US20180263936A1 - Gamma-hydroxybutyrate compositions and their use for the treatment of disorders - Google Patents

Gamma-hydroxybutyrate compositions and their use for the treatment of disorders Download PDF

Info

Publication number
US20180263936A1
US20180263936A1 US15/709,262 US201715709262A US2018263936A1 US 20180263936 A1 US20180263936 A1 US 20180263936A1 US 201715709262 A US201715709262 A US 201715709262A US 2018263936 A1 US2018263936 A1 US 2018263936A1
Authority
US
United States
Prior art keywords
ghb
pharmaceutical composition
certain embodiments
mixture
salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/709,262
Other languages
English (en)
Inventor
Clark P. Allphin
Gunjan Junnarkar
Roman Skowronski
Cuiping Chen
Katayoun Zomorodi
Mark Eller
Philip McGarrigle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jazz Pharmaceuticals Ireland Ltd
Original Assignee
Jazz Pharmaceuticals Ireland Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=63521436&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20180263936(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Jazz Pharmaceuticals Ireland Ltd filed Critical Jazz Pharmaceuticals Ireland Ltd
Priority to US15/709,262 priority Critical patent/US20180263936A1/en
Priority to TW111146727A priority patent/TWI812557B/zh
Priority to JP2019550565A priority patent/JP2020510060A/ja
Priority to TW107109130A priority patent/TW201836596A/zh
Priority to EP18712555.4A priority patent/EP3595648A1/en
Priority to CA3056316A priority patent/CA3056316A1/en
Priority to PCT/EP2018/056745 priority patent/WO2018167303A1/en
Assigned to JAZZ PHARMACEUTICALS IRELAND LIMITED reassignment JAZZ PHARMACEUTICALS IRELAND LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Jazz Pharmaceuticals, Inc.
Assigned to Jazz Pharmaceuticals, Inc. reassignment Jazz Pharmaceuticals, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SKOWRONSKI, ROMAN, ELLER, MARK, ZOMORODI, Katayoun, JUNNARKAR, GUNJAN, CHEN, CUIPING, MCGARRIGLE, PHILIP, ALLPHIN, CLARK P.
Publication of US20180263936A1 publication Critical patent/US20180263936A1/en
Priority to US16/575,213 priority patent/US20200113853A1/en
Priority to US17/131,418 priority patent/US11426373B2/en
Priority to US17/860,498 priority patent/US20220362185A1/en
Priority to JP2022196041A priority patent/JP2023036649A/ja
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • compositions and formulations comprising salts of gamma-hydroxybutyrate (GHB).
  • the salts encompass more than one type of cation.
  • methods of making the pharmaceutical compositions and formulations, and methods of the treatment of disorders including fibromyalgia and sleep disorders are also provided herein.
  • Such pharmaceutical compositions and formulations are for treating diseases or disorders including fibromyalgia and sleep disorders.
  • sleep disorders include apnea, sleep time disturbances, narcolepsy, cataplexy, sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • Na.GHB sodium oxybate
  • Xyrem® Jazz Pharmaceuticals
  • Na.GHB has also been reported to be effective for relieving pain and improving function in patients with fibromyalgia syndrome (See Scharf et al., 2003 , J. Rheumatol. 30: 1070; Russell et al., 2009 , Arthritis. Rheum.
  • Xyrem® for use with patients with narcolepsy, is a chronically used product which requires high levels of the drug.
  • the amount of sodium intake from the drug significantly increases the daily sodium intake for patients, which is undesirable for patients with hypertension, heart disease, renal disease or at risk of stroke.
  • Xyrem® is administered to a broad population, there is a need for GHB formulations that minimize the undesirable side effects of the sodium, particularly in patients with hypertension, heart disease, renal disease or at risk of stroke, yet provide additional health benefits from the presence of the other salts. It is desirable that such modified formulations provide good solubility, stability and purity in order to provide safe, effective and consistent doses to patients, and also display acceptable pharmacodynamic and pharmacokinetic properties. See U.S. Pat. Nos. 8,591,922; 8,901,173; and 9,132,107; which are incorporated by reference in their entireties.
  • compositions and formulations comprising salts of gamma-hydroxybutyrate (“GHB”) which are useful in the treatment of conditions responsive to GHB, for example, fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, excessive daytime sleepiness (EDS) cataplexy, sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • GHB gamma-hydroxybutyrate
  • One embodiment, as provided herein, is a GHB formulation with a reduction in sodium content.
  • Another embodiment, as provided herein, is a GHB formulation with a reduced sodium content and which is bioequivalent to Xyrem®.
  • the reduction in sodium content involves use of other cations such as potassium, calcium, magnesium, and others.
  • compositions expressed as percentages in this application refer to molar equivalent percentage (% molar equivalents) of each salt of oxybate or GHB. This is usually close to, but not the same as, a composition that would be expressed as wt/wt %.
  • oxybate and “GHB” are used interchangeably.
  • the formulation is a pharmaceutical composition of GHB comprising a mixture of two or more salts of GHB, wherein the mixture comprises at least 50% of a sodium salt of gamma-hydroxybutyrate (Na.GHB), and wherein the mixture further comprises one or more of a potassium salt of gamma-hydroxybutyrate (K.GHB) and a calcium salt of gamma-hydroxybutyrate (Ca.(GHB) 2 ).
  • the Na.GHB salt is present in the mixture in about 50%, and up to 55%, 60%, 70% or 80%.
  • the pharmaceutical composition does not comprise a substantial amount of a magnesium salt of gamma-hydroxybutyrate (Mg.(GHB) 2 ).
  • the pharmaceutical composition is given to the patient in an aqueous solution with a volume of between 25 and 100 mL, 25 and 75 mL, or 55 and 65 mL.
  • the pharmaceutical composition when administered to a patient, is bioequivalent to the average maximum GHB plasma concentration (Cmax) and the average maximum GHB plasma area under the curve (AUC) of the Cmax of Na.GHB within 80% to 125%.
  • the pharmaceutical composition comprises a mixture of three salts of GHB, wherein the mixture comprises at least 50% of Na.GHB, and further comprises K.GHB and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of three GHB salts, wherein the mixture comprises between 50 and 60% of Na.GHB, and further comprises between 20 and 40% K.GHB, and between 10 and 20% Ca.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of three GHB salts, wherein the mixture comprises about 50% of Na.GHB, 34% K.GHB, and 16% Ca.(GHB) 2 for each GHB salt.
  • compositions and/or formulations disclosed herein can be used to treat a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g., Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g., Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety,
  • the pharmaceutical compositions disclosed herein comprise less than 100 mL of an aqueous solution, wherein the aqueous solution comprises a mixture of two or more GHB salts, the mixture comprising between 40% to 50% Na.GHB and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • the pharmaceutical compositions disclosed herein do not comprise a substantial amount Ca.(GHB) 2 ) or Mg.(GHB) 2 .
  • the pharmaceutical composition comprises about 8% Na.GHB, 23% K.GHB, 48% Ca.(GHB) 2 and 21% Mg.(GHB) 2 .
  • this pharmaceutical composition can be used to treat the diseases or conditions listed above.
  • compositions and/or formulations disclosed herein when administered to a patient, have a lower average maximum GHB plasma concentration (Cmax) than the Cmax of Na.GHB.
  • Xyrem® is a commercially sold product comprised of 100% sodium oxybate (Na.GHB), and is prescribed for twice nightly use for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy.
  • Another embodiment has the doses in reverse order and a further embodiment uses similar doses of either formulation.
  • the first dose can be administered within 4 hours of eating and produces a GHB Cmax lower than the Cmax of Na.GHB, but may have less of a food effect.
  • compositions and formulations provided herein can be used to treat a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g., Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g., Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • the formulations and pharmaceutical compositions provided herein can be used to treat conditions responsive to GHB, for example, fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • compositions and formulations disclosed herein is for use in a method of treating a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g. Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • a disease or condition selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g. Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • the formulations and pharmaceutical compositions disclosed herein are used in a method of treating conditions responsive to GHB, for example, fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • a disease or condition in a patient that is suitable for treatment with GHB, comprising administering to the patient the pharmaceutical compositions and formulations disclosed herein.
  • the disease or condition is selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder (e.g., Parkinson's Disease and depression), an endocrine disturbance, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • the disease or condition is elected from the group consisting of fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • methods of treatment disclosed herein comprises one or more steps, as follows: (i) diluting an aqueous solution comprising a mixture of two or more GHB salts, the mixture comprising less than 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , to provide a first dose of GHB salts; (ii) diluting an aqueous solution comprising a mixture of two or more GHB salts, the mixture comprising from about 50% to about 80% of Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , to provide a second dose of GHB salts; (iii) orally administering to a patient having a disease or condition that is suitable for treatment with GHB the first dose; and (iv) orally administering to the patient the second dose within 2.5 to 4 hours following the first dose.
  • compositions and formulations disclosed herein is for use in a method of treating a disease or condition in a patient that is suitable for treatment with GHB, comprising administering to the patient the pharmaceutical compositions and formulations disclosed herein.
  • the pharmaceutical compositions and formulations disclosed herein is for use in a method of treating a disease or condition in a patient further comprises one or more steps, as follows: (i) diluting an aqueous solution comprising a mixture of two or more GHB salts, the mixture comprising less than 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , to provide a first dose of GHB salts; (ii) diluting an aqueous solution comprising a mixture of two or more GHB salts, the mixture comprising from about 50% to about 80% of Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , to provide a second dose of GHB salts; (iii) orally administering to a patient having a disease or condition that is suitable for treatment with GHB the first dose; and (i) diluting
  • compositions disclosed herein are methods of making the pharmaceutical compositions disclosed herein.
  • FIG. 1 shows the plasma GHB concentration vs time for Formulation “O” (8% Na.GHB, 23% K.GHB, 48% Ca.(GHB), and 21% Mg.(GHB) 2 ) compared to Xyrem® (“X”) given in either the fed or fasted state ( , Xyrem® fasted; , Formulation “O” fasted; Xyrem® fed; Formulation “O” fed).
  • X Xyrem®
  • FIG. 2 shows the plasma GHB concentration vs time for blends of Formulation “O” and Xyrem® (“X”) in proportions of 100% Xyrem®, 44% Xyrem®, and 17% Xyrem®, respectively ( , fasted 4.5 g “X”; , fasted 2.5 g “O”+2.0 g “X”; , fasted 3.75 g “O”+0.75 g “X”).
  • the objective was to determine how much sodium (or Xyrem®) would be required to achieve bioequivalence in the fasted state.
  • FIG. 3 shows the plasma GHB concentration vs time for various mixed oxybate salt formulations compared to Xyrem® in the fasted state where both are given at a lower volume of administration of 60 mL ( , Xyrem® (100% Na); , Formulation 507D (50% Na, 34% K, 16% Ca, 0% Mg); , 507C (33% Na, 0% K, 48% Ca, 19% Mg); , 507A (33% Na, 34% K, 33% Ca, 0% Mg); , 507G (23% Na, 19% K, 40% Ca, 18% Mg)).
  • FIG. 4A-4B compare Xyrem® and Formulation “O” when given fasted with 60 mL or 240 mL water or when given fed with 60 mL water.
  • FIG. 4A Plasma GHB concentration when Xyrem® was given (fasted) with 60 mL or 240 mL water or when Xyrem® was given (fed) with 60 mL water ( , fasted 240 mL; , fasted 60 mL; , fed 60 mL).
  • FIG. 4A Plasma GHB concentration when Xyrem® was given (fasted) with 60 mL or 240 mL water or when Xyrem® was given (fed) with 60 mL water ( , fasted 240 mL; , fasted 60 mL; , fed 60 mL).
  • FIG. 5A-5B show the relationship between Cmax ratio (to Xyrem®) and calcium content or sodium content of the example formulations subjected to fasted-state PK evaluations when administered in either 240 mL aqueous volume or 60 mL aqueous volume.
  • FIG. 5A (Top) Relationship between Cmax ratio (to Xyrem®) and calcium content of the example formulations subjected to fasted-state PK evaluations when administered in either 240 mL aqueous volume ( , Cmax, 60 mL; , Cmax, 240 mL).
  • FIG. 5A (Top) Relationship between Cmax ratio (to Xyrem®) and calcium content of the example formulations subjected to fasted-state PK evaluations when administered in either 240 mL aqueous volume ( , Cmax, 60 mL; , Cmax, 240 mL).
  • FIG. 6 is a graph showing the expected behavior of taking separate formulations as part of an equally divided dose given 4 h apart ( , 1st dose Xyrem® fed, 2nd dose Xyrem® fasted; , 1st dose Formulation “O” fed, 2nd dose Formulation 507D fasted).
  • Formulation “O” is given initially and then formulation “507D” is given 4 h later. This is compared to Xyrem® given both times.
  • GHB Gamma-hydroxybutyrate
  • oxybate is an endogenous compound with hypnotic properties that is found in human body tissues, such as the mammalian brain.
  • GHB is an endogenous compound with hypnotic properties that is found in human body tissues, such as the mammalian brain.
  • the neuropharmacologic effects of GHB include increases in brain acetylcholine, increases in brain dopamine, inhibition of GABA-ketoglutarate transaminase and depression of glucose utilization but not oxygen consumption in the brain.
  • GHB treatment substantially reduces the signs and symptoms of narcolepsy, i.e., daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations.
  • GHB increases total sleep time and REM sleep, and it decreases REM latency, reduces sleep apnea, and improves general anesthesia (see, e.g., U.S. Pat. Nos. 6,472,431; 6,780,889; 7,262,219; 7,851,506; 8,263,650; 8,324,275; and 8,772,302 each of which is incorporated herein by reference in its entirety).
  • Xyrem® is a commercially sold product comprised of 100% sodium oxybate (Na.GHB) and is approved for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy.
  • Na.GHB has also been reported to be effective for relieving pain and improving function in patients with fibromyalgia syndrome, and in alleviating excessive daytime sleepiness and fatigue in patients with Parkinson's disease, improving myoclonus and essential tremor, and reducing tardive dyskinesia and bipolar disorder. See the references that are incorporated at the end of U.S. Pat. No. 6,472,431.
  • Xyrem® for use with patients with narcolepsy, is a chronically used product which requires high levels of the drug.
  • the amount of sodium intake from the drug significantly increases the daily sodium intake for patients, which is undesirable for patients with hypertension, heart disease, renal disease or at risk of stroke.
  • GHB formulations with lower sodium such as those provided herein, particularly for patients with hypertension, heart disease, renal disease or at risk of stroke, yet provide additional health benefits from the presence of the other salts.
  • the therapeutic dose of 71.4 mEq/day (9 g sodium oxybate) is sufficiently high that shifting from sodium to another cation can push limits on acceptable daily intake of other cations and potentially cause other problems for certain patients.
  • potassium has poor tolerability in solution at high doses given on an empty stomach and can also be problematic for patients with kidney impairment. Therefore, formulations which reduce or eliminate sodium without exceeding levels of concern for other cations are particularly desirable.
  • Xyrem® is provided as an oral solution consisting of 500 mg/mL sodium oxybate (Na.GHB) that is pH adjusted with malic acid. Xyrem® is rapidly and well absorbed when given on an empty stomach. The absolute bioavailability for 2.25 g and 4.45 g sodium oxybate doses, relative to IV administration, is 88%. See the Xyrem® Product Insert. As a result, sodium oxybate is generally considered to be a high solubility, high permeability drug. (See Yu et al., Pharm. Res. 19 (7) 921-925).
  • one object of the present disclosure is to provide alternative formulations of GHB which are bioequivalent to Xyrem®. Provided herein are such alternative formulations which surprisingly display the desired bioequivalence.
  • GHB gamma-hydroxybutyrate
  • gamma-hydroxybutyric acid refers to the protonated form (conjugate acid) of gamma-hydroxybutyrate. Without being limited by theory, gamma-hydroxybutyric acid is believed to have the following structure:
  • sodium gamma-hydroxybutyrate Na.GHB
  • sodium oxybate Na*oxybate
  • K.GHB potassium gamma-hydroxybutyrate
  • K.oxybate potassium salt form of gamma-hydroxybutyric acid having the molecular weight of 142.19.
  • K.GHB is believed to have the following structure:
  • magnesium gamma-hydroxybutyrate Mg.(GHB) 2
  • magnesium oxybate Mg.oxybate refers to the magnesium salt form of gamma-hydroxybutyric acid having the molecular weight of 230.50. Without being limited by theory, Mg.(GHB) 2 is believed to have the following structure:
  • calcium gamma-hydroxybutyrate Ca.(GHB) 2
  • calcium oxybate Ca.oxybate
  • GBL gamma-butyrolactone
  • the term “patient” refers to a mammal, particularly a human.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value.
  • pharmaceutically acceptable it is meant the active ingredient, cation, salt, diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not unduly deleterious, for example, that the active ingredient, cation, salt, diluent, excipient or carrier does not produce an adverse, allergic or other untoward reaction, when administered to an animal, or a human, as appropriate.
  • salt refers to a compound formed by the interaction of an acid and a base, the hydrogen atoms of the acid being replaced by the positive ion or cation of the base.
  • Pharmaceutically acceptable salts include inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as malic, acetic, oxalic, tartaric, mandelic, and the like. Salts formed can also be derived from inorganic bases such as, for example, sodium, potassium, silicates, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the salt is formed from an inorganic base that is a metal, for example, an alkali metal, such as lithium, potassium, sodium, or the like, an alkaline earth metal, such as magnesium, calcium, barium, or the like, or aluminum or zinc.
  • Other salts may comprise ammonium.
  • Alkali metals, such as lithium, potassium, sodium, and the like may be used, preferably with an acid to form a pH adjusting agent.
  • Examples of pharmaceutically acceptable base addition salts include those derived from inorganic bases like sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, or ammonium hydroxide, and the like (See, e.g., Berge et al., 1977 , J. Pharm. Sci. 66: 1).
  • salt of GHB refers to a compound formed by the interaction of gamma-hydroxybutyric acid (the conjugate acid of GHB) with a base, for example, NaOH, KOH, Mg(OH) 2 , and Ca(OH) 2 , and the like, the hydrogen atoms of the acid being replaced by the positive ion or cation of the base.
  • a base for example, NaOH, KOH, Mg(OH) 2 , and Ca(OH) 2 , and the like, the hydrogen atoms of the acid being replaced by the positive ion or cation of the base.
  • Such salts may include, for example, Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 , and the like.
  • salts may be in solid form, or such salts may be in partially or fully solvated form, for example, as when dissolved in an aqueous medium. It will be further understood by those skilled in the art, that, depending on the solubility of the salt in the aqueous medium, that the salt may be present in the aqueous medium as solvated cation(s) and anion(s), or as a precipitated solid, as illustrated below for the solubility equilibrium of Ca.(GHB) 2 :
  • mixture of salts refers to salts of GHB where two or more different cations are present in combination with each other in a composition.
  • Such mixtures of salts may include, for example, two or more salts selected from the group consisting of Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 .
  • Xyrem® contains 500 mg/mL Na.GHB.
  • concentration in mg/mL will vary between formulations and/or pharmaceutical compositions of the same GHB strength.
  • a GHB concentration of 409 mg/mL is equivalent to the GHB content in 500 mg/mL of Na.GHB.
  • wt/wt % refers to the normalized weight percent of a particular salt in a salt mixture. A sample calculation of wt/wt % is provided in Example 1 of the present disclosure.
  • wt/wt % ratio refers to the ratio of wt/wt % values in a mixture of salt.
  • the salts Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 are present in a wt/wt %'s of 8%, 32%, 20% and 40%, respectively
  • the wt/wt % ratio of Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 in the mixture is 8%:32%:20%:40%.
  • % molar equivalents and “% mol. equiv.,” as used herein, refer to molar composition of salts expressed as a percent of GHB (or “oxybate”) equivalents.
  • formulations and/or pharmaceutical compositions as described herein comprise mixtures with varying percentages of oxybate, expressed as % molar equivalents (% mol. equiv.) of Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 .
  • each GHB unit is considered to be one molar equivalent
  • the monovalent cations, Na + and K + have one molar equivalent per salt
  • the divalent cations, Mg +2 and Ca +2 have two molar equivalents per salt.
  • a sample calculation of % mol. equiv. is provided in the Examples of the present disclosure.
  • compositions expressed as percentages in this application refer to molar equivalent percentage (% molar equivalents) of each oxybate salt. This is usually close to, but not the same as, the composition that would be expressed as wt/wt %.
  • buffering agent refers to a weak acid or base used to maintain the pH of a solution near a chosen pH value after the addition of another acidic or basic compound.
  • the function of such an agent is to prevent the change in pH when acids or bases are added to a solution.
  • agents may be acids, bases, or combinations thereof.
  • adjusting agent refers to an acid or base used to alter the pH of a solution to a chosen pH value.
  • the function of such an agent is to alter the pH of a solution to the desired value subsequent to the addition of acidic or basic compounds.
  • acid refers to a substance which accepts a share in a pair of electrons. Such substances include malic acid, citric acid, acetic acid, boric acid, lactic acid, hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, nitric acid, and the like.
  • base refers to a substance which shares a pair of electrons.
  • Such substances include sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and the like.
  • chemically stable refers to a chemical compound which is not particularly reactive in a specific environment and retains its useful properties on a timescale of its expected usefulness. Specifically, the usefulness of the compound is maintained in the presence of air, moisture, or heat. Conversely, the compound lacks chemical stability if it decomposes under the conditions of a specific environment. As used herein in certain embodiments, “chemically stable” may mean resistant to degradation of GHB into its known or unknown decomposition elements. The level of GBL that is acceptable can be up to 0.15% of the formulation as per the ICH guidelines for shelf-life determination.
  • microbial refers to a microscopic organism that comprises either a single cell, cell cluster or multicellular organism.
  • resistant to microbial growth or “resistant to microbial challenge,” as used herein, means that the compositions or formulations meet the criteria set by the Food and Drug Administration and the U.S. Pharmacopoeia for products made with aqueous bases or vehicles, which for bacteria means not less than a 1.0 log reduction from the initial count at 14 days, and no increase from the 14 days count at 28 days, and for yeast and molds, no increase from the initial calculated count at 14 and 28 days.
  • preservative refers to a naturally occurring or synthetically produced substance which can be added to food, pharmaceuticals, paints, biological samples, wood, etc. to prevent decomposition by microbial growth or by chemical decomposition.
  • formulation refers to a stable and pharmaceutically acceptable preparation of a pharmaceutical composition disclosed herein.
  • liquid formulation refers to a water-based formulation, in particular, a formulation that is an aqueous solution.
  • low volume or “low aqueous volume” or “reduced volume,” as used herein, refers to an aqueous solution of about 100 mL or less
  • volume of administration refers to the volume of aqueous material used to ingest or swallow the formulations and/or pharmaceutical compositions comprising the GHB salts, as disclosed herein, including before or immediately after the formulations and/or pharmaceutical compositions are ingested or swallowed.
  • This amount can, for example, include the formulations and/or pharmaceutical disclosed herein and any additional aqueous material used to dilute, wash down or chase the formulations and/or pharmaceutical compositions.
  • the additional aqueous material includes for example, water and flavored beverages.
  • treating refers to ingesting or consuming calories and/or nutrients by way of solid or liquid food substances.
  • cataplexy refers to a condition where a patient exhibits a sudden and transient loss of muscle tone, often triggered by emotions.
  • daytime sleepiness refers to a condition where a patient exhibits persistent sleepiness, and often a general lack of energy, even after apparent adequate night time sleep.
  • neuropsy refers to a chronic sleep disorder characterized by excessive sleepiness and sleep attacks at inappropriate times.
  • apnea refers to a condition where a patient suspends external breathing.
  • sleep time disturbances refers to a condition where a patient exhibits abnormal sleep patterns. Sleep time disturbances can be serious enough to interfere with normal physical, mental and emotional functioning.
  • muscle paralysis refers to a condition in which a patient who is falling asleep or awakening form sleep experience an inability to move. It is a transition state between wakefulness and rest characterized by complete muscle weakness.
  • hypoxia refers to a transition state between wakefulness and sleep where a patient experiences vivid hallucinations.
  • sleep arousal refers to a condition where a patient engages in sexual acts while still asleep.
  • insomnia refers to a condition where a patient has difficulties falling asleep and maintaining sleep.
  • nocturnal myoclonus refers to a condition where a patient has repetitive movement of the limbs during sleep or even wakefulness which is sometimes confused with a seizure.
  • flavoring refers to a substance that alters the flavor of the composition during oral consumption.
  • a type of “flavoring agent” would be a sweetener.
  • coloring refers to a substance that alters the color of the composition.
  • bioequivalent describes a formulation and/or pharmaceutical composition that is therapeutically equivalent to a reference product (e.g. Xyrem®) when given under the same conditions in a pharmacokinetic evaluation conforming to FDA Guidance on Bioequivalence Testing; regardless of biopharmaceutical class (see http://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf, see also https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4241B1-02-23-FDA-Bioequiv%20OGD%20Oct%206%202006%20Background.pdf).
  • a reference product e.g. Xyrem®
  • a value that is “bioequivalent”, as used herein, is meant to refer to a pharmacokinetic value (such as the Cmax or AUC of a formulation described herein) that exhibits substantially similar pharmacokinetic profiles or therapeutic effects. Bioequivalence may be demonstrated through several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies.
  • bioequivalence may be demonstrated using any suitable pharmacokinetic measures or combination of pharmacokinetic measures known in the art, including loading dose, steady-state dose, initial or steady-state concentration of drug, biological half-life, elimination rate, area under the curve (AUC), clearance, the peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency.
  • a value is bioequivalent to a reference pharmacokinetic value when the geometric mean of the AUC and/or the Cmax is between 80% and 125% (e.g., at 90% confidence interval) of the reference pharmacokinetic value.
  • a pharmaceutical composition is bioequivalent to a reference pharmaceutical composition when the pharmaceutical composition produces an average Cmax and/or AUC that is substantially the same as the Cmax and/or AUC of the reference pharmaceutical composition when administered under the same conditions.
  • a pharmaceutical composition is bioequivalent to a reference pharmaceutical composition when the pharmaceutical composition produces a Cmax and/or AUC that is within 80% and 125% of the Cmax and/or AUC of the reference pharmaceutical composition when administered under the same condition.
  • a pharmaceutical composition is bioequivalent to Xyrem® when the pharmaceutical composition produces an average Cmax and/AUC is between 80% and 125% of the Cmax and/or AUC of Xyrem® when administered under the same conditions.
  • compositions comprising gamma-hydroxybutyrate (GHB) and one or more pharmaceutically acceptable cations of an alkali metal or an alkaline earth metal.
  • alkali metal means any of the elements found in Group IA of the periodic table, including, for example, lithium, sodium, and potassium.
  • alkaline earth metal means any of the elements found in Group II of the periodic table, including, for example, magnesium and calcium.
  • the pharmaceutical compositions comprise GHB and more than one pharmaceutically acceptable cations of an alkali metal or an alkaline earth metal.
  • the pharmaceutical compositions comprise GHB and more than one (two or more) cations selected from the group consisting of Na + , K + , Mg +2 , and Ca +2 . In certain embodiments, the pharmaceutical compositions comprise GHB and all three cations selected from the group consisting of Na + , K + , and Ca +2 . In certain embodiments, the pharmaceutical compositions comprise less than 100% of the cation Na + , so as to minimize the amount of sodium, particularly in patients with hypertension, heart disease, renal disease or at risk of stroke or to improve the taste of the compositions. In certain embodiments, the pharmaceutical compositions comprise from about 50% to about 80% of the cation Na + . In other embodiments, the pharmaceutical compositions comprise from about 0% to about 40% of the cation Na + . Each embodiment has a different advantage.
  • compositions comprising salts of GHB.
  • salt of GHB or “salts of GHB” is used interchangeably with the term “cation.”
  • a pharmaceutical composition comprising GHB and the four cations Na + , K + , Mg +2 , and Ca +2 will be understood by those skilled in the art to also mean a pharmaceutical composition comprising the salts Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 .
  • salts may be in solid form, or may be in partially or fully solvated form, for example, as when dissolved in an aqueous medium.
  • the salt may be present in the aqueous medium as solvated cation(s) and anion(s), or as a precipitated solid.
  • the pharmaceutical composition comprises a mixture of two or more GHB salts, wherein the mixture comprises Na.GHB, and further comprises any one of the salts selected from the group consisting of K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises Na.GHB, K.GHB, and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises Na.GHB, and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises Na.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises Na.GHB and K.GHB.
  • the pharmaceutical composition comprises Na.GHB, K.GHB, and Mg.(GHB) 2 .
  • the pharmaceutical composition comprises Na.GHB and Mg.(GHB) 2 .
  • the Na.GHB salt is present in the mixture in a percentage of at least 50%. In certain embodiments, the Na.GHB salt is present in about 50% to about 80%. In certain embodiments, the Na.GHB salt is present in about 50% to about 70%. In certain embodiments, the Na.GHB salt is present in about 50% to about 60%. In certain embodiments, the Na.GHB salt is present in about 50% to about 55%. In certain embodiments, the Na.GHB salt is present between 40% and 50% and in others between 5% to 45%. In certain embodiments, the Na.GHB salt is present in about 5% to 35%. In certain embodiments, the Na.GHB salt is present in about 5% to 25%. In certain embodiments, the Na.GHB salt is present in about 5% to 10%.
  • the mixture comprises between 40% and 50% Na.GHB, and in others between 45% and 50% Na.GHB. In certain embodiments, the mixture comprises about 5% to 45% Na.GHB.
  • the mixture comprises at least 50% Na.GHB. In certain embodiments, the mixture comprises about 50% to about 80% Na.GHB. In certain embodiments, the mixture comprises about 50% to about 70% Na.GHB. In certain embodiments, the mixture comprises about 50% to about 60% Na.GHB. In certain embodiments, the mixture comprises about 50% to about 55% Na.GHB. In certain embodiments, the mixture comprises between 40% and 50% Na.GHB, and in others between 5% to 45% Na.GHB. In certain embodiments, the mixture comprises about 5% to 35% Na.GHB. In certain embodiments, the mixture comprises about 5% to 25% Na.GHB. In certain embodiments, the mixture comprises about 5% to 10% Na.GHB.
  • the mixture comprises between 40% and 50% Na.GHB, and in others between 45% and 50% Na.GHB. In certain embodiments, the mixture comprises about 5% to 45% Na.GHB.
  • the remaining one, two or three or more cations that are present in the mixture in amounts to make up the remainder of the cations in the formulation and/or pharmaceutical composition.
  • the amount of each depends on the amount of Na + and the amount of other cations. For example, if Na + is present at 50% and Ca +2 and K + are also present, then Ca +2 and K + can each be present in varying amount from 5-40% to add up to the remaining 50%. If Mg +2 is also present in the mixture then the non-sodium component 50% is divided three ways.
  • the mixture does not comprise a significant amount of Mg.(GHB) 2 or Ca.(GHB) 2 , and therefore the formulation and/or pharmaceutical composition does not have a significant amount of Mg.(GHB) 2 or Ca.(GHB) 2 .
  • Care can be taken to adjust any specific cation concentration to levels that are acceptable to patients. It may not be preferred to add any cation to a level that might be disadvantageous to patients generally. For example, potassium has poor tolerability in solution at high doses given on an empty stomach and can also be a problem for patients with kidney impairment.
  • Na + is present at 50% and Ca 2+ and K + are also present, then Ca 2+ and K + can each be present in varying amount from 5-45% to add up to the remaining 50%.
  • the K.GHB, Mg.(GHB) 2 or Ca.(GHB) 2 salt is present in the mixture at about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%.
  • the K.GHB, Mg.(GHB) 2 or the Ca.(GHB) 2 salt is absent.
  • the mixture comprises K.GHB, Mg.(GHB) 2 or the Ca.(GHB) 2 in about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%.
  • the mixture comprises about 0% K.GHB.
  • the mixture comprises about 0% Mg.(GHB) 2 .
  • the mixture comprises about 0% Ca.(GHB) 2 .
  • the mixture comprises K.GHB in about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%.
  • the mixture comprises about 0% K.GHB.
  • the mixture comprises Mg.(GHB) 2 in about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%.
  • the mixture comprises about 0% Mg.(GHB) 2 .
  • the mixture comprises Ca.(GHB) 2 in about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%.
  • the mixture comprises about 0% Ca.(GHB) 2 .
  • the pharmaceutical composition has reduced sodium compared to Xyrem®, wherein the Na.GHB salt is present in the mixture at about 50% to about 80%.
  • the pharmaceutical composition comprises a mixture of two or more GHB salts, wherein the mixture comprises at least 50% of a sodium salt of Na.GHB, and further comprises one or more of the following salts, K.GHB, Ca.(GHB) 2 and Mg.(GHB) 2 .
  • the Na.GHB salt is present in the mixture at about 50% to 80%.
  • the Na.GHB salt is present in the mixture at about 50% to 70%.
  • the Na.GHB salt is present in the mixture at about 50% to 60%.
  • the Na.GHB salt is present in the mixture at about 50% to 55%.
  • the pharmaceutical composition comprises a mixture of two or more salts of GHB, wherein the mixture comprises of at least 50% of Na.GHB and further comprises one or more of K.GHB and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of two or more salts of GHB, wherein the mixture consists essentially of at least 50% of Na.GHB and one or more of K.GHB and Ca.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of three or more salts of GHB.
  • the pharmaceutical composition does not comprise a substantial amount of Mg.(GHB) 2 or Ca.(GHB) 2 .
  • the mixture does not comprise a substantial amount of Mg.(GHB) 2 or Ca.(GHB) 2 .
  • the mixture consists of 50% to 80% Na.GHB, at least 10% K.GHB, and at least 10% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises between 50% to 80% Na.GHB, between 30% to 40% K.GHB, and between 10% to 20% Ca.(GHB) 2 . In certain embodiments, the mixture comprises between 50% to 80% Na.GHB, between 10% to 40% K.GHB, and between 10% to 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture consists essentially of between 50% to 80% Na.GHB, between 10% to 40% K.GHB, and between 10% to 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises about 50% to 80% Na.GHB, about 30% to 40% K.GHB, and about 10% to 20% Ca.(GHB) 2 . In certain embodiments, the mixture comprises about 50% to 80% Na.GHB, about 10% to 40% K.GHB, and about 10% to 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture consists essentially of about 50% to 80% Na.GHB, about 10% to 40% K.GHB, and about 10% to 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises between about 50% to 80% Na.GHB, between about 30% to 40% K.GHB, and between about 10% to 20% Ca.(GHB) 2 . In certain embodiments, the mixture comprises between about 50% to 80% Na.GHB, between about 10% to 40% K.GHB, and between about 10% to 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture consists essentially of between about 50% to 80% Na.GHB, between about 10% to 40% K.GHB, and between about 10% and 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises between 50% and 60% Na.GHB, between 20% and 40% K.GHB, and between 10% and 20% Ca.(GHB) 2 . In certain embodiments, the mixture comprises between 50% and 60% Na.GHB, between 10% and 40% K.GHB, and between 10% and 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises about 50% to about 60% Na.GHB, about 20% to about 40% K.GHB, and about 10% to about 20% Ca.(GHB) 2 . In certain embodiments, the mixture comprises about 50% to 60% Na.GHB, about 10% to 40% K.GHB, and about 10% to 20% Ca.(GHB) 2 .
  • the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises between about 50% and about 60% Na.GHB, between about 20% and about 40% K.GHB, and between about 10% and about 20% Ca.(GHB) 2 . In certain embodiments, the mixture comprises between about 50% and about 60% Na.GHB, between about 10% and about 40% K.GHB, and between about 10% and about 20% Ca.(GHB) 2 .
  • the mixture comprises 45% to 55% Na.GHB, 30% to 40% K.GHB, and 10% to 20% Ca.(GHB) 2 . In certain embodiments the mixture comprises 48% to 52% Na.GHB, 32% to 36% K.GHB, and 14% to 18% Ca.(GHB) 2 . In certain embodiments, the mixture does not have a substantial amount of Mg.(GHB) 2 . In other embodiments, the mixture does not have a substantial amount of Ca.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of three GHB salts, wherein the mixture comprises at least 50% Na.GHB, and further comprises K.GHB and Ca.(GHB) 2 , In certain embodiments, the mixture comprises between 50% and 60% of Na.GHB, between 10% and 40% K.GHB, and between 10% and 20% Ca.(GHB) 2 .
  • the pharmaceutical composition does not comprise a substantial amount of Mg.(GHB) 2 .
  • the mixture does not comprise a substantial amount of Mg.(GHB) 2 .
  • the Na.GHB, K.GHB, and Ca.(GHB) 2 salts are present in the mixture in a ratio of about 50%:34%:16%.
  • the pharmaceutical composition of GHB comprising less than 100 mL of an aqueous solution, wherein the aqueous solution comprises a mixture of two or more salts of GHB, the mixture comprising between 40% and 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • the mixture comprises about 40% to about 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 . In certain embodiments, the mixture comprises between about 40% and about 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • the pharmaceutical composition of GHB comprising less than 100 mL of an aqueous solution, wherein the aqueous solution comprises a mixture of two or more salts of GHB, the mixture essentially consists of about 40% to about 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture which contains between 40% and 50% Na.GHB, wherein the composition is provided to the patient in an aqueous solution of between 25 and 100 mL. In certain embodiments, the pharmaceutical composition comprises the mixture dissolved or dispersed in an aqueous solution of between 40 and 75 mL. In certain embodiments, the pharmaceutical composition comprises the mixture dissolved or dispersed in an aqueous solution of between 55 and 65 mL.
  • the aqueous solution has a volume of about 25 mL to about 100 mL. In certain embodiments, the aqueous solution has a volume of about 40 mL to about 75 mL. In certain embodiments, the aqueous solution has a volume of about 55 mL to about 65 mL. In certain embodiments, the aqueous solution has a volume of about 60 mL.
  • the pharmaceutical composition comprises the mixture dissolved or dispersed in an aqueous solution of between 25 and 75 mL. In certain embodiments, the pharmaceutical composition comprises about 60 mL of an aqueous solution.
  • the pharmaceutical composition comprises between 25 and 100 mL of an aqueous solution. In certain embodiments the pharmaceutical composition comprises between 40 and 75 mL of an aqueous solution. In certain embodiments the pharmaceutical composition comprises between 55 and 65 mL of an aqueous solution.
  • the pharmaceutical composition is an aqueous solution having a volume of about 25 mL to about 100 mL. In certain embodiments the pharmaceutical composition is an aqueous solution having a volume of about 40 mL to about 75 mL. In certain embodiments the pharmaceutical composition is an aqueous solution having a volume of about 55 mL to about 65 mL.
  • the pharmaceutical composition is bioequivalent to Xyrem® which is Na.GHB.
  • the pharmaceutical composition produces an average maximum GHB plasma concentration (Cmax) that is substantially the same as the Cmax of Na.GHB.
  • the pharmaceutical composition produces a Cmax that is within 80% and 125% of the Cmax of Na.GHB.
  • the pharmaceutical composition produces an average maximum GHB plasma area under the curve (AUC) and Cmax that is substantially the same as Na.GHB.
  • the pharmaceutical composition produces an AUC that is between 80% and 125% of the AUC of Na.GHB.
  • the pharmaceutical composition is bioequivalent to a pharmaceutical composition comprising about 100% Na.GHB when administered to a patient.
  • the average maximum GHB plasma concentration (Cmax) is within 10% of the Cmax of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient.
  • the AUC is within 10% of the AUC of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient.
  • the pharmaceutical composition is formulated as a liquid formulation, wherein the Na.GHB salt is present at less than 40%.
  • the pharmaceutical composition is more resistant to a food effect and has a lower Cmax compared to Na.GHB.
  • the pharmaceutical composition comprises a mixture of two or more GHB salts, wherein the mixture comprises less than 40% Na.GHB, and further comprises one or more of the following salts, K.GHB, Ca.(GHB) 2 and Mg.(GHB) 2 .
  • the Na.GHB salt is present in the mixture at about 0% to 30%. In certain embodiments, the Na.GHB salt is present in the mixture at about 5% to 25%. In certain embodiments, the Na.GHB salt is present in the mixture at about 5% to 10%.
  • the pharmaceutical composition comprises a mixture of three or more GHB salts, wherein the mixture comprises at least 10% K.GHB, at least 10% Ca.(GHB) 2 and at least 10% Mg.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of two or three GHB salts, in addition to Na.GHB, wherein the mixture further comprises 20 to 80%, K.GHB, Ca.(GHB) 2 or Mg.(GHB) 2 .
  • the pharmaceutical composition comprises a mixture of three or more GHB salts, wherein the mixture comprises between 10 and 50% K.GHB, between 10 and 50% Ca.(GHB) 2 and between 10 and 50% Mg.(GHB) 2 for the non-sodium salts.
  • the Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 salts are present in the mixture at a ratio of about 8%:23%:21%:48%, respectively.
  • the pharmaceutical composition comprises an aqueous solution.
  • the concentration of the mixture of salts of GHB in the solution is about 250 mg/mL to about 750 mg/mL, about 350 mg/mL to about 650 mg/mL, about 400 mg/mL to about 600 mg/mL, about 450 mg/mL to about 550 mg/mL. In certain embodiments, the concentration of the mixture of salts of GHB in the solution is centered around 409 mg/mL GHB, which equates to 500 mg/mL Na.GHB. See U.S. Pat. No. 6,472,431, which is incorporated by reference in its entirety.
  • the maximum solubility of GHB is affected by the pH of the aqueous medium. For example, at about pH 4, the maximum amount of Na.GHB that can be dissolved is about 450 mg/mL. The value of pH that is conducive to GHB solubility increases so that the minimal pH that will dissolve 750 mg/mL GHB was found to be about pH 6.8.
  • the pharmaceutical composition has a pH of about 7.0 to about 9.0, about 7.0 to about 8.5, about 7.3 to about 8.5.
  • the pharmaceutical composition is chemically stable and resistant to microbial growth. In certain embodiments, the pharmaceutical composition is free of preservatives.
  • the pH of the aqueous solution affects the resistance of the pharmaceutical composition to microbial growth at about 409 mg/mL GHB, which equates to, e.g., 500 mg/mL Na.GHB.
  • GHB e.g. 500 mg/mL
  • Na.GHB at this concentration 500 mg/mL
  • Compositions at about pH 6 to about pH 7.5 are particularly resistant to microbial growth.
  • concentrations of GHB greater than about 750 mg/mL above about pH 7.5 the resistance to microbial growth is reduced. See U.S. Pat. No. 6,472,431.
  • the chemical stability of GHB is affected by pH. Accordingly, the method for preparing GHB, as described herein, particularly as disclosed in the specific examples, varies with pH.
  • the impurity gamma butyrolactone (GBL) begins to form substantially if the pH is about 6 or less. Compositions with a pH of greater than about 6.0 are preferred to produce chemically stable formulations of GHB.
  • a preferred range for chemically stable GHB would be from about pH 6 to about pH 9.
  • any pH or range of pH values where a clinically acceptable amount of GBL is present is also contemplated as being preferred, and is encompassed by the present invention.
  • a pH adjusting or buffering agent may be added to the composition.
  • the choice of a pH adjusting or buffering agent may affect the resistance to microbial challenge and/or the stability of GHB, as measured by the reduction in assayable GHB.
  • Compositions of GHB, pH adjusted or buffered with malic or other acids are resistant to both microbial growth and chemical degradation of GHB, and are preferred.
  • Other pH adjusting or buffering agents may be selected. Agents that adjust pH that are selected on this basis may undergo a taste testing study.
  • any pH adjusting or buffering agent disclosed herein or as would be known to those skilled in the art is contemplated as being useful from the compositions or formulations disclosed herein.
  • the pH adjusting or buffering agent is an acid. In certain embodiments, the pH adjusting or buffering agent is an inorganic acid or an organic acid. In certain embodiments, the pH adjusting or buffering agent is selected from the group consisting of malic acid, citric acid, acetic acid, boric acid, lactic acid, hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, and nitric acid. In certain embodiments, the pH adjusting or buffering agent is malic acid. See U.S. Pat. No. 6,472,431.
  • aqueous solutions disclosed herein typically comprise an effective amount of GHB, or a salt or mixture of salts of GHB as disclosed herein, which may be dissolved or dispersed in a pharmaceutically acceptable carrier and/or an aqueous medium.
  • “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is not appropriate. Supplementary compatible active ingredients can be incorporated into the compositions. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the Food and Drug Administration (FDA). See Remington, The Science and Practice of Pharmacy, 22 nd Ed. 2013.
  • compositions disclosed herein are provided in a formulation, preferably, a liquid formulation, although solid formulations are also contemplated.
  • a formulation preferably, a liquid formulation, although solid formulations are also contemplated.
  • excipients, colorants, flavorants, or other components of the formulation see Remington, The Science and Practice of Pharmacy, 22 nd Ed. 2013.
  • the formulation is chemically stable and resistant to microbial growth. In certain embodiments, the formulation does not need, and may be free of preservatives. In certain embodiments, the level of gamma-butyrolactone (GBL) is 0.1% or less of the formulation.
  • preservatives may include, but are not limited to, xylitol, sodium benzoate, methylparaben, propyl gallate BP, sorbic acid, chlorobutanol, dihydroacetic acid, monothioglycerol, potassium benzoate, propylparaben, benzoic acid, benzalkonium chloride, alcohol, benzoic acid, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylparaben, cetylpyridinium chloride, ethylenediamine, ethylparaben, ethyl vanillin, glycerin, hypophosphorus acid, methylparaben, phenol, phenylethyl alcohol, phenylmercuric nitrate, propylparaben, sassafras oil, sodium benzoate, sodium propionate, thimerosal and potassium sorbate.
  • Preferred preservatives may be selected from the group comprising, but not limited to, xylitol, sodium benzoate, methylparaben, propylparaben and potassium sorbate.
  • Xylitol is particularly preferred in certain compositions disclosed herein, because it acts as an preservative and a sweetener, is a caries preventative, is less laxative than other sweeteners, and is recommended for diabetics. See U.S. Pat. Nos. 8,324,275 and 8,952,062, and Remington, The Science and Practice of Pharmacy, 22 nd Ed. 2013, each of which is incorporated hereby by reference in its entirety.
  • the formulation is suitable for oral administration.
  • the formulation additionally comprises a flavoring agent.
  • Preferred sweeteners or flavoring agents would be microbially non-metabolizable.
  • Especially preferred sweeteners or flavoring agents would be carbohydrates such as xylitol and sorbitol.
  • Such flavoring agents include, but are not limited to, acacia syrup, anethole, anise oil, aromatic elixir, benzaldehyde, benzaldehyde elixir-compound, caraway, caraway oil, cardamom oil, cardamom seed, cardamom spirit, cardamom tincture-compound, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, coca, coca syrup, coriander oil, dextrose, eriodictyon, eriodictyon fluid extract, eriodictyon syrup-aromatic, ethyl acetate, ethyl, vanillin, fennel oil, ginger, ginger fluid extract, ginger oleoresin, glucose, glycerin, glycyrrhiza, glycyrrhiza elixir, glycyrrhiza extract, gly
  • the formulation additionally comprises a coloring agent.
  • coloring agents would be microbially non-metabolizable.
  • the formulation is administered in a single or multiple dosage regimen.
  • any of the above formulations may be prepared and/or packaged as a powdered or dry form for mixing with an aqueous medium before oral administration, or they may be prepared in an aqueous medium and packaged. After mixing with an aqueous medium, preferably to prepare a solution, these formulations are resistant to both microbial growth and chemical conversion of GHB to GBL, thereby increasing the shelf-life of therapeutic formulations of GHB, or salt or mixture of salts of GHB, in an aqueous medium. These formulations then provide an easily titratable liquid medium for measuring the dosage of GHB, or salt or mixture of salts of GHB, to be administered to a patient. Additional embodiments of the composition and methods of preparation are described below and in the examples.
  • the formulation is present in a low volume of aqueous solution.
  • low volume it is meant to include an aqueous solution of about 100 mL or less, including the aqueous medium and any wash or chase volume, for administration of a single GHB dose.
  • the low volume is between about 25 mL to 75 mL, or between 55 mL to 65 mL of total aqueous volume given to the patient.
  • the formulation requires less aqueous volume in order to be ingested, is more palatable, provides better patient compliance, is more tolerable, and/or is bioequivalent in comparison to GHB formulations of Na.GHB.
  • 25-100 mL (or about 1-3 ounces) of fluid is an acceptable amount of aqueous solvent to dilute the formulations disclosed herein, in order to ingest, improve taste, and/or “wash down” the GHB salts.
  • having a reduced-volume for administration offers an improved nightly dosing regimen which may alleviate unwanted side-effects associated with consuming liquids before bedtime, such as bed-wetting, restlessness and/or other sleep time disturbances.
  • the GHB, or salt or mixture of salts of GHB disclosed herein may be lyophilized for more ready formulation into a desired vehicle or medium where appropriate.
  • the GHB or salt(s) thereof may also be formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, intramuscular, sub-cutaneous, intralesional, intraperitoneal or other parenteral routes.
  • parenteral administration e.g., formulated for injection via intravenous, intraarterial, intramuscular, sub-cutaneous, intralesional, intraperitoneal or other parenteral routes.
  • the preparation of a pharmaceutical composition that comprises an aqueous solution that contains GHB or salt(s) thereof as an active component or ingredient will be known to those of skill in the art in light of the present disclosure.
  • such compositions can be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including, e.g., aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions of the active compounds as free acid or pharmacologically acceptable salts can be prepared in water suitably mixed with hydroxypropyl cellulose and/or a pharmaceutically acceptable surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof as well as in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to further prevent the growth of microorganisms.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, or the like), suitable mixtures thereof, and vegetable oils.
  • a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, or the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a substance, such as lecithin (e.g., a coating), by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • microorganisms can be brought about by any of the preservatives described herein, or as would be known to those skilled in the art, including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with, various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 mL of isotonic NaCl solution and either added to 1000 mL of fluid or injected at the proposed site of infusion, (see, e.g., “Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the GHB may be prepared in a formulation and/or pharmaceutical composition disclosed herein to comprise about 100 to about 10,000 milligrams per dose as administered to the patient.
  • the typical dose range is approximately 4.5-9 g/day; see the Xyrem® Product Insert.
  • Other dose ranges include 6-8 g/day multiple or single doses can be administered but it is typical to give two divided doses per day.
  • the Xyrem® instructions recommend two equally divided doses.
  • compositions formulated for parenteral administration such as intravenous or intramuscular injection
  • other pharmaceutically acceptable forms include, e.g., tablets or other solids; liposomal formulations; time release capsules, such as sustained or delayed release forms, including beads, pellets, or resins; and any other form currently used, including creams, which then may be admixed with an aqueous medium for oral administration.
  • Nasal solutions are usually aqueous solutions designed to be administered to the nasal passages in drops or sprays. Nasal solutions are prepared so that they are similar in many respects to nasal secretions, so that normal ciliary action is maintained.
  • the aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to 6.5, though other pH ranges disclosed herein the specific examples, such as pH 3 to about pH 9, or pH 6 to about 7.5, are contemplated.
  • preservatives similar to those used in ophthalmic preparations, and appropriate drug stabilizers, if required, may be included in the formulation.
  • Various commercial nasal preparations are known and include, for example, antibiotics and antihistamines and are used for asthma prophylaxis.
  • the preferred oral formulations may include such normally employed excipients, as, for example, pharmaceutical grades of xylitol, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. These compositions can take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders to be admixed with an aqueous medium.
  • oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or the GHB or salt(s) thereof may be packaged separately from or in combination with the excipients, salts, flavorings or any other components described herein, to be admixed with an aqueous medium for oral or injectable formulations, or they may be incorporated directly with the food (i.e. a beverage) of the diet.
  • an inert diluent or assimilable edible carrier or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or the GHB or salt(s) thereof may be packaged separately from or in combination with the excipients, salts, flavorings or any other components described herein, to be admixed with an aqueous medium for oral or injectable formulations, or they may be incorporated directly with the food (i.e. a beverage) of the diet
  • the active compounds may be incorporated with excipients and used in the form of tablets, buccal tablets or tabs, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, to be admixed with an aqueous medium.
  • Such compositions and preparations should contain at least 0.1% of the active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%.
  • the amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, natural as gum tragacanth, acacia, cornstarch, or gelatin or synthetic as polyvinyl acetate; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a natural or synthetic flavoring agent.
  • a binder natural as gum tragacanth, acacia, cornstarch, or gelatin or synthetic as polyvinyl acetate
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or sac
  • tablets, pills, or capsules may be coated with sugar, natural or synthetic polymers, or both.
  • a syrup or elixir may contain the active compounds, sucrose as a sweetening agent, a preservative, a dye and/or a flavoring.
  • One embodiment of the formulations disclosed herein can be a solid with different release properties.
  • One embodiment is a unit dosage form that is a tablet for immediate release comprising a relatively high weight-percentage of sodium oxybate, in combination with a relatively small weight-percentage of total excipients. This permits the tablets to contain/deliver a pharmaceutically effective amount of sodium oxybate in each tablet with a delivery profile similar to that of the liquid form. The tablets are bioequivalent to the liquid form. See U.S. Pat. Nos. 8,771,735 and 8,778,398. Other embodiments provide controlled release dosage forms for delivery of GHB or salt(s) thereof. The controlled release dosage forms may incorporate both controlled release and immediate release formulations in a single unit dosage form. See U.S.
  • Another embodiment includes the use of both immediate release and controlled release forms mixed together or one after the other.
  • the immediate release portion could be between 10-50%, or 20-30% and the controlled release portion comprising the remaining amount.
  • the amounts of the different salts can be different in each of the immediate or controlled release portions.
  • One or more of these compositions may be packaged with GHB or salt(s) thereof, or packaged separately from GHB or salt(s) thereof prior to consumption. If packaged separately, useful pharmaceutical compositions may be obtained by mixing GHB or salt(s) thereof with the other components with an aqueous medium prior to consumption. Such components may be packaged in a kit, described below.
  • kits comprising GHB, or a salt or mixture of salts of GHB, as disclosed herein.
  • Such kits will generally contain, in suitable container, a pharmaceutically acceptable formulation of the GHB or salt(s) thereof.
  • the kit may have a single container, or it may have distinct container for each component, or distinct container for various combinations of components.
  • the liquid formulation is an aqueous medium, with a sterile aqueous solution being particularly preferred.
  • the pharmaceutical compositions may also be formulated into a syringeable composition.
  • the container means may itself be a syringe, pipette, vial, ampule or other such like apparatus, from which the formulation may be applied to an infected area of the body, injected into an animal, or even applied to and mixed with the other components of the kit.
  • the components of the kit may be provided as dried powder(s).
  • the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.
  • the container means will generally include at least one vial, test tube, flask, bottle, pouch syringe or other container means, into which the formulation or components thereof are placed, preferably, suitably allocated.
  • the kits may also comprise a second container means for containing a sterile, pharmaceutically acceptable buffer or other diluent.
  • kits will also typically include a means for containing the vials in close confinement for commercial sale, such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • kits contain one or more bottles of liquid formulation comprising GHB or salt(s) thereof, two dosing cups with child-resistant caps, a liquid measuring device and a medication guide.
  • kits contain two different GHB formulations in separate bottles. In certain embodiments, the kits contain two bottles of liquid formulation comprising GHB or salt(s) thereof, wherein two different formulations are provided in at least two separate bottles. In certain embodiments, the kits contain two or more bottles of liquid formulation comprising GHB or salt(s) thereof, wherein two different formulations are provided in at least two separate bottles, and wherein also provided are two dosing cups with child-resistant caps, one or more liquid measuring device and a medication guide.
  • the two different formulations are a first-dose formulation comprising an aqueous solution
  • the aqueous solution is a mixture of two or more GHB salts, the mixture comprising less than 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2
  • the second-dose formulation comprising an aqueous solution comprising from 50% to about 80% of Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • kits may also comprise, or be packaged with, an instrument for assisting with the injection/administration or placement of the pharmaceutical composition within the body of an animal.
  • an instrument may be a drinking cup, syringe, pipette, or any such medically approved delivery vehicle.
  • an instrument may be a drinking cup, syringe, pipette, or any such medically approved delivery vehicle.
  • one or more of the instruments or formulations can be color-matched or labeled to indicate which of the two doses are contained within it.
  • the drug product containers can be differentiated by color, shape or other identifying features.
  • the containers can be bound together (for example, by shrink wrapping) or assembled into the kit in such a way to minimize misplacement or discourage dispensing of one product for both dosings.
  • twin sachets with a perforated divider can facilitate dose preparation. These could be labeled, for example, as “1 st dose” and “2nd dose”.
  • one or both of the formulations can include a flavorant, odorant, or colorant to render it substantially different from the other.
  • the additive may also be provided separately in the kit so that it can be added to the water either immediately before or after dispensing each formulation.
  • the administration devices for each dose may be distinguished based on a number of features such as color, shape, etc. so that that patient can easily administer each dose.
  • compositions and formulations provided herein can be used in all the methods provided herein.
  • the pharmaceutical compositions and formulations provided herein can be used in all the methods for treating all diseases, disorders or conditions provided herein.
  • the pharmaceutical compositions and formulations provided herein are for use as a medicament.
  • the pharmaceutical compositions and formulations provided herein are for use in a method for treating cataplexy or daytime sleepiness in a patient who has been diagnosed with narcolepsy.
  • the pharmaceutical compositions and formulations provided herein are for use in a method for treating cataplexy or daytime sleepiness in a patient who has been diagnosed with narcolepsy.
  • the pharmaceutical compositions and formulations provided herein are for use in a method for treating a disease or condition in a subject that is suitable to treatment by GHB, comprising administering a pharmaceutical composition or formulation disclosed herein
  • compositions and formulations comprising mixed salts of GHB, disclosed herein are also contemplated to be useful in the treatment of any of these disorders or conditions in patients.
  • GHB has also been used alone as a narcotic in patients with terminal cancer.
  • GHB has been used with other analgesics, neuroleptics, or with a subliminal barbiturate dose for use as an anesthesia.
  • the pharmaceutical compositions and formulations disclosed herein may be used as a narcotic, hypnotic, or as a soporific.
  • compositions and formulations comprising mixed salts of GHB may be used in combination with analgesics, neuroleptics or barbiturates for use as an anesthesia. See the methods described at the end of U.S. Pat. No. 6,472,431.
  • compositions and formulations comprising mixed salts of GHB may be prepared and administered by any of the means described herein, particularly those described in the section “Formulations” and the examples, or by any means as would be known to those of skill in the art.
  • compositions or formulations comprising mixed salts GHB disclosed herein comprising administration to a patient of the pharmaceutical compositions or formulations comprising mixed salts GHB disclosed herein.
  • compositions or formulations comprising mixed salts of GHB, disclosed herein are useful in the treatment of cataplexy or daytime sleepiness in a patient who has been diagnosed with narcolepsy.
  • the pharmaceutical compositions or formulations comprising mixed salts of GHB, disclosed herein are useful in the treatment of conditions responsive to GHB, for example, sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • provided herein is a method for treating a disease or condition in a subject that is suitable to treatment by GHB, comprising administering a pharmaceutical composition or formulation disclosed herein.
  • a method of treating a disease or condition that is suitable for treatment with GHB comprising administering to a patient a pharmaceutical composition comprising from 50% to about 80% of Na.GHB, wherein the pharmaceutical composition is in an oral dosage form and wherein administration of the pharmaceutical composition produces a GHB Cmax which is bioequivalent to the Cmax of Na.GHB.
  • the pharmaceutical composition does not comprise a substantial amount of Mg.(GHB) 2 or Ca.(GHB) 2 .
  • the disease or condition is selected from the group consisting of sleeping disorders, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, neurological disorders (e.g., Parkinson's Disease and depression), endocrine disturbances, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • the disease is cataplexy and/or narcolepsy.
  • the disease or condition is selected from the group consisting of fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • the mixture of salts which from about 50% to about 80% of Na.GHB further comprises one or more salts selected from the group consisting of K.GHB and Ca.(GHB) 2 .
  • a method of treating a disease or condition that is suitable for treatment with GHB comprises administering to a patient a pharmaceutical composition of GHB comprising less than 100 mL of an aqueous solution, wherein the aqueous solution comprises a mixture of two or more salts of GHB, the mixture comprising between 40% and 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • the disease is cataplexy and/or narcolepsy.
  • the pharmaceutical composition when administered to a patient, produces a GHB Cmax which is within 10% of the Cmax of Na.GHB. In certain embodiments, the Cmax is within 10% of the Cmax of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient. In certain embodiments, when administered to a patient, the pharmaceutical composition produces a GHB Cmax that is bioequivalent to the Cmax of Na.GHB. In certain embodiments, the pharmaceutical composition is bioequivalent to a pharmaceutical composition comprising about 100% Na.GHB when administered to a patient. In certain embodiments, the AUC is within 10% of the AUC of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient.
  • the pharmaceutical composition does not comprise a substantial amount of Mg.(GHB) 2 or Ca.(GHB) 2 .
  • the disease or condition is selected from the group consisting of sleeping disorders, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, neurological disorders (e.g., Parkinson's Disease and depression), endocrine disturbances, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure.
  • the disease is cataplexy and/or narcolepsy.
  • the disease or condition is selected from the group consisting of fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
  • the methods of treatment comprising administration of the pharmaceutical compositions or formulations comprising mixed salts GHB disclosed herein.
  • the method comprises oral administration of the pharmaceutical compositions or formulations comprising mixed salts GHB, disclosed herein, in a multiple dosage regimen.
  • the multiple dosage regimen comprises one or more steps, as follows: (i) diluting an aqueous solution comprising about 409 mg/mL of gamma-hydroxybutyrate (GHB) with an aqueous medium to provide a first dose of the mixture of salts; (ii) diluting an aqueous solution comprising about 409 mg/mL of GHB with an aqueous medium to provide a second dose of the mixture of salts; (iii) orally administering to a patient having narcolepsy the first dose; and (iv) orally administering to the patient having narcolepsy the second dose within 2.5 to 4 hours following the first dose.
  • the first and/or second doses can be administered according to the instructions on the label as appropriate.
  • two nightly doses of GHB or a salt there are administered to the patient.
  • the first dose of GHB salts is a pharmaceutical composition of GHB comprising an aqueous solution of a mixture of two or more GHB salts, the mixture comprising less than 40% Na.GHB, and further comprising one, two, three or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , and wherein the first dose is administered within 4 hours of eating and produces a GHB Cmax which is less than the Cmax of Na.GHB; and the second dose of GHB salts is a pharmaceutical composition of GHB comprising a mixture of two or more GHB salts, the mixture comprising at least 50% of Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , and wherein the second dose produces a GHB Cmax which is substantially equivalent to the Cmax of Na.GHB.
  • the multiple dosage regimen comprises one or more steps, as follows: (i) diluting an aqueous solution comprising a mixture of two or more GHB salts, the mixture comprising 0% to 40% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , with an aqueous medium to provide a first dose of GHB salts; (ii) diluting an aqueous solution comprising a mixture of two or more GHB salts, the mixture comprising from about 50% to about 80% of Na.GHB, and further comprising one or more salts selected from KGHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , to provide a second dose of GHB salts; (iii) orally administering the first dose to a patient suitable for treatment with GHB; and (iv) orally administering the second dose to the patient within 2.5 to 4 hours following the first dose.
  • the first dose comprises a pharmaceutical composition comprising less than 40% Na.GHB and at least two other GHB salts selected from the group of K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 . In certain embodiments, the first dose is administered within 4 hours of eating. In certain embodiments, the mixture further comprises two or more salts selected from the group consisting of K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 .
  • the disease or condition is selected from the group consisting of a sleeping disorder, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, a neurological disorder, an endocrine disturbance, hypoxia or anoxia of tissues, and an increased level of intracranial pressure.
  • the first dose of GHB salts is a pharmaceutical composition of GHB comprising an aqueous solution of less than 100 mL, the aqueous solution comprises a mixture of three GHB salts, the mixture comprising less than 50% Na.GHB, and further comprising one or more salts selected from between 10-60% K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , and wherein the first dose is administered within 4 hours of eating and produces a GHB Cmax which is less than the Cmax of Na.GHB.
  • the second dose of GHB salts is a pharmaceutical composition of GHB comprising an aqueous solution, the aqueous solution comprising from 50% to about 80% of Na.GHB, and from between 10-60% K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , and wherein administration of the second dose produces a GHB Cmax which is substantially bioequivalent to the Cmax of Na.GHB.
  • the second dose of GHB salts is a pharmaceutical composition of GHB comprising an aqueous solution which comprises a mixture from 50% to about 80% of Na.GHB, and wherein administration of the second dose produces a GHB Cmax which is substantially bioequivalent to a composition comprising Na.GHB.
  • 4.5 and 9 grams/day are administered to the patient in two divided doses.
  • 6 and 8 grams/day are administered to the patient in two divided doses.
  • the disease or condition is selected from the group consisting of sleeping disorders, drug abuse, alcohol and opiate withdrawal, a reduced level of growth hormone, anxiety, analgesia, neurological disorders (e.g., Parkinson's Disease and depression), endocrine disturbances, hypoxia or anoxia of tissues (such as from stroke or myocardial infarction), or an increased level of intracranial pressure
  • compositions or formulations comprising mixed salts GHB disclosed herein.
  • Several different methods of making have been reported in the literature (see, e.g., U.S. Pat. Nos. 4,393,236; 4,983,632; 6,472,431; 8,461,203; 8,591,922; 8,901,173; and 9,132,107; and U.S. Publication No. 2016/0058720, each of which is incorporated by reference in its entirety; see also Ferris and Went, 2012 , Forensic Science International 216: 158-162). Those skilled in the art will recognize that these methods can be incorporated in the making of the compositions or formulations comprising mixed salts GHB disclosed herein. Other methods will be known to those of skill in the art.
  • mixtures of GHB salts can be made by direct reaction of GBL with an aqueous mixture of one of more of the following bases: sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide. After reaction the mixture may then be filtered under mild vacuum.
  • a solvent such as water, is used to dissolve the GHB salt mixture to a desired concentration, for example, by adjusting the amount of water in the mixture.
  • the concentration of a GHB salt solution is adjusted by concentrating the mixture using standard methods, such as evaporators, reverse osmosis, and similar techniques known to those skilled in the art.
  • the method of making comprises reacting gamma-butyrolactone (GBL) with one or more bases selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide.
  • GBL gamma-butyrolactone
  • the method of making comprises, for example, reacting GBL with one or more of sodium carbonate, potassium carbonate, or magnesium carbonate to provide the sodium, potassium, and magnesium oxybate (Na.GHB, K.GHB, and Mg.(GHB) 2 ) mixture.
  • Such embodiments are particularly suitable to avoid precipitation of calcium carbonate when carbonate salts of sodium, potassium, and/or magnesium are employed.
  • a solution of calcium oxybate can be transformed to a mixture of oxybate salts by exchanging with a mixture of cation exchange resins loaded with the desired cations.
  • a solution of calcium oxybate can be transformed to a mixture of oxybate salts by precipitation with a mixture of acid salts of other cations when the calcium salt is practically insoluble. After filtration or other means of removing the precipitated calcium salt or the exchanged cation exchange resin, the mixed oxybate salt solution is obtained.
  • a mixture of cations associated with oxybate may include a proton. This can be achieved in similar fashion as cation exchange or displacement precipitation described above, with the exception that a H-form cation exchange resin or the free acid or partially neutralized salt of the precipitating anion is employed, respectively. Ideally to promote chemical stability, such embodiments should be produced in solid form and suspended or dissolved in water upon administration. In yet another embodiment, the undissolved solid (exchanged cationic resin or precipitated salt) can be ingested with the dose provided neither dissolves appreciably in the GI tract.
  • the reaction is carried out in a single vessel.
  • a mixture of Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 may be made by direct addition of GBL to in a single vessel containing an aqueous mixture of sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide.
  • the reaction is carried out in multiple vessels and the product is subsequently combined.
  • Ca.(GHB) 2 may be made by direct addition of GBL to aqueous sodium hydroxide, and the product combined with Mg.(GHB) 2 .
  • the methods of making include methods of making the pharmaceutical compositions and formulations disclosed herein.
  • Mixed oxybate salt solutions can be made conveniently by at least two methods. When multiple different formulations are desired, one of skill in the art can mix solutions of individual salts having the same molar oxybate concentration to arrive at the desired cation blend. On the other hand, for commercial implementation or single-batch manufacturing one can perform a one-pot reaction with GBL and the two or more bases in the desired cationic proportions. Both methods are described below.
  • Gram Amount Amount in grams, of each base charged to the reaction Base mMols Corresponding amount, in millimoles, of pure base (that is, Purity ⁇ Gram-Amount ⁇ 1000/Base-MW) Stoichiometry Ratio The number of GHB moles reacted with each mole of base Base mEQ Base equivalents for reaction with GHB (that is, Base-mMols ⁇ Stiochiometry-Ratio). This is also the Oxybate or GHB equivalents value.
  • % molar equiv GHB Molar composition of salts expressed as Percent of Oxybate Equivalents Salt
  • the oxybate salt species Salt MW Molecular weight of the oxybate salt Salt-mass-grams Mass of salt produced by reaction (that is, Base-mMols ⁇ Salt-MW/1000) Salt wt/wt % Normalized weight percent Conc. (mg/ml) Concentration in mg/ml equivalent to a 3.97M Na-GHB solution (500 mg/ml sodium oxybate). That is, 3.97 ⁇ (% equiv-GHB) ⁇ (Salt-MW)/(Stoich. Ratio)
  • Magnesium oxybate (Mg.(GHB) 2 ) solution was made by combining 124.6 g water and 20.36 g magnesium hydroxide in a magnetically-stirred 250 mL square glass bottle. 58.04 g of GBL was then added to the base suspension and then heated up to 80° C. with stirring. After 4 hours, a pH verification indicated completion of reaction (pH 8.5). Water was added to compensate for evaporation. The reaction mixture was then centrifuged, and supernatant filtered through 0.45p PVDF Stericup under vacuum. The pH of filtrate was 8.1. Yield: 177.4 g solution. Assay (HPLC-UV): 100.1%
  • Potassium oxybate (K.GHB) solution was made by adding 60.10 g potassium hydroxide to 144.01 g water in a magnetically-stirred 250 mL square glass bottle. After complete dissolution, 78.52 g GBL was weighed into a separate glass beaker. Approximately half the GBL was added initially with instant reaction, and then the solution was cooled in ice water to approximately 30° C. The remainder of the GBL was then added with stirring, and the solution maintained at 60° C. for 2.5 hours. The pH was 13.5. The pH was then adjusted to 8.1 by adding 10% HCl solution. Water was added to restore the initial reaction mass. The solution was then filtered through 0.45 PVDF Stericup under vacuum. Yield: 281.8 g solution. Assay (HPLC-UV): 98.6%.
  • Calcium oxybate (Ca.(GHB) 2 ) solution was made by combining 210.5 g water and 45.41 g calcium hydroxide in a magnetically stirred 500 mL square glass bottle. Next, 102.41 g GBL was added slowly while stirring, and then the reaction was maintained at 80° C. on a temperature-controlled hotplate (surface set point ⁇ 183° C.). After 2 hours, the mixture was cooled and water was added to compensate for evaporation. The solution was centrifuged, and supernatant was then filtered through 0.45 ⁇ PVDF Stericup under vacuum. The initial pH of filtrate was 10.5, and was adjusted to 7.9 by addition of 10% HCl solution. Yield: 328.6 g solution. Assay (HPLC-UV): 99.0%
  • Sodium oxybate (Na.GHB) solution was made by adding 46.6 g sodium hydroxide to 200.1 g water in a magnetically stirred 500 mL square glass bottle. 99.00 g GBL was weighed into a separate beaker. After complete dissolution of the sodium hydroxide, about half of the GBL was added to the reaction mixture causing it to heat. After cooling to about 30° C. in ice water, the remaining GBL was added and then allowed to react with stirring on a hotplate at 60° C. for 2 hours. The pH after reaction was 12.36, and was adjusted to 8.13 by addition of 10% HCl solution. Water was added to restore the initial reaction mass. The solution was then filtered through a 0.45 ⁇ PVDF Stericup under vacuum. Yield: 340.3 g. Assay (HPLC-UV): 100.6%.
  • Example 1.2 Direct, One-Pot Reaction Method to Achieve Various Mixtures
  • the stoichiometry calculations are adjusted to reflect (a) the strength of individual bases and (b) the use of an excess for the weakest base (calcium or magnesium).
  • the strength of bases used in the Example above were 99.7% (NaOH), 86.0% (KOH), 99.0% (Ca(OH) 2 ), and 98.5% (Mg(OH) 2 ).
  • a 1% excess is applied as the weakest divalent base present (calcium or magnesium, in that order of precedence).
  • a larger or smaller excess may be warranted, depending on the level of confidence in the assay values or repeatability of dispensing to the process. A larger excess will increase confidence in completing the reaction, but incur more filtration load. A smaller excess threatens to inadequately complete the reaction, resulting in higher than desired GBL levels.
  • the water is weighed into a tared 250 mL beaker with spinbar.
  • bases are weighed and added in order of sodium, potassium, calcium, and magnesium as applicable.
  • sodium or potassium hydroxide is added, the mixture is stirred until complete dissolution is observed. The required excess is added at the same time as the respective base is charged.
  • 51.27 g of GBL is added slowly while monitoring temperature and with stirring. If the temperature exceeds about 80° C., then GBL addition is slowed until the temperature cools to about 60° C. After GBL addition is complete, the setup is moved to a 60° C. environmental chamber to complete the reaction. (Alternatively, a temperature-controlled hotplate can be employed.) Sodium and potassium hydroxide react almost instantly with GBL.
  • Ca(OH) 2 requires about 1 h to react at 60° C., and Mg(OH) 2 requires about 3 h at 80° C. or overnight (12 h) at 60° C. Therefore, mixtures lacking Mg(OH) 2 (507-A and 507-D) are held at 60° C. for about 1 h. Mixtures 507-G and 507-C are held at 60° C. overnight or 80° C. for 3 h.
  • reaction water is added to compensate for evaporation and restore the original reaction mass (178.5 g net).
  • the reaction mixtures are then centrifuged followed by vacuum filtration through a 0.45 t PVDF Stericup. Finally, the pH is adjusted with 10% HCl solution, as needed, to a value of 8.0. For mixtures containing magnesium, no adjustment is required if the pH is below 9. Finally, 0.18 g of sucralose is added and dissolved into the solution.
  • Formulation “O” was manufactured as (equivalent %) 8% sodium, 23% potassium, 48% calcium, and 21% magnesium oxybate at 409 mg/mL mixed salt concentration or 409 mg/mL oxybate.
  • the four bases were suspended or dissolved in water, then gamma butyrolactone was added and the reaction mixture was held at 80° C. for about 3 hours. Subsequently, mixture was cooled and then depth filtered, carbon filtered, and then flowed through a polishing filter. Finally, sucralose was added to a level of 0.1% w/v in the final solution.
  • Formulation “O” was tested for bioequivalence relative to Xyrem® (Formulation “X”, commercial sodium oxybate solution of the same molar concentration and comparable pH as “0”) and in the fasted as well as fed state.
  • the study was compliant with the FDA guidance for food effect studies (“Guidance for Industry: Food-Effect bioavailability and Fed Bioequivalence Studies”, FDA December 2002), incorporated herein by reference in its entirety.
  • the Guidance indicates that the drug product should be administered with 240 mL of water. Thirty-six patients were recruited and 34 patients completed successfully. The results are shown in FIG. 1 and in Table 4 below.
  • Example 2.2 Testing of Blends of Xyrem® and Formulation “O”
  • Example 2.1 As an extension to the study described in Example 2.1, the same formulation “0” and Xyrem® reference were tested in two different proportions to determine whether bioequivalence could be achieved with the same proportion of the three non-sodium cations but with higher sodium content. New patients were recruited for the single dose crossover study, but the study was otherwise done in a manner comparable to Example 2.1 except fewer patients were evaluated. The results are shown in FIG. 2 and Table 5 as expressed in mean values. Bioequivalence was not achieved even at 49% sodium (the confidence interval for that formulation was between 73.8-97.5%).
  • Example 1.1 To test for negative effects of certain cations and also to investigate other four-cation blends, the formulations of Example 1.1 were tested in a crossover fasted state bioequivalence study involving 35 patients. In contrast to the preceding two examples, the volume of administration was reduced to 60 mL. The results are shown in FIG. 3 and Table 6.
  • Formulation 507-D with 50% sodium met the bioequivalence criteria, as it had a Cmax ratio of 92% and nearly identical average plasma profile compared to Xyrem®.
  • Formulations 507-A and 507-C, both with 33% sodium but differing by exclusion of either potassium or magnesium had nearly identical and lower Cmax values (78% and 76%, respectively), and therefore did not meet the bioequivalence criteria.
  • Formulation 507-D having 50% sodium and tested at 60 mL volume was bioequivalent to Xyrem®, yet the four-cation blend of Example 2.2 having 49% sodium and tested at 240 mL volume was not bioequivalent. The difference between the two results is statistically significant and meaningful.
  • Formulation “O” was tested and compared to Xyrem® in three treatments—fasted with 60 mL volume given, fasted with 240 mL volume, and fed with 60 mL volume. Thus, six treatments were administered in a crossover fashion involving 33 patients in a food effect bioequivalence study. The results are shown in FIG. 4 and Table 7.
  • FIG. 5A shows the Cmax ratio as a function of the percent of calcium in the formulation.
  • FIG. 5B shows the Cmax ratio as a function of the percent of sodium in the formulation.
  • the calcium model was arrived at by stepwise regression of main effect and interaction of calcium % and volume of administration using JMP software (SAS Institute). Volume of administration and its interaction were both dropped as insignificant terms. (An alternative model process employing calcium % and diluted concentration—which is volume-dependent—provided no better fit.) The result has significant lack of fit.
  • test treatment consists of administering formulation “O” of preceding examples and administering a second dose of formulation “507-D” 4 hours later.
  • the reference treatment consists of Xyrem® given in the same fashion. Test and reference treatments have the same oxybate dose and are administered in 60 mL of water in the evening approximately two hours after dinner. Plasma is sampled at the same intervals as in preceding examples.
  • the outcome can be estimated by assuming additive contributions from each dose based on the single dose PK evaluations presented in preceding examples.
  • the expected results are shown in FIG. 6 compared to those of the reference Xyrem® given under the same conditions.
  • This Example demonstrates that a mixed oxybate salt having low sodium displays acceptable resistance to microbial growth.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
US15/709,262 2017-03-17 2017-09-19 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders Abandoned US20180263936A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US15/709,262 US20180263936A1 (en) 2017-03-17 2017-09-19 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
TW111146727A TWI812557B (zh) 2017-03-17 2018-03-16 伽瑪(γ)-羥基丁酸鹽組合物及其用於治療病症之用途
JP2019550565A JP2020510060A (ja) 2017-03-17 2018-03-16 γ−ヒドロキシブチレート組成物及び障害の治療のためのそれらの使用
TW107109130A TW201836596A (zh) 2017-03-17 2018-03-16 伽瑪(γ)-羥基丁酸鹽組合物及其用於治療病症之用途
EP18712555.4A EP3595648A1 (en) 2017-03-17 2018-03-16 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
CA3056316A CA3056316A1 (en) 2017-03-17 2018-03-16 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
PCT/EP2018/056745 WO2018167303A1 (en) 2017-03-17 2018-03-16 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US16/575,213 US20200113853A1 (en) 2017-03-17 2019-09-18 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US17/131,418 US11426373B2 (en) 2017-03-17 2020-12-22 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US17/860,498 US20220362185A1 (en) 2017-03-17 2022-07-08 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
JP2022196041A JP2023036649A (ja) 2017-03-17 2022-12-08 γ－ヒドロキシブチレート組成物及び障害の治療のためのそれらの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762473232P 2017-03-17 2017-03-17
US15/709,262 US20180263936A1 (en) 2017-03-17 2017-09-19 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/575,213 Continuation US20200113853A1 (en) 2017-03-17 2019-09-18 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders

Publications (1)

Publication Number Publication Date
US20180263936A1 true US20180263936A1 (en) 2018-09-20

Family

ID=63521436

Family Applications (4)

Application Number Title Priority Date Filing Date
US15/709,262 Abandoned US20180263936A1 (en) 2017-03-17 2017-09-19 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US16/575,213 Abandoned US20200113853A1 (en) 2017-03-17 2019-09-18 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US17/131,418 Active US11426373B2 (en) 2017-03-17 2020-12-22 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US17/860,498 Pending US20220362185A1 (en) 2017-03-17 2022-07-08 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders

Family Applications After (3)

Application Number Title Priority Date Filing Date
US16/575,213 Abandoned US20200113853A1 (en) 2017-03-17 2019-09-18 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US17/131,418 Active US11426373B2 (en) 2017-03-17 2020-12-22 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US17/860,498 Pending US20220362185A1 (en) 2017-03-17 2022-07-08 Gamma-hydroxybutyrate compositions and their use for the treatment of disorders

Country Status (6)

Country Link
US (4) US20180263936A1 (zh)
EP (1) EP3595648A1 (zh)
JP (2) JP2020510060A (zh)
CA (1) CA3056316A1 (zh)
TW (2) TW201836596A (zh)
WO (1) WO2018167303A1 (zh)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10195168B2 (en) 2012-12-14 2019-02-05 Jazz Pharmaceuticlas Ireland Limited Gamma-hydroxybutyrate compositions and their uses for the treatment of disorders
WO2021133778A1 (en) 2019-12-24 2021-07-01 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate (ghb) dosing
US11077079B1 (en) 2015-02-18 2021-08-03 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US11090269B1 (en) 2010-03-24 2021-08-17 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
WO2021168403A1 (en) 2020-02-21 2021-08-26 Jazz Pharmaceuticals Ireland Limited Methods of treating idiopathic hypersomnia
WO2022076824A1 (en) 2020-10-08 2022-04-14 Jazz Pharmaceuticals Ireland Limited Sodium oxybate to treat idiopathic hypersomnia
WO2022082105A2 (en) 2020-10-16 2022-04-21 Jazz Pharmaceuticals Ireland Limited Treatment methods using ghb
US11400065B2 (en) 2019-03-01 2022-08-02 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US11400052B2 (en) 2018-11-19 2022-08-02 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations
US11426373B2 (en) 2017-03-17 2022-08-30 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
WO2023062018A1 (en) 2021-10-11 2023-04-20 Jazz Pharmaceuticals Ireland Limited Method of administering oxybate
WO2023135150A1 (en) 2022-01-11 2023-07-20 Jazz Pharmaceuticals Ireland Limited Method of administering oxybate
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022020621A1 (en) 2020-07-24 2022-01-27 XWPharma Ltd. Pharmaceutical compositions and pharmacokinetics of a gamma-hydroxybutyric acid derivative
JP2023544420A (ja) 2020-10-05 2023-10-23 エックスダブリューファーマ リミテッド ガンマ－ヒドロキシ酪酸誘導体の調節放出組成物
JP2024511991A (ja) 2021-03-19 2024-03-18 エックスダブリューファーマ リミテッド ガンマ－ヒドロキシ酪酸誘導体の組み合わされた放出製剤の薬物動態
CN113237942B (zh) * 2021-05-07 2023-09-26 上海科技大学 在微量细胞中检测多种微量元素的方法及应用

Family Cites Families (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB922029A (en) 1960-05-19 1963-03-27 Equilibre Biolog L Therapeutic composition
US3051619A (en) 1960-05-19 1962-08-28 Equilibre Biolog L 4-hydroxy butyric acid therapeutic compositions and process of use for clinical sedation, hypnosis, or anaesthesia
DE1642902A1 (de) 1965-09-30 1971-05-19 Unilever Nv Verfahren zur kontinuierlichen Entsaeuerung von Glyceridoelen
US4221778A (en) 1979-01-08 1980-09-09 Pennwalt Corporation Prolonged release pharmaceutical preparations
US4374441A (en) 1980-05-23 1983-02-22 Book Covers, Inc. Method of making a book cover and pocket element therefor
EP0044801B1 (de) 1980-07-17 1984-02-15 Josef Dr. Klosa Nichthygroskopische Salze der 4-Hydroxybuttersäure, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung pharmazeutischer Mittel
ZA814854B (en) 1980-07-17 1982-07-28 J Klosa Nonhygroscopic salts of 4-hydroxybutryric acid, methods of their production and pharmaceutical preparations containing these salts
CH655507B (zh) 1983-01-12 1986-04-30
US4524217A (en) 1984-06-08 1985-06-18 Celanese Corporation Process for producing N-acyl-hydroxy aromatic amines
EP0235408B1 (en) 1984-08-06 1991-01-09 The University Of Toronto Innovations Foundation Pharmaceutical composition and treatment
IE59106B1 (en) 1985-05-31 1994-01-12 Warner Lambert Co A therapeutic effervescent composition and a method of preparing the same
US4687662A (en) 1985-08-30 1987-08-18 Warner-Lambert Company Therapeutic effervescent composition
US4738985A (en) 1986-03-19 1988-04-19 The University Of Toronto Innovations Foundations Pharmaceutical composition and treatment
DE3804168A1 (de) 1988-02-11 1989-08-24 Gewerk Eisenhuette Westfalia Planetenueberlagerungsgetriebe und ueberlagerungsantrieb fuer kettenbaender u. dgl., insbesondere fuer kettenfoerderer und kettengezogene bergbau-gewinnungsmaschinen
IT1217783B (it) 1988-06-03 1990-03-30 Farmaceutico Ct S R L Lab Impiego di salo dell,acido gamma idrossi butirrico per la preparazione di composizioni farmaceutiche adatta ad essereimpiegate nella terapia dell,alcolismo e composizioni relative
US5294430A (en) 1988-09-12 1994-03-15 University Of Rochester Use of dithiocarbamates to treat myelosuppression
US4916161A (en) 1988-10-25 1990-04-10 Bristol-Myers Squibb Taste-masking pharmaceutical agents
JP2564690B2 (ja) 1990-06-14 1996-12-18 三省製薬 株式会社 メラニン生成抑制外用剤
DE4113984C2 (de) 1991-04-29 2002-05-08 Koehler Chemie Dr Franz Salze der 4-Hydroxy-Buttersäure
US5415870A (en) 1991-07-01 1995-05-16 Gerhard Gergely Effervescent systems using reaction doping agents
IT1271403B (it) 1993-03-26 1997-05-28 Ct Lab Farm Srl Sali dell'acido gamma-idrossibutirrico ad attivita' ansiolitica e per il trattamento degli stati depressivi
CN1071570C (zh) 1993-06-14 2001-09-26 詹森药业有限公司 阿司咪唑和假麻黄碱的缓释薄膜包衣片
IT1266565B1 (it) 1993-07-22 1997-01-09 Ct Lab Farm Srl Composizioni farmaceutiche a rilascio controllato a base di uno o piu' sali farmaceuticamente accettabili dell'acido gamma-idrossi-butirrico.
US5833599A (en) 1993-12-13 1998-11-10 Multum Information Services Providing patient-specific drug information
DE4432757A1 (de) 1994-09-14 1996-03-21 Boehringer Mannheim Gmbh Pharmazeutische Zubereitung enthaltend Metformin und Verfahren zu deren Herstellung
FR2725623A1 (fr) 1994-10-18 1996-04-19 Flamel Tech Sa Microcapsules medicamenteuses et/ou nutritionnelles pour administration per os
US7072840B1 (en) 1994-10-28 2006-07-04 Cybear, L.L.C. Prescription management system
US5845255A (en) 1994-10-28 1998-12-01 Advanced Health Med-E-Systems Corporation Prescription management system
GB9423542D0 (en) 1994-11-22 1995-01-11 Marples Brian A Pharmaceutical compounds
JP4072597B2 (ja) 1994-12-27 2008-04-09 ナムローゼ・フェンノートシャップ・オルガノン 持続性製剤
US5758095A (en) 1995-02-24 1998-05-26 Albaum; David Interactive medication ordering system
US5840331A (en) 1995-06-07 1998-11-24 Arch Development Corporation Use of γ-hydroxybutyrate for the stimulation of sleep-related secretion growth hormone and prolactin
US6112182A (en) 1996-01-16 2000-08-29 Healthcare Computer Corporation Method and apparatus for integrated management of pharmaceutical and healthcare services
IT1283782B1 (it) 1996-08-09 1998-04-30 Ct Lab Farm Srl Uso di ammidi dell'acido gamma-idrossibutirrico nel trattamento di tossicodipendenze,ed in particolare sell'alcolismo
US20080292700A1 (en) 1997-04-21 2008-11-27 Biovail Laboratories Controlled release formulations using intelligent polymers
US6495598B1 (en) 1997-04-22 2002-12-17 Ophtecs Corporation Perfusate preparation for ophthalmic operation
US5990162A (en) 1997-08-29 1999-11-23 Orphan Medical, Inc. Method for treatment of fibromyalgia and chronic fatigue syndrome
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
US6472432B1 (en) 1997-11-17 2002-10-29 Nicholas V. Perricone Treatment of rosacea using lipoic acid
US6014631A (en) 1998-04-02 2000-01-11 Merck-Medco Managed Care, Llc Computer implemented patient medication review system and process for the managed care, health care and/or pharmacy industry
US6322819B1 (en) 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
EP1140061B1 (en) 1998-12-23 2003-05-02 Orphan Medical Inc. Microbiologically sound and stable solutions of gamma-hydroxybutyrate salt for the treatment of narcolepsy
EP1316309A1 (en) 1998-12-23 2003-06-04 Orphan Medical Inc. Microbiologically sound and stable solutions of gamma-hydroxybutyrate salt for the treatment of narcolepsy
US6067524A (en) 1999-01-07 2000-05-23 Catalina Marketing International, Inc. Method and system for automatically generating advisory information for pharmacy patients along with normally transmitted data
US6565872B2 (en) 1999-02-16 2003-05-20 Xiao Yu Wu Polymeric system for drug delivery and solute separation
US6384020B1 (en) 1999-07-14 2002-05-07 Shire Laboratories, Inc. Rapid immediate release oral dosage form
AU2001291173A1 (en) 2000-09-22 2002-04-02 Orphan Medical, Inc. Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers
FR2817256B1 (fr) 2000-11-27 2005-07-15 Univ Pasteur Derives de l'acides 4-hydroxybutanoique et de son homologue superieur comme ligands des recepteurs du gamma- hydroxybutyrate (ghb), compositions pharmaceutiques les contenant et utilisations pharmaceutiques
JP2004514732A (ja) 2000-12-06 2004-05-20 ファルマシア・コーポレーション 迅速に分散する医薬組成物
FR2830447B1 (fr) 2001-10-09 2004-04-16 Flamel Tech Sa Forme galenique orale microparticulaire pour la liberation retardee et controlee de principes actifs pharmaceutiques
US8101209B2 (en) 2001-10-09 2012-01-24 Flamel Technologies Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
US20030180249A1 (en) 2002-03-18 2003-09-25 Khanna Satish Chandra Dosage forms for hygroscopic active ingredients
US7985422B2 (en) 2002-08-05 2011-07-26 Torrent Pharmaceuticals Limited Dosage form
US8216609B2 (en) 2002-08-05 2012-07-10 Torrent Pharmaceuticals Limited Modified release composition of highly soluble drugs
RU2210360C1 (ru) 2002-09-19 2003-08-20 Общество С Ограниченной Ответственностью "Консорциум-Пик" Психотропное средство
US7668730B2 (en) 2002-12-17 2010-02-23 JPI Commercial, LLC. Sensitive drug distribution system and method
EP1578412B1 (en) 2002-12-23 2010-09-29 Merck Frosst Company Pharmaceutical compositions and method of treating parkinson's disease
US20050031688A1 (en) 2003-08-04 2005-02-10 Ayala William J. Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration
ES2336913T3 (es) 2003-08-08 2010-04-19 Biovail Laboratories International Srl Comprimido de liberacion modificada de hidrocloruro de bupropion.
WO2005013944A1 (en) 2003-08-11 2005-02-17 Merck Frosst Canada Ltd. Flavored taste-masked pharmaceutical formulation made using a one-step coating process
US20050142192A1 (en) 2003-10-15 2005-06-30 Wyeth Oral administration of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and derivatives
MX2007002682A (es) 2004-09-07 2008-03-05 Orphan Medical Inc Composiciones mejoradas de gamma-hidroxibutirato ghb.
US8193211B2 (en) 2004-09-30 2012-06-05 Supernus Pharmaceuticals, Inc. Controlled release compositions of gamma-hydroxybutyrate
AR051397A1 (es) 2004-10-21 2007-01-10 Novartis Ag Composicion farmaceutica
EP1809286A4 (en) 2004-11-10 2010-09-01 Univ Columbia METHOD FOR TREATING MOTION TROUBLESHOOTING
ZA200707250B (en) 2005-01-27 2009-06-24 Alembic Ltd Extended release formulation of levetiracetam
FR2881652B1 (fr) 2005-02-08 2007-05-25 Flamel Technologies Sa Forme pharmaceutique orale microparticulaire anti-mesuage
WO2006124609A2 (en) 2005-05-16 2006-11-23 Joseph Johnson Methods and compositions for treating arg
US7645802B2 (en) 2005-06-27 2010-01-12 Biovail Laboratories International Srl. Bupropion hydrobromide and therapeutic applications
CA2617164A1 (en) 2005-08-01 2007-02-08 Alpharma Inc. Alcohol resistant pharmaceutical formulations
PL116330U1 (en) 2005-10-31 2007-04-02 Alza Corp Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation
US20090317355A1 (en) 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20070264346A1 (en) 2006-02-16 2007-11-15 Flamel Technologies Multimicroparticulate pharmaceutical forms for oral administration
US8309104B2 (en) 2006-03-02 2012-11-13 Watson Pharmaceuticals, Inc. Oral controlled release formulation for sedative and hypnotic agents
DK2018160T3 (da) 2006-03-16 2012-02-06 Tris Pharma Inc Modificeret depotformuleringer indeholdende lægemiddel-ionbytterharpikskomplekser
US9023400B2 (en) 2006-05-24 2015-05-05 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
CA2671200A1 (en) 2006-07-21 2008-01-24 Lab International Srl Hydrophilic abuse deterrent delivery system
US20080085304A1 (en) 2006-10-10 2008-04-10 Penwest Pharmaceuticals Co. Robust sustained release formulations
US8394845B2 (en) 2006-10-30 2013-03-12 Hanall Biopharma Co., Ltd. Method of using combination preparation comprising angiotensin-II-receptor blocker and HMG-CoA reductase inhibitor
CN101534795B (zh) 2006-11-21 2013-04-03 麦克内尔-Ppc股份有限公司 改进释放的镇痛悬浮液
CA2930487A1 (en) 2007-01-16 2008-07-24 Egalet Ltd. Use of i) a polyglycol and ii) an active drug substance for the preparation of a pharmaceutical composition for i)mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
US7568822B2 (en) 2007-03-28 2009-08-04 Visteon Global Technologies, Inc. Predictive adaptive front lighting algorithm for branching road geometry
US8202542B1 (en) 2007-05-31 2012-06-19 Tris Pharma Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings
US8778398B2 (en) 2008-11-04 2014-07-15 Jazz Pharmaceuticals, Inc. Immediate release formulations and dosage forms of gamma-hydroxybutyrate
US8771735B2 (en) * 2008-11-04 2014-07-08 Jazz Pharmaceuticals, Inc. Immediate release dosage forms of sodium oxybate
FR2938431B1 (fr) 2008-11-14 2013-12-20 Debregeas Et Associes Pharma Nouvelle composition a base d'acide gamma-hydroxybutyrique
US8410304B2 (en) 2009-04-15 2013-04-02 Norac Pharma Process for preparing gamma-hydroxybutyrate
US8461197B2 (en) 2009-04-23 2013-06-11 Concert Pharmaceuticals, Inc. 4-hydroxybutyric acid analogs
AU2010261341B2 (en) 2009-06-18 2014-02-06 Cadila Healthcare Limited Novel GPR 119 agonists
FR2951378B1 (fr) 2009-10-16 2012-06-01 Flamel Tech Sa Forme pharmaceutique orale solide anti-mesusage et dotee d'un profil specifique de liberation modifiee
US20120076865A1 (en) 2010-03-24 2012-03-29 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
CN102905688B (zh) 2010-04-06 2015-11-25 阿勒根公司 用于前房内药物递送的缓释储库式植入物
WO2011127252A2 (en) 2010-04-07 2011-10-13 Proteus Biomedical, Inc. Miniature ingestible device
EP2386289A1 (en) 2010-04-29 2011-11-16 Ipsen Pharma S.A.S. Clay compositions
EP2566462B1 (en) 2010-05-04 2020-07-08 Jazz Pharmaceuticals Inc. Immediate release formulations and dosage forms of gamma-hydroxybutyrate
EP2566488B1 (en) 2010-05-07 2016-07-13 Microdermis Corporation Povidone-iodine topical composition
SG186855A1 (en) 2010-06-28 2013-02-28 Merck Patent Gmbh 2,4- diaryl - substituted [1,8] naphthyridines as kinase inhibitors for use against cancer
GB201014633D0 (en) 2010-09-02 2010-10-13 Avexxin As Rheumatoid arthritis treatment
US8617602B2 (en) 2010-09-03 2013-12-31 William Wayne Howard Immediate release compositions and methods for delivering drug formulations using weak acid ion exchange resins in abnormally high pH environments
ES2554630T3 (es) 2010-09-30 2015-12-22 Toyama Chemical Co., Ltd. Sal sódica de 6-fluoro-3-hidroxi-2-pirazinocarboxamida
SG188662A1 (en) 2010-09-30 2013-05-31 Toyama Chemical Co Ltd Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide
US8623409B1 (en) 2010-10-20 2014-01-07 Tris Pharma Inc. Clonidine formulation
US20130230587A1 (en) 2010-11-10 2013-09-05 Rubicon Research Private Limited Sustained release compositions
US20140141090A1 (en) 2011-02-02 2014-05-22 Edward S. Wilson Pharmaceutical Composition Comprising Opioid Agonist And Sequestered Antagonist
FR2971422B1 (fr) 2011-02-11 2016-05-20 Debregeas Et Associes Pharma Granules d'acide gamma-hydroxybutyrique
MX355742B (es) 2011-02-14 2018-04-26 Concert Pharmaceuticals Inc Análogos deuterados del ácido 4-hidroxibutírico.
EP2696858A4 (en) 2011-04-15 2014-09-03 Threshold Pharmaceuticals Inc UNIT DOSE FOR ORAL ADMINISTRATION
EP2760911B1 (en) 2011-09-27 2017-11-22 Tepha, Inc. Controlled hydrolysis of poly-4-hydroxybutyrate and copolymers
ES2774932T3 (es) 2012-11-14 2020-07-23 Cj Cheiljedang Corp Producción de sales de 4-hidroxibutirato utilizando materias primas de base biológica
FR2999426B1 (fr) 2012-12-13 2015-01-02 Flamel Tech Sa Forme orale multiparticulaire a liberation immediate d'au moins un compose actif, comprenant des particules enrobees resistantes au broyage.
US8591922B1 (en) 2012-12-14 2013-11-26 Jazz Pharmacuticals, Inc. Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US9050302B2 (en) 2013-03-01 2015-06-09 Jazz Pharmaceuticals Ireland Limited Method of administration of gamma hydroxybutyrate with monocarboxylate transporters
US20150005334A1 (en) 2013-03-15 2015-01-01 Inspirion Delivery Technologies, Llc Abuse deterrent compositions and methods of use
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9801852B2 (en) 2013-08-30 2017-10-31 Jazz Pharmaceuticals, Inc. Devices and methods for facilitating and controlling use of a medication
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
RS59800B1 (sr) 2014-02-06 2020-02-28 Lan Bo Chen Kompozicija i postupak za potpomaganje sna
EP3102190A4 (en) 2014-02-07 2017-09-06 Auspex Pharmaceuticals, Inc. Novel pharmaceutical formulations
WO2015166473A1 (en) 2014-05-01 2015-11-05 Sun Pharmaceutical Industries Limited Extended release suspension compositions
US20160317388A1 (en) 2014-05-01 2016-11-03 Sun Pharmaceutical Industries Limited Dual-chamber pack for extended release suspension compositions
US9962336B2 (en) 2014-05-01 2018-05-08 Sun Pharmaceutical Industries Limited Extended release suspension compositions
MA41124A (fr) 2014-12-05 2017-10-10 Sun Pharmaceutical Ind Ltd Compositions en suspension à libération prolongée à rétention gastrique
US10398662B1 (en) 2015-02-18 2019-09-03 Jazz Pharma Ireland Limited GHB formulation and method for its manufacture
EP3288518A4 (en) 2015-05-01 2018-12-12 Sun Pharmaceutical Industries Limited Dual-chamber pack for extended release suspension compositions
CA3015500A1 (en) 2016-02-24 2017-08-31 Chemapotheca, Llc Amphetamine controlled release, prodrug, and abuse-deterrent dosage forms
US11000498B2 (en) 2016-07-22 2021-05-11 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
UY37341A (es) 2016-07-22 2017-11-30 Flamel Ireland Ltd Formulaciones de gamma-hidroxibutirato de liberación modificada con farmacocinética mejorada
US20180263936A1 (en) 2017-03-17 2018-09-20 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
WO2019123269A1 (en) 2017-12-20 2019-06-27 Flamel Ireland Limited Packaged modified release gamma-hydroxybutyrate formulations having improved stability
AU2019383389A1 (en) 2018-11-19 2021-05-06 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations
CA3127871A1 (en) 2019-03-01 2020-09-10 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US20210186907A1 (en) 2019-12-24 2021-06-24 Jazz Pharmaceuticals Ireland Limited Ghb dosing

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11090269B1 (en) 2010-03-24 2021-08-17 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US11207270B2 (en) 2010-03-24 2021-12-28 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US10195168B2 (en) 2012-12-14 2019-02-05 Jazz Pharmaceuticlas Ireland Limited Gamma-hydroxybutyrate compositions and their uses for the treatment of disorders
US10675258B2 (en) 2012-12-14 2020-06-09 Jazz Pharmaceuticals Ireland Limited Method of using gamma-hydroxybutyrate compositions for the treatment of disorders
US11554102B2 (en) 2012-12-14 2023-01-17 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate compositions and their uses for the treatment of disorders
US11077079B1 (en) 2015-02-18 2021-08-03 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US11364215B1 (en) 2015-02-18 2022-06-21 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US11147782B1 (en) 2015-02-18 2021-10-19 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US12115145B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115144B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12097176B2 (en) 2016-07-22 2024-09-24 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12097175B2 (en) 2016-07-22 2024-09-24 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11896572B2 (en) 2016-07-22 2024-02-13 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11826335B2 (en) 2016-07-22 2023-11-28 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11766418B2 (en) 2016-07-22 2023-09-26 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115143B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12109186B2 (en) 2016-07-22 2024-10-08 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115142B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11426373B2 (en) 2017-03-17 2022-08-30 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US11400052B2 (en) 2018-11-19 2022-08-02 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations
US11400065B2 (en) 2019-03-01 2022-08-02 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
WO2021133778A1 (en) 2019-12-24 2021-07-01 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate (ghb) dosing
CN115209885A (zh) * 2019-12-24 2022-10-18 爵士制药爱尔兰有限公司 γ-羟基丁酸盐(GHB)给药
CN115151254A (zh) * 2020-02-21 2022-10-04 爵士制药爱尔兰有限公司 治疗特发性嗜睡症的方法
WO2021168403A1 (en) 2020-02-21 2021-08-26 Jazz Pharmaceuticals Ireland Limited Methods of treating idiopathic hypersomnia
WO2022076824A1 (en) 2020-10-08 2022-04-14 Jazz Pharmaceuticals Ireland Limited Sodium oxybate to treat idiopathic hypersomnia
WO2022082105A2 (en) 2020-10-16 2022-04-21 Jazz Pharmaceuticals Ireland Limited Treatment methods using ghb
WO2023062018A1 (en) 2021-10-11 2023-04-20 Jazz Pharmaceuticals Ireland Limited Method of administering oxybate
WO2023135150A1 (en) 2022-01-11 2023-07-20 Jazz Pharmaceuticals Ireland Limited Method of administering oxybate
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal

Also Published As

Publication number Publication date
US20200113853A1 (en) 2020-04-16
US11426373B2 (en) 2022-08-30
US20220362185A1 (en) 2022-11-17
TW201836596A (zh) 2018-10-16
TW202335663A (zh) 2023-09-16
EP3595648A1 (en) 2020-01-22
US20210121423A1 (en) 2021-04-29
TWI812557B (zh) 2023-08-11
WO2018167303A1 (en) 2018-09-20
CA3056316A1 (en) 2018-09-20
JP2020510060A (ja) 2020-04-02
JP2023036649A (ja) 2023-03-14

Similar Documents

Publication Publication Date Title
US11426373B2 (en) Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US11554102B2 (en) Gamma-hydroxybutyrate compositions and their uses for the treatment of disorders

Legal Events

Date Code Title Description
AS Assignment

Owner name: JAZZ PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ALLPHIN, CLARK P.;JUNNARKAR, GUNJAN;SKOWRONSKI, ROMAN;AND OTHERS;SIGNING DATES FROM 20170717 TO 20170731;REEL/FRAME:046728/0602

Owner name: JAZZ PHARMACEUTICALS IRELAND LIMITED, IRELAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:JAZZ PHARMACEUTICALS, INC.;REEL/FRAME:046963/0136

Effective date: 20180315

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION