Injectable sustained-release formulations of naltrexone

Abstract

The present disclosure provides an injectable sustained-release pharmaceutical formulation comprising 3-acyl-naltrexone or a pharmaceutically acceptable salt thereof, a biocompatible organic solvent, and, optionally, a biocompatible polymeric material. The present disclosure also provides a method for treating opioid use disorder or alcoholism, comprising administering the injectable sustained-release pharmaceutical formulation to a subject in need thereof. The pharmaceutical formulation provides a sustained-release profile after a single injection, and can provide sustained-release naltrexone plasma levels in minipigs for two months.

Description

[Technical field]

[0001] The present disclosure relates to an injectable sustained release pharmaceutical formulation, in particular to an injectable sustained release pharmaceutical formulation comprising a naltrexone derivative. The present disclosure also relates to a method of treating opioid use disorder (OUD) or alcohol use disorder (AUD, also known as alcoholism) by administering the injectable sustained release pharmaceutical formulation to a subject in need thereof. [Background technology]

[0002] Naltrexone is 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, a derivative of thebaine, which belongs to the opioid alkaloid family. The structure of naltrexone is shown in Formula I below, and it has a molecular weight of 341.40.

[0003] [ka]

[0004] As a competitive antagonist with high affinity for the μ receptor, naltrexone has great potential to compete with other full agonists such as morphine and heroin. Naltrexone has twice the antagonistic effect of naloxone and is indicated for the treatment of opioid use disorder and alcoholism in several dosage forms, such as Revia (oral tablet) and Vivitrol (intramuscular injection). The clinical dose (Cmax) of Vivitrol is 380 mg, which is 3-4 times the daily oral dose of naltrexone (i.e., 50 mg) over a 28-day period. Also disclosed are combinations of naltrexone hydrochloride with other compounds, such as Contrave (oral tablet, 8 mg naltrexone hydrochloride and 90 mg bupropion hydrochloride), Embeda (oral capsule, 25:1 ratio of naltrexone hydrochloride to morphine sulfate), and Troxyca ER (oral capsule, 1.2 mg naltrexone hydrochloride and 10 mg oxycodone hydrochloride). These products are indicated for obesity or moderate to severe pain. As a nonselective opioid antagonist with no agonist activity, naltrexone is used in combination with opioid full agonists (e.g., methadone) or partial agonists (e.g., buprenorphine) to reduce opioid abuse during the course of treatment.

[0005] Previous studies have disclosed various naltrexone derivatives. Among them, it is more common to modify the 3-hydroxyl group by forming an ester bond linkage. These ester derivatives are synthesized and compared with naltrexone and its hydrochloride salt. In 1987, Hussain et al. published an article in J.Pharm.Sci.(1987),75(5),356-358 on 3-alkyl ester derivatives of naltrexone, shown in the following formula II, where R represents anthranilate, acetylsalicylate, benzoate or pivalate. These derivatives are provided as prodrugs to improve the physiochemical properties of naltrexone and enhance its oral bioavailability in dogs.

[0006] [ka]

[0007] Stinchcomb et al., J. Pharm. Sci. (2002), 91(12), 2571-2578, disclosed naltrexone-3-alkyl ester prodrugs of formula II above, where R represents acetate, propanoate, butanoate, pentanoate, hexanoate or heptanoate. These naltrexone derivatives improved the physicochemical properties of naltrexone and increased the rate of human skin penetration in vitro. The extent of naltrexone regeneration in intact skin ranged from 28% to 91%.

[0008] Valiveti et al., in J. Control. Release (2005), 102(2), 509-520, disclosed the in vivo transdermal delivery in hairless guinea pigs of three 3-O-alkyl ester prodrugs of naltrexone, as shown in formula II above, where R represents acetate, propionate or hexanoate. The pharmacokinetic parameters of naltrexone and 3-O-alkyl ester prodrugs of naltrexone were detected after intravenous administration and topical application of transdermal therapeutic systems (TTS) in guinea pigs. The results of the in vivo study showed mean steady-state plasma concentrations of naltrexone. These naltrexone plasma concentrations were maintained for 48 hours.

[0009] In addition, some C3 esterified naltrexone derivatives and their uses have been disclosed in different patents. For example, European Patent No. 2064215B1 from Zinerva Pharmaceuticals Ltd. describes naltrexone prodrugs as shown in the above formula II, where R represents pivaloate, isovalerate, 2-ethylbutyrate, isobutyrate, isopropyloxycarbonoate or tert-butyloxycarbonoate. Naltrexone and its prodrugs as opioid antagonists have been used in combination with opioid agonists such as buprenorphine or its prodrugs to treat opioid use disorder or alcoholism by transdermal administration.

[0010] Naltrexone ester derivatives were also disclosed in U.S. Patent No. 6,569,449B1 from the University of Kentucky Research Foundation. In this U.S. Patent, naltrexone was modified with an ester as shown in formula II above, where R represents valerate or heptanoate. In vitro diffusion studies showed that the prodrug valeroyl-naltrexone, when delivered transdermally through skin samples, increased the cumulative amount of naltrexone by approximately 8-fold compared to naltrexone. This formulation for transdermal delivery of an effective amount of naltrexone was used to treat opioid use disorder and alcoholism.

[0011] Naltrexone, indicated for the treatment of opioid use disorder and alcoholism, is available in a variety of sustained release designs. For example, Southern Research Institute has developed an injectable naltrexone microsphere composition containing naltrexone in a poly(D,L-lactide) matrix with a residual amount of ethyl acetate. This composition was also disclosed in U.S. Patent No. 6,306,425 B1. In this U.S. patent, human subjects were intramuscularly injected with a clinical study formulation, and administration of such a formulation demonstrated that the release profile of naltrexone was maintained over a period of 31 days.

[0012] The technology of microsphere formulations was disclosed in several patents of Alkermes. For example, US Patent No. 6,264,987 B1 disclosed a controlled release microparticle product containing naltrexone and a polymer having a selected molecular weight. Also, US Patent No. 7,799,345 B2 disclosed an injectable suspension of naltrexone, microparticles and an aqueous injection medium, the injection medium consisting of water, a thickener, a wetting agent and a tonicity adjuster. Furthermore, US Patent No. 7,919,499 B2 disclosed an injectable microsphere suspension of naltrexone, namely Vivitrex, utilizing Medisorb's proprietary technology. This formulation was used to treat alcoholism and was administered by monthly intramuscular injection.

[0013] BioCorRx has developed BICX102, a sustained-release naltrexone implant used to treat opioid use disorder and alcoholism. The implant is surgically inserted into the patient's upper arm and can provide three- and six-month release profiles. Additionally, BioCorRx has also developed BICX101, an injectable naltrexone. This formulation is an intramuscularly or subcutaneously injectable suspension that utilizes TheraKine's patented microdelivery technology to maintain therapeutic plasma levels for up to three months. This technology is also disclosed in U.S. Patent Publication No. 2017 / 0065579A1.

[0014] Akala et al. disclosed naltrexone-loaded poly(D,L-lactide-co-glycolide) microspheres in Drug Dev. Ind. Pharm. (2011), 37(6), 673-684. In vitro feasibility studies showed that the drug could be sustained-released for 30-150 days. This drug delivery system is useful for patients with alcoholism.

[0015] Liu et al., Drug Dev. Ind. Pharm. (2006), 32(1), 85-94, disclosed naltrexone poly(lactide) microspheres injected into the subcutaneous region of rats. Plasma concentrations in the rats showed that naltrexone concentrations were consistently above 2ng / mL for 28 days. The biodegradable depot system can provide long-term treatment for opioid addiction.

[0016] Sustained release formulations of naltrexone have been provided for treatment in related fields. However, these formulations still have drawbacks such as complicated manufacturing processes, unreachable administration procedures, low drug loading, and variable release profiles. The effective plasma concentration level of Vivitrol in clinical trials was limited to only one month. Therefore, the present disclosure provides formulations of naltrexone including 3-acyl-naltrexone derivatives with different treatment durations ranging from one week to several months for patients requiring various treatment regimens. For example, the present disclosure provides formulations of naltrexone with durations after a single injection for treating opioid use disorder or alcoholism. Summary of the Invention

[0017] The present disclosure provides an injectable sustained release pharmaceutical formulation comprising a 3-acyl-naltrexone derivative or a pharma- ceutically acceptable salt thereof, and a biocompatible solvent.

[0018] In one embodiment of the present disclosure, the injectable sustained release pharmaceutical formulation further comprises a biocompatible polymeric material.

[0019] In one embodiment of the present disclosure, the pharma- ceutically acceptable salts of 3-acyl-naltrexone may be, but are not limited to, the salt forms of HCl, formate, and acetate.

[0020] The injectable sustained release pharmaceutical formulations of the present disclosure provide sustained release of 3-acyl-naltrexone prodrugs for at least one week to several months, thus providing an achievable administration procedure, sustained release profile, and long duration of treatment.

[0021] The present disclosure also provides a method of treating opioid use disorder, comprising administering the injectable sustained release pharmaceutical formulation to a subject in need thereof.

[0022] The present disclosure also provides a method of treating alcoholism, comprising administering the injectable sustained release pharmaceutical formulation to a subject in need thereof.

[0023] Other aspects of the present disclosure will become apparent from the accompanying drawings and the detailed description that follows. [Brief description of the drawings]

[0024] [Figure 1] 1 shows the in vitro dissolution profiles of injectable sustained release pharmaceutical formulations containing various naltrexone derivatives according to Example 2 of the present disclosure.

[0025] [Diagram 2] FIG. 2 shows the in vitro dissolution profiles of injectable sustained release pharmaceutical formulations comprising naltrexone hexanoate dissolved in different organic solvents according to Example 2 of the present disclosure.

[0026] [Diagram 3] 1 shows the mean plasma levels of naltrexone following subcutaneous injection of NL023 at a dose of 10.3 mg naltrexone / kg in minipigs according to an embodiment of the present disclosure.

[0027] [Figure 4] 1 shows the mean plasma levels of naltrexone following subcutaneous injection of NL024 at a dose of 10.3 mg naltrexone / kg in minipigs according to an embodiment of the present disclosure.

[0028] [Diagram 5] 1 shows the mean plasma levels of naltrexone following subcutaneous injection of NL024 at a dose of 60 mg naltrexone / kg in rats, according to an embodiment of the present disclosure.

[0029] [Figure 6] 1 shows the mean plasma levels of naltrexone following subcutaneous injection of NL004 at a dose of 120 mg naltrexone / kg in rats, according to an embodiment of the present disclosure.

[0030] [Figure 7] 1 shows the mean naltrexone release profile following subcutaneous injection of NL023 and NL024 at a dose of 10.3 mg naltrexone / kg in minipigs according to an embodiment of the present disclosure.

[0031] [Figure 8] 1 shows the mean naltrexone release profiles following subcutaneous injection of NL004 at a dose of 120 mg naltrexone / kg and NL024 at a dose of 60 mg naltrexone / kg in rats according to embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] In one embodiment of the present disclosure, a formulation of a naltrexone derivative is provided that exhibits a long therapeutic duration following a single dose for the treatment of opioid use disorder (OUD) and alcohol use disorder (AUD, also known as alcoholism).

[0033] In one embodiment of the present disclosure, the injectable sustained release pharmaceutical formulation comprises 3-acyl-naltrexone or a pharmaceutically acceptable salt thereof and a biocompatible solvent. In one embodiment of the present disclosure, the injectable sustained release pharmaceutical formulation comprises 3-acyl-naltrexone or a pharmaceutically acceptable salt thereof at a lower limit of 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight, and the injectable sustained release pharmaceutical formulation comprises 3-acyl-naltrexone or a pharmaceutically acceptable salt thereof at an upper limit of 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55% or 50% by weight, based on the total weight of the injectable sustained release pharmaceutical formulation. For example, 3-acyl-naltrexone or a pharma- ceutical acceptable salt thereof is present in an amount of 1% to 99% by weight, 1% to 90% by weight, 5% to 90% by weight, 5% to 80% by weight, 10% to 70% by weight, or 10% to 60% by weight, based on the total weight of the injectable sustained release pharmaceutical formulation.

[0034] In another embodiment of the present disclosure, the injectable sustained release pharmaceutical formulation is an injectable sustained release pharmaceutical polymer-based formulation comprising a biocompatible polymeric material. In one embodiment of the present disclosure, the injectable sustained release pharmaceutical formulation comprises a lower limit of 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, or 50 wt% of the biocompatible polymeric material, and the injectable sustained release pharmaceutical formulation comprises an upper limit of 95 wt%, 90 wt%, 85 wt%, 80 wt%, 75 wt%, 70 wt%, 65 wt%, 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, or 5 wt% of the biocompatible polymeric material, based on the total weight of the injectable sustained release pharmaceutical formulation. For example, the biocompatible polymeric material is present in an amount of 1% to 10% by weight, 1% to 8% by weight, 3% to 8% by weight, or 5% to 7% by weight, based on the total weight of the injectable sustained release pharmaceutical formulation.

[0035] In one embodiment of the present disclosure, 3-acyl-naltrexone or a pharma- ceutically acceptable salt thereof comprises an ester group formed between the 3-hydroxy (phenolic) group of naltrexone and an alkylcarbonylating agent or an arylcarbonylating (acylation) reagent.

[0036] In one embodiment of the present disclosure, the alkylcarbonylating or arylcarbonylating reagent (i.e., acylating reagent) has the formula R-CO-X, where R is an alkyl or aryl residue and may be an acyl chloride, acyl anhydride, or acyl active ester. The alkyl portion of the alkylcarbonyl group may be a straight or branched chain alkyl group. In one embodiment, the alkyl portion is a 1-20 (C1-C 20 ), 1-12(C1-C 12 ), 1 to 10 (C1-C 10 The alkylcarbonyl group may contain an appropriate number of carbons, such as 1-6 (C1-C6), 1-5 (C1-C5), 1-4 (C1-C4) or 1 to 2 (C1-C2). Examples of alkylcarbonyl (acyl) groups include, but are not limited to, acetyl, butyryl, valeryl, hexanoyl, decanoyl or lauroyl. The aryl portion of the arylcarbonyl group includes an aryl group or an aryl-alkyl group, and the alkyl portion is as defined above. The aryl portion of the arylcarbonyl group includes a C6-C8 group, such as a phenyl group or a naphthyl group. 18 In another embodiment of the present disclosure, the 3-acyl-naltrexone pharma- ceutically acceptable salt is HCl. Salt form of , formate, acetate, pamoate salt , Citric Acid salt , tartaric acid salt and maleic acid salt It may be, but is not limited to, these.

[0037] In one embodiment of the present disclosure, 3-acyl-naltrexone can be synthesized by conventional methods. Naltrexone or its salt can be purchased from several commercial sources, such as Sigma-Aldrich. To prepare naltrexone derivatives, naltrexone (or its salt) is reacted with acyl chloride in the presence of a non-nucleophilic base (e.g., triethylamine) to form an ester bond. The product (3-acyl-naltrexone or 3-alkylcarbonyl-naltrexone) can be purified by conventional methods, such as column chromatography.

[0038] In one embodiment of the present disclosure, 3-acyl-naltrexone, including 3-alkylcarbonyl-naltrexone or 3-arylcarbonyl-naltrexone, or a salt thereof, can be used as a prodrug, which can then be converted to the parent compound, naltrexone, i.e., the pharma- ceutical active compound.

[0039] In one embodiment of the present disclosure, the biocompatible solvent may be an organic solvent, such as N-methyl-2-pyrrolidone (NMP), ethyl acetate, ethanol (EtOH), butanol, 2-butanol, isopropanol (IPA), isobutanol, glycerin, benzyl benzoate (BnBzO), dimethyl sulfoxide (DMSO), propylene glycol (PG), dimethyl glycol, N,N-dimethylacetamide (DMAc), benzyl alcohol, esters, ethers, amides, carbonates, lactams, sulfonyls, or combinations thereof.

[0040] In one embodiment of the present disclosure, biocompatible polymeric materials are used as excipients, such as poly(D,L-lactide) (PLA) and poly(D,L-lactide / glycolide) (PLGA). In one embodiment of the present disclosure, the molar ratio of PLA to PLGA is 75:25. In another embodiment of the present disclosure, the molar ratio of PLA to PLGA is 50:50.

[0041] In one embodiment of the present disclosure, the injectable sustained release pharmaceutical formulation is formulated for subcutaneous, intramuscular, or intradermal injection. EXAMPLES

[0042] Embodiments of the present disclosure are further described in the following examples, however, those skilled in the art will appreciate that these examples are provided for illustrative purposes only, and that other modifications and variations are still possible without departing from the scope of the present disclosure.

[0043] Example 1: Preparation of Naltrexone Derivatives The naltrexone derivatives were synthesized using conventional methods as described below. In a three-neck round-bottom flask, naltrexone hydrochloride and dichloromethane were mixed to form a suspension and cooled in an ice bath. Triethylamine was then slowly added to the three-neck round-bottom flask with stirring, followed by the addition of acyl chlorides having 1 to 20 carbon atoms. The esterification reaction was carried out at ambient temperature under nitrogen atmosphere. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude naltrexone derivatives of 3-acyl-naltrexone were purified by silica gel column chromatography.

[0044] Example 2: Preparation of an injectable sustained release pharmaceutical formulation 15% to 70% by weight of the naltrexone derivative was added to a glass vial and dissolved in one or a combination of two or more of biocompatible organic solvents such as N-methyl-2-pyrrolidone (NMP), ethyl acetate, ethanol (EtOH), butanol, 2-butanol, isopropanol (IPA), isobutanol, glycerin, benzyl benzoate (BnBzO), dimethyl sulfoxide (DMSO), propylene glycol (PG), dimethyl glycol, N,N-dimethylacetamide (DMAc) and benzyl alcohol.

[0045] Alternatively, 15% to 70% by weight of the naltrexone derivative and a biocompatible polymeric material having a molar ratio of (D,L-lactide) to poly(D,L-lactide / glycolide) of 75:25 or 50:50 were added to a glass vial and dissolved in one or a combination of two or more of biocompatible organic solvents, such as N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isopropanol, isobutanol, glycerin, benzyl benzoate, dimethyl sulfoxide, propylene glycol, dimethyl glycol, N,N-dimethylacetamide, and benzyl alcohol.

[0046] The mixture was continued to stir at ambient temperature or slightly heated until all ingredients were dissolved. The resulting injectable sustained release pharmaceutical formulation is shown in Table 1 below.

[0047] [Table 1] TIFF0007634481000004.tif243170

[0048] Example 3: In vitro dissolution testing of injectable sustained release pharmaceutical formulations Formulations NL003, NL005, NL006, NL007, NL008 and NL010 prepared in Example 2 were evaluated for their in vitro dissolution profiles, respectively. Formulations NL005, NL006, NL007 and NL008 were mixed in a single tube with a dissolution medium of phosphate buffered saline containing 0.1% sodium dodecyl sulfate and 0.02% sodium azide, respectively, and formulations NL003 and NL010 were mixed in a single tube with a dissolution medium of phosphate buffered saline dissolution containing 0.2% sodium dodecyl sulfate and 0.02% sodium azide, respectively. Each tube was shaken at 60 rpm in a water bath at 37°C. At specific time points, 1 mL of sample was taken from each tube and applied to HPLC for analysis of naltrexone derivatives and naltrexone free base. Each tube was refilled with 1 mL of fresh dissolution medium. The dissolution rate profiles of formulations NL005, NL006, NL007 and NL008 are shown in Table 2 and Figure 1, and the dissolution rates of formulations NL003 and NL010 are shown in Table 3 and Figure 2. As a result, formulations NL003, NL006, NL007, NL008 and NL010 demonstrated the ability to sustainedly release the naltrexone derivative for one week to one month or more.

[0049] [Table 2]

[0050] [Table 3]

[0051] Example 4: Pharmacokinetic profile of an injectable sustained release pharmaceutical formulation in minipigs The formulation prepared in Example 2 was subcutaneously injected into male Lanyu minipigs at a dose of 10.3 mg naltrexone / kg. Blood samples were collected from the external jugular vein at specific time points. Plasma samples were separated by centrifuge and stored in frozen state for later analysis. LC-MS / MS was used to analyze the concentration of naltrexone in the plasma samples. The pharmacokinetic profile of formulation NL023 was shown in Table 4 and Figure 3. The results showed that formulation NL023 could provide 2 months of naltrexone sustained release. The pharmacokinetic profile of formulation NL024 was shown in Table 5 and Figure 4. The results showed that formulation NL024 could provide 1 month of naltrexone sustained release.

[0052] [Table 4]

[0053] [Table 5]

[0054] Example 5: Pharmacokinetic profile of an injectable sustained release pharmaceutical formulation in rats. The formulations prepared in Example 2 were subcutaneously injected into male CD(SD)IGS rats at doses of 60 and 120 mg naltrexone / kg. Blood samples were collected from the tail vein at specific time points. Plasma samples were separated by centrifuge and stored frozen for later analysis. The concentration of naltrexone in the plasma samples was analyzed using LC-MS / MS. The pharmacokinetic profile of formulation NL024 was shown in Table 6 and Figure 5. The pharmacokinetic profile of formulation NL004 was shown in Table 7 and Figure 6.

[0055] [Table 6]

[0056] [Table 7]

[0057] Example 6: In vivo release profile of injectable sustained release pharmaceutical formulations in minipigs and rats Pharmacokinetic data in minipigs and rats were analyzed using area under the curve (AUC 0-t ) and the area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC 0-∞ The percentage of naltrexone released in the release profile was analyzed by AUC 0-t and AUC 0-∞ It was estimated by the ratio of

[0058]

number

[0059] The in vivo release profiles of formulations NL023 and NL024 in minipigs were shown in Table 8 and Figure 7. The in vivo release profiles of formulations NL004 and NL024 in rats were shown in Table 9 and Figure 8. The release profiles in two different animal models showed that the formulations could consistently release naltrexone for various periods ranging from 1 week to 2 months.

[0060] [Table 8]

[0061] [Table 9]

[0062] Thus, the injectable sustained release formulation of the present disclosure can maintain a long therapeutic period after a single administration and provide a high drug loading. The subcutaneous injection administration system is less painful than intramuscular injection and can provide a relatively small amount of the formulation. Furthermore, the dissolution release profile and pharmacokinetic profile in miniature pigs of the formulation demonstrated that the naltrexone derivatives can be used as prodrugs and converted to the parent compound naltrexone for at least one week to several months of treatment.

[0063] While the present disclosure has been described with respect to a limited number of embodiments, those skilled in the art, having the benefit of this disclosure, will be able to It is understood that other embodiments may be devised that do not depart from the scope of the present disclosure disclosed herein. Accordingly, the scope of the present disclosure is defined solely by the appended claims. It should be. <Additional Notes> Item 1 3-Acyl-naltrexone or a pharma- ceutically acceptable salt thereof, and a biocompatible organic An injectable sustained release pharmaceutical formulation comprising a solvent. Section 2 The 3-acyl-naltrexone may be an alkylcarbonyl or arylcarbonyl group. Item 1. The injectable sustained release pharmaceutical formulation according to item 1, comprising a group. Section 3 The alkylcarbonyl group is a straight or branched alkyl group having 1 to 20 carbon atoms. Item 3. The injectable sustained release pharmaceutical formulation according to item 2, having a moiety. Section 4 The arylcarbonyl group has an aryl portion that contains an aromatic group having 6 to 18 carbon atoms. Item 2. The injectable sustained release pharmaceutical formulation according to item 2. Section 5 The biocompatible organic solvent is N-methyl-2-pyrrolidone, ethyl acetate, ethanol, Butanol, 2-butanol, isopropanol, isobutanol, glycerin, benzoin Benzyl acetate, dimethyl sulfoxide, propylene glycol, dimethyl glycol, N, N-Dimethylacetamide, benzyl alcohol, esters, ethers, amides, carbohydrates Item 2. The injectable sustained release pharmaceutical formulation according to item 1, wherein the compound is selected from the group consisting of nates, lactams, sulfonyls and combinations thereof. Section 6 The 3-acyl-naltrexone or a pharma- ceutically acceptable salt thereof is Item 1, the injectable sustained release pharmaceutical formulation being present in an amount of 1% by weight to 99% by weight based on the total weight of the sustained release pharmaceutical formulation. Section 7 Item 1. The injectable sustained release pharmaceutical formulation according to item 1, further comprising a biocompatible polymer material. Section 8 The biocompatible polymeric material is poly(D,L-lactide) (PLA), poly(D,L -lactide / glycolide (PLGA) and combinations thereof. Item 8. The injectable sustained release pharmaceutical formulation according to Item 7. Section 9 The biocompatible polymeric material comprises, based on the total weight of the injectable sustained release pharmaceutical formulation: Item 8. The injectable sustained release pharmaceutical formulation according to item 7, which is present in an amount of 1% by weight to 10% by weight. Section 10 A method for treating opioid use disorder or alcoholism, comprising administering the injectable sustained-release pharmaceutical formulation according to item 1 to a subject in need thereof. Section 11 The injectable sustained release pharmaceutical formulation is administered by subcutaneous injection, intramuscular injection, or intradermal injection. Item 11. The method according to item 10, wherein Section 12 The injectable sustained release pharmaceutical formulation provides a sustained release profile for at least one week. Item 11. The method according to item 10. Item 13 The injectable sustained release pharmaceutical formulation provides a sustained release profile for at least one month. The method according to item 10, Section 14 The injectable sustained release pharmaceutical formulation provides a sustained release profile for at least two months. The method according to item 10,

Claims

1. 1. An injectable sustained release pharmaceutical formulation comprising 3-acyl-naltrexone or a pharma- ceutically acceptable salt thereof, and a biocompatible organic solvent, The 3-acyl-naltrexone comprises an alkylcarbonyl group or an arylcarbonyl group, the alkylcarbonyl group having an alkyl portion containing a straight or branched chain having from 2 to 20 carbon atoms, and the arylcarbonyl group having an aryl portion containing an aromatic group having from 6 to 18 carbon atoms; the biocompatible organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and combinations thereof; The injectable sustained release pharmaceutical formulation does not contain poly(D,L-lactide) (PLA) or poly(D,L-lactide / glycolide) (PLGA).

2. 2. The injectable sustained release pharmaceutical formulation of claim 1, wherein the 3-acyl-naltrexone or a pharma- ceutically acceptable salt thereof is present in an amount of 1% to 99% by weight, based on the total weight of the injectable sustained release pharmaceutical formulation.

3. A pharmaceutical composition for treating opioid use disorder or alcoholism comprising the injectable sustained release pharmaceutical formulation of claim 1 and administered to a subject in need thereof.

4. The pharmaceutical composition of claim 3, wherein the injectable sustained release pharmaceutical formulation is administered by subcutaneous injection, intramuscular injection, or intradermal injection.

5. 4. The pharmaceutical composition of claim 3, wherein the injectable sustained release pharmaceutical formulation provides a sustained release profile for at least one week.

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