I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US010188652B2
`
`c12) United States Patent
`Moline et al.
`
`(IO) Patent No.: US 10,188,652 B2
`(45) Date of Patent:
`Jan.29,2019
`
`(54) COMPOSITIONS AND METHODS FOR
`TREATING INSOMNIA
`
`(71) Applicant: Eisai R&D Management Co., Ltd.,
`Tokyo (JP)
`
`(72)
`
`Inventors: Margaret Moline, Woodcliff Lake, NJ
`(US); Gina Pastino, Woodcliff Lake,
`NJ (US); Yurie Akimoto,
`Kakamigahara (JP); Yasuhiro Zaima,
`Kakamigahara (JP); Nobuya Suzuki,
`Kakamigahara (JP); Nobuo Yoshida,
`Kakamigahara (JP)
`
`(73) Assignee: Eisai R&D Management Co., Ltd.,
`Tokyo (JP)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.:
`
`15/519,676
`
`(22) PCT Filed:
`
`Oct. 21, 2015
`
`(52) U.S. Cl.
`CPC .......... A61K 31/506 (2013.01); A61K 9/0053
`(2013.01); A61K 9/2018 (2013.01);
`(Continued)
`(58) Field of Classification Search
`CPC .. A61K 31/506; A61K 9/0053; A61K 9/2018;
`A61K 9/2054; A61K 9/4858; A61K
`9/4866
`See application file for complete search history.
`
`(56)
`
`References Cited
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`U.S. PATENT DOCUMENTS
`
`5,935,814 A
`6,001,963 A
`
`8/ 1999 Bergsma et al.
`12/ 1999 Bergsma et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`JP
`JP
`
`9/1998
`10-229887
`12/1998
`10-327888
`(Continued)
`
`(86) PCT No.:
`
`PCT I JP2015/080304
`
`OTHER PUBLICATIONS
`
`§ 371 (c)(l),
`(2) Date:
`
`Apr. 17, 2017
`
`(87) PCT Pub. No.: W02016/063995
`
`PCT Pub. Date: Apr. 28, 2016
`
`(65)
`
`Prior Publication Data
`
`Sep. 7, 2017
`US 2017/0252342 Al
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 62/067,443, filed on Oct.
`23, 2014.
`
`(51)
`
`Int. Cl.
`A61K 31/506
`A61K 9/00
`
`(2006.01)
`(2006.01)
`(Continued)
`
`Clinical pharmacokinetic studies in pharmacueticals, Jun. 2001,
`Downloaded from the internet on O 18/ 18/2011) http://www.nihs.go.
`jp/phar/material/material2/CIPkEngO 11122.pdf. *
`(Continued)
`
`Primary Examiner - Savitha M Rao
`(74) Attorney, Agent, or Firm - Fish & Richardson P.C.
`
`ABSTRACT
`(57)
`In the present invention, compound such as (1R,2S)-2-(((2,
`4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)(cid:173)
`N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide have
`been found to be potent orexin receptor antagonists, and may
`be useful in the treatment of sleep disorders such as insom(cid:173)
`nia, as well as for other therapeutic uses.
`
`15 Claims, 2 Drawing Sheets
`
`Page 1 of 28
`
`EISAI EXHIBIT 1009
`
`

`

`US 10,188,652 B2
`Page 2
`
`(51)
`
`(52)
`
`Int. Cl.
`A61K 9/20
`A61K 9/48
`U.S. Cl.
`CPC
`
`(2006.01)
`(2006.01)
`
`A61K 9/2054 (2013.01); A61K 9/48
`(2013.01); A61K 9/4858 (2013.01); A61K
`9/4866 (2013.01)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,020,157 A
`6,166,193 A
`6,309,854 Bl
`2008/0076771 Al
`2010/0261644 Al
`2012/0095031 Al*
`
`2/2000 Bergsma et al.
`12/2000 Yanagisawa
`10/2001 Bergsma et al.
`3/2008 Reiter et al.
`10/2010 DeFossa et al.
`4/2012 Terauchi
`
`2012/0165339 Al
`
`6/2012 Terauchi et al.
`
`C07D 401/12
`514/269
`
`FOREIGN PATENT DOCUMENTS
`
`10-327889
`JP
`11-178588
`JP
`06-328057
`JP
`WO 96/034877
`WO
`WO WO 2005/118548
`WO WO 2007/105177
`WO WO 2007/129188
`WO WO 2008/031772
`WO WO 2008/038251
`WO WO 2008/069997
`WO WO 2008/081399
`WO WO 2009/039942
`WO WO 2009/047723
`
`12/1998
`7 /1999
`12/2006
`11/1996
`12/2005
`9/2007
`11/2007
`3/2008
`4/2008
`6/2008
`7/2008
`4/2009
`4/2009
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`OTHER PUBLICATIONS
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`Bettica et al., "Phase I studies on the safety, tolerability, pharmacokinet(cid:173)
`ics and pharmacodynamics of SB-649868, a novel dual orexin
`receptor antagonist," Journal of Psychopharrnacology, vol. 26, No.
`8, GB, Jul. 5, 2011, p. 1058-p. 1070, XP055473159.
`European Search Report in European Patent Application No. 15851934.
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`International Search Report and Written Opinion for International
`Patent Application No. PCT/JP2015/080304 dated Jan. 26, 2016.
`Vermeeren, "Residual Effects of Hypnotics Epidemiology and Clini(cid:173)
`cal Implications", CNS Drugs 2004; 18 (5): 297-328.
`Yamadera, "Recent progress in development of hypnotic drugs",
`Japanese Journal of Clinical Medicine, Feb. 1, 1998, vol. 56, No. 2,
`p. 245-250 (with partial English translation).
`Search Results, Clinica!Trials.gov, Aug. 15, 2018.
`[No Author Listed], "2-Part Multiple Ascending Dose Study for
`Safety and Pharmacokinetics in Healthy and Elderly Subjects",
`Clinica!Trials.gov, Aug. 28, 2012, E2006-A001-002.
`[No Author Listed], "A 2-Part Single Dose Study to Assess the
`Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of
`E2006", Clinica!Trials.gov, Nov. 1, 2011, E2006-AOO 1-001.
`[No Author Listed], "A 2-Part Study to Assess Potential Metabolism(cid:173)
`Based Drug-Drug Interactions of E2006 When Coadministered
`With Itraconazole, Rifampin, Midazolam, or Bupropion", Clinical Trials.
`gov, Mar. 13, 2014, E2006-A001-004.
`[No Author Listed], "A Multicenter, Randomized, Double-blind,
`Placebo-controlled, Parallel-group, Bayesian Adaptive Randomiza(cid:173)
`tion Design, Dose Response Study of the Efficacy of E2006 in
`Adults and Elderly Subjects With Chronic Insomnia", Clinica!Trials.
`gov, Nov. 27, 2013, E2006-G000-201.
`[No Author Listed], "A Study to Determine the Abuse Potential of
`Single Oral Doses ofLemborexant Compared to Zolpidem, Suvorex(cid:173)
`ant and Placebo in Healthy, Non-Dependent, Recreational Sedative
`Users", Clinica!Trials.gov, May 17, 2017, E2006-A001-103.
`
`[No Author Listed], "A Study to Determine the Effect of a High-Fat
`Meal on the Rate and Extent of E2006 Absorption in Healthy
`Subjects", Clinica!Trials.gov, Mar. 17, 2014, E2006-AOO 1008.
`[No Author Listed], "A Two-Part Study to Evaluate the Safety,
`Tolerability, Pharmacokinetics, and Pharmacodynamics ofE2006 in
`Healthy Japanese and White Subjects", Clinica!Trials.gov, Jan. 17,
`2014, E2006-A001-003.
`[No Author Listed], "A Two-Part, Randomized, Double-Blind,
`Placebo-Controlled, Multiple-Ascending Dose Study to Evaluate
`the Safety, Tolerability Pharmacokinetics, and Pharrnacodynamics
`of E2006 in Healthy Japanese and White Subjects", Clinical Study
`Report, Apr.17, 2015, 12 pages.
`[No Author Listed], "An Open-label, Single-dose Study to Deter(cid:173)
`mine the Metabolism and Excretion of [ l 4C]E2006 in Healthy Male
`Subjects", Clinica!Trials.gov, Jan. 27, 2014, E2006-A001-007.
`[No Author Listed], "Long-term Study ofLemborexant in Insomnia
`Disorder", Clinica!Trials.gov, Nov. 2, 2016, E2006-G000-303.
`[No Author Listed], "Open-Label Study ofBioavailability ofE2006
`Tablet Versus Capsule Formulations", Clinica!Trials.gov, Aug. 28,
`2012, E2006-A001-005.
`[No Author Listed], "Study of Lemborexant for Irregular Sleep(cid:173)
`Wake Rhythm Disorder and Mild to Moderate Alzheimer's Disease
`Dementia", ClinicalTrials.gov, Dec. 23, 2016, E2006-G000-202.
`[No Author Listed], "Study of Lemborexant-Alcohol Interaction in
`Healthy Subjects", Clinica!Trials.gov, Mar. 30, 2018, E2006-A001-
`009.
`[No Author Listed], "Study of the Efficacy and Safety ofLemborex(cid:173)
`ant in Subjects 55 Years and Older With Insomnia Disorder (SUN(cid:173)
`RISE l)", Clinica!Trials.gov, May 26, 2016, E2006-G000-304.
`[No Author Listed], "Study to Assess the Pharrnacokinetic Drug(cid:173)
`Drug Interactions of Lemborexant When Coadministered With an
`Oral Contraceptive, Famotidine, or Fluconazole in Healthy Sub(cid:173)
`jects", Clinica!Trials.gov, Mar. 1, 2018, E2006-A001-012.
`[No Author Listed], "Study to Evaluate the Effect of 2 Dosage
`Strengths of E2006 on a Multiple Sleep Latency Test in Subjects
`With Insomnia Disorder", Clinica!Trials.gov, Jan. 29, 2015, E2006-
`A001-107.
`[No Author Listed], "Study to Evaluate the Effect of Lemborexant
`Versus Placebo on Driving Performance in Healthy Adult and
`Elderly Subjects", Clinica!Trials.gov, Oct. 22, 2015, E2006-E044-
`106.
`[No Author Listed], "Study to Evaluate the Pharmacokinetics of
`Lemborexant (E2006) and its Metabolites in Subjects With Mild
`and Moderate Hepatic Impairment Compared to Healthy Subjects",
`Clinica!Trials.gov, Feb. 21, 2018, E2006-A001-104.
`[No Author Listed], "Study to Evaluate the Pharmacokinetics of
`Lemborexant and its Metabolites in Subjects With Normal Renal
`Function or With Severe Renal Impairment", Clinica!Trials.gov,
`Feb. 22, 2018, E2006-A001-105.
`[No Author Listed], "Study to Evaluate the Respiratory Safety of
`Lemborexant in Adult and Elderly Healthy Subjects and Adult and
`Elderly Subjects With Mild Obstructive Sleep Apnea", Clinical Trials.
`gov, Mar. 21, 2018, E2006-A001-102.
`[No Author Listed], "Crossover Study to Evaluate the Effect of
`Lemborexant Versus Placebo and Zolpidem on Postural Stability,
`Auditory Awakening Threshold, and Cognitive Performance in
`Healthy Subjects 55 Years and Older", Clinica!Trials.gov, Jan. 2,
`2017, E2006-A001-108.
`Beuckmann, "Development of Lemborexant: A Novel Sleep/Wake
`Regulator for the Treatment of Insomnia", The 43rd Annual Meet(cid:173)
`ing of Japanese Society of Sleep Research, Jul. 11-13, 2018.
`Borgland et al., "Orexin A in the VTA is critical for the induction of
`synaptic plasticity and behavioral sensitization to cocaine," Neu(cid:173)
`ron., 49:589-601 (2006).
`Brisbare-Roch et al., "Promotion of sleep by targeting the orexin
`system in rats, dogs and humans," Nat. Med., 13:150-155 (2007).
`Chemelli et al., "Narcolepsy in orexin knockout mice: molecular
`genetics of sleep regulation," Cell, 98:437-451 (1999).
`D.A. Prober et al., "26 The Journal of Neuroscience", 2003, p.
`13400-p. 13410.
`Decision to Grant JP 2012-500752 dated Feb. 28, 2012 (English
`translation).
`
`Page 2 of 28
`
`

`

`US 10,188,652 B2
`Page 3
`
`(56)
`
`References Cited
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`OTHER PUBLICATIONS
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`Decision to Grant JP 2012-500752 dated Feb. 28, 2012 (in Japa(cid:173)
`nese).
`Dorffner et al., "Effect of almorexant treatment on sleep variables in
`patients with primary insonmia compared with healthy controls,"
`European Neuropsychopharmacology, 20(Suppl 3):S252-S253 (2007).
`E Mignot et al., "5 Nature Neuroscience Supplement", 2002, p.
`1071-p. 1075.
`English translation of the allowed claims in JP 2012-500752 dated
`Feb. 28, 2012.
`IDA et al., "Possible involvement of orexin in the stress reaction in
`rats," Biochem. Biophys. Res. Commun., 270:318-323 (2000).
`International Search Report and Written opinion of PCT/JP2011/
`071325 dated Oct. 18, 2011 (English Translation).
`International Search Report and Written opinion of PCT/JP2011/
`071325 dated Oct. 18, 2011 (in Japanese).
`Moline et al., "Dual Orexin Receptor Antagonist Lemborexant
`(E2006) Shows Efficacy on Sleep Initiation and Maintenance on
`Sleep Diary Measures in Phase 2 Study," Poster, The 29th Annual
`Meeting of the Associated Professional Sleep Societies, LLC (APSS),
`Jun. 6-10, 2015.
`Murhpy et al., "Preliminary Efficacy ofE2006, a Novel Dual Orexin
`Receptor Antagonist, for the Treatment of Insonmia Disorder,"
`Poster, SLEEP 2014, the 28th Annual Meeting of the Associated
`Professional Sleep Societies, LLC (APSS); May 31-Jun. 4, 2014.
`Murphy et al., "A Phase 1 Study in Healthy Subjects of the Safety
`and Tolerability of E2006, a Novel Dual Orexin Receptor Antago(cid:173)
`nist, for the Treatment of Insonmia Disorder," Poster, SLEEP 2014,
`the 28th Annual Meeting of the Associated Professional Sleep
`Societies, LLC (APSS); May 31-Jun. 4, 2014.
`Murphy et al., "Dual Orexin Receptor Antagonist Lemborexant
`(E2006) Shows Equivalent Efficacy in Men and Women in Phase 2
`Study," Poster, SLEEP 2015, the annual meeting of the Associated
`Professional Sleep Societies LLC (APSS), Jun. 10, 2015.
`Murphy et al., "Effects of Lemborexant on Sleep Architecture in
`Subjects with Insonmia Disorder," Poster, SLEEP 2016, the 30th
`annual meeting of the Associated Professional Sleep Societies LLC
`(APSS), Jun. 11-15, 2016.
`Murphy et al., "Lemborexant, A Dual Orexin Receptor Antagonist
`(DORA) for the Treatment of Insonmia Disorder: Results From a
`Bayesian, Adaptive, Randomized, Double-Blind, Placebo(cid:173)
`Controlled Study", Journal of Clinical Sleep Medicine, Nov. 15,
`2017 13(11):1289-1299.
`
`Pastino et al., "Pharmacokinetics of Lemborexant (E2006): Rela(cid:173)
`tionship to Efficacy and Safety," Poster, SLEEP 2015, the 29th
`Annual Meeting of the Associated Professional Sleep Societies,
`LLC (APSS), Jun. 6-10, 2015.
`Pastino et al., "Lemborexant Does Not Affect the QT interval:
`high-precision QT analysis from early clinical studies," Poster, 2015
`Annual Meeting of the American College of Clinical Pharmacology
`(ACCP), Sep. 27-29, 2015.
`Pinner et al., "Effects of Lemborexant on Sleep Maintenance in the
`Latter Half of the Night," Poster, SLEEP 2016, the 30th annual
`meeting of the Associated Professional Sleep Societies LLC (APSS),
`Jun. 11-15, 2016.
`Pinner et al., "Lemborexant Effects on Sleep Maintenance in the
`Second Half of the Night," Poster, The 2017 Annual Scientific
`Meeting of the American Geriatrics Society (AGS), May 18-20,
`2017.
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`18, 2012 (English translation).
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`18, 2012 (in Japanese).
`Richey et al., "Pharmacological Advances in the Treatment of
`Insonmia,"Curr Pharm Des. 17(15):1471-75 (2011).
`Sakurai et al., "Orexins and orexin receptors: a family of hypotha(cid:173)
`lamic neuropeptides and G protein-coupled receptors that regglate
`feeding behavior," Cell, 92:573-585 (1998)
`Sadin et al., "Dual Orexin Receptor Antagonist E2006 Shows
`Efficacy on Sleep Initiation and Sleep Maintenance in Phase 2
`Study," Poster, ACNP 2014, the 53rd Annual Meeting of the
`American College ofNeuropsychopharmacology, Dec. 7-11, 2014.
`Shoblock et al., "Selective blockade of the orexin-2 receptor attenu(cid:173)
`ates ethanol self-administration, place preference, and reinstate(cid:173)
`ment," Psychopharmacology, 215:191-203 (2011).
`Vermeeren et al., "Results From an On-Road Driving Performance
`Study in Non-elderly and Elderly Healthy Subjects With Dual
`Orexin Receptor Antagonist Lemborexant," Poster, SLEEP 2018,
`the 32nd annual meeting of the Associated Professional Sleep
`Societies LLC (APSS), Jun. 2-6, 2018.
`Winrow et al., "Orexin receptor antagonism prevents transcriptional
`and behavioral plasticity resulting from stimulant exposure,"
`Neuropharmacology, 58:185-194 (2010).
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`17, 2018, 5 pages (with English Translation).
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`BR112017007063-4, dated Sep. 24, 2018, 16 pages. (English Trans(cid:173)
`lation).
`Submission Document in European Patent Application No. 15 851934.
`8, dated Nov. 26, 2018, 10 pages.
`
`* cited by examiner
`
`Page 3 of 28
`
`

`

`U.S. Patent
`
`Jan.29,2019
`
`Sheet 1 of 2
`
`US 10,188,652 B2
`
`FIG. l
`
`WO
`
`..-.. 80
`#-............
`
`60
`
`r,',,.··
`
`FIG. 2
`
`······,,;;, ...... :;;,5 mg. tablet
`
`40
`
`r ,.,:,,
`
`20 f
`
`.,~::;:w 5 fi'l!J tab!$!
`·•·•·•·•·•·•·•· iC mg tablet
`
`-25 "'' .. ...
`
`0 tf ........................ : .......................... : .......................... L ....................... , .......................... :·
`0
`10
`20
`3:0
`40
`50
`Time (min}
`
`Page 4 of 28
`
`

`

`U.S. Patent
`U.S. Patent
`
`Jan.29,2019
`Jan. 29, 2019
`
`Sheet 2 of 2
`Sheet 2 of2
`
`US 10,188,652 B2
`US 10,188,652 B2
`
`FIG. 3
`FIG. 3
`
`as,
`AE AN EAMAPAREI ON
`
`
`
`Page 5 of 28
`
`Page 5 of 28
`
`

`

`US 10,188,652 B2
`
`1
`COMPOSITIONS AND METHODS FOR
`TREATING INSOMNIA
`
`The present invention is directed to compositions and
`methods for treating insonmia. The present application 5
`claims priority on the basis of U.S. Patent Application No.
`62/067,443, filed in the United States on Oct. 23, 2014, the
`contents of which are incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`Background of the Invention
`
`2
`onset and the avoidance of the residual sleepiness, as com(cid:173)
`pared with the considering only the balance between side
`effects and efficacy. Furthermore, even if the dose of a
`certain drug for insonmia, the physiochemical properties of
`the API and the pharmacokinetic (hereinafter referred to as
`PK) profile after administration of the drug were known,
`such information would not be applicable to other APis for
`insonmia because it would be likely effected by a number of
`factors, including the mechanism of action, the route of
`10 administration, the rate of absorption, the physiochemical
`property such as the solubility and the stability in plasma or
`other factors of each APL Indeed, the relationship between
`the residual sleepiness and the characteristics of the hypnotic
`agents is not always consistent (CNS Drugs 2004; 18 (5):
`15 297-328). The relation between PK profile and the sleepi(cid:173)
`ness effect such as the sleep onset or the residual sleepiness
`has been unknown yet for compound A.
`There exists a need in the art for more effective methods
`of treating insonmia to achieve rapid sleep onset as well as
`20 sleep maintenance, throughout the sleep period, but avoid
`residual sleepiness and/or the next-day impairment, com(cid:173)
`prising administrating orally a solid dosage form of a
`hypnotic agent. Further, there exists a need in the art for a
`pharmaceutical composition comprising a hypnotic agent
`25 and at least one pharmaceutically acceptable excipient for
`the treatment of insomnia to achieve rapid sleep onset as
`well as sleep maintenance, throughout the sleep period, but
`avoid residual sleepiness and/or next-day impairment.
`
`Orexin receptors are G-protein coupled receptors found
`predominately in the brain. Their endogenous ligands,
`orexin-A and orexin-B, are expressed by neurons localized
`in the hypothalamus. Orexin-A is a 33 amino acid peptide;
`orexin-B consists of 28 amino acids (Sakurai T. et al., Cell,
`1998, 92 573-585). There are two subtypes of orexin recep(cid:173)
`tors, orexin receptor 1 (hereinafter referred to as OX!) and
`orexin receptor 2 (hereinafter referred to as OX2); OX!
`binds orexin-A preferentially, while OX2 binds both
`orexin-A and -B. Orexins stimulate food consumption in
`rats, and it has been suggested that orexin signaling could
`play a role in a central feedback mechanism for regulating
`feeding behavior (Sakurai et al., supra). It has also been
`observed
`that orexins control wake-sleep conditions
`(Chemelli R. M. et al., Cell, 1999, 98, 437-451). Orexins
`may also play roles in brain changes associated with opioid
`and nicotine dependence (S. L. Borgland et al., Neuron, 30
`2006, 49, 598-601; C. J. Winrow et al., Neuropharmacology,
`2010, 58, 185-194), and ethanol dependence (J. R. Shoblock
`et al., Psychopharmacology, 2011, 215, 191-203). Orexins
`have additionally been suggested to play a role in some
`stress reactions (T. Ida et al., Biochem. Biophys. Res. 35
`Commun., 2000, 270, 318-323). Compound such as (IR,
`2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-
`fluorophenyl)-N-(5-fluoropyridin-2-yl)
`cyclopropanecar(cid:173)
`boxamide (hereinafter referred to as Compound A) have
`been found to be potent orexin receptor antagonists, and may 40
`be useful in the treatment of sleep disorders such as insom(cid:173)
`nia, as well as for other therapeutic uses.
`The Formula of Compound A
`
`SUMMARY OF THE INVENTION
`
`It is an object of the present invention to provide methods
`of treating insonmia comprising administrating orally a solid
`dosage form of the drug compound A.
`It is further an object of the present invention to provide
`a pharmaceutical composition, comprising a therapeutically
`effective amount of compound A
`In certain embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single daily dose ranging from about 1 mg to
`about 15 mg.
`In certain embodiments, the present invention to provide
`45 methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single daily dose ranging from about 2 mg to
`about 15 mg.
`In certain embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single daily dose ranging from about 2 mg to
`55 about 10 mg.
`In certain embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`60 amount is single daily dose chosen from about 2, 2.5, 4, 5,
`8, 10, or 15 mg.
`In certain embodiment, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`65 of compound A, wherein said therapeutically effective
`amount is single daily dose providing a mean maximum
`plasma concentration (Cmax) of from about 3.0 ng/ml to
`
`50
`
`F A UY\-~
`N):Jo O rN~
`)-l) ~
`
`N
`
`F
`
`Regarding the hypnotic agent, when an active pharma(cid:173)
`ceutical ingredient (hereinafter referred to as API) in a
`pharmaceutical formulation to be taken a once-a-night dos(cid:173)
`ing is too high a dose, it has the potential to cause the
`next-day residual sleepiness, while the single insufficient
`dose may cause the patient to wake up during normal sleep
`period even if the patients are able to fall sleep with the
`hypnotic. Therefore, it is difficult to set the proper dose with
`considering the sensitive balance between easy of sleep
`
`Page 6 of 28
`
`

`

`US 10,188,652 B2
`
`3
`about 7 .2 ng/ml for each 1 mg of compound A, after single
`dose administration to human subjects.
`In certain embodiment, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single daily dose ranging from about 1 mg to
`about 15 mg, and wherein said single daily dose achieves a
`mean maximum plasma concentration (Cmax) of from about
`3 .0 ng/ml to about 7 .2 ng/ml for each 1 mg of compound A,
`after single dose administration to human subjects.
`In certain embodiment, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 1 mg daily dose, and wherein said single
`dose achieves a mean maximum plasma concentration
`(Cmax) within the range of about 80% to about 125% of 5.3
`ng/ml, after single dose administration to human subjects.
`In certain embodiment, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 2.5 mg daily dose, and wherein said single
`daily dose achieves a mean maximum plasma concentration 25
`(Cmax) within the range of about 80% to about 125% of 16
`ng/ml, after single dose administration to human subjects.
`In certain embodiment, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 5 mg daily dose, and wherein said single
`daily dose achieves a mean maximum plasma concentration
`(Cmax) of within the range of about 80% to about 125% of
`23 ng/ml, after single dose administration to human subjects.
`In certain embodiment, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 10 mg daily dose, and wherein said single
`daily dose achieves a mean maximum plasma concentration
`(Cmax) within the range of about 80% to about 125% of 36
`ng/ml, after single dose administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single daily dose to achieve a meanAUC(0-24) of
`from about 15.9 ng*hr/ml to about 23.8 ng*hr/ml for each 1
`mg of compound A, after single dose administration to
`human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 1 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(0-24) within the range of
`about 80% to about 125% of 17 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 2.5 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(0-24) within the range of 65
`about 80% to about 125% of 57 ng*hr/ml, after single dose
`administration to human subjects.
`
`4
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`5 amount is single 5 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(0-24) within the range of
`about 80% to about 125% of 95 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`10 methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 10 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(0-24) within the range of
`15 about 80% to about 125% of 159 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`20 of compound A, wherein said therapeutically effective
`amount is single daily dose to achieve a mean AUC(O-t) of
`from about 19 .1 ng*hr/ml to about 51.1 ng*hr/ml for each 1
`mg of compound A, after single dose administration to
`human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 1 mg daily dose, and wherein said single
`30 daily dose achieves a mean AUC(O-t) within the range of
`about 80% to about 125% of 19 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`35 orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 2.5 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(O-t) within the range of
`about 80% to about 125% of 80 ng*hr/ml, after single dose
`40 administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`45 amount is single 5 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(O-t) within the range of
`about 80% to about 125% of 128 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`50 methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 10 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(O-t) within the range of
`55 about 80% to about 125% of284 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`60 of compound A, wherein said therapeutically effective
`amount is single daily dose to achieve a meanAUC(O-inf) of
`from about 19.8 ng*hr/ml to about 53.1 ng*hr/ml for each 1
`mg of compound A, after single dose administration to
`human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`
`Page 7 of 28
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`US 10,188,652 B2
`
`5
`of compound A, wherein said therapeutically effective
`amount is single 1 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(O-inf) within the range of
`about 80% to about 125% of 20 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 2.5 mg daily dose, and wherein said single 10
`daily dose achieves a mean AUC(O-inf) within the range of
`about 80% to about 125% of 80 ng*hr/ml, after single dose
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating 15
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single 5 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(O-inf) within the range of
`about 80% to about 125% of 149 ng*hr/ml, after single dose 20
`administration to human subjects.
`In further embodiments, the present invention to provide
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective 25
`amount is single 10 mg daily dose, and wherein said single
`daily dose achieves a mean AUC(O-inf) within the range of
`about 80% to about 125% of311 ng*hr/ml, after single dose
`administration to human subjects.
`In certain embodiments, the present invention to provide 30
`methods of treating insomnia, comprises administrating
`orally a dosage form with a therapeutically effective amount
`of compound A, wherein said therapeutically effective
`amount is single daily dose ranging from about 1 mg to
`about 15 mg, and wherein said single daily dose provides a 35
`mean plasma compound A concentration of about 20 ng/ml
`or less at from 8 to 10 hours after single dose administration
`to human subjects.
`In another embodiment, the present invention provides an
`oral dosage form for treating insonmia comprising a thera- 40
`peutically effective amount of compound A and at least one
`pharmaceutically acceptable excipient, wherein said thera(cid:173)
`peutically effective amount is single daily dose ranging from
`about 1 mg to about 15 mg.
`In another embodiment, the present invention provides an 45
`oral dosage form for treating insonmia comprising a thera(cid:173)
`peutically effective amount of compound A and at least one
`pharmaceutically acceptable excipient, wherein said thera(cid:173)
`peutically effective amount is single daily dose to achieve a
`mean maximum plasma concentration (Cmax) of from about 50
`3 .0 ng/ml to about 7 .2 ng/ml for each 1 mg of the drug, after
`single dose administration to human subjects.
`In another embodiment, the present invention provides an
`oral dosage form for treating insonmia comprising a thera(cid:173)
`peutically effective amount of compound A and at least one 55
`pharmaceutically acceptable excipient, wherein said thera(cid:173)
`peutically effective amount is single 1 mg daily dose, and
`wherein said single daily dose achieves a mean maximum
`plasma concentration (Cmax) within the range of about 80%
`to about 125% of 5.3 ng/ml, after single dose admin