Liquid resin sustained release oral naltrexone formulations for the treatment of autism-related disorders - Patent Application 20070229633

Abstract

Disclosed is a liquid resin sustained release oral naltrexone suspension formulation comprising about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, where 30% or less of the total administered naltrexone dose is released within 1 hour and 60% or less of the total administered naltrexone dose is released within 2 hours. Specifically disclosed is a method for treating children with autistic disorder using about one teaspoon (about 5 ml) of a liquid resin sustained release oral naltrexone suspension formulation comprising about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, where 30% or less of the total administered naltrexone dose is released within 1 hour and 60% or less of the total administered naltrexone dose is released within 2 hours.

Description

[Technical field]

[0001] The present disclosure provides a liquid resin sustained release oral naltrexone suspension formulation comprising about 1.0 mg / mL to about 10.0 mg / mL naltrexone in the resin, where 30% or less of the total administered dose is released within 1 hour and 60% or less of the total administered dose is released within 2 hours. Specifically, the present disclosure provides a method for treating a child with autistic disorder using about one teaspoon (about 5 mL) of a liquid resin sustained release oral naltrexone suspension formulation comprising about 1.0 mg / mL to about 10.0 mg / mL naltrexone in the resin, where 30% or less of the total administered dose is released within 1 hour and 60% or less of the total administered dose is released within 2 hours. More specifically, the present disclosure provides a naltrexone formulation that releases 30% or less of a total administered naltrexone dose within 1 hour and 60% or less of a total administered naltrexone dose within 2 hours, the formulation comprising: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; (b) a material that coats the resin core to form particles, the coating material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose tetra ... and (c) a material selected from the group consisting of cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, 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; and (c) an aqueous, thick-flavored, sweetened liquid for suspending particles.Preferably, the liquid resin naltrexone formulation is administered qAM (upon awakening). [Background technology]

[0002] Autism spectrum disorder (ASD), a common pediatric health problem affecting 1 in 40 children in the United States, is a biological neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction, as well as restricted and repetitive patterns of behavior, interests, and activities, with symptoms typically observed in the first 2 years of life (Ozonoff et al. 2008, Autism Res, 1: 320-8). Autism is a complex developmental disorder that interferes with the normal development of the brain, particularly in the areas of social interaction and communication skills. It typically appears in the first 3 years of life and is the result of neurological disorders that affect brain function. Typically, children and adults with autism have difficulties with verbal and nonverbal communication, social interaction, and leisure or play activities.

[0003] Over the past few decades, a wide range of theories on the etiology of ASD have been proposed, including the opioid excess hypothesis. This theory was proposed by Panksepp in 1979 and posits that autism is an emotional disorder caused by excess opioid activity in the brain (Panksepp, 1979, Trends in Neurosciences, 2: 174-77). In the brain, opioid activity depends on the activation of endogenous opioid signaling through opioid receptors. Opioid receptors belong to a large family of G protein-coupled receptors (GPCRs) and include three members: μ, δ, and κ opioid receptors (Pellissier et al. 2018, Br. J. Pharmacol., 175: 2750-69). The endogenous opioid peptides enkephalins, endorphins, and dynorphins are preferential ligands that promote the activation of opioid receptors, respectively. According to the main premise of the opioid excess theory, peptides with opioid activity, derived from dietary sources, especially gluten and casein, cross the abnormally permeable intestinal membrane and enter the central nervous system (CNS). Such peptides exert neuromodulatory functions, upsetting the balance of opioid receptor activity in the brain and causing excessive and / or prolonged opioid stimulation. This theory has deleterious effects on social behavior (Shattock and Whiteley 2002, Expert Opin. Ther. Targets, 6: 175-83).

[0004] Exposure to high doses of opiates has long-term effects on social behavior, with mice exposed to increasing doses of morphine or heroin showing impaired social interactions up to 7 weeks after treatment was discontinued (Pellissier et al. 2018, Br. J. Pharmacol., 175: 2750-69). Clinical findings include increased levels of endorphin fractions in cerebrospinal fluid (CSF) and increased levels of β-endorphin in peripheral blood mononuclear cells (PBMCs) in autistic children (Cazzullo et al. 1999, Eur. Neuropsychopharmacol., 9: 361-6; and Gillberg et al., 1985., Arch. Gen. Psychiatry, 42: 780-3). Evidence of a possible familial association is also emerging. Leboyer et al. (1992, J. Autism Dev. Disord., 22: 309-19) found that more than half of the mothers of autistic children had elevated levels of beta-endorphin protein immunoreactivity. Based on these findings, opioid antagonists such as naltrexone may therefore be beneficial in the treatment of ASD.

[0005] A rare pediatric disorder is Schaff-Yang syndrome (SYS), a neurodevelopmental genetic disorder caused by truncating mutations in MAGEL2 located in the Prader-Willi critical region 15q11-15q13. SYS overlaps clinically with Prader-Willi syndrome (PWS) early in life but becomes increasingly distinct throughout childhood and adolescence. Features include intellectual disability / developmental delay and autism. Variation in phenotypic severity may depend on the specific location of the truncating mutation. These syndromes (i.e., SYS and PWS) share common features, including neonatal hypotonia, feeding difficulties / failure to thrive, respiratory distress, and DD / ID (developmental delay / intellectual disability), primarily during infancy. However, differences between the syndromes begin prenatally and increase throughout development. The earliest distinguishing feature of SYS is the presence of joint contractures, which are frequently seen in SYS but not typically seen in the PWS phenotype. SYS patients tend to show more significant delays in motor and language development and to have more severe intellectual disability than PWS patients. No action is taken against SYS.

[0006] Another related rare childhood disorder is Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). It is an extremely rare (fewer than 50 known cases) autosomal dominant disorder caused by pathogenic mutations in the NR2F1 gene. Features include developmental delay / moderate intellectual disability, optic atrophy, and autism. There is no treatment for BBSOAS.

[0007] There is no cure for autism, and treatment options are limited. Examples of drugs used to treat symptoms related to autism include serotonin reuptake inhibitors (e.g., clomipramine, fluvoxamine, and fluoxetine), which are used to treat depression, obsessive-compulsive behavior, and anxiety. Stimulants such as Ritalin, Adderall, and Dexedine, which are used to treat hyperactivity in children with ADHD, have also been used. These can increase focus and reduce impulsivity and hyperactivity, especially in high-functioning autistic children. Unfortunately, adverse behavioral side effects are often observed. Such drugs are accompanied by a variety of side effects.

[0008] Naltrexone (immediate release) and ASD Since first being approved in 1984, the therapeutic efficacy of oral immediate-release naltrexone has been clinically tested in pediatric patients, including those with ASD. In a double-blind, placebo-controlled, crossover study, 13 children (12 boys, 1 girl) with ASD, ages 3.4-8.3 years (mean 5.4 years), received immediate-release oral naltrexone 1.0 mg / kg or placebo once daily in a crossover fashion, with each treatment phase lasting 12 or 14 days (Kolmen et al. 1995, J. Am. Acad. Child Adolesc. Psychiatry, 34: 223-31). Changes in parent measures (Clinical Global Impression (CGI), Conners Impulsivity-Hyperactivity Factor (IHF) and Side-effect SE-Restlessness) and teacher CGI were statistically significant. In another double-blind, placebo-controlled crossover study of 23 children with ASD (ages 3-7), all subjects received 20 mg immediate-release naltrexone per day for 4 weeks (one boy received a tailored dose of 40 mg per day), with 20 completing the final analysis (Willemsen-Swinkels et al., 1996, Biol. Psychiatry, 39: 1023-31). Naltrexone treatment produced significant changes in teacher ratings of behavior (Aberrant Behavior Checklist (ABC) scores). Significant differences were also obtained in teacher CGI ratings. High doses of immediate-release oral 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). Decreased opioid tone in ASD patients correlated with treatment response (Cazullo et al., Eur. Neuropsychopharmacol. 1999; 9: 361-6).

[0009] Common side effects include sleep problems, anxiety, nausea and headaches. For people still taking opioids or alcohol, symptoms of opioid withdrawal may occur. Use is not recommended for people with liver failure. It is not known if use during pregnancy is safe. These adverse effects are similar to those of opioid withdrawal. Naltrexone side effects by incidence include: >10%: Sleep problems, anxiety, irritability, abdominal pain / cramps, nausea and / or vomiting, decreased energy, joint / muscle pain and headache. Less than 10%: loss of appetite, diarrhea, constipation, dry mouth, increased energy, depression, irritability, dizziness, skin rash, delayed ejaculation, erectile dysfunction and chills.

[0010] Therefore, to reduce or lessen the side effects, max There is a need for better dosing of naltrexone to reduce the peaks.

[0011] Pharmacokinetics and metabolism in humans The clinical pharmacokinetic profile of naltrexone immediate-release tablets (50 mg) is known and summarized in the REVIA® package insert and the National Institute on Drug Abuse Research Monograph (NIDA Research Monograph 28, 1981). Naltrexone is well absorbed orally and undergoes significant first-pass metabolism, with oral bioavailability estimated at 5-40%. Naltrexone activity is believed to be due to both the parent compound and the 6-β-naltrexol metabolite. Both the parent drug and metabolites are primarily excreted via the kidney (53%-79% of the administered dose). Urinary excretion of unchanged naltrexone is less than 2% of the oral dose based on the immediate-release formulation. Fecal excretion is a minor route of excretion. The mean elimination half-life (t 1 / 2 ) values ​​are 4 hours and 13 hours, respectively. Naltrexone and 6-β-naltrexol have AUC and C values ​​in the range of 50 to 200 mg. maxIt is dose proportional with respect to daily doses of 100 mg and does not accumulate beyond these doses.

[0012] Data reported in ANDA #075434 showed that the C-terminal amino acid sequence of REVIA® and its metabolite 6-β-naltrexol was significantly increased following a single dose of REVIA® 50 mg tablets in 36 healthy adult male volunteers. max were 7.3ng / mL (62.5%) and 85.6ng / mL (33.4%), respectively, and AUC (0-inf) were 23.1 ng·h / mL (55.1%) and 717.3 ng·h / mL (21.8%), suggesting that the systemic exposure of 6-β-naltrexol is more than 10-fold higher compared to naltrexone. Multiple-dose PK of immediate-release naltrexone tablets (REVIA® 50 mg tablets administered once daily for 7 days to 24 healthy adult volunteers (Mason et al. 2002, Neuropsychopharmacology, 27: 596-606)) was studied using the C max were 11.8 ± 6.55 ng / mL and 96.1 ± 21.05 ng / mL, respectively, and AUC (0-τ) The T of naltrexone was 38.6 ± 16.53 ng·h / mL and 788 ± 134.8 ng·h / mL. Thus, after oral administration, naltrexone is rapidly and almost completely absorbed, with approximately 96% of the administered dose being absorbed from the gastrointestinal tract. Peak plasma levels of both naltrexone and 6-β-naltrexol occur within 1 hour after administration. Data reported in ANDA#075434 showed that the T of naltrexone was significantly increased after a single dose of REVIA® 50 mg tablets in 36 healthy adult male volunteers. max The mean (CV%) of max The mean mean (CV%) of was 1.05 hours (27.9%).

[0013] In a placebo-controlled clinical trial, treatment with naltrexone 50 mg once daily resulted in significantly more side effects compared with placebo (Bonferroni-corrected p=0.003, p=0.049, and p=0.004 at weeks 1, 5, and 8, respectively), reduced compliance (approximately 50% vs. 70% for naltrexone vs. placebo at the end of week 11 of the randomized treatment period), and higher rates of early treatment discontinuation (Kranzler et al. Neuropsychopharmacology. 2000; 22(5):493-503). Additionally, data reported in ANDA#075434 demonstrated that the C of naltrexone 50 mg immediate-release tablets was significantly lower than that of placebo. max Provide PK parameters including:

[0014] Without being bound by theory, the adverse effects of naltrexone may be due to systemic exposure, particularly C max One study tested the tolerance of a sustained-release subcutaneous naltrexone formulation in alcohol-dependent subjects. After injection of the sustained-release formulation, naltrexone plasma concentrations averaged more than 1 ng / mL for 21 days (range 1-6 ng / mL), which was significantly higher than the plasma C of naltrexone administered as a 50 mg immediate-release tablet. max The concentration was lower than that of placebo (11.8 ng / mL). Under this PK profile, the frequency of adverse effects caused by the sustained-release formulation was higher than that of placebo, but the difference was not statistically significant. No serious complaints were reported during the injection period. All adverse effects resolved spontaneously (Kranzler et al. Alcohol Clin. Exp. Res. 1998; 22(5):1074-9).

[0015] Therefore, in view of the side effects of naltrexone treatment, there is a need in the art to provide a naltrexone formulation for autistic children / patients that (1) can be administered to autistic children / patients and (2) reduces the side effects associated with naltrexone treatment. The present disclosure provides a naltrexone formulation that addresses both of the above needs. Thus, there is a need in the art for a sustained release oral formulation that attenuates the exposure profile of naltrexone and reduces the undesirable acute side effects associated with oral administration of immediate naltrexone formulations. Summary of the Invention

[0016] The present disclosure addresses the problem of how to utilize new and pharmacokinetically improved formulations of naltrexone, particularly in liquid formulations, that can be administered to children to reduce the side effects of naltrexone, particularly to treat various autism spectrum disorder symptoms. Specifically, the present disclosure provides a liquid resin sustained release oral naltrexone suspension formulation comprising about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, wherein no more than 30% of the total administered naltrexone dose is released within 1 hour, and no more than 60% of the total administered naltrexone dose is released within 2 hours.Specifically, the disclosure provides a naltrexone formulation that releases 30% or less of the total administered naltrexone dose within 1 hour and 60% or less of the total administered naltrexone dose within 2 hours, comprising: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; a chelating agent, and a granulating agent; (b) a material that coats the resin core comprising a cellulose acetate-containing polymer and a plasticizer to form particles, the material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose tetra ... Reacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, 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; (c) an aqueous, thick flavored and sweetened liquid for suspending particles, and optionally (d) a preservative to achieve a naltrexone formulation.

[0017] The disclosure further provides a method for treating a child with an autistic disorder with about one teaspoon (about 5 ml) of a liquid resin sustained release oral naltrexone suspension formulation containing about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, wherein no more than 30% of the total administered naltrexone dose is released within 1 hour and no more than 60% of the total administered naltrexone dose is released within 2 hours. Preferably, the liquid resin formulation comprises: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; (b) a material coating the resin core to form particles, the coating material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, 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; and (c) an aqueous, thick flavored, sweetened liquid for suspending the particles. Preferably, the liquid resin naltrexone formulation is administered qAM (upon awakening).

[0018] The disclosure further provides a method for treating a child with the rare pediatric disease Scharf-Young Syndrome (SYS) or Bosch-Boonstra-Scharf Optic Atrophy Syndrome (BBSOAS) with about one teaspoon (about 5 ml) of a liquid resin sustained release oral naltrexone suspension formulation containing about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, wherein no more than 30% of the total administered naltrexone dose is released within 1 hour and no more than 60% of the total administered naltrexone dose is released within 2 hours. Preferably, the liquid resin formulation comprises: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; (b) a material coating the resin core to form particles, the coating material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, 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; and (c) an aqueous, thick flavored, sweetened liquid for suspending the particles. Preferably, the liquid resin naltrexone formulation is administered qAM (upon awakening). [Brief description of the drawings]

[0019] [Figure 1]FIG. 1 shows the release rates of immediate release (IR) and extended release (ER) of naltrexone (50 mg), the ER formulation being described in Example 1 herein. [Diagram 2] Figure 2 shows the modeled and observed first-order release model pharmacokinetics of naltrexone immediate release 50 mg tablets from the generic ANDA submission. The first-order release model was calculated as follows: dA / dt=-A*kr, A(0)=100%@t=0. [Diagram 3] 3A and 3B show simulated pharmacokinetic curves for single dose oral IR and ER formulations of naltrexone and the first pass hepatic metabolite 6-β-naltrexol on Day 1. [Figure 4] 4A and 4B show simulated pharmacokinetic curves for naltrexone and the first-pass hepatic metabolite 6-β-naltrexol administered orally in IR and ER formulations of the present disclosure on day 10 when administered once daily. [Diagram 5] FIG. 5 shows the drug release curves for immediate release naltrexone and the sustained release liquid oral suspension of the present disclosure. [Figure 6] Figure 6 shows the drug release profiles of three liquid naltrexone sustained release formulations with different particle coatings, where CAB is the cellulose acetate butyrate coated particle formulation in Table 3, CAB and HPMCP (hypromellose phthalate) are formulations in Table 6, and EC (ethylcellulose) is a formulation in Table 7. The EC formulation is believed to meet the present criteria of 25% or less of the total naltrexone dose administered within 1 hour and 60% or less of the total naltrexone dose administered within 2 hours. [Figure 7] FIG. 7 shows the pharmacokinetic profile of oral naltrexone as described in Tables 18 and 19 of Example 8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Pharmacokinetics The treatment strategy for autism spectrum disorder is qAM (once daily in the morning) dosing as soon as possible after awakening. Naltrexone has a half-life of only about 4 hours, but its main metabolite, 6-beta-naltrexol, is also active as an opioid antagonist with a half-life of up to 13 hours. There are various reasons for the qAM dosing schedule, duration of the study, and targeted formulation properties: 1. Give the drug in the morning so that it is at its peak effect during the day when behavioral problems are most severe, but let the drug's effect wane before bedtime so as not to interfere with sleep. 2. Currently approved naltrexone tablet formulations have a 15 minute onset and peak plasma concentration at 1 hour. Thus, the current liquid resin formulation and pharmacokinetic model provided herein demonstrate that the formulation helps reduce side effects (nausea, hyperalgesia, dizziness) in clinical trials. Opioid agonists have the greatest effect on euphoria and analgesia when the "slope" to serum exposure is steepest, i.e., an opioid injection has a more dramatic effect than the slower-absorbed orally administered equivalent dose. Similarly, naltrexone has a steeper "slope" to exposure and induces the most side effects. As the PK model shows, the naltrexone release profile of the disclosed liquid resin formulation provides a superior slope and C to significantly reduce side effects. max While providing the same properties, the disclosed ER formulation provides substantially the same AUC (area under the curve) as the dose-equivalent IR (immediate release) marketed approved formulation. However, the disclosed ER formulation provides a lower C max and a smaller slope of the concentration / time curve (Figures 2 and 3). This type of drug profile delays and blunts any resistance that may develop to the treatment, as shown in the model at day 10 in Figure 4.

[0021] The present disclosure further provides a liquid resin sustained release oral naltrexone liquid suspension formulation comprising about 1 mg / ml to about 10 mg / ml in an ion exchange resin and coated with a sustained release polymer for administration at one teaspoon (about 5 ml) to a child with autism across the spectrum of autism symptoms, wherein the naltrexone is in a coated naltrexone-anion exchange resin complex, the resin complex being in a matrix having a water insoluble polymer or copolymer or a hydrophilic polymer, comprising: (a) naltrexone bound to a pharma- ceutically acceptable water insoluble anion exchange resin to form coated particles of naltrexone-ion exchange resin; and the naltrexone comprises about 40% to about 75% by weight of the naltrexone-ion exchange resin complex-matrix. Preferably, the ion exchange resin is a copolymer comprising styrene and divinylbenzene containing quaternary ammonium functional groups. Preferably, the anion exchange resin is a cholestyramine resin. Preferably, the controlled release barrier coating comprises a water-permeable, water-insoluble polymer and a plasticizer. More preferably, the water-permeable, water-insoluble polymer in the barrier coating comprises polyvinyl acetate. Preferably, the matrix comprises a naltrexone-anion exchange resin complex and a hydrophilic polymer. More preferably, the hydrophilic polymer in the matrix comprises polyvinylpyrrolidone. Preferably, the matrix comprises a particulate drug-anion exchange resin complex, polyvinylpyrrolidone and a surfactant.

[0022] The present disclosure further provides the following embodiments of coated granules based on the pharmacokinetic parameters achieved in Example 8:

[0023] The coated drug-ion exchange resin complex granules have the following characteristics a to e: 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 hours1 / 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 ∞ The coated granules 1 provide a pharmacokinetic profile having one or more of the following:

[0024] Coated granule 1.1, wherein the coated drug-ion exchange resin complex granule has a pharmacokinetic profile having two or more of features a-e, or three or more of features a-e, or four or more of features a-e, or all five of features a-e. More specifically, the coated drug-ion exchange resin complex granule has a pharmacokinetic profile substantially in accordance with Formulation 1 or Formulation 2 in Example 8 or Figure 7. Alternatively, the patient's mean plasma naltrexone concentration (ng / ml) over the time period from 2.5 hours post-administration to 4 hours post-administration is increased by at least 4%; or about 4% to about 20%; or about 4% to about 15%; or about 4% to about 12%, or about 5% to about 12%, or about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12%.

[0025] or 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%, in any of the preceding coated granules, the mean plasma naltrexone concentration (ng / ml) in the patient from 4 hours post-administration to 6 hours post-administration is increased by at least about 80%; or about 80% to about 120%; or about 80% to about 110%; or 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%.

[0026] or 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% decrease in the patient's mean plasma naltrexone concentration (ng / ml) from 6 hours post-dose to 8 hours post-dose.

[0027] Patients' mean plasma naltrexone concentrations (C t ng / ml) and maximum plasma naltrexone concentration (C max ;ng / ml) is from about 0.4 to about 0.6; such as from about 0.4 to about 0.55, for example from about 0.45 to about 0.5.

[0028] Patients' mean plasma naltrexone concentrations (C t ng / ml) and maximum plasma naltrexone concentration (C max ;ng / ml) is from about 0.8 to about 1.2; such as from about 0.9 to about 1.1, for example from about 0.95 to about 1.05.

[0029] Patients' mean plasma naltrexone concentrations (C t ng / ml) and maximum plasma naltrexone concentration (C max ;ng / ml) is from about 0.5 to about 0.9; for example, from about 0.6 to about 0.8, such as from about 0.65 to about 0.8.

[0030] Patients' mean plasma naltrexone concentrations (C t ng / ml) and maximum plasma naltrexone concentration (C max ;ng / ml) is from about 0.4 to about 0.8; for example, from about 0.5 to about 0.7.

[0031] Patients' mean plasma naltrexone concentrations 12 hours after administration (C t ng / ml) and maximum plasma naltrexone concentration (C max ;ng / ml) is from about 0.3 to about 0.7; for example, from about 0.4 to about 0.6.

[0032] Patients' 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, 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 coated granules, which is one or more of:

[0033] Alternatively, the patient's 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 It is.

[0034] Alternatively, the patient's 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 It is.

[0035] Alternatively, the patient's 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 It is.

[0036] Preferably, the ion exchange resin comprises a matrix of polystyrene polymer, or a copolymer of polystyrene and divinylbenzene, or a sulfonated polymer in which polystyrene is crosslinked with about 8% divinylbenzene. Preferably, the ion exchange resin has an ion exchange capacity of about 4.5-5.5 meq / g dry resin, wherein the w / w ratio of ion exchange resin to naltrexone or a pharma- ceutically acceptable salt thereof present in the coated granule is about 5:1-1:5, such as about 3:1-1:3, such as about 2:1-1:2, such as about 2:1.

[0037] Preferably, the cellulose acetate-containing polymer is selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof. More preferably, the cellulose acetate-containing polymer is selected from cellulose acetate, cellulose acetate butyrate, and combinations thereof. Most preferably, the cellulose acetate-containing polymer comprises cellulose acetate butyrate.

[0038] Preferably, the coated drug-ion exchange resin complex granules further comprise an enteric polymer; the enteric polymer is selected from the group consisting of phthalate-containing polymers; cellulose acetate trimellitate; polymethacrylates; hydroxypropyl methylcellulose acetate succinate (HPMC AS; Aqoat®); sodium alginate; alginic acid; shellac, and combinations thereof.

[0039] Preferably, the coated drug-ion exchange resin complex granules further comprise an anti-adherent agent; for example, but not limited to, talc, glycerol monostearate, magnesium stearate or kaolin.

[0040] Preferably, the coated drug-ion exchange resin complex granules are 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 propionate, diethyl phthalate, diethyl sebacate. ethyl succinate, diethyl tartrate, dimethoxyethyl adipate, dimethoxyethyl phthalate, dimethyl phthalate, dipropyl phthalate, ethyl benzoyl benzoate, ethylene glycol diacetate, ethylene glycol dibutyrate, ethylene glycol propionate, ethyl phthalyl ethyl glycolate, methyl benzoyl benzoate, methyl phthalyl ethyl glycolate, o- or p-toluene ethyl sulfonamide, triacetin, tributyl citrate, tributary 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), adipic acids (e.g., bis(2-ethylhexyl) adipate), sebacillus acid, carboxylic acids (e.g., dibutyl sebacate, di-(2-ethylhexyl) sebacic acid), 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, azelaic acids, dibenzoic acids, terephthalic acids, 1,The composition further comprises a contrast agent selected from 2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organic phosphoric acids (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, lipids, and combinations thereof. Preferably, the granulating agent is polyethylene glycol.

[0041] Preferably, the plasticizer in the coating 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 propionate, 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 propionate, ethyl phthalyl ethyl glycolate, methyl benzoyl benzoate, methyl phthalyl ethyl glycolate, o- or p-toluene ethyl sulfonamide, triacetin, tributyl citrate, tributyl phosphate, tributary , 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), adipic acids (e.g., bis(2-ethylhexyl) adipic acid), sebacic acids (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, azelaic acids, dibenzoic acids, terephthalic acids, 1,The plasticizer is selected from 2-cyclohexanedicarboxylic acid diisononyl ester, alkylsulfonic acid phenyl ester, organic phosphates (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, lipids, and combinations thereof. Preferably, the plasticizer comprises about 2.5 to about 25% w / w, or about 5 to about 15% w / w, or about 8 to about 12% w / w, or about 10% w / w of the solids in the coating.

[0042] Naltrexone Particles The particles are coated naltrexone-ion exchange resin (drug-resin complex) having a resin core surrounded by a polymer coating. Naltrexone-resin complexes are formed by mixing naltrexone HCl with a resin (e.g., polystyrene sulfonic acid resin) to promote protonation of the naltrexone HCl (salt or free base form) and subsequent bonding (e.g., ionic bonding) between the resin polymer and naltrexone. The reaction may be carried out with an excess of drug until no more drug is bound to the resin polymer. The drug-resin complex 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.

[0043] 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 particles. In some embodiments, a drug loading of about 10% to about 40% by weight, e.g., about 15% to about 30% by weight of the drug ion exchange resin particles can be achieved.

[0044] The polymer coating comprises a combination of cellulose acetate-containing polymers, alone or in combination with one or more enteric polymers. As used herein, the term "cellulose acetate-containing polymer" refers to a polymer that contains at least one mono-, di-, or tri-acetylated cellulose (i.e., β(1→4)-linked glucose) monomer. The cellulose acetate-containing polymer is selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof. Preferably, the cellulose acetate polymer is cellulose acetate or cellulose acetate butyrate.

[0045] Optionally, the cellulose acetate polymer is mixed with a phthalate-containing polymer to facilitate a more uniform coating of the naltrexone-ion exchange resin complex and / or to increase the tensile strength of the barrier coating, where the phthalate-containing polymer is selected from the group consisting of phthalate-containing polymers; cellulose acetate trimellitate; polymethacrylates; hydroxypropyl methylcellulose acetate succinate (HPMCAS; Aqoat®); sodium alginate; alginic acid; shellac, monomeric 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, butyric acid phthalate, methyl cellulose acetate ... 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 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.

[0046] The polymer coating comprises from about 1% to about 30% by weight of the uncoated naltrexone-ion exchange resin complex granules, e.g., from about 3% to about 25% by weight, from about 10% to about 20% by weight, or about 15% by weight of the uncoated drug-resin complex.

[0047] Liquid resin preparation The coated naltrexone-ion exchange resin particles are formulated into a finished ingestible dosage form, such as a liquid suspension. It has also been observed that when used in liquid compositions, the film-forming coating of the drug-ion exchange resin complex, when formulated into a liquid suspension, does not result in undesirable clumping and color transfer of the suspended particles in the liquid in the presence of colorants used in medicines taken by children.

[0048] Suitable flavors include both natural and artificial flavors, and contemplated are mints, such as peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors (both individual and mixed), essential oils (i.e., thymol, eucalyptol, menthol, and methyl salicylate), and the like. The amount of flavor used is usually a matter of preference depending on factors such as the type of flavor, the individual flavor, and the strength desired. Thus, the amount may vary to obtain the desired results in the final product. Flavors 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 final composition weight.

[0049] Colorants include pigments such as titanium dioxide, which may be incorporated in amounts up to about 1% by weight / volume, preferably up to about 0.6% by weight / volume. 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]. A complete description of all FD&C and D&C and their corresponding chemical structures can be found in the Kirk-Othmer Encyclopedia of Chemical Technology, Volume 5, Pages 857-884, the contents of which are incorporated herein by reference.

[0050] Suitable oils and fats that can be used include partially hydrogenated vegetable or animal fats, such as coconut oil, palm kernel oil, beef tallow and lard. These ingredients are generally used in edible products in amounts up to about 7.0% by weight of the final product, preferably up to about 3.5% by weight.

[0051] Wetting agents may also be used to promote the dispersion of hydrophobic components. The concentration of wetting agent in the composition should be selected to achieve optimal dispersion of the components in the composition with the lowest concentration of wetting agent feasible. It should be noted that excessive concentration of wetting agent may cause the composition to aggregate as a suspension. Suitable wetting agents are listed in the United States Pharmacopoeia 29.

[0052] Naltrexone HCl Naltrexone HCl can be prepared from noroxymorphone by various direct and indirect alkylation methods. One method is the direct alkylation of noroxymorphone with cyclopropylmethyl bromide. This method is disclosed in WO91 / 05768, the disclosure of which is incorporated herein by reference. WO2008 / 034973, the disclosure of which is incorporated herein by reference, describes a method of preparation in which noroxymorphone hydrochloride is reacted with cyclopropylmethyl bromide in dimethylacetamide in the presence of sodium bicarbonate to obtain naltrexone in 88.6% yield. WO2008 / 138605, the disclosure of which is incorporated herein by reference, describes the N-alkylation of noroxymorphone with cyclopropylmethyl bromide in N-methyl-pyrrolidone in the presence of sodium bicarbonate. WO2010 / 039209 (the disclosure of which is incorporated herein by reference) describes the N-alkylation of noroxymorphone with cyclopropylmethyl bromide in the presence of an aprotic solvent. Specifically, WO2010 / 039209 describes the addition of water, isopropanol or ethanol as the aprotic solvent.

[0053] Naltrexone can be synthesized by alkylating noroxymorphone [4,5-α-epoxy-3,14-dihydroxy-morphinan-6-one] with cyclopropylmethyl halide to produce naltrexone [17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-morphinan-6-one]. Naltrexone can be produced by a variety of methods, for example, as described in WO91 / 05768, WO2008 / 034973, WO2008 / 138605, WO2010 / 039209, and WO2010 / 039209 (each of which disclosures are incorporated herein by reference). EXAMPLES

[0054] Example 1 This example provides a liquid resin naltrexone formulation that achieves a liquid resin sustained release oral naltrexone suspension formulation containing from about 1.0 mg / ml to about 10.0 mg / ml in the resin, which releases greater than 25% of the total administered dose within 1 hour and releases no more than 60% of the total administered dose within 2 hours. Specifically, a naltrexone-resin complex was coated according to the formulation shown in Table 1. [Table 1]

[0055] 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%.

[0056] The formulation in Table 1 was used to manufacture 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 a 400 μm mesh screen. The passed granules were dried until the moisture reached less than 7%. [Table 2]

[0057] The resulting complex was 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 apparatus until a 15% weight gain was achieved. [Table 3]

[0058] The resulting formulation was then used to prepare the naltrexone extended release suspensions summarized in Table 4 below. A placebo 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 volume of 1.2 L. To the main vessel, the coated naltrexone resin complex was added under continuous mixing to form the naltrexone ER suspension. [Table 4]

[0059] Example 2 In vitro drug release A coated naltrexone resin complex was prepared according to Example 1. In this example, the final suspension was prepared using cherry flavor and FD&C red 40. Ascorbic acid was used as the antioxidant instead of sodium metabisulfite. [Table 5]

[0060] 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 propylene glycol and mixed until completely dissolved. Xanthan gum was added to the preservative solution and mixed well until uniformly dispersed. 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 500 mL of suspension base, FD&C red number 40, cherry flavor and coated naltrexone resin were added under continuous mixing to form the naltrexone ER suspension. The naltrexone ER suspension was 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.

[0061] Example 3 Coated Drug Ion-Exchange Particles 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 6]

[0062] 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.

[0063] Example 4 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 7]

[0064] 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 apparatus until a weight gain of 15 w / w% was achieved.

[0065] 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.

[0066] Example 5 Naltrexone resin complexes were prepared according to the formulations shown in Table 8. [Table 8]

[0067] 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%.

[0068] 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 9]

[0069] 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 10]

[0070] 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 11]

[0071] Example 6 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 added slowly to the main vessel under continuous mixing. Color and flavor were added to the main 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 12]

[0072] Example 7 This example provides drug release profiles over time (IR, steep blue line) of immediate release naltrexone, which is uncoated resin suspension and naltrexone in solution, and the extended release formulation described in Example 1, referred to as the "coated resin complex," which is the red line. Figure 5 shows a comparison of the release rates between the two formulations.

[0073] Example 8 A naltrexone resin complex was prepared according to the formulation shown in Table 13. [Table 13]

[0074] 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%.

[0075] 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. [Table 14]

[0076] 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 15]

[0077] 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 16]

[0078] A clinical pharmacokinetic study was conducted comparing Formulation 1 and Formulation 2 in Table 16. The study was an open-label, single-dose, randomized, 3-period, 3-treatment, 3-sequence crossover comparative bioavailability study in healthy adults (n=18) in the fasted state. 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.

[0079] Both naltrexone and its active metabolite (6-β-naltrexol) were analyzed.

[0080] 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 17]

[0081] The mean plasma naltrexone and mean plasma 6-β-naltrexol concentrations are shown in Tables 18 and 19, respectively: [Table 18] [Table 19]

[0082] Naltrexone formulations 1 and 2 and the commercial formulation (naltrexone HCl 50 mg tablets; Mallinckrodt TM Pharmacokinetic profiles of the naltrexone formulations (SpecGx LLC) are shown in Figure 8. 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 a 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.

[0083] Tmax 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.

[0084] 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.

[0085] 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.

[0086] Example 9 (Prophetic) This example provides a clinical protocol for testing a liquid resin sustained release oral naltrexone formulation in children with autism spectrum disorder (ASD). The drug formulation is a sustained release oral suspension formulation of naltrexone HCl. The active ingredient, naltrexone, is loaded onto a cation exchange resin, sodium polystyrene sulfonate (DuPont). TM Amberlite TMThe drug-resin complex is then complexed with naltrexone-containing phosphate buffered saline (IRP69) to form a naltrexone-resin complex. The drug-resin complex is further granulated and subsequently coated with a sustained release polymer (polyethylene glycol). The final suspensions were produced by dispersing the coated naltrexone-resin particles in a suspension base to provide dose strengths of 22.6 mg / 5 mL or 11.3 mg / 5 mL (equivalent to 5 mg / mL or 2.5 mg / mL naltrexone HCl). The final suspensions were packaged in 8 oz (240 mL) high density polyethylene (HDPE) bottles with 24 mm white child-resistant closures (CRC). The placebo composition was qualitatively the same as the 25 mg / 5 mL suspension but did not contain the active pharmaceutical ingredient, naltrexone HCl.

[0087] Primary endpoint: 1. Number of participants who experienced a reduction in severity of ASD symptoms as defined by the Social Responsiveness Scale (SRS). 2. Number of participants who achieve a 30% or greater reduction in Social Responsiveness Scale (SRS) score from baseline and a reduction in the severity of their presenting ASD symptoms. The SRS is a 65-item informant-completed rating scale to measure the severity of autism spectrum symptoms occurring in natural settings.

[0088] Secondary endpoints: 1. Number of participants who experienced a reduction in severity of ASD symptoms as defined by the NIMH Clinical Global Impression for Pervasive Developmental Disorders (CGI-PDD) improvement score. 2. Number of participants who experienced a reduction in severity of ASD symptoms, defined as an NIMH Clinical Global Impression (CGI) Pervasive Developmental Disorder (PDD) improvement score of 2 or less. CGI Improvement is a clinician-rated measure of improvement. PDD scores range from 1 (very much improved) to 7 (very much worse).

[0089] Inclusion · Male and female outpatients aged over 12 years. A confirmed diagnosis of ASD by gold standard clinical interview using Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) criteria and administration of the Autism Diagnostic Observation Schedule-2, Module 3 or 4. · Subjects and / or their legal representatives must be of sufficient understanding to communicate intelligently with the Investigators and Study Coordinators and to cooperate with all tests and examinations required by the protocol. Subjects and / or their legal representatives must be considered reliable reporters. Each subject and / or their legally authorized representative must understand the nature of the study. The subject and / or their legally authorized representative must sign an informed consent document. Subjects must be able to participate in mandatory blood draws. Subjects must be able to drink a measured amount of the liquid preparation. Subjects with mood, anxiety, or disruptive behavior disorders will be allowed to participate in the study, provided they do not meet any exclusion criteria.

[0090] exclusion IQ<85. Allergy or hypersensitivity to naltrexone. -I can't speak the language at all. -Relevant gastroesophageal reflux disease as determined by the investigator. · Determined to be clinically unstable or at serious risk of suicide. ·Currently diagnosed with a psychotic disorder or unstable bipolar disorder. · Recent or current (past 30 days) history of clinically significant depression or anxiety disorder requiring treatment. Currently diagnosed with schizophrenia. · History of substance use (other than nicotine or caffeine) within the past 3 months. ·Severe, stable or unstable systemic disease, including hepatic, renal, gastrointestinal, respiratory, cardiovascular (including ischemic heart disease), endocrine, neurological, immune or hematological disorders. Subjects with severe hepatic impairment (LFTs >3x ULN) and subjects with severe renal impairment (eGFR<30). ·Untreated hypothyroidism or hyperthyroidism. ·Patients with untreated and / or unstable diabetes. · Non-febrile seizures with no clear cause and that have not resolved. Pregnant or breastfeeding women. · Severe allergic or multiple adverse drug reactions. ·History of non-response or intolerance to memantine after treatment with appropriate doses as determined by a physician. Investigators and their immediate family members, defined as their spouses, parents, children, grandparents or grandchildren.

[0091] Primary endpoint: 1. Changing Maladaptive Behaviors Changes in frequency and intensity of maladaptive behaviors as measured by the Aberrant Behavior Checklist (ABC). The checklist consists of 20 questions about behavior, with a total score reported on a scale of 0 to 60. Lower scores can be interpreted as less frequency and / or intensity of undesirable behaviors. The values ​​below are the differences in ABC scores from baseline to 8 weeks. Negative differences indicate improvement in behavior. 2. Primary Safety Endpoint Number of serious adverse events

[0092] Secondary endpoints: 1. Changes in aggressive behavior It shows a trend towards a decrease in aggressive behavior as measured by the Overt Aggression Scale (OAS), which consists of a scale ranging from 0 to 40, with lower scores interpreted as less frequent and / or less intense unwanted behavior. The mean difference in scores from baseline to 8 weeks is reported; positive scores indicate more aggressive behavior and negative scores indicate less aggressive behavior.

Claims

1. A liquid resin sustained release oral naltrexone suspension formulation comprising about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, wherein no more than 30% of the total administered naltrexone dose is released within 1 hour and no more than 60% of the total administered naltrexone dose is released within 2 hours.

2. 2. The liquid resin sustained release oral naltrexone suspension formulation of claim 1, comprising: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; (b) a material for coating the resin core to form particles, the coating material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, cellulose acetate phthalate (CAP), hypromellose phthalate (hydroxypropyl methylcellulose phthalate; HPMCP), polyvinyl acetate phthalate (PVAP); cellulose acetate trimellitate; hydroxypropyl methylcellulose acetate succinate; sodium alginate; alginic acid, shellac, and combinations thereof; and (c) an aqueous, rich flavored and sweetened liquid for suspending the particles.

3. 10. The liquid resin sustained release oral naltrexone liquid suspension formulation of claim 1, wherein the ion exchange resin is polystyrene.

4. 2. The liquid resin sustained release oral naltrexone liquid suspension formulation of claim 1, wherein the material that coats the resin core to form the particles is a cellulose acetate selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, and cellulose acetate phthalate (CAP).

5. 2. The liquid resin sustained release oral naltrexone liquid suspension formulation of claim 1, wherein the aqueous, rich flavored and sweetened liquid for suspending the particles comprises water, about 300 to about 500 g / L sucrose, about 0.1 to about 0.3 g / L citric acid (anhydrous), about 30 to about 55 g / L starch, about 150 to about 350 g / L propylene glycol, about 3 to about 5 g / L parabens, about 2.0 to about 5.0 xanthan gum, and about 0.5% to about 2% Tween 80.

6. 1. A method for treating a child with autistic disorder with about one teaspoon (about 5 ml) of a liquid resin sustained release oral naltrexone suspension formulation containing about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, wherein no more than 30% of the total administered naltrexone dose is released within 1 hour and no more than 60% of the total administered naltrexone dose is released within 2 hours.

7. The liquid resin formulation comprises: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; and (b) a material coating the resin core to form particles, the coating material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, 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; and (c) an aqueous thick flavored and sweetened liquid for suspending the particles.

8. 7. The method of claim 6, wherein the liquid resin sustained release oral naltrexone suspension formulation is administered qAM (upon awakening).

9. 1. A method for treating a child with the rare pediatric diseases Scharf-Young Syndrome (SYS) or Bosch-Boonstra-Scharf Optic Atrophy Syndrome (BBSOAS) with about one teaspoon (about 5 ml) of a liquid resin sustained release oral naltrexone suspension formulation containing about 1.0 mg / ml to about 10.0 mg / ml naltrexone in the resin, wherein no more than 30% of the total administered naltrexone dose is released within 1 hour and no more than 60% of the total administered naltrexone dose is released within 2 hours.

10. The liquid resin formulation comprises: (a) a resin core comprising naltrexone HCl and an ion exchange resin selected from the group consisting of polystyrene, copolymers of polystyrene and divinylbenzene; and (b) a material coating the resin core to form particles, the coating material being selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), cellulose acetate propionate, 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; and (c) an aqueous, thick flavored and sweetened liquid for suspending the particles.

11. 10. The method of claim 9, wherein the liquid resin sustained release oral naltrexone suspension formulation is administered qAM (upon awakening).

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