Modified-release gamma-hydroxybutyrate formulation with improved pharmacokinetics

Abstract

To provide a controlled-release gamma-hydroxybutyrate formulation with improved pharmacokinetics. [Solution] The present invention provides a controlled-release formulation of gamma-hydroxybutyrate with improved solubility and pharmacokinetic properties, and its therapeutic use. Thus, one object of the present invention is to provide a controlled-release formulation of gamma-hydroxybutyrate with improved solubility and pharmacokinetic profiles, which is administered only once at bedtime. Another object of the present invention is to optimize the bioavailability of gamma-hydroxybutyrate and provide a controlled-release formulation of gamma-hydroxybutyrate that is approximately equal to the bioavailability of an immediate-release solution of equidose of oxybart sodium administered twice overnight.

Description

[Technical Field]

[0001] Previous application This application claims priority to U.S. Provisional Patent Applications No. 62 / 365,812 (filed July 22, 2016), No. 62 / 399,413 (filed September 25, 2016), and No. 62 / 474,330 (filed March 21, 2017). The contents of the above applications are incorporated by reference herein and constitute part of this Specified as they are incorporated herein.

[0002] The present invention relates to a controlled-release formulation of gamma-hydroxybutyrate with improved pharmacokinetic (PK) properties, and its therapeutic use. [Background technology]

[0003] Narcolepsy is a destructive physical disorder. Its main symptoms are excessive daytime sleepiness (EDS), cataplexy (sudden loss of muscle tone triggered by strong emotions, affecting approximately 60% of patients), hypnagogic hallucinations (HH), sleep paralysis (SP), and nocturnal sleep disturbances (DNS). Aside from EDS, DNS is the most common symptom among narcolepsy patients.

[0004] The diagnosis of narcolepsy is partly based on clinical evidence. When narcolepsy is suspected, standard practice involves performing a polysomnography (PSG) followed by a multiple sleep latency test (MSLT) to record the characteristic rapid eye movement (REM) abnormalities of the disorder. For MSLT, a mean sleep latency of 8 minutes or less and at least two initial REM sleep periods (SOREMP) are required to confirm a diagnosis of type 1 or type 2 narcolepsy. In cases where the above PSG and / or MSLT requirements are not met, narcolepsy can also be diagnosed by measuring hypocretin in cerebrospinal fluid (CSF), although this is generally undesirable. In these cases, a hypocretin concentration of less than 110 pg / nL confirms a diagnosis of type 1 narcolepsy.

[0005] One of the main treatments for narcolepsy is oxyvert sodium, a neuroactive agent with pharmacological properties affecting various parts of the central nervous system (CNS). This species is endogenously present in many tissues and acts as a neurotransmitter for gamma-hydroxybutyrate (GHB) receptors (GHBR) in these tissues, possessing neuromodulatory properties with significant effects on dopamine and gamma-aminobutyric acid (GABA). Previous studies have suggested that oxyvert sodium, in contrast to antidepressants, improves rapid eye movement sleep (REM sleep, REMS) in narcolepsy.

[0006] Oxybart sodium is also known as 4-hydroxybutyrate sodium or gamma-hydroxybutyrate sodium salt, and has the following chemical structure: [ka] It has.

[0007] Oxybart sodium is marketed in the United States as Xyrem®. This product is taken once immediately before bedtime, and a second dose of the same amount approximately 2.5 to 4 hours later. It is formulated as an immediate-release solution. Sleep onset can be dramatic and rapid, and patients are advised to remain seated in bed until they have finished taking the prescribed dose. The most commonly reported side effects are confusion, depression, incontinence, and sleepwalking.

[0008] When initiating treatment with oxybart sodium, it is essential to carefully escalate the dose to an appropriate level to achieve both the desired outcome and avoid side effects. The recommended starting dose is 4.5 g, which can be divided into two 2.25 g doses, taken first at bedtime and second 2.5 to 4 hours later. This starting dose may be reduced to 3.0 g / day, or increased by 1.5 g / day (0.75 g per dose) up to a maximum of 9.0 g / day. A 2-week interval between dose adjustments is recommended to optimize daytime symptom relief and minimize side effects. The ideal dose effectively allows for 8 hours of sleep, with little residual drug in the patient's bloodstream at the end of the 8-hour period, thus having little effect on the patient's wakefulness.

[0009] The requirement to take Xyrem® twice nightly is considerably inconvenient for narcolepsy patients. Patients typically have to set an alarm clock to take the second dose, which can disrupt ongoing effective sleep. Several efforts have been made to provide a once-night, controlled-release dosage form of oxybart sodium, but none have yet been approved by the U.S. Food and Drug Administration ("FDA") or proven effective in a clinical setting.

[0010] One of the biggest drawbacks of these once-overnight formulations is the reduced bioavailability, measured by the area under the blood concentration / time curve ("AUC"), that occurs when oxybart sodium is formulated in a controlled-release dosage form. For example, US2012 / 0076865A1 ("Allphin") by Allphin et al. conducted two separate crossover bioavailability studies involving three separate controlled-release formulations and an immediate-release solution, and reported the following bioavailability results. [Table A-1] [Table A-2]

Table A-3

[0011] As is clear from the table above, for a given dose, the mean AUC inf , which is a measure of the total exposure of the body to oxybate sodium, was significantly lower for the drug with the release-modulating component when compared to the immediate-release formulation. The mean AUC inf for Treatment B, which contains the same dose of oxybate sodium as Treatment A exactly, was inf only 56% of the mean AUC inf for Treatment A. Similarly, the mean AUC inf for Treatment C, which also contains the same dose of oxybate sodium as Treatment A, was inf only 63% of the mean AUC inf for Treatment A. Despite Treatment E administering 2 g more oxybate sodium than Treatment A, the mean AUC inf for Treatment E was inf only 81% of the mean AUC inf for Treatment A, which was inf only 61% of the mean AUC inf for Treatment A when compared to the same dose. Despite Treatment D administering 2 g less oxybate sodium than Treatment A, the mean AUC inf for Treatment D was inf only 22% of the mean AUC inf for Treatment A, which was inf only 33% of the mean AUC inf for Treatment A when compared to the same dose. As shown in Figures 12 and 14 of US2012 / 0076865Al, Allphin's formulation was also troubled by excessive oxybate sodium remaining in the bloodstream at the 8-hour mark.

[0012] Liang et al.'s U.S. Patent No. 8,193,211 (referred to as "Liang") reports that the bioavailability of the once-daily formulation is even lower. Liang developed several delayed-release formulations of enteric-coated oxybate sodium, tested these formulations in dogs together with the immediate-release formulation, and compared the relative pharmacokinetics (PK) of these formulations. The test results of Liang are reported below. [Table B-1] [Table B-2]

[0013] As is clear from the table above, in Liang, encapsulating oxybart sodium in an enteric-coated / delayed-release coating significantly reduced the AUC of oxybart sodium. The relative bioavailability of one of these formulations, DR1-w / acid, was only 22% compared to the immediate-release formulation. DR2 had the highest relative bioavailability, but it was still only 53% compared to the immediate-release formulation. As described in column 5, lines 3-28 of U.S. Patent No. 8,193,211, it can be easily calculated that no conceivable combination of immediate-release (IR) and delayed-release (DR) components would yield a relative bioavailability exceeding 78%.

[0014] All of these formulations are problematic for at least two reasons: (1) their low relative bioavailability necessitates increased doses compared to current IR treatments, which already require large doses (4.5-9 g per day); and (2) when provided in pill form, patients must swallow approximately 4-9 pills per administration, which is a serious inconvenience for patients and a potential drawback to patient adherence.

[0015] For example, various other techniques for formulating controlled-release dosage forms are known, including the technique described in U.S. Patent No. 8,101,209 by Legrand et al. ("Legrand"). Legrand provides a system for reliably releasing the active ingredient from a controlled-release dosage form through a dual mechanism of “time-dependent” and “pH-dependent” release. Legrand did not describe any dosage form for delivering oxyvert sodium or other forms of gamma-hydroxybutyrate.

[0016] Another drawback of Xyrem® is its high daily dose, typically involving 7.5g or 9g of oxybart sodium taken daily over a long period. This represents a very high sodium intake and is not recommended for people with high blood pressure, cardiovascular disease, stroke, or those at risk of coronary heart disease (WHO. Guideline: Sodium intake for adults and children. Geneva, World Health Organization (WHO), 2012).

[0017] Therefore, one object of the present invention is to provide a release-controlled formulation of gamma-hydroxybutyrate with improved solubility and pharmacokinetic profiles, which is administered only once at bedtime.

[0018] Another object of the present invention is to optimize the bioavailability of gamma-hydroxybutyrate and the bioavailability of an immediate-release solution of oxybart sodium administered twice overnight in equidose doses. The objective is to provide a release-controlled formulation of gamma-hydroxybutyrate that is equivalent to [a certain type of] gamma-hydroxybutyrate.

[0019] A further object of the present invention is to provide a once-overnight release-regulated formulation of gamma-hydroxybutyrate that is substantially equal to or exceeds the bioavailability of an immediate-release solution of equidose of oxyvert sodium administered twice overnight across the entire therapeutic range of oxyvert sodium administration.

[0020] A further object of the present invention is to provide a controlled-release formulation of gamma-hydroxybutyrate in which, 8 hours after administration, the residual drug content in the bloodstream of most patients is very low, but still similar to the residual drug content observed after administration of an immediate-release solution of oxyvert sodium administered twice overnight.

[0021] Another object of the present invention is to improve the therapeutic efficacy and safety profile of gamma-hydroxybutyrate based on novel solubility and pharmacokinetic profiles.

[0022] A further object of the present invention is to provide a controlled-release formulation of gamma-hydroxybutyrate that gives a similar pharmacokinetic profile to an immediate-release solution of oxybart sodium administered twice overnight, while potentially reducing the dose.

[0023] A further object of the present invention is to provide a gamma-hydroxybutyrate release-regulated formulation that allows for once-daily administration and dose reduction compared to the commercially available therapeutic agent Xyrem®.

[0024] Another object of the present invention is to provide gamma-hydroxybutyrate in an easy-to-swallow dosage form. A further object of the present invention is to provide a controlled-release formulation of gamma-hydroxybutyrate that is administered only once at bedtime, has improved solubility and pharmacokinetic profiles, and has a reduced sodium content compared to an immediate-release solution of oxybart sodium administered twice overnight. [Prior art documents] [Patent Documents]

[0025] [Patent Document 1] U.S. Patent Application Publication No. 2012 / 0076865 [Patent Document 2] U.S. Patent No. 8,193,211 [Patent Document 3] U.S. Patent No. 8,101,209 [Overview of the Initiative] [Means for solving the problem]

[0026] As prior art demonstrates, it is extremely difficult to find a controlled-release formulation of gamma-hydroxybutyrate that, when administered only once a night, has bioavailability comparable to that of an immediate-release solution of oxyvert sodium administered twice a night. Even if such a formulation could be found, it would likely still be insufficient because the dose of gamma-hydroxybutyrate varies among individuals, and the magnitude of the dose affects the amount of drug absorbed through the gastrointestinal tract. In other words, even if the prior art formulation achieves equivalent bioavailability at one dose (which it does not actually achieve), it would not be equivalent at other doses.

[0027] The present inventors have developed a release-controlled formulation of gamma-hydroxybutyrate, the bioavailability of which is equivalent to the bioavailability of an immediate-release solution of oxybart sodium administered twice overnight. We have discovered a novel relationship between the in vitro release profile and in vivo absorption of a controlled-release gamma-hydroxybutyrate formulation, which for the first time makes possible a formulation that is nearly equal to the bioavailability of the above-mentioned solution formulation over the therapeutic dose range and nearly equal to the bioavailability of the above-mentioned solution formulation. In particular, we have found that the in vivo bioavailability of a controlled-release gamma-hydroxybutyrate formulation that rapidly releases half of the gamma-hydroxybutyrate of the formulation in a 0.1N hydrochloric acid dissolution medium and rapidly releases the remaining half of the gamma-hydroxybutyrate of the formulation in a phosphate buffer pH 6.8 dissolution medium is nearly equal to or exceeds the in vivo bioavailability of an equivalent immediate-release solution of oxyvert sodium administered twice overnight. This is evident by comparing the formulations of Example 1 and Example 4, which satisfy the dissolution requirements of the present invention and achieve the bioavailability required for commercially available formulations, with the comparative formulation of Example 7, which exhibits a dissolution profile similar to the dissolution profile of the prior art and does not achieve the bioavailability required for commercially available formulations.

[0028] This phenomenon is particularly observed with high doses of gamma-hydroxybutyrate. For example, the inventors have found that the release-modulating composition of gamma-hydroxybutyrate according to the present invention, administered as a single dose equivalent to 7.5 g of oxybart sodium approximately 2 hours after a standardized dinner, controls t0 and t 4h We found that administering two separate 4.5g equal doses of oxybart sodium at different time points resulted in a pharmacokinetic profile similar to that of an immediate-release solution of oxybart sodium.

[0029] The controlled-release formulation of gamma-hydroxybutyrate preferably comprises both an immediate-release portion and a controlled-release portion. The release of gamma-hydroxybutyrate from the immediate-release portion is substantially unsuppressed and occurs almost immediately in a 0.1N hydrochloric acid solution. In contrast, when fully induced, the controlled-release portion also releases gamma-hydroxybutyrate, preferably almost immediately, but the release is not induced until a predetermined delay time has elapsed or until the drug is exposed to a suitable solution, such as a phosphate buffer pH 6.8 solution. While we do not wish to be bound by any theory, this rapid release in the two solutions is thought to compress the in vivo blood concentration-time curve, resulting in a relative bioavailability of gamma-hydroxybutyrate comparable to or exceeding that of an immediate-release solution of oxyvert sodium administered twice overnight at equivalent doses.

[0030] Formulations that achieve this improvement in bioavailability can be described using several different pharmacokinetic and in vitro solubility parameters. In a first primary embodiment, the present invention relates to a release-modulated formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-modulated portion, wherein a 7.5 g dose of the formulation has an average AUC greater than 340 hours × micrograms / mL. inf The present invention provides the above-mentioned formulation, which has been shown to achieve the above-mentioned objective.

[0031] In a second primary embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, wherein a 7.5 g dose of the formulation has an average AUC greater than 340 hours × micrograms / mL. inf , and approximately two hours after the standardized dinner, t0 and t 4h At that point, the average C is given by an immediate-release solution of equidose of oxyvert sodium administered in equal doses. 8h The average C is 50% to 130% of the average C. 8h The present invention provides the above-mentioned formulation, which has been shown to achieve the above-mentioned objective.

[0032] In a third main embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, (a) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, at least 8 gamma-hydroxybutyrate of the above formulation was found. It releases 0%, and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. The above-mentioned formulation is provided.

[0033] In a fourth main embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 3 hours. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours, and (c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0034] In a fifth primary embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 3 hours. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. (c) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 60% of the above formulation's gamma-hydroxybutyrate is released after 10 hours, and (d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0035] In a sixth primary embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation at a 7.5g dose has an average AUC greater than 340 hours × micrograms / mL inf , and approximately two hours after the standardized dinner, t0 and t 4h At that point, the average C is given by an immediate-release solution of equidose of oxyvert sodium administered in equal doses. 8h The average C is 50% to 130% of the average C. 8h It has become clear that this can be achieved, and (b) The above preparation is (i) USP38 <711> In dissolution apparatus 2 conforming to the standard, 900 mL of 0.05 M When tested in potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm, at 3 hours, at least 80% or 90% of the gamma-hydroxybutyrate of the above formulation is released, and (ii) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours, and (c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0036] In a seventh main embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The immediate release portion mentioned above is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% of the immediate release portion of gamma-hydroxybutyrate was released after 1 hour. (b) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, less than 20% of the gamma-hydroxybutyrate in the release control portion is released after 1 hour, and (c) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released after 3 hours. The above-mentioned formulation is provided.

[0037] In the eighth main embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The immediate release portion mentioned above is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% of the immediate release portion of gamma-hydroxybutyrate was released after 1 hour. (b) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, less than 20% of the gamma-hydroxybutyrate in the release control portion was released after 1 hour. (c) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released after 3 hours, and (d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0038] In the ninth main embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, in amounts of 4.5 g, 6 g, 7.5 g, And when the above formulation in a 9g dose is administered approximately 2 hours after a standardized dinner, t0 and t 4h The present invention provides a formulation that, at that point in time, has been shown to achieve a relative bioavailability (RBA) of more than 80% when compared to an equidose immediate-release solution of oxybart sodium administered in equidivisible doses.

[0039] In a tenth main embodiment, the present invention relates to a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, wherein when the formulation is administered in 4.5 g and 9 g doses approximately two hours after a standardized dinner, t0 and t 4h The present invention provides a formulation that, at that point in time, has been shown to achieve a relative bioavailability (RBA) of more than 80% when compared to an equidose immediate-release solution of oxybart sodium administered in equidivisible doses.

[0040] In an eleventh main embodiment, the present invention provides a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, which, when administered once overnight at a strength of 4.5 g, 6.0 g, or 7.5 g approximately two hours after a standardized dinner, gives substantially the plasma concentration-time curve shown in Figure 12 or Figure 13 for the corresponding strength.

[0041] In a twelfth major embodiment, the present invention provides a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, which, when administered once overnight at an intensity of 4.5 g approximately two hours after a standardized dinner, substantially gives the plasma concentration-time curve shown in Figure 22.

[0042] In a thirteenth major embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, which substantially gives the solubility profile shown in Figures 7 and 8.

[0043] In a fourteenth major embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate, which preferably comprises an immediate-release portion and a release-controlled portion, giving substantially the solubility profile shown in Figures 20 and 21.

[0044] In a 15th main embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, wherein the release-controlled portion substantially gives a solubility profile shown in Figure 3 or Figure 16.

[0045] In a sixteenth major embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, which gives a dissolution profile between the minimum and maximum values ​​shown in Figures 25 and 26.

[0046] In the 17th main embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, which gives a dissolution profile between the minimum and maximum values ​​shown in Figures 27 and 28.

[0047] In the eighteenth main embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate that substantially gives a solubility profile shown in any one of Figures 29 to 89.

[0048] A nineteenth primary embodiment of the present invention provides a plasma concentration-time curve substantially shown in Figure 90 for corresponding concentrations when administered once overnight at concentrations of 4.5 g, 7.5 g, or 9.0 g approximately two hours after a standardized dinner, preferably with an immediate-release portion and The present invention provides a release-regulated formulation of gamma-hydroxybutyrate containing a release-regulating portion.

[0049] A 20th major embodiment of the present invention provides a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, which gives a dissolution profile between the minimum and maximum values ​​shown in Figures 26 and 28.

[0050] Further embodiments relate to methods of using the formulations of the present invention for the treatment of narcolepsy and related disorders and symptoms, as well as to the physical aspects of the formulations of the present invention. Some of the further major embodiments and some of the subordinate embodiments thereof are described below, some of which may be obvious from the above description or acquired through the practice of the present invention. Embodiments and advantages of the present invention will be understood and achieved, in particular, by the elements and combinations set forth in the appended claims. It should be understood that both the above general description and the following detailed description are for illustrative and descriptive purposes only and do not limit the present invention as described in the claims.

[0051] The accompanying drawings are incorporated herein by reference and constitute part of this specification, illustrating several embodiments of the present invention and serving to illustrate the principles of the present invention together with the description of the specification. [Brief explanation of the drawing]

[0052] [Figure 1] This figure shows the qualitative and quantitative structures of the immediate-release (IR) and controlled-release (MR) microparticles of gamma-hydroxybutyrate in Example 1. [Figure 2] This figure plots the time-release dissolution profiles of IR microparticles of gamma-hydroxybutyrate for Example 1 (◆) and Example 1bis (■) in a 0.1N HCl dissolution medium. [Figure 3] This figure plots the time-release dissolution profiles of gamma-hydroxybutyrate MR microparticles from Example 1 in two sequential dissolution media (0.1N HCl / phosphate buffer pH 6.8). [Figure 4] This figure plots the time-release dissolution profiles (indicated by ▲) of MR microparticles from Example 1 in two sequential dissolution media (0.1N HCl / phosphate buffer pH 6.8) overlaid on the dissolution profiles (indicated by ●) shown in Figure 3 of US8,193,211. [Figure 5] This figure plots the time-release dissolution profile of the completed formulation of Example 1 in deionized water. [Figure 6] This figure shows the time-release dissolution profile (▲ symbol) of the completed composition of Example 1 in deionized water superimposed on the dissolution profile (● symbol) shown in Figure 2 of USP2012 / 0076865. [Figure 7] This figure plots the time-release dissolution profiles in 0.1N HCl for four separate batches of the finished composition prepared according to Example 1 or Example 1bis. [Figure 8] This figure plots the time-release dissolution profiles in phosphate buffer pH 6.8 for four separate batches of the finished composition prepared according to Example 1 or Example 1bis. [Figure 9] This figure plots the time-release dissolution profiles of gamma-hydroxybutyrate MR microparticles prepared according to Example 1, at 75 rpm (■ symbol) and 100 rpm (▲ symbol) in 0.1 N HCl. [Figure 10] This figure plots the time-release dissolution profiles of the finished composition prepared according to Example 1, measured in 0.1N HCl at paddle rotation speeds of 75 rpm (■ symbol) and 100 rpm (▲ symbol). [Figure 11]This figure plots the mean + SD (standard deviation) of plasma gamma-hydroxybutyrate concentration (micrograms / mL) over time for two different controlled-release formulations of gamma-hydroxybutyrate tested in vivo according to the method of Example 3. The time profiles are shown for the completed composition of Example 1bis (● symbol) (N=26) at a single 4.5g dose and for Xyrem® (- symbol) (N=15) at a 4.5g dose in two divided doses. [Figure 12] This figure plots the mean + SD (standard deviation) of plasma gamma-hydroxybutyrate concentration (micrograms / mL) over time, after a single oral administration of the completed compositions of Example 1bis in 4.5g (● symbol) and 6g (▲ symbol) to the same seven subjects who were tested in vivo according to the method of Example 3. [Figure 13] This figure plots the mean + SD (standard deviation) of plasma gamma-hydroxybutyrate concentration (micrograms / mL) over time for three distinct doses of the finished compositions prepared according to Example 1bis, tested in vivo according to the method of Example 3. The mean time profiles are shown for single oral administrations of 4.5 g (N=26) (●), 6.0 g (N=19) (▲), or 7.5 g (N=11) (■). [Figure 14] This figure plots the mean plasma gamma-hydroxybutyrate concentration (micrograms / mL) (■) of the finished composition prepared according to Example 1bis for a single dose of 7.5 g, compared to 2 × 4.5 g of Xyrem® after a meal (source: NDA 21-196 review). [Figure 15] This figure shows the qualitative and quantitative structures of the immediate-release (IR) and controlled-release (MR) microparticles of gamma-hydroxybutyrate in Example 4. [Figure 16] This figure plots the time-release dissolution profiles of the gamma-hydroxybutyrate MR microparticles of Example 4 in two sequential dissolution media (0.1N HCl and phosphate buffer pH 6.8). [Figure 17]This figure shows the time-release dissolution profile (▲ symbol) of MR microparticles from Example 4 in two sequential dissolution media (0.1N HCl and phosphate buffer pH 6.8) superimposed on the dissolution profile (● symbol) shown in Figure 3 of US8,193,211. [Figure 18] This figure plots the time-dependent release and dissolution profile of the completed composition of Example 4 in deionized water. [Figure 19] This figure shows the time-release dissolution profile (● symbol) of the completed composition of Example 4 in deionized water superimposed on the dissolution profile (▲ symbol) shown in Figure 2 of USP2012 / 0076865. [Figure 20] This figure plots the time-release dissolution profiles in 0.1N HCl for three separate batches of the finished composition prepared according to Example 4 or Example 4bis. [Figure 21] This figure plots the time-release dissolution profile of the finished composition prepared according to Example 4 in phosphate buffer at pH 6.8. [Figure 22] This figure plots the time profile of the mean plasma gamma-hydroxybutyrate concentration (micrograms / mL) (■) of the completed composition of a single 4.5g dose of Example 4bis (N=15) compared with a 2 × 2.25g dose of Xyrem® (N=15) administered after a meal. [Figure 23] This figure shows the qualitative and quantitative structures of the immediate-release (IR) and controlled-release (MR) microparticles of gamma-hydroxybutyrate in Example 7. [Figure 24] This figure plots the time-release dissolution profile (▲ symbol) of gamma-hydroxybutyrate MR microparticles from Example 7 in two sequential dissolution media (0.1N HCl and phosphate buffer pH 6.8) overlaid on the dissolution profile (● symbol) shown in Figure 3 of US8,193,211. [Figure 25] This figure plots the minimum (■) and maximum (▲) values ​​of the preferred solubility profile of the completed composition according to the present invention in 0.1N HCl. [Figure 26]This figure plots the minimum (■) and maximum (▲) values ​​of the preferred solubility profile of the completed composition according to the present invention in phosphate buffer at pH 6.8. [Figure 27] This figure plots the minimum (■) and maximum (▲) values ​​of another preferred solubility profile of the completed composition according to the present invention in phosphate buffer pH 6.8. [Figure 28] This figure plots the minimum (■) and maximum (▲) values ​​of another preferred solubility profile of the completed composition according to the present invention in 0.1N HCl. [Figure 29] This figure shows the dissolution profiles of the formulation from Example 9.1, measured in 0.1N HCl using USP instrument 2 5 minutes and 15 minutes after reconstitution in water. [Figure 30] This figure shows the dissolution profiles of the formulation from Example 9.2, measured in 0.1N HCl using USP instrument 2 5 minutes and 15 minutes after reconstitution in water. [Figure 31] This figure shows the dissolution profiles of the formulation from Example 9.3, measured in 0.1N HCl using USP instrument 2 5 minutes and 15 minutes after reconstitution in water. [Figure 32] This figure shows the dissolution profiles of the 9g dose formulation of Example 10, measured in 0.1N HCl using USP instrument 2, with and without rinsing. [Figure 33] This figure shows the dissolution profile of the MR portion of the formulation of Example 11a in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 34] This figure shows the dissolution profile of the formulation of Example 11a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 35] This figure shows the dissolution profile of the formulation of Example 11a in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 36]This figure shows the dissolution profile of the MR portion of the formulation of Example 11b in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 37] This figure shows the dissolution profile of the formulation of Example 11b in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 38] This figure shows the dissolution profile of the formulation of Example 11b in pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 39] This figure shows the dissolution profile of the formulation of Example 11c in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 40] This figure shows the dissolution profile of the formulation of Example 11c in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 41] This figure shows the dissolution profile of the MR portion of the formulation of Example 12a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 42] This figure shows the dissolution profile of the formulation of Example 12a in 0.1N HCl using USP apparatus 2. [Figure 43] This figure shows the dissolution profile of the formulation of Example 12b in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 44] This figure shows the dissolution profile of the formulation of Example 12b in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 45] This figure shows the dissolution profile of the MR portion of the formulation of Example 13 in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 46]This figure shows the dissolution profile of the formulation of Example 13 in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 47] This figure shows the dissolution profile of the formulation of Example 13 in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 48] This figure shows the dissolution profile of the MR portion of the formulation of Example 14 in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 49] This figure shows the dissolution profile of the formulation of Example 14 in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 50] This figure shows the dissolution profile of the formulation of Example 14 in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 51] This figure shows the dissolution profile of the MR portion (35% of the coating weight) of the formulation of Example 15a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 52] This figure shows the dissolution profile of the MR portion (50% of the coating weight) of the formulation of Example 15a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 53] This figure shows the dissolution profile of the formulation of Example 15a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 54] This figure shows the dissolution profile of the MR portion of the formulation of Example 15b in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 55] This figure shows the dissolution profile of the formulation of Example 15b in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 56]This figure shows the dissolution profile of the formulation of Example 15b in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 57] This figure shows the dissolution profile of the MR portion of the formulation of Example 15c in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 58] This figure shows the dissolution profile of the formulation of Example 15c in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 59] This figure shows the dissolution profile of the formulation of Example 15c in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 60] This figure shows the dissolution profile of the MR portion of the formulation of Example 15d in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 61] This figure shows the dissolution profile of the formulation of Example 15d in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 62] This figure shows the dissolution profile of the formulation of Example 15d in pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 63] This figure shows the dissolution profile of the MR portion of the formulation of Example 16a in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 64] This figure shows the dissolution profile of the formulation of Example 16a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 65]This figure shows the dissolution profile of the formulation of Example 16a in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 66] This figure shows the dissolution profile of the MR portion of the formulation of Example 16b in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 67] This figure shows the dissolution profile of the formulation of Example 16b in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 68] This figure shows the dissolution profile of the formulation of Example 16b in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 69] This figure shows the dissolution profile of the MR portion of the formulation of Example 16c in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 70] This figure shows the dissolution profile of the formulation of Example 16c in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 71] This figure shows the dissolution profile of the formulation of Example 16c in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 72] This figure shows the dissolution profile of the MR portion of the formulation of Example 16d in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 73] This figure shows the dissolution profile of the MR portion of the formulation of Example 17a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 74] This figure shows the dissolution profile of the formulation of Example 17a in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 75] This figure shows the dissolution profile of the formulation of Example 17a in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 76] This figure shows the dissolution profile of the MR portion of the formulation of Example 17b in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 77] This figure shows the dissolution profile of the formulation of Example 17b in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 78] This figure shows the dissolution profile of the formulation of Example 17b in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP instrument 2. [Figure 79] This figure shows the dissolution profile of the MR portion of the formulation of Example 17c in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 80] This figure shows the dissolution profile of the formulation of Example 17c in 900 ml of 0.1 N HCl using USP apparatus 2. [Figure 81] This figure shows the dissolution profile of the formulation of Example 17c in a pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 82] This figure shows the preferred dissolution profile of MR microparticles of oxyvert sodium in 900 ml of 0.1 N HCl at 75 rpm using USP apparatus 2. [Figure 83]This figure shows the preferred dissolution profile of MR microparticles of oxyvert sodium at 75 rpm in 900 ml of pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) using USP apparatus 2. [Figure 84] This figure shows the preferred dissolution profile of the finished formulation of oxyvert sodium containing IR and MR microparticles in 900 ml of 0.1 N HCl at 75 rpm using USP apparatus 2. [Figure 85] This figure shows the preferred dissolution profile of the finished formulation of oxybart sodium containing IR and MR microparticles in 900 ml of pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) at 75 rpm using USP apparatus 2. [Figure 86] This figure shows the dissolution profiles in 0.1N HCl of MR particles of oxyvert sodium present in the finished composition of Example 18 from two separate batches. [Figure 87] This figure shows the dissolution profiles of MR microparticles of oxyvert sodium present in the finished composition of Example 18 from two separate batches, in phosphate buffer pH 6.8. [Figure 88] This figure shows the dissolution profiles in 0.1N HCl for two unit doses, 3g (▲ symbol) and 4.5g (● symbol), of the completed compositions in Example 18. [Figure 89] This figure shows the dissolution profiles of the completed compositions in two unit doses, 3g (▲ symbol) and 4.5g (● symbol), in phosphate buffer at pH 6.8. [Figure 90] This figure plots the mean + SD-time profile of plasma gamma-hydroxybutyrate concentration (micrograms / mL) after single oral administration of the completed compositions of Example 18 in 4.5g (● symbol), 7.5g (■ symbol), and 9g (▲ symbol). [Modes for carrying out the invention]

[0053] The present invention can be more readily understood by referring to the following detailed description of preferred embodiments of the invention and the examples included in those preferred embodiments.

[0054] Definitions and Use of Terms Wherever analysis or testing is required to understand a given property or feature described herein, it will be understood that such analysis or testing will be conducted in accordance with the applicable guidelines, draft guidelines, rules, and monographs of the U.S. Food and Drug Administration ("FDA") and the United States Pharmacopeia ("USP") applicable to pharmaceutical products in the United States, as of November 1, 2015, unless otherwise specified. Clinical endpoints will be determined by the American Academy of Sleep Medicine (the The criteria adopted by the American Academy of Sleep Medicine can be used for judgment, and these criteria include those published in C Iber, S Ancoli- Israel, A Chesson, SF Quan. The AASM Manual for the Scoring of Sleep and Associated Events. Westchester, IL: American Academy of Sleep Medicine; 2007.

[0055] When comparing the pharmacokinetics of a formulation described or claimed in this application with a reference product, it will be understood that such comparison is preferably carried out in a well-planned crossover study. However, it will also be understood that a crossover study is not necessary unless otherwise specified. It will also be understood that such comparison can be carried out directly or indirectly. For example, even if a formulation has not been directly tested against a reference formulation, if it has been tested against another formulation and a comparison with the reference formulation can be inferred from that, then it may still be suitable for comparison with the reference formulation.

[0056] In this specification and the appended claims, the singular nouns "a," "an," and "the" encompass multiple referents unless otherwise indicated by the context. For example, a reference to "an ingredient" encompasses a mixture of ingredients, and a reference to "an active pharmaceutical agent" encompasses two or more active pharmaceutical agents, and so on.

[0057] "Bioavailability" refers to the proportion and extent to which the active ingredient or active portion is absorbed from the drug product and becomes available at the site of action.

[0058] "Relative bioavailability," or "Rel BA" or "RBA," refers to the average AUC of a reference product. inf The average AUC of the test product relative to the given product. inf This refers to a percentage. Unless otherwise specified, relative bioavailability is the mean AUC observed for two 1 / 2 doses of the immediate-release solution administered at 4-hour intervals. inf The mean AUC observed for the total dose of the test product against inf It refers to the percentage.

[0059] "Bioequivalence" means that the active ingredient or active portion of a pharmaceutical equivalent or substitute can be administered in the same molar dose under similar conditions in a properly designed study. This means there is no significant difference in the proportion or extent to which the drug becomes available at the site of action.

[0060] Where a range is described by specifying a lower limit to that range separately from its upper limit, it will be understood that the range may be defined by selectively combining one of the lower limit variables with one of the upper limit variables that are mathematically and physically possible. Therefore, for example, if a formulation may contain 1 to 10 parts by weight of a particular ingredient, or 2 to 8 parts of a particular ingredient, it will be understood that the formulation may also contain 2 to 10 parts of that ingredient. Similarly, if a formulation may contain more than 1 or 2 parts by weight of a particular ingredient, and up to 10 or 9 parts by weight, it will be understood that the formulation may contain 1 to 10 parts by weight of the ingredient, 2 to 9 parts by weight of the ingredient, and so on. Unless otherwise explicitly stated, the boundaries of the range (the lower and upper limits of the range) are included within the claimed scope.

[0061] Similarly, if various lower embodiments of a higher (i.e., principal) embodiment are described herein, it will be understood that these multiple lower embodiments of the higher embodiment may be combined to define another lower embodiment. Therefore, for example, if a principal embodiment includes lower embodiments 1, 2, and 3, it will be understood that the principal embodiment may be further limited by any one of lower embodiments 1, 2, and 3, or any mathematically and physically possible combination of lower embodiments 1, 2, and 3. Similarly, multiple principal embodiments described herein may be combined in any mathematically and physically possible way, and it will be understood that the present invention extends to such combinations as well.

[0062] In this specification, the terms “about,” “substantially,” or “approximately” complement variations acceptable in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in product strength due to manufacturing variability and product degradation over time. This terminology is based on the FDA’s March 2003 Guidance for Industry on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General. As described in CONSIDERATIONS, in pharmaceutical practice, any variations that can be assessed as being bioequivalent to the stated potency of the product are to be expected.

[0063] In this specification, the term “gamma-hydroxybutyrate” or GHB means, unless otherwise specified, the free base of gamma-hydroxybutyrate, pharmaceutically acceptable salts of gamma-hydroxybutyrate, and combinations thereof, their hydrates, solvates, complexes, or tautomers. Gamma-hydroxybutyrate can be selected from the form of the sodium salt of gamma-hydroxybutyrate, i.e., oxybart sodium, the potassium salt of gamma-hydroxybutyrate, the magnesium salt of gamma-hydroxybutyrate, the calcium salt of gamma-hydroxybutyrate, the lithium salt of gamma-hydroxybutyrate, the tetraammonium salt of gamma-hydroxybutyrate, or any other pharmaceutically acceptable salt of gamma-hydroxybutyrate.

[0064] "Pharmacologically acceptable" means that a substance is generally safe, non-toxic, and not biologically or otherwise undesirable, and is useful in the preparation of a pharmaceutical composition, including those acceptable for veterinary and human pharmaceutical use. The term "formulation" or "composition" refers to the quantitative and qualitative characteristics of a pharmaceutical product or dosage form prepared in accordance with the present invention.

[0065] In this specification, the dose and strength of gamma-hydroxybutyrate are expressed in grams (g) of equivalent oxybart sodium unless otherwise specified. Therefore, when considering the dose of gamma-hydroxybutyrate other than the sodium salt of gamma-hydroxybutyrate, the stated dose or strength should be obtained from oxybart sodium to the gamma-hydroxybutyrate being evaluated. It is necessary to convert it to hydroxybutyrate. Therefore, if an embodiment is described as 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 in question includes 4.5 g of oxyvert sodium, 5.1 g of potassium gamma-hydroxybutyrate (with an MW of 126.09 g / mol for oxyvert sodium and an MW of 142.20 g / mol for potassium gamma-hydroxybutyrate), and 3.7 g of free base (with an MW of 126.09 g / mol for oxyvert sodium and an MW of 104.1 g / mol for the free base of gamma-hydroxybutyrate), or any mixture of salts of gamma-hydroxybutyrate in a weight that gives the same amount of GHB as 4.5 g of oxyvert sodium.

[0066] In this specification, “microparticles” means particles of any fine solid material. These particles may consist of a single material, or they may have a complex structure with a core and shell and be composed of several materials. The terms “microparticles,” “particles,” “microspheres,” and “pellets” are interchangeable and synonymous. Unless otherwise specified, these microparticles do not have a specific particle size, i.e., diameter, and are not limited to particles with a volume-average diameter D(4,3) of less than 1 mm.

[0067] In this specification, the "volume-average diameter D(4,3)" is given by the following formula D(4,3) = Σ(d 4 i ·n i ) / Σ(d 3 i ·n i ) The calculation is performed according to the formula (wherein the given particle diameter d is the diameter of a rigid sphere having the same volume as the particle).

[0068] In this specification, the terms “finished composition,” “finished formulation,” or “formulation” are interchangeable and refer to a gamma-hydroxybutyrate-release-modulated formulation comprising, preferably, gamma-hydroxybutyrate-release-modulated microparticles, gamma-hydroxybutyrate-immediate-release microparticles, and any other excipients.

[0069] In this specification and the appended claims, “immediate-release (IR) portion” includes physically careful portions of a formulation, mechanically careful portions of a formulation, and pharmacokinetically careful portions of a formulation that serve or assist a defined immediate-release (IR) pharmacokinetic property. Therefore, any formulation that releases the active ingredient at the rate and degree required for the immediate-release portion of the formulation of the present invention includes an “immediate-release portion,” even if the immediate-release portion is physically integrated into a formulation that may otherwise be considered a sustained-release formulation. Thus, the IR portion may be structurally careful from the MR portion or not structurally separate (i.e., integrated). In a preferred embodiment, the IR portion and the MR portion are provided as particles, and in a more preferred embodiment, the IR portion and the MR portion are provided as particles careful from one another.

[0070] Therefore, in one embodiment of the present invention, the release control portion and the immediate release portion include structurally careful release control particles and immediate release particles. In another embodiment of the present invention, the release control portion and the immediate release portion include particles that are not structurally separate.

[0071] In this specification, "immediate-release formulation" or "immediate-release portion" means a composition that complies with USP38 <711> The above-mentioned composition is one that, when tested in a dissolution apparatus 2 conforming to the above, in a 0.1N HCl dissolution medium at a temperature of 37°C and a paddle speed of 75 rpm, releases at least 80% of the gamma-hydroxybutyrate of the composition in 1 hour.

[0072] Similarly, the "release regulation (MR) portion" is a pharmaceutical formulation in which the above-mentioned MR portion is integrated. Regardless of the physical form in which it is administered, it encompasses a release-modulating portion of a formulation or dosage form that is beneficial to or assists specific MR pharmacokinetic characteristics. This release-modulating drug delivery system is designed to deliver the drug at a specific point in time or over a period of time after administration, or at a specific location within the body. The USP defines a release-modulating system as a system selected to achieve therapeutic efficacy or convenience objectives that cannot be achieved by conventional IR dosage forms, either over time or at a specific location within the body. More specifically, MR solid oral dosage forms include sustained-release (ER) and delayed-release (DR) products. DR products release the entire drug at once, not immediately after administration. Generally, a coating (e.g., enteric coating) is used to delay the release of the drug substance until the dosage form has finished passing through the acidic medium of the stomach. ER products are formulated to make the drug available over a long period after ingestion, thus allowing for a reduction in the frequency of administration compared to drugs presented as conventional dosage forms, such as solutions or immediate-release formulations. In the case of oral administration, the term "extended-release" is usually interchangeable with "sustained-release," "prolonged-release," or "controlled-release."

[0073] Traditionally, sustained-release systems have provided a constant drug release, maintaining a steady drug concentration. However, for some drugs, zero-order delivery may not be optimal, leading to the development of more complex and sophisticated systems to provide multi-phase delivery. Oral MR delivery systems can be classified into four categories: (1) delayed release using enteric-coated membranes, (2) site-directed or time-delayed release (e.g., for colonic delivery), (3) sustained release (e.g., zero-order release, primary release, bi-phase release, etc.), and (4) programmed release (e.g., pulsed release, delayed sustained release, etc.). (Gibaldi's DRUG DELIVERY SYSTEMS IN PHARMACEUTICAL CARE, AMERICAN SOCIETY OF HEALTH-SYSTEM PHARMACISTS) Modified Oral Drug Delivery Systems and Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice, page 34, 2007. See page 469 of Academic Press, Elsevier, 2009, for reference. In this specification, in one embodiment, “modified-release formulation” or “modified-release portion” means a composition that releases gamma-hydroxybutyrate of the formulation or portion by multiphase delivery contained in an MR product of the fourth category, for example, a delayed-sustained release product. Therefore, the formulation or portion is different from a delayed-release product classified as an MR product of the first category.

[0074] In this specification, the terms “coating,” “coating layer,” “coating film,” “film coating,” and similar terms are interchangeable and synonymous. This term refers to a coating applied to particles containing gamma-hydroxybutyrate that controls the regulation of gamma-hydroxybutyrate release.

[0075] In all pharmacokinetic studies described herein, unless otherwise specified, if a dosage form or administration regimen requires two or more doses, the first dose of the dosage form is administered approximately two hours after the intake of a standardized dinner consisting of 25.5% fat, 19.6% protein, and 54.9% carbohydrates.

[0076] "Similar PK profiles" or "equivalent bioavailability" refers to the mean AUC of the test product in a properly designed crossover trial. inf The average AUC of the reference product inf The mean plasma concentration (C) of the test product at 8 hours has to be between 80% and 125% of the total. 8h ) is the mean plasma concentration (C) of the reference product at 8 hours. 8h This means it is between 50% and 130% of ).

[0077] Type 1 narcolepsy (NT1) is a type of narcolepsy characterized by excessive daytime sleepiness ("EDS") and cataplexy. Type 2 narcolepsy (NT2) is a type of narcolepsy characterized by excessive daytime sleepiness without cataplexy. A diagnosis of narcolepsy (with or without cataplexi) can be confirmed by (i) overnight polysomnography (PSG) and multiple sleep latency tests (MSLT) performed within the last two years, (ii) all written evidence from the sleep laboratory confirming the PSG and MSLT diagnosis, (iii) current symptoms of narcolepsy, including current EDS disturbances (more than 10 ESSs) in the last three months, (iv) mean MWT of less than 8 minutes, (v) mean number of 8 cataplexi events per week as recorded in the sleep / cataplexi diary at the time of pretreatment measurement, and / or (vi) one or a combination of cataplexi occurrences in the last three months and 28 events per week during the screening period.

[0078] Unless otherwise specified herein, percentages, ratios, and numerical values ​​are weight-based, averages and means are arithmetic means, and all pharmacokinetic measurements based on body fluid measurements are plasma concentration-based.

[0079] Where a composition is defined in this specification by its pharmacokinetic or solubility properties, it will be understood that, instead, the formulation may be defined as a “means for” achieving the described pharmacokinetic or solubility properties. Accordingly, a formulation in which the release-modulating portion releases less than 20% of the gamma-hydroxybutyrate of the portion at 1 hour may instead be defined as a “means for” releasing less than 20% of the gamma-hydroxybutyrate of the portion at 1 hour, or a formulation comprising such a “release-modulating means for” achieving that portion. It will be further understood that a preferred structure for achieving the described pharmacokinetic or solubility properties is the structure described in the examples of this specification for achieving the described pharmacokinetic or solubility properties.

[0080] Description of Major Embodiments The present invention can be described in terms of its main embodiments, and similarly, other main embodiments can be provided by recombining the above main embodiments, and other main embodiments can be provided by limiting the above main embodiments with lower embodiments.

[0081] A first main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, wherein a 7.5 g dose of the formulation has an average AUC of 245, 300, 325, 340, 375, 400, 425, or 450 hours × micrograms / mL, most preferably 340 hours × micrograms / mL. inf The present invention provides the above-mentioned formulation, which has been shown to achieve the above-mentioned objective.

[0082] A second main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, wherein a 7.5 g dose of the formulation has an average AUC of 245, 265, 285, 300, 315, 325, 340, 350, 375, 400, 425, or 450 hours × micrograms / mL, most preferably 340 hours × micrograms / mL. inf , and approximately two hours after the standardized dinner, t0 and t 4h At that point, the mean C is given by equidose of an immediate-release solution of oxybart sodium (e.g., Xyrem®) administered in equal doses. 8h The average C is 50%~130%, 60%~130%, 70%~130%, 75%~125%, 80%~125%, 80%~120%, 90%~110%, 50%~95%, 60%~90%, most preferably 60%~90% or 60%~130%. 8h The present invention provides the above-mentioned formulation, which has been shown to achieve the above-mentioned objective.

[0083] A third main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, (a) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour, at least 80% or 90% of the gamma-hydroxybutyrate of the above formulation is released, and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 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%, of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. The above-mentioned formulation is provided.

[0084] A fourth main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% or 90% of the gamma-hydroxybutyrate of the above formulation is released at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 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%, of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours, and (c) The present invention provides a formulation in which, in a dissolution test in which the release-regulating portion is preferably dissolved in 750 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm for 2 hours, and then switched to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, more than 80% or 90% of the gamma-hydroxybutyrate of the release-regulating portion is released at 3 hours.

[0085] A fifth main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% or 90% of the gamma-hydroxybutyrate of the above formulation is released at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 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%, of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. (c) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, at 10 hours, more than 60%, 70%, or 80%, preferably more than 80%, of the above formulation gamma-hydroxybutyrate is released, and (d) The above release control unit releases 750 mL at a temperature of 37°C and a paddle speed of 75 rpm. In a dissolution test starting in 0.1N hydrochloric acid for 2 hours, followed by switching to 950 mL of 0.05M potassium dihydrogen phosphate buffer adjusted to pH 6.8, more than 80% of the gamma-hydroxybutyrate of the release-regulated portion was released at 3 hours. The above-mentioned formulation is provided.

[0086] A sixth main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation in a 7.5g dose has an average AUC of 245, 300, 325, 340, 375, 400, 425, or 450 hours × micrograms / mL, preferably 340 hours × micrograms / mL. inf , and approximately two hours after the standardized dinner, t0 and t 4h At this point, the mean C is given by equidose of an immediate-release solution of gamma-hydroxybutyrate (e.g., Xyrem®) administered in equal doses. 8h The average C is 50%~130%, 60%~130%, 70%~130%, 75%~125%, 80%~125%, 80%~120%, 90%~110%, 50%~95%, 60%~90%, preferably 60%~90% or 60%~130%. 8h It has become clear that this can be achieved, and (b) The above preparation is (i) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour, at least 80% or 90% of the gamma-hydroxybutyrate of the above formulation is released, and (ii) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, at 1 hour and 3 hours, 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%, of the gamma-hydroxybutyrate of the above formulation is released, and c) In a dissolution test in which the release control portion starts at 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0087] A seventh main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The immediate release portion mentioned above is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% or 90% of the immediate release portion of gamma-hydroxybutyrate is released at 1 hour. (b) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, less than 20% or 10% of the gamma-hydroxybutyrate in the release control portion is released after 1 hour, and (c) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, more than 80% or 90% of the gamma-hydroxybutyrate of the release-controlled portion is released at 3 hours, 2 hours, or 1 hour. The above-mentioned formulation is provided.

[0088] An eighth main embodiment of the present invention is a gamma-hydr comprising an immediate release portion and an emission control portion. A release-controlled formulation of roxybutyrate, (a) The immediate release portion mentioned above is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% or 90% of the immediate release portion of gamma-hydroxybutyrate is released at 1 hour, 2 hours, or 3 hours. (b) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, less than 20% or 10% of the gamma-hydroxybutyrate in the release control portion is released after 1 hour. (c) The above release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, more than 80% or 90% of the gamma-hydroxybutyrate of the release control portion is released at 3 hours, 2 hours, or 1 hour, and (d) In a dissolution test in which the release control portion starts at 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% or 90% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0089] A ninth main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, wherein when the formulation is administered in doses of 4.5 g, 6 g, 7.5 g, and 9 g, approximately 2 hours after a standardized dinner, t0 and t 4h The present invention provides a formulation that, at a given time, achieves relative bioavailability (RBA) exceeding 80%, 85%, or 90% compared to an equidose immediate-release solution of oxybart sodium administered in equidivisible doses. The above relative bioavailability is even higher at higher doses, and at 6.0g, 7.5g, or 9.0g doses, when administered approximately 2 hours after a standardized dinner, t0 and t0 are higher. 4h At that point, the concentration is preferably greater than 90, 95, or 100% when compared to an equidose of an immediate-release solution of oxyvert sodium administered in equal doses.

[0090] A tenth main embodiment of the present invention is a release-controlled formulation of gamma-hydroxybutyrate, wherein when the formulation in 4.5 g and 9 g doses is administered approximately 2 hours after a standardized dinner, t0 and t 4h The present invention provides a formulation that, at that point in time, has been shown to achieve a relative bioavailability (RBA) of more than 80% when compared to an equidose immediate-release solution of oxybart sodium administered in equidivisible doses.

[0091] An eleventh main embodiment of the present invention provides a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, which, when administered once overnight at a strength of 4.5 g, 6.0 g, or 7.5 g approximately two hours after a standardized dinner, gives substantially the plasma concentration-time curve shown in Figure 12 or Figure 13 for the corresponding strength.

[0092] A twelfth main embodiment of the present invention provides a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, which, when administered once overnight at an intensity of 4.5 g approximately two hours after a standardized dinner, substantially gives the plasma concentration-time curve shown in Figure 22.

[0093] A thirteenth major embodiment of the present invention provides a release-controlled formulation of gamma-hydroxybutyrate, which preferably includes an immediate-release portion and a release-controlled portion, and substantially gives the solubility profile shown in Figures 7 and 8.

[0094] A fourteenth major embodiment of the present invention provides a release-controlled formulation of gamma-hydroxybutyrate, which preferably includes an immediate-release portion and a release-controlled portion, and substantially gives the solubility profile shown in Figures 20 and 21.

[0095] A 15th major embodiment of the present invention provides a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion that substantially gives a solubility profile shown in Figure 3 or Figure 16.

[0096] In a sixteenth major embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, which gives a dissolution profile between the minimum and maximum values ​​shown in Figures 25 and 26.

[0097] In the 17th main embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, which gives a dissolution profile between the minimum and maximum values ​​shown in Figures 27 and 28.

[0098] In the eighteenth major embodiment, the present invention provides a release-controlled formulation of gamma-hydroxybutyrate that substantially gives a solubility profile shown in any one of Figures 29-89. It will be understood that this seventeenth major embodiment may be limited to only one of these solubility profiles.

[0099] A nineteenth primary embodiment of the present invention provides a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, which, when administered once overnight at a strength of 4.5 g, 7.5 g, or 9.0 g approximately two hours after a standardized dinner, gives substantially the plasma concentration-time curve shown in Figure 90 for the corresponding strength.

[0100] In any of these primary embodiments, the formulation is preferably effective in treating type 1 or type 2 narcolepsy. The formulation is also preferably effective in inducing 6 to 8 hours of sleep, most preferably 8 consecutive hours.

[0101] In any of these main embodiments, the formulation preferably comprises an immediate-release portion and a release-regulating portion, wherein the release-regulating portion comprises a polymer having free carboxyl groups and gamma-hydroxybutyrate particles coated with a hydrophobic compound having a melting point of 40°C or higher, and the ratio of gamma-hydroxybutyrate in the immediate-release portion to the release-regulating portion is 10 / 90 to 65 / 35. The polymer containing free carboxyl groups is preferably a methacrylic acid copolymer having a pH dissolution trigger of 5.5 to 6.97.

[0102] Major structural embodiments In a first major structural embodiment, the present invention relates to a release-regulated formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-regulated portion, (a) comprising gamma-hydroxybutyrate particles coated with the above release-regulating portion, (b) The above coating comprises a polymer having free carboxyl groups and a hydrophobic compound having a melting point of 40°C or higher, (c) The ratio of gamma-hydroxybutyrate in the immediate-release portion to the release-controlled portion is 10 / 90 to 65 / 35. The above-mentioned formulation is provided.

[0103] In a second major structural embodiment, the present invention includes an immediate release portion and a release control portion, A release-modulating formulation of gamma-hydroxybutyrate comprising a suspending agent or thickener, and an acidifying agent, (a) comprising gamma-hydroxybutyrate particles coated with the above release-regulating portion, (b) The above coating comprises a polymer having free carboxyl groups and a hydrophobic compound having a melting point of 40°C or higher, (c) The ratio of gamma-hydroxybutyrate in the immediate-release portion to the release-controlled portion is 10 / 90 to 65 / 35. The above-mentioned formulation is provided.

[0104] In a third major structural embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) comprising gamma-hydroxybutyrate particles coated with the above release-regulating portion, (b) The above coating comprises a polymer having free carboxyl groups and a hydrophobic compound having a melting point of 40°C or higher. (c) The weight ratio of the hydrophobic compound to the polymer having the free carboxyl group is 0.4 to 4. (d) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-regulating portion is 10 / 90 to 65 / 35, and (e) The above coating is 10 to 50% of the weight of the above particles. The above-mentioned formulation is provided.

[0105] In a fourth major structural embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) comprising gamma-hydroxybutyrate particles coated with the above release-regulating portion, (b) The above coating comprises a polymer having free carboxyl groups with a pH trigger of 5.5 to 6.97 and a hydrophobic compound with a melting point of 40°C or higher. (c) The weight ratio of the hydrophobic compound to the polymer having the free carboxyl group is 0.4 to 4. (d) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-regulating portion is 10 / 90 to 65 / 35, and (e) The above coating is 10 to 50% of the weight of the above particles. The above-mentioned formulation is provided.

[0106] In a fifth major structural embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) comprising gamma-hydroxybutyrate particles coated with the above release-regulating portion, (b) The above coating comprises a methacrylic acid copolymer having free carboxyl groups with a pH trigger of 5.5 to 6.97 and a hydrophobic compound with a melting point of 40°C or higher. (c) The weight ratio of the hydrophobic compound to the polymer having the free carboxyl group is 0.4 to 4. (d) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-regulating portion is 10 / 90 to 65 / 35, and (e) The above coating is 10 to 50% of the weight of the above particles. The above-mentioned formulation is provided.

[0107] Description of lower embodiments of pharmacokinetics and solubility As set forth in the section on definitions of terms in this specification, each of the principal embodiments described above may be further characterized and limited by each of the lower embodiments. Furthermore, each of the principal embodiments described above may be further characterized and limited by combining and using two or more of the following lower embodiments in any mathematically and physically possible form.

[0108] In various sub-embodied embodiments of the main embodiments described above, a 7.5 g dose of this controlled-release formulation of gamma-hydroxybutyrate, when administered once approximately 2 hours after a standardized dinner, yields an average AUC greater than 245, 265, 285, 300, 315, 325, 340, 350, 375, 400, 425, or 450 hours × micrograms / mL. inf It may also be characterized by the fact that it has been shown to achieve the above. Average AUC at the 7.5g dose. inf The upper limit may be set at 500 or 550 hours × micrograms / mL.

[0109] In further sub-embodied embodiments of the main embodiments described above, a 7.5 g dose of this controlled-release formulation of gamma-hydroxybutyrate, when administered once approximately two hours after a standardized dinner, yields an average C1c level exceeding 65, 70, 75, 80, 85, or 90 micrograms / mL. max It may also be characterized by the fact that it has been shown to achieve this. The average C for such 7.5g dosemax The upper limit can be set to 125 or 100 micrograms / mL.

[0110] In further sub-embodied embodiments of the main embodiments described above, when a 7.5 g dose of this controlled-release formulation of gamma-hydroxybutyrate is administered approximately two hours after a standardized dinner, t0 and t 4h At this point, the mean C is given by an immediate-release solution of an equidose of gamma-hydroxybutyrate administered in two equal doses. 8h The average C is 50%-130%, 60%-130%, 70%-130%, 75%-125%, 80%-125%, 80%-120%, or 90%-110%. 8h It may also be characterized by the fact that it has become clear that this can be achieved.

[0111] In one lower embodiment, a 7.5g dose of this formulation has an average AUC greater than 340 hours / microgram / mL. inf , and approximately two hours after the standardized dinner, t0 and t 4h At that point, the average C is given by an immediate-release solution of equidose of oxyvert sodium administered in equal doses. 8h The average C is 50% to 130% of the average C. 8h It has become clear that this can be achieved.

[0112] Further lower embodiments may be characterized based on the solubility of the complete (i.e., finished) controlled-release formulation of the gamma-hydroxybutyrate in a 0.1 N hydrochloric acid dissolution medium. Thus, in further lower embodiments, the complete controlled-release formulation of the gamma-hydroxybutyrate is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, gamma-hydroxybutyrate of the above formulation is released at a concentration exceeding 30%, 35%, 40%, or 45%, and less than 70%, 65%, 60%, or 55% after 1 hour.

[0113] Further lower embodiments may be defined based on the solubility characteristics of the release-modulating portion of the gamma-hydroxybutyrate formulation in a phosphate buffer pH 6.8 solubility medium. Thus, in further lower embodiments, the release-modulating portion is USP38 <711> In a dissolution apparatus 2 conforming to USP38, when tested 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, the gamma-hydroxybutyrate of the release-controlled portion exceeds 80%, 85%, 90%, 95%, 98%, or even more than 99% at 3, 2, 1, 0.5, or 0.25 hours. <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released after 1 hour.

[0114] Further embodiments may be defined based on the solubility of the release-modified portion of the release-modified formulation of gamma-hydroxybutyrate in a 0.1N HCl dissolution medium. Thus, in further lower embodiments, the release-modified portion is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, only 20%, 15%, 10%, 5%, or even less than 2% of the gamma-hydroxybutyrate in the release-controlled portion is released after 1 hour.

[0115] In a further embodiment, the emission control portion is USP38 <711> In a dissolution apparatus 2 conforming to the above, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, only 20%, 15%, 10%, 5%, or less than 2% of the gamma-hydroxybutyrate of the release-controlled portion is released at 1 hour and 3 hours, while more than 30%, 35%, 40%, and 45% of the gamma-hydroxybutyrate of the release-controlled portion is released at 10 hours.

[0116] Further embodiments may be defined based on the dissolution characteristics of the immediate release portion of the gamma-hydroxybutyrate release modulating formulation in a 0.1N HCl dissolution medium. Thus, in a further sub-embodiment, the immediate release portion, when tested in Dissolution Apparatus 2 in accordance with USP38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37 °C and a paddle speed of 75 rpm, releases gamma-hydroxybutyric acid of the immediate release portion exceeding 80%, 85%, 90%, 95%, 98%, or even exceeding 99% at the 1-hour time point.

[0117] In another sub-embodiment, the formulation (a) when tested in Dissolution Apparatus 2 in accordance with USP38 <711> in 900 mL of 0.05M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37 °C and a paddle speed of 75 rpm, releases at least 80% of the gamma-hydroxybutyrate of the formulation at the 3-hour time point, and (b) when tested in Dissolution Apparatus 2 in accordance with USP38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37 °C and a paddle speed of 75 rpm, releases 10% - 65% of the gamma-hydroxybutyrate of the formulation at the 1-hour and 3-hour time points.

[0118] In another sub-embodiment, the formulation comprises an immediate release portion and a release modulating portion, (a) the formulation, when tested in Dissolution Apparatus 2 in accordance with USP38 <711> in 900 mL of 0.05M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37 °C and a paddle speed of 75 rpm, releases at least 80% of the gamma-hydroxybutyrate of the formulation at the 3-hour time point, (b) the formulation, when tested in Dissolution Apparatus 2 in accordance with USP38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37 °C and a paddle speed of 75 rpm, releases 10% - 65% of the gamma-hydroxybutyrate of the formulation at the 1-hour time point, and (c) In a dissolution test in which the release-controlled portion is started at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switched to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released at 3 hours.

[0119] In another lower embodiment, the formulation comprises an immediate-release portion and a release-regulated portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 3 hours. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when testing in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, for 1 hour At this point and at 3 hours later, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released. (c) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 60% of the above formulation's gamma-hydroxybutyrate is released after 10 hours, and (d) In a dissolution test in which the release-controlled portion is started at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switched to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released at 3 hours.

[0120] Further lower embodiments may be defined based on a comparison of the pharmacokinetics of the controlled-release formulation of gamma-hydroxybutyrate with that of an immediate-release solution formulation of gamma-hydroxybutyrate. Therefore, in further lower embodiments, the controlled-release formulation of gamma-hydroxybutyrate in preferably 4.5 g, 6.0 g, 7.5 g, and 9.0 g doses, when administered approximately 2 hours after a standardized dinner, exhibits t0 and t 4h At that point, it has been shown that relative bioavailability (RBA) exceeding 80%, 85%, 90%, or 95% is achieved when compared to an equidose immediate-release solution of oxybart sodium administered in equal doses.

[0121] In further lower embodiments of the main embodiments described above, the present invention relates to a controlled-release formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a controlled-release portion, wherein when the formulation is administered in 4.5 g and 9 g doses approximately two hours after a standardized dinner, t0 and t 4h The present invention provides a formulation that, at that point in time, has been shown to achieve relative bioavailability (RBA) exceeding 80%, 85%, or 90% when compared to an equidose immediate-release solution of oxybart sodium administered in equidivisible doses.

[0122] In further lower embodiments, when a 6.0g, 7.5g, or 9.0g dose of this controlled-release formulation of gamma-hydroxybutyrate is administered approximately two hours after a standardized dinner, t0 and t 4h At that point, it has been shown that relative bioavailability (RBA) exceeding 80%, 85%, 90%, 95%, or 100% is achieved when compared to equidose immediate-release solutions of oxybart sodium administered in equal doses.

[0123] The controlled-release formulations of gamma-hydroxybutyrate of the present invention may also be defined by comparing the area under the 8-hour concentration / time curve with the area under the concentration / time curve calculated to infinity. Thus, in even further lower embodiments, the controlled-release formulations of gamma-hydroxybutyrate of the present invention in 4.5 g, 6.0 g, 7.5 g, or 9.0 g doses, when administered once approximately 2 hours after a standardized dinner, have an average AUC greater than 0.80, 0.85, 0.90, 0.95, or 0.98. inf Average AUC for 8h It has been shown that this ratio can be achieved.

[0124] In an even more sub-embodied embodiment, the controlled-release formulation of this gamma-hydroxybutyrate is defined based on the concentration of gamma-hydroxybutyrate in the bloodstream 8 hours after administration. Therefore, in another sub-embodied embodiment, when the formulation is administered once approximately 2 hours after a standardized dinner, the average C2 concentration is 4.7–9.0, 5.4–8.3, 6.1–7.6, 3.5–7.0, or 4.0–5.5 micrograms / mL. 8h The controlled-release formulations of gamma-hydroxybutyrate at a 4.5g dose have been shown to achieve the following average C levels: 6.3-16.7, 7.3-15.4, 8.2-14.1, 8.9-16.7, 10.2-15.4, or 5-14.1 micrograms / mL. 8h A 6.0g dose of gamma-hydroxybutyrate-releasing formulation has been shown to achieve this, or 13. Average C levels of 0-40.3, 16.0-26.0, 15.0-25.0, 17.5-22.0, 21.6-40.3, 24.7-37.2, or 27.8-34.1 micrograms / mL 8h The present invention may feature a 7.5 g dose of gamma-hydroxybutyrate with controlled release formulations, or any combination thereof, that has been shown to achieve the above.

[0125] The controlled-release formulations of gamma-hydroxybutyrate of the present invention may also be defined by the concentration / time curves and dissolution curves produced by the formulations when tested according to the examples of the present invention. Thus, in other lower embodiments, it has been shown that the controlled-release formulations of gamma-hydroxybutyrate of the present invention at doses of 4.5 g, 6.0 g, or 7.5 g substantially achieve the time / concentration curves shown in Figures 13(a), (b), and (c) herein, respectively. In another major embodiment or lower embodiment, it has been shown that the formulations substantially achieve the dissolution curves shown in Figures 7 and 8 or Figures 20 and 21 herein.

[0126] The controlled-release formulation of gamma-hydroxybutyrate of the present invention may also be defined based on the time required to reach the maximum blood concentration of gamma-hydroxybutyrate. Thus, in further lower embodiments, the controlled-release formulation of gamma-hydroxybutyrate, when administered once approximately two hours after a standardized dinner, has a median T of 1.25 to 3.25 hours, preferably about 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, or 3.25 hours. max It has become clear that this can be achieved. Median T in any of the above ranges max The lower limit may be set to 0.5 or 1.0 hours instead of the above.

[0127] Further embodiments may be defined by comparing a certain dose of the controlled-release formulation of gamma-hydroxybutyrate, administered once overnight, with the same dose of an immediate-release solution of oxyvert sodium, administered twice overnight in equal parts with a 4-hour interval. Thus, in another lower embodiment, a 4.5g, 6.0g, 7.5g, or 9.0g dose of the controlled-release formulation of gamma-hydroxybutyrate, when administered approximately 2 hours after a standardized dinner, provides a median T of half the dose of an immediate-release solution of oxyvert sodium. max Median T of 150 minutes, 120 minutes, 90 minutes, 60 minutes, or within 30 minutes max It has become clear that this can be achieved.

[0128] In yet another lower embodiment, when a 4.5g, 6.0g, 7.5g, or 9.0g dose of this controlled-release formulation of gamma-hydroxybutyrate is administered approximately two hours after a standardized dinner, the average C1250 of half the dose of an immediate-release solution of oxyvert sodium is obtained. 4h Average C exceeding 6h or average C 7h , and the above average C 4h Average C less than 10h It has become clear that this can be achieved.

[0129] Further embodiments may be defined by comparing the pharmacokinetic profile of a dose of the controlled-release formulation of gamma-hydroxybutyrate administered once overnight with the pharmacokinetic profile of the same dose of an immediate-release solution of oxyvert sodium administered twice overnight in equal doses with a 4-hour interval. Thus, in another lower embodiment, the controlled-release formulation of gamma-hydroxybutyrate according to the present invention has an average C of 0.6 to 1.2, preferably 0.7 to 1.1, most preferably 0.8 to 1, of the first half dose of the immediate-release solution of oxyvert sodium. max The average C of the above formulations relative to the above formulations 3h It has been shown that the ratio can be achieved. In another lower embodiment, the release-controlled formulation of gamma-hydroxybutyrate according to the present invention has an average C of 0.5 to 1.1, preferably 0.6 to 1, most preferably 0.7 to 0.9 of the immediate-release solution of oxyvert sodium in the first half dose. max The average C of the above formulations relative to the above formulations 4h It has been shown that a ratio of 0.5 to 1, preferably 0.5 to 0.9, can be achieved. In another lower embodiment, the release-controlled formulation of gamma-hydroxybutyrate according to the present invention has a ratio of 0.5 to 1, preferably 0.5 to 0.9 Most preferably 0.6 to 0.8, the average C of the first half dose of the immediate-release solution of oxyvert sodium. max The average C of the above formulations relative to the above formulations 4.5h It has been shown that this ratio can be achieved.

[0130] Further embodiments may be defined by the range of the average plasma concentration of gamma-hydroxybutyrate achieved 3, 4, 4.5, or 5 hours after once-daily administration with a dosage of 7.5 g of the gamma-hydroxybutyrate release-modulating preparation according to the invention. Thus, in another sub-embodiment, the gamma-hydroxybutyrate release-modulating preparation of the present 7.5 g dosage achieves an average C 3h in the range of 43 to 81 micrograms / mL, preferably 49 to 75 micrograms / mL, more preferably 55 to 69 micrograms / mL. In another sub-embodiment, the gamma-hydroxybutyrate release-modulating preparation of the present 7.5 g dosage achieves an average C 4h in the range of 40 to 75 micrograms / mL, preferably 45 to 69 micrograms / mL, more preferably 51 to 64 micrograms / mL. In another sub-embodiment, the gamma-hydroxybutyrate release-modulating preparation of the present 7.5 g dosage achieves an average C 4.5h in the range of 35 to 67 micrograms / mL, preferably 40 to 62 micrograms / mL, more preferably 45 to 56 micrograms. In another sub-embodiment, the gamma-hydroxybutyrate release-modulating preparation of the present 7.5 g dosage achieves an average C 5h in the range of 31 to 59 micrograms / mL, preferably 36 to 55 micrograms / mL, more preferably 40 to 50 micrograms / mL.

[0131] In another sub-embodiment, the present preparation of 7.5 g dosage achieves an average AUC inf exceeding 300 hour-micrograms / mL and an average C max exceeding 70 micrograms / mL when administered approximately 2 hours after a standardized dinner.

[0132] In yet another sub-embodiment, the present preparation of 7.5 g dosage achieves an average AUC inf exceeding 350 hour-micrograms / mL and an average C exceeding 80 micrograms / mL when administered approximately 2 hours after a standardized dinner.max has been shown to achieve.

[0133] In another lower embodiment, the 4.5, 6.0, 7.5, and 9.0 g doses of the formulation are administered in equal divided doses at approximately 2 hours after a standardized dinner, at the times of t0 and t 4h and achieve an average AUC that is greater than 80% of the average AUC inf given by an immediate release solution of equidose oxybate at the same times of t0 and t inf and, at approximately 2 hours after a standardized dinner, at the times of t0 and t 4h achieve an average C that is less than 95%, 90%, or 85% of the average C 8h given by an immediate release solution of equidose oxybate at the same times of t0 and t 8h has been shown to achieve.

[0134] A further embodiment may be defined by comparing the pharmacokinetic profile of a certain dose of the controlled release formulation of the present gamma-hydroxybutyrate, administered once a night, with the immediate release solution of oxybate for a second dose, administered twice a night at 4-hour intervals in equal divided doses. Thus, in another lower embodiment, the 7.5 g dose of the controlled release formulation of the present gamma-hydroxybutyrate achieves a pharmacokinetic profile similar to that given by a 2 × 4.5 g dose of oxybate as an immediate release solution, administered 2 hours after a standardized dinner for the first 4.5 g and 4 hours after the first dose for the second 4.5 g dose. Thus, in another lower embodiment, the controlled release formulation of gamma-hydroxybutyrate according to the present invention, administered at a dose of 7.5 g, has an average C of the above formulation relative to the average C of an immediate release solution of the first 4.5 g dose of oxybate max in the range of 0.5 to 1.1, preferably 0.6 to 1, most preferably 0.7 to 0.9. 3hIt has been clearly shown to achieve the ratio of. In another lower embodiment, the gamma-hydroxybutyrate release regulating preparation according to the present invention has an average C of an immediate release solution of 4.5 g dose of sodium oxybate of 0.5 to 1, preferably 0.6 to 0.9, most preferably 0.7 to 0.8 max of the average C of the above preparation with respect to 4h It has been clearly shown to achieve the ratio of. In another lower embodiment, the gamma-hydroxybutyrate release regulating preparation according to the present invention has an average C of an immediate release solution of 4.5 g dose of sodium oxybate of 0.4 to 9, preferably 0.5 to 0.8, most preferably 0.6 to 0.7 max of the average C of the above preparation with respect to 4.5h It has been clearly shown to achieve the ratio of.

[0135] In another lower embodiment, the gamma-hydroxybutyrate release regulating preparation of the present invention includes an immediate release portion and a release regulating portion, (a) When the above immediate release portion is tested in a dissolution apparatus 2 compliant with USP38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37 °C and a paddle speed of 75 rpm, more than 80% of the gamma-hydroxybutyrate of the above immediate release portion is released at the 1-hour time point, (b) When the above release regulating portion is tested in a dissolution apparatus 2 compliant with USP38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37 °C and a paddle speed of 75 rpm, less than 20% of the gamma-hydroxybutyrate of the above release regulating portion is released at the 1-hour time point, and (c) When the above release regulating portion is tested in a dissolution apparatus 2 compliant with USP38 <711> 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, more than 80% of the gamma-hydroxybutyrate of the above release regulating portion is released at the 1-hour time point.

[0136] In a preferred embodiment, the gamma-hydroxybutyrate release regulating preparation according to the present invention (a) USP38 <711> In dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 40% and 65%, (ii) At 3 hours, the percentage was between 40% and 65%, (iii) At 8 hours, the percentage was between 47% and 85%, (iv) At 10 hours, the percentage is 60% or higher, (v) More than 80% at 16 hours It is characterized by and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 0.25 hours, the percentage was between 43% and 94%. (ii) At 0.35 hours, the percentage is 65% or higher, and (iii) 88% or more after 1 hour Characterized by Achieves an in vitro dissolution profile.

[0137] In a preferred embodiment, the release-controlled formulation of gamma-hydroxybutyrate according to the present invention is (a) USP38 <711> In dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 40% and 65%, (ii) At 3 hours, the percentage was between 40% and 65%, (iii) If the percentage is 47% or higher after 8 hours, (iv) At 10 hours, the percentage is 60% or higher, (v) More than 80% at 16 hours It is characterized by and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 0.25 hours, the percentage was between 43% and 94%. (ii) At 0.35 hours, the percentage is 65% or higher, and (iii) 88% or more after 1 hour Characterized by Achieves an in vitro dissolution profile.

[0138] In another preferred embodiment, the release-controlled formulation of gamma-hydroxybutyrate according to the present invention is (a) USP38 <711> In dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 40% and 65%, (ii) At 3 hours, the percentage was between 40% and 65%, (iii) At 8 hours, the percentage was between 47% and 85%, (iv) At 10 hours, the percentage is 60% or higher, (v) More than 80% at 16 hours It is characterized by and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 45% and 67%, and (ii) 65% or more after 3 hours Characterized by Achieves an in vitro dissolution profile.

[0139] In another preferred embodiment, the release-controlled formulation of gamma-hydroxybutyrate according to the present invention is (a) USP38 <711> In dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 40% and 65%, (ii) At 3 hours, the percentage was between 40% and 65%, (iii) If the percentage is 47% or higher after 8 hours, (iv) At 10 hours, the percentage is 60% or higher, (v) More than 80% at 16 hours It is characterized by and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 45% and 67%, and (ii) 65% or more after 3 hours Characterized by Achieves an in vitro dissolution profile.

[0140] In yet another lower embodiment, the formulation is: (a) USP38 <711> In dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 40% and 65%, (ii) At 3 hours, the percentage was between 40% and 65%, (iii) More than 45% at 8 hours It is characterized by and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 0.5 hours, it exceeds 40%, and (ii) more than 85% at the 1-hour mark Characterized by Achieves an in vitro dissolution profile.

[0141] Alternatively, this product is subject to USP38 <711> In dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 1 hour, the percentage is between 40% and 65%, (ii) At 3 hours, the percentage is between 40% and 65%, and (iii) More than 45% at 8 hours It may also be described as achieving an in vitro solubility profile characterized by the following:

[0142] In another option, this formulation is USP38 <711> In a dissolution apparatus 2 conforming to the standard, the percentage of dissolved gamma-hydroxybutyrate was measured in 900 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, and was as follows: (i) At 0.5 hours, it exceeds 40%, and (ii) more than 85% at the 1-hour mark It may also be described as achieving an in vitro solubility profile characterized by the following:

[0143] Lower structural embodiments The controlled-release formulation of gamma-hydroxybutyrate of the present invention can be provided in any dosage form suitable for oral administration, including tablets, capsules, liquids, orally dissolvable tablets, but the formulation is preferably provided as a dry particulate formulation (i.e., granules, powders, coated particles, fine particles, pellets, microspheres, etc.) in a pouch or other appropriate careful packaging unit. The formulation is preferably in powder form. The preferred particulate formulation is to be mixed with tap water (preferably 50 mL) immediately before administration.

[0144] The above-mentioned gamma-hydroxybutyrate is preferably in the form of oxybart sodium.

[0145] In one lower embodiment, the formulation comprises an immediate-release portion and a release-regulated portion. (a) comprising fine particles of gamma-hydroxybutyrate coated with the above release control portion, (b) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-controlled portion is 10 / 90 to 65 / 35.

[0146] In one lower embodiment, the formulation comprises an immediate-release portion and a release-regulated portion. (a) comprising fine particles of gamma-hydroxybutyrate coated with the above release control portion, (b) The ratio of gamma-hydroxybutyrate in the immediate-release portion to the release-regulating portion is 40 / 60 to 60 / 40.

[0147] In another lower embodiment, the formulation comprises an immediate-release portion and a release-regulated portion, (a) comprising gamma-hydroxybutyrate fine particles coated with the release-regulating portion described above, (b) The coating of the gamma-hydroxybutyrate release-controlled particles contains a polymer having free carboxyl groups and a hydrophobic compound with a melting point of 40°C or higher, (c) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-regulating portion is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40.

[0148] In another lower embodiment, the formulation comprises an immediate-release portion and a release-regulated portion, (a) comprising gamma-hydroxybutyrate fine particles coated with the release-regulating portion described above, (b) The coating of the gamma-hydroxybutyrate release-controlled particles comprises a polymer having free carboxyl groups and a hydrophobic compound with a melting point of 40°C or higher. (c) The weight ratio of the hydrophobic compound to the polymer having the free carboxyl group is 0.4 to 4. (d) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-regulating portion is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40, and (e) The coating of the gamma-hydroxybutyrate release-regulating particles is 10-50% of the weight of the fine particles.

[0149] In another lower embodiment, the formulation comprises an immediate-release portion and a release-regulated portion, (a) comprising gamma-hydroxybutyrate fine particles coated with the release-regulating portion described above, (b) The coating of the gamma-hydroxybutyrate release-regulating particles comprises a polymer having free carboxyl groups with a pH trigger of 5.5 to 6.97 and a hydrophobic compound with a melting point of 40°C or higher. (c) The weight ratio of the hydrophobic compound to the polymer having the free carboxyl group is 0.4 to 4. (d) The ratio of gamma-hydroxybutyrate in the immediate release portion to the release-regulating portion is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40, and (e) The coating of the gamma-hydroxybutyrate release-regulating particles is 10-50% of the weight of the fine particles.

[0150] In a particularly preferred lower embodiment of the immediately preceding lower embodiment, the polymer having free carboxyl groups comprises 100% poly(methacrylate-ethyl acrylate (1:1)), 0% poly(methacrylate-methyl methacrylate (1:2)) to 2% poly(methacrylate-ethyl acrylate (1:1)), and 98% poly(methacrylate-methyl methacrylate (1:2)), and the hydrophobic compound comprises a hydrogenated vegetable oil.

[0151] In a preferred embodiment, the formulation includes an excipient for improving the viscosity and fluidity of the mixture of the particulate formulation and tap water. Thus, in addition to the immediate-release and release-controlled particles of gamma-hydroxybutyrate, the particulate formulation includes one or more suspending agents, thickeners, or lubricants.

[0152] Preferred suspending agents or thickeners include 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, and Guerlain. Selected from the group consisting of gum, iota-type, kappa-type, or lambda-type carrageenan gum, and medium viscosity hydroxypropyl methylcellulose.

[0153] Medium viscosity sodium carboxymethylcellulose corresponds to a grade of sodium carboxymethylcellulose in which the viscosity of a 2% aqueous solution at 25°C is greater than 200 mPa·s and less than 3100 mPa·s.

[0154] Medium viscosity hydroxyethylcellulose corresponds to a grade of hydroxyethylcellulose in which the viscosity of a 2% aqueous solution at 25°C is greater than 250 mPa·s and less than 6500 mPa·s. Medium viscosity hydroxypropyl methylcellulose corresponds to a grade of hydroxypropyl methylcellulose in which the viscosity of a 2% aqueous solution at 20°C is greater than 80 mPa·s and less than 3800 mPa·s.

[0155] A preferred suspending agent or thickener is xanthan gum, particularly Kelco's Xantural 75 (trademark), hydroxyethylcellulose, especially Natrosol of Ashland These include 250M (trademark), kappa-type carrageenan gum, particularly Gelcarin PH812 (trademark) of FMC Biopolymer, and lambda-type carrageenan gum, particularly Viscarin PH209 (trademark) of FMC Biopolymer.

[0156] In a preferred embodiment, the release-controlled formulation of gamma-hydroxybutyrate comprises 1 to 15%, preferably 2 to 10%, more preferably 2 to 5%, and most preferably 2 to 3% of the formulation of a thickening agent or suspending agent.

[0157] In a preferred embodiment, the controlled-release formulation of the gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water before administration, and further comprises 1 to 15% of a suspending agent or thickener selected from a mixture of xanthan gum, carrageenan gum, and hydroxyethylcellulose, or a mixture of xanthan gum and carrageenan gum.

[0158] In its most preferred embodiment, the controlled-release formulation of the gamma-hydroxybutyrate comprises about 1% lambda-type carrageenan gum or Viscarin PH209™, about 1% medium-viscosity grade hydroxyethylcellulose or Natrasol 250M™, and about 0.7% xanthan gum or Xantural 75™. For a 4.5 g dose unit, these percentages are generally equivalent to about 50 mg of xanthan gum (Xantural 75™), about 75 mg of carrageenan gum (Viscarin PH209™), and about 75 mg of hydroxyethylcellulose (Natrasol 250M™).

[0159] Alternative combinations of thickeners or suspending agents for a 4.5g dose include approximately 50mg of xanthan gum (Xantural 75®) and approximately 100mg of carrageenan gum (Gelcarin PH812®), or approximately 50mg of xanthan gum (Xantural 75®), approximately 75mg of hydroxyethylcellulose (Natrasol 250M®), and approximately 75mg of carrageenan gum (Viscarin PH109®).

[0160] In a preferred embodiment, the release-controlled formulation of gamma-hydroxybutyrate further comprises a lubricant or lubricant in addition to the immediate-release particles and release-controlled particles of gamma-hydroxybutyrate. Preferred lubricants and lubricants include salts of stearic acid, particularly magnesium stearate, calcium stearate, or zinc stearate, esters of stearic acid, particularly glyceryl monostearate or glyceryl stearate palmitate, stearic acid, glyceryl behenate, sodium stearyl fumarate, talc, and colloidal silicon dioxide. Selected from the following group.

[0161] A preferred lubricant or lubricant is magnesium stearate.

[0162] The above-mentioned lubricant or lubricant may be used in this particulate formulation in an amount of 0.1 to 5%. A preferred amount is approximately 0.5%.

[0163] The release-controlled formulation of this gamma-hydroxybutyrate most preferably contains approximately 0.5% magnesium stearate.

[0164] A preferred gamma-hydroxybutyrate release-modulated formulation further comprises an acidifying agent. The acidifying agent helps ensure that the release profile of the formulation in 0.1N HCl remains substantially unchanged for at least 15 minutes after mixing with tap water, which is the approximate maximum time a patient may need between mixing the formulation with tap water and taking the medication.

[0165] In one particular lower embodiment, the formulation is intended to be dispersed in water before administration and is preferably a powder further comprising an acidifying agent and a suspending agent or thickener in the weight percentages described herein.

[0166] Preferred 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 preferred embodiments, the above acidifying agent is present in the formulation at a concentration of 1.2 to 15%, preferably 1.2 to 10%, and preferably 1.2 to 5%. Preferred acidifying agents are tartaric acid and malic acid, with malic acid being the most preferred.

[0167] When tartaric acid is used, it is preferably used in amounts of 1-10%, 2.5-7.5%, or about 5%. In the most preferred embodiment, the amount of malic acid in the controlled-release formulation of the gamma-hydroxybutyrate is 1.2-15%, preferably 1.2-10%, preferably 1.2-5%, most preferably 1.6%, or 3.2%.

[0168] In the most preferred embodiment, the amount of malic acid in the controlled-release formulation of gamma-hydroxybutyrate is approximately 1.6%.

[0169] In a preferred embodiment, the controlled-release formulation of gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water before administration. a) A suspending or thickening agent 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, iota-type, kappa-type, or lambda-type carrageenan gum, medium viscosity hydroxypropyl methylcellulose, and mixtures thereof, b) An acidifying agent 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, and mixtures thereof. It also includes.

[0170] In its most preferred embodiment, the controlled-release formulation of the gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water before administration, and comprises 1.2–15% of an acidifying agent selected from malic acid and tartaric acid, and xanthan gum, carrageenan gum, and hydroxybutyrate. The mixture further comprises a mixture of ethylcellulose, or 1-15% of a suspending agent or thickener selected from a mixture of xanthan gum and carrageenan gum.

[0171] The controlled-release formulation of gamma-hydroxybutyrate preferably comprises an immediate-release portion and a controlled-release portion of gamma-hydroxybutyrate, and in a particularly preferred embodiment, the formulation is a particulate formulation comprising a plurality of immediate-release gamma-hydroxybutyrate particles and a plurality of controlled-release gamma-hydroxybutyrate particles. The molar ratio of gamma-hydroxybutyrate in the immediate-release portion to the controlled-release portion is preferably 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, and 0.8:1 to 1.22:1, and preferably about 1:1. The molar percentage of gamma-hydroxybutyrate in the immediate-release portion relative to the total amount of gamma-hydroxybutyrate in the formulation is preferably 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 a preferred embodiment, the molar percentage of gamma-hydroxybutyrate in the immediate-release portion relative to the total amount of gamma-hydroxybutyrate in the formulation is about 50%. The molar percentage of gamma-hydroxybutyrate in the release-controlled portion relative to the total amount of gamma-hydroxybutyrate in the formulation is preferably in the range of 90% to 35%, 85 to 40%, 80 to 45%, 75 to 45%, 70 to 45%, 65 to 45%, 60 to 45%, 60 to 40%, or 55 to 45%, preferably 60% to 40%. In a preferred embodiment, the molar ratio of gamma-hydroxybutyrate in the release-controlled portion relative to the total amount of gamma-hydroxybutyrate in the formulation is approximately 50%. The weight percentage of IR fine particles relative to the total weight of IR fine particles and MR fine particles is preferably 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 fine particles to the total weight of IR fine particles and MR fine particles is preferably in the range of 5.9% to 63.2%, 9.1% to 58.1%, 12.4% to 53.1%, 19.9% ​​to 53.1%, 19.6% to 53.1%, 23.4% to 53.1%, 27.4% to 53.1%, 27.4% to 58.1%, and preferably 31.7% to 53.1%.

[0172] In a preferred embodiment, the completed formulation contains 50% of the oxybart sodium content of the formulation in immediate-release particles consisting of 80.75% (w / w) oxybart sodium, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 10.5% (w / w) microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, and 56.5% (w / w) oxybart sodium laminated thereon. The release-controlled particles, comprising a coating composition consisting of a mixture of sodium oxyvertyl and 3% (w / w) Povidone® K30, and finally covering it with 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), contain 50% of the oxyvertyl sodium content of the formulation.

[0173] In a preferred embodiment, the completed formulation contains 80.75% (w / w) Oxybart sodium, 4.25% (w / w) Povidone K30, and 15% of the Oxybart sodium content of the formulation in immediate-release particles consisting of microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 170 microns, 10.5% (w / w) of microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 170 microns, a mixture of 56.5% (w / w) Oxybart sodium and 3% (w / w) Povidone® K30 laminated thereon, and finally a coating of 18% (w / w) hydrogenated vegetable oil (Lub The release-controlled particles, comprising a coating composition consisting of ritab (trademark) or equivalent, 4% C-type methacrylic acid copolymer (Eudragit (trademark) L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit (trademark) S100 or equivalent), contain 50% of the oxybart sodium content of the formulation.

[0174] In a preferred embodiment, the completed formulation contains 80.75% (w / w) oxybart sodium, 4.25% (w / w) povidone K30, and 15% immediate-release particles consisting of microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 450 microns, with 50% of the oxybart sodium content of the formulation contained therein. The release-controlled particles, comprising a coating composition consisting of a mixture of lium and 3.2% (w / w) Povidone® K30, and finally covering it with 15% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 9.25% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), contain 50% of the oxybart sodium content of the formulation.

[0175] In a preferred embodiment, the completed formulation contains 80.75% (w / w) Oxybart sodium, 4.25% (w / w) Povidone® K30, and 15% of immediate-release particles consisting of microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 170 microns, with 50% of the Oxybart sodium content of the formulation contained therein. The release-controlled particles of the formulation contain 50% of the sodium oxyvert of the formulation, comprising a coating composition consisting of a mixture of sodium oxyvert and 3.2% (w / w) of Povidone (trademark) K30, and finally covering it with 15% (w / w) of hydrogenated vegetable oil (Lubritab (trademark) or equivalent), 0.75% of type C methacrylic acid copolymer (Eudragit (trademark) L100-55 or equivalent), and 9.25% of type B methacrylic acid copolymer (Eudragit (trademark) S100 or equivalent).

[0176] In a preferred embodiment, the completed formulation contains 80.75% (w / w) potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% immediate-release particles consisting of microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 50% of the gamma-hydroxybutyrate content of the formulation, and 10.5% (w / w) microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 56.5% (w / w) of o The release-controlled particles, comprising a mixture of xibart sodium and 3% (w / w) Povidone® K30, and a coating composition consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), contain 50% of the gamma-hydroxybutyrate content of the formulation.

[0177] In a preferred embodiment, the completed formulation contains 80.75% (w / w) potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% immediate-release particles consisting of microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 170 microns, comprising 50% of the gamma-hydroxybutyrate content of the formulation. The formulation also contains 10.5% (w / w) microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 170 microns, laminated thereon a mixture of 56.5% (w / w) sodium oxybart and 3% (w / w) Povidone® K30, and finally a coating thereon, consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent) and 4% C-type methacrylic acid copolymer. The release-controlled particles, comprising a coating composition consisting of (Eudragit® L100-55 or equivalent) and 8% type B methacrylic acid copolymer (Eudragit® S100 or equivalent), contain 50% of the gamma-hydroxybutyrate content of the formulation.

[0178] In a preferred embodiment, the completed formulation contains 16.7% of the gamma-hydroxybutyrate content of the formulation in immediate-release particles consisting of 80.75% (w / w) potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 microns to approximately 450 microns; and 16.7% of the gamma-hydroxybutyrate content of the formulation in immediate-release particles consisting of 80.75% (w / w) magnesium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 microns to approximately 450 microns; and 80.75% (w / w) calcium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 The release-controlled particles consist of immediate-release particles made of microcrystalline cellulose spheres ranging from a micron to approximately 450 microns in size, containing 16.7% of the gamma-hydroxybutyrate content of the formulation. These particles contain 10.5% (w / w) of microcrystalline cellulose spheres with a volume average diameter of approximately 95 to approximately 450 microns, a coating composition laminated thereon consisting of a mixture of 56.5% (w / w) Oxybart sodium and 3% (w / w) Povidone® K30, and finally a coating composition covering the surface, consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), containing 50% of the gamma-hydroxybutyrate content of the formulation.

[0179] In a preferred embodiment, the completed formulation contains 80.75% (w / w) potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, with 16.7% of the gamma-hydroxybutyrate content of the formulation in the immediate-release particles, and 80.75% (w / w) magnesium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, with 16.7% of the gamma-hydroxybutyrate content of the formulation in the immediate-release particles, and 80.75% (w / w) calcium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 The release-controlled particles consist of immediate-release particles comprising microcrystalline cellulose spheres ranging from a micron to approximately 170 microns in size, containing 16.7% of the gamma-hydroxybutyrate content of the formulation. These particles contain 10.5% (w / w) of microcrystalline cellulose spheres with a volume average diameter of approximately 95 to approximately 170 microns, a coating composition laminated thereon consisting of a mixture of 56.5% (w / w) Oxybart sodium and 3% (w / w) Povidone® K30, and finally covering the surface, a coating composition consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), containing 50% of the gamma-hydroxybutyrate content of the formulation.

[0180] In a preferred embodiment, the completed formulation contains 80.75% (w / w) potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% immediate-release particles consisting of microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, comprising 50% of the gamma-hydroxybutyrate content of the formulation, 10.5% (w / w) microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, a mixture of 56.5% (w / w) calcium salt of gamma-hydroxybutyrate and 3% (w / w) Povidone® K30 layered thereon, and finally covering thereon, 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methamphetamine. The release-controlled particles, comprising a coating composition consisting of a lylic acid copolymer (Eudragit® L100-55 or equivalent) and 8% type B methacrylic acid copolymer (Eudragit® S100 or equivalent), contain 50% of the gamma-hydroxybutyrate content of the formulation.

[0181] In a preferred embodiment, the completed formulation contains 80.75% (w / w) potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% immediate-release particles consisting of microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 170 microns, with 50% of the gamma-hydroxybutyrate content of the formulation contained therein. The release-controlled particles, comprising a mixture of hydroxybutyrate calcium salt and 3% (w / w) Povidone® K30, and a coating composition consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), contain 50% of the gamma-hydroxybutyrate content of the formulation.

[0182] Other characteristics of the immediate release portion The immediate-release portion of this formulation can take any form that can achieve immediate release of gamma-hydroxybutyrate upon ingestion. For example, if the formulation is a particulate formulation, it may contain rapidly dissolving gamma-hydroxybutyrate granules, particles, or microparticles, consisting of a core covered with a layer filled with gamma-hydroxybutyrate containing undenatured "raw" gamma-hydroxybutyrate and a binder such as povidone.

[0183] The above gamma-hydroxybutyrate IR granules or particles are • Aggregation of gamma-hydroxybutyrate, preferably sprayed in a molten state, such as Glatt ProCell® technology. • Extrusion and sphere formation of gamma-hydroxybutyrate with one or more physiologically acceptable excipients of optional choice. • Wet granulation of gamma-hydroxybutyrate with one or more physiologically acceptable excipients of optional choice. • Compression molding of gamma-hydroxybutyrate with one or more physiologically acceptable excipients of optional choice. • Granulating and sphereizing gamma-hydroxybutyrate with one or more physiologically acceptable excipients of choice, the sphereization being carried out, for example, in a fluidized bed apparatus equipped with a rotor, particularly using Glatt CPS® technology. For example, in a fluidized bed apparatus equipped with a zigzag filter, in particular using Glatt MicroPx® technology, gamma-hydroxybutyrate can be sprayed together with one or more physiologically acceptable excipients of any choice, or For example, in a fluidized bed apparatus optionally equipped with a partition tube or Wurster tube, the gamma-hydroxybutyrate is sprayed onto the core in a dispersion or solution in an aqueous solvent or organic solvent, along with optionally one or more physiologically acceptable excipients. They can be manufactured using any manufacturing method suitable for producing the required particles, including [the specified element].

[0184] The immediate-release portion of this formulation is preferably in the form of microparticles containing immediate-release gamma-hydroxybutyrate and an optional pharmaceutically acceptable excipient. In a preferred embodiment, The volume-average diameter D(4,3) of the immediate-release particles of the above gamma-hydroxybutyrate is 10 to 1000 microns, preferably 95 to 600 microns, and more preferably 150 to 400 microns. The volume-average diameter of the above immediate-release particles is most preferably about 270 microns.

[0185] A preferred immediate-release particle of gamma-hydroxybutyrate according to the present invention comprises a core and a layer containing the gamma-hydroxybutyrate deposited on the core. The core is · Crystals or spheres of lactose, sucrose (such as Tereos' Compressuc® PS), microcrystalline cellulose (such as FMC Biopolymer's Avicel®, Pharmatrans' Cellet®, or Asahi Kasei's Celphere®), sodium chloride, calcium carbonate (such as Omya's Omyapure® 35), sodium bicarbonate, dicalcium phosphate (such as Budenheim's Dicafos® AC92-12), or tricalcium phosphate (such as Budenheim's Tricafos® SC93-15), For example, complex spheres or granules such as sugar spheres containing sucrose and starch (e.g., NP Pharm's Suglets®), spheres of calcium carbonate and starch (e.g., Particle Dynamics' Destab® 90 S Ultra 250), or spheres of calcium carbonate and maltodextrin (e.g., Huber's Hubercal® CCG4100). It may be any particle selected from the group consisting of [the specified elements].

[0186] The above core may also contain particles of other pharmaceutically acceptable excipients, such as hydroxypropylcellulose particles (e.g., Klucel® from Aqualon Hercules), guar gum particles (e.g., Grinsted® Guar from Danisco), or xanthan gum particles (e.g., Xantural® 180 from CP Kelco).

[0187] According to a particular embodiment of the present invention, the core is a sugar sphere or a microcrystalline cellulose sphere such as Cellets® 90, Cellets® 100, or Cellets® 127, or Celphere® CP203, Celphere® CP305, or Celphere® SCP 100, which are commercially available from Pharmatrans. The core is preferably a microcrystalline cellulose sphere. The core is most preferably Pharmatrans' Cellets® 127.

[0188] The average volume diameter of the above core is preferably about 95 to about 450 microns, preferably about 95 to about 170 microns, and most preferably about 140 microns.

[0189] The layer deposited on the core contains immediate-release gamma-hydroxybutyrate. This layer also contains a binder, the binder is Low molecular weight hydroxypropyl cellulose (such as Aqualon-Hercules' Klucel® EF), low molecular weight hydroxypropyl methylcellulose (i.e., hypromellose) (such as Dow's Methocel® E3 or E5), or low molecular weight methylcellulose (such as Dow's Methocel® A15), • Low molecular weight polyvinylpyrrolidone (i.e., povidone) (e.g., Plasdone® K29 / 32 from ISP or Kollidon® 30 from BASF), copolymer of vinylpyrrolidone and vinyl acetate (i.e., copovidone) (e.g., Plasdone® S630 from ISP or Kollidon® VA64 from BASF), Dextrose, pregelatinized starch, maltodextrin, and mixtures thereof You can choose from the group consisting of these.

[0190] Low molecular weight hydroxypropyl cellulose corresponds to a grade of hydroxypropyl cellulose with a molecular weight of less than 800,000 g / mol, preferably 400,000 g / mol or less, and particularly 100,000 g / mol or less. Low molecular weight hydroxypropyl methylcellulose (i.e., hypromellose) corresponds to a grade of hydroxypropyl methylcellulose with a solution viscosity of 1,000 mPa·s or less, preferably 100 mPa·s or less, and particularly 15 mPa·s or less, in a 2% aqueous solution at 20°C. Low molecular weight polyvinylpyrrolidone (i.e., povidone) corresponds to a grade of polyvinylpyrrolidone with a molecular weight of 1,000,000 g / mol or less, preferably 800,000 g / mol or less, and particularly 100,000 g / mol or less.

[0191] The above binder is selected from low molecular weight polyvinylpyrrolidone, i.e., povidone (e.g., Plasdone® K29 / 32 from ISP), low molecular weight hydroxypropyl cellulose (e.g., Klucel® EF from Aqualon-Hercules), low molecular weight hydroxypropyl methylcellulose, i.e., hypromellose (e.g., Methocel® E3 or E5 from Dow), and mixtures thereof.

[0192] Preferred binders are povidone K30 or K29 / 32, particularly Plasdone® K29 / 32 of ISP. The binder may be present in amounts 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%, based on the total weight of the immediate-release coating.

[0193] The preferred amount of binder is 5% of the total mass of gamma-hydroxybutyrate and the binder.

[0194] The layer deposited on the core may constitute at least 10% by weight of the total weight of the immediate-release particles of gamma-hydroxybutyrate, and moreover, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or more than 90% by weight. Most preferably, the layer deposited on the core constitutes about 85% by weight of the immediate-release particles of gamma-hydroxybutyrate.

[0195] According to a preferred embodiment, the immediate-release particles comprise 80.75% (w / w) gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres.

[0196] According to a preferred embodiment, the immediate-release particles contain 80.75% (w / w) gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 450 microns.

[0197] According to a preferred embodiment, the immediate-release particles contain 80.75% (w / w) gamma-hydroxybutyrate, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres having a volume-average diameter of approximately 95 to 170 microns.

[0198] According to a preferred embodiment, the immediate-release particles comprise 80.75% (w / w) oxybart sodium, 4.25% (w / w) povidone K30, and 15% microcrystalline cellulose spheres.

[0199] According to another preferred embodiment, the immediate-release particles comprise 80.75% (w / w) of potassium salt of gamma-hydroxybutyrate, 4.25% (w / w) of povidone K30, and 15% of microcrystalline cellulose spheres.

[0200] According to another preferred embodiment, the immediate-release particles comprise 80.75% (w / w) of a calcium salt of gamma-hydroxybutyrate, 4.25% (w / w) of povidone K30, and 15% of microcrystalline cellulose spheres.

[0201] According to another preferred embodiment, the immediate-release particles comprise 80.75% (w / w) of magnesium salt of gamma-hydroxybutyrate, 4.25% (w / w) of povidone K30, and 15% of microcrystalline cellulose spheres.

[0202] According to another embodiment, the immediate-release particles are produced 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 the microcrystalline cellulose spheres.

[0203] Other characteristics of the emission control section The release-modulating portion may be any formulation that provides a desired in vitro solubility profile for gamma-hydroxybutyrate. The release-modulating portion preferably consists of release-modulating particles obtained by coating immediately-release particles of gamma-hydroxybutyrate with a coating (or film) that inhibits the immediate release of the gamma-hydroxybutyrate. In one lower embodiment, the release-modulating portion comprises particles including (a) an inert core, (b) a coating, and (c) a layer containing the gamma-hydroxybutyrate sandwiched between the core and the coating.

[0204] In a preferred embodiment, the release control portion comprises a time-dependent release mechanism and a pH-dependent release mechanism.

[0205] In a preferred embodiment, the coating film comprises at least one polymer having free carboxyl groups and at least one hydrophobic compound, preferably characterized by having a melting point of 40°C or higher.

[0206] The polymer having the free carboxyl group described above is preferably selected from (meth)acrylic acid / (meth)acrylate alkyl copolymers, copolymers of methacrylic acid and methyl methacrylate, copolymers of methacrylic acid and ethyl acrylate, or type A, type B, or type C methacrylic acid copolymers, cellulose derivatives having free carboxyl groups, preferably cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginates, and mixtures thereof.

[0207] In a preferred embodiment, the methacrylic acid copolymer is selected from the group consisting of poly(methacrylic acid-methyl methacrylate (1:1)) or Eudragit® L100 or equivalent, poly(methacrylic acid-ethyl acrylate (1:1)) or Eudragit® L100-55 or equivalent, and poly(methacrylic acid-methyl methacrylate (1:2)) or Eudragit® S100 or equivalent.

[0208] In a preferred embodiment, the polymer having the free carboxyl group is selected from the group consisting of a 1:1 copolymer of methacrylic acid and ethyl acrylate, a 1:2 copolymer of methacrylic acid and methyl methacrylate, and mixtures thereof.

[0209] In another lower embodiment, the coating is free, which is substantially ionized at pH 7.5. It contains polymers that have carboxyl groups.

[0210] The hydrophobic compounds with a melting point of 40°C or higher can be selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, beeswax, white wax, microcrystalline waxes, lanolin, anhydrous milk fat, hard fat suppository bases, lauroyl macrogol glyceride, polyglyceryl diisostearate, fatty acid diesters or triesters of glycerin, and mixtures thereof.

[0211] The hydrophobic compounds with a melting point of 40°C or higher are more preferably selected from the following group of products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimiristin, beeswax, hard fats or fats useful as suppository bases, anhydrous milk fat, lanolin, glyceryl stearate palmitate, glyceryl stearate, lauroyl macrogol glyceride, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, omega-3 fatty acids, and mixtures thereof. Particularly preferred subgroups of products include hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimiristin, beeswax, hydrogenated poly-1-decene, carnauba wax, and mixtures thereof.

[0212] While not limiting, in practice, hydrophobic compounds with a melting point of 40°C or higher include the following products sold under the trademarks: Dynasan(trademark), Cutina(trademark), Hydrobase(trademark), Dub(trademark), Castorwax(trademark), Croduret(trademark), Compritol(trademark), Sterotex(trademark), Luburitab(trademark), Apifil(trademark), Akofine(trademark), Softisan(trademark), Hydrocote(trademark), Livopol(trademark), Super Hartolan(TM), MGLA(TM), Corona(TM), Protalan(TM), Akosoft(TM), Akosol(TM), Cremao(TM), Massupol(TM), Novata(TM), Suppocire(TM), We cobee(TM), Witepsol(TM), Lanolin(TM), Incromega(TM), Estaram(TM), Suppoweiss(TM), Gelucire(TM), Precirol(TM), Emulcire(TM), Plurol Preferably selected from diisostearique(trademark), Geleol(trademark), Hydrine(trademark), Monthyle(trademark), Kahlwax(trademark), and mixtures thereof, and more preferably from the group of products sold under the following trademarks: Dynasan(trademark) P60, Dynasan(trademark) 114, Dynasan(trademark) 116, Dynasan(trademark) 118, Cutina(trademark) HR, Hydrobase(trademark) 66-68, Dub(trademark) HPH, Compritol(trademark) 888, Sterotex(trademark) NF, Sterotex(trademark) K, Lubritab(trademark), and mixtures thereof.

[0213] A particularly suitable coating consists of a mixture of hydrogenated vegetable oil and methacrylic acid copolymer. The precise structure and amount of each component, as well as the amount of coating applied to the particles, control the release rate and release trigger. Eudragit® methacrylic acid copolymers, i.e., methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer, have pH-dependent solubility; that is, generally, the pH that induces the release of the active ingredient from the microparticles is set by the selection and mixing of appropriate Eudragit® polymers. In the case of gamma-hydroxybutyrate release-controlled microparticles, the theoretical pH that induces release is preferably 5.5 to 6.97 or 6.9, more preferably 6.5 to 6.9. "pH trigger" means the lowest pH above which the polymer dissolves.

[0214] In certain embodiments, the coating comprises a hydrophobic compound having a melting point of 40°C or higher and a polymer having free carboxyl groups, which are present in a weight ratio of 0.4 or 0.5-4, preferably 0.6 or 0.67-2.5, most preferably 0.6 or 0.67-2.33, and most preferably about 1.5.

[0215] Particularly preferred coatings consist of a mixture of a hardened vegetable oil and a methacrylic acid copolymer having a theoretical pH of 6.5 to a maximum of 6.97 that induces the above release, in a weight ratio of 0.4 or 0.5-4, preferably 0.6 or 0.67-2.5, most preferably 0.6 or 0.67-2.33, and most preferably about 1.5.

[0216] The volume-average diameter of the gamma-hydroxybutyrate release-regulating particles is preferably 100 to 1200 microns, 100 to 500 microns, 200 to 800 microns, and preferably about 320 microns.

[0217] The above coating may preferably constitute 10-50% by weight, 15-45% by weight, 20-40% by weight, or 25-35% by weight of the total weight of the coated release-modifying particles. Preferably, the above coating constitutes 25-30% by weight of the total weight of the gamma-hydroxybutyrate release-modifying particles.

[0218] In a preferred embodiment, the coating layer on the gamma-hydroxybutyrate release-regulating particles is obtained by spraying a solution, suspension, or dispersion containing the above-described coating composition onto the immediate-release gamma-hydroxybutyrate particles, particularly the immediate-release gamma-hydroxybutyrate particles, in a fluidized bed apparatus. The coating is formed by spraying a hot isopropyl alcohol solution of the coating excipient in an upward or downward spray direction in a fluidized bed equipped with a wurster tube or partition tube.

[0219] According to a preferred embodiment, the gamma-hydroxybutyrate release-controlled particles consist of 10.5% (w / w) microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 450 microns, a mixture of 56.5% (w / w) gamma-hydroxybutyrate and 3% (w / w) Povidone® K30 laminated thereon, and finally a coating composition consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), all percentages expressed relative to the total weight of the final gamma-hydroxybutyrate release-controlled particles.

[0220] According to a preferred embodiment, the gamma-hydroxybutyrate release-controlled particles consist of 10.5% (w / w) microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, a mixture of 56.5% (w / w) gamma-hydroxybutyrate and 3% (w / w) Povidone® K30 laminated thereon, and finally a coating composition consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), all percentages expressed relative to the total weight of the final gamma-hydroxybutyrate release-controlled particles.

[0221] According to a preferred embodiment, the gamma-hydroxybutyrate release-regulating particles consist of 10.5% (w / w) microcrystalline cellulose spheres with a volume-average diameter of approximately 95 to 450 microns, and stacked thereon, 56.5% (w / w) oxybart sodium and 3% (w / The product consists of a mixture of w) Povidone(trademark) K30 and a coating composition that covers it last, comprising 18% (w / w) hydrogenated vegetable oil (Lubritab(trademark) or equivalent), 4% C-type methacrylic acid copolymer (Eudragit(trademark) L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit(trademark) S100 or equivalent), all percentages expressed on the basis of the total weight of the final oxybart sodium release-regulating particles.

[0222] According to a preferred embodiment, the gamma-hydroxybutyrate release-controlled particles consist of 10.5% (w / w) microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, a mixture of 56.5% (w / w) Oxybart sodium and 3% (w / w) Povidone® K30 laminated thereon, and finally a coating composition consisting of 18% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 4% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 8% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent), all percentages expressed relative to the total weight of the final Oxybart sodium release-controlled particles.

[0223] According to another preferred embodiment, the gamma-hydroxybutyrate release-regulating particles consist of 11.3% (w / w) microcrystalline cellulose spheres with a volume-average diameter of about 95 to 450 microns, a mixture of 60.5% (w / w) gamma-hydroxybutyrate and 3.2% (w / w) Povidone® K30 laminated thereon, and finally a coating composition consisting of 15% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 9.25% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent) covering the above.

[0224] According to another preferred embodiment, the gamma-hydroxybutyrate release-regulating particles consist of 11.3% (w / w) microcrystalline cellulose spheres with a volume-average diameter of about 95 to 170 microns, a mixture of 60.5% (w / w) gamma-hydroxybutyrate and 3.2% (w / w) Povidone® K30 laminated thereon, and finally a coating composition consisting of 15% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 9.25% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent) covering the above.

[0225] According to another preferred embodiment, the gamma-hydroxybutyrate release-regulating particles consist of 11.3% (w / w) microcrystalline cellulose spheres with a volume-average diameter of about 95 to 450 microns, a mixture of 60.5% (w / w) oxybart sodium and 3.2% (w / w) Povidone® K30 laminated thereon, and finally a coating composition consisting of 15% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), and 9.25% B-type methacrylic acid copolymer (Eudragit® S100 or equivalent) covering the above.

[0226] According to another preferred embodiment, the gamma-hydroxybutyrate release-regulating particles consist of 11.3% (w / w) microcrystalline cellulose spheres with a volume-average diameter of about 95 to 170 microns, laminated thereon a mixture of 60.5% (w / w) oxybart sodium and 3.2% (w / w) Povidone® K30, and finally covering thereon 15% (w / w) hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit® L100-55 or equivalent), The coating consists of a film composition comprising 9.25% of type B methacrylic acid copolymer (Eudragit® S100 or equivalent).

[0227] packaging The controlled-release formulation of gamma-hydroxybutyrate is preferably supplied in pouches or stick packs containing particulate formulations. These pouches preferably contain an amount of gamma-hydroxybutyrate equivalent to 0.5g, 1.0g, 1.5g, 3.0g, 4.5g, 6.0g, 7.5g, 9.0g, 10.5g, and / or 12g of Oxybart sodium, and are available in several different doses. Depending on the required dose, one or more of these pouches may be opened and their contents mixed with tap water to prepare an overnight dose of gamma-hydroxybutyrate.

[0228] Treatment method The present invention provides a method for treating a gamma-hydroxybutyrate-treatable disorder in a human subject requiring such treatment, further comprising orally administering a single bedtime daily dose of gamma-hydroxybutyrate in an amount equivalent to 3.0 to 12.0 g of Oxibert sodium, using the formulation of the present invention, to the subject. The present invention further provides a method for treating type 1 and / or type 2 narcolepsy by orally administering, at bedtime, a therapeutically effective dose of the gamma-hydroxybutyrate formulation of the present invention, characterized by novel pharmacokinetic or solubility properties of gamma-hydroxybutyrate. The controlled-release formulation of the present invention is effective for the treatment of type 1 or type 2 narcolepsy, defined as reducing excessive daytime sleepiness or reducing the frequency of cataplexy attacks. The therapeutically effective dose preferably contains 3.0 to 12.0 g of Oxibert sodium, more preferably ~9.0 g of Oxibert sodium, most preferably an amount equivalent to 4.5, 6.0, 7.5, or 9.0 g of Oxibert sodium. The effectiveness of the above treatment is determined by the following diagnostic criteria: • Preferably increases mean sleep latency, as measured by the Maintenance of Wakefulness Test (MWT). • Improve the clinically-based overall impression (CGI) assessment of drowsiness. Preferably, reduce the number of cataplexy attacks (NCA) as measured from the cataplexy frequency item in a Sleep and Symptoms Daily Diary. • Decreases nocturnal sleep disturbances (DNS), nocturnal event disturbances, or adverse respiratory events, preferably as determined by measuring sleep segmentation using polysomnography (PSG). • Preferably, patient-reported reduction of excessive daytime sleepiness ("EDS"), as measured through the Epworth Sleepiness Scale (ESS). • Reduces daytime sleepiness, as measured by an EEG-based alertness maintenance test. • Reduces the transition from N2 to N3 and from REM sleep to wakefulness and N1 sleep (measured by C Iber, S Ancoli- Israel, A Chesson, SF Quan. The AASM Manual for the Scoring of Sleep and Associated Events. Westchester, IL: American Academy of Sleep Medicine; 2007) in PSG. Preferably, reduce the number of arousals (i.e., wakes) obtained from polysomnography (PSG) as defined by the American Academy of Sleep Medicine. Preferably, the method for improving sleep quality is obtained from one or more of the following: (i) a sleep and symptom diary, (ii) a visual analog scale (VAS) for sleep quality and sleep diary, and (iii) a VAS for sleep fatigue recovery. Preferably, one or any combination of reducing hypnagogic hallucinations (HH) or sleep paralysis (SP) symptoms in NT1 narcolepsy patients, as measured by sleep and symptom diaries. It can be measured by alignment.

[0229] Another object of the present invention is a controlled-release formulation of the present invention for the treatment of disorders treatable with oxybart sodium in human subjects requiring such treatment, the formulation being administered orally to such human subjects in a single bedtime dose equivalent to 3.0 to 12.0 g of oxybart sodium.

[0230] Another object of the present invention is a controlled-release formulation of the present invention for the treatment of cataplexy in narcolepsy or excessive daytime sleepiness ("EDS") in narcolepsy, which is administered orally to the above-mentioned human in a single bedtime dose equivalent to 3.0 to 12.0 g of oxybart sodium.

[0231] In particular, the administration of the above-mentioned controlled-release formulation of gamma-hydroxybutyrate is by using an immediate-release solution, with half of the above dose administered at time t0, and t 4h Compared to a dosing regimen consisting of administering another half of the above dose at that point, a) Reduce the number of cataplexy attacks. b) Reduces daytime sleepiness as measured by the Epworth Sleepiness Scale, c) Reduce daytime sleepiness as measured by an alertness maintenance test based on EEG measurement of wakefulness. d) To improve the clinically general impression (CGI) assessment of drowsiness in the above subjects, e) Reduce nocturnal disturbances or adverse respiratory events as measured by polysomnography (PSG), f) Reduce hypnagogic hallucinations, g) Reduce sleep paralysis, h) Increases sleep latency during MWT. i) Reduce PSG transitions from N2 to N3 and from REM sleep to wakefulness and N1 sleep. j) Reduce the number of awakenings in the target of NT1 and / or NT2 obtained from PSG. k) Measured using a visual analog scale (VAS), improve sleep quality and sleep fatigue recovery in NT1 and / or NT2 subjects. l) Reduce the number of awakenings, or m) Any combination of those It has become clear.

[0232] In a preferred embodiment, the therapeutic agent of the present invention is superior to an immediate-release solution of oxyvert sodium administered twice overnight, with the second dose administered 4 hours after the first dose, as measured by any one or a combination thereof of the above criteria.

[0233] The present invention is a method for treating type 1 or type 2 narcolepsy, wherein half of the above dose is administered at time t0, and t 4h The present invention further provides the above treatment method, which has been shown to result in less confusion, less depressive symptoms, less incontinence, less nausea, or less sleepwalking when administered at a single bedtime dose of the therapeutically effective dose of this preparation compared to a dosing regimen consisting of administering another half-dose of an immediate-release solution of oxybart sodium at the above dose.

[0234] Further Embodiments In a further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, (a) USP38 <711> In dissolution apparatus 2 conforming to the standard, 900 mL of 0.05 M When tested in potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 1 hour, and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. The above-mentioned formulation is provided.

[0235] In a second further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 1 hour. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours, and (c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0236] In a third further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 1 hour. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. (c) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 60% of the above formulation's gamma-hydroxybutyrate is released after 10 hours, and (d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0237] In a fourth further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, (a) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, at least 80% of the gamma-hydroxybutyrate of the above formulation is released, and (b) USP38 <711> In dissolution apparatus 2 conforming to the standard, 900 mL of 0.1N salt When tested in acid at a temperature of 37°C and a paddle speed of 75 rpm, 40% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. The above-mentioned formulation is provided.

[0238] In a fifth further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 3 hours. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 40% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours, and (c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0239] In a sixth further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 3 hours. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 40% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. (c) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 60% of the above formulation's gamma-hydroxybutyrate is released after 10 hours, and (d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0240] In a seventh further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate, preferably comprising an immediate-release portion and a release-controlled portion, (a) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 1 hour, at least 80% of the gamma-hydroxybutyrate of the above formulation is released, and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 40% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. The above-mentioned formulation is provided.

[0241] In an eighth further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 1 hour. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 40% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours, and (c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided.

[0242] In a ninth further embodiment, the present invention relates to a release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, (a) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at least 80% of the gamma-hydroxybutyrate of the above formulation is released after 1 hour. (b) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 40% to 65% of the gamma-hydroxybutyrate of the above formulation is released at 1 hour and 3 hours. (c) The above formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 60% of the above formulation's gamma-hydroxybutyrate is released after 10 hours, and (d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The above-mentioned formulation is provided. [Examples]

[0243] Example 1: Pharmaceutical Formulation Tables 1a to 1d show the qualitative and quantitative compositions of oxybart sodium IR microparticles, MR microparticles, and mixtures of IR and MR microparticles. Figure 1 shows the physical structures of the microparticles that represent the qualitative and quantitative compositions of the above IR and MR microparticles.

[0244] In short, immediate-release (IR) nanoparticles of sodium oxyvertex were prepared as follows: 1615.0 g of sodium oxyvertex and 85.0 g of polyvinylpyrrolidone (Plasdone® K29 / 32 of povidone K30-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127) in a fluidized bed spray coating apparatus. IR nanoparticles with a volume-average diameter of approximately 270 microns were obtained.

[0245] Oxybart sodium release controlled (MR) microparticles were prepared as follows: 22.8 g of C-type methacrylic acid copolymer (Eudragit® L100-55), 45.8 g of type B methacrylic acid copolymer (Eudragit® S100) and 102.9 g of hydrogenated cottonseed oil (Lubritab®) were dissolved in 1542.9 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of the above-mentioned oxybart sodium IR fine particles in a fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11 g per minute, and a spray pressure of 1.3 bar. The MR fine particles were dried for 2 hours with the inlet temperature set to 56°C. MR fine particles with a volume average diameter of approximately 320 microns were obtained.

[0246] A finished composition containing a 50:50 mixture of MR and IR microparticles (calculated based on the oxyvert sodium content of the microparticles) was prepared as follows: 353.36 g of the above IR microparticles, 504.80 g of the above MR microparticles, 14.27 g of malic acid (D / L malic acid), 6.34 g of xanthan gum (Kelco's Xantural® 75), 9.51 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 9.51 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 4.51 g of magnesium stearate were mixed. 7.11 g of individual samples (corresponding to a 4.5 g dose of oxyvert sodium, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed. [Table 1a] [Table 1b] [Table 1c] [Table 1d-1] [Table 1d-2]

[0247] Example 1bis: Alternative formulation to the above A substitute formulation for the formulation described in Example 1 is described in Example 1bis.

[0248] Oxybart sodium IR microparticles were prepared by coating the immediate-release (IR) microparticles described in Example 1 with a topcoat layer. The microparticles were prepared as follows: 170.0 g of hydroxypropyl cellulose (Hercules' Klucel® EF Pharm) was solubilized in 4080.0 g of acetone. The entire volume of this solution was sprayed onto 1530.0 g of the IR microparticles from Example 1 in a fluidized bed spray coating apparatus. IR microparticles with a volume-average diameter of approximately 298 microns were obtained (see Table 1bis-a).

[0249] Oxybart sodium release-controlled (MR) microparticles were prepared as described in Example 1. (See Table 1b.)

[0250] A finished composition containing a 50:50 mixture of MR and IR microparticles (calculated based on the oxybart sodium content of the microparticles) 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 (Kelco's Xantural® 75), 4.96 g of colloidal silicon dioxide (Degussa's Aerosil® 200), and 9.92 g of magnesium stearate were mixed. 7.45 g of individual samples (equivalent to a 4.5 g dose of oxybart sodium, with half of the dose as the immediate-release fraction and the other half as the release-controlling fraction) were weighed (see Tables 1bis-b and 1bis-c). [Table 1bis-a] [Table 1bis-b] [Table 1bis-c]

[0251] Compared to the completed composition described in Example 1, this alternative composition has the following characteristics: it contains the same MR microparticles, the same IR microparticles but with a topcoat, an increased amount of malic acid, only one type of suspending agent (xanthan gum), and the presence of a lubricant.

[0252] The finished compositions of Example 1 and Example 1bis exhibit substantially identical in vitro solubility profiles (see Figures 7 and 8).

[0253] Example 2: IR, MR, and in vitro release profiles of the formulations of Example 1 and Example 1bis and the finished composition. Dissolution test of IR microparticles Using USP apparatus 2, the dissolution profile of 2786 mg of IR microparticles from Example 1, equivalent to 2250 mg of oxybart sodium per tank, was measured in 0.1 N HCl dissolution medium. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 100 rpm. The release profiles of the above IR microparticles are shown in Figure 2 and Table 2a. All of the oxybart sodium was released after 1 hour. [Table 2a]

[0254] Example 1: Dissolution test of IR microparticles of bis Using USP apparatus 2, 2250 mg of HCl per tank was dissolved in 0.1 N HCl dissolution medium. The dissolution profile of IR microparticles of Example 1bis, equivalent to 3096 mg of Sivert sodium, was measured. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 100 rpm. The release profiles of the above IR microparticles are shown in Figure 2 and Table 2b. All of the Sivert sodium was released after 1 hour. [Table 2b]

[0255] Dissolution test of MR microparticles in Example 1 - Protocol (2 hours in 0.1N HCl / pH 6.8 phosphate buffer) 49.1 g of MR microparticles from Example 1 were mixed with 0.5 g of magnesium stearate (Peter Graven) and 0.25 g of colloidal silicon dioxide (Evonik's Aerosil® 200). Using USP apparatus 2, the dissolution profile of 4040 mg of the above mixture per tank, equivalent to 2250 mg of oxybart sodium, was measured. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm.

[0256] After 2 hours in 750 mL of 0.1 N HCl medium, 6.5 g of potassium dihydrogen phosphate was added to the dissolution vessel. Then, the pH and volume were adjusted to 6.8 and 950 mL, respectively, by adding NaOH and water as needed. The concentration of potassium phosphate in the dissolution medium after pH and volume adjustment was equal to 0.05 M.

[0257] The release profiles of the above MR particles are shown in Figure 3 and Table 2c. The above oxybart sodium was not released for 2 hours in the 0.1N HCl dissolution medium. After switching to a pH 6.8 dissolution medium, all of the oxybart sodium was released within 30 minutes. [Table 2c]

[0258] Figure 4 overlays the dissolution profile of the MR microparticles of Example 1 with the dissolution profile of the MR microparticles reported in Figure 3 of Supernus's USP8,193,211. Figure 4 shows that these dissolution profiles are different, and that the MR microparticles according to the present invention release more than 80% of the oxybart sodium of the particles at 3 hours, while the MR microparticles described in Figure 3 of Supernus's USP8,193,211 do not release such sodium. This indicates that there is no release, and that it exhibits a significantly slower release profile.

[0259] Dissolution test of the completed composition in deionized water according to Example 1 Using USP apparatus 2, the dissolution profile of the completed composition according to Example 1, equivalent to 4.5 g of oxybart sodium, was measured in 900 mL of deionized water. The dissolution medium was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was fixed at 50 rpm. The release profile is shown in Figure 5 and Table 2d. The IR fraction of oxybart sodium was solubilized in 15 minutes. The release of oxybart sodium from the release control fraction began approximately after 4 hours, and 90% of the total dose was released after 6 hours. [Table 2d]

[0260] Figure 6 shows the release profile of the completed formulation in Example 1 superimposed on the release profile reported in Figure 2 of USP2012 / 0076865. Figure 6 shows that these dissolution profiles are different. The formulation described in Figure 2 of USP2012 / 0076865 does not show a delay period after dissolution of the immediate-release portion.

[0261] Release testing of MR microparticles from different batches and the finished dosage form. Table 2e below shows the in vitro release profiles obtained in 900 mL of 0.1 N HCl dissolution medium for different batches of release-controlled (MR) microparticles prepared according to Example 1. Using USP apparatus 2, the dissolution profile of 4040 mg of microparticles, equivalent to 2250 mg of oxybart sodium, was measured per tank. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 100 rpm. [Table 2e]

[0262] Table 2f shows the in vitro release profiles obtained in 0.1N HCl for three batches of the completed composition containing IR microparticles (50% (w / w) Oxybart sodium dose) and MR microparticles (50% (w / w) Oxybart sodium dose), prepared as described in Example 1. The doses of Oxybart sodium per tank were 4.5 g, 6 g, and 7.5 g, respectively, and dissolution was measured in 900 mL of 0.1N HCl dissolution medium using USP apparatus 2. The dissolution medium was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was fixed at 100 rpm. Single dose units were poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 2f]

[0263] Figure 7 and Table 2g show the dissolution profiles of four batches of the completed composition, two prepared according to Example 1 and two prepared according to Example 1bis, measured using USP apparatus 2 in 900 mL of 0.1N HCl dissolution medium. The dissolution medium was maintained at 37.0 ± 0.5°C, and the rotation paddle speed was fixed at 100 rpm. Figure 7 and Table 2g show that the composition according to the present invention releases 10-65% of its oxyvert sodium at 1 hour and 3 hours, and more than 60% of its oxyvert sodium at 10 hours. [Table 2g]

[0264] Figure 8 and Table 2h show the results obtained using USP instrument 2 with 900 mL of pH 6.8 phosphate buffer solution. The dissolution profiles of four batches of the finished compositions prepared according to Example 1 or Example 1bis, measured in the body, are shown. The dissolution medium was maintained at 37.0 ± 0.5°C, and the rotating paddle speed was fixed at 100 rpm. Figure 8 and Table 2h show that the compositions according to the present invention release more than 80% of the oxyvert sodium of the composition at 3 hours. [Table 2h-1] [Table 2h-2]

[0265] Release tests of MR particles and the finished composition - Effect of paddle velocity Figure 9 and Table 2i show the release profile of a batch of MR microparticles prepared according to Example 1 in 0.1N HCl. Using USP instrument 2, the dissolution profile of 4040 mg of microparticles, equivalent to 2250 mg of oxybart sodium, was measured per tank. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 or 100 rpm. [Table 2i]

[0266] Figure 10 and Table 2j show the release profiles of the completed compositions prepared according to Example 1 in 0.1N HCl. The dose per tank was 4.5 g, and dissolution was measured using USP apparatus 2 in 900 mL of dissolution medium. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 or 100 rpm.

[0267] A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1 N HCl dissolving medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 2j-1] [Table 2j-2]

[0268] Example 3: In vivo pharmacokinetic study of the completed composition related to Example 1bis. In accordance with the principles outlined in the FDA's March 2003 Guidance for Industry on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, in vivo pharmacokinetic studies were conducted in healthy human volunteers. All studies were conducted in accordance with the principles outlined in the FDA's March 2003 Guidance for Industry on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. The study was conducted in subjects two hours after consuming a standardized dinner. Xyrem® was administered in two equipotentiated doses at 4-hour intervals. All other investigational drugs were prepared as described in Example 1bis. The standardized dinner consisted of 25.5% fat, 19.6% protein, and 54.9% carbohydrates.

[0269] The completed composition of Example 1bis, given as a single 4.5g overnight dose rather than the standard Xyrem® administered twice overnight at 4-hour intervals (2 × 2.25g), resulted in a dramatically different pharmacokinetic profile from that of Xyrem®, as shown in Figure 11. As summarized below (Tables 3a and 3b), the completed composition of the present invention at a bedtime dose of 4.5g, equivalent to two overnight doses (2 × 2.25g) of Xyrem®, showed a median T15 pharmacokinetic profile compared to the first dose of Xyrem®. max The reaction was delayed, resulting in slightly less total exposure to oxybart sodium. The relative bioavailability was approximately 88%. In the composition according to the present invention, the high peak concentration of the second dose of Xyrem® is avoided, and therefore an average C comparable to Xyrem® is achieved. 8h While achieving this, it does not show any substantial inter-dosing variation in concentration. [Table 3a] [Table 3b-1] [Table 3b-2]

[0270] The pharmacokinetic profile of the finished composition at a single 6g dose, manufactured according to Example 1bis, was also tested and found to have a similar pharmacokinetic profile to that of the 4.5g dose. Figure 12 shows a comparison of the pharmacokinetic profiles of the finished compositions at single 4.5g and 6g doses related to Example 1bis in the same seven subjects. The pharmacokinetic profile of the finished formulation at a 7.5g dose, manufactured according to Example 1bis, was also obtained. Figure 13 and Table 3c show the data for single 4.5g, 6g, and 7.5g doses. max , C max , C 8h AUC 8h , and AUC inf This shows the effect related to dose intensity. The above 7.5g dose is the same as the C obtained with Xyrem® administered at 2 × 3.75g. 8hAn average C equivalent to approximately 31 micrograms / mL, which is about 128.5% of the original C. 8h Achieved (C obtained with the above Xyrem(registered trademark) 8h (This was extrapolated to approximately 24.07 micrograms / mL from the published data). The above 7.5g dose has an AUC of approximately 0.89. inf AUC for 8h While the above ratio was achieved, the above ratios for the 4.5g dose and the 6g dose were 0.83 and 0.93, respectively. [Table 3c]

[0271] Figure 14 and Table 3d show the pharmacokinetic parameter AUC obtained for the completed composition of Example 1bis at 7.5g. inf and C 8h This is compared to the same parameters calculated for a total dose of Xyrem® of 2 × 4.5 g, i.e., 9 g. These data show that a 7.5 g dose of the formulation according to the present invention administered once overnight exhibits a similar PK profile to 9 g of Xyrem® administered in two separate equal doses. [Table 3d]

[0272] Example 4: Alternative formulations to the above Tables 4a to 4d show the qualitative and quantitative compositions of IR microparticles, MR microparticles, and mixtures of IR and MR microparticles. Figure 15 shows the physical structures of the microparticles that represent the qualitative and quantitative compositions of the above IR and MR microparticles.

[0273] In short, immediate-release (IR) nanoparticles of sodium oxyvertex were prepared as follows: 1615.0 g of sodium oxyvertex and 85.0 g of polyvinylpyrrolidone (Plasdone® K29 / 32 of povidone K30-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127) in a fluidized bed spray coating apparatus. IR nanoparticles with a volume-average diameter of approximately 270 microns were obtained.

[0274] Oxybart sodium release-controlled (MR) microparticles were prepared as follows: 4.0 g of C-type methacrylic acid copolymer (Eudragit® L100-55), 49.3 g of B-type methacrylic acid copolymer (Eudragit® S100), and 80 g of hydrogenated cottonseed oil (Lubritab®) were dissolved in 1200.0 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of the above-prepared MR microparticles in a fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11 g per minute, and a spray pressure of 1.3 bar. The MR microparticles were dried for 2 hours with the inlet temperature set to 56°C. MR microparticles with a volume-average diameter of approximately 330 microns were obtained.

[0275] A finished composition containing a 50:50 mixture of MR and IR microparticles (calculated based on the oxyvert sodium content of the microparticles) was prepared as follows: 27.86 g of IR microparticles, 37.15 g of MR microparticles, 1.13 g of malic acid (D / L malic acid), 0.50 g of xanthan gum (Kelco's Xantural® 75), 0.75 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 0.75 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 0.34 g of magnesium stearate were mixed. 6.85 g of individual samples (corresponding to a 4.5 g dose of oxyvert sodium, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed. [Table 4a] [Table 4b] [Table 4c] [Table 4d-1] [Table 4d-2]

[0276] Example 4bis Example 4bis describes an alternative formulation to that of Example 4. Oxybart sodium IR microparticles were prepared by coating the immediate-release (IR) microparticles described in Example 4 with a topcoat layer. The IR microparticles were prepared as follows: 170.0 g of hydroxypropyl cellulose (Hercules' Klucel® EF Pharm) was solubilized in 4080.0 g of acetone. The entire volume of this solution was sprayed onto 1530.0 g of the IR microparticles of Example 4 in a fluidized bed spray coating apparatus. IR microparticles with a volume-average diameter of approximately 298 microns were obtained (see Table 4bis-a).

[0277] Oxybart sodium release-controlled (MR) microparticles were prepared as described in Example 4 (see Table 4b).

[0278] Based on the Oxybart sodium content, a finished composition containing a 50:50 mixture of MR and IR microparticles was prepared as follows: 424.99 g of the above IR microparticles, 509.98 g of the above MR microparticles, 30.89 g of malic acid (D / L malic acid), 4.93 g of xanthan gum (Kelco's Xantural® 75), 4.93 g of colloidal silicon dioxide (Degussa's Aerosil® 200), and 9.86 g of magnesium stearate were mixed. 7.18 g of individual samples (corresponding to a 4.5 g dose of Oxybart sodium, with half of the dose as the immediate-release fraction and the other half as the release-controlling fraction) were weighed (see Tables 4bis-b and 4bis-c). [Table 4bis-a] [Table 4bis-b] [Table 4bis-c]

[0279] Compared to the completed composition described in Example 4, this alternative composition has the following characteristics: the same MR microparticles, the same but with a topcoat IR microparticles, an increased amount of malic acid, only one type of suspending agent (xanthan gum), and the presence of a lubricant.

[0280] Example 5: IR, MR, and in vitro release profiles of the finished compositions for Example 4 and Example 4bis. Dissolution test of MR microparticles in Example 4 - Protocol (2 hours in 0.1N HCl / pH 6.8 phosphate buffer) 49.1 g of MR microparticles from Example 4 were mixed with 0.5 g of magnesium stearate (Peter Graven) and 0.25 g of colloidal silicon dioxide (Evonik's Aerosil® 200).

[0281] Using USP apparatus 2, the dissolution profile of the above mixture, equivalent to 3770 mg of 2250 mg of oxybart sodium per tank, was measured. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm.

[0282] After 2 hours in 750 mL of 0.1 N HCl medium, 6.5 g of potassium dihydrogen phosphate was added to the dissolution vessel. The pH and volume were then adjusted to 6.8 and 950 mL, respectively. The potassium phosphate concentration in the dissolution medium after pH and volume adjustment was equal to 0.05 M. The release profiles are shown in Figure 16 and Table 5a. [Table 5a]

[0283] The above-mentioned oxyvert sodium was not released for 2 hours in the above-mentioned 0.1N HCl dissolution medium. After switching to pH 6.8, 40% of the active pharmaceutical ingredient (API) was released after 30 minutes, and 90% of the API was released after 1 hour. Figure 17 overlays the dissolution profile of the MR microparticles of Example 4 with the dissolution profile of the MR microparticles reported in Figure 3 of Supernus's USP8,193,211. Figure 17 shows that these dissolution profiles are different, and in particular, that the MR microparticles according to the present invention release more than 80% of the oxyvert sodium of the particles at 3 hours, while the MR microparticles described in Figure 3 of Supernus's USP8,193,211 do not release in this manner and show a significantly slower release profile.

[0284] Dissolution test of the completed composition in deionized water according to Example 4 Using USP apparatus 2, the dissolution profile of the completed composition of Example 4, equivalent to 4.5 g of oxybart sodium, was measured in 900 mL of deionized water. The dissolution medium was maintained at 37.0 ± 0.5 °C, and the rotating paddle speed was set to 50 rpm. The release profile is shown in Figure 18 and Table 5b. [Table 5b-1] [Table 5b-2]

[0285] The IR fraction of oxybart sodium described above was solubilized in 15 minutes. Release of oxybart sodium from the release-controlled fraction described above began after 5 hours, and 90% of the total dose was released after 8 hours.

[0286] Figure 19 shows the release profile of the completed composition in Example 4 superimposed on the release profile reported in Figure 2 of USP2012 / 0076865. Figure 19 shows that these dissolution profiles are different. The formulation described in Figure 2 of USP2012 / 0076865 does not show a delay period after the dissolution of the immediate-release portion.

[0287] Figure 20 and Table 5c show the dissolution profiles of three batches of the completed composition prepared according to Example 4bis, measured using USP apparatus 2 in 900 mL of 0.1 N HCl dissolution medium. The dissolution medium was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was fixed at 100 rpm. Figure 20 and Table 5c show that the composition according to the present invention releases 10–65% of its oxyvert sodium at 1 hour and 3 hours, and more than 60% of its oxyvert sodium at 10 hours. [Table 5c]

[0288] Figure 21 and Table 5d show the dissolution profiles of the completed compositions prepared according to Example 4bis, measured using USP instrument 2 in 900 mL of pH 6.8 phosphate buffer solution. The solution was maintained at 37.0 ± 0.5°C, and the rotation paddle speed was fixed at 100 rpm. Figure 21 and Table 5d show that the compositions according to the present invention release more than 80% of their oxyvert sodium after 3 hours. [Table 5d]

[0289] Example 6: In vivo pharmacokinetic study of the completed composition related to Example 4bis. In vivo pharmacokinetic studies were conducted in healthy human volunteers in accordance with the principles outlined in the FDA's March 2003 Guidance for Industry on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. All studies were conducted in subjects two hours after consuming a standardized dinner. Xyrem® was administered in two equipotentiated doses at 4-hour intervals. All other investigational drugs were prepared as described in Example 4bis. The standardized dinner consisted of 25.5% fat, 19.6% protein, and 54.9% carbohydrates.

[0290] The completed composition of Example 4bis, given as a single 4.5g overnight dose rather than the standard Xyrem® administered twice overnight at 4-hour intervals (2 × 2.25g), resulted in a dramatically different pharmacokinetic profile from that of Xyrem®, as shown in Figure 22. As summarized below (Tables 6a and 6b), the completed composition of the present invention at a 4.5g bedtime dose equivalent to two overnight doses (2 × 2.25g) of Xyrem® showed a median T15 pharmacokinetic profile compared to the first dose of Xyrem®. max The reaction was delayed, resulting in slightly less total exposure to oxybart sodium. The relative bioavailability was approximately 88%. In the composition according to the present invention, the high peak concentration of the second dose of Xyrem® is avoided, and therefore an average C comparable to Xyrem® is achieved. 8h While achieving this, it does not show any substantial inter-dosing variation in concentration. [Table 6a-1] [Table 6a-2] [Table 6b]

[0291] The above 4.5g dose is equivalent to an average C of approximately 6.85 micrograms / mL. 8h This was achieved, and this is the result obtained for Xyrem® administered at 2 × 2.25 g. 8h This corresponds to approximately 74.1% of AUC. inf AUC for 8h The ratio was approximately 0.89.

[0292] Example 7: Examination of in vitro and in vivo pharmacokinetics of the comparative formulation. Formulations with an in vitro solubility profile comparable to the formulation reported in Figure 3 of US8,193,211 were prepared to confirm the in vitro / in vivo correlation reported herein. Tables 7a-7c show the qualitative and quantitative compositions of the MR microparticles and mixtures of IR microparticles and MR microparticles. The physical structures of the microparticles showing the qualitative and quantitative compositions of the IR and MR microparticles are shown in Figure 23.

[0293] In short, oxybart sodium immediate-release (IR) microparticles were prepared according to Example 1bis. Oxybart sodium controlled-release (MR) microparticles were prepared in two steps. That is to say, Step 1: 106.7 g of water-insoluble polymer ethylcellulose (Ethocel® 20 Premium), 10.7 g of polyvinylpyrrolidone (ISP's Plasdone® K30), 10.7 g of castor oil (Olvea), and 5.3 g of polyoxyl 40 hydrogenated castor oil (BASF's Kolliphor RH40) were dissolved in a mixture of 828.0 g of acetone, 552.0 g of isopropanol, and 153.3 g of water. The entire solution was sprayed onto 400.0 g of immediately-release microparticles of the above-prepared sodium oxyvert in a Glatt GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 57°C, a spray rate of approximately 14.5 g per minute, and a spray pressure of 2.5 bar. Microparticles with a volume average diameter of approximately 310 microns were obtained. Step 2: 15.0 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 30.0 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 67.5 g of hydrogenated cottonseed oil (Lubritab®) were dissolved in 1012.5 g of isopropanol at 78°C. The entire solution was sprayed onto 450.0 g of the fine particles prepared above in a fluidized bed spray coating apparatus at an inlet temperature of 47°C, a spray rate of approximately 10.5 g per minute, and a spray pressure of 1.3 bar. The MR fine particles were dried for 2 hours with the inlet temperature set to 56°C. MR fine particles with a volume average diameter of approximately 335 microns were obtained.

[0294] A finished composition containing a 60:40 mixture of MR and IR microparticles (calculated based on the oxybart sodium content of the microparticles) was prepared as follows: 326.69 g of the IR microparticles, 735.04 g of the MR microparticles, 23.74 g of malic acid (D / L malic acid), 5.54 g of xanthan gum (Kelco's Xantural® 75), 5.54 g of colloidal silicon dioxide (Degussa's Aerosil® 200), and 11.08 g of magnesium stearate were mixed. 8.40 g of individual samples (corresponding to a 4.5 g dose of oxybart sodium, with 40% of the dose as an immediate-release fraction and 60% as a release-modulating fraction) were weighed. [Table 7a-1] [Table 7a-2] [Table 7b] [Table 7c]

[0295] The dissolution profiles obtained for MR microparticles in two sequential dissolution media (0.1N HCl for 2 hours, followed by phosphate buffer pH 6.8) are shown in Figure 24 and Table 7d. These data indicate that the dissolution profile of the MR microparticles produced according to Comparative Example 7 was very similar to the dissolution profile in Figure 3 of US8,193,211. In particular, the MR microparticles of Comparative Example 7 did not release more than 80% of the oxyvert sodium at the 3-hour mark. [Table 7d-1] [Table 7d-2]

[0296] The completed composition of Comparative Example 7 was tested in the same pharmacokinetic studies as the completed compositions of Examples 1 and 4. As summarized below (Table 7e), the completed composition of Comparative Example 7 at a 4.5 g dose administered at bedtime had a relative bioavailability of 67% compared to Xyrem® (2 × 2.25 g) administered twice overnight, and the total exposure to oxybart sodium was significantly lower. [Table 7e] [Table 7f-1] [Table 7f-2]

[0297] Pharmacokinetic profiles were also obtained for single doses of 6 g and 7.5 g of the finished compositions prepared according to Comparative Example 7. Table 7 shows the data for single doses of 4.5 g, 6 g, and 7.5 g. max , C 8h AUC 8h , and AUC inf This shows the effect related to dose intensity. [Table 7g]

[0298] Example 8: Alternative formulations to the above Example 8.1 Gamma-hydroxybutyrate release-controlled formulations including immediate-release microparticles of potassium gamma-hydroxybutyrate and controlled-release microparticles of sodium gamma-hydroxybutyrate (oxybart sodium). Immediate-release (IR) microparticles of potassium gamma-hydroxybutyrate can be prepared as follows: 1615.0 g of potassium gamma-hydroxybutyrate and 85.0 g of polyvinylpyrrolidone (Plasdone® K29 / 32 of povidone K30-ISP) are solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution is sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127) in a fluidized bed spray coating apparatus.

[0299] Immediate-release (IR) microparticles of the sodium salt of gamma-hydroxybutyrate were prepared as follows: 1615.0 g of the sodium salt of gamma-hydroxybutyrate and 85.0 g of polyvinylpyrrolidone (Plasdone® K29 / 32 of povidone K30-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127) in a fluidized bed spray coating apparatus.

[0300] Oxybart sodium release-controlled (MR) microparticles are prepared as follows: 22.8 g of C-type methacrylic acid copolymer (Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (Lubritab®) are dissolved in 1542.9 g of isopropanol at 78°C. The entire solution is sprayed onto 400.0 g of the above Oxybart sodium IR microparticles in a fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11 g per minute, and a spray pressure of 1.3 bar. The MR microparticles are dried for 2 hours with the inlet temperature set to 56°C. MR microparticles with an average volume diameter of approximately 320 microns are obtained.

[0301] A finished formulation containing a 50:50 mixture of MR and IR microparticles (calculated based on the gamma-hydroxybutyrate content of the microparticles) can be prepared as follows: 398.51 g of the above IR microparticles, 504.80 g of the above MR microparticles, 16.09 g of D / L malic acid, 6.34 g of xanthan gum (Kelco's Xantural® 75), 9.51 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 9.51 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 4.75 g of magnesium stearate were mixed. 7.49 g of individual samples of the above mixture (equivalent to a 4.5 g dose of Oxybart sodium, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed. [Table 8a] [Table 8b] [Table 8c-1] [Table 8c-2] [Table 8d]

[0302] Example 8.2 Release-controlled formulation of gamma-hydroxybutyrate containing immediate-release microparticles of potassium gamma-hydroxybutyrate, immediate-release microparticles of magnesium gamma-hydroxybutyrate, immediate-release microparticles of calcium gamma-hydroxybutyrate, and release-controlled microparticles of sodium gamma-hydroxybutyrate (oxyvert sodium). Immediate-release (IR) microparticles of the potassium salt of gamma-hydroxybutyrate are prepared according to Example 8.1.

[0303] Immediate-release (IR) microparticles of the magnesium salt or calcium salt of gamma-hydroxybutyrate can be prepared using the same manufacturing method by replacing the potassium salt of gamma-hydroxybutyrate with the same weight of the magnesium salt or calcium salt of gamma-hydroxybutyrate, respectively.

[0304] Prepare oxybart sodium-release controlled (MR) microparticles according to Example 8.1.

[0305] A finished formulation containing a 50:50 mixture of MR and IR microparticles (calculated based on the gamma-hydroxybutyrate content of the microparticles) can be prepared as follows: 132.84 g of IR microparticles of the potassium salt of the above gamma-hydroxybutyrate, 215.32 g of IR microparticles of the magnesium salt of the above gamma-hydroxybutyrate, 230.05 g of IR microparticles of the calcium salt of the above gamma-hydroxybutyrate, 504.80 g of MR microparticles of the sodium oxyvert, 23.35 g of D / L malic acid, 6.34 g of xanthan gum (Kelco's Xantural® 75), 9.51 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 9.51 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 5.69 g of magnesium stearate were mixed. Individual samples of the above mixture (8.96 g each, equivalent to 4.5 g of oxybart sodium, with half of the dose as the immediate-release fraction and the other half as the release-control fraction) were weighed. [Table 8e] [Table 8f-1] [Table 8f-2]

[0306] Example 8.3 Release-controlled formulation of gamma-hydroxybutyrate containing immediate-release microparticles of potassium gamma-hydroxybutyrate and release-controlled microparticles of calcium gamma-hydroxybutyrate. Immediate-release (IR) microparticles of the potassium salt of gamma-hydroxybutyrate are prepared according to Example 8.1.

[0307] Immediate-release (IR) particles of the calcium salt of gamma-hydroxybutyrate are formed by aligning the potassium salt of gamma-hydroxybutyrate with an equal weight of the calcium salt of gamma-hydroxybutyrate. By making this change, immediate-release (IR) microparticles of the potassium salt of gamma-hydroxybutyrate can be manufactured using the manufacturing method described in Example 8.1. Using these immediate-release (IR) microparticles of the calcium salt of gamma-hydroxybutyrate, controlled-release (MR) microparticles of the calcium salt of gamma-hydroxybutyrate are manufactured as follows: 22.8 g of C-type methacrylic acid copolymer (Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (Lubritab®) are dissolved in 1542.9 g of isopropanol at 78°C. The entire solution is sprayed onto 400.0 g of the above-mentioned immediate-release microparticles of the calcium salt of gamma-hydroxybutyrate in a fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11 g per minute, and a spray pressure of 1.3 bar. The MR particles are dried for 2 hours with the inlet temperature set to 56°C.

[0308] A finished formulation containing a 50:50 mixture of MR and IR microparticles (calculated based on the gamma-hydroxybutyrate content of the microparticles) can be prepared as follows: 398.53 g of IR microparticles of potassium gamma-hydroxybutyrate, 492.87 g of MR microparticles of sodium oxyvert, 16.10 g of D / L malic acid, 6.34 g of xanthan gum (Kelco's Xantural® 75), 9.51 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 9.51 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 4.69 g of magnesium stearate were mixed. 7.39 g of individual samples of the above mixture (equivalent to a 4.5 g dose of sodium oxyvert, with half of the dose as the immediate-release fraction and the other half as the release-controlled fraction) were weighed. [Table 8g-1] [Table 8g-2] [Table 8h]

[0309] Example 9: Alternative formulations with different concentrations of acidifying agents. To evaluate the effect of acidifying agents on the solubility stability of the formulation dispersed in water, various prototypes were developed. Experimental data using 0.8%, 1.6%, and 15% malic acid are detailed below.

[0310] Example 9.1 1.6% malic acid IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 268 microns were obtained.

[0311] MR-coated particles were prepared as follows: 39.9 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 80.1 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 180.0 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 2700.0 g of isopropanol at 78°C. The entire solution was sprayed onto 700.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 49°C, a spray rate of approximately 11.6 g per minute, and a spray pressure of 1.6 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 324 microns were obtained.

[0312] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 655.1 g of the above IR particles, 936.4 g of the above MR particles, 26.5 g of malic acid (Bartek's standard D / L malic acid), 11.7 g of xanthan gum (CP Kelco's Xantural® 75), 17.6 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 17.6 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 8.2 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.11 g of individual doses (equivalent to a 4.5 g dose, with half of this dose as the immediate-release fraction) were used. The amount (including half of the said dose as a release control fraction) was weighed.

[0313] Figure 29 and Table 9a below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. Single dose units were poured into a container containing 50 mL of tap water. After 5 minutes and 15 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 9a]

[0314] Example 9.2 0.8% malic acid IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 273 microns were obtained.

[0315] MR-coated particles were prepared as follows: 39.9 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 80.1 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 180.0 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 2700.0 g of isopropanol at 78°C. The entire solution was sprayed onto 700.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 47°C, a spray rate of approximately 10.7 g per minute, and a spray pressure of 1.6 bar. The MR particles were dried for 2 hours with the inlet temperature set to 60°C. Oxybart sodium MR-coated particles with an average diameter of 309 microns were obtained.

[0316] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 100.0 g of the above IR particles, 142.9 g of the above MR particles, 2.0 g of malic acid (Bartek's standard D / L malic acid), 1.2 g of xanthan gum (CP Kelco's Xantural® 75), 1.2 g of hydrophilic fumed silica (Degussa's Aerosil® 200), and 2.5 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 6.93 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0317] Figure 30 and Table 9b below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. Single dose units were poured into a container containing 50 mL of tap water. After 5 minutes and 15 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 9b]

[0318] Example 9.3 15% malic acid IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 255 microns were obtained.

[0319] MR-coated particles were prepared as follows: 22.8 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1544.8 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 49°C, a spray rate of approximately 12.0 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 298 microns were obtained.

[0320] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 36.2 g of the above IR particles, 51.8 g of the above MR particles, 16.1 g of malic acid (Bartek's standard D / L malic acid), 0.7 g of xanthan gum (CP Kelco's Xantural® 75), 1.0 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 1.0 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 0.6 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 8.25 g (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0321] Figure 31 and Table 9c below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The above dissolution medium was maintained at 37.0±0.5℃, and the rotating paddle speed was set to 75 The system was fixed at rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes and 15 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1 N HCl dissolving medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 9c]

[0322] Example 10 Alternative formulations The suspension agent is present in the formulation to limit the sedimentation of the reconstituted particles. Without the suspension agent, the particles begin to sediment immediately after shaking is stopped. With the suspension agent present, complete sedimentation of the particles does not occur in less than one minute. The following data illustrates the good fluidity of the suspension, which is evaluated by the high recovery rate of the oxybart sodium content in the dissolution test.

[0323] IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 271 microns were obtained.

[0324] MR-coated particles were prepared as follows: 39.9 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 80.1 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 180.0 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 2700.0 g of isopropanol at 78°C. The entire solution was sprayed onto 700.0 g of oxybart sodium IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11.5 g per minute, and a spray pressure of 1.6 bar. The MR-coated particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR particles with an average diameter of 321 microns were obtained.

[0325] A finished composition containing a 50:50 mixture of MR and IR oxybart sodium particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 634.0 g of the above IR particles, 907.6 g of the above MR particles, 25.7 g of malic acid (Bartek's standard D / L malic acid), 11.4 g of xanthan gum (CP Kelco's Xantural® 75), and 17.1 g of carrageenan gum (FMC Biopolymer Viscarin® PH209), 17.1 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 8.1 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 14.20 g of individual doses (equivalent to a 9 g dose, half of that dose) were prepared. A fraction (containing one portion as the immediate release fraction and half of the said fraction as the release control fraction) was weighed.

[0326] Figure 32 and Table 10a below show the dissolution profile of a 9g dose measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. The dissolution profile was measured with and without the rinsing step. [Table 10a-1] [Table 10a-2]

[0327] Example 11: Alternative formulations with different ratios of IR fraction to MR fraction. Various prototypes were prepared and evaluated, and the effect of the IR / MR ratio was measured.

[0328] Example 11a 15% IR microparticles / 85% MR pH * IR microparticles with a value of 6.5 IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1896.2 g of anhydrous ethyl alcohol and 1264.4 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 275 microns were obtained.

[0329] MR-coated particles were prepared as follows: 22.8 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1543.1 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 47°C, a spray rate of approximately 10.8 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 330 microns were obtained.

[0330] 17.1 g of MR microparticles were mixed with 0.09 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture, equivalent to 2250 mg of oxyvert sodium per tank, was measured in 900 ml of 0.1 N HCl and pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The dissolution medium temperature was 37.0 ± 0.5 °C. The paddle speed was set to 75 rpm and maintained at this setting. The release profiles are shown in Figure 33, Table 11a, and Table 11b. [Table 11a-1] [Table 11a-2] [Table 11b]

[0331] The qualitative composition of a 4.5g dose unit, in which 15% of the dose is the IR fraction and 85% of the dose is the MR fraction, is shown in Table 11c. [Table 11c]

[0332] A finished composition containing an 85:15 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) can be prepared as follows: 100.0 g of the above IR particles, 809.5 g of the above MR particles, and 4.0 g of malic acid (B Artek's standard D / L malic acid, 6.0 g of xanthan gum (CP Kelco's Xantural® 75), 9.0 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 9.0 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 4.7 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.88 g individual doses (equivalent to 4.5 g doses, with 15% of the dose as an immediate-release fraction and 85% as a release-modulating fraction) were weighed out.

[0333] After reconstitution with 50 ml of tap water and 10 ml of tap water for rinsing, the completed composition was dissolved using USP apparatus 2 in 840 ml of 0.1 N HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5 N NaOH) at 37.0 ± 0.5 °C and a rotating paddle speed of 75 rpm, resulting in the dissolution profiles shown in Figures 34 and 35 and Tables 11d and 11e. [Table 11d] [Table 11e]

[0334] Example 11b MR microparticles with 30% IR microparticles and 70% MR pH*6.2 IR particles were prepared as follows: 1615.0 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1903.2 g of anhydrous ethyl alcohol and 1267.1 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 268 microns were obtained.

[0335] MR-coated particles were prepared as follows: 36.6 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 32.1 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 103.0 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1543.5 g of isopropanol at 78°C. The entire solution was then sprayed into a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 12.0 g / min, and a spray pressure of 1. At 3 bar, the solution was sprayed onto 400.0 g of IR particles. The MR particles were dried for 2 hours with the inlet temperature set to 56°C. Oxybart sodium MR coated particles with an average diameter of 323 microns were obtained.

[0336] 17.0 g of Oxybart sodium MR particles were mixed with 0.09 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4050 mg of the above mixture, equivalent to 2280 mg of Oxybart sodium per tank, was measured in 900 ml of 0.1 N HCl dissolution medium. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The release profile in 0.1 N HCl is shown in Figure 36 and Table 11f. [Table 11f]

[0337] A finished composition containing a 70:30 mixture of MR and IR oxybart sodium particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 92.1 g of the above IR particles, 306.5 g of the above MR particles, 7.5 g of malic acid (Bartek's standard D / L malic acid), 2.8 g of xanthan gum (CP Kelco's Xantural® 75), 4.1 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 4.1 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 2.0 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.62 g (corresponding to 4.5 g doses, with 30% of the dose as an immediate-release fraction and 70% as a release-modulating fraction) were weighed out.

[0338] Figures 37 and 38 below, and Tables 11g and 11h, were prepared using USP apparatus 2, at 0.1N The solubility profiles measured in HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH) are shown. The above dissolution medium was maintained at 37.0 ± 0.5°C, and the rotating paddle speed was fixed at 75 rpm. Single dose units were poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of the dissolution medium. The above container was rinsed with 10 mL of water and added to the dissolution tank. [Table 11g-1] [Table 11g-2] [Table 11h]

[0339] Example 11c MR microparticles with 65% IR microparticles and 35% MR pH*6.2 IR particles were prepared as follows: 1615.0 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 270 microns were obtained.

[0340] MR-coated particles were prepared as follows: 22.8 g of type C methacrylic acid copolymer (Evonik's Eudragit® L100-55), 45.8 g of type B methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1543.1 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 47°C, a spray rate of approximately 10.8 g per minute, and a spray pressure of 1.3 bar. The MR-coated particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 330 microns were obtained.

[0341] For the dissolution profile of the above MR microparticles, please refer to Example 11a. The qualitative composition of the above dose unit, which is 4.5 g and contains 65% as the IR fraction and 35% as the MR fraction, is shown in Table 11i. [Table 11i-1] [Table 11i-2]

[0342] A finished composition containing an 85:15 mixture of Oxybart sodium MR and IR particles (calculated based on the Oxybart sodium content of the particles) can be prepared as follows: 100.0 g of the above IR particles, 76.9 g of the above MR coated particles, 3.0 g of malic acid (Bartek's standard D / L malic acid), 1.4 g of xanthan gum (CP Kelco's Xantural® 75), 2.1 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 2.1 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 0.9 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 6.75 g individual doses (equivalent to 4.5 g doses, with 65% of the dose as an immediate-release fraction and 35% as a release-modulating fraction) were weighed out.

[0343] Dissolution profile: After reconstitution with 50 ml of tap water and rinsing with 10 ml of tap water, the completed composition was dissolved using USP apparatus 2 in 840 ml of 0.1 N HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5 N NaOH) at 37.0 ± 0.5 °C and a rotating paddle speed of 75 rpm, resulting in the dissolution profiles shown in Figures 39 and 40 and Tables 11j and 11k. [Table 11j] [Table 11k]

[0344] Example 12: An alternative formulation having an IR fraction obtained using a different manufacturing method. We developed a prototype formulation and tested the effects of different manufacturing methods on the dissolution of the formulation.

[0345] Example 12a IR portion = raw sodium oxyvert IR particles, which serve as the core of MR-coated microparticles, were prepared as follows: 1615.0 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 256 microns were obtained.

[0346] MR-coated particles were prepared as follows: 22.8 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1542.9 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 10 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours with the inlet temperature set to 56°C. Oxybart sodium MR-coated particles with an average diameter of 308 microns were obtained.

[0347] 25.2 g of MR microparticles were mixed with 0.26 g of magnesium stearate (Peter Greven) and 0.13 g of colloidal silicon dioxide (Evonik's Aerosil® 200). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture per tank, equivalent to 2250 mg of oxybart sodium, was measured in 900 ml of 0.1 N HCl dissolution medium. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The release profile in 0.1 N HCl is shown in Figure 41 and Table 12a. [Table 12a]

[0348] A finished composition containing a 50:50 mixture of oxybart sodium MR-coated particles and raw oxybart sodium as the IR fraction (calculated based on the oxybart sodium content of the particles) was prepared as follows: 36 g of raw oxybart sodium, 63.7 g of the above MR-coated particles, 1.8 g of malic acid (Bartek's ordinary D / L malic acid), 1.6 g of xanthan gum (CP Kelco's Xantural® 75), 2.4 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 0.047 g of apple flavor, and 0.3 g of hydrophilic fumed Silica (Degussa Aerosil 200) was mixed in a Roue-Roehn mixer. Individual doses of 6.66 g (equivalent to 4.5 g doses, with half of the dose as the immediate release fraction and the other half as the release control fraction) were weighed out.

[0349] Figure 42 and Table 12b below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 12b]

[0350] Considering that the 0.1N HCl solubility profile of the above MR-coated particles is similar to that of the MR microparticles of Example 1 and Example 1bis, it is expected that, as long as the above MR particles are similar and only the properties of the immediate-release fraction change, the solubility profile of the completed composition in pH 6.8 phosphate buffer will be similar to the profile shown in Figure 8.

[0351] Example 12b Microparticles obtained by IR=extrusion-spheroidization IR particles were prepared as follows: 97 g of oxybart sodium and 3 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30, povidone-ISP) were mixed with 7.5 g of water. This mixture was extruded through a 400 micron mesh in an extruder-spheroidizer Fuji-Paudal MG-55 and sphericalized at 1500 rpm for 1.5 minutes. After drying in a ventilated dryer at 45°C for 4 hours, the fine particles were sieved between 150 microns and 500 microns.

[0352] MR-coated particles were prepared as described in Example 14.

[0353] A finished composition containing a 50:50 mixture of MR and IR oxybart sodium particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 67.4 g of the IR particles obtained by extrusion-spheroidization, 115.6 g of the MR coated particles, 3.3 g of malic acid (Bartek's standard D / L malic acid), 0.9 g of xanthan gum (CP Kelco's Xantural® 75), 0.9 g of hydrophilic fumed silica (Degussa's Aerosil 200), and 1.9 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 6.54 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-control fraction) were weighed out.

[0354] Figure 43 and Table 12c below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes... This suspension was poured into a dissolution tank containing 840 mL of 0.1 N HCl dissolving medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 12c]

[0355] Based on the dissolution profile of the MR-coated particles in pH 6.8 phosphate buffer, the completed composition is expected to have the dissolution profile in pH 6.8 phosphate buffer shown in Table 12d and Figure 44. [Table 12d]

[0356] Example 13: Alternative formulations that do not use binders. IR particles were prepared as follows: 1700.0 g of sodium oxybart was solubilized in 1899.4 g of anhydrous ethyl alcohol and 1261.3 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Pharmatrans Cellets 127) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 244 microns were obtained.

[0357] MR-coated particles were prepared as follows: 17.1 g of C-type methacrylic acid copolymer (Evonik's Eudragit L100-55), 34.3 g of B-type methacrylic acid copolymer (Evonik's Eudragit S100), and 77.1 g of hydrogenated cottonseed oil (JRS's Luburitab) were dissolved in 1157.9 g of isopropanol at 78°C. The entire solution was sprayed onto 300.0 g of IR particles prepared above in a Glatt GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 10.7 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours with the inlet temperature set to 56°C. Oxybart sodium MR-coated particles with an average diameter of 289 microns were obtained.

[0358] 25.3 g of MR-coated microparticles were mixed with 0.12 g of magnesium stearate (Peter Greven). Using a USP instrument, the dissolution profile of 4000 mg of the mixture (equivalent to 2368 mg of oxyvert sodium) per tank was measured in 900 ml of 0.1 N HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution adjusted to pH 6.8 with 5 N NaOH). The dissolution medium temperature was 37.0 ± 0. The temperature was maintained at 5°C, and the rotation paddle speed was set to 75 rpm. The above release profile is shown in Figure 45 and Tables 13a and 13b below. [Table 13a] [Table 13b]

[0359] The qualitative composition of a 4.5g dose unit, in which 50% of the dose is the IR fraction and 50% of the dose is the MR fraction, is shown in Table 13c. [Table 13c-1] [Table 13c-2]

[0360] After reconstitution with 50 ml of tap water and rinsing with 10 ml of tap water, the completed composition is expected to yield the dissolution profiles shown in Figures 46 and 47 and Tables 13d and 13e below when dissolved in 840 ml of 0.1 N HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution adjusted to pH 6.8 with 5 N NaOH) using USP apparatus 2 at 37.0 ± 0.5 °C and a rotating paddle speed of 75 rpm. [Table 13d] [Table 13e]

[0361] Example 14: MR particles with a larger (160 micron) core. We also developed different prototypes to evaluate the effect of core size on the dissolution of this formulation.

[0362] IR particles were prepared as follows: 1615.0 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 100 of Pharmatrans) (D[4,3]=160 microns) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 310 microns were obtained.

[0363] MR-coated particles were prepared as follows: 25.7 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 51.5 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 115.7 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1735.7 g of isopropanol at 78°C. The entire solution was sprayed onto 450.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 47°C, a spray rate of approximately 9.6 g per minute, and a spray pressure of 1.6 bar. The MR particles were dried for 2 hours with the inlet temperature set to 56°C. Oxybart sodium MR-coated particles with an average diameter of 370 microns were obtained.

[0364] 49.3 g of Oxybart sodium MR particles were mixed with 0.52 g of magnesium stearate (Peter Greven) and 0.26 g of colloidal silicon dioxide (Evonik's Aerosil® 200). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture, equivalent to 2250 mg of Oxybart sodium per tank, was measured in 900 ml of 0.1 N HCl medium and pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 100 rpm. The release profiles in 1N HCl and pH 6.8 phosphate buffer are shown in Figure 48 and Tables 14a and 14b below. [Table 14a] [Table 14b]

[0365] The qualitative composition of a 4.5g dose unit, in which 50% of the dose is the IR fraction and 50% of the dose is the MR fraction, is shown in Table 14c. [Table 14c-1] [Table 14c-2]

[0366] After reconstitution with 50 ml of tap water and rinsing with 10 ml of tap water, the completed composition is expected to yield the dissolution profiles shown in Figures 49 and 50 and Tables 14d and 14e when dissolved in 840 ml of 0.1 N HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution adjusted to pH 6.8 with 5 N NaOH) using USP apparatus 2 at 37.0 ± 0.5 °C and a rotating paddle speed of 75 rpm. [Table 14d] [Table 14e]

[0367] Example 15: MR microparticles containing Lubritab® and Eudragit® in various ratios. Various prototypes were developed, and the effect of the ratio of Luburitab (trademark) to Eudragit (trademark) on the formulation was evaluated.

[0368] Example 15a 30% Lubritab®, Cellets® 127, Coverage level = 35% IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 100 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 272 microns were obtained.

[0369] MR-coated particles were prepared as follows: 50.2 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 100.6 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 64.6 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1943.5 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11.0 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 403 microns were obtained.

[0370] 17.9 g of Oxybart sodium MR microparticles were mixed with 0.1 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4308 mg of the above mixture, equivalent to 2250 mg of Oxybart sodium per tank, was measured in 900 ml of 0.1 N HCl medium. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The release profile is shown in Figure 51 and Table 15a. [Table 15a]

[0371] Following the manufacturing protocol described above, the coating level was adjusted from 35% to 50% to prepare alternative oxivert sodium MR coated particles. The solubility profile of these alternative oxivert sodium MR particles was measured using the same protocol as above. The 0.1N HCl solubility profile is shown in Figure 52 and Table 15b. [Table 15b]

[0372] A finished composition containing a 50:50 mixture of MR and IR Oxybart sodium particles (calculated based on the Oxybart sodium content of the particles) was prepared as follows: 153.3 g of the above IR microparticles, 235.8 g of the above Oxybart sodium MR microparticles with a coating level of 30%, 6.2 g of malic acid (Bartek's standard D / L malic acid), 2.7 g of xanthan gum (CP Kelco's Xantural® 75), 4.1 g of carrageenan gum (FMC Biopolymer's Viscarin® PH109), 4.1 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 2.0 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.42 g (equivalent to a 4.5 g dose, with half of the dose as the immediate-release fraction and the other half as the controlled-release fraction) were weighed.

[0373] Figure 53 and Table 15c below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 15c]

[0374] Example 15b: Celphere® CP203 as a neutral core and coating level = 35% IR particles were prepared as follows: 665.0 g of oxybart sodium and 35.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 781.2 g of anhydrous ethyl alcohol and 521.6 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Celphere® CP203 of Asahi Kasei - average diameter D[4,3] = 250 microns) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 398 microns were obtained.

[0375] MR-coated particles were prepared as follows: 37.6 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 75.4 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 48.5 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1458.0 g of isopropanol at 78°C. The entire solution was sprayed onto 300.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11.7 g per minute, and a spray pressure of 1.6 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 491 microns were obtained.

[0376] 17.0 g of MR microparticles were mixed with 0.08 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 5210 mg of the above mixture per tank, equivalent to 2250 mg of oxyvert sodium, was measured in 900 ml of 0.1 N HCl medium and in pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The above release profiles are shown in Figure 54 and Tables 15d and 15e. [Table 15d] [Table 15e]

[0377] The qualitative composition of a 4.5g dose unit, in which 50% of the dose is the IR fraction and 50% of the dose is the MR fraction, is shown in Table 15f. [Table 15f-1] [Table 15f-2]

[0378] After reconstruction, the completed composition is expected to exhibit the dissolution profiles shown in Figures 55 and 56 and Tables 15 g and 15 h when dissolved in 0.1 N HCl and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution adjusted to pH 6.8 with 5 N NaOH) using USP apparatus 2 at 37.0 ± 0.5 °C and a rotating paddle speed of 75 rpm. [Table 15g] [Table 15h]

[0379] Example 15c 40% Lubritab (trademark) (coverage level = 40%) IR pellets were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1903.2 g of anhydrous ethyl alcohol and 1267.1 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 268 microns were obtained.

[0380] MR-coated particles were prepared as follows: 40.6 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 80.1 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 80.5 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1799.4 g of isopropanol at 78°C. The entire solution was sprayed onto 300.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 10.5 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 348 microns were obtained.

[0381] 20.0 g of MR-coated particles were mixed with 0.1 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4700 mg of the above mixture, equivalent to 2250 mg of oxybart sodium per tank, was measured in 900 ml of 0.1 N HCl medium. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The above release profiles are shown in Figure 57 and Table 15i. [Table 15i]

[0382] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 156.0 g of the above IR particles, 260.0 g of the above MR coated particles, 6.3 g of malic acid (Bartek's standard D / L malic acid), 2.8 g of xanthan gum (CP Kelco's Xantural® 75), 4.2 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 4.2 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 2.2 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.78 g of individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0383] Figures 58 and 59 and Tables 15j and 15k below were obtained using USP device 2, with a value of 0.1N The solubility profiles measured in HCl and a pH 6.8 buffer (0.05 M potassium dihydrogen phosphate solution adjusted to pH 6.8 with 5 N NaOH) are shown. The above dissolution medium was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1 N HCl dissolution medium. The above container was rinsed with 10 mL of water and added to the dissolution tank. [Table 15j-1] [Table 15j-2] [Table 15k]

[0384] Example 15d: 70% Lubritab (trademark) (coverage level 25%) IR particles were prepared as follows: 1615.1 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.4 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 272 microns were obtained.

[0385] MR-coated particles were prepared as follows: 13.3 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 26.8 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 93.3 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1200.3 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 10.6 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 313 microns were obtained.

[0386] 17.0 g of MR-coated particles were mixed with 0.06 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 3750 mg of the above mixture per tank, equivalent to 2250 mg of oxyvert sodium, was measured in 900 ml of 0.1 N HCl medium and pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The above release profiles are shown in Figure 60 and Tables 15 l and 15 m. [Table 15l-1] [Table 15l-2] [Table 15m]

[0387] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 153.3 g of the IR particles, 204.3 g of the MR-coated particles, 6.2 g of malic acid (Bartek's standard D / L malic acid), 2.7 g of xanthan gum (CP Kelco's Xantural® 75), 4.1 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 4.1 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 1.9 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 6.85 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0388] Figure 61 and Table 15n show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 15n]

[0389] Based on the solubility profile of the MR-coated particles in pH 6.8 phosphate buffer, the single dose unit is expected to have the solubility profile in pH 6.8 buffer shown in Figure 62 and Table 15o. [Table 15o]

[0390] Example 16: Evaluation of various hydrophobic compounds in a coating. We prepared and evaluated prototypes with various hydrophobic coatings to measure the effect of the coating type on the dissolution of the formulation.

[0391] Example 16a Glyceryl dibehenate (Compritol® AT0888) IR particles were prepared as follows: 1615.0 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1903.2 g of anhydrous ethyl alcohol and 1267.1 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 268 microns were obtained.

[0392] MR-coated particles were prepared as follows: 22.9 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of glyceryl dibehenate (Gattefosse's Compritol® ATO888) were dissolved in 1371.8 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11.7 g per minute, and a spray pressure of 1.6 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 322 microns were obtained.

[0393] 17.0 g of MR-coated particles were mixed with 0.1 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture, equivalent to 2250 mg of oxyvert sodium per tank, was measured in 900 ml of 0.1 N HCl medium and pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The above release profiles are shown in Figure 63 and Tables 16a and 16b. [Table 16a-1] [Table 16a-2] [Table 16b]

[0394] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 181.1 g of the IR particles, 258.7 g of the MR-coated particles, 7.3 g of malic acid (Bartek's standard D / L malic acid), 3.3 g of xanthan gum (CP Kelco's Xantural® 75), 4.9 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 4.9 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 2.3 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.12 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0395] Figure 64 and Table 16c show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 16c]

[0396] Based on the dissolution profile of the above MR microparticles alone in phosphate buffer at pH 6.8, the single dose unit has the dissolution profile at pH 6.8 shown in Figure 65 and Table 16d. It is expected. [Table 16d]

[0397] Example 16b 60% candelilla wax at a 20% coverage level IR particles were prepared as follows: 1615.1 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.4 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 255 microns were obtained.

[0398] MR-coated particles were prepared as follows: 13.3 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 26.7 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 60.0 g of candelilla wax (Brenntag's Kahlwax® 2039L) were dissolved in 902.2 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 12.8 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 289 microns were obtained.

[0399] 21.2 g of MR microparticles were mixed with 0.11 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture, equivalent to 2570 mg of oxyvert sodium per tank, was measured in 900 ml of 0.1 N HCl medium and pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5 N NaOH). The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. The above release profiles are shown in Figure 66 and Tables 16e and 16f below. [Table 16e-1] [Table 16e-2] [Table 16f]

[0400] The qualitative composition of a 4.5g dose unit, in which 50% of the dose is the IR fraction and 50% of the dose is the MR fraction, is shown in Table 16g. [Table 16g]

[0401] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) can be prepared as follows: 200.0 g of the above IR particles, 250.0 g of the above MR coated particles, 8.1 g of malic acid (Bartek's standard D / L malic acid), 3.6 g of xanthan gum (CP Kelco's Xantural® 75), 5.4 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 5.4 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 2.4 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 6.61 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0402] After reconstruction, the completed composition is expected to yield the dissolution profiles shown in Figures 67 and 68 and Tables 16a and 16i when dissolved in 0.1N HCl and pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution adjusted to pH 6.8 with 5N NaOH) using USP apparatus 2 at 37.0±0.5℃ and a rotating paddle speed of 75 rpm, as shown in Figures 67 and 68 and Tables 16a and 16i. [Table 16h] [Table 16i]

[0403] Example 16c 40% Candelilla Wax (Coating Level = 20%) IR particles were prepared as follows: 1615.1 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.4 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 270 microns were obtained.

[0404] MR-coated particles were prepared as follows: 20.0 g of type C methacrylic acid copolymer (Evonik's Eudragit® L100-55), 40.0 g of type B methacrylic acid copolymer (Evonik's Eudragit® S100), and 40.0 g of candelilla wax (Brenntag's Kahlwax® 2039L) were dissolved in 904.0 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 10.9 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 302 microns were obtained.

[0405] 17.0 g of MR microparticles were mixed with 0.08 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 3500 mg of the above mixture, equivalent to 2250 mg of oxyvert sodium per tank, was measured in 900 ml of 0.1 N HCl medium and pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The above profiles are shown in Figure 69 and Tables 16j and 16k. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. [Table 16j] [Table 16k]

[0406] The qualitative composition of a 4.5g dose unit, in which 50% of the dose is the IR fraction and 50% of the dose is the MR fraction, is shown in Table 16l. [Table 16l]

[0407] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 122.7 g of the above IR particles, 153.2 g of the above MR coated particles, 5.0 g of malic acid (Bartek's standard D / L malic acid), 2.2 g of xanthan gum (CP Kelco's Xantural® 75), 3.3 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 3.3 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 1.5 g of magnesium stearate. Nesium (Peter Greven) was mixed in a Roue-Roehn mixer. Individual doses of 6.62 g (equivalent to 4.5 g doses, with half of the dose as the immediate release fraction and the other half as the release control fraction) were weighed out.

[0408] Figure 70 and Table 16m show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 16m]

[0409] Based on the dissolution profile of the MR-coated particles in pH 6.8 phosphate buffer, it is expected that a 4.5 g single-dose unit of the completed composition will yield the dissolution profile in pH 6.8 phosphate buffer shown in Figure 71 and Table 16n. [Table 16n]

[0410] Example 16d: 60% cetyl alcohol (Kolliwax® CA) IR particles were prepared as follows: 1615.1 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1898.7 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 272 microns were obtained.

[0411] MR-coated particles were prepared as follows: 22.8 g of C-type methacrylic acid copolymer (Evonik's Eudragit® L100-55), 45.8 g of B-type methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of cetyl alcohol (BASF's Kolliwax® CA) were dissolved at room temperature in 1472.5 g of isopropanol and 77.7 g of water. The entire solution was then sprayed in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C and a spray rate of 1 / min. Approximately 14.5 g of the solution was sprayed onto 400.0 g of IR particles at a spraying pressure of 2.5 bar. Oxybart sodium MR-coated particles with an average diameter of 315 microns were obtained.

[0412] 16.4 g of MR microparticles were mixed with 0.08 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture, equivalent to 2250 mg of oxybart sodium per tank, was measured in 900 ml of 0.1 N HCl medium. The dissolution profile is shown in Figure 72 and Table 16o. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 75 rpm. [Table 16o]

[0413] Example 17: The impact of selecting Eudragit™ on coating MR microparticles. Furthermore, prototypes were developed and evaluated to measure the effect of selected Eudragit™ on the dissolution of MR microparticles.

[0414] Example 17a 100% Eudragit (trademark) S100 IR particles were prepared as follows: 1615.0 g of sodium oxybart and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1894.3 g of anhydrous ethyl alcohol and 1262.9 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Sodium oxybart IR particles with an average diameter of 285 microns were obtained.

[0415] Oxybart sodium IR seal-coated particles were prepared by coating the above-mentioned IR particles with a seal-coat layer. Specifically, 170.0 g of hydroxypropyl cellulose (Hercules' Klucel® EF Pharm) was solubilized in 4080.0 g of acetone. The entire volume of this solution was sprayed onto 1530.0 g of the above-mentioned IR particles in a fluidized bed spray coating apparatus. Oxybart sodium IR particles with a volume-average diameter of approximately 298 microns were obtained.

[0416] MR-coated particles were prepared as follows: 100.0 g of type B methacrylic acid copolymer (Eudragit™ S100 from Evonik) and 150.0 g of hydrogenated cottonseed oil (Lubritab™ from JRS) were dissolved in 2250.0 g of isopropanol at 78°C. The entire solution was sprayed onto 750.0 g of the above IR particles in a Glatt™ GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 12.0 g per minute, and a spray pressure of 1.6 bar. The MR particles were dried for 2 hours at an inlet temperature set to 56°C. Oxybart sodium MR-coated particles with an average diameter of 307 microns were obtained.

[0417] Using USP apparatus 2, the dissolution profile of 2100 mg of the above mixture, equivalent to 1253 mg of oxybart sodium per tank, was measured in 500 ml of 0.1 N HCl medium. The dissolution profiles are reported in Figure 73 and Table 17a. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 100 rpm. [Table 17a]

[0418] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 425.0 g of the IR seal-coated particles, 510.0 g of the MR coated particles, 30.9 g of malic acid (Bartek's standard D / L malic acid), 4.9 g of xanthan gum (CP Kelco's Xantural® 180), 4.9 g of Aerosil® 200 (Evonik's amorphous anhydrous colloidal silicon dioxide), and 9.9 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.18 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-control fraction) were weighed out.

[0419] Figure 74 and Table 17b below show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 100 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 17b]

[0420] Figure 75 and Table 17c show the solubility measured using USP instrument 2 in pH 6.8 phosphate buffer (0.05M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5N NaOH). The proof is shown. The above dissolution medium was maintained at 37.0 ± 0.5°C, and the rotation paddle speed was fixed at 100 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of pH 6.8 dissolution medium. The above container was rinsed with 10 mL of water and added to the dissolution tank. [Table 17c]

[0421] Example 17b 100% Eudragit (trademark) L100-55 IR particles were prepared as follows: 1615.0 g of oxybart sodium and 85.1 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1896.2 g of anhydrous ethyl alcohol and 1264.4 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 275 microns were obtained.

[0422] MR-coated particles were prepared as follows: 68.7 g of C-type methacrylic acid copolymer (Eudragit® L100-55 from Evonik) and 102.9 g of hydrogenated cottonseed oil (Lubritab® from JRS) were dissolved in 1543.2 g of isopropanol at 78°C. This solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 46°C, a spray rate of approximately 12.7 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 328 microns were obtained.

[0423] 17.0 g of MR microparticles were mixed with 0.09 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4000 mg of the above mixture, equivalent to 2250 mg of oxyvert sodium per tank, was measured in 900 ml of 0.1 N HCl medium and in pH 6.8 phosphate buffer (pH adjusted to 6.8 with 0.05 M potassium dihydrogen phosphate solution - 5 N NaOH). The above profiles are shown in Figure 76 and Tables 17d and 17e. The dissolution medium temperature was maintained at 37.0 ± 0.5 °C, and the rotation paddle speed was set to 100 rpm. [Table 17d] [Table 17e]

[0424] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 153.3 g of the IR particles, 219.0 g of the MR-coated particles, 6.2 g of malic acid (Bartek's standard D / L malic acid), 2.8 g of xanthan gum (CP Kelco's Xantural® 75), 4.1 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 4.1 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 1.9 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.12 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0425] Figure 77 and Table 17f show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 17f]

[0426] Based on the dissolution profile of the MR-coated particles in pH 6.8 phosphate buffer, it is expected that a 4.5 g single-dose unit of the completed composition will yield the dissolution profile in pH 6.8 phosphate buffer shown in Figure 78 and Table 17 g. [Table 17g]

[0427] Example 17c Eudragit(TM) L100-S100(50-50) mixture IR particles were prepared as follows: 1615.0 g of oxybart sodium and 85.0 g of the water-soluble polymer polyvinylpyrrolidone (Plasdone® K30 of povidone-ISP) were solubilized in 1903.2 g of anhydrous ethyl alcohol and 1267.1 g of water. The entire solution was sprayed onto 300 g of microcrystalline cellulose spheres (Cellets® 127 of Pharmatrans) in a fluidized bed spray coating apparatus GPCG1.1. Oxybart sodium IR particles with an average diameter of 268 microns were obtained.

[0428] MR-coated particles were prepared as follows: 34.3 g of type A methacrylic acid copolymer (Evonik's Eudragit® L100), 34.3 g of type B methacrylic acid copolymer (Evonik's Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (JRS's Luburitab®) were dissolved in 1543.0 g of isopropanol at 78°C. The entire solution was sprayed onto 400.0 g of IR particles in a Glatt® GPCG1.1 fluidized bed spray coating apparatus at an inlet temperature of 48°C, a spray rate of approximately 11.8 g per minute, and a spray pressure of 1.3 bar. The MR particles were dried for 2 hours at an inlet temperature of 56°C. Oxybart sodium MR-coated particles with an average diameter of 316 microns were obtained.

[0429] 24.0 g of MR microparticles were mixed with 0.12 g of magnesium stearate (Peter Greven). Using USP apparatus 2, the dissolution profile of 4050 mg of the above mixture per tank, equivalent to 2280 mg of oxybart sodium, was measured in 900 ml of 0.1 N HCl medium and in pH 6.8 phosphate buffer (0.05 M potassium dihydrogen phosphate solution - pH adjusted to 6.8 with 5 N NaOH). The dissolution profile is shown in Figure 79. The results are also shown in Tables 17h and 17i. The dissolution medium temperature was maintained at 37.0 ± 0.5°C, and the rotation paddle speed was set to 100 rpm. [Table 17h] [Table 17i]

[0430] A finished composition containing a 50:50 mixture of MR and IR particles (calculated based on the oxybart sodium content of the particles) was prepared as follows: 223.0 g of the above IR particles, 318.4 g of the above MR coated particles, 11.2 g of malic acid (Bartek's standard D / L malic acid), 4.0 g of xanthan gum (CP Kelco's Xantural® 75), 6.0 g of carrageenan gum (FMC Biopolymer's Viscarin® PH209), 6.0 g of hydroxyethylcellulose (Ashland's Natrosol® 250M), and 2.9 g of magnesium stearate (Peter Greven) were mixed in a Roue-Roehn mixer. 7.14 g individual doses (corresponding to 4.5 g doses, with half of the dose as the immediate-release fraction and the other half as the release-modulating fraction) were weighed out.

[0431] Figure 80 and Table 17j show the dissolution profiles measured in 0.1N HCl using USP apparatus 2. The dissolution medium was maintained at 37.0±0.5℃, and the rotation paddle speed was fixed at 75 rpm. A single dose unit was poured into a container containing 50 mL of tap water. After 5 minutes, this suspension was poured into a dissolution tank containing 840 mL of 0.1N HCl dissolution medium. The container was rinsed with 10 mL of water and added to the dissolution tank. [Table 17j]

[0432] Based on the dissolution profile of the MR-coated particles in pH 6.8 phosphate buffer, the completed composition in a 4.5 g single-dose unit is expected to have the dissolution profile in pH 6.8 phosphate buffer shown in Figure 81 and Table 17k. [Table 17k]

[0433] Example 18: In vivo pharmacokinetic study of the completed composition related to Example 1 (study of dose escalation) Pharmacokinetic studies were conducted in vivo in healthy human volunteers. Pharmacokinetic parameters were normalized by dose. To assess dose-proportionality, logarithmically transformed dose-normalized PK parameters were compared in pairs according to the statistical methodology described in the FDA's 2013 Draft Guidance, titled "BIOEQUIVALENCE STUDIES WITH PHARMACOKINETIC ENDPOINTS FOR DRUGS SUBMITTED UNDER AN ANDA (2013)". All studies were conducted in subjects 2 hours after consuming a standardized dinner. The test product, having the composition of the finished product in Example 1 but manufactured on a larger scale, was administered in sequentially increasing doses of 4.5 g, 7.5 g, and 9 g at one-week intervals. The test sample for 4.5 g was prepared as described in Table 1c, and the quantities were similarly adjusted for the other intensities. The dissolution profiles of the MR portion of the test product are shown in Figures 86 and 87. The solubility profiles of the test products are shown in Figures 88 and 89. The individual concentrations of gamma-hydroxybutyrate and the derived PK parameters are summarized below (Tables 18a and 18b) and in Figure 90. [Table 18a] AUC and C max The values ​​increased more significantly than dose-proportionally with increasing doses of gamma-hydroxybutyrate, which was formulated as the test product. [Table 18b]

[0434] Table 18c shows the pharmacokinetic parameter AUC obtained for 4.5 g of the test product. inf and C 8h This is compared with the same parameters calculated for a total dose of Xyrem® of 2 × 2.25 g, i.e., 4.5 g. [Table 18c-1] [Table 18c-2]

[0435] Table 18d shows the pharmacokinetic parameter AUC obtained for 7.5g of the test product. inf and C 8h This is compared with the same parameters calculated for a total dose of Xyrem® of 2 × 3.75 g, i.e., 7.5 g. [Table 18d]

[0436] Table 18e shows the pharmacokinetic parameter AUC obtained for 7.5g of the test product. inf and C 8h This is compared with the same parameters calculated for a total dose of Xyrem® of 2 × 4.5 g, i.e., 9 g. [Table 18e]

[0437] For the completed composition administered at 4.5g, the average C 6h , average C 7h This is the average C of Xyrem(registered trademark). 4h Larger than, and with an average C 10h The above average C 4h It is smaller than C 3h / C max The ratio of (Xyrem(registered trademark)) is 1.03. 4h / C max The ratio of (Xyrem(registered trademark)) is 0.81. 4.5h / C max The ratio of (Xyrem(registered trademark)) is 0.69.

[0438] For the completed composition administered at 7.5g, the average C 6h , average C 7h This is the average C of Xyrem(registered trademark). 4hLarger than, average C 10h The above average C 4h It is smaller than C 3h / C max The ratio of (Xyrem(registered trademark)) is 0.77. 4h / C max The ratio of (Xyrem(registered trademark)) is 0.63. 4.5h / C max The ratio of (Xyrem(registered trademark)) is 0.57.

[0439] For the completed composition administered at 9g, the average C 6h , average C 7h This is the average C of Xyrem(registered trademark). 4h Larger than, average C 10h The above average C 4h It is smaller than C 3h / C max The ratio of (Xyrem(registered trademark)) is 0.84. 4h / C max The ratio of (Xyrem(registered trademark)) is 0.78. 4.5h / C max The ratio of (Xyrem(registered trademark)) is 0.63.

[0440] For the completed composition administered at 7.5g, the C content was compared to that of Xyrem® at a total dose of 2 × 4.5g, i.e., 9g. 3h / C max The ratio of (Xyrem(registered trademark)) is 0.65. 4h / C max The ratio of (Xyrem(registered trademark)) is 0.53. 4.5h / C max The ratio of (Xyrem(registered trademark)) is 0.47.

[0441] Throughout this application, various publications are referenced. In order to more fully describe the state of the art in which the present invention pertains, the entire disclosures of these publications are incorporated herein by reference. It will be apparent to those skilled in the art that various modifications and changes can be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the present invention will be apparent to those skilled in the art from the discussion herein and the practices of the present invention disclosed herein. This specification and the examples are intended to be for illustrative purposes only, and the true scope and spirit of the invention are shown by the appended claims. For example, the following items are examples of embodiments of the present invention. (Item 1) A release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, a) The formulation is subject to USP38 <711> In dissolution apparatus 2 conforming to the standards, 900 mL When tested in 0.05M potassium dihydrogen phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm, at least 80% of the gamma-hydroxybutyrate of the formulation is released after 3 hours. b) The formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the formulation is released at 1 hour and 3 hours. c) The formulation is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 60% of the gamma-hydroxybutyrate of the formulation is released after 10 hours, and d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The aforementioned formulation. (Item 2) A release-controlled formulation of gamma-hydroxybutyrate, wherein a 7.5g dose of the formulation has an average AUC greater than 340 hours / microgram / mL. inf The aforementioned formulation, which has been shown to achieve this. (Item 3) A release-controlled formulation of gamma-hydroxybutyrate, wherein a 7.5g dose of the formulation has an average AUC greater than 340 hours / microgram / mL. inf , and approximately two hours after the standardized dinner, t0 and t 4h At that point, the average C is given by an immediate-release solution of equidose of oxyvert sodium administered in equal doses. 8h The average C is 50% to 130% of the average C. 8h The aforementioned formulation, which has been shown to achieve this. (Item 4) A release-controlled formulation of gamma-hydroxybutyrate, (a) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, at least 80% of the gamma-hydroxybutyrate of the formulation is released, and (b) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the formulation is released at 1 hour and 3 hours. The aforementioned formulation. (Item 5) A release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, a) The formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, at least 80% of the gamma-hydroxybutyrate of the formulation is released. b) The formulation is subject to USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the formulation is released at 1 hour and 3 hours, and c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The aforementioned formulation. (Item 6) A release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, a) The 7.5g dose of the formulation has an average AUC greater than 340 hours micrograms / mL. inf , and approximately two hours after the standardized dinner, t0 and t 4h At that point, the average C is given by an immediate-release solution of equidose of oxyvert sodium administered in equal doses. 8h The average C is 50% to 130% of the average C. 8h It has become clear that this can be achieved, and b) The formulation is (i) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, at 3 hours, at least 80% of the gamma-hydroxybutyrate of the formulation is released, and (ii) USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, 10% to 65% of the gamma-hydroxybutyrate of the formulation is released at 1 hour and 3 hours, and c) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm in 750 mL of 0.1 N hydrochloric acid for 2 hours, and then switches to 950 mL of 0.05 M potassium dihydrogen phosphate buffer adjusted to pH 6.8, the release control portion releases more than 80% of the gamma-hydroxybutyrate at 3 hours. The aforementioned formulation. (Item 7) A release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, a) The immediate release portion is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% of the immediate release portion of gamma-hydroxybutyrate was released after 1 hour. b) The release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, less than 20% of the gamma-hydroxybutyrate in the release control portion is released after 1 hour, and c) The release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested 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, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released after 3 hours. The aforementioned formulation. (Item 8) A release-controlled formulation of gamma-hydroxybutyrate comprising an immediate-release portion and a release-controlled portion, a) The immediate release portion is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% of the immediate release portion of gamma-hydroxybutyrate was released after 1 hour. b) The release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standard, when tested in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, less than 20% of the gamma-hydroxybutyrate in the release control portion was released after 1 hour. c) The release adjustment part is USP38 <711> In a dissolution apparatus 2 conforming to the standards, 90 When tested in 0 mL of 0.05 M potassium dihydrogen phosphate buffer at pH 6.8, at a temperature of 37°C and a paddle speed of 75 rpm, more than 80% of the gamma-hydroxybutyrate of the release-controlled portion is released at 3 hours, and d) In a dissolution test in which the release control portion starts at a temperature of 37°C and a paddle speed of 75 rpm...

Claims

[Claim 1] The invention as shown in the drawings.

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