Packaged modified release gamma-hydroxybutyrate formulations with improved stability

Abstract

A packaged modified-release formulation of gamma-hydroxybutyrate is provided that has a stable dissolution profile over time. The present invention provides a packaged pharmaceutical composition comprising a modified-release gamma-hydroxybutyrate pharmaceutical composition within a package, the pharmaceutical composition comprising: (a) an immediate-release component comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof; and (b) a modified-release component comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof, the package having an interior volume with a relative humidity of 29% to 54%, and the pharmaceutical composition having a stable dissolution profile over time.

Description

[Technical field]

[0001] The present invention relates to packaged modified release formulations of gamma-hydroxybutyrate having improved solubility and chemical stability, and to packaging to aid said stability and therapeutic uses thereof. [Background technology]

[0002] Narcolepsy is a devastating, disabling condition. The main symptoms are excessive daytime sleepiness (EDS), cataplexy (sudden loss of muscle tone triggered by strong emotions, seen in approximately 60% of patients), hypnagogic hallucinations (HH), sleep paralysis (SP) and nocturnal sleep disturbances (DNS). Besides EDS, DNS is the most common symptom seen in narcolepsy patients.

[0003] One of the primary treatments for narcolepsy is gamma-hydroxybutyrate, also known in its sodium form as sodium 4-hydroxybutanoate, sodium oxyvate, gamma-hydroxybutyric acid sodium salt or NaGHB. Gamma-hydroxybutyrate or GHB is a neuroactive drug with diverse central nervous system (CNS) pharmacological properties. Endogenous species exist in many tissues, which act as neurotransmitters at the gamma-hydroxybutyrate (GHB) receptor (GHBR) and have neuromodulatory properties with significant effects on dopamine and gamma-aminobutyric acid (GABA).

[0004] Gamma-hydroxybutyrate is commercially available in the United States as XYREM®. The product is formulated as an immediate release liquid solution and is taken in equal doses, once just prior to bedtime and once 2.5 to 4 hours later. For each dose, a measured amount of oral solution must be removed from the primary container and transferred to a separate container, which is diluted with water before administration. The second dose is prepared at bedtime and saved for administration overnight. Sleep onset can be dramatic and rapid, and patients are advised to sit in bed when consuming the dose.

[0005] When initiating treatment with gamma-hydroxybutyrate, careful titration to an appropriate level is essential to both obtain positive results and avoid adverse effects. The recommended starting dose is 4.5 g, divided into two equal doses of 2.25 g, with the first dose taken at bedtime and the second 2.5 to 4 hours later. The starting dose can be decreased to 3.0 g / day or increased in increments of 1.5 g / day (0.75 g per dose) up to as much as 9.0 g / day. Two weeks between dose adjustments are recommended to optimize reduction in daytime symptoms and minimize side effects. The ideal dose would result in an effective 8 hours of sleep, but at the end of the 8 hours only a small amount of drug would remain in the patient's bloodstream to have no effect on the patient's wakefulness.

[0006] The need to take XYREM® twice nightly presents a significant inconvenience to narcolepsy patients. Patients must typically set an alarm to take the second dose, which can interrupt ongoing productive sleep. This regimen is cumbersome and prone to error in the preparation of individual doses. For these reasons, a more convenient unit dosage form of the drug would be clinically beneficial.

[0007] Several efforts have been made to provide modified release dosage forms of gamma-hydroxybutyrate once a night, but none have yet been approved by the U.S. Food and Drug Administration ("FDA") or proven effective in the clinic. One of the most significant drawbacks of these once a night formulations is the reduced bioavailability, as measured by the area under the plasma concentration / time curve ("AUC"), that occurs when gamma-hydroxybutyrate is formulated in a modified release dosage form. U.S. Patent Publication 2012 / 0076865 and U.S. Patent No. 8,193,211 report the relative bioavailability of these once a night formulations at a small immediate release dose. There is a need for a once a day formulation of gamma-hydroxybutyrate that can provide bioavailability comparable to current treatments for high daily doses up to 9 g per day, without the need to increase the total daily dose. Because gamma-hydroxybutyrate is highly water-soluble, hygroscopic, and strongly alkaline, as well as for the large amounts of drug that would be required to achieve an adequate clinical response, there is a demand to formulate modified release solid dosage forms of gamma-hydroxybutyrate. Gamma-hydroxybutyrate is prone to attract water from the environment, which in turn promotes high local pH, gamma-hydroxybutyrate migration and interaction with excipients, which may promote the formation of GBL (gamma-butyrolactone) as a degradant or induce dissolution instability. These characteristics make it difficult to formulate a product that remains stable over time, especially in terms of dissolution and / or chemical stability during storage. Therefore, there is a demand for solid modified release formulations of gamma-hydroxybutyrate that retain their dissolution profile over time, i.e., they have a stable dissolution profile and are inactive over time and have reduced chemical degradation products. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US Patent Application Publication No. 2012 / 0076865 [Patent Document 2] U.S. Pat. No. 8,193,211 Summary of the Invention [Means for solving the problem]

[0009] The provision of packaged modified release formulations of gamma-hydroxybutyrate with stable dissolution profiles over time is one of the various aspects of the present invention. The packaged gamma-hydroxybutyrate compositions disclosed herein maintain chemical and dissolution stability, particularly when maintained within defined ranges of relative humidity values.

[0010] Thus, the present invention provides a packaged pharmaceutical composition comprising a modified release gamma-hydroxybutyrate pharmaceutical composition within a package, the pharmaceutical composition comprising: (a) an immediate release component comprising gamma-hydroxybutyrate or a pharma- ceutical acceptable salt thereof; and (b) a modified release component comprising gamma-hydroxybutyrate or a pharma- ceutical acceptable salt thereof, the package having an interior volume having a relative humidity of 29% to 54%, and the pharmaceutical composition having a stable dissolution profile over time.

[0011] In some aspects, the relative humidity of the package is between 29% and 54% for a period of at least two months when stored at 40° C. and 75% relative humidity. In other aspects, the relative humidity of the package is greater than 29% at one week and less than 54% at two months when stored at 40° C. and 75% relative humidity. In still other aspects, the relative humidity of the package is greater than 29%, less than 44% at one week, and less than 54% at two months when stored at 40° C. and 75% relative humidity. In further aspects, the relative humidity of the package is up to 35% to 39% after one week and 39% to 48% after two months when stored at 40° C. and 75% relative humidity.

[0012] In other iterations, the packaging prevents conversion of no more than 0.4% of the gamma-hydroxybutyrate in the pharmaceutical composition to gamma-butyrolactone (GBL) when stored for 2 months at 40° C. and 75% relative humidity. In a further aspect, the packaging meets USP 38 <671> It has a water vapor transmission rate of less than 7 mg / day / liter when measured in accordance with the present invention.

[0013] In a further aspect, the pharmaceutical composition has a pH of 3.0 or higher in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm when the packaged composition is stored at 40° C. and 75% relative humidity for two months. <711> In yet another iteration, the pharmaceutical composition has a dissolution of gamma-hydroxybutyrate that differs by less than 10% from the dissolution of gamma-hydroxybutyrate prior to the storage period when tested at at least four consecutive hourly time points in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm when the packaged composition is stored for two months at 40° C. and 75% relative humidity. <711> When tested at least four consecutive hourly time points in dissolution apparatus 2 according to the method of the present invention, the dissolution of gamma-hydroxybutyrate differs by less than 10% from the dissolution of gamma-hydroxybutyrate prior to the storage period.

[0014] In a further aspect, the modified release component comprises a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof, and a coating comprising a mixture of a hydrophobic compound and a methacrylic acid copolymer. In some aspects, the hydrophobic compound is glyceryl tristearate or a hydrogenated vegetable oil, and the mixture of methacrylic acid copolymers comprises methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF. In other aspects, the coating comprises 40-70 parts by weight of the hydrophobic compound and 30-60 parts by weight of the methacrylic acid copolymer, and the coating is 10% to 50% by weight of the modified release component. In a further aspect, the hydrophobic compound has a melting point of 40°C or greater, and the mixture of methacrylic acid copolymers has a pH trigger above 5.6. In some embodiments, the immediate release component comprises particles having an average diameter of 95-600 micrometers, and / or the modified release component comprises particles having an average diameter of 200-800 micrometers.

[0015] In some aspects, the weight ratio of gamma-hydroxybutyrate in the immediate release and modified release components is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40. In certain aspects, the package contains, for example, 0.5 grams to 12.0 grams of sodium salt of gamma-hydroxybutyrate, 3.0 4.5, 6.0, 7.5, or 9.0 grams of sodium oxyvert. In specific aspects, the package is a pouch or sachet, for example an aluminum foil pouch or sachet having an aluminum foil thickness of at least 6 micrometers.

[0016] Additional aspects and sub-aspects will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The aspects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief description of the drawings]

[0017] [Figure 1] 1 shows the qualitative and quantitative structure of immediate release (IR) and modified release (MR) microparticles of gamma-hydroxybutyrate of Example 1 (first formulation). [Diagram 2] The dissolution profiles of the packaged formulations before and after one month of storage at 40° C. and 75% relative humidity are plotted to illustrate the calculation of lag time according to the present invention as described in Example 2. [Diagram 3] Figure 2 shows the dissolution profile of the formulation packaged in PET / ALU / PE aluminum pouches (9 μm aluminum foil) from Bischof & Klein (Lengerich Germany) at 40°C / 75% RH over 6 months as described in Example 3. [Figure 4] 1 shows the dissolution profile of a formulation packaged in CONSTANTIA™ stick-packs (PET / adhesive layer / ALU / copolymer with 12 μm aluminum foil) at 40° C. / 75% RH over a 6 month period as described in Example 3.

[0018] [Diagram 5] 1 shows the dissolution profile of a formulation packaged in a LOG™ H2O02 bottle at 40° C. / 75% RH over a 6 month period, as described in Example 3. [Figure 6]1 shows the dissolution profile of a formulation packaged in a LOG™ H2O02 bottle at 40° C. / 75% RH over a period of 5 months as described in Example 4. [Figure 7] 1 shows the dissolution profile of a formulation packaged without desiccant in DUMA™ bottles (30 ml) at 40° C. / 75% RH over a period of 3 months as described in Example 4. [Figure 8] 1 shows the dissolution profile of a formulation packaged as described in Example 4 in a DUMA™ bottle (30 ml) with 2 g of silica gel desiccant at 40° C. / 75% RH over a period of 1 month. [Figure 9] 1 shows the dissolution profile of a formulation packaged as described in Example 4 in a DUMA™ bottle (30 ml) with 2 g of Intelisorb™ desiccant at 40° C. / 75% RH over a period of 1 month. [Figure 10] Plots are made of relative humidity over time in sachets with aluminum foil, Duma bottles, Duma bottles with silica gel desiccant, Duma bottles with INTELLISORB™ desiccant and LOG™ H2002 bottles when maintained in a climate chamber at 40° C. and 75% RH as described in Example 4. [Figure 11] FIG. 10 with dots overlaid to indicate the RH values ​​at which packaged formulations were considered stable (clear circles), unstable with a slowing dissolution profile (shaded circles) or unstable with an accelerating dissolution profile (black circles), as described in Examples 3 and 4. [Figure 12] Figure 2 shows the dissolution profile of a packaged modified release formulation over 3 months at 40°C / 75% RH, the modified release particles have 40% LUBRITAB™ in the coating and the formulation is packaged in PET / ALU / PE aluminum pouches (9 μm aluminum foil) from Bischof & Klein (Lengerich Germany) as described in Example 6. [Figure 13]1 shows the dissolution profile of a modified release formulation packaged over 2 months at 40° C. / 75% RH, where the modified release particles have 40% LUBRITAB™ in the coating and the formulation is packaged in DUMA™ bottles (30 ml) with 2 g of silica gel desiccant as described in Example 6. [Figure 14] Dissolution profiles of formulations packaged before and after storage for 0 and 18 months at 30° C. and 65% relative humidity in DUMA™ bottles without desiccant, as described in Example 7, are plotted. [Figure 15] The dissolution profiles of the formulations packaged before and after storage for 0 and 18 months at 30° C. and 65% relative humidity in DUMA™ bottles with 2 g of silica gel desiccant in the cap, as described in Example 7, are plotted. [Figure 16] Dissolution profiles of formulations packaged before and after storage for 0 and 18 months at 30° C. and 65% relative humidity in heat-sealed REXAM™ bottles without desiccant, as described in Example 7, are plotted. [Figure 17] The dissolution profiles of formulations packaged in Bischof & Klein PET / ALU / PE sachets with 9 μm ALU foil, as described in Example 7, are plotted before and after storage for 0 and 18 months at 30° C. and 65% relative humidity. [Figure 18] Plots the mean + SD (standard deviation) plasma gamma-hydroxybutyrate concentration (micrograms / mL) versus time for two different formulations of gamma-hydroxybutyrate tested in vivo according to the method of Example 8. Time profiles are shown for a 4.5 g dose of the second formulation of Example 1 administered in a single dose (● symbol) (N=26) and for a 4.5 g dose of XYREM® administered in two divided doses (- symbol). [Figure 19]The mean + SD (standard deviation) plasma gamma-hydroxybutyrate concentrations (micrograms / mL) versus time are plotted following single oral doses of 4.5 g (● symbol) and 6 g (▲ symbol) of the second formulation of Example 1 in the same seven subjects tested in vivo according to the method of Example 8. [Figure 20] Plots the mean + SD (standard deviation) plasma gamma-hydroxybutyrate concentrations (micrograms / mL) versus time for three separate doses of a second formulation prepared according to Example 1 tested in vivo according to the method of Example 8. Mean time profiles are shown for single oral administration of 4.5 g (N=26) (●), 6.0 g (N=19) (▲) or 7.5 g (■) doses (N=11). [Figure 21] Plots the mean plasma gamma-hydroxybutyrate concentrations (micrograms / mL) of a single dose of 7.5 g (■) of a second formulation prepared according to Example 1 compared to after 2 x 4.5 g of XYREM® exposure (source NDA 21-196 overview). [Figure 22] Figures 22A and 22B show plan views of a sachet-type packaging for use in the present invention. The packaging comprises two flat sheets of the same dimensions sealed together at their periphery in Figure 22A to define a hollow interior in which the drug product is packaged. In Figure 22B, the packaging is cut end to end so that the drug product can be dispensed. [Figure 23] The left hand of an individual is shown holding open the sachet shown in FIG. 22B, with the drug contents exposed and ready to be poured into a cup of water, which is also shown. [Figure 24] 1 shows an alternative type of packaging for the drug product of the present invention. The packaging is a bottle constructed of a moisture resistant material and has a screw-top cap that is removed, thereby exposing the drug product within the bottle. [Diagram 25] As reported in Example 9, the design of a human comparative study of formulations manufactured at two different scales is shown. [Figure 26] Concentration curves are plotted against gamma-hydroxybutyrate plasma concentrations for the formulations reported in Table 9b prepared during the human comparative study reported in Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention will be more readily understood by reference to the following detailed description of certain non-limiting embodiments of the invention described herein and the Examples included therein.

[0020] Definitions and Use of Terms It will be understood that whether or not an analysis or test is required to understand a given property or characteristic detailed herein, the analysis or test will be performed in accordance with the applicable guidelines, draft guidelines, regulations, and monographs of the U.S. Food and Drug Administration ("FDA") and the United States Pharmacopeia ("USP") / National Formulary ("NF") applicable to drug products in the United States, effective October 1, 2017, unless otherwise specified.

[0021] As used herein and in the claims that follow, the singular forms "a," "an," and "the" include plural references unless the context dictates otherwise. Thus, for example, reference to "a component" includes mixtures of components, and reference to "an active pharmaceutical agent" includes one or more active pharmaceutical agents, and the like.

[0022] When a range is stated by specifying a lower limit of the range separately from an upper limit of the range, it will be understood that the range can be defined by combining any one of the lower limit variables in the alternative, which are mathematically and physically possible, with any one of the upper limit variables. Thus, for example, if a formulation may contain 1-10 parts by weight of a particular component, or 2-8 parts by weight of a particular component, it will also be understood that the formulation may contain 2-10 parts by weight of the component. Similarly, if a formulation may contain more than 1 or 2 parts by weight of a component, and 10 or 9 parts by weight of a component, it will be understood that the formulation may contain 1-10 parts by weight of the component, 2-9 parts by weight of the component, etc., unless otherwise specified, and the boundaries of the range (lower and upper limits of the range) are included in the claims.

[0023] Similarly, when various subembodiments of a main embodiment are described herein, it will be understood that the subembodiments of the main embodiment can be combined to define further subembodiments. Thus, for example, when a main embodiment includes subembodiments 1, 2, and 3, it will be understood that the main embodiment can be further limited by any one of subembodiments 1, 2, and 3, or any combination of subembodiments 1, 2, and 3 that is mathematically and physically possible. Similarly, it will be understood that the main embodiments described herein can be combined in any manner that is mathematically and physically possible, and that the invention extends to such combinations.

[0024] As used herein, the terms "about" or "substantially" or "approximately" will account for variations that are accepted in the pharmaceutical industry and are inherent in pharmaceutical products, such as differences in product strength due to manufacturing variations and time-induced product degradation. This term allows for any variation that is evaluated in pharmaceutical practice to be considered bioequivalent to the specified strength, as described in the FDA's March 2003 guidance for industry in BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS GENERAL CONSIDERATIONS.

[0025] "Bioavailability" refers to the rate and extent to which an active ingredient or moiety is absorbed from a drug product and becomes available at the site of action.

[0026] "Relative Bioavailability" or "Rel BA" or "RBA" is the average AUC of a reference product inf Mean AUC of the tested products for inf Unless otherwise stated, relative bioavailability refers to the mean AUC observed for a dose of immediate release liquid solution when two half doses are administered 4 hours apart. inf Mean AUC observed for all doses of test product versus inf This refers to the percentage of.

[0027] In all pharmacokinetic studies described herein, unless otherwise specified, the dosage form, or the first dosage form if the dose regimen requires more than one administration, is administered approximately 2 hours after consumption of a standardized evening meal consisting of 25.5% fat, 19.6% protein and 54.9% carbohydrates.

[0028] The term "chemically stable" means that the GHB in the formulation under consideration does not exhibit unacceptable chemical degradation during storage. Thus, for example, if after 6 months of storage at 40°C and 75% relative humidity, the formulation will be considered chemically stable if it does not contain more than 3% GHB degradation products. In one particular embodiment, a packaged formulation is chemically stable if the package prevents not more than 0.4% of gamma-hydroxybutyrate in the composition from converting to gamma-butyrolactone (GBL) when stored for 2 months at 40°C and 75% relative humidity.

[0029] "Dissolution stability" refers to the ability of a formulation to maintain its stability profile over time. Examples of methods for measuring dissolution stability and criteria that can be used to evaluate dissolution stability are provided herein in Example 2. In one embodiment, a formulation is considered to have a stable dissolution profile if after 2 months of 40°C / 75% relative humidity storage period the composition exhibits a lag time that differs by less than 70, 60, or 50 minutes from the lag time at the beginning of the storage period, where the lag time is determined by the USP 38 standard in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm. <711> In another embodiment, the formulations are tested according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm for the percentage of gamma-hydroxybutyrate dissolved after a 2 month 40° C. / 75% relative humidity storage period at all tested time points or at 4, 6 or 8 consecutive hourly time points. <711> A formulation is considered to have a stable dissolution profile if the percentage of gamma-hydroxybutyrate dissolved at the same time point prior to the storage period when tested in dissolution apparatus 2 according to the method of the present invention differs by less than 10%.

[0030] As used herein, the term "gamma-hydroxybutyrate" or GHB includes hydrates, solvates, complexes and tautomers. Gamma-hydroxybutyrate salts can be selected from the sodium salt of gamma-hydroxybutyric acid (i.e., sodium oxyvate), the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric acid, the tetraammonium salt of gamma-hydroxybutyric acid or any other pharma- ceutically acceptable salt form.

[0031] "Lag time" refers to the latency period for release of gamma-hydroxybutyrate from a given formulation as determined according to the method described in Example 2 herein.

[0032] "Packaging" or "packaging" refers to any packaging material suitable for packaging any unit dose of a bulk pharmaceutical product. Thus, the term includes bottles (glass and plastic), barrels, bags, vials, ampoules, blister packs, sachets, stick-packs, and other containers. The size, type, and physical characteristics of the packaging or package are limited only by the compatibility of the packaging with the pharmaceutical product contained therein and the distribution requirements for the packaging.

[0033] "Pharmaceutically acceptable" means that which is useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those that are acceptable for veterinary use as well as human pharmaceutical use. The term "formulation" or "composition" refers to the quantitative and qualitative characteristics of a drug product or dosage form prepared according to the present invention.

[0034] As used herein, doses and strengths of gamma-hydroxybutyrate are expressed in equivalent-gram (g) weight of sodium oxyvert unless expressly stated to the contrary. Therefore, when considering a dose of gamma-hydroxybutyrate other than the sodium salt of gamma-hydroxybutyrate, the recited dose or strength must be converted from sodium oxyvert to gamma-hydroxybutyrate during the evaluation step. Thus, when an embodiment refers to providing a 4.5 g dose of gamma-hydroxybutyrate, since the form of gamma-hydroxybutyrate is not specified, it will be understood that the dose encompasses a 4.5 g dose of sodium oxyvert, a 5.1 g dose of potassium gamma-hydroxybutyrate (estimated 126.09 g / mol MW for sodium oxyvert and 142.20 g / mol MW for potassium gamma-hydroxybutyrate) and a 3.7 g dose of free base (estimated 126.09 g / mol MW for sodium oxyvert and 104.1 g / mol MW for gamma-hydroxybutyrate free base) or any mixture by weight of salts of gamma-hydroxybutyric acid that provides the same amount of GHB as 4.5 g of sodium oxyvert.

[0035] As used herein, "microparticle" refers to any discrete particle of a solid substance. The particle can be made of a single material or have a composite structure with a core and a shell and be made of several materials. The terms "microparticle", "particle", "microsphere" or "pellet" are interchangeable and have the same meaning. Unless otherwise stated, microparticles do not have a specific particle size or diameter and are not limited to particles with a volume average diameter D(4,3) of 1 mm or less.

[0036] As used herein, the "volume mean diameter D(4,3)" is calculated according to the following formula:

number

[0037] As used herein, the terms "RH" and "relative humidity" are used interchangeably.

[0038] As used herein, the terms "final composition", "final formulation" or "formulation" are interchangeable and preferably a modified release formulation of gamma-hydroxybutyrate, including modified release microparticles of gamma-hydroxybutyrate, immediate release microparticles of gamma-hydroxybutyrate and any other excipients. A "composition" can always be a "final composition".

[0039] As used herein and in the claims that follow, the "immediate release (IR) component" of a formulation includes physically discrete portions of the formulation, mechanically discrete portions of the formulation, and discrete portions of the formulation that provide or support a defined IR dissolution characteristic. Thus, for example, any formulation that releases an active ingredient at the required rate and extent of the immediate release component of the formulation of the present invention includes an "immediate release component" even if the immediate release component is physically incorporated into what might otherwise be considered a sustained release formulation. Thus, the IR component can be structurally discreet or not structurally discreet (i.e., incorporated) from the MR component. In certain embodiments, the IR component and the MR component are provided as particles, and even in more specific subembodiments, the IR component and the MR component are provided as particles that are discrete from each other.

[0040] As used herein, an "immediate release formulation" or "immediate release component" refers to a formulation that is formulated according to USP 38 in 0.1 N HCl dissolution medium at a temperature of 37° C. and a paddle speed of 75 rpm. <711> "Gamma-hydroxybutyrate" refers to a composition that releases at least 80% of gamma-hydroxybutyrate in one hour when tested in dissolution apparatus 2 according to the method of the present invention.

[0041] Similarly, "modified-release (MR) components" include that portion of a formulation or dosage form that confers or supports specific MR properties, regardless of the physical formulation in which the MR component is incorporated. Modified release drug delivery systems are designed to deliver a drug at a specific time, or over a period of time after administration, or to a specific location in the body. The USP defines modified release systems as those in which the time course or location of drug release, or both, are selected to achieve an objective of therapeutic efficacy or convenience not achieved by conventional IR dosage forms. More specifically, MR solid oral dosage forms include extended release (ER) and delayed release (DR) products. DR products are those that release the drug all at once, at a time other than immediately after administration. Typically, a coating (e.g., an enteric coating) is used to delay the release of the drug substance until the dosage form has passed through the acidic medium of the stomach. ER products are formulated to make the drug available for an extended period of time after ingestion, thus reducing dosing frequency compared to drugs presented as conventional dosage forms, e.g., solutions or immediate release dosage forms. For oral applications, the term "controlled release" is generally interchangeable with "sustained release," "sustained release," or "sustained release."

[0042] Traditionally, sustained release systems have provided constant drug release to maintain a stable concentration of drug, however, for some drugs, zero order delivery may not be optimal, and more complex and sophisticated systems have been developed to provide multi-phase delivery. A distinction can be made between four categories of oral MR delivery systems: (1) delayed release using enteric coatings, (2) site-specific or timed release (e.g., for colonic delivery), (3) sustained release (e.g., zero-order, first-order, biphasic release, etc.) and (4) programmed release (e.g., pulsatile, delayed sustained release, etc.), see Modified Oral Drug Delivery Systems in Gibaldi's DRUG DELIVERY SYSTEMS IN PHARMACEUTICAL CARE, AMERICAN SOCIETY OF HEALTH-SYSTEM PHARMACISTS, 2007, p. 34 and Rational Design of Oral Modified-release Drug Delivery Systems in DEVELOPING SOLID ORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Academic Press, Elsevier, 2009, p. 469. As used herein, "modified release formulation" or "modified release component" refers to a composition that releases its gamma-hydroxybutyrate according to a multi-stage delivery, such as delayed sustained release, which in one embodiment is included in the fourth category of MR products.It is therefore different from the delayed release products that are included in the first category of MR products.

[0043] As used herein, the terms "coating," "coating layer," "coating film," "film coating," and similar terms are interchangeable and have the same meaning. The terms refer to a coating applied to particles containing gamma-hydroxybutyrate that controls the modified release of gamma-hydroxybutyrate.

[0044] Narcolepsy type 1 (NT1) refers to narcolepsy characterized by excessive daytime sleepiness ("EDS") and cataplexy. Narcolepsy type 2 (NT2) refers to narcolepsy characterized by excessive daytime sleepiness without cataplexy. A diagnosis of narcolepsy (with or without cataplexy) can be confirmed by one or a combination of: (i) an overnight polysomnogram (PSG), multiple sleep latency test (MSLT) performed within the last 2 years; (ii) all documentation confirming the diagnosis by PSG and MSLT from a sleep laboratory which must be made available; (iii) current evidence of narcolepsy including: current complaints of EDS (Epworth Sleepiness Index (ESS) greater than 10) in the past 3 months; (iv) a mean maintenance of wakefulness test (MWT) of less than 8 minutes; (v) a mean number of 8 cataplexy events per week on a baseline sleep / cataplexy diary; and / or (vi) the presence of cataplexy in the past 3 months and 2 events per week during the screening period.

[0045] Unless otherwise specified herein, percentages, ratios and values ​​recited herein are based on weight; averages and means are arithmetic means.

[0046] It will be understood that when a composition is defined herein by its dissolution characteristics, the formulation is alternatively defined as a "means for" achieving the stated dissolution characteristics. Thus, a formulation in which a modified release component releases less than 20% of its gamma-hydroxybutyrate in 1 hour can instead be defined as a formulation that includes a "means for" or a "modified release means for" that releases less than 20% of its gamma-hydroxybutyrate in 1 hour. It will be further understood that the preferred structures for achieving the stated dissolution characteristics are those described in the examples herein that achieve the stated dissolution characteristics.

[0047] Explanation of the main aspects The present invention can be described in terms of main embodiments, which can then be combined to create other main embodiments, and limited by subembodiments to create other main embodiments.

[0048] In one subject embodiment, the present invention provides a packaged pharmaceutical composition having a stable dissolution profile, the pharmaceutical composition comprising immediate release and modified release components of gamma-hydroxybutyrate or a pharma- ceutical acceptable salt thereof.

[0049] In another major aspect, the present invention provides a packaged pharmaceutical composition comprising a modified release gamma-hydroxybutyrate pharmaceutical composition within a package, the pharmaceutical composition comprising immediate release and modified release components of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof, and the package having an interior volume having a relative humidity of 29% to 54%. In some iterations, the relative humidity of the package is 29% to 54% for a period of at least two months when stored at 40°C and 75% relative humidity. In other iterations, the relative humidity of the package is greater than 29% at one week and less than 54% at two months when stored at 40°C and 75% relative humidity. In further iterations, the relative humidity of the package is 35% to 39% after one week and 39% to 48% after two months when stored at 40°C and 75% relative humidity. In yet another iteration, greater than 0.4% of the gamma-hydroxybutyrate in the pharmaceutical composition is not converted to gamma-butyrolactone (GBL) upon storage for 2 months at 40° C. and 75% relative humidity. In other iterations, the package meets USP 38 <671> In some replicates, after a 40° C. / 75% relative humidity storage period of 2 months, the pharmaceutical composition exhibited a lag time that differed by less than 70 minutes from the lag time at the beginning of the storage period, and the lag time was measured according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> In another repeat, after a 40° C. / 75% relative humidity storage period of 2 months, the pharmaceutical composition had a dissolution rate of 1.0 mg / mL according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> when tested at least four consecutive hourly time points in dissolution apparatus 2 according to the method of the present invention, has a dissolution of gamma-hydroxybutyrate that differs by less than 10% from the dissolution of gamma-hydroxybutyrate prior to the storage period.

[0050] In yet another main aspect, the present invention is a packaged pharmaceutical composition having a stable dissolution profile, comprising a pharmaceutical composition in a package, the pharmaceutical composition comprising an immediate release and modified release component of gamma-hydroxybutyrate or a pharma-ceutically acceptable salt thereof, and the modified release component comprises a core comprising gamma-hydroxybutyrate or a pharma-ceutically acceptable salt thereof and a coating comprising a mixture of a hydrophobic compound and a methacrylic acid copolymer. In some iterations, the hydrophobic compound is glyceryl tristearate or a hydrogenated vegetable oil, and the mixture of methacrylic acid copolymers comprises methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF. In certain iterations, the coating comprises 40-70 parts by weight of the hydrophobic compound and 30-60 parts by weight of the mixture of methacrylic acid copolymer. In other iterations, the weight ratio of the hydrophobic compound to the mixture of methacrylic acid copolymer is about 1.5:1. In still other iterations, the mixture of the hydrophobic compound and the methacrylic acid polymer is greater than 90% by weight of the coating. In yet another iteration, the coating is 10-50% by weight of the modified release component. In another iteration, the mixture of methacrylic acid copolymers is substantially ionized at pH 7.5. In an alternative iteration, the hydrophobic compound comprises a hydrogenated vegetable oil. In yet another iteration, the hydrophobic compound has a melting point of 40° C. or higher, and the mixture of methacrylic acid copolymers has a pH trigger above 5.6. In a further iteration, the modified release component does not comprise a barrier coat between the core comprising gamma hydroxybutyrate and the coating. In a detailed embodiment, and the modified release component comprises particles having an average diameter of 200-800 microns. In certain iterations, the immediate release component comprises particles. For example, the immediate release component comprises particles having an average diameter of 95-600 microns. In a further iteration, the pharmaceutical composition can further comprise an acidifier and a suspending or thickening agent, as detailed below.

[0051] In a further main aspect, the present invention provides a packaged solid particle pharmaceutical composition having a stable dissolution profile over time, comprising an immediate release and modified release component of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof: (a) the modified release component comprises: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers comprising methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; and (b) the relative humidity within the packaging is in the range of 29% to 54% after one week at 40° C. and 75% relative humidity, and the package maintains a relative humidity within the range of 29% to 54% for a period of at least two months when stored at 40° C. and 75% relative humidity.

[0052] In another principal aspect, the present invention is a packaged solid particle pharmaceutical composition having a stable dissolution profile over time, comprising immediate release and modified release components of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof: (a) the modified release components comprise: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers comprising methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; and (b) after a 40° C. / 75% relative humidity storage period of 2 months, the composition exhibits a lag time that differs from the lag time at the start of the storage period by less than 70, 60, or 50 minutes, and the lag time is greater than or equal to 100 mg / kg of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm, the lag time being less ... <711> The present invention provides a pharmaceutical composition, the composition being determined by testing in a dissolution apparatus 2 according to the method of the present invention.

[0053] In yet another principal aspect, the present invention is a packaged solid particle pharmaceutical composition having a stable dissolution profile over time, comprising immediate release and modified release components of gamma-hydroxybutyrate or a pharma- ceutical acceptable salt thereof: (a) the modified release components comprise: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutical acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and a hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers comprising methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; and (b) the percentage of gamma-hydroxybutyrate dissolved after a 40° C. / 75% relative humidity storage period of 2 months is stable to 100% by weight in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm at all time points tested or at 4, 6 or 8 consecutive hourly time points. <711> The pharmaceutical composition provides a pharmaceutical composition which, when tested in dissolution apparatus 2 according to the above, differs from the percentage of gamma-hydroxybutyrate dissolved prior to the storage period by less than 10% at the same 4, 6 or 8 consecutive hourly time points.

[0054] In yet another principal aspect, the present invention provides a packaged solid particle pharmaceutical composition having a stable dissolution profile over time, comprising an immediate release and modified release component of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof: (a) the modified release component comprises: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers including methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; and (b) the package is compliant with USP 38 <671> The pharmaceutical composition has a water vapor transmission rate of less than 7 mg / day / liter as measured according to the method of claim 1.

[0055] In another aspect, the present invention provides a packaged solid particle pharmaceutical composition having a stable dissolution profile over time, comprising an immediate release and modified release component of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof: (a) the modified release component comprises: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers including methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; (b) the package is compliant with USP 38 <671> and (c) the package prevents conversion of no more than 0.4% of gamma-hydroxybutyrate to gamma-butyrolactone (GBL) when stored for 2 months at 40° C. and 75% relative humidity.

[0056] In a further aspect, the present invention provides a solid particle pharmaceutical composition having a stable dissolution profile over time comprising an immediate release and modified release component of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof, the modified release component comprising: (a) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (b) a coating comprising a mixture of a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a methacrylic acid copolymer comprising methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF.

[0057] In yet another aspect, the present invention provides a solid particulate pharmaceutical composition having a stable dissolution profile over time comprising an immediate release and modified release component of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof: (a) the modified release component comprises: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers comprising methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; and (b) after a 40° C. / 75% relative humidity storage period of 2 months, the composition exhibits a lag time that differs from the lag time at the start of the storage period by less than 70, 60, or 50 minutes, and the lag time is greater than or equal to 100 mg / kg of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm, the lag time being within the range of 100 mg / kg of 0.1 N hydrochloric acid in 900 mL of USP 380. <711> The present invention provides a solid particle pharmaceutical composition, the solid particle size distribution of which is determined by testing in dissolution apparatus 2 according to the method of the present invention.

[0058] In yet another embodiment, the present invention provides a solid particulate pharmaceutical composition having a stable dissolution profile over time comprising immediate release and modified release components of gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof: (a) the modified release components comprise: (i) a core comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and (ii) a coating comprising a hydrophobic compound selected from glyceryl tristearate and hydrogenated vegetable oil, and a mixture of methacrylic acid copolymers comprising methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF; and (b) the percentage of gamma-hydroxybutyrate dissolved after a 40° C. / 75% relative humidity storage period of 2 months is measured according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm at 4, 6, or 8 consecutive hourly time points. <711> The solid particle pharmaceutical composition has a percentage of gamma-hydroxybutyrate dissolved at the same 4, 6 or 8 consecutive hourly time points when tested in dissolution apparatus 2 according to the method of the present invention that differs by less than 10% from the percentage of gamma-hydroxybutyrate dissolved prior to the storage period.

[0059] In yet another aspect, the present invention provides a method of treating narcolepsy type 1 or type 2 using a packaged pharmaceutical composition. The composition is also effective to induce sleep for 6 to 8, most preferably 8, consecutive hours. The method includes administering the pharmaceutical composition to an individual in need thereof. Generally, the method includes opening a package containing a gamma-hydroxybutyrate composition, mixing (e.g., via shaking, stirring, or otherwise agitating) the solid pharmaceutical composition with a liquid (e.g., water) to form a mixture, and orally administering the mixture to the individual.

[0060] Sub-mode As noted in the definitions section of this document, each sub-aspect can be used to further characterize and limit each preceding main aspect. In addition, two or more of the following sub-aspects can be combined and further used to characterize and limit each preceding main aspect in any manner that is mathematically and physically possible.

[0061] In various subembodiments, the composition is defined based on its dissolution stability. Thus, in some subembodiments, after 2 months of 40° C. / 75% relative humidity storage, the composition exhibits a lag time that differs from the lag time at the beginning of the storage period by less than 70, 60, or 50 minutes, and the lag time is less than or equal to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> This is determined by testing in dissolution apparatus 2 according to

[0062] In other subembodiments, the amount of gamma-hydroxybutyrate dissolved after a 40° C. / 75% relative humidity storage period of 2 months is measured using a USP 380 standard in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm for 4, 6, or 8 consecutive hourly time points. <711> This differs by less than 10% from the amount of gamma-hydroxybutyrate dissolved prior to the storage period when tested in dissolution apparatus 2 according to

[0063] In other subembodiments, the packaged composition is defined based on its chemical stability. Thus, in another subembodiment, the package prevents not more than 0.4% gamma-hydroxybutyrate from converting to gamma-butyrolactone (GBL) upon storage at 40° C. and 75% relative humidity for 2 months.

[0064] Packaging In one particular subembodiment applicable to any of the major embodiments, the composition is contained within an internal volume of the package. The atmosphere within the internal volume is preferably defined by its humidity or its humidity over time. In one subembodiment, the atmosphere within the internal volume has a relative humidity in the range of 29% to 54%, and the package maintains a relative humidity in said range for a period of at least 2 months when stored at 40° C. and 75% relative humidity. In another subembodiment, the internal volume has a relative humidity greater than 29% at 1 week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. In another subembodiment, the internal volume has a relative humidity greater than 29% at 1 week and less than 44% at 1 week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. In yet another subembodiment, the internal volume has a relative humidity of 35-39% after 1 week and 39-48% after 2 months when stored at 40° C. and 75% relative humidity.

[0065] In one subembodiment, the dissolution profile is unstable and the packaging is not adequate if: After 1 week at 40°C / 75% RH, the RH is less than 29%; or Before February at 40℃ / 75%RH, RH is higher than 54%.

[0066] The package can be further defined based on its water vapor transmission rate. In various subembodiments, the package meets USP 38 <671> Specific packaging materials include aluminum foil pouches or sachets or stick-packs, as well as modified HDPE bottles with reduced water permeability, such as the H2OO2™ bottles manufactured by LOG Pharma Packaging (Israel).

[0067] When an aluminum foil pouch or sachet or stick-pack is used, further subembodiments can be defined based on the thickness of the aluminum film, which in various other subembodiments means that the aluminum film used in the packaging has a thickness of 6 μm, 9 μm, or 12 μm or more.

[0068] The modified release formulation of gamma-hydroxybutyrate is typically provided in a sachet or stick-pack containing the particulate formulation. The sachet or stick-pack is available in several different doses, typically containing 0.5g, 1.0g, 1.5g, 3.0g, 4.5g, 6.0g, 7.5g, 9.0g, 10.5g and / or 12g of sodium oxyvert and the equivalent amount of gamma-hydroxybutyrate. Depending on the required dose, one or more of these sachets or stick-packs can be opened and the contents mixed with tap water or drinking water to provide a nightly dose of gamma-hydroxybutyrate.

[0069] Turning now to Figures 22-24, reference can be made to various embodiments of exemplary packaging and uses of the packaging of the present invention. Figures 22A and 22B show plan views of sachet-type packaging for use in the present invention. The packaging comprises two flat sheets (1) of equal dimensions sealed to one another at their periphery (2) in Figure 22A to define a hollow interior (3) in which the drug product is packaged. In Figure 22B, the packaging is cut from one end (4) to the other so that the drug product can be dispensed.

[0070] Figure 23 shows an individual's left hand (5) holding open the sachet shown in Figure 22B, with the drug contents (6) exposed in the hollow interior (3) and ready to be poured into a cup (7) of water (8), which is also shown. After the drug contents (6) have been poured into the cup (7) and mixed with the water (8), a cap (9) is screwed onto the top of the cup (7) so that the contents can be shaken into a uniform suspension.

[0071] Figure 24 shows an alternative type of packaging for the drug product of the present invention. The packaging is a bottle (10) constructed of a moisture resistant material and has a screw-top cap (11) that is removed, thereby exposing the drug product (6) inside the bottle.

[0072] Composition Subaspects The gamma-hydroxybutyrate compositions of the present invention can be provided in any dosage form suitable for oral administration, including tablets, capsules, liquids, orally dissolving tablets, and the like, but they are typically provided as dry particle formulations (i.e., granules, powders, coated particles, microparticles, pellets, microspheres, etc.) in sachets or other suitable discreet packaging units. Preferred particle formulations will be mixed with water, preferably 50 ml, immediately prior to administration.

[0073] In various subembodiments, when the composition is a particulate formulation, the formulation will include excipients to improve the viscosity and pourability of the mixture of water and the particulate formulation. Thus, the particulate formulation will include one or more suspending or thickening agents or lubricants in addition to the immediate release and modified release particles of gamma-hydroxybutyrate.

[0074] Particular suspending or thickening agents are selected from the group consisting of xanthan gum, medium viscosity sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and guar gum, medium viscosity hydroxyethylcellulose, agar, sodium alginate, a mixture of sodium alginate and calcium alginate, gellan gum, carrageenan gum grades iota, kappa or lambda, and medium viscosity hydroxypropyl methylcellulose.

[0075] Intermediate viscosity sodium carboxymethylcellulose corresponds to the grade of sodium carboxymethylcellulose having a viscosity greater than 200 mPa·s and less than 3100 mPa·s for a 2% solution in water at 25° C.

[0076] Intermediate viscosity hydroxyethylcellulose corresponds to the grade of hydroxyethylcellulose having a viscosity greater than 250 mPa·s and less than 6500 mPa·s for a 2% solution in water at 25° C. Intermediate viscosity hydroxypropyl methylcellulose corresponds to the grade of hydroxypropyl methylcellulose having a viscosity greater than 80 mPa·s and less than 3800 mPa·s for a 2% solution in water at 20° C.

[0077] Particular suspending or thickening agents are xanthan gum, particularly Xantural™ from Kelco, hydroxyethylcellulose, particularly Natrosol 250M™ from Ashland, kappa carrageenan gum, particularly Gelcarin PH812™ from FMC Biopolymer, and lambda carrageenan gum, particularly Viscarin PH209™ from FMC Biopolymer.

[0078] In certain embodiments, the gamma-hydroxybutyrate formulation comprises a thickening or suspending agent at 1-15% of the formulation, typically 2-10%, more typically 2-5% and most preferably 2-3%.

[0079] In certain embodiments, the formulation of gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water prior to administration and further comprises a suspending or thickening agent selected from 1-15% xanthan gum, carrageenan gum and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum.

[0080] In certain embodiments, the formulation of gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water prior to administration and further comprises 1.2-15% of an acidifying agent selected from malic acid and tartaric acid; and 1-15% of a suspending or thickening agent selected from xanthan gum, carrageenan gum and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum.

[0081] In a most preferred embodiment, the formulation of gamma-hydroxybutyrate contains about 1% lambda carrageenan gum or Viscarin PH209™, about 1% medium viscosity grade hydroxyethylcellulose or Natrosol 250M™, and about 0.7% xanthan gum or Xantural 75™. For a 4.5 g dosage unit, these proportions would typically equate to about 50 mg xanthan gum (Xantural 75™), about 75 mg carrageenan gum (Viscarin PH209™), and 75 mg hydroxyethylcellulose (Natrasol 250M™).

[0082] An alternative package of thickening or suspending agent contains, for a 4.5 g dose, about 50 mg xanthan gum (Xantural 75™) and about 100 mg carrageenan gum (Gelcarin PH812™) or about 50 mg xanthan gum (Xantural 75™), about 75 mg hydroxyethylcellulose (Natrasol 250M™) and about 75 mg carrageenan gum (Viscarin PH109™).

[0083] In certain embodiments, the formulation of gamma-hydroxybutyrate further comprises a lubricant or glidant in addition to the immediate release and modified release particles of gamma-hydroxybutyrate.Specific lubricants and glidants are selected from the group consisting of salts of stearic acid, particularly magnesium stearate, calcium stearate or zinc stearate, esters of stearic acid, particularly glyceryl monostearate or glyceryl palmitoleate, stearic acid, glyceryl behenate, sodium stearyl fumarate, talc and colloidal silicon dioxide.Preferred lubricant or glidant is magnesium stearate.

[0084] A lubricant or glidant may be used in the microparticle formulation in an amount of 0.1-5%. A preferred amount is about 0.5%. Most preferably, the modified release formulation of gamma-hydroxybutyrate contains about 0.5% magnesium stearate.

[0085] Certain formulations of gamma-hydroxybutyrate further include an acidifier that helps ensure that the dissolution profile of the formulation in 0.1 N HCl will remain substantially unchanged after at least 15 minutes of mixing, and even after 30 minutes of mixing, which is approximately the maximum amount of time a patient may require before consuming a dose after mixing the formulation with tap water.

[0086] In one particular subembodiment, the formulation is a powder and further comprises an acidifying agent and a suspending or thickening agent, typically in the weight percentages detailed herein.

[0087] Particular acidifying agents are selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid and benzoic acid. In particular embodiments, the acidifying agent is typically present in the formulation at 1.2-15%, 1.2-10% or 1.2-5%. Preferred acidifying agents are tartaric acid and malic acid, with malic acid being most preferred.

[0088] When tartaric acid is used, it is typically used in an amount of 1-10%, 2.5-7.5% or about 5%. In the most preferred embodiment, the amount of malic acid in the modified release formulation of gamma-hydroxybutyrate is 1.2-15%, typically 1.2-10%, typically 1.2-5% and most preferably 1.6% or 3.2%.

[0089] In a most particular embodiment, the amount of malic acid in the modified release formulation of gamma-hydroxybutyrate is 1.6%.

[0090] The molar ratio of gamma-hydroxybutyrate in the immediate release and modified release components is typically in the range of 0.11:1 to 1.86:1, 0.17:1 to 1.5:1, 0.25:1 to 1.22:1, 0.33:1 to 1.22:1, 0.42:1 to 1.22:1, 0.53:1 to 1.22:1, 0.66:1 to 1.22:1, 0.66:1 to 1.5:1, 0.8:1 to 1.22:1, and preferably about 1:1. The molar percentage of gamma-hydroxybutyrate in the immediate release component relative to the total amount of gamma-hydroxybutyrate in the formulation is typically in the range of 10% to 65%, 15 to 60%, 20 to 55%, 25 to 55%, 30 to 55%, 35 to 55%, 40 to 55%, 40 to 60% or 45 to 55%, preferably 40% to 60%. In certain embodiments, the molar percentage of gamma-hydroxybutyrate in the immediate release component relative to the total amount of gamma-hydroxybutyrate in the formulation is about 50%. The molar percentage of gamma-hydroxybutyrate in the modified release component relative to the total amount of gamma-hydroxybutyrate in the formulation is typically in the range of 90% to 35%, 85% to 45%, 80% to 45%, 75% to 45%, 70% to 45%, 65% to 45%, 60% to 45%, 60% to 40% or 55% to 40%, preferably 60% to 40%. In certain embodiments, the molar ratio of gamma-hydroxybutyrate in the modified release component relative to the total amount of gamma-hydroxybutyrate in the formulation is about 50%. The weight percentage of the IR microparticles relative to the total weight of the IR microparticles and MR microparticles is typically in the range of 7.2% to 58.2%, 11.0% to 52.9%, 14.9% to 47.8%, 18.9% to 47.8%, 23.1% to 47.8%, 27.4% to 47.8%, 31.8% to 47.8%, 31.8% to 52.9%, or 36.4% to 47.8%. In other embodiments, the weight percentage of IR microparticles relative to the total weight of IR microparticles and MR microparticles is typically in the range of 5.9% to 63.2%, 9.1% to 53.1%, 12.4% to 53.1%, 19.9% ​​to 53.1%, 19.6% to 53.1%, 23.4% to 58.1%, 27.4% to 58.1, 27.4% to 53.1%, and preferably 31.7% to 53.1%.

[0091] In certain embodiments, the final formulation contains 80.75% w / w Sodium Oxyvert, 4.25% w / w Povidone 50% of its sodium oxyvert content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, and 50% of its sodium oxyvert content in modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% Eudragit® L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit® S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0092] In certain embodiments, the final formulation contains 80.75% w / w Sodium Oxyvert, 4.25% w / w Povidone 50% of its sodium oxyvert content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, and 50% of its sodium oxyvert content in modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% Eudragit® L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit® S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0093] In certain embodiments, the final formulation contains 80.75% w / w Sodium Oxyvert, 4.25% w / w Povidone 50% of its sodium oxyvert content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, and 50% of its sodium oxyvert content in modified release particles consisting of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 60.5% w / w sodium oxyvert mixed with 3.2% w / w Povidone® K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% Eudragit® L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 9.25% Eudragit® S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0094] In a particular embodiment, the final formulation comprises 80.75% w / w sodium oxyvert, 4.25% w / w Povidone™ K30, and 50% of its sodium oxyvert content in immediate release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, and 50% of its sodium oxyvert content in modified release particles consisting of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, and 3.2 % w / w of Povidone™ K30, and finally coated with a coating composition consisting of 15% w / w of hydrogenated vegetable oil (Lubritab™ or equivalent), 0.75% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 9.25% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0095] In certain embodiments, the final formulation comprises 80.75% w / w potassium salt of gamma-hydroxybutyric acid, 4.25% w / w Povidone 50% of its gamma-hydroxybutyrate content in modified release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, and 50% of its gamma-hydroxybutyrate content in immediate release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0096] In certain embodiments, the final formulation comprises 80.75% w / w potassium salt of gamma-hydroxybutyric acid, 4.25% w / w Povidone 50% of its gamma-hydroxybutyrate content in modified release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, and 50% of its gamma-hydroxybutyrate content in immediate release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0097] In a particular embodiment, the final formulation comprises 80.75% w / w of the potassium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30, and 16.7% of its gamma-hydroxybutyrate content in fast-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, 80.75% w / w of the magnesium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30, and 16.7% of its gamma-hydroxybutyrate content in fast-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, 80.75% w / w of the calcium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30, and 16.7% of its gamma-hydroxybutyrate content in fast-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, 16.7% of its gamma-hydroxybutyrate content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, and 50% of its gamma-hydroxybutyrate content in modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0098] In a particular embodiment, the final formulation comprises 80.75% w / w of the potassium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30, and 16.7% of its gamma-hydroxybutyrate content in fast-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, 80.75% w / w of the magnesium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30, and 16.7% of its gamma-hydroxybutyrate content in fast-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, 80.75% w / w of the calcium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30, and 16.7% of its gamma-hydroxybutyrate content in fast-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, 16.7% of its gamma-hydroxybutyrate content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, and 50% of its gamma-hydroxybutyrate content in modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0099] In certain embodiments, the final formulation comprises 80.75% w / w potassium salt of gamma-hydroxybutyric acid, 4.25% w / w Povidone 50% of its gamma-hydroxybutyrate content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, and 50% of its gamma-hydroxybutyrate content in modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w of the calcium salt of gamma-hydroxybutyric acid mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0100] In certain embodiments, the final formulation comprises 80.75% w / w potassium salt of gamma-hydroxybutyric acid, 4.25% w / w Povidone 50% of its gamma-hydroxybutyrate content in immediate release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, and 50% of its gamma-hydroxybutyrate content in modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w of the calcium salt of gamma-hydroxybutyric acid mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0101] Other features of immediate release formulations The immediate release component of the formulation can take any form that can achieve immediate release of gamma-hydroxybutyrate when ingested. For example, when the formulation is a particulate formulation, the formulation can include unmodified "raw" gamma-hydroxybutyrate, rapidly dissolving gamma-hydroxybutyrate granules, particles or microparticles consisting of a core coated with a layer filled with gamma-hydroxybutyrate containing a binder such as povidone.

[0102] The IR granules or particles of gamma-hydroxybutyrate can be made using any manufacturing process suitable to produce the required particles, including: Agglomerates of gamma-hydroxybutyrate, typically sprayed in the molten state, such as Glatt ProCell™ technology; extrusion and spheronization of gamma-hydroxybutyrate, optionally together with one or more physiologically acceptable excipients; wet granulation of gamma-hydroxybutyrate, optionally together with one or more physiologically acceptable excipients; forming gamma-hydroxybutyrate, optionally together with one or more physiologically acceptable excipients; granulation and spheronization of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients, the spheronization being carried out in particular using the Glatt CPS™ technology, for example in a fluidized bed apparatus equipped with a rotor; spraying of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients, in particular using Glatt MicroPx™ technology, for example in a fluidized bed type device equipped with a zigzag filter, or Spraying of gamma-hydroxybutyrate, optionally together with one or more physiologically acceptable excipients, in a dispersion on cores or in a solution in water or an organic solvent, e.g. in a fluidized bed apparatus optionally equipped with a split tube or Worcester tube.

[0103] Typically, the immediate release component of the formulation is in the form of microparticles comprising immediate release gamma-hydroxybutyrate and optional pharma-ceutically acceptable excipients. In certain embodiments, the immediate release microparticles of gamma-hydroxybutyrate have a volume average diameter D(4,3) of 10 to 1000 microns, typically 95 to 600 microns, more typically 150 to 400 microns. Most preferably, their volume average diameter is about 270 microns.

[0104] The preferred immediate release particles of gamma-hydroxybutyrate of the present invention comprise a core and a layer deposited on the core that comprises gamma-hydroxybutyrate. The core can be any particle selected from the group consisting of: · Lactose crystals or spheres, sucrose (such as Compressuc™ PS from Tereos), microcrystalline cellulose (such as Avicel™ from FMC Biopolymer, Cellet™ from Pharmatrans or Celphere™ from Asahi Kasei), sodium chloride, calcium carbonate (such as Omyapure™ 35 from Omya), sodium bicarbonate, dicalcium phosphate (such as Dicafos™ AC 92-12 from Budenheim) or calcium phosphate (such as Tricafos™ SC 93-15 from Budenheim); Composite spheres or granules, for example sugar spheres containing sucrose and starch (such as Suglets™ from NP Pharm), calcium carbonate and starch spheres (such as Destab™ 90 S Ultra 250 from Particle Dynamics) or calcium carbonate and maltodextrin spheres (such as Hubercal™ CCG4100 from Huber).

[0105] The core may also contain other particles of pharma- ceutically acceptable excipients such as particles of hydroxypropylcellulose (such as Klucel™ from Aqualon Hercules), guar gum particles (such as Grinsted™ Guar from Danisco), xanthan particles (such as Xantural™ 180 from CP Kelco).

[0106] According to a particular embodiment of the invention, the core is a sugar sphere or a microcrystalline cellulose sphere, such as Cellets™ 90, Cellets™ 100 or Cellets™ 127 marketed by Pharmatrans or CP 203, Celphere™ CP305, Celphere™ SCP 100 by Celphere™. Typically, the core is a microcrystalline cellulose sphere. Most preferably, the core is Cellets™ 127 from Pharmatrans.

[0107] The core typically has an average volume diameter of from about 95 to about 450 microns, more typically from about 95 to about 170 microns, and most preferably 140 microns.

[0108] The layer deposited onto the core comprises the immediate release gamma-hydroxybutyrate. Typically, the layer also comprises a binder, which may be selected from the group consisting of: low molecular weight hydroxypropylcellulose (such as Klucel™ EF from Aqualon- Hercules), low molecular weight hydroxypropylmethylcellulose (or hypromellose) (such as Methocel™ E3 or E5 from Dow) or low molecular weight methylcellulose (such as Methocel™ A15 from Dow); low molecular weight polyvinylpyrrolidone (or Povidone) (such as Plasdon® K29 / 32 from ISP or Kollidon® 30 from BASF), vinylpyrrolidone and vinyl acetate copolymers (or CoPovidone) (such as Plasdon®: S630 from ISP or Kollidon® VA 64 from BASF); Dextrose, pregelatinized starch, maltodextrin; and mixtures thereof.

[0109] Low molecular weight hydroxypropylcellulose corresponds to a grade of hydroxypropylcellulose having a molecular weight of less than 800,000 g / mol, typically less than or equal to 400,000 g / mol, and in particular less than or equal to 100,000 g / mol. Low molecular weight hydroxypropylmethylcellulose (or hypromellose) corresponding to the grade of hydroxypropylmethylcellulose has a solution viscosity of less than or equal to 1,000 mPa·s, typically less than or equal to 100 mPa·s, and in particular less than or equal to 15 mPa·s for a 2% solution in water and at 20° C. Low molecular weight polyvinylpyrrolidone (or povidone) corresponds to a grade of polyvinylpyrrolidone having a molecular weight of less than or equal to 1,000,000 g / mol, typically less than or equal to 800,000 g / mol, and in particular less than or equal to 100,000 g / mol.

[0110] Typically the binder is selected from low molecular weight polyvinylpyrrolidone or povidone (e.g. Plasdon™ K29 / 32 from ISP), low molecular weight hydroxypropylcellulose (e.g. Klucel™ EF from Aqualon-Hercules), low molecular weight hydroxypropylmethylcellulose or hypromellose (e.g. Methocel™ E3 or E5 from Dow) and mixtures thereof.

[0111] A preferred binder is povidone K30 or K29 / 32 (especially Plasdon® K29 / 32 from ISP). The binder may be present in an amount of 0-80%, 0-70%, 0-60%, 0-50%, 0-40%, 0-30%, 0-25%, 0-20%, 0-15%, 0-10% or 1-9%, most preferably 5% binder based on the total weight of the immediate release coating.

[0112] The preferred amount of binder is 5% binder based on the total weight of gamma-hydroxybutyrate and binder.

[0113] The layer deposited on the core can represent at least 10% by weight of the total weight of the immediate release particles of gamma-hydroxybutyrate, and even more than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% by weight. Most preferably, the layer deposited on the core is about 85% by weight of the immediate release particles of gamma-hydroxybutyrate.

[0114] According to a particular embodiment, the fast acting particles comprise 80.75% w / w gamma-hydroxybutyrate, 4.25% w / w Povidone K30 and 15% microcrystalline cellulose spheres.

[0115] According to a particular embodiment, the fast-acting particles comprise 80.75% w / w gamma-hydroxybutyrate, 4.25% w / w Povidone K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns.

[0116] According to a particular embodiment, the fast-acting particles comprise 80.75% w / w gamma-hydroxybutyrate, 4.25% w / w Povidone K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns.

[0117] According to a particular embodiment, the fast-acting particles comprise 80.75% w / w sodium oxyvert, 4.25% w / w Povidone K30 and 15% microcrystalline cellulose spheres.

[0118] According to another particular embodiment, the fast-acting particles comprise 80.75% w / w of the potassium salt of gamma-hydroxybutyric acid, 4.25% w / w of Povidone K30 and 15% microcrystalline cellulose spheres.

[0119] According to another particular embodiment, the fast acting particles comprise 80.75% w / w calcium salt of gamma-hydroxybutyric acid, 4.25% w / w Povidone K30 and 15% microcrystalline cellulose spheres. According to another particular embodiment, the fast acting particles comprise 80.75% w / w magnesium salt of gamma-hydroxybutyric acid, 4.25% w / w Povidone K30 and 15% microcrystalline cellulose spheres.

[0120] According to another embodiment, fast-acting particles are prepared by dissolving gamma-hydroxybutyrate and Povidone K30 in a mixture of water / ethanol 40 / 60 w / w and spraying the resulting solution onto the surface of microcrystalline cellulose spheres.

[0121] Other features of modified release components The modified release component typically consists of modified release particles obtained by coating immediate release particles of gamma-hydroxybutyrate with a coating (or coating film) that inhibits immediate release of gamma-hydroxybutyrate. In a particular subembodiment, there is no barrier coating between the gamma-hydroxybutyrate and the modified release coating. In one subembodiment, the modified release component comprises a particle comprising: (a) an inert core; (b) a coating; and (c) a layer comprising gamma-hydroxybutyrate interposed between the core and the coating.

[0122] In certain embodiments, the modified release component includes a time-dependent release mechanism and a pH-dependent release mechanism, and typically includes a mixture of a hydrophobic compound and a methacrylic acid copolymer selected from hydrogenated vegetable oils and glyceryl tristearate and mixtures thereof. The mixture of methacrylic acid copolymers is preferably substantially ionized at pH 7.5. The hydrophobic compound typically has a melting point of 40° C. or higher. The mixture of hydrophobic compound and methacrylic acid polymer typically comprises more than 80%, 90%, 95% or the entire weight of the coating.

[0123] A particularly suitable coating is composed of a mixture of hydrogenated vegetable oils and a mixture of methacrylic acid copolymers. The exact structure and amount of each component, as well as the amount of coating applied to the particles, control the release rate and the release trigger. Eudragit™ methacrylic acid copolymers, i.e. methacrylic acid-methyl methacrylate copolymers and methacrylic acid-ethyl acrylate copolymers, have a pH-dependent solubility: typically, the pH that triggers the release of the active ingredient from the microparticles is set by the selection and mixture of suitable Eudragit™ polymers. In the case of gamma-hydroxybutyrate modified release microparticles, the theoretical pH that triggers the release is typically 5.6 to 6.97 or 6.9, more preferably 6.5 to 6.9. By "pH trigger" is meant the minimum pH at which dissolution of the polymer occurs.

[0124] In certain subembodiments, the weight ratio of the mixture of hydrophobic compound to methacrylic acid copolymer is from 0.67 to 2.33; most preferably, it is about 1.5.

[0125] A particularly suitable coating is comprised of a mixture of hydrogenated vegetable oil and methacrylic acid copolymer, with a theoretical pH to trigger release of 6.5 to 6.97, and a weight ratio of 0.67 to 2.33, most preferably about 1.5.

[0126] The modified release particles of gamma-hydroxybutyrate typically have a volume average diameter of from 100 to 1200 microns, 100 to 500 microns, 200 to 800 microns and preferably about 320 microns.

[0127] The coating may typically represent 10-50%, 15-45%, 20-40% or 25-35% by weight of the total weight of the coated modified release particle. Preferably, the coating is 25-30% by weight of gamma-hydroxybutyrate of the total weight of the modified release particle.

[0128] In a particular embodiment, the coating layer of the modified release particles of gamma-hydroxybutyrate is obtained by spraying a solution, suspension or dispersion comprising the coating composition as previously defined, particularly in a fluidized bed apparatus, onto the immediate release particles of gamma-hydroxybutyrate, particularly the immediate release particles of gamma-hydroxybutyrate as previously described. Typically, the coating is formed by spraying a solution of the coating excipients in hot isopropyl alcohol in a fluidized bed equipped with a Worcester or split tube and with an upward spray orientation or a bottom spray.

[0129] According to a particular embodiment, the modified release particles of gamma-hydroxybutyrate consist of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w gamma-hydroxybutyrate mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF), all percentages expressed based on the total weight of the final modified release particles of gamma-hydroxybutyrate.

[0130] According to a particular embodiment, the modified release particles of gamma-hydroxybutyrate consist of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w gamma-hydroxybutyrate mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF), all percentages expressed based on the total weight of the final modified release particles of gamma-hydroxybutyrate.

[0131] According to a particular embodiment, modified release particles of gamma-hydroxybutyrate are made from 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF), all percentages expressed based on the total weight of the final modified release particles of sodium oxyvert.

[0132] According to a particular embodiment, modified release particles of gamma-hydroxybutyrate are comprised of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w sodium oxyvert mixed with 3% w / w Povidone™ K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 4% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 8% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF), all percentages expressed based on the total weight of the final modified release particles of sodium oxyvert.

[0133] According to another particular embodiment, the modified release particles of gamma-hydroxybutyrate consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 60.5% w / w gamma-hydroxybutyrate mixed with 3.2% w / w Povidone™ K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 0.75% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 9.25% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0134] According to another particular embodiment, the modified release particles of gamma-hydroxybutyrate consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 60.5% w / w gamma-hydroxybutyrate mixed with 3.2% w / w Povidone™ K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 0.75% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 9.25% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0135] According to another particular embodiment, the modified release particles of gamma-hydroxybutyrate consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 60.5% w / w sodium oxyvert mixed with 3.2% w / w Povidone™ K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 0.75% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 9.25% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0136] According to another particular embodiment, the modified release particles of gamma-hydroxybutyrate consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 60.5% w / w sodium oxyvert mixed with 3.2% w / w Povidone™ K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab™ or equivalent), 0.75% Eudragit™ L100-55 (methacrylic acid and ethyl acrylate copolymer NF) and 9.25% Eudragit™ S100 (methacrylic acid and methyl methacrylate copolymer (1:2) NF).

[0137] Dissolution submode Further subembodiments are defined based on the dissolution characteristics of the formulation. Thus, in one subembodiment, (a) the composition is dissolved in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm, according to USP 38 <711> (b) the composition releases at least 80% of its gamma-hydroxybutyrate in 3 hours when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C.; <711> and (c) the modified release component releases greater than 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution test starting in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switching to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

[0138] In another subembodiment, (a) the immediate release component is formulated according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> (b) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 1 hour when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm; <711> (c) the modified release component releases less than 20% of its gamma-hydroxybutyrate in 1 hour when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm; <711> and (d) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 3 hours when tested in dissolution apparatus 2 according to the procedure set forth above; and (d) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 3 hours in a dissolution test starting in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switching to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

[0139] In another subembodiment, the modified release component is formulated according to USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm. <711> It releases more than 80% of its gamma-hydroxybutyrate in 1 hour when tested in dissolution apparatus 2 according to

[0140] In a preferred embodiment, the formulation of gamma-hydroxybutyrate according to the present invention comprises: The following in vitro dissolution profile is achieved: (a) USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 40% to 65% in 1 hour, (ii) 40% to 65% in 3 hours; (iii) 47% to 85% at 8 hours; (iv) 60% or more at 10 hours; (v) 80% or more in 16 hours and (b) USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 43% to 94% in 0.25 hours, (ii) 65% or more at 0.5 hours; and (iii) 88% or more in 1 hour It is characterized by being.

[0141] In preferred embodiments, formulations of gamma-hydroxybutyrate according to the present invention achieve the following in vitro dissolution profile: (a) USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 40% to 65% in 1 hour, (ii) 40% to 65% in 3 hours; (iii) 47% or more at 8 hours; (iv) 60% or more at 10 hours; (v) 80% or more at 16 hours, and and characterized by: (b) USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 43% to 94% in 0.25 hours, (ii) 65% or more at 0.5 hours; and (iii) 88% or more in 1 hour It is characterized by being.

[0142] In another preferred embodiment, formulations of gamma-hydroxybutyrate according to the present invention achieve the following in vitro dissolution profile: (a) USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 40% to 65% in 1 hour, (ii) 40% to 65% in 3 hours; (iii) 47% to 85% at 8 hours; (iv) 60% or more at 10 hours; (v) 80% or more in 16 hours and characterized by: (b) USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 45% to 67% in 1 hour, and (ii) 65% or more in 3 hours It is characterized by being.

[0143] In another preferred embodiment, formulations of gamma-hydroxybutyrate according to the present invention achieve the following in vitro dissolution profile: (a) USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 40% to 65% in 1 hour, (ii) 40% to 65% in 3 hours; (iii) 47% or more at 8 hours; (iv) 60% or more at 10 hours; (v) 80% or more in 16 hours and characterized by: (b) USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm <711> The percentage of dissolved gamma-hydroxybutyrate was measured in dissolution apparatus 2 according to: (i) 45% to 67% in 1 hour, and (ii) 65% or more in 3 hours It is characterized by being.

[0144] In yet another subembodiment, (a) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 3 hours in a dissolution test initiated in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switched to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm; and (b) the immediate release component releases greater than 80% of its gamma-hydroxybutyrate in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm in USP 38 <711> It releases more than 80% of its gamma-hydroxybutyrate in 1 hour when tested in dissolution apparatus 2 according to

[0145] In another subembodiment, (a) a 7.5 g dose of the composition has a mean AUC greater than 340 hr·micrograms / mL inf , and at t0 and t2 in equally divided doses approximately 2 hours after a standardized dinner. 4h The mean C provided by the same dose of an immediate release liquid solution of sodium oxyvert administered at 8h Average C that is less than 200% (arbitrarily 50% to 130%) of 8hand (b) the composition has been shown to achieve (i) a viscosity of 380 nm in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm. <711> and (ii) at least 80% of its gamma-hydroxybutyrate in 3 hours when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. <711> and (c) the modified release component releases greater than 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution test starting in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switching to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

[0146] In yet another subembodiment, the composition comprises immediate release and modified release components, and (a) the immediate release component is hydrated according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm; <711> (b) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 1 hour when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm; <711> (c) the modified release component releases less than 20% of its gamma-hydroxybutyrate in 1 hour when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm; <711> and (d) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 3 hours in a dissolution test starting in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switching to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

[0147] In another subembodiment, the composition is (a) dissolved in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm, in a solution containing 100% USP 38 <711> and (b) at least 80% of its gamma-hydroxybutyrate in 3 hours when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> According to the present invention, the compound releases 10% to 65% of its gamma-hydroxybutyrate at 1 hour and 3 hours when tested in dissolution apparatus 2.

[0148] In another subembodiment, the composition comprises immediate release and modified release components: (a) the composition is dissolved in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm, in a solution containing 100% USP 38 <711> and (b) the composition releases at least 80% of its gamma-hydroxybutyrate in 3 hours when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm; <711> and (c) the composition releases 10% to 65% of its gamma-hydroxybutyrate at 1 hour and 3 hours when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> and (d) the modified release component releases greater than 80% of its gamma-hydroxybutyrate in 3 hours in a dissolution test starting in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switching to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

[0149] Pharmacokinetic Aspects and Sub-Aspects The compositions of the invention may also be defined in terms of pharmacokinetics, optionally in combination with any of the dissolution or structural characteristics described above. Thus, in one pharmacokinetic embodiment or subembodiment, the invention provides a composition of gamma-hydroxybutyrate, wherein a 7.5 g dose of the composition has a mean AUC greater than 340 hr·micrograms / mL. inf , and at t0 and t2 in equally divided doses approximately 2 hours after a standardized dinner. 4h The mean C provided by the same dose of an immediate release liquid solution of sodium oxyvert administered at 8h Average C is less than 200% of 8h The present invention provides compositions which have been shown to achieve the above.

[0150] In another pharmacokinetic embodiment or subembodiment, the present invention provides a composition comprising an immediate release and a modified release portion, wherein (a) a 7.5 g dose of the composition has a mean AUC greater than 340 hr·micrograms / mL. inf , and at t0 and t2 in equally divided doses approximately 2 hours after a standardized dinner. 4h The mean C provided by the same dose of an immediate release liquid solution of sodium oxyvert administered at 8h Average C is less than 200% of 8h and (b) the formulation has been shown to achieve (i) USP 38 in 900 mL of 0.05 M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm. <711> and (ii) at least 80% of its gamma-hydroxybutyrate in 3 hours when tested in dissolution apparatus 2 according to USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. <711> and (c) the modified release component releases greater than 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution test starting in 750 mL of 0.1 N hydrochloric acid for 2 hours and then switching to 950 mL 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

[0151] In any of the embodiments of the present invention, a dose of 7.5 g of the formulation is administered approximately 2 hours after a standardized evening meal in equally divided doses at t0 and t 4h The mean C provided by the same dose of an immediate release liquid solution of sodium oxyvert administered at 8h Average C that is 100%, 75%, 50%, or 45% of 8h Alternatively or in addition, doses of 4.5 g, 6 g, 7.5 g or 9 g of the formulation have been shown to achieve t0 and t2 in equally divided doses approximately 2 hours after a standardized evening meal. 4hIt has been shown to achieve greater than 80% relative bioavailability (RBA) when compared to the same dose of an immediate release liquid solution of sodium oxyvert administered at 100 mg / kg.

[0152] In another pharmacokinetic embodiment or subembodiment, a 7.5 g dose of the composition has a mean AUC greater than 340 hr·micrograms / mL. inf In yet another pharmacokinetic aspect or sub-aspect, a 7.5 g dose of the composition has been shown to achieve a mean AUC of greater than 340 hr·micrograms / mL. inf , and at t0 and t2 in equally divided doses approximately 2 hours after a standardized dinner. 4h The mean C provided by the same dose of an immediate release liquid solution of sodium oxyvert administered at 8h Average C less than 130% of 8h In yet another pharmacokinetic embodiment or subembodiment, doses of 4.5 g and 9 g of the composition were shown to achieve t0 and t2 in evenly divided doses approximately 2 hours after a standardized evening meal. 4h It has been shown to achieve greater than 80% relative bioavailability (RBA) when compared to the same dose of an immediate release liquid solution of sodium oxyvert administered at 100 mg / kg.

[0153] Treatment methods The present invention further provides a method of treating a gamma-hydroxybutyrate treatable disorder in a human subject in need thereof, comprising orally administering to said human a single bedtime daily dose of gamma-hydroxybutyrate equivalent to 3.0-12.0 g of sodium oxyvert in the formulation of the present invention. The present invention further provides a method of treating narcolepsy type 1 and / or type 2 by orally administering at bedtime a therapeutically effective amount of a gamma-hydroxybutyrate formulation characterized by the novel gamma-hydroxybutyrate dissolution profile of the present invention. The formulation of the present invention is effective in treating narcolepsy type 1 or type 2, said treatment of narcolepsy being defined as reducing excessive daytime sleepiness or reducing the frequency of episodic attacks. A therapeutically effective amount typically comprises the equivalent of 3.0-12.0 g of sodium oxyvert, more preferably 9.0 g of sodium oxyvert and most preferably 4.5, 6.0, 7.5 or 9.0 g of sodium oxyvert.

[0154] In general, the method includes opening a packaged solid composition, contacting the solid composition with a suitable liquid, mixing the solid composition and the liquid to form a mixture (e.g., a suspension), and orally administering the mixture to an individual in need thereof. The solid composition may be added to a glass or other container containing the liquid, the solid composition may be added to a glass or other container, and the liquid may then be added to the glass or other container, or the liquid may be added to the package containing the solid composition. The solid composition and the liquid are then mixed to form a mixture, where mixing includes stirring, shaking, agitating, mixing, inverting, or other suitable means to mix the ingredients. The liquid is typically water (i.e., tap water or potable water, which can be still or bubbly, flavored or unflavored), although other liquids (e.g., fruit juice, carbonated soda, etc.) can be used. The amount of liquid mixed with the solid composition may vary. For example, the amount of liquid may range from about 30 mL to about 100 mL, or for example, about 50 mL. EXAMPLES

[0155] Example 1: Methods for preparing the formulations used in the following examples.

[0156] The following examples and the two formulations used in these manufacturing processes are provided below. The test results from these two different formulations were virtually indistinguishable.

[0157] First preparation Tables 1a-1d provide the qualitative and quantitative composition of sodium oxyvert IR microparticles, MR microparticles and mixtures of IR and MR microparticles in the first formulation. The physical structure of the microparticles showing the qualitative and quantitative composition of the IR and MR microparticles is shown in FIG.

[0158] Briefly, sodium oxyvert immediate release (IR) microparticles were prepared as follows: 1615.0 g of sodium oxyvert and 85.0 g of polyvinylpyrrolidone (Povidone K30 Plasdone™ K29 / 32 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water. The solution was thoroughly sprayed onto 300 g of microcrystalline cellulose spheres (Cellets™ 127) in a fluidized bed spray coater apparatus. IR microparticles with a volume average diameter of about 270 microns were obtained.

[0159] Sodium oxyvert modified release (MR) microparticles were prepared as follows: 22.8 g Eudragit L100-55, 45.8 g Eudragit S100, 102.9 g hydrogenated cottonseed oil (Lubritab) were dissolved in 1542.9 g isopropanol at 78° C. The solution was thoroughly sprayed onto 400.0 g sodium oxyvert IR microparticles described above in a fluidized bed spray coater apparatus with an inlet temperature of 48° C., a spray rate of about 11 g per minute, and 1.3 bar. The MR microparticles were dried for 2 hours with the inlet temperature set at 56° C. MR microparticles were obtained with a mean volume diameter of about 320 microns.

[0160] The final composition contained a 50:50 mixture of MR and IR microparticles calculated for their sodium oxyvert content and was prepared as follows: 353.36 g of the IR microparticles, 504.80 g of the MR microparticles, 14.27 g of malic acid (D / L malic acid), 6.34 g of xanthan gum (Xantural 75 from Kelco), 9.51 g of carrageenan gum (Viscarin PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol 250M from Ashland) and 4.51 g of magnesium stearate were mixed. 7.11 g of individual sample (corresponding to a 4.5 g dose of sodium oxyvert, half the dose as the immediate release fraction and half the dose as the modified release fraction) was weighed out. Table 1a: Composition of IR microparticles [Table 1a]

[0161] Table 1b: Composition of MR microparticles [Table 1b] Table 1c: Qualitative final composition [Table 1c] Table 1d: Quantitative final composition [Table 1d-1] [Table 1d-2]

[0162] Second formulation The second formulation and its manufacturing process are described as follows. Briefly, sodium oxyvert immediate release (IR) microparticles were prepared by coating the IR microparticles of the first method with a topcoat layer. The microparticles were prepared as follows: 170.0 hydroxypropyl cellulose (Klucel™ from Hercules EF Pharm) was dissolved in 4080.0 g acetone. The solution was thoroughly sprayed onto the IR microparticles of the first method in 1530.0 g fluidized bed spray coater equipment. The IR microparticles with a volume average diameter of about 298 microns were obtained (see Table 1e).

[0163] Sodium oxyvate modified release (MR) microparticles were prepared as described in the first method (see Table 1b).

[0164] The final composition, which contains a 50:50 mixture of MR and IR microparticles based on their sodium oxyvert content, was prepared as follows: 412.22 g of the above IR microparticles, 530.00 g of the above MR microparticles, 29.96 g of malic acid (D / L malic acid), 4.96 g of xanthan gum (Xantural 75 from Kelco), 4.96 g of colloidal silicon dioxide (Aerosil 200 from Degussa) and 9.92 g of magnesium stearate were mixed. 7.45 g of individual sample (corresponding to a 4.5 g dose of sodium oxyvert, half the dose as the immediate release fraction and half the dose as the modified release fraction) was weighed out (see Tables 1f and 1e). Table 1e: Composition of IR microparticles [Table 1e-1] [Table 1e-2] Table 1f: Qualitative final composition [Table 1f] Table 1g: Quantitative final composition [Table 1g]

[0165] Compared to the first formulation, the second formulation has the following features: the same MR microparticles, IR microparticles but with the same topcoat, an increased amount of malic acid, the presence of only one suspending agent (xanthan gum) and a glidant.

[0166] Example 2: Methods for assessing the dissolution stability of exemplary formulations. An analysis was conducted to evaluate the dissolution stability of a packaged formulation containing 50% of the sodium oxyvert dose in immediate release particles and 50% of the sodium oxyvert dose in modified release particles, corresponding to the second formulation in Example 1. The formulation was packaged in a DUMA bottle with 2 g of silica gel desiccant. The formulation was dissolved in 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm according to USP 38 <711> The formulations were tested in dissolution apparatus 2 according to the method described in Example 1. The single dose units were poured into a vessel containing 50 mL of tap water and shaken to form a suspension. After 5 minutes, the suspension was poured into a dissolution vessel containing 840 mL of 0.1 N HCl dissolution medium. 10 mL of water was then poured to rinse the vessel before being added to the dissolution vessel. Samples of the formulations were tested immediately after 0 months of their preparation and subsequently after 1 month of storage at 40° C. and 75% relative humidity. The percentage dissolved at various time points is reported in Tables 2A (0 months) and 2B (1 month) and shown in FIG. 2. Table 2A [Table 2A] Table 2B [Table 2B-1] [Table 2B-2]

[0167] For this and the following examples, a formulation was considered stable for dissolution testing if the absolute value (t'-t0) was less than 0.83 hours (=50 minutes) or the difference in API dissolved at all dissolution sampling times was less than 10%. t0 was determined by drawing a horizontal line across the y-axis at 50% dissolution, which corresponds to the percentage of the sodium oxyvert dose present in the immediate release fraction. A first tangent was then drawn on the month 0 release profile between two time points separated by 2 hours, which corresponds to the percentage of maximum release. The intersection between the first tangent and the horizontal line was assigned as t0. A second tangent was then drawn on the month 1 release profile between two time points separated by 2 hours, which corresponds to the percentage of maximum release in the month 1 release profile. The intersection between the second tangent and the horizontal line was assigned as t'.

[0168] In this example, after just one month, t'-t0 was equal to 0.9 hours, which was greater than the pre-specified standard of 0.83 hours (=50 minutes). 8h and t 10h The difference in API dissolved at was greater than 10%. As a result, the formulation in this packaging was considered unstable for dissolution testing.

[0169] This formulation showed instability after just one month, but more typically, the evolution of the dissolution behavior after two months would be further evidence of the formulation's long-term stability. As a result, a formulation can also be defined as stable after at least two months at 40° C. / 75% RH: the absolute value (t′-t0) is less than 0.83 hours (=50) and / or the difference in the active ingredient dissolved at any dissolution sampling time is less than 10%.

[0170] However, most preferably, the formulation will be evaluated over its entire shelf life in real world storage conditions. Thus, a formulation is most preferably defined as stable after at least 18 or 24 months at 25° C. / 60% RH or 30° C. / 65% RH if: the absolute value (t′-t0) is 0.83 hours (=50 minutes) and / or there is less than a 10% difference in the dissolved active ingredient at any dissolution sampling time.

[0171] Example 3: Evaluation of the effect of packaging type on dissolution stability. To determine the effect of packaging type on the dissolution stability of formulations of the present invention, formulations prepared according to Example 1 (first formulation) were packaged in various containers and evaluated via dissolution testing according to the method described in Example 2. The results of the testing are reported in Table 3: Table 3 [Table 3] *Corresponds to the maximum difference (in %) of dissolved API at month 0 and at a given dissolution sampling time during stability.

[0172] The dissolution profiles of the packaged compositions from Bischof & Klein (Lengerich Germany) sachets, Constantia stick-packs and LOG bottles are illustrated in Figures 3, 4 and 5, respectively. According to the dissolution criteria presented in Example 2 and the data listed in Table 3, the three packaged compositions are stable. The dissolution profiles of the packaged compositions including Gerresheimer Duma bottles with and without desiccant are illustrated based on further experiments in Example 4.

[0173] Example 4: Determination of stabilizing humidity range. Based on earlier studies showing that absorption of water by the formulation affected the stability of the formulation's dissolution profile, a study was conducted to determine whether the humidity at which the formulation was packaged would affect dissolution stability. Drug units were packaged in sachets by sealing the drug units at different relative humidity conditions ranging from dry to moist. No modification of the dissolution profile was observed at 40°C / 75% RH for 2 months, regardless of the relative humidity at the time of sealing.

[0174] Based on these results, humidity within the packaging, including any ingress or egress of humidity during storage, indicates the stability of the dissolution profile, and studies were conducted to quantify the effect of humidity within the packaging on the stability of the dissolution profile. A small temperature and humidity probe (Tomprobe™ from BioMerieux™) was used to assess the relative humidity within the different types of packaging.

[0175] Five stability studies were initiated at 40°C / 75% RH to provide RH data for the different types of packaging already investigated: · Sealed aluminum sachets (PET / Al / PE) from BK (Bischof + Klein) ·LOG™ H2O02 bottle with child-resistant cap (with barrier layer for low water vapor permeability) ·DUMA™ bottle with child-resistant cap Closed DUMA bottle with 2g desiccant (silica gel) · and 2g INTELISORB™ desiccant in a closed DUMA™ bottle.

[0176] In parallel, dissolution profiles were determined during the stability studies to provide further and complementary dissolution data to the data contained in Example 3.

[0177] Dissolution profile test results Dissolution testing was performed according to the method described in Example 2. The results of the testing are reported in Table 4.

[0178] LOG(trademark) H2OO2 bottle Since an unchanged dissolution profile was previously observed for this packaging after 3 months at 40° C. / 75% RH, and an accelerated dissolution profile was observed after 6 months, the dissolution profile was determined and the RH was measured at 3, 4, 5 and 6 months to determine the upper RH threshold (FIG. 5). As shown in FIG. 6, an accelerated dissolution profile is unexpectedly observed after 3 months at 40° C. / 75% RH. Therefore, it was concluded that the behavior after 3 months at 40° C. / 75% RH was erratic and that the RH at 3 months was too high to guarantee formulation stability in a reproducible manner.

[0179] As illustrated in Figure 7, the dissolution profile in this packaging is stable after 1 month in DUMA™ bottles without desiccant at 40°C / 75% RH and unstable after 2 months (accelerated dissolution profile). A comparison of the relative humidity in the packaging after 1 and 2 months will help determine the upper limit for RH.

[0180] DUMA™ bottle (30 ml) with 2 g silica gel As shown in Figure 8, a slowing of the dissolution profile was observed in this packaging after one week with no further progression of the dissolution profile through one month. The dissolution profile was judged to be unstable based on the criteria in Example 2 after one week.

[0181] DUMA™ Bottle (30ml) with 2g Intelisorb As shown in Figure 9, a slowing of the dissolution profile was observed in this packaging after one week with no further progression of the dissolution profile through one month. The dissolution profile was judged to be unstable based on the criteria in Example 2 after one week. Table 4 [Table 4-1] [Table 4-2]

[0182] Measuring RH with a T / RH probe As shown in Figure 10: The relative humidity at 40°C / 75%RH decreased quickly to just a few percent in the bottle with silica gel desiccant, with only a slight increase over a month. In bottles with Intellisorb™ desiccant, the relative humidity is very high and increases slightly over time. In the sachet, the relative humidity equilibrates at a value close to 40% over the course of 6 months. In bottles without a desiccant, there is a gradual increase in relative humidity over time.

[0183] Correlation between relative humidity and dissolution profile stability The dissolution profile stability conclusions are plotted against the relative humidity values ​​from FIG. 10 in FIG.

[0184] The clear circle indicates the point at which the dissolution profile of the drug product is considered stable, using the criteria in Example 2. · The shaded circle indicates the time point at which the dissolution profile of the drug product is considered unstable due to a slowing down of the dissolution profile. · The filled circles indicate the time points at which the dissolution profile of the drug product is unstable due to an acceleration of the dissolution profile. For the LOG bottles, an acceleration of the dissolution profile occurred after 3 months (Figure 6), while no such acceleration was observed during the initial stability study (Figure 5).

[0185] Based on this analysis, it can be concluded that under the conditions tested, the dissolution profile is unstable and packaging is not suitable if: After one week at 40°C / 75% RH, the RH is less than 29%; or Before February (2), at 40℃ / 75% RH, RH is higher than 54%.

[0186] Example 5: Correlation between water vapor permeability of packaging and stability of dissolution profile. Based on previous studies demonstrating dissolution profile stability in some packages and instability in others, a decision was made to investigate the water vapor permeability of these packaging types and to correlate water vapor permeability with the stability of the drug's dissolution profile. We determined the following: If the packaging is not sufficiently permeable, the dissolution profile remains stable; And no desiccant is required. If the water vapor transmission rate is too high, some water ingress will occur, leading to an accelerated dissolution profile (in the absence of a desiccant).

[0187] The stability of the different package types investigated under water vapor isoacceleration and their dissolution profiles as reported in Example 4 are summarized in Table 5. The data are based on a mixture of manufacturer information and applicant testing, with some limited extrapolation based on comparison of packaging types. The test results are consistent with USP 38 <671> or USP 38 <671> It is expected that this will be generated by testing under Table 5 [Table 5] *Packaged formulations were considered stable after 2 months at 40°C / 75% RH if the absolute value (t' t0) was 0.83 hours (=50 minutes) or the difference in dissolved active ingredient at all dissolution sampling times was less than 10% as described in Example 2.

[0188] Example 6: Correlation between stability of coating composition, packaging / RH and dissolution profile. The stability of alternative formulations was also investigated at 40° C. / 75% RH using the method reported in Example 2: in Gerresheimer DUMA™ bottles with desiccant (bottle: 035030-3000 30 ml bottle / cap (with 2 g silica gel desiccant inserted): 02827T-300T over a 2 month period to determine if a slowing of the dissolution profile occurs; and To determine the dissolution profile stability over a 3 month period in Bischof & Klein (sachets).

[0189] Dissolution profiles were assessed for: IR / MR Oxyvert formulation with MR composition containing pH-dependent polymer Eudragit® L100-55 / Eudragit® S100, but in a different ratio compared to the formulation described in Example 1. · IR / MR Oxyvert formulations with MR compositions containing an amount of Lubritab™ in the coating other than 60% Lubritab™; ·IR / MR oxyvert formulations with an amount of IR oxyvert less than 50% of the dose.

[0190] Table 6 reports the results of the aforementioned tests: [Table 6-1] [Table 6-2]

[0191] The dissolution profiles of compositions containing MR coated microparticles with 40% Lubritab in the coating are illustrated for compositions packaged in sachets and bottles with desiccant in Figures 12 and 13, respectively. All of the compositions packaged in sachets were stable when evaluated by the criteria in Example 2, but none were stable in bottles with desiccant.

[0192] Example 7: Chemical and dissolution profile stability based on packaging type. Chemical stability and dissolution profile stability for the first formulation of Example 1 was investigated using various packaging types during three stability studies conducted at 30° C. / 65% RH: ·DUMA(TM) bottles without desiccant DUMA™ bottle with 2g of silica gel desiccant in the cap Heat sealed REXAM™ bottles without desiccant (REXAM 30410 HDPE blank 60ml / cap: REXAM 28 / 400 FG PP BLANC Word FS M-1 Liner.

[0193] Each experiment evaluated the stability of a 4.50 g formulation dose. Initial formulation moisture content was 1.2%. Initial degradants were less than 0.05%. Chemical stability test results are reported in Table 7a for 30° C. / 65% RH conditions: Table 7a [Table 7a-1] [Table 7a-2]

[0194] As can be seen, the only packaged formulations that remained stable in these experiments were those in the bottles with desiccant, when the relative humidity within the bottle was kept the lowest.

[0195] The results of the dissolution tests are shown in Figures 14, 15 and 16 and the following can be observed: Accelerated dissolution profile in DUMA™ bottles without desiccant (Figure 14); A slower dissolution profile for DUMA™ bottles with desiccant in the cap ( FIG. 15 ); and Accelerated dissolution profile for heat sealed REXAM™ bottles without desiccant (Figure 16).

[0196] None of the three packaged compositions have a stable dissolution profile after 18 months at 30° C. / 65% RH according to the dissolution stability criteria described in Example 2, as illustrated in Table 7b. Table 7b [Table 7b]

[0197] The stability of the first formulation of Example 1 was previously investigated during two stability studies conducted at 40° C. / 75% RH in two of the three packages described above: ·DUMA(TM) bottles without desiccant -DUMA™ bottle with desiccant in the cap. Dissolution profile stability of the two packaged compositions already discussed in Example 4 (see Figure 7 for DUMA™ bottle without desiccant and Figure 8 for DUMA™ bottle with desiccant in the cap). Neither of the two packaged compositions has a stable dissolution profile after 2 months at 40°C / 75% RH.

[0198] In a parallel dissolution profile evaluation, the chemical stability of the packaged formulation was also evaluated. In DUMA™ bottles without desiccant, the amount of degradants formed after 2 months at 40° C. / 75% RH was 0.4%. In DUMA™ bottles with desiccant in the cap, the amount of degradants formed after 2 months at 40° C. / 75% RH was less than 0.05%.

[0199] Chemical stability and dissolution profile stability for the first formulation of Example 1 was also investigated in Bischof & Klein PET / ALU / PE sachets with 9 μm ALU foil for a dosage of 4.50 g of formulation. The initial formulation moisture content was 1.0%. The initial degradants were less than 0.05%. After 18 months at 30° C. / 65% RH, the formulation moisture content is equal to 0.8% and the amount of degradants is 0.1%.

[0200] The results of the dissolution test are shown in FIG. 17 and it can be observed that the packaged composition has a stable dissolution profile after 18 months at 30° C. / 65% RH according to the dissolution criteria described in Example 2. Table 7c [Table 7c]

[0201] Example 8. In vivo pharmacokinetic study of the second formulation according to Example 1 Pharmacokinetic studies were performed in vivo in healthy human volunteers following the principles described in the FDA's March 2003 Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS GENERAL CONSIDERATIONS. All studies were performed in subjects 2 hours after consuming a standardized dinner. XYREM® doses were administered in two equal doses 4 hours apart. All other tested doses were prepared as described in the second formulation of Example 1. The standardized dinner consisted of 25.5% fat, 19.6% protein and 54.9% carbohydrate.

[0202] The second formulation of Example 1, given as a single nightly dose of 4.5 g rather than two standard XYREM® doses (2 x 2.25 g) four hours apart each night, resulted in a dramatically different pharmacokinetic profile than XYREM®, as shown in Figure 18. As summarized below (Tables 8a and 8b), a nighttime dose of 4.5 g of the final composition of the invention, equivalent to two nightly doses of XYREM® (2 x 2.25 g), resulted in a later median T max The relative bioavailability was about 88%. The composition according to the invention avoids the high second dose peak concentration of XYREM® and therefore does not show substantial dose-to-dose variation in concentration, while still providing comparable mean C 8h Achieve this. Table 8a. Pharmacokinetic parameters of the second formulation vs. the final composition of XYREM® [Table 8a] Table 8b. Mean plasma concentrations [Table 8b]

[0203] The pharmacokinetic profile of a single 6 g dose of the second formulation was also tested and found to have a similar pharmacokinetic profile to the 4.5 g dose. Figure 19 provides a pharmacokinetic profile comparison of a single 4.5 g or 6 g dose of the second formulation in the same seven subjects. A pharmacokinetic profile was also obtained for a 7.5 g dose of the second formulation. Figure 20 and Table 8c provide data for single 4.5 g, 6 g and 7.5 g doses, showing T max , C max , C 8h , AUC 8h and AUC inf The effect on β-lactamase activity was related to dose intensity. The 7.5 g dose produced a mean C 8hThis is in line with the C obtained for XYREM® at 2×3.75 g doses. 8h The 7.5 g dose had an AUC of approximately 0.89, which was estimated from published data to be approximately 24.07 micrograms / mL. 8h vs. AUC inf achieved ratios of 0.83 and 0.93 for the 4.5 g and 6 g doses, respectively. Table 8c. Pharmacokinetic parameters of the second formulation at 4.5 g, 6 g and 7.5 g [Table 8c]

[0204] FIG. 21 and Table 8d show the pharmacokinetic parameters AUC inf and C 8h is compared to the same parameters calculated for a total use of 2 x 4.5, or 9 g of XYREM®. The data show that a 7.5 g dose of a formulation according to the invention given once nightly exhibits a similar PK profile as 9 g of XYREM® given in two separate equal doses. Table 8d. Pharmacokinetic parameters of the second formulation at 7.5 g compared to 2 x 4.5 g of XYREM® [Table 8d]

[0205] Example 9. In vivo comparison of two different batch sizes of the first formulation according to Example 1 A comparative, open-label, randomized, single-dose, crossover study was conducted to evaluate two different batch sizes (scale 1 and scale 2) of a first formulation manufactured as described in Example 1 in healthy volunteers at a dose of 4.5 g administered 2 hours after dinner. Twenty-two subjects were randomized to treatment sequences in a 1:1 ratio and assigned to the following treatment sequences, as illustrated in Figure 25: - 4.5g of FT218 Batch Scale 1 (Period 1) followed by 4.5g of FT218 Batch Scale 2 (Period 2) or - 4.5g of FT218 Batch Scale 2 (Period 2) followed by 4.5g of FT218 Batch Scale 1 (Period 1).

[0206] There was a washout of at least 3 days between drug administrations. 22 and 21 healthy volunteers received scale 1 and scale 2 batches, respectively (one subject discontinued the study after the first phase and received only FT218 scale 1). Blood sampling for the pharmacokinetics of sodium oxyvert in plasma was taken at pre-dose, 10 and 20 minutes after dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12 and 14 hours after dose for each period. PK parameters were calculated from the plasma concentration-time data for sodium oxyvert using non-compartmental analysis.

[0207] The data presented below in Tables 9a and 9b (mean PK parameters and plasma concentrations) and FIG. 26 demonstrate that Scale 1 and Scale 2 formulations according to the present invention exhibit similar PK profiles. Table 9a. Mean PK parameters [Table 9a] Table 9b. Mean plasma concentrations (micrograms / mL) [Table 9b-1] [Table 9b-2] NC: Not calculated.

[0208] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. The present invention provides, for example, the following items. (Item 1) 1. A packaged pharmaceutical composition comprising a pharmaceutical composition within a package, the pharmaceutical composition comprising: a. an immediate release component comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; and b. a modified release component comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; Including, A pharmaceutical composition, wherein the package has an interior volume having a relative humidity of 29% to 54%, and wherein the pharmaceutical composition has a stable dissolution profile over time. (Item 2) 2. The packaged pharmaceutical composition of item 1, wherein the relative humidity of the package is 29% to 54% for a period of at least 2 months when stored at 40° C. and 75% relative humidity. (Item 3) 3. The packaged pharmaceutical composition of item 1 or 2, wherein the relative humidity of the package is greater than 29% at 1 week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. (Item 4) 3. The packaged pharmaceutical composition of item 1 or 2, wherein the relative humidity of the package is greater than 29% and less than 44% at 1 week, and less than 54% at 2 months, when stored at 40° C. and 75% relative humidity. (Item 5) 3. The packaged pharmaceutical composition of item 1 or 2, wherein the relative humidity of the package is 35% to 39% after 1 week and 39% to 48% after 2 months when stored at 40° C. and 75% relative humidity. (Item 6) 6. The packaged pharmaceutical composition of any one of items 1-5, wherein greater than 0.4% of the gamma-hydroxybutyrate in the pharmaceutical composition is not converted to gamma-butyrolactone (GBL) when stored for 2 months at 40° C. and 75% relative humidity. (Item 7) The package conforms to USP 38 <671> 7. The packaged pharmaceutical composition of any one of items 1 to 6, having a water vapor transmission rate of less than 7 mg / day / liter when measured according to (Item 8) After a 40° C. / 75% relative humidity storage period of 2 months, the pharmaceutical composition exhibited a lag time that differed from the lag time at the beginning of the storage period by less than 70 minutes and was consistent with USP 38 in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> 8. The packaged pharmaceutical composition according to any one of items 1 to 7, as determined from a test in a dissolution apparatus 2 according to (Item 9) After a 40° C. / 75% relative humidity storage period of 2 months, the pharmaceutical composition was dissolved in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm, according to USP 38 <711> 9. The packaged pharmaceutical composition of any one of items 1 to 8, having a dissolution of gamma-hydroxybutyrate that differs by less than 10% from the dissolution of gamma-hydroxybutyrate prior to the storage period, when tested at least four consecutive hourly time points in dissolution apparatus 2 according to. (Item 10) 10. The packaged pharmaceutical composition of any one of items 1 to 9, wherein the modified release component comprises a core comprising gamma-hydroxybutyrate or a pharma-ceutically acceptable salt thereof, and a coating comprising a mixture of a hydrophobic compound and a methacrylic acid copolymer. (Item 11) Item 11. The packaged pharmaceutical composition of item 10, wherein the hydrophobic compound is glyceryl tristearate or hydrogenated vegetable oil, and the mixture of methacrylic acid copolymers includes methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF. (Item 12) 12. The packaged pharmaceutical composition of item 10 or 11, wherein the coating comprises a mixture of 40 to 70 parts by weight of the hydrophobic compound and 30 to 60 parts by weight of the methacrylic acid copolymer. (Item 13) 13. The packaged pharmaceutical composition of any one of items 10 to 12, wherein the coating is 10% to 50% by weight of the modified release component. (Item 14) 14. The packaged pharmaceutical composition of any one of items 10 to 13, wherein the hydrophobic compound has a melting point of 40° C. or higher and the mixture of methacrylic acid copolymers has a pH trigger above 5.6. (Item 15) 16. The packaged pharmaceutical composition of any one of items 10 to 15, wherein the modified release component has no barrier coat between the core and the coating. (Item 16) 16. The packaged pharmaceutical composition of any one of items 1 to 15, wherein the modified release component comprises particles having an average diameter of 200 to 800 micrometers. (Item 17) 17. The packaged pharmaceutical composition of any one of items 1 to 16, wherein the pharmaceutical composition further comprises an acidifying agent and a suspending or thickening agent. (Item 18) 18. The packaged pharmaceutical composition of item 17, wherein the acidifying agent is selected from malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, or a mixture thereof; and the suspending agent or thickening agent is selected from xanthan gum, medium viscosity sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and guar gum, medium viscosity hydroxyethylcellulose, agar, sodium alginate, a mixture of sodium alginate and calcium alginate, gellan gum, carrageenan gum grades iota, kappa or lambda, medium viscosity hydroxypropyl methylcellulose, or a mixture thereof. (Item 19) 19. The packaged pharmaceutical composition of item 17 or 18, wherein the acidifying agent is malic acid or tartaric acid and is present in an amount of 1.2% to 15% by weight; and the suspending or thickening agent is a mixture of xanthan gum, carrageenan gum and hydroxyethyl cellulose or a mixture of xanthan gum and carrageenan gum and is present in an amount of 1% to 15% by weight. (Item 20) 20. The packaged pharmaceutical composition of any one of items 1-19, wherein the gamma-hydroxybutyrate is present in the immediate release and modified release components in a weight ratio of 10 / 90 to 65 / 35. (Item 21) 21. The packaged pharmaceutical composition of any one of items 1 to 20, wherein the package contains 0.5 grams to 12.0 grams of the sodium salt of gamma-hydroxybutyrate. (Item 22) 22. The packaged pharmaceutical composition of any one of items 1 to 21, wherein the package is an aluminum foil pouch or sachet having an aluminum foil thickness of at least 6 micrometers. (Item 23) 23. Use of the packaged pharmaceutical composition of any one of items 1 to 22 for treating narcolepsy type 1 or type 2, the use comprising opening the package, mixing the pharmaceutical composition with a liquid to form a mixture, and orally administering the mixture to an individual in need thereof.

Claims

1. 1. A packaged pharmaceutical composition comprising a once-nightly pharmaceutical composition for a human subject in need thereof in a package, the once-nightly pharmaceutical composition comprising: a. an immediate release component comprising gamma-hydroxybutyrate or a pharma-ceutically acceptable salt thereof; and b. a modified release component comprising gamma-hydroxybutyrate or a pharma- ceutically acceptable salt thereof; Including, the package has an interior volume that has a relative humidity of 29% to 54% when stored at 40° C. and 75% relative humidity for 1 week to 2 months, the once-nightly pharmaceutical composition contains less than 0.05% gamma-hydroxybutyrate degradation products prior to storage at 40° C. and 75% relative humidity, and the once-nightly pharmaceutical composition has a stable dissolution profile over time; A pharmaceutical composition, wherein the modified release component comprises a coating comprising a mixture of a hydrophobic compound and a methacrylic acid copolymer, wherein the hydrophobic compound has a melting point of 40° C. or greater.

2. After 18 months of storage, nightly dissolution testing of the pharmaceutical composition showed absolute values ​​(t'-t 0 2. The packaged pharmaceutical composition of claim 1, wherein the composition has a mean concentration of 0.01 to 0.15% by weight and / or a difference in dissolved gamma-hydroxybutyrate at any dissolution sampling time of less than 10%.

3. 3. The packaged pharmaceutical composition of claim 1 or 2, wherein the relative humidity of the package is greater than 29% at 1 week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity.

4. 3. The packaged pharmaceutical composition of claim 1 or 2, wherein the relative humidity of the package is greater than 29% and less than 44% at 1 week, and less than 54% at 2 months, when stored at 40° C. and 75% relative humidity.

5. 5. The packaged pharmaceutical composition of any one of claims 1-4, wherein the once-nightly pharmaceutical composition contains no more than 3% gamma-hydroxybutyrate degradation products after 6 months of storage at 40°C and 75% relative humidity.

6. 6. The packaged pharmaceutical composition of any one of claims 1 to 5, wherein not more than 0.4% of the gamma-hydroxybutyrate in the nightly pharmaceutical composition is converted to gamma-butyrolactone (GBL) when stored for 2 months at 40°C and 75% relative humidity.

7. The package conforms to USP 38 <671> 7. The packaged pharmaceutical composition of claim 1, having a water vapor transmission rate of less than 7 mg / day / liter as measured according to

8. After a 2 month 40° C. / 75% relative humidity storage period, the once-nightly pharmaceutical composition exhibited a lag time that differed by less than 70 minutes from the lag time at the beginning of the storage period, and the lag time was determined to be within the USP 38 standard in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. <711> 8. The packaged pharmaceutical composition of any one of claims 1 to 7, characterized in that the composition is determined from a test in a dissolution apparatus 2 according to:

9. After a 40° C. / 75% relative humidity storage period of 2 months, the once-nightly pharmaceutical composition was diluted in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm according to USP 38 <711> 9. The packaged pharmaceutical composition of any one of claims 1 to 8, characterized in that the dissolution of gamma-hydroxybutyrate when tested at least four consecutive hourly time points in dissolution apparatus 2 according to the method of claim 1 differs by less than 10% from the dissolution of gamma-hydroxybutyrate prior to the storage period.

10. 10. The packaged pharmaceutical composition of any one of claims 1 to 9, wherein the hydrophobic compound is glyceryl tristearate or hydrogenated vegetable oil, and the mixture of methacrylic acid copolymers comprises methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF.

11. 11. The packaged pharmaceutical composition of any one of claims 1 to 10, wherein the coating comprises a mixture of 40 to 70 parts by weight of a hydrophobic compound and 30 to 60 parts by weight of a methacrylic acid copolymer.

12. 12. The packaged pharmaceutical composition of any one of claims 1 to 11, wherein the coating is 10% to 50% by weight of the modified release component.

13. 13. The packaged pharmaceutical composition of any one of claims 1 to 12, wherein the mixture of methacrylic acid copolymers has a pH trigger above 5.

6.

14. 14. The packaged pharmaceutical composition of any one of claims 1 to 13, wherein the modified release component is characterized in that there is no barrier coat between the core and the coating.

15. 15. The packaged pharmaceutical composition of any one of claims 1 to 14, wherein the modified release component comprises particles having an average diameter of 200 to 800 micrometers.

16. 16. The packaged pharmaceutical composition of any one of claims 1 to 15, wherein the once nightly pharmaceutical composition further comprises an acidifying agent and a suspending or thickening agent.

17. 17. The packaged pharmaceutical composition of claim 16, wherein the acidifying agent is selected from malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, or mixtures thereof; and the suspending or thickening agent is selected from xanthan gum, medium viscosity sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and guar gum, medium viscosity hydroxyethylcellulose, agar, sodium alginate, a mixture of sodium alginate and calcium alginate, gellan gum, carrageenan gum grades iota, kappa or lambda, medium viscosity hydroxypropyl methylcellulose, or mixtures thereof.

18. 18. The packaged pharmaceutical composition of claim 16 or 17, wherein the acidifying agent is malic acid or tartaric acid and is present in an amount of 1.2% to 15% by weight; and the suspending or thickening agent is a mixture of xanthan gum, carrageenan gum and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum and is present in an amount of 1% to 15% by weight.

19. 19. The packaged pharmaceutical composition of any one of claims 1 to 18, wherein gamma-hydroxybutyrate is present in the immediate release and modified release components in a weight ratio of 10 / 90 to 65 / 35.

20. 20. The packaged pharmaceutical composition of any one of claims 1 to 19, wherein the package contains 0.5 grams to 12.0 grams of the sodium salt of gamma-hydroxybutyrate.

21. 21. The packaged pharmaceutical composition of any one of claims 1 to 20, wherein the package is an aluminium foil pouch or sachet having an aluminium foil thickness of at least 6 micrometers.

22. 22. The packaged pharmaceutical composition of any one of claims 1 to 21 for use in preparing a mixture for oral administration to an individual in need thereof, wherein the package can be opened and the preparation comprises mixing the pharmaceutical composition once each night with a liquid to form the mixture.

23. 22. Use of a packaged pharmaceutical composition as defined in any one of claims 1 to 21 in the manufacture of a medicament for treating narcolepsy type 1 or type 2.

24. 22. The packaged pharmaceutical composition of any one of claims 1 to 21 for use in treating narcolepsy type 1 or type 2.

25. Use of a packaged pharmaceutical composition as defined in any one of claims 1 to 21 in the manufacture of a medicament for reducing excessive daytime sleepiness.

26. A packaged pharmaceutical composition as defined in any one of claims 1 to 21 for use in reducing excessive daytime sleepiness.

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