Immediate-release unit doses of hydroxybutyric acid or one of its therapeutically acceptable salts, administered orally, and their use in maintaining alcohol abstinence

Description

[0001] The present invention relates to immediate-release unit doses of GHB or one of its therapeutically acceptable salts administered orally and their use for maintaining alcohol abstinence.

[0002] Sodium oxybate, which is the most widely used salt of hydroxybutyric acid (GHB), is used therapeutically in the treatment of the following conditions: Alcohol dependence: treatment of alcohol withdrawal syndrome and maintenance of alcohol abstinence in alcohol-dependent patients; narcolepsy in patients with cataplexy; anesthesia.

[0003] It is listed under the 1971 Convention on Psychotropic Substances.

[0004] In the context of therapeutic use, it is important to determine the optimal dosage of sodium oxybate in order to promote the benefit-risk ratio of the treatment and avoid any risk of over- or under-dosing.

[0005] Treatment for alcohol dependence takes place in two phases.

[0006] During the first phase, patients are weaned and possibly treated in case of severe withdrawal syndrome. Alcohol withdrawal syndrome is commonly used to describe the group of symptoms that occur during a gradual or abrupt cessation of alcohol in alcohol-dependent patients. These manifestations reflect a state of psychological, behavioral and physical withdrawal. The syndrome is, in the majority of cases, resolved spontaneously or with treatment in two to five days but mortality is not zero (French Society of Alcoholology, 2006). It is treated with anticonvulsants, antipsychotics or sodium oxybate.

[0007] After withdrawal, a phase of maintaining abstinence is necessary to improve the patient's health and avoid the occurrence of pathologies linked to alcoholism. Abstinence seems to be the only effective method to stop or reduce the psychological effects of alcoholism. It is also the only way to reduce its impact on physical health because it has been shown in numerous publications that the risks of occurrence of alcohol-related morbidities and mortality are a function of the level of daily alcohol consumption.

[0008] Treatment for maintaining abstinence consists of psychosocial monitoring and pharmacological treatments over periods of several months.

[0009] In Italy and Austria, sodium oxybate has been indicated and used in the treatment of alcohol withdrawal and in the maintenance of abstinence for over 20 years and 15 years, respectively. Its efficacy in these indications and its safety have been studied in numerous published clinical studies and the treatment has been administered to hundreds of thousands of patients.

[0010] An article by Giovanni Addolorato, Lorenzo Leggio, Anna Ferrulli, Fabio Caputo, and Antonio Gasbarrini (Expert Opinion on Investigational Drugs. 2009; 18 (5): 675-686) confirms that GHB is of interest in the treatment of alcohol-dependent patients. In this article, effective doses range from 50 to 100 mg / kg per day (administered in three doses) depending on the indication, namely treatment of alcohol withdrawal or maintenance of abstinence.

[0011] Patent application WO 2011 / 119839 describes a pharmaceutical composition with controlled release, not immediate release, although the latter type of release is essential in the treatment of alcohol abstinence. Furthermore, this application refers to the use of GHB in the treatment of narcolepsy and fibromyalgia, which has nothing to do with a treatment intended to maintain alcohol abstinence.

[0012] Patent application WO 2011 / 139271 describes an immediate-release pharmaceutical composition, but concerns the treatment of narcolepsy.

[0013] US patent application US 2010 / 112056 also describes an immediate-release pharmaceutical composition, but relates to the treatment of narcolepsy, fibromyalgia and sleep disorders.

[0014] Patent application WO 2006 / 053186 describes a pharmaceutical composition intended to treat abnormal movements.

[0015] According to a more recent study by K. Skala et al., (Expert Opin. Pharmacoter. 2013; 15 (2)), the recommended dose in the field of maintaining alcohol abstinence is 50 mg / kg divided into three doses per day.

[0016] Based on the set of clinical studies, the Austrian and Italian health authorities have authorized the prescription of sodium oxybate for the maintenance of abstinence with a dosage of 50 mg / kg / day divided into three doses which can be increased up to 100 mg / kg / day.

[0017] In the treatment of narcolepsy, a drug using sodium oxybate as the active ingredient and marketed under the brand name XYREM ®< is recommended with doses of 4.5 to 9 g per day, divided into two doses per night. In addition, various patents describe the application of GHB in the treatment of narcolepsy, for example international application WO 2010 / 053691 or patent application US 2014 / 0348917, both in the name of JAZZ Pharmaceuticals Inc.

[0018] Similarly, US patent 8591922 (Jazz Pharmaceuticals) describes the application of GHB in the treatment of various sleep disorders (including apnea, narcolepsy, cataplexy, insomnia, sleep paralysis).

[0019] It should be noted that patent EP 1017381 (Orphan Medical Inc.) relates to butyrate derivatives, including sodium oxybate, used in the treatment of fibromyalgia and chronic fatigue syndrome. However, since sodium oxybate has not demonstrated a positive benefit-risk ratio in the treatment of fibromyalgia and chronic fatigue syndrome, it has no indication for these pathologies and is therefore theoretically not used for this purpose.

[0020] Document US8729070 discloses a GHB treatment for alcohol dependence in an oral dosage of 50 / mg / kg / day.

[0021] Regardless of the indications used, it is known that, for patients with moderate or severe hepatic impairment, the main pharmacokinetic parameters of GHB or one of its salts are increased by a factor of up to more than 120% for the same dose administered compared to patients without hepatic impairment (Ferrara et al., 1996). Consequently, it is indicated to halve the doses of GHB or its salts for these patients compared to the dosage recommended for patients without hepatic impairment.

[0022] Depending on the dosage and therefore the indication chosen, GHB does not act on the same receptors in the central nervous system due to a different dosage of the active ingredient; the latter always being calculated according to the patient's weight in the context of the treatment of alcohol dependence.

[0023] GHB appears to act primarily on the GABA-B (gamma-aminobutyric acid) receptor but directly or indirectly modulates the activity of other neurotransmitters, including the dopaminergic, serotonergic, opioid, cholinergic, noradrenergic, and glutamatergic systems (Pardi et al., 2006).

[0024] The table below summarizes these different parameters according to the indication. Alcohol addiction Narcolepsy Anesthesia Dosage 50 to 100 mg / kg / day 4.5 to 9 g / day > 10 g Mode of administration Orally 3 doses / day Orally 2 doses / night Intravenous injection Receptors / neurotransmitters predominantly involved at the doses considered Dopaminergics GABA GABA Pharmaceutical effects Stimulant and anxiolytic, can mimic the effects of alcohol Restoration of REM sleep quality Sedative Anesthetic adjuvant

[0025] It is clear from this table that the effect of GHB ranges from a simple stimulant effect to sedation and anesthesia, depending on the doses used.

[0026] Within the scope of the present invention, GHB finds its application in the treatment of alcohol-related disorders.

[0027] More specifically, the application of GHB according to the present invention is in maintaining abstinence from alcohol.

[0028] In this indication, the prior art always gives dosages for GHB expressed in mg / kg, i.e., relative to the patient's weight. These dosages would mean that the optimal dose is a function of the patient's weight. Furthermore, the scientific literature provides no reason to justify a dose relative to the patient's weight, so that the precise choice of dose is essentially empirical, which does not necessarily correspond to the patient's needs.

[0029] Contrary to this practice, the applicant found, quite surprisingly, that there was no correlation between the effective dose and the patient's weight and that better management of alcohol abstinence problems was possible by no longer relying on the patient's weight but on their daily alcohol consumption, regardless of their weight.

[0030] In a recent phase IIb / III clinical study involving 496 patients, four doses of sodium oxybate were compared with placebo to verify that the existing dosage (50 mg / kg / day, which could be increased to 100 mg / kg / day) was optimal in terms of efficacy, safety, and tolerability. The following doses were studied: 0.75 g sodium oxybate three times a day - or 2.25 g per day (99 patients) 1.25 g sodium oxybate three times a day - or 3.75 g per day (99 patients) 1.75 g sodium oxybate three times a day - or 5.25 g per day (99 patients) 2.25 g sodium oxybate three times a day - or 6.75 g per day (100 patients) Placebo group (99 patients)

[0031] The unit doses, packaged in sachets, were administered orally, in solid form, more specifically in the form of granules.

[0032] Efficacy was measured by percentage of abstinent days (PDA), reduction in daily alcohol consumption (DAC), and number of heavy drinking days (HDD). The aim was to analyze the correlation between treatment efficacy and dose in mg / kg / day. For this purpose, conversion to mg / kg / day was performed using the following formula: unit dose in g of sodium oxybate x 3 / patient weight.

[0033] The results for the entire population treated with sodium oxybate (397 patients) are collected in the Figure 1 illustrating the efficacy vs dose relationship in mg / kg.

[0034] Based on the results illustrated in this Figure, there is no relationship between the efficacy of the treatment expressed as a percentage of abstinent days and the dose / weight ratio. Indeed, the correlation coefficient R 2< is close to 0 (it is very precisely 0.0014) showing that there is no correlation between the efficacy and the dose / weight ratio; as for the slope of the line, it can be considered as zero (it is not significantly negative).

[0035] This observation on a large number of patients goes against the state of the art.

[0036] In the remainder of this description, reference will be made to two categories of alcoholic patients: mildly or moderately alcoholic patients; severely or very severely alcoholic patients.

[0037] These categories are based on the daily alcohol consumption of these different patients which appears in the following table: Daily alcohol consumption Patient category Men Women Mildly alcoholic 1 - 40 g / day 1 - 20 g / day Moderately alcoholic 41 - 60 g / day 21 - 40 g / day Heavy alcoholics 61 - 100 g / day 41 - 60 g / day Very heavily alcoholic > 101 g / day > 61 g / day

[0038] These values ​​correspond to the different levels of risk to the patient's health in relation to daily alcohol consumption - low, moderate, high and very high risk - defined by the WHO in its document "WHO / MSD / MSB / 00.4".

[0039] Although it varies slightly from country to country, a standard drink is roughly 10-12g of pure alcohol.

[0040] In the analysis of the results of the phase IIb / III clinical study presented above, the applicant discovered, quite surprisingly, that the optimal dose of sodium oxybate in maintaining abstinence depended on the patient's level of alcohol consumption before withdrawal.

[0041] Low doses (and not weight-dependent) being the most effective for patients with low or moderate alcoholism and higher doses being optimal for patients with high or very high alcoholism; the optimal doses discovered by the applicant are significantly different from those commonly recommended in the prior art, namely 50 to 100 mg / kg / day divided into three doses. Furthermore, the applicant was able to show that an overdose or an underdose compared to the dosage defined by the applicant could significantly reduce the effectiveness of the treatment and increase its side effects.

[0042] Thus, the application of the dosage which the applicant originated leads to an improvement in the effectiveness of the treatment, the prevention of an overdose which could generate undesirable side effects and a simplification in the treatment of the alcoholic patient, whose weight no longer has to be taken into account to adjust the quantity of GHB or one of its therapeutically acceptable salts to be delivered to him daily.

[0043] The present invention therefore relates to immediate-release unit doses containing GHB or one of its therapeutically acceptable salts, such as the sodium salt, which will be administered to patients three times a day and in whom maintenance of alcohol abstinence is sought. The invention is defined in the appended claims.

[0044] In the remainder of the description, the term “GHB” will cover both gamma-hydroxybutyric acid, its pharmaceutically acceptable salts and in particular its sodium salt, called sodium oxybate.

[0045] The unit dose of GHB will be administered in solid, semi-solid, semi-liquid or liquid oral form and will be immediate release as defined below.

[0046] Sodium oxybate is a salt of a weak organic acid, gamma-hydroxybutyric acid, with a pKa of around 4.5, and a strong base, sodium hydroxide. It therefore has a basic pH and is therefore naturally found in ionic form above a pH of around 4.5. No active transport systems are known for sodium oxybate. It is therefore in its non-ionic form, at a pH lower than its pKa (4.5), that it can be absorbed by the digestive mucosa. These conditions are only found in the stomach.

[0047] The average gastric half-emptying time (T50%) in "fasting" conditions, i.e. 30 minutes before and 2 hours after meals, is 15 to 20 minutes. We therefore expect a pharmaceutical form delivering an active product absorbed significantly only in the upper part of the digestive tract to release this product in a time compatible with that of gastric emptying.

[0048] To define immediate-release forms, the US Department of Health and Human Services Food and Drug Administration describes the physical characteristics they must meet in a release model in vitro (Dissolution Testing of Immediate Release Solid Dosage Forms).

[0049] Furthermore, sodium oxybate is classified in case 1 of the BCS (Biopharmaceutics Classification System), i.e. highly soluble and permeable products, in this case more particularly under the aforementioned pH conditions.

[0050] Logically, to include a safety margin, the FDA Guide recommends a standard of more than 85% of active product released in a medium at pH 1 (0.1N HCl), the pH of the stomach under "fasting" conditions, in 15 minutes to respect gastric emptying constraints.

[0051] With regard to the aforementioned granules taken as an example, these include: the active ingredient (GHB or one of its therapeutically acceptable salts); an effervescent agent, such as sodium bicarbonate; a diluent, such as magnesium aluminosilicate, for example that sold under the brand name Neusilin ®<; a binder, such as povidone; a carrier, such as that consisting of sugar spheres (sucrose mixed with starch); a coating agent comprising, for example, hypromellose, stearic acid and talc, optionally a flavoring agent and a sweetening agent;

[0052] The various ingredients, other than the active ingredient, namely the effervescent agent, the diluent, the binder, the carrier, the coating agent, the flavoring agent and the sweetening agent are chosen from those cited in international application WO 2012 / 107652 in the name of the applicant; similarly, the process for obtaining said granules may be that described in said international application.

[0053] Advantageously, these granules have the following composition (% relative to the total weight of the granule): Active ingredient (sodium oxybate): 50 to 60%; Effervescent agent: 5 to 15%; Diluent: 2 to 18%; Binder: 3 to 10%; Carrier (solid core of the granule): 15 to 25%; Coating agent / flavoring agent / sweetening agent / lubricant: 3 to 6%.

[0054] More specifically, these granules have the following composition (% relative to the total weight of the granule): Sodium oxybate: 56.02%; Sodium bicarbonate: 8.40%; Magnesium aluminosilicate: 5.04%; Povidone: 5.60%; Sugar spheres: 19.66% (62.5% to 91.5% sucrose to 8.5% to 37.5% starch); Glazing agent: 0.95% hypromellose, 0.10% stearic acid, 0.05% flavoring agent, 0.83% sucralose (sweetening agent) and 3.34% talc.

[0055] Advantageously, these granules are packaged in sachets, particularly in sticks, which will facilitate things for the practitioner and the patient, avoiding for example any risk of error regarding the dosage, while allowing easier and safer storage and transport.

[0056] In addition to the “granule” form which has just been described, other pharmaceutical forms (solid, semi-solid, semi-liquid or liquid), always for oral administration and immediate release, may be envisaged without departing from the scope of the present invention, provided that these forms have a pharmacokinetic profile similar to that of said granules.

[0057] In the absence of presenting such a profile, the applicant observed a drop in bioavailability of the active product incompatible with the maintenance of efficacy.

[0058] The following tables compare the behaviors in vitro And in vivo of an immediate-release form (SMO.IR) and a non-immediate-release form (SMO.SR). This study was carried out in 12 healthy volunteers in crossover.

[0059] For a pharmaceutical form of sodium oxybate to be considered bioequivalent according to the EMA Guidance on Bioequivalence Studies and likely to meet the efficacy characteristics, the critical pharmacokinetic parameters (CMax and AUC) must be within a range of 80 to 125% of those of the reference product. When the TMax value is critical, which is the case for rapid-acting immediate-release forms, these values ​​must not show a statistically significant difference. PK Parameters (Mean + / - Standard Deviation) SMO.IR Dose of 1.75 g of sodium oxybate SMO.SR 1.75g ​​dose of sodium oxybate CMax (µg / mL) 54.5 + / - 15.7 31.3 + / - 20.7 TMax (h) 0.50 1.25 AUC t (µg / mL*h) 70 + / - 46 52 + / - 39 T ½ (h) 0.56 + / - 0.26 0.56 + / - 0.26 MRT 1.20 + / - 0.47 1.78 + / - 0.45

[0060] T ½: elimination half-life representing the time to eliminate 50% of the absorbed molecules.

[0061] To assess patient exposure to two formulations of the same active product, it is preferable to compare the MRT (Mean Residence Time), which represents the average residence time in the body of a sodium oxybate molecule and which, in this case, takes into account the absorption kinetics.

[0062] Despite logically equivalent elimination T½s, the MRT of the SR form is significantly increased and comes from slower absorption.

[0063] The most important parameter in this evaluation (development of an immediate-release solid form) is the TMax. The TMax of the immediate form (30 minutes) is consistent with the average gastric emptying times and allows for an optimal AUC and CMax (no product loss) and therefore controlled patient exposure. A form that is not immediate-release (SMO.SR) would induce a drop in exposure (significantly reduced AUC and CMax) and a loss of efficacy.

[0064] The applicant found the following values ​​of AUC and CMax, which depend on the doses used for doses of 0.32 g, 0.75 g, 1.75 g and 1.9 g: 0,32 g 0,75 g 1,75 g 1,9 g Average Standard deviation Average Standard deviation Average Standard deviation Average Ecart Type CMax (µg / mL) 10 2,9 23 6,7 54,5 15,7 59,2 17 AUCt (µg / mL*h) 13 8 30 19,7 70 46 76 50

[0065] To meet the characteristics of the invention, the pharmaceutical form must ideally have a TMax of approximately 30 minutes and in any case not greater than 40 minutes (twice the maximum time of a gastric emptying half-life on an empty stomach, i.e. 20 minutes).

[0066] There Figure 2 illustrates the comparison in vivo - in vitro of an immediate-release form and a non-immediate-release form of sodium oxybate; it is clear from this Figure that the release kinetics in vitro and absorption in vivo have the same slope. The dissolution model in vitro is therefore predictive of the PK behavior of formulations.

[0067] In this context, pharmaceutical forms should ideally present a release in vitro of the active product greater than 90% in 15 minutes and in any case greater than 85% to meet the definitions of immediate forms in force (FDA Guides for the development of immediate-release forms).

[0068] Analysis of data from the aforementioned phase IIb / III study showed a statistically highly significant interaction (p = 0.0012) between treatment efficacy, daily alcohol consumption level and the unit dose of sodium oxybate used three times daily.

[0069] For both categories of patients analyzed (see categories described above), linear and quadratic models on the PDA showed statistically significant relationships between the level of efficacy and the dose of sodium oxybate administered to the patients. • Patients with severe or very severe alcoholism

[0070] In patients with severe or very severe alcoholism without liver failure, these statistical models showed that the efficacy of sodium oxybate in maintaining abstinence increased progressively as the unit doses administered three times a day increased, with a statistically significant result achieved with the 1.75 g dose (p < 0.05). This is illustrated in Figure 3 . Polynomial regression models also showed that the optimum in heavily or very heavily alcoholic patients without liver failure is achieved with a dose of approximately 1.5g. Above doses of 1.75g ​​or below 1.25g, the efficacy decreases significantly.

[0071] Thus, doses between 1.25 g and 1.75 g of sodium oxybate three times a day have the highest efficacy results. The dose of 1.50 g three times a day can be considered the optimal dose.

[0072] It is important to emphasize that doses lower than 1.25 g or higher than 1.75 g have shown efficacy results up to 80% lower than the optimal dose. • Patients with low or moderate alcoholism

[0073] In mildly or moderately alcoholic patients without hepatic impairment, statistical models showed optimum efficacy achieved with a dose of 0.75 g three times daily, followed by a decrease in efficacy for doses above 1.25 g of sodium oxybate three times daily.

[0074] Thus, in patients with mild to moderate alcoholism, single doses of 0.75 g to 1.25 g of sodium oxybate three times a day have the highest efficacy results, and the single dose of 0.75 g three times a day represents the optimal dose.

[0075] Doses above 1.25 g have shown a decrease in efficacy of up to approximately 20% of the efficacy of the optimal dose. • Dose-Response Relationship

[0076] As previously mentioned, the unit dose according to the invention is determined based on the patient's level of alcoholism.

[0077] There Figure 4 represents the dose-response identified based on pre-withdrawal alcohol consumption for patients without liver failure.

[0078] For mildly or moderately alcoholic patients without liver failure, the dose of 0.75 g three times a day appears to be the optimal dose.

[0079] For patients with high or very high alcohol consumption without liver failure, the dose of 1.50 g three times a day appears to be the optimal dose.

[0080] As previously stated, doses should be halved for patients with hepatic impairment. Thus, for these patients, the dose ranges for mild to moderate alcoholics are 0.37 to 0.62 g three times a day, and for heavy or very heavy alcoholics, 0.62 to 0.87 g three times a day. The optimal doses within these ranges, 0.37 g for mild to moderate alcoholics and 0.75 g for heavy or very heavy alcoholics, three times a day, are illustrated in Figure 5 .

[0081] As mentioned above, the applicant went against the state of the art which systematically recommends a dosage taking into account the patient's weight.

[0082] Furthermore, it has been demonstrated that an incorrect dosage compared to the optimal dosage defined by the applicant could lead to a significant loss of efficacy with an increase in side effects linked to sodium oxybate.

[0083] The applicant has also illustrated in the Figures below that these situations of delivery of non-optimal dosage can be very frequent for patients without hepatic insufficiency ( Figures 6 And 7 ) or with liver failure ( Figures 8 And 9 ) : Patients sans insuffisance hepatic: the Figure 6 represents the difference (in %) between the dosage based on the state of the art (50 mg / kg / day) and the dosage discovered by the applicant for patients without hepatic insufficiency. This Figure indicates that for a mildly or moderately alcoholic patient weighing 75 kg without hepatic insufficiency, the lower limit of the dosage as defined in the state of the art (50 mg / kg / day) would have resulted in an overdose of around 40% compared to the optimal dosage discovered and established by the applicant. Conversely, for highly or very highly alcoholic patients without hepatic insufficiency, the dosage as defined by the state of the art at 50 mg / kg / day would amount to an underdose of up to -125% depending on the patient's weight compared to the optimal dosage defined by the applicant. Figure 7 presents the differences (expressed in %) between the upper limit of the dosage from the state of the art (100 mg / kg / day) and the dosage discovered by the applicant. This Figure indicates that for a patient with low or moderate alcoholism without hepatic insufficiency, the upper limit of the dosage as defined in the state of the art (100 mg / kg / day) would have resulted in an overdose of the order of 44% to 80% compared to the optimal dosage discovered and established by the applicant. Conversely, and for patients with high or very high alcoholism without hepatic insufficiency, the dosage as defined by the state of the art at 100 mg / kg / day would result in an overdose of between 10% and 55% for patients weighing more than 50 kg compared to the optimal dosage defined by the applicant. Patients avec insuffisance hepatic: the Figure 8 represents the difference (in %) between the dosage based on the state of the art (50 mg / kg / day) and the dosage discovered by the applicant for patients with hepatic insufficiency. This Figure indicates that for a patient with low or moderate alcoholism with hepatic insufficiency, the lower limit of the dosage as defined in the state of the art (50 mg / kg / day) would have resulted in an overdose of the order of 45% to 80% compared to the optimal dosage discovered and established by the applicant. Conversely, and for patients with high or very high alcoholism with hepatic insufficiency, the dosage as defined by the state of the art at 50 mg / kg / day would result in an overdose of between 10% and 55% for patients weighing more than 50 kg compared to the optimal dosage defined by the applicant. Figure 9presents the differences (expressed in %) between the upper limit of the dosage from the state of the art (100 mg / kg / day) and the dosage discovered by the applicant for a patient with hepatic insufficiency. This Figure indicates that for a patient with low or moderate alcoholism with hepatic insufficiency, the upper limit of the dosage as defined in the state of the art (100 mg / kg / day) would have resulted in an overdose of the order of 72% to 89% compared to the optimal dosage discovered and established by the applicant. For patients with high or very high alcoholism with hepatic insufficiency, the dosage as defined by the state of the art at 100 mg / kg / day would result in an overdose of between 44% and 78% compared to the optimal dosage defined by the applicant.

[0084] It is clear from the above that the unit doses according to the invention vary from 0.37 g to 1.75 g in three doses per day, with more restricted ranges and optimal doses having also been determined, taking into account both the patient's blood alcohol level (low to moderately alcoholic on the one hand, or high to very high alcoholic on the other), and whether or not the patient has hepatic insufficiency.

[0085] In summary, the applicant was able to determine that for mildly or moderately alcoholic patients without liver failure, a single dose of 0.75 to 1.25 g, three times a day, gave excellent results. Below 0.75 g, the results appeared to be insufficiently conclusive. Furthermore, doses above 1.25 g three times a day showed significantly less efficacy for mildly or moderately alcoholic patients. The best results were obtained for a single dose of 0.75 g, with three daily doses.

[0086] For mildly or moderately alcoholic patients with hepatic impairment, a single dose range of 0.37 to 0.62 g three times a day has given satisfactory results, with 0.37 g three times a day appearing to be the optimal dose.

[0087] With regard to patients with high or very high alcohol consumption without liver failure, the applicant was able to demonstrate that a single dose of 1.25 to 1.75 g taken three times a day gave the best results; below 1.25 g, the dose was not sufficient for patients with high or very high alcohol consumption and was intended, as just mentioned, for patients with low or moderate alcohol consumption. Above 1.75 g, the effectiveness decreased significantly and the side effects became more numerous and more frequent, in particular a sedation effect with nausea and pronounced fatigue for the patient; the applicant was able to demonstrate that the optimal dose for patients with high or very high alcohol consumption without liver failure was 1.50 g taken three times a day.

[0088] For patients with this level of alcohol consumption and liver failure, doses ranging from 0.62 to 0.87 g three times a day are recommended, with the optimal dose being 0.75 g three times a day.

[0089] Finally, it is only exceptionally that a patient for whom the classic method (dosage determined according to weight) would be used would have the appropriate dose such as that recommended by the applicant;

[0090] In this respect, the applicant was able to show that the classic method could result in significant underdoses or overdoses, which could be up to more than 10 times the optimal dose determined by the applicant.

Claims

1. Unit dose of GHB or of one of therapeutically acceptable salts thereof for use in the maintaining of alcohol abstinence in patients with an alcohol dependence, <b>characterized in that the in vitro release of the active ingredient is more than 85% in fifteen minutes in a medium with pH 1 (HCl 0,1N), and preferably than 90% in fifteen minutes, said unit dose being selected from - a dose comprised between 1,25 and 1,75 g, preferably 1,50 g for use three times per day in the maintaining of alcohol abstinence in patients with severe or very severe alcohol dependence without a liver failure as defined by WHO in WHO / MSD / MSB / 00.4; - a dose comprised between 0,75 and 1,25 g, preferably 0,75 g, for use three times per day in the maintaining of alcohol abstinence in patients with mild or moderate alcohol dependence without a liver failure as defined by WHO in WHO / MSD / MSB / 00.4; - a dose comprised between 0,62 and 0,87 g, preferably 0,75 g, for use three times per day in the maintaining of alcohol abstinence in patients with severe or very severe alcohol dependence with a liver failure as defined by WHO in WHO / MSD / MSB / 00.4; and a dose comprised between 0,37 and 0,62 g, preferably 0,37 g, for use three times per day in the maintaining of alcohol abstinence in patients with mild or moderate alcohol dependence with a liver failure as defined by WHO in WHO / MSD / MSB / 00.4.

2. Unit dose for use according to claim 1, characterized in that it is in a solid, semisolid, semi-liquid or liquid oral form, those different forms having the same pharmacokinetic profile.

3. Unit dose for use according to claim 2, characterized in that said oral form has a TMax less than 40 mn, and preferably less than 30 minutes.

4. Unit dose for use according to one of claims 2 or 3, characterized in that said solid oral form is composed of granules.

5. Unit dose for use according to claim 4, characterized in that said granules are packaged in sachets, in particulars in sticks.

6. Unit dose for use according to one of the preceding claims wherein said active ingredient is sodium oxybate.

7. Unit dose for use according to one of claims 4 or 5, characterized in that said granules have the following composition (given in relation to the weight of the granules): ∘ active ingredient: 50 to 60%; ∘ effervescent agent: 5 à 15%; ∘ diluent: 2 to 18%; ∘ binder: 3 to 10%; ∘ substrate (solid core of the granule): 15 à 25%; ∘ coating agent / flavouring agent / sweetening agent / lubricant: 3 to 6%;8. Unit dose for use according claim 7, <b>characterized in that said granules have the following composition (given in relation to the weight of the granules): ∘ Sodium oxybate (active ingredient): 56,02%; ∘ Sodium bicarbonate (effervescent agent): 8,40% ∘ Magnesium aluminosilicate (diluent): 5,04%; ∘ Povidone (binder): 5,60%; ∘ Sugar spheres (substrate): 19,66% (in a proportion of 62,5% to 91,5% sucrose per 8,5% to 37,5% starch); ∘ Coating agent: 0,95% hypromellose, 0,10% stearic acid, 0,05% flavouring agent, 0,83% sucralose (sweetening agent) and 3,34% talc.