Treatment of refractory chronic cough

Abstract

The present invention relates to methods for treating patients with refractory chronic cough (RCC) with nalbuphine compositions, wherein the method provides a therapeutic effect in a patient.

Description

Attorney Matter No.: TREV-016 / 01WO 318488-2310 TREATMENT OF REFRACTORY CHRONIC COUGH CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 675,915, filed July 26, 2024, which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND

[0002] Cough is the most common symptom for which individuals seek medical advice. Cough is a three-phase expulsive motor act characterized by inspiration effort (inspiratory phase), followed by a forced expiratory effort against a closed glottis (compressive phase) and then by opening of the glottis and rapid expiratory airflow (expulsive phase). There are two general types of cough: acute cough and chronic cough. Chronic cough is a cough that lasts for at least 8 weeks and may be of an explained (e.g., postnasal drip, asthma, gastroesophageal reflux disease (GERD), chronic bronchitis) or unexplained origin. Chronic cough severely impacts a patient’s quality of life with patients often avoiding social interactions for fear of cough-induced emesis, incontinence or syncope.

[0003] Chronic cough is often refractory to treatment with common antitussive agents, and there is a need for alternative effective treatments. SUMMARY OF THE INVENTION

[0004] The present disclosure, among other things, provides methods of treating refractory chronic cough (RCC) comprising administering an effective amount of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to a patient in need of such treatment.

[0005] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof; (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a),Attorney Matter No.: TREV-016 / 01WO 318488-2310 wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

[0006] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof once daily for at least one week. In embodiments, the once daily dose is administered at nighttime.

[0007] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient who has received and failed at least one prior RCC standard-of-care therapy, comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to the patient. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG.1 shows the screening and treatment regimens of two randomized patient groups from Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; QD = once daily; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0009] FIG.2 shows the study design and treatment regimens, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; QD = once daily; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0010] FIG.3 shows the relative change in 24-hour cough frequency (coughs / hr) from baseline at Day 21 in NAL ER treated and placebo groups following 108 mg BID treatment, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0011] FIG.4 shows the relative change in 24-hour cough frequency (coughs / hr) from baseline at Day 7 (27 mg BID), Day 14 (54 mg BID), Day 21 (108 mg BID) in NAL ER treated and placebo groups, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0012] FIG.5 shows the relative change in 24-hour cough frequency (coughs / hr) from baseline at Day 21 in NAL ER treated and placebo groups, in both moderately severe (10-19 coughs / hr) or severe (more than 20 coughs / hr) groups following 108 mg BID, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0013] FIG. 6 shows the proportion of responders at Day 21 in NAL ER treated and placebo groups following 108 mg BID, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0014] FIG. 7 shows the changes in 24-hour Cough Severity Visual Analog Scale (CS-VAS) at Day 7 (27 mg BID), Day 14 (54 mg BID), Day 21 (108 mg BID) in NAL ER treated and placebo groups following 108 mg BID, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0015] FIG.8 shows the changes in Patient-Reported Cough Frequency at Day 7 (27 mg BID), Day 14 (54 mg BID), Day 21 (108 mg BID) in NAL ER treated and placebo groups, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.

[0016] FIG. 9 shows the changes in Leicester Cough Questionnaire (LCQ) from baseline (units) at Day 21 in NAL ER treated and placebo groups following 108 mg BID, as described in Example 2. NAL ER = nalbuphine ER tablet treated group; PBO = placebo group; BID = twice daily. Nalbuphine doses expressed as Equivalent Amount of Nalbuphine Free Base.Attorney Matter No.: TREV-016 / 01WO 318488-2310 DETAILED DESCRIPTION Definitions

[0017] Throughout this disclosure, various patents, patent applications and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0018] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0019] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, …”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0020] The terms “administer,” “administering” or “administration” as used herein refer to either directly administering a compound or pharmaceutically acceptable salt or ester of the compound or a composition comprising the compound or pharmaceutically acceptable salt or ester of the compound to a patient.

[0021] The term “carrier” as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient,Attorney Matter No.: TREV-016 / 01WO 318488-2310 solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body.

[0022] The term “refractory chronic cough”, also known as “RCC”, “chronic refractory cough” and “CRC”, is used in this disclosure to mean cough that lasts for at least 8 weeks that persists despite investigation and treatment of an identified underlying medical condition(s).

[0023] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0024] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate or ester thereof, that, when administered to a patient, is capable of performing the intended result. For example, an effective amount of nalbuphine is that amount that is required to reduce at least one symptom of refractory chronic cough in a patient, e.g., the amount required to reduce the cough frequency in a patient. The actual amount that comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration.

[0025] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0026] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic,Attorney Matter No.: TREV-016 / 01WO 318488-2310 mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3- hydroxybutyric, galactaric and galacturonic acid.

[0027] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient’s disorder. Treating can be improving or at least partially ameliorating a disorder.

[0028] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and / or the composition. For example, the method for treating RCC provides a therapeutic effect when the method reduces at least one symptom of RCC, e.g., cough frequency in a patient. Nalbuphine

[0029] In embodiments, nalbuphine used herein forms a part of a pharmaceutical composition by combining nalbuphine, or a pharmaceutically acceptable salt, solvate or ester thereof, with a pharmaceutically acceptable carrier. In embodiments, the nalbuphine compositions includes an additive selected from the group consisting of adjuvants, excipients, diluents, release- modifying agents and stabilizers. In embodiments, the composition is an immediate release formulation, a delayed release formulation, a sustained release formulation or an extended release formulation.

[0030] Nalbuphine HCl (17-(cyclobutylmethyl)-4,5 -epoxymorphinian-3, 6 , 14-triol,hydrochloride) is a synthetic opioid. Structurally, nalbuphine is a derivative of 14 hydroxymorphine.

[0031] Nalbuphine HCl is currently available only as a generic medication in an injectable form. An injectable form of nalbuphine has been available as an approved drug formulation since 1978. Nubain® was the innovator brand injectable form of nalbuphine on which the presently sold generic bioequivalent injectable formulations are based. The injectableAttorney Matter No.: TREV-016 / 01WO 318488-2310 formulation is currently approved for use in the relief of moderate to severe pain, a supplement to balanced anesthesia, for pre-operative and post-operative analgesia and obstetrical analgesia during labor and delivery.

[0032] In embodiments, the present disclosure provides pharmaceutically acceptable esters of nalbuphine. The term “ester” denotes a derivative of the agent containing an ester functional group (as described herein), which is capable of releasing the agent when the ester form is administered to a patient. Release of the active ingredient occurs in vivo. In embodiments, the pharmaceutically acceptable esters can be prepared by techniques known to one skilled in the art, and the techniques generally modify appropriate functional groups in a given compound. In embodiments, the modified functional groups regenerate original functional groups by metabolism of the compound in vivo. In embodiments, esters include compounds wherein a hydroxy, carboxylic, or a similar group is modified.

[0033] In embodiments, the pharmaceutically acceptable esters for a hydroxyl group comprise inorganic esters such as phosphate esters and -acyloxyalkyl ethers and related compounds which, as a result of in vivo hydrolysis of the ester, provide the parent hydroxy group. In embodiments, In vivo hydrolyzable ester forming groups for hydroxy comprise alkanoyl (e.g., C1-10 linear, branched or cyclic alkyl), benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(N, N- dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), N, N-dialkylaminoacetyl and carboxyacetyl.

[0034] In embodiments, the nalbuphine used in the formulations and methods of the present disclosure is a pharmaceutically acceptable co-crystal of nalbuphine. Nalbuphine Formulations

[0035] In embodiments, the methods of the present disclosure employ various formulations for administration to patients, e.g., humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, inhalable dry powders, dispersions, solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of nalbuphine, or pharmaceutically acceptable salts or esters thereof.

[0036] In embodiments, the oral pharmaceutical dosage forms are solid or liquid. In embodiments, the solid dosage forms are tablets, capsules, granules, or bulk powders. In embodiments, the oral tablets comprise compressed, chewable lozenges or tablets, which canAttorney Matter No.: TREV-016 / 01WO 318488-2310 be enteric-coated, sugar-coated or film-coated. In embodiments, the capsules comprise hard or soft gelatin capsules, while granules and powders are provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. In embodiments, the oral dosage form comprises an osmotic-controlled release oral delivery system (OROS). In embodiments, the oral dosage form comprises matrix-embedded dosage forms or related devices. In embodiments, the present oral dosage forms comprise orally- disintegrating tablets.

[0037] In embodiments, the pharmaceutically acceptable carriers utilized in tablets further comprise binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.

[0038] In embodiments, the liquid oral dosage forms comprise aqueous solutions, emulsions, suspensions, solutions, or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.

[0039] In embodiments, the aqueous solutions comprise, for example, elixirs and syrups. In embodiments, emulsions comprise either oil-in water or water-in-oil. In embodiments, the pharmaceutically acceptable carriers used in elixirs (i.e., clear, sweetened, hydroalcoholic preparation) comprise solvents. In embodiments, syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and further comprise a preservative. In embodiments, an emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. In embodiments, the pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. In embodiments, the suspensions further comprise pharmaceutically acceptable suspending agents and preservatives. In embodiments, the pharmaceutically acceptable substances used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, further comprise diluents, sweeteners and wetting agents. In embodiments, the pharmaceutically acceptable substance used in effervescent granules, to be reconstituted into a liquid oral dosage form, comprises organic acids and a source of carbon dioxide. In embodiments, the dosage forms comprise coloring and flavoring agents.

[0040] In embodiments, parenteral administration of the formulations of the present disclosure comprises intravenous, subcutaneous and intramuscular administrations of immediate, sustained (e.g., depot), extended, and / or modified release formulations (e.g., as described herein). In embodiments, preparations for parenteral administration comprise sterile solutionsAttorney Matter No.: TREV-016 / 01WO 318488-2310 ready for injection, sterile dry soluble products ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. In embodiments, the solutions are aqueous or nonaqueous. In embodiments, the pharmaceutically acceptable carriers used in parenteral preparations comprise aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

[0041] In embodiments, the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. In embodiments, the exact dose is adjusted based on the age, weight and condition of the patient or animal, as is known in the art. In embodiments, the unit-dose parenteral preparations are packaged in an ampoule or a syringe with a needle. In embodiments, preparations for parenteral administration are sterile, as is known and practiced in the art. In embodiments, a sterile aqueous solution containing nalbuphine is administered via intravenous or intra-arterial infusion.

[0042] In embodiments, the compositions described herein are administered in an amount sufficient to provide relief from RCC that is within safety guidelines established by the FDA. In embodiments, determining the appropriate amount to administer to a patient is within the skill of the person of ordinary skill in the art in association with teachings provided by the present disclosure.

[0043] In embodiments, the pharmaceutical excipients or vehicles suitable for administration of the compositions comprise any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In embodiments, the nalbuphine is administered in carriers in amounts sufficient to exert a therapeutically useful effect without serious toxic effects on the treated individual. Nalbuphine Sustained Release (ER) formulation

[0044] In embodiments, the nalbuphine formulations employed in the present methods comprise oral sustained release nalbuphine formulations as described in U.S. Patent Nos. 8,765,175, 8,394,812, and 8,771,732; U.S. Pat. Publication No. 2015 / 0359789; and PCT Publication No. 2015 / 192071; each of which is incorporated herein by reference in their entireties.Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0045] “Sustained release” or “extended release” means that the nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof is released from the formulation at a controlled rate so that therapeutically beneficial blood levels (but below toxic levels) of the nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof are maintained over an extended period of time. Alternatively, “sustained release” or “extended release” means that the desired pharmacologic effect is maintained over an extended period of time.

[0046] The half-life of nalbuphine injectable formulations (i.e., IV or IM or SC) has been reported to be relatively short, only about 2-3 hours. In embodiments, the present methods employ oral sustained release formulations of nalbuphine including an effective amount of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. In embodiments, the oral sustained release formulations provide a controlled release and a lower Cmax of nalbuphine over a longer period than observed for bolus injections or immediate release oral formulations (e.g., at least about 8-12 hours). In embodiments, reducing the frequency of dosing provides the potential for enhanced patient convenience and compliance with the present methods. In embodiments, the lower dosing frequency provides reduced side effects by exposing the patient to lower peak concentrations of agent over time.

[0047] Without wishing to be bound by a particular theory, the longer than expected duration of antitussive is attributed to the enterohepatic recirculation of nalbuphine. Nalbuphine forms a glucuronic acid or other type of conjugated metabolite in vivo through enzymatic reaction with an enzyme system such as UDP-glucuronyl transferase. It is also possible that enterohepatic recirculation also occurs when parent drug in the bile is released from the gallbladder into the intestine and reabsorbed. Once formed, the conjugated nalbuphine product is thought to be transported into the gastrointestinal tract via biliary secretion whereby the drug conjugate is cleaved liberating nalbuphine, which can be reabsorbed from the intestine. In embodiments, the sustained release formulation improves the duration of antitussive by more slowly releasing nalbuphine into the in vivo system and allowing more drug to be conjugated and therefore available for recirculation and later reabsorption from the intestine.

[0048] In embodiments, the present methods employ compositions including nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof and a sustained release delivery system. In embodiments, the sustained release delivery system comprises (i) at least one hydrophilic compound, at least one cross-linking agent, and at least one pharmaceutical diluent; (ii) at least one hydrophilic compound, at least one cross-linking agent, at least one pharmaceutical diluent, and at least one cationic cross-linking agent different from the firstAttorney Matter No.: TREV-016 / 01WO 318488-2310 cross-linking agent; or (iii) at least one hydrophilic compound, at least one cationic cross- linking compound, and at least one pharmaceutical diluent. In embodiments, the present methods employ compositions including nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof and a sustained release delivery system, which employs a hydrophobic compound in a sustained release system.

[0049] In embodiments, the nalbuphine is homogeneously dispersed in the sustained release delivery system. In embodiments, the nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof is present in the composition in an amount of about 1 mg to about 240 mg; about 1 mg to about 150 mg; about 1 mg to about 125 mg; or about 1 mg to about 100 mg, including any values or ranges therebetween. In embodiments, the nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof is present in the composition in an amount of about 5 mg to about 80 mg; about 10 mg to about 70 mg; about 15 mg to about 60 mg; about 40 mg to about 80 mg; about 50 mg to about 70 mg; or about 45 mg to about 60 mg, including any values or ranges therebetween. In embodiments, the nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof is present in the composition in an amount of about 9 mg, about 15 mg, about 18 mg, about 20 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 240 mg. In embodiments, the nalbuphine or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 9 mg, about 15 mg, about 18 mg, about 27 mg, about 30 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg.

[0050] In embodiments, the pharmaceutically acceptable salt of nalbuphine, e.g., nalbuphine HCl, is present in the composition in an amount of about 15 mg, about 30 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg. In embodiments, the compositions comprising a pharmaceutically acceptable salt of nalbuphine, the amount of nalbuphine in said compositions is expressed as the Equivalent Amount of Nalbuphine Free Base, which is the calculated amount of nalbuphine free base in the composition based on the actual amount of the pharmaceutically acceptable salt of nalbuphine in the composition. In embodiments, the amount of the Equivalent Amount of Nalbuphine Free Base in a composition vary within the manufacturing process, and the compositions of the present disclosure encompassAttorney Matter No.: TREV-016 / 01WO 318488-2310 pharmaceutically-acceptable deviations (i.e., FDA-acceptable) from the nalbuphine content that is recited in the present disclosure.

[0051] The following table shows the Equivalent Amount of Nalbuphine Free Base for compositions containing 15 mg, 30 mg, 60 mg, 90 mg, 120 mg, 180 mg and 240 mg of nalbuphine HCl:The amount of Equivalent Amount of Nalbuphine Free Base is rounded to the nearest 0.1 decimal place using the equation below.

[0052] In embodiments, the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride. In embodiments, the present disclosure provides the amount of nalbuphine in a composition expressed in terms of the amount of nalbuphine hydrochloride present in a composition. In embodiments, the present disclosure provides methods of using the nalbuphine present in another nalbuphine form (such as a different pharmaceutically acceptable salt and / or ester) that is expressed in terms of about the same Equivalent Amount of Nalbuphine Free Base. For example, about 251 mg of nalbuphine citrate (FW= 549.57 g / mol) provides about the same Equivalent Amount of Nalbuphine Free Base as about 180 mg of nalbuphine hydrochloride. The Equivalent Amount of Nalbuphine Free Base in said compositions may be calculated by the following formula:

[0053] Equivalent Amount of Nalbuphine Free Base = Mass of Pharmaceutically Acceptable Salt g X 357.45 (Formula Weight of Nalbuphine Free Base, gmol)Formula Weight of Pharmaceutically Acceptable Salt ( gmol)Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0054] The Equivalent Amount of Nalbuphine Free Base content of the dosage form calculated using the equation above may be adjusted by a pharmaceutically acceptable amount (for example, within an amount permitted by FDA safety standards, which in embodiments is 1% or less of the calculated Equivalent Amount of Nalbuphine Free Base) to allow product labeling using a whole number integer when referencing the dosage strength. For example, the calculated Equivalent Amount of Nalbuphine Free Base for 240 mg of nalbuphine hydrochloride is 217.6 mg. In embodiments, the nalbuphine content of the composition is adjusted for a product labelling of 216 mg of Equivalent Amount of Nalbuphine Free Base.

[0055] In embodiments, the nalbuphine or pharmaceutically acceptable salt thereof, e.g., HCL is present in the composition in an amount of about 15 mg, about 30 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg.

[0056] In embodiments, the sustained release delivery system is present in the composition in an amount from about 10 mg to about 420 mg; from about 25 mg to about 225 mg; from about 21 mg to about 198 mg; or from about 80 mg to about 200 mg; from about 80 mg to about 220 mg; from about 90 mg to about 210 mg; from about 100 mg to about 200 mg; from about 110 mg to about 190 mg; from about 120 mg to about 180 mg; from about 130 mg to about 170 mg; from about 140 mg to about 160 mg; from about 30 mg to about 60 mg; from about 60 mg to about 180 mg; from about 30 mg to about 180 mg, from about 75 mg to about 150 mg, from about 80 mg to about 160 mg, from about 90 mg to about 150 mg, from about 100 mg to about 140 mg, from about 110 mg to about 130 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg or from about 200 mg to about 250 mg, including any values and ranges therebetween.

[0057] In embodiments, the sustained release delivery system is present in the composition in an amount of about 15 mg, about 30 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 112 mg, about 115 mg, about 117 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg or about 420 mg, including any values and ranges therebetween.

[0058] In embodiments, the ratio of nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof in the compositions to the sustained release delivery system is from about 4:1 toAttorney Matter No.: TREV-016 / 01WO 318488-2310 about 1:25. In embodiments, the ratio of nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system is generally from about 2.5:1 to about 1:4. In embodiments, the ratio of nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system is generally from about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, about 1:1 to about 1.2, and about 1:2 to about 1:3. In embodiments, the ratio of nalbuphine or pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system is about 1:1, about 1:2, about 1:2.5, about 1:3, about 1:4, or about 1:5.

[0059] In embodiments, the sustained release formulations of nalbuphine are orally administrable solid dosage formulations. In embodiments, the oral solid dosage formulations comprise tablets, capsules including a plurality of granules, sublingual tablets, powders, granules, syrups, and buccal dosage forms or devices (e.g., buccal patches, tablets, etc.). In embodiments, tablets have an enteric coating or a hydrophilic coating. Methods of the present disclosure

[0060] In embodiments, the present disclosure provides a method of treating chronic cough or refractory chronic cough (RCC) in a subject in need thereof comprising administering to the subject an effective amount of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof.

[0061] In embodiments, the methods of the present disclosure are used for the treatment of RCC comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient’s cough frequency is from 10 to 19 coughs per hour (i.e., moderate cough frequency, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 coughs per hour, including any values or ranges therebetween) prior to treatment.

[0062] In embodiments, the methods are used for the treatment of RCC comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient’s cough frequency is from at least 20 coughs per hour (i.e., severe cough frequency, for example, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more coughs per hour, including any values or ranges therebetween) prior to treatment.Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0063] In embodiments, the patient has a Cough Severity Visual Analogue Scale (CS-VAS) score of about 30 mm to about 40 mm (moderate cough) prior to treatment. In embodiments, the patients has a CS-VAS score of about 40 mm (severe cough) to about 100 mm (worst cough) prior to treatment. In embodiments, the patient has a CS-VAS score of about 40 mm prior to treatment. In embodiments, the patient has a CS-VAS score of about 40 mm to about 60 mm (moderate cough) prior to treatment. In embodiments, the patient has a CS-VAS score of about 60 mm to about 80 mm (severe cough). In embodiments, the patient has a CS-VAS score of about 70 mm to about 100 mm prior to treatment.

[0064] In embodiments, the patient has a Cough Severity-Numeric Rating Scale (CS-NRS) of about 4-6 (moderate cough) prior to treatment. In embodiments, the patient has a Cough Severity-Numeric Rating Scale (CS-NRS) of about 7-10 (severe cough) prior to treatment.

[0065] In embodiments, the present disclosure provides a method of treating RCC, unexplained RCC, or suppression of the sensation of the urge to cough. In embodiments, the patient’s underlying condition is postnasal drip, asthma, gastroesophageal reflux disease (GERD), or chronic bronchitis.

[0066] In embodiments, the RCC is refractory to treatment with tramadol. In embodiments, the RCC is refractory to treatment with morphine. In embodiments, the RCC is refractory to treatment with codeine. In embodiments, the RCC is refractory to treatment with amitriptyline. In embodiments, the methods of the present disclosure are used to treat RCC where the cough is refractory to treatment with an antitussive agent. In embodiments, the antitussive agent is lidocaine, gefapixant, serlopitant, camlipixant, nocion, or orvepitant. In embodiments, the methods are used to treat RCC, where the cough is refractory to treatment with μ-opioid agonists. In embodiments, the μ-opioid agonist is morphine, tramadol, dihydrocodeine or diamorphine. In embodiments, the methods of the present disclosure are used to treat RCC where the cough is refractory to treatment with pirfenidone. In embodiments, the methods of the present disclosure are used to treat RCC, where the cough is refractory to treatment with nintedanib. In embodiments, the methods of the present disclosure are used to treat RCC where the cough is refractory to treatment with thalidomide. In embodiments, the methods of the present disclosure are used to treat RCC where the cough is refractory to treatment with cromolyn sodium.

[0067] In embodiments, the RCC is refractory to RCC standard-of-care treatment. In embodiments, the present disclosure provides a method of treating RCC in a patient who hasAttorney Matter No.: TREV-016 / 01WO 318488-2310 received and failed at least one prior RCC standard-of-care therapy, comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to the patient. In embodiments, the standard-of-care therapy comprises treatment with gefapixant, camlipixant, orvepitant, serlopitant, albuterol, levalbuterol, ipratropium, epinephrine, beclomethasone, budesonide, ciclesonide, fluticasone, mometasone, salmetrerol, lormoterol, vilanterol, umeclidinium, montelukast, zafirlukast, omalizumab, mepolizumb, benralizumab, reslizumab, duplilumab, tezepelumab, prednisone, methylpresdnisolone, prednisolone, calcium carbonate, magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, famotidine, cimetidine, nizatidine, ranitidine, omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, vonoprazan, metoclopramide, domperidone, phenylephrine, pseudoephedrine, doxylamine, fluticasone, triamcinolone, loratadine, cetirizine, fexofenadine, diphenhydramine, chlorpheniramine, azelastine, olopatadine, oxymetazoline, amitriptyline, gabapentin, pregabalin, tramadol, nortriptyline, baclofen, duloxetine, topiramate, morphine, codeine, hydrocodone, hydromorphone, fentanyl, oxycodone, pentazocine, butorphanol, dihydrocodeine, diamorphine, buprenorphine, dextromethorphan, menthol, benzonatate, cromolyn sodium, diplatinum, lidocaine, thalidomide, Ifenprodil, AX-8, or a combination thereof. Dosing

[0068] The disclosure provides methods for treating RCC by administering an effective amount of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, to a patient in need thereof. An effective amount is an amount sufficient to eliminate or significantly reduce RCC symptoms or to alleviate those symptoms (e.g., reduce the symptoms, such as cough frequency, compared to the symptoms present prior to treatment). In embodiments, nalbuphine is in a sustained release formulation such that the formulation provides therapeutically effective blood plasma levels of nalbuphine for the treatment of RCC.

[0069] In embodiments, the amount of nalbuphine administered to a patient in need thereof is in the form of a pharmaceutically acceptable salt and is expressed in terms of the Equivalent Amount of Nalbuphine Free Base provided to said patient.

[0070] In embodiments, the nalbuphine is administered on a once or twice a day basis to provide effective relief of the cough symptoms of RCC. In embodiments, a total daily dose of about 6 mg to about 360 mg, for example, about 6 mg to about 300 mg, about 6 mg to aboutAttorney Matter No.: TREV-016 / 01WO 318488-2310 240 mg, about 6 mg to about 216 mg, about 12.5 mg to about 360 mg, about 12.5 mg to about 240 mg, about 12.5 mg to about 216 mg, about 6 mg, about 6.25 mg, about 8 mg, about 10 mg, about 12 mg, about 12.5 mg, about 14 mg, about 15 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 27 mg, about 28 mg, about 30 mg, about 40 mg, about 50 mg, about 54 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 108 mg, about 110 mg, about 120 mg, about 140 mg, about 160 mg, about 162 mg, about 180 mg, about 200 mg, about 216 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg of an Equivalent Amount of Nalbuphine Free Base, including any values or ranges therebetween, is administered to the patient for the treatment of RCC. In embodiments, a total daily dose of about 9 mg, about 18 mg, about 27 mg, about 36 mg, about 54 mg, or about 108 mg, of an Equivalent Amount of Nalbuphine Free Base is administered to the patient for the treatment of RCC. In embodiments, a total daily dose of about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered. In embodiments, a total daily dose of about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered.

[0071] In embodiments, a total daily dose of about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 18 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 27 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 27 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 54 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 108 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 9 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 18 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered forAttorney Matter No.: TREV-016 / 01WO 318488-2310 the treatment of RCC. In embodiments, a total daily dose of about 162 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC. In embodiments, a total daily dose of about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered for the treatment of RCC.

[0072] In embodiments of the present disclosure, the nalbuphine is administered on a twice a day (BID) basis to provide effective relief of the RCC symptoms. In embodiments, about 6 mg to about 110 mg, for example, about 6 mg to about 300 mg, about 6 mg to about 240 mg, about 6 mg to about 216 mg, about 12.5 mg to about 360 mg, about 12.5 mg to about 240 mg, about 12.5 mg to about 216 mg, about 6 mg, about 6.25 mg, about 8 mg, about 10 mg, about 12 mg, about 12.5 mg, about 14 mg, about 15 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 27 mg, about 28 mg, about 30 mg, about 40 mg, about 50 mg, about 54 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 108 mg, or about 110 mg of an Equivalent Amount of Nalbuphine Free Base, including any values or ranges therebetween, is administered once or twice daily for the treatment of RCC.

[0073] In embodiments, about 6.25 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC. In embodiments, about 9 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC (total daily dose of 18 mg of an Equivalent Amount of Nalbuphine Free Base). In embodiments, about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC (total daily dose of 54 mg of an Equivalent Amount of Nalbuphine Free Base). In embodiments, about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC (total daily dose of 108 mg of an Equivalent Amount of Nalbuphine Free Base). In embodiments, about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC (total daily dose of 216 mg of an Equivalent Amount of Nalbuphine Free Base). In embodiments, about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC. In embodiments, about 18 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC. In embodiments, about 27 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC. In embodiments, about 54 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily for the treatment of RCC.Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0074] In embodiments of the present disclosure, the nalbuphine is administered on once a day basis to treat the patient’s RCC symptoms. In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof once daily. In embodiments, the once daily dose is administered at nighttime. In embodiments, the once daily dose is administered at daytime. In embodiments, about 6 mg to about 360 mg, for example, about 6 mg to about 300 mg, about 6 mg to about 240 mg, about 6 mg to about 216 mg, about 12.5 mg to about 360 mg, about 12.5 mg to about 240 mg, about 12.5 mg to about 216 mg, about 6 mg, about 6.25 mg, about 8 mg, about 10 mg, about 12 mg, about 12.5 mg, about 14 mg, about 15 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 27 mg, about 28 mg, about 30 mg, about 40 mg, about 50 mg, about 54 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 108 mg, about 110 mg, about 120 mg, about 140 mg, about 160 mg, about 162 mg, about 180 mg, about 200 mg, about 216 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg of an Equivalent Amount of Nalbuphine Free Base, including any values or ranges therebetween, is administered once daily for the treatment of RCC.

[0075] In embodiments, about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. In embodiments, about 9 mg to about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. In embodiments, about 9 mg to about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. In embodiments, about 18 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. In embodiments, about 27 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. In embodiments, about 54 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. In embodiments, about 12.5 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC. In embodiments, about 9 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC. In embodiments, about 18 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC. In embodiments, about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC. In embodiments, about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC. In embodiments, about 108 mgAttorney Matter No.: TREV-016 / 01WO 318488-2310 of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC. In embodiments, about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily for the treatment of RCC.

[0076] In embodiments, the therapeutically effective dose is a total daily dose of the Equivalent Amount of Nalbuphine Free Base is about 6 mg to about 60 mg, about 6 mg to about 54 mg, about 6 mg, about 7 mg, about 6.25 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg of an Equivalent Amount of Nalbuphine Free Base, including any values or ranges therebetween, for the treatment of RCC.

[0077] In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 6 mg to about 54 mg a day for the treatment of RCC. In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 6.25 mg a day for the treatment of RCC. In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 12.5 mg a day for the treatment of RCC. In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 27 mg a day for the treatment of RCC. In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 54 mg a day for the treatment of RCC. In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 108 mg a day for the treatment of RCC. In embodiments, the total daily dose of the Equivalent Amount of Nalbuphine Free Base can be at least about 216 mg a day for the treatment of RCC.

[0078] In embodiments, the therapeutically effective dose is a total daily dose of about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base. In embodiments, the therapeutically effective dose is a total daily dose of about 9 mg of an Equivalent Amount of Nalbuphine Free Base. In embodiments, the therapeutically effective dose is a total daily dose of about 18 mg of an Equivalent Amount of Nalbuphine Free Base. In embodiments, the therapeutically effective dose is a total daily dose of about 27 mg of an Equivalent Amount of Nalbuphine Free Base. In embodiments, the therapeutically effective dose is a total daily doseAttorney Matter No.: TREV-016 / 01WO 318488-2310 of about 54 mg of an Equivalent Amount of Nalbuphine Free Base. In embodiments, the therapeutically effective dose is a total daily dose of about 108 mg of an Equivalent Amount of Nalbuphine Free Base.

[0079] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof; (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a).

[0080] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof; (b) administering the therapeutically effective dose for at least one week.

[0081] In embodiments, the daily dose of the nalbuphine is in a once or twice daily dose, and then titrated upward until the patient experiences satisfactory relief from the symptoms of RCC. In embodiments, the daily dose is titrated in increments ranging from about 6 mg to about 108 mg (e.g., about 6.25 mg, about 9 mg, about 12.5 mg, about 27 mg, about 54 mg, or about 108 mg of an Equivalent Amount of Nalbuphine Free Base) or about 6 mg to about 54 mg (e.g., about 6.25 mg, about 9 mg, about 12.5 mg, about 27 mg, or about 54 mg of an Equivalent Amount of Nalbuphine Free Base). In embodiments, the daily dose is titrated in one or more steps. In embodiments, the daily dosage is titrated by increasing a single daily dosage, or each dose of a twice-daily dosing regimen. In embodiments, the amount a dosage stepped for the multiple titration steps is the same. In embodiments, the dosages stepped for the multiple titration steps are different.

[0082] In embodiments, the titration is initiated with about 6.25 mg, about 9 mg, about 12.5 mg, about 15 mg, about 18 mg, about 27 mg, about 30 mg, about 54 mg, or about 60 mg of an Equivalent Amount of Nalbuphine Free Base once or twice daily. In embodiments, the nalbuphine is administered at an initial dose of about 6.25 mg of an Equivalent Amount of Nalbuphine Free Base once a day and then titrated to a therapeutically effective dose. In embodiments, the nalbuphine is administered at an initial dose of about 9 mg of an EquivalentAttorney Matter No.: TREV-016 / 01WO 318488-2310 Amount of Nalbuphine Free Base once a day and then titrated to a therapeutically effective dose. In embodiments, the nalbuphine is administered at an initial dose of about 12.5 mg of an Equivalent Amount of Nalbuphine Free Base once a day and then titrated to a therapeutically effective dose. In embodiments, the nalbuphine is administered at an initial dose of about 18 mg of an Equivalent Amount of Nalbuphine Free Base once a day and then titrated to a therapeutically effective dose. In embodiments, the nalbuphine is administered at an initial dose of about 27 mg of an Equivalent Amount of Nalbuphine Free Base once a day and then titrated to a therapeutically effective dose.

[0083] In embodiments, the nalbuphine is administered at an initial dose of about 27 mg of an Equivalent Amount of Nalbuphine Free Base once a day (QD) and then titrated to a therapeutically effective dose of about 108 mg twice daily (BID). In embodiments, the nalbuphine is administered at an initial dose of about 12.5 mg of an Equivalent Amount of Nalbuphine Free Base once a day (QD) and then titrated to a therapeutically effective dose of about 27 mg twice daily (BID). In embodiments, the nalbuphine is administered at an initial dose of about 9 mg of an Equivalent Amount of Nalbuphine Free Base once a day (QD) and then titrated to a therapeutically effective dose of about 54 mg twice daily (BID). In embodiments, the nalbuphine is administered at an initial dose of about 18 mg of an Equivalent Amount of Nalbuphine Free Base once a day (QD) and then titrated to a therapeutically effective dose of about 54 mg twice daily (BID). In embodiments, the nalbuphine is administered at an initial dose of about 27 mg of an Equivalent Amount of Nalbuphine Free Base once a day (QD) and then titrated to a therapeutically effective dose of about 54 mg twice daily (BID). In embodiments, the nalbuphine is administered at an initial dose of about 54 mg of an Equivalent Amount of Nalbuphine Free Base once a day (QD) and then titrated to a therapeutically effective dose of about 54 mg twice daily (BID).

[0084] In embodiments, doses are adjusted in about 10 mg, about 15 mg, or about 30 mg of an Equivalent Amount of Nalbuphine Free Base increments every 1 to 4 days. In embodiments, the Patients self-titrate to effect over from about 7 days to about 30 days (for example, from about 12 days to about 20 days) to a dose that provides adequate relief from RCC and minimizes adverse reactions. In embodiments, the titration is conducted for at least about one week, 2 weeks, 3 weeks, 4 weeks or 5 weeks until a steady state is achieved in the patient. In embodiments, the titration is conducted for at least 3 days. In embodiments, the titration is conducted for at least 5 days. In embodiments, the titration is conducted for at least 6 days. InAttorney Matter No.: TREV-016 / 01WO 318488-2310 embodiments, the titration is conducted for at least 7 days. In embodiments, the titration is conducted for at least 10 days. In embodiments, the titration is conducted for at least 14 days.

[0085] In embodiments, patients are provided initially with 9 mg, 15 mg, 18 mg, 27 mg, 30 mg, 54 mg, or 60 mg tablets to self-titrate to effect up to about 54 mg, about 60 mg, about 90 mg, about 108 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or about 480 mg of an Equivalent Amount of Nalbuphine Free Base once or twice a day. In embodiments, nalbuphine extended release (ER) tablet containing about 27 mg of nalbuphine (equivalent to 30 mg nalbuphine HCl) is provided to the patient to self-titrate up to a total daily dose of about 54 mg, about 108 mg, or about 216 mg of an Equivalent Amount of Nalbuphine Free Base. In embodiments, nalbuphine extended release (ER) tablet containing about 54 mg of nalbuphine (equivalent to 60 mg nalbuphine HCl) is provided to the patient to self-titrate up to a total daily dose of about 108 mg, or about 216 mg of an Equivalent Amount of Nalbuphine Free Base.

[0086] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt thereof; and (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a), wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0087] In embodiments, the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

[0088] In embodiments, the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

[0089] In embodiments, the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0090] In embodiments, the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0091] In embodiments, the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

[0092] In embodiments, the therapeutically effective dose in Step (b) is administered once a day. In embodiments, the therapeutically effective dose in Step (b) is administered twice a day.

[0093] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising:Attorney Matter No.: TREV-016 / 01WO 318488-2310 (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt thereof; and (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a), wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

[0094] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt thereof; andAttorney Matter No.: TREV-016 / 01WO 318488-2310 (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a), wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

[0095] In embodiments, the present disclosure provides a method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof; (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a),Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0096] wherein the therapeutically effective dose is a daily dose of about 6 mg to about 54 mg of an Equivalent Amount of Nalbuphine Free Base:

[0097] In embodiments, the therapeutically effective dose in Step (b) is administered once a day. In embodiments, the therapeutically effective dose in Step (b) is administered twice a day.

[0098] In embodiments, the therapeutically effective dose is administered to the patient for at least 3 days, at least 5 days, at least one week, at least two weeks, at least three weeks, at least four weeks, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least a year, at least two years or longer, including any values or ranges therebetween.

[0099] In embodiments, the therapeutically effective dose (e.g., the dose of Step (b)) is administered to the patient for at least one week. In embodiments, the therapeutically effectiveAttorney Matter No.: TREV-016 / 01WO 318488-2310 dose is administered to the patient for at least 8 weeks, 10 weeks, 12 weeks, 24 weeks or 52 weeks. In embodiments, the therapeutically effective dose is administered to the patient for at least one week. In embodiments, the therapeutically effective dose is administered to the patient for at least 4 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks or 52 weeks.

[0100] In embodiments, the methods of the present disclosure provide therapeutically effective blood plasma levels of nalbuphine for treating patients with RCC. Blood plasma levels of nalbuphine may be expressed using pharmacokinetic parameters that are known to those skilled in the art, such as steady state plasma levels, AUC, Cmax and Cmin. Blood plasma levels of nalbuphine are described in U.S. Publication Nos. 2014 / 0171459, 2014 / 0350042, 2015 / 0359789, and 2017 / 0216277, which are hereby incorporated by reference in their entirety.

[0101] In embodiments, the present methods provide steady state plasma levels of nalbuphine that correlate to one or more statistically significant therapeutic effects. In embodiments, the therapeutically effective steady state plasma level of nalbuphine provided by the methods of the present disclosure range from about 10 ng / mL to about 80 ng / mL, including about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL and about 80 ng / mL, including all ranges there between. In embodiments, the therapeutically effective steady state plasma level of nalbuphine is provided by administering a daily dose of nalbuphine or a pharmaceutically acceptable salt or ester is about 216 mg of an Equivalent Amount of Nalbuphine Free Base once daily. In embodiments, the therapeutically effective steady state plasma level of nalbuphine is provided by administering about 108 mg of an Equivalent Amount of Nalbuphine Free Base twice a day. In embodiments, the therapeutically effective steady state plasma level of nalbuphine is provided by administering a daily dose of about 54 mg of an Equivalent Amount of Nalbuphine Free Base.

[0102] In embodiments, the nalbuphine, and the metabolites include glucuronides (most likely on the phenol and cyclohexane rings), two hydroxylated nalbuphine metabolites (on the cyclobutane ring) and three ketones (hydroxylation of the cyclobutane ring, followed by oxidation to a carbonyl or followed by ring opening of the cyclobutane ring). In embodiments, the nalbuphine metabolites include nalbuphine 3-glucuronide or 6-glucuronide. In embodiments, the nalbuphine metabolites include triple hydroxylated nalbuphine, mono- hydroxylated nalbuphine, or mono-glucuronidated nalbuphine or a combination thereof. In embodiments, the one or more metabolites of the nalbuphine do not have detectable antitussiveAttorney Matter No.: TREV-016 / 01WO 318488-2310 activity. In embodiments, one or more of the metabolites of nalbuphine exhibit anti- antitussive activity.

[0103] In embodiments wherein one or more metabolites of nalbuphine exhibit antitussive activity, the dosing regimen of the nalbuphine may be adjusted and / or titrated as described hereinabove depending on the clearance rate of the one or more metabolites exhibiting antitussive activity. In embodiments, the dosage adjustment and / or titration of the dosage of the nalbuphine prevents accumulation of either the nalbuphine and / or one or more metabolites, which can also exhibit antitussive activity, to avoid toxicity effects in a patient treated with nalbuphine.

[0104] In embodiments, the nalbuphine is completely metabolized (e.g., about 100% metabolized). In embodiments, the nalbuphine is not completely metabolized (e.g., less than about 100% metabolized). For example, in embodiments, the nalbuphine is about 100% metabolized, about 95% metabolized, about 90% metabolized, about 85% metabolized, about 80% metabolized, about 75% metabolized, about 70% metabolized, about 65% metabolized, about 60% metabolized, about 55% metabolized, about 50% metabolized, about 45% metabolized, about 40% metabolized, about 35% metabolized, about 25% metabolized, about 20% metabolized, about 15% metabolized, about 10% metabolized, about 5% metabolized, about 1% metabolized, or about 0% metabolized. In embodiments, the amount of dialyzable agent can be measured or monitored by the level of accumulation, e.g., blood plasma level of the nalbuphine or one or more of its metabolites.

[0105] In embodiments, reduction of cough in patients with RCC can be determined by various methods known in the art. In embodiments, the effectiveness of a dosage regimen can be determined by assessing a Cough Severity Visual Analogue Scale (CS-VAS), cough severity Numerical Rating Scale (CS-NRS) test value, a Leicester Cough Questionnaire (LCQ) score, daytime (or awake) cough frequency measured using cough count monitor device, 24-hour cough frequency measured using cough count monitor device, night-time (or sleep) cough frequency measured using cough count monitor device, cough quality of life questionnaire (CQLQ©) total value, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), Patient-Reported Change in Cough Frequency (PR-CF), PROMIS Item Bank v1.0-Fatigue Short Form 7a scale, St. George’s Questionnaire for the IPF population (SGRQ-I) total score, EXAcerbation of Chronic pulmonary disease Tool (EXACT®) version 1.1 e-diary tool total score, Evaluating Respiratory Symptoms,(E-RSTM) daily diary (the E-RSTMis a 11 respiratory symptoms item derivative instrument of theAttorney Matter No.: TREV-016 / 01WO 318488-2310 EXACT® tool) cough subscale score, chest symptoms subscale score as well as the E-RSTMtotal score or any combination thereof. In embodiments, the effectiveness of a dosage regimen can be determined by evaluation via a 24-hour cough frequency measured using cough count monitor device as a primary efficacy endpoint in association with secondary efficacy endpoints such as a Leicester Cough Questionnaire score (LCQ) or Cough Severity Visual Analogue Scale (CS-VAS).

[0106] In embodiments, the dosing frequency and dose amount per administration of the nalbuphine are selected to provide therapeutic effects for the treatment of chronic cough. In embodiments, the dosing frequency and dose amount per administration of nalbuphine are selected to provide therapeutic effects for the treatment of chronic cough selected from RCC and unexplained chronic cough.

[0107] In embodiments, the dosing frequency and dose amount per administration of nalbuphine are selected to provide therapeutic effects for the treatment of RCC. In embodiments, the dosing frequency and dose amount per administration of nalbuphine are selected to provide therapeutic effects for the treatment of RCC.

[0108] In embodiments, the substantial reduction in RCC provided by the methods of the present disclosure requires treatment for a specified time interval (e.g., at least one week) before the patient experiences substantial reduction of RCC (i.e., there is an induction period before the patient experiences a substantial reduction in RCC). In embodiments, after treatment for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks or at least eight weeks, the patient experiences a substantial reduction of RCC compared to prior to the treatment. In embodiments, after treatment for at least one week the patient experiences a substantial reduction of RCC compared to prior to the treatment. In embodiments, the substantial reduction in RCC may be expressed using any of the methods described herein (for example, decline in evaluating 24-hour cough frequency compared to prior to the treatment, reduction in daytime cough frequency measured using cough count monitor device compared to prior to the treatment).

[0109] In embodiments, after the treatment the patient experiences a substantial reduction of RCC that is characterized by at least a one-point improvement in the Clinical Global Impression of Change (CGIC) compared to prior to the treatment. In embodiments, the reduction of RCC symptoms is characterized by an improvement in CGIC value ranging fromAttorney Matter No.: TREV-016 / 01WO 318488-2310 about 1.0 to about 3.0 points, for example, about 1.0 point, about 2.0 point, about 3.0 points, compared to prior to the treatment.

[0110] In embodiments, after the treatment the patient experiences a substantial reduction of RCC that is characterized by at least 10% improvement in the Patient Global Impression of Change (PGIC) compared to prior to the treatment. In embodiments, the reduction of RCC symptoms is characterized by an improvement in PGIC value by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, compared to prior to the treatment.

[0111] In embodiments, after the treatment the patient experiences a substantial reduction of RCC that is characterized by at least 10% improvement in the Patient-Reported Change in Cough Frequency (PR-CF) compared to prior to the treatment. In embodiments, the reduction of RCC symptoms is characterized by an improvement in PR-CF value by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, compared to prior to the treatment.

[0112] In embodiments, the reduction of cough is characterized by a decline in 24-hour cough frequency ranging from 10% to about 100%, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 30% reduction in the 24-hour cough frequency measured using cough count monitor device compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 50% reduction in the 24-hour cough frequency measured using cough count monitor device compared to prior to the treatment.

[0113] In embodiments, the reduction of cough is characterized by an increase in the total score on the patient’s Leicester Cough Questionnaire (LCQ) ranging from 10% to about 100%, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 30% increase in the total score on the patient’s LCQ compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 50% increase in the total score on the patient’s LCQ compared to prior to the treatment. In embodiments, after the treatment theAttorney Matter No.: TREV-016 / 01WO 318488-2310 patient experiences a substantial improvement in health status related to reduction in cough frequency that is characterized by at least about 1.0 point improvement in the total score on the patient’s Leicester Cough Questionnaire (LCQ) score compared to prior to the treatment. In embodiments, the improvement in health status related to reduction of cough frequency is characterized by an improvement in LCQ score ranging from about 0.5 to about 2.0 points, for example, about 0.5 points, about 1.0 point, about 1.5 points and about 2.0 points compared to prior to the treatment. In embodiments, the improvement in health status related to reduction of cough frequency is characterized by an improvement in any of the three LCQ domains (physical, psychological or social) score ranging from about 0.5 to about 2.0 points, for example, at least about 0.5 points, at least about 1.0 point, at least about 1.5 points and at least about 2.0 points compared to prior to the treatment.

[0114] In embodiments, after said treating the patient experiences a reduction of cough that is characterized by improvement in the total score on the patient’s LCQ score of at least about 1 unit, at least about 2 units, at least about 3 units, at least about 4 units, or at least about 5 units, compared to prior to the treatment. In embodiments, after said treating the patient experiences a reduction of cough that is characterized by at least 1 unit improvement in the total score on the patient’s LCQ score compared to prior to the treatment. In embodiments, after said treating the patient experiences a reduction of cough that is characterized by at least 4 unit improvement in the total score on the patient’s LCQ score compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least a one-point reduction in the cough severity Visual Analogue Scale (CS-VAS) value compared to prior to the treatment. In embodiments, the reduction of cough is characterized by a decline in CS-VAS value ranging from at least about 1.0 to about 9.0 points, for example, at least about 1.0 point, about 2.0 point, about 3.0 points, about 4.0 points, about 5.0 points, about 6.0 points, about 7.0 points, about 8.0 points, about 9.0 points, and about 10.0 points compared to prior to the treatment. In embodiments, the reduction of cough is characterized by a decline in CS-VAS value ranging from at least about 10 mm to about 90 mm, for example, at least about 10 mm, about 20 mm, about 30 mm, about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, about 90 mm, and about 10 mm compared to prior to the treatment. In embodiments, after said treating the patient experiences a reduction of cough severity that is characterized by at least 10 mm reduction in the Cough Severity Visual Analogue Scale (CS-VAS) score compared to prior to the treatment. In embodiments, after said treating the patient experiences a reduction of cough severity that is characterized by at leastAttorney Matter No.: TREV-016 / 01WO 318488-2310 30 mm reduction in the Cough Severity Visual Analogue Scale (CS-VAS) score compared to prior to the treatment.

[0115] In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least a one-point reduction in the Cough Severity Numeric Rating Scale (CS-NRS) value compared to prior to the treatment. In embodiments, the reduction of cough is characterized by a decline in CS-NRS value ranging from at least about 1.0 to about 9.0 points, for example, at least about 1.0 point, about 2.0 point, about 3.0 points, about 4.0 points, about 5.0 points, about 6.0 points, about 7.0 points, about 8.0 points, about 9.0 points, and about 10.0 points compared to prior to the treatment.

[0116] In embodiments, the reduction of cough is characterized by a decline in awake cough frequency ranging from 10% to about 100%, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 30% reduction in awake cough frequency measured using cough count monitor device compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 50% reduction in awake cough frequency measured using cough count monitor device compared to prior to the treatment.

[0117] In embodiments, the reduction of cough is characterized by a decline in sleep cough frequency ranging from 10% to about 100%, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 30% reduction in sleep cough frequency measured using cough count monitor device compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial reduction of cough that is characterized by at least about a 50% reduction in sleep cough frequency measured using cough count monitor device compared to prior to the treatment.

[0118] In embodiments, after the treatment the patient experiences a substantial improvement in health-related quality of life as a result of reduction in cough frequency that is characterized by at least 1 point improvement in cough quality of life questionnaire (CQLQ©) total value compared to prior to the treatment. In embodiments, the improvement in health-related quality of life is characterized by an improvement in CQLQ©total value ranging from about 1.0 toAttorney Matter No.: TREV-016 / 01WO 318488-2310 about 6.0 points, for example, about 1.0 point, about 2.0 point, about 3.0 point, about 3.5 points, about 4.0 points, about 4.5 points, about 5.0 points, about 5.5 points, and about 6.0 points compared to prior to the treatment. In embodiments, after the treatment the patient experiences a substantial improvement in health-related quality of life as a result of reduction in cough frequency that is characterized by at least 2 points improvement in any of the six CQLQ©subscales (physical complaints, psychosocial issues, functional abilities, emotional well-being, extreme physical complaints or personal safety fears) compared to prior to the treatment. In embodiments, the improvement in health-related quality of life is characterized by an improvement in a CQLQ©subscale score ranging from about 3.0 to about 6.0 points, for example, about 6.0 points, about 5.0 points, about 4.0 points, about 3.0 points, compared to prior to the treatment.

[0119] In embodiments, after the treatment the patient experiences a substantial improvement determined by changes in the patient-reported cough frequency (PR-CF), PGI-S (patient global impression of severity), PGI-C (patient global impression of change), cough (patient global impression of severity and change for cough), CGI-S (clinical global impression of severity), and / or CGI-C (clinicians global impression of severity and change) by at least about 1.0 point, for example, about 1.0 point, about 2.0 point, about 3.0 point, about 3.5 points, about 4.0 points, about 4.5 points, about 5.0 points, about 5.5 points, or about 6.0 points compared to prior to the treatment.

[0120] In embodiments, the patient experiences a substantial improvement within 3-7 days of treatment. In embodiments, the patient experiences a substantial improvement within 5 days of treatment. In embodiments, the patient experiences a substantial improvement within 4 days of treatment. In embodiments, the patient experiences a substantial improvement within 3 days of treatment.

[0121] The embodiments described herein should be understood to be illustrative of the present disclosure, and should not be construed as limiting. On the contrary, the present disclosure embraces alternatives and equivalents thereof, as embodied by the appended claims. Each reference disclosed herein is incorporated by reference herein in its entirety.

[0122] The following non-limiting examples illustrate various aspects of the present invention.

[0123] NUMBERED EMBODIMENTS 1. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereofAttorney Matter No.: TREV-016 / 01WO 318488-2310 to a patient in need thereof, wherein the patient’s cough frequency is from 10 to 19 coughs per hour prior to treatment. 2. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient’s cough frequency is at least 20 coughs per hour prior to treatment. 3. The method of embodiment 1 or 2, wherein the patient has a Cough Severity Visual Analogue Scale (CS-VAS) score of about 40 mm prior to treatment. 4. The method of any one of embodiments 1-3, wherein a total daily dose of about 12.5 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered. 5. The method of any one of embodiments 1-4, wherein a total daily dose of about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered. 6. The method of any one of embodiments 1-4, wherein about 6.25 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 7. The method of any one of embodiments 1-4 and 6, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 8. The method of any one of embodiments 1-4 and 6, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 9. The method of any one of embodiments 1-4 and 6, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 10. The method of any one of embodiments 1-4, wherein about 12.5 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 11. The method of any one of embodiments 1-4 and 10, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 12. The method of any one of embodiments 1-4 and 10, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 13. The method of any one of embodiments 1-4 and 10, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 14. The method of any one of embodiments 1-4 and 10, wherein about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.Attorney Matter No.: TREV-016 / 01WO 318488-2310 15. A method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt thereof; and (b) administering the therapeutically effective dose to the patient for at least one wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):16. The method of embodiment 15, wherein the administering in Step (b). is for at least 8 weeks, 10 weeks, 12 weeks, 24 weeks or 52 weeks.Attorney Matter No.: TREV-016 / 01WO 318488-2310 17. The method of embodiment 15 or 16, wherein the nalbuphine is administered at an initial dose of about 12.5 mg once a day and then titrated to a therapeutically effective dose. 18. The method of embodiment 15 or 16, wherein the nalbuphine is administered at an initial dose of about 27 mg once a day and then titrated to a therapeutically effective dose. 19. The method of embodiment 15, wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):20. A method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof;Attorney Matter No.: TREV-016 / 01WO 318488-2310 (b) administering the therapeutically effective dose for at least 1 week, wherein the therapeutically effective dose is a daily dose of about 6 mg to about 54 mg of an Equivalent Amount of Nalbuphine Free Base. 21. The method of embodiment 20, wherein about 6.25 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 22. The method of embodiment 20, wherein about 12.5 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 23. The method of embodiment 20, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 24. The method of embodiment 20, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 25. The method of embodiment 20, wherein the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-231026. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof once daily. 27. The method of embodiment 26, wherein the once daily dose is administered at nighttime. 28. The method of embodiment 26 or 27, wherein about 6 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 29. The method of any one of embodiments 26-28, wherein about 6.25 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 30. The method of any one of embodiments 26-28, wherein about 12.5 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 31. The method of any one of embodiments 26-28, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 32. The method of any one of embodiments 26-28, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 33. The method of any one of embodiments 26-28, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 34. The method of any one of embodiments 26-28, wherein about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 35. The method of any one of embodiments 1-34, wherein after said treating the patient experiences a substantial reduction in cough compared to prior to the treatment. 36. The method of any one of embodiments 1-35, wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 30% reduction in the 24- hour cough frequency measured using cough count monitor device compared to prior to the treatment.Attorney Matter No.: TREV-016 / 01WO 318488-2310 37. The method of any one of embodiments 1-36, wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 50% reduction in the 24- hour cough frequency measured using cough count monitor device compared to prior to the treatment. 38. The method of any one of embodiments 1-37, wherein after said treating the patient experiences a reduction of cough that is characterized by an at least one point improvement in the total score on the patient’s Leicester Cough Questionnaire (LCQ) score compared to prior to the treatment. 39. The method of any one of embodiments 1-38, wherein after said treating the patient experiences a reduction of cough severity that is characterized by at least 10 unit improvement in the Cough Severity Visual Analogue Scale (CS-VAS) score compared to prior to the treatment. 40. The method of any one of embodiments 1-39, wherein after said treating the patient experiences a reduction in cough that is characterized by at least a 30%-50% reduction in awake cough frequency measured using cough count monitor device compared to prior to the treatment. 41. The method of any one of embodiments 1-40, wherein after said treating the patient experiences a reduction of cough that is characterized by at least a 30%-50% reduction in sleep cough frequency measured using cough count monitor device compared to prior to the treatment. 42. The method of any one of embodiments 1-41, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride. 43. The method of any one of embodiments 1-42, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is in the form of an extended release oral dosage form.

[0124] NUMBERED EMBODIMENTS II 1. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient’s cough frequency is from 10 to 19 coughs per hour prior to treatment.Attorney Matter No.: TREV-016 / 01WO 318488-2310 2. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient’s cough frequency is at least 20 coughs per hour prior to treatment. 3. The method of embodiment 1 or 2, wherein the patient has a Cough Severity Visual Analogue Scale (CS-VAS) score of about 40 mm prior to treatment. 4. The method of any one of embodiments 1-3, wherein a total daily dose of about 12.5 mg to about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered. 5. The method of any one of embodiments 1-4, wherein a total daily dose of about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered. 6. The method of any one of embodiments 1-4, wherein about 6.25 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 7. The method of any one of embodiments 1-4 and 6, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 8. The method of any one of embodiments 1-4 and 6, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 9. The method of any one of embodiments 1-4 and 6, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily. 10. A method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt thereof; and (b) administering the therapeutically effective dose to the patient for at least one week, wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-231011. The method of embodiment 10, wherein the administering in Step (b). is for at least 8 weeks, 10 weeks, 12 weeks, 24 weeks or 52 weeks. 12. The method of embodiment 10 or 11, wherein the nalbuphine is administered at an initial dose of about 12.5 mg once a day and then titrated to a therapeutically effective dose. 13. The method of embodiment 10 or 11, wherein the nalbuphine is administered at an initial dose of about 27 mg once a day and then titrated to a therapeutically effective dose. 14. The method of embodiment 10, wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-231015. A method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof; (b) administering the therapeutically effective dose for at least 1 week, wherein the therapeutically effective dose is a daily dose of about 6 mg to about 54 mg of an Equivalent Amount of Nalbuphine Free Base. 16. The method of embodiment 15, wherein about 6.25 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 17. The method of embodiment 15, wherein about 12.5 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 18. The method of embodiment 15, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b). 19. The method of embodiment 15, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered in Step (b).Attorney Matter No.: TREV-016 / 01WO 318488-2310 20. The method of embodiment 15, wherein the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):21. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof once daily. 22. The method of embodiment 21, wherein the once daily dose is administered at nighttime. 23. The method of embodiment 21 or 22, wherein about 6 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.Attorney Matter No.: TREV-016 / 01WO 318488-2310 24. The method of any one of embodiments 21-23, wherein about 6.25 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 25. The method of any one of embodiments 21-23, wherein about 12.5 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 26. The method of any one of embodiments 21-23, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 27. The method of any one of embodiments 21-23, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 28. The method of any one of embodiments 21-23, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 29. The method of any one of embodiments 21-23, wherein about 216 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily. 30. The method of any one of embodiments 1-29, wherein after said treating the patient experiences a substantial reduction in cough compared to prior to said treatment. 31. The method of any one of embodiments 1-30, wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 30% reduction in the 24- hour cough frequency measured using cough count monitor device compared to prior to the treatment. 32. The method of any one of embodiments 1-31, wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 50% reduction in the 24- hour cough frequency measured using cough count monitor device compared to prior to the treatment. 33. The method of any one of embodiments 1-32, wherein after said treating the patient experiences a reduction of cough that is characterized by an at least one point increase in the total score on the patient’s Leicester Cough Questionnaire (LCQ) score compared to prior to the treatment. 34. The method of any one of embodiments 1-33, wherein after said treating the patient experiences a reduction of cough severity that is characterized by at least 10 unit improvement in the Cough Severity Visual Analogue Scale (CS-VAS) score compared to prior to the treatment.Attorney Matter No.: TREV-016 / 01WO 318488-2310 35. The method of any one of embodiments 1-34, wherein after said treating the patient experiences a reduction in cough that is characterized by at least a 30%-50% reduction in awake cough frequency measured using cough count monitor device compared to prior to the treatment. 36. The method of any one of embodiments 1-35, wherein after said treating the patient experiences a reduction of cough that is characterized by at least a 30%-50% reduction in sleep cough frequency measured using cough count monitor device compared to prior to the treatment. 37. The method of any one of embodiments 1-36, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride. 38. The method of any one of embodiments 1-37, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is in the form of an extended release oral dosage form. 39. The method of any one of embodiments 1-38, wherein after said treating the patient experiences at least one point reduction in the CS-VAS score within 3 days of treatment. 40. The method of any one of embodiments 1-39, wherein after said treating the patient experiences at least one point reduction in the CS-NRS score within 3 days of treatment. EXAMPLES Example 1. Nalbuphine ER Formulation

[0125] A 30 mg, 60 mg or 180 mg extended release (ER) nalbuphine tablet was prepared as follows: Nalbuphine HCl, mannitol, xanthan gum, locust bean gum and calcium sulfate dihydrate were added to a high shear mixer and dried mix at low speed. A granulating solution (water for injection or purified water) was introduced into the mixer at low speed. The wet granulation was granulated at high speed and dried in a fluid bed processor. The dried granules were milled and sized using a conventional mill. The milled granulation was transferred into a diffusion (tumble) mixer. Hydroxypropylcellulose and, when applicable, fumaric acid (180 mg formulations only) were added to the diffusion mixer and blended. Thereafter, magnesium stearate was added to the diffusion mixer and blended. The final blend was compressed using a rotary tablet press. Tablets may be coated with a non-functional Opadry white coating.Attorney Matter No.: TREV-016 / 01WO 318488-2310 Table 1 30 mg, 60 mg, 120 mg and 180 mg Extended Release Nalbuphine TabletAttorney Matter No.: TREV-016 / 01WO 318488-2310

[0126] The tablets were coated with a non-functional coat (Opadry II White).Attorney Matter No.: TREV-016 / 01WO 318488-2310 Table 2 Nalbuphine HCl ER Tablets, 30 mg, 60 mg, or 180 mg CompositionsAttorney Matter No.: TREV-016 / 01WO 318488-2310Example 2. A Phase 2a, Double-Blind, Randomized, Placebo-Controlled, Two-Period Crossover Efficacy and Safety of Nalbuphine for the Treat of Refractory Chronic Cough

[0127] The primary objective of this study was to evaluate the effect of nalbuphine (nalbuphine ER tablet formulation of Example 1, “NAL ER”) treatment on 24-hour cough frequency (coughs per hour). The primary endpoint was relative change from baseline in 24-hour coughAttorney Matter No.: TREV-016 / 01WO 318488-2310 frequency (coughs per hour) as assessed by objective cough monitoring at Day 21 for NAL ER compared with placebo.

[0128] The secondary objectives included to evaluate safety and tolerability of NAL ER in treating refractory chronic cough (RCC); and to evaluate relative change from baseline in 24- hour cough frequency (coughs per hour), awake cough frequency (coughs per hour), sleep cough frequency (coughs per hour), CS-VAS (cough severity visual analogue scale), LCQ (Leicester Cough Questionnaire), patient-reported cough frequency (PR-CF), PGI-S (patient global impression of severity), PGI-C (patient global impression of change), cough (patient global impression of severity and change for cough), CGI-S (clinical global impression of severity), and CGI-C (clinicians global impression of severity and change).

[0129] The secondary endpoints were as follows: adverse events, clinical laboratory assessments, vital signs, and physical examination summaries; ECG summaries; subjective opiate withdrawal scale (SOWS) daily summaries for the 14 days following the last dose of investigational product; relative change from baseline in 24-hour cough frequency (coughs per hour) at Days 7 and 14 for NAL ER compared with placebo; proportion of responders with 30%, 50% and 75% reduction in the 24-hour cough frequency at Days 7, 14, and 21 for NAL ER compared with placebo; relative change from baseline in awake cough frequency (coughs per hour) and sleep cough frequency at Days 7, 14, and 21 for NAL ER compared with placebo; change from baseline in the CS-VAS, LCQ, PR-CF, PGI-S, and PGI-C for NAL ER compared with placebo; proportion of PR-CF responders, with response defined as at least a one category improvement at Days 7, 14, and 21 for NAL ER compared with placebo; and change from baseline in the CGI-S and CGI-C at Day 21 for NAL ER compared with placebo.

[0130] The study enrolled subjects in a 1:1 ratio to subgroups of 10-19 coughs / hour (moderately severe) and 20 coughs / hour (severe). During the screening period, subjects were randomly assigned (1:1) to either i) NAL ER Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2; or ii) PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2. The 21-day treatment periods were separated by a 21-day washout period. NAL ER was titrated according to the dosing scheme as shown in Table A.Attorney Matter No.: TREV-016 / 01WO 318488-2310 Table A. NAL dosing Scheme

[0131] Study visits in each treatment period was at Day -1 for baseline cough assessments, and at Days 6, 13, and 20. At these time points, an electronic cough monitor was placed on the subject, which was worn for a 24- hour recording period to assess cough frequency. At the end of each recording session (Days 7, 14, and 21), the monitor was removed by the subject, and the subjects completed Patient Reported Outcomes (PROs) questionnaires in the diary. The schedule for visits and assessments is illustrated in FIG.1 and FIG.2.Attorney Matter No.: TREV-016 / 01WO 318488-2310

[0132] Inclusion Criteria

[0133] Subjects must meet all the following criteria to participate in the study. • Diagnosis of refractory chronic cough (RCC) for at least one year. • Chest radiograph or computed tomography (CT) of the thorax performed within the last 24 months or during the screening period not demonstrating any abnormality considered to be significantly contributing to the refractory chronic cough. • Score of 40 mm on the Cough Severity VAS at the Screening visit. • 24-hour objective cough frequency 10 or 20 coughs / hour based on cough monitor recording performed during the Screening Period, with results reviewed prior to baseline visit. Study will enroll subjects in a 1:1 ratio to subgroups of 10-19 coughs / hour and 20 coughs / hour. • FEV1 (forced expiratory volume in 1 second) or FVC (forced vital capacity) 60% predicted of normal, as determined by spirometry. • Males or females ages 18 years and older at the time of consent. • Willing and able to provide written informed consent, comply with study requirements and restrictions.

[0134] Exclusion Criteria

[0135] Subjects meeting any of the following criteria are not eligible for participation in the study. • Clinical diagnosis of sleep apnea and / or use of CPAP. • Upper or lower respiratory tract infection or change in pulmonary status in the last 6 weeks prior to the baseline visit. • History of bronchiectasis, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). • History of uncontrolled asthma. • Current smokers / vapers, individuals who have given up smoking 12 months, individuals using nicotine patches, gum, or any other nicotine supplements, or individuals with a smoking history of 20 pack-years or more.Attorney Matter No.: TREV-016 / 01WO 318488-2310 • Speech therapy / physiotherapy for RCC is acceptable if the subject has started the therapy at least 4 weeks prior to the baseline visit and continues the therapy through the Treatment Periods. It may not be started within 4 weeks of starting the study or for the duration of the study. • Cardiac Safety: Mean QTcF (the corrected QT interval by Fridericia) value of 3 centrally read screening Electrocardiograms (ECG) calculated as o 470ns if QRS <120ms or o 500ms in the presence of Right Bundle Branch Block (RBBB) and / or QRS 120ms.• Heart Rate <50 bpm or >100 bpm, as determined by vital signs pulse obtained over 30- 60 seconds o Subjects with a resting heart rate of <50 bpm will have it treated once after 5 minutes in the supine position, and if it remains <50 bpm during the repeat, they will be considered a screen failure. o Subjects with a rate >100 bpm should be considered a screen failure. • Kidney Function: Estimated glomerular filtration rate 44 mL / min / 1.73 m2at Screening. • Liver Function: Total Bilirubin >3mg / dl [>50 μmol / L] and Serum Albumin <2.8g / dl. • History of major psychiatric disorder. • History of substance abuse including excessive alcohol consumption. Alcohol consumption should be limited for the duration of study treatment. • Significant medical condition or other factors that may interfere with the subject’s ability to successfully complete the study. • Pregnant or lactating female subject. • Known intolerance (gastrointestinal, central nervous system symptoms), hypersensitivity, drug allergy following the use of an opioid drug. • Known hypersensitivity to nalbuphine or to NAL ER excipients. • Previous enrollment in a NAL ER clinical study.Attorney Matter No.: TREV-016 / 01WO 318488-2310 • Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent clinical trial.

[0136] Medication-related Exclusions • Use of opiates was prohibited within 14 days prior to the baseline visit. • Use of benzodiazepines, monoamine oxidase inhibitors (MAOIs) including methylene blue (methylthioninium chloride), the antibiotic linezolid, pregabalin, gabapentin, thalidomide, ACE inhibitors, cough suppressants, medications that affect serotonergic neurotransmission, strong inhibitors / inducers of the P450 isozymes were prohibited within 14 days prior to the baseline visit and for the duration of the study.

[0137] Efficacy Analysis

[0138] The treatment efficacy was analyzed by assessing relative change in 24-hour cough frequency (coughs per hour) using a mixed-effects repeated model. Secondary endpoints relating to relative change from baseline to 24-hour, awake, or sleep cough frequency were analyzed with the same mixed-effect model, with the response and baseline covariates adjusted accordingly. Comparisons between NAL ER and placebo for secondary efficacy endpoints that were not objective cough frequencies (CS-VAS, LCQ, single cough item, PGI, and CGI scales) were analyzed.

[0139] Responders were defined as those with 20%, 30%, 50%, or 75% reduction in 24- hour cough frequency from baseline at Days 7, 14, or 21.

[0140] The efficacy model was re-run separately for subjects whose baseline objective cough frequency was 10-19 coughs / hour and those whose baseline objective cough frequency was 20 coughs / hour. Summaries of cough frequency, including change and relative change from baseline, were provided by treatment arm for subjects of all baseline objective cough frequencies, and also were presented for the 10-19 coughs / hour and 20 coughs / hour subgroups separately.

[0141] Results and Discussion

[0142] Two treatment periods (Period 1 and Period 2) were conducted with washout period in between, and no significant period effect on cough frequency was observed. As shown in FIG. 3, treatment with 108 mg NAL ER administered twice daily (BID) resulted in a statistically significant reduction 57% (placebo adjusted) reduction in 24-hour cough frequency from baseline at Day 21. The treatment also demonstrated a rapid onset of action, with effectsAttorney Matter No.: TREV-016 / 01WO 318488-2310 observed as early as Day 7 at a lowest dose setting (FIG. 4). Placebo-adjusted relative reductions in cough frequency following NAL ER treatment were comparable between moderately severe and severe groups. At Day 21, consistent reduction in cough frequency were observed in both moderately severe (10-19 coughs / hr, reporting 68% reduction in 24-hourcoughs / hr from baseline, 75% placebo adjusted change) and severe ( 20 coughs / hr, reporting66% reduction in 24-hour coughs / hr from baseline, 51% placebo adjusted change) groups following 108 mg BID treatment, as shown in FIG.5.

[0143] NAL ER treatment exhibited a broad, clinically-meaningful response, with a significantly higher proportion of responders in the NAL ER treated group compared to placebo at 30%, 50%, and 75% response thresholds, as summarized in FIG.6.

[0144] Importantly, patient-reported outcomes were consistent with objective cough measures. Significant improvement in patient-perceived cough severity, measured by the cough severity visual analog scale (CS-VAS) was observed following 27 mg BID, 54 mg BID, and 108 mg BID treatment at Day 7, Day 14, and Day 21, respectively (FIG. 7). Patient-reported cough frequency (PR-CF) agreed with the objective primary endpoint result of cough frequency measurement: in response to “over the past 24 hours, how often did you cough?”, statistically significant reductions were reported across all doses (27 mg BID at Day 7, 54 mg BID at Day 14, and 108 mg BID at Day 21) (FIG.8).

[0145] At Day 21 following 108 mg BID NAL ER treatment, patient-reported cough-related quality of life significantly improved, as shown by 4.5-unit increase in LCQ total score from baseline compared to placebo (1.3-unit improvement is considered clinically important) (FIG.9). No treatment emergent serious adverse events were reported, demonstrating NAL ER’s excellent safety and efficacy profile.

[0146] Study Summary

[0147] A statistically-significant reduction in the objective 24-hour cough frequency of 67% from baseline a 57% on a placebo-adjusted basis (p<0.0001) was observed. The results demonstrated a statistically-significant reduction in 24-hour cough frequency of 66% in the severe cough (20+ coughs / hour) subgroup (p<0.0001) and 68% in the moderate cough (10-19 coughs / hour) subgroup (p<0.0001). 84% of participants had at least a 30% reduction in 24- hour cough frequency vs. baseline, as compared to 29% of placebo patients, a difference of 55% (p<0.0001). A statistically-significant reduction in 24-hour cough frequency, as measured by an objective cough monitor, was seen as early as Day 7 (27 mg BID) for the participantsAttorney Matter No.: TREV-016 / 01WO 318488-2310 (p<0.0001). Participants experienced a statistically-significant improvement in patient reported outcomes compared to placebo as early as Day 7 (27 mg BID) in the Cough Severity Visual Analog Scale and the Patient-Reported Cough Frequency. The safety results of the study were generally consistent with the known safety profile. The most common adverse events experienced included: constipation, nausea, somnolence, headache, dizziness, and fatigue and there were no treatment emergent serious adverse events. Example 3. Efficacy and Safety of Nalbuphine for the Treatment of Refractory Chronic Cough with Extended Titration Period

[0148] Efficacy and safety of Nalbuphine (nalbuphine ER tablet formulation of Example 1, “NAL ER”) treatment will be assessed. The titration dosing regimens of NAL ER are summarized in Tables B-C. Table B. NAL titration dosing schemeAttorney Matter No.: TREV-016 / 01WO 318488-2310Table C. NAL titration dosing scheme

[0149] RCC patients who have previously received standard-of-care therapy and experienced treatment failure will be allowed to participate in the study (subject to eligibility review during the screening phase).

[0150] The treatment efficacy will be analyzed by assessing relative change in 24-hour cough frequency (coughs per hour) using a mixed-effects repeated model; relating to relative change from baseline to 24-hour, awake, or sleep cough frequency were analyzed with the same mixed- effect model; CS-VAS, LCQ, single cough item, PGI, and / or CGI scales.

Claims

Attorney Matter No.: TREV-016 / 01WO 318488-2310 CLAIMS 1. A method of treating refractory chronic cough (RCC) in a patient in need thereof, comprising: (a) titrating to a therapeutically effective dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof; (b) administering a therapeutically effective dose once a day or twice a day after the titration Step (a), wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

2. The method of claim 1, wherein the therapeutically effective dose is a total daily dose of about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base.

3. The method of claim 1 or 2, wherein the therapeutically effective dose is a total daily dose of about 54 mg of an Equivalent Amount of Nalbuphine Free Base.

4. The method of claim 1 or 2, wherein the therapeutically effective dose is a total daily dose of about 108 mg of an Equivalent Amount of Nalbuphine Free Base.Attorney Matter No.: TREV-016 / 01WO 318488-2310 5. The method of claim 4, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily in Step (b).

6. The method of any one of claims 1-5, wherein the administering in Step (b) is for at least 4 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, or 52 weeks.

7. The method of any one of claims 1-6, wherein the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

8. The method of any one of claims 1-6, wherein the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):Attorney Matter No.: TREV-016 / 01WO 318488-23109. The method of any one of claims 1-6, wherein the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

10. The method of any one of claims 1-9, the nalbuphine is administered at an initial dose of about 9 mg once a day and then titrated to a therapeutically effective dose.

11. The method of any one of claims 1-9, the nalbuphine is administered at an initial dose of about 18 mg once a day and then titrated to a therapeutically effective dose.

12. The method of any one of claims 1-9, the nalbuphine is administered at an initial dose of about 27 mg once a day and then titrated to a therapeutically effective dose.Attorney Matter No.: TREV-016 / 01WO 318488-2310 13. The method of claim 1, wherein the titrating in Step (a) comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base):

14. The method of any one of claims 1-4 and 6-13, wherein the therapeutically effective dose in Step (b) is administered once a day.

15. The method of any one of claims 1-13, wherein the therapeutically effective dose in Step (b) is administered twice a day.Attorney Matter No.: TREV-016 / 01WO 318488-2310 16. A method of treating refractory chronic cough (RCC) comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to a patient in need thereof once daily for at least one week.

17. The method of claim 16, wherein the once daily dose is administered at nighttime.

18. The method of claim 16 or 17, wherein about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

19. The method of any one of claims 16-18, wherein about 9 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

20. The method of any one of claims 16-18, wherein about 18 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

21. The method of any one of claims 16-18, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

22. The method of any one of claims 16-18, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

23. The method of any one of claims 16-18, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

24. A method of treating refractory chronic cough (RCC) in a patient who has received and failed at least one prior RCC standard-of-care therapy, comprising orally administering a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof to the patient.Attorney Matter No.: TREV-016 / 01WO 318488-2310 25. The method of claim 24, wherein the prior RCC standard-of-care therapy comprises treatment with gefapixant, camlipixant, orvepitant, serlopitant, albuterol, levalbuterol, ipratropium, epinephrine, beclomethasone, budesonide, ciclesonide, fluticasone, mometasone, salmetrerol, lormoterol, vilanterol, umeclidinium, montelukast, zafirlukast, omalizumab, mepolizumb, benralizumab, reslizumab, duplilumab, tezepelumab, prednisone, methylpresdnisolone, prednisolone, calcium carbonate, magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, famotidine, cimetidine, nizatidine, ranitidine, omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, vonoprazan, metoclopramide, domperidone, phenylephrine, pseudoephedrine, doxylamine, fluticasone, triamcinolone, loratadine, cetirizine, fexofenadine, diphenhydramine, chlorpheniramine, azelastine, olopatadine, oxymetazoline, amitriptyline, gabapentin, pregabalin, tramadol, nortriptyline, baclofen, duloxetine, topiramate, morphine, codeine, hydrocodone, hydromorphone, fentanyl, oxycodone, pentazocine, butorphanol, dihydrocodeine, diamorphine, buprenorphine, dextromethorphan, menthol, benzonatate, cromolyn sodium, diplatinum, lidocaine, thalidomide, ifenprodil, or AX-8, or a combination thereof.

26. The method of claim 24 or 25, wherein the therapeutically effective dose is a total daily dose of about 9 mg to about 108 mg of an Equivalent Amount of Nalbuphine Free Base.

27. The method of any one of claims 24-26, wherein a total daily dose of about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered.

28. The method of any one of claims 24-26, wherein a total daily dose of about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered.

29. The method of claim 28, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered twice daily.

30. The method of any one of claims 22-24, wherein about 9 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.Attorney Matter No.: TREV-016 / 01WO 318488-2310 31. The method of any one of claims 24-26, wherein about 18 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

32. The method of any one of claims 24-26, wherein about 27 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

33. The method of any one of claims 24-26, wherein about 54 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

34. The method of any one of claims 24-26, wherein about 108 mg of an Equivalent Amount of Nalbuphine Free Base is administered once daily.

35. The method of any one of claims 30-34, wherein the once daily dose is administered at nighttime.

36. The method of any one of claims 1-35, wherein after said treating the patient experiences a substantial reduction in cough compared to prior to the treatment.

37. The method of any one of claims 1-36, wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 30% reduction in the 24- hour cough frequency measured using cough count monitor device compared to prior to the treatment.

38. The method of any one of claims 1-37, wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 50% reduction in the 24- hour cough frequency measured using cough count monitor device compared to prior to the treatment.Attorney Matter No.: TREV-016 / 01WO 318488-2310 39. The method of any one of claims 1-38, wherein after said treating the patient experiences a reduction of cough that is characterized by at least one unit improvement in the total score on the patient’s Leicester Cough Questionnaire (LCQ) score compared to prior to the treatment.

40. The method of any one of claims 1-39, wherein after said treating the patient experiences a reduction of cough severity that is characterized by at least 10 mm reduction in the Cough Severity Visual Analogue Scale (CS-VAS) score compared to prior to the treatment.

41. The method of any one of claims 1-40, wherein after said treating the patient experiences a reduction in cough that is characterized by at least a 30%-50% reduction in awake cough frequency measured using cough count monitor device compared to prior to the treatment.

42. The method of any one of claims 1-41, wherein after said treating the patient experiences a reduction of cough that is characterized by at least a 30%-50% reduction in sleep cough frequency measured using cough count monitor device compared to prior to the treatment.

43. The method of any one of claims 1-42, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride.

44. The method of any one of claims 1-43, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is in the form of an extended-release oral dosage form.

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