WO2023102489A1

WO2023102489A1 - Compounds, nanoparticles, and pharmaceutical compositions for the treatment of drug addiction

Info

Publication number: WO2023102489A1
Application number: PCT/US2022/080765
Authority: WO
Inventors: Benson EDAGWA; Howard E. Gendelman
Original assignee: Board Of Regents Of The University Of Nebraska
Priority date: 2021-12-03
Filing date: 2022-12-01
Publication date: 2023-06-08

Abstract

Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: Formula (I). Further disclosed are nanoparticles comprising one of the compounds and methods of using the same for treating drug addiction, drug dependence, drug overdose, opioid use disorder, pain, chronic pain, fibromyalgia, arthritis, or obesity.

Description

COMPOUNDS, NANOPARTICLES, AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DRUG ADDICTION

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/264,902 filed December 3, 2021, which is incorporated herein by reference in its entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This disclosure was made with government support under P01 DA028555 awarded by the National Institutes of Health. The government has certain rights in the disclosure.

BACKGROUND

[0003] The means to treat opioid use disorder (OUD) is timely. For example, buprenorphine (BUP) is an agonist of the p-opioid receptors (MOR) that can be administered in sublingual pill or film form that requires daily dosing. Use of long-acting (LA) formulations of BUP are a preferred route of administration to overcome variability, dose diversion, misuse, and non-adherence. The first BUP implant was approved as a non- degradable ethylene vinyl acetate rod for subdermal insertion. Duration can last for up to 6- month termination necessitates its removal with numerous reported adverse events.

[0004] Two injectable, LA BUP formulations are available for monthly subcutaneous injection forming a solid slow dissolving release. After administration of LA BUP, complete blockade of hydromorphone effects and improved patient-reported outcomes and abstinence are reported. However, existing formulations have shown limitations towards wide-spread application. Such limitations include, but are not limited to, withdrawal, misuse and limited adherence to repeated injections, implantation/removal, and injection/implant site-associated adverse events underscoring the need for better treatments with improved efficacy and safety. [0005] Therefore, there is an immediate need for a long duration, safe and efficacious LA formulations that can effectively treat drug and alcohol dependencies while greatly overcoming the above drawbacks.

SUMMARY

[0006] In certain embodiments, provided herein is a compound of Formula (I):

Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

A is Ci -30 alkyl, Ci-6 alkylene-phenyl, or phenyl, wherein the Ci-6 alkylene-phenyl or phenyl is each optionally substituted with one or more Y;

Y is hydrogen, halogen, Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 alkoxy, Ci-6 heteroalkoxy, or

L is bond, -O-, -S-, -NR’-, Ci-6 alkylene, or Ci-6 heteroalkylene;

R is Ci -30 alkyl, C2-30 alkenyl, C1-30 heteroalkyl, C2-30 heteroalkenyl, phenyl, heteroaryl, or amino acid moiety; and

R’ is hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 heteroalkoxy, or C3-8 carbocyclyl.

[0007] In certain embodiments, provided herein is a compound of Formula (II):

Formula (II), or a pharmaceutically acceptable salt thereof, wherein:

Rx is C1-C30 alkylene, C2-C30 alkenylene, C1-C30 heteroalkylene, C2-C30 heteroalkenylene, phenyl, or heteroaryl.

[0008] In certain embodiments, provided herein are nanoparticles, comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant. [0009] In certain embodiments, disclosed herein are pharmaceutical compositions, comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a nanoparticle disclosed herein, and a pharmaceutically acceptable carrier.

[00010] In certain embodiments, disclosed herein are methods of treating drug addiction, drug dependence, drug overdose, opioid use disorder, pain, chronic pain, fibromyalgia, arthritis, or obesity in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, a nanoparticle disclosed herein, or a pharmaceutical composition disclosed herein.

[00011] In certain embodiments, the compound, nanoparticle, or composition is administered one time in a 1 to 12 month period.

BRIEF DESCRIPTION OF THE DRAWINGS

[00012] FIG. 1 depicts a ’H-NMR spectrum of M2BUP.

[00013] FIG. 2A and FIG. 2B depict 'H-NMR and ¹³C-NMR spectra, respectively, for M3BUP.

[00014] FIG. 3A and FIG. 3B depict 'H-NMR and ¹³C-NMR spectra, respectively, demonstrating ion pairing of M3BUP and pamoic acid.

[00015] FIG. 4A illustrates cellular viability in human monocyte derived macrophages (MDM) for BUP or M3BUP.

[00016] FIG. 4B illustrates cellular uptake of nanoformulation of M3BUP.

DETAILED DESCRIPTION

[00017] As generally described herein, the present disclosure provides compounds, nanoparticles, and pharmaceutical compositions comprising the same, and their use for treating drug addiction, drug dependence, drug overdose, opioid use disorder, pain, chronic pain, fibromyalgia, arthritis, or obesity.

Definitions

[00018] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[00019] Unless defined otherwise, 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 disclosure belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [00020] Throughout the present disclosure, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps. [00021] In the present disclosure, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from the group consisting of two or more of the recited elements or components.

[00022] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein.

[00023] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element.

[00024] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[00025] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[00026] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[00027] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context. For example, the term “about 10 mg” means 10 mg with a ±10% variation from 10 mg, i.e., an amount in the range of 9 mg to 11 mg.

[00028] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual sub-combination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[00029] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[00030] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[00031] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. [00032] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[00033] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., the compound of Formula (I)), which salt is compatible with pharmaceutical administration.

[00034] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[00035] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NWf, wherein W is Ci-4 alkyl, and the like.

[00036] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na⁺, K⁺, Ca²⁺, NH4⁺, and NW₄ ⁺ (where W can be a Ci-4 alkyl group), and the like.

[00037] For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[00038] As used herein, “pharmaceutically acceptable carrier” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. For examples of carriers, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[00039] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non- human animal. “Subject,” “patient”, or “individual” are used interchangeably herein. None of these terms requires supervision of medical personnel.

[00040] As used herein, “administering” means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, transmucosal (e.g., buccal, sublingual, nasal, or transdermal) administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[00041] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from a specified disease, disorder or condition, which action reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition or an action that occurs before a subject begins to suffer from the specified disease, disorder or condition, which action prevents a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevents its recurrence.

[00042] The phrase "therapeutically effective amount" as used herein means an amount of a composition (e.g., a composition described herein), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is effective for producing the desired therapeutic effect in a subject.

[00043] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,

Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

[00044] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[00045] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[00046] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R- compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[00047] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including

²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; F may be in any isotopic form, including ¹⁸F and ¹⁹F; and the like.

[00048] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. When describing the disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[00049] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, c₅, c₆, C1-6, Ci-5, Ci-4, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[00050] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 30 carbon atoms (“C1-30 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[00051] The term “heteroalkyl” as used herein refers to an “alkyl” group in which at least one carbon atom has been replaced with an O, S, or N atom. The heteroalkyl may be, for example, an -O-Ci-Cioalkyl group, an -Ci-Cealkylene-O-Ci-Cealkyl group, or a Ci-Ce alkylene-OH group. In certain embodiments, the “heteroalkyl” may be 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In yet other embodiments, the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen). In certain embodiments, the heteroalkyl is an “alkyl” group in which 1-3 carbon atoms have been replaced with oxygen atoms. One type of heteroalkyl group is an “alkoxy” group.

[00052] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carboncarbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-30 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.

[00053] As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carboncarbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-30 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.

[00054] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.

[00055] As used herein, “heteroalkylene” refers to a divalent radical of a heteroalkyl group. When a range or number of carbons is provided for a particular “heteroalkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Heteroalkylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[00056] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom e.g., 5-indolyl).

[00057] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[00058] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothi azolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [00059] Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ is independently hydrogen, Ci-Cs alkyl, C3-C10 carbocyclyl, 4-10 membered heterocyclyl, Ce-Cio aryl, and 5- 10 membered heteroaryl.

[00060] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a nonaromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I / -in deny! (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[00061] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[00062] As used herein, “halo” or ’’halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[00063] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.

[00064] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[00065] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR^aa, -N(R^CC)2, -CN, - C(=O)R^aa, -C(=O)N(R^CC)₂, -CO₂R^aa, -SO₂R^aa, -C(=NR^bb)R^aa, -C(=NR^cc)OR^aa, - C(=NR^CC)N(R^CC)₂, -SO₂N(R^CC)₂, -SO₂R^CC, -SO₂OR^CC, -SOR^aa, -C(=S)N(R^CC)₂, -C(=O)SR^CC, - C(=S)SR^CC, -P(=O)₂R^aa, -P(=O)(R^aa)₂, -P(=O)₂N(R^CC)₂, -P(=O)(NR^CC)₂, CI-IO alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R³³, R^bb, R^cc and R^dd are as defined above. Compounds

[00066] Disclosed herein, in certain embodiments, are compounds of Formula (I):

Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

L is bond, -O-, -S-, -NR’-, Ci-6 alkylene, or Ci-6 heteroalkylene;

[00067] In certain embodiments, A is C13-30 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y. In certain embodiments, A is C13-27 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y. In certain embodiments, A is C15-27 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene- phenyl or phenyl is each optionally substituted with one or two Y. In certain embodiments, A is C15-23 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y. In certain embodiments, A is C15-21 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y. In certain embodiments, A is C15-19 alkyl, C1-2 alkylene- phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y. [00068] In certain embodiments, A is C1-30 alkyl. In certain embodiments, A is C13-30 alkyl. In certain embodiments, A is C13-25 alkyl. In certain embodiments, A is C13-19 alkyl. In certain embodiments, A is C15-19 alkyl. In certain embodiments, A is C13-17 alkyl. In certain embodiments, A is linear C1-30 alkyl. In certain embodiments, A is linear C13-30 alkyl. In certain embodiments, A is linear C13-25 alkyl. In certain embodiments, A is linear C13-19 alkyl. In certain embodiments, A is linear C15-19 alkyl. In certain embodiments, A is linear C13-17 alkyl.

[00069] In certain embodiments, A is C1-6 alkylene-phenyl optionally substituted with one or more Y. In certain embodiments, A is C1-3 alkylene-phenyl optionally substituted with one or more Y. In certain embodiments, A is C1-2 alkylene-phenyl optionally substituted with one or more Y. In certain embodiments, A is -CFh-phenyl optionally substituted with one or more Y. In certain embodiments, A is C1-6 alkylene-phenyl optionally substituted with 1 or 2 Y. In certain embodiments, A is C1-3 alkylene-phenyl optionally substituted with 1 or 2 Y. In certain embodiments, A is C1-2 alkylene-phenyl optionally substituted with 1 or 2 Y. In certain embodiments, A is -CFb-phenyl optionally substituted with 1 or 2 Y.

[00070] In certain embodiments, A is phenyl optionally substituted with one or more Y. In certain embodiments, A is phenyl optionally substituted with 1 or 2 Y.

[00071] In certain embodiments, the compound is a compound of Formula (I-a):

Formula (I-a), or a pharmaceutically acceptable salt thereof, wherein n is an integer of 0-5.

[00072] In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[00073] In certain embodiments, the compound is a compound of Formula (I-b):

Formula (I-b), or a pharmaceutically acceptable salt thereof, wherein n is an integer of 0-5.

[00074] In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[00075] In certain embodiments, the compound is a compound of Formula (I-c), Formula (I-d), or Formula (I-e):

Formula (I-e), or a pharmaceutically acceptable salt thereof. [00076] In certain embodiments, the compound is a compound of Formula (I-f),

Formula (I-g), or Formula (I-h):

Formula (I-f) Formula (I-g) Formula (I-h), or a pharmaceutically acceptable salt thereof.

[00077] In certain embodiments, L is -O-. In certain embodiments, L is -S-. In certain embodiments, L is -NR’. In certain embodiments, L is Ci-6 heteroalkylene. Exemplary Ci-6 heteroalkylene for L is -CH2-O- or -O-CH2-.

[00078] In certain embodiments, R is C9-C25 alkyl. In certain embodiments, R is C11- C21 alkyl. In certain embodiments, R is C11-C19 alkyl. In certain embodiments, R is C11-C15 alkyl. In certain embodiments, R is C13-C19 alkyl. In certain embodiments, R is C13-C17 alkyl In certain embodiments, R is C13 alkyl. In certain embodiments, R is C17 alkyl. In certain embodiments, R is linear C9-C25 alkyl. In certain embodiments, R is linear C11-C21 alkyl. In certain embodiments, R is linear C11-C19 alkyl. In certain embodiments, R is linear C11-C15 alkyl. In certain embodiments, R is linear C13-C19 alkyl. In certain embodiments, R is linear C13-C17 alkyl. In certain embodiments, R is linear, saturated C13 alkyl. In certain embodiments, R is linear, saturated C17 alkyl.

[00079] In certain embodiments, the compound is one of the following:

or a pharmaceutically acceptable salt thereof, wherein X is -O-, -S-, or -NH.

[00080] In certain embodiments, X is -O-. In certain embodiments, X is -S-. In certain embodiments, X is -NH-.

[00081] In certain embodiments, provided herein are compounds of Formula (II):

Formula (II), or a pharmaceutically acceptable salt thereof, wherein:

[00082] In certain embodiments, Rx is C1-C30 alkylene. In certain embodiments, Rx is C2-C30 alkenylene. In certain embodiments, Rx is C1-C30 heteroalkylene. In certain embodiments, Rx is C2-C30 heteroalkenylene.

[00083] In another aspect, provided herein are prodrugs of naltrexone, naloxone, methylnaltrexone, nalodeine, samidorphan, nalmefene, or other opioid antagonists and agonists.

[00084] In certain embodiments, the prodrugs of the present disclosure comprise a modification to the parent compound including, but not limited to, additions of ester groups, fatty acid ester groups (including diester and mono-ester groups), amino acid fatty esters, and fatty ester dimer-based prodrugs.

[00085] In various embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is a salt of the compound of Formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[00086] In various embodiments, the pharmaceutically acceptable salt of the compound of Formula (II) is a salt of the compound of Formula (II) with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[00087] In some embodiments, the compounds of Formula (I) or (II) are formed into nanocrystals or other crystalline forms. In certain embodiments, the compounds are complexed with a hydrophobic counterion, including but not limited to pamoic acid, myristic acid, palmitic acid, stearic acid, behenic acid, napsylate, mandelic acid, tosylate, benzenesulfonate, benzoate, besylate, hydroxynaphthoate and isothionates used to form a crystalline and/or solid salt compound forms. In certain embodiments, the pharmaceutically acceptable salt is a pamoate salt.

[00088] In certain embodiments, the pharmaceutically acceptable salt can be characterized by a ratio of drug to counterion of 1 : 1 or 2: 1. The compound salt can be crystalline or an amorphous solid.

[00089] In certain embodiments, the compounds disclosed herein modulate the opioid receptor. For example, buprenorphine (BUP) is a high affinity partial agonist for the p-opioid receptor (MOR). Buprenorphine greatly reduces the effect of most other MOR agonists, can cause precipitated withdrawal when used in actively opioid dependent subjects, and has a lower incidence of respiratory depression and fatal overdose relative to full MOR agonists. See, e.g., Gudin, Jeffrey; Fudin, Jeffrey, "A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain" Pain and Therapy, 2020, 9 (1): 41-54; Robinson SE, "Buprenorphine: an analgesic with an expanding role in the treatment of opioid addiction" CNS Drug Reviews, 2002, 8 (4): 377-90; and Khanna, Ish K.; Pillarisetti, Sivaram "Buprenorphine - an attractive opioid with underutilized potential in treatment of chronic pain" Journal of Pain Research, 2015, 8: 859-870. Buprenorphine is also hypothesized to be a high affinity antagonist of K-opioid receptor (KOR), a high affinity antagonist for 6-opioid receptor (DOR), and a weak affinity, weak partial agonist of nociception receptor (NOP, ORL-1).

[00090] In certain embodiments, the compounds disclosed herein are very high affinity partial agonist of MOR. In certain embodiments, the compounds disclosed herein are high affinity antagonist of KOR. In certain embodiments, the compounds disclosed herein are high affinity antagonist of DOR. In certain embodiments, the compounds disclosed herein are weak partial agonist of NOP or ORL-1.

[00091] In certain embodiments, the compounds disclosed herein reduce the severity of or prevent adverse events associated with administration of opioid receptor modulators such as buprenorphine. Exemplary adverse events associated with administration of opioid receptor modulators such as buprenorphine includes, but are not limited to, constipation, dizziness, drowsiness, headache, nausea, drug withdrawal, fatigue, vomiting, hyperhidrosis, xerostomia, stomach pain, difficulty falling asleep or staying asleep, blurred vision, back pain, hives, rash, itching, overdose, and respiratory depression. In certain embodiments, administration of a compound disclosed herein provides for a controlled release of opioid receptor modulators such as buprenorphine relative to the administration of opioid receptor modulators such as buprenorphine.

Nanoparticles

[00092] Disclosed herein, in certain embodiments, are nanoparticles, comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a polymer or surfactant. Typically, the compound (including any crystalline or solid salt form of the compound) maybe encapsulated by a polymer or surfactant coating to form nanoparticles (or nanoformulations).

[00093] In certain embodiments, the compound: polymer (or surfactant) ratio (by weight) is about 10: 1, about 10:6 to about 1000:6, about 20:6 to about 500:6, about 50:6 to about 200:6, or about 100:6.

[00094] In certain embodiments, the nanoparticles comprise a pharmaceutically acceptable salt of the compound of Formula (I) or (II), and a polymer or surfactant.

[00095] In a particular embodiment, the nanoparticles are a submicron colloidal dispersion of nanosized compound crystals or solid salt forms of the compound stabilized by polymers (or surfactants) (e.g., polymer-coated compound crystals; a nanoformulation). In a particular embodiment, the compound of the nanoparticles may be crystalline or a solid salt form complexed with a hydrophobic counterion. In certain embodiments, the nanoparticles containing the compound are crystalline. In certain embodiments, the nanoparticles and/or the compound may be crystalline, amorphous, or are solid-state nanoparticles of the compound that is formed as crystal that combines the compound and polymer (or surfactant). As used herein, the term “crystalline” refers to an ordered state (i.e. non-amorphous) and/or a substance exhibiting long-range order in three dimensions. In a particular embodiment, the majority e.g., at least 50%, 60%, 70%, 80%, 90%, 95% or more) of the compound (and, optionally the hydrophobic portion of the polymer (or surfactant) are crystalline or a solid salt form complexed with a hydrophobic counterion.

[00096] In certain embodiments, the resultant nanoparticle is up to about 2 or 3 pm in diameter (e.g., average diameter) or its longest dimension, particularly up to about 1 pm (e.g., about 100 nm to about 1 pm). For example, the diameter or longest dimension of the nanoparticle may be about 50 to about 800 nm. In a particular embodiment, the diameter or longest dimension of the nanoparticle is about 50 to about 750 nm, about 50 to about 500 nm, about 200 nm to about 500 nm, or about 200 nm to about 400 nm. The nanoparticles may be, for example, rod shaped, elongated rods, irregular, or round shaped. The nanoparticles of the instant disclosure may be neutral or charged. The nano particles may be charged positively or negatively.

[00097] Methods of synthesizing the nanoparticles of the instant disclosure are known in the art. In certain embodiment, the methods generate nanoparticles comprising a compound (e.g., crystalline or amorphous) coated (either partially or completely) with a polymer (or surfactant). Examples of synthesis methods include, without limitation, milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, and/or sonication techniques. For example, U.S. Patent Application Publication No. 2013/0236553, incorporated by reference herein, provides methods suitable for synthesizing nanoparticles of the instant disclosure. In a particular embodiment, the polymers (or surfactants) are firstly chemically modified with targeting ligands and then used directly or mixed with non-targeted polymers (or surfactants) in certain molar ratios to coat on the surface of drug suspensions - e.g, by using a nanoparticle synthesis process (e.g, a crystalline nanoparticle synthesis process) such as milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, and/or sonication techniques, thereby preparing targeted nanoformulations. The nanoparticles may be used with or without further purification, although the avoidance of further purification is desirable for quicker production of the nano particles. In a particular embodiment, the nanoparticles are synthesized using milling and/or homogenization.

[00098] In a particular embodiment, the nanoparticles are synthesized by adding the compound to a polymer (or surfactant) (described below) solution and then generating the nanoparticles (e.g., by wet milling or high pressure homogenization). The compound and polymer (or surfactant) solution may be agitated prior to wet milling or high pressure homogenization to form nanoparticles.

[00099] Examples of polymers (or surfactants) include, without limitation, synthetic or natural phospholipids, PEGylated lipids (e.g., PEGylated phospholipid), lipid derivatives, polysorbates, amphiphilic copolymers, amphiphilic block copolymers, polyethylene glycol)- co-poly(lactide-co-glycolide) (PEG-PLGA), their derivatives, ligand-conjugated derivatives and combinations thereof. Further examples of surfactants include, without limitation: 1) nonionic surfactants (e.g., pegylated and/or polysaccharide-conjugated polyesters and other hydrophobic polymeric blocks such as poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), other polyesters, polypropylene oxide), poly(l,2-butylene oxide), poly(n-butylene oxide), poly(tetrahydrofuran), and poly(styrene); glyceryl esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, polypropyleneglycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, poloxamines, cellulose, methylcellulose, hydroxylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polysaccharides, starch and their derivatives, hydroxy ethyl starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone, and their combination thereof); and 2) ionic surfactants (e.g., phospholipids, amphiphilic lipids, 1,2-dialkylglycero- 3-alkylphophocholines, 1, 2- di stearoyl -snglecro-3 -phosphocholine (DSPC), 1,2-distearoyl- sn-glycero-3- phosphoethanolamine-N[carboxy(polyethylene glycol) (DSPE-PEG), dimethylaminoethanecarbamoyl cholesterol (DC-Chol), N-[l-(2,3-Dioleoyloxy)propyl]- N,N,N-trimethylammonium (DOTAP), alkyl pyridinium halides, quaternary ammonium compounds, lauryldimethylbenzylammonium, acyl carnitine hydrochlorides, dimethyldioctadecylammonium (DDAB), n-octylamines, oleylamines, benzalkonium, cetyltrimethylammonium, chitosan, chitosan salts, poly(ethylenimine) (PEI), poly(N- isopropyl acrylamide(PNIPAM), and poly(allylamine) (PAH), poly (dimethyldiallylammonium chloride) (PDDA), alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecyl sulfate, alkyl polyoxyethylene sulfates, alginic acid, alginic acid salts, hyaluronic acid, hyaluronic acid salts, gelatins, dioctyl sodium sulfosuccinate, sodium carboxymethylcellulose, cellulose sulfate, dextran sulfate and carboxymethylcellulose, chondroitin sulfate, heparin, synthetic poly(acrylic acid) (PAA), poly (methacrylic acid) (PMA), poly(vinyl sulfate) (PVS), poly(styrene sulfonate) (PSS), bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, derivatives thereof, and combinations thereof).

[000100] The polymer (or surfactant) of the instant disclosure may be charged or neutral. In a particular embodiment, the polymer (or surfactant) is neutral or negatively charged (e.g., poloxamers, polysorbates, phospholipids, and their derivatives).

[000101] In a particular embodiment, the polymer (or surfactant) is an amphiphilic block copolymer or lipid derivative. In a particular, embodiment, at least one polymer (or surfactant) of the nanoparticle is an amphiphilic block copolymer, particularly a copolymer comprising at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene). In a particular embodiment, the polymer (or surfactant) is a triblock amphiphilic block copolymer. In a particular embodiment, the polymer (or surfactant) is a triblock amphiphilic block copolymer comprising a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol.

[000102] In a particular embodiment, the amphiphilic block copolymer is a copolymer comprising at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene).

[000103] Examples of pol oxamers include, without limitation, Pluronic® L31, L35, F38, L42, L43, L44, L61, L62, L63, L64, P65, F68, L72, P75, F77, L81, P84, P85, F87, F88, L92, F98, L101, P103, P104, PIOS, F108, L121, L122, L123, F127,10RS, 10R8, 12R3,17R1,17R2,17R4, 17R8,22R4,25R1,25R2,2SR4,25RS,2SR8,31R1, 31R2, and 31R4. [000104] In a particular embodiment, the polymer (or surfactant) is poloxamer 407 (Pluronic® F 127).

[000105] In a particular embodiment of the disclosure, the polymer (or surfactant) is present in the nano particle and/or surfactant solution to synthesize the nanoparticle (as described hereinabove) at a concentration ranging from about 0.0001% to about 10% or 15% by weight. In a particular embodiment, the concentration of the polymer (or surfactant) ranges from about 0.01% to about 15%, about 0.01% to about 10%, or about 0.1% to about 6% by weight. In a particular embodiment, the nanoparticle comprises at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or higher therapeutic agent by weight.

[000106] The compounds and nanoformulations thereof of the present disclosure may be used for the treatment and or prevention of drug and alcohol addiction, drug abuse, abstinence or overdose. In one embodiment the compounds and/or nanoformulations thereof are used for the treatment of opioid use disorders such as opioid dependence/addiction. In addition, the compounds and nanoformulations thereof of the present disclosure can also be used for treating diseases/disorders not related to drug addiction including but not limited to cancer, pain {including chronic pain, degenerative pain, inflammatory pain, visceral pain, neuropathic pain or trauma-related (broken bones, dental, burns, surgery) pain, fibromyalgia, arthritis and obesity.

[000107] The compounds may also be packaged with additional drugs or compounds into nanoparticles (or nanoformulations) or co-administered with other drugs.

Pharmaceutical Compositions

[000108] Disclosed herein, in certain embodiments, are pharmaceutical compositions, comprising a compound of Formula (I) or (II) or a nanoparticle comprising the same, and a pharmaceutically acceptable carrier. The compounds and nanoformulations of the present disclosure may be conveniently formulated for administration with any pharmaceutically acceptable carrier(s).

[000109] In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of Formula (I) or (II) or a nanoparticle comprising the same, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is an aqueous suspension.

[000110] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally. In certain embodiments, the pharmaceutical compositions disclosed herein are administered via injection.

[000111] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the compound or nanoparticle is administered one time in a 1 to 12 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 1 month period. In certain embodiments, the compound or nanoparticle is administered one time in a2 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 3 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 4 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 5 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 6 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 7 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 8 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 9 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 10 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 11 month period. In certain embodiments, the compound or nanoparticle is administered one time in a 12 month period. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[000112] It is envisioned that the compounds and nanoformulations of the compounds will be useful as long acting slow release treatments for diseases. The compounds and nanoformulations will allow for decreased dosing regimens. For example it is envisioned that the compounds and/or nanoformulations of the compounds can be given once every month to once a year. Examples include administration once every month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, and once every 12 months.

[000113] The pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. [000114] In various embodiments, the pharmaceutical compositions provided herein comprise the compound of Formula (I) or (II) as the sole active agent, or in combination with other active agents.

[000115] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21^st ed., Lippincott Williams & Wilkins, 2005. Methods of treatment

[000116] The compounds, nanoparticles, and pharmaceutical compositions of the present disclosure are useful in treating drug addiction, drug dependence, drug overdose, opioid use disorder, pain, acute pain, chronic pain, fibromyalgia, arthritis, or obesity. Drug Addiction and Drug Dependence

[000117] Drug addiction, also called substance use disorder, refers to a disease that affects an individual’s brain and behavior and leads to an inability to control the use of a legal or illegal drug or medication. When addicted, the individual may continue using the drug despite the harm it causes. As drug use increases, the individual may need larger doses of the drug to feel its effect or find that it is increasingly difficult to go without the drug (drug dependence). Attempts to stop drug use may cause intense cravings and make the individual feel physically ill (withdrawal symptoms). Drug addiction symptoms or behaviors include, among others: feeling of having to use the drug regularly — daily or even several times a day; having intense urges for the drug that block out any other thoughts; needing more of the drug to get the same effect, over time; taking larger amounts of the drug over a longer period of time than intended; ensuring a supply of the drug; not meeting obligations and work responsibilities, or cutting back on social or recreational activities because of drug use; continuing to use the drug, despite knowledge that it causes social problems or physical or psychological harm; failing to stop using the drug; and experiencing withdrawal symptoms upon attempt to stop taking the drug. Exemplary drugs where the individual has an addiction or dependence include, but are not limited to, marijuana, hashish and other cannabiscontaining substances, K2, Spice, bath salts, barbiturates (such as phenobarbital and secobarbital (Seconal)), benzodiazepines, (sedatives, such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin) and chlordiazepoxide (Librium)), hypnotics (such as prescription sleeping medications such as zolpidem (Ambien, Intermezzo, others) and zaleplon (Sonata)), methamphetamine, cocaine and other stimulants (such as methylphenidate (Ritalin, Concerta, others) and amphetamine-dextroamphetamine (Adderall, Adderall XR, others)), inhalants (such as glue, paint thinners, correction fluid, felt tip marker fluid, gasoline, cleaning fluids and household aerosol products), and opioids (such as heroin, morphine, codeine, methadone and oxycodone).

Drug Overdose

[000118] A drug overdose (overdose or OD) refers to the ingestion or application of a drug or other substance in quantities greater than are recommended. Drug overdose may be accidental overuse or intentional misuse. A drug overdose may result in a toxic state or death. Signs and symptoms of a drug overdose vary depending on the drug or exposure to toxins. Generally, in an overdose, the effects of the drug may be a heightened level of the therapeutic effects seen with regular use. In overdose, side effects become more pronounced, and other effects can take place, which would not occur with normal use. Large overdoses of some medications cause only minimal effects, while smaller overdoses of other medications can cause severe effects, possibly death. A single dose of some medications can be lethal to a young child. Some overdoses may worsen a person's chronic disease. Symptoms of opioid overdoses include slow breathing, heart rate and pulse. Opioid overdoses can also cause pinpoint pupils, and blue lips and nails due to low levels of oxygen in the blood. An individual experiencing an opioid overdose might also have muscle spasms, seizures and decreased consciousness. A individual experiencing an opiate overdose usually will not wake up even if their name is called or if they are shaken vigorously.

[000119] Opioid use disorder refers to use (e.g., chronic use) of opioids that causes clinically significant distress or impairment in a subject. Opioid use disorder diagnosis is generally based on the American Psychiatric Association DSM-5 and includes a desire to obtain and take opioids despite social and professional consequences. Examples of opioids include, but are not limited to, heroin, morphine, codeine, fentanyl, and synthetic opioids such as oxycodone. Symptoms of opioid use disorder includes, but are not limited to, an overpowering desire to use opioids, increased opioid tolerance, withdrawal syndrome when discontinued, dependence and addiction with addiction representing the most severe form of the disorder.

Pain

[000120] Pain refers to an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. Pain includes acute pain, chronic pain, neuropathic pain, nociceptive pain, and radicular pain.

Acute pain

[000121] Acute pain refers to pain is short in duration, lasting from minutes to about three months (sometimes up to six months). Acute pain is typically related to a soft-tissue injury or a temporary illness. Acute pain from an injury may evolve into chronic pain if the injury does not heal correctly or if the pain signals malfunction.

Chronic pain

[000122] Chronic pain refers to pain that lasts longer in duration. It can be constant or intermittent. For example, headaches can be considered chronic pain when they continue over many months or years - even if the pain is not always present. Chronic pain is often due to a health condition, such as arthritis, fibromyalgia, or a spine condition.

Neuropathic pain

[000123] Neuropathic pain is generally due to damage to the nerves or other parts of the nervous system. It is often described as shooting, stabbing, or burning pain, or it feels like pins and needles. It can also affect sensitivity to touch and can make someone have difficulty feeling hot or cold sensations. Neuropathic pain is a common type of chronic pain. It may be intermittent (meaning it comes and goes), and it can be so severe that it makes performing everyday tasks difficult. Because the pain can interfere with normal movement, it can also lead to mobility issues.

Nociceptive pain

[000124] Nociceptive pain refers to a type of pain caused by damage to body tissue. It is often described as being a sharp, achy, or throbbing pain. It is often caused by an external injury. This type of pain is often experienced in the joints, muscles, skin, tendons, and bones. It can be both acute and chronic.

Radicular pain

[000125] Radicular pain refers to a specific type of pain can occur when the spinal nerve gets compressed or inflamed. It radiates from the back and hip into the leg(s) by way of the spine and spinal nerve root. Individuals who have radicular pain may experience tingling, numbness, and muscle weakness. Pain that radiates from the back and into the leg is called radiculopathy. It is commonly known as sciatica because the pain is due to the sciatic nerve being affected. This type of pain is often steady, and individuals can feel it deep in the leg. Walking, sitting, and some other activities can make sciatica worse. It is one of the most common forms of radicular pain.

Fibromyalgia

[000126] Fibromyalgia refers to a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Symptoms include pain and stiffness all over the body, fatigue and tiredness, depression and anxiety, sleep problems, problems with thinking, memory, and concentration, headaches, including migraines, tingling or numbness in hands and feet, pain in the face or jaw, including disorders of the jaw known as temporomandibular joint syndrome (also known as TMJ), and digestive problems, such as abdominal pain, bloating, constipation, and even irritable bowel syndrome (also known as IBS) Arthritis

[000127] Arthritis refers to the swelling and tenderness of one or more joints. The main symptoms of arthritis are joint pain and stiffness, which typically worsen with age. Arthritis includes, but are not limited to, osteoarthritis, fibromyalgia, gout, psoriatic arthritis, rheumatoid arthritis, lupus, ankylosing spondylitisjuvenile arthritis, adult-onset Still’s disease, Behget’s Disease, bursitis, Calcium Pyrophosphate Deposition Disease (CPPD), carpal tunnel syndrome, chondromalacia patella, chronic fatigue syndrome, complex regional pain syndrome, Cryopyrin-Associated Periodic Syndromes (CAPS), degenerative disc disease, developmental-dysplasia of hip, Ehlers-Danlos, familial Mediterranean fever, giant cell arteritis, hemochromatosis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease, Juvenile Dermatomyositis (JD), juvenile scleroderma, Kawasaki disease, mixed connective tissue disease, myositis (including polymyositis, dermatomyositis), osteoporosis, Pagets, palindromic rheumatism, patellofemoral pain syndrome, pediatric rheumatic diseases, polymyalgia rheumatica, pseudogout, Rynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter’s syndrome, rheumatic fever, rheumatism, scleroderma, Sjogren’s disease, spinal stenosis, spondyloarthritis, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, systemic lupus erythematosus, systemic sclerosis, temporal arteritis, tendinitis, vasculitis, and Wegener’s granulomatosis.

Obesity

[000128] Obesity is a complex disease involving an excessive amount of body fat. Obesity increases the risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure and certain cancers. Animal studies suggest that endogenous opioid system has an important role in the control of appetite. MOR agonists increase and opioid antagonists decrease food intake and hedonic pleasures caused by palatable foods (Gosnell and Levine, 2009; Pecina and Smith, 2010). Opioid antagonists also prevent food seeking and binge-like eating (Giuliano et al., 2012; Cambridge et al., 2013). Moreover, stimulation of the MOR in the shell of nucleus accumbens increases the pleasure responses for foods and may also trigger eating behavior (Pecina and Berridge, 2005). The p-opioid receptor gene 0PRM1 also modulates the intake of fat and possibly the risk for gaining weight in humans (Haghighi et al., 2014). Accordingly, changes in MOR rather than D2R availability can maintain excessive energy uptake due to altered hedonic processing of food. EXAMPLES

[000129] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Synthesis of compounds of Formula (I)

[000130] BUP was chemically modified to produce M2BUP and M3BUP:

where X is -O-.

[000131] The samples were dissolved in CDCh and analyzed on a Varian Unity /Inova- 500 NB (500 MHz). Buprenorphine (BUP) (400 mg, 0.793 mmol) was added to 10.0 mL of anhydrous pyridine and the resultant slurry was evaporated to dryness on a rotavapor. The BUP powder was then redissolved in anhydrous pyridine (10.0 mL) and added to a solution of the acylating aryl moiety (as an acyl chloride) in anhydrous tetrahydrofuran (10.0 mL) at - 10°C under an argon atmosphere. The reaction mixture was then warmed to 45°C under stirring for 24h. The resultant BUP prodrug was purified by silica gel column chromatography using an eluent of 4:1 mixture of hexanes and ethyl acetate. The desired compound fractions from the columns were dried on a rotary evaporator to obtain solids that were dried under high vacuum to give the desired oily compounds in high chemical yields. The synthesized oily prodrugs were then transformed into free flowing pamoate salt powders. To make the pamoate salts, the prodrug and pamoic acid (1 : 1 or 2: 1) were dissolved in DMSO (10.0 mL) and warmed to 75°C for at least 40 minutes, the salt solution was then poured in a beaker of stirring HPLC grade water (200.0 mL) to form BUP prodrug salt precipitates that were collected and dried under vacuum. Successful synthesis of prodrugs and salts was confirmed by proton and carbon nuclear magnetic resonance (^XH and ¹³C NMR) spectra using Bruker Avance-III HD (Billerica, MA) operating at 500 MHz, a magnetic field strength of 11.7 T. Nanocrystals of BUP prodrug salts were manufactured by high-pressure homogenization in aqueous buffers stabilized by non-ionic surfactants. Specifically, the BUP prodrug salt was dispersed in a P407 solution in endotoxin free water and allowed to form a presuspension. The prodrug to P407 ratio was maintained at 10: 1 (w/w). The presuspensions were homogenized on an Avestin EmulsiFlex-C3 high-pressure homogenizer at 15,000- 20,000 psi until the desired particle size of 250-350 nm was achieved. Nanoparticles were characterized for particle size, PDI and zeta potential by dynamic light scattering using a Malvern Zetasizer Nano-ZS.

[000132] FIG. 1 depicts a 'H-NMR spectrum of M2BUP. FIG. 2A and FIG. 2B depict ’H-NMR and ¹³C-NMR spectra, respectively, for M3BUP. FIG. 3A and FIG. 3B depict ¹H- NMR and ¹³C-NMR spectra, respectively, demonstrating ion pairing of M3BUP and pamoic acid.

Example 2. In vitro characterization of M3BUP.

[000133] The cellular viability and cellular uptake of a nanoformulation of M3BUP were evaluated. FIG. 4A shows cellular viability in human monocyte derived macrophages (MDM) for BUP or M3BUP. Cellular viability in human monocyte derived macrophages (MDM) was determined after 8 hours of BUP or M3BUP treatment over a range of concentrations (4-128 ng/mL) by using MTT assay. M3BUP treatment did not show cytotoxicity at any concentration. Data are expressed as the mean ± SEM for N = 4 biological replicates. FIG. 4B shows cellular uptake of nanoformulation of M3BUP. Nanoformulation uptake was assessed in human MDMs. Specifically, nanoformulated M3BUP (NM3BUP) was evaluated for intracellular uptake. NM3BUP was readily taken up by macrophages and, released compound (M3BUP) from nanoformulations was steadily hydrolyzed intracellularly into its active drug BUP and metabolite NorBUP. Compound, active drug and metabolite levels were quantified by mass spectrometer.

EQUIVALENTS

[000134] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A compound of Formula (I):

Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

L is bond, -O-, -S-, -NR’-, Ci-6 alkylene, or Ci-6 heteroalkylene;

2. The compound of claim 1, wherein A is C15-27 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y.

3. The compound of claim 1, wherein A is C15-21 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one or two Y.

4. The compound of claim 1, wherein A is C15-19 alkyl, C1-2 alkylene-phenyl, or phenyl, wherein the C1-2 alkylene-phenyl or phenyl is each optionally substituted with one Y.

5. The compound of claim 1, wherein the compound is a compound of Formula (I-a):

6. The compound of claim 1, wherein the compound is a compound of Formula (I-b):

7. The compound of claim 5, wherein the compound is a compound of Formula (I-c), Formula (I-d), or Formula (I-e):

Formula (I-c) Formula (I-d) Formula (I-e), or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, wherein the compound is a compound of Formula (I-f), Formula (I-g), or Formula (I-h):

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9. The compound of claim 1, wherein L is -O-.

10. The compound of claim 1, wherein L is -CH2-O- or -O-CH2-.

11. The compound of claim 1, wherein R is C11-C19 alkyl.

12. The compound of claim 11, wherein R is C13-C17 alkyl.

13. The compound of claim 12, wherein R is C13 alkyl.

14. The compound of claim 12, wherein R is C17 alkyl.

15. The compound of claim 1, wherein the compound is one of the following:

or a pharmaceutically acceptable salt thereof, wherein X is -O-, -S-, or -NH.

16. The compound of claim 15, wherein X is -O-.

17. A compound of Formula (II):

Formula (II), or a pharmaceutically acceptable salt thereof, wherein:

18. The compound of any one of claims 1-17, wherein the compound is complexed with a hydrophobic counterion selected the group consisting of pamoic acid, myristic acid, palmitic acid, stearic acid, behenic acid, napsylate, mandelic acid, tosylate, benzenesulfonate, benzoate, besylate, hydroxynaphthoate, and isethionate.

19. The compound of any one of claims 1-17, wherein the pharmaceutically acceptable salt is a pamoate salt.

20. A nanoparticle, comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant.

21. A nanoparticle, comprising a pharmaceutically acceptable salt of the compound of any one of claims 1-17, and a polymer or surfactant.

22. The nanoparticle of claim 21, wherein the pharmaceutically acceptable salt of the compound is a pamoate salt.

23. The nanoparticle of any one of claims 20-22, wherein the polymer or surfactant is an amphiphilic block copolymer.

24. The nanoparticle of claim 23, wherein the amphiphilic block copolymer comprises at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene).

25. The nanoparticle of claim 23, wherein said polymer or surfactant is a poloxomer.

26. The nanoparticle of claim 23, wherein said polymer or surfactant is P407.

27. The nanoparticle of any one of claim 20-26, wherein the diameter of the nanoparticle is about 100 nm to 1 pm.

28. A pharmaceutical composition, comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a nanoparticle of any one of claims 20-27, and a pharmaceutically acceptable carrier.

29. A method of treating drug addiction, drug dependence, drug overdose, opioid use disorder, pain, chronic pain, fibromyalgia, arthritis, or obesity in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, a nanoparticle of any one of claims 20-27, or a pharmaceutical composition of claim 28.

30. The method of claim 29, wherein the disease or disorder is opioid use disorder.

31. The method of claim 29, wherein the compound, nanoparticle, or composition is administered via injection.

32. The method of claim 31, wherein the compound, nanoparticle, or composition is administered one time in a 1 to 12 month period.

33. The method of claim 31, wherein the compound, nanoparticle, or composition is administered one time in a 3 month period.

34. The method of claim 31, wherein the compound, nanoparticle, or composition is administered one time in a 6 month period.

35. The method of claim 31, wherein the compound, nanoparticle, or composition is administered one time in a 9 month period.

36. The method of claim 31, wherein the compound, nanoparticle, or composition is administered one time in a 12 month period.

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