Low sodium oxybate composition for once-night use

Abstract

A composition is provided that provides oxibate for once-night administration. The composition, comprising bilayer-coated oxibate-anion exchange resin complex multiparticles, regulates the release of oxibate over a period of 5 to 8 hours after administration. A method is also provided for treating patients in need using a pharmaceutical composition containing the oxibate-anion exchange resin complex.

Description

[Background technology]

[0001] Narcolepsy is a devastating disorder. The main symptoms are excessive daytime sleepiness (EDS), cataplexy (sudden loss of muscle tone triggered by strong emotions, occurring in approximately 60% of patients), hypnagogic hallucinations (HH), sleep paralysis (SP), and nocturnal sleep disturbances (DNS). Aside from EDS, DNS is the most common symptom in narcolepsy patients. One of the primary treatments for narcolepsy is sodium oxibate. While the exact mechanism by which sodium oxibate works is unknown, it is thought to work by promoting delta sleep (SWS) and enhancing nocturnal sleep. Administering sodium oxibate before nighttime sleep prolongs stage 3 and 4 sleep and lengthens sleep latency while reducing the frequency of sleep-onset REM sleep (SOREMP). Other mechanisms, not yet fully understood, may also be involved.

[0002] Gamma-hydroxybutyrate (GHB), also known as "oxybate," is an endogenous compound with hypnotic effects found in human tissues, including the brain of mammals. In the brain, the highest GHB concentrations are found in the hypothalamus and basal ganglia, and GHB is hypothesized to function as a neurotransmitter (Snead and Morley, 1981, Brain Res. 227(4):579-89). The neuropharmacological effects of GHB include increased acetylcholine and dopamine in the brain, inhibition of GABA-ketoglutarate transaminase, and suppression of glucose utilization in the brain, but not suppression of oxygen consumption in the brain. Treatment of GHB substantially reduces the signs and symptoms of narcolepsy, namely daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. In addition, GHB prolongs total sleep time and REM sleep, shortens REM latency, reduces sleep apnea, and improves general anesthesia (e.g., U.S. Patents 6,472,431, 6,780,889, 7,262,219, 7,851,506, 8,263,650, 8,324,275, and 8,772,302, each of which is incorporated herein by reference in whole). GHB has also been reported to alleviate pain and improve function in patients with fibromyalgia syndrome, reduce excessive daytime sleepiness and fatigue in patients with Parkinson's disease, improve myoclonus and essential tremor, and reduce tardive dyskinesia and bipolar disorder. See the references incorporated at the end of U.S. Patent 6,472,431.

[0003] Sodium GHB is highly water-soluble, hygroscopic, and strongly alkaline. See, for example, WO2011 / 119839. Despite its high water solubility, it forms a gel when dissolved in water. See, for example, U.S. Patent No. 8,193,211, also published as U.S. Patent Application US2006 / 0210630 A1. These properties present challenges in preparing solid-unit dosage forms designed for the immediate release of sodium GHB into the user's gastrointestinal tract, along with the large doses of the drug required to achieve clinical efficacy. See, for example, also U.S. Patent No. 8,193,211.

[0004] Two proprietary products approved for the treatment of cataplexy or excessive daytime sleepiness in patients aged 7 years and older with narcolepsy are Xyrem® (sodium oxidate oral solution) and Xywav® (low sodium oxidate oral solution formulation containing a mixture of calcium, magnesium, potassium, and sodium oxidate). Xyrem® is a commercially available product composed of 100% sodium oxidate (Na.GHB) and is approved for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. Na.Xyrem® for use in patients with narcolepsy is a chronically used product requiring a high level of medication. The sodium intake from this medication significantly increases the patient's daily sodium intake, and this This is undesirable for patients with hypertension, heart disease, kidney disease, or those at risk of stroke.

[0005] Another approved formulation is Xywav® (a low-sodium oxidate oral solution formulation containing a mixture of calcium, magnesium, potassium, and sodium oxidate). Xywav® is a low-sodium oxidate oral solution containing a mixture of calcium, magnesium, potassium, and sodium oxidate. However, the therapeutic dose of 71.4 mg equivalents / day (9 g of sodium oxidate) is sufficiently high, and switching from sodium to other cations may push up the limits of the acceptable daily intake of those other cations, potentially causing other undesirable side effects in certain patients. For example, potassium is poorly tolerated in solution when administered in high doses on an empty stomach and may be problematic for patients with renal impairment. Excessive magnesium can cause diarrhea. Therefore, a treatment that reduces or eliminates sodium without adding any additional cations is preferable for a once-night sustained-release composition.

[0006] Despite the general safety record when used as prescribed, there is a risk of abuse and misuse of Xyrem® that may cause serious medical problems, including seizures, loss of consciousness, coma, and death (see, for example, the FDA product label dated November 13, 2006, NDA number 021196, which is incorporated in its entirety by reference). Furthermore, both Xyrem® and Xywav® are immediate-release compositions and require two doses per night.

[0007] Therefore, there is a need for the development of a once-night sustained-release formulation of GHB with lower sodium content, and a formulation with a lower potential for abuse. [Overview of the Initiative]

[0008] In one embodiment, a sustained-release oxybate powder for use in an oral suspension is provided, administered once overnight. Advantageously, this oral suspension powder (POS) provides a desirable release profile and has a low sodium content.

[0009] In one embodiment, a powder (POS) for oral suspension of sustained-release (ER) oxibate is provided, which provides oxibate for once-night administration. The ER oxibate POS comprises a mixture of oxibate-containing polyparticles having different release profiles as defined below: (a) immediate-release oxibate-anion exchange resin composite polyparticles containing oxibate bound to ion exchange sites in anion exchange resin; (b) pH-independent diffusion barrier coated oxibate-anion exchange resin composite-optional matrix polyparticles, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer that imparts sustained release to the oxibate, and the pH-independent diffusion barrier coating layer lies on the oxibate-anion exchange resin composite-optional matrix. (c)(b) Oxybate multiparticles comprising an intestinal targeted drug coating system (SITCS) on an oxibate-anion exchange resin complex-optional matrix, wherein the SITCS is a bilayer coating layer comprising a mixture of pH-dependent polymers and pH-independent polymers on an inner pH-independent diffusion barrier coating layer directly above the oxibate-anion exchange resin-optional matrix, the coating system imparting delayed and sustained release to the oxibate in the SITCS-coated oxibate-anion exchange resin-optional matrix. The oxibate-anion exchange resin complex-optional matrix of (a), (b), or (c) comprises oxibate bound to the ion exchange site of the anion exchange resin in the optional matrix, further comprising at least one hydrophilic or hydrophobic polymer. The complex-optional matrix in each of (a), (b), or (c) may be the same or different from each other. This may also be the case. Furthermore, POS further contains an amount of calcium chloride equivalent of about 1 milliequivalent to about 12 milliequivalents per 9 gm of oxybate dose of POS, and less than 200 mg of total sodium equivalent per 9 gm of oxybate dose of POS. In certain embodiments, the calcium chloride equivalent is a pharmaceutically acceptable salt selected from one or more of magnesium chloride, sodium chloride, zinc chloride, potassium chloride, calcium carbonate, potassium carbonate, sodium bicarbonate, and / or combinations thereof.

[0010] In a particular embodiment, an oral suspension is provided which has been resuspended by mixing oxibate powder with an aqueous oral suspension agent.

[0011] In certain embodiments, a sustained-release oxibate oral suspension powder (POS) provides an oxibate for once-night administration, the POS composition being a mixture of oxibate-containing polyparticles having different release profiles as defined by (a) and (b): (a) Immediate-release oxibate-anion exchange resin complex polyparticles containing oxibate bound to ion exchange sites in anion exchange resin; and (b) At least two different sustained-release oxibate components containing a drug-ion exchange resin complex. The POS further comprises about 1 milliequivalent to about 12 milliequivalents of calcium chloride per 9 gm of oxibate dose of the POS, and less than 200 mg of total sodium equivalent per 9 gm of oxibate dose of the POS. In certain embodiments, after administration to a patient, the suspension containing POS provides a pharmacokinetic profile of at least one of the following oxibates: (i) a Cmax of 87.98 μg / mL to 126 μg / mL, or approximately 107 μg / mL, 85.6 μg / mL to 133.76 μg / mL, or 77.04 μg / mL to 117.711 μg / mL, and / or (ii) a Cmax of approximately 105 μg / mL, or 84.38 μg / mL to 131.84 μg / mL, or 94.92 μg / mL to 116.01 μg / mL, when calculated using the geometric mean. When calculated using the arithmetic mean, the AUCinf is 518.20 hours*μg / mL to 719.725 hours*μg / mL, or approximately 575 hours*μg / mL, or 304.11 hours*μg / mL to 846.67 hours*μg / mL, 460.62 hours*μg / mL to 719.725 hours*μg / mL, and / or when calculated using the geometric mean, approximately 520 hours*μg / mL, or 428.58 hours*μg / mL to 669.66 hours*μg / mL, or approximately 482.16 hours*μg / mL to 589.30 hours*μg / mL.

[0012] In certain embodiments, POS contains an equivalent amount of sodium oxybate in doses of approximately 1 g, 4.5 g, 6 g, 7.5 g, 9 g, or 10 g, when determined based on the equivalent amount of sodium oxybate. For doses higher than 10 g or 9 g, lower concentrations may correspond to doses proportional to higher concentrations.

[0013] In a further embodiment, a method is provided for treating a patient having narcolepsy or idiopathic hypersomnia using an oxibate composition. In yet another embodiment, a composition(s) is provided for use in treating a patient having or being prone to hypertension due to a condition responsive to GHB (oxibate). The method comprises administering a therapeutically effective amount of the composition(s) described herein to the patient, wherein the composition(s) have a reduced sodium content compared to a composition(s) having an equivalent dose of sodium oxibate.

[0014] In another embodiment, a method is provided for treating patients with cataplexy and alcohol withdrawal and dependence. This method comprises administering a therapeutically effective amount of the composition described herein to the patient.

[0015] In further embodiments, chronic fatigue syndrome, cataplexy, sleep apnea, Parkinson's disease, A method is provided for treating patients with schizophrenia, bulimia nervosa, essential tremor and non-Parkinsonian movement disorders, chronic cluster headache, and / or for alleviating constipation associated with opioids and opioid-related drugs. The method comprises administering a therapeutically effective amount of the composition described herein to the patient.

[0016] In another embodiment, a kit is provided for treating a patient using one or more oxybate-anion exchange resin compositions.

[0017] Further aspects and advantages of the present invention will become apparent from the following detailed description of the invention. [Brief explanation of the drawing]

[0018] [Figure 1] The present invention provides the percentage of cumulative oxibate release from a 30% sustained-release (ER) coated oxibate-anion exchange resin composite (resinate), such as that described in Example 6 (uncoated sodium content of 360 μg / g) or Example 7 (30% ER coated resinate, uncoated sodium content of 30 μg / mg). [Figure 2] The present invention provides the percentage of cumulative oxibate release from a two-layer, 40% delayed sustained release (DER) coated oxibate-anion exchange resin composite (resinate), such as those described in Example 12 (40% DER coated resinate, 3000 μg / g uncoated sodium content), Example 11 (40% DER coated resinate, 2500 μg / mg uncoated sodium content), or Example 19 (40% DER coated resinate, 30 μg / g uncoated sodium content). [Figure 3] The present invention provides the percentage of cumulative oxibate release from a two-layer, 45% delayed sustained release (DER) coated oxibate-anion exchange resin composite (resinate), such as those described in Example 17 (45% DER coated resinate, 3000 μg / g uncoated sodium content), Example 18 (45% DER coated resinate, 2500 μg / mg uncoated sodium content), or Example 19 (45% DER coated resinate, 30 μg / g uncoated sodium content). [Figure 4] This provides the results of the effect of calcium chloride on the release of the final ER POS products over 6 hours for Examples 20 (1 mg equivalent relative to Cl-), 21 (4 mg equivalent relative to Cl-), 22 (8 mg equivalent relative to Cl-), and 23 (12 mg equivalent relative to Cl-). [Figure 5] This curve shows the plasma concentration curve (mcg / mL) of oxidate over 10 hours, provided by an oxidate-releasing suspension powder (equivalent to 9g of sodium oxidate).

Best Mode for Carrying Out the Invention

[0019] This specification provides a once-daily drug product in the form of an oxybate extended release (ER), oral suspension powder (POS) containing sodium oxybate in complex with cholestyramine resin. Inclusion of cholestyramine resin in the drug product is intended to delay the release of oxybate from the ER product. It has been observed that drug release from the oxybate ER formulation is regulated by the concentration of sodium content in the formulation. The unique formulation technique developed controls the sodium content in the formulation. The sodium content in the coated drug resin complex significantly contributes to the dissolution characteristics of the drug resin particles, which in turn affects the bioavailability of oxybate in vivo. The dissolution characteristics of the oxybate resin complex are also adjusted by the addition of calcium chloride equivalents in the oxybate ER formulation.

[0020] As used herein, a combination of sodium ions with calcium chloride or its equivalents can be used to achieve the desired dissolution profile in vitro / in vivo. In certain embodiments, the calcium chloride equivalent is a pharmaceutically acceptable salt selected from one or more of magnesium chloride, sodium chloride, zinc chloride, potassium chloride, calcium carbonate, potassium carbonate, sodium bicarbonate, and / or combinations thereof. In certain embodiments, the POS contains an equivalent amount of calcium chloride of about 1 milliequivalent to about 12 milliequivalents per 9 gm of the oxybate dose of the POS and contains less than an equivalent amount of 200 mg of total sodium per 9 gm of the oxybate dose of the POS. In other formulations, an appropriate amount of calcium chloride equivalent may be selected.

[0021] Initial release from the formulation is required to achieve the desired Cmax for formulations that administer oxybate once a night. In certain embodiments, combining immediate release (IR), extended release (ER), and small intestine targeted drug coating system (SITCS) oxybate components with low sodium and calcium chloride concentrations (1 - 12 milliequivalents) provides the desired maximum plasma concentration (Cmax) of oxybate and allows maintenance of therapeutic levels until about 5 - 6 hours after dosing. Thereafter, the composition allows complete clearance of oxybate levels within about 10 hours after dosing.

[0022] As used herein, the composition comprises a combination of oxybate-containing components each having a different release profile. Each of the three components comprises a complex of oxybate and an anion exchange resin, with oxybate bound to the anion exchange resin via available anion groups on the resin. The three components are: (1) an immediate release component comprising an oxybate-anion exchange resin complex; (2) an extended release component comprising an oxybate anion exchange complex coated with a layer of a pH-independent diffusion barrier comprising a water-insoluble film-forming polymer or copolymer; and (3) a SITCS component comprising an oxybate-anion exchange resin complex coated with a pH-independent barrier coating layer and a delayed release coating layer having a mixture of a pH-dependent enteric polymer or copolymer system and a pH-independent diffusion barrier polymer or copolymer system, a calcium chloride, or its equivalent counterion, per 9 gm dose, and an equivalent amount of sodium less than 200 mg.

[0023] When used herein, the sodium content in a composition (e.g., POS) is important for the initial release of oxibate when measured in vitro or in vivo. In certain embodiments, the sodium content in a composition is present in an equivalent amount of less than 200 mg of sodium per 9 g of oxibate dose (the oxibate dose is determined based on the sodium oxibate equivalent). In certain embodiments, the sodium content is about 5 mg to about 175 mg per 9 g of oxibate dose, or about 150 mg (by weight) per 9 g of oxibate dose. For doses less than 9 g, the amount of sodium is titrated so that the ratio of sodium to the equivalent amount of 9 g of oxibate dose is similar (e.g., 0.2 g or less of sodium / equivalent amount of 9 g of oxibate dose, or about 0.005 g of sodium / equivalent amount of 9 g of oxibate to about 0.175 g of sodium / equivalent amount of 9 g of oxibate dose, or about 0.150 g of sodium / equivalent amount of 9 g of oxibate dose).

[0024] The concentration of calcium chloride is important for the initial release of oxybate in vitro / in vivo. As used herein, the oxybate ER formulation contains calcium chloride at a concentration of 1 to 12 milliequivalents for ease of use. In preferred embodiments, the chloride ion is selected from the group consisting of calcium chloride, sodium chloride, magnesium chloride, and / or zinc chloride, or other chloride salts and / or combinations thereof. Calcium chloride is preferred for the oxybate ER formulation.

[0025] The formula for milliequivalent is calculated based on the following equation, which is well known to those skilled in the art: Milliequal = Mass × Valence / Molecular Weight

[0026] When used herein, the compositions and methods minimize and / or eliminate adverse events associated with high levels of sodium and certain other salts, thereby improving patient compliance. Furthermore, the compositions provided herein are taken once night, thus avoiding the need to get up at night for a second dose.

[0027] As used herein, “Suspension Powder” or “POS” refers to a composition formulated as a powder designed to be suspended in a suspension base before oral ingestion by a patient.

[0028] In certain embodiments, the manufacturing process for the drug resinate complex was developed so that the sodium content concentration is less than 200 mg / 9 gm. A dose of 9 gm of sodium oxibate contains 1640 mg of sodium. The manufacturing method presented in certain embodiments reduces the sodium content of the formulation from 1640 mg to less than 200 mg per 9 gm dose. In certain embodiments, this required sodium content of less than 200 mg per 9 gm dose is necessary to achieve the desired dissolution in the first few hours for sustained release of the dosage form overnight. These sodium ions in the coated drug resinate complex act as pore-forming agents to enhance the dissolution of oxibate from the coated drug resinate complex.

[0029] The oxibate ER POS composition may contain calcium chloride to promote the dissolution of oxibate ER POS in the first few hours after administration. In certain embodiments, the oxibate composition (e.g., ER POS) provided herein contains about 1 to 12 milliequivalents of calcium chloride to obtain the desired dissolution profile. While we do not wish to be bound by theory, it is thought that calcium chloride generates calcium ions in body fluids, exchanging oxibate ions from the drug resinate (complex), thereby increasing the dissolution of oxibate in the first few hours after administration. The dissolution of oxibate in the first few hours contributes to providing the desired initial plasma concentration of oxibate from the oxibate ER composition (e.g., POS) provided herein. Oxibate has a short plasma half-life of about 30 to 45 minutes.

[0030] The combination of immediate-release (IR) and sustained-release (ER) drug resinate particles, low sodium content, and calcium chloride provides the desired maximum plasma concentration level (Cmax) of oxybate, allowing therapeutic levels to be maintained for approximately 5 hours after administration. The composition then allows for complete clearance of oxybate levels within approximately 10 hours after administration. Optionally, one or more of the immediate-release, sustained-release, or delayed-release components include an oxybate-anion exchange resin complex-optional matrix. If at least one coating layer is present in the component, this at least one coating is on the oxybate-anion exchange resin complex-matrix.

[0031] This specification provides pharmaceutical compositions and formulations comprising 30% to 75% w / w total oxybate immediate-release (IR) component(s), 25% to 70% w / w total oxybate reginate sustained-release (ER) component, less than 200 mg of sodium and 75 mg (1 milliequivalent) to 882 mg (12 milliequivalents) of calcium chloride per 9 g dose. In certain embodiments... The composition further comprises a floating interpermeable network (IPN) forming system.

[0032] In certain embodiments, the immediate-release oxidate component is present in amounts of approximately 30% w / w to 80% w / w, or approximately 20% to 75%, or approximately 65% ​​to 70% w / w (based on the total oxidate in the composition). In certain embodiments, the sustained-release oxidate component is present in amounts of approximately 25% w / w to 70% w / w, or approximately 25% w / w to 60% w / w, or approximately 40% w / w (based on the total oxidate in the composition).

[0033] In certain embodiments, as described herein, there are two different sustained-release components, and the total oxybate in the sustained-release component, which includes a functional enteric coating or a pH-independent coating without a pH-dependent coating, is about 5% to about 30% w / w of the total oxybate in the composition. In certain embodiments, the total oxybate in the sustained-release component, which includes a functional enteric coating or a pH-independent coating without a pH-dependent coating, is about 10% to about 15% w / w of the total oxybate in the composition.

[0034] The SITCS component does not release a significant amount of oxibate in the first few hours after administration, even if the immediate-release component releases oxibate at a significantly faster rate, as defined herein. In certain embodiments, novel combinations of the immediate-release component, the sustained-release component, and the SITCS coating component work together to achieve an effective plasma oxibate concentration at 1 hour post-administration (C1), a controlled Cmax, and effective plasma levels without a decrease in AUC up to 5 hours post-administration (C5). While we do not wish to be bound by theory, this is considered helpful in controlling Cmax and initial plasma concentrations, and therefore in controlling side effects. The SITCS-releasing component initiates oxibate release at higher pH levels, most preferably above about 4, which is the pH present in the small intestine.

[0035] In certain embodiments, the SITCS component provides a delayed effect of approximately 2 hours after administration, while the ER is approximately 3 to 6 hours. In certain embodiments, the best results are obtained when the dosage form is administered approximately 2 hours after dinner.

[0036] Immediate-release components initiate the release of oxibate immediately after administration with no lag time (e.g., it may begin in less than 10 minutes or about 10 minutes) and contribute to the initial plasma concentration level of oxibate. In certain embodiments, the immediate-release component (i.e., oxibate-anion exchange resin complex) releases about 75% to over 80% of its oxibate in about 1 hour, or about 75% to over 80% of its oxibate in 1 hour. This can be evaluated, for example, in an in vitro lysis assay as defined later. Sustained-release components provide the release of oxibate for about 5 to 8 hours after administration.

[0037] This specification describes solid and liquid dosage forms. In one particularly suitable embodiment, the composition is in the form of a suspension powder. In a particular embodiment, the suspension powder is prepared using all components in a specific ratio selected based on the w / w of the oxibate dose, together with diluent granules containing excipients.

[0038] Certain pharmaceutically acceptable salts of GHB are called “oxybates,” e.g., sodium oxybate. Using similar terminology, the complex formed between a GHB salt (with its counterion removed) and an anion exchange resin is referred to herein as an “oxybate-anion exchange resin complex.” The terms GHB and oxybate may be used interchangeably herein unless otherwise specified.

[0039] Optionally, the powder composition may contain a dye that dissolves in an aqueous alcoholic liquid to produce a specific color, in order to enhance safety. In another alternative example, the composition may contain an alcoholic liquid. The composition may contain flavorings that impart an unpleasant taste when mixed with other substances. Furthermore, the composition is clinically advantageous because it provides a sustained release of oxybate, avoiding the need for patients to get up for a second dose at night. The composition also reduces the possibility of errors that may occur in the preparation of multiple individual doses.

[0040] In certain embodiments, the compositions provided herein provide a single plasma concentration peak. In certain embodiments, the compositions provided herein feature a plateau of mean plasma concentration levels of oxybate, which can be measured using the arithmetic mean and / or geometric mean.

[0041] As used herein, “functional coating” is a coating layer that functions to modify the release profile of a coated active drug, such as GHB. Such release may be time-dependent, pH-dependent, pH-independent, or a combination thereof. In one embodiment, the functional coating is a pH-independent diffusion barrier coating. In another embodiment, the functional coating is a pH-dependent (e.g., enteric) delayed-release coating combined with a diffusion barrier coating. These coatings and other suitable coatings are described in more detail below.

[0042] As provided herein, “suspended IPN” includes whole IPN or partial IPN and a sealing gas. Preferably, suspended IPN includes an active drug(s).

[0043] As used herein, “interinterpenetrating polymer network (IPN)” comprises two or more polymer networks that are at least partially interlocked at the molecular scale but are not covalently bonded to each other and cannot be separated unless chemical bonds are broken. IPNs may be formed sequentially, i.e., in sequential IPNs, the second polymer network is formed after the completion of crosslinking of the first polymer network. Alternatively, IPNs may be formed simultaneously, i.e., they may be prepared by a process in which all polymer networks are formed simultaneously.

[0044] As used herein, “semi-IPN” refers to an IPN system in which fewer than all of the polymer network components are interlocked at the molecular scale. For example, in an IPN system containing two crosslinkable polymer / polysaccharide components, semi-IPN refers to a system in which only one of the two components is crosslinked (networked). For example, in an IPN system containing two crosslinkable polymer / polysaccharide components, semi-IPN refers to a system in which only one of the two polymer components is crosslinked (networked). Compositions suitable for oral administration provided herein may include fully crosslinked (full IPN) or semi-IPN.

[0045] Oxybate-anion exchange resin composite Oxybate-anion exchange resin composites may be used in the immediate-release and release-modulated oxibate components of the compositions described herein. In the immediate-release oxibate components, typically no functional coating is provided on the oxibate-anion exchange resin composite. Such composites may be in an optional matrix. The immediate-release oxibate-anion exchange resin composite-optional matrix may have a non-functional coating. If present, the non-functional coating is typically present in a single coating layer. In the following embodiments, the term “resinate” is used interchangeably with “anion exchange resin composite,” i.e., oxibate reginate and oxibate-anion exchange resin composite refer to the same component.

[0046] An "anion exchange resin" is an insoluble organic polymer containing a basic group for exchanging an anion with a second portion containing an anion when in a suspension. In this context, "strong anion exchange resin" is equivalent to "strong basic anion exchange resin."

[0047] Unless otherwise specified, references to “anion exchange resins” throughout this specification shall be understood to include the “strongly basic anion exchange resins” and “cholestyramine resins” described herein. Examples of anion exchange resins are pharmaceutically acceptable grades of cholestyramine resin, strongly basic (Type 1) anion exchange resin powders containing a polystyrene matrix and quaternary ammonium functional groups (e.g., polystyrenetrimethylbenzylammonium chloride). The exchangeable anionic counterions are generally chlorides and can be exchanged with or substituted with substantially any anionic species. Other commercially available pharmaceutical-grade cholestyramine resins may include Type II resins, e.g., PUROLITE® A430MR resin (DuPont De Nemours). As described by its manufacturer, this resin has an average particle size range of less than 150 microns, a pH range of 4 to 6, and an exchange capacity of 1.8 to 2.2 equivalents / dry gram. Another pharmaceutical-grade cholestyramine resin is available as DUOLITE® AP143 / 1094 [DuPont De Nemours], with particle sizes ranging from 95% less than 100 microns and 40% less than 50 microns, according to the manufacturer's description. Commercial literature from suppliers of these and other resins is incorporated herein by reference (PUROLITE® A-430 MR, DOW Cholestyramine USP, Form No. 177-01877-204 [DuPont De Nemours; DUOLITE® AP143 / 1083, DuPont De Nemours). Further embodiments refer to USP <811> and <796> When determined using a dry sieving method derived from [source], DUOLITE® AP143 / 1096 is selected, having a particle size where more than 55% of the particles are less than 150 microns and the average diameter is 130 microns or more. Dow Chemical resins are [unclear] USP <891> It has a pH in the range of 4 to 6, determined by the method, and an ion exchange capacity of 1.8 to 2.2, determined by the HPLC / UV method. In certain embodiments, a weakly basic anion exchange resin may be selected for use in the methods and / or compositions provided herein.Ion exchange resins having primary, secondary, and tertiary amine groups as active functional groups exhibit weak basicity and are therefore called weakly basic anion exchange resins (WBAERs). There are several types of WBAERs. Some have only one amine group, while others have two or more amine groups. Examples include DIAION® WA10 (acrylic acid type with tertiary amine group), WA20, WA21J (a mixture of primary and secondary amine groups), and WA30 (tertiary amine group). For example, the "DIAION"® series [Mitsubishi Chemical Corporation] is a weakly basic anion exchange resin, described by the manufacturer as having two types with different alkaline strengths: Type I with a trimethylammonium group and Type II with a dimethylethanolammonium group. Other products may contain chitosan hydrochloride. Other suitable anion exchange resins may include, for example, POROS® XQ anion exchange resin, available from Thermo Fisher Scientific.

[0048] Both regularly and irregularly shaped particles can be used as resins. Regularly molded particles are particles that substantially conform to geometric shapes such as spheres, ellipses, and cylinders (e.g., three-dimensional shapes described in the description by a three-dimensional space group). Irregularly molded particles are all particles that are not considered to have regular geometric shapes (e.g., those not readily described by a three-dimensional space group), such as particles with amorphous shapes and particles with increased surface area due to surface channels or strains. Particles of both regularly and irregular shapes may include any of the anion exchange resins disclosed herein.

[0049] Oxybate-anion exchange resin composites can be prepared using conventional ion exchange resin filling (composite) processes or variations thereof. For example, U.S. Patent No. 8,062,667, U.S. Patent Publications US2005 / 181050, U.S. Patent Publications US8,343,546, with the following modifications. Refer to the technique described in US5,980,882. This compounding involves dissolving an oxidate salt (e.g., sodium oxidate or magnesium oxidate) as a starting material and mixing it with a water-insoluble anion exchange resin in an aqueous medium. Typically, the oxidate-anion exchange resin composite thus formed is collected by filtration and washed to remove any counterions (e.g., sodium, calcium, potassium, or magnesium), unbound oxidates, or by-products. Such a washing step may involve water or another aqueous solution. The composite can be air-dried at room temperature or high temperature in a tray, fluidized bed dryer, or other suitable dryer.

[0050] In certain embodiments, one or more filling steps (equilibriumization) are used to achieve a desired level of oxidate compounded onto the anion exchange resin. Two or more filling steps separating the resin from the liquid phase between steps may be used to maximize the filling of oxidate into the anion exchange resin. For example, a single equilibration (compounding) may provide about 0.1% w / w to about 20% w / w of oxidate, or 1% w / w to 20% w / w, or 5% w / w to 15%, or 7% w / w to 10% w / w of oxidate in the resulting oxidate-anion exchange resin composite. However, in certain embodiments, filling levels of about 15% w / w to about 35% w / w, about 15% w / w to about 25% w / w, or more than 25% are desirable, and it has been found that this requires multiple filling steps. In certain embodiments, an oxybate content of approximately 25% w / w to approximately 30% w / w, or 25% w / w to 29% w / w, can be achieved, the weight of which is based on the total weight of the oxybate-anion exchange resin composite. In certain embodiments, an oxybate content of approximately 27% w / w to 29.5% w / w is present, the weight of which is based on the total weight of the oxybate-anion exchange resin composite. In certain embodiments, an oxybate content of 28% w / w to 29.5% w / w is present, the weight of which is based on the total weight of the oxybate-anion exchange resin composite. In certain embodiments, an oxybate content of approximately 27% w / w is present, the weight of which is based on the total weight of the oxybate-anion exchange resin composite. Such an oxybate-anion exchange resin composite can be mixed with a suitable hydrophilic or hydrophobic polymer component to form a matrix, and this oxybate-anion exchange resin composite-matrix can be optionally coated. Optionally, a non-functional seal coat may be applied to the oxybate-anion exchange resin composite, the oxybate-anion exchange resin composite-matrix, and / or the coated oxybate-anion exchange resin composite-optional matrix. Optionally or additionally, one or more functional coatings may be provided on the oxybate-anion exchange resin composite matrix, without the use of a separate non-functional coating.

[0051] The oxybate-anion exchange resin composite can be mixed with a suitable granulator, such as a hydrophilic polymer or hydrophobic excipient, to form a matrix. The resulting matrix contains the oxybate-anion exchange resin composite in a matrix containing a hydrophilic or hydrophobic polymer or hydrophobic excipient. In certain embodiments, the matrix-forming polymer or excipient is present in an amount of about 10% to about 50% by weight, more preferably about 20% to about 40% by weight, or about 30% by weight of the resulting matrix. In the following specific embodiments, "medium" molecular weight polyvinylpyrrolidone (PVP) is used. (e.g., KOLLIDON® K30) This product has the chemical formula (C6H9NO) n It has a K value of 27.0 to 32.4 and an average molecular weight of approximately 44,000 to 54,000 Da, according to the European and American Pharmacopoeia. This is its relative viscosity in water [H. Fikentscher, Cellulos It is calculated from Chemie 13 (1932): 58-64 and 71-74. For example, BASF's Volker Buehler KOLLIDON (registered trademark) Polyvinylpyrrolidone excipients for the See Pharmaceutical Industry, 9th revised edition, pp. 1-330 (March 2008).

[0052] For example, the average molecular weight (MW) can be measured using light scattering or ultracentrifugation. Alternative methods include number-average (Mn, measured by osmotic analysis or membrane filtration) or average viscosity. However, other PVP polymers may also be selected, for example, those with an average molecular weight of approximately 28,000 to 100,000 and soluble in water at room temperature.

[0053] In certain embodiments, the oxybate-anion exchange resin composite is granulated with a hydrophobic material (such as glyceryl behenate) that provides a release delay function. However, another hydrophobic material is preferably selected, which is pH-independent, has a high melting temperature, is matrix-forming, and is a water-insoluble wax or waxy substance. As used herein, “pH-independent, high melting temperature, matrix-forming, water-insoluble wax or waxy substance” includes hydrophobic waxes or waxy substances that are solid at room temperature. Waxes having melting points in the range of about 30°C to about 50°C may be used, but blending or other processing may need to be carried out at lower temperatures to counteract the heat generated during processing of waxes or waxy substances with lower melting points. Particularly desirable are waxes and waxy substances having melting points in the range of about 50°C to about 80°C. Examples of suitable pH-independent, high-melting-temperature, matrix-forming, water-insoluble waxes or waxy substances include, for example, waxes selected from one or more of the following: stearyl alcohol, acetyl alcohol, glyceryl palmitostearate, glyceryl monostearate, carnauba wax, beeswax, candelilla wax, microcrystalline wax, ozokerite wax, paraffin wax, glyceryl behenate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl palmitate, cetyl caprylate, stearyl palmitate, stearyl stearate, their derivatives and mixtures. In one embodiment, glyceryl behenate is used. Glyceryl behenate is available under the trademark name COMPRITOL® 888 ATO (Gattefosse, France), has a melting point of about 70°C, and a hydrophilic-lipophilic balance (HLB) value of 2. In another embodiment, glyceryl palmitostearate or glyceryl behenate is used. Glyceryl palmitostearate, marketed under the trademark name PRECIROL® ATO5 (Gattefosse, France), is a wax-type lipid excipient with a melting point of approximately 56°C and an HLB value of 2. In yet another embodiment, cetostearyl alcohol having a melting point in the range of approximately 48°C to approximately 56°C, or approximately 52°C, is used.In further embodiments, acetyl alcohols having a melting point in the range of about 45°C to about 52°C may be used alone or in combination with one or more waxes or waxy substances. Preferably, pharmaceutical-grade waxes or waxy substances are used in the composition. Other examples of such substances include carnauba wax, vegetable waxes, fruit waxes, stearic acid, microcrystalline waxes, beeswax, hydrocarbon waxes, paraffin waxes, cetyl ester waxes, emulsifying waxes, candelilla wax, free wax acids (stearic acid being one example), esters of wax acids, propylene glycol monostearate, glycerol monostearate, palm wax, lignite wax, ozokerite, ceresin wax, ladacein, china wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, hydrogenated vegetable oils, hydrogenated castor oil, fatty acids, fatty acid esters, fatty acid glycerides, and polyethylene glycol (molecular weight greater than 3000). Optionally, the resin may be granulated with a polymer material to be used for coating (e.g., SURELEASE®, EUDRAGIT® RLS / RS, or KOLLICOAT® SR30D), and then coated again with these polymers. In other embodiments, the polymers and copolymers may include hydrophobic polymers / copolymers and / or mixtures of hydrophobic polymers / copolymers and hydrophilic polymers / copolymers. See, for example, U.S. Published Patent Applications US2005 / 0232986, US2005 / 0232987, US2005 / 0232993, US2005 / 0266032, U.S. Patent No. 7,067,116, U.S. Patent No. 6,667,058, and U.S. Patent No. 6,001,392 of the application, among others (these disclosures are incorporated herein by reference).

[0054] Alternatively, in certain embodiments, the matrix component avoids the use of polymers (e.g., hydrophobic polymers) that may function to delay the release of oxidates. In such embodiments, the matrix-forming component mainly comprises hydrophilic polymers. Examples of suitable hydrophilic polymers and copolymers (e.g., polyvinylpyrrolidone) are described above. Other suitable hydrophilic polymer systems for mixing with the complex may include, for example, propylene glycol, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, mannitol, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, and sorbitol. Further other polymers may be selected and mixed or granulated with the complex to form a matrix.

[0055] In certain embodiments, the oxybate-anion exchange resin composite-matrix comprises 5% to about 50% by weight of the matrix-forming polymer, or about 20% to about 40% by weight, or about 25% by weight, with the remaining weight provided by the oxybate-anion exchange resin composite.

[0056] immediate release component In certain embodiments, the compositions described herein include an immediate-release oxibate component. Suitablely, such an immediate-release component may be an oxibate-anion exchange resin composite-optional matrix that satisfies the immediate-release profile described below. Such components typically lack any functional coatings to maintain the immediate-release profile. In certain embodiments, a strong anion exchange resin, such as a cholestyramine anion exchange resin, is selected.

[0057] "Immediate release" means a composition in which 75% or more of the oxibate is released within less than one hour after ingestion (after administration), typically about 0.1 hours to about 1 hour, and in certain embodiments within about 0.75 hours. In certain embodiments, the immediate release oxibate-cholestyramine anion exchange resin complex of (a) releases at least 80% of its oxibate within one hour. The release rate can be determined by an in vitro release assay, for example, 900 mL in 0.1 HCl, and other conditions described herein in the figures and examples.

[0058] Any suitable GHB drug (e.g., oxibate salts) or mixtures thereof may be selected to compound with an anion exchange resin for the immediate-release component. In certain embodiments, the immediate-release component is a powder comprising an oxibate-anion exchange resin complex. The compositions provided herein are designed to avoid the presence of uncompounded oxibate, oxibate salts (e.g., calcium oxibate, magnesium oxibate, or potassium oxibate), and counterions of oxibate salts. As used herein, the immediate-release powder is a relatively homogeneous mixture of individual particles. As used herein, the immediate-release particles generally have an average particle size of about 250 microns to about 425 microns. In certain embodiments, the matrix of the oxibate-anion exchange resin complex—of any choice—has a moisture barrier coating. Such a moisture barrier coating helps maintain the integrity and stability of the active drug during storage for its shelf life and / or facilitates the application of color.

[0059] As used herein, “non-functional coating” is optional and refers to a coating that does not impart a detectable drug release regulation function to the coated drug, and is also alternatively called “seal coating.” In other words, such coatings do not alter the drug release profile of an immediate-release drug to a release regulation profile. Non-functional coatings do not affect the completeness of the coated drug (granules) during storage and / or further processing. The non-functional coating may include polymer or non-polymer materials that act as a moisture barrier to maintain integrity. The non-functional coating may additionally or alternatively include oxygen barrier properties. In certain embodiments, the non-functional coating helps protect the coated drug product from interaction with the packaging in which the product is stored (e.g., aluminum foil pouches). Some of these non-functional materials are commercially available as described herein. See, for example, low molecular weight hypromellose, methylhydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol (see, for example, OPADRY® II (polyvinyl alcohol, polyethylene glycol, talc) or OPADRY® AMB (Colorcon Inc., Harleysville, PA)), carboxymethylcellulose, polyacrylic resins, carbomers, and combinations of powdered cellulose coatings. As used herein, “low molecular weight” refers to a viscosity of about 100 cP to about 5000 cP. The weight percentages of these non-functional coatings are provided as amounts added to the finished resinate particles or microparticles, if present, ranging from approximately 1% to approximately 50%, or approximately 10% to approximately 40%, or approximately 20% to approximately 30% of the total weight.

[0060] The immediate-release component may comprise one or more different immediate-release forms, for example, two different anion exchange resins may be utilized, and / or one complex may have a matrix while the other complex does not. In certain embodiments, the immediate-release component is the oxybate-anion exchange resin complex-optional matrix described herein, but lacks a functional coat. In certain embodiments, the immediate-release component lacks any counterions of any pharmaceutically acceptable salts from the GHB salts used to produce the oxybate-anion exchange resin (i.e., sodium-free, sodium and / or potassium-free, etc.).

[0061] Modified release component In addition to the immediate-release oxibate component described above, the composition includes a sustained-release oxibate component (also called an ER component) and an oxibate component having a bilayer coating system comprising a mixture of a delayed-release coating polymer and a sustained-release coating polymer in a layer on an oxibate-anion exchange resin complex (resinate) or an oxibate reginate matrix (also called a SITCS component). These two release-modulated oxibate components include a first oxibate reginate-optional matrix as described for the immediate-release component having a single diffusion barrier coating layer, and a second oxibate reginate-optional matrix having a double-layer SITCS coating. The sustained-release oxibate component comprises a pH-independent diffusion barrier coating layer on an oxibate-anion exchange resin complex-optional matrix, the barrier coating layer providing a sustained-release profile for the oxibate in the complex. The SITCS oxibate component provides a bilayer coating that provides delay or lag time, which helps in the sustained release of oxibate after administration.

[0062] Generally, the term “release regulation” includes sustained release, controlled release, extended release, delayed release, timed release, slow release, gradual release, and prolonged release. The release rate can be controlled by the use of release regulation polymers as described herein. As described herein, due to the properties of the active ingredient of the composition, i.e., the oxybate-anion exchange resin complex, the release regulation of oxybate is designed to have a release regulation that provides release of 3 to 8 hours, 3.5 to 8 hours, 4 to 8 hours, 4.5 to 8 hours, 5 to 8 hours, preferably about 7.5 hours or less, more preferably 7 hours or less. In certain embodiments, oxybate is substantially completely released within about 8 hours after administration. In certain embodiments, plasma levels are less than 25 micrograms / ml at 8 hours. In yet another embodiment, there are no detectable plasma levels of the oxybate drug at 10 hours, preferably at 9 hours. No detectable plasma levels are present, and more preferably, no detectable plasma levels are present at 8.5 hours. In other embodiments, higher dose compositions are designed to have a therapeutic effect within about 6 hours or within about 5 hours. For example, the compositions described herein have a controlled release profile and may exert a therapeutic effect for about 3.5 to 7 hours. In certain embodiments, release may be determined using an in vitro release assay.

[0063] In a particular embodiment, the composition comprises three oxibate multiparticle components, each having a different release profile, namely (a) immediate-release oxibate-anion exchange resin composite-optional matrix multiparticles, (b) sustained-release oxibate reginate multiparticle component, and (c) SITCS oxibate reginate multiparticle component.

[0064] In certain preferred embodiments, the coating layer does not contain any active compounds (e.g., it does not contain oxidative components).

[0065] A. Sustained-release ingredients In one embodiment, the sustained-release component comprises a barrier-coating oxibate-anion exchange resin complex-optional matrix. In certain embodiments, the matrix is ​​present. In other embodiments, the matrix is ​​absent. As described herein, the sustained-release component of the composition is thought to help achieve significantly higher plasma concentration levels 5 hours post-administration (C5), which is desirable for a single nightly dosing regimen.

[0066] As used herein, the term “sustained-release coating” refers to a coating layer that functions to alter the rate of oxidate release from a coated oxidate-anion exchange resin composite-optional matrix compared to an immediate-release oxidate such as a free oxidate active ingredient (API) (e.g., sodium oxidate or other pharmaceutically acceptable salt thereof) which may be used as a reference point, or to an immediate-release oxidate-anion exchange resin composite-optional matrix provided herein.

[0067] Appropriately, the diffusion barrier coating is a water-insoluble, water-permeable coating material that has pH-independent release (i.e., not an enteric or reverse enteric coating with pH-dependent release). The diffusion barrier coating is applied (e.g., as an aqueous dispersion or solution) onto a matrix of oxidate-anion exchange complex-optional, and the barrier coating matrix is ​​dried, ground, or screened so that the multiplicity of the oxidate-anion exchange complex-optional is, for example, about 125 microns to about 1 mm on average, or about 300 microns to about 900 microns on average, or about 400 microns to about 800 microns.

[0068] In one embodiment, the diffusion barrier coating layer is about 10% w / w to about 90% w / w, or about 15% w / w to about 80% w / w, or about 15% w / w to about 50% w / w, based on the weight of the oxybate-anion exchange resin composite before coating (and the weight of the composite before any matrix components). In a particular embodiment, the diffusion barrier coating layer comprises a polyvinyl acetate polymer containing stabilizers and plasticizers, as described herein. However, other diffusion barrier coatings as described herein, such as barrier coatings comprising a low-permeability pH-independent polymer or copolymer containing trimethylammonium methyl methacrylate chloride, methyl methacrylate, ethyl acrylate polymer (e.g., EUDRAGIT® RS), and a plasticizer, barrier coatings comprising cellulose acetate and a plasticizer, and / or pH-independent coatings, such as a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g., poly(ethyl acrylate-co-methyl methacrylate) 2:1 of the EUDRAGIT® NM brand) together with a plasticizer, or mixtures thereof, may be selected. It can also be used as an option.

[0069] Generally, plasticizers or mixtures of plasticizers are combined in a total amount of about 2% to about 50% by weight of the coating layer, more preferably about 2% to about 30% by weight of the coating layer on a coated oxibate-anion exchange resin composite-optional matrix. Preferably, the suitable plasticizer is in the range of about 2.5% to about 15% by weight of the coating layer based on the coated composite, providing the most desirable properties. The suitable plasticizer may be water-soluble or water-insoluble. Examples of suitable plasticizers include, for example, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethyl citrate, triethyl acetyl citrate, tributyl acetyl citrate, tributyl citrate, triacetin, and SOLUPHOR® P(2-pyrrolidone), as well as mixtures thereof. Other plasticizers are described on page 4 (0041) of the patent application publication US2003 / 0099711 A1, May 29, 2003, and their disclosures are incorporated herein by reference.

[0070] In one embodiment, the diffusion barrier coating is applied as an aqueous dispersion and dried to provide a desired release control profile. The coating may be mixed with a plasticizer and / or cured to provide a desired release profile, for example, in the case of an aqueous-based polyvinyl acetate coating. In one embodiment, the barrier coating is applied as an aqueous dispersion of a water-insoluble polymer containing a polyvinyl acetate polymer, or a mixture of polymers containing a polyvinyl acetate polymer. In one embodiment, the barrier coating further comprises a plasticizer that increases the tensile strength of the barrier coating layer.

[0071] In certain embodiments, the diffusion barrier coating is applied in the form of an aqueous coating dispersion based on polyvinyl acetate (PVA) polymer and an aqueous dispersion containing a plasticizer. PVA is insoluble in water at room temperature. PVA may be used in substantially pure form or as a mixture. Preferably, a hydrophilic polymer is combined with PVA to provide a desired release profile for the oxidative agent. For example, if the barrier coating contains a PVA polymer, the PVA polymer is present in amounts of about 10% to about 80% w / w of the final barrier coating layer, at least about 75%, at least about 50%, and about 15% w / w of the final barrier coating layer. In one embodiment, the barrier coating layer contains a hydrophilic polymer in amounts of about 5% to about 70% w / w of the coating layer, or about 10% to about 50%, or about 15% to about 45% w / w. The use of polyvinylpyrrolidone is described below as a suitable hydrophilic polymer. However, other suitable hydrophilic polymers, such as propylene glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., KOLLIDON® K30), mannitol, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, and sorbitol, can be readily selected.

[0072] Commercially available polyvinyl acetate mixtures primarily consist of polyvinyl acetate polymer, stabilizing components, and small amounts of surfactants such as sodium lauryl sulfate. When the barrier coating contains PVP as a stabilizing component, the final barrier coating layer generally contains about 5 to about 10% w / w of polyvinylpyrrolidone. In a preferred embodiment, the aqueous barrier coating solution is KOLLICOAT® SR 30D (BASF Corporation), whose composition is about 27% PVA polymer, about 2.7% polyvinylpyrrolidone (PVP), and about 0.3% sodium lauryl sulfate (anionic surfactant) (solid content 30% w / w), which is mixed with a plasticizer. Generally, the stabilizing components are present in an amount of less than about 10% w / w in total, preferably less than about 5% w / w. See also U.S. Patents 6,066,334 and 6,026,277, which are incorporated herein by reference. When selecting this product, faster release, as described herein, i.e. To promote release in less than 8 hours, additional hydrophilic polymers may be added. Optionally, the selected surfactant is present in an amount of about 1% or less. In one embodiment, the surfactant is a nonionic surfactant. Optionally, an ionic surfactant may be selected.

[0073] In certain embodiments, the barrier coating layer is formed by applying an aqueous dispersion containing the plasticizer KOLLICOAT® SR-30D, drying, and curing it. Preferably, the coating is cured for about 1 to about 24 hours. In alternative embodiments, the coating is cured at a high temperature, for example, about 50°C to about 65°C, preferably about 60°C, for about 4 to about 16 hours, preferably about 5 hours. See, for example, U.S. Patent Application US2007 / 0215511A and its corresponding application WO2007 / 109104, published on September 20, 2007, the disclosures of which are incorporated herein by reference.

[0074] Other diffusion barrier coating polymers or copolymers may be selected. In such other embodiments, non-aqueous solvent-based ethylcellulose, such as commercially available ETHOCEL® products (DuPont DeNemours) or aqueous SURELEASE® ethylcellulose [Colorcon], may be modified to achieve the barrier coating properties defined herein, for example, by adding a sufficient amount of plasticizer to improve flexibility and / or by curing at a temperature sufficient to achieve a desired release rate. Dow's website states that three of these products, Std7 (viscosity 6-8 mPa-s(CP)), Std10 (9-11 mPa-s(CP)), and Std20 (18-22 mPa-s(CP)) (all with an ethoxyl content of 48.0-49.5%), are useful for tablet coating. Furthermore, it is stated that one of these polymers may be optionally combined with water-soluble surfactants and / or water-soluble excipients such as METHOCEL® cellulose ether and / or CARBOWAX® polyethylene glycol. Alternatively, to achieve the release-controlled barrier coating properties required herein, for example, by adding a sufficient amount of plasticizer to improve flexibility and / or to achieve the desired release rate... By curing at a sufficient temperature, it may be possible to modify the aqueous-based ethylcellulose barrier coating. See, for example, the barrier coatings described in U.S. Patent Nos. 6,066,334 and 6,046,277, and also, for example, U.S. Patent Nos. 6,046,277 and 6,001,392, U.S. Published Patent Application No. 2003 / 0099711 and related applications WO03 / 020242, WO2006 / 022996 and related applications U.S. Published Patent Applications US2005 / 0232986, US2005 / 0232987, US2005 / 0232993, US2005 / 0266032, U.S. Patent Nos. 7,067,116, 6,667,058 and 6,001,392 (these disclosures are incorporated herein by reference).

[0075] Other aqueous or non-aqueous solvent-based systems that do not require curing may be available. For example, aqueous-based acrylic polymers (described herein as mixtures of Eudragit® RL30D and Eudragit® RS30D) benefit from the addition of anti-tack agents to facilitate processing and ensure a uniform coating. Suitable anti-tack agents include, for example, talc, glycerol monostearate (GMS), and mixtures thereof. These agents are present in an amount of about 0.2% to 4.5% w / w, based on the dry weight of the coating polymer applied to form a coating layer of release-regulating components. In certain embodiments, the coating layer obtained from the application of an acrylic polymer-based coating does not require curing.

[0076] In one embodiment, the coating is an acrylate-based copolymer coating material of the EUDRAGIT® brand [e.g., poly(ethyl acrylate-copolymer)]. The polymer system may include [ethyl acrylate-co-methylmethacrylate-co-trimethylammoniumethyl methacrylate chloride]. For example, Eudragit® RS 30D [pH-independent, 30% aqueous dispersion of poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammoniumethyl methacrylate chloride) 1:2:0.1] or Eudragit® RL 30D [30% aqueous dispersion, pH-independent polymer, poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammoniumethyl methacrylate chloride) 1:2:0.2] may be selected as a barrier coating. In one embodiment, a mixture of Eudragit® RS 30D and Eudragit® RL 30D may be prepared to optimize the hydrophilicity or hydrophobicity of the film in order to achieve a desired release profile.

[0077] The diffusion barrier coatings described herein may be applied using techniques described by polymer manufacturers and / or techniques known to those skilled in the art. Suitable methods and apparatus are described in the patent and non-patent documents and include, for example, the use of spraying or pan coating in a fluidized bed apparatus. The coating solution can be sprayed in a fluidized bed apparatus (e.g., a VECTOR™ FLM-1 fluidized bed apparatus) using the Ulster method. The diffusion barrier coating oxibate-anion exchange resin composite (of any choice of matrix) is then dried and / or cured.

[0078] B. Bilayer Small Intestine Targeted Drug Coating System (SITCS) Oxybate Component In addition to sustained-release components, SITCS release-modulating components are provided. In certain embodiments, the composition comprises a bilayer SITCS-coated oxidate-anion exchange resin complex-optional matrix. The SITCS bilayer system comprises a pH-independent barrier coating on the oxidate-anion exchange resin complex-optional matrix, which further comprises a coating layer on the barrier-coated oxidate-anion exchange resin complex comprising a mixture of at least one pH-dependent polymer or copolymer (i.e., enteric coating) and at least one pH-independent diffusion barrier coating polymer or copolymer. In preferred embodiments, the component comprises only two functional coating layers, the barrier coating being an inner layer directly above the oxidate resin complex-optional matrix, and the blended pH-independent / pH-dependent release coating layer being an outer layer.

[0079] In certain embodiments, the blended polymer coating layer comprises two different pH-independent barrier coating polymers / copolymers. In one embodiment, a first pH-independent barrier coating layer is present on an oxidate-anion exchange resin composite. This may be the same as or different from the pH-independent barrier coating layer in the sustained-release component. In certain embodiments, the pH-independent polymer / copolymer in the blended pH-dependent / pH-independent layer, further comprising an enteric polymer / copolymer, is different from the polymer / copolymer used in the pH-independent diffusion barrier coating layer. Preferably, the blended pH-dependent / pH-independent coating layer comprises a mixture of compatible pH-independent polymers / copolymers and pH-dependent enteric coating polymers / copolymers. Examples of suitable polymer / copolymer combinations for a blended pH-dependent / pH-independent coating layer include, for example, polyvinyl acetate (pH-independent, barrier coating) and polyvinyl acetate phthalate (enteric coating), or a methyl acrylic acid copolymer enteric coating polymer and an ethyl acrylate and methyl methacrylate copolymer pH-independent coating polymer. Other suitable combinations may be selected as described herein.

[0080] The blended pH-dependent / pH-independent outer coating ensures that the components reach the small intestine and are exposed to bodily fluids with a pH greater than 4, or in certain embodiments, a pH of 4.5 or higher. To further reduce exposure of the sustained-release coating to bodily fluids, a lag time occurs between administration (oral ingestion) and the onset of oxibate release in the delayed-release component. In certain embodiments, the SITCS component provides a lag time of approximately 1 to 3 hours after administration and a reduction in oxibate release in the acidic medium of the stomach. In certain embodiments, the lag time is approximately 1.5 to 2.5 hours, or approximately 1.75 to 2.5 hours, and is a value between these two.

[0081] In certain embodiments, the blended pH-independent / pH-dependent release coating layer includes a range of about 1:9 to about 9:1, more preferably about 3:7 to about 7:3, and more preferably about 4:6 to about 6:4. In certain embodiments, the blended pH-independent / pH-dependent release coating layer includes, based on the weight of polymers / copolymers in the coating layer, about 40% w / w of pH-dependent enteric coating polymer or copolymer to about 60% w / w of pH-independent diffusion barrier coating polymer or copolymer. In certain embodiments, the blended pH-independent / pH-dependent release coating includes, based on the weight of polymers / copolymers in the coating layer, about 60% w / w of pH-dependent enteric coating polymer to about 40% w / w of pH-independent enteric coating polymer or copolymer. In certain embodiments, the blended pH-independent / pH-dependent release coating layer includes, based on the weight of polymers / copolymers in the coating layer, about 50% w / w of enteric coating polymer / copolymer to about 50% w / w of pH-independent barrier coating polymer / copolymer. Optionally, the blended pH-independent / pH-dependent release coating layer further comprises approximately 0.5% w / w to approximately 10% w / w of plasticizer, as well as one or more homogenizers and / or one or more surfactants.

[0082] Ideally, the pH-dependent enteric polymer component of a blended pH-independent / pH-dependent release coating layer is selected so that the delayed-release coating component allows for the release of oxibate when the dosage form reaches the small intestine or a region where the pH exceeds pH 4, more commonly in the pH range of 4–8. Preferred coating materials are pH-sensitive materials that remain intact in the lower pH environment of the stomach but disintegrate or dissolve at pH levels commonly found in a patient's small intestine. Enteric polymer coating materials begin to dissolve in aqueous solutions at pH approximately 4.5–5.5 and dissolve more rapidly at pH levels above approximately 5.5. The pH dissolution behavior of the enteric polymer in this invention is such that no significant dissolution of the enteric polymer coating occurs until the dosage form is empty from the stomach. The pH of the small intestine gradually increases from approximately 4.5–6.5 in the duodenal bulb to approximately 7.2 in the distal part of the small intestine (ileum). To provide predictable dissolution corresponding to a small intestinal transit time of approximately 3 hours and to enable reproducible release within the small intestine, the coating must begin dissolving within the duodenal pH range and continue dissolving within the small intestinal pH range. Therefore, the amount of enteric-coated polymer coating must be such that it substantially dissolves during a transit time of approximately 3 hours in the small intestine.

[0083] In certain embodiments, this sustained-release component of the blended pH-dependent / pH-independent-release coating layer may be the same sustained-release polymer present in the non-delayed sustained-release coating layer, but in a lower weight percentage.

[0084] In other embodiments, the sustained-release coating layer of the delayed sustained-release component includes a sustained-release polymer system different from that present in the sustained-release component.

[0085] An oxybate-anion exchange resin composite matrix of any choice is prepared as described herein and coated with an inner barrier coating layer. The barrier coating layer may be applied as described for the sustained-release component, but the weight percentage of the barrier coating layer is generally lower than the weight percentage present in the sustained-release component. In certain embodiments, the pH-independent barrier coating layer is based on the coated composite. Therefore, the weight percentage is approximately 10% w / w to approximately 50% w / w, or approximately 20% w / w to approximately 45% w / w. In certain embodiments, the weight percentage is approximately 15% w / w to approximately 50% w / w, or approximately 20% w / w to 50% w / w, or 25% w / w to 40% w / w, or approximately 30% w / w to approximately 45% w / w, approximately 25% w / w, approximately 30% w / w, or approximately 35% w / w.

[0086] In this embodiment, the barrier-coated oxidate-anion exchange resin composite-optional matrix is ​​provided with a second coating layer, which is an outer pH-dependent enteric coating applied on top of the barrier coating layer.

[0087] A variety of delayed-release (enteric-coated) coating materials are known and can be selected. Examples include, for example, cellulose acetate trimellitate, methacrylic acid, methyl methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, sodium cellulose acetate phthalate, starch phthalate, cellulose acetate butyrate, cellulose acetate malate, cellulose acetate propionate, styrene maleate dibutyl phthalate copolymer, styrene maleate polyvinyl acetate phthalate copolymer propionate, shellac, and mixtures thereof. Further enteric polymers include, for example, hydroxypropyl methylcellulose (HPMC) phthalate, HPMC acetate succinate, and pH-dependent acrylate polymers and copolymers, and / or mixtures thereof. Further enteric polymers include, for example, one or more of methacrylic acid copolymer dispersions, ethyl acrylate and methyl methacrylate copolymer dispersions, and / or mixtures thereof. Certain some of these polymers are commercially available in Evonik Industries' EUDRAGIT® product line (e.g., EUDRAGIT® L series (L30 D-55 or L100-55 (solubility above pH 5.5), L100 or L12.5 (solubility above pH 6.0)), or S series (S100, S12.5, FS 30D (solubility above pH 7.0))).EUDRAGIT® L-30-D 55 is an aqueous acrylic resin dispersion, an anionic copolymer derived from methacrylic acid and ethyl acrylate, with a free carboxyl group to ester ratio of approximately 1:1, an average molecular weight of approximately 250,000, and supplied as an aqueous dispersion containing 30% w / w dry lacquer material. In certain embodiments, the pH-dependent polymer or copolymer is selected from one or more of methacrylic acid copolymer, methyl acrylate copolymer, or polyvinyl acetate phthalate, methacrylic acid copolymer dispersion, ethyl acrylate and methyl methacrylate copolymer dispersion, hydroxypropyl methylcellulose (HPMC) acetate succinate, HPMC phthalate, polyvinyl acetate phthalate, and / or mixtures containing them. Other commercially available enteric coating polymers may include hydroxypropyl methylcellulose phthalate HP50 (HPMCP-HP50) (USP / NF220824), HP55 (HPMCP-HP55) (USP / NF type 200731), and HP55S, available from Shin-Etsu Chemical Co., Ltd., COATERIC® (polyvinyl acetate phthalate) (Berwind Pharmaceutical Services, Inc.), SURETERIC® (polyvinyl acetate phthalate) (Colorcon, Ltd.), or AQUATERIC® (cellulose acetate phthalate) (FMC Corp.).

[0088] The enteric coating layer also preferably contains a plasticizer, such as diethyl phthalate or citrate. It may contain triethyl(citroflex-2), triacetin, tributyl sebesate, or polyethylene glycol. Optionally, the anti-fouling agent (anti-aggregating agent) is preferably a hydrophobic material such as talc, magnesium stearate, or fumed silica.

[0089] As discussed above, the blended pH-independent / pH-dependent coating layer further comprises a pH-independent diffusion barrier coating polymer or copolymer, which may be the same or different in the sustained-release barrier layer and the blended coating layer. These may be selected from materials described in other sections of this application. In certain embodiments, the water-insoluble polymer or copolymer is one or more of polyvinyl acetate, ethyl cellulose, or copolymers of ethyl acrylate and methyl methacrylate, and / or mixtures containing them.

[0090] The blended pH-independent and pH-dependent coating layers may contain other components, such as surfactants, pore-forming agents, stabilizers, plasticizers, defoamers, solubilizers, and colorants. If present, these constitute about 5% to 15% by weight of the enteric-coated polymer based on the total weight of the blended coating layer, with a preferred range being about 9% to 12% based on the same weight. Examples of suitable stabilizers may include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, magnesium oxide, calcium oxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, magnesium silicate, magnesium aluminate, magnesium aluminometasilicate, synthetic hydrotalcite, aluminum magnesium hydroxide, meglumine, lysine, ethylenediamine, N,N′-dibenzylethylenediamine, procaine, chloroprocaine, choline, diethanolamine, and mixtures thereof. Suitable pore-forming materials may include, but are not limited to, mannitol, dextrose, sucrose, lactose, HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, mannitol, organic acids, and mixtures thereof. Optionally, colorants or dyes may be incorporated into this outer layer, or another color coat may be applied. These enteric polymer systems can be applied as aqueous or solvent-based systems using suitable coating techniques such as spray coating or pan coating of a barrier-coated oxidate-anion exchange resin composite-optional matrix. After coating, the delayed-release coated, barrier-coated oxidate-anion exchange resin composite-optional matrix is ​​dried and optionally cured.

[0091] In certain embodiments, the total weight of solids in the coating layer of the SITCS-releasing component is about 30% w / w to about 90% w / w, more preferably about 50% w / w to about 80% w / w, based on the total weight of the component. In certain embodiments, the total weight of solids in the SITCS coating is about 35% w / w to about 70% w / w, or about 40% w / w to 65% w / w, or 35% w / w to 75% w / w, or about 45% w / w to about 75% w / w, or about 45% to about 65% w / w. In certain embodiments, the sustained-release coating layer includes about 15% w / w to about 35% w / w, or about 20% w / w to about 35% w / w, or about 25% w / w to about 35% w / w, or about 30% w / w of the total coating in the delayed-release component. In certain embodiments, the blended emission layer is approximately 20% w / w to 80% w / w, 25% w / w to 65% w / w, 30% w / w to 40% w / w of the diffusion barrier coated resinate, or approximately 45% w / w to 75% w / w, 50% w / w to 70% w / w, or 55% w / w to 65% w / w of the coated resinate.

[0092] In certain embodiments, the ratio of the blended pH-independent / pH-dependent coating layer to the pH-independent diffusion barrier coating layer is approximately 10:90 to approximately 90:10. .

[0093] C. Final Formulation The composition may be, for example, a powder, a powder for suspension (POS), a powder in capsules, or a suspension. Excipients for the composition are selected accordingly. For example, excipients in tablets may include binders, diluents, disintegrants, osmotic agents, release-delaying polymers, flow aids, compression aids, lubricants, and / or anti-adhesion agents. Excipients in suspensions and / or ER POS may include suspending agents and / or thickeners, wetting agents, and / or preservatives. Excipients will be described in a later section.

[0094] In certain embodiments, the final product comprises at least (a) an immediate-release component, (b) a sustained-release barrier-coated oxibate-anion exchange resin composite-optional matrix, (c) a SITCS-coated oxibate-anion exchange resin composite-optional matrix, and (d) an equivalent amount of calcium chloride of about 1 milliequivalent to about 12 milliequivalents per 9 gm of oxibate dose of the composition, wherein the POS comprises less than an equivalent amount of 200 mg of total sodium per 9 gm of oxibate dose of the POS, and optional diluent granules.

[0095] Examples of compositions and suitable excipients are described in U.S. Patent No. 11,337,920 and U.S. Patent No. 11,666,546, which are incorporated herein by reference. In certain embodiments, an orally administered composition is provided comprising the GHB components described herein and a floating IPN forming system comprising at least one non-toxic gas generating agent, two or more anionic polymers, and at least one crosslinking agent. In certain embodiments, the composition comprises two or more anionic polymers, based on the total dry components (e.g., POS, powder mixture, or tablet), in amounts of 0.5% w / w to 10 w / w%, or about 0.5% w / w to 5% w / w, or values ​​in between, e.g., about 1% w / w, about 2% w / w, etc. In certain embodiments, the anionic polymers are selected from pectin, gellan gum, carrageenan, or a combination thereof. In certain embodiments, the crosslinking agent(s) may comprise about 0.5% w / w to 15% w / w, or 0.5% w / w to 5% w / w, of the composition, based on the total dry components (e.g., powder mixture). In certain embodiments, the gas generating agent(s) may comprise about 0.5 wt% to about 15 wt%, or about 1 wt% to about 10 wt%, or about 7 wt%, or about 11 wt%, of the composition, based on the total dry components (e.g., powder mixture). In certain embodiments, the gas generating agent is sodium bicarbonate. In certain embodiments, the bicarbonate is potassium bicarbonate. In certain embodiments, the remainder of the composition comprises excipients such as diluents, binders, and disintegrants. One or more anionic polymers may be optionally used in combination with galactomannan and / or other polymers, such as nonionic polymers, to form IPN or semi-IPN. Such anionic polymers may include, but are not limited to, at least each of pectin, alginic acid, gellan gum, carrageenan, xanthan gum, and / or combinations thereof. In certain embodiments, pectin is included. Pectin has a polymer backbone mainly consisting of α-(1-4)-D galacturonic acid residues. Free calcium ions crosslink the galacturonic acid chains. A source of divalent ions, generally calcium ions, is required for the manufacture of drug delivery carriers.The main advantage of using pectin in these formulations is that, being water-soluble, organic solvents are not required in the formulations. Calcium ions may be included in the formulations in the form of a complex to induce crosslinking of pectin. In other embodiments, alginic acid is included. Alginic acid is a linear block copolymer polysaccharide consisting of β-D-mannuronic acid and α-L-glucuronic acid residues linked by 1,4-glycosidic bonds. Diluted aqueous solutions of alginic acid crosslink with divalent and trivalent metal ions by a cooperative process involving consecutive glucuronic acid residues in the α-L-glucuronic acid block of the alginic acid chain. Gellan gum (marketed as Gelrite® or Kelcogel®) is an anionic deacetylated extracellular polysaccharide secreted by Pseudomonas elodea, and contains one α- It has a tetrasaccharide repeating unit consisting of L-rhamnose, one β-D-glucuronic acid residue, and two β-D-glucuronic acid residues. The chemical structure of this polysaccharide has a tetrasaccharide repeating unit consisting of two glucose (Glc) residues, one glucuronic acid (GlcA) residue, and one rhamnose (Rha) residue. Similar to alginic acid and pectin, the gellan gum chain is crosslinked by divalent or trivalent metal ions. Carrageenan is a linear sulfated polysaccharide extracted from edible red seaweed. There are mainly three types of carrageenan, differing in the degree of sulfatedness. Kappa-carrageenan has one sulfate group per disaccharide, iota-carrageenan has two, and lambda-carrageenan has three. Iota-carrageenan is crosslinked by divalent cations, while kappa-carrageenan is crosslinked by monovalent cations. Xanthan gum is an anionic polysaccharide composed of pentasaccharide repeating units containing glucose, mannose, and glucuronic acid in a molar ratio of 2:2:1. In certain embodiments, the IPN-forming system includes one or more anionic polymers in about 1% w / w to about 30% w / w, or about 1% w / w to about 20% w / w, or about 1% w / w to about 15% w / w, or about 1% w / w to about 10% w / w, or about 2%, or about 1% w / w to about 5% w / w, or about 10% w / w to about 30% w / w, or about 15% w / w to about 25% w / w. One or more crosslinking agents suitable for the anionic polymer may be selected from a non-limiting list of divalent and trivalent metal salts, such as calcium salts (e.g., calcium carbonate, calcium chloride, calcium gluconate), magnesium salts, ferrous salts, ferric salts, aluminum salts, zinc salts, or combinations thereof. In certain embodiments, the crosslinking agent may be a counterion derived from an excipient and / or activator. In other embodiments, the crosslinking metal ion may be provided by a crosslinking agent in the composition, or such a metal ion may be provided in the form of a monovalent, divalent, or polyvalent metal ion salt. Otherwise, such a crosslinking metal ion may be provided by an excipient. For example, calcium carbonate can be used as a gas generator, but calcium ions also provide for crosslinking anionic polymers, including pectin, carrageenan iota, gellan gum, xanthan gum, and the like.In certain embodiments, the IPN forming system comprises approximately 0.5% w / w to approximately 15% w / w of anionic polymer(s) crosslinking agent(s), or approximately 0.5% w / w to approximately 5%, or 0.7% to approximately 1.5%, or approximately 1%.

[0096] In certain embodiments, the composition includes a gas-generating agent. As provided herein, “gas-generating agent” refers to an agent that generates a non-toxic gas upon contact with gastric juice. Suitable gas-generating agents include, but are not limited to, alkali metal or alkaline earth metal carbonates or bicarbonates such as potassium carbonate or potassium bicarbonate, sodium carbonate or sodium bicarbonate, calcium carbonate, sodium glycine carbonate, magnesium carbonate, and aluminum carbonate, as well as sulfites such as sodium sulfite, sodium bisulfite, and sodium metabisulfite. These salts may be used alone or in combination with an acid source as a gas-generating pair.

[0097] In one embodiment, silicon dioxide (Syloid® 244FP) is provided in an amount of about 0.001% to about 1% w / w. In one embodiment, sodium methylparaben is provided in an amount of about 5.26% to about 10% w / w. In one embodiment, sodium propylparaben is provided in an amount of about 1.05% to about 2% w / w. In one embodiment, povidone USP (Kollidon® K30) is present in an amount of about 1% w / w to about 15% w / w. In one embodiment, sucralose is provided in an amount of about 0.01% w / w to about 3% w / w, or about 0.5% w / w to about 2% w / w, or about 1% w / w to about 2% w / w, or about 1.5% w / w, or about 9.47% to 18% w / w. In one embodiment, carrageenan is provided in an amount of about 0.25% w / w to about 5% w / w, or about 0.5% w / w to about 2% w / w, based on the total weight of solids in the composition (e.g., POS). In one embodiment, potassium bicarbonate is provided in an amount of about 5% w / w to about 30% w / w, or about 7.27% w / w to about 11.82% w / w, based on the total weight of solids in the composition. One embodiment In one embodiment, gellan gum is provided in an amount of about 0.5 w / w to about 12.22% w / w (based on the total weight of solids in the composition). In one embodiment, calcium chloride is provided in an amount of about 0.5% w / w to about 10% w / w, or about 0.5% w / w to about 5% w / w, or about 1% w / w (based on the total weight of solids in the composition). In one embodiment, calcium chloride dihydrate is provided in an amount of about 1 to 5% w / w. In one embodiment, Eudragit L100, which is a copolymer (1:1) of methacrylic acid and methyl methacrylate, is provided in an amount of about 1% w / w to about 5% w / w. In one embodiment, microcrystalline cellulose, hypromellose, and / or mannitol are provided in an amount of about 15% w / w to about 40% w / w (based on the total weight of solids in the composition). In other embodiments, larger or smaller amounts are selected.

[0098] One or more super-disintegrants can be selected from low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fibers, cross-linked polyvinylpyrrolidone, cross-linked polyacrylic acid, cross-linked amberlite resin, alginates, colloidal magnesium aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinized starch, and sodium carboxymethyl starch. Suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinylpyrrolidone (PVP), copovidone, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (CMC)), and their salts. Suitable diluents include, but are not limited to, starch, dicalcium phosphate, microcrystalline cellulose, lactose monohydrate, dextrose monohydrate, and the like. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. The composition may optionally also include, but is not limited to, flow enhancers such as colloidal silica, silica gel, precipitated silica, or combinations thereof.Suitable examples of osmotic agents or pharmaceutically acceptable inert water-soluble compounds are selected from the group including carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose, and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and trisodium phosphate; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, and methionine; urea or its derivatives; propylene glycol, glycerin, polyethylene oxide, xanthan gum, hydroxypropyl methylcellulose, or mixtures thereof.

[0099] For example, one or more desired excipients, including flavorings, sweeteners, viscosity improvers, flow aids, pH adjusters, preservatives, or other excipients, may be blended into the final powder mixture or added to the suspension. Optionally, one or more excipients may be included as diluent granules in the final suspension powder mixture, thereby facilitating the reconstruction of particulate oxidative oxybate-anion exchange resin complexes, particulate barrier coating oxidative oxybate-anion exchange resin complexes, and optionally providing agents that improve powder flow (e.g., flow promoters), sweeteners or other flavorings, or suspending agents. In one embodiment, the diluent granules include buffer species used to control the pH in the liquid suspension formulation. Optionally, the diluent granules may include one or more other excipients, such as flow promoters, flavorings, preservatives, suspending agents, or mixtures of such excipients.

[0100] In certain embodiments, the composition is a blended mixed particulate powder for suspension. In certain embodiments, the powder is formulated into a solid dosage form selected from capsules, tablets, molded tablets, pellets, layered tablets, or tablets within tablets. In certain embodiments, a composition is provided in which a single dose of oxibate has a therapeutic effect over a period of about 5 to 8 hours.

[0101] As discussed above, the immediate-release component advantageously avoids the use of any oxibate salt, e.g., free API. The sustained-release component comprises a pH-independent diffusion barrier coating layer having a water-insoluble film-forming polymer that imparts sustained release to oxibate in the matrix of the complex—of choice. The bilayer SITCS component comprises an inner coating layer and an outer coating layer on top of a matrix of a cholestyramine anion exchange resin complex—of choice, which contains oxibate bound to the ion exchange site of the oxybate-cholestyramine anion exchange resin. If the complex is present in the matrix, it further comprises at least one hydrophilic or hydrophobic polymer.

[0102] The first (e.g., inner) coating layer is a pH-independent diffusion barrier coating layer having a water-insoluble film-forming polymer that imparts sustained release to oxibate in the complex (optional matrix), the second coating layer is a blended coating layer on top of the pH-independent diffusion barrier coating layer that includes a mixture of pH-dependent polymers and pH-independent polymers / copolymers, and the pH-dependent release coating layer imparts delayed release to the oxibate-cholestyramine anion exchange resin-optional matrix, including the pH-independent barrier coating inner layer.

[0103] In certain embodiments, the composition is a suspension powder that has a therapeutic effect for at least about 5 to about 8 hours after oral ingestion by a patient (human subject). The formulations provided herein may be packaged, stored, and shipped as powders designed to be reconstituted with an aqueous liquid (e.g., drinking water) before being administered as a liquid suspension. In other embodiments, two or more different types of oxybate-anion exchange resin complex components may be formulated together into solid tablets or filled into capsules.

[0104] As an additional safety feature, the composition may further contain a pharmaceutically acceptable dye that dissolves when the composition is placed in an aqueous liquid to provide a specific color.

[0105] 1. Powdered formulation To provide a final powder formulation suitable for reconstitution in water, the powdered oxidate-anion exchange resin complex can be mixed with excipients. Such excipients may be one or more flow promoters or lubricants, one or more preservatives, pH buffers, thickeners, or combinations thereof, and the powder is packaged in appropriate packaging (e.g., aluminum foil sachets) or bottles. In certain embodiments, the powder includes a buffer designed to adjust the pH to a range of about 4 to about 8, or about 5.5 to 7.5, or about 6.0.

[0106] Optionally, one or more desired excipients, including, for example, flavorings, sweeteners, viscosity improvers, flow promoters, pH adjusters, preservatives, or other excipients, may be blended into the final powder mixture or added to the suspension. Optionally, one or more excipients may be included in the final suspension powder mixture as diluent granules, thereby facilitating the reconstitution of particulate oxidative oxybate-anion exchange resin complexes, particulate barrier coating oxidative-anion exchange resin complexes, and particulate STICS coating oxidative-anion exchange resin complexes, and optionally, providing agents that improve powder flow (e.g., flow promoters), sweeteners or other flavorings, or suspending agents. In one embodiment, the diluent granules are liquid It contains buffer species used to control the pH in the suspension formulation. Optionally, the diluent granules may contain one or more other excipients, such as flow enhancers, flavoring agents, preservatives, suspending agents, or mixtures of such excipients.

[0107] 2. Tablet formulations Oxybate tablets may be prepared using the three components described above, a solid oxibate-anion exchange resin complex-optional matrix, and one or more fillers, one or more disintegrants, one or more binders, one or more buffers, one or more lubricants, one or more flow enhancers, one or more diluents, super-disintegrants, osmotic agents, release retarders, flow aids, compression aids, lubricants and / or anti-adhesion agents, or one or more combinations of these components. Preferably, the tablets also include flavor and / or mouthfeel enhancers, such as one or more sweeteners, flavorings, gums, or mixtures of these components.

[0108] In one embodiment, the tablets are formulated as orally disintegrating tablets. Such orally disintegrating tablets may disintegrate in the mouth in less than about 30 seconds. In another embodiment, the tablets are formulated as chewable tablets. Typically, chewable tablets will contain fillers or mixtures of fillers in the range of about 10% w / w to about 90% w / w, about 50% w / w to about 85% w / w, or about 50% w / w to about 70% w / w of the total weight of the tablet. Suitable fillers may include, for example, mannitol, lactose, maltose, fructose, sucrose, xylitol, maltitol, microcrystalline cellulose, dicalcium phosphate, guar gum, xanthan gum, tragacanth gum, pregelatinized starch, compressible sugars, calcium carbonate, magnesium carbonate, calcium sulfate, dextrate, and maltodextrin. In one embodiment, the chewable tablet contains a mixture of mannitol, xanthan gum, microcrystalline cellulose, and guar gum in an amount of about 60% w / w to about 75% w / w. In one embodiment, the gum or combination of gums is provided in an amount of about 0.25% w / w to about 5% w / w, or about 0.25% to about 1% w / w. In another embodiment, the microcrystalline cellulose is provided in an amount of about 5% w / w to about 25% w / w, or about 10% w / w to about 15% w / w, based on the total weight of the tablet, before the non-functional coating. Products containing a combination of microcrystalline cellulose and guar gum are marketed as AVICEL® and contain a ratio of 80 parts by weight of microcrystalline cellulose to 20 parts by weight of guar gum. This mixture of microcrystalline cellulose (MCC) and guar gum may be present in an amount of about 5% w / w to about 25% w / w of the total weight of the tablet. The chewable tablets also contain a disintegrant or mixture of disintegrants in the range of about 1% w / w to about 25% w / w, or about 5% w / w to about 15% w / w, or about 10% w / w to about 14% w / w, based on the total weight of the tablet. Suitable disintegrants include, for example, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose sodium, and carboxymethylcellulose calcium starch. In one embodiment, the tablets described herein contain crospovidone in the range of about 5% w / w to about 10% w / w, or about 12% w / w, based on the weight of the tablet before the application of a non-functional coating.

[0109] The binder may be absent (i.e., 0%) or optionally present in an amount of approximately 1% w / w to approximately 15% w / w of the total weight of the tablet. Examples of suitable binders include polyvinylpyrrolidone (povidone), hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, starch, acacia, alginic acid, and sodium alginate.

[0110] In one embodiment, the tablets contain sweeteners in amounts of about 0.01% w / w to about 3% w / w, or about 0.5% w / w to about 2% w / w, or about 1% w / w to about 2% w / w, or about 1.5% w / w, based on the total weight of the tablets excluding any optional non-functional coatings. Suitable sweeteners include, for example, aspartame, saccharin, sodium saccharin, sucralose, sodium cyclamate, xylitol, potassium acesulfamate, and mixtures thereof. It may include the following. Optionally, the excipient may function as a filler in addition to functioning as a sweetener. Examples of suitable sweeteners / fillers include, for example, fructose, sucrose, xylitol, and maltitol. Optionally, if it performs both functions, the excipient may be present in amounts exceeding approximately 10% w / w of the tablet. In such cases, additional sweeteners may be omitted (e.g., present when the added sweetener is 0%). Alternatively, a combination of sweeteners different from the second sweetener or filler may be added in the amounts provided in this paragraph to further enhance the flavor.

[0111] Ideally, the tablets are supplied with a buffer in an amount of about 0.1% w / w to about 5% w / w, or about 0.5% w / w to about 1.5% w / w, based on the total weight of the tablets. Examples of suitable buffers include, for example, citric acid, tartaric acid, malic acid, lactic acid, and their acceptable salts, as well as mixtures thereof.

[0112] If additional flavorings are added, the flavoring(s) may be added in amounts of approximately 0.05% w / w to approximately 3% w / w, or approximately 0.1% to approximately 1% w / w, or approximately 0.5% w / w, based on the total weight of the tablet (excluding any optional non-functional coatings). Suitable flavorings may include both natural and artificial flavorings, such as those commonly available from several custom manufacturers worldwide, including Fona International [Illinois, USA], Givaudan International (Vernier, Switzerland), Ungerer & Company (Lincoln Park, New Jersey), and International Flavors & Fragrances (New York, New York). Those skilled in the art will recognize that several commercial sources, including custom blenders, are available. Flavorings may be blended before being added to the pharmaceutical composition or added separately. Further flavorings may be selected, such as bubblegum, cherry, strawberry, vanilla, grape, banana, and other flavors or mixtures thereof.

[0113] Optionally, colorants may be provided to the tablets to provide desired visual appeal or trade dress. Such colorants may be added in amounts ranging from about 0.001 to about 1% w / w, or about 0.01% w / w to about 0.08% w / w, or about 0.05% w / w, based on the total weight of the tablet (excluding any non-functional coatings). Such colorants are available from various sources, including, for example, Colorcon (Harleysville, Pennsylvania, USA), Lubrizol Pharmaceuticals (UK), and Spectra Colourtech (Pvt Ltd, India). In one embodiment, no colorant is used in the tablets.

[0114] Excipients such as lubricants and flow enhancers may be used to facilitate the manufacture of chewable tablets. Lubricants may be used in amounts of about 0.1% w / w to about 5% w / w, about 0.2% w / w to about 4.5% w / w, or about 1.5% w / w to about 3% w / w of the total weight of the tablet. Examples of lubricants may include, for example, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, calcium stearate, magnesium trisilicate, polyethylene glycol, and mixtures thereof. In one embodiment, a flow enhancer may be used in amounts of about 0.01% w / w to about 0.5% w / w, or about 0.1% w / w to about 0.3% w / w, based on the total weight of the tablet. Examples of suitable flow enhancers include, for example, silicon dioxide and tricalcium phosphate. In one embodiment, the flow accelerator is silicon dioxide, used in an amount of about 0.001% w / w to about 0.3% w / w or about 0.2% w / w.

[0115] Optionally, other excipients may be selected from conventional pharmaceutically acceptable carriers or excipients and well-established techniques. Such conventional carriers or excipients include, but are not limited to, diluents, binders and adhesives (i.e., cellulose derivatives and acrylic derivatives), lubricants (i.e., magnesium stearate or calcium stearate, or vegetable oils). These include various materials such as polyethylene glycol, talc, sodium lauryl sulfate, polyoxyethylene monostearate, thickeners, solubilizers, humectants, disintegrants, colorants, flavorings, stabilizers, sweeteners, and buffers and adsorbents for preparing certain pharmaceutical compositions. Stabilizers may include preservatives and antioxidants, among other components readily apparent to those skilled in the art. [Table 1]

[0116] Further suitable excipients may be selected in consideration of the teachings provided herein.

[0117] Excipients for suspensions The compositions described herein are typically administered in the form of suspensions from powders mixed with a suspension base, preferably an aqueous suspension base. As used herein, an aqueous suspension refers to a suspension in which at least about 50% w / v of the liquid component of the suspension is water, preferably more than about 60% w / v, more than about 80% w / v, and at least about 90% to 100% is water. The suspension base may further contain binders, diluents, salivary gland stimulants, surfactants, flavors, sweeteners, colorants, acidulants, viscosity modifiers, flow promoters, chelating agents, lubricants, solubilizers, stabilizers, suspending agents, preservatives, cosolvents, anticaking agents, buffers, etc., or any combination thereof. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinylpyrrolidone, copovidone, cellulose derivatives (e.g., hydroxypropyl methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose), and salts thereof. Examples of suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, xylitol, mannitol (e.g., Pearlitol® 100SD), maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dicalcium phosphate, coprocessed mannitol, and calcium silicate, or any combination thereof. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. Suitable flow enhancers include, but are not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. Suitable salivary secretion enhancers include, but are not limited to, micronized polyethylene glycol, sodium chloride, or precipitated micronized silica.Examples of solubilizers include, but are not limited to, cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glycerol monostearate, isopropyl myristic acid, lecithin, medium-chain glycerides, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ethers, polyoxyethylene castor oil glycosides, polyoxyethylene sorbitan fatty acid esters, polyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid esters, stearic acid, sunflower oil, triethanolamine, or combinations thereof. Acidulants include, but are not limited to, sodium fumarate and / or citric acid. The composition also includes, but is not limited to, stabilizers such as those described above under drug-resin complexes. Suitable chelating agents that may be used are discussed above herein.Suitable viscosity modifiers include, but are not limited to, co-treated microcrystalline cellulose such as Avicel RC591, Avicel CL-611, and D-sorbitol solution; polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and microcrystalline cellulose; and, but are not limited to, gum arabic, alginate, agar, sodium alginate, guar gum, carob, carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan, and maltodextrin. Gums such as galactomannan, pustrane, laminarin, scleroglucan, gum arabic, inulin, karaya, welan, etc., polyols such as dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol, and glycerol, etc., carbopols such as pregelatinized starch, acrylic acid and methacrylic acid polymers and their esters, maleic anhydride polymer, starch, and starch-based polymers, polymaleic acid, poly(acrylamide), poly(olefin alcohol), poly(N-vinyl lactam), polyoxyethylated sugars, polyoxy. Suitable surfactants include, but are not limited to, sazolin, polyvinylamine, polyvinyl acetate, polyimines, povidone (e.g., povidone USP (marketed as Kollidon® K30)), vinylpyrrolidone / vinyl acetate copolymer and polyvinyl acetate, mixtures of polyvinyl acetate and polyvinylpyrrolidone, chitin, cyclodextrin, gelatin, chitosan, etc., or any mixture thereof. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants, or mixtures thereof.The nonionic surfactants used in the composition include ethoxylated fatty acid esters, ethoxylated fatty acid ethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerol esters, glycerol sugar esters, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene-20-cetyl stearate, polyoxyethylene-25-cetyl stearate, polyoxyethylene (25)-oxypropylene monostearate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-16-tert-octylphenol, polyoxyethylene-20-cetyl ether, polyethylene glycol (1000) monocetyl ether, ethoxylated castor oil, and polyoxyethylene sorbitol-lanolin derivative. The conductor may include, but is not limited to, PEG sorbitan fatty acid esters such as PEG-20 sorbitan monostearate (Tween 20), PEG-20 sorbitan monostearate (Tween 60), PEG-20 sorbitan monooleate (Tween 80), sorbitan fatty acid esters such as sorbitan monolaurate (Span 20), glyceryl stearate (Cithrol GMS), and mixtures thereof. Suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds, alkylamidoamines and quaternary ester compounds, distearyldimethylammonium chloride, dimyristyldimethylammonium chloride, dipalmityldimethylammonium chloride, and mixtures thereof.Suitable anionic surfactants include, but are not limited to, fatty alcohol sulfates, alpha-olefin sulfons, sulfosuccinates, phosphate esters, carboxylates, sarcosinates, alkylbenzene sulfons, alkyl sulfons, olefin sulfons, alkyl ether sulfons, glycerol ether sulfons, α-methyl ester sulfons, sulfonic acid fatty acids, alkyl sulfates, fatty alcohol ether sulfates, glycerol ether sulfates, mixed hydroxy ether sulfates, monoglyceride (ether) sulfates, fatty acid amide (ether) sulfates, sulfosuccinates, sulfosuccinates, sulfotriglycerides, amide soaps, ether carboxylic acids, isethionates, sarcosinates, taurids, alkyl oligoglycoside sulfates, alkyl (ether) phosphates, and mixtures thereof. Suitable amphoteric surfactants to be used include, but are not limited to, N-alkyl-N,N-dimethylammonium glycinates, such as cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinate, cocoacylaminoethylhydroxyethyl carboxymethyl glycinate, and mixtures thereof. Furthermore, the compositions of the present invention may further contain, but are not limited to, preservatives such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium methylparaben, sodium propylparaben, and sodium benzoate. Suitable cosolvents that may be used include, but are not limited to, ethanol and polyhydric alcohols such as glycerin, propylene glycol, and low molecular weight polyethylene glycol, and mixtures thereof. Further anticaking agents that may be optionally incorporated include colloidal silicon dioxide (e.g., Syloid® 244FP) and triphosphate. The composition may include, but is not limited to, calcium, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof. Suitable sweeteners may include, but are not limited to, aspartame, stevia extract, licorice, saccharin, sodium saccharin, acesulfame, sucralose, dipotassium glycyrrhizinate, galactose, fructose, high-fructose corn syrup, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch, corn syrup solids, sorbitol, xylitol, mannitol, or mixtures thereof. The composition may also include, but is not limited to, one or more natural and / or artificial flavors such as mint flavor, orange flavor, lemon flavor, strawberry flavor, vanilla flavor, raspberry flavor, cherry flavor, tutti frutti flavor, Magna Sweet 135, key lime flavor, grape flavor, Tolcylart 511815, and fruit extracts. Suitable colorants include, but are not limited to, pigments and dyes such as FD&C Red, FD&C Yellow, FD&C Green, and FD&C Blue, titanium dioxide, or combinations thereof.

[0118] In certain embodiments, the compositions described herein are storable at room temperature to maintain their physical stability for about 18 to about 24 months. In certain embodiments, the compositions described herein are storable at room temperature to maintain their chemical stability for about 18 to about 24 months. In certain embodiments, the composition is a powder formulated for reconstitution in water. In certain embodiments, the storable solid oxibate composition is a reconstituted aqueous liquid suspension that provides therapeutic levels of oxibate for about 3 to about 8 hours after oral ingestion of the reconstituted aqueous liquid suspension.

[0119] In one particular embodiment, ER oxybate POS provides a dose equivalent to 4.5 g of sodium oxybate once night. In another embodiment, ER oxybate POS provides a dose equivalent to 6.0 g of sodium oxybate once night. In yet another embodiment, ER oxybate POS provides a dose equivalent to 7.5 g of sodium oxybate once night. In one particular embodiment, ER oxybate POS provides a dose equivalent to 9.0 g of sodium oxybate once night. POS comprises a mixture of oxybate-containing particles having the following different release profiles. (a) Immediate-release oxidate-anion exchange resin composite multiparticles containing oxidate bound to the ion exchange site of an anion exchange resin; (b) pH-independent diffusion barrier coated oxidate-anion exchange resin composite-optional matrix multiparticles, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer that imparts sustained release to the oxidate, and the pH-independent diffusion barrier coating layer is located on the oxidate-anion exchange resin composite-optional matrix; and (c) Bilayer SITCS oxidate multiparticles comprising a blended pH-independent / pH-dependent release coating layer on the pH-independent diffusion barrier coated oxidate-anion exchange resin composite-optional matrix of (b), wherein the bilayer coating layer comprises a mixture of pH-dependent polymers and pH-independent polymers, and the SITCS bilayer coating imparts delayed and sustained release to the oxidate in the oxidate-anion exchange resin composite-optional matrix, which comprises a first pH-independent barrier coating inner layer. The oxybate-anion exchange resin complex-optional matrix of each of these components may be the same or different from one another. The POS optionally further comprises diluent granules.

[0120] In certain embodiments, the ER oxidative composition provides a dose equivalent to 6 g of sodium oxidative. In certain embodiments, the ER oxidative composition provides a dose equivalent to 7.5 g of sodium oxidative. In certain embodiments, the ER oxidative composition provides a dose equivalent to 8 g of sodium oxidative, once per night. In certain embodiments, the ER oxidative composition provides a dose equivalent to 9 g of sodium oxidative, once per night. In certain embodiments, the ER oxidative composition This provides a dose equivalent to 10 g of sodium oxidate, once per night. In a particular embodiment, the ER oxidate composition provides a dose equivalent to 11 g of sodium oxidate, once per night. In a particular embodiment, the ER oxidate composition provides a dose equivalent to 12 g of sodium oxidate, once per night.

[0121] In certain embodiments, the compositions herein provide a pharmacokinetic profile of oxybate in which the ratio of the arithmetic mean maximum plasma concentration peak (Cmax) at 5 hours post-ingestion (C5) to the arithmetic mean plasma concentration (Cmax / C5 ratio) is less than 5, when determined at least about 2 hours after dietary conditions in a patient after oral ingestion of an oral suspension.

[0122] In certain embodiments, administration of the compositions provided herein provides a pharmacokinetic profile of oxibate having one or more of Cmax, AUCinf, and / or Tmax or Cmax. AUCinf and / or Tmax are 80%–125%, 90%–115%, or 95%–110% of the values ​​in the following table when determined after a single dose of 9 g to a patient: [Table 2]

[0123] In a particular embodiment, the oxybate ER POS provided herein at a dose equivalent to 9 g of oxybate provides the following oxybate pharmacokinetic profile in adults after administration. When calculated using the arithmetic mean, the Cmax ranges from 87.98 μg / mL to 126 μg / mL, or approximately 107 μg / mL; from 85.6 μg / mL to 133.76 μg / mL; or from 77.04 μg / mL to 117.711 μg / mL; and / or When calculated using the arithmetic mean, the AUCinf is 518.20 hours*μg / mL to 719.725 hours*μg / mL, or approximately 575 hours*μg / mL, or 304.11 to 846.67, 460.62 hours*μg / mL to 719.725 hours*μg / mL, and / or When calculated using arithmetic mean time, Tmax is approximately 1.944 hours to 2.376 hours, approximately 2 hours, or 1.2 hours to 3 hours, or 1.728 hours to 2.7 hours.

[0124] When calculated using the geometric mean, the Cmax is approximately 105 μg / mL, or 84.38 μg / mL to 131.84 μg / mL, 94.92 μg / mL to 116.01 μg / mL, and / or when calculated using the geometric mean, the AUCinf is approximately 520 hours* μg / mL, or 428.58 hours* μg / mL to 669.66 hours* μg / mL, or approximately 482.16 hours* μg / mL to 589.30 hours* μg / mL, and / or When calculated using the geometric mean, it takes approximately 2 hours, or 1.59h to 2.49h. Alternatively, the Tmax is approximately 1.79 to 2.19 hours.

[0125] "Cmax" is the observed maximum plasma concentration, calculated as the geometric or arithmetic mean of individual maximum plasma concentrations. The term "C5" refers to the plasma concentration 5 hours after administration.

[0126] For the purposes of this invention, the term "mean maximum plasma concentration" (mean Cmax) is defined as the maximum mean plasma drug concentration.

[0127] "Mean plasma concentration" can be calculated as either arithmetic mean plasma level or geometric mean plasma concentration.

[0128] The term "Tmax" refers to the time at which the peak (maximum) plasma drug concentration is observed for each individual participating in a bioavailability study. This can be calculated using geometric or arithmetic methods.

[0129] The terms "AUC0-∞" or "AUCinf" refer to the mean area under the plasma concentration-time curve extrapolated to infinity. This is calculated as the arithmetic mean of the area under the plasma concentration-time curve extrapolated from time 0 to infinity, calculated for each individual participating in the bioavailability study. The release profile may be evaluated via in vitro lysis using techniques known to those skilled in the art [e.g., USP basket method, paddle method, channel flow method, or other methods known in the literature]. The release profile may be evaluated in vivo (e.g., for bioavailability determination) using plasma concentrations to assess maximum plasma concentration (Cmax) and area under the curve (AUC). Such assays are well known to those skilled in the art [see, for example, W. Wargin, et al., Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther 1983 August 226:382-386].

[0130] In certain embodiments, the ratio of oxybate in the immediate-release component (i.e., oxybate-anion exchange resin composite-optional matrix) to oxybate in the combined release-modulating component is approximately 1:10 to approximately 10:1, or approximately 1:5 to approximately 5:1, or approximately 1:2 to approximately 2:1, or approximately 1:2, or approximately 1:1. This ratio is determined based on the weight of uncompounded oxybate (free oxybate) in each component, rather than the weight of the entire composite.

[0131] In certain embodiments, the ratio of oxybate in the barrier-coated oxybate-anion exchange resin composite-optional matrix to oxybate in the pH-dependent enteric-coated barrier-coated oxybate-anion exchange resin composite-optional matrix is ​​approximately 1:2 to 2:1, or approximately 1 to approximately 1.

[0132] In certain embodiments, the combination of the barrier-coated oxybate-anion exchange resin composite-optional matrix to the enteric-coated barrier-coated oxybate-anion exchange resin composite-optional matrix is ​​about 65 to about 90 parts by weight, or about 75 to about 85 parts by weight, based on the total weight of oxybate in the powder. In certain embodiments, the immediate-release oxybate-anion exchange resin composite-optional matrix is ​​about 15 to about 35 parts by weight, or about 20 to about 30 parts by weight, based on the total weight of oxybate in the composition.

[0133] The composition can be formulated in appropriate doses, taking into account the patient's age and the condition being treated. In one embodiment, the composition contains oxybate equivalent to 4.5 g of sodium oxybate. The present invention provides a suspension powder that provides a dosage. In another embodiment, the composition provides a suspension powder that provides an oxidate dosage equivalent to 6 g of sodium oxidate. In another embodiment, the composition provides a suspension powder that provides an oxidate dosage equivalent to 7.5 g of sodium oxidate. In another embodiment, the composition provides a suspension powder that provides an oxidate dosage equivalent to 9 g of sodium oxidate. In another embodiment, the composition provides a suspension powder that provides an oxidate dosage equivalent to 12 g of sodium oxidate.

[0134] Method of Use and Treatment In certain embodiments, this specification provides an oral suspension powder (POS) of low sodium sustained-release (ER) oxibate containing less than 200 mg of sodium and 1 to 12 milliequivalents of calcium chloride, providing oxibate for once-night administration. The oxibate ER POS comprises a mixture of oxibate-resinate particles having different release profiles as defined by (a) and (b): (a) an immediate-release (IR) oxibate-anion exchange resin complex bound to the ion exchange site of an anion exchange resin; and (b) a pH-independent diffusion barrier coated matrix of the oxibate-anion exchange resin complex of choice, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer that imparts sustained release to the oxibate, and the pH-independent and / or pH-dependent diffusion barrier coating layer lies on the matrix of the oxibate-anion exchange resin complex of choice. The composition optionally further comprises diluent granules.

[0135] This specification provides pharmaceutical compositions and formulations useful for treating GHB-responsive conditions, such as fibromyalgia and sleep disorders including apnea, sleep duration disorders, narcolepsy, excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic hallucinations, sleep-wake cycles, insomnia, and nocturnal myoclonus.

[0136] This specification provides pharmaceutical compositions and formulations containing a 10% to 80% w / w oxybate reginate immediate-release component, a 5% to 70% w / w oxybate reginate sustained-release component, and less than 200 mg of sodium per 9 gm dose.

[0137] This specification provides pharmaceutical compositions and formulations comprising 10% to 80% w / w of an oxybate immediate-release component, 5% to 70% w / w of an oxybate reginate sustained-release component, less than 200 mg of sodium per 9 g dose, and 75 mg (1 milliequivalent) to 882 mg (12 milliequivalents) of calcium chloride.

[0138] In certain embodiments, the reduction of sodium content involves using a manufacturing process that reduces the sodium content in the oxybate reginate sustained-release formulation to achieve a desired solubility profile for the drug reginate sustained-release particles of the coated final product.

[0139] In another embodiment, the pharmaceutical composition of the oxybate reginate ER formulation comprises a mixture of sodium ions and calcium chloride to achieve a desired solubility profile.

[0140] In another embodiment, the pharmaceutical composition is administered to the patient as a once-night sustained-release powder for suspension. The required amount for redispersion is 20 mL to 300 mL, 50 mL to 300 mL, 100 mL to 250 mL, or 175 mL to 225 mL.

[0141] In an additional embodiment, a method for treating narcolepsy and related disorders and symptoms in a patient in need is to administer an oral pharmaceutical composition containing gamma-hydroxybutyrate once night. The composition may contain and have dose-proportionality. A formulation composition for one or more concentrations (1 g, 4.5 g, 6 g, 7.5 g, and 9 g) may have dose-proportionality to higher concentrations. The Cmax of the composition may have dose-proportionality over one or more of the 1 g, 4.5 g, 6 g, 7.5 g, and 9 g doses of the composition.

[0142] This specification provides uses and methods for treating conditions suitable for treatment with oxibate, such as those discussed below, by administering an effective amount of one or more dosage forms (e.g., suspensions reconstituted from POS). In certain embodiments, the dosage forms described herein can be administered to treat a person suffering from narcolepsy, idiopathic insomnia, to alleviate cataplexy and / or excessive daytime sleepiness (EDS), apnea, sleep paralysis, hypnagogic hallucinations, sleep-wake cycles, insomnia, and nocturnal myoclonus. In yet another embodiment, the dosage forms of the present invention can be administered to a person, particularly an elderly person (over 50 years of age), to improve sleep quality or in a condition where an increase in growth hormone levels in vivo is desired. In a certain embodiment, the formulations and pharmaceutical compositions provided herein can be used to treat conditions that respond to GHB, such as fibromyalgia.

[0143] In another embodiment, the pharmaceutical compositions and / or formulations disclosed herein can be used to treat diseases or conditions selected from the group consisting of sleep disorders, drug abuse, alcohol and opioid withdrawal, decreased growth hormone levels, anxiety, analgesia, neurological disorders (e.g., Parkinson's disease and depression), endocrine disorders, tissue hypoxia or anoxia (e.g., due to stroke or myocardial infarction), or elevated intracranial pressure levels. The dosage forms described herein may be provided as kits comprising containers separately packaged in sachets or other suitable packaging containing an effective amount of the oxibate powder composition. For example, the powder may be packaged in an aluminum foil envelope or blister pack. The powder can be packaged in many forms, with or without a desiccant or other material to prevent water ingress. Means such as instructional materials or printed labels may also be included for administration over a pre-selected period and / or at pre-selected intervals to deliver a desired level of sodium oxibate in vivo over a pre-selected period and / or to treat a pre-selected condition.

[0144] A kit for treating a patient with an oxibate composition, the kit comprising (a) a container containing the oxibate composition described herein, (b) a syringe, (c) a measuring cup, (d) a press-in bottle adapter, (e) a dosing cup, and optionally, at least one empty drug container having a child safety cap.

[0145] A daily dose of a composition containing an equivalent amount of sodium oxybate, approximately 1 mg / kg to approximately 50 mg / kg, provided herein can be administered to achieve the desired therapeutic outcome. For example, a daily dose equivalent to approximately 0.5 g to 20 g of sodium oxybate, preferably approximately 1 to 15 g, can be administered as a single dose. In other embodiments, the dose may range from approximately 1.5 g to approximately 12 g per night, or approximately 4.5 g to approximately 9 g, or approximately 6 g per night, based on the equivalent amount of sodium oxybate.

[0146] The compositions described herein may be useful in treating a variety of conditions suitable for sodium oxidate treatment, such as narcolepsy, to reduce cataplexy and / or daytime sleepiness, to improve sleep quality, or in conditions where an increase in growth hormone levels in vivo is desired, and to treat fibromyalgia or chronic fatigue syndrome. The dosage forms of the present invention may be useful in treating drug and alcohol abuse, anxiety, cerebrovascular disease, central nervous system disorders, neurological disorders including Parkinson's disease and Alzheimer's disease, multiple sclerosis, autism, depression, inflammatory diseases (including inflammatory bowel diseases such as irritable bowel syndrome, focal ileitis and ulcerative colitis), and autoimmune diseases. It can be used to treat inflammatory diseases, certain endocrine disorders, and many other indications, including diabetes.

[0147] The composition may be administered for tissue protection purposes, including protection after hypoxia / anoxia, such as protection after increased intracranial pressure levels due to stroke, organ transplantation, organ preservation, myocardial infarction or ischemia, reperfusion injury, chemotherapy, radiation, progeria, or head trauma. The dosage form of the present invention may also be used to treat other medical conditions that are thought to be caused by or exacerbated by lipid peroxidation and / or free radicals, such as conditions related to oxidative stress, including normal aging. See Patent Publication US2004 / 0092455 A1, incorporated herein by reference. The composition may also be used to treat movement disorders, including restless legs syndrome, myoclonus, dystonia, and / or essential tremor. See Frucht et al, Movement Disorders, 20(10), 1330(2005), incorporated herein by reference.

[0148] As described herein, the composition may be administered orally once daily at bedtime, for example, between 10 p.m. and 12 p.m. This is particularly well suited for the treatment of narcolepsy. Optionally, smaller doses may be delivered at bedtime and at different intervals during the night, or at morning and daytime intervals. Other variations may be selected depending on the patient and the indication being treated (e.g., fibromyalgia).

[0149] As used herein, the term “powder” refers to a plurality of “particles” or “granules.” In certain embodiments, each particle or granule is a subunit comprising one immediate-release component and / or at least one release-modulating component. In other embodiments, the particles or granules contain a mixture of distinct immediate-release GHB components and a distinct release-modulating GHB component. The terms “particles,” “granules,” “microparticles,” or “multiparticles” and “resinate” are used herein interchangeably to refer to an oxybate-anion exchange resin complex (which may be further present in the matrix and coated). “Oxybate-ion exchange resin complex” refers to the product resulting from filling an anion exchange resin with at least an oxybate. Complexation occurs when an active drug(s) and an ion exchange resin are mixed together in an aqueous medium to facilitate “exchange” between the “ions” of the drug and the “ions” of the ion exchange resin and the formation of a complex.

[0150] As used herein, “GHB drug” includes GHB, as well as pharmaceutically acceptable salts, hydrates, tautomers, solvates, prodrugs and complexes of GHB, and mixtures thereof. Suitable salts of GHB include, for example, salts of calcium, lithium, potassium, sodium and magnesium. Representative salts are also described in US2012 / 0076865, which is incorporated herein by reference. “Sodium oxybate,” which is a sodium salt of GHB, refers to the compound of the following formula (Ia): [ka] In one embodiment, a substitute for sodium oxybate may be used as an immediate-release component or as a starting material for preparing the drug-ion exchange resin complex provided herein. Such substitute salts useful in the present invention include compounds of formula (I). [ka] In the formula, X is a pharmaceutically acceptable cation, which may be selected from the group consisting of potassium, calcium, lithium, and magnesium, and Y is OH. “Oxybate salt” means the compound of formula I, where X is a pharmaceutically acceptable cation, which may be selected from the group consisting of sodium, potassium, calcium, lithium, and magnesium, and Y is OH. Sodium oxibate is a white to off-white crystalline powder that is very soluble in aqueous solution. Other salts such as calcium oxibate, magnesium oxibate, potassium oxibate, and / or lithium oxibate may be selected. Methods for preparing GHB salts are described, for example, in U.S. Patent No. 4,393,236, the disclosure of which is incorporated herein by reference.

[0151] "Dissolution rate" refers to the amount of drug released in vitro from the dosage form into the release medium per unit time. The in vitro dissolution rates in the tests described herein are performed on dosage forms placed in a USP Type II or USP Type 7 dissolving apparatus set to 37°C ± 2°C under appropriate experimental conditions, see, for example, US2012 / 007685 incorporated herein by reference. The dissolving medium may be purified water, 0.1N HCl, artificial gastric or artificial intestinal fluid, or other media known in the art.

[0152] Unless otherwise expressly stated, doses and concentrations of oxibate are expressed in terms of the equivalent weight in grams (g) of sodium oxibate. As used herein, the term “equivalent amount” for sodium oxibate refers to the weight of the oxibate portion of the anion exchange resin composite and does not take into account the weight of the anion exchange resin or any matrix or coating components.

[0153] Where used herein with respect to the figures provided herein, the term “approximately” may indicate a variation of up to 10% (±10%).

[0154] Various embodiments will be further described with reference to the following detailed examples. [Examples]

[0155] The following examples are for illustrative purposes only and are not intended to limit the invention. In the following examples, the terms “oxybate-anion exchange resin composite” and “oxybate reginate” or “oxybate-cholestyramine reginate” are used interchangeably unless otherwise specified.

[0156] Example 1: Removal of exchangeable ions from an oxidate-anion exchange resin composite for use in sustained-release powder (ER POS) for oral solutions. Uncoated oxybate-cholestyramine resinate. Oxybate-cholestyramine resinates were manufactured using a multi-step compounding process. Throughout the multi-step compounding process, unbound sodium oxibate is removed. The sodium content in the drug resinate complex is controlled by the amount of water or other aqueous solution, mixing time, mixing rate, and process temperature. The sodium content in the drug resinate complex is further controlled by the amount of water used in each multi-step compounding and final equilibrium stage. [Table 3] 1 Amount based on actual yield after multi-step drug-resinate complex formation. 2 Removed during processing

[0157] (Part I) Dissolve sodium oxidate in purified water (45% w / w) and gradually add cholestyramine resin. Continue stirring at room temperature for 2 hours. Then, filter the dispersion to remove excess sodium oxidate. Treat the wet resinate twice with 35.0 L of purified water. Process the resinate dispersion. Filter the resinate dispersion to remove the water used to remove excess API. Disperse the wet resinate (process step 1) in the fresh sodium oxidate solution of step 2 and stir for 2 hours. Filter this and treat the wet resinate twice with 35.0 L of purified water. Filter the resinate dispersion to remove the water used to remove excess API. In the process of step 3, the wet resinate of step 2 is compounded, filtered, and treated twice in the same manner as in the process of step 2. Dry the resulting wet resinate until the target LOD% is 7% w / w, and then sieve it through a #60 sieve.

[0158] (Part II) The sodium oxybate filtrate from Part I / Stage 1 is used for complexing with fresh cholestyramine resinate in Part II. Disperse the resinate in the filtrate and stir for 2 hours. Filter the complex and treat twice with 35.0 L of purified water.

[0159] The wet complex is used in the next step, where the sodium oxidate filtrate from Part I / Stage 2 is added and the mixture is stirred for 2 hours. The dispersion is filtered and treated twice with 35.0 L of purified water. The wet complex is used in the next step, where the sodium oxidate filtrate from Part I / Stage 3 is added and the mixture is stirred for 2 hours. The dispersion is filtered and treated twice with 35.0 L of purified water. Similarly, in the processes of Stages 4 and 5, the wet resinate is compounded with the fresh sodium oxidate solutions of Stages 4 and 5 for 2 hours, then filtered and treated twice with 35.0 L of purified water.

[0160] The wet complex is dispersed in sodium oxidate solution along with the complex from Part I in the Part III step. The dispersion is stirred for 4 hours, filtered, and then the wet mass is treated with 60 L of purified water. The resulting wet resinate is dried until the target LOD% reaches 7% w / w, and then sieved through a #50 sieve.

[0161] The resinate assay is performed with approximately 29% w / w oxibate, approximately 6.5% w / w LOD%, and approximately 2500 μg / g of elemental sodium.

[0162] Example 2: In another experiment, the sodium content is adjusted by changing the amount of purified water used at each stage of equilibrium. A similar process is followed, by changing the amount of purified water used between each stage to control the sodium content in the drug-resinate complex. [Table 4] 1 Amount based on actual yield after multi-step drug-resinate complex formation. 2 Removed during processing

[0163] The resinate assay is performed with approximately 29% w / w oxibate, approximately 6.5% w / w LOD%, and approximately 3000 μg / g of elemental sodium.

[0164] Example 3: In another experiment (Example 3), the sodium content is controlled by changing the amount of purified water used in the final stage of equilibrium. The process is similar to that of Example 1, but with variations in the amount of purified water used between each stage of the compounding process. [Table 5] 1 Amount based on actual yield after multi-step drug-resinate complex formation. 2 Removed during processing

[0165] The resinate assay is performed with approximately 28% w / w oxibate, approximately 6.0% w / w LOD%, and approximately 30 μg / g of elemental sodium.

[0166] Example 4: In another experiment (Example 4), the sodium content is controlled by changing the amount of purified water used in the final stage of equilibrium. The process is the same as in Example 1, but with a change in the amount of purified water used in the final stage of the compounding process.

Table 6

[0167] The assay of the resinate is about 28% w / w of oxybate, about 6.0% w / w of LOD% and about 360 μg / g of elemental sodium content.

[0168] Examples 5 and Example 6: A. Coated oxybate - cholestyramine resinate The coated oxybate - cholestyramine resinate can be prepared by coating the resin particles using water - insoluble film - forming polymer(s). As one approach, a combination of a polyvinyl acetate - based aqueous coating system and a copolymer dispersion of ethyl acrylate and methyl methacrylate is used (Table 5).

Table 7

[0169] Triacetin is dissolved in purified water and mixed, then talc is added. The dispersion is stirred for 15 minutes and divided into two equal parts. One part is gradually added to a polyvinyl acetate dispersion while stirring, and the other part is added to an ethyl acrylate and methyl methacrylate copolymer dispersion. Both dispersions are gradually mixed together and stirred for 1 hour, then sieved through a #60 screen. Oxybate-cholestyramine resinates with different sodium content levels are coated using the prepared dispersions in a fluidized bed coater (VFC FLO-COATER VFC-60) at a product temperature of approximately 22°C to 27°C. The coated particles are cured and sieved through a #45 sieve. The coated oxybate resinate particles are tested in vitro for oxybate release. The dissolution conditions are as follows: USP instrument II (paddle), 75 RPM, 1 L container, 0.02 N HCl, pH changed after 2 hours. The results are summarized in Figure 1.

[0170] Examples 7-13: The release of oxybate from coated oxybate reginate complexes depends on the amount of sodium content in the drug reginate complex, as presented below. Faster release was observed with higher sodium content in the oxybate reginate complex at the same level of barrier coating.

[0171] The rate of oxibate release from oxibate reginate can be further controlled by applying an additional sustained-release coating using a water-insoluble film-forming polymer, or a pH-independent or pH-dependent water-insoluble film-forming polymer.

[0172] One approach involves coating the oxybate reginates of Examples 1, 2, and 3 with a 30% w / w pH-independent water-insoluble barrier coating, followed by an additional coating with a polyvinyl acetate-based aqueous coating system.

[0173] The coating solution is first prepared by dissolving a triacetin plasticizer solution in purified water, and then gradually adding this to a polyvinyl acetate dispersion while stirring. The dispersion is stirred for 60 minutes and sieved through a #40 screen (Step 1). Oxybate-cholestyramine resinate is coated in a fluidized bed coater (FLM-5) using the dispersion from Step 1 at a product temperature of approximately 29°C to 37°C. The coated particles are cured in an oven and sieved through a #40 screen. The coated oxibate reginate particles are tested in vitro for oxibate release. The dissolution conditions are as follows: USP instrument II (paddle), 75 RPM, 1 L container, 0.02 N HCl, pH changed after 2 hours. The results are summarized in Figure 2. [Table 8] 1 Removed during processing

[0174] A coating with a 40% weight increase is applied to an already coated oxybate reginate. Faster release of oxybate is observed with a higher sodium content in the oxybate reginate complex with the same level of barrier coating.

[0175] Delayed-release (DER) coated oxybate-cholestyramine resinates can be prepared by coating resin particles with a water-insoluble film-forming polymer, followed by coating with a pH-dependent polymer coating system. One approach uses a water-insoluble coating system, a combination of a polyvinyl acetate-based aqueous coating system and a copolymer dispersion of ethyl acrylate and methyl methacrylate (pH-independent), followed by a blend of a pH-dependent / pH-independent methacrylic acid-based coating system (pH-dependent). [Table 9] 1 Removed during processing

[0176] Purified water was heated for a blended coating layer based on a methacrylic acid dispersion. Polysorbate 80, monoglycerides / diglycerides, and dibutyl sebacate (plasticizer) were dispersed in the heated purified water. This dispersion was divided into two equal parts. One part of the plasticizer dispersion was added to a pH-dependent methacrylic acid copolymer enteric coating dispersion system, and the other part was added to a pH-independent ethyl acrylate and methyl methacrylate copolymer barrier coating dispersion. The two dispersions were mixed for 15 minutes. After stirring for approximately 2 hours, the mixture was sieved through a #40 sieve. The barrier coating oxybate-cholestyramine resinate was further coated in a fluidized bed coater at a product temperature of approximately 22°C to 30°C with the blended pH-independent / pH-dependent layer. The resulting coated particles were cured and sieved through a #40 sieve.

[0177] A DER coating with a 45% weight increase was applied to already coated oxybate reginate. Intermediates (Examples 17, 18, and 19) were tested for in vitro drug release. The data are summarized in Figure 3. The dissolution conditions were as follows: USP instrument II (paddle), 75 RPM, 1 L container, 0.02 N HCl, pH changed after 2 hours. Significant enteric protection was observed with the same level of barrier coating at lower sodium content in the oxybate reginate complex, and therefore slower release was observed.

[0178] Examples 20-23: Effect of calcium chloride on ER POS release Oxybate sustained-release powder for suspension (ER POS) is prepared by combining uncoated oxibate reginate and diffusion barrier-coated oxibate reginate in different proportions with other excipients such as silicon dioxide (Syloid 244FP), sodium methylparaben, sodium propylparaben, povidone, USP (Kollidon K30), sucralose, carrageenan (Gelcarin GP-911), potassium bicarbonate, gellan gum, calcium chloride dihydrate, hypromellose K100M, Pearlitol 100SD, Eudragit L100, titanium dioxide, microcrystalline cellulose, and NF (Avicel® PH102). One of the functional excipients is calcium chloride, which contributes to the immediate-release dose of the formulation.

[0179] Four different levels of calcium chloride formulations were prepared according to Table 8, and the release of oxibate from the reconstituted suspensions was tested in vitro. Dissolution test: USP type II, 65 rpm, pH change method - 0.02 N HCl for 2 hours, then pH 6 using phosphate buffer. [Table 10]

[0180] As shown in Figure 4, it is observed that the higher the amount of calcium chloride, the greater the initial release of oxibate.

[0181] B. The final product, oxybate sustained-release powder for suspension (ER POS), consists of uncoated oxybate reginate, diffusion barrier coated oxybate reginate, and delayed sustained-release coated oxybate reginate, with silicon dioxide (Syl It is prepared by combining it with other excipients such as oid244FP, sodium methylparaben, sodium propylparaben, povidone, USP (Kollidon K30), sucralose, carrageenan, potassium bicarbonate, gellan gum, calcium chloride dihydrate, hypromellose K100M, Pearlitol 100SD, Eudragit L100, titanium dioxide, microcrystalline cellulose, NF (Avicel® PH102), and calcium chloride. This formulation contains 6 milliequivalents of calcium chloride and less than 100 mg of sodium. [Table 11-1] [Table 11-2] [Table 11-3]

[0182] The preparation contains less than 100 mg of sodium.

[0183] Example 24: Clinical evaluation of the final product, sustained-release oxidative powder for suspension (ER POS): The final product, Suspension Oxybate Sustained Release Powder (ER POS), contains uncoated oxibate reginate and diffusion barrier coated oxibate reginate, along with silicon dioxide (Syloid244FP), sodium methylparaben, sodium propylparaben, povidone, USP (Kollidon K30), sucralose, carrageenan, potassium bicarbonate, gellan gum, calcium chloride dihydrate, hypromellose K100M, Pearlitol100SD, Eudragit L100, titanium dioxide, microcrystalline cellulose, NF (Avicel® PH102), and calcium chloride. It is prepared by combining it with other excipients such as Calcium in different proportions.

[0184] An open-label, single-dose, randomized crossover trial was conducted to evaluate the sustained-release formulation (equivalent to 9 gm of sodium oxibate). The trial was conducted in healthy male and female subjects. A high-fat, high-calorie diet was consumed two hours before the once-night administration of the sustained-release formulation. Blood samples were collected from each patient at various time intervals, and the total sodium oxibate content in the plasma was analyzed by LC / MS. A summary of the mean plasma concentrations and pharmacokinetic parameters of sodium oxibate over time is shown below. See also Figure 5. [Table 12]

[0185] All patents, patent publications, and other publications listed herein are incorporated herein by reference. While the present invention has been described with reference to particularly preferred embodiments, it will be understood that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A sustained-release oxibate oral suspension powder (POS) that provides oxibate for once-night administration, wherein the oral suspension powder comprises (a), (b), and (c) below, namely (a) A rapid-release oxidate-anion exchange resin composite multiparticle containing oxidate bound to the ion exchange site in the anion exchange resin, (b) pH-independent diffusion barrier coating oxidate-anion exchange resin composite-optional matrix multiparticles, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer that imparts sustained release to the oxidate, and the pH-independent diffusion barrier coating layer is located on the oxidate-anion exchange resin composite-optional matrix multiparticles, (c) Oxybate particles coated with an intestinal targeted drug coating system (SITCS) comprising a pH-independent diffusion barrier coating oxibate-anion exchange resin complex-optional matrix of particles, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer, the pH-independent diffusion barrier coating layer is on the oxibate-anion exchange resin complex-optional matrix, the blended coating layer comprises a pH-dependent polymer and a pH-independent polymer, and the bilayer coating imparts a delayed and sustained-release profile to the oxibate in the bilayer-coated oxibate-anion exchange resin-optional matrix of (c), A mixture of oxidate-containing multiparticles having different release profiles as defined by, The oxybate-anion exchange resin composite-optional matrix of (a), (b), or (c) comprises oxybate bound to the ion exchange site in the anion exchange resin in an optional matrix further comprising at least one hydrophilic or hydrophobic polymer, and the composite-optional matrix in each of (a), (b), or (c) may be the same or different from one another. A mixture of oxidate-containing multiparticles, (d) an amount equivalent to approximately 1 mg to approximately 12 mg of calcium chloride per 9 g g of oxybate dose of the POS, Includes, The POS contains less than 200 mg of total sodium equivalent per 9 g of oxybate dose of the POS. Sustained-release oxibate oral suspension powder (POS).

2. The powder (POS) for oral suspension of sustained-release oxidate according to claim 1, wherein about 10% w / w to about 80% w / w of the total oxidate in the POS is present in the immediate-release multiparticles (a).

3. The powder for oral suspension of sustained-release oxidate according to any one of claims 1 to 3, wherein about 30% w / w to about 75% w / w of the total oxidate in the POS is present in the immediate-release multiparticles (a).

4. The powder for oral suspension of sustained-release oxidate according to any one of claims 1 to 3, wherein about 50% w / w to about 70% w / w of the total oxidate in the POS is present in the immediate-release multiparticles (a).

5. Approximately 25% w / w to approximately 70% w / w of the total oxybate in the POS is the sustained release A powder (POS) for oral suspension of the sustained-release oxibate according to any one of claims 1 to 4, which is present in components (b) and (c).

6. The powder for oral suspension of sustained-release oxidate according to any one of claims 1 to 5, wherein about 25% w / w to about 50% w / w of the total oxidate in the POS is present in the sustained-release components (b) and (c).

7. The powder for oral suspension of sustained-release oxidate according to any one of claims 1 to 6, wherein about 40% w / w of the total oxidate in the POS is present in the sustained-release components (b) and (c).

8. The powder for oral suspension of sustained-release oxidate according to any one of claims 1 to 7, wherein about 5% w / w to about 30% w / w of the total oxidate in the POS is present in the sustained-release component.

9. The powder for oral suspension of sustained-release oxidate according to claim 8, wherein about 10% w / w to about 15% w / w of the total oxidate in the POS is present in the sustained-release component (b).

10. The POS is a powder (POS) for oral suspension of sustained-release oxibate according to any one of claims 1 to 7, comprising an equivalent amount of 175 mg or less of total sodium per 9 g dose.

11. The POS is a powder for oral suspension of sustained-release oxibate according to any one of claims 1 to 8, comprising an amount equivalent to about 5 mg to about 175 mg of total sodium per 9 g dose.

12. The POS is a powder for oral suspension of sustained-release oxibate according to any one of claims 1 to 9, comprising an amount equivalent to about 150 mg of total sodium per 9 g dose.

13. The POS is a powder for oral suspension of sustained-release oxibate according to any one of claims 1 to 9, wherein the POS contains an equivalent amount of oxibate in a dose of about 1 g, 4.5 g, 6 g, 7.5 g, 9 g, or 10 g / m when determined based on the equivalent amount of sodium oxibate.

14. The calcium chloride equivalent comprises one or more of magnesium chloride, sodium chloride, zinc chloride, potassium chloride, calcium carbonate, potassium carbonate, sodium bicarbonate, and / or combinations thereof, in the powder (POS) for oral suspension of sustained-release oxibate according to any one of claims 1 to 13.

15. The oxybate-anion exchange resin composite comprises about 15% w / w to about 35% w / w of oxybate based on the total weight of the oxybate-anion exchange resin, which does not contain any matrix or coating components, as a powder (POS) for oral suspension of sustained-release oxybate according to any one of claims 1 to 14.

16. The oxybate-anion exchange resin composite comprises 25% w / w to about 30% w / w of oxybate based on the total weight of the oxybate-anion exchange resin, which does not contain any matrix or coating components, as a powder (POS) for oral suspension of sustained-release oxybate according to claim 12.

17. The sustained-release coating oxidate-anion exchange resin of (b) and / or (c) The powder (POS) for oral suspension of sustained-release oxibate according to any one of claims 1 to 16, wherein the composite comprises the matrix in an amount of matrix-forming polymer of about 20% w / w to about 40% w / w, based on the total weight of the oxibate-anion exchange resin-matrix, which does not contain any coating components.

18. The POS further comprises an interpenetrating polymer network (IPN) release forming system, wherein the IPN forming system optionally comprises two independently crosslinked portions crosslinked with at least one crosslinking agent and an optionally selected gas generating agent, the powder (POS) for oral suspension of sustained-release oxibate according to any one of claims 1 to 16.

19. The POS further comprises potassium bicarbonate, calcium bicarbonate, carrageenan gum, gellan gum, a pH adjuster, polysorbate, a flow enhancer, a bulking agent, a filler, a coloring agent, or a combination thereof, as described in any one of claims 1 to 18.

20. A powdered oral suspension (POS) of sustained-release oxibate that provides sustained-release oxibate for once-night administration, (a) A rapid-release oxidate-anion exchange resin composite multiparticle containing oxidate bound to the ion exchange site in the anion exchange resin, (b) At least two different sustained-release oxibate components containing a drug-ion exchange resin complex, (c) an amount equivalent to approximately 1 mg to approximately 12 mg of calcium chloride per 9 g of oxybate dose of the POS, and (d) The POS contains less than 200 mg of total sodium per 9 g of oxybate dose, After administration to the patient, the suspension containing the POS is (i) When calculated using the arithmetic mean, Cmax values ​​of 87.98 μg / mL to 126 μg / mL or approximately 107 μg / mL, 85.6 μg / mL to 133.76 μg / mL, or 77.04 μg / mL to 117.711 μg / mL, and / or (ii) When calculated using the geometric mean, Cmax values ​​of approximately 105 μg / mL, or 84.38 μg / mL to 131.84 μg / mL, 94.92 μg / mL to 116.01 μg / mL, (i) AUCinf of 518.20 hours*μg / mL to 719.725 hours*μg / mL, or approximately 575 hours*μg / mL, when calculated using the arithmetic mean, or AUCinf of 304.11 hours*μg / mL to 846.67 hours*μg / mL, 460.62 hours*μg / mL to 719.725 hours*μg / mL, and / or (ii) AUCinf of approximately 520 hours*μg / mL, or 428.58 hours*μg / mL to 669.66 hours*μg / mL, or approximately 482.16 hours*μg / mL to 589.30 hours*μg / mL when calculated using the geometric mean. Provides a pharmacokinetic profile of at least one of the oxibates. Sustained-release oxibate oral suspension powder (POS).

21. The suspension is a reconstituted suspension comprising a powder for oral suspension of sustained-release oxibate according to any one of claims 1 to 20, comprising about 20 mL to about 300 mL of aqueous suspending agent.

22. The reconstituted suspension according to claim 21, wherein the suspension comprises about 100 mL to about 250 mL of aqueous suspending agent.

23. The reconstituted suspension according to claim 21, wherein the suspension comprises about 175 mL to about 225 mL of aqueous suspending agent.

24. The composition comprises a dose of 1 g of oxybart when measured based on an equivalent amount relative to sodium oxybate, according to any one of claims 21 to 23, in the reconstituted suspension according to any one of claims 21 to 23.

25. The reconstituted suspension according to any one of claims 21 to 24, wherein the composition comprises a dose of 4.5 g of oxidate when measured based on an equivalent amount relative to sodium oxidate.

26. The reconstituted suspension according to any one of claims 21 to 24, wherein the composition comprises a dose of 6 g of oxibate when measured based on an equivalent amount relative to sodium oxibate.

27. The reconstituted suspension according to any one of claims 21 to 24, wherein the composition comprises a dose of 7.5 g of oxidate when measured based on an equivalent amount relative to sodium oxidate.

28. The reconstituted suspension according to any one of claims 21 to 24, wherein the composition comprises a dose of 9 g of oxidate when measured based on an equivalent amount relative to sodium oxidate.

29. The reconstituted suspension according to any one of claims 21 to 24, wherein the composition comprises a dose of 10 g of oxibate when measured based on an equivalent amount relative to sodium oxibate.

30. A method for treating narcolepsy, idiopathic hypersomnia, or cataplexy, comprising administering to a patient a reconstituted suspension according to any one of claims 21 to 29.

31. Use of the POS according to any one of claims 1 to 20 or the reconstituted suspension according to any one of claims 21 to 29.

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