 10. The pharmaceutical composition for use according to claim 1, wherein the subject has oily skin.

13. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the dexmecamylamine, or a pharmaceutically acceptable salt thereof, is administered orally, by inhalation, intranasally, or topically.

14. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the subject is administered 0.1 mg to 16 mg of dexmecamylamine, or a pharmaceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine.

15. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the subject is administered 0.1 mg to 16 mg of dexmecamylamine, or a pharmaceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, for two weeks or for more than two weeks.

16. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein dexmecamylamine hydrochloride is administered.

17. 16. The pharmaceutical composition for use of claim 15, wherein the subject is administered 2 mg of dexmecamylamine, or a pharmaceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine.

18. 16. The pharmaceutical composition for use of claim 15, wherein the subject is administered 4 mg of dexmecamylamine, or a pharmaceutically acceptable salt thereof, that is substantially free of exo-R-mecamylamine.

19. Prior to treatment, the subject received 100 μg / cm 2 or 100 μg / cm 2 13. A pharmaceutical composition for use according to any one of claims 1 to 12, which produces a greater amount of sebum.

20. The subject received 125 μg / cm 2 , 135 μg / cm 2 , 150 μg / cm 2 , 175 μg / cm 2 , 200 μg / cm 2 20. The pharmaceutical composition for use according to claim 19, wherein the skin produces an amount of sebum equal to or greater than that of the skin.

21. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein after said treatment with dexmecamylamine, or a pharmaceutically acceptable salt thereof, substantially free of exo-R-mecamylamine, said subject exhibits sebum production that is at least 20% less than the subject's sebum production before said treatment with dexmecamylamine, or a pharmaceutically acceptable salt thereof, substantially free of exo-R-mecamylamine.

22. 22. The pharmaceutical composition for use according to claim 21, wherein said sebum production is facial sebum production.