Methods and devices for treating pruritus associated with chronic kidney disease

Abstract

To provide a method and device for treating pruritus associated with chronic kidney disease. [Solution] The subject matter of this disclosure relates to an effective method for treating pruritus associated with chronic kidney disease. Specifically, the method comprises administering nalmefene transmucosally to treat pruritus associated with chronic kidney disease, as well as cholestatic pruritus and / or nodular prurigo. The nalmefene is disposed on a monolayer film comprising at least two distinct domains. The film may contain a first distinct domain comprising about 50–100 weight percent of a polymer matrix, and the second distinct domain may contain nalmefene or a pharmaceutically acceptable nalmefene salt.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 62 / 747,506 (filed October 18, 2018), the entire contents of which are incorporated herein by reference.

[0002] The subject matter of this disclosure relates to methods and devices for treating pruritus associated with chronic kidney disease. Specifically, the subject matter of this disclosure includes transmucosal film compositions containing nalmefene that can be administered buccally or sublingually to subjects in need of treatment. [Background technology]

[0003] Pruritus occurs in many diseases and conditions, including chronic kidney disease. In particular, pruritus associated with chronic kidney disease is common in patients suffering from chronic renal failure, occurring in approximately 20% to 50% of patients. As a result, more than 4.1 million people 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 up to a 37% higher adjusted mortality risk compared to patients with mild or no pruritus. 3 In addition, patients often have nodular prurigo. 4、5 Skin diseases characterized by inflammatory, scaly, and exfoliating nodules and lesions. 6 The disease develops. Mild forms of pruritus and nodular prurigo are generally 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 (kidney) patients. 7 As a result, clinicians generally use a variety of off-label drug therapies for treatment. 8Approximately 18% of patients suffering from chronic kidney disease experience severe pruritus that cannot be managed with current treatment methods. Furthermore, there are no approved products in the United States for the treatment of pruritus associated with chronic kidney disease, cholestatic pruritus, or nodular prurigo. Therefore, it would be beneficial to provide improved methods for treating uremic pruritus and related conditions, for example, by the use of transmucosal film devices. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] In some embodiments, the subject matter of this disclosure relates to methods for treating pruritus in subjects. Specifically, the methods include transmucosal administration of a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof to subjects in need of such treatment.

[0005] In some embodiments, the subjects have chronic kidney disease, impaired renal function, itching as a symptom of liver disease, nodular prurigo, or a combination thereof.

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

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

[0008] In some embodiments, a therapeutically effective dose comprises about 1 mg to about 32 mg of nalmefene or a pharmaceutically acceptable nalmefene salt.

[0009] In some embodiments, nalmefene or a pharmaceutically acceptable nalmefene salt is administered to the subject once or twice daily. In some embodiments, about 1 mg to about 8 mg of nalmefene or a pharmaceutically acceptable nalmefene salt is administered to the subject once daily, and then adjusted to an effective dose. In some embodiments, about 1 mg to about 8 mg of nalmefene or a pharmaceutically acceptable nalmefene salt is administered to the subject twice daily 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 pharmaceutically acceptable nalmefene salt is administered as a first dose and a second dose within 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, transmucosal administration is selected from buccal or sublingual administration. In some embodiments, sublingual or buccal administration delivers approximately 1 mg to approximately 32 mg of nalmefene or a pharmaceutically acceptable nalmefene salt to the target bloodstream within approximately 5, 30, or 60 minutes.

[0011] In some embodiments, sublingual or buccal administration delivers approximately 1 ng / mL to approximately 5 ng / mL of nalmefene or a pharmaceutically acceptable nalmefene salt to the target bloodstream within approximately 5 minutes.

[0012] In some embodiments, the maximum blood concentration of nalmefene or a pharmaceutically acceptable nalmefene salt after administration is C max The concentration ranges from approximately 1 ng / mL to approximately 50 ng / mL.

[0013] In some embodiments, the blood AUC of the subject at time 0 to infinity after administration of nalmefene or a pharmaceutically acceptable nalmefene salt is approximately 5 ng-hr / mL to approximately 500 ng-hr / mL.

[0014] In some embodiments, nalmefene or a pharmaceutically acceptable nalmefene salt is provided in an immediate-release transmucosal administration form.

[0015] In some embodiments, nalmefene or a pharmaceutically acceptable nalmefene salt is dialyzable at least about 50%.

[0016] In some embodiments, nalmefene or a pharmaceutically acceptable nalmefene salt is administered via a single-layer self-supporting mucosal adhesive film. Specifically, the film comprises a first distinct domain containing a polymer matrix of about 50–100 weight percent based on the total weight of the first distinct domain, and one or more of a penetration enhancer, a pH-adjusting buffer, a taste masking agent, and a flavor-masking agent, of about 0–50 weight percent based on the total weight of the first distinct domain. The film comprises a second distinct domain containing nalmefene or a pharmaceutically acceptable nalmefene salt. In some embodiments, the second distinct domain is non-self-supporting.

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

[0018] In some embodiments, the subject matter of the present disclosure relates to a single-layer self-supporting mucosal adhesive film. The film comprises a first distinct domain comprising about 50 to 100 weight percent of a polymer matrix based on the total weight of the first distinct 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 flavor-masking agent based on the total weight of the first distinct domain. The film further comprises a second distinct domain comprising nalmefene or a pharmaceutically acceptable nalmefene salt, wherein the second distinct domain is non-self-supporting.

[0019] In some embodiments, naloxone or a pharmaceutically acceptable salt of naloxone is present as a solid solution on the surface of the first distinct domain, or as amorphous microparticles or monomorphic crystalline microparticles dispersed as a solid solution, which are substantially uniform.

[0020] In some embodiments, naloxone or a pharmaceutically acceptable salt of naloxone has a size 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 disposed immediately adjacent to the second distinct domain.

[0024] In some embodiments, the local pH of the first distinct domain is about 3.5 to about 8.5, the local pH of the second distinct domain is 4 to 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 distinct domain further comprises a self-aggregating moiety, a self-assembling moiety, or both in an amount of about 0.1 to 50 weight percent based on the total weight of the layer. In other embodiments, the self-aggregating moiety and / or 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 portion is selected from one or more phospholipids, bile acids, bile salts, nanoplatelet structures, or edible clay.

[0028] In some embodiments, the ratio of the pharmaceutically active ingredient to the self-aggregating or self-assembling portion is approximately 100:1 to approximately 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 directional delivery of the active pharmaceutical ingredient when placed in contact with the target oral mucosa.

[0032] In some embodiments, the film further comprises one or more additional distinct domains, in which case each of the additional distinct domains is substantially inseparable from the film device.

[0033] The above summary and the following detailed description should be read in consideration of the drawings illustrating some, but not all, embodiments of the subject matter of this disclosure. [Brief explanation of the drawing]

[0034] [Figure 1a] This figure represents a transmucosal film containing a first and second distinct domain. [Figure 1b] This figure represents a transmucosal film containing a first and second distinct domain. [Figure 1c] This figure represents a transmucosal film containing a first and second distinct domain. [Figure 1d] This figure represents a transmucosal film containing a first and second distinct domain. [Figure 1e] This figure represents a transmucosal film containing a first and second distinct domain. [Figure 2a] This bar graph illustrates the total number of scratches in mice injected with SP (Group 1) and mice injected with physiological saline (Group 2). [Figure 2b] This bar graph illustrates the total number of scratches in mice injected with low and high concentrations of SP (Group 1 and Group 3). [Figure 3] This bar graph illustrates the average number of scratches per mouse at 0-30 minutes and 0-60 minutes after administration of PBS (group 5), PBS and SP (group 6), or nalmefene and SP (group 4). [Figure 4] This bar graph illustrates 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. [Figure 5] This bar graph illustrates the average number of scratches for mice in groups 10, 11, and 12 during the 0-30 minute and 30-60 minute periods. [Figure 6] This bar graph illustrates the number of scratches per 10-minute interval after administration of low-dose SP (group 13) and high-dose SP (group 14). [Figure 7] This is a line graph illustrating plasma concentrations over a 20-hour period. [Figure 8] This is a line graph illustrating plasma concentrations over a one-hour period. [Modes for carrying out the invention]

[0035] The subject matter of this disclosure is presented with sufficient detail to enable an understanding of one or more specific embodiments of the broader inventive subject matter. Through these various descriptions, various features of those embodiments are described and illustrated in detail without limiting the inventive subject matter to the explicitly described embodiments and features. Considering these descriptions, it is likely that further embodiments and features, as well as similar embodiments and features, will be presented without departing from the scope of the subject matter of this disclosure.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the subject matter relating to this disclosure. Any method, device, and material similar to or equivalent to those described herein may be used in the implementation or testing of the subject matter relating to this disclosure, but representative methods, devices, and materials are described below.

[0037] In accordance with long-standing patent law convention, the terms “a,” “an,” and “the” indicate “one or more” when used herein, including in claims. Therefore, for example, a reference to “a film” may include multiple such films.

[0038] Unless otherwise indicated, all figures used herein and in the claims, representing quantities and conditions of components, etc., should be understood in all cases to be modified by the term “about.” Therefore, unless otherwise indicated, numerical parameters expressed herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained by the subject matter of this disclosure.

[0039] As used herein, the term “about” can mean, when referring to a value or amount of mass, weight, time, volume, concentration and / or percentage, a variation of + / -20% in some embodiments, + / -10% in some embodiments, + / -5% in some embodiments, + / -1% in some embodiments, + / -0.5% in some embodiments, and + / -0.1% in some embodiments, from a specified amount, as such variation is appropriate in the disclosed packaging and method.

[0040] The subject of this disclosure is an effective method for treating pruritus associated with chronic kidney disease. The term "chronic kidney disease" refers to a patient who (i) has a GFR (glomerular filtration rate) of 1.73 m³. 2 (ii) A medical condition having either a sustained decrease of less than 60 mi / min per body surface for about three months or longer, or (ii) a structural or functional abnormality of renal function for about three months or longer, even in the absence of decreased GFR. The term “pruritus” generally refers to the intense itching sensation associated with chronic kidney disease. In some embodiments, the disclosed methods include transmucosal administration of nalmefene to subjects in need (e.g., across mucosal tissue such as buccal and / or sublingual tissue).

[0041] In some embodiments, transmucosal administration of nalmefene can treat chronic renal disease-associated pruritus, as well as cholestatic pruritus and / or nodular prurigo. Cholestatic pruritus is a sensation of itchiness resulting from liver disease. Cholestasis indicates a slowing or cessation 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 conduits that allow 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. Bile salts deposited in the skin are thought to be the cause of the itchiness.

[0042] Nodular prurigo is a skin disease characterized by pruritic (itchy) nodules that typically appear on the arms or legs of the subject. Patients often present with multiple excoriated lesions caused by scratching.

[0043] Substance P (SP) is a neuropeptide that plays a role in the induction and maintenance of itching. Since SP is expressed by NK-1 receptors in presynaptic afferent nerves and KOR receptors in postsynaptic afferent nerves, and both of these receptors are abundantly expressed in the skin and CNS, SP is therefore a reasonable target for novel itch relief therapies. Without being bound by theory, naloxone is thought to act through multiple pathways, for example, 1) blocking the expression of substance P at the NK-1 receptor (antagonist), and / or 2) blocking pain signals to the CNS as a high-affinity kappa opioid (KOR) receptor. Without being distinguished as either, itching is reduced by either or both of these mechanisms of action.

[0044] The disclosed method of treatment involves transmucosally administering naloxone to a subject having chronic kidney disease-related itching, cholestatic itching, and / or nodular prurigo. Naloxone (C 21 H 25 NO3, 6-methylene-6-deoxy-N-cyclopropylmethyl-14-hydroxy-dihydronormorphine) has a structure shown below as structure (I):

Chemical formula

[0045] Naloxone 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 depression, and other effects of opioids, nalmefene has also been found to be useful in treating a wide variety of conditions, particularly hyperactivity in children, senile dementia, and sudden infant death syndrome. Oral administration of nalmefene has also been shown to be safe and effective in treating alcohol dependence.

[0046] As indicated above, nalmefene can be administered transmucosally to subjects to treat chronic renal disease-associated pruritus, as well as cholestatic pruritus and / or nodular prurigo. Transmucosal delivery refers to the delivery of a medicinal drug across the mucosa in the oral cavity, pharyngeal cavity, or esophagus. Thus, the medicinal drug 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. As used herein, “buccal” refers to administration directed towards the cheek, passing through the mucosa lining the cheek (i.e., through the buccal mucosa) from inside the mouth. The term “sublingual” refers to administration under the tongue, passing through the mucosa lining the floor of the mouth (i.e., through the sublingual mucosa).

[0047] In some embodiments, nalmefene can be formulated as tablets (e.g., orally dissolvable tablets), liquids, gels, gums, discs, and / or oral soluble films. However, oral administration of nalmefene may pose a significant safety risk in patients with renal or hepatic impairment because the kidneys cannot remove its undesirable metabolites. For use in patients with end-stage renal disease or hepatic failure, nalmefene can be delivered via a route of administration that avoids first-pass metabolism. In particular, avoiding first-pass metabolism significantly reduces oxidative glucuronide metabolites that must be reduced in patients with impaired hepatic 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 encompass coating films and film products. Specifically, thin oral films containing amorphous or crystalline nalmefene nanoparticles and fine particles can be formulated. The term “nanoparticles” refers to nalmefene particles having a submicron size. In some embodiments, the average longest dimension of preferred 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 having a relatively clearly defined crystalline structure. The term “amorphous” refers to a compound in an amorphous state that does not have crystalline regions.

[0049] In some embodiments, nalmefene nanoparticles and fine particles are present in distinct domains on the surface of an oral film. In some embodiments, the film may be a monolayer film comprising two or more distinct domains, where at least one domain comprises nalmefene nanoparticles and fine particles. As used herein, the term “domain” refers to a region within a film that has a substantially different physical composition, chemical composition, and / or measurable physical properties (e.g., nalmefene solubility, mucosal adhesion, and / or water content) compared to another region of the film.

[0050] Figure 1 illustrates one embodiment of a monolayer oral film 5 comprising multiple distinct domains, at least one of which comprises nalmefene or a salt thereof. Specifically, the film 5 comprises a first domain 10 comprising one or more polymer matrices and a second domain 15 comprising a pharmaceutically active 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” describes a structure that cannot be physically separated to maintain mechanical integrity. Such domains may include (but are not limited to) extremely thin, brittle, distinct, and / or non-adjacent regions. In some embodiments, the first domain 10 is self-supporting. In some embodiments, the first distinct domain is located adjacent to or directly adjacent to the second distinct domain. As used herein, the term “adjacent” means that two layers are arranged in direct contact with each other, or in contact with another layer between them. The term “directly adjacent” means that layers 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 penetration enhancers, pH-adjusting buffers, taste masking agents and / or fragrances. Any desired polymer matrix can be used, including (but not limited to) water-soluble polymers, water-swellable polymers and / or water-disintegrating polymers. For example, in some embodiments, the polymer matrix may be selected from hydroxypropyl methylcellulose (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, acacia gum, locust bean gum, gellan gum and combinations thereof, polyacrylic acid, Polycarbophil®, methyl methacrylate copolymer, carboxyvinyl copolymer, natural starch and hydrolyzed starch, type A gelatin and type B gelatin, carrageenan and combinations thereof.

[0052] As used herein, the expression “water-soluble polymer” and its variations refer to polymers that are at least partially soluble in water, completely soluble in water, mostly soluble in water, or water-absorbing polymers. Water-absorbing polymers are often referred to as water-swellable polymers. In some embodiments, the material 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 (for example, it can be present in an amount of 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, if necessary, include taste masking agents and / or flavor / odor masking agents to improve the flavor of the film. The term “taste masking agent” refers to an agent added to a composition to mask the taste of one or more unpleasant taste components. The term “flavor / odor masking 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, ethylcellulose, methylcellulose, and combinations thereof. Suitable flavor and odor modifiers may include 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 (however, suitable flavor and odor modifiers are not limited to these). In some embodiments, the taste masking agent and / or flavor and odor modifier may be present in an amount of about 0 to 5 weight percent of the total weight of the first domain (for example, in an amount of 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 approximately 3.5 to approximately 8.5, for example, approximately 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, for example, between 5 and 8 or between 6 and 7. In some embodiments, the pH of film 5 is between 3 and 9, for example, between 4.5 and 7.5 or between 5 and 7.

[0056] In some embodiments, the second domain of film 5 contains a therapeutically effective amount of nalmefene. The term “therapeutically effective amount” refers to the amount of the active pharmaceutical ingredient that is effective in reducing, eliminating, treating, and / or suppressing the symptoms of chronic renal disease-associated pruritus, cholestatic pruritus, and / or nodular prurigo. In some embodiments, the second domain of film 5 contains about 1 mg to about 32 mg of nalmefene. Thus, film 5 can contain 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 Figure 1b, in some embodiments, the second domain 15 may contain a plurality of pharmaceutically active ingredients 20. Thus, the film of Figure 1b may contain nalmefene and one or more further compounds (e.g., NK-1 antagonist compounds). For example, in some embodiments, the disclosed film may contain one or more pharmaceutical agents in an effective dose, e.g., (but not limited to) cerulopitant (C 29 H 28 It may include F7NO2, etc. Ceruropitant acts as an NK-1 receptor antagonist and has the structure shown in the following structure (II): [ka]

[0058] In some embodiments, film 5 may contain about 1 mg to about 32 mg of a further pharmaceutical agent (e.g., cerulopitant). Thus, the second activator (or subsequent activator) may be present in an amount of about 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, or 1 to 5 mg.

[0059] In some embodiments, the second domain of film 5 may contain nalmefene and cerulopitant in a constant drug ratio. For example, when combined, a constant drug ratio can be approximately 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, or 10:1 (nalmefene:cerulopitant). However, film 5 is not limited and may include drug combinations with constant drug ratios outside the range shown above.

[0060] Figures 1c, 1d, and 1e illustrate alternative embodiments of film 5 in which the pharmaceutically active ingredient 20 resides in a second domain 15 that constitutes a barrier matrix on the surface of the first domain. As shown in Figure 1d, the second domain 15 can be substantially thinner than the first domain 10, for example, 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 film 5 can be physically inseparable from the first domain. Similarly, for example, the surface area of ​​the first domain 10 can be approximately 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the surface area of ​​the second domain 15.

[0061] As shown in Figure 1c, the second domain 15 can be approximately the same thickness as the first domain 10, for example, the second domain being about 0-50% of the total thickness of the film and the first domain being about 50-100% (or about 1:1) of the total 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 Figure 1e.

[0062] In some embodiments, the second separate domain 15 may include one or more self-aggregating and / or self-assembling moieties that result in enhanced penetration properties. The term “self-assembling” as used herein refers to a molecular structure that aligns during 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 a structure resulting from the ability of molecules to aggregate into high-concentration domains or “high-content domains.” In some embodiments, the self-aggregating and / or self-assembling moieties may be present in amounts of about 0 to 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 portions may be present in amounts of about 25 to 75 weight percent of the total weight of the second domain (for example, in amounts of 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 weight percent). The self-aggregating and / or self-assembling portions result in directional penetration.

[0063] In some embodiments, suitable self-aggregating and / or self-assembling moieties may include phospholipids, bile salts, nanoplatelets, clays, polar lipids, or combinations thereof (however, suitable self-aggregating and / or self-assembling moieties are not limited to these). 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 are 1,2-didecanoyl-sn-glycero-3-phosphocholine, 1,2-dielcyl-sn-glycero-3-phosphate (sodium salt), 1,2-dielcyl-sn-glycero-3-phosphocholine, 1,2-dielcyl-sn-glycero-3-phosphoethanolamine, 1,2-dielcyl-sn-glycero-3[phospho-rac-(1-glycerol...) (sodium salt), 1,2-dilinoleyl-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 Min, 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-dimiristoyl-sn-glycero-3-phosphophalate(sodium salt), 1,2-dimiristoyl-sn-glycero-3-phosphocholine, 1,2-dimiristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimiristoyl-sn-glycero-3[phospho-rac-(1-glycerol...)(sodium salt), 1,2-dimiristoyl-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-phosphophalate(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-phosphophalate(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-phosphophosphate (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 soybean 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 components, e.g., sodium bentonite, polyphosphates, montmorillonite This may include materials such as kite, kaolin, and cloisite; bile acids and bile salts, e.g., cholic acid, sodium and calcium salts of cholic acid, chenodeoxycholic acid, sodium and calcium salts of chenodeoxycholic acid, glycocholic acid, sodium and calcium salts of glycocholic acid, glycyrrhetinic acid, sodium glycyrrhentinate sodium, 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 as needed. The term “oxygen scavenger,” as used herein, refers to a composition that reduces or eliminates the formation of unwanted oxidation products. In some embodiments, the oxygen scavenger is effective in absorbing oxygen. Suitable oxygen scavengers that may be incorporated into the second domain 15 may include ascorvert, isoascorvert, tannins, sulfites, easily 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, phytokeratin, hemoglobin, chlorophyll, humic acid, transferrin, desferrioxamine, vitamin E acetate, tocopherol, and combinations thereof (but suitable oxygen scavengers are not limited to these). In some embodiments, the oxygen scavenger may be present in an amount of about 0 to 5 weight percent of the total weight of the second domain (for example, in amounts of 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent).

[0065] In some embodiments, the first and / or second domains of film 5 may contain one or more bioenhancers, pH-controlling components, solubility enhancers, and / or solvents to maximize absorption from the target oral mucosa. The term "bioenhancer" refers to a substance that increases the bioactivity, bioavailability, and / or potency of nalmefene. Suitable bioenhancers may include, but are not limited to, one or more fatty acids, alkaloids, piperine, allicin, curcumin, and quercetin. In some embodiments, the bioenhancer 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).

[0066] The term "pH-controlling component" refers to any component (e.g., buffer) that can prevent changes in pH. For example, in some embodiments, the pH-controlling component may be selected from one or more phosphate buffers, acetate buffers, citrate buffers, arginine buffers, TRIS buffers, or histidine buffers. In some embodiments, the pH-controlling component 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).

[0067] The term "solubility enhancer" refers to an agent that forms the solubilizing phase of the pharmaceutically active ingredient (e.g., nalmefene). Suitable drug solubilizers may include solvents, oils, surfactants, and / or phospholipids (however, suitable drug solubilizers are not limited to these). In some embodiments, the drug solubilizer may be present in an amount of about 0 to 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 the solute. Suitable solvents may include water, alcohols, polyols, or combinations thereof (but are not limited to these). 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 (for example, in amounts of 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent).

[0069] In some embodiments, film 5 may include three or more distinct domains. For example, the disclosed film may include a film-forming polymer matrix and, if necessary, one or more pH-adjusting buffers, taste-masking agents and / or fragrances, to provide effective taste shielding and / or directional penetration. The film may include a second distinct domain containing self-assembling phospholipids and / or bile salts to provide enhanced penetration. The film may further include a third distinct domain containing at least one pharmaceutically active ingredient or a salt thereof and, if necessary, a mucosal-adhering polymer, a pH-adjusting buffer and / or oxygen scavengers, to provide mucosal adhesion 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, film 5 can be a mucoadhesion film. The term “mucoadhesion” as used herein indicates that a synthetic or natural polymer adheres to a biological adherend, as defined by Robinson, Jr., “Rationale of Bioadhesion / mucoadhesion” (Gurny R. and Junginger HE., eds., Bioadhesion: Possibilities and Future Trends, Stuttgart: Wissenchaftliche Verlagsesellschaft, Stuttgart, p. 13, p. 15 (1990), the entire content of which is incorporated herein by reference). No single-layer film structure is currently known that comprises multiple distinct domains, at least one of which is rich in a pharmaceutically active ingredient, and at least one distinct domain provides effective taste shielding and enhanced transmucosal absorption when the distinct domain containing the pharmaceutically active ingredient is placed in contact with the oral mucosa. In some embodiments, enhanced transmucosal absorption is provided by at least one distinct domain. In some embodiments, when the first distinct domain is placed in contact with the target mucosal tissue, enhanced absorption is provided by a mucosal adhesive polymer.

[0071] As shown above, film 5 is a single-layer film. The term “single-layer” refers to a structure that does not contain layers that can be easily separated from each other, for example, by peeling the regions apart or tearing them apart with a wedge. Thus, the disclosed film comprises a single layer having two or more domains, but is not a multilayer laminated structure. It should be understood that domains 10 and 15 can be distinct in structure or adjacent, unlike layers that must be adjacent. In some embodiments, the disclosed single-layer film comprises at least one domain having a thickness of only 500 μm in an unhydrated state. In some embodiments, each domain in film 5 has a thickness of 500 μm or less.

[0072] The subject matter of this disclosure further includes a method for forming a continuous, homogeneous monolayer film product comprising a first distinct domain and a second distinct domain, wherein the first and second distinct domains are substantially inseparable and have different concentrations of pharmaceutically active ingredients. For example, in some embodiments, the disclosed film can be constructed by preparing a first domain comprising a wet polymer matrix and, if necessary, one or more of a penetration enhancer, a pH-adjusting buffer, a taste masking agent, and / or a flavoring agent, using a first solvent. The first wet film is formed by casting the first wet polymer matrix. A drying apparatus 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. Subsequently, a second wet solution or suspension containing a pharmaceutically active ingredient (e.g., nalmefene) can be prepared using the second solvent. A predetermined amount of a second wetting solution is deposited onto selected areas on the surface of a first dry film by a spraying process, electro-spraying process, atomized coating process, and / or ultrathin web coating process 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 single-layer film laminate containing 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 film 5 is a transmucosal single-layer film device, the film can be prepared by sourcing a dry, drug-free, web-coated polymer matrix laminate roll from a suitable supplier (e.g., Lohmann Therapie Systeme (LTS), Tapemark Inc, Aquestive Therapeutics, or ARx LLC). A second wet solution or suspension containing the pharmaceutically active ingredient can then be prepared using a second solvent. A predetermined amount of the second wet solution or suspension can be deposited onto a selected area of ​​the surface of the first dry film by a spraying process, electrostatic spraying process, spray coating process, and / or ultrathin 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 single-layer film laminate containing the first and second distinct domains. In some embodiments, the second distinct domain containing the pharmaceutically active ingredient is substantially thinner than the first distinct domain containing the polymer.

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

[0075] In some embodiments, a transmucosal single-layer film device 5 can be constructed by preparing a first wet polymer matrix and one or more of a penetration enhancer, a pH-adjusting buffer, a taste masking agent, a self-aggregating moiety (e.g., bentonite), and / or a fragrance 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 single-layer film laminate. Subsequently, a second wet solution or suspension containing a pharmaceutically active 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 bile salt) can be prepared in a second solvent. A predetermined amount of the second wet solution or suspension can be deposited on the surface (or a selected area of ​​the surface) of the first dry film using a spray process, an electrostatic spraying process, a spray coating process, and / or an ultrathin web coating process. Subsequently, the wet multi-domain film can be deposited in a drying apparatus and exposed to a temperature sufficient to remove the first and / or second solvent to form a dry, continuous monolayer film laminate containing the first and second distinct domains (e.g., about room temperature to 250°C). In some embodiments, the second distinct domain is substantially thinner than the first distinct domain.

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

[0077] The film 5 can be formed from a continuous roll of film, or it can be made to a desired length and width in terms of size.

[0078] When used, the disclosed film containing the active pharmaceutical ingredient (e.g., nalmefene) is placed under the tongue of the subject (e.g., in the sublingual or buccal space). The film rapidly adheres, disintegrates, and dissolves, thereby allowing the active pharmaceutical ingredient to dissolve and subsequently be absorbed directly into the bloodstream. As indicated above, nalmefene is both a KOR agonist and an NK-1 receptor antagonist. In this way, SP expression is thought to be reduced in presynaptic afferent neurons while blocking pruritus signals as a KOR agonist. Therefore, by administering nalmefene to bind to the NK-1 receptor, SP expression is modified (e.g., reduced or inhibited), blocking pruritus signaling to the CNS that has been associated with itching.

[0079] When administered, the active pharmaceutical ingredient exists in high concentrations in molecular form in the microenvironment immediately adjacent to the target mucosa. This results in rapid transmucosal absorption of the active pharmaceutical ingredient. 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, film 5 can be administered to subjects in need approximately once or twice per day. However, it should be understood that the dosage may depend on many factors, such as the severity of the condition, the concentration of nalmefene, and the subject's body weight. The term "subject," as used herein, refers to animals, including primates (such as monkeys, apes, and humans) or non-primates (such as cattle, horses, pigs, cats, dogs, rats, mice, birds, and fish).

[0081] The transmucosal film can be administered buccally or sublingually to deliver approximately 1–32 mg of nalmefene to the target. For example, in some embodiments, nalmefene can be administered transmucosally once or twice daily at an initial dose of approximately 1–5 mg, and then set to an effective dose (e.g., approximately 5–32 mg). In some embodiments, nalmefene can be administered transmucosally by a first dose at a first time of day (e.g., in the morning) and a second dose at a second time of day (e.g., in the afternoon), in which case the first and second doses may or may not be equal.

[0082] In some embodiments, nalmefene is an immediate-release transmucosal dosage form with an average dose of approximately 1-50 ng / mL. max It is administered to the patient via the buccal or sublingual route. max This indicates the maximum plasma concentration, maximum serum concentration, or maximum blood concentration of the drug (e.g., nalmefene or a pharmaceutically acceptable salt thereof) after administration. For example, sublingual or buccal administration can deliver approximately 1-5 ng / mL of nalmefene or a pharmaceutically acceptable nalmefene salt to the target bloodstream within approximately 5 minutes.

[0083] In some embodiments, nalmefene is an immediate-release transmucosal dosage form, administered buccally or sublingually, with an average AUC of approximately 5-500 ng-hr / mL. 0~無限大 This brings about the following in the target. "AUC" represents the area under the time / plasma concentration curve after administration of the pharmaceutical composition. 0~無限大 This refers to the area under the plasma concentration curve from time 0 to infinity.

[0084] In some embodiments, the subject has chronic kidney disease-related pruritus, cholestatic pruritus, and / or nodular prurigo. In some embodiments, the subject is undergoing dialysis. As is widely known in the art, dialysis is a process for purifying the blood of a subject having acute or chronic renal failure. In some embodiments, the subject has chronic kidney disease or impaired renal function. Nalmefene and / or nalmefene glucuronide may be dialyzable at least about 50% (e.g., at least 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, or 100 percent) when the patient is undergoing dialysis. "Dialysis-enabled" indicates a molecule that can pass through a dialysis membrane (i.e., a semipermeable membrane).

[0085] Therefore, the disclosed film can be used to treat chronic renal disease-associated pruritus, cholestatic pruritus, and / or nodular prurigo. To date, there are no oral or transmucosal formulations of nalmefene for treating these conditions. As a result, the subject of this disclosure provides life-changing relief to suffering patients.

[0086] Due to at least some of its safe pharmacology and / or suitable oral-to-mucosal administration routes, nalmefene has the potential to become a standard treatment for chronic pruritus, pruritus associated with chronic renal disease, and cholestatic pruritus. [Examples]

[0087] The following examples are included to guide those skilled in the art in carrying out typical embodiments of the subject matter of this disclosure. In light of this disclosure and the general level of skill in the art, those skilled in the art will understand that the following examples are intended to be illustrative only, and that numerous variations, modifications, and substitutions may be used without departing from the scope of the subject matter of this disclosure.

[0088] Example 1 SP injection in mice The treatment of pruritus was established using C57BL mice, in which substance P (SP)-induced pruritus is induced to induce the disease state. The C57BL mouse model and the ICR mouse model are well-established and validated pruritic models and have been successfully used to elucidate the pharmacodynamics of intradermal pruritus induced by SP.

[0089] Healthy male C57BL / 6 mice, approximately 6–8 weeks old and weighing between 21.2 and 26.8 grams at the start of the study, were used as examples. The mice were acclimated for at least 5 days prior to the start of the study. Mice were identified by tail tagging and cage labeling. The study was not blinded. Mice were given species-specific food, and food and water were freely available to the animals.

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

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

[0092] Example 2 Injection of SP and nalmefene in mice I To investigate the effect of nalmefene on SP-induced scratching behavior, a fixed dose of nalmefene was administered to male C57BL mice (N=5, group 4) by subcutaneous (SC) injection mimicking 100% bioavailability, one hour before ID injection of 33.7 μg of SP. 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 placebo doses of PBS and ID doses of SP (N=4, group 6).

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

[0094] Example 3 Injection II of SP and nalmefene in mice Male C57BL mice were administered 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 evaluated.

[0095] Fifteen male C57BL / 6 mice received a single intradermal (ID) bolus injection of either 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 0.075 mg / 75 μL of nalmefene subcutaneously (SC) 30 minutes before receiving SP in PBS at a dose of 0.5 mM / 50 μL. Scratching behavior was videotaped and evaluated.

[0096] Subsequently, the administration of the medication during life for each group was carried out according to the following procedure: Group 7: All mice were placed in a transparent cylindrical enclosure 30 minutes prior to the test to allow for adaptation. They were administered an ID bolus injection of SP in sodium acetate. Groups 8 and 9: All mice were placed in a clear cylindrical enclosure 30 minutes prior to the experiment to allow them to adapt. They were administered an ID bolus injection of SP in PBS. Recording began immediately after the SP injection and continued for 30 minutes. Groups 10 and 11: All mice were placed in a clear cylindrical enclosure 60 minutes prior to the experiment to allow for adaptation. They were administered an ID bolus injection of SP in PBS. Recording began immediately after the SP injection and continued for 60 minutes. Group 12: All mice were placed in a clear cylindrical enclosure 60 minutes prior to the test to allow for adaptation. They were administered an SC bolus injection of nalmefene. Thirty minutes after the nalmefene injection, they were administered an ID bolus injection of SP in PBS. Recording began immediately after the SP injection and continued for 60 minutes.

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

[0098] [Table 1]

[0099] Animals in groups 7-9 were allowed to acclimate for one hour prior to recording. Behavioral recording continued for 30 minutes (T0-T30).

[0100] Animals in groups 10-12 were acclimatized for one hour prior to recording. Behavioral recording lasted for 60 minutes (T0-T60). Six animals in group 12 were administered the drug, but one animal was excluded as an outlier because it did not respond to the SP injection, so only five animals were tested.

[0101] The number of scratches per 0-30 minutes for groups 7-9 is shown in Table 2 below. 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 to 12 is shown in Table 3 below. The data is also shown graphically in Figure 4.

[0103] [Table 2] [Table 3]

[0104] The number of scratches per time interval of 0-30 minutes and 30-60 minutes is shown in Table 4 below for group 10 (PBS), group 11 (0.5 mM SP), and group 12 (0.75 mg nalmefene). The data is also shown graphically in Figure 5.

[0105] The data reveals that nalmefene can suppress scratching behavior and, consequently, itching, and this effect lasts for one hour.

[0106] [Table 4]

[0107] Example 4 Dosage gradual increase of SP The dose of SP administered to male C57BL / 6 mice was gradually increased, and itching was recorded for analysis. Group 13 (N=8) received an ID injection of 135 μg of SP in the right rostral dorsal region. Group 14 (N=8) received an ID injection of 233 μg of SP in the right rostral dorsal region. From T0 to T60, camera recording was started immediately after dose administration to monitor itching behavior. At T60, the final itching assessment was completed, camera recording was stopped, and the study was concluded.

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

[0109] The test design is shown in Table 5 below, and the average number of scratches is shown in Table 6.

[0110] [Table 5]

[0111] Scratching over time was observed for each animal tested at 10-minute intervals. The data is shown in Table 6 and graphed in Figure 6 below.

[0112] [Table 6]

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

[0114] References

number

Claims

1. A method for treating itching, comprising administering a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof via the mucous membrane to a subject in need of such treatment.

2. The method according to claim 1, wherein the subject has chronic kidney disease, impaired renal function, itching as a symptom of liver disease, nodular prurigo, or a combination thereof.

3. The method according to claim 1, wherein the treatment of itching reduces the level of substance P in the subject.

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

5. The method according to claim 1, comprising a therapeutically effective amount of about 1 mg to about 32 mg of nalmefene or a pharmaceutically acceptable nalmefene salt.

6. The method according to claim 1, wherein nalmefene or a pharmaceutically acceptable nalmefene salt is administered to the subject once or twice daily.

7. The method according to claim 1, wherein approximately 1 mg to approximately 8 mg of nalmefene or a pharmaceutically acceptable nalmefene salt is administered to a subject once daily, and thereafter adjusted to an effective dose.

8. The method according to claim 1, wherein approximately 1 mg to approximately 8 mg of nalmefene or a pharmaceutically acceptable nalmefene salt is administered to the subject twice daily as an initial dose, and thereafter adjusted to an effective dose of approximately 5 mg to approximately 32 mg.

9. The method according to claim 1, wherein nalmefene or a pharmaceutically acceptable nalmefene salt is administered as a first dose and a second dose within 24 hours, wherein the first dose is greater than the second dose, or the second dose is greater than the first dose.

10. The method according to claim 1, wherein transmucosal administration is selected from buccal administration or sublingual administration.

11. The method according to claim 10, wherein sublingual or buccal administration delivers approximately 1 mg to approximately 32 mg of nalmefene or a pharmaceutically acceptable nalmefene salt to the bloodstream of a target within approximately 5 minutes, 30 minutes, or 60 minutes.

12. The method according to claim 1, wherein sublingual or buccal administration delivers approximately 1 ng / mL to approximately 5 ng / mL of nalmefene or a pharmaceutically acceptable nalmefene salt to the target bloodstream within approximately 5 minutes.

13. Blood C levels of nalmefene or pharmaceutically acceptable nalmefene salts after administration ｍａｘ The method according to claim 1, wherein the concentration is approximately 1 ng / mL to approximately 50 ng / mL.

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

15. The method according to claim 1, wherein nalmefene or a pharmaceutically acceptable nalmefene salt is provided in an immediate-release transmucosal administration form.

16. The method according to claim 1, wherein at least about 50% of nalmefene or a pharmaceutically acceptable nalmefene salt is dialyzable.

17. Nalmefene or a pharmaceutically acceptable nalmefene salt is administered via a single-layer self-supporting mucosal adhesive film, and the film is A first separate domain comprising a polymer matrix of about 50 to 100 weight percent based on the total weight of the first separate domain, and one or more of a penetration enhancer, a pH adjusting buffer, a taste masking agent, and a flavor and odor masking agent of about 0 to 50 weight percent based on the total weight of the first separate domain, and A second distinct domain containing nalmefene or a pharmaceutically acceptable nalmefene salt. Includes, The method according to claim 1, wherein the second separate domain is non-self-supporting.

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

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

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

21. A single-layer self-supporting mucosal adhesive film device, A first separate domain comprising a polymer matrix in an amount of approximately 50% to 100% by weight based on the total weight of the first separate domain, and one or more of a penetration enhancer, a pH adjusting buffer, a taste masking agent, and a flavor and odor masking agent in an amount of approximately 0% to 50% by weight based on the total weight of the first separate domain, and A second distinct domain containing nalmefene or a pharmaceutically acceptable nalmefene salt. Includes, The above-described single-layer self-supporting mucosal adhesive film device, wherein the second separate domain is non-self-supporting.

22. The film according to claim 20, wherein nalmefene or a pharmaceutically acceptable nalmefene salt is present as a solid solution on the surface of a first distinct domain, or as substantially homogeneous amorphous or monomorphic crystalline microparticles dispersed as a solid solution.

23. The film according to claim 20, wherein the nalmefene or pharmaceutically acceptable nalmefene salt has a size of about 25 μm, 10 μm, or less than 1 μm.

24. The film according to claim 20, wherein the thickness of the first separate domain is approximately 100%, 500%, 750%, 1000%, 2000%, 3000%, 4000%, 5000%, 7500%, or 10000% of the thickness of the second domain.

25. The film according to claim 20, wherein the second separate domain is physically inseparable from the first separate domain.

26. The film according to claim 20, wherein the first separate domain is arranged directly adjacent to the second separate domain.

27. The film according to claim 20, wherein the local pH of the first separate domain is approximately 3.5 to approximately 8.5, and the local pH of the second separate domain is 4 to 9, and the pH of these two domains is different.

28. The film according to claim 20, wherein the polymer matrix is ​​selected from a water-soluble polymer, a water-swellable polymer, and / or a water-erodible polymer.

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

30. The film according to claim 28, wherein the self-aggregating portion or self-assembling portion is selected from one or more phospholipids, bile acids, bile salts, nanoplatelet structures, or edible clay.

31. The film according to claim 28, wherein the ratio of the active pharmaceutical ingredient to the self-aggregating portion or self-assembling portion is approximately 100:1 to approximately 1:10 by weight.

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

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

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

35. The film according to claim 20, further comprising one or more additional distinct domains, each of which is substantially inseparable from the film device by physical means.

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