U.S. patent application number 12/517507 was filed with the patent office on 2011-03-31 for combination therapy using low-dose doxepin for the improvement of sleep.
This patent application is currently assigned to SOMAXON PHARMACEUTICALS, INC.. Invention is credited to Philip Jochelson, Robert Mansbach, Michael Skinner.
Application Number | 20110077200 12/517507 |
Document ID | / |
Family ID | 39434112 |
Filed Date | 2011-03-31 |
United States Patent
Application |
20110077200 |
Kind Code |
A1 |
Jochelson; Philip ; et
al. |
March 31, 2011 |
COMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF
SLEEP
Abstract
A composition comprising doxepin, or a pharmaceutically
acceptable salt, or prodrug thereof, and a compound that enhances
sleep onset, sleep maintenance or reduces early morning awakenings.
These compositions are useful for treating multiple manifestations
of insomnia.
Inventors: |
Jochelson; Philip; (San
Diego, CA) ; Mansbach; Robert; (San Diego, CA)
; Skinner; Michael; (San Diego, CA) |
Assignee: |
SOMAXON PHARMACEUTICALS,
INC.
San Diego
CA
|
Family ID: |
39434112 |
Appl. No.: |
12/517507 |
Filed: |
December 6, 2007 |
PCT Filed: |
December 6, 2007 |
PCT NO: |
PCT/US2007/086682 |
371 Date: |
April 5, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60873056 |
Dec 6, 2006 |
|
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60910586 |
Apr 6, 2007 |
|
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Current U.S.
Class: |
514/11.4 ;
514/17.7; 514/171 |
Current CPC
Class: |
A61K 31/4985 20130101;
A61K 31/335 20130101; A61P 25/20 20180101; A61P 25/00 20180101;
A61K 31/343 20130101; A61K 31/505 20130101; A61K 31/4162 20130101;
A61K 31/4535 20130101; A61K 31/437 20130101; A61K 31/335 20130101;
A61K 2300/00 20130101; A61K 31/343 20130101; A61K 2300/00 20130101;
A61K 31/4162 20130101; A61K 2300/00 20130101; A61K 31/437 20130101;
A61K 2300/00 20130101; A61K 31/4535 20130101; A61K 2300/00
20130101; A61K 31/4985 20130101; A61K 2300/00 20130101; A61K 31/505
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/11.4 ;
514/171; 514/17.7 |
International
Class: |
A61K 38/27 20060101
A61K038/27; A61K 31/565 20060101 A61K031/565; A61K 38/08 20060101
A61K038/08; A61P 25/00 20060101 A61P025/00 |
Claims
1. A composition comprising doxepin, or a pharmaceutically
acceptable salt or prodrug thereof, and one or more of a compound
that promotes sleep onset.
2. The composition of claim 1, wherein the compound that promotes
sleep onset is selected from the group consisting of a GABA
modulator, an H3 agonist, an orexin receptor antagonist, a
melatonin agonist and a galanin agonist.
3. The composition of any of claims 1-2, wherein said composition
comprises doxepin in an amount of about 0.001 to about 10 mg.
4. The composition of any of claims 1-3, wherein the one or more of
a compound that promotes sleep onset in a dosage that is the same
as the approved prescription dosage for that compound, the same as
the clinical trial dosage for the compound, the same as a
literature reported dosage for treating a sleep disorder, or the
same as the dosage for the compound when used to treat a sleep
disorder as a monotherapy.
5. The composition of any of claims 1-3, wherein the one or more of
a compound that promotes sleep onset in a dosage that is less than
the approved prescription dosage for that compound to treat a sleep
disorder, less than the clinical trial dosage for the compound for
treating a sleep disorder, less than a literature reported dosage
for treating a sleep disorder, less than the dosage for the
compound when used to treat a sleep disorder as a monotherapy, or
less than the monotherapy dosage of the compound required to
achieve substantially the same sleep therapy benefit as the
compound used in combination with doxepin.
6. The composition of any of claims 1-5, wherein said compound that
promotes sleep onset comprises a GABA modulator.
7. The composition of any of claims 1-5, wherein said compound that
promotes sleep onset comprises an H3 agonist.
8. The composition of any of claims 1-5, wherein said compound that
promotes sleep onset comprises an orexin receptor antagonist.
9. The composition of any of claims 1-5, wherein said compound that
promotes sleep onset comprises a melatonin agonist.
10. The composition of any of claims 1-5, wherein said compound
that promotes sleep onset comprises a galanin agonist.
11. A method of reducing a side effect of a sleep medication,
comprising: identifying a patient suffering from a side effect
caused by a non-doxepin sleep medication; providing the patient
with doxepin in an amount of about 0.0001 to about 10 mg of
doxepin, a pharmaceutically acceptable salt of doxepin, or a
prodrug of doxepin; and providing the patient with the non-doxepin
sleep medication in a dosage less than the dosage which causes the
side effect when the medication is used as sleep therapy alone.
12. A method of treating a sleep disorder while minimizing side
effects of at least one combination drug, comprising providing at
least one non-doxepin sleep drug and a doxepin compound, wherein
the combination of the at least one non-doxepin sleep drug and the
doxepin compound promote a sleep effect that is at least equivalent
to the sleep effect of a greater amount of the at least one
non-doxepin sleep drug when used without doxepin or when used as a
monotherapy for the sleep disorder; and where the doxepin compound
is doxepin, a pharmaceutically acceptable salt of doxepin, or a
prodrug of doxepin, in an amount of about 0.0001 mg to about 20
mg.
13. The method of claim 11, wherein said side effect includes one
or more of decreased inhibition, hallucinations, complex behaviors
such as sleep driving, amnesia, anxiety, suicidal thinking;
withdrawal symptoms; CNS depressant effects; impaired motor or
cognitive performance; bad taste; headaches; parasomnias such as
sleep walking; anaphylactic and anaphylactoid reactions; weight
gain; and rebound insomnia or tolerance.
14. A method of treating a sleep disorder, comprising: identifying
a patient, wherein said patient is or has been administered a
non-doxepin sleep medication at a first dosage; and providing to
said patient the non-doxepin sleep medication at a second dosage
and doxepin, a pharmaceutically acceptable salt of doxepin or a
prodrug of doxepin, wherein said second dosage of the non-doxepin
sleep medication is less than said first dosage.
15. The method of claim 14, wherein said sleep medication is
selected from the group consisting of a GABA modulator, an H3
agonist, an orexin receptor antagonist, a melatonin agonist and a
galanin agonist.
16. A composition comprising doxepin, or a pharmaceutically
acceptable salt or prodrug thereof, and one or more of a compound
that enhances gamma-aminobutyric acid (GABA) activity, a 5HT2a
antagonist, a melatonin agonist, an ion channel blocker, a
serotonin-2 antagonist/reuptake inhibitor (SARIs), a 5HT1a agonist,
a GABA-B agonist and an orexin receptor antagonist.
17. The composition of claim 16, wherein said compound that
enhances GABA activity is selected from the group consisting of
alprozolam, bromazepam, clobazam, clonazepam, clorazepate,
diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,
nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,
eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine
and estazolam.
18. The composition of claim 16, wherein the 5HT2a antagonist is
selected from the group consisting of ketanserin, risperidone,
eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488.
19. The composition of claim 16, wherein the melatonin agonist is
selected from the group consisting of melatonin, ramelteon and
agomelatine.
20. The composition of claim 16, wherein the ion channel blocker is
selected from the group consisting of lamotrigine, gabapentin and
pregabalin.
21. The composition of claim 16, wherein the serotonin-2
antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin,
nefazodone, serzone or trazodone.
22. The composition of claim 16, wherein the 5HT1a agonist is
repinotan, sarizotan, eptapirone, buspirone or MN-305.
23. The composition of claim 16, wherein the orexin receptor
antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or
a benzamide derivative.
24. The composition of any of claims 16-23, wherein said
composition comprises doxepin, pharmaceutically acceptable salt or
prodrug thereof, in a dosage of 0.01-49 mg.
25. The composition of claim 16 or claim 17, wherein the dosage is
between about 0.5 mg and about 6 mg.
26. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof, and a compound that enhances
gamma-aminobutyric acid (GABA) activity.
27. The composition of claim 26, wherein said compound that
enhances GABA activity is selected from the group consisting of
alprozolam, bromazepam, clobazam, clonazepam, clorazepate,
diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,
nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,
eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine
and estazolam.
28. The composition of claim 26 or claim 27, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
29. The composition of claim 26 or claim 27, wherein the dosage is
between about 0.1 mg and about 20 mg.
30. The composition of claim 26 or claim 27, wherein the dosage is
between about 0.5 mg and about 10 mg.
31. The composition of claim 26 or claim 27, wherein the dosage is
between about 1 mg and about 6 mg.
32. A pharmaceutical formulation comprising the composition of any
of claims 26-31 and a pharmaceutically acceptable excipient or
diluent.
33. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 16-31 to said individual.
34. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 32 to said individual.
35. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 16-31.
36. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a compound that enhances gamma-aminobutyric acid (GABA) activity;
and informing the patient to take the doxepin and said one or more
compounds without food or without fatty food.
37. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 16-31.
38. The method of claim 37, in which the compound that enhances
GABA activity is selected from the group consisting of alprozolam,
bromazepam, clobazam, clonazepam, clorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,
oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone,
zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine and
estazolam.
39. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof, and a 5HT2a antagonist.
40. The composition of claim 39, wherein the 5HT2a antagonist is
selected from the group consisting of ketanserin, risperidone,
eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488.
41. The composition of claim 39 or claim 40, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
42. The composition of claim 39 or claim 40, wherein the dosage is
between about 0.1 mg and about 20 mg.
43. The composition of claim 39 or claim 40, wherein the dosage is
between about 0.5 mg and about 10 mg.
44. The composition of claim 39 or claim 40, wherein the dosage is
between about 1 mg and about 6 mg.
45. A pharmaceutical formulation comprising the composition of any
of claims 39-44 and a pharmaceutically acceptable excipient or
diluent.
46. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 39-44 to said individual.
47. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 45 to said individual.
48. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 39-44.
49. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 39-44.
50. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a 5HT2a antagonist; and informing the patient to take the doxepin
and said 5HT2a antagonist without food or without fatty food.
51. The method of claim 50, in which the 5HT2a antagonist is
selected from the group consisting of ketanserin, risperidone,
eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488.
52. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and a melatonin agonist.
53. The composition of claim 52, wherein the melatonin agonist is
selected from the group consisting of melatonin, ramelteon and
agomelatine.
54. The composition of claim 52 or claim 53, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
55. The composition of claim 52 or claim 53, wherein the dosage is
between about 0.1 mg and about 20 mg.
56. The composition of claim 52 or claim 53, wherein the dosage is
between about 0.5 mg and about 10 mg.
57. The composition of claim 52 or claim 53, wherein the dosage is
between about 1 mg and about 6 mg.
58. A pharmaceutical formulation comprising the composition of any
of claims 52-57 and a pharmaceutically acceptable excipient or
diluent.
59. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 52-57 to said individual.
60. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 58 to said individual.
61. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 52-57.
62. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 52-57.
63. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a melatonin antagonist; and informing the patient to take the
doxepin and said melatonin antagonist without food or without fatty
food.
64. The method of claim 63, in which the melatonin agonist is
selected from the group consisting of melatonin, ramelteon and
agomelatine.
65. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and an ion channel blocker.
66. The composition of claim 65, wherein the ion channel blocker is
selected from the group consisting of lamotrigine, gabapentin and
pregabalin.
67. The composition of claim 65 or claim 66, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
68. The composition of claim 65 or claim 66, wherein the dosage is
between about 0.1 mg and about 20 mg.
69. The composition of claim 65 or claim 66, wherein the dosage is
between about 0.5 mg and about 10 mg.
70. The composition of claim 65 or claim 66, wherein the dosage is
between about 1 mg and about 6 mg.
71. A pharmaceutical formulation comprising the composition of any
of claims 65-70 and a pharmaceutically acceptable excipient or
diluent.
72. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 65-70 to said individual.
73. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 71 to said individual.
74. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 65-70.
75. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 65-70.
76. The method of claim 75, in which the ion channel blocker is
selected from the group consisting of lamotrigine, gabapentin and
pregabalin.
77. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
an ion channel blocker; and informing the patient to take the
doxepin and said ion channel blocker without food or without fatty
food.
78. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and a serotonin-2
antagonist/reuptake inhibitor (SARIs).
79. The composition of claim 78, wherein the serotonin-2
antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin,
nefazodone, serzone or trazodone.
80. The composition of claim 78 or claim 79, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
81. The composition of claim 78 or claim 79, wherein the dosage is
between about 0.1 mg and about 20 mg.
82. The composition of claim 78 or claim 79, wherein the dosage is
between about 0.5 mg and about 10 mg.
83. The composition of claim 78 or claim 79, wherein the dosage is
between about 1 mg and about 6 mg.
84. A pharmaceutical formulation comprising the composition of any
of claims 78-83 and a pharmaceutically acceptable excipient or
diluent.
85. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 78-83 to said individual.
86. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 84 to said individual.
87. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 78-83.
88. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 78-83.
89. The method of claim 88, in which the serotonin-2
antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin,
nefazodone, serzone or trazodone.
90. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a serotonin-2 antagonist/reuptake inhibitor (SARIs); and informing
the patient to take the doxepin and said serotonin-2
antagonist/reuptake inhibitor (SARIs) without food or without fatty
food.
91. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and a 5HT1a agonist.
92. The composition of claim 91, wherein the 5HT1a agonist is
repinotan, sarizotan, eptapirone, buspirone or MN-305.
93. The composition of claim 91 or claim 92, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
94. The composition of claim 91 or claim 92, wherein the dosage is
between about 0.1 mg and about 20 mg.
95. The composition of claim 91 or claim 92, wherein the dosage is
between about 0.5 mg and about 10 mg.
96. The composition of claim 91 or claim 92, wherein the dosage is
between about 1 mg and about 6 mg.
97. A pharmaceutical formulation comprising the composition of any
of claims 91-96 and a pharmaceutically acceptable excipient or
diluent.
98. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 91-96 to said individual.
99. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 97 to said individual.
100. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 91-96.
101. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 91-96.
102. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a 5HT1a agonist; and informing the patient to take the doxepin and
said 5HT1a agonist without food or without fatty food.
103. The method of claim 102, in which the 5HT1a agonist is
repinotan, sarizotan, eptapirone, buspirone or MN-305.
104. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and an orexin receptor
antagonist.
105. The composition of claim 104, wherein the orexin receptor
antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or
a benzamide derivative.
106. The composition of claim 104 or claim 105, wherein said
composition comprises doxepin, a pharmaceutically acceptable
doxepin salt or a doxepin prodrug, in a dosage between about 0.01
mg and about 49 mg.
107. The composition of claim 104 or claim 105, wherein the dosage
is between about 0.1 mg and about 20 mg.
108. The composition of claim 104 or claim 105, wherein the dosage
is between about 0.5 mg and about 10 mg.
109. The composition of claim 104 or claim 105, wherein the dosage
is between about 1 mg and about 6 mg.
110. A pharmaceutical formulation comprising the composition of any
of claims 104-109 and a pharmaceutically acceptable excipient or
diluent.
111. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 104-109 to said individual.
112. The method of claim 111, wherein said doxepin, said
pharmaceutically acceptable salt or prodrug thereof, is
administered at a dosage between about 0.01 mg and about 49 mg.
113. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 111 to said individual.
114. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 104-109.
115. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 104-109.
116. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a orexin receptor; and informing the patient to take the doxepin
and said orexin receptor without food or without fatty food.
117. The method of claim 116, in which the orexin receptor
antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or
a benzamide derivative.
118. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and a GABA-B agonist.
119. The composition of claim 118, wherein said composition
comprises doxepin, a pharmaceutically acceptable doxepin salt or a
doxepin prodrug, in a dosage between about 0.01 mg and about 49
mg.
120. The composition of claim 118, wherein the dosage is between
about 0.1 mg and about 20 mg.
121. The composition of claim 118, wherein the dosage is between
about 0.5 mg and about 10 mg.
122. The composition of claim 118, wherein the dosage is between
about 0.5 mg and about 10 mg.
123. A pharmaceutical formulation comprising the composition of any
of claims 118-122 and a pharmaceutically acceptable excipient or
diluent.
124. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of claims 118-122 to said individual.
125. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 124 to said individual.
126. The method of claim 124, wherein said doxepin, said
pharmaceutically acceptable doxepin salt or doxepin prodrug, is
administered at a dosage between about 0.01 mg and about 49 mg.
127. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 118-122.
128. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a GABA-B agonist; and informing the patient to take the doxepin and
said GABA-B agonist without food or without fatty food.
129. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 118-122.
130. A pharmaceutical formulation comprising the composition of any
of claims 118-122 and a pharmaceutically acceptable excipient or
diluent.
131. A composition comprising doxepin or a pharmaceutically
acceptable salt or prodrug thereof and a compound selected from an
H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH
antagonist, human growth hormone, a growth hormone agonist,
estrogen and an estrogen agonist.
132. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
composition of any of any of claims 118-122 to said individual.
133. A method of treating insomnia, comprising identifying an
individual in need of such treatment, and administering the
pharmaceutical formulation of claim 132 to said individual.
134. A method for selecting a sleep drug therapy for a patient from
among available therapies, comprising: evaluating whether the
patient is in need of both sleep onset and sleep maintenance
therapy, and if so; selecting for the patient a composition of any
of claims 118-122.
135. A method for reducing a risk of drug abuse, comprising:
identifying a patient in need of sleep drug therapy and in need of
avoidance of drugs with potential for abuse; and administering to
the patient a composition of any of claims 118-122.
136. A method for treating insomnia, comprising: coadministering to
an insomnia patient effective amounts of doxepin, a
pharmaceutically acceptable doxepin salt or a doxepin prodrug, and
a compound selected from an H3 agonist, a noradrenergic antagonist,
a galanin agonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen and an estrogen agonist; and informing
the patient to take the doxepin and said compound without food or
without fatty food.
Description
RELATED APPLICATIONS
[0001] This application claims priority to, and incorporates by
reference in their entireties, U.S. Patent Application No.
60/873,056, filed Dec. 6, 2006, and U.S. Patent Application No.
60/910,586, filed Apr. 6, 2007, both entitled COMBINATION THERAPY
USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP.
FIELD OF THE INVENTION
[0002] The present invention relates to compositions comprising
low-dose doxepin combined with at least one other compound or
composition and to methods of treating sleep disorders using these
compositions.
BACKGROUND OF THE INVENTION
[0003] Sleep is essential for health and quality of life. Insomnia
is a growing health problem in the United States. It is believed
that more than 30-45 million people suffer from chronic insomnia
and up to an additional 70 million people suffer from some form of
insomnia each year. Insomnia is a condition characterized by
difficulty falling asleep (sleep onset), waking frequently during
the night (fragmented sleep), waking too early (premature final
awakening), and/or waking up feeling un-refreshed. In the National
Sleep Foundation's (NSF) Sleep in America Poll 2005, 42% of survey
respondents reported that they awoke frequently during the night,
22% of adults reported waking too early and not being able to
return to sleep and 38% reported waking and feeling
un-refreshed.
[0004] Sleep maintenance difficulty is the most commonly reported
symptom in primary care patients with chronic insomnia, and is the
most common insomnia complaint in depressed patients, medically ill
populations, especially those with pain symptoms, and in the
elderly.
[0005] Medications commonly used to treat sleep disorders, such as
insomnia, include sedative anti depressants, antihistamines,
antipsychotics, benzodiazepines, non-benzodiazepine GABA modulators
and a recently approved melatonin receptor agonist. Benzodiazepines
enhance the activity of gamma amino butyric acid (GABA), the main
inhibitory neurotransmitter of the central nervous system,
resulting in activation of GABA receptors which favors sleep.
[0006] Unfortunately, many of these existing medications have very
undesirable side effects, including abnormal thinking and
behavioral changes such as decreased inhibition, hallucinations,
complex behaviors such as sleep driving, amnesia, anxiety, suicidal
thinking; withdrawal symptoms; CNS depressant effects; impaired
motor or cognitive performance (particularly in the elderly); bad
taste; headaches; parasomnias such as sleep walking; anaphylactic
and anaphylactoid reactions; weight gain; or result in rebound
insomnia or tolerance.
[0007] In addition, existing sleep medications have failed to
satisfactorily treat sleep disorders. For example, although
benzodiazepines and other GABA modulators, as well as melatonin
receptor agonists, promote sleep onset, they have limited
effectiveness in promoting a full night's sleep into the 7.sup.th
and 8.sup.th hours of the night and have no demonstrated benefit in
reducing early awakenings.
[0008] Embodiments of the present invention relate to the use of
doxepin in combination with other drugs to provide safer and
improved sleep therapies.
SUMMARY OF THE INVENTION
[0009] Embodiments of the present invention generally relate to
compounds, compositions and methods for treating sleep disorders
using doxepin in combination with one or more other medications. In
particular, these combinations surprisingly and unexpectedly have
the ability to provide improved sleep, but also can be used with a
reduced dosage (e.g., reduced when compared to the normal dosage
when used alone) of one or both of doxepin and the one or more
other medications while more effectively treating the sleep
disorders with fewer adverse side effects. For example, the
combinations can avoid or reduce the side effects seen with the
therapeutically effective dose of the drug when used alone or when
an approved mono treatment dosage is used.
[0010] Furthermore, as discussed herein, doxepin is very effective
at addressing sleep maintenance aspects of insomnia and at reducing
early morning awakenings that can occur in some cases of insomnia.
Some embodiments described herein relate to combination
compositions comprising doxepin and at least one other medication
that is effective for providing sleep onset, as well as methods of
using the combination compositions. It should be noted that the
combinations can include other sleep maintenance drugs, as well.
Preferred sleep onset drugs for the combinations include
gamma-aminobutyric acid (GABA) compounds (e.g., modulate GABA
activity and/or facilitate GABA transmission), H3 agonists, orexin
receptor antagonists, melatonin agonists and galanin agonists.
[0011] Thus, some embodiments of the present invention relate to
compositions that include doxepin, or a pharmaceutically acceptable
salt or prodrug thereof, and one or more of a compound that
modulates GABA activity (e.g., enhances the activity and
facilitates GABA transmission, a GABA-B agonist, a 5-HT modulator
(e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a 5-HT2a inverse
agonist, etc.), a melatonin agonist, an ion channel modulator
(e.g., blocker) a serotonin-2 antagonist/reuptake inhibitor
(SARIs), an orexin receptor antagonist, an H3 agonist, a
noradrenergic antagonist, a galanin agonist, a CRH antagonist,
human growth hormone, a growth hormone agonist, estrogen, an
estrogen agonist, a neurokinin-1 drug, and the like. In some
preferred embodiments, doxepin, doxepin salt or doxepin prodrug can
be utilized in a dosage that is the same as the approved dosage for
the drug, the clinical test dosage or the dosage used for the drug
as a monotherapy for a sleep disorder. In some aspects, the dosage
of doxepin can be, for example, between about 0.0001 mg and 49 mg.
Preferably the amount of doxepin is between about 0.0001 mg and 20
mg, between about 0.001 mg and 10 mg, more preferably between about
0.01 mg and 9 mg, and still more preferably between about 0.01 mg
and 6 mg. In some embodiments, the one or more drugs used in
combination with doxepin, including those drugs of the listed
categories can be utilized in a dosage that is the same as the
approved dosage for the drug, the clinical or literature test
dosage of the drug, or the dosage used for the drug as a
monotherapy for a sleep disorder. In some aspects, both the doxepin
and the one or more combination drugs can be used at a dosage that
is the same as or lower than the approved dosage for the drug, the
clinical or literature test dosage or the dosage used for the drug
as a monotherapy, preferably at a dosage that is lower than when
used in their respective monotherapies.
[0012] In one embodiment, without being limited thereto, the GABA
compound can be, for example, one or more of alprozolam,
bromazepam, clobazam, clonazepam, clorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,
oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone,
zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201
(Evotec Pharmaceuticals) or estazolam. Without being limited
thereto, the 5HT2a antagonist may be, for example, one or more of
ketanserin, risperidone, eplivanserin, volinanserin
(Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis,
France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San
Diego, Calif.), ITI-722 (Intra-Cellular Therapies) or AVE8488
(Sanofi-Aventis, France). In another embodiment, the melatonin
agonist can be for example, one or more of melatonin, ramelteon
(ROZEREM.RTM., Takeda Pharmaceuticals, Japan), VEC-162 (Vanda
Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery) or
agomelatine. The ion channel blocker may be, without limitation,
one or more of lamotrigine, gabapentin or pregabalin. The orexin
receptor antagonist may be one or more of orexin, a 1,3-biarylurea,
SB-334867-a (GlaxoSmithKline, UK), ACT-078573 (Actelion,
Switzerland), GW649868 (GlaxoSmithKline) or a benzamide derivative,
for example. Without being limited thereto, the serotonin-2
antagonist/reuptake inhibitor (SARI) may be one or more of Org
50081 (Organon-Netherlands), ritanserin, nefazodone, serzone or
trazodone. The 5HT1a agonist may be, for example, one or more of
repinotan, sarizotan, eptapirone, buspirone or MN-305 (MediciNova,
San Diego, Calif.). The neurokinin-1 drug can be for example,
Casopitant (GlaxoSmithKline). It should be understood that the
combination compositions can include mixtures of the combined
drugs, as well as two or more separate compositions of the drugs,
which individual compositions can be, for example, co-administered
together to a patient. Again, in some preferred embodiments the
dosages of these drugs can be the same as or lower than the
approved dosage for the drug, the clinical or literature test
dosage or the dosage used for the drug as a monotherapy.
[0013] Some embodiments of the present invention also provide
pharmaceutical compositions or formulations that include any of the
compositions described above and a pharmaceutically acceptable
excipient or diluent.
[0014] Some embodiments relate to compositions comprising doxepin,
a pharmaceutically acceptable salt or prodrug thereof, and one or
more of a compound that promotes sleep onset. The compound that
promotes sleep onset can be, for example, a GABA modulator, an H3
agonist, an orexin receptor antagonist, a melatonin agonist a
galanin agonist or the like. The composition can include doxepin in
an amount of about 0.001 to about 10 mg, for example. The one or
more of a compound that promotes sleep onset can be, for example,
in a dosage that is the same as the approved prescription dosage
for that compound, the same as the clinical trial dosage for the
compound, the same as a literature reported dosage for treating a
sleep disorder, or the same as the dosage for the compound when
used to treat a sleep disorder as a monotherapy. Also, the one or
more of a compound that promotes sleep onset can be, for example,
in a dosage that is less than the approved prescription dosage for
that compound to treat a sleep disorder, less than the clinical
trial dosage for the compound for treating a sleep disorder, less
than a literature reported dosage for treating a sleep disorder,
less than the dosage for the compound when used to treat a sleep
disorder as a monotherapy, or less than the monotherapy dosage of
the compound required to achieve substantially the same sleep
therapy benefit as the compound used in combination with
doxepin.
[0015] Still some embodiments relate to methods of reducing a side
effect of a sleep medication, comprising identifying a patient
suffering from a side effect caused by a non-doxepin sleep
medication; providing the patient with doxepin in an amount of
about 0.0001 to about 10 mg or a pharmaceutically acceptable salt
of doxepin, or a prodrug of doxepin; and providing the patient with
the non-doxepin sleep medication in a dosage less than the dosage
which causes the side effect when the medication is used as sleep
therapy alone.
[0016] Some embodiments relate to methods of treating a sleep
disorder while minimizing side effects of at least one drug in a
drug combination, comprising providing at least one non-doxepin
sleep drug and at least one doxepin compound, wherein the
combination of the at least one non-doxepin sleep drug and the
doxepin compound promote a sleep effect that is at least equivalent
to the sleep effect of a greater amount of the at least one
non-doxepin sleep drug when used without doxepin or when used as a
monotherapy for the sleep disorder; and where the doxepin compound
is doxepin, a pharmaceutically acceptable salt of doxepin, or a
prodrug of doxepin, in an amount of about 0.0001 mg to about 20 mg.
For example the sleep effect can be an improvement in a sleep
parameter such as time to sleep onset, sleep maintenance time,
WASO, WTDS, WTDS, or any other parameter for measuring sleep
quality. The side effect can include, for example, one or more of
decreased inhibition, hallucinations, complex behaviors such as
sleep driving, amnesia, anxiety, suicidal thinking; withdrawal
symptoms; CNS depressant effects; impaired motor or cognitive
performance; bad taste; headaches; parasomnias such as sleep
walking; anaphylactic and anaphylactoid reactions; weight gain;
rebound insomnia or tolerance, and the like.
[0017] Some embodiments relate to methods of treating a sleep
disorder while minimizing side effects of at least one non-doxepin
sleep drug, comprising providing at least one non-doxepin sleep
drug and a doxepin compound, wherein the combination of the at
least one non-doxepin sleep drug and the doxepin compound promote a
sleep effect that is at least equivalent to the sleep effect of a
greater amount of the at least non-doxepin sleep drug individually
or the to the sleep effect of a greater amount of the doxepin
compound when used individually to treat the sleep disorder; and
where the doxepin compound is doxepin, a pharmaceutically
acceptable salt of doxepin, or a prodrug of doxepin, in an amount
of about 0.0001 mg to about 20 mg.
[0018] Still further embodiments relate to methods of treating a
sleep disorder, comprising identifying a patient, wherein said
patient is or has been administered a non-doxepin sleep medication
at a first dosage (for example to treat a sleep disorder as without
the use of doxepin); and providing to said patient the non-doxepin
sleep medication at a second dosage and doxepin, a pharmaceutically
acceptable salt of doxepin or a prodrug of doxepin; wherein said
second dosage of the non-doxepin sleep medication is less than said
first dosage. In some aspects, the providing of the second dosage
of the non-doxepin medication results in fewer side effects while
still providing a beneficial sleep therapy. The sleep medication
can be, for example, a GABA modulator, an H3 agonist, an orexin
receptor antagonist, a melatonin agonist and a galanin agonist.
[0019] Still some embodiments of the present invention relate to
methods of treating insomnia, for example, including identifying an
individual in need of such treatment, and administering any of the
compositions described above to the individual. In one embodiment,
the doxepin or pharmaceutically acceptable salt or prodrug thereof
can be administered at any dosage described herein, for example, a
dosage of 0.01 to 49 mg. In another embodiment, the doxepin or
pharmaceutically acceptable salt or prodrug thereof is administered
at a dosage of 0.1 to 20 mg. In yet another embodiment, the doxepin
or pharmaceutically acceptable salt or prodrug thereof is
administered at a dosage of about 0.5 to 10 mg. In still another
embodiment, the doxepin or pharmaceutically acceptable salt or
prodrug thereof is administered at a dosage of about 1 to 6 mg.
[0020] Another embodiment of the present invention relates to
methods of treating insomnia, comprising identifying an individual
in need of such treatment, and administering any of the
pharmaceutical formulations described above to the individual. In
one embodiment, the doxepin or pharmaceutically acceptable salt or
prodrug thereof can be administered at any dosage described
herein.
[0021] The present invention also provides methods of enhancing
sleep maintenance, comprising identifying an individual in need of
such enhancement, and administering any of the compositions
described above or elsewhere herein to the individual. In one
embodiment, the doxepin or pharmaceutically acceptable salt or
prodrug thereof can be administered at any dosage described
herein.
[0022] Another embodiment of the invention relates to method of
enhancing sleep maintenance and preventing early awakenings,
comprising identifying an individual in need of such enhancement,
and administering any of the pharmaceutical formulations described
above or elsewhere herein to the individual. In one embodiment, the
doxepin or pharmaceutically acceptable salt or prodrug thereof can
be administered at any dosage described herein. Doxepin or a
pharmaceutically acceptable salt or prodrug thereof may be
administered with a drug disclosed herein, such as a sleep
maintenance drug, a gamma-aminobutyric acid (GABA) compound, an H3
agonist, an orexin receptor antagonist, an melatonin agonist or a
galanin agonist, wherein the drug is administered at substantially
the same approved dosage for the drug, the same as the clinical or
literature test dosage of the drug, the same dosage used for the
drug as a monotherapy for a sleep disorder, or lower than any of
those dosages for the drug.
[0023] The present invention also relates to methods for selecting
a sleep drug therapy for a patient from among available therapies,
comprising evaluating whether the patient is in need of both sleep
onset and sleep maintenance therapy, and if so; selecting for the
patient any of the drug combinations described above. In some
aspects the methods can also comprise evaluating whether the
patient is in need of a drug to minimize early awakenings, and if
so, selecting for any of the combinations described herein.
[0024] Another embodiment of the invention relates to methods for
treating insomnia, comprising administering or coadministering to
an insomnia patient effective amounts of doxepin or a
pharmaceutically acceptable salt or prodrug thereof, and one or
more of a compound that modulates gamma-aminobutyric acid (GABA)
activity (e.g., enhances the activity) and facilitates GABA
transmission, a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a
agonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), a
melatonin agonist (including melatonin), an ion channel modulator
(e.g., blocker) a serotonin-2 antagonist/reuptake inhibitor
(SARIs), an orexin receptor antagonist, an H3 agonist, a
noradrenergic antagonist, a galanin agonist, a CRH antagonist,
human growth hormone, a growth hormone agonist, estrogen, an
estrogen agonist, a neurokinin-1 drug, and the like. In some
aspects the methods can further include informing the patient to
take the doxepin and said one or more compounds with or without
food, or with or without fatty food, preferably without food or
without fatty food.
[0025] Some embodiments of the present invention relate to methods
for reducing a risk of drug abuse, comprising identifying a patient
in need of sleep drug therapy and in need of avoidance of drugs
with potential for abuse; and administering to the patient any of
the drug combinations described above. In one embodiment, the drug
combination can be doxepin or a pharmaceutically acceptable salt or
prodrug thereof, and a compound that enhances GABA activity. The
compound that enhances GABA activity may be alprozolam, bromazepam,
clobazam, clonazepam, clorazepate, diazepam, flunitrazepam,
flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam,
triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem,
gabaxadol, vigabatrin, EVT 201 (Evotec Pharmaceuticals), tiagabine
or estazolam.
[0026] Another embodiment of the invention relates to methods for
treating insomnia, comprising administering to a patient in need
thereof an effective amount of doxepin or a pharmaceutically
acceptable salt or prodrug thereof, in combination with an
effective amount of a 5HT2a receptor antagonist or reverse agonist.
The 5HT2a antagonist may be for example, one or more of ketanserin,
risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France),
pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY10275 (Eli
Lilly), APD125 (Arena Pharmaceuticals, San Diego, Calif.), ITI-722
(Intra-Cellular Therapies) or AVE8488 (Sanofi-Aventis, France).
[0027] Further embodiments of the present invention relate to
methods for treating insomnia, comprising administering to a
patient in need thereof an effective amount of doxepin or a
pharmaceutically acceptable salt or prodrug thereof, in combination
with an effective amount of a sleep-onset-enhancing drug. In one
embodiment, the sleep-onset-enhancing drug can be one or more of a
GABA compound (e.g., modulate GABA activity and facilitate GABA
transmission), H3 agonists, orexin receptor antagonists, melatonin
agonists and galanin agonists. The sleep-onset-enhancing drug may
be ramelteon, eszopiclone, zolpidem tartrate or zaleplon. In some
aspects the methods can include a GABA-B agonist, a 5-HT modulator
(e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a 5-HT2a inverse
agonist, etc.), an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), a noradrenergic
antagonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, a neurokinin-1
drug, and the like.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Sleep disorders are a growing health problem. Unfortunately,
as mentioned above, many sleep drugs fail to satisfactorily treat
all or certain aspects of sleep disorders. For example, some drugs
may be effective at promoting sleep onset, while others may promote
sleep maintenance, or visa versa. Further, many of the medications
that may have some therapeutic efficacy against aspects of sleep
disorders cause very undesirable side effects. Side effects caused
by sleep medications include abnormal thinking and behavioral
changes such as decreased inhibition, hallucinations, complex
behaviors such as sleep driving, amnesia, anxiety, suicidal
thinking; withdrawal symptoms; CNS depressant effects; impaired
motor or cognitive performance (particularly in the elderly); bad
taste; headaches; parasomnias such as sleep walking; anaphylactic
and anaphylactoid reactions; weight gain; rebound insomnia or
tolerance.
[0029] Embodiments of the invention relate to compositions and
methods for improved treatments of sleep disorders utilizing
doxepin in combination with at least one other sleep medication.
Also, some embodiments relate to methods of treating sleep
disorders with combinations of doxepin and other sleep medications,
while avoiding or reducing the side effects that a patient
experiences. Surprisingly, the combinations and methods can result
in an unexpected synergy both in terms of their therapeutic effect
on sleep and/or in terms of the reduced side effects.
[0030] In some aspects the methods and compositions permit the use
of a reduced dosage of one or both of the doxepin and the other
medication(s), while still providing effective treatment (ie.
providing sleep onset, sleep maintenance, and preventing early
awakenings) of the sleep disorder, including in some aspects,
improved treatment compared to the use of either doxepin or the
combination medication(s) alone.
[0031] A number of existing sleep drugs can promote sleep onset,
but are less effective for promoting sleep maintenance, promoting
fewer awakenings during the night or delaying the final awakening
in the morning. Doxepin is an all around effective sleep
medication, but is particularly effective at promoting sleep
maintenance throughout the night and in preventing early morning
awakenings. Some preferred embodiments relate to methods and
compositions that combine doxepin with one or more drugs that are
effective at promoting sleep onset. The combined drugs can provide
greater than expected sleep benefit, in some cases, even when using
a lower dose of one or more of the drugs. The lower dose can be a
dosage that is lower compared to the approved dosage of the
drug(s), the clinical tested or literature reported dosage for
sleep therapy for the drug(s), the dosage of the drug(s) used in a
mono sleep therapy, or the dosage required to provide the patient
with an approximately similar sleep benefit (time to sleep onset,
total sleep time, sleep efficiency, wake time after sleep onset,
etc.). Examples of some preferred sleep onset medications include
gamma-aminobutyric acid (GABA) compounds (e.g., modulate GABA
activity and/or facilitate GABA transmission), H3 agonists, orexin
receptor antagonists, melatonin agonists and galanin agonists.
[0032] In some embodiments, the combined drugs can provide
substantially the same sleep benefit as expected when using a
higher dosage of one or both of the drugs, but provide fewer side
effects than occur at such a higher dosage. In some embodiments,
the combined drugs can provide surprisingly improved sleep benefit
compared to when using a higher dosage of one or both of the drugs,
and provide fewer side effects than occur at such a higher
dosages.
[0033] Some embodiments relate to the use doxepin in combination
with one or more drugs that promote sleep maintenance and/or one or
more drugs that promote a reduced number of awakenings during the
night. Still further embodiments relate to the use of doxepin in
combination with a drug or drugs that promote two or more of sleep
onset, sleep maintenance, or reduced awakenings. Again, due to the
unexpected therapeutic efficacy, lower dosages of one or all
compounds can be used.
[0034] Embodiments of the present invention generally relate to
methods of using low dosages of doxepin, doxepin prodrugs, and
pharmaceutically acceptable salts of the same, in combination with
any one or more compounds that enhance sleep, for example, sleep
onset, sleep maintenance or the prevention of early awakenings.
[0035] Examples of compounds that can be used in the combinations
include, but are not limited to, GABA compounds (e.g., modulate
GABA activity and facilitate GABA transmission), melatonin receptor
agonists, 5-HT modulators (e.g., 5-HT1A agonists, 5-HT2A receptor
antagonists or inverse agonists, etc.), serotonin-2
antagonists/reuptake inhibitors (SARIs), ion channel modulators, H3
agonists, orexin receptor antagonists, noradrenergic antagonists,
galanin agonists, CRH antagonists, Gabaxodol, other GABA-A direct
antagonists, GABA-B direct agonists GABA reuptake inhibitors,
growth hormone and growth hormone agonists, estrogen and estrogen
agonists, neurokinin-1 (NK-1) drugs, and the like. Gabaxodol and
GABA-A direct agonists differ in that gabaxodol is
extrasynaptic.
[0036] In some embodiments, one or more compounds described herein
(e.g., a compound that enhances sleep) and a doxepin-related
compound may be provided in relative ratios equal to about
0.1:99.9, about 0.5:99.5, about 1:99, about 5:95, about 10:90,
about 20:80, about 30:70, about 40:60, about 50:50, about 60:40,
about 70:30, about 80:20, about 90:10, about 95:5, about 99:1,
about 99.5:0.5, or about 99.1:0.1.
[0037] In some embodiments, one or more compounds that enhance
sleep may be provided in a first compound dosage that is about 1%,
about 5%, about 10%, about 20%, about 30%, about 40%, about 50%,
about 60%, about 70%, about 80%, about 90%, about 95%, or about 99%
a second compound dosage. The second compound dosage is defined as
a dosage that is: a dosage that is an approved prescription dosage
for the one or more compounds, a clinical trial dosage for the one
or more compounds, a literature-reported dosage of the one or more
compounds for treating a sleep disorder, a dosage of the one or
more compounds used to treat a sleep disorder as a monotherapy, a
dosage of the one or more compounds used to treat a sleep disorder
when doxepin is not also used to treat the sleep disorder, or a
dosage of the one or more compounds required to achieve
substantially the same sleep therapy benefit as the one or more
compounds used in combination with doxepin.
[0038] In some embodiments, a doxepin-related compound may be
provided in a first doxepin dosage that is about 1%, about 5%,
about 10%, about 20%, about 30%, about 40%, about 50%, about 60%,
about 70%, about 80%, about 90%, about 95%, or about 99% a second
doxepin dosage. The second doxepin dosage is defined as a dosage
that is: a dosage that is an approved prescription dosage for the
doxepin-related compound, a clinical trial dosage for the
doxepin-related compound, a literature-reported dosage of the
doxepin-related compound, a dosage of the doxepin-related compound
used to treat a sleep disorder as a monotherapy, a dosage of the
doxepin-related compound used to treat a sleep disorder when other
sleep-enhancing compounds are not used to treat the sleep disorder,
or a dosage of the doxepin-related compound required to achieve
substantially the same sleep therapy benefit as the one or more
doxepin-related compound used in combination with one or more
sleep-enhancing compounds.
[0039] In some embodiments, the combined dosage of the first
compound dosage and the first doxepin dosage is less than about
100%, less than about 90%, less than about 80%, less than about
70%, less than about 60%, less than about 50%, less than about 40%,
less than about 30%, less than about 20%, or less than about 10%
the combined reference dosage of the second compound dosage and the
second doxepin dosage. For example, the one or more compounds that
enhance sleep may act synergistically. In one instance, the
sleep-enhancing compound(s) are primarily effective at treating
onset insomnia, while the doxepin-related compound is primarily
effective at treating maintenance insomnia. However, the
combination drug may include reduced dosages of the sleep-enhancing
compound(s) and/or the doxepin-related compound, due to synergistic
effects of treating one or both types of insomnia. In some
embodiments, the sleep-enhancing compound is provided at a dosage
that is a first percentage of the second compound dosage, and the
doxepin-related compound is provided at a dosage that is a second
percentage of the second doxepin dosage, wherein the combination of
the first percentage and the second percentage is less than about
100%, less than about 90%, less than about 80%, less than about
70%, less than about 60%, less than about 50%, less than about 40%,
less than about 30%, less than about 20%, or less than about
10%.
[0040] Doxepin is a tricyclic compound approved for the treatment
of depression and anxiety.
[0041] It is contemplated that doxepin for use in the methods
described herein can be obtained from any suitable source or made
by any suitable method. As mentioned, doxepin is approved and
available for the treatment of depression and anxiety. It is
generally administered at a daily dose of 75-300 milligrams but, in
patients with very mild symptomatology or emotional symptoms
accompanying organic disease, lower doses of 25-50 mg/day have been
found to be effective
[0042] Doxepin HCl is available commercially and may be obtained in
capsule form from a number of sources. Doxepin is marketed under
the commercial name SINEQUAN.RTM. and in generic form, and can be
obtained in the United States generally from pharmacies in capsule
form in amounts of 10, 25, 50, 75, 100 and 150 mg dosage, and in
liquid concentrate form at 10 mg/mL. Doxepin HCl can be obtained
from Plantex Ltd. Chemical Industries (Hakadar Street, Industrial
Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A. (Via
Livelli 1--Frazione, Mairano, Italy), or from Dipharma S.p.A.
(20021 Baranzate di Bollate, Milano, Italy). Also, doxepin is
commercially available from PharmacyRx (NZ) (2820 1.sup.st Avenue,
Castlegar, B.C., Canada) in capsule form in amounts of 10, 25, 50,
75, 100 and 150 mg. Furthermore, Doxepin HCl is available in
capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg and in a
10 mg/ml liquid concentrate from CVS Online Pharmacy Store
(CVS.com).
[0043] Furthermore, doxepin
(11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo(b,e)oxepin)
can be prepared according to the method taught in U.S. Pat. No.
3,438,981, which is incorporated herein by reference in its
entirety. An example preparation is described below in Example
1.
[0044] Doxepin, unlike most FDA approved products for the treatment
of insomnia, is not a Schedule IV controlled substance. U.S. Pat.
Nos. 5,502,047 and 6,211,229, the entire contents of which are
incorporated herein by reference, describe the use of doxepin for
the treatment chronic and non-chronic (e.g., transient/short term)
insomnias at dosages far below those used to treat depression.
[0045] As mentioned above, some embodiments relate to methods of
using doxepin pharmaceutically acceptable salts of doxepin, and/or
prodrugs of doxepin to treat a patient suffering from a sleep
disorder such as insomnia, by administering a dosage of the
"doxpein compound(s)," including a low dosage of any of the
above-referenced doxepin compounds in combination with one or more
of the compounds described herein.
Definitions
[0046] The term "insomnia" generally refers to sleep problems
characterized by difficulty falling asleep, wakings during the
night, or waking up earlier than desired ("early awakenings").
Examples of insomnia include chronic and non-chronic insomnias.
Transient and short term insomnia are examples of non-chronic
insomnias. Also, sleep onset insomnia and sleep maintenance
insomnia are examples of insomnia conditions that can be chronic or
non-chronic in nature and duration.
[0047] As used herein, the term "transient insomnia" is an insomnia
that is present for one to several days, and is less than one week
in duration. Short term insomnia is insomnia of one to three or
four weeks in duration.
[0048] "Chronic insomnia" is typically accepted to involve episodes
greater than three (3) or four (4) weeks in duration.
[0049] "Onset insomnia" refers to difficulty in falling asleep.
[0050] "Maintenance insomnia" refers to difficulty in maintaining
uninterrupted sleep.
[0051] It is well known that the sleep deprivation resulting from
such insomnia adversely affects cognition, safety and quality of
life. Even in otherwise healthy young people, sleep deprivation has
been associated, for example, with changes in body physiology such
as changes in thyroid function, changes in glucose metabolism and
insulin resistance.
[0052] As used herein, the term "sedative tolerance" refers to a
decreased response to a repeated drug dose which requires
increasing amounts to produce the same effect. Tolerance is usually
manifested by a decreased duration or magnitude of sedation. Thus,
the patient requires larger doses to produce the sedative effects.
In contrast, sedative drugs which avoid sedative tolerance achieve
sustained efficacy over periods of prolonged or long term use, for
example during treatment of chronic sleep disorders.
[0053] The term "rebound insomnia" refers to the common occurrence
that a person may have more trouble sleeping the first few nights
after a sedative medicine is stopped than before starting the
medicine. After more than a few days' use, discontinuing a hypnotic
can make the original sleep problem worse and increase anxiety.
Rebound insomnia may be measured as the mean change in mean wake
time after sleep onset (WASO) from baseline to the first night of
discontinuation.
[0054] The term "early awakenings" refers to final awakenings that
occur during what would normally be the last hours of sleep,
particularly in the last hour of a sleep period for an
individual.
[0055] The term "residual next day sedation" refers to the
continued sedative effect of a drug the day after it is
administered.
[0056] The term "administer" and its variants contemplate both
self-administration (by the patient) and administration by a third
party.
[0057] The term "coadminister" and its variants contemplates
administering two or more drugs so that their pharmacological
effects are substantially simultaneously present in the patient.
Thus, one drug can be administered before the other, or one drug
can be administered in multiple doses while the other is
administered in a single dose. It also contemplates administering
the drugs in a physically mixed composition, or administering them
simultaneously without mixing outside the body. It further covers
administering two or more drugs by different routes of
administration, as well as administering the two or more drugs that
have different delivery profiles or mechanisms, such as buccal,
sublingual, sustained or controlled release, inhalation,
transdermal patch, and the like.
[0058] As used herein, "doxepin-related compounds" means doxepin,
or a pharmaceutically acceptable salt or prodrug thereof.
[0059] The term "prodrug" refers to an agent that is converted into
the active drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the active drug.
They may, for instance, be bioavailable by oral administration
whereas the active drug is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the active drug. An
example, without limitation, of a prodrug would be a compound of
the present invention which is administered as an ester (the
"prodrug") to facilitate entry into systemic circulation. A further
example of a prodrug might be a short peptide (polyaminoacid)
bonded to an acid group where the peptide is metabolized to reveal
the active moiety.
[0060] The term "pharmaceutically acceptable salt" refers to an
ionic form of a compound that does not cause significant irritation
to an organism to which it is administered and does not abrogate
the biological activity and properties of the compound.
Pharmaceutical salts can be obtained by reacting a compound of the
invention with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid and the like. Pharmaceutical salts can also be
obtained by reacting a compound of the invention with a base to
form a salt such as an ammonium salt, an alkali metal salt, such as
a sodium or a potassium salt, an alkaline earth metal salt, such as
a calcium or a magnesium salt, a salt of organic bases such as
dicyclohexylamine, N-methyl-D-glutamine,
tris(hydroxymethyl)methylamine, and salts with amino acids such as
arginine, lysine, and the like. Pharmaceutically acceptable salts
are more fully described below.
[0061] The term "low-dose" refers to a dose of 0.0001 to 49 mg,
preferably 0.001 to 20 mg, more preferably 0.01 to 10 mg, also 0.1
to about 8 mg, and even more preferably 0.5 or 1 to about 6 mg. The
term "low dose" can also refer to a daily dose range of between
about 0.0001 and 6 milligrams. In some embodiments, low dosages can
be about 1, 2, 3, 4, 5 or 6 milligrams. These dosages have reduced
side effects, are surprisingly effective, and have a relatively
rapid onset. In one embodiment, an initial daily dosage of about 1
milligram can be given. If the desired improvement in sleep is not
achieved, then the dosage may be incrementally increased until the
desired dosage is achieved or until a maximum desired dosage is
reached which can be, for example, 2 milligrams, 3 milligrams, 4
milligrams, 5 milligrams or 6 milligrams. It should be noted that
other dosages of a doxepin-related compound can be used in the
embodiments described herein. For example, the dosage can be about
0.001 to about 20 milligrams, for example.
[0062] Compounds which enhance GABA activity for use in the
compositions and methods of the present invention include, but are
not limited to, alprozolam, bromazepam, chlorodiazepoxide,
clobazam, clonazepam, clorazepate, diazepam, flunitrazepam,
flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam,
triazolam, zolpidem, zaleplon, zopiclone, eszopiclone, gabaxadol,
estazolam (Prosom) vigabatrin, tiagabine, EVT 201 (Evotec
Pharmaceuticals) and indiplon.
[0063] Melatonin receptor agonists for use in the compositions and
methods of the present invention include, but are not limited to,
melatonin (e.g., Circadin.RTM.), ramelteon (ROZEREM.RTM., Takeda
Pharmaceuticals, Japan), agomelatine, PD-6735 (Phase II Discovery)
and VEC-162 (Vanda Pharmaceuticals, Rockville, Md.). Preferred
melatonin receptor agonists are those that are selective for
MT.sub.1 and/or MT.sub.2 receptors, in comparison to MT.sub.3
receptors.
[0064] 5-HT2a receptor antagonists preferably include, but are not
limited to, any sleep-enhancing 5-HT2a antagonist or reverse
agonist, which in particular embodiments may include eplivanserin
(Sanofi-Aventis, France), volinanserin (Sanofi-Aventis, France),
ketanserin, risperidone, pruvanserin (Eli Lilly), HY10275 (Eli
Lilly), MDL100907 (Sanofi-Aventis, France), APD125 (Arena
Pharmaceuticals, San Diego, Calif.), ITI-722 (Intra-Cellular
Therapies) or AVE 8488 (Sanofi-Aventis, France).
[0065] 5-HT1a receptor agonists preferably include, but are not
limited to, repinotan, sarizotan, eptapirone, buspirone and MN-305
(MediciNova, San Diego, Calif.).
[0066] Serotonin-2 antagonists/reuptake inhibitors (SARIs) include,
but are not limited to, Org 50081 (Organon, The Netherlands),
ritanserin, nefazodone, serzone and trazodone.
[0067] Orexin receptor antagonists include, but are not limited to,
1,3-biarylureas, SB-334867-A (GlaxoSmithKline, UK), GW649868
(GlaxoSmithKline), ACT-078573 (Actelion, Switzerland) and benzamide
derivatives, such as those disclosed in U.S. Pat. No. 7,078,565,
the contents of which are incorporated herein by reference.
[0068] GABA-B agonists include, but are not limited to, (-)baclofen
(.beta.-(4-chloro-phenyl)-.gamma.-aminobutyric acid)
("Baclofen")
[0069] Other drugs that may be combined with doxepin include
gabapentinoids (alpha2 delta ligands), neurokinin-1 drugs
(casopitant (GlaxoSmithKline), histamine antagonist compounds
(HY10275 Eli Lilly) and ion channel modulators (e.g., gabapentin,
pregabalin, lamotrigine).
[0070] It should be understood that in some embodiments, one or
more compounds from the classes mentioned herein, including the
drugs that are specifically mentioned, can be specifically excluded
from one or more embodiments of the embodiments described herein.
Thus, it is contemplated that one or more of the drugs alone in any
combination or number can be specifically excluded from certain
embodiments.
Obtaining and Method of making Doxepin Compounds
[0071] It is contemplated that doxepin for use in the methods
described herein can be obtained from any suitable source or made
by any suitable method. As mentioned, doxepin is approved and
available in high doses (generally 75-300 milligrams) for the
treatment of depression and anxiety. Doxepin HCl is available
commercially and may be obtained in capsule form from a number of
sources. Doxepin is marketed under the commercial name
SINEQUAN.RTM. and in generic form, and can be obtained in the
United States generally from pharmacies in capsule form in amounts
of 10, 25, 50, 75, 100 and 150 mg dosage, and in liquid concentrate
form at 10 mg/mL. Doxepin HCl can be obtained from Plantex Ltd.
Chemical Industries (Hakadar Street, Industrial Zone, P.O. Box 160,
Netanya 42101, Israel), Sifavitor S.p.A. (Via Livelli 1--Frazione,
Mairano, Italy), or from Dipharma S.p.A. (20021 Baranzate di
Bollate, Milano, Italy). Also, doxepin is commercially available
from PharmacyRx (NZ) (2820 1.sup.st Avenue, Castlegar, B.C.,
Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150
mg. Furthermore, Doxepin HCl is available in capsule form in
amounts of 10, 25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid
concentrate from CVS Online Pharmacy Store (CVS.com).
[0072] Also, doxepin
(11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo (b,e)oxepin)
can be prepared according to the method taught in U.S. Pat. No.
3,438,981, which is incorporated herein by reference in its
entirety. An example preparation is described below in Example 1.
As another illustration, doxepin can be prepared from
11-[3-(Dimethylamino)propyl]-6,11-dihydrodibenzo[b,e]oxepin-11-ol
as taught in U.S. Pat. No. 3,420,851, which is incorporated herein
by reference in its entirety.
[0073] As mentioned above, the methods and other embodiments
described herein can utilize any suitable pharmaceutically
acceptable salt or prodrug of doxepin. The substitution or use in
combination of salts and prodrugs is specifically contemplated in
the embodiments described herein. The pharmaceutically acceptable
salts and prodrugs can be made by any suitable method. The acids
that may be used to prepare pharmaceutically acceptable acid
addition salts are those that form non-toxic acid addition salts,
i.e., salts containing pharmacologically acceptable anions, such as
the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate, disylate,
estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, iodide, isothionate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate,
methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate
(embonate), palmitate, pantothenate, phospate/diphosphate,
polygalacturonate, salicylate, stearate, subacetate, succinate,
tannate, tartrate, teoclate, tosylate, triethiodode, and valerate
salts.
[0074] The term "prodrug" refers to a chemical entity that is
rapidly transformed in vivo to yield an active entity, for example,
such as by hydrolysis in blood or inside tissues, for example.
Examples of prodrug groups can be found in, for example, T. Higuchi
and V. Stella, in "Pro-drugs as Novel Delivery Systems," Vol. 14,
A.C.S. Symposium Series, American Chemical Society (1975); H.
Bundgaard, "Design of Prodrugs," Elsevier Science, 1985; and
"Bioreversible Carriers in Drug Design: Theory and Application,"
edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987), each
of which is hereby incorporated by reference in its entirety.
Methods of Using Doxepin
[0075] Embodiments relate to methods for improving sleep in a
patient in need thereof, for example, by administering a doxepin
compound and at least one other sleep enhancing medication. The
sleep enhancing medication can be, for example, a sleep-onset or
maintenance enhancing drug, including a compound from those classes
listed above and elsewhere herein e.g., a GABA-B agonist, a 5-HT
modulator (e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a 5-HT2a
inverse agonist, etc.), an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), a noradrenergic
antagonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, a neurokinin-1
drug, and the like.
[0076] Some embodiments relate to methods of reducing sleep drug
side effects in a patient by administering a doxepin compound in
combination with one or more sleep drugs in a dosage sufficient to
reduce the side effects normally associated with the non-doxepin
sleep drug(s). In some aspects, the combination promotes sleep
therapy that is at least equivalent to the sleep therapy by the
non-doxepin drug(s) when used alone in a greater amount, even
though less of the non-doxepin drug is used in the combination.
[0077] As mentioned above and elsewhere, the methods described
herein can be used to treat individuals suffering from a sleep
disorder, such as insomnia. The individual can suffer from a
chronic insomnia or a non-chronic insomnia. For chronic (e.g.,
greater than 3-4 weeks) or non-chronic insomnias, a patient may
suffer from difficulties in sleep onset, sleep maintenance
(interruption of sleep during the night by periods of wakefulness),
sleep duration, sleep efficiency, premature early-morning
awakening, or a combination thereof Also, the insomnia may be
attributable to the concurrent use of other medication, for
example. The non-chronic insomnia can be, for example, short term
insomnia or transient insomnia. The chronic or non-chronic insomnia
can be a primary insomnia or an insomnia that is secondary or
attributable to another condition, for example a disease such as
depression or chronic fatigue syndrome. In some aspects, the
patient can be one that is not suffering from an insomnia that is a
component of a disease, or a patient can be treated that is
otherwise healthy. In some embodiments, the patient can be one that
suffers from or is at risk of suffering from drug abuse and/or
alcoholism. In some embodiments, the patient can be taking a
narcotic medication. As previously mentioned, the chronic or
non-chronic insomnia can be a primary insomnia, that is, one that
is not attributable to another mental disorder, a general medical
condition, or a substance. In many cases, such conditions may be
associated with a chronic insomnia and can include, but are not
limited to, insomnia attributable to a diagnosable DSM-IV disorder,
a disorder such as anxiety or depression, or a disturbance of the
physiological sleep-wake system. In some aspects the insomnia can
be non-chronic, or of short duration (e.g., less than 3-4 weeks).
Examples of causes of such insomnia may be extrinsic or intrinsic
and include, but are not limited to environmental sleep disorders
as defined by the International Classification of Sleep Disorders
(ICSD) such as inadequate sleep hygiene, altitude insomnia or
adjustment sleep disorder (e.g., bereavement). Also, short-term
insomnia may also be caused by disturbances such as shift-work
sleep disorder. In some aspects, the methods can occur without the
untoward side effects of unwanted weight gain, rebound insomnia, or
sedative tolerance.
[0078] It should be noted that in some aspects, the methods can
specifically exclude one or more of any of the sleep disorders
described in the previous paragraph or elsewhere herein. For
example, without being limited thereto, in some aspects the methods
can specifically exclude treating a chronic insomnia. As another
example, without being limited thereto, in some aspects the methods
can specifically exclude treating an insomnia that is attributable
to a condition such as depression, anxiety or chronic fatigue.
[0079] In one embodiment, the doxepin, pharmaceutically acceptable
salt or prodrug and at least one other compound that enhances or
facilitates sleep (e.g., accelerates sleep onset or enhances sleep
maintenance), can be administered separately (in two distinct
formulations or dosage forms). In various embodiments, the two or
more components can be administered at the same time, the doxepin
component can be administered prior to the compound that enhances
sleep, or vice versa. In another embodiment, the two compounds can
be presented in a single formulation (e.g., are present in the same
capsule or tablet, such as a bilayer tablet) and are therefore
simultaneously coadministered. In some such cases, the combination
can be in a fixed ratio combination. Other types of
coadministration are expressly contemplated, including
administering the doxepin or related drug before the other drug
(e.g., 10, 20, 30, 40, 50 or 60 minutes before), administering the
doxepin or related drug after the other drug (e.g., 10, 20, or 30
minutes after), administering one drug in a sustained or controlled
release form but not the other, administering one by one route of
administration and the other by a different route.
[0080] One advantage of many of these drug combinations is the
ability to treat a particular subset of insomnia patients that has
not previously been adequately treated. For example, these patients
include those patients that are in need of both rapid sleep onset
and sleep maintenance, including maintenance of sleep into the
seventh or eighth hour of the night without early awakenings. Also,
many of the combinations work unexpectedly well or synergistically.
Thus, the methods contemplated herein include methods for providing
sleep therapy to a patient, including evaluating whether the
patient is in need of both enhanced sleep onset at the beginning of
a desired sleep period, and also in need of sleep maintenance at
the end of a desired sleep period, and if so, coadministering to
the patient the combination therapy disclosed herein, e.g.,
effective doses of both a doxepin compound and a
sleep-onset-enhancing compound. Also contemplated is selecting the
presently-disclosed sleep therapy drug combination from available
therapies for patients in need of both sleep onset and sleep
maintenance therapy. A sleep therapy drug combination disclosed
herein may be used to treat patient suffering from early
awakenings.
[0081] In one embodiment, the patient can be advised to take the
drug combination at bedtime. In another, the patient can be advised
to take the drug combination with or without food. A food effect
has not heretofore been reported for doxepin. In prescribing or
administering a combination of doxepin and a melatonin agonist,
such as ramelteon, to a patient, one may further advise the patient
(verbally or in writing) that the combination should be taken
orally, without food, for example, within 30 minutes of bedtime,
and not with or immediately after eating, particularly when the
food is fatty food. The patient may further be informed orally or
in writing that T.sub.max for the combination therapy will be
delayed if taken with food.
[0082] Another aspect of the present disclosure is the relative
safety of the doxepin-related component of the combination.
Combinations that include a doxepin-related component and a
non-scheduled agent such as melatonin or a melatonin agonist can
have an increased safety profile and a reduced risk of abuse, when
both ingredients are non-scheduled drugs in the U.S. Thus, some of
the contemplated methods include a method for providing insomnia
drug therapy for a patient, by evaluating whether the patient
should avoid therapies with significant potential for abuse, and if
so, administering a doxepin-related drug in combination with, for
example, a melatonin agonist. Also contemplated is selecting that
drug therapy from available drug therapies based on the desire or
need to avoid potential for abuse or to avoid or reduce side
effects. In some embodiments, a decreased amount of the combination
drug or drugs can be used due to the combined effects of the
combination. Decreased amount can mean, for example, an amount less
than what would be used when using the drug or drugs alone or not
combined.
[0083] Combinations that include a doxepin-related component and a
non-scheduled or a scheduled agent such as a GABA modulator can
have an increased safety profile. For example, by administering a
doxepin-related component in combination with the scheduled agent,
a lower dosage of the scheduled agent may have substantially the
same efficacy of a higher dosage of the scheduled agent
administered without the doxepin-related component. Thus, side
effects associated with the scheduled agent may be reduced by
administering the drug combination comprising a decreased amount of
the scheduled agent.
[0084] The drug combinations disclosed herein have surprising
efficacy, even in low doses, and also can allow a full 7 or 8 hours
of sleep, without significant next-day sedation. It is believed
that these combinations are surprisingly complementary, or even
synergistic, filling a long-felt need for a sleep drug that is
safe, provides rapid sleep onset, maintains sleep throughout the
night for a full 7 or 8 hour sleep cycle, reduces the incidence of
early awakenings and allows normal activity the next day without
hangover or unsafe levels of sedation.
[0085] Also, some embodiments relate to the use of doxepin prodrugs
or salts of the same in combination with other insomnia or sleep
medications. For example, the methods can include the use of one or
more of a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a agonist,
a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), an ion
channel modulator (e.g., blocker) a serotonin-2 antagonist/reuptake
inhibitor (SARIs), a noradrenergic antagonist, a CRH antagonist,
human growth hormone, a growth hormone agonist, estrogen, an
estrogen agonist, a neurokinin-1 drug, and the like. In some
aspects, doxepin prodrugs or salts thereof in combination with
another sleep medication, including those listed above and
elsewhere herein, can be administered to a patient without untoward
side effects including, but not limited to, decreased inhibition,
hallucinations, complex behaviors such as sleep driving, amnesia,
anxiety, suicidal thinking; withdrawal symptoms; CNS depressant
effects; impaired motor or cognitive performance (particularly in
the elderly); bad taste; headaches; parasomnias such as sleep
walking; anaphylactic and anaphylactoid reactions; weight gain; or
rebound insomnia or tolerance.
[0086] Some non-limiting examples of specific drugs and dosages
that can be used in combination with a doxepin-related compound are
described in the following paragraphs.
[0087] Ramelteon
((S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionam-
ide) can be used in any dosage, but preferably can be used in a
dosage of about 0.5 milligrams to about 20 milligrams. More
preferably, about 4, 8 or 16 milligrams can be used, for example.
Even more preferably, the dosage of Ramelteon can be less than
about 4 mg, about 8 mg, or about 16 mg, for example between about
0.001 and about 3.9 mg.
[0088] Eszopiclone also can be used in any suitable dosage. For
example, the dosage can be about 0.1 to about 10 milligrams.
Preferably, as an example, the dosage can be about 1, 2, or 3
milligrams. Even more preferably, the dosage of Eszopiclone can be
less than about 1 mg, about 2 mg, or about 3 mg, for example
between about 0.001 and about 0.9 mg.
[0089] Zolpidem
(N,N,6-trimethyl-2-p-tolylimidazo[1,2-a]pyridine-3-acetamide
L-(+)-tartrate (2:1)) also can be used in any suitable dosage. For
example, the dosage can be about 0.1 to about 20 milligrams.
Preferably, as an example, the dosage can be about 6.25-milligrams,
about 12.5 milligrams or a dosage that is a factor thereof, for
example. Even more preferably, the dosage of zolpidem can be less
than about 6.25 mg or about 12.5 mg, for example between about
0.0001 and about 5, or between about 0.0001 and about 6 mg. The
dosage may be between about 0.001 and about 19.9 milligrams, about
0.001 and about 12.4 milligrams, about 0.001 and about 9.9
milligrams, about 0.001 and about 6.24 milligrams, or about 0.001
and about 4.9 milligrams. It is worth noting that zolpidem (not
just zolpidem but all the GABAs) is known to have various
undesirable side effects. Use of the low doses described herein
when in combination with a doxepin compound provides efficacy as a
sleep medication with reduced side effects.
[0090] Furthermore, zaleplon
(N-[3-(3-cyantopryazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide)
can be used in any suitable dosage. For example, the dosage can be
between about 0.1 and about 20 milligrams, about 0.001 and about
19.9 milligrams, about 0.001 and about 12.4 milligrams, about 0.001
and about 9.9 milligrams, about 0.001 and about 6.24 milligrams, or
about 0.001 and about 4.9 milligrams. Preferably, as an example,
the dosage can be about 5, about 10 or about 20 milligrams, for
example. Even more preferably, the dosage of zaleplon can be less
than 5 mg, 10 mg, or 20 mg, for example between about 0.01 and 4.9
mg.
[0091] Gabaxadol (7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol) can be
used in any suitable dosage. For example, the dosage can be about
0.1 to about 40 milligrams. Preferably, as an example, the dosage
can be between about 0.5 and about 20 milligrams, about 10 and
about 15 milligrams, about 0.001 and about 39.9 milligrams, about
0.001 and about 19.9 milligrams, about 0.001 and about 12.4
milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and
about 6.24 milligrams, or about 0.001 and about 4.9 milligrams for
example.
[0092] VEC-162 can be used in any suitable dosage. For example, the
dosage can be about 0.1 to about 150 milligrams. Preferably, as an
example, the dosage can be about 10, about 20, about 50 or about
100 milligrams, for example. The dosage can be between about 0.001
and about 149.9 milligrams, about 0.001 and about 99.9 milligrams,
about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9
milligrams, or about 0.001 and about 9.9 milligrams. Even more
preferably, the dosage of VEC-162 can be about 0.001 to about 9
mg.
[0093] Indiplon
(N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-.alpha.]pyrimidin-7-yl-
]phenyl]acetamide) can be used in any suitable dosage. For example,
the dosage can be about 0.1 to about 10 milligrams. Preferably, as
an example, the dosage can be about 5 or about 10 milligrams, for
example. The dosage can be between about 0.001 and about 9.9
milligrams or about 0.001 and about 4.9 milligrams. Even more
preferably, the dosage of indiplon can be about 0.001 to about 4.9
mg.
[0094] MDL 100907 (Sanofi-Aventis) can be used in any suitable
dosage. For example, the dosage can be about 0.5 to about 100
milligrams, preferably from about 1 to about 50 milligrams. The
dosage can between about 0.001 and about 99.9 milligrams, about
0.001 and about 49.9 milligrams, about 0.001 and about 19.9
milligrams, or about 0.001 and about 9.9 milligrams. Even more
preferably, the dosage of MDL 100907 can be about 0.001 to about
0.5 mg.
[0095] APD125 (Arena Pharmaceuticals) can be used in any suitable
dosage. For example, the dosage can be about 1 to about 160
milligrams, preferably about 5 to about 80 milligrams, or more
preferably about 10 to about 40 milligrams. The dosage can between
about 0.001 and about 159.9 milligrams, about 0.001 and about 79.9
milligrams, about 0.001 and about 39.9 milligrams, or about 0.001
and about 9.9 milligrams. Even more preferably, the dosage of
ADP125 can be about 0.001 to about 5 mg.
[0096] AVE 8488 (Sanofi-Aventis) can be used in any suitable
dosage. For example, the dosage can be about 0.5 to about 100
milligrams, preferably from about 1 to about 50 milligrams. The
dosage can between about 0.001 and about 99.9 milligrams, about
0.001 and about 49.9 milligrams, about 0.001 and about 19.9
milligrams, or about 0.001 and about 9.9 milligrams. Even more
preferably, the dosage of AVE 8488 can be about 0.001 to about 1
mg.
[0097] MN-305 (MediciNova) can be used in any suitable dosage. For
example, the dosage can be about 0.1 to about 50 milligrams,
preferably from about 0.5 to about 10 milligrams or 1-6 milligrams.
The dosage can between about 0.001 and about 49.9 milligrams, about
0.001 and about 9.9 milligrams, about 0.001 and about 5.9
milligrams, about 0.001 and about 4.9, about 0.001 and about 3.9,
about 0.001 and about 2.9 or about 0.001 and about 1.9 milligrams.
For example, in some aspects the dosage of MN-305 can be about 1
mg, about 3 mg or about 6 mg. Even more preferably, the dosage of
MN-305 can be about 0.001 to about 0.5 mg.
[0098] ORG 50081 (Organon; Akzo Novel) can be used in any suitable
dosage. For example, the dosage can be about 0.5 to about 100
milligrams, preferably from about 1 to about 50 milligrams. The
dosage can between about 0.001 and about 99.9 milligrams, about
0.001 and about 49.9 milligrams, about 0.001 and about 19.9
milligrams, or about 0.001 and about 9.9 milligrams. Even more
preferably, the dosage of ORG 50081 can be about 0.001 to about 1
mg.
[0099] ACT-078573 (Actelion) can be used in any suitable dosage.
For example, the dosage can be about 0.5 to about 100 milligrams,
preferably from about 1 to about 50 milligrams. The dosage can
between about 0.001 and about 99.9 milligrams, about 0.001 and
about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or
about 0.001 and about 9.9 milligrams. Even more preferably, the
dosage of ACT-078573 can be about 0.001 to about 1 mg.
[0100] Baclofen
((-)baclofen(.beta.-(4-chloro-phenyl)-.gamma.-aminobutyric acid)
can be used in any suitable dosage. For example, the dosage can be
about 1 mg to about 100 mg, preferably from, about 5 to about 40
mg. The dosage can between about 0.001 and about 99.9 milligrams,
about 0.001 and about 39.9 milligrams, about 0.001 and about 19.9
milligrams, or about 0.001 and about 9.9 milligrams. Even more
preferably, the dosage of baclofen can be about 0.001 to about 1
mg.
[0101] Eplivanserin can be used in any suitable dosage. For
example, the dosage can be about 0.1 mg to about 20 mg. The dosage
can between about 0.001 and about 19.9 milligrams, about 0.001 and
about 9.9 milligrams, or about 0.001 and about 4.9 milligrams. Even
more preferably the dosage can be about 0.001 mg to about 5 mg.
[0102] Pruvanserin (Eli Lilly) can be used in any suitable dosage.
For example, the dosage can be about 0.1 mg to about 50 mg. The
dosage can between about 0.001 and about 49.9 milligrams, about
0.001 and about 19.9 milligrams, or about 0.001 and about 9.9
milligrams. Even more preferably the dosage can be about 0.001 mg
to about 10 mg.
[0103] ACT-078573 (Actelion; GlaxoSmithKline) can be used in any
suitable dosage. For example, the dosage can be about 100 mg to
about 1200 mg. The dosage can between about 0.001 and about 1199.9
milligrams, about 0.001 and about 999.9 milligrams, about 0.001 and
about 499.9 milligrams, or about 0.001 and about 9.9 milligrams.
Even more preferably the dosage can be about 0.001 mg to about 100
mg.
[0104] EVT 201 (Evotec) can be used in any suitable dosage. For
example, the dosage can be about 0.01 mg to about 30 mg. The dosage
can between about 0.001 and about 99.9 milligrams, about 0.001 and
about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or
about 0.001 and about 9.9 milligrams. Even more preferably the
dosage can be about 0.001 mg to about 1 mg.
[0105] Volinanserin (Sanofi-Aventis) can be used in any suitable
dosage. For example, the dosage can be about 0.01 mg to about 20
mg. The dosage can between about 0.001 and about 19.9 milligrams,
about 0.001 and about 9.9 milligrams, or about 0.001 and about 4.9
milligrams, or about 0.001 and about 1.9 milligrams. Even more
preferably the dosage can be about 0.001 mg to about 2 mg.
[0106] HY10275 (Eli Lilly) can be used in any suitable dosage. For
example, the dosage can be about 0.1 to about 50 milligrams,
preferably from about 0.5 to about 10 milligrams or 1-6 milligrams.
For example, in some aspects the dosage of HY10275 can be about 1
mg, about 3 mg or about 6 mg. The dosage can between about 0.001
and about 49.9 milligrams, about 0.001 and about 19.9 milligrams,
about 0.001 and about 9.9 milligrams, about 0.001 and about 4.9
milligrams, about 0.001 and about 3.9 milligrams, about 0.001 and
about 2.9 milligrams, about 0.001 and about 1.9 milligrams, or
about 0.001 and about 0.9 milligrams. Even more preferably, the
dosage of HY10275 can be about 0.001 to about 1 mg.
[0107] PD-6735 (6-chloro-(beta)-methyl melatonin; Phase II
Discovery) can be used in any suitable dosage. For example, the
dosage can be about 0.01 mg to about 150 mg. The dosage can between
about 0.001 and about 149.9 milligrams, about 0.001 and about 99.9
milligrams, about 0.001 and about 49.9 milligrams, or about 0.001
and about 19.9 milligrams. Even more preferably the dosage can be
about 0.001 mg to about 20 mg.
[0108] ITI-722 (Intracellular Therapies) can be used in any
suitable dosage. For example, the dosage can be about 0.01 mg to
about 500 mg. The dosage can between about 0.001 and about 499.9
milligrams, about 0.001 and about 99.9 milligrams, about 0.001 and
about 49.9 milligrams, or about 0.001 and about 9.9 milligrams.
Even more preferably the dosage can be about 0.001 mg to about 100
mg.
[0109] GW649868 (GlaxoSmithKline) can be used in any suitable
dosage. Preferably, as an example, the dosage can be about
6.25-milligrams, 12.5 milligrams or a dosage that is a factor
thereof, for example. The dosage can between about 0.001 and about
19.9 milligrams, about 0.001 and about 6.24 milligrams, about 0.001
and about 12.4 milligrams, or about 0.001 and about 4.9 milligrams.
Even more preferably, the dosage of GW649868 can be less than 6.25
mg or 12.5 mg, for example between about 0.001 and 5 mg.
[0110] Casopitant (GlaxoSmithKline) can be used in any suitable
dosage. For example, the dosage can be about 0.01 mg to about 500
mg. The dosage can between about 0.001 and about 499.9 milligrams,
about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9
milligrams, or about 0.001 and about 9.9 milligrams. Even more
preferably the dosage can be about 0.001 mg to about 100 mg.
[0111] Circadin.RTM. (H. Lundbeck A/S) can be used in any suitable
dosage. For example, the dosage can be about 0.01 mg to about 30
mg. The dosage can between about 0.001 and about 29.9 milligrams,
about 0.001 and about 9.9 milligrams, about 0.001 and about 4.9
milligrams, or about 0.001 and about 1.9 milligrams. Even more
preferably the dosage can be about 0.001 mg to about 2 mg.
Preparation and Administration of Drug Compositions
[0112] In performing the methods, a doxepin-related (doxepin, a
pharmaceutically acceptable salt of doxepin or a doxepin prodrug)
compound can be administered using any suitable route or method of
delivery. Also, a doxepin-related compound can be administered
alone or in combination with other substances, such as for example,
other insomnia or sleep medications, or with other medications that
treat a primary illness. For example, a doxepin-related compound
can be administered with one or more of a GABA-B agonist, a 5-HT
modulator (e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a 5-HT2a
inverse agonist, etc.), an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), a noradrenergic
antagonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, a neurokinin-1
drug, and the like. A doxepin-related compound alone or in
combination can be included and administered as a composition.
[0113] In some embodiments, the drugs of the combination can be
physically combined or mixed, together with suitable excipients. In
others, they are separately contained in the same unit dosage form,
but are physically separated. This includes unit dosage forms in
which a single capsule, lozenge or tablet (such as a multilayer
tablet or lozenge) contains two or more physically-separated drugs,
which can be (for example) two layers or halves of a single tablet;
a two-part capsule; or a capsule containing distinct particulate or
bead forms of the individual drugs. Alternatively, the drugs of the
combination can be physically separated in separate dosage forms,
but packaged together; for example, in the same blister pack, or in
the same primary or secondary container.
[0114] Suitable routes of administration include oral, buccal,
sublingual, transdermal, rectal, topical, transmucosal, or
intestinal administration; parenteral delivery, including
intramuscular, subcutaneous, intravenous, intramedullary
injections, as well as intrathecal, direct intraventricular,
intraperitoneal, intranasal, or intraocular injections.
[0115] For oral administration, the compounds can be formulated as
pills, tablets, lozenges, powders, granules, dragees, capsules,
liquids, sprays, gels, syrups, slurries, suspensions and the like,
in bulk or unit dosage forms, for oral ingestion by a patient to be
treated. The compounds can be formulated readily, for example, by
combining the active compound with any suitable pharmaceutically
acceptable carrier or excipient.
[0116] Pharmaceutical preparations for oral use can be obtained by
mixing one or more solid excipients with a pharmaceutical
composition as described herein, optionally grinding the resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients are listed below. Some examples include
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate.
[0117] The formulation can be in form suitable for bolus
administration, for example. Oral administration can be
accomplished using fast-melt formulations, for example. As a
further example, the formulations can be included in pre-measured
ampules or syringes, push-fit capsules made of gelatin, as well as
soft, sealed capsules made of gelatin and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain a
pharmaceutical composition as described herein in admixture with
fillers such as lactose, binders such as starches, and/or
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active compounds may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0118] For buccal administration, a pharmaceutical composition as
described herein may take any suitable form, for example, tablets
or lozenges.
[0119] For topical administration, a pharmaceutical composition as
described herein may be formulated for administration to the
epidermis as ointments, gels, creams, pastes, salves, gels, creams
or lotions, or as a transdermal patch. Ointments and creams may,
for example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
containing one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents.
[0120] For injection, a pharmaceutical composition as described
herein may be formulated in aqueous solutions, preferably in
physiologically compatible buffers such as Hanks's solution,
Ringer's solution, or physiological saline buffer. For transmucosal
administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art.
[0121] For administration by inhalation, a pharmaceutical
composition as described herein for use according to the present
invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide,
or other suitable gas. In the case of a pressurized aerosol the
dosage unit may be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, e.g., gelatin for use
in an inhaler or insufflator may be formulated containing a powder
mix of the compound and a suitable powder base such as lactose or
starch.
[0122] A pharmaceutical composition as described herein may be
formulated for parenteral administration by injection, e.g., by
bolus injection or continuous infusion. Formulations for injection
may be presented in unit dosage form, e.g., in ampoules or in
multi-dose containers, with an added preservative. The composition
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents.
[0123] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of a pharmaceutical composition as
described herein may be prepared as appropriate oily injection
suspensions. Suitable lipophilic solvents or vehicles include fatty
oils such as sesame oil, or synthetic fatty acid esters, such as
ethyl oleate or triglycerides, or liposomes. Aqueous injection
suspensions may contain substances which increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, the suspension may also contain suitable
stabilizers or agents which increase the solubility of the
compounds to allow for the preparation of highly concentrated
solutions.
[0124] In addition, any of the compounds and compositions described
herein can also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt. Furthermore, any of the compounds and compositions described
herein also can be formulated as a fast-melt preparation. The
compounds and compositions can also be formulated and administered
as a drip, a suppository, a salve, an ointment, an absorbable
material such a transdermal patch, or the like.
[0125] One can also administer a pharmaceutical composition as
described herein in sustained release forms or from sustained
release drug delivery systems. A description of representative
sustained release materials can be found in the incorporated
materials in Remington: The Science and Practice of Pharmacy
(20.sup.th ed, Lippincott Williams & Wilkens Publishers
(2003)), which is incorporated herein by reference in its
entirety.
[0126] A variety of techniques for formulation and administration
can be found in Remington: The Science and Practice of Pharmacy
(20.sup.th ed, Lippincott Williams & Wilkens Publishers
(2003)), which is incorporated herein by reference in its
entirety.
[0127] As mentioned above, the compositions and formulations
disclosed herein also can include one or more pharmaceutically
acceptable carrier materials or excipients. Such compositions can
be prepared for storage and for subsequent administration.
Acceptable carriers or diluents for therapeutic use are well known
in the pharmaceutical art, and are described, for example, in the
incorporated material of Remington: The Science and Practice of
Pharmacy (2003). The term "carrier" material or "excipient" herein
can mean any substance, not itself a therapeutic agent, used as a
carrier and/or diluent and/or adjuvant, or vehicle for delivery of
a therapeutic agent to a subject or added to a pharmaceutical
composition to improve its handling or storage properties or to
permit or facilitate formation of a dose unit of the composition
into a discrete article such as a capsule or tablet suitable for
oral administration. Excipients can include, by way of illustration
and not limitation, diluents, disintegrants, binding agents,
adhesives, wetting agents, polymers, lubricants, glidants,
substances added to mask or counteract a disagreeable taste or
odor, flavors, dyes, fragrances, and substances added to improve
appearance of the composition. Acceptable excipients include
lactose, sucrose, starch powder, maize starch or derivatives
thereof, cellulose esters of alkanoic acids, cellulose alkyl
esters, talc, stearic acid, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulfuric acids, gelatin,
acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or
polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin,
albumin, sodium glutamate, cysteine hydrochloride, and the like.
Examples of suitable excipients for soft gelatin capsules include
vegetable oils, waxes, fats, semisolid and liquid polyols. Suitable
excipients for the preparation of solutions and syrups include,
without limitation, water, polyols, sucrose, invert sugar and
glucose. Suitable excipients for injectable solutions include,
without limitation, water, alcohols, polyols, glycerol, and
vegetable oils. The pharmaceutical compositions can additionally
include preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorings, buffers, coating
agents, or antioxidants. Sterile compositions for injection can be
formulated according to conventional pharmaceutical practice as
described in the incorporated material in Remington: The Science
and Practice of Pharmacy (2003). For example, dissolution or
suspension of the active compound in a vehicle such as water or
naturally occurring vegetable oil like sesame, peanut, or
cottonseed oil or a synthetic fatty vehicle like ethyl oleate or
the like may be desired. Buffers, preservatives, antioxidants and
the like can be incorporated according to accepted pharmaceutical
practice. The compound can also be made in microencapsulated form.
In addition, if desired, the injectable pharmaceutical compositions
may contain minor amounts of nontoxic auxiliary substances, such as
wetting agents, pH buffering agents, and the like. If desired,
absorption enhancing preparations (for example, liposomes), can be
utilized.
[0128] The compositions and formulations can include any other
agents that provide improved transfer, delivery, tolerance, and the
like. These compositions and formulations can include, for example,
powders, pastes, ointments, jellies, waxes, oils, lipids, lipid
(cationic or anionic) containing vesicles (such as Lipofectin.TM.),
DNA conjugates, anhydrous absorption pastes, oil-in-water and
water-in-oil emulsions, emulsions carbowax (polyethylene glycols of
various molecular weights), semi-solid gels, and semi-solid
mixtures containing carbowax. Any of the foregoing mixtures may be
appropriate in treatments and therapies in accordance with the
present invention, provided that the active ingredient in the
formulation is not inactivated by the formulation and the
formulation is physiologically compatible and tolerable with the
route of administration. See also Baldrick P. "Pharmaceutical
excipient development: the need for preclinical guidance." Regul.
Toxicol. Pharmacol. 32(2):210-8 (2000), Charman W N "Lipids,
lipophilic drugs, and oral drug delivery-some emerging concepts." J
Pharm Sci. 89(8):967-78 (2000), Powell et al. "Compendium of
excipients for parenteral formulations" PDA J Pharm Sci Technol.
52:238-311 (1998) and the citations therein for additional
information related to formulations, excipients and carriers well
known to pharmaceutical chemists.
Dosage
[0129] The selected dosage level can depend upon, for example, the
route of administration, the severity of the condition being
treated, and the condition and prior medical history of the patient
being treated. However, it is within the skill of the art to start
doses of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved with an acceptable safety
profile. It will be understood, however, that the specific dose
level for any particular patient can depend upon a variety of
factors including the genetic makeup, body weight, general health,
diet, time and route of administration, combination with other
drugs and the particular condition being treated, and its severity.
For the treatment of insomnia, preferably one dose is administered
prior to bedtime.
[0130] As mentioned above, in some embodiments the dosage of the
doxepin compound can be about 0.001 to about 0.49 milligrams, about
0.05 to about 24 milligrams, preferably about 0.5 to about 20
milligrams, and more preferably about 1 to about 10 milligrams. In
some embodiments the preferable dosage of doxepin can be between
about 1 milligram and 6 milligrams. Preferably, the dosage can be
about 1 milligram, about 2 milligrams, about 3 milligrams, about 4
milligrams, about 5 milligrams, about 6 milligrams, about 7
milligrams, about 8 milligrams or about 9 milligrams.
[0131] Other sleep-promoting drugs in the combination are used in
their art-recognized sleep-promoting dosages, in their approved
dosages, their dosages used in clinical testing, laboratory
testing, or in dosages reported in the scientific literature, or in
higher doses or in smaller dosages than any of the aforementioned.
In some aspects, the combinations can provide at the least
equivalent sleep therapy benefit even when the amount of the
sleep-promoting drug is less than the higher amount of that same
drug that is needed to have the equivalent or lesser therapeutic
benefit. Due to the co-action of the two drugs of the combination,
a synergistic or complimentary activity results, so that the
conventional monotherapy dosages of the drugs can be reduced by
about any where from 5%, 10%, 20%, 30%, 40%, 50%, or more, for
example.
[0132] Many modifications and variations of the embodiments
described herein may be made without departing from the scope, as
is apparent to those skilled in the art. The specific embodiments
described herein are offered by way of example only.
EXAMPLES
Example 1
[0133] Doxepin is prepared by the following method.
[0134] (a) A Grignard compound is prepared in the conventional
manner from 4.8 g (0.2 gram-atom) magnesium in 100 ml ether and 30
g (34 ml) (3-chloropropyl)-tertbutyl-ether and 16.40 grams (0.078
mol) 6,11-dihydrodibenzo-[b,e]-oxepine-11-one dissolved in 100 ml
ether is added in dropwise fashion so that the contents of the
flask boil lightly. The mixture is heated for 1 hour with agitation
in a reflux condenser to complete the reaction and then it is
decomposed with ammonium chloride solution. The product which is
obtained by separating, drying and eliminating the solvent
produced, when the ether residue (24.0 g) is extracted with
ligroin, amounts to 20.3 g (80.0% of theory) of
11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine,
having a melting point of 124-126.degree. C. The
(3-chloropropyl)-tertbutyl ether is thereafter obtained in the
following manner: 19 g (0.2 mol) 1-chloropropanol-(3), 50 ml liquid
isobutylene and 0.5 ml concentrated sulfuric acid are permitted to
stand for 24 hours in an autoclave, then are poured into excess
sodium bicarbonate solution and extracted with ether. The ether
solution is dried with calcium chloride and distilled. 23.6 grams
of (3-chloropropyl)-tertbutylether having a boiling point of
150-156.degree. C. (78% of theory) are recovered.
[0135] (b) 30.8 grams of the 11-(3
-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine
obtained according to (a) above and 150 ml absolute alcoholic
hydrochloric acid are heated for 1 hour at ebullition. After
removing the solvent by evaporation, the residue is crystallized
with ligroin, 21.0 grams (88.5% of theory) of
11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine having
a melting point of 108-111.degree. C. were obtained. After
recrystallization from acetic acid ester, the compound melts at
112-114.degree. C.
[0136] (c) 5.0 ml thionyl chloride dissolved in 5 ml benzene is
added dropwise at room temperature to 12.6 g (0.05 mol) of the
11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine
obtained in part (b) above. After 1 hour of standing, the contents
of the flask are heated at ebullition for 2 hours. The volatile
components are thereafter removed and the remainder distilled using
high vacuum. The yield amounts to 10.6 g (78.5% of theory) of
11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine having a
B.P.0.1 169-172.degree. C., a melting point of 106-111.degree. C.
After recrystallization from 20 ml of acetic acid ester, 9.1 g
(67.5% of theory) of pure product having a melting point of
113-115.degree. C. is obtained. The crude product can however be
used quite easily for further processing.
[0137] (d) 5.4 g (0.02 mol) of the
11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine,
prepared according to (c) above, in 20 ml tetrahydrofuran and 5.5 g
(0.12 mol) dimethylamine in 20 ml ethanol is heated together for 3
hours using a glass autoclave and a temperature of 95-100.degree.
C. (boiling water bath). Water and 6 N hydrochloric acid are added
to the contents of the autoclave and the mixture is extracted with
ether. The separated, aqueous-acid components are then made
alkaline with dilute caustic soda solution, and the oil thereby
separated is taken up in ether. The ether residue, after
distillation in a high vacuum, produces 4.1 g (73.5% of theory) of
11-(3 -dimethyl
amino-propylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, having a
B.P..sub.0.1 147-150.degree. C. The melting point of the
hydrochloride is 182-184.degree. C. (recrystallized from
isopropanol).
Example 2
[0138] The patient suffers from transient or short-term insomnia.
At the time of consultation, he is otherwise healthy with normal
affect with no depression, anxiety or substance overuse. He is
prescribed a doxepin or a pharmaceutically acceptable salt or
prodrug thereof and one or more of a compound that modulates
gamma-aminobutyric acid (GABA) activity (e.g., enhances the
activity), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a
agonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), a
melatonin agonist, an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin
receptor antagonist, an H3 agonist, a noradrenergic antagonist, a
galanin agonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, and the like,
wherein the doxepin or the pharmaceutically acceptable salt or
prodrug thereof is in a daily dosage of 0.0001 milligram, 0.1
milligram, 1 milligram, 3 milligrams, 6 milligrams, 10 milligrams,
20 milligrams or 40 milligrams, taken prior to bedtime. Follow up
reveals that the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the insomnia and has him sleeping well.
Example 3
[0139] The patient suffers from chronic insomnia. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and one or more of a compound that modulates gamma-aminobutyric
acid (GABA) activity (e.g., enhances the activity), a GABA-B
agonist, a 5-HT modulator (e.g., a 5-HT1a agonist, a 5-HT2a
antagonist, a 5-HT2a inverse agonist, etc.), a melatonin agonist,
an ion channel modulator (e.g., blocker) a serotonin-2
antagonist/reuptake inhibitor (SARIs), an orexin receptor
antagonist, an H3 agonist, a noradrenergic antagonist, a galanin
agonist, a CRH antagonist, human growth hormone, a growth hormone
agonist, estrogen, an estrogen agonist, and the like, wherein the
doxepin or the pharmaceutically acceptable salt or prodrug thereof
is in a daily dosage of 0.0001 milligram, 0.1 milligram, 1
milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams
or 40 milligrams, taken prior to bedtime. Follow up reveals that
the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the insomnia and has him sleeping well.
Example 4
[0140] The patient suffers from maintenance (non-chronic) insomnia.
At the time of consultation, he is otherwise healthy with normal
affect with no depression, anxiety or substance overuse. He is
prescribed a doxepin or a pharmaceutically acceptable salt or
prodrug thereof and one or more of a compound that modulates
gamma-aminobutyric acid (GABA) activity (e.g., enhances the
activity), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a
agonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), a
melatonin agonist, an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin
receptor antagonist, an H3 agonist, a noradrenergic antagonist, a
galanin agonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, and the like,
wherein the doxepin or the pharmaceutically acceptable salt or
prodrug thereof is in a daily dosage of 0.0001 milligram, 0.1
milligram, 1 milligram, 3 milligrams, 6 milligrams, 10 milligrams,
20 milligrams or 40 milligrams, taken prior to bedtime. Follow up
reveals that the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the insomnia and has him sleeping well.
Example 5
[0141] The patient suffers from onset (non-chronic) insomnia. At
the time of consultation, he is otherwise healthy with normal
affect with no depression, anxiety or substance overuse. He is
prescribed a doxepin or a pharmaceutically acceptable salt or
prodrug thereof and one or more of a compound that modulates
gamma-aminobutyric acid (GABA) activity (e.g., enhances the
activity), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a
agonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), a
melatonin agonist, an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin
receptor antagonist, an H3 agonist, a noradrenergic antagonist, a
galanin agonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, and the like,
wherein the doxepin or the pharmaceutically acceptable salt or
prodrug thereof is in a daily dosage of 0.0001 milligram, 0.1
milligram, 1 milligram, 3 milligrams, 6 milligrams, 10 milligrams,
20 milligrams or 40 milligrams, taken prior to bedtime. Follow up
reveals that the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the insomnia and has him sleeping well.
Example 6
[0142] The patient suffers from a sleep disorder. At the time of
consultation, he also suffers from depression. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and one or more of a compound that modulates gamma-aminobutyric
acid (GABA) activity (e.g., enhances the activity), a GABA-B
agonist, a 5-HT modulator (e.g., a 5-HT1a agonist, a 5-HT2a
antagonist, a 5-HT2a inverse agonist, etc.), a melatonin agonist,
an ion channel modulator (e.g., blocker) a serotonin-2
antagonist/reuptake inhibitor (SARIs), an orexin receptor
antagonist, an H3 agonist, a noradrenergic antagonist, a galanin
agonist, a CRH antagonist, human growth hormone, a growth hormone
agonist, estrogen, an estrogen agonist, and the like, wherein the
doxepin or the pharmaceutically acceptable salt or prodrug thereof
is in a daily dosage of 0.0001 milligram, 0.1 milligram, 1
milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams
or 40 milligrams, taken prior to bedtime. Follow up reveals that
the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the sleep disorder and has him sleeping well.
Example 7
[0143] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and one or more of a compound that modulates gamma-aminobutyric
acid (GABA) activity or a GABA-B agonist. Follow up reveals that
the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the sleep disorder and has him sleeping well.
Example 8
[0144] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and a 5-HT modulator (e.g., a 5-HT1a agonist, a 5-HT2a antagonist,
a 5-HT2a inverse agonist, etc.). Follow up reveals that the
administration of the combination doxepin or the pharmaceutically
acceptable salt or prodrug thereof and the 5-HT modulator relieves
the sleep disorder and has him sleeping well.
Example 9
[0145] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and a melatonin agonist. Follow up reveals that the administration
of the combination doxepin or the pharmaceutically acceptable salt
or prodrug thereof and the melatonin agonist relieves the sleep
disorder and has him sleeping well.
Example 10
[0146] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and an ion channel modulator. Follow up reveals that the
administration of the combination doxepin or the pharmaceutically
acceptable salt or prodrug thereof and the ion channel modulator
relieves the sleep disorder and has him sleeping well.
Example 11
[0147] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and a serotonin-2 antagonist/reuptake inhibitor (SARIs). Follow up
reveals that the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
serotonin-2 antagonist/reuptake inhibitor (SARIs) relieves the
sleep disorder and has him sleeping well.
Example 12
[0148] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and an orexin receptor antagonist. Follow up reveals that the
administration of the combination doxepin or the pharmaceutically
acceptable salt or prodrug thereof and the orexin receptor
antagonist relieves the sleep disorder and has him sleeping
well.
Example 13
[0149] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and an H3 agonist. Follow up reveals that the administration of the
combination doxepin or the pharmaceutically acceptable salt or
prodrug thereof and the H3 agonist relieves the sleep disorder and
has him sleeping well.
Example 14
[0150] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and a noradrenergic antagonist. Follow up reveals that the
administration of the combination doxepin or the pharmaceutically
acceptable salt or prodrug thereof and the noradrenergic antagonist
relieves the sleep disorder and has him sleeping well.
Example 15
[0151] The patient suffers from a sleep disorder. At the time of
consultation, he is otherwise healthy with normal affect with no
depression, anxiety or substance overuse. He is prescribed a
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and a galanin agonist. Follow up reveals that the administration of
the combination doxepin or the pharmaceutically acceptable salt or
prodrug thereof and the galanin agonist relieves the sleep disorder
and has him sleeping well.
Example 16
[0152] The patient suffers from transient or short-term insomnia.
At the time of consultation, he also suffers from or is at risk of
suffering from substance abuse. He is prescribed doxepin or a
pharmaceutically acceptable salt or prodrug thereof and a melatonin
agonist, wherein the doxepin or the pharmaceutically acceptable
salt or prodrug thereof is in a daily dosage of 0.0001 milligram,
0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10
milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.
Follow up reveals that the administration of the combination
doxepin or the pharmaceutically acceptable salt or prodrug thereof
and the compound relieves the insomnia and has him sleeping
well.
Example 17
[0153] The patient suffers from transient or short-term insomnia.
At the time of consultation, he also suffers from or is at risk of
suffering from alcoholism. He is prescribed doxepin or a
pharmaceutically acceptable salt or prodrug thereof and a melatonin
agonist, wherein the doxepin or the pharmaceutically acceptable
salt or prodrug thereof is in a daily dosage of 0.0001 milligram,
0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10
milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.
Follow up reveals that the administration of the combination
doxepin or the pharmaceutically acceptable salt or prodrug thereof
and the compound relieves the insomnia and has him sleeping
well.
Example 18
[0154] The patient suffers from transient or short-term insomnia.
At the time of consultation, he is also being administered a
narcotic medication. He is prescribed doxepin or a pharmaceutically
acceptable salt or prodrug thereof and a melatonin agonist, wherein
the doxepin or the pharmaceutically acceptable salt or prodrug
thereof is in a daily dosage of 0.0001 milligram, 0.1 milligram, 1
milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams
or 40 milligrams, taken prior to bedtime. Follow up reveals that
the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the
compound relieves the insomnia and has him sleeping well.
Example 19
[0155] The patient suffers from a sleep disorder. At the time of
consultation, the patient experiences or has experienced
undesirable side effects associated with administration of one or
more of a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a agonist,
a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), an ion
channel modulator (e.g., blocker) a serotonin-2 antagonist/reuptake
inhibitor (SARIs), a noradrenergic antagonist, a CRH antagonist,
human growth hormone, a growth hormone agonist, estrogen, an
estrogen agonist, a neurokinin-1 drug, and the like in a first
dosage effective at treating the sleep disorder. He is prescribed
doxepin or a pharmaceutically acceptable salt or prodrug thereof
and one or more drugs selected from a GABA-B agonist, a 5-HT
modulator (e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a 5-HT2a
inverse agonist, etc.), an ion channel modulator (e.g., blocker) a
serotonin-2 antagonist/reuptake inhibitor (SARIs), a noradrenergic
antagonist, a CRH antagonist, human growth hormone, a growth
hormone agonist, estrogen, an estrogen agonist, a neurokinin-1
drug, and the like, wherein the one or more of a GABA-B agonist, a
5-HT modulator (e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a
5-HT2a inverse agonist, etc.), an ion channel modulator (e.g.,
blocker) a serotonin-2 antagonist/reuptake inhibitor (SARIs), a
noradrenergic antagonist, a CRH antagonist, human growth hormone, a
growth hormone agonist, estrogen, an estrogen agonist, a
neurokinin-1 drug, and the like, wherein the one or more drugs are
present in a dosage less than the first dosage. Follow up reveals
that the administration of the combination doxepin or the
pharmaceutically acceptable salt or prodrug thereof and the drug is
effective in treating the sleep disorder and reduces the experience
of the undesirable side effect.
Example 20
[0156] The patient suffers from onset and maintenance insomnia.
Doxepin is effective at treating the maintenance insomnia but is
not effective or only partially effective at treating the onset
insomnia. The patient is prescribed doxepin or a pharmaceutically
acceptable salt or prodrug thereof and one or more drugs selected
from a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a agonist, a
5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), an ion channel
modulator (e.g., blocker) a serotonin-2 antagonist/reuptake
inhibitor (SARIs), a noradrenergic antagonist, a CRH antagonist,
human growth hormone, a growth hormone agonist, estrogen, an
estrogen agonist, a neurokinin-1 drug, and the like, wherein the
one or more of a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a
agonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), an
ion channel modulator (e.g., blocker) a serotonin-2
antagonist/reuptake inhibitor (SARIs), a noradrenergic antagonist,
a CRH antagonist, human growth hormone, a growth hormone agonist,
estrogen, an estrogen agonist, a neurokinin-1 drug, and the like,
wherein the one or more drugs are present in a dosage less than the
first dosage. Follow up reveals that the administration of the
combination doxepin or the pharmaceutically acceptable salt or
prodrug thereof and the drug is effective in treating both the
onset insomnia and the maintenance insomnia.
* * * * *