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`US009050302B2
`
`c12) United States Patent
`Eller
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,050,302 B2
`*Jun. 9, 2015
`
`(54) METHOD OF ADMINISTRATION OF
`GAMMA HYDROXYBUTYRATE WITH
`MONOCARBOXYLATE TRANSPORTERS
`(71) Applicant: Jazz Pharmaceuticals Ireland Limited,
`Dublin (IE)
`Inventor: Mark Eller, Redwood City, CA (US)
`(72)
`(73) Assignee: Jazz Pharmaceuticals Ireland Limited,
`Dublin (IE)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`( *) Notice:
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`(21) Appl. No.: 13/837,714
`Mar. 15, 2013
`(22) Filed:
`Prior Publication Data
`(65)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`US 2014/0249115 Al
`
`Sep. 4, 2014
`
`Related U.S. Application Data
`
`Provisional application No. 61/771,557, filed on Mar.
`1, 2013, provisional application No. 61/777,873, filed
`on Mar. 12, 2013.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A01N37/36
`A61K 31119
`A61K 311616
`A61K 31120
`A61K 31133
`A61K 311505
`A61K 31155
`U.S. Cl.
`CPC ............... A61K 31119 (2013.01); A61K 311616
`(2013.01); A61K 31120 (2013.01); A61K 31133
`(2013.01); A61K 311505 (2013.01); A61K
`31155 (2013.01)
`
`Field of Classification Search
`USPC .................................................. 514/163, 557
`See application file for complete search history.
`
`References Cited
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`FOREIGN PATENT DOCUMENTS
`
`DE
`GB
`GB
`GB
`WO
`WO
`WO
`WO
`WO
`
`237 309
`922 029
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`OTHER PUBLICATIONS
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`
`(Continued)
`
`Primary Examiner - Shirley V Gembeh
`(74) Attorney, Agent, or Firm -
`Jones Day
`
`(57)
`
`ABSTRACT
`
`One embodiment of the present invention is to improve the
`safety and efficacy of the administration of GHB or a salt
`thereof to a patient. It has been discovered that the concomi(cid:173)
`tant administration of an MCT inhibitor, such as diclofenac,
`valproate, or ibuprofen, will affect GHB administration. For
`example, it has been discovered that diclofenac lowers the
`effect of GHB in the body, thereby potentially causing an
`unsafe condition. Furthermore, it has been discovered that
`valproate increases the effect of GHB on the body, thereby
`potentially causing an unsafe condition.
`
`31Claims,10 Drawing Sheets
`Ranbaxy Ex. 1001
`IPR Petition - USP 9,050,302
`
`Page 1
`
`

`

`US 9,050,302 B2
`Page 2
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`(56)
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`Copy of Notification Letter dated Jan. 16, 2015, fromAmneal Phar(cid:173)
`maceuticals to Jazz Pharmaceuticals, Inc. re: Notice of Paragraph IV
`Certification of U.S. Patent No. 8,731,963; 8,772,306; and 8859619,
`22 pages.
`* cited by examiner
`
`Page 3
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`US 9,050,302 B2
`
`1
`METHOD OF ADMINISTRATION OF
`GAMMA HYDROXYBUTYRATE WITH
`MONOCARBOXYLATETRANSPORTERS
`
`2
`arousal, insonmia, and nocturnal myoclonus in a human
`patient, comprising: determining if the patient is has taken, or
`will take a concomitant dose ofvalproate; orally administer-
`ing a reduced amount of the GHB or GHB salt to the patient
`compared to the normal dose so as to diminish the additive
`effects of the GHB or GHB salt when administered with
`valproate. The amount of GHB is reduced at least 10% to
`30%, or at least+15% of the normal administration.
`One embodiment of the present invention is a method for
`10 treating a patient who is suffering from excessive daytime
`sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy
`sleep time disturbances, hypnagogic hallucinations, sleep
`arousal, insonmia, and nocturnal myoclonus with GHB or a
`salt thereof, comprising: orally administering to the patient in
`15 need of treatment, an adjusted dosage amount of the salt of
`GHB when the patient is receiving a concomitant administra(cid:173)
`tion of diclofenac. In certain embodiments, the adjusted
`amount is at least about 1 %, 5%, 10%, 15%, 20%, 25%, 30%,
`35%, 40%, 45%, or 50% higher than the normal dose of the
`20 salt of GHB normally given to the patient. In certain embodi(cid:173)
`ments, the increased amount of GHB is at least about 15%
`more than the normal administration and the daily adminis(cid:173)
`tration of the GHB salt is between 1 gram and 10 grams. In
`certain embodiments, the adjusted amount is increased
`25 between the range of about 1 % to 5%, about 5% to 10%, about
`10% to 15%, about 15% to 20%, about 20% to 25%, about
`25% to 30%, about 30% to 35%, about 35% to 40%, about
`40% to 45%, or about 45% or 50%, relative to the normal dose
`of the salt of GHB normally given to the patient. In certain
`30 embodiments, the adjusted amount is increased between the
`range of about 1 % to 50%, about 1 % to 45%, about 1 % to
`40%, about 1 % to 35%, about 1 % to 30%, about 1 % to 25%,
`about 1 % to 20%, about 1 % to 15%, about 1 % to 10%, about
`1 % to 5%, about 5% to 50%, about 5% to 45%, about 5% to
`35 40%, about 5% to 35%, about 5% to 30%, about 5% to 25%,
`about 5% to 20%, about 5% to 15%, about 5% to 10%, about
`10% to 50%, about 10% to 45%, about 10% to 40%, about
`10% to 35%, about 10% to 30%, about 10% to 25%, about
`10% to 20%, about 10% to 15%, about 15% to 50%, about
`40 15% to 45%, about 15% to 40%, about 15% to 35%, about
`15% to 30%, about 15% to 25%, about 15% to 20%, about
`15% to 15%, about 15% to 10%, about 20% to 50%, about
`20% to 45%, about 20% to 40%, about 20% to 35%, about
`20% to 30%, about 20% to 25%, about 25% to 50%, about
`45 25% to 45%, about 25% to 40%, about 25% to 35%, about
`25% to 30%, about 30% to 50%, about 30% to 45%, about
`30% to 40%, about 30% to 35%, about 35% to 50%, about
`35% to 45%, about 35% to 40%, about 40% to 50%, relative
`to the normal dose of the salt of GHB normally given to the
`50 patient. See the product insert for normal dose ranges ofGHB
`as sold by Jazz Pharmaceuticals. GHB is commercially
`known as Xyrem®.
`In another embodiment, the invention is a method of safely
`administering a GHB salt for excessive daytime sleepiness,
`55 cataplexy, sleep paralysis, apnea, narcolepsy, sleep time dis(cid:173)
`turbances, hypnagogic hallucinations, sleep arousal, insom(cid:173)
`nia, and nocturnal myoclonus in a human patient, comprising:
`determining ifthe patient has taken, or will take a concomi(cid:173)
`tant dose of diclofenac; orally administering an increased
`60 amount of a GHB salt to the patient so as to compensate for
`the effects of diclofenac on the GHB salt when concomitantly
`administered.
`Another embodiment of the present invention is a method
`for treating a patient who is suffering from narcolepsy
`wherein said patient is currently taking or has been prescribed
`GHB or a salt thereof, comprising determining if the patient is
`taking or has also been prescribed valproate or diclofenac;
`
`This application claims the benefit of U.S. Provisional 5
`Application No. 61/771,557, filed Mar. 1, 2013, and U.S.
`Provisional Application No. 61/777,873, filed Mar. 12, 2013,
`each of which is hereby incorporated by reference in its
`entirety.
`
`BACKGROUND
`
`This application relates to methods for safely administer(cid:173)
`ing gamma hydroxybutyrate (GHB) together with one or
`more other monocarboxylate transporter (MCT) inhibitors
`for therapeutic purposes. Example transporter inhibitors are
`valproate, diclofenac, and ibuprofen and combinations
`thereof.
`
`SUMMARY OF THE INVENTION
`
`One embodiment of the present invention is a method for
`treating a patient who is suffering from excessive daytime
`sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy
`sleep time disturbances, hypnagogic hallucinations, sleep
`arousal, insonmia, and nocturnal myoclonus with gamma(cid:173)
`hydroxybutyrate (GHB) or a salt thereof, comprising: orally
`administering to the patient in need of treatment, an adjusted
`dosage amount of the salt ofGHB when the patient is receiv(cid:173)
`ing a concomitant administration of valproate. In certain
`embodiments, the adjusted amount is reduced at least about
`1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or
`50% of the normal dose of the salt of GHB normally given to
`the patient. In certain embodiments, the amount of GHB is
`reduced at least about 10% and about 30% of the normal
`administration and the daily administration of the GHB salt is
`between 1 gram and 10 grams. In certain embodiments, the
`adjusted amount is reduced between the ranges of about 1 % to
`5%, about 5% to 10%, about 10% to 15%, about 15% to 20%,
`about 20% to 25%, about 25% to 30%, about 30% to 35%,
`about 35% to 40%, about 40% to 45%, or about 45% or 50%,
`relative to the normal dose of the salt of GHB normally given
`to the patient. In certain embodiments, the adjusted amount is
`reduced between the range of about 1 % to 50%, about 1 % to
`45%, about 1 % to 40%, about 1 % to 35%, about 1 % to 30%,
`about 1 % to 25%, about 1 % to 20%, about 1 % to 15%, about
`1 % to 10%, about 1 % to 5%, about 5% to 50%, about 5% to
`45%, about 5% to 40%, about 5% to 35%, about 5% to 30%,
`about 5% to 25%, about 5% to 20%, about 5% to 15%, about
`5% to 10%, about 10% to 50%, about 10% to 45%, about 10%
`to 40%, about 10% to 35%, about 10% to 30%, about 10% to
`25%, about 10% to 20%, about 10% to 15%, about 15% to
`50%, about 15% to 45%, about 15% to 40%, about 15% to
`35%, about 15% to 30%, about 15% to 25%, about 15% to
`20%, about 15% to 15%, about 15% to 10%, about 20% to
`50%, about 20% to 45%, about 20% to 40%, about 20% to
`35%, about 20% to 30%, about 20% to 25%, about 25% to
`50%, about 25% to 45%, about 25% to 40%, about 25% to
`35%, about 25% to 30%, about 30% to 50%, about 30% to
`45%, about 30% to 40%, about 30% to 35%, about 35% to
`50%, about 35% to 45%, about 35% to 40%, about 40% to
`50%, relative to the normal dose of the salt of GHB normally
`given to the patient.
`Another embodiment of the invention is a method of safely
`administering GHB a salt thereof for excessive daytime 65
`sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy,
`sleep time disturbances, hypnagogic hallucinations, sleep
`
`Page 14
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`US 9,050,302 B2
`
`3
`and adjusting the dose of the GHB or GHB salt to compensate
`for the effect caused by valproate or diclofenac. In certain
`embodiments, the method additionally comprises administer(cid:173)
`ing the adjusted dose to the patient.
`Another embodiment of the present invention is a method
`for treating a patient who is suffering from excessive daytime
`sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy,
`sleep time disturbances, hypnagogic hallucinations, sleep
`arousal, insomnia, and nocturnal myoclonus with a salt of
`gamma GHB, wherein said patient is also being treated with 10
`valproate or diclofenac, comprising: administering to the
`patient a daily dose of a GHB salt wherein said daily dose is
`administered at an amount sufficient to reduce or eliminate
`additive effects.
`The embodiments of the present invention can administer 15
`the GHB at a level of between 1 and 4.5 grams/day or between
`6 and 10 grams/day. The concentration of the formulation can
`be between 350-750 mg/ml or 450-550 mg/ml and a pH
`between 6-10 or 6.5-8.
`Another embodiment of the present invention is a method
`for treating a patient who is suffering from narcolepsy, com(cid:173)
`prising: administering a salt of GHB or a salt thereof to a
`patient or determining whether the patient is currently on a
`GHB drug regimen; determining if the patient is also being
`administered ibuprofen; and advising a patient to cease or
`ceasing the administration of ibuprofen. In some embodi(cid:173)
`ments, patients benefiting from this directive when the patient
`has will have a renal impairment.
`Another embodiment of the present invention is a method
`for treating a patient who is suffering from narcolepsy, com- 30
`prising: administering a therapeutically effective amount of a
`formulation containing GHB or a salt thereof to a patient at a
`concentration of between 450 and 550 mg/ml and a pH
`between 6 and 8, said formulation being administered before
`bed and 1-2 hours thereafter; determining ifthe patient is also 35
`being administered valproate; warning of a potential drug/
`drug interaction due to the combination of valproate and
`GHB; and reducing the dose of the GHB or GHB salt at least
`15% to compensate for the effect caused by valproate.
`Another embodiment of the present invention is a method for 40
`treating a patient who is suffering from narcolepsy, compris(cid:173)
`ing: administering a therapeutically effective amount of a
`formulation containing GHB or a salt thereof to a patient at a
`concentration of between 450 and 550 mg/ml and a pH
`between 6 and 8, said formulation being administered before 45
`bed and 1-2 hours thereafter; determining ifthe patient is also
`being administered diclofenac; warning of a potential drug/
`drug interaction due to the combination of diclofenac and the
`GHB salt; and increasing the dose of the GHB salt at least
`15% to compensate for the effect caused by diclofenac.
`In each of the embodiments of the invention the method
`includes administering GHB at between 1 and 4.5 grams/day
`or between 6 and 10 grams/day and at a concentration of
`between 350-750 or 450-550 mg/ml, and a pH between 6-10
`or between 6.5-8. In further embodiments the valproate or 55
`diclofenac is administered within three days, one or two
`weeks (before or after) of GHB administration. In another
`embodiment, the present invention is a method wherein aspi(cid:173)
`rin is also administered to the patient, especially with val(cid:173)
`proate.
`In a further embodiment the method can include adminis(cid:173)
`tering GHB as a single salt or a mixture of salts of GHB
`selected from the group consisting of a sodium salt of
`hydroxybutyrate (Na.GHB), a potassium salt of gamma-hy(cid:173)
`droxybutyrate (K.GHB), a magnesium salt of gamma-hy- 65
`droxybutyrate (Mg.(GHB)2 ), and a calcium salt of gamma(cid:173)
`hydroxybutyrate (Ca.(GHB)2 ).
`
`4
`In a further embodiment the method can include adminis(cid:173)
`tering GHB to a patient suffering from excessive daytime
`sleepiness, comprising: administering a
`therapeutically
`effective amount of GHB to the patient; determining if the
`patient has concomitant administration of an MCT inhibitor;
`and adjusting the GHB dose or ceasing administering of the
`MCT inhibitor to maintain the effect of the GHB.
`In any of the versions of the invention, the methods option(cid:173)
`ally further include administering aspirin to the patient.
`In a further embodiment the method of administering GHB
`to a patient in need thereof comprises administering to the
`patient a therapeutically effective amount of GHB while
`avoiding concomitant of a diclofenac or valproate.
`Another embodiment of the invention comprises a method
`of administering GHB or a salt thereof (GHB) to a patient
`with narcolepsy, wherein said patient is also in need of
`diclofenac, comprising administering to the patient a daily
`dosage of between 6 g and 10 g GHB or a GHB salt per day
`20 while avoiding diclofenac concomitant administration, and
`any one or more of the following: (a) advising the patient that
`diclofenac should