New composition

Abstract

The present disclosure relates to coated drug ion-exchange particles and granules comprising a resin core, one or more active pharmaceutical agents, and a coating comprising a cellulose acetate polymer, optionally in combination with an enteric polymer. Related compositions and methods of manufacture are disclosed.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 303,354, filed January 26, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure relates generally to novel coated drug-ion exchange resin particles (also referred to as coated drug-ion exchange resin granules) and pharmaceutical compositions containing the particles. More specifically, the present disclosure provides compositions designed to provide extended release of a drug over time after administration. [Background technology]

[0003] Sustained-release pharmaceutical formulations, which release drugs over a period of time, are widely used in the pharmaceutical industry. Such formulations offer several potential benefits to patients, including (1) convenience through reduced dosing frequency, (2) optimization of therapy by providing smoother and more consistent plasma drug concentrations, and (3) potential reduction in side effects.

[0004] The use of ion exchange resin to form drug-ion exchange resin complexes is also known in the art.However, these drug-ion exchange resin complexes have some drawbacks.For example, it has been described that ion exchange resins are used to form complexes with ionic drugs and delay the release of the drugs from such complexes.However, in many cases, such delay in drug release is only for a short period of time.

[0005] Various sustained or prolonged release dosage forms of drugs are known and commercially available. However, providing a coating to sustain the release of drugs from coated drug-ion exchange complex particles has proven difficult. For example, various compositions in the art require time-consuming steps in manufacture and careful monitoring of processing parameters with sophisticated equipment. Furthermore, manufacture may involve a potentially hazardous step of coating with a solvent-based solution, which must be thoroughly removed from the pharmaceutical product before ingestion.

[0006] Various prior art documents suggest treating the drug-ion exchange resin complex with a water-soluble hydrophilic impregnating (solvating) agent such as polyethylene glycol to provide a water-permeable diffusion barrier to the coating. However, these drugs swell the drug-ion exchange resin when in contact with water, disrupting the coating layer and prematurely releasing the drug.

[0007] Similarly, there have been drawbacks associated with the acrylate and methacrylate-based aqueous dispersion coating system polymers that have been used to coat drug-ion exchange resin complexes. Among these drawbacks observed is significant adhesion during application and curing of the coating, which complicates the drug-ion exchange resin complex coating process and / or requires the addition of additional ingredients such as anti-adhesive substances to combat this undesirable property.

[0008] The main risk of sustained release dosage forms is that the drug may be released faster than intended. Such rapid drug release from sustained release dosage forms results in the administration of a single bolus dose, which increases exposure levels, potential safety issues and causes adverse events. For example, alcohol is known to disrupt the drug release of many sustained release formulations, with the ingestion of ethanol resulting in the entire dose being released at once. Thus, alcohol-induced dose dumping (AIDD) can be defined as the unintended rapid release of large amounts of drug from a sustained release composition due to accidental misuse or intentional abuse of drugs and alcohol. Concurrent ingestion of alcohol can further complicate the issue, as it can affect the absorption, metabolism and / or excretion of the drug.

[0009] Therefore, new coated drug-ion exchange resin particles and compositions containing them are needed to overcome the problems of the prior art. Thus, it would be beneficial to provide coated drug-resin-exchanged particles and compositions containing them that can be efficiently and safely manufactured and provide extended release of one or more drugs. It would also be beneficial to provide such particles and compositions that can be used with a variety of drugs and tailored to release drugs at specific rates. It would also be beneficial to provide particles and compositions that are resistant to drug dumping, such as alcohol-induced drug dumping.

[0010] Naltrexone, a prescription drug with brand names such as Revia® and Vivitrol®, is an oral opioid receptor antagonist approved by the U.S. Food and Drug Administration (FDA) in 1984 for opiate addiction and in 1994 for alcoholism at doses of 50-100 mg / day. High doses of naltrexone (0.5, 1.0 and 2.0 mg / kg) have been shown to reverse autistic behavior and gaze aversion (Lensing et al., Neuropsychobiology. 1995; 31: 16-23). ​​Also, reductions in opioid tone in patients with autism spectrum disorder (ASD) correlated with treatment response (Cazullo et al., Eur. Neuropsychopharmacol. 1999; 9: 361-6).

[0011] However, in view of the side effects of naltrexone treatment, there is a need in the art to provide naltrexone formulations that reduce the side effects associated with naltrexone treatment. The present disclosure provides naltrexone formulations that address these needs. Summary of the Invention

[0012] Provided herein are coated drug resin-exchanged particles (or granules) ("coated granules" or "coated particles") and compositions comprising them that overcome the problems of the prior art. The coated granules and compositions of the present disclosure can be efficiently and safely manufactured and can provide sustained release of one or more drugs. The coated granules and compositions of the present disclosure can be used with a variety of drugs and can be tailored to release drugs at specific rates. Additionally, the coated granules and compositions of the present disclosure are resistant to drug dumping, such as alcohol-induced drug dumping.

[0013] In a first embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: a) ion exchange resins; One or more active pharmaceutical substances; optionally, a chelating agent; Optionally, a granulating agent a drug-ion exchange resin complex (or resin core) comprising: b) cellulose acetate-containing polymers; Optionally, an enteric polymer; and Optionally, a plasticizer Coatings including The present invention provides coated drug-ion exchange resin particles (or coated drug-ion exchange resin granules) [coated granules 1] comprising:

[0014] In some embodiments, the ion exchange resin is, for example, a polystyrene polymer. In some embodiments, the cellulose acetate-containing polymer is selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, and combinations thereof. In some further embodiments, the enteric polymer is selected from phthalate-containing polymers, such as cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), polyvinyl acetate phthalate (PVAP); cellulose acetate trimellitate; polymethacrylates (e.g., Eudragit® L series, Eudragit® S series, Eudragit® FS, Kollicoat® MAE 100P, Acryl-EZE® 93A, Acryl-EZE® MP); hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid, shellac, and combinations thereof. In some embodiments, the enteric polymer may be a cellulose acetate-containing polymer, preferably cellulose acetate phthalate (CAP). In some preferred embodiments, the ion exchange resin comprises a polystyrene polymer; a chelating agent is present and comprises EDTA, citric acid or a combination of EDTA and citric acid; a granulating agent is present and comprises polyethylene glycol; and a plasticizer is present and comprises polyethylene glycol.

[0015] In some embodiments, the present disclosure provides a composition for sustained release of active drug substances, comprising the coated drug-ion exchange resin particles (or coated drug-ion exchange resin granules) described herein and pharma- ceutically acceptable additives.In some preferred embodiments, the composition is a liquid suspension, comprising coated granules, one or more solvents, and one or more components selected from sugar, antioxidants, chelating agents, thickening agents, stabilizers, preservatives, surfactants, flavorings, and coloring agents.In some preferred embodiments, the composition is a liquid suspension, comprising sugar; one or more chelating agents; one or more thickening agents; preservatives; surfactants; and antioxidants.

[0016] In some further embodiments, the present disclosure provides methods of making the particles and compositions described herein. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows the in vitro drug release profile for the naltrexone ER suspension formulations described in Table 5 of Example 2 herein.

[0018] [Diagram 2] Figure 2 shows the drug release profiles of coated naltrexone resin particles with various polymer coatings, where CAB is the cellulose acetate butyrate coated particle formulation in Table 3, CAB and HPMCP (hypromellose phthalate) are the formulations in Table 6, and EC (ethylcellulose) is the formulation in Table 7.

[0019] [Diagram 3] FIG. 3 shows the in vitro drug release profiles for naltrexone ER suspension formulations 1 and 2 described in Table 16.

[0020] [Figure 4] FIG. 4 shows the in vivo naltrexone drug release rates for Formulations 1 and 2 and naltrexone HCl 50 mg tablets described in Table 18.

[0021] [Diagram 5] FIG. 5 shows the in vivo 6-β-naltrexol drug release rates for Formulations 1 and 2 and naltrexone HCl 50 mg tablets described in Table 19. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] In a first aspect, the present disclosure provides a method for producing a method for manufacturing a method for ... semiconductor device, c) ion exchange resins; One or more active pharmaceutical substances; optionally, a chelating agent; Optionally, a granulating agent a drug-ion exchange resin complex (or resin core) comprising: d) cellulose acetate containing polymers; Optionally, an enteric polymer; and Optionally, a plasticizer Coatings including The present invention provides coated drug-ion exchange resin particles (or coated drug-ion exchange resin granules) [coated granules 1] comprising:

[0023] The present disclosure further provides the following embodiments of the coated granules 1: 1.1 A coated granule 1, the resin core of which comprises a polystyrene polymer. 1.2 Coated granules 1 or 1.1, wherein the ion exchange resin comprises a copolymer of polystyrene and divinylbenzene. 1.3 Any of the preceding coated granules in which the ion exchange resin contains a matrix of sulfonated polymer composed of polystyrene crosslinked with about 8% divinylbenzene. 1.4 Any of the preceding coated granules, wherein the ion exchange resin has an ion exchange capacity of about 4.5-5.5 meq / g dry resin. 1.5 Any of the pre-coated granules having a resin core particle size of about 45 μm to 150 μm. 1.6 Any pre-coated granule in which the resin core contains spherical or irregularly shaped particles. 1.7 Any pre-coated granules in which the ion exchange resin comprises Amberlite IRP-69. 1.8 Any of the preceding coated granules, wherein the ion exchange resin and one or more active pharmaceutical agents are present in a w / w ratio of about 5:1 to 1:5, such as about 3:1 to 1:3, such as about 2:1 to 1:2, such as about 2:1. 1.9 Any of the preceding coated granules wherein the cellulose acetate containing polymer is selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof. 1.10 Any of the preceding coated granules wherein the cellulose acetate-containing polymer is selected from cellulose acetate, cellulose acetate butyrate, and combinations thereof. 1.11 Any of the preceding coated granules in which the cellulose acetate-containing polymer comprises cellulose acetate. 1.12 Any of the preceding coated granules in which the cellulose acetate-containing polymer consists essentially of, or consists of, cellulose acetate. 1.13 Any of the preceding coated granules in which the cellulose acetate-containing polymer comprises cellulose acetate butyrate. 1.14 Any of the preceding coated granules in which the cellulose acetate-containing polymer consists essentially of, or consists of, cellulose acetate butyrate. 1.15 Any of the preceding coated granules wherein the enteric polymer is selected from phthalate-containing polymers; cellulose acetate trimellitate; polymethacrylates; hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid; shellac, and combinations thereof. 1.16 The enteric polymer is dimethyl phthalate, diethyl phthalate, diallyl phthalate, di-n-propyl phthalate, di-n-butyl phthalate, diisobutyl phthalate, butyl cyclohexyl phthalate, di-n-pentyl phthalate, dicyclohexyl phthalate, butyl benzyl phthalate, di-n-hexyl phthalate, diisohexyl phthalate, diisoheptyl phthalate, butyl decyl phthalate, dibutoxyethyl phthalate, di(2-ethylhexyl) phthalate, di(n-octyl) phthalate, diisooctyl phthalate, n-octyl n-decyl Any of the preceding coated granules that are or comprise a phthalate-containing polymer, including monomers of phthalate, diisononyl phthalate, di(2-propylheptyl) phthalate, diisodecyl phthalate, diundecyl phthalate, diisoundecyl phthalate, ditridecyl phthalate, diisotridecyl phthalate, polyethylene terephthalate, cellulose phthalate, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), and combinations thereof. 1.17 Any of the preceding coated granules wherein the enteric polymer comprises a phthalate-containing polymer selected from cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP). 1.18 Any of the preceding coated granules wherein the enteric polymer is a phthalate-containing polymer selected from cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP). 1.19 Any of the pre-coated granules in which the enteric polymer comprises cellulose acetate trimellitate. 1.20 Any of the previously coated granules in which the enteric polymer is cellulose acetate trimellitate. 1.21 Any of the pre-coated granules in which the enteric polymer comprises a polymethacrylate. 1.22 Any of the pre-coated granules in which the enteric polymer is a polymethacrylate. 1.23 Any of the preceding coated granules where the enteric polymer comprises a polymethacrylate selected from Eudragit® L series, Eudragit® S series, Eudragit® FS, Kollicoat® MAE 100P, Acryl-EZE® 93A, and Acryl-EZE® MP. 1.24 Any of the preceding coated granules where the enteric polymer is a polymethacrylate selected from Eudragit® L series, Eudragit® S series, Eudragit® FS, Kollicoat® MAE 100P, Acryl-EZE® 93A, or Acryl-EZE® MP. 1.25 Any of the previously coated granules where the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®). 1.26 Any of the previously coated granules where the enteric polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®). 1.27 Any pre-coated granule in which the enteric polymer comprises sodium alginate or alginic acid. 1.28 Any of the pre-coated granules in which the enteric polymer is sodium alginate or alginic acid. 1.29 Any pre-coated granule in which the enteric polymer includes shellac. 1.30 Any of the pre-coated granules in which the enteric polymer is shellac. 1.31 Further comprising an anti-adherent agent; anti-adherent agents include, but are not limited to, talc, glycerol monostearate, magnesium stearate, or kaolin, of any of the preceding coated granules. 1.32 Any pre-coated granule in which a granulating agent is present. 1.33 The granulating agent in the drug-ion exchange resin complex is benzophenone, butylphthalyl butyl glycolate, camphor, α-cresyl-p-toluenesulfonate, cyclohexyl-p-toluenesulfonamide, diamyl phthalate, dibutyl phthalate, dibutyl sebacate, dibutyl succinate, dibutyl tartrate, diethoxyethyl adipate, diethoxyethyl phthalate, diethyl adipate, diethylene glycol dipropionate, diethyl phthalate, diethyl sebacate, diethyl succinate. ethyl phthalate, diethyl tartrate, dimethoxyethyl adipate, dimethoxyethyl phthalate, dimethyl phthalate, dipropyl phthalate, ethyl benzoyl benzoate, ethylene glycol diacetate, ethylene glycol dibutyrate, ethylene glycol dipropionate, ethyl phthalyl ethyl glycolate, methyl benzoyl benzoate, methyl phthalyl ethyl glycolate, o- or p-toluene ethyl sulfonamide, triacetin, tributyl citrate, tributyl phosphate, Tributyrin, tricresyl phosphate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, triphenyl phosphate, tripropionin, trimellitates (e.g., tri-(2-ethylhexyl) trimellitate, tri-(isononyl) trimellitate, tri-(isodecyl) trimellitate, tri-(isotridecyl) trimellitate), adipates (e.g., bis(2-ethylhexyl) adipate), sebacates (e.g., dibutyl sebacate, di-(2-ethylhexyl) sebacate), glycerol triacetate, alkyl citrates (triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, tri(2-ethylhexyl) citrate, acetyl trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate), vegetable oils, epoxidized soybean oil, epoxidized linoleic oil, azelates, dibenzoates, terephthalates, 1,Any of the preceding coated granules selected from 2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organophosphates (e.g., tricresyl (methylphenyl) phosphate, 2-ethylhexyl diphenyl phosphate), glycols (e.g., propylene glycol, polyethylene glycol, triethylene glycol di-2-hexanoate), triacetin, triethyl citrate, dibutyl sebacate, vegetable oils, oils, and combinations thereof. 1.34 Any of the preceding coated granules where the granulating agent in the drug-ion exchange resin complex comprises polyethylene glycol; e.g., polyethylene glycol 3350. 1.35 Any of the preceding coated granules in which the granulating agent in the drug-ion exchange resin complex consists of polyethylene glycol; e.g., polyethylene glycol 3350. 1.36 Any pre-coated granule in which a plasticizer is present. 1.37 The plasticizer is benzophenone, butyl phthalyl butyl glycolate, camphor, α-cresyl-p-toluenesulfonate, cyclohexyl-p-toluenesulfonamide, diamyl phthalate, dibutyl phthalate, dibutyl sebacate, dibutyl succinate, dibutyl tartrate, diethoxyethyl adipate, diethoxyethyl phthalate, diethyl adipate, diethylene glycol dipropionate, diethyl phthalate, diethyl sebacate, diethyl succinate, diethyl tartrate. ethyl phthalate, dimethoxyethyl adipate, dimethoxyethyl phthalate, dimethyl phthalate, dipropyl phthalate, ethyl benzoyl benzoate, ethylene glycol diacetate, ethylene glycol dibutyrate, ethylene glycol dipropionate, ethyl phthalyl ethyl glycolate, methyl benzoyl benzoate, methyl phthalyl ethyl glycolate, o- or p-toluene ethyl sulfonamide, triacetin, tributyl citrate, tributyl phosphate, tributyrin, Licresyl phosphate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, triphenyl phosphate, tripropionin, trimellitates (e.g., tri-(2-ethylhexyl) trimellitate, tri-(isononyl) trimellitate, tri-(isodecyl) trimellitate, tri-(isotridecyl) trimellitate), adipates (e.g., bis(2-ethylhexyl) adipate), sebacates (e.g., , dibutyl sebacate, di-(2-ethylhexyl) sebacate), glycerol triacetate, alkyl citrates (triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, tri(2-ethylhexyl) citrate, acetyl trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate), vegetable oils, epoxidized soybean oil, epoxidized linoleic oil, azelates, dibenzoates, terephthalates, 1,Any of the preceding coated granules selected from 2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organophosphates (e.g., tricresyl (methylphenyl) phosphate, 2-ethylhexyl diphenyl phosphate), glycols (e.g., propylene glycol, polyethylene glycol, triethylene glycol di-2-hexanoate), triacetin, triethyl citrate, dibutyl sebacate, vegetable oils, oils, and combinations thereof. 1.38 Any of the preceding coated granules wherein the plasticizer is selected from propylene glycol, polyethylene glycol, triacetin, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, acetyl tributyl citrate, tributyl citrate, Soluphor P, vegetable oils, oils, and combinations thereof. 1.39 Any of the preceding coated granules where the plasticizer in the coating comprises polyethylene glycol; e.g., polyethylene glycol 3350. 1.40 Any of the preceding coated granules where the plasticizer in the coating consists of polyethylene glycol; e.g., polyethylene glycol 3350. 1.41 Any pre-coated granule in which a plasticizer is dispersed throughout the coating. 1.42 Any of the preceding coated granules, wherein the plasticizer constitutes from about 2.5 to about 25% w / w, or from about 5 to about 15% w / w, or from about 8 to about 12% w / w, or about 10% w / w of the solids in the coating. 1.43 Any of the preceding coated granules further comprising one or more additional active pharmaceutical agents, e.g., 2-10 active pharmaceutical agents. 1.44 Any of the preceding coated granules in which the resin core contains one or more active pharmaceutical agents that are small molecule drugs, for example up to 10 small molecule drugs. 1.45 Any pre-coated granule in which the active pharmaceutical substance is a free base compound. 1.46 Any of the preceding coated granules in which the active pharmaceutical agent is a compound that can be protonated at one or more positions on the molecule. 1.47 Any of the preceding coated granules, wherein the active pharmaceutical agent is present in an amount of about 1% to about 99%, about 5% to about 70%, about 10% to about 30%, about 15% to about 25%, or about 20% by weight based on the total weight of the coated drug-ion exchange resin granule. 1.48 Any of a number of pre-coated granules in which the active pharmaceutical substance is released at a higher initial rate that tapers off over an extended period of time. 1.49 Any of the preceding coated granules, wherein the coated granule provides a sustained release of the active pharmaceutical agent for at least 1 hour, at least 4 hours, at least 8 hours, at least 16 hours, or at least 24 hours. 1.50 Any pre-coated granule in which the coated granule provides a sustained release of the active pharmaceutical substance for 8 to 24 hours. 1.51 Any of the preceding coated granules, in which the coated granules provide a sustained release of the active pharmaceutical substance for up to 24 hours. 1.52 Any of a number of previously coated granules, wherein the coated granules are included within a composition that is in the form of a suspension, caplet, sachet, tablet, chewable tablet, dispersible tablet or orally disintegrating tablet (ODT). 1.53 Any of the preceding coated granules in which the active pharmaceutical agent is dispersed (e.g., substantially uniformly dispersed) throughout the resin core, e.g., within and on the surface of the resin core; coated granules. 1.54 Any pre-coated granule in which a pharma- ceutical active drug is bound (e.g., by covalent or ionic bonds) to a resin core. 1.55 Any pre-coated granule in which the pharma- ceutical active drug is bound to a resin core by ionic bonds. 1.56 Any of the previously coated granules in which the coating comprises a mixture (e.g., a substantially homogeneous mixture) of a cellulose acetate-containing polymer and an enteric polymer. 1.57 Any of the previously coated granules in which the coating comprises a mixture (e.g. a substantially homogeneous mixture) of cellulose acetate or cellulose acetate butyrate with an enteric polymer. 1.58 Any of the preceding coated granules, wherein the coating comprises a mixture (e.g., a substantially homogenous mixture) of cellulose acetate or cellulose acetate butyrate with one or more of cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP). 1.59 Any of the preceding coated granules, in which the cellulose acetate containing polymer and the enteric polymer are present in a w / w ratio of about 5:1 to about 1:5. 1.60 Any of the preceding coated granules, wherein the cellulose acetate containing polymer and the enteric polymer are present in a w / w ratio of about 2:1 to about 1:2. 1.61 Any of the pre-coated granules in which the cellulose acetate-containing polymer and the enteric polymer are present in a w / w ratio of about 1:1. 1.62 Any of the preceding coated granules, wherein the particle size of the coated granule is from about 10 μm to about 500 μm, such as from about 50 μm to about 250 μm, such as from about 100 μm to about 410 μm, such as from about 100 μm to about 250 μm, such as from about 150 to 250 μm. 1.63 Any of a number of previously coated granules in which the particle size of the majority of the coated granules is approximately 150-250 μm. 1.64 Any of the previously coated granules in which the coated drug-ion exchange resin particles are spherical, polyhedral or irregular in shape. 1.65 Any pre-coated granule in which the coated drug-ion exchange resin particles are irregularly shaped. 1.66 Any of the preceding coated granules in which the coating is bonded to the outer surface of the resin core, e.g., covering substantially the entire outer surface. 1.67 Any of the preceding coated granules, in which the coating comprises a substantially uniform mixture of cellulose acetate polymer alone or in combination with an enteric polymer and is applied to and / or present on the outer surface, e.g., the entire outer surface, of the resin core. 1.68 Any of the preceding coated granules in which the coating comprises a substantially homogeneous mixture of cellulose acetate or cellulose acetate butyrate and cellulose acetate phthalate and is applied to and / or present on the exterior surface, e.g., the entire exterior surface, of a resin core. 1.69 Any of the preceding coated granules, in which the coated granule comprises a cellulose acetate-containing polymer and an enteric polymer. 1.70 Any of the preceding coated granules in which the coating comprises a mixture (e.g. a substantially homogeneous mixture) of a cellulose acetate-containing polymer, such as cellulose acetate butyrate, and polyethylene glycol. 1.71 Any of the preceding coated granules, wherein the coating comprises a substantially uniform mixture of cellulose acetate butyrate and polyethylene glycol, e.g., the mixture is applied to the outer surface of the drug-ion exchange resin complex granule, as desired. 1.72 The active pharmaceutical substance is a pharmaceutical product that meets the requirements of Chapter 43 of the United States Pharmacopeia (USP). <711> at 50 rpm, 37±0.5° C. in 900 mL 0.4 M KH2PO4 using the Apparatus II described in, at a rate of 20%-45% in 2 hours, and / or 40%-65% in 4 hours, and / or greater than 80% in 12 hours; for example, but not limited to, any of the preceding coated granules where no more than 25% of the active pharmaceutical agent is released within 1 hour and no more than 60% of the active pharmaceutical agent is released within 2 hours. 1.73 Any of the preceding coated granules, wherein the ion exchange resin comprises Amberlite IRP-69; the cellulose acetate-containing polymer comprises cellulose acetate, cellulose acetate butyrate, or a combination thereof; and the enteric polymer comprises one or more of cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP). 1.74 Any pre-coated granule in which a chelating agent is present. 1.75 Any pre-coated granules in which a granulating agent is present. 1.76 Any pre-coated granule in which a plasticizer is present. 1.77 Any pre-coated granule in which chelating agents, granulating agents and plasticizers are present. 1.78 Coated granules 1.77, wherein the chelating agent comprises or consists of EDTA; the granulating agent comprises or consists of polyethylene glycol, e.g., polyethylene glycol 3550; and the plasticizer comprises or consists of polyethylene glycol, e.g., polyethylene glycol 3550. 1.79 The ion exchange resin comprises Amberlite IRP69; Chelating agents are present and include EDTA; A granulating agent is present and comprises a polyethylene glycol, e.g., polyethylene glycol 3550; and A plasticizer is present and includes polyethylene glycol, e.g., polyethylene glycol 3550; Any of the preceding coating granules. 1.80 Any of the preceding coated granules, wherein the resin core constitutes from about 70% w / w to about 90% w / w of the coated granule; e.g., from about 75% w / w to about 90% w / w of the coated granule; e.g., from about 80% w / w to about 85% w / w of the coated granule; e.g., from about 83% w / w to about 84% w / w of the coated granule. 1.81 Any of the preceding coated granules, wherein the cellulose acetate containing polymer constitutes from about 5% w / w to about 25% w / w of the coated granule; e.g., from about 10% w / w to about 20% w / w of the coated granule; e.g., from about 12% w / w to about 18% w / w of the coated granule; e.g., from about 14% w / w to about 16% w / w of the coated granule; e.g., about 15% w / w of the coated granule. 1.82 Any of the preceding coated granules, wherein the granulating agent constitutes from about 0.5% w / w to about 5% w / w of the coated granule; e.g., from about 0.5% w / w to about 3% w / w of the coated granule; e.g., from about 1% w / w to about 2% w / w of the coated granule; e.g., about 1.5% w / w of the coated granule. 1.83 Composition of: [Table 1] Any of the preceding coated granules having 1.84 Any of the pre-coated granules in which the active pharmaceutical substance comprises naltrexone or a pharma- ceutically acceptable salt thereof. 1.85 Any of the preceding coated granules, wherein the drug-ion exchange resin complex granule comprises naltrexone-ion exchange resin complex in combination (e.g., bound) with a chelating agent and a granulating agent. 1.86 Coated granule 1.83, wherein the naltrexone-ion exchange resin complex comprises an ion exchange resin and naltrexone or a pharma- ceutically acceptable salt thereof.

[0024] The present disclosure further provides a composition comprising a plurality of any of the preceding coated granules 1 or 1.1 to 1.86. For example, in a second aspect, the present disclosure provides a composition comprising: Coated granules 1 or coated drug-ion exchange resin particles (or granules) according to 1.1 to 1.86; and Pharmaceutically acceptable excipients The present invention provides a composition for the sustained release of an active drug substance [Composition 1], comprising:

[0025] The present disclosure further provides the following embodiments of Composition 1: 1.1 Composition 1, wherein the composition is in the form of a suspension, caplet, sachet, tablet, chewable tablet, dispersible tablet or orally disintegrating tablet (ODT). 1.2 Composition 1 or 1.1, wherein the composition is in the form of a liquid suspension. 1.3 Any of the preceding compositions, wherein the composition is a suspension comprising coated granules, one or more solvents, and one or more ingredients selected from sugars, antioxidants, chelating agents, buffers, thickening agents, stabilizers, preservatives, surfactants, flavors, and colorants. 1.4 Any of the preceding compositions wherein the solvent in the suspension comprises water. 1.5 Any of the preceding compositions, wherein the suspension comprises coated granules in an amount of about 0.01 g to about 0.03 g of coated granules per ml of suspension. 1.6 Any of the preceding compositions, wherein the coated granules are present in the composition in an amount of about 0.01% w / v to about 10% w / v based on the total weight of the composition; or about 0.01% w / v to about 10% w / v based on the total weight of the composition; or about 0.1% w / v to about 5% w / v based on the total weight of the composition; or about 0.1% w / v to about 5% w / v based on the total weight of the composition; or about 1% w / v to about 5% w / v based on the total weight of the composition; or about 1% w / v to about 5% w / v based on the total weight of the composition; or about 2% w / v to about 3% w / v based on the total weight of the composition; or about 2% w / v to about 3% w / v based on the total weight of the composition. 1.7 Any of the preceding compositions wherein the pharma- ceutically acceptable excipient comprises one or more of carriers, diluents, thickeners, binders, lubricants, wetting agents, disintegrants, antioxidants, surfactants, colorants, flavorants, preservatives, sweeteners, buffers, and combinations thereof. 1.8 Any of the preceding compositions, wherein the composition is in the form of a suspension, e.g., a liquid suspension, and the active pharmaceutical agent is present in an amount of from about 0.1 mg / mL to about 100 mg / mL, such as from about 1 mg / mL to about 25 mg / mL, such as from about 3 mg / mL to about 8 mg / mL, e.g., about 5 mg / mL. 1.9 Any of the preceding compositions, wherein the composition is in the form of a suspension, e.g. a liquid suspension, and the active pharmaceutical agent is present in an amount of from about 0.1% w / v to about 2% w / v, such as from about 0.1% w / v to about 1% w / v; such as from about 0.2% w / v to about 0.8% w / v, such as from about 0.4% w / v to about 0.6% w / v, such as from about 0.5% w / v, for example 0.49% to 0.51% w / v. 1.10 Any of the preceding compositions, wherein the composition comprises a plurality of said coated granules. 1.11 Any of the preceding compositions, wherein the coated granules are present in an amount of from 0.5% w / v to about 5% w / v; such as from about 1.0% w / v to about 3.0% w / v; such as from 2.0% w / v to about 2.5% w / v, such as about 2.3% w / v. 1.12 Any of the preceding compositions wherein the composition comprises a chelating agent, e.g., EDTA. 1.13 Any of the preceding compositions, wherein the composition comprises a buffer, e.g., citric acid, e.g., anhydrous citric acid. 1.14 Composition 1.13, wherein a chelating agent, e.g. EDTA, is present in an amount of from about 0.05% w / v to about 0.15% w / v; such as from about 0.08% w / v to about 0.12% w / v; such as from about 0.09% w / v to about 0.10% w / v; such as from about 0.095% w / v; and / or a buffering agent, e.g. citric acid, is present in an amount of from about 0.1% w / v to about 0.8% w / v; such as from about 0.2% w / v to about 0.6% w / v; such as from about 0.3% w / v to about 0.5% w / v; such as about 0.4% w / v. 1.15 Any of the preceding compositions, wherein the composition comprises an antioxidant, e.g., propyl gallate, in an amount from about 0.01% to about 0.03%, e.g., about 0.02%. 1.16 Any of the preceding compositions, wherein the composition comprises a surfactant, e.g., Tween 80, in an amount of about 0.01% w / v to about 0.3% w / v; such as about 0.05% w / v to about 0.2% w / v; for example, about 0.1% w / v. 1.17 Any of the preceding compositions wherein the composition comprises a solvent, e.g., water. 1.18 Any of the preceding compositions, wherein the composition comprises a sugar, e.g., sucrose, in an amount of about 5% w / v to about 40% w / v; such as about 10% w / v to about 30% w / v; such as about 15% w / v to about 25% w / v; such as about 20% w / v. 1.19 Any of the preceding compositions, wherein the composition comprises a preservative, e.g., sodium benzoate, in an amount of about 0.1% w / v to about 0.5% w / v; e.g., about 0.15% w / v to about 0.3% w / v; e.g., about 0.2% w / v. 1.20 Any of the preceding compositions wherein the composition comprises a thickening agent, such as starch, xanthan gum, or a combination of starch and xanthan gum. 1.21 Composition 1.20, wherein the composition comprises both starch and xanthan gum. 1.22 Composition 1.21, wherein the starch is present in an amount of about 0.1% w / v to about 5% w / v; such as about 1% w / v to about 3% w / v; such as about 2% w / v; and the xanthan gum is present in an amount of about 0.05% w / v to about 0.5% w / v; such as about 0.1% w / v to about 0.2% w / v; such as about 0.15% w / v. 1.23 The composition comprises: Coated granules according to any one of coated granules 1 or 1.1 to 1.84; sugars (e.g. sucrose); Chelating agents (e.g. EDTA); buffering agents (e.g., citric acid); one or more thickening agents (e.g., starch and / or xanthan gum); preservatives (e.g. sodium benzoate); A surfactant (e.g., Tween 80); and Antioxidants (e.g. propyl gallate) Any of the preceding compositions, including 1.24 Any of the preceding compositions wherein the coated granule is a coated granule as described in coated granule 1.79. 1.25 Composition 1.23 or 1.24 further comprising one or more colorants and / or fragrances. 1.26 Composition 1.25, wherein the composition is a liquid suspension. 1.27 The composition is in the form of a liquid suspension, and The solvent comprises water; Sugars include sucrose; The chelating agent comprises EDTA; The buffer comprises citric acid, e.g., anhydrous citric acid; Antioxidants are present and include propyl gallate; the thickening agent comprises one or more of starch and xanthan gum; and The surfactant includes Tween 80. Any of the preceding compositions. 1.28 Composition of: [Table 2] Any of the preceding compositions, having the formula: 1.29 Any of the preceding compositions wherein the composition is a solid suspension and the suspension does not contain glycerin or polyethylene glycol other than in the coating granules. 1.30 Any of the preceding compositions in which the active pharmaceutical agent is released at a higher initial rate that tapers off over an extended period of time. 1.31 Any of the precursor particles from which the active pharmaceutical substance is released at a higher initial rate that tapers off over an extended period of time. 1.32 Any of the preceding compositions in which the active pharmaceutical substance is released over an extended period of time. 1.33 Any of the preceding compositions, wherein the drug ion-exchange particles provide a sustained release of the active pharmaceutical agent for at least 1 hour, at least 4 hours, at least 8 hours, at least 16 hours, or at least 24 hours. 1.34 Any of the preceding compositions wherein the drug ion-exchange particles provide a sustained release of the active pharmaceutical agent for up to 24 hours. 1.35 Any of the preceding compositions wherein the coated drug ion-exchange particles provide a sustained release of the active pharmaceutical agent for 8 to 24 hours. 1.36 Any of the preceding compositions wherein the particle size of the majority of the coated granules is about 150-250 μm. 1.37 Any of the preceding compositions wherein the active pharmaceutical agent comprises naltrexone or a pharma- ceutically acceptable salt thereof. 1.38 The composition is in the form of a liquid suspension and has one or more of the following characteristics: a) a T of about 5 to about 7 hours, for example about 5 hours, about 6 hours, or about 7 hours max ; b) a T of about 5 to about 12 hours, e.g., about 5 to about 11 hours; about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or about 11 hours 1 / 2 ; c) about 1.5 to about 4 hours, for example about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours C max ; d) AUC of about 26 to about 32 hr ng / mL, for example about 26, about 27, about 28, about 29, about 30, about 31, or about 32 hr ng / mL t ; and e) AUC of about 28 to about 35 hr ng / mL, for example about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 hr ng / mL ∞ Any of the preceding compositions provides a pharmacokinetic profile in healthy subjects having one or more of: 1.39 Composition 1.38, wherein the sustained release suspension has a pharmacokinetic profile having two or more of characteristics a) through e), or three or more of characteristics a) through e), or four or more of characteristics a) through e), or all five of characteristics a) through e). 1.40 Composition 1.38 or 1.39, wherein the sustained release suspension pharmacokinetic profile is substantially as shown for Formulation 1 or Formulation 2 in Figure 4. 1.41 Any of the preceding compositions 1.38 and subsequent, wherein the mean plasma naltrexone concentration (ng / ml) over the time period from 2.5 hours post-dose to 4 hours post-dose is increased by at least 4%; or from about 4% to about 20%; or from about 4% to about 15%; or from about 4% to about 12%, or from about 5% to about 12%, or by about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11% or about 12%. 1.42 Any of the preceding compositions 1.38 and subsequent, wherein the mean plasma naltrexone concentration (ng / ml) over the time period from 4 hours post-dose to 6 hours post-dose is increased by at least about 80%; or from about 80% to about 120%; or from about 80% to about 110%; or from about 85% to about 105%, or about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104% or about 105%. 1.43 Any of the preceding compositions 1.38 and subsequent, wherein the mean plasma naltrexone concentration (ng / ml) over the time period from 6 hours post-dose to 8 hours post-dose is reduced by more than about 40%; or by between about 15% and about 40%; or by between about 20% and about 35%; or by about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%. 1.44 Mean plasma naltrexone concentration 3 hours after administration (C t ng / ml) and maximum plasma naltrexone concentration (C max Any of the preceding compositions 1.38 and thereafter, wherein the ratio of 0.4 to 0.6; such as from about 0.4 to about 0.55, such as from about 0.45 to about 0.5. 1.45 Mean plasma naltrexone concentration 6 hours after administration (C t ng / ml) and maximum plasma naltrexone concentration (C max Any of the preceding compositions 1.38 and thereafter, wherein the ratio of 0.8 to 1.2; such as from about 0.9 to about 1.1, for example from about 0.95 to about 1.05. 1.46 Mean plasma naltrexone concentration 8 hours after administration (C t ng / ml) and maximum plasma naltrexone concentration (C max Any of the preceding compositions 1.38 and thereafter, wherein the ratio of 0.5 to 0.9; such as from about 0.6 to about 0.8, for example from about 0.65 to about 0.8. 1.47 Mean plasma naltrexone concentration 10 hours after administration (C tng / ml) and maximum plasma naltrexone concentration (C max Any of the preceding compositions 1.38 and thereafter, wherein the ratio of 0.1 to 0.5 ng / mL is from about 0.4 to about 0.8; such as from about 0.5 to about 0.7. 1.48 Mean plasma naltrexone concentration 12 hours after administration (C t ng / ml) and maximum plasma naltrexone concentration (C max Any of the preceding compositions 1.38 and thereafter, wherein the ratio of 0.1 to 0.5 ng / mL is from about 0.3 to about 0.7; such as from about 0.4 to about 0.6. 1.49 Mean plasma naltrexone concentration (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) are as follows: a) to e): a) 3 hours after administration, about 0.4 to about 0.6; for example, about 0.4 to about 0.55, for example, about 0.45 to about 0.5; b) 6 hours after administration, about 0.8 to about 1.2; for example, about 0.9 to about 1.1, for example, about 0.95 to about 1.05; c) 8 hours after administration, about 0.5 to about 0.9; for example, about 0.6 to about 0.8, for example, about 0.65 to about 0.8; d) 10 hours after administration, about 0.4 to about 0.8; for example, about 0.5 to about 0.7; and e) 12 hours after administration, about 0.3 to about 0.7; for example, about 0.4 to about 0.6 Any of the preceding compositions 1.38 et seq., 1.50 Mean plasma naltrexone concentration (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) ratio, a) 3 hours after administration, about 0.4 to about 0.6; for example, about 0.4 to about 0.55, for example, about 0.45 to about 0.5; and b) 6 hours after administration, about 0.8 to about 1.2; for example, about 0.9 to about 1.1, for example, about 0.95 to about 1.05 Composition 1.49. 1.51 Mean plasma naltrexone concentration (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) ratio, b) 6 hours after administration, about 0.8 to about 1.2; for example, about 0.9 to about 1.1, for example, about 0.95 to about 1.05; and c) 8 hours after administration, about 0.5 to about 0.9; for example, about 0.6 to about 0.8, for example, about 0.65 to about 0.8 Composition 1.49. 1.52 Mean plasma naltrexone concentration (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) ratio, c) 8 hours after administration, about 0.5 to about 0.9; for example, about 0.6 to about 0.8, for example, about 0.65 to about 0.8; and d) 10 hours after administration, about 0.4 to about 0.8; for example, about 0.5 to about 0.7 Composition 1.49. 1.53 Mean plasma naltrexone concentration (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) ratio, a) 3 hours after administration, about 0.4 to about 0.6; for example, about 0.4 to about 0.55, for example, about 0.45 to about 0.5; and b) 6 hours after administration, about 0.8 to about 1.2; for example, about 0.9 to about 1.1, for example, about 0.95 to about 1.05; and c) 8 hours after administration, about 0.5 to about 0.9; for example, about 0.6 to about 0.8, for example, about 0.65 to about 0.8; and d) 10 hours after administration, about 0.4 to about 0.8; for example, about 0.5 to about 0.7 Composition 1.49. 1.54 Any of the preceding compositions wherein 25% or less of the active pharmaceutical agent is released within 1 hour and 60% or less of the active pharmaceutical agent is released within 2 hours. 1.55 Any of the preceding compositions wherein 30% or less of the active pharmaceutical agent is released within 1 hour and 60% or less of the active pharmaceutical agent is released within 2 hours.

[0026] In a third aspect, the present disclosure provides a method for producing coated drug-ion exchange resin particles (or granules), comprising the steps of: (a) contacting an active drug substance with an ion exchange resin in a solvent to form a drug-ion exchange resin complex (or resin core); (b) optionally isolating and drying the drug-ion exchange resin complex; (c) granulating the drug-ion exchange resin complex to form drug-ion exchange resin complex granules; (d) optionally drying the product of step (c), e.g. to a moisture content of 15-25% or 15-20%, and optionally grinding the product, e.g. using a co-mill equipped with a about 400 μm mesh screen; or optionally sieving the product to a predetermined size, e.g. by forcing the product through a mesh screen, e.g. a 20 mesh screen; (e) optionally further drying the product of step (d), for example to a moisture content of less than 7%; (f) optionally milling the product of step (e), for example using a co-mill equipped with an 813 μm mesh screen; and (g) The following: Cellulose acetate-containing polymers, such as cellulose acetate butyrate; Optionally, an enteric polymer; Optionally, a plasticizer, such as a polyethylene glycol, e.g., polyethylene glycol 3550; and A solvent, such as water, acetone, or water and acetone Coating the product of the previous step with a coating composition comprising Here, for example, the coating is applied to a weight gain of 15-20% w / w, Forming coated drug-ion exchange resin particles (or granules) The present invention provides a method [Method 1] comprising the steps of:

[0027] The present disclosure further provides the following embodiments of Method 1: 1.1 Method 1, wherein the solvent in step (a) comprises water. 1.2 Step (b) is carried out and the drug-ion exchange resin complex is isolated by filtration and drying, for example using a fluid bed processor, Methods 1 and 1.1. 1.3 Any of the preceding methods, wherein step (b) is carried out and the drug-ion exchange resin complex is dried to a moisture content of about 15%. 1.4 The granulation step (c) comprises the steps of: (i) contacting the product of step (b) with a composition comprising a solvent (e.g., water), optionally a chelating agent (e.g., EDTA), optionally a granulating agent (e.g., polyethylene glycol, e.g., polyethylene glycol 3550); and (ii) granulating the product of step (i) to form uncoated drug-ion exchange resin complex granules. Any of the preceding methods, including 1.5 Method 1.4, wherein step (i) is carried out by spraying the product of step (b) with the composition. 1.6 Method 1.4 or 1.5, wherein step (ii) is carried out using a high shear granulator. 1.7 Any of the preceding methods, wherein step (c) further comprises the steps of comminuting the drug-ion exchange resin complex granules and separating them by size (e.g., by sieving; e.g., using a 400 μm mesh screen). 1.8 Any of the previous methods, wherein the coating composition is sprayed onto the drug-ion exchange resin complex granules to a weight gain of 15% w / w to 20% w / w. 1.9 Any of the preceding methods, comprising carrying out step (d). 1.10 Any of the preceding processes, wherein step (d) is carried out and the product of step (c) is dried to a moisture content of 15-25%. 1.11 Pass the product, having a moisture content of 15-25%, through a 20 mesh screen, Method 1.9. 1.12 Any of the preceding processes, wherein step (e) is carried out and the product of step (d) is dried to a moisture content of less than 7%. 1.13 Any of the preceding methods, comprising carrying out step (f). 1.14 The grinding in step (f) is carried out using a Co-Mill equipped with an 813 μm mesh screen, Method 1.12. 1.15 Any of the preceding processes, wherein in step (g), the coating composition is sprayed onto uncoated drug-ion exchange resin complex granules. 1.16 Any of the preceding methods, wherein in step (g), the coating composition comprises one or more solvents. 1.17 Any of the preceding methods, wherein the coating composition comprises one or more solvents selected from water, acetone, ethanol, isopropyl alcohol, and methanol; for example, the one or more solvents are selected from water, acetone, and combinations thereof. 1.18 Any of the preceding methods wherein the coating composition comprises a plasticizer, such as polyethylene glycol. 1.19 Any of the prior processes, Any of the prior processes, wherein step (g) comprises contacting the drug-ion exchange resin complex granules produced by the prior process with a coating composition comprising cellulose acetate butyrate and polyethylene glycol in a solvent, e.g., a mixture of water and acetone. 1.20 Any of the preceding processes in which the ion exchange resin comprises a polystyrene polymer. 1.21 Any of the preceding processes in which the ion exchange resin comprises a copolymer of polystyrene and divinylbenzene. 1.22 Any of the preceding methods in which the ion exchange resin contains a matrix of a sulfonated polymer composed of polystyrene crosslinked with about 8% divinylbenzene. 1.23 Any of the preceding processes wherein the ion exchange resin has an ion exchange capacity of about 4.5-5.5 meq / g dry resin. 1.24 Any of the preceding methods, wherein the particle size of the resin core is from about 45 μm to 150 μm. 1.25 Any of the preceding processes in which the resin core comprises spherical or irregularly shaped particles. 1.26 Any of the preceding processes wherein the ion exchange resin comprises Amberlite IRP-69. 1.27 Any of the preceding processes, wherein the ion exchange resin and the one or more active pharmaceutical agents are present in a w / w ratio of about 5:1 to 1:5, such as about 3:1 to 1:3, such as about 2:1 to 1:2, such as about 2:1. 1.28 Any of the preceding processes wherein the cellulose acetate-containing polymer is selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof. 1.29 Any of the preceding processes wherein the cellulose acetate polymer is selected from cellulose acetate, cellulose acetate butyrate, and combinations thereof. 1.30 Any of the preceding processes wherein the cellulose acetate polymer comprises cellulose acetate. 1.31 Any of the preceding processes in which the cellulose acetate polymer is cellulose acetate. 1.32 Any of the preceding processes in which the cellulose acetate polymer comprises cellulose acetate butyrate. 1.33 Any of the preceding processes wherein the cellulose acetate polymer is cellulose acetate butyrate. 1.34 Any of the preceding methods, wherein the coating composition of step (g) comprises an enteric polymer selected from a phthalate-containing polymer; cellulose acetate trimellitate; polymethacrylate; hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid; shellac, and combinations thereof. 1.35 The enteric polymer is dimethyl phthalate, diethyl phthalate, diallyl phthalate, di-n-propyl phthalate, di-n-butyl phthalate, diisobutyl phthalate, butyl cyclohexyl phthalate, di-n-pentyl phthalate, dicyclohexyl phthalate, butyl benzyl phthalate, di-n-hexyl phthalate, diisohexyl phthalate, diisoheptyl phthalate, butyl decyl phthalate, dibutoxyethyl phthalate, di(2-ethylhexyl) phthalate, di(n-octyl) phthalate, diisooctyl phthalate, n-octyl n- Any of the prior methods being or comprising a phthalate-containing polymer, including monomers of decyl phthalate, diisononyl phthalate, di(2-propylheptyl) phthalate, diisodecyl phthalate, diundecyl phthalate, diisoundecyl phthalate, ditridecyl phthalate, diisotridecyl phthalate, polyethylene terephthalate, cellulose phthalate, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), and combinations thereof. 1.36 Any of the preceding methods wherein the enteric polymer comprises a phthalate-containing polymer selected from cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP). 1.37 Any of the preceding methods, wherein the enteric polymer is a phthalate-containing polymer selected from cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP). 1.38 Any of the preceding processes wherein the enteric polymer comprises cellulose acetate trimellitate. 1.39 Any of the preceding methods, wherein the coated drug ion exchange particles further comprise an anti-adherent agent; the anti-adherent agent includes, but is not limited to, for example, talc, glycerol monostearate, magnesium stearate, or kaolin. 1.40 Any of the preceding methods wherein the enteric polymer comprises a polymethacrylate. 1.41 Any of the preceding processes wherein the enteric polymer is a polymethacrylate. 1.42 Any of the preceding methods wherein the enteric polymer comprises a polymethacrylate selected from Eudragit® L series, Eudragit® S series, Eudragit® FS, Kollicoat® MAE 100P, Acryl-EZE® 93A, and Acryl-EZE® MP. 1.43 Any of the preceding processes wherein the enteric polymer is a polymethacrylate selected from Eudragit® L series, Eudragit® S series, Eudragit® FS, Kollicoat® MAE 100P, Acryl-EZE® 93A, or Acryl-EZE® MP. 1.44 Any of the preceding methods wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®). 1.45 Any of the preceding processes wherein the enteric polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®). 1.46 Any of the preceding methods wherein the enteric polymer comprises sodium alginate or alginic acid. 1.47 Any of the preceding methods wherein the enteric polymer is sodium alginate or alginic acid. 1.48 Any of the preceding processes wherein the enteric polymer comprises shellac. 1.49 Any of the preceding processes wherein the enteric polymer is shellac. 1.50 Any of the preceding processes wherein the coating composition comprises a plasticizer. 1.51 The plasticizer in the coating composition may be selected from the group consisting of benzophenone, butylphthalyl butyl glycolate, camphor, α-cresyl-p-toluenesulfonate, cyclohexyl-p-toluenesulfonamide, diamyl phthalate, dibutyl phthalate, dibutyl sebacate, dibutyl succinate, dibutyl tartrate, diethoxyethyl adipate, diethoxyethyl phthalate, diethyl adipate, diethylene glycol dipropionate, diethyl phthalate, diethyl sebacate, diethyl succinate, diethyl tartrate, dimethoxyethyl adipate, dimethoxyethyl phthalate, dimethyl phthalate, dipropyl phthalate, ethyl benzoyl benzoate, ethylene glycol diacetate, ethylene glycol dibutyrate, ethylene glycol dipropionate, ethyl phthalyl ethyl glycolate, methyl benzoyl benzoate, methyl phthalyl ethyl glycolate, o- or p-toluene ethylsulfonamide, triacetin, tributyl citrate, tributyl phosphate ... Butyrin, tricresyl phosphate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, triphenyl phosphate, tripropionin, trimellitates (e.g., tri-(2-ethylhexyl) trimellitate, tri-(isononyl) trimellitate, tri-(isodecyl) trimellitate, tri-(isotridecyl) trimellitate), adipates (e.g., bis(2-ethylhexyl) adipate), sebacates ( For example, dibutyl sebacate, di-(2-ethylhexyl) sebacate), glycerol triacetate, alkyl citrates (triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, tri(2-ethylhexyl) citrate, acetyl trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate), vegetable oils, epoxidized soybean oil, epoxidized linoleic oil, azelates, dibenzoates, terephthalates, 1,Any of the preceding methods, wherein the organic solvent is selected from 2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organophosphates (e.g., tricresyl(methylphenyl)phosphate, 2-ethylhexyldiphenylphosphate), glycols (e.g., propylene glycol, polyethylene glycol, triethylene glycol di-2-hexanoate), triacetin, triethyl citrate, dibutyl sebacate, vegetable oils, oils, and combinations thereof. 1.52 Any of the preceding methods wherein the plasticizer in the coating composition is selected from propylene glycol, polyethylene glycol, triacetin, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, acetyl tributyl citrate, tributyl citrate, Soluphor P, vegetable oils, oils, and combinations thereof. 1.53 Any of the preceding methods in which a plasticizer is dispersed throughout the coating. 1.54 Any of the preceding processes wherein the plasticizer comprises polyethylene glycol; e.g., polyethylene glycol 3350. 1.55 Any of the preceding processes wherein the plasticizer consists of polyethylene glycol; e.g., polyethylene glycol 3350. 1.56 Any of the preceding methods in which a plasticizer is dispersed throughout the coating. 1.57 Any of the preceding methods, wherein the plasticizer constitutes from about 2.5 to about 25% w / w, or from about 5 to about 15% w / w, or from about 8 to about 12% w / w, or about 10% w / w of the solids in the coating. 1.58 Any of the preceding methods 1.4 onwards, wherein the composition of step (c)(i) comprises a solvent (e.g. water), optionally a chelating agent (e.g. EDTA) and a granulating agent. 1.59 The granulating agent is benzophenone, butylphthalyl butyl glycolate, camphor, α-cresyl-p-toluenesulfonate, cyclohexyl-p-toluenesulfonamide, diamyl phthalate, dibutyl phthalate, dibutyl sebacate, dibutyl succinate, dibutyl tartrate, diethoxyethyl adipate, diethoxyethyl phthalate, diethyl adipate, diethylene glycol dipropionate, diethyl phthalate, diethyl sebacate, diethyl succinate, diethyl tartrate. ethyl phthalate, dimethoxyethyl adipate, dimethoxyethyl phthalate, dimethyl phthalate, dipropyl phthalate, ethyl benzoyl benzoate, ethylene glycol diacetate, ethylene glycol dibutyrate, ethylene glycol dipropionate, ethyl phthalyl ethyl glycolate, methyl benzoyl benzoate, methyl phthalyl ethyl glycolate, o- or p-toluene ethyl sulfonamide, triacetin, tributyl citrate, tributyl phosphate, tributyrin, Licresyl phosphate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, triphenyl phosphate, tripropionin, trimellitates (e.g., tri-(2-ethylhexyl) trimellitate, tri-(isononyl) trimellitate, tri-(isodecyl) trimellitate, tri-(isotridecyl) trimellitate), adipates (e.g., bis(2-ethylhexyl) adipate), sebacates (e.g., , dibutyl sebacate, di-(2-ethylhexyl) sebacate), glycerol triacetate, alkyl citrates (triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, tri(2-ethylhexyl) citrate, acetyl trioctyl citrate, trihexyl citrate, butyryl trihexyl citrate), vegetable oils, epoxidized soybean oil, epoxidized linoleic oil, azelates, dibenzoates, terephthalates, 1,Method 1.58, wherein the additive is selected from 2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organophosphates (e.g., tricresyl(methylphenyl)phosphate, 2-ethylhexyldiphenylphosphate), glycols (e.g., propylene glycol, polyethylene glycol, triethylene glycol di-2-hexanoate), triacetin, triethyl citrate, dibutyl sebacate, vegetable oils, oils, and combinations thereof. 1.60 Method 1.59, wherein the granulating agent comprises polyethylene glycol; e.g., polyethylene glycol 3350. 1.61 Method 1.59, wherein the granulating agent comprises polyethylene glycol; e.g., polyethylene glycol 3350. 1.62 Any of the preceding methods, wherein the coated drug-ion exchange resin granules further comprise a plurality of active pharmaceutical agents (e.g., 2-10 active pharmaceutical agents). 1.63 Any of the preceding methods, wherein the resin core is combined with one or more active pharmaceutical agents (e.g., one or more small molecule drugs, e.g., up to 10 small molecule drugs). 1.64 Any of the preceding methods, wherein the active pharmaceutical agent is a free base compound. 1.65 Any of the preceding processes wherein the active pharmaceutical agent is a compound that can be protonated at one or more positions on the molecule. 1.66 Any of the preceding methods, wherein the active pharmaceutical agent comprises naltrexone or a pharma- ceutically acceptable salt thereof. 1.67 Any of the preceding methods, wherein the active pharmaceutical agent is present in an amount of about 1% to about 99% by weight, about 5% to about 70% by weight, about 10% to about 30% by weight, about 20% to about 30% by weight, about 20% to about 25% by weight, or about 22-24% by weight based on the total weight of the coated drug ion exchange resin complex granule; or about 22% by weight, about 23% by weight, or about 24% by weight based on the total weight of the coated drug ion exchange resin complex granule. 1.68 A process comprising the steps of: (h) combining the coated drug-ion exchange resin particles (or granules) produced by step (g) with a suspension base composition to form a coated drug-ion exchange resin sustained release suspension. Any of the preceding methods further comprising: 1.69 Method 1.68, wherein the suspension base composition is in the form of a liquid suspension and comprises one or more solvents and one or more ingredients selected from sugars, antioxidants, chelating agents, buffers, thickening agents, stabilizers, preservatives, surfactants, flavors, and colorants. 1.70 Method 1.68 or 1.69, wherein the solvent in the drug-ion exchange resin sustained release suspension comprises water. 1.71 Any of the preceding methods 1.68 and after, wherein the drug-ion exchange resin sustained-release suspension comprises coated granules in an amount of about 0.01 g to about 0.03 g of coated granules per ml of suspension. 1.72 Any of the preceding methods 1.68 and after, wherein the coated granules are present in the composition in an amount of about 0.01% w / v to about 10% w / v based on the total weight of the composition; or about 0.01% w / v to about 10% w / v based on the total weight of the composition; or about 0.1% w / v to about 5% w / v based on the total weight of the composition; or about 0.1% w / v to about 5% w / v based on the total weight of the composition; or about 1% w / v to about 5% w / v based on the total weight of the composition; or about 1% w / v to about 5% w / v based on the total weight of the composition; or about 2% w / v to about 3% w / v based on the total weight of the composition; or about 2% w / v to about 3% w / v based on the total weight of the composition. 1.73 Any of the preceding methods 1.68 and following, wherein the drug-ion exchange resin sustained release suspension is in the form of a suspension, e.g., a liquid suspension, and the active pharmaceutical agent is present in an amount of from about 0.1 mg / mL to about 100 mg / mL, e.g., from about 1 mg / mL to about 25 mg / mL, e.g., from about 3 mg / mL to about 8 mg / mL, e.g., about 5 mg / mL. 1.74 Any of the preceding methods 1.68 and following, wherein the drug-ion exchange resin sustained release suspension is in the form of a suspension, e.g., a liquid suspension, and the active pharmaceutical agent is present in an amount of from about 0.1% w / v to about 2% w / v, e.g., from about 0.1% w / v to about 1% w / v; such as from about 0.2% w / v to about 0.8% w / v, such as from about 0.4% w / v to about 0.6% w / v, such as about 0.5% w / v, e.g., 0.49% to 0.51% w / v. 1.75 Any of the preceding methods 1.68 and following, wherein the drug-ion exchange resin sustained release suspension comprises a plurality of said coated granules. 1.76 Any of the preceding methods 1.68 and following, wherein the coated granules are present in an amount of from 0.5% w / v to about 5% w / v; such as from about 1.0% w / v to about 3.0% w / v; such as from 2.0% w / v to about 2.5% w / v, such as about 2.3% w / v. 1.77 A drug-ion exchange resin sustained release suspension comprising: a chelating agent, such as EDTA, where for example EDTA is present in an amount of about 0.05% w / v to about 0.15% w / v; such as about 0.08% w / v to about 0.12% w / v; such as about 0.09% w / v to about 0.10% w / v; such as about 0.095% w / v; a buffering agent, such as citric acid, where for example citric acid is present in an amount of from about 0.1% w / v to about 0.8% w / v; such as from about 0.2% w / v to about 0.6% w / v; such as from about 0.3% w / v to about 0.5% w / v; such as about 0.4% w / v; an antioxidant, such as propyl gallate, in an amount of about 0.01% to about 0.03%, e.g., about 0.02%; A surfactant, such as Tween 80, in an amount of about 0.01% w / v to about 0.3% w / v; for example, about 0.05% w / v to about 0.2% w / v; for example, about 0.1% w / v; A solvent, such as water; a sugar, such as sucrose, in an amount of about 5% w / v to about 40% w / v; for example, about 10% w / v to about 30% w / v; for example, about 15% w / v to about 25% w / v; for example, about 20% w / v; a preservative, such as sodium benzoate, in an amount of about 0.1% w / v to about 0.5% w / v; for example, about 0.15% w / v to about 0.3% w / v; for example, about 0.2% w / v; and A thickening agent, such as starch, xanthan gum, or a combination of starch and xanthan gum, such as both starch and xanthan gum, where, for example, the starch is present in an amount of about 0.1% w / v to about 5% w / v; such as about 1% w / v to about 3% w / v; such as about 2% w / v; and the xanthan gum is present in an amount of about 0.05% w / v to about 0.5% w / v; such as about 0.1% w / v to about 0.2% w / v; such as about 0.15% w / v. Any of the preceding methods 1.68 and later, including 1.78 A drug-ion exchange resin sustained release suspension comprising: Coated granules according to any one of coated granules 1 or 1.1 to 1.86; sugars (e.g. sucrose); Chelating agents (e.g. EDTA); Buffers (e.g. citric acid, e.g. anhydrous citric acid); one or more thickening agents (e.g., starch and / or xanthan gum); preservatives (e.g. sodium benzoate); A surfactant (e.g., Tween 80); and Antioxidants (e.g. propyl gallate) Any of the preceding methods 1.68 and later, including 1.79 A drug-ion exchange resin sustained release suspension having the following composition: [Table 3] Any of the preceding methods 1.68 and later. 1.80 Any of the preceding methods 1.68 et seq., wherein the coated drug-ion exchange resin sustained release suspension is a composition described in any of compositions 1 and 1.1-1.55 herein. 1.81 Any of the preceding methods 1.68 and after, in which the coated drug-ion exchange resin sustained-release suspension does not contain glycerin or polyethylene glycol other than the granulating agent and plasticizer in the coated granules.

[0028] As used herein, the terms "coated drug-ion exchange resin particles", "coated drug-ion exchange resin granules" and "coated particles" and "coated granules" have the same meaning; i.e., as defined above, Ion exchange resins; One or more active pharmaceutical substances; optionally, a chelating agent; Optionally, a granulating agent a drug-ion exchange resin complex (or resin core) comprising: Cellulose acetate-containing polymers; Optionally, an enteric polymer; and Optionally, a plasticizer Coatings including A composition comprising is intended.

[0029] In the steps of the methods of the present disclosure, the term "contacting" as used herein is intended to mean bringing the indicated components into contact with each other, either directly or in a suitable solvent, such that the indicated reaction or complex formation occurs.

[0030] As used herein, the term "substantially" when used in connection with the pharmacokinetic profiles and figures of this application means that the AUC t , AUC ∞ and C max The value of AUC shown in the profile t , AUC ∞ and C max is intended to mean within ±20% of the mean value of

[0031] In various embodiments, the coated particles or granules of the present disclosure are irregularly shaped. However, some of the particles or granules are spherical or polyhedral in shape. Thus, the term "particle size" as used herein is generally used to refer to one or more of: (a) the diameter of a spherical particle; (b) the length of the longest axis of the particle; (c) the length of the shortest axis of the particle; (d) any measurement between the length of the longest axis and the length of the shortest axis (including the average of the two). In various embodiments, the particle size is determined according to the length of the longest axis of the particle. The diameter is generally expressed in micrometers (μm or microns). The diameter can be determined by any suitable means known in the art, for example, by optical measurement.

[0032] The coated particle granules of the present disclosure include a resin core surrounded by a polymer coating. Drug-resin complexes or drug-ion exchange resin complexes can be formed by mixing a drug, such as naltrexone or a salt thereof, such as naltrexone hydrochloride, with a resin, such as an ion exchange resin (e.g., polystyrene sulfonic acid resin), to promote protonation of the drug and subsequent binding (e.g., ionic binding) between the resin polymer and the drug. Without being bound by theory, it is believed that the drug binds to the resin polymer within the core and on the surface of the core. It is recognized that different drugs exhibit different affinities for binding with the resin polymer. The reaction can be carried out with an excess of drug until no drug binds to the resin polymer.

[0033] Binding of a selected drug or combination of drugs to an ion exchange resin can be accomplished using methods known in the art. Several different reaction types can be used to bind basic drugs to the resin polymer of the present disclosure. For example, a resin polymer (e.g., in the form of a sodium salt) can be reacted with a drug in the form of a salt or free base. Alternatively, a resin polymer (e.g., in a deprotonatable form) can be reacted with a drug in the form of a salt or free base. These reactions can have cationic by-products that can compete with cationic drugs for binding sites on the resin polymer, thereby reducing the amount of drug bound at equilibrium.

[0034] The drug-resin complex thus formed is recovered by filtration and washed with a suitable solvent to remove unbound drug or by-products. The complex may be air dried at room temperature or elevated temperature in a tray, fluid bed dryer or other suitable dryer.

[0035] Batch equilibration can be used to load finely divided resin powder with drugs to produce complexes. It is recognized that the ability of the resin polymer to bind a particular drug is affected by factors such as the inherent selectivity of the resin for the drug, the concentration of the drug in the loading solution, and the concentration of competing ions present in the loading solution. The rate of binding is affected by the activity of the drug and its molecular size, as well as the degree to which the polymer phase swells during loading.

[0036] It is usually desirable to load as much drug as possible onto the resin. Complete transfer of drug from the loading solution is not expected in a single equilibration step. Thus, multiple equilibrations may be required to achieve the desired loading onto the ion exchange resin. Using two or more loading steps, with separation of the resin from the liquid phase between steps, is a means of achieving maximum loading of drug onto the resin.

[0037] Without being bound by theory, drugs with higher charge density generally exhibit higher loading capacity on the resin. Similarly, drugs with relatively low molecular weights are loaded more efficiently than drugs with relatively high molecular weights. The higher the drug concentration in the loading solution with minimal competing ions, the higher the adsorption capacity on the resin.

[0038] In various embodiments, the amount of drug that can be loaded onto the resin ranges from about 1% to about 75% by weight of the drug-ion exchange resin complex. In some aspects of embodiments 1 and 2, drug loadings of about 10% to about 40% by weight, e.g., about 15% to about 30% by weight of the drug-ion exchange resin complex can be achieved.

[0039] In some embodiments, the drug-ion exchange resin complex is granulated, for example, by wet granulation. Typically, the drug-ion exchange resin complex is contacted with a composition comprising a solvent (e.g., water), optionally a chelating agent (e.g., EDTA), and a granulating agent (e.g., polyethylene glycol, e.g., polyethylene glycol 3550), and the drug-ion exchange resin complex granules are formed by spraying the composition onto the drug-ion exchange resin complex and granulating the mixture, for example, using a high shear granulator. Suitable granulating agents are water-soluble and water-insoluble. Examples of suitable granulating agents include, for example, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triacetin, and Soluphor P, and mixtures thereof. In some embodiments, the granulating agent comprises or consists of polyethylene glycol. Polyethylene glycol of any molecular weight can be used. In some embodiments, the granulating agent comprises or consists of polyethylene glycol 3550.

[0040] In various embodiments, the polymer coating comprises a combination of cellulose acetate-containing polymers alone or in combination with one or more enteric polymers. The term "cellulose acetate-containing polymer" as used herein is intended to mean a polymer that comprises at least one mono-, di- or tri-acetylated cellulose (i.e., β(1→4)-linked glucose) monomer. In various embodiments, the cellulose acetate-containing polymer can be selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate propionate, and combinations thereof. In some preferred embodiments, the cellulose acetate polymer is selected from cellulose acetate and cellulose acetate butyrate. In some further preferred embodiments, the cellulose acetate polymer comprises or consists of cellulose acetate butyrate.

[0041] In some embodiments, the coated drug-ion exchange resin complex particles and / or granules may further comprise an enteric polymer, which may be selected from phthalate-containing polymers; cellulose acetate trimellitate; polymethacrylates; hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid; shellac, and combinations thereof.

[0042] In some embodiments, the enteric polymer is or comprises a phthalate-containing polymer; i.e., a polymer that comprises a phthalate-containing monomer. In various embodiments, the enteric polymer is dimethyl phthalate, diethyl phthalate, diallyl phthalate, di-n-propyl phthalate, di-n-butyl phthalate, diisobutyl phthalate, butyl cyclohexyl phthalate, di-n-pentyl phthalate, dicyclohexyl phthalate, butyl benzyl phthalate, di-n-hexyl phthalate, diisohexyl phthalate, diisoheptyl phthalate, butyl decyl phthalate, dibutoxyethyl phthalate, di(2-ethylhexyl) phthalate, di(n-octyl) phthalate, diisooctyl ... In some embodiments, the polymer may be or comprise a phthalate-containing polymer, the polymer may comprise monomers of cellulose phthalate, n-octyl n-decyl phthalate, diisononyl phthalate, di(2-propylheptyl) phthalate, diisodecyl phthalate, diundecyl phthalate, diisoundecyl phthalate, ditridecyl phthalate, diisotridecyl phthalate, polyethylene terephthalate, cellulose phthalate, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), or combinations thereof.

[0043] In some preferred embodiments, the phthalate-containing polymer is selected from cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP).

[0044] In some embodiments, the enteric polymer can comprise cellulose acetate trimellitate.In some embodiments, the enteric polymer can comprise polymethacrylate, for example, polymethacrylate is selected from methacrylic acid-methyl methacrylate copolymer (1:1), such as Eudragit L series, methacrylic acid-methyl methacrylate copolymer (1:2), such as Eudragit S series, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), such as Eudragit FS, or methacrylic acid-ethyl acrylate copolymer (1:1), such as Kollicoat MAE 100P.In some aspects of embodiment 1 and 2, the enteric polymer can comprise acrylic enteric coating system, such as Acryl-EZE 93A, and Acryl-EZE MP.

[0045] In some further embodiments, the enteric polymer may include hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid; shellac, and combinations thereof.

[0046] In some embodiments, the polymer coating comprises about 1% to about 30% by weight, e.g., about 3% to about 25% by weight, about 10% to about 20% by weight, or about 15% by weight, of the uncoated drug-ion exchange resin complex granules (i.e., drug bound to the resin polymer in particulate form).

[0047] In some embodiments, the barrier coating further comprises a plasticizer, e.g., one or more of the plasticizers disclosed herein, which may facilitate uniform coating of the drug-ion exchange resin complex and / or increase the tensile strength of the barrier coating layer.

[0048] Generally, the plasticizer is used in a proportion ranging from about 2% to about 50% by weight of the polymer coating, more preferably from about 2.5% to about 25% by weight of the coated drug-resin complex coating layer, or a mixture of plasticizers combined. Preferably, a plasticizer in the range of about 5% to about 15% by weight of the coating layer provides the most desirable properties.

[0049] Suitable plasticizers are water-soluble and water-insoluble. Examples of suitable plasticizers include, for example, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triacetin, and Soluphor P, and mixtures thereof. In some preferred embodiments, the granulating agent in the resin core and the plasticizing agent in the coating each independently comprise or consist of polyethylene glycol. Polyethylene glycol of any molecular weight can be used. In some embodiments, the granulating agent comprises or consists of polyethylene glycol 3550.

[0050] In some embodiments, the polymeric coating of the present disclosure has a release rate over a period of at least 1 hour, at least 4 hours, at least 8 hours, at least 16 hours, or at least 24 hours. In some embodiments, the polymeric coating of the present disclosure has a release rate over a period of about 8 to 24 hours, preferably 12 to 24 hours.

[0051] The coated drug-ion exchange resin granules of the present disclosure can be easily formulated with pharma- ceutically acceptable additives according to methods well known to those skilled in the art. In certain embodiments, these formulations contain the coated drug-ion exchange resin complex particles of the present disclosure. In some embodiments, a mixture of coated and uncoated drug-ion exchange resin complex particles can be present. These formulations can contain the appropriate ratio of coated and uncoated particles.

[0052] It is further envisioned that the formulation of the present disclosure may include one or more active pharmaceutical substances. For example, the formulation may include one or more drugs that are loaded into the resin polymer to form a complex. As another example, the formulation may include a first coated drug-ion exchange resin complex particle that includes a first active pharmaceutical substance of the present disclosure in combination with a second coated drug-ion exchange resin complex particle that includes a second active pharmaceutical substance. In another example, the formulation may include coated drug-ion exchange resin particles in combination with one or more active pharmaceutical substances that are not in the coated drug-ion exchange resin particles or granules.

[0053] The coated drug-ion exchange resin particles of the present disclosure are typically formulated for oral delivery.

[0054] The resin composition thus produced can be stored for future use or can be immediately formulated with conventional pharma- ceutically acceptable carriers to produce a final ingestible composition for oral administration.The composition according to the present disclosure can take the form of, for example, a liquid formulation, such as a suspension, or a solid formulation, such as a caplet, sachet, tablet, chewable tablet, caplet, sublingual tablet, powder, wafer, strip, gel (including Liquigel), etc.In one embodiment, the tablet of the present disclosure is formulated as an orally disintegrating tablet (ODT).Such an orally dissolving tablet can disintegrate in the mouth in less than about 60 seconds.

[0055] The composition according to the present disclosure, including coated drug-ion exchange resin complex particles and granules, can be formulated using conventional pharma-ceutically acceptable carriers or additives and known technology.For example, the composition of the present disclosure can include conventional carriers or additives, including diluents (e.g., crystalline cellulose, lactose), thickeners (e.g., starch, xanthan gum), binders (e.g., cellulose derivatives and acrylic derivatives), lubricants (i.e., magnesium stearate or calcium stearate, or vegetable oils, polyethylene glycol, talc, sodium lauryl sulfate, amorphous silica, polyoxyethylene monostearate), thickeners, wetting agents, disintegrants (e.g., crospovidone), antioxidants (propyl gallate, ascorbic acid, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene), colorants, flavors, preservatives, sweeteners, buffers, and other ingredients that are easily apparent to those skilled in the art.

[0056] Carrier Suitable pharma- ceutically acceptable carriers may include one or more of fatty acid esters, fatty acids and their salts, fatty alcohols (e.g., lauryl, myristylstearyl, cetyl or cetostearyl alcohol), fatty amines, fatty amides, glycerides (e.g., mono-, di- and tri-glycerides), hydrogenated fats, glycolipids, steroids, natural and synthetic waxes, polyethylene glycol (PEG) or its derivatives, and the like. Specific examples include, but are not limited to, hydrogenated vegetable oils, hydrogenated cottonseed oil, hydrogenated castor oil, stearic acid, cocoa butter, glyceryl behenate, glyceryl dipalmitostearate, stearyl alcohol. Mixtures of mono-, di- and tri-glycerides, and mono- and di-fatty acid esters of polyethylene glycol are also suitable fatty substances. Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons and conventional waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffin, and candelilla wax.

[0057] Polyethylene glycol or derivatives thereof may include PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 12000, PEG 20000, polyglycolized glycerides, polyethylene glycol-polyoxyethylene, polyethylene glycol polypropylene, and polyethylene glycol-polyoxypropylene.

[0058] Suspending / Thickening Agents Suitable thickening agents include, for example, tragacanth; xanthan gum; bentonite; starch; acacia and lower alkyl ethers of cellulose (including hydroxy and carboxy derivatives of cellulose ethers). Examples of cellulose include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose (MCC), and MCC and sodium carboxymethylcellulose. In some embodiments, the composition according to the present disclosure comprises xanthan gum in an amount of about 0.01 to about 1.0 volume (w / v)% based on the weight of the composition, more preferably about 0.1% w / v to about 0.2% w / v, for example about 0.15% w / v, based on the weight of the composition. In some embodiments, the composition of the present disclosure comprises starch in an amount of about 1% w / v to about 10% w / v, for example about 1.5% w / v to about 2.5% w / v, for example about 2.0% w / v or about 2.1% w / v.

[0059] Suitable thickening agents may also include diluents, such as cellulose, dry starch, microcrystalline cellulose, dicalcium phosphate, calcium sulfate, sodium chloride, confectioners' sugar, compressible sugar, dextrates, dextrin, dextrose, sucrose, mannitol, powdered cellulose, sorbitol, and lactose.

[0060] Binder Binders may be used to impart adhesiveness to the composition and may include, but are not limited to, starch, gelatin, sugars, natural and synthetic gums, polyethylene glycol, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, waxes, and polyvinylpyrrolidone.

[0061] Wetting Agent The compositions of the present disclosure may also include a humectant. Suitable humectants useful in the final formulation include glycerin, xylitol, polyethylene glycol, propylene glycol and mixtures thereof.

[0062] Disintegrants The compositions of the present disclosure may contain disintegrants to facilitate disintegration or breakup after administration. Materials used for this purpose include starches, clays, celluloses, aligns, gums and cross-linked polymers.

[0063] Surfactants The compositions of the present disclosure may include one or more surfactants in an amount of up to about 5.0% w / v, preferably about 0.02 to about 3.0% w / v, e.g., about 0.1% w / v, based on the total formulation. Surfactants useful in the preparation of the final compositions of the present disclosure are generally organic substances that aid in the stabilization and dispersion of ingredients in aqueous systems for a suitable homogeneous composition. Preferably, the surfactant selected is a non-ionic surfactant, such as poly(oxyethylene)(20) sorbitan monooleate (available under the trade name Tween 80) and sorbitan monooleate. For example, in various embodiments, the compositions of the present disclosure include poly(oxyethylene)(20) sorbitan monooleate in an amount of about 0.02 to about 3.0% w / v, e.g., about 0.1% w / v, based on the total formulation.

[0064] Exemplary nonionic surfactants that can be included in the formulations of the present disclosure include, for example, alkyl poly(ethylene oxide), alkyl polyglucosides (e.g., octyl glucoside and decyl maltoside), fatty alcohols such as cetyl alcohol and oleyl alcohol, cocamide MEA, cocamide DEA and cocamide TEA.Specific nonionic surfactants that can be included in the formulations produced by the present disclosure include, for example, polysorbates, such as polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81 and polysorbate 85; poloxamers, such as poloxamer 188, poloxamer 407; polyethylene-polypropylene glycol; or polyethylene glycol (PEG).

[0065] Antioxidants The particles and compositions of the present disclosure may also include one or more antioxidants, up to about 5.0% w / v, preferably about 0.02 to about 3.0% w / v, for example about 0.1% w / v, based on the total formulation. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium pyrosulfite, sodium bisulfite, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, tartaric acid, phosphoric acid, tocopherol (vitamin E), sesamol, and tertiary butyl hydroquinone. In some embodiments, the antioxidant is present in the coated granules 1 and 1.1 to 1.186 described herein. In some embodiments, the antioxidant is present in the compositions 1 and 1.1 to 1.55 described herein.

[0066] Preservatives The composition of the present disclosure may contain one or more preservatives.Useful preservatives include, but are not limited to, sodium benzoate, benzoic acid, potassium sorbate, salts of edetic acid (also known as ethylenediaminetetraacetic acid or EDTA salts, for example, disodium EDTA), parabens (for example, methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.), and sorbic acid. Useful preservatives include the chelating agents listed above, as well as other chelating agents, such as nitrilotriacetic acid (NTA); ethylenediaminetetraacetic acid (EDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DPTA), 1,2-diaminopropanetetraacetic acid (1,2-PDTA); 1,3-diaminopropanetetraacetic acid (1,3-PDTA); 2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA); 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA). ; ethylenediamine (EDAMINE); trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA); ethylenediamine-N,N'-diacetic acid (EDDA); phenazine methosulfate (PMS); 2,6-dichloro-indophenol (DCPIP); bis(carboxymethyl)diaza-18-crown-6; porphine; chlorophyll; dimercaprol (2,3-dimercapto-1-propanol); citric acid (e.g., anhydrous citric acid); tartaric acid; fumaric acid; malic acid; ascorbic acid; and salts thereof. The above preservatives are exemplary, but each preservative needs to be evaluated with each formulation to ensure compatibility and effectiveness of the preservative. Methods for evaluating the effectiveness of preservatives in pharmaceutical formulations are known to those skilled in the art. Preferred preservatives are paraben preservatives, including methylparaben, ethylparaben, propylparaben and butylparaben, as well as benzoates such as sodium benzoate. Preferably, both methylparaben and propylparaben are present in the formulation in a ratio of about 2.5:1 to about 16:1, preferably 9:1, of methylparaben to propylparaben.In certain embodiments, the composition comprises paraben in an amount of about 0.01% w / v to about 0.5% w / v, such as about 0.1% w / v to about 0.3% w / v, such as about 0.2% w / v. In some embodiments, the composition of the present disclosure comprises citric acid in an amount of about 0.001% w / v to about 0.1% w / v, such as about 0.01% w / v. In some embodiments, the composition comprises ascorbic acid in an amount of about 0.001% w / v to about 0.1% w / v, such as about 0.06% w / v.

[0067] Chelating Agents As noted above, suitable chelating agents include those listed above and other chelating agents such as nitrilotriacetic acid (NTA); ethylenediaminetetraacetic acid (EDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DPTA), 1,2-diaminopropanetetraacetic acid (1,2-PDTA); 1,3-diaminopropanetetraacetic acid (1,3-PDTA); 2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA); 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA); ethylenediamine (EDAMINE); trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA); ethylenediamine-N,N'-diacetic acid (EDDA).

[0068] Buffer Suitable buffering agents include acetic acid and its salts, phosphoric acid and its salts; citric acid and its salts, and glutamic acid and its salts, as well as other buffering agents known to be useful in pharmaceutical compositions.

[0069] Plasticizer Plasticizers may be included in the coating material to modify the mechanical properties. Examples of plasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol, triacetin, triethyl citrate, glycerol, and the like. Further examples of plasticizers that may be used in the compositions of the present disclosure include benzophenone, butylphthalylbutyl glycolate, camphor, α-cresyl-p-toluenesulfonate, cyclohexyl-p-toluenesulfonamide, diamylphthalate, dibutylphthalate, dibutylsebacate, dibutylsuccinate, dibutyltartrate, diethoxyethyladipate, diethoxyethylphthalate, diethyladipate, diethyleneglycoldipropionate, diethylphthalate, diethylsebacate, diethylsuccinate, diethyltartrate, dimethoxyethyladipate, dimethoxyethylphthalate, dimethylphthalate, dipropylphthalate, ethylbenzoylbenzoate, ethyleneglycoldiacetate, ethyleneglycoldibutyrate, ethyleneglycoldipropionate, ethylphthalylethylglycolate, methylbenzoylbenzoate, methylphthalylethylglycolate, o- or p-tolueneethyl Sulfonamides, triacetin, tributyl citrate, tributyl phosphate, tributyrin, tricresyl phosphate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, triphenyl phosphate, tripropionin, trimellitates (e.g., tri-(2-ethylhexyl) trimellitate, tri-(isononyl) trimellitate, tri-(isodecyl) trimellitate, tri-( isotridecyl) trimellitate), adipates (e.g., bis(2-ethylhexyl) adipate), sebacates (e.g., dibutyl sebacate, di-(2-ethylhexyl) sebacate), glycerol triacetate, alkyl citrates (triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, tri(2-ethylhexyl) citrate, acetyl trioctyl citrate, trihexyl citrate,butyryl trihexyl citrate), vegetable oils, epoxidized soybean oil, epoxidized linoleic oil, azelates, dibenzoates, terephthalates, 1,2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organophosphates (e.g., tricresyl (methylphenyl) phosphate, 2-ethylhexyl diphenyl phosphate), glycols (e.g., propylene glycol, polyethylene glycol, triethylene glycol di-2-hexanoate), triacetin, triethyl citrate, dibutyl sebacate, vegetable oils, oils, and combinations thereof.

[0070] Colorants / Fragrances The composition of the present disclosure may comprise one or more flavors.For example, flavors may comprise one or more sweeteners well known in the art, including both natural and artificial sweeteners.Thus, the additional sweetener may be selected from the non-limiting list of water-soluble sweeteners, such as monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose, mannose, galactose, fructose, high fructose corn syrup, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch or corn syrup solids and sugar alcohols, such as sorbitol, xylitol, mannitol and mixtures thereof.

[0071] In general, the amount of sweetener may be from 0.001 to about 90% w / v of the final liquid composition when an easily extractable sweetener is used. The water-soluble sweeteners described above are preferably used in an amount of from about 5 to about 70% w / v, most preferably from about 10 to about 50% w / v of the final liquid composition.

[0072] Flavorings included in the compositions of the present disclosure may include mints, such as peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, essential oils (i.e., thymol, ecryptol, menthol, and methyl salicylate), and the like. The amount of flavoring used is usually a matter of preference depending on factors such as the type of flavor, the individual flavor, and the strength desired. Flavorings are generally used in amounts that vary depending on the individual flavor, and may range, for example, in amounts of about 0.01% to about 3% by weight per volume of the weight of the final composition.

[0073] Colorants useful in the compositions of the present disclosure include pigments such as titanium dioxide, which may be incorporated in amounts up to about 1% w / v, preferably up to about 0.6% w / v. Colorants may also include dyes suitable for food, drug, and cosmetic applications, known as D&C and FD&C dyes. Materials acceptable for the above range of uses are preferably water-soluble. Specific examples include the indigoid dye known as FD&C Blue No. 2, which is the disodium salt of 5,5' indigotin disulfonic acid. Similarly, the dye known as FD&C Green No. 1 includes a triphenylmethane dye, which is the monosodium salt of 4-[4-N-ethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-Np-sulfonium benzyl)-2,5-cyclohexadienimine]. Other such materials may be used as known to those skilled in the art.

[0074] Dosage form In some embodiments, the coated drug-ion exchange resin particles and granules of the present disclosure are in a ready-to-administer form, such as a blister pack, bottle, syringe, foil pack, pouch or other suitable container.In other embodiments, the composition of the present disclosure is in a concentrated form in a pack, optionally with a diluent required to produce a final form for administration.In yet other embodiments, the formulation comprises a compound useful in the present disclosure in solid form, and optionally a separate container that contains a suitable suspension base or other carrier for the drug-ion exchange resin complex useful in the present disclosure in solid form.

[0075] In yet other embodiments, the above-mentioned pack / kit contains other components, such as a metered dose dispenser / device, instructions for diluting, mixing and / or administering the formulation, other containers. Such other pack / kit components are readily apparent to those skilled in the art. In some preferred embodiments, the coated drug-ion exchange resin particles and granules of the present disclosure are in liquid suspension as described herein. EXAMPLES

[0076] Example 1 Preparation of a Naltrexone Sustained Release Suspension Naltrexone can be prepared by a variety of methods, for example those described in WO 91 / 05768, WO 2008 / 034973, WO 2008 / 138605, WO 2010 / 039209, and WO 2010 / 039209, the disclosures of each of which are incorporated herein by reference.

[0077] The naltrexone-resin complex was coated according to the formulation shown in Table 1. [Table 4]

[0078] Naltrexone can be prepared by a variety of methods, for example those described in WO 91 / 05768, WO 2008 / 034973, WO 2008 / 138605, WO 2010 / 039209, and WO 2010 / 039209, the disclosures of each of which are incorporated herein by reference.

[0079] Purified water was poured into a container and naltrexone HCl was added and mixed until dissolved. Sodium polystyrene sulfonate (Amberlite IRP69 resin) was added to the tank and mixed. The resulting dispersion was passed through a filter paper and the retained drug-resin complex was washed with purified water. The drug-resin complex was placed in an oven and dried until the moisture content was less than 10%.

[0080] The formulation in Table 1 was used to produce the naltrexone resin complex granules summarized in Table 2 below. Polyethylene glycol was added to purified water and mixed until dissolved. The resulting PEG solution was sprayed onto the wet resin complex and granulated using a high shear granulator. The wet granules were dried in an oven until the moisture reached 15%-20%. The partially dried granules were milled using a co-mill equipped with an approximately 400 μm mesh screen. The passed granules were dried until the moisture reached less than 7%. [Table 5]

[0081] The resulting naltrexone resin complex granules were coated to form the formulations summarized in Table 3 below. Acetone and purified water were added to a vessel and mixed well. Polyethylene glycol was added to a vessel and mixed until dissolved. Cellulose acetate butyrate was added and mixed until dissolved. The coating solution was sprayed onto the naltrexone resin complex granules of Table 2 using a fluid bed processor until a 15% weight gain was achieved. [Table 6]

[0082] The resulting coated naltrexone resin was then used to prepare the naltrexone sustained release suspensions summarized in Table 4 below. A suspension base was prepared by adding sucrose to a main vessel containing purified water and mixing until dissolved, followed by the addition of citric acid. Starch was dispersed in the vessel and mixed well. In a separate vessel, methylparaben and propylparaben were added to propylene glycol and mixed until completely dissolved. Xanthan gum was added to the preservative solution and mixed well until uniformly dispersed. This gum dispersion was slowly added to the main vessel and mixed well. Sodium metabisulfite and Tween 80 were added to the main vessel and mixed until dissolved. Purified water was added to the main vessel to a final suspension base volume of 1.2 L. To 900 ml of suspension base, the coated naltrexone resin complex was added under continuous mixing to form the naltrexone ER suspension. [Table 7]

[0083] Example 2 In vitro drug release A coated naltrexone resin was prepared according to Example 1. In this example, cherry flavor and FD&C red 40 were used to prepare a final suspension containing ascorbic acid as an antioxidant. [Table 8]

[0084] Purified water was added to the main vessel followed by sucrose and mixed until dissolved. Citric acid was added to the main vessel and mixed until dissolved. Starch was then dispersed in the vessel and mixed well. In a separate vessel, methylparaben and propylparaben were added to the propylene glycol and mixed until completely dissolved. Xanthan gum was added to the preservative solution and mixed well until evenly dispersed. The xanthan gum dispersion was slowly added to the main vessel and mixed well. Ascorbic acid and Tween 80 were added to the main vessel and mixed until dissolved. Purified water was added to the main vessel to a final suspension base volume of 1.6 L. To the 500 mL suspension base, FD&C red number 40, cherry flavor and coated naltrexone resin were added under continuous mixing to form the naltrexone ER suspension.

[0085] Naltrexone ER suspensions were tested for in vitro drug release using USP Apparatus II, 0.4 M KH2PO4, 900 mL, 50 rpm, 37±0.5° C. The results are summarized in FIG.

[0086] Example 3 Coated Naltrexone Resin Naltrexone resin complex granules were prepared according to Example 1. In this example, cellulose acetate butyrate and hypromellose phthalate were used to coat the naltrexone resin complex granules. The formulations were prepared according to Table 6. [Table 9]

[0087] Acetone and purified water were added to the vessel and mixed well. Polyethylene glycol was added to the vessel and mixed until dissolved. Cellulose acetate butyrate was added and mixed until dissolved. Hypromellose phthalate was then added and mixed until dissolved. The coating solution was sprayed onto the naltrexone resin complex granules using a fluid bed apparatus until a weight gain of 15% w / w was achieved.

[0088] Example 4 Coated Naltrexone Resin Naltrexone resin complex granules were prepared according to Example 1. In this example, ethyl cellulose (EC) was used to coat the naltrexone resin complex granules. The formulations were prepared according to Table 7. [Table 10]

[0089] Acetone and purified water were added to a container and mixed well. Myvacet 9-45 was added and mixed until dissolved. Ethylcellulose was added and mixed until dissolved. A total of 1502 g of coating solution was sprayed onto the naltrexone resin complex granules using a fluid bed processor until a weight gain of 15 w / w% was achieved.

[0090] The coated naltrexone resin prepared according to Example 4 was tested for in vitro drug release using USP Apparatus II, 0.4M KH2PO4, 900 mL, 50 rpm, 37±0.5° C. The results are summarized in FIG.

[0091] Example 5 Naltrexone sustained release suspension Naltrexone resin complexes were prepared according to the formulations shown in Table 8. [Table 11]

[0092] Purified water was poured into a container and naltrexone HCl was added and mixed until dissolved. Sodium polystyrene sulfonate (Amberlite IRP69 resin) was added to the tank and mixed. The supernatant from the resulting dispersion was decanted, followed by washing with purified water, and finally the dispersion was filtered using a filter housing. The wet drug-resin complex was dried using a fluid bed processor until the moisture content was approximately 15%.

[0093] The formulation in Table 8 was used to manufacture the naltrexone resin complex granules summarized in Table 9 below. EDTA was added to purified water and mixed until dissolved. Polyethylene glycol was added to a vessel and mixed until dissolved. The resulting PEG solution was sprayed onto the wet resin complex and granulated using a high shear granulator. The wet granules were dried using a fluid bed processor until a moisture content of 15%-20% was reached. The partially dried granules were milled using a co-mill equipped with an 813 μm mesh screen. The passed granules were dried using a fluid bed processor until a moisture content of less than 7% was reached. [Table 12]

[0094] The resulting complex was coated to form the formulations summarized in Table 10 below. Acetone and purified water were added to a vessel and mixed well. Polyethylene glycol was added to a vessel and mixed until dissolved. Cellulose acetate butyrate was added and mixed until dissolved. The coating solution was sprayed onto the naltrexone resin complex granules of Table 9 using a fluid bed processor until a weight gain of 15% w / w was achieved. [Table 13]

[0095] The resulting coated naltrexone resin was used to prepare the naltrexone sustained release suspensions summarized in Table 11 below. A suspension was prepared by adding glycerin to a vessel and heated to 45-60°C. Methylparaben and propylparaben were added to the vessel and mixed until dissolved. Xanthan gum was added to the preservative solution and mixed until uniformly dispersed (gum dispersion). Added to a main vessel containing purified water, sucrose, EDTA and citric acid and mixed until dissolved. Starch was added to the main vessel and mixed until uniformly dispersed. Gum dispersion was slowly added to the main vessel and mixed well. Tween 80, color and flavor were added to the main vessel and mixed well. The coated naltrexone resin was added to the main vessel and purified water was added to bring the final suspension volume to 1.6 L. [Table 14]

[0096] Example 6 Naltrexone sustained release suspension Coated naltrexone resin was prepared according to Example 5. Naltrexone sustained release suspension was prepared as summarized in Table 12 below. Suspension was prepared by adding glycerin to a vessel and heated to 45-55°C. Methylparaben and propylparaben were added to the vessel and mixed until dissolved. Xanthan gum was added to the preservative solution and mixed until uniformly dispersed (gum dispersion). Added to a main vessel containing purified water, EDTA and citric acid and mixed until dissolved. Tween 80 was added and mixed well. Starch and sucrose were added together to the main vessel and mixed until uniformly dispersed. Gum dispersion was slowly added to the main vessel under continuous mixing. Color and flavor were added to the main vessel and mixed well. Coated naltrexone resin was added to the main vessel and purified water was added to bring the final suspension volume to 1.6L. [Table 15]

[0097] Example 7 Preparation of a Naltrexone Sustained Release Suspension A naltrexone resin complex was prepared according to the formulation shown in Table 13. [Table 16]

[0098] Purified water was poured into a container and naltrexone HCl was added and mixed until dissolved. Sodium polystyrene sulfonate (Amberlite IRP69 resin) was added to the tank and mixed. The supernatant from the resulting dispersion was decanted, followed by washing with purified water, and finally the dispersion was filtered using a filter housing. The wet drug-resin complex was dried using a fluid bed processor until the moisture content was approximately 15%.

[0099] The formulation in Table 13 was used to manufacture the naltrexone resin complex granules summarized in Table 14 below. EDTA was added to purified water and mixed until dissolved. Polyethylene glycol (PEG) was added to a container and mixed until dissolved. The PEG solution was sprayed onto the wet resin complex and granulated using a high shear granulator. The wet granules were dried using a fluid bed processor until the moisture reached 15%-20%. The partially dried granules were passed through a #20 mesh screen and dried using a fluid bed dryer until the moisture reached less than 7%. The partially dried granules were milled using a co-mill equipped with an 813 μm mesh screen. These dry granules were milled using a co-mill equipped with an 813 μm mesh screen.

[0100] [Table 17]

[0101] The resulting complex was coated to various weight gains with the coating compositions shown in Table 15. Acetone and purified water were added to a container and mixed well. Polyethylene glycol was added to a container and mixed until dissolved. Cellulose acetate butyrate was added and mixed until dissolved. The coating solutions were sprayed onto the naltrexone resin complex granules of Table 14 using a fluid bed processor to achieve coating weight gains of 15% w / w and 20% w / w. [Table 18]

[0102] The resulting coated naltrexone resin was used to prepare the naltrexone sustained release suspensions summarized in Table 16 below. Added to the main vessel containing purified water, Tween 80, propyl gallate, sodium benzoate, EDTA and anhydrous citric acid and mixed until dissolved. The xanthan gum, starch and sucrose were mixed together and added to the main tank and mixed until evenly dispersed. The color solution was added to the main tank with mixing. The coated naltrexone resin and flavor were added to the main vessel and purified water was added to bring the final suspension volume to 4 L. [Table 19]

[0103] FIG. 3 shows the in vitro drug release profiles for naltrexone extended release suspension formulations 1 and 2 described in Table 16.

[0104] Pharmacokinetic studies: Study Summary: This was an open-label, single-dose, randomized, three-period, three-treatment, three-sequence crossover comparative bioavailability study in healthy adults (n=18) in the fasted state.

[0105] treatment: Treatment A - Formulation 1: 10 mL of 5 mg / mL oral suspension (total dose = 50 mg naltrexone HCl) administered after an overnight fast of at least 10 hours. Treatment B - Formulation 2: 10 mL of 5 mg / mL oral suspension (total dose = 50 mg naltrexone HCl) was administered after an overnight fast of at least 10 hours. Treatment C - Reference formulation: Naltrexone HCl 50 mg tablets (Mallinckrodt TM , SpecGx LLC): One 50 mg tablet was administered after an overnight fast of at least 10 hours. Analytes: Both naltrexone and its active metabolite (6-β-naltrexol) were analyzed.

[0106] result: AUCs obtained for naltrexone and 6-β-naltrexol t , AUC ∞ , C max , T max and T 1 / 2 Values ​​are shown in Table 17: [Table 20]

[0107] The mean plasma naltrexone and mean plasma 6-β-naltrexol concentrations are shown in Tables 18 and 19, respectively: [Table 21] [Table 22]

[0108] Naltrexone formulations 1 and 2 and the commercial formulation (naltrexone HCl 50 mg tablets; Mallinckrodt TM The pharmacokinetic profile of the 6-β-naltrexol formulation (SpecGx LLC) is shown in Figure 4. The pharmacokinetic profiles of the 6-β-naltrexol formulation and the marketed formulation are shown in Figure 5.

[0109] Test findings: The results show that, overall, the disclosed formulations exhibit better bioavailability (approximately 50% higher bioavailability) compared to the commercially available immediate release formulations. For naltrexone, formulation 1 showed C max was reduced by approximately 65%, and C max was reduced by approximately 75%, which significantly reduces the side effects caused by the rapid increase in plasma concentration of the immediate release formulation.

[0110] T max was delayed from less than 1 hour for the reference intermediate release (IR) tablet to approximately 6 hours for both formulations 1 and 2, indicating the sustained release properties of the test formulations. The duration of efficacy of formulations 1 and 2 was increased compared to the immediate release reference formulation due to a slower rise and fall in plasma concentrations. Formulations 1 and 2 maintained plasma concentrations above 0.75 ng / mL for approximately 16 hours after oral ingestion, compared to only approximately 6 hours for the reference formulation.

[0111] For 6-β-naltrexol, formulation 1 had C max was reduced by approximately 66%, and C max The C was reduced by approximately 77%, which significantly reduces the side effects caused by the rapid rise in plasma concentration of the immediate release formulation. Similar to the pattern of the plasma profile of naltrexone, the active metabolite 6-β-naltrexol from formulations 1 and 2 showed a significantly higher C compared to the reference formulation. max is low, T max However, comparable bioavailability was observed for formulations 1 and 2 and the reference formulation.

[0112] The biological half-life of 6-β-naltrexol is comparable between Formulations 1 and 2 and the reference formulation. The plasma profiles of sustained release Formulations 1 and 2 show higher concentrations than the reference formulation from 10 hours after oral ingestion onwards.

[0113] While the present invention has been described in connection with what are presently considered to be the most practical and preferred embodiments, it is to be understood that the invention is not intended to be limited to the described embodiments, but rather is intended to cover various modifications or equivalent arrangements included within the spirit and scope of the appended claims, which scope should be accorded the broadest interpretation so as to encompass all such modifications or equivalent arrangements permitted under law.

[0114] Each of the patents, books, articles and other printed publications referenced herein is incorporated by reference in its entirety for all purposes.

Claims

1. a) ion exchange resin; one or more active pharmaceutical substances; Optionally, a chelating agent; Optionally, a granulating agent a drug-ion exchange resin complex (or resin core) comprising: b) cellulose acetate-containing polymers; Optionally, an enteric polymer; and Optionally, a plasticizer Coatings including 1. A coated drug-ion exchange resin particle comprising:

2. 2. The coated drug-ion exchange resin particles of claim 1, wherein the ion exchange resin comprises a copolymer of polystyrene and divinylbenzene; e.g., Amberlite IRP-69.

3. The coated drug-ion exchange resin particles of claim 1 or 2, wherein the cellulose acetate polymer is selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof; for example, cellulose acetate butyrate.

4. 4. The coated drug-ion exchange resin particles of any one of claims 1 to 3, wherein the enteric polymer is selected from one or more of: phthalate-containing polymers; cellulose acetate trimellitate; polymethacrylates; hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid; shellac, and combinations thereof; such as cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), and polyvinyl acetate phthalate (PVAP).

5. The coated drug-ion exchange resin particles of any one of claims 1 to 4, wherein a chelating agent, a granulating agent and a plasticizer are each present.

6. 6. The coated drug-ion exchange resin particles of claim 5, wherein the chelating agent comprises EDTA; the granulating agent comprises polyethylene glycol; and the plasticizer comprises polyethylene glycol.

7. 7. The coated drug-ion exchange resin particles of any one of claims 1 to 6, wherein the active pharmaceutical agent is present in an amount of about 1% to about 99% by weight, about 5% to about 70% by weight, about 10% to about 30% by weight, about 15% to about 25% by weight, or about 20% by weight based on the total weight of the coated drug-ion exchange resin granules.

8. Composition as follows: 【Table 1】 8. The coated drug-ion exchange resin particle of claim 7, having

9. A plurality of coated drug-ion exchange resin particles (or granules) according to any one of claims 1 to 8; and Pharmaceutically acceptable excipients 1. A composition for the sustained release of an active drug substance comprising: The composition is in the form of a liquid suspension and further comprises one or more solvents, and one or more ingredients selected from sugars, antioxidants, buffers, chelating agents, thickening agents, stabilizers, preservatives, surfactants, flavoring agents, and coloring agents.

10. the coated granules are present in the composition in an amount of about 0.01% w / v to about 10% w / v based on the total weight of the composition; or about 0.01% w / v to about 10% w / v based on the total weight of the composition; or about 0.1% w / v to about 5% w / v based on the total weight of the composition; or about 0.1% w / v to about 5% w / v based on the total weight of the composition; or about 1% w / v to about 5% w / v based on the total weight of the composition; or about 1% w / v to about 5% w / v based on the total weight of the composition; or about 2% w / v to about 3% w / v based on the total weight of the composition; or about 2% w / v to about 3% w / v based on the total weight of the composition; the active pharmaceutical agent is present in an amount of about 0.1 mg / mL to about 100 mg / mL, e.g., about 1 mg / mL to about 25 mg / mL, e.g., about 3 mg / mL to about 8 mg / mL, e.g., about 5 mg / mL; The composition comprises: Chelating agents, such as EDTA; Buffers, such as citric acid; sugar; one or more thickening agents; Preservatives; A surfactant; and Antioxidants Further comprising:

10. The composition for sustained release according to claim 9. ［１０］ The following ingredients: 【Table 2】 The composition for sustained release according to claim 9, comprising:

11. 11. The composition for sustained release according to claim 9 or 10, wherein no more than 25% or 30% of the active pharmaceutical agent is released within 1 hour; no more than 60% of the active pharmaceutical agent is released within 2 hours.

12. The active pharmaceutical agent is released at a higher initial rate that tapers off over an extended period of time, and the composition Sustained release of the active pharmaceutical agent for at least 1 hour, at least 4 hours, at least 8 hours, at least 16 hours, or at least 24 hours; and / or Sustained release of the active pharmaceutical agent for up to 24 hours; and / or Sustained release of active pharmaceutical ingredients for 8 to 24 hours The composition for sustained release according to claim 9 or 10,

13. 1. A method for producing coated drug-ion exchange resin particles comprising the steps of: (a) contacting an active drug substance with an ion exchange resin in a solvent to form a drug-ion exchange resin complex (or resin core); (b) optionally isolating and drying the drug-ion exchange resin complex; (c) granulating the drug-ion exchange resin complex to form drug-ion exchange resin complex granules; (d) optionally drying the product of step (c), e.g. to a moisture content of 15-25% or 15-20%, and optionally grinding the product, e.g. using a co-mill equipped with about a 400 μm mesh screen; or optionally sieving the product to a predetermined size, e.g. by forcing the product through a mesh screen, e.g. a 20 mesh screen; (e) optionally further drying the product of step (d), for example to a moisture content of less than 7%; (f) optionally milling the product of step (e), for example using a co-mill equipped with an 813 μm mesh screen; and (g) The following: Cellulose acetate-containing polymers, such as cellulose acetate butyrate; Optionally, an enteric polymer; Optionally, a plasticizer, such as a polyethylene glycol, e.g., polyethylene glycol 3550; and A solvent, such as water, acetone, or water and acetone Coating the product of the previous step with a coating composition comprising For example, applying a coating to a weight gain of 15-20% w / w to form coated drug-ion exchange resin particles (or granules). The method includes:

14. The method according to claim 13, wherein the coated drug-ion exchange resin particles produced are the coated drug-ion exchange resin particles according to any one of claims 1 to 8.

15. The method includes the steps of: (h) combining the coated drug-ion exchange resin particles (or granules) produced by step (g) with a suspension base composition to form a coated drug-ion exchange resin sustained release suspension. Further comprising: The suspension base composition is in the form of a liquid suspension and comprises one or more solvents and one or more ingredients selected from sugars, antioxidants, buffers, chelating agents, thickening agents, stabilizers, preservatives, surfactants, flavors, and colorants.

15. The method of claim 13 or 14.

16. The method of claim 15, wherein the composition formed is a composition according to any one of claims 9 to 11.

17. A liquid sustained release oral naltrexone suspension formulation comprising naltrexone or a pharma- ceutical acceptable salt thereof in an amount of about 1.0 mg / mL to about 10.0 mg / mL, wherein the naltrexone or a pharma- ceutical acceptable salt thereof is bound to a resin, e.g., an ion exchange resin; The formulation has the following characteristics a) to e): a) a T of about 5 to about 7 hours, e.g., about 5 hours, about 6 hours, or about 7 hours max ; b) a T of about 5 to about 12 hours, e.g., about 5 to about 11 hours; about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or about 11 hours 1 / 2 ; c) about 1.5 to about 4 hours, e.g., about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours C max ; d) an AUC of about 26 to about 32 hr·ng / mL, for example about 26, about 27, about 28, about 29, about 30, about 31, or about 32 hr·ng / mL t and e) an AUC of about 28 to about 35 hr·ng / mL, e.g., about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 hr·ng / mL ∞ providing an in vivo pharmacokinetic profile having one or more of: formulation.

18. 10. The liquid sustained release oral naltrexone suspension formulation of claim 1, wherein the formulation provides an in vivo pharmacokinetic profile having two, three, four or all five of said characteristics a) through e).

19. 10. The liquid sustained release oral naltrexone suspension formulation of claim 1, having an in vivo pharmacokinetic profile substantially in accordance with Formulation 1 or Formulation 2 of FIG.

20. Mean plasma naltrexone concentrations (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) are as follows: a) to e): a) 3 hours after administration, from about 0.4 to about 0.6; for example, from about 0.4 to about 0.55, for example, from about 0.45 to about 0.5; b) 6 hours after administration, from about 0.8 to about 1.2; for example, from about 0.9 to about 1.1, for example, from about 0.95 to about 1.05; c) 8 hours after administration, from about 0.5 to about 0.9; for example, from about 0.6 to about 0.8, for example, from about 0.65 to about 0.8; d) 10 hours after administration, from about 0.4 to about 0.8; for example, from about 0.5 to about 0.7; and e) 12 hours after administration, from about 0.3 to about 0.7; for example, from about 0.4 to about 0.6 2. The liquid sustained release oral naltrexone suspension formulation of claim 1, wherein said liquid sustained release oral naltrexone suspension formulation is one or more of:

21. 1. A composition for the sustained release of naltrexone, comprising: The composition comprises: a) ion exchange resin; naltrexone or a pharma- ceutical acceptable salt thereof; Optionally, a chelating agent; Optionally, a granulating agent a drug-ion exchange resin complex (or resin core) comprising: b) cellulose acetate-containing polymers; Optionally, an enteric polymer; and Optionally, a plasticizer a coating comprising: And Pharmaceutically acceptable excipients A plurality of coated drug-ion exchange resin particles (or granules) comprising Including; the composition is in the form of a liquid suspension and further comprises one or more solvents and one or more ingredients selected from sugars, antioxidants, chelating agents, thickening agents, stabilizers, preservatives, surfactants, flavors, and colorants; The formulation has the following characteristics a) to e): a) a T of about 5 to about 7 hours, e.g., about 5 hours, about 6 hours, or about 7 hours max ; b) a T of about 5 to about 12 hours, e.g., about 5 to about 11 hours; about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or about 11 hours 1 / 2 ; c) about 1.5 to about 4 hours, e.g., about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours C max ; d) an AUC of about 26 to about 32 hr·ng / mL, for example about 26, about 27, about 28, about 29, about 30, about 31, or about 32 hr·ng / mL t and e) an AUC of about 28 to about 35 hr·ng / mL, e.g., about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 hr·ng / mL ∞ providing an in vivo pharmacokinetic profile having one or more of: composition.

22. Mean plasma naltrexone concentrations (C t ng / ml) and maximum plasma naltrexone concentration (C max ng / mL) are as follows: a) to e): a) 3 hours after administration, from about 0.4 to about 0.6; for example, from about 0.4 to about 0.55, for example, from about 0.45 to about 0.5; b) 6 hours after administration, from about 0.8 to about 1.2; for example, from about 0.9 to about 1.1, for example, from about 0.95 to about 1.05; c) 8 hours after administration, from about 0.5 to about 0.9; for example, from about 0.6 to about 0.8, for example, from about 0.65 to about 0.8; d) 10 hours after administration, from about 0.4 to about 0.8; for example, from about 0.5 to about 0.7; and e) 12 hours after administration, from about 0.3 to about 0.7; for example, from about 0.4 to about 0.6 22. The composition for sustained release according to claim 21, wherein said composition is one or more of the following:

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