U.S. patent application number 16/575213 was filed with the patent office on 2020-04-16 for gamma-hydroxybutyrate compositions and their use for the treatment of disorders.
This patent application is currently assigned to Jazz Pharmaceuticals Ireland Limited. The applicant listed for this patent is Jazz Pharmaceuticals Ireland Limited. Invention is credited to Clark P. Allphin, Cuiping Chen, Mark Eller, Gunjan Junnarkar, Philip McGarrigle, Roman Skowronski, Katayoun Zomorodi.
Application Number | 20200113853 16/575213 |
Document ID | / |
Family ID | 63521436 |
Filed Date | 2020-04-16 |
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United States Patent
Application |
20200113853 |
Kind Code |
A1 |
Allphin; Clark P. ; et
al. |
April 16, 2020 |
GAMMA-HYDROXYBUTYRATE COMPOSITIONS AND THEIR USE FOR THE TREATMENT
OF DISORDERS
Abstract
Provided herein are pharmaceutical compositions and formulations
comprising mixed salts of gamma-hydroxybutyrate (GHB). Also
provided herein are methods of making the pharmaceutical
compositions and formulations, and methods of their use for the
treatment of sleep disorders such as apnea, sleep time
disturbances, narcolepsy, cataplexy, sleep paralysis, hypnagogic
hallucination, sleep arousal, insomnia, and nocturnal
myoclonus.
Inventors: |
Allphin; Clark P.; (Seattle,
WA) ; Junnarkar; Gunjan; (Palo Alto, CA) ;
Skowronski; Roman; (Palo Alto, CA) ; Chen;
Cuiping; (Palo Alto, CA) ; Zomorodi; Katayoun;
(San Jose, CA) ; Eller; Mark; (Redwood City,
CA) ; McGarrigle; Philip; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Jazz Pharmaceuticals Ireland Limited |
Dublin |
|
IE |
|
|
Assignee: |
Jazz Pharmaceuticals Ireland
Limited
Dublin
IE
|
Family ID: |
63521436 |
Appl. No.: |
16/575213 |
Filed: |
September 18, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15709262 |
Sep 19, 2017 |
|
|
|
16575213 |
|
|
|
|
62473232 |
Mar 17, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 2300/00 20130101; A61K 31/19 20130101; A61K 31/19 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 31/19 20060101
A61K031/19 |
Claims
1. A pharmaceutical composition of gamma-hydroxybutyrate comprising
a mixture of two or more salts of gamma-hydroxybutyrate (GHB),
wherein the mixture comprises at least 50% of a sodium salt of
gamma-hydroxybutyrate (Na GHB) and further comprises one or more of
a potassium salt of gamma-hydroxybutyrate (K GHB) and a calcium
salt of gamma-hydroxybutyrate (Ca (GHB).sub.2).
2. The pharmaceutical composition of claim 1, wherein the mixture
comprises about 50% to about 80% Na GHB.
3-6. (canceled)
7. The pharmaceutical composition of claim 1, wherein the
composition is an aqueous solution having a volume of about 25 mL
to about 100 mL.
8-9. (canceled)
10. The pharmaceutical composition of claim 1, wherein the
composition comprises a mixture of three or more salts of GHB,
wherein the mixture comprises between 50% to 80% Na GHB, between
10% to 40% K GHB, and between 10% and 20% Ca (GHB).sub.2.
11. The pharmaceutical composition of claim 1, wherein the
composition is bioequivalent to a pharmaceutical composition
comprising about 100% Na GHB when administered to a patient.
12. The pharmaceutical composition of claim 1, wherein 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.
13. The pharmaceutical composition of claim 1, wherein the average
maximum GHB plasma area under the curve (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.
14. The pharmaceutical composition of claim 1, wherein the
composition comprises a mixture of three salts of GHB, wherein the
mixture comprises at least 50% Na GHB, and further comprises K GHB
and Ca (GHB).sub.2.
15. The pharmaceutical composition of claim 14, wherein the
composition comprises between 50% and 60% of Na GHB, between 20%
and 40% K GHB, and between 10% and 20% Ca (GHB).sub.2.
16. The pharmaceutical composition of claim 15, wherein the mixture
comprises about 50% Na GHB, about 34% K GHB, and about 16% Ca
(GHB).sub.2.
17. 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 about
40% to about 50% Na GHB, and further comprising one or more salts
selected from K GHB, Ca (GHB).sub.2, and Mg (GHB).sub.2.
18. The pharmaceutical composition of claim 17, wherein 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.
19. The pharmaceutical composition of claim 17, wherein the aqueous
solution has a volume of about 25 mL to about 75 mL.
20-21. (canceled)
22. The pharmaceutical composition of claim 17, wherein the
composition comprises Na GHB and K GHB.
23. The pharmaceutical composition of claim 17, wherein the
composition is formulated as a liquid formulation.
24. The pharmaceutical composition of claims 17, wherein the
pharmaceutical composition is bioequivalent to a pharmaceutical
composition comprising about 100% Na GHB when administered to a
patient.
25. The pharmaceutical composition of claim 17, wherein 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.
26. (canceled)
27. A method for treating a disease or condition in a patient that
is suitable to treatment by GHB, comprising administering the
pharmaceutical composition of claim 1 to the patient.
28. The method according to claim 27, wherein the disease is
cataplexy or narcolepsy.
29. A method of treating a patient who is in need of GHB comprising
administering to the patient two nightly doses of GHB or a salt
thereof, wherein 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).sub.2, and Mg
(GHB).sub.2, and the second dose comprises the pharmaceutical
composition of claim 1.
30. (canceled)
Description
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 62/472,232, filed Mar. 17, 2017, the content
of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] Provided herein are pharmaceutical compositions and
formulations comprising salts of gamma-hydroxybutyrate (GHB). In
one embodiment, the salts encompass more than one type of cation.
Also provided herein are methods of making the pharmaceutical
compositions and formulations, and methods of the treatment of
disorders including fibromyalgia and sleep disorders. Also
described herein is that such pharmaceutical compositions and
formulations are for treating diseases or disorders including
fibromyalgia and sleep disorders. Such sleep disorders include
apnea, sleep time disturbances, narcolepsy, cataplexy, sleep
paralysis, hypnagogic hallucination, sleep arousal, insomnia, and
nocturnal myoclonus.
BACKGROUND OF THE INVENTION
[0003] Sodium oxybate (Na GHB), commercially sold as Xyrem.RTM.
(Jazz Pharmaceuticals), 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 (See
Scharf et al., 2003, J. Rheumatol. 30: 1070; Russell et al., 2009,
Arthritis. Rheum. 60: 299), 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 Ondo et al., 2008, Arch.
Neural. 65: 1337; Frucht et al., 2005, Neurology 65: 1967; Berner,
2008, J. Clin. Psychiatry 69: 862).
[0004] Xyrem.RTM., 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.
[0005] Since Xyrem.RTM. 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.
SUMMARY OF THE INVENTION
[0006] Provided herein are pharmaceutical 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.
[0007] 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.RTM.. In certain embodiments, the
reduction in sodium content involves use of other cations such as
potassium, calcium, magnesium, and others.
[0008] For convenience in comparing various salt compositions at
the same oxybate or GHB molar dose, 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 %. As used herein, the terms "oxybate"
and "GHB" are used interchangeably.
[0009] Accordingly, in one aspect, provided herein are
pharmaceutical compositions and formulations comprising salts of
GHB. In one embodiment, 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).sub.2). In certain embodiments, the Na GHB salt is present in
the mixture in about 50%, and up to 55%, 60%, 70% or 80%. In
certain embodiments, the pharmaceutical composition does not
comprise a substantial amount of a magnesium salt of
gamma-hydroxybutyrate (Mg (GHB).sub.2).
[0010] In another embodiment 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.
[0011] In another embodiment, 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%.
[0012] In another embodiment, 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).sub.2. In certain embodiments, 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).sub.2. In certain embodiments, 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).sub.2
for each GHB salt.
[0013] In another embodiment, the pharmaceutical compositions
and/or formulations disclosed herein can be used to treat a disease
or condition selected from the group consisting of 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.
[0014] In another embodiment, 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).sub.2,
and Mg (GHB).sub.2 In certain embodiments, the pharmaceutical
compositions disclosed herein do not comprise a substantial amount
Ca (GHB).sub.2) or Mg (GHB).sub.2.
[0015] In another embodiment, the pharmaceutical composition
comprises about 8% Na GHB, 23% K GHB, 48% Ca (GHB).sub.2 and 21% Mg
(GHB).sub.2. In certain embodiments, this pharmaceutical
composition can be used to treat the diseases or conditions listed
above.
[0016] In another embodiment, the pharmaceutical 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.
[0017] Xyrem.RTM., as disclosed herein, 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.
Accordingly, in another aspect, provided herein is a first dose of
a first pharmaceutical composition and/or formulation having a Na
GHB of less than 50% and a second dose of a second pharmaceutical
composition and/or formulation having a Na GHB above 50%. Another
embodiment has the doses in reverse order and a further embodiment
uses similar doses of either formulation. In certain embodiments,
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.
[0018] In another aspect, the pharmaceutical 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. In one embodiment, 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.
[0019] The pharmaceutical 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. In
certain embodiment, 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.
[0020] In another aspect, provided herein are methods 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. In
certain embodiments, 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. In certain embodiments, 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.
[0021] In another embodiment, 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).sub.2, and Mg (GHB).sub.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).sub.2,
and Mg (GHB).sub.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.
[0022] The pharmaceutical 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.
[0023] In certain embodiments, 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).sub.2, and Mg (GHB).sub.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).sub.2, and Mg (GHB).sub.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.
[0024] In other aspects, provided herein are methods of making the
pharmaceutical compositions disclosed herein.
BRIEF DESCRIPTION OF THE FIGURES
[0025] 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).sub.2) compared to Xyrem.RTM. ("X") given in either the fed
or fasted state (, Xyrem.RTM. fasted; , Formulation "O" fasted;
Xyrem.RTM. fed; , Formulation "O" fed). The objective was to
characterize bioequivalence of Formulation "O" to Xyrem.RTM..
[0026] FIG. 2 shows the plasma GHB concentration vs time for blends
of Formulation "O" and Xyrem.RTM. ("X") in proportions of 100%
Xyrem.RTM., 44% Xyrem.RTM., and 17% Xyrem.RTM., 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.RTM.) would be required to achieve bioequivalence in the
fasted state.
[0027] FIG. 3 shows the plasma GHB concentration vs time for
various mixed oxybate salt formulations compared to Xyrem.RTM. in
the fasted state where both are given at a lower volume of
administration of 60 mL (, Xyrem.RTM. (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)).
[0028] FIG. 4A-4B compare Xyrem.RTM. and Formulation "O" when given
fasted with 60 mL or 240 mL water or when given fed with 60 mL
water. FIG. 4A. (Left) Plasma GHB concentration when Xyrem.RTM. was
given (fasted) with 60 mL or 240 mL water or when Xyrem.RTM. was
given (fed) with 60 mL water (, fasted 240 mL; , fasted 60 mL; ,
fed 60 mL). FIG. 4B (Right) Plasma GHB concentration when
Formulation "O" was given (fasted) with 60 mL or 240 mL water or
when Formulation "O" was given (fed) with 60 mL water (, fasted 240
mL; , fasted 60 mL; , fed 60 mL).
[0029] FIG. 5A-5B show the relationship between Cmax ratio (to
Xyrem.RTM.) 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.RTM.) 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.
5B (Bottom) Relationship between Cmax ratio (to Xyrem.RTM.) and
sodium 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).
[0030] 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.RTM. fed, 2nd dose Xyrem.RTM. 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.RTM. given both
times.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Gamma-hydroxybutyrate (GHB), also known as "oxybate," is an
endogenous compound with hypnotic properties that is found in human
body tissues, such as the mammalian brain. In the brain, the
highest GHB concentration is found in the hypothalamus and basal
ganglia and GHB is postulated to function as a neurotransmitter
(See Snead and Morley, 1981, Brain Res. 227(4): 579-89). 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. In addition, 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).
[0032] Xyrem.RTM. 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. Further, despite a general record of
safety when used as prescribed, there are risks of abuse and misuse
of Xyrem.RTM. which can cause serious medical problems, including
seizures, loss of consciousness, coma, and death (see, e.g., FDA
product label dated Nov. 13, 2006 for NDA no. 021196, which is
incorporated by reference in its entirety).
[0033] Xyrem.RTM. 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. Thus, there is a need for 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.
[0034] However, 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. For
example, 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.
[0035] Xyrem.RTM. is provided as an oral solution consisting of 500
mg/mL sodium oxybate (Na GHB) that is pH adjusted with malic acid.
Xyrem.RTM. 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.RTM. 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). As such, for alternative
formulations of GHB, such as those comprising cations other than
sodium, but having comparable solubility, bioequivalence might be
expected and a pharmacokinetic evaluation waived. See 21 CFR Part
320.22 Subpart B paragraph b(3).
[0036] However, as disclosed herein, despite the apparently rapid
absorption of sodium oxybate, its presentation as an aqueous
solution, and the absence of any other ingredients that would be
expected to modify absorption behavior, formulations having the
same GHB concentration do not display pharmacokinetics equivalent
to Xyrem.RTM.. Furthermore, as also disclosed herein, the
pharmacokinetic behavior of such formulations appears to depend on
the amount of sodium and/or other cations present, as well as the
amount of water in the formulation. Accordingly, one object of the
present disclosure is to provide alternative formulations of GHB
which are bioequivalent to Xyrem.RTM.. Provided herein are such
alternative formulations which surprisingly display the desired
bioequivalence.
[0037] The following patents and applications referred to
throughout the application are hereby incorporated by reference in
their entireties for all purposes, including the following: U.S.
Pat. Nos. 6,472,431; 7,895,059; 8,461,197; 8,591,922; 8,759,394;
8,771,735; 8,772,306; 8,778,301 8,778,398; 8,952,029; and
9,050,302; and U.S. Publication No. 2012/0076865.
[0038] Objects, features and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
6.1 Definitions
[0039] As used herein, the term "gamma-hydroxybutyrate" (GHB) or
"oxybate" refers to the negatively charged or anionic form
(conjugate base) of gamma-hydroxybutyric acid. Without being
limited by theory, GHB is believed to have the following
structure:
##STR00001##
[0040] As used herein, the term "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:
##STR00002##
[0041] As used herein, the terms "sodium gamma-hydroxybutyrate" (Na
GHB) or "sodium oxybate" (Na oxybate) refers to the sodium salt
form of gamma-hydroxybutyric acid having the molecular weight of
126.09. Without being limited by any theory, Na GHB is believed to
have the following structure:
##STR00003##
[0042] As used herein, the term "potassium gamma-hydroxybutyrate"
(K GHB) or "potassium oxybate" (K oxybate) refers to the potassium
salt form of gamma-hydroxybutyric acid having the molecular weight
of 142.19. Without being limited by any theory, K GHB is believed
to have the following structure:
##STR00004##
[0043] As used herein, the term "magnesium gamma-hydroxybutyrate"
(Mg (GHB).sub.2) or "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).sub.2 is believed to have the following structure:
##STR00005##
[0044] As used herein, the term "calcium gamma-hydroxybutyrate" (Ca
(GHB).sub.2) or "calcium oxybate" (Ca oxybate) refers to the
calcium salt form of gamma-hydroxybutyric acid having the molecular
weight of 246.27. Without being limited by theory, Ca (GHB).sub.2
is believed to have the following structure:
##STR00006##
[0045] As used herein, the term "gamma-butyrolactone" (GBL) refers
to a colorless oily liquid. Without being limited by theory, GBL is
believed to have the following structure:
##STR00007##
[0046] As used herein, the term "patient" refers to a mammal,
particularly a human.
[0047] The terms "treat," "treating" or "treatment," as used
herein, refer to a method of alleviating or abrogating a disease
and/or its attendant symptoms.
[0048] As used herein, 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.
[0049] The term "substantial amount" shall mean over 1%.
[0050] By "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.
[0051] The term "salt" or "salts," as used herein, 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.
In certain preferred embodiments, 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).
[0052] As used herein, the terms "salt of GHB" or "salts of GHB,"
as used herein, refer 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).sub.2, and Ca(OH).sub.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).sub.2, and Ca (GHB).sub.2, and the like. It
will be understood by those skilled in the art that such 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).sub.2:
##STR00008##
[0053] The terms "mixture of salts" or "salt mixture," as used
herein, 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).sub.2, and Ca (GHB).sub.2.
[0054] Xyrem.RTM. contains 500 mg/mL Na GHB. When referring to a
mixture of GHB salts with different cations, the concentration in
mg/mL will vary between formulations and/or pharmaceutical
compositions of the same GHB strength. As used herein, a GHB
concentration of 409 mg/mL is equivalent to the GHB content in 500
mg/mL of Na GHB.
[0055] The term "wt/wt %," are used herein, 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.
[0056] The term "wt/wt % ratio," as used herein, refers to the
ratio of wt/wt % values in a mixture of salt. For example, where
the salts Na GHB, K GHB, Mg (GHB).sub.2, and Ca (GHB).sub.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).sub.2, and Ca (GHB).sub.2
in the mixture is 8%:32%:20%:40%.
[0057] The terms "% molar equivalents" and "% mol. equiv.," as used
herein, refer to molar composition of salts expressed as a percent
of GHB (or "oxybate") equivalents. For example, 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).sub.2, and
Ca (GHB).sub.2. Those skilled in the art will understand that as
each GHB unit is considered to be one molar equivalent, the
monovalent cations, Na.sup.+ and K.sup.+, have one molar equivalent
per salt, and the divalent cations, Mg.sup.+2 and Ca.sup.+2, have
two molar equivalents per salt. A sample calculation of % mol.
equiv. is provided in the Examples of the present disclosure. For
convenience in comparing various salt compositions at the same
oxybate molar dose, 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
%.
[0058] The term, "buffering agent," as used herein, 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. Such agents may be
acids, bases, or combinations thereof
[0059] The term, "adjusting agent," as used herein, 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.
[0060] The term, "acid," as used herein, 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.
[0061] The term, "base," as used herein, refers to a substance
which shares a pair of electrons. Such substances include sodium
hydroxide, potassium hydroxide, magnesium hydroxide, calcium
hydroxide, and the like.
[0062] The term, "chemically stable," as used herein, 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.
[0063] The term, "microbial," as used herein, refers to a
microscopic organism that comprises either a single cell, cell
cluster or multicellular organism.
[0064] The term "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.
[0065] The term, "preservative," as used herein, 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.
[0066] The term, "formulation," as used herein, refers to a stable
and pharmaceutically acceptable preparation of a pharmaceutical
composition disclosed herein.
[0067] The term, "liquid formulation," as used herein, refers to a
water-based formulation, in particular, a formulation that is an
aqueous solution.
[0068] The term, "low volume" or "low aqueous volume" or "reduced
volume," as used herein, refers to an aqueous solution of about 100
mL or less
[0069] The term, "volume of administration" as used here, 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.
[0070] The term, "eating" as used herein, refers to ingesting or
consuming calories and/or nutrients by way of solid or liquid food
substances.
[0071] The term, "cataplexy," as used herein, refers to a condition
where a patient exhibits a sudden and transient loss of muscle
tone, often triggered by emotions.
[0072] The term, "daytime sleepiness," as used herein, refers to a
condition where a patient exhibits persistent sleepiness, and often
a general lack of energy, even after apparent adequate night time
sleep.
[0073] The term, "narcolepsy," as used herein, refers to a chronic
sleep disorder characterized by excessive sleepiness and sleep
attacks at inappropriate times.
[0074] The term, "apnea," as used herein, refers to a condition
where a patient suspends external breathing.
[0075] The term, "sleep time disturbances," as used herein, 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.
[0076] The term, "sleep paralysis," as used herein, 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.
[0077] The term, "hypnagogic hallucination," as used herein, refers
to a transition state between wakefulness and sleep where a patient
experiences vivid hallucinations.
[0078] The term, "sleep arousal," as used herein, refers to a
condition where a patient engages in sexual acts while still
asleep.
[0079] The term, "insomnia," as used herein, refers to a condition
where a patient has difficulties falling asleep and maintaining
sleep.
[0080] The term, "nocturnal myoclonus," as used herein, 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.
[0081] The term "flavoring" or "flavoring agent," as used herein,
refers to a substance that alters the flavor of the composition
during oral consumption. A type of "flavoring agent" would be a
sweetener.
[0082] The term "coloring" or "coloring agent," as used herein,
refers to a substance that alters the color of the composition.
[0083] The term "bioequivalent", as used herein, describes a
formulation and/or pharmaceutical composition that is
therapeutically equivalent to a reference product (e.g. Xyrem.RTM.)
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-Bi-
oEquiv.pdf, see also
https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4241B1-02-23-FDA-Bi-
oequiv%20OGD%20Oct%206%202006%20Background.pdf). 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. In some embodiments, 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. In some embodiments, 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.
[0084] In some embodiments, 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. In some embodiments, 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. For example, a pharmaceutical composition is
bioequivalent to Xyrem.RTM. when the pharmaceutical composition
produces an average Cmax and/AUC is between 80% and 125% of the
Cmax and/or AUC of Xyrem.RTM. when administered under the same
conditions.
[0085] The expression "consists essentially of" as used herein,
means that specific further components can be present in a mixture
or composition, namely those not materially affecting the essential
characteristics of the mixture or composition.
6.2 Pharmaceutical Compositions Comprising Salt Mixtures of GHB
[0086] In certain aspects, provided herein are pharmaceutical
compositions comprising gamma-hydroxybutyrate (GHB) and one or more
pharmaceutically acceptable cations of an alkali metal or an
alkaline earth metal. As used herein, "alkali metal" means any of
the elements found in Group IA of the periodic table, including,
for example, lithium, sodium, and potassium. As used herein,
"alkaline earth metal" means any of the elements found in Group II
of the periodic table, including, for example, magnesium and
calcium.
[0087] In certain embodiments, the pharmaceutical compositions
comprise GHB and more than one pharmaceutically acceptable cations
of an alkali metal or an alkaline earth metal.
[0088] In certain embodiments, the pharmaceutical compositions
comprise GHB and more than one (two or more) cations selected from
the group consisting of Na.sup.30 , K.sup.+, Mg.sup.+2, and
Ca.sup.+2. In certain embodiments, the pharmaceutical compositions
comprise GHB and all three cations selected from the group
consisting of Na.sup.+, K.sup.+, and Ca.sup.+2. In certain
embodiments, the pharmaceutical compositions comprise less than
100% of the cation Na.sup.+, 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.sup.+. In other embodiments, the pharmaceutical compositions
comprise from about 0% to about 40% of the cation Na.sup.+. Each
embodiment has a different advantage.
[0089] In certain aspects, provided herein are pharmaceutical
compositions comprising salts of GHB. As used herein, the term
"salt of GHB" or "salts of GHB" is used interchangeably with the
term "cation." For example, a pharmaceutical composition comprising
GHB and the four cations Na.sup.+, K.sup.+, Mg.sup.+2, and
Ca.sup.+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).sub.2, and Ca (GHB).sub.2. It will be also understood
by those skilled in the art that such salts may be in solid form,
or 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.
[0090] In certain embodiments, 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).sub.2, and Ca
(GHB).sub.2. In certain embodiments, the pharmaceutical composition
comprises Na GHB, K GHB, and Ca.PSI.(GHB).sub.2. In certain
embodiments, the pharmaceutical composition comprises Na GHB, and
Ca (GHB).sub.2. In certain embodiments, the pharmaceutical
composition comprises Na GHB, Mg (GHB).sub.2, and Ca (GHB).sub.2.
In certain embodiments, the pharmaceutical composition comprises Na
GHB and K GHB. In certain embodiments, the pharmaceutical
composition comprises Na GHB, K GHB, and Mg (GHB).sub.2.
[0091] In certain embodiments, the pharmaceutical composition
comprises Na GHB and Mg (GHB).sub.2.
[0092] The amounts of the cations below are described in various
ranges. The cations can be present in the ranges found in U.S. Pat.
Nos. 8,591,922; 8,901,173; and 9,132,107.
[0093] In certain embodiments, 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%.
[0094] In certain embodiments, 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.
[0095] In certain embodiments, 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.
[0096] In certain embodiments, 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.
[0097] In certain embodiments, 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.sup.+ and the amount of other cations. For example, if
Na.sup.+ is present at 50% and Ca.sup.+2 and K.sup.+ are also
present, then Ca.sup.+2 and K.sup.+ can each be present in varying
amount from 5-40% to add up to the remaining 50%. If Mg.sup.+2 is
also present in the mixture then the non-sodium component 50% is
divided three ways. In some embodiments, the mixture does not
comprise a significant amount of Mg (GHB).sub.2 or Ca (GHB).sub.2,
and therefore the formulation and/or pharmaceutical composition
does not have a significant amount of Mg (GHB).sub.2 or Ca
(GHB).sub.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.
[0098] In certain embodiments, Na.sup.+ is present at 50% and
Ca.sup.2+ and K.sup.+ are also present, then Ca.sup.2+ and K.sup.+
can each be present in varying amount from 5-45% to add up to the
remaining 50%.
[0099] In certain embodiments, the K GHB, Mg (GHB).sub.2 or Ca
(GHB).sub.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%. In
certain embodiments, the K GHB, Mg (GHB).sub.2 or the Ca
(GHB).sub.2 salt is absent.
[0100] In certain embodiments, the mixture comprises K GHB, Mg
(GHB).sub.2 or the Ca (GHB).sub.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%. In certain
embodiments, the mixture comprises about 0% K GHB. In certain
embodiments, the mixture comprises about 0% Mg (GHB).sub.2. In
certain embodiments, the mixture comprises about 0% Ca
(GHB).sub.2.
[0101] In certain embodiments, 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%. In certain embodiments, the mixture comprises about
0% K GHB.
[0102] In certain embodiments, the mixture comprises Mg (GHB).sub.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%. In certain embodiments, the mixture comprises
about 0% Mg (GHB).sub.2.
[0103] In certain embodiments, the mixture comprises Ca (GHB).sub.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%. In certain embodiments, the mixture comprises
about 0% Ca (GHB).sub.2.
[0104] In certain embodiments, the pharmaceutical composition has
reduced sodium compared to Xyrem.RTM., wherein the Na GHB salt is
present in the mixture at about 50% to about 80%.
[0105] In certain embodiments, 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).sub.2
and Mg (GHB).sub.2. In certain embodiments, the Na GHB salt is
present in the mixture at about 50% to 80%. In certain embodiments,
the Na GHB salt is present in the mixture at about 50% to 70%. In
certain embodiments, the Na GHB salt is present in the mixture at
about 50% to 60%. In certain embodiments, the Na GHB salt is
present in the mixture at about 50% to 55%.
[0106] In certain embodiments, 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).sub.2.
[0107] In certain embodiments, 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).sub.2.
[0108] In certain embodiments, the pharmaceutical composition
comprises a mixture of three or more salts of GHB.
[0109] In certain embodiments, the pharmaceutical composition does
not comprise a substantial amount of Mg (GHB).sub.2 or Ca
(GHB).sub.2. In certain embodiments, the mixture does not comprise
a substantial amount of Mg (GHB).sub.2 or Ca (GHB).sub.2. In
certain embodiments, the mixture consists of 50% to 80% Na GHB, at
least 10% K GHB, and at least 10% Ca (GHB).sub.2.
[0110] In certain embodiments, 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).sub.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).sub.2.
[0111] In certain embodiments, 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).sub.2.
[0112] In certain embodiments, 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).sub.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).sub.2.
[0113] In certain embodiments, 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).sub.2.
[0114] In certain embodiments, 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).sub.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).sub.2.
[0115] In certain embodiments, 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).sub.2.
[0116] In certain embodiments, 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).sub.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).sub.2.
[0117] In certain embodiments, 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).sub.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).sub.2.
[0118] In certain embodiments, 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).sub.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).sub.2.
[0119] In certain embodiments the mixture comprises 45% to 55% Na
GHB, 30% to 40% K GHB, and 10% to 20% Ca (GHB).sub.2. In certain
embodiments the mixture comprises 48% to 52% Na GHB, 32% to 36% K
GHB, and 14% to 18% Ca (GHB).sub.2. In certain embodiments, the
mixture does not have a substantial amount of Mg (GHB).sub.2. In
other embodiments, the mixture does not have a substantial amount
of Ca (GHB).sub.2.
[0120] In certain embodiments, 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).sub.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).sub.2.
[0121] In certain embodiments, the pharmaceutical composition does
not comprise a substantial amount of Mg (GHB).sub.2. In certain
embodiments, the mixture does not comprise a substantial amount of
Mg (GHB).sub.2. In certain embodiments, the Na GHB, K GHB, and Ca
(GHB).sub.2 salts are present in the mixture in a ratio of about
50%:34%:16%.
[0122] In certain embodiments, 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).sub.2,
and Mg (GHB).sub.2.
[0123] In certain embodiments, the mixture comprises about 40% to
about 50% Na GHB, and further comprising one or more salts selected
from K GHB, Ca (GHB).sub.2, and Mg (GHB).sub.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).sub.2, and Mg (GHB).sub.2.
[0124] In certain embodiments, 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).sub.2, and Mg (GHB).sub.2.
[0125] In certain embodiments, 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.
[0126] In certain embodiments, 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.
[0127] In certain embodiments, 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.
[0128] In certain embodiments, 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.
[0129] In certain embodiments 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.
[0130] In certain embodiments, the pharmaceutical composition is
bioequivalent to Xyrem.RTM. which is Na GHB. In certain
embodiments, the pharmaceutical composition produces an average
maximum GHB plasma concentration (Cmax) that is substantially the
same as the Cmax of Na GHB. In certain embodiments, the
pharmaceutical composition produces a Cmax that is within 80% and
125% of the Cmax of Na GHB. In certain embodiments, the
pharmaceutical composition produces an average maximum GHB plasma
area under the curve (AUC) and Cmax that is substantially the same
as Na GHB. In certain embodiments, the pharmaceutical composition
produces an AUC that is between 80% and 125% of the AUC of Na
GHB.
[0131] In certain embodiments, the pharmaceutical composition is
bioequivalent to a pharmaceutical composition comprising about 100%
Na GHB when administered to a patient.
[0132] In certain embodiments, 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. 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.
[0133] In certain embodiments, the pharmaceutical composition is
formulated as a liquid formulation, wherein the Na GHB salt is
present at less than 40%. In these embodiments, the pharmaceutical
composition is more resistant to a food effect and has a lower Cmax
compared to Na GHB.
[0134] In certain embodiments, 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).sub.2 and Mg (GHB).sub.2.
In certain embodiments, 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%.
[0135] In certain embodiments, 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).sub.2 and at
least 10% Mg (GHB).sub.2. In certain embodiments, 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).sub.2 or Mg (GHB).sub.2. In certain
embodiments, 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).sub.2 and between 10 and
50% Mg (GHB).sub.2 for the non-sodium salts.
[0136] In certain embodiments, the Na GHB, K GHB, Mg (GHB).sub.2,
and Ca (GHB).sub.2 salts are present in the mixture at a ratio of
about 8%:23%:21%:48%, respectively.
6.2.1 Concentrations and pH Values
[0137] In certain embodiments, the pharmaceutical composition
comprises an aqueous solution.
[0138] In certain embodiments, 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.
[0139] It will be understood that 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.
[0140] Accordingly, in certain embodiments, 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.
[0141] In certain embodiments, the pharmaceutical composition is
chemically stable and resistant to microbial growth. In certain
embodiments, the pharmaceutical composition is free of
preservatives.
[0142] It will also be understood that 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. For example, Na GHB at this concentration (500
mg/mL) is resistant to microbial growth in an aqueous medium when
the pH is between about pH 5 and pH 9. Compositions at about pH 6
to about pH 7.5 are particularly resistant to microbial growth.
However, at 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.
[0143] It will be further understood that 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. Thus, a preferred
range for chemically stable GHB would be from about pH 6 to about
pH 9. However, 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.
[0144] In certain embodiments, 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. However,
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. Of course,
any salt, flavoring agent, excipient, or other pharmaceutically
acceptable addition described herein, or as would be known to those
skilled in the art, is contemplated as being useful for the
compositions or formulations disclosed herein. See U.S. Pat. No.
6,472,431, and Remington, The Science and Practice of Pharmacy,
22nd Ed. 2013, each of which is hereby incorporated by reference in
its entirety.
[0145] In certain embodiments, 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.
6.2.2 Formulations
[0146] The 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.
[0147] As used herein, "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.sup.nd Ed. 2013.
[0148] In certain embodiments, the compositions disclosed herein
are provided in a formulation, preferably, a liquid formulation,
although solid formulations are also contemplated. For any examples
of excipients, colorants, flavorants, or other components of the
formulation; see Remington, The Science and Practice of Pharmacy,
22.sup.nd Ed. 2013.
[0149] In certain embodiments, 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. However, if preservatives are added
they 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.sup.nd Ed. 2013, each of which is incorporated hereby
by reference in its entirety.
[0150] In certain embodiments, the formulation is suitable for oral
administration.
[0151] In certain embodiments, 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
fluidextract, eriodictyon syrup-aromatic, ethyl acetate, ethyl,
vanillin, fennel oil, ginger, ginger fluidextract, ginger
oleoresin, glucose, glycerin, glycyrrhiza, glycyrrhiza elixir,
glycyrrhiza extract, glycyrrhiza extract-pure, glycyrrhiza
fluidextract, glycyrrhiza syrup, honey, non-alcoholic elixir,
lavender oil, citrus extract or oil, lemon oil, lemon tincture,
mannitol, methyl salicylate, nutmeg oil, orange-bitter-elixir,
orange-bitter-oil, orange flower oil, orange flower water, orange
oil, orange peel-bitter, orange-peel-sweet-tincture, orange
spirit-compound, compound, orange syrup, peppermint, peppermint
oil, peppermint spirit, peppermint water, phenylethyl alcohol,
raspberry juice, raspberry syrup, rosemary oil, rose oil, rose
water, saccharin, saccharin calcium, saccharin sodium, sarsaparilla
syrup, sorbitol solution, spearmint, spearmint oil, sucralose,
sucrose, syrup, thyme oil, tolu balsam, tolu balsam syrup, vanilla,
vanilla tincture, vanillin or wild cherry syrup.
[0152] In certain embodiments, the formulation additionally
comprises a coloring agent. Preferred coloring agents would be
microbially non-metabolizable.
[0153] In certain embodiments, the formulation is administered in a
single or multiple dosage regimen.
[0154] 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.
[0155] In certain embodiments, especially with Na GHB amounts
between 40% and 50%, the formulation is present in a low volume of
aqueous solution. As described herein, by "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. Preferably 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. In certain embodiments, for example,
formulations with reduced sodium, 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. It
should be understood by those skilled in these arts that 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. For
certain individuals, 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.
[0156] 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. 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.
Typically, 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 be emulsified.
[0157] 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. In all cases 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.
[0158] 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.
[0159] 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. 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. The prevention of the action of 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.
[0160] 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. Generally,
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. In the case of sterile powders for the
preparation of sterile injectable solutions, 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. The
preparation of more, or highly, concentrated solutions for direct
injection is also contemplated, where the use of DMSO as solvent
(although DMSO may not now be a permitted human drug) is envisioned
to result in extremely rapid penetration, delivering high
concentrations of the active agents to a small area.
[0161] 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.
[0162] 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. These particular aqueous solutions are especially
suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal administration. In this connection, sterile aqueous
media which can be employed will be known to those of skill in the
art in light of the present disclosure. For example, 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.
[0163] 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.RTM. 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.RTM. instructions
recommend two equally divided doses.
[0164] In addition to the pharmaceutical 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.
[0165] One may also use nasal solutions or sprays, aerosols or
inhalants in connection with the pharmaceutical compositions and/or
formulations disclosed herein. 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. Thus, 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. In addition, 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.
[0166] 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. In certain defined embodiments,
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.
[0167] For oral therapeutic administration, 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.
[0168] 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. When the dosage unit form is a capsule
for admixing with a specific volume of an aqueous medium, it may
contain, in addition to materials of the above type, a liquid
carrier. Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For
instance, 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.
[0169] 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. Publication No.
2012/0076865. Another embodiment includes the use of both immediate
release and controlled release forms mixed together or one after
the other. In one embodiment the immediate release portion could be
between 10-50%, or 20-30% and the controlled release portion
comprising the remaining amount. In some embodiments the amounts of
the different salts can be different in each of the immediate or
controlled release portions.
[0170] Additionally, any excipient, salt, acid, pH-mediating,
adjusting or buffering compound or agent, flavoring, solution,
solvent, dispersion, glycerol, glycol, oil, antibacterial and
antifungal agents, antibiotics and antihistamines, binders,
disintegrating agents, lubricants, sweetening agents, or any other
additive or ingredient from those enumerated above or in the
examples, or in any pharmaceutically acceptable composition or
carrier described herein, or as would be known by one of skill in
the art, is contemplated for use in aqueous mediums or solid forms
of the pharmaceutical compositions disclosed herein. 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.
[0171] Also provided herein are therapeutic 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.
[0172] When the components of the kit are provided in one or more
liquid formulations, 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. In which case, 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.
[0173] However, the components of the kit may be provided as dried
powder(s). When reagents or components are provided as a dry
powder, 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.
[0174] 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.
[0175] The 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.
[0176] In certain embodiments, the 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.
[0177] In certain embodiments, the 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. Preferably, 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).sub.2,
and Mg (GHB).sub.2, and 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).sub.2, and Mg (GHB).sub.2.
[0178] Irrespective of the number or type of containers, the 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. Such an
instrument may be a drinking cup, syringe, pipette, or any such
medically approved delivery vehicle. Where two more formulations
are provided in the kit, optionally, 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. Furthermore, 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. Where two or more formulations are
provided as granules or other rapidly dissolving dosage form, twin
sachets with a perforated divider can facilitate dose preparation.
These could be labeled, for example, as "1.sup.st dose" and
"2.sup.nd dose".
[0179] Furthermore and to distinguish between prepared formulations
prior to administration, 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.
Also, 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.
6.2.3 Methods of Treatment
[0180] All the pharmaceutical compositions and formulations
provided herein can be used in all the methods provided herein. For
example, the the pharmaceutical compositions and formulations
provided herein can be used in all the methods for treating all
diseases, disorders or conditions provided herein. Thus, the
pharmaceutical compositions and formulations provided herein are
for use as a medicament. In certain embodiments, 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. In certain embodiments, 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. In certain
embodiments, 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
[0181] The pharmaceutical 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. It is also contemplated that the pharmaceutical
compositions and formulations disclosed herein may be used as a
narcotic, hypnotic, or as a soporific. It is further contemplated
that the pharmaceutical compositions and formulations comprising
mixed salts of GHB, disclosed herein, 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.
[0182] The pharmaceutical compositions and formulations comprising
mixed salts of GHB, disclosed herein, 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.
[0183] Accordingly, in certain aspects, are methods of treatment
comprising administration to a patient of the pharmaceutical
compositions or formulations comprising mixed salts GHB disclosed
herein.
[0184] In certain embodiments, the pharmaceutical 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.
[0185] In certain embodiments, 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.
[0186] Accordingly, in certain embodiments, 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.
[0187] In certain embodiments, also provided herein is a method of
treating a disease or condition that is suitable for treatment with
GHB wherein the method comprises 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.
In certain embodiments, the pharmaceutical composition does not
comprise a substantial amount of Mg (GHB).sub.2 or Ca (GHB).sub.2.
In certain embodiments, 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. In preferred embodiments, the
disease is cataplexy and/or narcolepsy. In certain embodiments, 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.
[0188] In certain embodiments, 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).sub.2.
[0189] In certain embodiments, also provided herein is a method of
treating a disease or condition that is suitable for treatment with
GHB wherein the method 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).sub.2, and Mg (GHB).sub.2. In certain embodiments,
the disease is cataplexy and/or narcolepsy.
[0190] In certain embodiments, when administered to a patient, the
pharmaceutical composition 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. In certain embodiments,
the pharmaceutical composition does not comprise a substantial
amount of Mg (GHB).sub.2 or Ca (GHB).sub.2. In certain embodiments,
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. In preferred embodiments, the disease is cataplexy and/or
narcolepsy. In certain embodiments, 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.
[0191] In certain embodiments, the methods of treatment comprising
administration of the pharmaceutical compositions or formulations
comprising mixed salts GHB disclosed herein.
[0192] In certain embodiments, the method comprises oral
administration of the pharmaceutical compositions or formulations
comprising mixed salts GHB, disclosed herein, in a multiple dosage
regimen.
[0193] In certain embodiments, 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.
[0194] In certain embodiments, two nightly doses of GHB or a salt
there are administered to the patient.
[0195] n certain embodiments, 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).sub.2, and Mg (GHB).sub.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).sub.2, and Mg (GHB).sub.2,
and wherein the second dose produces a GHB Cmax which is
substantially equivalent to the Cmax of Na GHB. In certain
embodiments, 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).sub.2, and Mg (GHB).sub.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 K GHB, Ca (GHB).sub.2,
and Mg (GHB).sub.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. In
preferred embodiments, the patient is suitable for treatment with
GHB has cataplexy or narcolepsy.
[0196] In certain embodiments, 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).sub.2, and Mg (GHB).sub.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).sub.2, and Mg
(GHB).sub.2.
[0197] In certain embodiments, 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.
[0198] In certain embodiments, 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).sub.2, and Mg (GHB).sub.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.
[0199] In certain embodiments, 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).sub.2, and Mg (GHB).sub.2,
and wherein administration of the second dose produces a GHB Cmax
which is substantially bioequivalent to the Cmax of Na GHB. In
certain embodiments, 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.
[0200] In certain embodiments, 4.5 and 9 grams/day are administered
to the patient in two divided doses.
[0201] In certain embodiments, 6 and 8 grams/day are administered
to the patient in two divided doses.
[0202] In certain embodiments, 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
[0203] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including: the metabolic
stability and length of action, the age, body weight, general
health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular
condition, and the host undergoing therapy.
6.2.4 Methods of Making
[0204] In certain aspects, provided herein are some exemplary
methods of making the 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.
[0205] In certain embodiments, 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.
[0206] In certain embodiments, 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.
[0207] In certain embodiments, 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.
[0208] In certain embodiments, 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.
[0209] In other embodiments, 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).sub.2) mixture. Such embodiments are particularly suitable to
avoid precipitation of calcium carbonate when carbonate salts of
sodium, potassium, and/or magnesium are employed.
[0210] In still other embodiments, 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. Alternatively, 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.
[0211] In other embodiments, 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.
[0212] In certain embodiments, the reaction is carried out in a
single vessel. For example, a mixture of Na GHB, K GHB, Mg
(GHB).sub.2, and Ca (GHB).sub.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.
[0213] In certain embodiments, the reaction is carried out in
multiple vessels and the product is subsequently combined. For
example, Ca (GHB).sub.2 may be made by direct addition of GBL to
aqueous sodium hydroxide, and the product combined with Mg
(GHB).sub.2.
[0214] In certain embodiments, the methods of making include
methods of making the pharmaceutical compositions and formulations
disclosed herein.
[0215] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
and scope of the invention.
EXAMPLES
Example 1
Synthesis of Mixed Oxybate Solutions
[0216] The following synthetic examples provide exemplary syntheses
of mixture of oxybate salts. Alternate methods of synthesizing
mixtures of oxybate salts, including methods of synthesizing
additional salts of oxybate are described below; still other
alternate synthetic methods will be apparent to those skilled in
the art. See also U.S. Pat. Nos. 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.
[0217] 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.
[0218] Example calculations of molar equivalents and % wt/wt for
salt mixtures are also shown below Table 1.
TABLE-US-00001 TABLE 1 Example Calculations % molar Base Grams Base
Stoich. Base equiv Salt Salt mass Salt Conc Base MW Purity Amount
mMols Ratio mEQ GHB Salt MW grams wt/wt % mg/mL NaOH 40.00 98.50%
1.398 34.43 1 34.43 8.5% Na.cndot.GHB 126.09 4.34 8.5% 42.61 KOH
56.11 86.72% 7.337 113.40 1 113.40 28.0% K.cndot.GHB 142.20 16.12
31.4% 158.29 Ca(OH).sub.2 74.10 99.00% 6.268 83.74 2 167.49 41.4%
Ca.cndot.(GHB).sub.2 246.27 20.62 40.2% 202.46 Mg(OH).sub.2 58.32
99.50% 2.611 44.55 2 89.09 22.0% Mg.cndot.(GHB).sub.2 230.50 10.27
20.0% 100.80 Total 17.614 276.11 404.40 100.0% 51.36 100.0% 504.17
Base Each of four bases used in this example Base MW Molecular
weight of the base Purity Purity provided by manufacturer. It is
assumed that impurities are non-reactive. Gram Amount Amount, in
grams, of each base charged to the reaction Base mMols
Corresponding amount, in millimoles, of pure base (that is, Purity
.times. Gram-Amount .times. 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 .times.
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 .times.
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 .times. (% equiv-GHB) .times.
(Salt-MW)/(Stoich. Ratio)
Example 1.1
Manufacturing Mixed Salts Solutions
[0219] Four individual oxybate salt solutions at equal oxybate
strength (409 mg/mL) were made as follows:
[0220] Magnesium oxybate (Mg (GHB).sub.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.degree.
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 0.45.mu. PVDF Stericup under vacuum.
The pH of filtrate was 8.1. Yield: 177.4 g solution. Assay
(HPLC-UV): 100.1%
[0221] 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.degree. C. The
remainder of the GBL was then added with stirring, and the solution
maintained at 60.degree. 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.mu. PVDF Stericup under vacuum. Yield: 281.8
g solution. Assay (HPLC-UV): 98.6%.
[0222] Calcium oxybate (Ca (GHB).sub.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.degree. C. on a temperature-controlled hotplate
(surface set point .about.183.degree. 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.mu. 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%
[0223] 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.degree. C. in ice water, the
remaining GBL was added and then allowed to react with stirring on
a hotplate at 60.degree. 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.mu. PVDF Stericup under vacuum.
Yield: 340.3 g. Assay (HPLC-UV): 100.6%.
[0224] For each desired oxybate salt mixture below, the individual
solutions were blended volumetrically with an oral dosing syringe
into a 250 mL glass beaker with stirring. The blend order, where
applicable, was sodium, potassium, calcium, and then magnesium
oxybate. 178 mg of sucralose was then added and dissolved. The
target cation blends (in equivalents) and volumes of individual
solutions used are shown in Table 2 below.
TABLE-US-00002 TABLE 2 Target Cation Blends and Volumes of
Exemplary Solutions Volume (mL) of oxybate solution (#1-#4 above)
for total batch 150 mL Assay % equivalents Na K Ca Mg % Solution Na
K Ca Mg (#4) (#2) (#3) (#1) Label 507-A 33 34 33 0 49.5 51.0 49.5 0
98.9 507-G 23.3 19.2 40 17.5 35.0 28.8 60.0 26.3 99.2 507-C 33 0 48
19 49.5 0 72.0 28.5 100.0 507-D 50 34 16 0 75.0 51.0 24.0 0
98.8
Example 1.2
Direct, One-Pot Reaction Method to Achieve Various Mixtures
[0225] To achieve any combination of oxybate salts, 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).sub.2),
and 98.5% (Mg(OH).sub.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.
[0226] To make 150 mL batches roughly equivalent in composition to
those of Example 1.1, the stoichiometry is as shown in Table 3
below.
TABLE-US-00003 TABLE 3 Stoichiometry of Bases used for Exemplary
Solutions grams base required Excess GBL Water Total Solution NaOH
KOH Ca(OH).sub.2 Mg(OH).sub.2 As base grams grams grams grams 507-A
7.88 13.21 7.35 0.00 Ca(OH).sub.2 0.22 51.27 98.56 178.5 507-G 5.57
7.46 8.91 3.12 Mg(OH).sub.2 0.17 51.27 102.00 178.5 507-C 7.88 0.00
10.70 3.38 Mg(OH).sub.2 0.17 51.27 105.09 178.5 507-D 11.95 13.21
3.57 0.00 Ca(OH).sub.2 0.22 51.27 98.29 178.5
[0227] The water is weighed into a tared 250 mL beaker with
spinbar. Next, bases are weighed and added in order of sodium,
potassium, calcium, and magnesium as applicable. After 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. Next, 51.27 g of GBL is
added slowly while monitoring temperature and with stirring. If the
temperature exceeds about 80.degree. C., then GBL addition is
slowed until the temperature cools to about 60.degree. C. After GBL
addition is complete, the setup is moved to a 60.degree. 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).sub.2
requires about 1 h to react at 60.degree. C., and Mg(OH).sub.2
requires about 3 h at 80.degree. C. or overnight (12 h) at
60.degree. C. Therefore, mixtures lacking Mg(OH).sub.2 (507-A and
507-D) are held at 60.degree. C. for about 1 h. Mixtures 507-G and
507-C are held at 60.degree. C. overnight or 80.degree. C. for 3
h.
[0228] After 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.mu. 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.
Example 2
Pharmacokinetic Testing of Formulations
[0229] This Example provides protocols and results for
bioequivalence testing of the formulations disclosed herein. Four
sets of bioequivalence testing were performed with various mixed
salt formulations compared with Xyrem.RTM. as the reference. Unless
stated otherwise, this and subsequent examples have oxybate salt
concentrations stated in a "molar equivalent percent" basis.
Furthermore, in the tables and figures where applicable: [0230]
"Treatment" refers to the formulation and the dosing regimen (fed
or fasted), for which various formulations were tested at a dose
equivalent to 4.5 g sodium oxybate. [0231] "N" refers to the number
of subjects for which evaluable results were obtained "Vol" refers
to the volume of administration (mL) given with the 9 mL dose of
drug product [0232] "Cmax" refers to the average of the maximum
plasma concentration (in oxybate mg/L or ug/mL) achieved in
individual patients [0233] "Cmax Ratio" refers to the ratio of Cmax
value compared to that of fasted state Xyrem.RTM. and expressed as
a percentage [0234] "AUC" refers to the area under the curve of
plasma vs time, either the last time point where the concentration
was above the limit of quantitation or projected out to infinite
time and expressed in units of h*mg/L. [0235] "AUC ratio" refers to
the ratio of AUC to that of fasted state Xyrem.RTM. and expressed
as percentage [0236] "Na", "K", "Ca", and "Mg" refer to the cation
content of the formulation given, in Molar Equivalent%, of sodium,
potassium, calcium, and magnesium, respectively.
Example 2.1
Testing of Formulation "O"
[0237] 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.degree. 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.
[0238] Formulation "O" was tested for bioequivalence relative to
Xyrem.RTM. (Formulation "X", commercial sodium oxybate solution of
the same molar concentration and comparable pH as "O") 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.
In both fasted and fed treatments, 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.
TABLE-US-00004 TABLE 4 Conditions and Results in Study 13-010 Using
240 mL Liquid Volume Number of Vol Cmax Cmax AUC AUC % equivalent
Treatment Patients (mL) (mg/L) ratio (mg h/L) ratio Na K Ca Mg O,
fasted 34 240 102.3 76% 238.7 89% 8 23 48 21 O, fed 36 240 77.7 58%
216.0 81% 8 23 48 21 X, fasted 32 240 134.6 100% 268.1 100% 100 0 0
0 X, fed 36 240 84.9 63% 233.0 87% 100 0 0 0
Example 2.2
Testing of Blends of Xyrem.RTM. and Formulation "O"
[0239] As an extension to the study described in Example 2.1, the
same formulation "O" and Xyrem.RTM. 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%).
TABLE-US-00005 TABLE 5 Conditions and Results in Study 13-010 Part
2 using 240 mL Liquid Volume Number of Vol Cmax Cmax AUC AUC %
equivalent Treatment Patients (mL) (mg/L) Ratio (mg h/L) Ratio Na K
Ca Mg 2.5 g O + 2.0 g X, 21 240 109.4 84% 241.3 96% 49 13 27 12
fasted 3.75 g O + 0.75g X, 19 240 98.18 75% 228.4 91% 23 19 40 18
fasted X, fasted 17 240 130.2 100% 251.4 100% 100
Example 2.3
Testing of Alternative Cationic Blends
[0240] 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.
[0241] Surprisingly, as 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.RTM.. In contrast, 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.
TABLE-US-00006 TABLE 6 Conditions and Results in Study 15-008 using
60 mL Liquid Volume, n = 35 patients Vol Cmax Cmax AUC AUC %
equivalent Treatment (mL) (mg/L) Ratio (mg h/L) Ratio Na K Ca Mg
507-A, fasted (no Mg) 60 102.2 77% 241 85% 33 34 33 0 507-C, fasted
(no K) 60 101.0 77% 252 89% 33 0 48 19 507-D, fasted (higher 60
120.8 92% 257 90% 50 34 16 0 Na, No Mg) 507-G (3.75 g O + 60 95.6
72% 246 87% 23 19 40 18 0.75 g X, fasted X, fasted 60 131.9 100%
284 100% 100 0 0 0
Example 2.4
Testing Effect of Dilution Volume
[0242] Formulation 507-D having 50% sodium and tested at 60 mL
volume was bioequivalent to Xyrem.RTM., 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. To determine whether or
how the volume of administration affects behavior of formulations,
Formulation "O" was tested and compared to Xyrem.RTM. 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.
[0243] There is little difference in the primary PK parameters
(Cmax and AUC) as a result of volume of administration; however,
there appears to be a difference in the mean plasma profile for
Xyrem.RTM. at the two volumes when given fasted (FIG. 4).
TABLE-US-00007 TABLE 7 Results of Study JZP258-101, n = 33 patients
AUC Vol Cmax Cmax Mg AUC % equivalent Treatment (mL) (mg/L) ratio
h/L) ratio Na K Ca Mg O, fasted 60 93.0 77% 238 95% 8 23 48 21 O,
fasted 240 92.7 74% 233 90% 8 23 48 21 O, fed 60 63.0 52% 202 80% 8
23 48 21 X, fasted 60 120.5 100% 251 100% 100 0 0 0 X, fasted 240
125.9 100% 258 100% 100 0 0 0 X, fed 60 68.6 57% 206 82% 100 0 0
0
[0244] Although the effect of dilution volume on food effect was
not directly challenged in a single study, comparison of data from
two crossover studies is possible for formulations "O" and
Xyrem.RTM.. Table 8 shows the comparison of data from study
JZP258-101 for 60 mL dilution volume and from study 13-010 Part 1
for 240 mL dilution volume. The results indicate that formulation
"O" has a reduced food effect compared to Xyrem.RTM. and that, in
both cases, the higher dilution volume has a smaller food
effect.
TABLE-US-00008 TABLE 8 Comparison of Food Effect at 60 mL and 240
mL dilution Cmax (mg/L) AUC (mg h/L) Treatment Volume 60 mL 240 mL
60 mL 240 mL O, fasted 93.0 102.3 238 239 O, fed 63.0 77.7 202 216
Ratio of O, fed 68% 76% 85% 90% to O, fasted X, fasted 120.5 134.6
251 268 X, fed 68.6 84.9 206 233 Ratio of X, fed 57% 63% 82% 87% to
X, fasted
[0245] In similar fashion, comparison of fasted data across studies
can be done. 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.
[0246] The calcium model was arrived at by stepwise regression of
main effect and interaction of calcium % and volume of
administration using IMP 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.
[0247] On the other hand, when sodium level and sodium diluted
concentration (and interaction) are considered, a significantly
better fit to results was obtained. All three terms were
significant at 90% confidence or better, yet the main effect of
diluted sodium concentration was least significant of the three).
Sodium level and its interaction with diluted sodium concentration
were highly significant, respectively). That model fit is shown in
FIG. 5B.
Example 3
Expected Pharmacokinetics of Two Formulations Dosed 4 Hours
Apart
[0248] The following proposed 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.RTM. 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.
[0249] 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.RTM.
given under the same conditions.
Example 4
Microbial Challenge
[0250] This Example demonstrates that a mixed oxybate salt having
low sodium displays acceptable resistance to microbial growth. A
solution having, on a molar equivalents basis, 8% sodium, 23%
potassium, 48% calcium, and 21% magnesium oxybate salts (Na GHB, K
GHB, Mg (GHB).sub.2, and Ca (GHB).sub.2) with a pH value of 8 and a
total concentration of 409 mg/mL oxybate salts was tested for
antimicrobial effectiveness according to USP<51>. Individual
samples were inoculated with each of five microorganisms and stored
for 28 days at 20-25.degree. C. At 7, 14, and 28 days microbial
enumeration tests revealed effective reductions for all strains, as
shown in Table 9 below.
TABLE-US-00009 TABLE 9 Microbial Effective Test of 8% Na.cndot.GHB,
23% K.cndot.GHB, 48% Ca.cndot.(GHB).sub.2, and 21%
Mg.cndot.(GHB).sub.2 at 409 mg/mL Log reduction in colony forming
units/mL Organism Day 7 Day 14 Day 28 S. aureaus >5.2 >5.2
>5.2 E. coli >5.7 >5.7 >5.7 P. aeruginosa >5.8
>5.8 >5.8 C. albicans 3.0 >5.6 >5.6 A. niger 2.6 3.6
>4.2
* * * * *
References