Low sodium hydroxybutyrate composition once per night

Abstract

The present invention provides compositions that provide a dosage of hydroxybutyrate once per night. Compositions containing bilayer coated hydroxybutyrate anion exchange resin complex multiparticulates provide regulated release of the hydroxybutyrate within 5 to 8 hours after administration. The invention also provides a method of treating a patient in need thereof with a pharmaceutical composition containing the hydroxybutyrate-anion exchange resin complex.

Description

BACKGROUND

[0001] Narcolepsy is a devastatingly disabling condition. The main symptoms are excessive daytime sleepiness (EDS), cataplexy (sudden loss of muscle tone triggered by strong emotions, seen in about 60% of patients), hypnagogic hallucinations (HH), sleep paralysis (SP), and disturbed night sleep (DNS). DNS is the most common symptom in patients with narcolepsy, in addition to EDS. Sodium oxybate is one of the main therapeutic drugs for narcolepsy. The exact mechanism by which sodium oxybate produces its effects is not known, but sodium oxybate is thought to act by promoting SWS (delta sleep) and consolidating night sleep. Administration of sodium oxybate before night sleep increases stage 3 and stage 4 sleep and increases sleep latency, while reducing the frequency of sleep onset REM periods (SOREMP). Other mechanisms can be involved, but remain to be elucidated.

[0002] Gamma-hydroxybutyrate (GHB), also known as “sodium oxybate,” is an endogenous compound with hypnotic properties that is found in human tissues, such as the brain. In the brain, the highest concentrations of GHB are found in the hypothalamus and the basal ganglia, where it is postulated to act as a neurotransmitter (Snead and Morley, 1981, Brain Res. 227(4):579-89). The neuropharmacological effects of GHB include increasing brain acetylcholine, increasing brain dopamine, inhibiting GABA- ketoglutarate transaminase, and inhibiting brain glucose utilization without oxygen consumption. GHB treatment substantially reduces the signs and symptoms of narcolepsy, i.e., daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. In addition, GHB increases total sleep time and REM sleep, reduces REM latency, reduces sleep apnea, and improves general anesthesia (e.g., U.S. Patents Nos. 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 by reference herein in its entirety). GHB has been reported to be effective in alleviating pain and improving function in patients with fibromyalgia syndrome, reducing daytime sleepiness and fatigue in patients with Parkinson’s disease, improving myoclonus and essential tremor, and reducing tardive dyskinesia and bipolar disorder. See references incorporated at the end of U.S. Patent No. 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, coupled with the large amounts of drug required to achieve clinical efficacy, present challenges in preparing solid unit dosage forms designed to immediately release sodium GHB into the user's gastrointestinal tract. See also U.S. Patent 8,193,211.

[0004] Two patented products have been approved for the treatment of cataplexy or excessive daytime sleepiness in patients aged 7 years and older with narcolepsy. (Sodium hydroxybutyrate oral solution) and (A low-hydroxybutyrate sodium oral solution formulation containing a mixture of calcium, magnesium, potassium and hydroxybutyrate sodium). This is a commercially available product composed of 100% sodium hydroxybutyrate (Na.GHB) and approved for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. It is intended for use in patients with narcolepsy. This is a product for long-term use, requiring high drug levels. The sodium intake from this medication will significantly increase a patient's daily sodium intake, which is undesirable for patients with high blood pressure, heart disease, kidney disease, or those at risk of stroke.

[0005] Another approved formulation is (A low-hydroxybutyrate sodium oral solution formulation containing a mixture of calcium, magnesium, potassium and hydroxybutyrate sodium). This is a low-hydroxybutyrate sodium oral solution containing a mixture of calcium, magnesium, potassium, and sodium hydroxybutyrate. However, the therapeutic dose of 71.4 mEq / day (9 g sodium hydroxybutyrate) is very high, and shifting from sodium to another cation may limit the acceptable daily intake of other cations and may cause other undesirable side effects in some patients. For example, high doses of potassium solution administered on an empty stomach are poorly tolerated and may cause problems in patients with impaired renal function. Excess magnesium can cause diarrhea. Therefore, for a once-nightly delayed-release composition, a treatment that reduces or eliminates sodium without adding any additional cations is desirable.

[0006] Despite following general safety records when used as a prescription, abuse and misuse... There are also risks that could lead to serious medical problems, including seizures, loss of consciousness, coma, and death (see, for example, the FDA product label with NDA number 021196 dated November 13, 2006, which is incorporated herein by reference in its entirety). Furthermore, and Both drug products are immediate release compositions and require twice daily dosing.

[0007] Accordingly, there is a need to develop a once nightly low sodium GHB extended release formulation and a formulation with low potential for abuse. SUMMARY

[0008] In one embodiment, a once nightly extended release gamma hydroxy butyrate powder for oral suspension is provided. Advantageously, this oral suspension is provided with a powder for oral suspension (POS) that provides the desired release profile and has a low sodium content.

[0009] In one embodiment, there is provided an extended release (ER) sodium oxybate oral suspension powder (POS) that provides a once nightly dose of sodium oxybate. The ER sodium oxybate POS comprises a blend of oxybate-containing multiparticulates with different release profiles as defined in (a), (b) and (c): (a) immediate release sodium oxybate-anion exchange resin complex multiparticulates comprising sodium oxybate bound to ion exchange sites in an anion exchange resin; (b) pH-independent diffusion barrier coated sodium oxybate-anion exchange resin complex-optional matrix multiparticulates, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film- forming polymer that imparts extended release to the sodium oxybate, and wherein the pH- independent diffusion barrier coating layer is located over the sodium oxybate-anion exchange resin complex-optional matrix; (c) sodium oxybate multiparticulates comprising a small intestinal targeting drug coating system (SITCS) located over the sodium oxybate-anion exchange resin complex-optional matrix of (b), wherein the SITCS is a dual layer coating system, wherein the outer layer comprises a blend of a pH-dependent polymer and a pH-independent polymer, the outer layer is located over an inner pH-independent diffusion barrier coating layer that is located directly over the sodium oxybate-anion exchange resin-optional matrix, and wherein the coating system imparts delayed and extended release to the sodium oxybate in the SITCS-coated sodium oxybate-anion exchange resin-optional matrix. The sodium oxybate-anion exchange resin complex-optional matrix in (a), (b) or (c) comprises sodium oxybate bound to ion exchange sites in an anion exchange resin in an optional matrix that further comprises at least one hydrophilic or hydrophobic polymer. The complex-optional matrix in each of (a), (b) or (c) can be the same or can be different from one another. Further, the POS further comprises calcium chloride equivalent of about 1 mEq to about 12 mEq per 9 gm sodium oxybate dose equivalent of the POS; and wherein the POS contains less than 200 mg total sodium per 9 gm sodium oxybate dose equivalent of the POS. In certain embodiments, the calcium chloride equivalent is a pharmaceutically acceptable salt selected from one or more of the following: magnesium chloride, sodium chloride, zinc chloride, potassium chloride, calcium carbonate, potassium carbonate, sodium bicarbonate, and / or combinations thereof.

[0010] In certain embodiments, there is provided an oral suspension re-suspended by mixing a sodium oxybate powder and an aqueous oral suspension.

[0011] In certain embodiments, the time-released sodium oxybate oral suspension is provided as a powder for a once nightly dose of sodium oxybate, wherein the POS composition is a blend of sodium oxybate-containing multiparticulates having different release profiles as defined in (a) and (b): (a) immediate release sodium oxybate-anion exchange resin complex multiparticulates comprising sodium oxybate bound to ion exchange sites in an anion exchange resin; (b) at least two different time-released sodium oxybate components comprising drug-ion exchange resin complexes. The POS further comprises calcium chloride equivalent to about 1 mEq to about 12 mEq per 9 gm sodium oxybate dose of the POS; and less than 200 mg sodium equivalent per 9 gm sodium oxybate dose of the POS. In certain embodiments, upon administration to a patient, the suspension comprising the POS provides a pharmacokinetic profile of at least one of the following for sodium oxybate: a Cmax of (i) 87.98 pg / mL to 126 pg / mL, or about 107 pg / mL, a Cmax of 85.6 pg / mL to 133.76 pg / mL, or 77.04 pg / mL to 117.711 pg / mL, as calculated using arithmetic mean, and / or (ii) a Cmax of about 105 pg / mL, or 84.38 pg / mL to 131.84 pg / mL, 94.92 pg / mL to 116.01 pg / mL, as calculated using geometric mean; an AUCinf of 518.20 hr*pg / mL to 719.725 hr*pg / mL; or about 575 hr*pg / mL, or 304.11 hr*pg / mL to 846.67 hr*pg / mL, 460.62 hr*pg / mL to 719.725 hr*pg / mL, as calculated using arithmetic mean, and / or an AUCinf of about 520 hr*pg / mL, or 428.58 hr*pg / mL to 669.66 hr*pg / mL; or about 482.16 hr*pg / mL to 589.30 hr*pg / mL, as calculated using geometric mean.

[0012] In certain embodiments, the POS contains about 1 g, 4.5 g, 6 g, 7.5 g, 9 g, or 10 gm dose equivalent of sodium oxybate, as determined based on the sodium oxybate equivalent. In the case of 10 g or above 9 g doses, the lower strength versus the higher strength can be dose proportional.

[0013] In a further aspect, a method of treating a patient suffering from narcolepsy or idiopathic hypersomnia with a salt of gamma-hydroxybutyric acid composition is provided. In still other aspects, compositions for treating a patient suffering from or susceptible to hypertension, a condition responsive to GHB (salt of gamma-hydroxybutyric acid) are provided. The method comprises providing to the patient a therapeutically effective amount of a composition as described herein, wherein the composition has a reduced sodium content as compared to a composition having an equivalent dose of sodium gamma-hydroxybutyrate.

[0014] In another aspect, a method for treating a patient suffering from cataplexy and alcohol withdrawal and alcohol dependence is provided. The method comprises providing to the patient a therapeutically effective amount of a composition as described herein.

[0015] In a further embodiment, a method of treating a patient suffering from chronic fatigue syndrome, cataplexy, sleep apnea, Parkinson's disease, schizophrenia, binge eating, essential tremor and non-Parkinsonian movement disorders, chronic cluster headache and / or reducing constipation associated with opioid and opioid-related drugs is provided. The method comprises providing to the patient a therapeutically effective amount of a composition as described herein.

[0016] In another aspect, a kit for treating a patient with one or more salt of gamma-hydroxybutyric acid-anion exchange resin compositions is provided.

[0017] Still other aspects and advantages of the application will be readily apparent from the following detailed description of the application, wherein: BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The cumulative percent release of a salt of gamma-hydroxybutyric acid from a 30% ER coated salt of gamma-hydroxybutyric acid-anion exchange resin complex (resinate) as described in Example 6 (360 μg / g uncoated sodium content) or Example 7 (30% extended release (ER) coated resinate, uncoated sodium content 30 μg / g) is provided.

[0019] Figure 2 The cumulative percent release of a salt of gamma-hydroxybutyric acid from a double layer, 40% DER coated salt of gamma-hydroxybutyric acid-anion exchange resin complex (resinate) as described in Example 12 (40% delayed, extended release (DER) coated resinate, 3000 μg / g uncoated sodium content), Example 11 (40% DER coated resinate, uncoated sodium content 2500 μg / mg) or Example 19 (40% DER coated resinate, uncoated sodium content 30 μg / g) is provided.

[0020] Figure 3The cumulative percent release of oxybutynin from a double layer 45% DER coated oxybutynin-anion exchange resin complex (resinate) as described in Example 17 (45% delayed, delayed release (DER) coated resinate, 3000 μg / g uncoated sodium content), Example 18 (45% DER coated resinate, uncoated sodium content 2500 μg / mg) or Example 19 (45% DER coated resinate, uncoated sodium content 30 μg / g) is provided.

[0021] Figure 4 The results of the effect of calcium chloride on the release of the final ER POS product of Example 20 (1 mEq of Cl-), Example 21 (4 mEq of Cl-), Example 22 (8 mEq of Cl-) and Example 23 (12 mEq of Cl-) over 6 hours are provided.

[0022] Figure 5 is a graph showing the plasma concentration profile of oxybutynin (mcg / mL) over 10 hours provided by a powder for a suspension of oxybutynin (9 g of sodium oxybutynin equivalent) releasing oxybutynin. DETAILED DESCRIPTION

[0023] Provided herein is a powder for a delayed release (ER) oral suspension of oxybutynin (POS) that contains sodium oxybutynin in a complex with cholestyramine resin. The inclusion of cholestyramine resin in the drug product is intended to delay the release of oxybutynin from the ER product. It was observed that the release of drug from the oxybutynin ER formulation is modulated by the concentration of sodium content in the formulation. A unique formulation technique was developed to control the sodium content in the formulation. The sodium content in the coated drug resin complex has a significant impact on the dissolution characteristics of the drug resin particles, which in turn will affect the bioavailability of oxybutynin in vivo. The solubility characteristics of the oxybutynin resin complex can also be modulated by the addition of calcium chloride equivalents in the oxybutynin ER formulation.

[0024] As used herein, the combination of sodium ions and calcium chloride or equivalents thereof can be used to achieve the desired dissolution profile in vitro / in vivo. In certain embodiments, the calcium chloride equivalents are pharmaceutically acceptable salts 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 comprises from about 1 mEq to about 12 mEq of calcium chloride equivalents per 9 gm dose of oxybutynin equivalent of the POS; and wherein the POS contains less than 200 mg of total sodium per 9 gm dose of oxybutynin equivalent of the POS. In other formulations, appropriate amounts of calcium chloride equivalents can be selected.

[0025] The once nightly sodium oxybate formulation requires an initial release from the formulation to achieve the desired Cmax. In certain embodiments, the combination of an immediate release (IR), extended release (ER), and a small intestinal targeted drug coating system (SITCS) sodium oxybate component with low sodium and calcium chloride concentrations (1 mEq to 12 mEq) provides the desired maximum plasma concentration level (Cmax) of sodium oxybate and allows for maintenance of therapeutic levels for about five to six hours post-dose. Thereafter, these compositions allow for complete clearance of sodium oxybate levels within about 10 hours post-dose.

[0026] As used herein, the composition contains a combination of sodium oxybate containing components, each with a different release profile. Each of the three components comprises a complex of sodium oxybate and an anion exchange resin, wherein the sodium oxybate is bound to the anion exchange resin through available anionic groups on the resin. The three components include: (1) an immediate release component comprising a sodium oxybate-anion exchange resin complex; (2) an extended release component comprising a sodium oxybate-anion exchange complex coated with a pH independent diffusion barrier comprising a water insoluble film forming polymer or copolymer; (3) a SITCS component comprising a coated sodium oxybate-anion exchange resin complex having a pH independent barrier coating layer over the sodium oxybate-anion exchange resin complex, and a delayed release coating layer comprising a blend of a pH dependent enteric polymer or copolymer system and a pH independent diffusion barrier polymer or copolymer system, calcium chloride or its equivalent counterion, and less than 200 mg of sodium per 9 gm dose equivalent.

[0027] As used herein, the sodium content in the composition (e.g., POS) is more critical for the initial release of sodium oxybate as measured in vitro or in vivo. In certain embodiments, the sodium content in the composition is present in an amount of less than 200 mg of sodium equivalent per 9 g sodium oxybate dose (where the sodium oxybate dose is determined based on the sodium oxybate sodium equivalent). In certain embodiments, the sodium content is about 5 mg to about 175 mg per 9 g sodium oxybate dose, or about 150 mg (by weight) per 9 g sodium oxybate dose. For doses less than 9 g, the sodium amount is adjusted downward in a similar ratio of sodium to equivalent of 9 g sodium oxybate dose (e.g., no more than 0.2 g sodium per 9 g sodium oxybate dose equivalent, or about 0.005 g sodium per 9 g sodium oxybate to about 0.175 g sodium per 9 g sodium oxybate dose equivalent, or about 0.150 g sodium per 9 g sodium oxybate dose equivalent).

[0028] The concentration of calcium chloride is critical to the initial release of the sebacate in vitro / in vivo. As used herein, the sebacate ER formulation contains calcium chloride in a concentration of 1 mEq to 12 mEq to facilitate. In a preferred embodiment, the chloride ion is selected from the group consisting of calcium chloride, sodium chloride, magnesium chloride, and / or zinc chloride or any other chloride salt and / or combinations thereof. Calcium chloride is preferred for the sebacate ER formulation.

[0029] The formula for mEq is calculated based on the following formula and is well known to those skilled in the art: mEq = mass X valence / molecular weight

[0030] As used herein, the compositions and methods minimize and / or eliminate adverse events associated with high levels of sodium and certain other salts, improve patient compliance. In addition, the compositions provided herein are taken once a night, thus eliminating the need for a second dose at night.

[0031] As used herein, "powder for suspension" or "POS" refers to a composition that is formulated as a powder designed to suspend in a suspension matrix prior to oral ingestion by a patient.

[0032] In certain embodiments, a manufacturing process for the drug resin acid salt complex is developed such that the concentration of sodium content is less than 200 mg / 9 gm dose. A 9 gm dose of sodium sebacate contains 1640 mg of sodium. The manufacturing process presented in certain embodiments reduces the sodium content in the formulation from 1640 mg per 9 gm dose to at least 200 mg. In certain embodiments, the required sodium content of less than 200 mg per 9 gm dose is necessary for achieving the desired solubility profile in the first few hours for a once-a-night extended release dosage form. These sodium ions in the coated drug resin acid salt complex act as pore formers, thereby enhancing the solubility of the sebacate in the coated drug resin acid salt complex.

[0033] Calcium chloride can be included in the composition of the sebacate ER POS to facilitate the solubility of the sebacate ER POS in the first few hours after administration. In certain embodiments, the sebacate compositions provided herein (e.g., ER POS) contain approximately 1 mEq to 12 mEq of calcium chloride to achieve the desired solubility profile. Without wishing to be bound by theory, it is believed that the calcium chloride will generate calcium ions in the biological fluid and exchange sebacate ions with the drug resin acid salt (complex), thereby increasing the solubility of the sebacate in the first few hours after administration. The solubility of the sebacate in the first few hours helps the sebacate ER compositions provided herein (e.g., POS) to provide the desired initial plasma concentration of sebacate. The plasma half-life of sebacate is short, approximately 30-45 minutes.

[0034] The combination of immediate release (IR) and extended release (ER) drug resin acid salt particles, low sodium content, and calcium chloride provides a desired hydroxybutyrate maximum plasma concentration level (Cmax) and allows for maintenance of therapeutic levels for about five hours post-dose. Thereafter, these compositions allow for complete clearance of hydroxybutyrate levels within about 10 hours post-dose. Optionally, one or more of the immediate release component, the extended release component, or the delayed release component comprises a hydroxybutyrate-anion exchange resin complex-optional matrix. At least one coating layer is present in the component, the at least one coating layer being over the hydroxybutyrate-anion exchange resin complex-matrix. Optionally, one or more of the immediate release component, the extended release component, or the delayed, extended release component comprises a hydroxybutyrate-anion exchange resin complex-optional matrix. If at least one coating layer is present in the component, the at least one coating layer is over the hydroxybutyrate-anion exchange resin complex-matrix.

[0035] Provided herein are pharmaceutical compositions and formulations comprising 30% w / w to 75% w / w total hydroxybutyrate immediate release (IR) component, 25% w / w to 70% w / w total hydroxybutyrate resin acid salt extended release (ER) component, less than 200 mg sodium, and 75 mg (1 mEq) - 882 mg (12 mEq) calcium chloride per 9 g dose. In certain embodiments, the compositions further comprise a floating interpenetrating network (IPN) forming system.

[0036] In certain embodiments, the hydroxybutyrate immediate release component is present in an amount of about 30% w / w to 80% w / w, or about 20% w / w to 75% w / w, or about 65% w / w to 70% w / w (based on total hydroxybutyrate in the composition). In certain embodiments, the hydroxybutyrate extended release component is present in an amount of about 25% w / w to 70% w / w, or 25% w / w to 60% w / w, or about 40% w / w (based on total hydroxybutyrate in the composition).

[0037] In certain embodiments, as described herein, there are two different extended release components, wherein the total hydroxybutyrate in the extended release component comprising a pH independent coating without a functional enteric or pH dependent coating is about 5% w / w to about 30% w / w of the total hydroxybutyrate in the composition. In certain embodiments, the total hydroxybutyrate in the extended release comprising a pH independent coating without a functional enteric or pH dependent coating is about 10% w / w to about 15% w / w of the total hydroxybutyrate in the composition.

[0038] As defined herein, the SITCS component does not release a substantial amount of oxybutynin within the first few hours after administration when the immediate release component releases oxybutynin at a substantially faster rate. In certain embodiments, the novel combination of the immediate release component, the time delayed release component, and the SITCS coated component work together to achieve effective plasma oxybutynin levels at 1 hour (Cl) after administration, controlled Cmax, effective plasma levels at 5 hours (C5) after administration, without a decrease in AUC: Without wishing to be bound by theory, it is believed that this helps control Cmax and initial plasma concentrations, and thus side effects. The SITCS release component begins to release oxybutynin at a higher pH, most preferably a pH higher than about 4, i.e., the pH in the small intestine.

[0039] In certain embodiments, the delayed effect is provided within about 2 hours after administration, and the SITCS component provides ER from about 3 hours to about 6 hours. In certain embodiments, best results are obtained with administration of the dosage form about 2 hours after dinner.

[0040] The immediate release component begins to release oxybutynin after administration, without any lag time (e.g., can begin within or about 10 minutes), and helps to increase initial oxybutynin plasma concentration levels. In certain embodiments, the immediate release component (i.e., the oxybutynin-anion exchange resin complex) releases no less than about 75% to about 80% of the oxybutynin within about 1 hour, or releases no less than 75% to 80% of the oxybutynin within 1 hour. This can be evaluated in an in vitro dissolution assay, e.g., as defined later. The time delayed release component provides oxybutynin release from about 5 hours to about 8 hours after administration.

[0041] Both solid and liquid dosage forms are described herein. In one particularly suitable embodiment, the composition is a suspension powder dosage form. In certain embodiments, the suspension powder is prepared using all components in specific ratios selected on a w / w basis of the oxybutynin dose, as well as diluent granules containing excipients.

[0042] Certain pharmaceutically acceptable salts of GHB are referred to as "oxybutynin," e.g., sodium oxybutynin. 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 "oxybutynin-anion exchange resin complex." Unless otherwise specified, GHB and oxybutynin are used interchangeably in this document.

[0043] Optionally, the powder composition can contain a dye that dissolves in the aqueous alcoholic liquid to produce a unique color that is advantageous for safety. Alternatively, the composition can contain a flavoring that, when mixed with the alcohol, imparts a stimulating mouth feel to the composition. In addition, the composition provides a time-release of the oxybutynate, which is clinically advantageous because it avoids the need for the patient to get up at night to take a second dose. This composition also reduces the possibility of errors that can occur when multiple individual doses are prepared.

[0044] In certain embodiments, the compositions provided herein provide a single peak of plasma concentration. In certain embodiments, the compositions provided herein are characterized by a plateau value of the mean plasma concentration level of oxybutynate, which can be measured using an arithmetic mean and / or a geometric mean.

[0045] As used herein, a "functional coating" is a coating layer whose function is to alter the release profile of the active drug (e.g., GHB) of the coating. Such release can be in a time-dependent, pH-dependent, or pH-independent manner, 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, which is combined with a diffusion barrier coating. These coatings and other suitable coatings are described in detail below.

[0046] As provided herein, a "floating IPN" comprises a full IPN or a semi-IPN and entrapped gas. Suitably, the floating IPN further contains an active drug.

[0047] As used herein, an "interpenetrating polymer network (IPN)" comprises two or more polymer networks that are at least partially interlaced on a molecular scale, but are not covalently bonded to each other, and cannot be separated without breaking chemical bonds. IPNs can be formed sequentially, i.e., in a sequential IPN, the second polymer network is formed after the first polymer network is crosslinked. Alternatively, IPNs can also be formed simultaneously, i.e., by a process that forms all of the polymer networks at the same time.

[0048] As used herein, a "semi-IPN" refers to an IPN system in which not all of the polymer networks are interlaced on a molecular scale. For example, in an IPN system containing two crosslinkable polymer / polysaccharide components that can be crosslinked, a 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 that can be crosslinked, a semi-IPN refers to a system in which only one of the two polymer components is crosslinked (networked). As provided herein, a composition suitable for oral ingestion can contain a full crosslinked (full IPN) or a semi-IPN.

[0049] Hydroxybutyrate-anion exchange resin complex

[0050] Hydroxybutyrate-anion exchange resin complexes can be used in the immediate release component and the modified release hydroxybutyrate component of the compositions described herein. In the immediate release hydroxybutyrate component, no functional coating is typically provided over the hydroxybutyrate-anion exchange resin complex. Such complexes can be in an optional matrix. The immediate hydroxybutyrate-anion exchange resin complex-optional matrix can have a non-functional coating. If present, the non-functional coating is typically present in a single coating layer. In the examples below, the term "resinate" is used interchangeably with "anion exchange resin complex"; i.e., hydroxybutyrate resinate and hydroxybutyrate-anion exchange resin complex refer to the same component.

[0051] "Anion exchange resin" is an insoluble organic polymer containing basic groups that can exchange anions with a second moiety containing anions when in suspension. In certain embodiments, "strong anion exchange resin" is "strong basic anion exchange resin".

[0052] Unless otherwise indicated, it is to be understood that references throughout this specification of "anion exchange resin" include "strong basic anion exchange resin" and "cholestyramine resin" as described herein. An example of an anion exchange resin is a pharmaceutically acceptable grade of cholestyramine resin, a strong basic (Type 1) anion exchange resin powder comprising a polystyrene matrix and quaternary ammonium functional groups (e.g., polystyrene trimethylbenzylammonium chloride). The exchangeable anion counterion is typically chloride, which can be exchanged or replaced by virtually any anion. Other commercially available pharmaceutical grade cholestyramine resins can include Type II resins, such as A430MR resin (DuPont De Nemours). According to its manufacturer's description, this resin has an average particle size range of less than 150 microns, a pH of 4-6, and an exchange capacity of 1.8-2.2 equivalents per dry gm. Another pharmaceutical grade cholestyramine resin is DUOLITE TM AP143 / 1094 [DuPont De Nemours], according to manufacturer's description, has a particle size range of 95% less than 100 microns, 40% less than 50 microns. Commercial literature from these and other resin suppliers is incorporated herein by reference A-430MR; DOW Cholestyramine USP, Table No. 177-01877-204, [DuPont De Nemours]; DUOLITE TM AP143 / 1083, DuPont De Nemours). In a further embodiment, DUOLITE TMAP143 / 1096, which has a particle size of < 150 microns for 55% of the particles and an average diameter of > 130 microns, as determined using the dry sieving method from USP <811> and <796>. The Dow Chemical resin has a pH range of 4 to 6, as determined using USP <891>, and an ion exchange capacity of 1.8 to 2.2, as determined using the HPLC / UV method. In certain embodiments, a weakly basic anion exchange resin can be selected for use in the methods and / or compositions provided herein. Ion exchange resins with primary, secondary, and tertiary amine groups as active functional groups show weak basicity, and thus are referred to as weakly basic anion exchange resins (WBAERs). There are several types of WBAERs: one with only one amine group, and another with more than two amine groups, for example WA10 (acrylic type with tertiary amine groups), WA20, WA21J (mixture of primary and secondary amine groups), and WA30 (tertiary amine groups). For example, weakly basic anion exchange resins include Chromabead® series [Mitsubishi Chemical Corporation], which according to the manufacturer description has two types with different basicity: type I with trimethylammonium groups and type II with dimethylethanolammonium groups. Other products can include chitosan hydrochloride. Other suitable anion exchange resins can include, for example, DOWEX® available from Thermo Fisher Scientific XQ anion exchange resin.

[0053] Both shape regular particles and shape irregular particles can be used as resins. Shape regular particles are those that substantially conform to a geometric shape, such as a sphere, an ellipsoid, a cylinder, and the like (e.g., a three-dimensional shape that is readily described in terms of a three-dimensional point group). Shape irregular particles refer to all particles that are not considered to have a regular geometric shape (e.g., not readily described in terms of a three-dimensional point group), such as particles of amorphous shape and particles with increased surface area due to surface channels or deformations. Shape regular and shape irregular particles can include any of the anion exchange resins disclosed herein.

[0054] The oxybutyrate-anion exchange resin complex can be prepared using traditional ion exchange resin loading (complexing) processes or variations thereof. See, for example, the techniques described in U.S. Patent No. 8,062,667; U.S. Patent Publication Nos. US2005 / 181050; US 8,343,546; US 5,980,882 with the following modifications. Such complexing involves dissolving the oxybutyrate salt (e.g., sodium oxybutyrate or magnesium oxybutyrate) (as a starting material) and mixing with a water-insoluble anion exchange resin in an aqueous medium. The oxybutyrate-anion exchange resin complex thus formed is typically collected by filtration and washed to remove any counterions (e.g., sodium, calcium, potassium, or magnesium), unbound oxybutyrate, or byproducts. Such washing steps can use water or other aqueous solutions. The complex can be air-dried at room temperature or elevated temperature in trays, fluidized bed dryers, or other suitable dryers.

[0055] In certain embodiments, more than one loading step (equilibration) is utilized to achieve the desired level of complexed oxybutyrate on the anion exchange resin. Two or more loading stages can be used, with separation of the resin from the liquid phase between stages, to maximize loading of oxybutyrate onto the anion exchange resin. For example, one equilibration (complexation) can provide about 0.1% w / w to about 20% w / w of oxybutyrate in the resulting oxybutyrate-anion exchange resin complex, or 1% w / w to 20% w / w, or 5% w / w to 15% w / w or 7% w / w to 10% w / w. However, in certain embodiments, it is desirable to load about 15% w / w to about 35% w / w, about 15% w / w to about 25% w / w, or more than 25% w / w, which has been found to require multiple loading steps. In certain embodiments, about 25% w / w to about 30% w / w of oxybutyrate can be achieved, or 25% w / w to 29% w / w, where the weight is based on the total weight of the oxybutyrate-anion exchange resin complex. In certain embodiments, there is about 27% w / w to about 29.5% w / w of oxybutyrate, where the weight is based on the total weight of the oxybutyrate-anion exchange resin complex. In certain embodiments, there is about 28% w / w to about 29.5% w / w of oxybutyrate, where the weight is based on the total weight of the oxybutyrate-anion exchange resin complex. In certain embodiments, there is about 27% w / w of oxybutyrate, where the weight is based on the total weight of the oxybutyrate-anion exchange resin complex. Such oxybutyrate-anion exchange resin complex can be mixed with an appropriate hydrophilic or hydrophobic polymeric component to form a matrix, optionally the oxybutyrate-anion exchange resin complex-matrix is coated. Optionally, a non-functional seal coat can be applied to the oxybutyrate-anion exchange resin complex, oxybutyrate-anion exchange resin complex-matrix, and / or coated oxybutyrate-anion exchange resin complex-matrix. Optionally or additionally, one or more functional coatings can be provided over the oxybutyrate-anion exchange resin complex matrix, and no separate non-functional coating is utilized.

[0056] The oxybutyrate-anion exchange resin complex can be mixed with an appropriate granulating agent (e.g., a hydrophilic polymer or a hydrophobic excipient) to form a matrix. The resulting matrix contains the oxybutyrate-anion exchange resin complex in the matrix, along with the hydrophilic polymer or the hydrophobic polymer, or the 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, relative to the resulting matrix. In certain working examples below, a "medium" molecular weight polyvinylpyrrolidone (PVP) was used. (e.g., K30) The K value of this product (chemical formula (C6H9NO) n ) is 27.0-32.4 and the average molecular weight is about 44,000 Daltons to about 54,000 Daltons according to the European Pharmacopoeia and the U.S. Pharmacopoeia. Average molecular weight is calculated from relative viscosity in water [H. Fikentscher, Cellulos Chemie 13 (1932): 58-64 and 71-74. See, e.g., Volker Bühler, BASF, “Polyvinylpyrrolidone,” in Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co. KG: Weinheim, Germany, 2005, DOI: 10.1002 / 14356007.a20_457.

[0057] Polyvinylpyrrolidone excipients for the pharmaceutical industry, 9th Revision, pp. 1-330 (March 2008). For example, the average molecular weight (MW) can be determined using light scattering or ultracentrifugation. Alternative methods include number average (Mn, determined by osmometry, membrane filtration) or average viscosity. However, other PVP polymers can be selected, for example, those having an average molecular weight of about 28,000 to about 100,000, which are soluble in water at room temperature.

[0058] In certain embodiments, the oxybutynin salt-anion exchange resin complex is granulated with a hydrophobic material that provides a release delaying function, such as glyceryl behenate. Then, another hydrophobic material can be selected, preferably a pH independent, high melting temperature, matrix forming, 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. While waxes having a melting point in the range of about 30°C to about 50°C can be utilized, for waxes or waxy substances having a lower melting point, it can be necessary to conduct the blending or other processing at a low temperature to offset the heat generated during processing. Waxes and waxy substances having a melting point in the range of about 50°C to about 80°C are particularly desirable. Examples of suitable pH independent, high melting temperature, matrix forming, water insoluble waxes or waxy substances include, for example, stearyl alcohol, acetyl alcohol, glyceryl palmitostearate, glyceryl monostearate; and a wax selected from one or more of carnauba wax, beeswax, candelilla wax, microcrystalline wax, ozokerite wax, paraffin wax, glyceryl behenate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl palmitate, cetyl octanoate, stearyl palmitate, stearyl stearate, derivatives thereof, and mixtures thereof. In one embodiment, glyceryl behenate is used. Glyceryl behenate is available under the trade name 888 ATO (Gattefosse, France) having 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 under the trade name Glyceryl palmitostearate under the trade name ATO 5 (Gattefosse, France) is a wax-type lipid excipient having a melting point of about 56°C and a HLB value of 2. In still another embodiment, cetyl stearyl alcohol is used, having a melting point in the range of about 48°C to about 56°C, or about 52°C. In a further example, acetyl alcohol having a melting point in the range of about 45°C to about 52°C can be used alone or in combination with one or more waxes or waxy substances; suitably, pharmaceutical grade waxes or waxy substances are used in the composition. Examples of other such substances include carnauba wax, vegetable wax, fruit wax, stearic acid, microcrystalline wax, beeswax, hydrocarbon wax, paraffin wax, cetyl ester wax, emulsifying wax, candelilla wax, free wax acids (of which stearic acid is an example), wax esters, propylene glycol monostearate, glyceryl monostearate, palmitic wax, montan wax, ozokerite wax, ceresin wax, lardaceine, Chinese wax, stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, lauryl alcohol, myristyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil, fatty acids, fatty acid esters, fatty acid glycerides, and polyethylene glycol (molecular weight greater than 3000). Optionally, the resin can be combined with a polymeric material used to perform the coating, for example, RLS / RS or In other embodiments, the polymers and copolymers can contain hydrophobic polymers / copolymers, and / or blends of hydrophobic and hydrophilic polymers / copolymers. See, for example, U.S. Published Patent Application Nos. US 2005 / 0232986; US 2005 / 0232987; US 2005 / 0232993; US 2005 / 0266032; U.S. Patent 7,067,116; U.S. Patent 6,667,058, U.S. Patent 6,001,392, and the like, the disclosures of which are incorporated herein by reference.

[0059] Alternatively, in certain embodiments, the matrix component avoids the use of polymers (e.g., hydrophobic polymers) that can have a function of delaying release of the oxybutynin salt. In such embodiments, the matrix-forming component comprises primarily hydrophilic polymers. Examples of suitable hydrophilic polymers and copolymers (e.g., polyvinylpyrrolidone) are described above. Other suitable hydrophilic polymer systems that can be mixed with the complex can include, for example, propylene glycol, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, mannitol, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and sorbitol. Still other polymers can be selected and mixed with or granulated with the complex to form the matrix.

[0060] In certain embodiments, the oxybutynin salt-anion exchange resin complex-matrix can contain from about 5% to about 50% by weight, or from about 20% to about 40% by weight, or about 25% by weight of a matrix-forming polymer, with the remainder of the weight provided by the oxybutynin salt-anion exchange resin complex.

[0061] Immediate release component

[0062] In certain embodiments, the compositions as provided herein contain an immediate release oxybutynin salt component. Suitably, such immediate release component can be an oxybutynin salt-anion exchange resin complex - optionally a matrix - that conforms to an immediate release profile as described below. Such component is typically devoid of any functional coating to maintain its immediate release profile. In certain embodiments, a strong anion exchange resin (i.e., cholestyramine anion exchange resin) is selected.

[0063] "Immediate release" means that not less than (> 75%) of the oxybutynin salt in the composition is released within less than one hour (typically between about 0.1 hour to about 1 hour), and in certain embodiments, within less than about 0.75 hours, after ingestion (post-dosing). In certain embodiments, the immediate release oxybutynin-chelating resin complex of (a) releases at least 80% of the oxybutynin within less than one hour. The rate of release can be determined in an in vitro release assay. See, e.g., 900 mL in 0.1 HC1 and other conditions described in the Figures and Examples herein.

[0064] Any suitable GHB drug (e.g., oxybutynin salts) or mixture thereof can be selected to complex with the anion exchange resin as the immediate release component. In certain embodiments, the immediate release component is a powder comprising the oxybutynin-anion exchange resin complex. The compositions provided herein are designed to avoid the presence of uncomplexed oxybutynin, oxybutynin salts (e.g., calcium oxybutynin, magnesium oxybutynin, or potassium oxybutynin), and counterions of the oxybutynin salts. As used herein, the immediate release powder is a mixture of relatively uniform, discrete particles. As described herein, the average particle size of the immediate release particles is generally from 250 microns to about 425 microns. In certain embodiments, the oxybutynin-anion exchange resin complex - optional matrix has a moisture barrier coating. Such moisture barrier coatings maintain the integrity and stability of the active drug during shelf life storage, and / or facilitate coloration.

[0065] As used herein, "non-functional coating" is optional and refers to a coating that does not cause the coated drug to exhibit a detectable modulated drug release function, and can alternatively be referred to as a "sealing coating." In other words, such a coating does not change the drug release profile of the immediate release drug to a modulated release profile. The non-functional coating can contain a polymeric or non-polymeric material that is a moisture barrier to maintain the integrity of the coated drug (granules) during storage and / or further processing. Additionally or alternatively, the non-functional coating can include oxygen barrier properties. In certain embodiments, the non-functional coating helps to protect the coated drug product from interacting with the packaging in which the product is stored (e.g., an aluminum foil pouch). Some of the non-functional materials provided herein are commercially available. See, e.g., Hypromellose Phthalate; Methyihydroxyethylcellulose; Hydroxypropylcellulose; Polyvinylpyrrolidone; Polyvinyl alcohol (see, e.g., II (polyvinyl alcohol, polyethylene glycol, talc), or AMB (Colorcon Inc., Harleysville, PA); carboxymethylcellulose; combination of polyacrylic acid resins, carbomer; and powdered cellulose coating. As used herein, "low molecular weight" has a viscosity of about 100 cP to about 5000 cP. The weight percent of these non-functional coatings, if present, is provided as added weight, which is added to the amount of the final resin acid salt granule or microparticle in an amount of about 1 wt% to about 50 wt%, or about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%.

[0066] The immediate release component can contain one or more different immediate release forms, for example, two different anion exchange resins can be utilized, and / or one complex can have a matrix and another complex can not have a matrix. In certain embodiments, the immediate release component is a glycuril-anion exchange resin complex-optional matrix as described herein, but lacks a functional coating. In certain embodiments, the immediate release component lacks counterions for any pharmaceutically acceptable salt of the GHB salt class used to generate the glycuril-anion exchange resin (i.e., sodium free, sodium and / or potassium free, etc.).

[0067] Modified release component

[0068] In addition to the immediate release glycuril component discussed above, the composition contains a delayed release glycuril component (also referred to as the ER component) and a glycuril component with a double layer coating system containing a blend of delayed and delayed release coating polymers in one layer above a diffusion barrier coating layer (also referred to as the SITCS component) above a glycuril-anion exchange resin complex (resinate) or glycuril resinate matrix. These two modified release glycuril components contain a first glycuril resinate-optional matrix as described in the immediate release component (with a single diffusion barrier coating layer) and a second glycuril resinate-optional matrix (with a double layer SITCS coating). The delayed release glycuril component contains a pH independent diffusion barrier coating layer above a glycuril-anion exchange resin complex-optional matrix, where the barrier coating layer provides a delayed release profile for the glycuril in the complex. The SITCS glycuril component provides a double layer coating that provides a delay or lag and aids in the post-dose delayed release of the glycuril.

[0069] In general, the term "modified release" includes sustained release, controlled release, extended release, delayed release, timed release, delayed-onset release, slow release, and time-release. The release rate can be controlled by the use of a modified release polymer, such as those described herein. As described herein, due to the nature of the active component of the composition (i.e., the hydroxybutyrate-anion exchange resin complex), the modified release of the hydroxybutyrate is designed to have a modified release that provides release for a period of 3 hours to 8 hours, 3.5 hours to 8 hours, 4 hours to 8 hours, 4.5 hours to 8 hours, 5 hours to 8 hours, preferably no more than about 7.5 hours, and more preferably no more than 7 hours. In certain embodiments, the hydroxybutyrate is substantially completely released about 8 hours after administration. In certain embodiments, the plasma concentration at 8 hours is less than 25 micrograms / ml. In other embodiments, no plasma hydroxybutyrate drug level is detected at 10 hours, preferably at 9 hours, and more preferably at 8.5 hours. In other embodiments, compositions with higher doses are designed to have therapeutic effect at no more than about 6 hours or at no more than about 5 hours. For example, the compositions as provided herein can have a modified release profile and provide therapeutic effect at about 3.5 hours to 7 hours. In certain embodiments, in vitro release assays can be used to determine release.

[0070] In certain embodiments, the composition contains three hydroxybutyrate multiparticulate components, each with a different release profile: (a) an immediate release hydroxybutyrate-anion exchange resin complex-optional matrix multiparticulate, (b) a time-release hydroxybutyrate resin salt multiparticulate component, and (c) a SITCS hydroxybutyrate resin salt multiparticulate component.

[0071] In certain preferred embodiments, the coating layer does not contain any active compound (e.g., does not contain a hydroxybutyrate component).

[0072] A. Time-Release Component

[0073] In one embodiment, the time-release component comprises a coated barrier, a hydroxybutyrate-anion exchange resin complex-optional matrix. In certain embodiments, a matrix is present. In other embodiments, a matrix is not present. As described herein, the time-release component in the composition is believed to contribute to achieving substantially higher plasma concentration levels at 5 hours (C5) after administration, which is desirable for a once-a-night dosage regimen.

[0074] As used herein, the term "delayed release coating" refers to a coating layer that functions to modulate the release rate of the oxybutynin from the coated oxybutynin-anion exchange resin complex-optional matrix as compared to an immediate release oxybutynin salt such as free oxybutynin active pharmaceutical ingredient (API) (e.g., sodium oxybutynin or another pharmaceutically acceptable salt thereof) or an immediate release oxybutynin salt-anion exchange resin complex-optional matrix provided herein, which can serve as a point of reference.

[0075] Suitably, the diffusion barrier coating has a pH independent release (i.e., it is not an enteric or reverse enteric coating that has a pH dependent release) and is a water insoluble, water permeable coating material. The diffusion barrier coating is applied over the oxybutynin-anion exchange complex-optional matrix (e.g., as an aqueous dispersion or solution), dried and milled or passed through a screen such that the oxybutynin-anion exchange complex-optional matrix multiparticulates of the barrier coating are, for example, on average from about 125 microns to about 1 mm, or on average from about 300 microns to about 900 microns, or from about 400 microns to about 800 microns.

[0076] In one embodiment, the diffusion barrier coating layer is from about 10% w / w to about 90% w / w, or from about 15% w / w to about 80% w / w, or from about 15% w / w to about 50% w / w, based on the weight of the oxybutynin-anion exchange resin complex prior to coating (and the weight of the complex prior to any matrix component). In certain embodiments, the diffusion barrier coating layer comprises a polyvinyl acetate polymer and a stabilizer and plasticizer, as described herein. However, other diffusion barrier coatings can be selected, as described herein, for example, a barrier coating comprising a low permeability, pH independent polymer or copolymer comprising trimethylammonium methyl methacrylate chloride, methyl methacrylate, ethyl acrylate polymer (e.g., RS) and a plasticizer; a barrier coating comprising cellulose acetate and a plasticizer; and / or a pH independent coating, for example, a coating comprising a neutral copolymer of ethyl acrylate and methyl methacrylate (e.g., a neutral copolymer of poly(ethyl acrylate-co-methyl methacrylate) 2:1) of the brand Eudragit® NM and a plasticizer or mixtures thereof.

[0077] Generally, the total amount of plasticizer or plasticizer combination combined is about 2% to about 50% relative to the weight of the coating layer, more preferably about 2% to about 30% relative to the weight of the coating layer on the hydroxybutyrate-anion exchange resin complex-optional matrix of the coating. Preferably, a suitable plasticizer provides the most desirable properties in the range of about 2.5% to about 15% relative to the weight of the coating layer based on the coated complex. Suitable plasticizers can be water soluble and water insoluble. Examples of suitable plasticizers include, for example, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triacetin, and P(2-pyrrolidone) and mixtures thereof. Other plasticizers are described in patent application publication US 2003 / 0099711 Al, May 29, 2003, page 4 (0041), the disclosure of which is incorporated herein by reference.

[0078] In one embodiment, the diffusion barrier coating is applied as an aqueous dispersion that is dried to provide the desired modified release profile. The coating can be mixed with a plasticizer and / or cured to provide the desired release profile, for example in the case of a water-based polyvinyl acetate coating. In one embodiment, the barrier coating is applied as an aqueous dispersion of a water-insoluble polymer comprising a polyvinyl acetate polymer, or a blend of polymers comprising a polyvinyl acetate polymer. In one embodiment, the barrier coating further contains a plasticizer that enhances the tensile strength of the barrier coating layer.

[0079] In certain embodiments, the diffusion barrier coating is applied in the form of an aqueous dispersion that contains an aqueous coating dispersion based on a polyvinyl acetate (PVA) polymer and a plasticizer. PVA is not water soluble at room temperature. PVA can be used in substantially pure form or as a blend. Suitably, a hydrophilic polymer is combined with the PVA in order to provide the desired release profile for the hydroxybutyrate drug. For example, if the barrier coating comprises a PVA polymer, the PVA polymer is present in an amount of about 10% w / w to about 80% w / w of the final barrier coating layer, at least about 75% w / w of the final barrier coating layer, at least about 50% w / w, about 15% w / w. In one embodiment, the barrier coating layer includes a hydrophilic polymer in an amount of about 5% w / w to about 70% w / w of the coating layer, or about 10% w / w to about 50% w / w, or about 15% w / w to about 45% w / w. The use of polyvinylpyrrolidone as a suitable hydrophilic polymer is described below. However, other suitable hydrophilic polymers can also be readily selected, for example, propylene glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., K30) mannitol, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sorbitol.

[0080] Commercial polyvinyl acetate blends primarily contain polyvinyl acetate polymers, stabilizer components, and a small amount of surfactant (e.g., sodium lauryl sulfate). If the barrier coating contains PVP as a stabilizer component, the final barrier coating layer typically contains about 5% w / w to about 10% w / w of polyvinylpyrrolidone. In one desirable embodiment, the water-based barrier coating solution is SR 30D (BASF) and its composition is about 27% PVA polymer, about 2.7% polyvinylpyrrolidone (PVP), and about 0.3% sodium lauryl sulfate (an anionic surfactant) (30% w / w solids), and mixed with a plasticizer. Typically, the stabilizer components are present in an amount totaling less than about 10% w / w, and preferably less than about 5% w / w. See also U.S. Patent 6,066,334 and U.S. Patent 6,026,277, which are incorporated herein by reference. If this product is selected, additional hydrophilic polymers can be added to facilitate a more rapid (i.e., less than 8 hours as described herein) release. Optionally, the selected surfactant is present in an amount of about 1% or less. In one embodiment, the surfactant is a non-ionic surfactant. Optionally, an ionic surfactant can also be selected.

[0081] In certain embodiments, the barrier coating layer is formed by applying an aqueous dispersion containing SR-30D - plasticizer, drying, and curing. Preferably, the coating is cured for about 1 hour to about 24 hours. In alternative embodiments, the coating is cured at an elevated temperature (e.g., about 50°C to about 65°C, and preferably about 60°C) for about 4 hours to about 16 hours, and preferably about 5 hours. See, for example, U.S. Published Patent Application No. US 2007 / 0215511 A, published September 20, 2007, and its counterpart application WO 2007 / 109104, the disclosures of which are incorporated herein by reference.

[0082] Another diffusion barrier coating polymer or copolymer can be selected. In such other embodiments, an ethyl cellulose based on a non-aqueous solvent (e.g., commercially available ETHOCEL TM Klucel® product (DuPont) or an aqueous Ethyl cellulose [Karo Corp.] can be modified to achieve the barrier coating properties defined herein, for example, by adding sufficient amounts of plasticizers to increase flexibility and / or by curing to sufficient temperatures to achieve the desired release rates. Three of the products are described on the Dow website: Standard 7 (viscosity of 6-8 mPa-s (CP)); Standard 10 (9-11 mPa-s (CP)); and Standard 20 (18-22 mPa-s (CP)), each having an ethoxyl content of 48.0-49.5%), which can be used for tablet coating. In addition, it is further described that optionally one of these polymers can be combined with a water-soluble active and / or a water-soluble excipient (such as cellulose ether and / or polyethylene glycol). Alternatively, water-based ethyl cellulose barrier coatings can be modified in order to achieve the modified release barrier coating properties required herein, for example, by adding sufficient amounts of plasticizers to increase flexibility and / or by curing to sufficient temperatures to achieve the desired release rates. See, for example, the barrier coatings described in U.S. Patent 6,066,334 and U.S. Patent 6,046,277; see 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 WO 03 / 020242; WO 2006 / 022996 and related applications U.S. Published Patent Application Nos. US 2005 / 0232986; US 2005 / 0232987; US 2005 / 0232993; US 2005 / 0266032; U.S. Patent 7,067,116; U.S. Patent No. 6,667,058, U.S. Patent 6,001,392, etc., the disclosures of which are incorporated herein by reference.

[0083] Other water-based or non-water-based solvent-based systems that do not require curing can be utilized. For example, water-based acrylic polymers (described herein RL30D and RS30D blends) but benefit from the addition of an anti-tacking agent to facilitate handling and uniform coating. Suitable anti-tacking agents include, for example, talc, glycerol monostearate (GMS), and mixtures thereof. These agents are present in amounts of about 0.2% w / w to 4.5% w / w, based on the dry weight of the coating polymer applied to form the coating layer of the modified release component. In certain embodiments, the coating layer resulting after application of the acrylic polymer-based coating does not require curing.

[0084] In one embodiment, the coating can be Brands' acrylate-based copolymer coating material [including, for example, poly(ethyl acrylate-co-methyl methacrylate-co-methyl methacrylate trimethylammonium ethyl chloride) polymer system]. For example, one can select RS 30D [pH independent, 30% aqueous dispersion of poly(ethyl acrylate-co-methyl methacrylate-co-methyl methacrylate trimethylammonium ethyl chloride) 1:2:0.1] or RL 30D [30% aqueous dispersion, pH independent polymer, poly(ethyl acrylate-co-methyl methacrylate-co-methyl methacrylate trimethylammonium ethyl chloride) 1:2:0.2] as a barrier coating. In one embodiment, one can prepare a blend of RS 30D and RL 30D to optimize the hydrophilicity or hydrophobicity of the film in order to obtain the desired release profile.

[0085] Diffusion barrier coatings as described herein can be applied using techniques described by the polymer manufacturers and / or known to those skilled in the art. Suitable methods and equipment have been described in the patent and non-patent literature and include, for example, spray coating in a fluid bed processor or using a pan coating. The coating solution can be sprayed using a Wurster process in a fluid bed processor (e.g., VECTORTM FLM-1 fluid bed processor). The hydroxybutyrate-anion exchange resin complex (optional matrix) of the diffusion barrier coating is then dried and / or cured.

[0086] B. Double Layer Small Intestine Targeted Coating System (SITCS) Hydroxybutyrate Component

[0087] In addition to the time delay release component, a SITCS modified release component is provided. In certain embodiments, the composition comprises a double layer SITCS coated hydroxybutyrate-anion exchange resin complex-optional matrix. The SITCS double layer system comprises a pH independent barrier coating over a hydroxybutyrate-anion exchange resin complex-optional matrix which further comprises a coating layer comprising a blend 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 over the hydroxybutyrate-anion exchange resin complex of the barrier coating. In preferred embodiments, such components comprise only two functional coating layers, with the barrier coating being the inner layer directly over the hydroxybutyrate resin complex-optional matrix and the blended pH independent / pH dependent release coating layer being the outer layer.

[0088] In certain embodiments, the blend polymer coating layer comprises two different pH independent barrier coating polymers / copolymers. In one embodiment, the first pH independent barrier coating layer is over the glycolate-anion exchange resin complex. This can be the same or different from the pH independent barrier coating layer in the delayed release component. In certain embodiments, the pH independent polymer / copolymer in the blend pH dependent / pH independent layer, which further comprises an enteric polymer / copolymer, is different from the polymer / copolymer used in the pH independent diffusion barrier coating layer. Suitably, the blend pH dependent / pH independent coating layer comprises a blend of a pH independent polymer / copolymer and a pH dependent enteric coating polymer / copolymer, which two polymers / copolymers are compatible. Examples of suitable polymer / copolymer combinations for the blend pH dependent / pH independent coating layer include, for example, polyvinyl acetate (pH independent; barrier coating) and polyvinyl acetate phthalate (enteric) or methacrylic acid copolymer enteric polymer and ethyl acrylate and methyl methacrylate copolymer pH independent coating polymer. Other suitable combinations can be selected as described herein.

[0089] Because the blend pH dependent / pH independent outer coating reduces exposure of the delayed release coating to body fluids until after the components reach the small intestine and are exposed to body fluids having a pH greater than 4 or in certain embodiments a pH of 4.5 and above, there is a lag time between administration (oral ingestion) and the onset of release of the glycolate in the delayed, time release component. In certain embodiments, the SITCS component provides a lag time of about 1 hour to about 3 hours after administration and reduces release of the glycolate in gastric acid media. In certain embodiments, the lag time is about 1.5 hours to about 2.5 hours, or about 1.75 hours to about 2.5 hours, values therebetween.

[0090] In certain embodiments, the blended pH-independent / pH-dependent release coating layer comprises a range of about 1 :9 to about 9: 1, more preferably about 3:7 to about 7:3, more preferably about 4:6 to about 6:4. In certain embodiments, the blended pH-independent / pH-dependent release coating layer comprises about 40% w / w of a pH-dependent enteric coating polymer or copolymer to about 60% w / w of a pH-independent diffusion barrier coating polymer or copolymer, based on the weight of the polymer / copolymer in the coating layer. In certain embodiments, the blended pH-independent / pH-dependent release coating layer comprises about 60% w / w of a pH-dependent enteric coating polymer to about 40% w / w of a pH-independent enteric coating polymer or copolymer, based on the weight of the polymer / copolymer in the coating layer. In certain embodiments, the blended pH-independent / pH-dependent release coating layer comprises about 50% w / w of an enteric coating polymer / copolymer to about 50% w / w of a pH-independent barrier coating polymer / copolymer, based on the weight of the polymer / copolymer in the coating layer. Optionally, the blended pH-independent / pH-dependent release coating layer further comprises about 0.5% w / w to about 10% w / w of a plasticizer, one or more homogenizing agents, and / or one or more surfactants.

[0091] Suitably, the pH-dependent enteric polymer component in the blended pH- independent / pH-dependent release coating layer is selected so that the delayed release coating component allows release of the oxybutynin salt when the dosage form reaches the small intestine or a region where the pH is greater than pH 4 and more typically ranges from pH 4 to 8. Preferred are pH sensitive materials that remain intact in the lower pH environment of the stomach but disintegrate or dissolve at the pH commonly found in the small intestine of a patient. Enteric polymer coating materials begin to dissolve in aqueous solutions at a pH of about 4.5 to about 5.5, and dissolve more rapidly at a pH above about 5.5. The pH dissolution behavior of the enteric polymers of the present invention is such that the enteric polymer coating does not dissolve significantly until after the dosage form has been expelled from the stomach. The pH of the small intestine increases gradually from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal portion of the small intestine (ileum). In order to provide a predictable degree of solubility corresponding to the transit time of the small intestine (about 3 hours), and to allow for repeated release therein, the coating should begin to dissolve at the pH range of the duodenum and continue to dissolve at the pH range within the small intestine. Thus, the amount of enteric polymer coating should be such that it dissolves significantly during the transit time of about three hours within the small intestine.

[0092] In certain embodiments, such delayed release components in the blended pH- dependent / pH-independent release coating layer can use the same delayed release polymers as are present in the non-delayed delayed release coating layer, but at a lower weight percentage.

[0093] In other embodiments, the delayed-release coating layer of the delayed-release component comprises a delayed-release polymer system different from the delayed-release polymer system present in the delayed-release component.

[0094] The hydroxybutyrate-anion exchange resin complex—optionally a matrix—is prepared as described herein and coated with an inner barrier coating layer. The barrier coating layer can be applied as described in the delayed-release component, but the weight percentage of the barrier coating layer is typically lower than the weight percentage of the barrier coating layer present in the delayed-release component. In some embodiments, based on the coated complex, the pH-independent barrier coating layer is about 10% w / w to about 50% w / w, or about 20% w / w to about 45% w / w. In some embodiments, the weight percentage is about 15% w / w to about 50% w / w, or about 20% w / w to 50% w / w, or 25% w / w to 40% w / w, or about 30% w / w to about 45% w / w, about 25% w / w, about 30% w / w, or about 35% w / w.

[0095] In this embodiment, the barrier-coated hydroxybutyrate-anion exchange resin complex-optional matrix is ​​provided with a second coating layer, and an outer pH-dependent enteric coating is applied on top of the barrier coating layer.

[0096] Various delayed-release (enteric) 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 hydrogen phthalate, phthalic acid amylase, cellulose phthalate, cellulose phthalate ether, sodium cellulose acetate phthalate, phthalic acid starch, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate propionate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate copolymer propionate, shellac, and mixtures thereof. Other enteric polymers include, for example, hydroxypropyl methylcellulose phthalate (HPMC), succinic acid acetate (HPMC), and pH-dependent acrylate polymers and copolymers and / or mixtures thereof. Other enteric polymers include, for example, one or more of the following: methacrylic acid copolymer dispersions, ethyl acrylate and methyl methacrylate copolymer dispersions and / or mixtures thereof. Some of these polymers are available from Evonik Industries. Commercially acquired (e.g., product lines) L series (L30 D-55 or L100-55 (dissolves at pH 5.5 or higher), L100 or L12,5 (dissolves at pH 6.0 or higher)) or S series (S100, S12,5, FS 30D (dissolves at pH 7.0 or higher)). L-30-D 55 is an aqueous acrylic resin dispersion, an anionic copolymer derived from methacrylic acid and ethyl acrylate, having a free carboxyl to ester ratio of approximately 1:1 and an average molecular weight of approximately 250,000, supplied as an aqueous dispersion containing 30% w / w of dry paint material. In some embodiments, the pH-dependent polymer or copolymer is selected from one or more of the following: methacrylic acid copolymers, methacrylate copolymers or polyvinyl acetate phthalate, methacrylic acid copolymer dispersions, ethyl acrylate and methyl methacrylate copolymer dispersions, hydroxypropyl methylcellulose acetate succinate (HPMC), HPMC phthalate, polyvinyl acetate phthalate, and / or mixtures containing these substances. Other commercially available enteric coating polymers may include, for example, hydroxypropyl methyl cellulose phthalate HP50 (HPMCP-HP50) (USP / NF 220824), HP55 (HPMCP-HP55) (USP / NF type 200731), and HP55S, which are available from Shin Etsu Chemical Co., Ltd. (Polyvinyl acetate phthalate) (Berwind Pharmaceutical Services, Inc.) (Polyvinyl acetate phthalate) (Carrefour Corporation) or (Cellulose phthalate) (FMC Corporation)

[0097] The enteric coating layer may also preferably contain a plasticizer, such as diethyl phthalate, triethyl citrate (Citroflex-2), triacetin, tributyl sebacate, or polyethylene glycol. Optionally, an anti-blocking agent (anti-agglomeration agent) may be included, which is advantageously a hydrophobic material, such as talc, magnesium stearate, or fumed silica.

[0098] 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 delayed-release barrier layer and the blended coating layer. These can be selected from the materials described in other parts of this application. In some embodiments, the water-insoluble polymer or copolymer is one or more of the following: polyvinyl acetate, ethyl cellulose, or a copolymer of ethyl acrylate and methyl methacrylate and / or a mixture containing these substances.

[0099] Other components can be present in the blended pH independent and pH dependent coating layers including, for example, surfactants, pore forming components, stabilizers, plasticizers, antifoaming agents, solubilizers, and colorants, among others. If present, the amount of these components will range from about 5% to about 15% by weight of the enteric polymer, preferably ranging from about 9% to about 12% by weight of the same, based on the total weight of the blended coating layer. Examples of suitable stabilizers can 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, disodium hydrogen phosphate, magnesium silicate, magnesium aluminate, magnesium aluminum silicate, synthetic hydrotalcite, aluminum magnesium hydroxide, meglumine, lysine, ethylenediamine, Ν,Ν'-dibenzylethylenediamine, procaine, chloroprocaine, choline, diethanolamine, and mixtures thereof. Examples of suitable pore forming materials can include, but are not limited to, mannitol, dextrose, sucrose, lactose, HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, mannitol, organic acids, and mixtures thereof. Optionally, a colorant or dye can be incorporated in this outer layer, or a separate colored coating can be applied. These enteric polymer systems can be applied as aqueous solutions or solvent-based systems using suitable coating techniques, for example, a barrier coated hydroxybutyrate-anion exchange resin complex-optional matrix spray or pan coating. After coating, the barrier coated hydroxybutyrate-anion exchange resin complex-optional matrix of the delayed release coating is dried and optionally cured.

[0100] In certain embodiments, the total weight of solids in the coating layer in the SITCS release component ranges from about 30% w / w to about 90% w / w, more preferably from about 50% w / w to about 80% w / w, based on the total weight of the SITCS release component. In certain embodiments, the total weight of solids in the SITCS coating ranges from about 35% w / w to about 70% w / w, or from about 40% w / w to 65% w / w, or from 35% w / w to 75% w / w, or from about 45% w / w to about 75% w / w, or from about 45% to about 65% w / w. In certain embodiments, the time delay release coating layer ranges from about 15% w / w to about 35% w / w, or from about 20% w / w to 35% w / w, or from 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 release layer ranges from 20% w / w to about 80% w / w, from about 25% w / w to about 65% w / w, from about 30% w / w to about 40% w / w, of the resin of the diffusion barrier coating, or from about 45% w / w to about 75% w / w, or from about 50% w / w to about 70% w / w, or from about 55% w / w to about 65% w / w, of the resin of the coating.

[0101] In certain embodiments, the ratio of the pH-independent / pH-dependent coating layer and the pH-independent diffusion barrier coating layer is about 10:90 to about 90:10.

[0102] C. Final Formulation

[0103] The composition can be, for example, a powder, a powder for suspension (POS), a capsule powder or suspension, etc. The excipients of the composition are selected accordingly. For example, the excipients in a tablet can include a binder, a diluent, a disintegrant, an osmotic agent, a release retarding polymer, a flow aid, a compression aid, a lubricant, and / or an anti-sticking agent. The excipients in a suspension and / or an ER POS can include a suspending agent and / or a thickening agent, a wetting agent, and / or a preservative. The excipients are discussed in subsequent sections.

[0104] In certain embodiments, the final product contains at least: (a) an immediate release component; (b) a time delayed release barrier coated hydroxybutyrate-anion exchange resin complex-optional matrix; (c) a SITCS coated hydroxybutyrate-anion exchange resin complex-optional matrix; (d) calcium chloride in an amount equivalent to about 1 mEq to about 12 mEq of composition per 9 gm hydroxybutyrate dose; wherein the POS contains less than a total sodium equivalent to 200 mg of sodium per 9 gm hydroxybutyrate dose, and optionally diluent granules.

[0105] Examples of compositions and suitable excipients are described in U.S. Patents 11,337,920 and US 11,666,546, which are incorporated herein by reference. In certain embodiments, an orally administrable composition is provided comprising a GHB component 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, which comprise from 0.5% w / w to 10 w / w %, or from about 0.5% w / w to 5% w / w, or a value therebetween, for example, about 1% w / w, about 2% w / w, etc., of the total dry component (e.g., POS, powder blend, or tablet). In certain embodiments, the anionic polymer is selected from pectin, gellan gum, carrageenan, or a combination thereof. In certain embodiments, the crosslinking agent comprises from 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 component (e.g., powder blend). In certain embodiments, the gas generating agent comprises from about 0.5 wt% to about 15 wt%, or from about 1 wt% to about 10 wt%, or about 7 wt%, or about 11 wt%, of the composition, based on the total dry component (e.g., powder blend). In certain embodiments, the gas generating agent is a bicarbonate salt. In certain embodiments, the bicarbonate salt is potassium bicarbonate. In certain embodiments, the remainder of the composition comprises excipients, such as diluents, binders, disintegrants, etc. One or more anionic polymers, optionally in combination with a galactomannan and / or another polymer (e.g., a non-ionic polymer), can be used to form an IPN or semi-IPN. Such anionic polymers can include, but are not limited to, at least one of the following: pectin, alginic acid, gellan gum, carrageenan, xanthan gum, and / or combinations thereof. In certain embodiments, pectin is included. The polymeric backbone of pectin consists mainly of a-(1-4)-D galacturonic acid residues. Free calcium ions cross-link the galacturonic acid chains. A divalent ion source, typically a calcium ion source, is required to produce the vehicle for drug delivery. The main advantage of using pectin in these formulations is that it is water soluble, thus no organic solvents are required in the formulation. Calcium ions in complex form can be included in the formulation to induce pectin cross-linking. In other embodiments, alginic acid is included. Alginic acid is a linear block copolymer consisting of beta-D-mannuronic and alpha-L-guluronic acid residues linked by 1,4-glycosidic bonds. Dilute aqueous solutions of alginates cross-link with divalent and trivalent metal ions through a cooperative process involving successive guluronic residues in the alpha-L-guluronic acid blocks of the alginate chain. Gellan gum (may be Gelrite TM or Kelcogel TMGellan gum (commercially available as Kelgin®) is an anionic deacetylated exopolysaccharide secreted by Pseudomonas elodea with a tetrasaccharide repeating unit of one a-L-rhamnose, one b-D-glucuronate, and two b-D-glucuronate residues. The chemical structure of the polysaccharide has a tetrasaccharide repeating unit consisting of two glucose (Glc) residues, one glucuronic acid (GlcA) residue, and one rhamnose (Rha) residue. Like alginic acid and pectin, gellan gum chains are cross-linked by divalent or trivalent metal ions. Carrageenan belongs to the family of linear sulfated polysaccharides extracted from red edible seaweed. Carrageenan is mainly divided into three types, which differ in their degree of sulfation. Kappa-carrageenan has one sulfate group per disaccharide, iota-carrageenan has two sulfate groups per disaccharide, and lambda-carrageenan has three sulfate groups per disaccharide. Iota carrageenan is cross-linked by divalent cations, while kappa carrageenan is cross-linked 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 comprises 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 of one or more anionic polymers. Suitable cross-linking agents for the one or more anionic polymers can be selected from the non-limiting list of divalent and trivalent metal salts: calcium salts, such as calcium carbonate, calcium chloride, calcium gluconate; magnesium salts, ferrous salts, ferric salts, aluminum salts, zinc salts, or combinations thereof. In certain embodiments, the cross-linking agent can be a counterion from an excipient and / or an active agent. In other embodiments, the cross-linking metal ions can be provided by a cross-linking agent in the composition, or such metal ions can be provided by a moiety in the form of a monovalent or divalent or multivalent metal ion salt. Otherwise, such cross-linking metal ions can be provided by an excipient. For example, calcium carbonate can be used as a gas generator, but it can also provide calcium ions for cross-linking anionic polymers, including pectin, carrageenan, gellan gum, xanthan gum, and the like. In certain embodiments, the IPN-forming system comprises about 0.5% w / w to about 15% w / w, or about 0.5% w / w to about 5% w / w, or 0.7% w / w to about 1.5% w / w, or about 1% w / w of an anionic polymer cross-linking agent.

[0106] In some embodiments, the composition includes a gas generating agent. As described herein, a "gas generating agent" refers to an agent that produces a non-toxic gas upon contact with gastric juices. Suitable gas generating agents include, but are not limited to, carbonates or bicarbonates of alkali metals or alkaline earth metals, such as potassium carbonate or potassium bicarbonate, sodium carbonate or sodium bicarbonate, calcium carbonate, sodium glycine carbonate, magnesium carbonate, and aluminum carbonate; and 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 coupling.

[0107] In one embodiment, silicon dioxide ( 244FP) is provided in an amount of about 0.001% w / w to about 1% w / w. In one embodiment, sodium methylparaben is provided in an amount of about 5.26% w / w to about 10% w / w. In one embodiment, sodium propylparaben is provided in an amount of about 1.05% w / w to about 2% w / w. In one embodiment, povidone, USP ( 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). 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% w / w to 5% w / w. In one embodiment, methacrylic acid and methyl methacrylate copolymer (1:1) Eudragit L100 is provided in an amount of about 1% w / w to about 5% w / w. In one embodiment, microcrystalline cellulose, hydroxypropyl methylcellulose 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, higher or lower amounts are selected.

[0108] One or more superdisintegrants can be selected from the group consisting of low-substituted hydroxypropylcellulose, microcrystalline cellulose, crosscarmellose sodium or calcium, cellulose fiber, crosslinked polyvinylpyrrolidone, crosslinked polyacrylic acid, crosslinked Amberlite resin, alginate, colloidal magnesium aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinized starch, and sodium carboxymethyl starch. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinylpyrrolidone (PVP), copovidone, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (CMC) and salts thereof. Examples of suitable diluents include, but are not limited to, starch, dicalcium phosphate, microcrystalline cellulose, lactose monohydrate, hydrated dextrose, and the like. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. The composition can optionally further include a glidant such as, but not limited to, colloidal silicon dioxide, silica gel, precipitated silicon dioxide, or combinations thereof. Suitable examples of osmotic agents or pharmaceutically acceptable inert water-soluble compounds are selected from the group comprising: 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, methionine; urea or derivatives thereof; propylene glycol; glycerol; polyethylene oxide; xanthan gum; hydroxypropyl methylcellulose; or mixtures thereof.

[0109] One or more desired excipients, including, for example, flavorants, sweeteners, viscosity builders, flow aids, pH adjusters, preservatives, or other excipients, can be blended into the final powder mixture and / or added to the suspension. Optionally, one or more excipients are included in the final suspension-use powder blend as diluent granules, which facilitate reconstitution of the microparticulate hydroxybutyrate-anion exchange resin complex, the microparticulate barrier-coated hydroxybutyrate-anion exchange resin complex, and optionally also provide agents for improving powder flowability (e.g., a glidant), a sweetener or other flavoring agent, or a suspending agent. In one embodiment, the diluent granules contain a buffering species for controlling pH in the liquid suspension formulation. Optionally, the diluent granules can contain one or more other excipients, including, for example, a glidant, a flavoring agent, a preservative, a suspending agent, or a mixture of such excipients.

[0110] In certain embodiments, the composition is a powder for suspension of blended microparticles. In certain embodiments, the powder is formulated into a solid dosage form selected from a capsule, a tablet, a molded tablet, a pellet, a layered tablet, or a tablet-in-tablet. In certain embodiments, a composition is provided, a single dose of the oxybutynin salt has a therapeutic effect within about 5 hours to about 8 hours.

[0111] As discussed above, the immediate release component advantageously avoids the use of any oxybutynin salt, such as free API. The time delayed release component comprises a pH independent diffusion barrier coating layer having a water insoluble film forming polymer that imparts time delayed release to the oxybutynin salt in the complex - optional matrix. The bilayer SITCS component comprises an inner coating layer and an outer coating layer over the oxybutynin salt - cholestyramine anion exchange resin complex - optional matrix comprising oxybutynin salt bound to ion exchange sites in the cholestyramine anion exchange resin. When the complex is in the matrix, it further comprises at least one hydrophilic or hydrophobic polymer.

[0112] The first (e.g., inner) coating layer is a pH independent diffusion barrier coating layer having a water insoluble film forming polymer that imparts time delayed release to the oxybutynin salt in the complex - optional matrix, and the second coating layer is a blended coating layer over the pH independent diffusion barrier coating layer comprising a blend of a pH dependent polymer and a pH independent polymer / copolymer, wherein the pH dependent release coating layer imparts delayed release to the oxybutynin salt - cholestyramine anion exchange resin - optional matrix comprising the pH independent barrier coating inner layer.

[0113] In certain embodiments, the composition is a powder for suspension that has a therapeutic effect within at least about 5 hours to about 8 hours after oral ingestion by a patient (a human subject). The formulations provided herein can be packaged, stored, and transported as a powder, which is designed to be reconstituted in an aqueous liquid (e.g., drinking water) prior to administration as a liquid suspension. In other embodiments, two or more different types of oxybutynin - anion exchange resin complex components are formulated together as a solid dosage tablet, made or loaded into a capsule.

[0114] As an additional safety feature, the composition can further contain a pharmaceutically acceptable dye that will dissolve to provide a distinctive color when the composition is placed in an aqueous liquid.

[0115] 1. Powder formulation

[0116] To provide a final powder formulation suitable for reconstitution in water, the powder oxybutynin-anion exchange resin complex can be mixed with excipients. Such excipients can be one or more of a flow or lubricant, one or more preservatives, a pH buffer, a viscosity enhancer, or combinations thereof, can be mixed and the powder packaged in a suitable package, such as an aluminum foil pouch or a bottle. 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.

[0117] Optionally, one or more desired excipients, including, for example, flavorants, sweeteners, viscosity enhancers, flow aids, pH adjusters, preservatives, or other excipients, can be blended into the final powder mixture and / or added to the suspension. Optionally, one or more excipients are included in the final suspension-blended powder as diluent granules, which facilitate reconstitution of the micro-particulate oxybutynin-anion exchange resin complex, the micro-particulate barrier-coated oxybutynin-anion exchange resin complex, and the micro-particulate STICS-coated oxybutynin-anion exchange resin complex, and optionally also provide agents to improve powder flowability (e.g., flow aids), sweeteners or other flavoring agents, or suspending agents. In one embodiment, the diluent granules contain a buffering species for controlling the pH in the liquid suspension formulation. Optionally, the diluent granules can contain one or more other excipients, including, for example, flow aids, flavoring agents, preservatives, suspending agents, or mixtures of such excipients.

[0118] 2. Tablet Formulations

[0119] Oxybutynin tablets can be prepared using the three components described above and a solid oxybutynin-anion exchange resin complex - optionally a matrix, and one or more of a filler, one or more disintegrants, one or more binders, one or more buffering agents, one or more lubricants, one or more flow aids, one or more diluents, superdisintegrants, osmotic agents, release retarding agents, flow aids, compression aids, lubricants, and / or anti-sticking agents, or combinations of one or more of these components. Suitably, the tablets also include taste and / or mouth feel enhancers, including, for example, one or more of a sweetener, a flavorant, a gum, or a blend of these components.

[0120] In one embodiment, the tablet is formulated as an orally disintegrating tablet. Such an orally disintegrating tablet may disintegrate in the mouth in less than about 30 seconds or less. In another embodiment, the tablet is formulated as a chewable tablet. Typically, chewable tablets will contain fillers or filler mixtures ranging from 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 tablet weight. 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 sugar, calcium carbonate, magnesium carbonate, calcium sulfate, glucose binders, maltodextrin, etc. In one embodiment, the chewable tablet contains a blend 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 gum combination is provided in an amount of about 0.25% w / w to about 5% w / w, or about 0.25% w / w to about 1% w / w. In another embodiment, prior to any non-functional coating, 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 tablet weight. A commercially available product containing a combination of microcrystalline cellulose and guar gum, wherein the ratio of microcrystalline cellulose to guar gum is 80 parts by weight: 20 parts by weight. This blend 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 tablet weight. Based on the total tablet weight, the chewable tablets will also contain a disintegrant or disintegrant blend ranging from 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. Suitable disintegrants include, for example, crospovidone, sodium glycolate starch, croscarmellose sodium, sodium carboxymethyl cellulose and calcium carboxymethyl cellulose, and starch. In one embodiment, prior to the application of any non-functional coating, the tablets described herein contain crospovidone ranging from about 5% w / w to about 10% w / w, or about 12% w / w, based on the tablet weight.

[0121] The binder may be absent (i.e., 0%), or optionally present in an amount of about 1% w / w to about 15% w / w of the total tablet weight. Examples of suitable binders include polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, polyvinyl alcohol, starch, gum arabic, alginate, and sodium alginate.

[0122] In one embodiment, the tablet contains a sweetener 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, based on the total tablet weight (excluding any optional non-functional coating). Suitable sweeteners can include, for example, aspartame, saccharin, sodium saccharin, sucralose, cyclamate, xylitol, acesulfamate potassium, and blends thereof. Optionally, in addition to functioning as a sweetener, the excipient can also function as a filler. Examples of suitable sweeteners / fillers include, for example, dextrose, sucrose, xylitol, maltitol. Optionally, when performing both functions, the excipient can be present in an amount that exceeds about 10% w / w of the tablet. In such cases, additional sweetener can be omitted (e.g., added sweetener is present at 0%). Alternatively, a second sweetener or combination of sweeteners different from the filler is added in the amounts provided in this paragraph to further enhance taste.

[0123] Suitably, a buffering agent is provided in the tablet 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 tablet weight. Examples of suitable buffering agents include, for example, citric acid, tartaric acid, malic acid, lactic acid, and acceptable salts thereof, and mixtures thereof.

[0124] When additional flavoring agents are added, the agents can be added in an amount of about 0.05% w / w to about 3% w / w, or about 0.1% w / w to about 1% w / w, or about 0.5% w / w, based on the total weight of the tablet (excluding any optional non-functional coating). Suitable flavoring agents can include natural and artificial flavoring agents, as are generally available through several custom manufacturers around the world, such as Fona International (Illinois, US), Givaudan International (Vernier, Switzerland), Ungerer & Company (Lincoln Park, N.J.), and International Flavors & Fragrances (New York, N.Y.), to name a few. Those skilled in the art will recognize that several commercial sources are available, including custom blends. The flavoring agents can be blended prior to addition to the pharmaceutical composition or added individually. Still other flavoring agents can be selected, such as bubble gum, cherry, strawberry, vanilla, grape, banana, and other flavors or mixtures thereof.

[0125] Optionally, a colorant can be provided for the tablet to provide a desired visual appeal or commercial appearance. Such colorants can be added in an amount of about 0.001% w / w 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 a number of sources, including, for example, Colorcon, Inc. (Harleysville, PA, USA), Lubrizol Pharmaceuticals (UK), and SpectraColourtech (India Private Limited). In one embodiment, no colorant is used in the tablet.

[0126] To facilitate the production of the chewable tablet, excipients such as lubricants and glidants can be utilized. Lubricants can be utilized in an amount 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 can include, for example, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, calcium stearate, magnesium trisilicate, polyethylene glycol, and blends thereof. In one embodiment, a glidant can be used in an amount 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 glidants include, for example, silicon dioxide and tribasic calcium phosphate. In one embodiment, the glidant is silicon dioxide, which is used in an amount of about 0.001% w / w to about 0.3% w / w, or about 0.2% w / w.

[0127] Optionally, other excipients can be selected from conventional pharmaceutically acceptable carriers or excipients and well- established techniques. Without being limited thereto, such conventional carriers or excipients include diluents, binders and adhesives (i.e., cellulose derivatives and acrylic acid derivatives), lubricants (i.e., magnesium stearate or calcium stearate, or vegetable oils, polyethylene glycol, talc, sodium lauryl sulfate, polyoxyethylene monostearate), thickening agents, solubilizers, humectants, disintegrants, colorants, flavorants, stabilizers, sweeteners, and miscellaneous materials such as buffers and adsorbents, to prepare a particular pharmaceutical composition. Stabilizers can include preservatives and antioxidants, as well as other components apparent to those of ordinary skill in the art.

[0128]

[0129] Still other suitable excipients can be selected in view of the teachings provided herein.

[0130] Suspension excipients

[0131] The compositions provided herein are generally administered in the form of a suspension that is mixed from a powder and a suspending base, preferably an aqueous suspending base. As used herein, an aqueous suspension refers to a suspension in which at least 50% v / v, preferably greater than about 60% w / v, greater than about 80% w / w, at least about 90% to 100% of the liquid component of the suspension is water. The suspending base can further contain a binder, a diluent, a salivator, a surfactant, a flavorant, a sweetener, a colorant, an acidulant, a viscolizer, a glidant, a chelator, a lubricant, a solubilizer, a stabilizer, a suspending agent, a preservative, a co-solvent, an anti-caking agent, a buffer, or any combination thereof. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinylpyrrolidone, copovidone, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and carboxymethyl cellulose and salts thereof. Examples of suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, xylitol, mannitol (e.g., Suitable fluidizers include, but are not limited to, 100 SD), maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dicalcium phosphate, co-treated 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 stearate fumarate. Suitable fluidizers include, but are not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. Suitable fluidizers include, but are not limited to, micronized polyethylene glycol, sodium chloride, or precipitated micronized silica. Examples of solubilizers include, but are not limited to, cetearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene stearate palmitate, glycerin, glyceryl monostearate, isopropyl myristate, 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 seed oil, triethanolamine, or combinations thereof. Acidulants include, but are not limited to, sodium fumarate and / or citric acid. The composition may also include stabilizers, such as, but not limited to, those described above in the pharmaceutical-resin complex section. Suitable chelating agents that may be used have been discussed above. Suitable thickeners include, but are not limited to, co-treated microcrystalline cellulose, such as, but not limited to, Avicel. RC591, AvicelCL-611, D-sorbitol solution, polyalkylene oxides such as, but not limited to, polyethylene oxide; cellulose ethers such as, but not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, microcrystalline cellulose; gums such as, but not limited to, gum arabic alginate, agar, sodium alginate, guar gum, locust bean gum, carrageenan, tara gum, gum arabic, tragacanth gum, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, stearyl gluconate Gum gum, gum arabic, inulin, kalayan gum, whelan gum; polyols, such as, but not limited to, dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol, and glycerol; carbopol, starch, and starch-based polymers, such as, but not limited to, pregelatinized starch, acrylic and methacrylic acid polymers and their esters, maleic anhydride polymers; polymaleic acid; poly(acrylamide); poly(enol); poly(N-vinyl lactam); polyoxyethylene sugars; polyoxazoline; polyethyleneamine; polyvinyl acetate; polyimide; povidone (e.g., povidone USP (as described above)). K30 sold by Kobo Products, Inc.), vinylpyrrolidone / vinyl acetate copolymer and polyvinyl acetate, a mixture of polyvinyl acetate and polyvinylpyrrolidone, chitin, cyclodextrin, gelatin, chitosan, and the like or mixtures thereof. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and zwitterionic surfactants or mixtures thereof. Nonionic surfactants employed in the composition can include, but are not limited to, ethoxylated fatty acid esters, ethoxylated fatty acid ethers, ethoxylated sorbitan ethers, ethoxylated alkyl phenols, glycerol esters, glycerol sugar esters, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene-20-cetylstearyl ether, polyoxyethylene-25-cetylstearyl ether, polyoxyethylene (25)-oxypropylene monostearate, polyoxyethylene-20-sorbitan monopalmitate, poly-oxyethylene-16-tert-octylphenol, polyoxyethylene-20-cetostearyl ether, polyethylene glycol (1000) monocetyl ether, ethoxylated castor oil, polyoxyethylene sorbitol-lanolin derivatives, polyoxyethylene (25) propylene glycol stearate, polyoxyethylene sorbitol ester, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-16-tert-octylphenol, polyoxyethylene-20-cetostearyl ether, glyceryl undecylenate, and polysorbate 60, capmul (medium chain glycerides), peceol (glyceryl monooleate), glyceryl laurate and glyceryl caprylate (Capmul MCM), PEG-sorbitan fatty acid esters such as PEG-20 sorbitan monolaurate (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), or similar substances and mixtures thereof. Suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds, alkyl amido amines, and quaternary ester compounds, distearyl dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmitoyl dimethyl ammonium chloride, or similar substances and mixtures thereof. Suitable anionic surfactants include, but are not limited to, fatty alcohol sulfates, alpha olefin sulfonates, sulfosuccinates, phosphate esters, carboxylates, sarcosinates, alkyl benzene sulfonates, alkyl sulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, a-methyl ester sulfonates, 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, sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids, isethionates, sarcosinates, taurinates, alkyl oligoglycoside sulfates, alkyl (ether) phosphates, or similar substances and mixtures thereof.Suitable zwitterionic surfactants employed include, but are not limited to, N-alkyl-N,N-dimethylammonium glycinate, such as cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinate, cocoacylaminethylhydroxyethylcarboxymethyl glycinate, or the like, and mixtures thereof. In addition, the compositions of the present application can further comprise a preservative, such as, but not limited to, methyl paraben, propyl paraben, sodium methyl paraben, sodium propyl paraben, and sodium benzoate. Suitable cosolvents that can be used include, but are not limited to, ethanol and polyhydric alcohols, such as, but not limited to, glycerin, propylene glycol, low molecular weight polyethylene glycols, and mixtures thereof. Additional anti-caking agents that can be optionally incorporated include, but are not limited to, colloidal silicon dioxide (e.g., Aerosil®. 244FP), tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof. Suitable sweeteners include, but are not limited to, aspartame, stevia extract, glycyrrhiza, saccharin, saccharin sodium, acesulfame, sucralose, dipotassium glycyrrhizinate, galactose, fructose, high fructose corn syrup, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch, corn syrup solids, sorbitol, xylitol, mannitol, and the like, or mixtures thereof. The compositions can comprise one or more natural and / or artificial flavors, such as, but not limited to, peppermint flavor, orange flavor, lemon flavor, strawberry flavor, vanilla flavor, raspberry flavor, cherry flavor, mixed flavor, magnasweet 135, lime flavor, grape flavor, trusilart 511815, and fruit extracts, and the like. 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, and the like, or combinations thereof.

[0132] In certain embodiments, the compositions described herein are shelf stable in that they can maintain their physical stability for about 18 months to about 24 months. In certain embodiments, the compositions described herein are shelf stable in that they can maintain their chemical stability for about 18 months to about 24 months. In certain embodiments, the compositions are powders that are formulated with water to reconstitute into a suspension. In certain embodiments, the shelf stable solid salt of hydroxybutyrate composition is a reconstituted aqueous liquid suspension that provides therapeutic levels of salt of hydroxybutyrate from about 3 hours to about 8 hours after oral ingestion of the reconstituted aqueous liquid suspension.

[0133] In certain embodiments, the ER oxybate POS provides a dose of 4.5 g sodium oxybate equivalent once nightly. In other embodiments, the ER oxybate POS provides a dose of 6.0 g sodium oxybate equivalent once nightly. In other embodiments, the ER oxybate POS provides a dose of 7.5 g sodium oxybate equivalent once nightly. In certain embodiments, the ER oxybate POS provides a dose of 9.0 g sodium oxybate equivalent once nightly. The POS comprises a blend of oxybate-containing multiparticulates with different release profiles: (a) immediate release oxybate-anion exchange resin complex multiparticulates comprising oxybate bound to ion exchange sites in an anion exchange resin; (b) pH-independent diffusion barrier coated oxybate-anion exchange resin complex-optional matrix multiparticulates, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film- forming polymer that imparts a time-delayed release to the oxybate, and wherein the pH- independent diffusion barrier coating layer is located over the oxybate-anion exchange resin complex-optional matrix; and (c) double-layer SITCS oxybate multiparticulates comprising a blended pH- independent / pH-dependent release coating layer located over the pH-independent diffusion barrier coated oxybate-anion exchange resin complex-optional matrix of (b), wherein the double-layer coating layer comprises a blend of a pH-dependent polymer and a pH-independent polymer, wherein the SITCS double-layer coating imparts a delayed and time-delayed release of the oxybate in the oxybate-anion exchange resin-optional matrix comprising a first pH-independent barrier inner layer. The oxybate-anion exchange resin complex-optional matrix of each of these components can be the same or can be different from one another. The POS further optionally comprises diluent granules.

[0134] In certain embodiments, the ER oxybate composition provides a dose of 6 g sodium oxybate equivalent. In certain embodiments, the ER oxybate composition provides a dose of 7.5 g sodium oxybate equivalent. In certain embodiments, the ER oxybate composition provides a dose of 8 g sodium oxybate equivalent once nightly. In certain embodiments, the ER oxybate composition provides a dose of 9 g sodium oxybate equivalent once nightly. In certain embodiments, the ER oxybate composition provides a dose of 10 g sodium oxybate equivalent once nightly. In certain embodiments, the ER oxybate composition provides a dose of 11 g sodium oxybate equivalent once nightly. In certain embodiments, the ER oxybate composition provides a dose of 12 g sodium oxybate equivalent once nightly.

[0135] In certain embodiments, the compositions of the present application provide a pharmacokinetic profile of the oxybate salt: a ratio of the arithmetic mean maximum plasma concentration peak (Cmax) to the arithmetic mean plasma concentration at 5 hours post ingestion (C5) (Cmax / C5 ratio) of less than 5, as determined in patients following oral ingestion of the oral suspension under fed conditions for at least about two hours post ingestion.

[0136] In certain embodiments, the administration of the compositions provided herein provides a pharmacokinetic profile of the oxybate salt comprising one or more of: Cmax, AUCinf, and / or Tmax or Cmax. AUCinf and / or Tmax are 80% to 125%, 90% to 115%, or 95% to 110% of the values in the following table, as determined in patients following a single 9 g dose:

[0137]

[0138] In certain embodiments, the oxybate ER POS as provided herein, at a 9 g oxybate equivalent dose, provides the following pharmacokinetic profile of the oxybate salt following administration in adults:

[0139] Cmax is 87.98 ug / mL to 126 ug / mL, or about 107 ug / mL, Cmax is 85.6 ug / mL to 133.76 ug / mL or 77.04 ug / mL to 117.711 ug / mL, as calculated using the arithmetic mean; and / or

[0140] AUCinf is 518.20 hr*ug / mL to 719.725 hr*ug / mL; or about 575 hr*ug / mL, or 304.11 hr*ug / mL to 846,67 hr*ug / mL, 460.62 hr*ug / mL to 719.725 hr*ug / mL, as calculated using the arithmetic mean; and / or

[0141] Tmax is about 1.944 hours to 2.376 hours, about 2 hours, or 1.2 hours to 3 hours, 1.728 hours to 2.7 hours, or as calculated using the arithmetic mean hours.

[0142] Cmax is about 105 ug / mL, or 84.38 ug / mL to 131.84 ug / mL, 94.92 ug / mL to 116.01 ug / mL, as calculated using the geometric mean; and / or AUCinf is about 520 hr*ug / mL, or 428.58 hr*ug / mL to 669.66 hr*ug / mL; or about 482.16 hr*ug / mL to 589.30 hr*ug / mL, and / or

[0143] Tmax is about 2 hours, or 1.59 hours to 2.49 hours, or about 1.79 hours to 2.19 hours, as calculated using the geometric mean.

[0144] "Cmax" is the maximum observed plasma concentration, calculated as the geometric or arithmetic mean of the individual maximum plasma concentrations. The term "C5" refers to the plasma concentration at 5 hours post-dose.

[0145] For purposes of the present invention, the term "mean maximum plasma concentration" (mean Cmax) is defined as the maximum mean plasma drug concentration.

[0146] "Mean plasma concentration" can be calculated as the arithmetic mean plasma level or the geometric mean plasma concentration.

[0147] The term "Tmax" refers to the time at which the peak (maximum) plasma drug concentration is observed for each individual participating in the bioavailability study. This can be calculated using the geometric or arithmetic method.

[0148] The term "AUC0-∞" or "AUCinf" is the mean area under the plasma concentration-time curve extrapolated to infinity. It is calculated as the arithmetic mean of the area under the plasma concentration-time curve extrapolated to infinity from time zero, calculated for each individual participating in the bioavailability study. Release profiles can be assessed in vitro by solubility using techniques known to those skilled in the art [e.g., USP Basket Method, Paddle Method, Paddle-Over-Tube Method, or other methods known in the literature]. Release profiles can be assessed in vivo (e.g., for bioavailability determination) using plasma concentrations to assess maximum plasma concentration (Cmax) and area under the curve (AUC). Such determinations are well known to those skilled in the art. [See, e.g., W. Wargin, et al., "Pharmacokinetics of methylphenidate in man, rat and monkey" J Pharmacol Exp Ther 1983 Aug 226:382-386].

[0149] In certain embodiments, the ratio of sodium oxybate in the immediate release component (i.e., the oxybate-anion exchange resin complex-optional matrix) to the oxybate salt in the combined modified release component is about 1 : 10 to about 10: 1, or about 1 :5 to about 5: 1, or about 1 :2 to about 2: 1, or about 1 :2, or about 1 : 1. The ratio is determined based on the weight of the uncomplexed oxybate salt (free oxybate salt) in each component, not the weight of the entire complex.

[0150] In certain embodiments, the ratio of hydroxybutyrate in the barrier-coated hydroxybutyrate-anion exchange resin complex - optional matrix to hydroxybutyrate in the pH dependent enteric-coated barrier-coated hydroxybutyrate-anion exchange resin complex - optional matrix in the composition is about 1 :2 to 2: 1, or about 1 to about 1.

[0151] In certain embodiments, the combination of barrier-coated hydroxybutyrate-anion exchange resin complex - optional matrix and enteric-coated barrier-coated hydroxybutyrate-anion exchange resin complex - optional matrix is about 65 parts by weight to about 90 parts by weight, or about 75 parts by weight to about 85 parts by weight, based on the total weight of hydroxybutyrate in the powder. In certain embodiments, the immediate release hydroxybutyrate-anion exchange resin complex - optional matrix is about 15 parts by weight to about 35 parts by weight, or about 20 parts by weight to about 30 parts by weight, based on the total weight of hydroxybutyrate in the composition.

[0152] The composition can be formulated in an appropriate dose taking into account the age of the patient and the condition being treated. In one embodiment, the composition provides a suspension powder that provides a hydroxybutyrate dose of 4.5 g of sodium oxybate equivalent. In another embodiment, the composition provides a suspension powder that provides a hydroxybutyrate dose of 6 g of sodium oxybate equivalent. In another embodiment, the composition provides a suspension powder that provides a hydroxybutyrate dose of 7.5 g of sodium oxybate equivalent. In another embodiment, the composition provides a suspension powder that provides a hydroxybutyrate dose of 9 g of sodium oxybate equivalent. In another embodiment, the composition provides a suspension powder that provides a hydroxybutyrate dose of 12 g of sodium oxybate equivalent.

[0153] Uses and methods of treatment

[0154] In certain embodiments provided herein, the low sodium extended release (ER) sodium oxybate oral suspension powder for suspension (POS) provided herein contains less than 200 mg of sodium and 1 mEq to 12 mEq of calcium chloride, which provides a once nightly dose of sodium oxybate. The sodium oxybate ER POS is comprised of a blend of sodium oxybate-resinate microparticles with different release profiles as defined in (a) and (b): (a) an immediate release (IR) sodium oxybate-anion exchange resin complex comprising sodium oxybate bound to ion exchange sites in an anion exchange resin; (b) a pH independent diffusion barrier coated sodium oxybate-anion exchange resin complex - optional matrix, wherein the pH independent diffusion barrier coating layer comprises a water insoluble film forming polymer that imparts an extended release to the sodium oxybate, and wherein the pH independent and / or pH dependent diffusion barrier coating layer is located on top of the sodium oxybate-anion exchange resin complex - optional matrix. The composition optionally further comprises diluent granules.

[0155] Provided herein are pharmaceutical compositions and formulations comprising a once nightly extended release gamma-hydroxybutyrate ("GHB") resinate oral suspension powder for suspension with less than 200 mg of sodium, which can be used to treat conditions responsive to GHB, such as fibromyalgia and sleep disorders, such as apnea, sleep time disturbances, narcolepsy, excessive daytime sleepiness (EDS) cataplexy, sleep paralysis, hypnogogic hallucinations, sleep-wakefulness, insomnia, and nocturnal muscle cramps. Provided herein are pharmaceutical compositions and formulations comprising 10% w / w to 80% w / w of an immediate release component of a sodium oxybate resinate, 5% w / w to 70% w / w of an extended release component of a sodium oxybate resinate, and less than 200 mg of sodium per 9 gm dose. Provided herein are pharmaceutical compositions and formulations comprising 10% w / w to 80% w / w of an immediate release component of a sodium oxybate, 5% w / w to 70% w / w of an extended release component of a sodium oxybate resinate, less than 200 mg of sodium, and 75 mg (1 mEq) to 882 mg (12 mEq) of calcium chloride per 9 g dose.

[0156] In certain embodiments, the reduction in sodium content involves the use of a manufacturing process to reduce the sodium content in the sodium oxybate resinate extended release formulation such that it achieves the desired dissolution profile of the coated and final product pharmaceutical resinate extended release granules.

[0157] In another embodiment, the pharmaceutical composition of the sodium oxybate-resinate ER formulation is comprised of a mixture of sodium ions and calcium chloride to achieve the desired dissolution profile.

[0158] In another embodiment, the pharmaceutical composition is administered to the patient as a time-released suspension powder once per night. The desired volume for re-dispersion is 20 mL to 300 mL, 50 mL to 300 mL, 100 mL to 250 mL, or 175 mL to 225 mL.

[0159] In a further aspect, a method of treating narcolepsy and related disorders and symptoms in a patient in need thereof can include administering an oral pharmaceutical composition comprising gamma-hydroxybutyrate once per night, wherein the composition is dose-proportional. Formulation compositions of one or more strengths (1 g, 4.5 g, 6 g, 7.5 g, and 9 g) can be dose-proportional to higher strengths. The Cmax of the composition can be dose-proportional across one or more of the 1 g, 4.5 g, 6 g, 7.5 g, and 9 g dose compositions.

[0160] Provided herein are uses and methods of treatment by administering an effective amount of one or more dosage forms (e.g., a suspension reconstituted from POS) to treat conditions amenable to treatment with gamma-hydroxybutyrate (as those discussed below). In certain embodiments, the dosage forms described herein can be administered to treat a person with narcolepsy, idiopathic hypersomnia, to reduce cataplexy and / or excessive daytime sleepiness (EDS), sleep disorders such as apnea, sleep paralysis, hypnagogic hallucinations, sleep-wakefulness, insomnia, and nocturnal muscle cramps. In still further embodiments, the dosage forms of the present application can be administered to a person, especially an elderly person (>50 years old), to improve sleep quality, or in conditions where an increase in growth hormone levels in the body is desired. In a particular embodiment, the formulations and pharmaceutical compositions provided herein can be used to treat conditions responsive to GHB, such as fibromyalgia.

[0161] In another embodiment, the pharmaceutical compositions and / or formulations disclosed herein can be used to treat a disease or condition selected from the group consisting of sleep disorders, drug abuse, alcohol and opiate withdrawal, decreased growth hormone levels, anxiety, analgesia, neurological disorders (e.g., Parkinson’s disease and depression), endocrine disorders, tissue hypoxia or anoxia (as caused by stroke or myocardial infarction), or elevated intracranial pressure. The dosage forms described herein can be provided in a kit comprising individually packaged containers comprising an effective amount of a gamma-hydroxybutyrate powder composition in a sachet or other suitable packaging. For example, the powder can be packaged in an aluminum foil envelope, or in a blister pack. The powder can be packaged in a number of shapes, with or without desiccants or other materials to prevent water ingress. Instructions or methods for its administration, such as sequential administration over a preselected period of time and / or at preselected intervals, to produce desired levels of sodium oxybate in the body over a preselected period of time, to treat a preselected condition, can also be included, such as printed labels.

[0162] A kit for treating a patient with a salt of hydroxybutyrate, the kit comprising (a) a container comprising a salt of hydroxybutyrate composition as described herein; (b) a syringe; (c) a measuring cup; (d) a press-to-bottle adapter (e) a dosing cup; and optionally at least one empty pharmaceutical container with a child-resistant closure.

[0163] A daily dose of the composition as provided herein in an amount of sodium oxybate equivalent to about 1 mg / kg to about 50 mg / kg can be administered to achieve the desired therapeutic result. For example, a daily dose of about 0.5-20 g (preferably, about 1 g to 15 g) of sodium oxybate equivalent can be administered in a single dose. In other embodiments, the dose can be in the range of about 1.5 g to about 12 g per night, or about 4.5 g to about 9 g per night, or about 6 g, based on sodium oxybate equivalent.

[0164] The compositions described herein can be useful in treating various conditions suitable for treatment with sodium oxybate, such as narcolepsy, to reduce cataplexy and / or daytime sleepiness, to improve sleep quality, or can be useful in treating conditions where an increase in growth hormone levels in vivo is desired, and for treating fibromyalgia or chronic fatigue syndrome. The dosage forms of the present invention can be used to treat a number of other indications, including drug and alcohol abuse, anxiety, cerebrovascular disease, central nervous system disorders, neurological disorders including Parkinson's disease and Alzheimer Disease, multiple sclerosis, autism, depression, inflammatory disorders, including inflammatory disorders of the intestinal tract, such as irritable bowel disorder, regional ileitis and ulcerative colitis, autoimmune inflammatory disorders, certain endocrine disorder disorders, and diabetes.

[0165] The compositions can also be administered for the purpose of tissue protection, including protection following hypoxia / hypoxia (such as stroke, organ transplantation, organ preservation, myocardial infarction or ischemia, reperfusion injury), protection following chemotherapy, radiation therapy, premature aging, or elevated intracranial pressure (e.g., due to head trauma). The dosage forms of the present invention can also be used to treat other conditions believed to be caused or exacerbated by lipid peroxidation and / or free radicals, such as conditions associated with oxidative stress, including normal aging. See patent publication US 2004 / 0092455 Al, which is incorporated herein by reference. The compositions can also be used to treat movement disorders, including restless leg syndrome, myoclonus, dystonia, and / or essential tremor. See Frucht et al., Movement Disorders, 20(10), 1330 (2005).

[0166] As described herein, the composition can be administered orally once per day at bedtime (e.g., 10 p.m. to 12 a.m.). This is particularly suitable for the treatment of narcolepsy. Optionally, smaller doses can be delivered at bedtime and at different time intervals during the night, or in the morning and at time intervals during the day. Other variations can be selected depending on the patient and the indication being treated (e.g., fibromyalgia, etc.).

[0167] As used herein, the term "powder" is a plurality of "particles" or "granules." In certain embodiments, each particle or granule is a subunit that contains one immediate release component and / or at least one modified release component. In other embodiments, the particles or granules contain separate immediate release GHB components and separate modified release GHB components that are mixed. The terms "particle," "granule," "microparticle," or "multiparticulate," and "resin" are used interchangeably herein to refer to a salt of hydroxybutyrate-anion exchange resin complex (which can be further in a matrix and be coated). "Salt of hydroxybutyrate-ion exchange resin complex" refers to the product resulting after loading at least a salt of hydroxybutyrate to an anion exchange resin. The complexation occurs when the active drug and ion exchange resin are mixed together in an aqueous medium to facilitate the "exchange" between the salt of the drug and the "ions" of the ion exchange resin and the formation of the complex.

[0168] As used herein, "GHB drug" includes GHB, and pharmaceutically acceptable salts, hydrates, tautomers, solvates, prodrugs, and complexes of GHB, and mixtures thereof. Suitable GHB salts include, for example, calcium, lithium, potassium, sodium, and magnesium salts. Representative salts are also described in US 2012 / 0076865, which is incorporated herein by reference. The sodium salt of GHB, "sodium oxybate," refers to the compound of formula (la):

[0169] In one embodiment, a substitute for sodium oxybate can be used as the immediate release component, or as a starting material for the preparation of the drug-ion exchange resin complex as provided herein. Such substitute salts useful in the present application include the compound of formula (I):

[0170] wherein X is a pharmaceutically acceptable cation and can be selected from the group consisting of potassium, calcium, lithium, and magnesium, and Y is OH. "Salt of hydroxybutyrate" refers to the compound of formula I, wherein X is a pharmaceutically acceptable cation and can be selected from the group consisting of sodium, potassium, calcium, lithium, and magnesium, and Y is OH. Sodium oxybate is a white to off-white crystalline powder, freely soluble in aqueous solutions. Other salts can be selected, such as calcium hydroxybutyrate, magnesium hydroxybutyrate, potassium hydroxybutyrate, and / or lithium hydroxybutyrate. Methods of preparing GHB salts are described, for example, in U.S. Patent No. 4,393,236, the disclosure of which is incorporated herein by reference.

[0171] “Dissolution rate” refers to the amount of drug released from a dosage form in vitro into a release medium per unit time. The in vitro dissolution rate in the studies described herein is determined under appropriate experimental conditions on a dosage form placed in a USP Type II or USP 7 dissolution apparatus set at 37°C ± 2°C; see, e.g., US 2012 / 007685, which is incorporated herein by reference. The dissolution medium can be purified water, 0.1 N HC1, simulated gastric fluid or intestinal fluid, or other media known in the art.

[0172] Unless expressly stated to the contrary, the dosage and strength of the oxybate salt is expressed as grams (g) of sodium oxybate equivalent. As used herein, the term sodium oxybate “equivalent” is used to refer to the weight of the oxybate salt portion of the anion exchange resin complex, without regard to the weight of the anion exchange resin or any matrix or coating components.

[0173] As used herein with reference to numerical values provided herein, the term “about” can indicate variability of up to 10% (+ / - 10%).

[0174] Various embodiments will be further described with reference to the following detailed examples.

[0175] Example

[0176] The following examples are illustrative only and are not intended to limit the present application. In the following examples, the terms “oxybate-anion exchange resin complex” and “oxybate-resin acid salt” or “oxybate-cholestyramine resin acid salt” are used interchangeably, unless otherwise specified.

[0177] Example 1: Removal of exchangeable ions in sodium oxybate-anion exchange resin complex for extended release oral solution powder (ERPOS)

[0178] Uncoated oxybate-cholestyramine resin acid salt:

[0179] The oxybate-cholestyramine resin acid salt is prepared using a multi-stage polymerization process. Throughout the multi-stage polymerization process, unbound sodium oxybate is removed. The sodium content in the drug resin acid salt complex is controlled by the amount of water or other aqueous solution, the mixing time, the mixing speed, and the process temperature. The sodium content in the drug resin acid salt complex is further controlled by the amount of water used in each multi-stage complexation and final equilibration stage.

[0180]

[0181] 1Amount based on actual yield after multi-stage drug resin acid salt complexation

[0182] 2Removed during processing

[0183] (Part I) Sodium hydroxybutyrate was dissolved in purified water (45% w / w) and cholestyramine resin was gradually added to it. Stirring was continued for 2 hours at room temperature. The dispersion was then filtered to remove excess sodium hydroxybutyrate. The wet resinate was treated twice with 35.0 L of purified water. The resinate dispersion was filtered to remove the water used to remove excess API. The wet resinate (process phase 1) was dispersed in fresh sodium hydroxybutyrate solution for phase 2 and stirred for 2 hours. It was filtered and the wet resinate was treated twice with 35.0 L of purified water. The resinate dispersion was filtered to remove the water used to remove excess API. In phase 3 process, similar to phase 2 process, the wet resinate of phase 2 was re-complexed, filtered and treated twice. The resulting resinate was dried to achieve a target %LOD of 7% w / w, followed by sieving through a 60 mesh sieve.

[0184] (Part II) The sodium hydroxybutyrate filtrate from Part I / Phase 1 was used to re-complex with fresh cholestyramine resinate in Part II. The resinate was dispersed in the filtrate and stirred for 2 hours. The complex was filtered and treated twice with 35.0 L of purified water.

[0185] The wet complex was used in the next step where the Part I / Phase 2 sodium hydroxybutyrate filtrate was added and stirred for 2 hours. The dispersion was filtered and treated twice with 35.0 L of purified water. The wet complex was used in the next step where the Part I / Phase 3 sodium hydroxybutyrate filtrate was added and stirred for 2 hours. The dispersion was filtered and treated twice with 35.0 L of purified water. Similarly, in phase 4 and phase 5 processes, the wet resinate was re-complexed with phase 4 and phase 5 sodium hydroxybutyrate fresh solution for 2 hours, followed by filtration and treatment twice with 35.0 L of purified water.

[0186] In Part III step, the wet complex along with Part I complex was dispersed in sodium hydroxybutyrate solution. The dispersion was stirred for 4 hours and filtered, followed by treating the wet material with 60 L of purified water. The resulting resinate was dried to achieve a target %LOD of 7% w / w, followed by sieving through a 50 mesh sieve.

[0187] The measured value of the resinate was about 29% w / w of hydroxybutyrate, %LOD was about 6.5% w / w, and elemental sodium content was about 2500 μg / g.

[0188] Example 2:

[0189] In another experiment, the sodium content was adjusted by varying the amount of purified water used in each equilibration phase. This was followed by a similar process where the amount of purified water used between each phase was varied to control the sodium content in the drug resinate complex.

[0190]

[0191] 1 Amounts are based on actual yield after multi-stage drug resin acid salt complexation

[0192] 2 Removed during processing

[0193] The resin acid salt had an assay of about 29% w / w of hydroxybutyrate, a %LOD of about 6.5% w / w, and an elemental sodium content of about 3000 μg / g.

[0194] Example 3:

[0195] In another experiment (Example 3), the sodium content was controlled by varying the amount of purified water used in the final equilibration stage. The procedure was then followed similarly to Example 1, except that the amount of purified water used between each stage of the complexation process was varied.

[0196]

[0197] 1 Amounts are based on actual yield after multi-stage drug resin acid salt complexation

[0198] 2 Removed during processing

[0199] The resin acid salt had an assay of about 28% w / w of hydroxybutyrate, a %LOD of about 6.0% w / w, and an elemental sodium content of about 30 μg / g.

[0200] Example 4: In another experiment (Example 4), the sodium content was controlled by varying the amount of purified water used in the final equilibration stage. The procedure was then followed similarly to Example 1, except that the amount of purified water used in the final stage of the complexation process was varied.

[0201]

[0202]

[0203] 1 Amounts are based on actual yield after multi-stage drug resin acid salt complexation

[0204] 2 Removed during processing

[0205] The resin acid salt had an assay of about 28% w / w of hydroxybutyrate, a %LOD of about 6.0% w / w, and an elemental sodium content of about 360 μg / g.

[0206] Example 5 and Example 6:

[0207] A. Coated Oxybutynin Resinate-Cholestyramine Resinate

[0208] Coated oxybutynin resinate-cholestyramine resinate can be prepared by coating the resinate granules with water insoluble film forming polymers. One of the methods is to use a polyvinyl acetate based aqueous coating system in combination with ethyl acrylate and methyl methacrylate copolymer dispersion (Table 5).

[0209]

[0210] 1 Removal during processing

[0211] Triacetin was dissolved in purified water and after mixing, talc was added to it. The dispersion was stirred for 15 minutes and divided into two equal parts, one was gradually added to the polyvinyl acetate dispersion under stirring while the other was added to the ethyl acrylate and methyl methacrylate copolymer dispersion. The two dispersions were gradually mixed together and stirred for 1 hour, followed by sieving through a 60 mesh sieve. The prepared dispersion was used to coat oxybutynin resinate-cholestyramine resinate having different sodium content levels in a fluid bed coater (VFC FLO-COATER VFC-60) at a product temperature of about 22°C to 27°C. The coated granules were cured and sieved through a 45 mesh sieve. The release of oxybutynin from the coated oxybutynin resinate granules was tested in vitro. The dissolution conditions were: USP App. II (paddle), 75 RPM, 1 L vessel, 0.02 N HC1, pH change after 2 hours. Figure 1 Results are summarized in Table 6.

[0212] Example 7 - 13:

[0213] The release of oxybutynin from the coated oxybutynin resinate complex depends on the amount of sodium content in the drug resinate complex, as presented below. It was observed that at the same level of barrier coating, the higher the sodium content in the oxybutynin resinate complex, the faster the release.

[0214] The release rate of oxybutynin from the oxybutynin resinate was further controlled by using water insoluble film forming polymers or applying an additional time release coating with pH independent or pH dependent water insoluble film forming polymers.

[0215] One of the methods is to coat the Example 1, 2 and 3 oxybutynin resinate with 30% w / w of pH independent water insoluble barrier coating followed by a polyvinyl acetate based aqueous coating system.

[0216] The plasticizer solution for triacetin was prepared by first dissolving in purified water and then gradually adding to the polyvinyl acetate dispersion under agitation. The dispersion was stirred for 60 minutes and sieved through a 40 mesh screen (Step 1). The hydroxybutylate cholestyramine resin was coated in a fluid bed coater (FLM-5) using the Step 1 dispersion at a product temperature of about 29°C to 37°C. The coated granules were cured in an oven and sieved through a 40 mesh screen. The release of hydroxybutylate from the coated hydroxybutylate cholestyramine resin granules was tested in vitro. The dissolution conditions were: USP App. II (paddle), 75 RPM, 1 L vessel, 0.02 N HC1, pH change after 2 hours. Figure 2 Results are summarized in Table 2.

[0217]

[0218]

[0219] 1 Removal during processing

[0220] A 40% weight gain coating was applied on the coated hydroxybutylate cholestyramine resin. It was observed that at the same barrier coating level, the higher the sodium content in the hydroxybutylate cholestyramine resin complex, the faster the release of hydroxybutylate.

[0221] The delayed extended release (DER) coated hydroxybutylate cholestyramine resin can be prepared by coating the resin granules with a water insoluble film forming polymer followed by coating with a pH dependent polymer coating system. In one of the methods, a water insoluble coating system, a polyvinyl acetate based aqueous coating system and a combination of ethyl acrylate and methyl methacrylate copolymer dispersion (pH independent) followed by a blended pH dependent / pH independent methacrylic acid based coating system (pH dependent) was used.

[0222]

[0223]

[0224] 1 Removal during processing

[0225] For blend coating layer based on methacrylic dispersion, purified water was heated. Polysorbate 80, mono / diglycerides and dibutyl sebacate (plasticizer) were dispersed in heated purified water. The dispersion was divided into two equal parts. One part of plasticizer dispersion was added to pH dependent methacrylic enteric coating dispersion system while the other part was added to pH independent ethyl acrylate and methyl methacrylate copolymer barrier coating dispersion. Both dispersions were mixed for 15 minutes. The stirring was continued for about 2 hours followed by sieving through 40 mesh sieve. The barrier coated hydroxybutyrate-resinate was further coated with blend pH independent / pH dependent layer in fluid bed coater at product temperature of about 22°C to 30°C. The resulting coated granules were cured and sieved through 40 mesh sieve.

[0226] In-vitro drug release studies were carried out on the coated hydroxybutyrate resinate. Figure 3 The data is summarized in Table 6. The dissolution conditions were: USP App. II (paddle), 75 RPM, 1 L vessel, 0.02N HC1, pH change after 2 hours. At the same level of barrier coating, the sodium content in the hydroxybutyrate resinate complex was low, significant enteric protection was observed and hence slower release was observed.

[0227] Examples 20-23: Effect of calcium chloride on ER POS release

[0228] Hydroxybutyrate extended release suspension powder (ER POS) was prepared from a combination of uncoated hydroxybutyrate resinate, diffusion barrier coated hydroxybutyrate resinate and other excipients such as silicon dioxide (Syloid 244FP), sodium methyl paraben, sodium propyl paraben, povidone, USP (Kollidon K30), sucralose, carrageenan (Gelcarin GP-911), potassium bicarbonate, gellan gum, calcium chloride dihydrate, hypromellose K100M, Pearlitol 100 SD, Eudragit L100, titanium dioxide, microcrystalline cellulose, NF (Avicel PH 102), and magnesium stearate. One of the functional excipients was calcium chloride which helped in immediate release dose of the formulation.

[0229] Four different levels of calcium chloride formulations were prepared according to Table 8 and in-vitro tested for release of hydroxybutyrate from reconstituted suspension. Dissolution test: USP Type II, 65 rpm, pH change method - 0.02N HC1 for 2 hours followed by pH 6 using phosphate buffer.

[0230] ​

[0231] As Figure 4 presented, the higher the amount of calcium chloride, the higher the initial release of the oxybutynin salt observed.

[0232] B. The final product, Oxybutynin Extended Release Suspension Powder (ER POS) is prepared by combining uncoated oxybutynin resinate, diffusion barrier coated oxybutynin resinate, and delayed extended release coated oxybutynin resinate with other excipients such as silicon dioxide (Syloid 244FP), sodium methyl paraben, sodium propyl paraben, povidone, USP (Kollidon K30), sucralose, carrageenan, potassium bicarbonate, gellan gum, calcium chloride dihydrate, hypromellose K100M, Pearlitol 100 SD, Eudragit L100, titanium dioxide, microcrystalline cellulose, NF (Avicel PH 102), and calcium chloride. The formulation contains 6 mEq of calcium chloride and less than 100 mg of sodium.

[0233]

[0234]

[0235]

[0236] The formulation contains less than 100 mg of sodium.

[0237] Example 24: Clinical evaluation of the final product, Oxybutynin Extended Release Suspension Powder (ER POS):

[0238] The final product, Oxybutynin Extended Release Suspension Powder (ER POS) is prepared by combining uncoated oxybutynin resinate and diffusion barrier coated oxybutynin resinate in different ratios with other excipients such as silicon dioxide (Syloid 244FP), sodium methyl paraben, sodium propyl paraben, povidone, USP (Kollidon K30), sucralose, carrageenan, potassium bicarbonate, gellan gum, calcium chloride dihydrate, hypromellose K100M, Pearlitol 100 SD, Eudragit L100, titanium dioxide, microcrystalline cellulose, NF (Avicel PH 102), and calcium chloride.

[0239] ​​An open-label, single-dose, randomized, crossover study was conducted to evaluate the above-mentioned extended release formulation (equivalent to 9 gm of sodium oxybate). The study was conducted between healthy male and female subjects. A high fat, high calorie meal was consumed by each patient 2 hours prior to administration of the extended release once nightly formulation. Blood samples were collected from each patient at various time intervals and analyzed for total sodium oxybate content in plasma by LC / MS. The mean plasma concentration of sodium oxybate over time and pharmacokinetic parameters are presented below. See also Figure 5 .

[0240]

[0241] All patents, patent publications, and other publications listed in this specification are herein incorporated by reference. While this invention has been described with particular reference to particular embodiments thereof, it is to be understood that modifications can be made without departing from the spirit of the application. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A time-released sodium oxybate oral suspension powder (POS) that provides a once nightly dose of sodium oxybate, the oral suspension powder comprising a blend of sodium oxybate-containing multiparticulates with different release profiles as defined in (a), (b) and (c): (a) immediate release sodium oxybate-anion exchange resin complex multiparticulates comprising sodium oxybate bound to ion exchange sites in an anion exchange resin; (b) pH-independent diffusion barrier coated sodium oxybate-anion exchange resin complex-optional matrix multiparticulates, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer that imparts a time-release to the sodium oxybate, and wherein the pH-independent diffusion barrier coating layer is on the sodium oxybate-anion exchange resin complex-optional matrix; (c) SITCS-coated sodium oxybate multiparticulates comprising a blend coating layer on the pH-independent diffusion barrier coated sodium oxybate-anion exchange resin complex-optional matrix multiparticulates, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble film-forming polymer, and wherein the pH-independent diffusion barrier coating layer is on the sodium oxybate-anion exchange resin complex-optional matrix; wherein the blend coating layer comprises a pH-dependent polymer and a pH-independent polymer, wherein the double layer coating imparts a delayed and time-release profile to the sodium oxybate in the double layer coated sodium oxybate-anion exchange resin-optional matrix of (c), and wherein (a), (b) or (c) is present in the POS in an amount effective to provide a once nightly dose of sodium oxybate; wherein the sodium oxybate-anion exchange resin complex-optional matrix in (a), (b) or (c) comprises sodium oxybate bound to ion exchange sites in an anion exchange resin in an optional matrix further comprising at least one hydrophilic or hydrophobic polymer, wherein the complex-optional matrix in each of (a), (b) or (c) can be the same or can be different from one another; (d) the POS is equivalent to about 1 mEq to about 12 mEq of calcium chloride per 9 gm sodium oxybate dose; and (e) the POS contains less than a total sodium equivalent of 200 mg per 9 gm sodium oxybate dose of the POS.

2. The time-released sodium oxybate oral suspension powder (POS) of claim 1, wherein about 10% w / w to about 80% w / w of the total sodium oxybate in the POS is in the immediate release multiparticulates (a).

3. The time-released sodium oxybate oral suspension powder (POS) of any one of claims 1 to 3, wherein about 30% w / w to about 75% w / w of the total sodium oxybate in the POS is in the immediate release multiparticulates (a). ​ ​ ​ ​ ​ ​ 4. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 3, wherein about 50% w / w to about 70% w / w of the total sodium oxybate in the POS is in the immediate release multiparticulate (a).

5. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 4, wherein about 25% w / w to about 70% w / w of the total sodium oxybate in the POS is in the time-release components (b) and (c).

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

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

8. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 7, wherein about 5% w / w to about 30% w / w of the total sodium oxybate in the POS is in the time-release components.

9. The time-released sodium oxybate oral suspension powder (POS) according to claim 8, wherein about 10% w / w to about 15% w / w of the total sodium oxybate in the POS is in the time-release component (b).

10. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 7, wherein the POS contains a total sodium of 175 mg or less per 9 gm dose equivalent.

11. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 8, wherein the POS contains a total sodium of about 5 mg to about 175 mg per 9 gm dose equivalent.

12. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 9, wherein the POS contains a total sodium of about 150 mg per 9 gm dose equivalent.

13. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 9, wherein the POS contains a dose equivalent of about 1 g, 4.5 g, 6 g, 7.5 g, 9 g, or 10 gm of sodium oxybate as determined based on sodium oxybate equivalent.

14. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 13, wherein 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.

15. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 14, wherein the sodium oxybate-anion exchange resin complex comprises about 15% w / w to about 35% w / w of sodium oxybate, based on the total weight of the sodium oxybate-anion exchange resin absent any matrix or coating components.

16. The time-released sodium oxybate oral suspension powder (POS) according to claim 12, wherein the sodium oxybate-anion exchange resin complex comprises 25% w / w to about 30% w / w of sodium oxybate, based on the total weight of the sodium oxybate-anion exchange resin absent any matrix or coating components.

17. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 16, wherein the time-released coated sodium oxybate-anion exchange resin complex of (b) and / or (c) comprises a matrix of a matrix-forming polymer in an amount of about 20% w / w to about 40% w / w, based on the total weight of the sodium oxybate-anion exchange resin-matrix absent any coating components.

18. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 16, wherein the POS further comprises an interpenetrating polymer network (IPN) release forming system, optionally wherein the IPN forming system comprises two independently crosslinking moieties crosslinked with at least one crosslinking agent, an optional gas generating agent.

19. The time-released sodium oxybate oral suspension powder (POS) according to any one of claims 1 to 18, wherein the POS further comprises potassium bicarbonate, calcium bicarbonate, carrageenan, gellan gum, a pH adjuster, a polysorbate, a glidant, a bulking agent, a filler, a colorant, or a combination thereof.

20. A time-released sodium oxybate oral suspension powder (POS) providing a once nightly time-released sodium oxybate dose, the oral suspension powder comprising: (a) an immediate release sodium oxybate-anion exchange resin complex multiparticulate comprising sodium oxybate bound to ion exchange sites in an anion exchange resin; (b) at least two different time-released sodium oxybate components comprising a drug-ion exchange resin complex; (c) about 1 mEq to about 12 mEq of calcium chloride equivalent per 9 gm sodium oxybate dose of the POS; and (d) less than 200 mg of total sodium equivalent per 9 gm sodium oxybate dose of the POS, wherein upon administration to a patient, a suspension comprising the POS provides a pharmacokinetic profile of at least one of the following for sodium oxybate: Cmax is (i) 87.98 pg / mL to 126 pg / mL, or about 107 pg / mL, Cmax is 85.6 pg / mL to 133.76 pg / mL, or 77.04 pg / mL to 117.711 pg / mL, as calculated using arithmetic mean, and / or (ii) Cmax is about 105 pg / mL, or 84.38 pg / mL to 131.84 pg / mL, 94.92 pg / mL to 116.01 pg / mL, as calculated using geometric mean; AUCinf is (i) 518.20 hr*pg / mL to 719.725 hr*pg / mL; or about 575 hr*pg / mL, or 304.11 hr*pg / mL to 846.67 hr*pg / mL, 460.62 hr*pg / mL to 719.725 hr*pg / mL, as calculated using arithmetic mean, and / or (ii) AUCinf is about 520 hr*pg / mL, or 428.58 hr*pg / mL to 669.66 hr*pg / mL; or about 482.16 hr*pg / mL to 589.30 hr*pg / mL, as calculated using geometric mean.

21. A reconstituted suspension comprising the time-released sodium oxybate oral suspension powder of any one of claims 1 to 20, wherein the suspension comprises about 20 mL to about 300 mL of an aqueous suspending agent.

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

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

24. The reconstituted suspension of any one of claims 21 to 23, wherein the composition comprises a 1 g sodium oxybate dose, as measured based on the equivalent of sodium oxybate.

25. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a 4.5 g sodium oxybate dose, as measured based on the equivalent of sodium oxybate.

26. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a 6 g sodium oxybate dose, as measured based on the equivalent of sodium oxybate.

27. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a 7.5 g sodium oxybate dose, as measured based on the equivalent of sodium oxybate.

28. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a 9 g sodium oxybate dose, as measured based on the equivalent of sodium oxybate.

29. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a 10 g sodium oxybate dose, as measured based on the equivalent of sodium oxybate.

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

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

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