Method and device for treating chronic renal disease-associated pruritus

Abstract

To provide a method and a device for treating chronic renal disease-associated pruritus.SOLUTION: The invention relates to an effective method for treating chronic renal disease-associated pruritus. More specifically, the method includes transmucosally administering nalmefene in order to treat chronic renal disease-associated pruritus and cholestatic pruritus and / or prurigo nodularis. Nalmefene is arranged on a single-layer film including at least two separate domains. The film can include a first separate domain containing approximately 50 to 100 wt.% of polymer matrix, and a second separate domain can include nalmefene or pharmaceutically acceptable nalmefene salt.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 747,506, filed October 18, 2018, the entire contents of which are hereby incorporated by reference herein.

[0002] The presently disclosed subject matter relates to methods and devices for treating pruritus associated with chronic kidney disease. Specifically, the presently disclosed subject matter includes a transmucosal film composition comprising nalmefene that can be administered bucally or sublingually to a subject in need of treatment. [Background technology]

[0003] Pruritus occurs in many diseases and conditions, including chronic kidney disease. In particular, chronic kidney disease-associated pruritus is common in patients suffering from chronic renal insufficiency, occurring in approximately 20% to 50% of patients. As a result, more than 4.1 million patients in the United States suffer from pruritus associated with chronic kidney disease. 1、2 The presence of pruritus is associated with poor quality of life, insufficient sleep, depression, and an adjusted risk of death that is up to 37% greater than patients with mild or no pruritus. 3 In addition, patients often have prurigo nodularis. 4、5 A skin disease characterized by inflammatory, scaly, and peeling nodules and lesions 6 Mild forms of pruritus and prurigo nodularis are commonly treated with corticosteroids and antihistamines, but such drugs are relatively ineffective in moderate and / or severe forms of chronic pruritus in both cholestatic (liver) and uremic (renal) patients. 7 As a result, clinicians commonly use a variety of off-label medications for treatment. 8Approximately 18% of patients suffering from chronic kidney disease experience severe pruritus that cannot be managed by current treatment methods. Furthermore, there are no approved products in the United States for treating chronic kidney disease-associated pruritus, cholestatic pruritus, or prurigo nodularis. Therefore, it would be beneficial to provide improved methods of treating uremic pruritus and related conditions, such as by use of a transmucosal film device. Summary of the Invention [Problem to be solved by the invention]

[0004] In some embodiments, the presently disclosed subject matter relates to a method of treating pruritus in a subject, specifically, the method comprises transmucosally administering to a subject in need of such treatment a therapeutically effective amount of nalmefene or a pharma- ceutically acceptable salt thereof.

[0005] In some embodiments, the subject has pruritus, prurigo nodularis, or a combination thereof as a symptom of chronic kidney disease, reduced renal function, liver disease.

[0006] In some embodiments, treating itch reduces the level of substance P in the subject.

[0007] In some embodiments, the subject is undergoing dialysis treatment.

[0008] In some embodiments, the therapeutically effective amount comprises from about 1 mg to about 32 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene.

[0009] In some embodiments, nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered to the subject once or twice per day. In some embodiments, about 1 mg to about 8 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered to the subject once per day, and then adjusted to an effective dose. In some embodiments, about 1 mg to about 8 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered to the subject twice per day as an initial dose, and then adjusted to an effective dose of about 4 mg to about 32 mg. In some embodiments, nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered as a first dose and a second dose in a 24-hour period, where the first dose is greater than the second dose, or the second dose is greater than the first dose.

[0010] In some embodiments, the transmucosal administration is selected from buccal or sublingual administration, hi some embodiments, the sublingual or buccal administration delivers about 1 mg to about 32 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene to the bloodstream of the subject in less than about 5 minutes, 30 minutes, or 60 minutes.

[0011] In some embodiments, sublingual or buccal administration delivers about 1 ng / mL to about 5 ng / mL of nalmefene or a pharma- ceutical acceptable salt of nalmefene into the subject's bloodstream within about 5 minutes.

[0012] In some embodiments, the maximum blood concentration C of the subject of nalmefene or a pharma- ceutical acceptable salt of nalmefene after administration is max is about 1 ng / mL to about 50 ng / mL.

[0013] In some embodiments, the subject's blood AUC from time 0 to infinity after administration of nalmefene or a pharma- ceutical acceptable salt of nalmefene is from about 5 ng-hr / mL to about 500 ng-hr / mL.

[0014] In some embodiments, the nalmefene or a pharma- ceutical acceptable salt of nalmefene is comprised in an immediate release transmucosal dosage form.

[0015] In some embodiments, the nalmefene or pharma- ceutical acceptable salt of nalmefene is at least about 50% dialysable.

[0016] In some embodiments, nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered via a single layer, self-supporting mucoadhesive film. Specifically, the film comprises a first separate domain comprising about 50-100 weight percent of a polymer matrix based on the total weight of the first separate domain, and about 0-50 weight percent of one or more of a permeation enhancer, a pH adjusting buffer, a taste masking agent, and a flavoring agent based on the total weight of the first separate domain. The film comprises a second separate domain comprising nalmefene or a pharma- ceutical acceptable salt of nalmefene. In some embodiments, the second separate domain is non-self-supporting.

[0017] In some embodiments, the subject is a human.

[0018] In some embodiments, the subject matter disclosed herein relates to a monolayer, self-supporting mucoadhesive film comprising a first discrete domain comprising about 50-100 weight percent of a polymer matrix, based on the total weight of the first discrete domain, and about 0-50 weight percent of one or more of a permeation enhancer, a pH adjusting buffer, a taste masking agent, and a flavoring agent, based on the total weight of the first discrete domain. The film further comprises a second discrete domain comprising nalmefene or a pharma- ceutical acceptable salt of nalmefene, where the second discrete domain is non-self-supporting.

[0019] In some embodiments, nalmefene or a pharma- ceutical acceptable salt of nalmefene is present as a solid solution present on the surface of the first discrete domain, or as substantially uniform, amorphous microparticles or monomorphous crystalline microparticles dispersed as a solid solution.

[0020] In some embodiments, the nalmefene or pharma- ceutical acceptable salt of nalmefene has a size of less than about 25 μm, 10 μm, or 1 μm.

[0021] In some embodiments, the thickness of the first distinct domain is about 50%, 100%, 500%, 750%, 1000%, 2000%, 3000%, 4000%, 5000%, 7500% or 10000% of the thickness of the second domain.

[0022] In some embodiments, the second distinct domain is physically inseparable from the first distinct domain.

[0023] In some embodiments, the first distinct domain is positioned immediately adjacent to the second distinct domain.

[0024] In some embodiments, the local pH of a first distinct domain is between about 3.5 and about 8.5, and the local pH of a second distinct domain is between 4 and 9, and the pH of these two domains is different.

[0025] In some embodiments, the polymer matrix is ​​selected from water soluble polymers, water swellable polymers and / or water erodible polymers.

[0026] In some embodiments, the second discrete domain further comprises about 0.1 to 50 weight percent of a self-aggregating moiety, a self-assembling moiety, or both, based on the total weight of the layer, hi other embodiments, the self-aggregating moiety and / or the self-assembling moiety may be present in an amount of about 25 to 70 weight percent of the total weight of the second domain.

[0027] In some embodiments, the self-aggregating or self-assembling moiety is selected from one or more of phospholipids, bile acids, bile salts, nanoplatelet structures, or edible clays.

[0028] In some embodiments, the ratio of active pharmaceutical ingredient to self-aggregating or self-assembling moiety is from about 100:1 to about 1:10 by weight.

[0029] In some embodiments, the second domain further comprises about 0.1 to 5 weight percent of an oxygen scavenger.

[0030] In some embodiments, the second domain further comprises about 0.1 to 5 weight percent of a drug solubilizer.

[0031] In some embodiments, the film is configured to provide a directional delivery of the active pharmaceutical ingredient when placed in contact with the oral mucosa of a subject.

[0032] In some embodiments, the film further comprises one or more additional separate domains, wherein said each of the additional separate domains is substantially physically inseparable from the film device.

[0033] The foregoing summary and the following detailed description should be read in light of the drawings that illustrate some, but not all, embodiments of the subject matter according to the present disclosure. [Brief description of the drawings]

[0034] [Figure 1a] FIG. 1 depicts a transmucosal film comprising first and second distinct domains. [Figure 1b] FIG. 1 depicts a transmucosal film comprising first and second distinct domains. [Figure 1c] FIG. 1 depicts a transmucosal film comprising first and second distinct domains. [Figure 1d] FIG. 1 depicts a transmucosal film comprising first and second distinct domains. [Figure 1e] FIG. 1 depicts a transmucosal film comprising first and second distinct domains. [Figure 2a] 1 is a bar graph illustrating the total number of scratches in SP-injected mice (Group 1) and saline-injected mice (Group 2). [Figure 2b] 1 is a bar graph illustrating the total number of scratches in mice injected with low and high concentrations of SP (Groups 1 and 3). [Diagram 3] FIG. 1 is a bar graph illustrating the average number of scratches per mouse after administration of PBS (group 5), PBS and SP (group 6), or nalmefene and SP (group 4) at time points 0-30 and 0-60 minutes. [Figure 4] FIG. 1 is a bar graph illustrating the number of scratches per mouse after injection of PBS (Group 10), 0.5 mM SP (Group 11), or 0.75 mg nalmefene (Group 12) at 10 minute intervals. [Diagram 5] 1 is a bar graph illustrating the average number of scratches for mice in Groups 10, 11, and 12 at 0-30 minutes and 30-60 minutes. [Figure 6] 1 is a bar graph illustrating the number of scratches per 10 minute interval after administration of low dose SP (Group 13) and high dose SP (Group 14). [Figure 7] 1 is a line graph illustrating plasma concentrations over a 20 hour period. [Figure 8] 1 is a line graph illustrating plasma concentrations over a one hour period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The subject matter according to the present disclosure is presented with sufficient detail to provide an understanding of one or more specific embodiments of the broader inventive subject matter. Various descriptions thereof have detailed and illustrated various features of those embodiments without limiting the inventive subject matter to the embodiments and features expressly described. Upon consideration of these descriptions, further and similar embodiments and features will likely emerge without departing from the scope of the subject matter according to the present disclosure.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the present disclosure pertains. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the subject matter of the present disclosure, representative methods, devices, and materials are described below.

[0037] Following long-standing patent law convention, the terms "a," "an," and "the" refer to "one or more" when used herein, including in the claims. Thus, for example, a reference to "a film" may include a plurality of such films, and so forth.

[0038] Unless otherwise indicated, all numbers expressing quantities of components, conditions and the like used in the specification and claims should be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the subject matter disclosed herein.

[0039] As used herein, the term "about," when referring to values ​​or amounts of mass, weight, time, volume, concentration, and / or percentage, can encompass in some embodiments a + / - 20% variation, in some embodiments a + / - 10% variation, in some embodiments a + / - 5% variation, in some embodiments a + / - 1% variation, in some embodiments a + / - 0.5% variation, and in some embodiments a + / - 0.1% variation from the specified amount, as such variations are appropriate in the disclosed packages and methods.

[0040] The presently disclosed subject matter relates to an effective method for treating pruritus associated with chronic kidney disease. The term "chronic kidney disease" refers to a condition in which a patient has: (i) a glomerular filtration rate (GFR) of 1.73 m 2 or (ii) a medical condition in which there is a sustained decrease in renal function of less than 60 mi / min per body surface area for about 3 months or more, or (ii) a structural or functional abnormality in renal function for about 3 months or more, even in the absence of a decreased GFR. The term "pruritus" refers to an intense itchy sensation commonly associated with chronic kidney disease. In some embodiments, the disclosed methods include administering nalmefene transmucosally (e.g., across a mucosal tissue, such as a buccal tissue and / or a sublingual tissue) to a subject in need thereof.

[0041] In some embodiments, transmucosal administration of nalmefene can treat chronic kidney disease-associated pruritus, as well as cholestatic pruritus and / or prurigo nodularis. Cholestatic pruritus is the itchy sensation caused by liver disease. Cholestasis refers to the slowing or stopping of bile flow, which can be caused by several diseases of the liver (which produces bile), the gallbladder (which stores bile), or the biliary tract (the duct that allows bile to leave the liver and gallbladder and enter the small intestine). When cholestasis occurs, conjugated bilirubin and related waste products reflux into the bloodstream and are deposited. It is believed that bile salts deposited in the skin are the cause of pruritus.

[0042] Prurigo nodularis is a skin disorder characterized by pruritic (itchy) nodules that typically appear on the subject's arms or legs. Patients often present with numerous peeling lesions caused by scratching.

[0043] Substance P (SP) is a neuropeptide that plays a role in the induction and maintenance of itch. SP is expressed by NK-1 receptors on presynaptic afferents and KOR receptors on postsynaptic afferents, and since both of these receptors are abundantly expressed in the skin and CNS, SP is therefore a logical target for novel anti-itch treatments. Without being bound by theory, nalmefene is thought to work in a number of ways, for example, by 1) blocking the expression of substance P on NK-1 receptors (antagonist), and / or 2) blocking pain signals to the CNS as a high affinity kappa opioid (KOR) receptor. No distinction is made between the two, but itch is relieved by either or both mechanisms of action.

[0044] The disclosed method of treatment involves transmucosally administering nalmefene to a subject with chronic kidney disease-associated pruritus, cholestatic pruritus and / or prurigo nodularis. 21 H 25 The structure of NO3, 6-methylene-6-deoxy-N-cyclopropylmethyl-14 hydroxydihydronormorphine) is shown below as structure (I): [ka]

[0045] Nalmefene is a mixed mu opioid receptor (MOR) antagonist and kappa opioid receptor (KOR) agonist approved for use in the United States as an antidote for opioid overdose. 9Apart from its usefulness in counteracting the sedative, respiratory depressant and other effects of opioid drugs, nalmefene has also been found to be useful in treating a wide variety of conditions, such as hyperkinesia in children, senile dementia, and sudden infant death syndrome, among others. Oral administration of nalmefene has also been shown to be safe and effective for use in treating alcoholism.

[0046] As indicated above, nalmefene can be administered transmucosally to a subject to treat chronic kidney disease-associated pruritus, as well as cholestatic pruritus and / or prurigo nodularis. Transmucosal delivery refers to the delivery of a pharmaceutical agent across mucous membranes in the oral cavity, pharyngeal cavity, or esophagus. Thus, the pharmaceutical agent is absorbed through the buccal mucosa, sublingual mucosa, gingival mucosa, pharyngeal mucosa, and / or esophageal mucosa. In some embodiments, transmucosal administration of nalmefene is buccal or sublingual delivery. As used herein, "buccal" refers to administration from within the mouth, through the mucous membrane lining the cheek (i.e., through the buccal mucosa) and directed toward the cheek. The term "sublingual" refers to administration to the underside of the tongue through the mucous membrane lining the floor of the oral cavity, which is below the tongue (i.e., through the sublingual mucosa).

[0047] In some embodiments, nalmefene can be formulated as a tablet (e.g., a dissolving tablet in the mouth), liquid, gel, gum, disk, and / or oral dissolving film. However, oral administration of nalmefene may pose significant safety risks to patients with renal or hepatic impairment, since the kidney cannot eliminate its undesirable metabolites. For use in patients with end-stage renal disease or hepatic failure, nalmefene can be delivered via an administration route that avoids first-pass metabolism. In particular, avoiding first-pass metabolism significantly reduces oxidative glucuronide metabolites, which must be reduced in patients with impaired liver and renal function.

[0048] For example, in some embodiments, nalmefene can be delivered transmucosally via the use of oral films. The term "film" as used herein refers to a thin, flexible sheet-like material and is intended to include coated films and film preparations. Specifically, oral thin films can be formulated that contain amorphous or crystalline nalmefene nanoparticles and microparticles. The term "nanoparticles" refers to nalmefene particles that are submicron in size. In some embodiments, the average longest dimension of suitable nanoparticles never exceeds about 1,000 nanometers, 500 nanometers, 200 nanometers, 100 nanometers, 75 nanometers, 50 nanometers, 40 nanometers, 25 nanometers, or 20 nanometers. The term "crystalline" refers to a compound that has a relatively well-defined crystal structure. The term "amorphous" refers to a compound that is in a non-crystalline state without crystalline regions.

[0049] In some embodiments, the nalmefene nanoparticles and microparticles are present in distinct domains on the surface of the oral film. In some embodiments, the film can be a monolayer film comprising two or more distinct domains, with at least one domain comprising nalmefene nanoparticles and microparticles. As used herein, the term "domain" refers to a region within a film that comprises a substantially different physical composition, chemical composition and / or measurable physical property (e.g., nalmefene dissolution, mucoadhesion, and / or moisture content) compared to another region of the film.

[0050] FIG. 1 illustrates one embodiment of a monolayer oral film 5 that includes multiple distinct domains, at least one of which includes nalmefene or a salt thereof. Specifically, the film 5 includes a first domain 10 that includes one or more polymer matrices and a second domain 15 that includes an active pharmaceutical ingredient 20 (e.g., nalmefene or a salt thereof). In some embodiments, the second domain 15 is not a self-supporting domain and cannot be physically separated from the first domain to maintain mechanical integrity. The term "non-self-supporting" refers to a structure that cannot be physically separated to maintain mechanical integrity. Such domains can include (but are not limited to) very thin, fragile, separate, and / or non-adjacent regions. In some embodiments, the first domain 10 is self-supporting. In some embodiments, the first distinct domain is disposed adjacent to or directly adjacent to the second distinct domain. As used herein, the term "adjacent" refers to two layers that are placed in direct contact with each other or with another layer between them. The term "directly adjacent" refers to layers that are in contact with each other without any other layers in between.

[0051] The first domain 10 may include one or more polymer matrices and, if necessary, one or more permeation enhancers, pH adjusting buffers, taste masking agents, and / or flavorings. Any desired polymer matrix may be used, including, but not limited to, water-soluble polymers, water-swellable polymers, and / or water-disintegrable polymers. For example, in some embodiments, the polymer matrix may be selected from hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose (HPC), hydroxypropylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, polyethylene oxide (PEO), pullulan, alginic acid, sodium alginate, polyethylene glycol, pectin, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, locust bean gum, gellan gum, and combinations thereof, polyacrylic acid, Polycarbophil®, methyl methacrylate copolymers, carboxyvinyl copolymers, native and hydrolyzed starches, type A and type B gelatins, carrageenan, and combinations thereof.

[0052] As used herein, the phrase "water-soluble polymer" and variations thereof refer to a polymer that is at least partially soluble in water, completely soluble in water, or mostly soluble in water, or that absorbs water. Polymers that absorb water are often referred to as being water-swellable polymers. In some embodiments, materials used in the polymer matrix of the first domain 10 can be water-soluble or water-swellable at room temperature and / or other temperatures (e.g., temperatures above room temperature).

[0053] In some embodiments, the polymer matrix can be present in an amount of about 5 to 100 weight percent of the total weight of the first domain (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 weight percent based on the total weight of the first domain). The polymer matrix provides a self-supporting structure and a desired residence time for improved bioavailability.

[0054] The first domain may optionally include a taste masking agent and / or flavoring agent to improve the taste of the film. The term "taste masking agent" refers to an agent added to the composition to mask the taste of one or more unpleasant tasting components. The term "flavoring agent" refers to any additive that imparts a desired taste or odor to the disclosed film. Suitable taste masking agents may include (but are not limited to) cellulose acetate, cellulose acetate butyrate, ethyl cellulose, methyl cellulose, and combinations thereof. Suitable flavoring agents may include, but are not limited to, natural and artificial flavors, such as peppermint oil, menthol, spearmint oil, vanilla, cinnamon oil, wintergreen oil, lemon oil, orange oil, grape oil, lime oil, grapefruit oil, apple flavor oil, raspberry oil, strawberry oil, pear oil, blueberry oil, blackberry oil, watermelon flavor, cherry oil, licorice oil, apricot essential oil, clove oil, anise oil, cardamom oil, coriander oil, eucalyptus oil, fennel oil, lemongrass oil, nutmeg oil, and combinations thereof. In some embodiments, the taste masking agent and / or flavoring agent may be present in an amount of about 0 to 5 weight percent of the total weight of the first domain (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent).

[0055] In some embodiments, the local pH of the first distinct domain is between about 3.5 and about 8.5, such as about 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, or 8.5. In some embodiments, the local pH of the second distinct domain is between 4 and 9, such as between 5 and 8 or between 6 and 7. In some embodiments, the pH of film 5 is between 3 and 9, such as between 4.5 and 7.5 or between 5 and 7.

[0056] In some embodiments, the second domain of the film 5 comprises a therapeutically effective amount of nalmefene. The term "therapeutically effective amount" refers to an amount of a pharmaceutical active ingredient that is effective in reducing, eliminating, treating, and / or suppressing symptoms of chronic kidney disease-associated pruritus, cholestatic pruritus, and / or prurigo nodularis. In some embodiments, the second domain of the film 5 comprises about 1 mg to about 32 mg of nalmefene. Thus, the film 5 can comprise at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, or 32 mg (or less) of nalmefene.

[0057] As shown in FIG. 1b, in some embodiments, the second domain 15 can include multiple active pharmaceutical ingredients 20. Thus, the film of FIG. 1b can include nalmefene and one or more additional compounds (e.g., NK-1 antagonist compounds). For example, in some embodiments, the disclosed films can include an effective dose of one or more pharmaceutical agents, such as (but not limited to) serlopitant (C 29 H 28 F7NO2), etc. Serlopitant acts as an NK-1 receptor antagonist and has the structure shown as structure (II) below: [ka]

[0058] In some embodiments, the film 5 can include about 1 mg to about 32 mg of an additional pharmaceutical agent (e.g., serlopitant). Thus, the second active agent (or subsequent active agent) can be present in an amount of about 1-20 mg, 1-15 mg, 1-10 mg, or 1-5 mg.

[0059] In some embodiments, the second domain of the film 5 can include a fixed drug ratio of nalmefene and serlopitant. For example, when combined, the fixed drug ratio can be about 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, or 10:1 (nalmefene:serlopitant). However, the film 5 is not limited and can include drug combinations with fixed drug ratios outside the ranges set forth above.

[0060] 1c, 1d and 1e illustrate alternative embodiments of the film 5 in which the active pharmaceutical ingredient 20 is present in a second domain 15 configured as a barrier matrix at the surface of the first domain. As shown in FIG. 1d, the second domain 15 can be substantially thinner than the first domain 10, e.g., at least an order of magnitude thinner than the overall thickness of the film. For example, the thickness of the first domain 10 can be about 500%, 750%, 1000%, 2000%, 3000%, 4000%, 5000%, 7500% or 10000% of the thickness of the second domain 15. In some embodiments, the second domain of the film 5 can be physically inseparable from the first domain. Similarly, for example, the surface area of ​​the first domain 10 can be about 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450% or 500% of the surface area of ​​the second domain 15.

[0061] As shown in FIG. 1c, the second domain 15 can be about the same thickness as the first domain 10, e.g., the second domain is about 0-50% of the overall thickness of the film, and the first domain is about 50-100% (or about 1:1) of the overall thickness of the film. For example, the thickness of the second domain 15 can be about 10%, 25%, 50%, 75% or 90% of the thickness of the first domain 10. In some embodiments, the second domain 15 of the film 5 can be physically inseparable from the first domain. Furthermore, the surface area of ​​the first domain 10 can be about 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450% or 500% of the surface area of ​​the second domain 15, as shown in FIG. 1e.

[0062] In some embodiments, the second discrete domain 15 can include one or more self-aggregating and / or self-assembling moieties that provide permeation enhancing properties. The term "self-aggregating" as used herein refers to molecular structures that align upon induced physical changes and / or induced phase transitions to minimize the overall free energy of the device, thereby resulting in a thermodynamically stable device. The term "self-aggregating" refers to structures that result from the ability of molecules to aggregate into high concentration or "high content domains". In some embodiments, the self-aggregating and / or self-assembling moieties can be present in an amount of about 0-5 weight percent of the total weight of the second domain (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent). In other embodiments, the self-aggregating and / or self-assembling moieties can be present in an amount of about 25 to 75 weight percent of the total weight of the second domain (e.g., 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 weight percent). The self-aggregating and / or self-assembling moieties provide directional penetration.

[0063] In some embodiments, suitable self-aggregating and / or self-assembling moieties may include, but are not limited to, phospholipids, bile salts, nanoplatelets, clays, polar lipids, or combinations thereof. Suitable examples of self-aggregating and / or self-assembling moieties may include phosphatidylcholine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylinositol phosphate, phosphatidylinositol diphosphate, phosphatidylinositol triphosphate, and / or sphingomyelin. More specifically, the self-aggregating and / or self-assembling moieties include 1,2-didecanoyl-sn-glycero-3-phosphocholine, 1,2-dierucoyl-sn-glycero-3-phosphate (sodium salt), 1,2-dierucoyl-sn-glycero-3-phosphocholine, 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine, 1,2-dierucoyl-sn-glycero-3[phospho-rac-(1-glycerol...) (sodium salt), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphate (sodium salt), 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine. amine, 1,2-dilauroyl-sn-glycero-3[phospho-rac-(1-glycerol)(sodium salt), 1,2-dilauroyl-sn-glycero-3[phospho-rac-(1-glycerol)(ammonium salt), 1,2-dilauroyl-sn-glycero-3-phosphoserine(sodium salt), 1,2-dimyristoyl-sn-glycero-3-phosphate(sodium salt), 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3[phospho-rac-(1-glycerol...)(sodium salt), 1,2-dimyristoyl-sn-glycero-3[phospho-rac-(1-glycerol...)(ammonium salt), 1,2-dimyristoyl-sn-glycero-3[phospho-rac-(1-glycerol...)(sodium / ammonium salt), 1,2-dimyristoyl-sn-glycero-3-phosphoserine(sodium salt), 1,2-dioleoyl-sn-glycero-3-phosphate(sodium salt), 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3[phospho-rac-(1-glycerol...)(sodium salt), 1,2-dioleoyl-sn-glycero-3-phosphoserine(sodium salt), 1,2-dipalmitoyl-sn-glycero-3-phosphate(sodium salt), 1,2-dipal Mitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)(sodium salt), 1,2-dipalmitoyl-sn-glycero-3[phospho-rac-(1-glycerol)(ammonium salt), 1,2-dipalmitoyl-sn-glycero-3-phosphoserine(sodium salt), 1,2-distearoyl-sn-glycero-3-phosphate(sodium salt), 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3[phospho-rac-(1-glycerol...) (sodium salt), 1,2-distearoyl-sn-glycero-3[phospho-rac-(1-glycerol)ammonium salt), 1,2-distearoyl-sn-glycero-3-phosphoserine (sodium salt), hydrogenated egg PC, hydrogenated soy PC, 1-myristoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycero-3-phosphocholine, 1-myristoyl-2-palmitoyl-sn -glycero-3-phosphocholine, 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, 1-palmitoyl-2-oleoyl-sn-glycero-3[phospho-rac-(1-glycerol)](sodium salt) , 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine; edible clay ingredients, such as sodium bentonite, polyphosphates, montmorillonite, nite, kaolin, cloisite, and the like; bile acids and bile salts, such as cholic acid, sodium and calcium salts of cholic acid, chenodeoxycholic acid, sodium and calcium salts of chenodeoxycholic acid, chenodeoxycholic acid, sodium and calcium salts of chenodeoxycholic acid, glycocholic acid, sodium and calcium salts of glycocholic acid, glycyrrhetinic acid, sodium glycyrrhentinate, taurocholic acid, sodium and calcium salts of taurocholic acid, lithocholic acid, sodium and calcium salts of lithocholic acid; nanoplatelets, bentonite, cloisite, and / or combinations thereof.

[0064] In some embodiments, the second domain 15 may include one or more oxygen scavengers, if necessary. The term "oxygen scavengers" as used herein refers to compositions that reduce or eliminate the production of undesired oxidation products. In some embodiments, the oxygen scavengers are effective for absorbing oxygen. Suitable oxygen scavengers that may be incorporated into the second domain 15 may include, but are not limited to, ascorbate, isoascorbate, tannins, sulfites, oxidizable polymers, polyacids, polynucleic acids, proteins, polysaccharides, polypeptides, ethylenediaminetetraacetic acid (EDTA) and its salts, organic glutamic acid and its salts, citric acid and its salts, phosphonates, histidine, phytochelatin, hemoglobin, chlorophyll, humic acid, transferrin, desferrioxamine, vitamin E acetate, tocopherol, and combinations thereof. In some embodiments, the oxygen scavenger can be present in an amount of about 0 to 5 weight percent (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent) of the total weight of the second domain.

[0065] In some embodiments, the first domain and / or the second domain of the film 5 can include one or more bioenhancers, pH controlling components, solubility enhancers and / or solvents to maximize absorption through the oral mucosa of the subject. The term "bioenhancer" refers to a substance that increases the bioactivity, bioavailability and / or efficacy of nalmefene. Suitable bioenhancers can include, but are not limited to, one or more fatty acids, alkaloids, piperine, allicin, curcumin and quercetin. In some embodiments, the bioenhancer can be present in an amount of about 0 to 5 weight percent of the total weight of the first domain (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 weight percent).

[0066] The term "pH controlling component" refers to any component (e.g., a buffer, etc.) that can inhibit changes in pH. For example, in some embodiments, the pH controlling component can be selected from one or more of a phosphate buffer, an acetate buffer, a citrate buffer, an arginine buffer, a TRIS buffer, or a histidine buffer. In some embodiments, the pH controlling component can be present in an amount of about 0-5 weight percent (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent) of the total weight of the first domain.

[0067] The term "solubility enhancer" refers to an agent that forms a solubilized phase for the active pharmaceutical ingredient (e.g., nalmefene). Suitable drug solubilizers may include, but are not limited to, solvents, oils, surfactants, and / or phospholipids. In some embodiments, the drug solubilizer may be present in an amount of about 0-5 weight percent of the total weight of the second domain (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent).

[0068] The term "solvent" refers to a substance that dissolves a solute. Suitable solvents may include, but are not limited to, water, alcohol, polyol, or combinations thereof. In some embodiments, the solvent may be present in an amount of about 0 to 5 weight percent of the total weight of the first domain (e.g., 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent).

[0069] In some embodiments, the film 5 can include three or more distinct domains. For example, the disclosed film can include a first distinct domain that includes a film-forming polymer matrix and, optionally, one or more pH-adjusting buffers, taste-masking agents, and / or flavorings to provide effective taste masking and / or directional permeation. The film can include a second distinct domain that includes self-assembling phospholipids and / or bile salts to provide enhanced permeation. The film can further include a third distinct domain that includes at least one active pharmaceutical ingredient or a salt thereof and, optionally, a mucoadhesive polymer, a pH-adjusting buffer, and / or an oxygen scavenger to provide mucoadhesion and / or a large driving force resulting from a high concentration microenvironment when the film is placed in contact with the oral mucosa.

[0070] In some embodiments, the film 5 can be a mucoadhesive film. The term "mucoadhesive" as used herein refers to the adhesion of a synthetic or natural polymer to a biological substrate, as defined by Robinson, JR, "Rationale of Bioadhesion / mucoadhesion" (Gurny R. and Junginger HE, eds., Bioadhesion: Possibilities and Future Trends, Stuttgart: Wissenschaftliche Verlagsesellschaft, Stuttgart, pp. 13, 15 (1990), the entire contents of which are incorporated herein by reference). There is currently no known single layer film structure that includes multiple distinct domains, at least one of which is rich in a pharmaceutical active ingredient, and at least one distinct domain provides effective taste masking and enhanced transmucosal absorption when the distinct domain containing the pharmaceutical active ingredient is placed in contact with the oral mucosa. In some embodiments, at least one distinct domain provides enhanced transmucosal absorption, hi some embodiments, the mucoadhesive polymer provides enhanced absorption when the first distinct domain is placed in contact with mucosal tissue of a subject.

[0071] As indicated above, film 5 is a monolayer film. The term "monolayer" refers to a structure that does not include layers that can be easily separated from one another, such as by peeling the regions apart or wedging them apart. Thus, the disclosed film includes a monolayer having two or more domains, but is not a multilayer laminate structure. It should be understood that domains 10, 15 can be separate or adjacent in structure, unlike layers that must be adjacent. In some embodiments, the disclosed monolayer film includes at least one domain that has a thickness in the unhydrated state of no more than 500 μm. In some embodiments, each domain in film 5 has a thickness of 500 μm or less.

[0072] The subject matter according to the present disclosure further includes a method of forming a continuous homogenous monolayer film product comprising a first separate domain and a second separate domain, the first and second separate domains being substantially inseparable and having different concentrations of the active pharmaceutical ingredient. For example, in some embodiments, the disclosed film can be constructed by preparing a first domain comprising a wet polymer matrix and, optionally, one or more of a permeation enhancer, a pH adjusting buffer, a taste masking agent, and / or a flavoring agent, using a first solvent. A first wet film is formed by casting the first wet polymer matrix. A drying device can be used to dry the wet polymer matrix and expose the wet film to a temperature sufficient to remove the first solvent, thereby drying the film as a continuous monolayer film laminate. A second wetting solution or suspension comprising the active pharmaceutical ingredient (e.g., nalmefene) can then be prepared using a second solvent. A quantity of the second wetting solution is deposited by a spraying process, an electro-spraying process, an atomized coating process, and / or an ultra-thin web coating process on selected areas of the surface of the first dry film to form a wet multi-domain film. The film is then dried in a drying apparatus and exposed to a temperature sufficient to remove the second solvent to form a dry continuous monolayer film laminate comprising the first and second distinct domains. In some embodiments, the temperature can range from about room temperature to about 250°C.

[0073] In embodiments where the film 5 is a transmucosal monolayer film device, the film can be prepared by procuring a dry drug-free web-coated polymer matrix laminate roll from a suitable vendor (e.g., Lohmann Therapie Systeme (LTS), Tapemark Inc, Aquestive Therapeutics, or ARx LLC, etc.). A second wetting solution or suspension containing the active pharmaceutical ingredient can then be prepared using a second solvent. A predetermined amount of the second wetting solution or suspension can be deposited on selected areas of the surface of the first dry film by a spraying process, an electrostatic spraying process, a spray coating process, and / or an ultra-thin web coating process. The wet multi-domain film can then be deposited in a drying apparatus and exposed to a temperature sufficient to remove the second solvent (e.g., about room temperature to 250° C.) to form a dry continuous monolayer film laminate containing the first and second distinct domains. In some embodiments, the second distinct domain containing the active pharmaceutical ingredient is substantially thinner than the first distinct domain containing the polymer.

[0074] In some embodiments, the transmucosal monolayer film device 5 can be constructed by preparing a first wet polymer matrix and one or more of a permeation enhancer, a pH adjusting buffer, a taste masking agent, and / or a flavoring using a first solvent. The first wet film can be formed by casting the wet polymer matrix. A second wetting solution or suspension can be prepared in a second solvent, comprising an active pharmaceutical ingredient 20 (or a salt thereof) and an oxygen scavenger and / or a drug solubilizer. A predetermined amount of the second wetting solution or suspension can then be deposited on the surface of the first wet film using a spraying process, an electrostatic spraying process, a spray coating process, and / or an ultra-thin web coating process to form a wet multi-domain film. The wet multi-domain film can be deposited in a drying apparatus and exposed to a sufficient temperature (e.g., about room temperature to 250° C.) to remove the first and second solvents to form a monolayer transmucosal film device comprising the first and second distinct domains. In some embodiments, the second distinct domains are substantially thinner than the first distinct domains.

[0075] In some embodiments, the transmucosal monolayer film device 5 can be constructed by preparing a first wet polymer matrix and one or more of a permeation enhancer, a pH adjusting buffer, a taste masking agent, a self-aggregating moiety (e.g., bentonite, etc.) and / or a flavoring using a first solvent. The first wet film can be formed by casting the wet polymer matrix. The first wet polymer matrix can be deposited in a drying apparatus and exposed to a temperature sufficient to remove the first solvent to form a first dry film that is cast as a continuous monolayer film laminate. A second wetting solution or suspension can then be prepared in a second solvent, including the active pharmaceutical ingredient 20 (or a salt thereof) and, if necessary, an oxygen scavenger and / or a drug solubilizer (e.g., a self-assembling phospholipid and / or a bile salt, etc.). A predetermined amount of the second wetting solution or suspension can be deposited on the surface (or selected areas of the surface) of the first dry film using a spraying process, an electrostatic spraying process, a spray coating process and / or an ultra-thin web coating process. The wet multi-domain film can then be deposited in a drying apparatus and exposed to a temperature sufficient to drive off the first and / or second solvents (e.g., from about room temperature to 250° C.) to form a dry continuous monolayer film laminate comprising the first and second distinct domains. In some embodiments, the second distinct domain is substantially thinner than the first distinct domain.

[0076] The film 5 can be configured in any desired form, such as, but not limited to, a film strip, sheet, disk, and wafer. The disclosed films can have any desired thickness, such as, for example, about 50 μm to about 500 μm, although films of greater or lesser thickness are within the scope of the subject matter of the present disclosure. The film 5 can be configured in any desired shape, such as, for example, rectangular, square, rounded, triangular, and abstract shapes. It should be understood that the film 5 can have any desired thickness and / or size that is suitable for the intended use. For example, the film can be a unit of a single dosage size to be placed in the mouth of a user.

[0077] The film 5 can be formed from a continuous roll of film or can be cut in size to any desired length and width.

[0078] In use, the disclosed film containing a pharmaceutical active ingredient (e.g., nalmefene) is placed under the tongue of a subject (e.g., in the sublingual or buccal space). The film quickly adheres, disintegrates, and dissolves, allowing the pharmaceutical active ingredient to dissolve and then be absorbed directly into the bloodstream. As shown above, nalmefene is a KOR agonist and an NK-1 receptor antagonist. In this way, it is believed that the expression of SP is reduced in presynaptic afferents while blocking itch signals as a KOR agonist. Thus, by administering nalmefene to bind to the NK-1 receptor, the expression of SP is altered (e.g., reduced or inhibited), blocking itch signaling to the CNS that has been linked to itch.

[0079] When administered, the active pharmaceutical ingredient is present in a molecular state at a high concentration in the microenvironment immediately adjacent to the mucosa of the subject. In this way, rapid transmucosal absorption of the active pharmaceutical ingredient is achieved. In some embodiments, the dissolution rate of the active pharmaceutical ingredient is significantly faster than the dissolution rate of the matrix.

[0080] In some embodiments, the film 5 can be administered to a subject in need thereof about once to twice a day. However, it should be understood that the dosage can depend on many factors, such as the severity of the condition, the concentration of nalmefene, and the weight of the subject. The term "subject" as used herein refers to animals, including primates (monkeys, apes, humans, etc.) or non-primates (cows, horses, pigs, cats, dogs, rats, mice, birds, fish, etc.).

[0081] The transmucosal film can be administered bucally or sublingually to deliver about 1-32 mg of nalmefene to a subject. For example, in some embodiments, nalmefene can be administered transmucosally once or twice daily at an initial dose of about 1-5 mg, and then titrated to an effective dose (e.g., about 5-32 mg, etc.). In some embodiments, nalmefene can be administered transmucosally in a first dose at a first time point (e.g., in the morning) and a second dose at a second time point (e.g., in the afternoon), where the first and second doses may or may not be equal.

[0082] In some embodiments, nalmefene is in an immediate release transmucosal dosage form having a mean C of about 1 to 50 ng / mL. max The drug is administered via the buccal or sublingual route, which results in a max " indicates the maximum plasma, serum, or blood concentration of a drug (e.g., nalmefene or a pharma- ceutically acceptable salt thereof) following administration. For example, sublingual or buccal administration can deliver about 1-5 ng / mL of nalmefene or a pharma- ceutically acceptable salt of nalmefene to the subject's bloodstream within about 5 minutes.

[0083] In some embodiments, nalmefene is an immediate release transmucosal dosage form administered bucally or sublingually and has a mean AUC of about 5 to 500 ng-hr / mL. 0~無限大 in a subject. "AUC" refers to the area under the time / plasma concentration curve following administration of a pharmaceutical composition. "AUC 0~無限大 " means the area under the plasma concentration curve from time 0 to infinity.

[0084] In some embodiments, the subject has chronic kidney disease-associated pruritus, cholestatic pruritus, and / or prurigo nodularis. In some embodiments, the subject is undergoing dialysis treatment. As is well known in the art, dialysis is a process for blood purification in subjects with acute or chronic renal failure. In some embodiments, the subject has chronic kidney disease or reduced renal function. Nalmefene and / or nalmefene glucuronide may be at least about 50% dialysable (e.g., at least 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, or 100 percent dialysable) when the patient is undergoing dialysis treatment. "Dialysable" refers to a molecule that can pass through a dialysis membrane (i.e., a semipermeable membrane).

[0085] Thus, the disclosed film can be used to treat chronic kidney disease-associated pruritus, cholestatic pruritus and / or prurigo nodularis in a subject.To date, there are no oral transmucosal formulations of nalmefene to treat these conditions.As a result, the subject matter of the present disclosure provides life-changing relief to afflicted patients.

[0086] Due at least in part to nalmefene's safe pharmacology and / or preferred oral transmucosal route of administration, nalmefene has the potential to become a standard of care for treating chronic pruritus, pruritus associated with chronic renal disease, and cholestatic pruritus. EXAMPLES

[0087] The following examples are included to provide guidance to those of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of this disclosure and the general level of skill in this art, those skilled in the art will appreciate that the examples below are intended to be illustrative only, and that numerous variations, modifications, and substitutions may be employed without departing from the scope of the presently disclosed subject matter.

[0088] Example 1 Injection of SP in mice A method for treating pruritus was established using C57BL mice in which substance P (SP)-induced pruritus was induced to induce the disease state. The C57BL and ICR mouse models are well-established and validated pruritic models and have been successfully used to clarify pruritic pharmacodynamics when intradermally induced with SP.

[0089] Healthy male C57BL / 6 mice, approximately 6-8 weeks of age and weighing between 21.2 and 26.8 grams at the start of the study, were used in the examples. Mice were acclimated for at least 5 days prior to the start of the study. Mice were identified by tail tags and cage labels. The study was unblinded. Mice were fed a species-specific diet and food and water were available to the animals ad libitum.

[0090] Male C57BL mice were given an intradermal (ID) injection of 0.0168 μg of SP (N=4, group 1) or PBS (N=2, group 2) either on the right side only or on both sides. Scratching behavior at the injection site was monitored for 30 min from the time of injection by two independent observers. As shown in Figure 2a, scratching behavior at the local site was more frequent in SP-injected mice than in PBS-injected mice, demonstrating that SP injection effectively induced pruritus.

[0091] An initial dose of 0.0168 μg SP (Group 1) was compared to a higher dose of 33.7 μg SP (N=4, Group 3). As shown in Figure 2b, the higher dose of SP correlated with increased scratching in mice compared to the lower dosage. Therefore, it was concluded that the scratching behavior was a direct response to the presence and amount of SP.

[0092] Example 2 Injection of SP and Nalmefene in Mice I To examine the effect of nalmefene on SP-induced scratching behavior, a fixed dose of nalmefene was given by subcutaneous (SC) injection to mimic 100% bioavailability 1 hour before ID injection of SP at 33.7 μg in male C57BL mice (N=5, group 4). Scratching behavior was monitored for 30 and 60 minutes after SP injection. Controls included mice receiving PBS instead of SP (N=6, group 5) and mice receiving a placebo dose of PBS and an ID dose of SP (N=4, group 6).

[0093] As shown in FIG. 3, nalmefene completely attenuated the pruritic response to SP.

[0094] Example 3 Injection of SP and Nalmefene in Mice II Male C57BL mice received SP or nalmefene as follows: Group 7 (N=4) received SP in sodium acetate at a dose of 250 nM / 50 μL; Group 8 (N=4) received SP in phosphate buffered saline (PBS) at a dose of 250 nM / 50 μL; Group 9 (N=4) received SP in PBS at a dose of 0.5 mM / 50 μL. Various scratching behaviors were videotaped and assessed.

[0095] Fifteen male C57BL / 6 mice received a single intradermal (ID) bolus injection of substance P (SP) or PBS. Group 10 (N=6) received a single 50 μL injection of PBS. Group 11 (N=4) received SP in PBS at a dose of 0.5 mM / 50 μL. Group 12 (N=5) received nalmefene subcutaneously (SC) at 0.075 mg / 75 μL 30 min before receiving SP in PBS at a dose of 0.5 mM / 50 μL. Scratching behavior was videotaped and assessed.

[0096] Thereafter, in-life dosing for each group was performed according to the following procedure: Group 7: All mice were placed in a clear cylindrical enclosure 30 min prior to testing for acclimation. An ID bolus injection of SP in sodium acetate was administered. Groups 8 and 9: All mice were placed in a transparent cylindrical enclosure 30 min prior to testing for acclimation. An ID bolus injection of SP in PBS was administered. Video recordings were started immediately after SP injection and continued for 30 min. Groups 10 and 11: All mice were placed in a transparent cylindrical enclosure 60 min prior to testing to allow for acclimation. An ID bolus injection of SP in PBS was administered. Video recordings were started immediately after SP injection and continued for 60 min. Group 12: All mice were placed in a transparent cylindrical enclosure 60 min before testing to allow for acclimation. A SC bolus injection of nalmefene was administered. Thirty minutes after nalmefene injection, an ID bolus injection of SP in PBS was administered. Video recording began immediately after SP injection and continued for 60 min.

[0097] An overview of the study design is shown below in Table 1.

[0098] [Table 1]

[0099] Animals in groups 7 to 9 were acclimated for 1 h prior to recording. Behavioral recording lasted for 30 min (T0 to T30).

[0100] Animals in groups 10-12 were acclimated for 1 h prior to recording. Behavioral recording lasted for 60 min (T0-T60). For group 12, six animals were dosed, but only five animals were tested, as one animal was excluded as an outlier due to no response to SP injection.

[0101] The number of scratches per 0-30 minutes for Groups 7-9 is shown below in Table 2. The number of scratches for Groups 7 and 8 were averaged together.

[0102] The number of scratches per 10 minute time interval for Groups 10-12 is shown below in Table 3. The data is also presented graphically in FIG.

[0103] [Table 2] [Table 3]

[0104] The number of scratches per time intervals 0-30 minutes and 30-60 minutes are shown below in Table 4 for Groups 10 (PBS), 11 (0.5 mM SP) and 12 (0.75 mg nalmefene). The data are also shown graphically in FIG.

[0105] The data demonstrate that nalmefene can inhibit scratching behavior, and therefore pruritus, that is maintained over an hour.

[0106] [Table 4]

[0107] Example 4 SP dose escalation Increasing doses of SP were administered to male C57BL / 6 mice, and itch was videotaped for analysis. Group 13 (N=8) received an ID injection of 135 μg of SP into the rostral dorsal right side. Group 14 (N=8) received an ID injection of 233 μg of SP into the rostral dorsal right side. Camera videotaping was initiated to monitor itch behavior immediately after dose administration at T0-60. At T60, the final itch assessment was completed, camera videotaping ended, and the study was terminated.

[0108] The recordings were reviewed and itch behavior was calculated. Two research assistants reviewed the recordings and counted the number of scratches for each mouse during the 60-minute collection period. The average of the two observations was recorded as the number of scratches per 60 minutes.

[0109] The test design is shown below in Table 5 and the average scratch numbers are shown in Table 6.

[0110] [Table 5]

[0111] Scratching over time was observed per 10 minute period for each animal tested, and the data is presented below in Table 6 and graphically depicted in FIG.

[0112] [Table 6]

[0113] Example 5 Measurement of plasma concentrations in dogs A study was conducted using dogs to evaluate the plasma concentration of nalmefene over time when delivered using the exemplary film device. Two exemplary film devices were tested. A control tablet was also tested for comparison. One 18 mg tablet was administered to the dog, followed by a 10 mL wash with drinking water. The nalmefene film device was administered buccally. Two 8 mg films were administered simultaneously for a total dosage of 16 mg. The dog was anesthetized, after which the film device was placed in place. Blood was collected as follows: pre-dose, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours after dosing. Figure 7 is a line graph showing the plasma concentration in ng / mL for two film device samples and a control tablet over a 20 hour period. As can be seen in Figure 7, the plasma concentration of nalmefene administered using the film device reached up to 50 ng / mL within 1 hour. The plasma concentration of nalmefene administered using the tablet never exceeded 1 ng / mL. Thus, higher concentrations of nalmefene were much more rapidly achievable using the film device. Figure 8 is a line graph showing the plasma concentration in ng / mL for three dogs to which nalmefene was each administered using the exemplary film device. Figure 8 shows the plasma concentration over a one hour period, which is helpful in understanding how quickly nalmefene can be delivered using the exemplary film device. Individual plasma concentration data points for each dog are shown. The plotted line is the average plasma concentration of the three dogs. As can be seen in Figure 8, the average plasma concentration of nalmefene approached 5 ng / mL within 5 minutes. Within 10 minutes, the average plasma concentration of nalmefene exceeded 5 ng / mL.

[0114] References

number

Claims

1. 1. A method of treating pruritus in a subject, comprising transmucosally administering to a subject in need of such treatment a therapeutically effective amount of nalmefene or a pharma- ceutical acceptable salt thereof.

2. 2. The method of claim 1, wherein the subject has pruritus as a symptom of chronic kidney disease, reduced renal function, liver disease, or a combination thereof.

3. 2. The method of claim 1, wherein treating itch reduces levels of substance P in the subject.

4. The method of claim 1 , wherein the subject is undergoing dialysis treatment.

5. 10. The method of claim 1, wherein the therapeutically effective amount comprises from about 1 mg to about 32 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene.

6. 10. The method of claim 1, wherein nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered to the subject once or twice per day.

7. 13. The method of claim 1, wherein about 1 mg to about 8 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered to the subject once daily, and thereafter adjusted to an effective dose.

8. 13. The method of claim 1, wherein about 1 mg to about 8 mg of nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered to the subject twice daily as an initial dose, thereafter adjusted to an effective dose of about 5 mg to about 32 mg.

9. 2. The method of claim 1, wherein nalmefene or a pharma- ceutically acceptable salt of nalmefene is administered as a first dose and a second dose within a 24-hour period, the first dose being greater than the second dose or the second dose being greater than the first dose.

10. 2. The method of claim 1, wherein the transmucosal administration is selected from buccal administration or sublingual administration.

11. 11. The method of claim 10, wherein sublingual or buccal administration delivers about 1 mg to about 32 mg of nalmefene or a pharma- ceutical acceptable nalmefene salt to the subject's bloodstream in less than about 5 minutes, 30 minutes, or 60 minutes.

12. 10. The method of claim 1, wherein sublingual or buccal administration delivers about 1 ng / mL to about 5 ng / mL of nalmefene or a pharma- ceutically acceptable salt of nalmefene to the subject's bloodstream within about 5 minutes.

13. Blood C of Nalmefene or a Pharmaceutically Acceptable Nalmefene Salt Following Administration ｍａｘ The method of claim 1, wherein the concentration of the IgG4 antibody is from about 1 ng / mL to about 50 ng / mL.

14. 2. The method of claim 1, wherein the blood AUC from time 0 to infinity after administration of nalmefene or a pharma- ceutical acceptable salt of nalmefene is from about 5 ng-hr / mL to about 500 ng-hr / mL.

15. 10. The method of claim 1, wherein the nalmefene or a pharma- ceutical acceptable salt of nalmefene is comprised in an immediate release transmucosal dosage form.

16. 2. The method of claim 1, wherein at least about 50% of the nalmefene or pharma- ceutically acceptable nalmefene salt is dialysable.

17. Nalmefene or a pharma- ceutical acceptable salt of nalmefene is administered via a single layer, self-supporting mucoadhesive film, the film comprising: a first discrete domain comprising about 50 to 100 weight percent of a polymer matrix, based on the total weight of the first discrete domain, and about 0 to 50 weight percent of one or more of a penetration enhancer, a pH adjusting buffer, a taste masking agent, and a flavoring agent, based on the total weight of the first discrete domain; A second separate domain comprising nalmefene or a pharma- ceutically acceptable salt of nalmefene. Including, The method of claim 1 , wherein the second distinct domain is non-self-supporting.

18. The method of claim 1 , wherein the subject is a human.

19. 2. The method of claim 1, wherein the plasma concentration of nalmefene glucuronide in the subject after administration is from about 0.1 ng / mL to about 25 ng / mL.

20. 20. The method of claim 18, wherein the plasma concentration in the subject after administration is from about 0.25 ng / mL to about 10 ng / mL.

21. 1. A single layer, self-supporting mucoadhesive film device comprising: a first discrete domain comprising about 50 weight percent to about 100 weight percent of a polymer matrix, based on the total weight of the first discrete domain, and about 0 weight percent to about 50 weight percent of one or more of a penetration enhancer, a pH adjusting buffer, a taste masking agent, and a flavoring agent, based on the total weight of the first discrete domain; and A second separate domain comprising nalmefene or a pharma- ceutically acceptable salt of nalmefene. Including, The monolayer, self-supporting mucoadhesive film device above, wherein the second distinct domain is non-self-supporting.

22. 21. The film of claim 20, wherein nalmefene or a pharma- ceutical acceptable salt of nalmefene is present as a solid solution present on the surface of the first discrete domains, or as substantially uniform, amorphous microparticles or monomorphous crystalline microparticles dispersed as a solid solution.

23. 21. The film of claim 20, wherein the nalmefene or pharma- ceutical acceptable salt of nalmefene has a size of less than about 25 μm, 10 μm, or 1 μm.

24. 21. The film of claim 20, wherein the thickness of the first distinct domain is about 100%, 500%, 750%, 1000%, 2000%, 3000%, 4000%, 5000%, 7500% or 10000% of the thickness of the second domain.

25. 21. The film of claim 20, wherein the second distinct domain is physically inseparable from the first distinct domain.

26. 21. The film of claim 20, wherein the first distinct domain is disposed immediately adjacent to the second distinct domain.

27. 21. The film of claim 20, wherein the first distinct domain has a local pH of about 3.5 to about 8.5 and the second distinct domain has a local pH of 4 to 9, the pH of the two domains being different.

28. 21. The film of claim 20, wherein the polymer matrix is ​​selected from water-soluble polymers, water-swellable polymers and / or water-erodible polymers.

29. 21. The film of claim 20, wherein the second distinct domain further comprises about 0.1 to 50 weight percent of a self-aggregating moiety, a self-assembling moiety, or both, based on the total weight of the layer.

30. 30. The film of claim 28, wherein the self-aggregating or self-assembling moieties are selected from one or more of phospholipids, bile acids, bile salts, nanoplatelet structures, or edible clays.

31. 30. The film of claim 28, wherein the ratio of active pharmaceutical ingredient to self-aggregating or self-assembling moieties is from about 100:1 to about 1:10 by weight.

32. 30. The film of claim 28, wherein the second domain further comprises about 0.1 to 5 weight percent of an oxygen scavenger.

33. 21. The film of claim 20, wherein the second domain further comprises about 0.1 to 5 weight percent of a drug solubilizer.

34. 21. The film of claim 20, configured to provide directional delivery of an active pharmaceutical ingredient when placed in contact with the oral mucosa of a subject.

35. 21. The film of claim 20, further comprising one or more additional separate domains, each of the additional separate domains being substantially physically inseparable from the film device.

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