Modified release compositions of nafamostat and methods of using same

Abstract

This disclosure includes compositions of nafamostat or a pharmaceutically acceptable salt thereof, which provide an individual with a controlled release of nafamostat or a pharmaceutically acceptable salt thereof for a prolonged period. According to certain embodiments, the composition comprises a plurality of controlled-release beads, each bead comprising a core, an active agent layer having nafamostat or a pharmaceutically acceptable salt thereof, and a controlled-release layer having one or more polymers formulated in an amount sufficient to provide a controlled release of nafamostat or a pharmaceutically acceptable salt thereof. Methods for administering (e.g., orally) controlled-release nafamostat compositions to an individual are also described.

Description

[Technical Field]

[0002] This disclosure includes compositions of nafamostat or pharmaceutically acceptable salts thereof, and also describes methods for administering (e.g., orally) controlled-release nafamostat compositions to an individual. Cross-Reference to Related Applications This application relates to U.S. Provisional Patent Application Serial No. 63 / 158,654, filed March 9, 2021; the disclosure of which is incorporated herein by reference. [Previous Technology]

[0004] Drug abuse, such as prescription opioid abuse, addiction, and overdose, is a major burden on patients and society, resulting in enormous costs, illness, and death. To avoid the harmful effects of these drug abuses, pharmaceutical ingredients that specifically reduce the chance of overdose are needed, especially even after an individual has overdosed on such drugs. [Summary of the Invention]

[0006] This disclosure provides pharmaceutical compositions (e.g., oral administration) and methods of use thereof, wherein the pharmaceutical composition comprises nafamostat or a pharmaceutically acceptable salt thereof and provides controlled release of nafamostat or a pharmaceutically acceptable salt thereof for a long period of time. In some embodiments, the nafamostat or a pharmaceutically acceptable salt thereof is present in the composition in an amount sufficient to inhibit one or more gastrointestinal (GI) enzymes, such as trypsin. In some embodiments, the controlled-release nafamostat composition provides controlled release of nafamostat to an individual over a period of 12 hours or longer (e.g., 24 hours or longer).

[0007] In some cases, controlled-release compositions of nafamostat or pharmaceutically acceptable salts thereof comprise a plurality of controlled-release beads, each bead comprising: a core, an active agent layer comprising nafamostat or a pharmaceutically acceptable salt thereof, and a controlled-release layer comprising one or more polymers formulated in an amount sufficient to provide controlled release of nafamostat or a pharmaceutically acceptable salt thereof. In some embodiments, the plurality of beads are encapsulated in a capsule.

[0008] In some embodiments, the core system is formed from one or more polysaccharides. In some cases, the core system is formed from cellulose polymers. In some cases, the core system is formed from microcrystalline cellulose.

[0009] In some embodiments, the active agent layer comprises nafamostat or a pharmaceutically acceptable salt thereof. In some cases, the active agent layer comprises a free nafamostat base. In some cases, the active agent layer comprises a pharmaceutically acceptable salt of nafamostat. In some cases, the active agent layer comprises nafamostat mesylate.

[0010] In some embodiments, the surfactant layer comprises an adhesive. In some cases, the adhesive is a water-soluble film-forming polymer. In some cases, the soluble film-forming polymer is a polysaccharide, such as a water-soluble cellulose polymer. In some embodiments, the surfactant layer comprises hydroxypropyl methylcellulose.

[0011] The controlled-release layer may comprise one or more acrylate polymers, methyl acrylate polymers, copolymers of one or more acrylate polymers or methyl acrylate polymers, or combinations thereof. In some embodiments, the controlled-release layer comprises an acrylate copolymer formed from monomers of ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate. In some cases, the controlled-release layer comprises poly(ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate). The poly(ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate) may contain varying amounts of quaternary ammonium groups, for example, about 50 mEq of quaternary ammonium groups per 100g of polymer (acrylate copolymer A) or about 25 mEq of quaternary ammonium groups per 100g of polymer (acrylate copolymer B). Beads containing a controlled-release layer are provided, the controlled-release layer comprising acrylate copolymer B and acrylate copolymer A in different ratios. For example, the controlled-release layer may contain 5% to 100% of acrylate copolymer B and 5% to 100% of acrylate copolymer A. In some embodiments, the controlled-release layer includes acrylate copolymer B to acrylate copolymer A in a ratio of 80:20, such as 87:13, such as 90:10, such as 92:8, and includes 95:5.

[0012] In certain embodiments, the desired composition may further comprise an immediately-release nafamostat or a pharmaceutically acceptable salt thereof, which provides an individual with an immediately released nafamostat or a pharmaceutically acceptable salt thereof. In some cases, the immediately-release nafamostat or a pharmaceutically acceptable salt thereof is present in the oral composition in powder or granule form. In some cases, the immediately-release nafamostat or a pharmaceutically acceptable salt thereof is present in the oral composition as an immediately-release layer coated on top of a controlled-release layer of a plurality of beads.

[0013] This disclosure also includes methods for administering (e.g., orally) one or more of the components described herein to an individual in need. In some embodiments, the component is administered to the individual to provide a sustained release of one or more doses of nafamostat or a pharmaceutically acceptable salt thereof for a prolonged period, such as 12 hours or longer, including 24 hours or longer. In some cases, the component is administered to the individual to provide a delayed, immediate release of one or more doses of nafamostat or a pharmaceutically acceptable salt thereof. In some cases, the component is administered to the individual to provide an immediate dose of nafamostat or a pharmaceutically acceptable salt thereof, followed by a sustained-release dose of nafamostat or a pharmaceutically acceptable salt thereof for a prolonged period. In some cases, the component is administered to the individual to provide a first immediate dose of nafamostat or a pharmaceutically acceptable salt thereof, followed by a second immediate release dose of nafamostat or a pharmaceutically acceptable salt thereof at a predetermined time after the first immediate dose.

Implementation Method

[0032] The present disclosure includes compositions of nafamostat or a pharmaceutically acceptable salt thereof, which provide an individual with a controlled release of nafamostat or a pharmaceutically acceptable salt thereof for a long period of time. According to certain embodiments, the composition includes a plurality of controlled-release beads, wherein each bead includes a core, an active agent layer having nafamostat or a pharmaceutically acceptable salt thereof, and a controlled-release layer having one or more polymers formulated in an amount sufficient to provide a controlled release of nafamostat or a pharmaceutically acceptable salt thereof. Methods for administering controlled-release nafamostat compositions to an individual (e.g., orally or via the respiratory system) are also described.

[0033] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described, and therefore variations are possible. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting, as the scope of the invention will be limited only by the appended claims.

[0034] Unless the context clearly indicates otherwise, the singular forms “a” and “the” as used herein are intended to include the plural forms as well. Furthermore, the terms “including”, “having”, “with”, or variations thereof, as used within the scope of the detailed description and / or the claims, are similar to the term “comprising”. The transitional terms / phrases (and any grammatical variations thereof) “comprising”, “consisting essentially of”, and “consisting” are used interchangeably.

[0035] The terms “about” or “approximately” mean within an acceptable range of error for a particular value determined by a person skilled in the art, the range of error depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of compositions containing the amount of the component in which the terms “about” or “approximately” are used, these compositions contain the claimed amount of the component and have a variation (range of error) of about 0 to 10% (X ± 10%) of that value.

[0036] In this disclosure, ranges are stated in abbreviated form to avoid the need for a lengthy listing and description of each and every value within the range. Where appropriate, any suitable numerical value within the range may be chosen as the upper limit, lower limit, or endpoint of the range. For example, a range of 0.1 to 1.0 represents the terminal values ​​0.1 and 1.0, and intermediate values ​​0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges contained within 0.1 to 1.0, such as 0.2 to 0.5, 0.2 to 0.8, 0.7 to 1.0, etc. Constructing a numerical range with at least two significant digits, such as a range of 5 to 10, representing values ​​between 5.0 and 10.0, and between 5.00 and 10.00, including all values ​​of the terminal values.

[0037] The publications discussed herein provide only their disclosures prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to precede such publications by virtue of prior art. Furthermore, the publication dates provided may differ from the actual publication dates that may require independent verification.

[0038] 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 this invention pertains. While any methods and materials similar to or equivalent to those described herein may be used to practice or test the invention, preferred methods and materials are currently described. All published documents mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials relevant to the reference of that publication.

[0039] Unless otherwise stated, the methods and techniques of this embodiment are generally performed in accordance with conventional methods known in the art and the descriptions in various general and more specialized references cited and discussed throughout this patent specification.

[0040] It should be understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combination within a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

[0041] As will be clearly understood by those skilled in the art upon reading this disclosure, the individual embodiments described and illustrated herein have individual components and characteristics that can be easily separated from or combined with the characteristics of any of the other embodiments without departing from the scope or spirit of the invention. Any enumerated method may be performed in the order of the enumerated events or in any other logically feasible order.

[0042] Although devices and methods have been or will be described for grammatical fluency and functional interpretation, it should be clearly understood that unless expressly stated in accordance with 35 USC §112, the scope of the patent application should not be construed in any way as necessarily limited by the construction of a “method” or “step,” but should be given the full meaning of the definition provided for in the scope of the patent application and the full scope of equivalents under the principle of judicial equivalence, and, where the scope of the patent application is expressly stated in accordance with 35 USC §112, the full legal equivalents provided for in 35 USC §112. (The following appears to be a separate, unrelated sentence: Nafamosstat or a pharmaceutically acceptable salt thereof.)

[0043] As summarized above, the form of this disclosure includes components of nafamostat or a pharmaceutically acceptable salt thereof, which provide an individual with a controlled release of nafamostat or a pharmaceutically acceptable salt thereof for a long period of time. As described herein, the compound nafamostat refers to 6-formamidinylnaphth-2-yl-4-(diaminomethyleneamino)benzoate: nafamostat (6-formamidinylnaphth-2-yl-4-(diaminomethyleneamino)benzoate)

[0044] In some embodiments, the composition includes a free base of nafamosstat. In other embodiments, the composition includes a pharmaceutically acceptable salt of nafamosstat. In the embodiments, the “salt” of nafamosstat may include, but is not limited to: (1) an acid addition salt formed with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or an acid addition salt formed with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid. , benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthalene acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) a salt formed when the acidic proton present in the compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or a salt formed by coordination with an organic base (such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.). In some embodiments, the salt of nafamostat is nafamostat methanesulfonate.

[0045] As used herein, the term "solvent" refers to a complex or aggregate formed of one or more molecules of solute and one or more molecules of solvent. Such solvates may be crystalline solids having a substantially fixed solute-solvent molar ratio. Representative solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid, etc. When the solvent is water, the formed solvate is a hydrate.

[0046] In some embodiments, the composition of nafamostat or a pharmaceutically acceptable salt thereof provides an individual with post-administered, controlled-release nafamostat or a pharmaceutically acceptable salt thereof for a prolonged period. In some embodiments, the composition described herein is an orally administered composition. In some embodiments, the composition is formulated for administration to an individual's respiratory system (e.g., by inhalation).

[0047] In some embodiments, the controlled-release composition provides an individual with a sustained release of one or more doses of nafamostat or a pharmaceutically acceptable salt thereof. In some cases, the sustained release of nafamostat is zero-order sustained release. In other cases, the sustained release of nafamostat is first-order sustained release. For example, controlled-release nafamostat formulations may provide sustained release of nafamostat at 0.000001 μg / min or more, such as 0.000005 μg / min or more, such as 0.00001 μg / min or more, such as 0.0005 μg / min or more, such as 0.001 μg / min or more, such as 0.005 μg / min or more, such as 0.01 μg / min or more, such as 0.05 μg / min or more, such as 0.1 μg / min or more, such as 0.5 μg / min or more, such as 1 μg / min or more, such as 5 μg / min or more, such as 10 μg / min or more, such as 100 μg / min or more, and include sustained release of nafamostat or a pharmaceutically acceptable salt thereof at 250 μg / min or more.

[0048] In some embodiments, controlled-release formulations of nafamostat provide delayed immediate release of nafamostat or a pharmaceutically acceptable salt thereof. As used herein, the term "delayed immediate release" refers to the point in time at which nafamostat or a pharmaceutically acceptable salt thereof is released after administration to the individual, wherein a certain amount of nafamostat is released from the formulation within a predetermined period after administration to the individual. In some cases, delayed immediate-release formulations of nafamostat are formulated to release 50% or more of nafamostat or a pharmaceutically acceptable salt thereof within a predetermined period, such as being formulated to release 60% or more, such as 70% or more, such as 80% or more, such as 90% or more, such as 95% or more, such as 97% or more, such as 99% or more, and include formulations that release all (100%) of the nafamostat in the formulation within a predetermined period after administration to the individual. The duration of delayed release may vary, and in some cases, the desired composition is formulated to release nafamostat or its pharmaceutically acceptable salts 5 minutes or longer after oral administration of the composition to an individual, such as 10 minutes or longer, such as 15 minutes or longer, such as 20 minutes or longer, such as 30 minutes or longer, such as 45 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 3 hours or longer, such as 4 hours or longer, such as 6 hours or longer, such as 8 hours or longer, such as 10 hours or longer, such as 12 hours or longer, such as 18 hours or longer, and including 24 hours or longer, and including 24 hours or longer.

[0049] In some embodiments, the controlled-release composition of nafamostine provides a release profile in which 50% or more, such as 55% or more, such as 60% or more, such as 65% or more, such as 70% or more, such as 75% or more, such as 80% or more, such as 85% or more, such as 90% or more, such as 95% or more, such as 97% or more, such as 99% or more, and includes all nafamostine (100%) in the composition that is formulated to release within 6 hours after administration to an individual.

[0050] In certain embodiments, the controlled-release composition provides the release of nafamostat or a pharmaceutically acceptable salt thereof at a first release rate during a first predetermined period, followed by the release of nafamostat or a pharmaceutically acceptable salt thereof at a second release rate during a second predetermined period. In some cases, the controlled-release composition is configured to release nafamostat at a rate of 0.000001 μg / min or higher, such as 0.000005 μg / min or higher, such as 0.00001 μg / min or higher, such as 0.0005 μg / min or higher, such as 0.001 μg / min or higher, such as 0.005 μg / min or higher, such as 0.01 μg / min or higher, such as 0.05 μg / min or higher, such as 0.1 μg / min or higher, such as 0.5 μg / min or higher, such as 1 μg / min or higher, such as 5 μg / min or higher, such as 10 μg / min or higher, such as 100 μg / min or higher, and includes releasing nafamostat at a rate of 250 μg / min or higher during the first predetermined period. In some cases, the first predetermined period is 5 minutes or longer, such as 10 minutes or longer, such as 15 minutes or longer, such as 20 minutes or longer, such as 30 minutes or longer, such as 45 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 3 hours or longer, such as 4 hours or longer, such as 6 hours or longer, such as 8 hours or longer, such as 10 hours or longer, such as 12 hours or longer, such as 18 hours or longer, and includes 24 hours or longer. In some cases, after the first period, nafamostat is controlled to be released at a rate of 0.000001 μg / min or higher, such as 0.000005 μg / min or higher, such as 0.00001 μg / min or higher, such as 0.0005 μg / min or higher, such as 0.001 μg / min or higher, such as 0.005 μg / min or higher, such as 0.01 μg / min or higher, such as 0.05 μg / min or higher, such as 0.1 μg / min or higher, such as 0.5 μg / min or higher, such as 1 μg / min or higher, such as 5 μg / min or higher, such as 10 μg / min or higher, such as 100 μg / min or higher, such as 100 μg / min or higher, and includes controlled release of nafamostat at a rate of 250 μg / min or higher during the second predetermined period. In some cases, the second predetermined period is 30 minutes or longer, such as 60 minutes or longer, such as 2 hours or longer, such as 3 hours or longer, such as 4 hours or longer, such as 6 hours or longer, such as 8 hours or longer, such as 12 hours or longer, such as 24 hours or longer, such as 48 hours or longer, and includes 72 hours or longer.

[0051] In some embodiments, the composition of nafamostat or a pharmaceutically acceptable salt thereof is formulated into a plurality of controlled-release beads, wherein each bead includes a core, an active agent layer having nafamostat or a pharmaceutically acceptable salt thereof, and a controlled-release layer having one or more polymers, the amount of which is sufficient to provide controlled release of nafamostat or a pharmaceutically acceptable salt thereof. In some embodiments, the diameter of the beads is in the range of 0.001 mm to 5 mm, such as from 0.005 mm to 4.5 mm, such as from 0.01 mm to 4 mm, such as from 0.05 mm to 3.5 mm, such as from 0.1 mm to 3 mm, such as from 0.5 mm to 2.5 mm, such as from 1 mm to 3 mm, and includes diameters of 0.2 mm and 3 mm.

[0052] In some cases, the core is formed from an inert material. Such materials include cellulose polymers, silicon dioxide, sugars, starch, or combinations thereof. The sugar may be glucose, sucrose, lactose, mannitol, xylitol, sorbitol, or combinations thereof. In some embodiments, the core may be formed from microcrystalline cellulose, such as Celllets® 100, Celllets® 200, Celllets® 350, Celllets® 500, Celllets® 700, or Celllets® 1000 (GlattAir Techniques Inc., Ramsey, New Jersey). In other embodiments, the core is re-prepared, for example by preparing a polymer mixture, extruding the mixture, and rounding the extruded mixture to form spherical or hemispherical beads. In some embodiments, the beads are expandable, allowing them to expand and rapidly and effectively release the active ingredient upon exposure to an aqueous medium. In some embodiments, the core comprises about 10% to about 50% of the total weight of the final formulated beads. In some embodiments, the core comprises about 15% to about 40% of the total weight of the final formulated beads. In some embodiments, the core comprises about 20% to about 30% of the total weight of the final formulated beads. In some embodiments, the core comprises about 20% of the total weight of the final formulated beads. In some embodiments, the core comprises about 25% of the total weight of the final formulated beads. In certain embodiments, the core is a microcrystalline cellulose (MCC) bead, such as Celllets microcrystalline cellulose beads.

[0053] In some embodiments, an active agent layer having nafamostat or a pharmaceutically acceptable salt thereof (e.g., nafamostat or nafamostat mesylate) is formed on the core. In some embodiments, the active agent layer accounts for about 1% to about 50% of the total weight of the beads. In some embodiments, the active agent layer accounts for about 2% to about 40% of the total weight of the beads. In some embodiments, the active agent layer accounts for about 5% to about 30% of the total weight of the beads. In some embodiments, the active agent layer accounts for about 7% to about 25% of the total weight of the beads. In some embodiments, the active agent layer accounts for about 8% to about 15% of the total weight of the beads. In some embodiments, the active agent layer accounts for about 8% of the total weight of the beads. In some embodiments, the active agent layer accounts for about 10% of the total weight of the beads. In some embodiments, the surfactant layer accounts for approximately 12% of the total weight of the beads. In some embodiments, the surfactant layer accounts for approximately 15% of the total weight of the beads.

[0054] In some embodiments, applying the surfactant layer results in a weight increase of approximately 1% to approximately 50% compared to the weight before applying the surfactant layer. Therefore, for example, if the weight of the core before applying the surfactant layer is X, and the weight increases by 1%, the weight of each bead after applying the surfactant layer is 1.01X, or if the weight increases by 50%, the weight of each bead after applying the surfactant layer is 1.5X. In some embodiments, the weight increase is between approximately 5% and approximately 45%. In some embodiments, the weight increase is between approximately 5% and approximately 40%. In some embodiments, the weight increase is between approximately 5% and approximately 35%. In some embodiments, the weight increase is between approximately 5% and approximately 30%. In some embodiments, the weight increase is between approximately 10% and approximately 25%.

[0055] The amount of nafamostat or its pharmaceutically acceptable salt present in the active agent layer of each bead may be 0.000001 mg or more, such as 0.00001 mg or more, such as 0.0001 mg or more, such as 0.001 mg or more, such as 0.01 mg or more, such as 0.1 mg or more, such as 0.5 mg or more, such as 1 mg or more and including 2 mg or more. In some embodiments, the drug loading of each bead of nafamosat or its pharmaceutically acceptable salt is 1% w / w to 25% w / w, such as 2% w / w to 24% w / w, such as 3% w / w to 23% w / w, such as 4% w / w to 22% w / w, such as 5% w / w to 21% w / w, such as 6% w / w to 20% w / w, such as 7% w / w to 19% w / w, such as from 8% w / w to 18% w / w, such as from 9% w / w to 15% w / w, and including 11% w / w to 13% w / w. As described in more detail below, an oral nafamostat composition according to an embodiment of this disclosure may contain 10 mg or more of nafamostat or a pharmaceutically acceptable salt thereof, such as 15 mg or more, such as 20 mg or more, such as 25 mg or more, such as 30 mg or more, such as 35 mg or more, such as 40 mg or more, such as 45 mg or more, such as 50 mg or more, such as 60 mg or more, such as 70 mg or more, such as 80 mg or more, such as 90 mg or more, such as 100 mg or more, such as 150 mg or more, and including 200 mg or more.

[0056] In addition to nafamostat or a pharmaceutically acceptable salt thereof, the active agent layer may further contain a binder. The binder may be a pharmaceutically acceptable polymer, such as hydroxyalkyl cellulose, maltodextrin, cellulose phthalate acetate, sucrose, modified starch, alginate salts, soluble gums, carrageenan, alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, hydroxypropyl methylcellulose phthalate, insoluble gums, polymethyl methacrylate, polyvinylpyrrolidone (PVP), or polyvinylpyrrolidone (PVPP), polyvinyl alcohol, shellac, and polyethylene phthalate acetate, or any combination thereof. Hydroxyalkyl cellulose may be hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, or any combination thereof. Alkyl cellulose may be cellulose, ethyl cellulose, ethyl methylcellulose, or any combination thereof. In some embodiments, the binder comprises hydroxypropyl methylcellulose.

[0057] In some embodiments, the active agent layer containing nafamostat or a pharmaceutically acceptable salt thereof may further contain an anti-adhesive or lubricating agent, such as talc, amorphous silica, such as syloid (e.g., syloid 244FP), monoglyceride, diglyceride, glyceryl monostearate, calcium stearate, and magnesium stearate.

[0058] In other embodiments, the active agent layer containing nafamostat or a pharmaceutically acceptable salt thereof includes lipid excipients such as glyceryl behenate, glyceryl esters of fatty acids, glyceryl dibenzene, glyceryl behenate polyethylene glycol ester, glyceryl distearate, glyceryl distearate, glyceryl palmitate, glyceryl lauryl polyethylene glycol ester, glyceryl stearate, abitec products, glyceryl monooleate, medium-chain mono- and diglycerides, glyceryl monocaprylate, glyceryl tricaprylate / capric acid / stearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated soybean oil and castor wax, polyoxyethylene 8-caprylate / capric acid ester, polyoxyethylene 6-caprylate / capric acid ester, polyoxyethylene 32-laurylate, polyoxyethylene 6-propylene glycol ester, polyoxyethylene 7-coconutyl ester, etc. Triglycerides, polyoxyethylene 30 coconut glycerides, polyoxyethylene 80 coconut glycerides, polyoxypropylene 15 stearyl ether, polyoxyethylene 26 glyceryl ether, polyoxyethylene 35 soybean glycerides, polyoxyethylene 20 sorbitol, polyoxypropylene myristyl ether, polyoxypropylene 10 cetearyl ether, palm kernel acetylated diethanolamine, triglycerides monooleate, Sasol products, hydrogenated cocoyl glycerides, cetyl palmitate, trimyristin, tripalmitin, tristearin, hydrogenated palm oil, glycerides monostearate, glycerides stearate, cetearyl alcohol, cetyl alcohol, decanoic acid triglycerides, acetylated glycerides, glycerides cocoyl glycerides, and polyethylene glycol, or combinations thereof.

[0059] In some embodiments, the active agent layer containing nafamostat or a pharmaceutically acceptable salt thereof comprises nafamostat or a pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose.

[0060] In some embodiments, the controlled-release beads include a controlled-release layer having one or more polymers formulated to provide controlled release of nafamostat or a pharmaceutically acceptable salt thereof. The polymer is pharmaceutically acceptable and suitable for providing controlled release of nafamostat as described above for a long period. In some cases, the polymer of the controlled-release layer includes, but is not limited to, cellulose ethers such as Ethocel™, acrylate polymers, methacrylate polymers, neutral (meth)acrylate-based polymers such as Eudragit™NE 30D, ionic (meth)acrylate-based polymers such as Eudragit™RS or RL, polyvinyl acetate, or combinations thereof. In some embodiments, the polymer of the controlled-release layer is stabilized using polyvinylpyrrolidone (PVP), such as Kollicoat™SR.

[0061] In some embodiments, the controlled-release layer comprises an acrylate copolymer. The acrylate copolymer may comprise copolymers of various monomers, such as “soft” monomers, “hard” monomers, or “functional” monomers. The acrylate copolymer may consist of copolymers comprising binary copolymers (i.e., made of two monomers), ternary copolymers (i.e., made of three monomers), or quaternary copolymers (i.e., made of four monomers), or copolymers having a greater number of monomers. The acrylate copolymer may be crosslinked or non-crosslinked. The polymer may be crosslinked by known methods to provide the desired polymer. The monomers from the acrylate copolymer may comprise two or more components selected from the group consisting of: acrylic acid, alkyl acrylates, methacrylates, copolymerizable secondary monomers, or monomers having functional groups. The monomers (“soft” and “hard” monomers) may be methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethyl methacrylate, etc. In some embodiments, the controlled-release layer comprises a methacrylate copolymer or a mixture of two or more methacrylate copolymers. In some cases, the desired methacrylate copolymer is substantially the same as the Eudragit™ acrylate copolymer described below. In some cases, the controlled-release layer comprises an acrylate copolymer substantially the same as Eudragit RS. In some cases, the controlled-release layer comprises an acrylate copolymer substantially the same as Eudragit RL. In some cases, the controlled-release layer comprises a first acrylate copolymer that is substantially the same as Eudragit RS and a second acrylate copolymer that is substantially the same as Eudragit RL.

[0062] In some embodiments, the controlled-release layer comprises two different polymers (e.g., two different acrylate copolymers). In some cases, the amount of the first polymer present in the controlled-release layer is in the range of 0.01 wt% to 99.99 wt%, such as 0.1 wt% to 99.9 wt%, such as 0.5 wt% to 99.5 wt%, such as 1 wt% to 99 wt%, such as 2 wt% to 98 wt%, such as 3 wt% to 97 wt%, such as 4 wt% to 96 wt%, such as 5 wt% to 95 wt%, such as 6 wt% to 94 wt%, such as 7 wt% to 93 wt%, such as 8 wt% to 92 wt%, such as 9 wt% to 91 wt%, such as 10 wt% to 90 wt%, such as 15 wt% to 85 wt%, such as 20 wt% to 80 wt%, such as 25 wt% to 75 wt%, such as 30 wt% to 70 wt%, such as 35 wt% to 65 wt%, such as 40 wt% to 60 wt%, and including 45 wt% to 55 wt%. In some cases, the amount of the second polymer present in the controlled-release layer is in the range of 0.01 wt% to 99.99 wt%, such as 0.1 wt% to 99.9 wt%, such as 0.5 wt% to 99.5%, such as 1 wt% to 99 wt%, such as 2 wt% to 98 wt%, such as 3 wt% to 97 wt%, such as 4 wt% to 96 wt%, such as 5 wt% to 95 wt%, such as 6 wt% to 94 wt%, such as 7 wt% to 93 wt%, such as 8 wt% to 92 wt%, such as 9 wt% to 91 wt%, such as 10 wt% to 90 wt%, such as 15 wt% to 85 wt%, such as 20 wt% to 80 wt%, such as 25 wt% to 75 wt%, such as 30 wt% to 70 wt%, such as 35 wt% to 65 wt%, such as 40 wt% to 60 wt%, and including 45 wt% to 55 wt%.

[0063] The weight ratio of the first polymer (e.g., the first acrylate copolymer) to the second polymer (e.g., the second acrylate copolymer) in the controlled release layer may vary, such as from 1:99 to 99:1, such as from 5:95 to 95:5, such as from 10:90 to 90:10, such as from 20:80 to 80:20, such as from 30:70 to 70:30, such as from 40:60 to 60:40, and includes a weight ratio of 50:50 for the first polymer to the second polymer in the controlled release layer. In some embodiments, the weight ratio of the first polymer to the second polymer in the controlled release layer may be 80:20, such as 87:13, such as 90:10, such as 92:8, and includes a weight ratio of 95:5.

[0064] In some cases, the controlled-release layer comprises a copolymer of ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate. In some cases, the polymer is a poly(ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate) containing quaternary ammonium groups. For example, the acrylate copolymer may be a combination of the following: 1) a poly(ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate) containing about 50 mEq of quaternary ammonium groups per 100g of polymer (hereinafter referred to as "acrylate copolymer A"; wherein in some cases, acrylate copolymer A is substantially the same as Eudragit™RL) and 2) a poly(ethyl acrylate, methyl methacrylate, and ethyl chloride trimethylammonium methacrylate) containing about 25 mEq of quaternary ammonium groups per 100g of polymer (hereinafter referred to as "acrylate copolymer B"; wherein in some cases, acrylate copolymer B is substantially the same as Eudragit™RS). In some cases, the amount of acrylate copolymer A in the polymer of the controlled-release layer is in the range of 0.01 wt% to 99.99 wt%, such as 0.1 wt% to 99.9 wt%, such as 0.5 wt% to 99.5 wt%, such as 1 wt% to 99 wt%, such as 2 wt% to 98 wt%, such as 3 wt% to 97 wt%, such as 4 wt% to 96 wt%, such as 5 wt% to 95 wt%, such as 6 wt% to 94 wt%, such as 7 wt% to 93 wt%, such as 8 wt% to 92 wt%, such as 9 wt% to 91 wt%, such as 10 wt% to 90 wt%, such as 15 wt% to 85 wt%, such as 20 wt% to 80 wt%, such as 25 wt% to 75 wt%, such as 30 wt% to 70 wt%, such as 35 wt% to 65 wt%, such as 40 wt% to 60 wt%, and includes 45 wt% to 55 wt%. In some cases, the amount of acrylate copolymer B in the polymer of the controlled-release layer is in the range of 0.01 wt% to 99.99 wt%, such as 0.1 wt% to 99.9 wt%, such as 0.5 wt% to 99.5 wt%, such as 1 wt% to 99 wt%, such as 2 wt% to 98 wt%, such as 3 wt% to 97 wt%, such as 4 wt% to 96 wt%, such as 5 wt% to 95 wt%, such as 6 wt% to 94 wt%, such as 7 wt% to 93 wt%, such as 8 wt% to 92 wt%, such as 9 wt% to 91 wt%, such as 10 wt% to 90 wt%, such as 15 wt% to 85 wt%, such as 20 wt% to 80 wt%, such as 25 wt% to 75 wt%, such as 30 wt% to 70 wt%, such as 35 wt% to 65 wt%, such as 40 wt% to 60 wt%, and includes 45 wt% to 55 wt%.

[0065] The weight ratio of acrylate copolymer A to acrylate copolymer B in the controlled release layer may vary, such as from 1:99 to 99:1, such as from 5:95 to 95:5, such as from 10:90 to 90:10, such as from 20:80 to 80:20, such as from 30:70 to 70:30, such as from 40:60 to 60:40, and includes a weight ratio of acrylate copolymer A to acrylate copolymer B in the controlled release layer of 50:50. In some embodiments, the controlled release layer includes a ratio of acrylate copolymer B to acrylate copolymer A of 80:20, such as a ratio of acrylate copolymer B to acrylate copolymer A of 87:13, such as a ratio of acrylate copolymer B to acrylate copolymer A of 90:10, such as a ratio of acrylate copolymer B to acrylate copolymer A of 92:8, and includes a ratio of acrylate copolymer B to acrylate copolymer A of 95:5.

[0066] In some cases, the polymer of the controlled-release layer comprises 20% by weight of acrylate copolymer B and 80% by weight of acrylate copolymer A.

[0067] In some cases, the polymer of the controlled-release layer comprises 50% by weight of acrylate copolymer B and 50% by weight of acrylate copolymer A.

[0068] In some cases, the polymer of the controlled-release layer comprises 80% by weight of acrylate copolymer B and 20% by weight of acrylate copolymer A.

[0069] In some cases, the polymer of the controlled-release layer comprises 100% by weight of acrylate copolymer B.

[0070] In some cases, the polymer of the controlled-release layer comprises 100% by weight of acrylate copolymer A.

[0071] In some cases, the polymer of the controlled-release layer comprises 95% by weight of acrylate copolymer B and 5% by weight of acrylate copolymer A.

[0072] In some cases, the polymer of the controlled-release layer comprises 93% by weight of acrylate copolymer B and 7% by weight of acrylate copolymer A.

[0073] In some cases, the polymer of the controlled-release layer comprises 92% by weight of acrylate copolymer B and 8% by weight of acrylate copolymer A.

[0074] In some cases, the polymer of the controlled-release layer comprises 90% by weight of acrylate copolymer B and 10% by weight of acrylate copolymer A.

[0075] In some cases, the polymer of the controlled-release layer comprises 87% by weight of acrylate copolymer B and 13% by weight of acrylate copolymer A.

[0076] In some embodiments, the controlled-release layer accounts for about 1% to about 50% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 2% to about 40% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 5% to about 30% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 7% to about 25% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 8% to about 15% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 8% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 10% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for about 12% of the total weight of the beads. In some embodiments, the controlled-release layer accounts for approximately 15% of the total weight of the beads.

[0077] In some embodiments, the application of the controlled-release layer results in a weight increase of approximately 1% to approximately 50% compared to the weight before the application of the controlled-release layer. Therefore, for example, if the weight of the core and active agent layer before the application of the controlled-release layer is X, and the weight increases by 1%, the weight of each bead after the application of the controlled-release layer is 1.01X, or if the weight increases by 50%, the weight of each bead is 1.5X. In some embodiments, the weight increase is between approximately 5% and approximately 45%. In some embodiments, the weight increase is between approximately 5% and approximately 40%. In some embodiments, the weight increase is between approximately 5% and approximately 35%. In some embodiments, the weight increase is between approximately 5% and approximately 30%. In some embodiments, the weight increase is between approximately 10% and approximately 25%, such as 15%.

[0078] Some non-limiting examples of the composition of nafamosta mesylate are provided in Tables 1 and 2 below: Table 1. Composition of pharmaceutical products, formulations I to IV Components Dosage unit (mg) Blend I (95:5 RS:RL) Formula II (80:20 RS:RL) Blend III (80:20 RS:RL) Blend IV (95:5 RS:RL) Nafamosta A sulfonates 100 100 1 1 Hydroxypropyl methylcellulose (hypromellose) capsule A unit A unit A unit A unit Microcrystalline cellulose spheres 526.4 526.4 5.264 5.264 Hydroxypropyl methylcellulose 100 100 1 1 Eudragit RL (Ammonium Methacrylate Copolymer) 4.5 18.1 0.181 0.045 Type B of ammonium methacrylate copolymer (Eudragit RS) 86.2 72.6 0.726 0.862 Triethyl citrate 9.1 9.1 0.091 0.091 talc 45.4 45.4 0.454 0.454 all 871.6 871.6 8.72 8.72 Formulation I = High dose, sustained release rate; Formulation II = High dose, rapid release rate; Formulation III = Low dose, rapid release rate; Formulation IV = Low dose, sustained release rate. Table 2. Nafamosstat controlled-release bead formulations. Blend V (100:0 RS:RL) Blend VI (87:13 RS:RL) Blend VII (100:0 RS:RL) Blend VIII (93:7 RS:RL) core Microcrystalline cellulose spheres 63.01% w / w Microcrystalline cellulose spheres 60.3865% w / w Microcrystalline cellulose spheres 60.39% w / w Microcrystalline cellulose spheres 60.3865% w / w active Agent layer Nafamosta 11.97% w / w Nafamosta 11.4734% w / w Nafamosta 11.47% w / w Nafamosta 11.4734% w / w Hydroxypropyl Methylcellulose 11.97% w / w Hydroxypropyl Methylcellulose 11.4734% w / w Hydroxypropyl Methylcellulose 11.47% w / w Hydroxypropyl Methylcellulose 11.4734% w / w Controlled release layer Type B of ammonium methacrylate copolymer (Eudragit RSPO) 8.15% w / w Type B of ammonium methacrylate copolymer (Eudragit RSPO) 9.0625% w / w Type B of ammonium methacrylate copolymer (Eudragit RSPO) 10.42% w / w Type B of ammonium methacrylate copolymer (Eudragit RSPO) 9.6875% w / w methacrylic acid Ammonium ester type A (Eudragit RLPO) 0.0% w / w methacrylic acid Ammonium ester type A (Eudragit RLPO) 1.3542% w / w methacrylic acid Ammonium ester type A (Eudragit RLPO) 0.0% w / w methacrylic acid Ammonium ester type A (Eudragit RLPO) 0.7292% w / w Triethyl citrate 0.82% w / w Triethyl citrate 1.0417% w / w Triethyl citrate 1.04% w / w Triethyl citrate 10.417% w / w talc 4.08% w / w talc 5.2083% w / w talc 5.21% w / w talc 5.2083% w / w

[0079] In some embodiments, the controlled-release layer further includes a release agent, such as glyceryl monostearate. In some embodiments, the controlled-release layer also contains one or more plasticizers. In some embodiments, the plasticizer is selected from the group consisting of: phthalate-based plasticizers, trimellitate-based plasticizers, adipate-based plasticizers, sebacic acid ester-based plasticizers, organophosphates, maleate esters, sulfonamides, glycols or polyethers, acetylated monoglycerides, and alkyl citrates. In some embodiments, the sebacic acid ester-based plasticizer is dibutyl sebate (DBS). In some embodiments, the plasticizer is triethyl citrate. In some embodiments, the amount of the plasticizer is from about 1% to about 20% by weight, or from about 5% to about 15% by weight, or from about 7% to about 10% by weight of the controlled-release layer. In some embodiments, the controlled-release layer may further contain a flavoring agent. In some cases, the active agent layer and / or the controlled-release layer contains magnesium silicate.

[0080] In certain embodiments, the multiple controlled-release beads include an immediate-release layer of nafamostat or a pharmaceutically acceptable salt coated above the controlled-release layer. In some cases, the immediate-release layer of nafamostat or a pharmaceutically acceptable salt is formulated to release 50% or more of the nafamostat or a pharmaceutically acceptable salt within 10 minutes or less of administration of the composition to the individual, such as 60% or more, such as 75% or more, such as 90% or more, such as 95% or more, and includes releasing 99% or more within 10 minutes or less of administration of the composition to the individual. In some cases, the immediate-release layer of nafamostat or a pharmaceutically acceptable salt is formulated to release all (i.e., 100%) of the nafamostat or a pharmaceutically acceptable salt within 10 minutes or less of administration of the composition to the individual. In some cases, the immediate-release layer of nafamostat or a pharmaceutically acceptable salt thereof is formulated to release 50% or more of nafamostat or a pharmaceutically acceptable salt thereof immediately upon administration of the composition to the individual, such as 60% or more, such as 75% or more, such as 90% or more, such as 95% or more, and including 99% or more immediately upon administration of the composition to the individual.

[0081] The amount of nafamostat or its pharmaceutically acceptable salt present in the immediate release layer of each bead may be 0.000001 mg or more, such as 0.00001 mg or more, such as 0.0001 mg or more, such as 0.001 mg or more, such as 0.01 mg or more, such as 0.1 mg or more, such as 0.5 mg or more, such as 1 mg or more and including 2 mg or more. In some embodiments, the loading of nafamostat or its pharmaceutically acceptable salt in the immediate release layer of each bead is 1% w / w to 25% w / w, such as 2% w / w to 24% w / w, such as 3% w / w to 23% w / w, such as 4% w / w to 22% w / w, such as 5% w / w to 21% w / w, such as 6% w / w to 20% w / w, such as 7% w / w to 19% w / w, such as 8% w / w to 18% w / w, such as 9% w / w to 15% w / w, and including 11% w / w to 13% w / w.

[0082] The controlled-release nafamostat or its pharmaceutically acceptable salts may be formulated in any convenient form suitable for oral (including oral and sublingual) administration, such as tablets, capsules, powders, suspensions, dispersants, or emulsions. In some embodiments, the controlled-release nafamostat or its pharmaceutically acceptable salts are formulated for administration to the individual's respiratory system, such as via the lungs. For example, the formulations described herein may be formulated for administration by inhalation (e.g., dry powder inhalation and nebulized drop inhalation), intratracheal instillation (delivery into the airway via a syringe), intratracheal delivery and blowing (delivery of the powder formulation into the airway via a syringe or any other similar device), or nebulized administration. In some cases, the formulations are formulated for dry powder inhalation or nebulized drop inhalation and may include propellants such as hydrofluorocarbons, chlorofluorocarbons, propane, nitrogen, or mixtures thereof. The atomized droplet formulation is a stabilizing dispersant or suspending agent for solid materials and droplets in a gaseous medium, and can be incorporated into pressurized, acceptable propellants such as hydrofluorocarbons (HFA, such as HFA-134a and HFA-227, or mixtures thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants, such as mixtures of propellants 11, 12 and / or 114), propane, nitrogen, etc.

[0083] The composition may contain components conventionally used in pharmaceutical preparations, such as one or more carriers, binders, lubricants, excipients (e.g., for imparting controlled-release properties), pH modifiers, sweeteners, fillers, colorants, or other active agents. The pharmaceutical composition according to this embodiment may further include a pharmaceutically acceptable carrier.

[0084] The amount of nafamostat or its pharmaceutically acceptable salt in a unit composition (e.g., a capsule of controlled-release nafamostat or a pharmaceutically acceptable salt thereof) may include 1 mg to 500 mg of nafamostat or its pharmaceutically acceptable salt, for example, between: 1 to 10 mg, 10 to 20 mg, 20 to 30 mg, 30 to 40 mg, 40 to 50 mg, 50 to 60 mg, 60 to 70 mg, 70 to 80 mg, 80 to 90 mg, 90 to 100 mg, 100 to 110 mg, 110 to 120 mg, 120 to 130 mg, 130 to 140 mg, 140 to 150 mg, 150 to 160 mg, 160 to 170 mg, 170 to 180 mg, 180 to 190 mg, 190 to 200 mg, 200 to 210 mg, 210 to 220 mg. mg, 220 to 230 mg, 230 to 240 mg, 240 to 250 mg, 250 to 260 mg, 260 to 270 mg, 270 to 280 mg, 280 to 290 mg, 290 to 300 mg, 300 to 310 mg, 310 to 320 mg, 320 to 330 mg, 330 to 340 mg, 340 to 350 mg, 350 to 360 mg, 360 to 370 mg, 370 to 380 mg, 380 to 390 mg, 390 to 400 mg, 400 to 410 mg, 410 to 420 mg, 420 to 430 mg, 430 to 440 mg, 440 to 450 mg, 450 to 460 mg, 460 to 470 mg, 470 to 480 mg, 480 to 490 mg mg and between 490 and 500 mg.

[0085] In some embodiments, the controlled-release composition further comprises an amount of immediately released nafamostat or a pharmaceutically acceptable salt thereof, such as contained within a capsule of the controlled-release beads. In some cases, the immediately released nafamostat or a pharmaceutically acceptable salt thereof is present in the composition in powder form (e.g., within a capsule). In other cases, the immediately released nafamostat or a pharmaceutically acceptable salt thereof is present in the composition in granular form (e.g., within a capsule). The amount of immediately released nafamostat or a pharmaceutically acceptable salt thereof present in the composition may range from 1 mg to 200 mg, such as 2 mg to 190 mg, such as 3 mg to 180 mg, such as 4 mg to 170 mg, such as 5 mg to 160 mg, such as 6 mg to 150 mg, such as 7 mg to 140 mg, such as 8 mg to 130 mg, such as 9 mg to 120 mg, and includes 10 mg to 100 mg.

[0086] This disclosure also includes methods for administering the controlled-release nafamostat or its pharmaceutically acceptable salts to an individual. In carrying out this method according to certain embodiments, one or more doses of the controlled-release nafamostat composition are administered orally (including buccally or sublingually) to the individual. In some cases, the controlled-release nafamostat composition is administered to the respiratory system, such as by pulmonary administration. For example, the composition described herein may be administered according to certain embodiments by inhalation (e.g., dry powder inhalation and nebulized drop inhalation), intratracheal instillation (delivered into the airway by syringe), intratracheal delivery and blowing (delivered into the airway by syringe or any other similar device), or nebulization. In some cases, the administration is by dry powder inhalation or nebulized drop inhalation, with the addition of a propellant such as hydrofluorocarbons, chlorofluorocarbons, propane, nitrogen, or mixtures thereof. The atomized droplet formulation is a stabilizing dispersant or suspending agent for solid substances and droplets in a gaseous medium, and can be incorporated into pressurized, acceptable propellants, such as hydrofluorocarbons (HFA, such as HFA-134a and HFA-227, or mixtures thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants, such as mixtures of propellants 11, 12 and / or 114), propane, nitrogen, etc.

[0087] The dose of the controlled-release nafamostat component administered to the individual may vary in the range of about 0.01 mg / kg to 20 mg / kg per day, such as 0.05 mg / kg to 19 mg / kg per day, such as 0.1 mg / kg to 18 mg / kg per day, such as 0.5 mg / kg to 17 mg / kg per day, such as 1 mg / kg to 16 mg / kg per day, and including 1 mg / kg to 15 mg / kg per day. In practice, the controlled-release nafamostat component may be administered to the individual once, twice, three times, four times, five times, or at some other interval.

[0088] Treatment intervals using controlled-release nafamostat components may be 1 day or longer, such as 2 days or longer, such as 3 days or longer, such as 4 days or longer, such as 5 days or longer, such as 6 days or longer, such as 7 days or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 8 weeks or longer, such as 12 weeks or longer, such as 16 weeks or longer, such as 20 weeks or longer, such as 24 weeks or longer, such as 28 weeks or longer, such as 32 weeks or longer, such as 36 weeks or longer, such as 40 weeks or longer, such as 44 weeks or longer, such as 48 weeks or longer, and including 52 weeks or longer. In some embodiments, the regimen may include multiple dosing intervals. In practicing the methods disclosed herein, the treatment regimen may include two or more dosing intervals, such as 3 or more dosing intervals, such as 4 or more dosing intervals, such as 5 or more dosing intervals, including 10 or more dosing intervals.

[0089] The duration between dose intervals in a multi-dose interval treatment regimen may vary depending on the individual's physiological condition or the treatment regimen determined by a healthcare professional. For example, the duration between dose intervals in a multi-dose interval treatment regimen may be a predetermined and regular interval. Therefore, the time between dose intervals may vary and may be 1 day or longer, such as 2 days or longer, such as 4 days or longer, such as 6 days or longer, such as 8 days or longer, such as 12 days or longer, such as 16 days or longer, and including 24 days or longer. In some implementations, the multi-dose interval regimen provides a duration of 1 week or longer between dose intervals, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 5 weeks or longer, including 6 weeks or longer.

[0090] In certain embodiments, the controlled-release nafamostat composition described herein may be administered before, simultaneously with, or after other therapeutic agents used to treat the same or unrelated conditions. If administered concurrently with another therapeutic agent, the controlled-release nafamostat composition may be administered in the same or different compositions. Therefore, the controlled-release nafamostat composition and other therapeutic agents may be administered to an individual via concurrent therapy. "Concurrent therapy" is intended to administer to an individual so as to produce the therapeutic effect of the combination of substances in the individual receiving the therapy. Individual pharmaceutical compositions may be administered simultaneously or at different times (i.e., sequentially, in any order, on the same day, or on different days), as long as the therapeutic effect of the combination of substances is produced in the individual receiving the therapy.

[0091] The forms of the subject matter described herein, including implementation forms, can be beneficial on their own or in combination with one or more other forms or implementation forms. Not limited to what is described, certain non-limiting forms of the disclosure numbered 1 to 40 are provided below. As will be clearly understood by those skilled in the art upon reading this disclosure, each individually numbered form can be used or combined with any of the aforementioned or following individually numbered forms. This is intended to support combinations of all such forms, but is not limited to combinations of forms explicitly provided below:

[0092] 1. A composition comprising nafamostat or a pharmaceutically acceptable salt thereof, wherein the composition provides an individual with controlled release of nafamostat or a pharmaceutically acceptable salt thereof for a long period of time.

[0093] 2. The composition of claim 1, wherein the composition comprises a plurality of controlled-release beads, each bead comprising: a core; an active agent layer comprising nafamostat or a pharmaceutically acceptable salt thereof; and a controlled-release layer comprising one or more polymers formulated in an amount sufficient to provide controlled release of nafamostat or a pharmaceutically acceptable salt thereof.

[0094] 3. The composition of paragraph 2, wherein the core comprises a cellulose polymer, or silicon dioxide, or a sugar selected from the group consisting of glucose, sucrose, lactose, mannitol, xylitol and sorbitol.

[0095] 4. The composition as described in item 3, wherein the core comprises microcrystalline cellulose (MCC).

[0096] 5. The composition of any one of items 1 to 4, wherein the active agent layer further comprises an adhesive.

[0097] 6. The composition of any one of items 1 to 4, wherein the adhesive comprises hydroxypropyl methylcellulose.

[0098] 7. The composition of any one of items 1 to 6, wherein the controlled-release layer comprises an acrylate copolymer.

[0099] 8. The composition of item 7, wherein the acrylate copolymer comprises poly(ethyl acrylate, methyl methacrylate and trimethylammonium chloride ethyl methacrylate).

[0100] 9. The composition of item 8, wherein the acrylate copolymer comprises a poly(ethyl acrylate, methyl methacrylate and trimethylammonium chloride ethyl methacrylate) containing a quaternary ammonium group.

[0101] 10. The composition of paragraph 9, wherein the acrylate copolymer comprises a combination of the following: acrylate copolymer A, comprising poly(ethyl acrylate, methyl methacrylate and trimethylammonium chloride ethyl methacrylate), each 100g of polymer containing about 50 mEq of quaternary ammonium groups; and acrylate copolymer B, comprising poly(ethyl acrylate, methyl methacrylate and trimethylammonium chloride ethyl methacrylate), each 100g of polymer containing about 25 mEq of quaternary ammonium groups.

[0102] 11. The composition of item 10, wherein the acrylate copolymer comprises 20% by weight of acrylate copolymer B and 80% by weight of acrylate copolymer A.

[0103] 12. The composition of item 10, wherein the acrylate copolymer comprises 50% by weight of acrylate copolymer B and 50% by weight of acrylate copolymer A.

[0104] 13. The composition of item 10, wherein the acrylate copolymer comprises 80% by weight of acrylate copolymer B and 20% by weight of acrylate copolymer A.

[0105] 14. The composition of item 10, wherein the acrylate copolymer comprises 100% by weight of acrylate copolymer A.

[0106] 15. The composition of item 10, wherein the acrylate copolymer comprises 100% by weight of acrylate copolymer B.

[0107] 16. The composition of item 10, wherein the acrylate copolymer comprises 95% by weight of acrylate copolymer B and 5% by weight of acrylate copolymer A.

[0108] 17. The composition of item 10, wherein the acrylate copolymer comprises 93% by weight of acrylate copolymer B and 7% by weight of acrylate copolymer A.

[0109] 18. The composition of item 10, wherein the acrylate copolymer comprises 92% by weight of acrylate copolymer B and 8% by weight of acrylate copolymer A.

[0110] 19. The composition of item 10, wherein the acrylate copolymer comprises 90% by weight of acrylate copolymer B and 10% by weight of acrylate copolymer A.

[0111] 20. The composition of item 10, wherein the acrylate copolymer comprises 87% by weight of acrylate copolymer B and 13% by weight of acrylate copolymer A.

[0112] 21. The composition of any one of items 7 to 20, wherein the acrylate copolymer accounts for 5% to 30% by weight of each of the plurality of beads.

[0113] 22. A composition of any one of claims 2 to 21, wherein one or more of the active agent layer and the controlled-release layer further comprise magnesium silicate.

[0114] 23. A composition of any one of claims 2 to 22, wherein one or more of the active agent layer and the controlled-release layer further comprises a plasticizer.

[0115] 24. The composition of item 23, wherein the plasticizer is triethyl citrate.

[0116] 25. The composition of any one of items 2 to 24, wherein each of the plurality of beads contains 5% to 20% by weight of nafamostat or a pharmaceutically acceptable salt thereof.

[0117] 26. The composition of the plurality of beads, wherein each bead contains 10% to 15% by weight of nafamostat or a pharmaceutically acceptable salt thereof.

[0118] 27. The composition of the plurality of beads, wherein each bead contains 11% to 12% by weight of nafamostat or a pharmaceutically acceptable salt thereof.

[0119] 28. A composition of any one of items 1 to 27, wherein the plurality of beads are configured to release 50% or more of nafamostat or a pharmaceutically acceptable salt thereof within 6 hours after administration.

[0120] 29. A composition of any one of items 1 to 27, wherein the plurality of beads are configured to release 75% or more of nafamostat or a pharmaceutically acceptable salt thereof within 6 hours after administration.

[0121] 30. A composition of any one of items 1 to 27, wherein the plurality of beads are configured to release 90% or more of nafamostat or a pharmaceutically acceptable salt thereof within 6 hours after administration.

[0122] 31. A composition of any one of claims 1 to 27, wherein the plurality of beads are configured to release nafamostat or a pharmaceutically acceptable salt thereof at a first rate during a first predetermined period, and then release nafamostat or a pharmaceutically acceptable salt thereof at a second rate during a second predetermined period.

[0123] 32. A composition of any one of items 1 to 31, further comprising an immediate-release nafamostat or a pharmaceutically acceptable salt thereof that provides an individual with immediate release of nafamostat or a pharmaceutically acceptable salt thereof.

[0124] 33. The composition of paragraph 32, wherein the immediate-release nafamostat or a pharmaceutically acceptable salt thereof comprises nafamostat or a pharmaceutically acceptable salt thereof in powder form.

[0125] 34. The composition of claim 32, wherein the immediate-release nafamostat or a pharmaceutically acceptable salt thereof comprises a layer of nafamostat or a pharmaceutically acceptable salt thereof on a controlled-release layer of the plurality of controlled-release beads.

[0126] 35. A composition as described in paragraph 32, wherein the immediate-release nafamostat or a pharmaceutically acceptable salt thereof comprises a plurality of immediate-release beads.

[0127] 36. A method comprising orally administering to an individual in need the composition of any one of items 1 to 35.

[0128] 37. A method comprising administering to the respiratory system of an individual in need the composition of any one of items 1 to 35.

[0129] 38. The method of claim 37, wherein the component is administered by inhalation, intratracheal instillation, intratracheal delivery, inhalation, nebulization, or a combination thereof.

[0130] 39. The method of any one of items 37 to 38, wherein the composition further comprises a propellant.

[0131] 40. The method of claim 39, wherein the propellant comprises hydrofluoroalkane, chlorofluorocarbon, propane, nitrogen or a mixture thereof.

[0132] The following embodiments are provided to provide a complete disclosure and description to those skilled in the art regarding how to manufacture and use these embodiments, and are not intended to limit the scope of the inventors' view of their invention, nor are they intended to represent all or only the experiments conducted. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise stated, parts are by weight, molecular weight is weight-average molecular weight, temperature is expressed in Celsius, and pressure is atmospheric pressure or close to atmospheric pressure. Standard abbreviations may be used.

[0133] The oxycodone derivative used in this experiment is referred to herein as KC-8 (N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid) and has the structure shown below. The left side of the molecule is the oxycodone group. Moving to the right is a linker with the structure -C(O)N(CH3)CH2C(CH3)2CH2-, followed by the peptide shown in the formula Arg-Gly-Mal.

[0134] Figure 1 shows how KC-8 is activated by the digestive system. First, the NC bond between the linker and the peptide group is cleaved or bioactivated by the digestive enzyme trypsin. Therefore, KC-8 can be referred to as trypsin-activated. Next, after the terminal amine group of the linker is separated from the peptide protecting group, the linker undergoes intramolecular cyclization, thereby releasing the cyclourea byproduct. As a result, an oxycodone molecule is formed, which can then induce pharmacological effects, such as pain suppression. Therefore, the production of active oxycodone can be achieved by cleaving the NC bond by trypsin (an enzyme located in the digestive tract). Example 1 - Effect of nalfamostat on the pharmacokinetics of KC-8 in rats

[0135] The drug nafamostat mesylate is added to a formulation containing a KC-8 oxycodone derivative. In the embodiments described herein, the terms "nafamostat mesylate" and "nafamostat" are used interchangeably.

[0136] Rats were orally administered a formulation containing KC-8 and, as needed, nafamostat. The KC-8 dose was 5 mg / kg and the nafamostat concentration was 0, 0.1, 0.5, or 1 mg / kg. Plasma concentrations of active oxycodone were measured at different time intervals within 24 hours after administration.

[0137] As shown in Figure 2, with 0 or 0.1 mg / kg nafamostat, the oxycodone concentration peak appears at approximately 2 hours, with a concentration of approximately 1.3 or 1.4 ng / ml. Conversely, additional nafamostat will reduce the maximum oxycodone concentration to a peak of approximately 0.75 ng / ml at approximately 5 hours. Error bars represent one standard deviation.

[0138] As shown in Figure 3, rats were administered higher concentrations of KC-8 and nafamostat, approximately equivalent to the dose received by a human if they had ingested 10 KC-8 pills. Specifically, the rats received 50 mg / kg of KC-8 and 0, 1, 5, or 10 mg / kg of nafamostat. With nafamostat at zero, plasma concentrations reached a maximum of approximately 22 ng / ml at approximately 2 hours, after which the concentration rapidly decreased. Consistent with the data in Figure 2, higher concentrations of nafamostat reduced the peak concentration to approximately 3 ng / ml at approximately 8 hours.

[0139] The rat experiment was repeated using a derivative of dihydromorphone (referred to herein as PF329, which is another known analgesic). Figures 4 and 5 show the blood concentrations of active dihydromorphone (HM) after administration of 1, 3, 6, or 10 pills (without or with nafamostat). In other words, the pills in Figure 5 contain nafamostat, while the pills in Figure 4 do not. The graph shows that administration of more pills in Figure 4 resulted in a significant increase in dihydromorphone concentration, but in Figure 5, due to the moderating effect of nafamostat, the dihydromorphone concentration showed almost no increase.

[0140] Therefore, Experiment 1 shows that co-administration of nafamostat with oxycodone or dihydromorphone derivatives significantly reduces the maximum concentration of the active drug in plasma and also leads to a more stable concentration of the active drug over time. Example 2: Effect of nafamostat on the pharmacokinetics of KC-8 in humans

[0141] Although Example 1 experimentally tested the effects of nafamostat in rats, Experiment 2 measured its effects when administered to humans. The pharmacokinetics in humans appear to differ from those in rats. As shown in Figure 6, the dihydromorphone derivative of PF329 was administered co-administered with 0, 1, or 10 mg of nafamostat. With 0 mg of nafamostat, the blood concentration of dihydromorphone increased from 0 hours to approximately 0.4 ng / ml. With 1 or 10 mg of nafamostat, this increase was delayed by 1 or 2 hours, but the peak concentration also appeared to reach approximately 0.4 ng / ml. Therefore, the effects of nafamostat in humans appear to differ from those in rats. Example 3: Preparation method of an immediate-release nafamostat formulation

[0142] Preparation of immediate-release beads containing nafamostat. Each immediate-release bead comprises a microcrystalline cellulose core and an active layer of nafamostat mesylate.

[0143] A coating solution of nafamosta mesylate was prepared by adding methocel to water and stirring at 250 rpm for 25 minutes. 29 g of nafamosta mesylate was slowly added and stirred for another 5 minutes until completely dissolved. This produced a 5 wt% nafamosta mesylate solution. The remaining nafamosta mesylate was then added over an additional 10 minutes and mixed for another 10 minutes to produce a white, homogeneous suspension. The suspension was stirred overnight. The coating solution was placed on a top-mounted pan balance with a top-mounted stirrer to ensure complete dispersion throughout the coating process. A summary of the components of this immediate-release nafamosta coating composition is shown in Table 3. Table 3. Immediate-release nafamosta mesylate coating solution

[0144] Weigh out 700g of MCC CP-305 beads and load them into a container to begin coating. Gradually increase the pump rate from 1 g / min every 10 to 20 minutes until the maximum spray rate is reached. Backflush circulation is not required. The coating process lasted a total of 4.75 hours, and no significant twinning or clumping was observed. Allow the beads to cure for 30 minutes before collection. Processing parameters are shown in Table 4. The beads were collected through a 600μm sieve, yielding 698g of acceptable individual beads; however, 72g were twinning. Table 4. Coating parameters for immediate-release nafamosta mesylate coating solution.

[0145] The beads were collected and passed through a 600 μm sieve, yielding 698 g of individual beads, of which 72 g were adhered. A total of 702 g of coating solution was sprayed, achieving a theoretical free drug loading of 7.99% w / w. The beads were subjected to LOD, analysis, related substances, and water content tests. The beads showed good uniformity, indicating that a uniform coating was achieved. Example 4: Preparation method of active agent layer of controlled-release nalfamostat composition

[0146] Preparation of the surfactant layer for nafamostat controlled-release beads. Beads were prepared from a microcrystalline cellulose core and a nafamostat methanesulfonate coating. The composition of the coating solution is shown in Table 5. Table 5. Surfactant layer coating solution for nafamostat controlled-release beads.

[0147] A coating solution of nafamosta mesylate was prepared according to the description above for the composition of immediately released nafamosta beads and stirred overnight. 650 g of microcrystalline cellulose CP-305 beads were weighed and filled into a container to begin coating. The pump rate was maintained at 1 g / min for 15 minutes, then increased to 1.5 g / min. Based on observations, the pump rate was gradually increased to 3.0 g / min over the next hour. During this period, the nozzle pressure was gradually increased with the pump rate to maintain a good spray pattern. The process ran for a total of 4.5 hours without any clogging or the need for backflushing. The beads were cured in a fluidized bed container at 40°C for 30 minutes, and the coating parameters are shown in Table 4.

[0148] The beads were collected and passed through a 600 μm sieve, yielding 532 g of individual beads, of which 194 g were adhered. A total of 655 g of coating solution was sprayed, achieving a theoretical free drug loading of 8.40% w / w. The beads were subjected to LOD, analysis, related substances, and water content tests. Example 6: Preparation method of controlled-release nalfamostat composition

[0149] Preparation of a nafamostat composition containing controlled-release beads. Each controlled-release bead comprises a microcrystalline cellulose core and an active agent layer of nafamostat methanesulfonate, and a controlled-release polymer coating. The active agent layer of nafamostat methanesulfonate was prepared as described in Example 4. A polymer controlled-release coating solution with an Eudragit RS:Eudragit RL ratio of 87:13 was prepared as described in Table 6. In another embodiment, as shown in Table 7, the talc ratio in the solution was halved relative to the other components. Table 6. Coating solution of controlled-release polymer layer of nafamostat controlled-release beads (87:13 Eudragit RS:Eudragit RL) Table 7. Coating solution of controlled-release polymer layer of nafamostat controlled-release beads (87:13 Eudragit RS:Eudragit RL)

[0150] Set up the Procept fluidized bed using a 1L container, a 0.4mm nozzle, and without a Wurster column. Weigh out 250g of beads containing the surfactant layer (microcrystalline cellulose coated with nafamostat mesylate as prepared above) and fill the container. Prepare the coating solution to produce a uniformly dispersed white opaque solution. Place the coating solution on a top-mounted pan balance and set the top-mounted stirrer to 250 rpm to ensure that the solution remains fully dispersed throughout the coating process. Pour the coating solution into the pipeline and spray gun to check for leaks / bubbles.

[0151] The coating process began with an initial spraying rate of 0.5 g / min, gradually increasing the rate until a maximum of 2.5 g / min was reached. Significant electrostatic problems were observed, with a large number of beads adhering to the inside of the container and the filter. The electrostatic gun had to be used almost continuously to ensure the beads did not accumulate and flow ceased. The process was stopped after 2.5 hours due to the formation of bead clumps. Talc was noted to have deposited in the pipeline, potentially contributing to bead agglomeration. Spraying approximately 207 g of coating solution resulted in a 4.73% increase in coating weight. Adhering ER-coated beads were sieved using a 600 μm sieve.

[0152] Figure 12 illustrates a comparison of the release profiles of nalfamostat from controlled-release beads having a ratio of 87:13 (Eudragit RS:Eudragit RL) as weight increases. Example 7: Method for preparing controlled-release nalfamostat composition

[0153] Controlled-release beads containing nafamostat components were prepared. Each controlled-release bead comprised a microcrystalline cellulose core, an active agent layer of nafamostat mesylate, and a controlled-release polymer coating. The active agent layer of nafamostat mesylate was prepared as described in Example 4. A polymer controlled-release coating solution with a Eudragit RS: Eudragit RL ratio of 90:10 was prepared as described in Table 8. Table 8. Coating solution of controlled-release polymer layer of nafamostat controlled-release beads (90:10 Eudragit RS: Eudragit RL)

[0154] To produce controlled-release beads with a slow-release rate, the ratio of Eudragit RS to Eudragit RL was changed to 90:10. A Procept fluidized bed was set up as described above, and 250 g of beads containing the nafamostat active agent layer (as described above) were weighed and packed into a container. A coating solution was prepared to produce a uniformly dispersed white opaque solution.

[0155] Coating was initiated and maintained at 2.0 g / min during the coating process. Static electricity issues were observed, with a large number of beads adhering to the inside of the container and the filter. During this coating run, the filter pressure increased rapidly, reaching 50 mbar in just 30 minutes. Backflush characteristics on the fluidized bed were tested, but they did not cause any significant difference in filter pressure. Therefore, reducing and strictly controlling the airflow rate, nozzle flow, and nozzle pressure allows the process to be sustained for a longer period.

[0156] The process takes approximately 4 hours and 30 minutes, achieving the theoretical 20% weight gain. Take 5%, 10%, and 20% bead samples. Place the bulk beads in a container, cure at 40°C for 30 minutes, and then place in a 40°C oven for overnight curing.

[0157] The next morning, the process was restarted using the same bulk beads and the same coating solution in the same container. The filter was replaced as it had exceeded 75 mbar. The purpose of this additional coating was to attempt and achieve a 30% weight gain (an additional 10% on top of the previously achieved 20%). The process was run for another 2 hours, and when the weight gain reached 30%, bead samples were taken and placed in an oven. Spraying approximately 772 g of coating solution resulted in a theoretical coating weight gain of 30%. Adhesive beads were sieved using a 600 μm sieve. All weight gain samples were collected and dissolved and LOD were analyzed. Figure 13 shows a comparison of the release profiles of nafamostat from controlled-release beads with a 90:10 (Eudragit RS:Eudragit RL) ratio as weight increases. Example 8: Preparation method of controlled-release nafamostat composition

[0158] Controlled-release beads containing nafamostat components were prepared. Each controlled-release bead comprised a microcrystalline cellulose core, an active agent layer of nafamostat mesylate, and a controlled-release polymer coating. The active agent layer of nafamostat mesylate was prepared as described in Example 4. A polymer controlled-release coating solution with a Eudragit RS: Eudragit RL ratio of 80:20 was prepared as described in Table 9. Table 9. Coating solution of controlled-release polymer layer of nafamostat controlled-release beads (80:20 Eudragit RS: Eudragit RL)

[0159] To produce controlled-release beads with a faster release rate, the ratio of Eudragit RS to Eudragit RL was changed to 80:20. Using the Procept fluidized bed setup described above, 250g of beads containing the nafamostat active agent layer (as described above) were weighed and packed into a container. A coating solution was prepared to produce a uniformly dispersed white opaque solution. Static electricity was noticeable in this experiment, but could be controlled using an electrostatic gun. Stalactites formed at the bottom of the filter, but they dispersed on their own. Contact with the glass container that helps reduce bead buildup on the glass was avoided.

[0160] The process ran for approximately 3 hours, achieving a 15% weight gain. Samples of 5% and 10% beads were taken. The bulk beads were solidified in a container, then transferred to a metal tray and placed in an oven at 40°C overnight along with the sample beads. By carefully controlling the nozzle pressure and flow rate, the filter did not exceed 40 mbar, allowing the process to continue smoothly. Spraying approximately 369 g of coating solution resulted in a theoretical coating weight gain of 15%. Beads that adhered to the ER coating were sieved using a 600 μm sieve.

[0161] Figure 14A shows a comparison of the average release profiles of nafamostat for coated beads with different Eudragit RS:Eudragit RL weight ratios of 5%. Figure 14B shows a comparison of the average release profiles of nafamostat for coated beads with different Eudragit RS:Eudragit RL weight ratios of 10%. Example 9: Preparation method of controlled-release nafamostat composition

[0162] Controlled-release beads containing nafamostat components were prepared. Each controlled-release bead comprised a microcrystalline cellulose core, an active agent layer of nafamostat mesylate, and a controlled-release polymer coating. The active agent layer of nafamostat mesylate was prepared as described in Example 4. A polymer controlled-release coating solution with a ratio of Eudragit RS: Eudragit RL of 92:8 was prepared as described in Table 10. Due to nozzle clogging and increased bead adhesion, Syloid 244FP was used instead of micronized talc. Table 10. Coating solution of controlled-release polymer layer of nafamostat controlled-release beads (80:20 Eudragit RS: Eudragit RL)

[0163] Using the Procept fluidized bed setup described above, 250g of beads containing a nalfamostat active agent layer (as described above) were weighed and packed into a container. The process ran for approximately 3 hours, achieving a theoretical weight gain of 15%. The bulk beads were placed in the container and cured at 40°C for 15 minutes, then transferred to a metal tray and placed in an oven at 40°C overnight. After overnight curing, a LOD was performed, and the result was comparable to the previous batch (0.85%). By carefully controlling the nozzle pressure and flow rate, with the filter not exceeding 40 mbar, the process could continue to operate smoothly. Spraying approximately 385g of the coating solution resulted in a 15% weight gain. Adhesive beads were sieved using a 600μm sieve. Figure 15 shows a comparison of the nalfamostat release profiles from controlled-release beads with a 5% weight gain from a (Eudragit RS: Eudragit RL) ratio of 92:8. Example 10: Preparation method of controlled-release nalfamostat components

[0164] Controlled-release beads containing nafamostat components were prepared. Each controlled-release bead comprised a microcrystalline cellulose core, an active agent layer of nafamostat mesylate, and a controlled-release polymer coating. The active agent layer of nafamostat mesylate was prepared as described in Example 4. A polymer controlled-release coating solution with an Eudragit RS:Eudragit RL ratio of 92:8 was prepared as described in Table 11. Due to nozzle clogging and increased bead adhesion, Syloid 244FP was used instead of micronized talc. Table 11. Coating solution of controlled-release polymer layer of nafamostat controlled-release beads (80:20 Eudragit RS:Eudragit RL)

[0165] Using the Procept fluidized bed setup described above, 250g of beads containing a nafamostat surfactant layer (as described above) were weighed and placed into a container. The process ran for approximately 3 hours, achieving a theoretical weight gain of 14.7%. The bulk beads were cured in the container at 40°C for 10 minutes, then transferred to a metal tray and placed in an oven at 40°C overnight. LOD was performed after overnight curing, and the result was comparable to the previous batch (0.68%). By carefully controlling the nozzle pressure and flow rate, with the filter pressure not exceeding 40 mbar, the process was allowed to continue smoothly. Spraying approximately 324g of coating solution resulted in a theoretical weight gain of 14.7% for the coating. Adhesive particles in the ER-coated beads were sieved using a 600μm sieve. Figure 16 shows a comparison of the average release profiles of nafamostat from controlled-release beads with a 15% weight gain, wherein the controlled-release polymer layer of these beads has a different ratio of Eudragit RS:Eudragit RL, and syloid 244FP is used instead of micronized talc. Example 11: Extended and immediate release of nafamostat in miniature pigs.

[0166] A pharmaceutical formulation containing nafamostat was synthesized using extended-release beads. In other words, Example 3 investigated the effect of using nafamostat in extended-release beads instead of nafamostat in the pharmaceutical formulations of Examples 1 and 2 (referred to herein as immediate-release). The effect of the nafamostat formulation was measured by blood concentrations of oxycodone, which was released from KC-8 that was also administered together.

[0167] This extended-release drug formulation is a capsule containing multiple beads, each bead having a spherical core of microcrystalline cellulose, the spherical core being coated with an active agent layer, which is then coated with a controlled-release layer (i.e., an extended-release layer or a modified release layer). The active agent layer comprises a mixture of nafamostat and hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose (HPMC)). The controlled-release layer comprises polymers A and B in different ratios, as well as triethyl citrate and talc. Polymer A is a poly(ethyl acrylate, methyl methacrylate, and chlorotrimethylammonium methyl methacrylate) containing approximately 50 mEq of quaternary ammonium groups per 100 g of polymer. Polymer A is purchased in the form of Eudragit RL. Polymer B is a poly(ethyl acrylate, methyl methacrylate, and chlorotrimethylammonium methyl methacrylate) containing approximately 25 mEq of quaternary ammonium groups per 100 g of polymer. Polymer B is purchased in the form of Eudragit RS.

[0168] As shown in the table below, five different types of controlled-release beads were synthesized based on different ratios of polymer A to polymer B. Controlled-release beads Polymer A: Polymer B ratio Bead B 50:50 Bead C 20:80 Bead D 80:20 Bead E 100:0 Bead F 87:13

[0169] Six different studies were conducted as described in the table below. In each study, KC-8 was administered together with nafamostat. While studies 1-5 contained either immediate-release or extended-release nafamostat, study 6 included equal amounts of immediate-release and extended-release nafamostat. Research serial number Release immediately Nafamosta Extended release Nafamosta beads annotation 1 none Beads B, C, or D 2 none Yes; Bead D; 0, 10, 50 or 100 mg Figure 7 3 none Yes; Bead E; 0, 1, 5 Or 10 mg / kg Figure 8 4 Yes; 0, 50 or 100 mg none Figure 9 5 none Yes; Beads F; 0, 50 Or 100 mg Figure 10 6 Yes; 0, 25 or 100 mg Yes; Bead F; 0.25 Or 100 mg Figure 11

[0170] Study 1 involved administering KC-8 and beads B, C, or D. Results showed that beads B and C corresponded to higher maximum oxycodone concentrations, while bead D resulted in lower maximum oxycodone concentrations.

[0171] Study 2 involved administering KC-8 to miniature pigs without nafamostat (control group) or with beads D containing 10, 50, or 100 mg of nafamostat. The results are shown in Figure 7. It was found that increasing the nafamostat concentration from 0 to 10 mg, and then to 50 mg, resulted in a Tmax delay from 2 hours to 4 hours and a decrease in the maximum oxycodone concentration from 10 ng / ml to approximately 5 ng / ml. It was found that 100 mg of nafamostat beads D resulted in a Tmax delay of 6 hours.

[0172] Study 3 involved the administration of beads E, in which the ratio of polymer A to polymer B was 100:0. When the nafamostat concentration was increased from 0 to 1, and then to 5 mg / kg, the maximum oxycodone concentration decreased from approximately 34 ng / ml to approximately 20 ng / ml, with a Tmax of 1 hour (as shown in Figure 8). At 10 mg / kg nafamostat, the time to reach the maximum oxycodone concentration (Tmax) was delayed to 2 hours.

[0173] Study 4 involved administration of immediate-release nafamostat, which was not part of the extended-release beads (as shown in Figure 9). Increasing the amount of immediate-release nafamostat from 0 to 50 mg resulted in a decrease in the maximum oxycodone concentration from 2 ng / ml to 1 ng / ml. Further increasing the amount of immediate-release nafamostat to 100 mg further reduced the maximum oxycodone concentration to approximately 0.2 ng / ml.

[0174] Study 5 involved the administration of nafamostat to bead F. As shown in Figure 10, the maximum oxycodone concentration without nafamostat was 2 ng / ml, but the maximum oxycodone concentration with bead F containing 100 mg nafamostat was only about 1.5 ng / ml, with a Tmax of 2 hours. Increasing the nafamostat dose to 100 mg resulted in a Tmax of oxycodone blood concentration of 6 hours.

[0175] Study 6 involved administering equal amounts of immediate-release nafamostat and Bead F nafamostat. Specifically, miniature pigs were either not receiving nafamostat (control group), or receiving 25 mg of immediate-release nafamostat and 25 mg of Bead F nafamostat, or receiving 100 mg of immediate-release nafamostat and 100 mg of Bead F nafamostat. Figure 11 shows not only the concentration of oxycodone but also the concentration of the oxycodone derivative of KC-8. Increasing the amount of Bead F nafamostat combined with immediate-release nafamostat reduced the maximum oxycodone concentration from about 2 ng / ml to about 0.3 or 0.1 ng / ml. Meanwhile, the KC-8 concentration increased with increasing combination of Bead F nafamostat and immediate-release nafamostat. Example 12: Human trials using KC-8 and nafamostat in immediate-release and extended-release formulations.

[0176] Human trials can be conducted to examine the effects of immediate-release and extended-release nafamostats on KC-8 metabolism.

[0177] This study may involve modifying the dosage of nafamostat and / or the ratio of polymer A to polymer B in extended-release nafamostat beads, such as based on observations of oxycodone concentrations in an individual's blood. In other words, the controlled-release layer containing polymers A and B can be modified, thereby modifying the release kinetics to obtain optimal concentrations of oxycodone in an individual's blood. In some cases, the formulation may also include nafamostat not contained within the controlled-release beads, for example, to make it readily available for pharmaceutical purposes in certain situations.

[0178] A single-dose, two-part study was conducted in healthy individuals to evaluate the pharmacokinetics of oxycodone, KC-8, PFR06082, and nafamostat in immediate-release solution and / or extended-release (ER) capsule formulations when co-administered with KC-8 solution.

[0179] The primary objective of Part 1 may be to evaluate the pharmacokinetics (PK) of oxycodone when administered alone with KC-8 solution and when administered in combination with nafamostat in immediate-release (IR) solution and / or extended-release (ER) capsule prototypes. The primary objective of Part 2 may be to determine the effect of selected combinations of nafamostat IR solution and / or ER capsule prototypes on the dose levels of multiple KC-8 solutions and the PK of selected nafamostat IR / ER formulations of oxycodone. Part 1 Methodology

[0180] Part 1 of this study is a 6-phase, randomized, open-label design. It plans to recruit 24 healthy individuals, roughly equal in number of men and women, who will participate in all 6 phases of Part 1. The 24 recruits will consist of an even number of men and an even number of women (e.g., 12 men and 12 women; 14 men and 10 women, etc.), and, where possible, roughly equal in number of men and women. The individuals will then be randomly assigned to two groups (Group 1 or Group 2) of 12 individuals each, to ensure approximately 8 evaluable individuals in each group.

[0181] In both groups, individuals will receive KC-8 solution alone (reference group; phase 1) and concurrently nafamostat (in IR solution and / or ER proto-capsule form, phases 2 to 6). In addition, individuals will receive a blocking dose of the opioid antagonist naltrexone before and after each regimen in all phases to reduce opioid-related side effects.

[0182] The plan is to administer the medication to the two groups in parallel (with some flexibility in the dosing dates for scheduling purposes); however, after Phase 3 (Programs 1C and 2C), the groups may be merged. Merging groups in subsequent phases (with all individuals receiving the same protocol at any dosing phase) can increase the accuracy of PK parameters in protocols that may be implemented in future studies. If this option is pursued, the merged groups may also be split back into Group 1 and Group 2 for subsequent protocols based on newly emerging PK and safety data.

[0183] Following phases 2, 3, 4, and 5, an interim review will be conducted on the safety and pharmacokinetic data of oxycodone, KC-8, and PFR06082 up to 48 hours after administration to determine the following:

[0184] The dose of nafamostat formulation to be administered in subsequent periods (dose of IR solution, and / or release rate and dose of ER prototype capsule, as applicable);

[0185] Only after Phase 3: Whether to merge or split groups;

[0186] Only after stage 4 (if stage 5 is split, then for each group): Dietary status in stage 5 (eating and fasting);

[0187] Only after phase 5 (or for each group if phase 6 is split): dosage levels of both KC-8 solution and nafamostat formulation in phase 6.

[0188] The extended-release prototype capsule formulation will be selected from a two-dimensional design space describing formulation variables of release rate (90% release within 2 to 16 hours, determined by the Eudragit RS:RL coating ratio) and dose (1 to 100 mg).

[0189] Note that the nafamostat formulation (IR and / or ER) intended to be administered in a fed state during phase 5 will be the formulation selected for administration in part 2 of the study.

[0190] The next part of the protocol (IMP KC-8 and nalfamostat, and NIMP naltrexone) will be administered to the groups in sequence. Part 2 Methodology

[0191] Part 2 of this study is a 5-phase, non-randomized, open-label design. The plan is to recruit 12 healthy individuals for Part 2 of the study, ensuring at least 8 evaluable individuals are available.

[0192] Individuals will receive a combination of KC-8 solution and nafamostat IR solution and / or ER proto-capsule selected from Part 1 (defined as 1 dose unit; i.e., 1 dose unit = KC-8 solution [25 mg] + selected nafamostat formulation [IR and / or ER proto-capsule {22 mg}]). In each phase, the individual will receive an increasing number of dose units. Therefore, a fixed ratio of KC-8:nafamostat will be administered at an increasing dose level to simulate overdose. Note that this is a simulation of overdose; however, the total dose of KC-8 will not exceed 200 mg (equivalent to 80 mg oxycodone), which was administered in the single escalation dose study in Phase 1 and will therefore remain within safe and well-tolerated levels. Furthermore, the fixed ratio selected for Part 2 will be a higher KC-8 / nafamostat dose ratio than in Part 1. A 10:1 KC-8 to nafamostat dose ratio is expected to be used in Part 2. Part 1 is planned to use a lower dose with a ratio in the range of 1:1 to 2.5:1; however, these ratios may be modified based on PK data from Part 1.

[0193] In addition, individuals will receive doses of the opioid antagonist naltrexone before and after each regimen to reduce opioid-related side effects.

[0194] The combination of nafamostat IR solution and / or ER prototype capsules, and the intended dose in Phase 1 (Program G), will be determined following an interim review of the safety and PK data from Part 1 up to 48 hours after administration. This interim review of the safety and PK data up to 48 hours after administration will also be conducted after Phases 1, 2, 3, and 4 to determine the appropriate dose unit number for escalation to the next program, and the intended dose unit number. Furthermore, nafamostat PK is planned to be evaluated in Program K (Phase 5), which is expected to be the highest dose level administered. However, if the highest dose level in Part 2 is not administered under this program, an option may be made to analyze the nafamostat PK using a backup PK sample from a previous program. This decision will be made during an interim review following Phase 4.

[0195] A final review will be conducted after Phase 5 to review the interim data before reporting the data in the clinical study report.

[0196] The highest dose level of KC-8 solution to be administered in Part 2 is 200 mg (8 × 25 mg), which is equivalent to 80 mg of oxycodone. Previous SAD studies using KC-8 have demonstrated that doses up to 200 mg (80 mg of oxycodone) are safe and well-tolerated. SAD data from healthy volunteers receiving 200 mg show that the highest dose of nafamostat that can be administered is 200 mg, which is safe and well-tolerated.

[0197] Although the invention has been described in some detail by way of illustration and examples for the purpose of clear understanding, those skilled in the art will readily understand from the teachings of the invention that certain changes and modifications may be made to the invention without departing from the spirit or scope of the appended claims.

[0198] Therefore, the foregoing only illustrates the principles of the invention. It should be understood that those skilled in the art will be able to design various layouts, although not explicitly described or shown herein, but these layouts embody the principles of the invention and are included within the spirit and scope of the invention. Furthermore, all examples and conditional language listed herein are primarily intended to assist the reader in understanding the principles of the invention and the concepts contributed by the inventors to facilitate the art, and should be interpreted as not being limited to such specifically listed examples and situations. Moreover, all statements herein referencing the principles, forms, and embodiments of the invention, as well as specific examples thereof, are intended to cover both their structural and functional equivalents. Furthermore, such equivalents are intended to include both currently known equivalents and future development equivalents, i.e., any developed element performing the same function, regardless of its structure. Furthermore, nothing disclosed herein is intended to be made public, whether or not such disclosures are explicitly stated in the claims.

[0199] Therefore, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied in the appended claims. In the claims, 35 USC §112(f) or 35 USC §112(6) is explicitly defined as being invoked only when the exact phrase “means for” or the exact phrase “step for” is used at the beginning of such limitation in the claims; if such exact phrase is not used in the limitation of the claims, then 35 USC §112(f) or 35 USC §112(6) is not invoked. [Simplified Explanation of the Diagram]

[0015] [Figure 1] shows the biochemical mechanism by which oxycodone derivatives are converted into active oxycodone by the action of digestive enzymes (such as trypsin).

[0016] [Figure 2] shows the mean blood concentration of oxycodone over time in rats orally administered 5 mg / kg of the oxycodone derivative KC-8 and 0, 0.1, 0.5, or 1 mg / kg of nafamoxicillin.

[0017] [Figure 3] shows the mean blood concentration of oxycodone over time in rats orally administered 50 mg / kg of the oxycodone derivative KC-8 and 0, 1, 5, or 10 mg / kg of nafamoxicillin.

[0018] [Figure 4] shows the mean blood concentration of dihydromorphone in rats orally administered 1, 3, 6 or 10 pills containing dihydromorphone derivatives but not nafamostat.

[0019] [Figure 5] shows the mean blood concentration of dihydromorphone in rats orally administered 1, 3, 6 or 10 pills containing dihydromorphone derivatives, which also contain nafamox.

[0020] [Figure 6] shows the blood concentrations of dihydromorphone in multiple human patients after administration of dihydromorphone derivatives and 0, 1, or 10 mg of nafamostat.

[0021] [Figure 7] shows the oxycodone concentrations in miniature pigs after being given various amounts of nafamosstat in KC-8 and Bead D.

[0022] [Figure 8] shows the oxycodone concentration in miniature pigs given nafamosstat in KC-8 and bead E.

[0023] [Figure 9] shows the concentration of oxycodone in miniature pigs after administration of KC-8 and immediate-release nalfamostat.

[0024] [Figure 10] shows the concentration of oxycodone in miniature pigs after nafamosstat was administered to beads F.

[0025] [Figure 11] shows the concentrations of oxycodone and KC-8 in miniature pigs given a combination of nafamostat in immediate-release form and nafamostat in bead F.

[0026] [Figure 12] shows a comparison of the release profiles of nafamosstat from controlled-release beads with a ratio of 87:13 (Eudragit RS:Eudragit RL) as weight increases.

[0027] [Figure 13] shows a comparison of the release profiles of nafamostat from controlled-release beads with a ratio of 90:10 (Eudragit RS: Eudragit RL) as weight increases.

[0028] [Figure 14A] shows a comparison of the average release profiles of nafamostat from controlled-release beads with a 5% weight gain, wherein the controlled-release beads have different ratios of Eudragit RS:Eudragit RL in the controlled-release polymer layer. [Figure 14B] shows a comparison of the average release profiles of nafamostat from controlled-release beads with a 10% weight gain, wherein the controlled-release beads have different ratios of Eudragit RS:Eudragit RL in the controlled-release polymer layer.

[0029] [Figure 15] shows a comparison of the release profiles of nalfamostar from controlled-release beads with a 5% weight gain and a 92:8 (Eudragit RS:Eudragit RL) ratio.

[0030] [Figure 16] shows a comparison of the average release profiles of nafamosstat from controlled-release beads with a 15% weight gain, wherein the controlled-release polymer layer has a different ratio of Eudragit RS:Eudragit RL and syloid 244FP is used instead of micronized talc.

Claims

1. An oral composition comprising nafamostat or a pharmaceutically acceptable salt thereof, wherein the oral composition provides an individual with controlled release of nafamostat or a pharmaceutically acceptable salt thereof for a prolonged period of time, wherein the oral composition comprises a plurality of controlled-release beads, each bead comprising: a core comprising a cellulose polymer, or silicon dioxide, or a sugar selected from the group consisting of glucose, sucrose, lactose, mannitol, xylitol, and sorbitol, wherein the core comprises the plurality of controlled-release beads. The plurality of controlled-release beads comprise 10% to 50% by weight of each of the beads; an active agent layer, wherein each of the plurality of controlled-release beads comprises 5% to 20% by weight of nafamostat or a pharmaceutically acceptable salt thereof; and a controlled-release layer comprising 5% to 30% by weight of each of the plurality of controlled-release beads, wherein the controlled-release layer comprises 5% to 100% by weight of a polymer, copolymer or combination of one or more acrylates and methacrylates, formulated in an amount sufficient to provide controlled release of nafamostat or a pharmaceutically acceptable salt thereof.

2. The oral composition of claim 1, wherein the active agent layer further comprises a binder.

3. The oral composition of claim 1, wherein the controlled-release layer comprises a combination of the following: acrylate copolymer A, comprising poly(ethyl acrylate, methyl methacrylate and trimethylammonium chloride ethyl methacrylate), each 100g polymer containing about 50 mEq of quaternary ammonium groups; and acrylate copolymer B, comprising poly(ethyl acrylate, methyl methacrylate and trimethylammonium chloride ethyl methacrylate), each 100g polymer containing about 25 mEq of quaternary ammonium groups.

4. The oral composition of claim 3, wherein the controlled-release layer comprises: an acrylate copolymer comprising: 95 wt% acrylate copolymer B and 5 wt% acrylate copolymer A; or an acrylate copolymer comprising: 93 wt% acrylate copolymer B and 7 wt% acrylate copolymer A; or an acrylate copolymer comprising: 92 wt% acrylate copolymer B and 8 wt% acrylate copolymer A; or an acrylate copolymer comprising: 90 wt% acrylate copolymer B and 10 wt% acrylate copolymer A; or an acrylate copolymer comprising: 87 wt% acrylate copolymer B and 13 wt% acrylate copolymer A; or an acrylate copolymer comprising: 80 wt% acrylate copolymer B and 20 wt% acrylate copolymer A; or an acrylate copolymer comprising: 70 wt% acrylate copolymer B and 30 wt% acrylate copolymer A.

5. The oral composition of claim 1, wherein one or more of the active agent layer and the controlled-release layer further comprises a plasticizer.

6. The oral composition of claim 1, wherein the oral composition comprises a plurality of controlled-release beads, each bead comprising: a microcrystalline cellulose core; an active agent layer comprising nafamostat or a pharmaceutically acceptable salt thereof and a water-soluble methylcellulose polymer; and a controlled-release layer comprising: a first polymer comprising poly(ethyl acrylate, methyl methacrylate and chlorotrimethylammonium ethyl methacrylate) containing about 50 mEq of quaternary ammonium groups per 100 g of polymer; a second polymer comprising poly(ethyl acrylate, methyl methacrylate and chlorotrimethylammonium ethyl methacrylate) containing about 25 mEq of quaternary ammonium groups per 100 g of polymer; triethyl citrate; and a lubricant selected from micronized talc and syloid, wherein the controlled-release layer is formulated to provide controlled release of nafamostat or a pharmaceutically acceptable salt thereof.

7. The oral composition of claim 6, wherein the controlled-release layer is formulated to provide the release of 60% or more of nafamostat or its pharmaceutically acceptable salt within 6 hours after administration.

8. The oral composition of claim 6, wherein the controlled-release layer is formulated to provide the release of nafamostat or a pharmaceutically acceptable salt thereof at a first rate during a first predetermined period, and subsequently the release of nafamostat or a pharmaceutically acceptable salt thereof at a second predetermined period at a second rate.

9. The oral composition of claim 1, further comprising an immediately released nafamostat or a pharmaceutically acceptable salt thereof, providing an individual with an immediately released nafamostat or a pharmaceutically acceptable salt thereof.

10. The use of an oral composition of any one of claims 1 to 9 for the preparation of a medicament for oral administration to an individual suffering from opioid use disorder.

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