U.S. patent application number 13/972851 was filed with the patent office on 2014-02-27 for methods of treating epilepsy or status epilepticus.
This patent application is currently assigned to SAGE THERAPEUTICS, INC.. The applicant listed for this patent is Stephen Jay Kanes, Kiran Reddy. Invention is credited to Stephen Jay Kanes, Kiran Reddy.
Application Number | 20140057885 13/972851 |
Document ID | / |
Family ID | 50148516 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140057885 |
Kind Code |
A1 |
Reddy; Kiran ; et
al. |
February 27, 2014 |
METHODS OF TREATING EPILEPSY OR STATUS EPILEPTICUS
Abstract
Described herein are methods of treating epilepsy or status
epilepticus, e.g., convulsive status epilepticus, e.g., early
status epilepticus, established status epilepticus, refractory
status epilepticus, super-refractory status epilepticus, e.g.,
super-refractory generalized status epilepticus; non-convulsive
status epilepticus, e.g., generalized status epilepticus, complex
partial status epilepticus; generalized periodic epileptiform
discharges; periodic lateralized epileptiform discharges; a
seizure, e.g., acute repetitive seizures, cluster seizures, the
method comprising administering to the subject a neuroactive
steroid.
Inventors: |
Reddy; Kiran; (Boston,
MA) ; Kanes; Stephen Jay; (Swarthmore, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Reddy; Kiran
Kanes; Stephen Jay |
Boston
Swarthmore |
MA
PA |
US
US |
|
|
Assignee: |
SAGE THERAPEUTICS, INC.
Cambridge
MA
|
Family ID: |
50148516 |
Appl. No.: |
13/972851 |
Filed: |
August 21, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61691545 |
Aug 21, 2012 |
|
|
|
61789491 |
Mar 15, 2013 |
|
|
|
Current U.S.
Class: |
514/182 |
Current CPC
Class: |
A61P 25/08 20180101;
A61K 45/06 20130101; A61P 25/12 20180101; A61P 43/00 20180101; A61K
31/57 20130101; A61P 23/00 20180101; A61P 25/10 20180101; A61K
31/573 20130101 |
Class at
Publication: |
514/182 |
International
Class: |
A61K 31/573 20060101
A61K031/573 |
Claims
1. A method of treating a subject having a seizure-related
disorder, the method comprising: administering to said subject, an
effective amount of allopregnanolone, wherein, concurrent with said
administering, said subject is under general anesthesia, thereby
treating said subject.
2. A method of treating a subject having a seizure-related
disorder, the method comprising: administering a first load dose of
allopregnanolone; administering a second dose of allopregnanolone,
which is lower than said first dose; and administering a third
downward taper dose of allopregnanolone, said allopregnanolone
doses being sufficient to treat said subject.
3. The method of claim 2, wherein said subject is not under general
anesthesia for one or both of: at least a portion of the second
dose and at least a portion of the third dose.
4. The method of claim 2, wherein said subject is under general
anesthesia during the administration of the first dose and during
administration of a portion of the second dose.
5. The method of claim 2, wherein the second dose is administered
over a period of time that is at least 60, 65, 70, 80, 90, 100,
110, or 120 times longer in duration than that of said first
dose.
6. The method of claim 2, wherein the second dose is administered
over a period of time that not more than 80, 90, 100, 110, 120,
130, or 140 times longer in duration than that of said first
dose.
7. The method of claim 2, wherein the second dose is administered
over a period of time that is at least 2, 3, 4, 5, 6 times longer
in duration than that of said third dose.
8. The method of claim 2, wherein the second dose is administered
over a period of time that is not more than 5, 6, 7, 8, 9, or 10
times longer in duration than that of said third dose.
9. The method of claim 2, wherein the amount of allopregnanolone
delivered/unit time in the second dose, as measured in
.mu.g/kg/hour, is at least 2, 3, 4, 5, or 6 times lower than that
of the first dose.
10. The method of claim 2, wherein one, two or all of said doses
are injected administrations.
11-14. (canceled)
15. The method of claim 2, further comprising a weaning period in
which said subject is weaned from said general anesthesia.
16. The method of claim 15, wherein said weaning period is
initiated during the administration of said second dose.
17. The method of claim 15, wherein said weaning period is
completed during the administration of said second dose.
18-52. (canceled)
53. The method of claim 2, said first dose is administered over a
period of time that is not longer than 6, 5, 4, 3, 2, or 1
hour.
54. (canceled)
55. The method of claim 2, said first dose is administered over a
period of time that is 30 to 120 minutes, 45 to 100 minutes, or 50
to 70 minutes, in duration.
56-59. (canceled)
60. The method of claim 2, wherein the administration said second
dose is initiated within a preselected time period, wherein said
time period begins with: the administration of said anesthetic; the
induction of general anesthesia; the beginning of the first dose;
the end of the first dose; or the achievement of a predetermined
level of allopregnanolone in the plasma.
61. The method of claim 60, wherein said time period begins with
the end of the first dose.
62-64. (canceled)
65. The method of claim 2, wherein the second dose begins 50 to 70,
55 to 65, or 60 minutes after the beginning or end of the
administration of the first dose.
66-67. (canceled)
68. The method of claim 2, wherein the first dose and the
initiation of the second dose are performed with the same delivery
device.
69. The method of claim 2, wherein said second dose is administered
for a period of time that is between 48 and 192 hours, 60 and 144
hours, 60 and 120 hours, 80 and 110 hours, or 90 and 100 hours.
70. The method of claim 2, wherein said second dose is administered
for 95+/-5 hours.
71-87. (canceled)
88. The method of claim 2, wherein said second dose is administered
at the same amount of allopregnanolone/unit time over the entire
second dose.
89-91. (canceled)
92. The method of claim 2, wherein said downward taper dose
comprises administering a continuously decreasing amount of
allopregnanolone.
93. (canceled)
94. The method of claim 2, wherein said downward taper dose
comprises administering a plurality of step doses, wherein each
subsequent step dose is lower than the step dose that precedes
it.
95. (canceled)
96. The method of claim 94, comprising administering a first,
second, and third step dose.
97. (canceled)
98. The method of claim 96, wherein: the amount of allopregnanolone
delivered/unit time in said first step dose is 60 to 90% of the
amount of allopregnanolone delivered/unit time in said
second/maintenance dose; the amount of allopregnanolone
delivered/unit time in said second step dose is 40 to 70% of the
amount of allopregnanolone delivered/unit time in said
second/maintenance dose; and the amount of allopregnanolone
delivered/unit time in said third step dose is 10 to 40% of the
amount of allopregnanolone delivered/unit time in said
second/maintenance dose.
99-102. (canceled)
103. The method of claim 96, wherein, after the completion of said
third step dose, no allopregnanolone is administered to the subject
for at least 10, 20, 30, 40, 50, or 60 days, or until the patient
has a subsequent episode of SRSE.
104-109. (canceled)
110. The method of claim 96, wherein the administration of the
third/taper dose begins no longer than 90, 80, 70, 60, or 30
minutes after the administration or end of the second dose.
111. (canceled)
112. The method of claim 96, wherein the administration of the
second dose and the initiation of third/taper dose are performed
with the same delivery device.
113-116. (canceled)
117. The method of claim 2, wherein the allopregnanolone is
provided in a composition comprising a cyclodextrin.
118. The method of claim 2, wherein the allopregnanolone is
provided at a concentration of 0.1 to 10 mg/mL
allopregnanolone.
119-123. (canceled)
124. The method of claim 117, wherein the cyclodextrin is present
in the composition at 1-30% by weight of cyclodextrin per volume of
composition.
125-133. (canceled)
134. The method of claim 1, further comprising evaluating the
subject, wherein the evaluating comprises performing EEG.
135-139. (canceled)
140. A method of treating a subject having, status epilepticus
(SE), refractory status epilepticus (RSE) or super-refractory
status epilepticus (SRSE), comprising: administering a first bolus,
dose concurrent with general anesthesia, wherein administration of
said first dose: begins 2-120 hours after induction of general
anesthesia and lasts for 30-90 minutes; administering a
second/maintenance dose, wherein, the administration of said second
dose begins not longer than 1-60 minutes after the end of the
second dose and lasts for 1-6 days; and administering a third
downward taper dose, wherein, the administration of said third
downward taper dose begins not longer than 1-60 minutes after the
end of the third dose and lasts for 10-100 hours; wherein,
collectively, the administrations are provided in sufficient amount
to treat said subject.
141-143. (canceled)
144. The method of claim 143, comprising: administering a
first/load dose concurrent with general anesthesia, wherein
administration of said first dose lasts for 60+/-5 minutes;
administering a second/maintenance dose, wherein, the
administration of said second dose begins not longer than 30
minutes after the end of the second dose and lasts for 96+/-4
hours; administering a third downward taper dose, wherein, the
administration of said third downward taper dose begins not longer
than 1-60 minutes after the end of the third dose and lasts for
24+/-2 hours and: the amount of allopregnanolone delivered/unit
time in said first step dose is 75% of the amount of
allopregnanolone delivered/unit time in said second/maintenance
dose; the amount of allopregnanolone delivered/unit time in said
second step dose is 50% of the amount of allopregnanolone
delivered/unit time in said second/maintenance dose; and the amount
of allopregnanolone delivered/unit time in said third step dose is
25% of the amount of allopregnanolone delivered/unit time in said
second/maintenance dose.
145. The method of claim 140, further comprising, administering an
amount of a composition selected from benzodiazepines, propofol,
and barbiturates, sufficient to place said subject under general
anesthesia;
146. A kit comprising one or more of: a preparation of
allopregnanolone at concentrations suitable for use at the first,
second, and third doses.
147-154. (canceled)
155. A method of making a series of dosages, the method comprising
combining a diluent and allopregnanolone in proportions to from
dosage forms suitable for use as the first, second and one or more
step doses for said third dose.
156. A method of adjusting the amount of diluents and or
allopregnanolone flowing into or out of a delivery device, the
method comprising altering, the flow rate of allopregnanolone
flowing into the delivery device, so as to release in succession,
two or more of a first dose, a second dose and one or more step
doses of the third dose.
157. The method of claim 2, wherein the administration of said
first dose is initiated while said subject is under general
anesthesia.
158. The method of claim 2, wherein the administration of said
first dose is initiated prior to said subject undergoing general
anesthesia.
159. The method of claim 2, wherein the administration of the first
dose is initiated prior to the initiation of the administration of
an anesthetic.
160. The method of claim 2, wherein the administration of the first
dose is initiated after the initiation of the administration of an
anesthetic.
161. The method of claim 2, wherein the administration of the first
dose, and the administration of an anesthetic, are initiated at the
same time.
162. The method of claim 2, wherein the administration of the first
dose, and the administration of an anesthetic, are initiated
within, 5, 10, 60, 120, 180, 240, or 300 minutes of one
another.
163. The method of claim 162, wherein the administration of the
first dose is initiated prior to the initiation of administration
of an anesthetic.
164. The method of claim 162, wherein the administration of the
first dose is initiated after the initiation of administration of
an anesthetic.
165. The method of claim 1, wherein said disorder is status
epilepticus (SE), refractory status epilepticus (RSE) or
super-refractory status epilepticus (SRSE).
166. The method of claim 2, wherein said disorder is status
epilepticus (SE), refractory status epilepticus (RSE) or
super-refractory status epilepticus (SRSE).
167. The method of claim 117, wherein said cyclodextrin is a
.beta.-cyclodextrin.
168. The method of claim 117, wherein said cyclodextrin is a sulfo
butyl ether .beta.-cyclodextrin.
169. The method of claim 117, wherein said cyclodextrin is
CAPTISOL.
Description
CLAIMS OF PRIORITY
[0001] This application claims priority to U.S. Ser. No.
61/691,545, filed Aug. 21, 2012 and U.S. Ser. No. 61/789,491, filed
Mar. 15, 2013, the entire contents of which are incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The present invention generally relates to methods of
treating epilepsy or status epilepticus by administering a
neuroactive steroid.
SUMMARY OF THE INVENTION
[0003] Described herein are methods of treating epilepsy or status
epilepticus. e.g., convulsive status epilepticus, e.g., early
status epilepticus, established status epilepticus, refractory
status epilepticus, super-refractory status epilepticus;
non-convulsive status epilepticus, e.g., generalized status
epilepticus, complex partial status epilepticus; generalized
periodic epileptiform discharges; periodic lateralized epileptiform
discharges; a seizure, e.g., acute repetitive seizures, cluster
seizures, the method comprising administering to the subject a
neuroactive steroid. In one aspect, the invention features a method
of treating a subject having epilepsy or status epilepticus by
administering in combination to the subject a neuroative steroid
and a benzodiazepine. In some embodiments, the method further
comprises administering at least one of the neuroative steroid or
benzodiazepine parenterally (e.g., intranasally, buccally,
intravenously or intramuscularly, for example, intravenously or
intramuscularly). In some embodiments, both the neuroative steroid
and benzodiazepine are administered parenterally.
[0004] In some embodiments, the neuroative steroid and
benzodiazepine are co-administered (e.g., administered
simultaneously). In some embodiments, the neuroative steroid and
benzodiazepine are administered sequentially. In some embodiments,
neuroative steroid and benzodiazepine are administered in a single
dosage form.
[0005] When the agents described herein (e.g., the neuroactive
steroid and a benzodiazepine) are administered in combination, both
of the agents should be present at dosage levels of between about 1
to 100%, and more preferably between about 5 to 95% of the dosage
normally administered in a in the absence of the combination
regimen. The agents may be administered separately, as part of a
multiple dose regimen. Alternatively, the agents may be part of a
single dosage form, mixed together with the compounds of this
invention in a single composition.
[0006] In some embodiments, the neuroactive steroid is a progestin
derivative, e.g., allopregnanolone. In an embodiment, the
neuroactive steroid is allopregnanolone.
[0007] In some embodiments, the neruroactive steroid, e.g.,
alloprenanolone, is formulated for parenteral administration (e.g.,
intranasally, buccally, intravenously or intramuscularly, for
example, intravenously or intramuscularly).
[0008] In some embodiments, the neneuroactive steroid, e.g.,
allopregnanolone, is administered in a composition comprising a
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a
sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex. a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo
butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM..
[0009] In some embodiments, the cyclodextrin is a
.beta.-cyclodextrin. In an embodiment, the cyclodextrin is a sulfo
butyl ether .beta.-cyclodextrin. In an embodiment, the cyclodextrin
is CAPTISOL.RTM.. In some embodiments, the cyclodextrin is a
.beta.-cyclodextrin disclosed in U.S. Pat. Nos. 5,874,418;
6,046,177; or 7,635,733, which are herein incorporated by
reference.
[0010] In some embodiments, the neuroactive steroid is a progestin
derivative, e.g., allopregnanolone, and the cyclodextrin is a
.beta.-cyclodextrin. In an embodiment, the neuroactive steroid is
allopregnanolone and the cyclodextrin is CAPTISOL.RTM..
[0011] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated for parenteral administration. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition. In some embodiments, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration between 0.25-30 mg/mL, 0.5-30 mg/mL; 1-30 mg/mL; 5-30
mg/mL, 10-30 mg/mL; 15-30 mg/mL, 0.25-20 mg/mL; 0.5-20 mg/mL; 1-20
mg/mL, 0.5-20 mg/mL; 1-20 mg/mL, 5-20 mg/mL, 10-20 mg/mL, 0.25-15
mg/mL, 0.5-15 mg/mL; 0.5-10 mg/mL; 1-15 mg/mL, 1-10 mg/mL; 1-5
mg/mL; 5-15 mg/mL; 5-10 mg/mL; 10-15 mg/mL; 1-10 mg/mL; 2-8 mg/mL;
2-7 mg/mL; 3-5 mg/mL; 5-15 mg/mL; 7-12 mg/mL; 7-10 mg/mL; 8-9
mg/mL; 3-5 mg/mL; or 3-4 mg/mL.
[0012] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid at a concentration of 0.25 mg/mL, 0.5 mg/mL;
1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL;
4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL, 5.5 mg/mL, 6.0 mg/mL, 6.5 mg/mL,
7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL, 9.0 mg/mL, 9.5 mg/mL,
10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mgmL, or 30 mg/mL. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising the neuroactive
steroid at a concentration of 1.5 mg/mL. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration of 5 mg/mL. In an embodiment, the neuroactive
steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid at a concentration
of 15 mg/mL.
[0013] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
between 25-400 mg/mL; 25-300 mg/mL; 25-200 mg/mL; 25-100 mg/mL;
25-50 mg/mL; 50-400 mg/mL; 50-300 mg/mL; 60-400 mg/mL; 60-300
mg/mL; 150-400 mg/mL; 150-300 mg/mL; 200-300 mg/mL; 200-400 mg/mL;
30-100 mg/mL; 300-400 mg/mL; 30-100 mg/mL; 45-75 mg/mL; 50-70
mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., at a concentration of 25 mg/mL; 30 mg/mL; 35
mg/mL; 40 mg/mL; 45 mg/mL; 50 mg/mL; 55 mg/mL; 60 mg/mL; 65 mg/mL;
70 mg/mL; 75 mg/mL; 80 mg/mL; 85 mg/mL; 90 mg/mL, 95 mg/mL; 100
mg/mL; 150 mg/mL; 200 mg/mL; 250 mg/mL; 300 mg/mL; 350 mg/mL; or
400 mg/mL. In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 60 mg/ml. In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising between
2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%,
6-40%, 6-30%, 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%,
25-40%, 25-30%, 3-10%, 4.5-7.5%, 5-7%, 5.5-6.5% of the
cyclodextrin, e.g., CAPTISOL.RTM.. In some embodiments, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%,
6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20%, 25%, 30%, 35% or
40% of the cyclodextrin, e.g., CAPTISOL.RTM.. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising 6% of the cyclodextrin. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising 15% of the
cyclodextrin. In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising 30% of
the cyclodextrin.
[0014] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition with a pH between
3-10, 4-9,4-8, 4-7,4-6, 4-5,5-9, 5-8,5-7, 5-6, 4.5-7.5, or 5.5-7.5.
In some embodiments, the allopregnanolone and CAPTISOL.RTM. complex
is formulated as an aqueous composition with a pH about 3, 3.5, 4,
4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In an embodiment, the
allopregnanolone and CAPTISOL.RTM. complex is formulated as an
aqueous composition with a pH about 6.
[0015] In an embodiment, a composition comprising a neuroactive
steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex, comprises less
than 100 ppm of a phosphate, and the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., has an absorption of less
than 0.2 A.U. due to a drug-degrading agent, as determined by
UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an
aqueous solution comprising 300 mg of the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL of solution in a
cell having a 1 cm path length.
[0016] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., has an absorption of less
than 0.2 A.U. due to a color forming agent, as determined by UV/vis
spectrophotometry at a wavelength of 320 nm to 350 nm for an
aqueous solution comprising 500 mg of the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL of solution in a
cell having a 1 cm path length.
[0017] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., further comprises: less
than 20 ppm of a sulfoalkylating agent; less than 0.5% wt. of an
underivatized cyclodextrin; less than 1% wt. of an alkali metal
halide salt; and less than 0.25% wt. of a hydrolyzed
sulfoalkylating agent.
[0018] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., has an absorption of less
than 0.2 A.U. due to a drug-degrading agent, as determined by
UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an
aqueous solution comprising 500 mg of the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL of solution in a
cell having a 1 cm path length.
[0019] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., further comprises: less
than 50 ppm of a phosphate; less than 10 ppm of a sulfoalkylating
agent; less than 0.2% wt. of an underivatized cyclodextrin; less
than 0.5% wt. of an alkali metal halide salt; and less than 0.1%
wt. of a hydrolyzed sulfoalkylating agent; and wherein the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a
sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., has an
absorption of less than 0.2 A.U. due to the color-forming agent, as
determined by U/vis spectrophotometry at a wavelength of 320 nm to
350 nm for an aqueous solution comprising 500 mg of the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a
sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL
of solution in a cell having a 1 cm path length.
[0020] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., further comprises: less
than 10 ppm of a phosphate; less than 2 ppm of a sulfoalkylating
agent; less than 0.1% wt. of an underivatized cyclodextrin; less
than 0.2% wt. of an alkali metal halide salt; and less than 0.08%
wt. of a hydrolyzed sulfoalkylating agent; and wherein the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a
sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., has an
absorption of less than 0.1 A.U. due to the color-forming agent, as
determined by UV/vis spectrophotometry at a wavelength of 320 nm to
350 nm for an aqueous solution comprising 500 mg of the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a
sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL
of solution in a cell having a 1 cm path length.
[0021] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., further comprises: less
than 5 ppm of a phosphate; less than 0.1% wt. of an alkali metal
halide salt; and less than 0.05% wt. of a hydrolyzed
sulfoalkylating agent.
[0022] In some embodiments, the neuroactive steroid (e.g.,
allopregnanolone) and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered within 10 hours, 8 hours, 5
hours, 3 hours, 1 hour, or 0.5 hour after a seizure, e.g., a status
epileptic seizure, e.g., a refractory status epileptic seizure has
started. In some embodiments, the allopregnanolone and
CAPTISOL.RTM. complex is formulated as an aqueous composition and
is administered within 60 minutes, 45 minutes, 30 minutes, 15
minutes, 10 minutes, or 5 minutes after a seizure, e.g., a status
epileptic seizure, e.g., a refractory status epileptic seizure has
started. In some embodiments, the neuroactive steroid (e.g.,
allopregnanolone) and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered after a seizure, e.g., a
status epileptic seizure, e.g., a refractory status epileptic
seizure has lasted 5 minutes, 10 minutes, 15 minutes, 20 minutes,
30 minutes or 60 minutes.
[0023] In some embodiments, the neuroactive steroid (e.g.,
allopregnanolone) and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered prior to the onset of a
seizure, e.g., a status epileptic seizure, e.g., a refractory
status epileptic seizure.
[0024] In some embodiments, the benzodiazepine is clonazepam,
lorazepam, midazolam, or diazepam.
[0025] In some embodiments, the benzodiazepine is formulated for
oral delivery. In some embodiments, the benzodiazepine is
formulated for parenteral delivery (e.g., intranasally, buccally,
intravenously or intramuscularly, for example, intravenously or
intramuscularly).
[0026] In some embodiments, both the neuroactive steroid and the
benzodiazepine are formulated for parenteral delivery (e.g.,
intranasally, buccally, intravenously or intramuscularly, for
example, intravenously or intramuscularly).
[0027] In some embodiments, the neuroactive steroid such as
allopregnanolone and benzodiazepine, when administered in
combination, are administered in an amount sufficient to achieve
burst suppression (e.g., a predetermined burst suppression pattern,
e.g., inter-burst intervals of between 2-30 seconds; as measured by
a method of neurophysiological monitoring, e.g., EEG, CFM). In some
embodiments, the neuroactive steroid such as allopregnanolone and
benzodiazepine, when administered in combination is administered at
a dose sufficient to achieve a predetermined burst suppression
pattern, e.g., inter-burst intervals of between 2-30 seconds, 5-30
seconds, 10-30 seconds, 15-30 seconds, 1-30 seconds, 0-30 seconds,
2-20 seconds, 2-10 seconds, 5-20 seconds, 10-20 seconds, 15-25
seconds, 5-15 seconds or 5-10 seconds; as measured by a method of
neurophysiological monitoring, e.g., EEG, CFM.
[0028] In one aspect, the invention features a method of treating a
subject (e.g., human subject) having a seizure-related disorder,
e.g., status epilepticus (SE), e.g., refractory status epilepticus
(RSE) or super-refractory status epilepticus (SRSE), comprising:
administering to said subject (e.g., human subject), an effective
amount of allopregnanolone, wherein, concurrent with said
administering, said subject (e.g., human subject) is under general
anesthesia, thereby treating said subject (e.g., human
subject).
[0029] In one aspect, the invention features a method of treating a
subject (e.g., human subject) having a seizure-related disorder,
e.g., status epilepticus (SE), e.g., refractory status epilepticus
(RSE) or super-refractory status epilepticus (SRSE), comprising
administering a first dose, e.g., a load dose, of allopregnanolone,
e.g., to a patient under general anesthesia; administering a second
dose, e.g., maintenance dose, of allopregnanolone, which is lower
than said first dose; and administering a third dose, e.g., a
downward taper dose, of allopregnanolone, said allopregnanolone
doses being sufficient to treat said subject (e.g., human
subject).
[0030] In some embodiments, said subject (e.g., human subject) is
not under general anesthesia for at least a portion of the second
dose. In some embodiments, said subject (e.g., human subject) is
not under general anesthesia for at least a portion of the third
dose. In some embodiments, said subject (e.g., human subject) is
under general anesthesia during the administration of the first
dose and during administration of a portion of the second dose,
e.g., for at least, or up to, 6, 12, 24, or 47 hours of the second
dose.
[0031] In some embodiments, the second dose is administered over a
period of time that is at least 60, 65, 70, 80, 90, 100, 110, 120
times longer in duration than that of said first dose. In some
embodiments, the second dose is administered over a period of time
that not more than 80, 90, 100, 110, 120, 130, or 140 times longer
in duration than that of said first dose.
[0032] In some embodiments, the second dose is administered over a
period of time that at least 2, 3, 4, 5, 6 times longer in duration
than that of said third dose. In some embodiments, the second dose
is administered over a period of time that not more than 5, 6, 7,
8, 9, or 10 times longer in duration than that of said third
dose.
[0033] In some embodiments, the infusion rate, e.g., amount of
allopregnanolone delivered/unit time in the second dose, e.g., as
measured in .mu.g/kg/hour, is at least 2, 3, 4, 5, or 6 times lower
than that of the first dose.
[0034] In some embodiments, one, two or all of said doses are
injected, e.g., IV administrations.
[0035] In some embodiments, said subject (e.g., human subject) has
failed to respond to a first line treatment, e.g., a benzodiazepine
(e.g. midazolam), e.g., as evidenced by a failure to induce an EEG
pattern of burst suppression, failure to control seizure, continued
seizure activity on EEG recording after 24 hours or more on the
first line treatment, or failure to wean from the first line
treatment without resuming seizure activity as evidenced by EEG
recording.
[0036] In some embodiments, said subject (e.g., human subject) has
failed to respond to a second line treatment, e.g., phenyloin,
fos-phenyloin, valproate, phenobarbitol, or levetiracetam, e.g., as
evidenced by a failure to induce an EEG pattern of burst
suppression, failure to control seizure, continued seizure activity
on EEG recording after 24 hours or more on the first line
treatment, or failure to wean from the first line treatment without
resuming seizure activity as evidenced by EEG recording.
[0037] In some embodiments, the method further comprises
administering an amount of an aesthetic effective to place said
subject (e.g., human subject) under general anesthesia. In some
embodiments, said anesthetic is selected from a benzodiazepine
(e.g. midazolam), propofol, and pentobarbital.
[0038] In some embodiments, the method further comprises a weaning
period in which said subject (e.g., human subject) is weaned from
said general anesthesia. In some embodiments, said weaning period
is initiated during the administration of said second dose. In some
embodiments, said weaning period is completed during the
administration of said second dose. In some embodiments, said
weaning period is initiated within 12, 24, 36, 48, 60 or 72 hours
after initiation or completion of the first dose of
allopregnanolone. In some embodiments, said weaning period is
initiated at 48 hours after initiation or completion of the first
dose of allopregnanolone. In some embodiments, said weaning period
is 18 to 30 hours, 20 to 28 hours, or 22 to 26 hours in duration.
In some embodiments, said weaning period is 24 hours in
duration.
[0039] In some embodiments, the administration of allopregnanolone,
e.g., the first or load dose, is initiated within a preselected
period of time, wherein said period begins with: the administration
of said anesthetic; or the induction of general anesthesia. In some
embodiments, said preselected period is not longer than 48, 24, 12,
6, 5, 4, 3, 2, or 1 hour. In some embodiments, said preselected
period is not longer than 120, 60, 30, 15, or 5 minutes.
[0040] In some embodiments, said second dose is initiated while the
subject (e.g., human subject) is under general anesthesia. In some
embodiments, the amount of allopregnanolone delivered per hour in
said second dose is the same or lower than the amount delivered per
hour in said first dose.
[0041] In some embodiments, the administration of the first dose of
allopregnanolone is initiated within a preselected period of time,
wherein said period begins with: the administration of said
anesthetic or the induction of general anesthesia. In some
embodiments, said preselected period is at least 6, 12, 24, 48 or
60 hours. In some embodiments, said preselected period is not
longer than 24, 48, or 60 hours. In some embodiments, said
preselected period is between 2 to 120, 2 to 60, 4 to 120, 4 to 60,
4 to 48, 4 to 36, or 4 to 24 hours. In some embodiments, said
preselected period is not longer than 48, 24, 12, 6, 5, 4, 3, 2, or
1 hour. In some embodiments, said preselected period is not longer
than 120, 60, 30, 15, or 5 minutes.
[0042] In some embodiments, said first dose is begun after failure
of the subject (e.g., human subject) to respond to prior treatment.
In some embodiments, the failure to respond is evidenced by one or
more of, a failure to induce an EEG pattern of burst suppression,
failure to control seizure, continued seizure activity on EEG
recording after 24 hours or more on the first line treatment, or
failure to wean from the first line treatment without resuming
seizure activity as evidenced by EEG recording. In some
embodiments, said prior treatment comprises administration of a
first line treatment, e.g., a benzodiazepine (e.g. midazolam). In
some embodiments, said prior treatment comprises administration of
a second line treatment, e.g., phenyloin, fos-phenyloin, valproate,
phenobarbitol, or levetiracetam.
[0043] In some embodiments, said first dose is a load, e.g., bolus,
dose. In some embodiments, said first dose results in a plasma
concentration of 50 to 500 nM, 100 to 400 nM, or 200 to 300 nM. In
some embodiments, said first dose results in a plasma concentration
of 500 to 1000 nM, 600 to 900 nM, or 700 to 800 nM. In some
embodiments, said first dose results in a plasma concentration of
1000 to 1500 nM, 1100 to 1400 nM, or 1200 to 1300 nM. In some
embodiments, said first dose results in a plasma concentration of
1500 to 2000 nM, 1600 to 1900 nM, or 1700 to 1800 nM. In some
embodiments, said first dose results in a plasma concentration of
2000 to 2500 nM, 2100 to 2400 nM, or 2200 to 2300 nM. In some
embodiments, said first dose results in a plasma concentration of
300 to 800 nM, 400 to 700 nM, or 500 to 600 nM. In some
embodiments, said first dose results in a plasma concentration of
800 to 1300 nM, 900 to 1200 nM, or 1000 to 1100 nM. In some
embodiments, said first dose results in a plasma concentration of
1300 to 1800 nM, 1400 to 1700 nM, or 1500 to 1600 nM. In some
embodiments, said first dose results in a plasma concentration of
1800 to 2300 nM, 1900 to 2200 nM, or 2000 to 2100 nM. In some
embodiments, said first dose results in a plasma concentration of
2300 to 2600 nM, 2400 to 2500 nM. In some embodiments, said first
dose results in a plasma concentration of 300 to 400 nM, 400 to 500
nM, 600 to 700 nM, 800 to 900 nM, 1100 to 1200 nM, 1300 to 1400 nM,
1400 to 1500 nM, 1600 to 1700 nM, 1800 to 1900 nM, 1900 to 2000 nM,
2100 to 2200 nM, 2300 to 2400 nM. In some embodiments, said first
dose results in a plasma concentration of 500 to 2500 nM, 500 to
1500 nM, 500 to 1000 nM, 500 to 800, or 500 to 600, nM. In some
embodiments, said first dose results in a plasma concentration of
50 to 250 nM, 100 to 200 nM, or 140 to 160 nM. In some embodiments,
said first dose results in a plasma concentration of 150+/-30 nM,
150+/-20 nM, 150+/-10 nM, or 150 nM.
[0044] In some embodiments, the plasma concentration of said first
dose is measured at a preselected time, e.g., at 10, 15, 20, 30,
45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days
after the initiation of said first dose.
[0045] In some embodiments, said first dose is administered over a
period of time that is not longer than 6, 5, 4, 3, 2, or 1 hour. In
some embodiments, said first dose is administered over a period of
time that is at least 10, 20, 30, 40, 50, 60, 70, 80, or 90 minutes
in duration. In some embodiments, said first dose is administered
over a period of time that is 30 to 120 minutes, 45 to 100 minutes,
or 50 to 70 minutes, in duration. In some embodiments, said first
dose is administered over a period of time that is 60+/-15 minutes,
60+/-10 minutes, 60+/-5 minutes, or 60 minutes, in duration.
[0046] In some embodiments, said first dose is administered at a
dosage rate of 200-3500 .mu.g/kg/hour. In some embodiments, said
first dose is administered at a dosage rate of 200-350
.mu.g/kg/hour, 250-300 .mu.g/kg/hour, 280-290 .mu.g/kg/hour, 286
.mu.g/kg/hour, 287 .mu.g/kg/hour, or 288 .mu.g/kg/hour, e.g., for
one hour.
[0047] In some embodiments, said second dose is a maintenance dose.
In some embodiments, the administration said second dose is
initiated within a preselected time period, wherein said time
period begins with the administration of said anesthetic. In some
embodiments, the administration said second dose is initiated
within a preselected time period, wherein said time period begins
with the induction of general anesthesia. In some embodiments, the
administration said second dose is initiated within a preselected
time period, wherein said time period begins with the beginning of
the first dose. In some embodiments, the administration said second
dose is initiated within a preselected time period, wherein said
time period begins with the end of the first dose. In some
embodiments, the administration said second dose is initiated
within a preselected time period, wherein said time period begins
with the achievement of a predetermined level of allopregnanolone,
e.g., in the plasma. In some embodiments, said time period begins
with the end of the first dose. In some embodiments, said
preselected time period begins with beginning or ending of the
administration of the first dose and is not longer than 240, 180,
120, 60, 30, 15, or 5 minutes. In some embodiments, said
preselected time period begins with beginning or ending of the
administration of the first dose and is not longer than 90, 80, 70,
or 60 minutes. In some embodiments, the administration of the
second dose begins no longer than 90, 80, 70, 60, or 30 minutes
after the beginning or end of the administration of the first dose.
In some embodiments, the administration of the second dose begins
50 to 70, 55 to 65, or 60 minutes after the beginning or end of the
administration of the first dose. In some embodiments, the
administration of the second dose begins no more than 60, 50, 40,
30, 20, 10, 5, 4, 3, 2, 1 minute after the end of administration of
the first dose. In some embodiments, the administration of the
second dose begins at the end of administration of the first
dose.
[0048] In some embodiments, the administration of the first dose
and the initiation of second dose are performed with the same
delivery device, e.g., with the same cannula or reservoir.
[0049] In some embodiments, said second dose is administered for a
period of time that is between 48 and 192 hours, 60 and 144 hours,
60 and 120 hours, 80 and 110 hours, and 90 and 100 hours. In some
embodiments, said second dose is administered for 95+/-5 hours. In
some embodiments, said second dose is administered for 95
hours.
[0050] In some embodiments, said second dose results in a plasma
concentration of 50 to 500 nM, 100 to 400 nM, or 200 to 300 nM. In
some embodiments, said second dose results in a plasma
concentration of 500 to 1000 nM, 600 to 900 nM, or 700 to 800 nM.
In some embodiments, said second dose results in a plasma
concentration of 1000 to 1500 nM, 1100 to 1400 nM, or 1200 to 1300
nM. In some embodiments, said second dose results in a plasma
concentration of 1500 to 2000 nM, 1600 to 1900 nM, or 1700 to 1800
nM. In some embodiments, said second dose results in a plasma
concentration of 2000 to 2500 nM, 2100 to 2400 nM, or 2200 to 2300
nM. In some embodiments, said second dose results in a plasma
concentration of 300 to 800 nM, 400 to 700 nM, or 500 to 600 nM. In
some embodiments, said second dose results in a plasma
concentration of 800 to 1300 nM, 900 to 1200 nM, or 1000 to 1100
nM. In some embodiments, said first dose results in a plasma
concentration of 1300 to 1800 nM, 1400 to 1700 nM, or 1500 to 1600
nM. In some embodiments, said second dose results in a plasma
concentration of 1800 to 2300 nM, 1900 to 2200 nM, or 2000 to 2100
nM. In some embodiments, said second dose results in a plasma
concentration of 2300 to 2600 nM, 2400 to 2500 nM. In some
embodiments, said second dose results in a plasma concentration of
300 to 400 nM, 400 to 500 nM, 600 to 700 nM, 800 to 900 nM, 1100 to
1200 nM, 1300 to 1400 nM, 1400 to 1500 nM, 1600 to 1700 nM, 1800 to
1900 nM, 1900 to 2000 nM, 2100 to 2200 nM, 2300 to 2400 nM. In some
embodiments, said second dose results in a plasma concentration of
500 to 2500 nM, 500 to 1500 nM, 500 to 1000 nM, 500 to 800 nM, or
500 to 600 nM. In some embodiments, said second dose results in a
plasma concentration of 50 to 250 nM, 100 to 200 nM, or 140 to 160
nM. In some embodiments, said second dose results in a plasma
concentration of 150+/-30 nM, 150+/-20 nM, 150+/-10 nM, or 150
nM
[0051] In some embodiments, the plasma concentration of said second
dose is measured at a preselected time, e.g., at 10, 15, 20, 30,
45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days
after the initiation of said second dose.
[0052] In some embodiments, said second dose results in a plasma
concentration of 150 nM, e.g., as measured at a preselected time,
e.g., at 10, 15, 20, 30, 45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12,
24 hours, 2, 3, 4 days after the initiation of said second
dose.
[0053] In some embodiments, said second dose is administered at the
same infusion rate, e.g. amount of allopregnanolone/unit time, over
the entire second dose. In some embodiments, the infusion rate,
e.g. amount of allopregnanolone delivered/unit time varies during
the second dose. In some embodiments, said second dose is
administered at an infusion rate, e.g. amount of
allopregnanolone/unit time of 25-1500 .mu.g/kg/hour. In some
embodiments, said second dose is administered at an infusion rate,
e.g. amount of allopregnanolone/unit time of 25-150 .mu.g/kg/hour,
50-100 .mu.g/kg/hour, 75-100 .mu.g/kg/hour, 85 .mu.g/kg/hour, 86
.mu.g/kg/hour, or 87 .mu.g/kg/hour.
[0054] In some embodiments, said downward taper dose comprises
administering a continuously decreasing amount allopregnanolone. In
some embodiments, said downward taper dose comprises administering
a continuously decreasing amount of allopregnanolone/unit time. In
some embodiments, said downward taper dose comprises administering
a plurality of step doses, wherein each subsequent step dose is
lower than the step dose that precedes it. In some embodiments,
said downward taper dose comprises administering a plurality of
step doses, wherein each subsequent step dose delivers a lower
amount of allopregnanolone/unit time than the step dose that
precedes it.
[0055] In some embodiments, the method comprises administering a
first, second, and third step dose. In some embodiments, said first
step dose is 60 to 90% of the second/maintenance dose; said second
step dose is 40 to 70% of the second/maintenance dose; and said
third step dose is 10 to 40% of the second/maintenance dose. In
some embodiments, the amount of allopregnanolone delivered/unit
time in said first step dose is 60 to 90% of the amount of
allopregnanolone delivered/unit time in said second/maintenance
dose; the amount of allopregnanolone delivered/unit time in said
second step dose is 40 to 70% of the amount of allopregnanolone
delivered/unit time in said second/maintenance dose; and the amount
of allopregnanolone delivered/unit time in said third step dose is
10 to 40% of the infusion rate, e.g. amount of allopregnanolone
delivered/unit time in said second/maintenance dose. In some
embodiments, said first step dose is 70 to 80% of the
second/maintenance dose; said second step dose is 40 to 60% of the
second/maintenance dose; and said third step dose is 20 to 30% of
the second/maintenance dose. In some embodiments, the amount of
allopregnanolone delivered/unit time in said first step dose is 70
to 80% of the amount of allopregnanolone delivered/unit time in
said second/maintenance dose; the amount of allopregnanolone
delivered/unit time in said second step dose is 40 to 60% of the
amount of allopregnanolone delivered/unit time in said
second/maintenance dose; and the amount of allopregnanolone
delivered/unit time in said third step dose is 20 to 30% of the
amount of allopregnanolone delivered/unit time in said
second/maintenance dose. In some embodiments, said first step dose
is 75% of the second/maintenance dose; said second step dose is 50%
of the second/maintenance dose; and said third step dose is 25% of
the second/maintenance dose. In some embodiments, the amount of
allopregnanolone delivered/unit time in said first step dose is 75%
of the amount of allopregnanolone delivered/unit time in said
second/maintenance dose. In some embodiments, the amount of
allopregnanolone delivered/unit time in said second step dose is
50% of the amount of allopregnanolone delivered/unit time in said
second/maintenance dose. In some embodiments, the amount of
allopregnanolone delivered/unit time in said third step dose is 25%
of the amount of allopregnanolone delivered/unit time in said
second/maintenance dose.
[0056] In some embodiments, after the completion of said third step
dose, no allopregnanolone is administered to the subject (e.g.,
human subject) for at least 10, 20, 30, 40, 50, or 60 days, or
until the patient has a subsequent episode of SRSE.
[0057] In some embodiments, said first step dose is administered at
an amount of allopregnanolone/unit time of 25-1000 .mu.g/kg/hour.
In some embodiment, said first step dose is administered at an
amount of allopregnanolone/unit time of 25-100 .mu.g/kg/hour, 50-75
.mu.g/kg/hour, 60-70 .mu.g/kg/hour, 63 .mu.g/kg/hour, 64
.mu.g/kg/hour, or 65 .mu.g/kg/hour. In some embodiments, said
second step dose is administered at an amount of
allopregnanolone/unit time of 10-700 .mu.g/kg/hour. In some
embodiments, said second step dose is administered at an amount of
allopregnanolone/unit time of 10-70 .mu.g/kg/hour, 25-55
.mu.g/kg/hour, 40-50 .mu.g/kg/hour, 42 .mu.g/kg/hour, 43
.mu.g/kg/hour, or 44 .mu.g/kg/hour. In some embodiments, said third
step dose is administered at an amount of allopregnanolone/unit
time of 5-500 .mu.g/kg/hour. In some embodiments, said third step
dose is administered at an amount of allopregnanolone/unit time of
5-50 .mu.g/kg/hour, 10-35 .mu.g/kg/hour, 15-25 .mu.g/kg/hour, 20
.mu.g/kg/hour, 21 .mu.g/kg/hour, or 22 .mu.g/kg/hour.
[0058] In some embodiments, the third/taper dose begins no longer
than 90, 80, 70, 60, or 30 minutes after the administration or end
of the second dose. In some embodiments, the third/taper dose
begins at the end of administration of the second dose.
[0059] In some embodiments, the administration of the second dose
and the initiation of third/taper dose are performed with the same
delivery device, e.g., the same cannula.
[0060] In some embodiments, the time between the end of the
administration of said first step dose and the initiation of
administration of said second step dose is less than 120, 60, 30,
15 or 5 minutes.
[0061] In some embodiments, the time between the end of the
administration of said second step dose and the initiation of
administration of said third step dose is less than 120, 60, 30, 15
or 5 minutes.
[0062] In some embodiments, said third dose is administered for a
period of time that is between 10 and 100 hours, 12 and 96 hours,
12 and 48 hours, 16 and 32 hours, or 20 and 30 hours.
[0063] In some embodiments, said third dose is administered over 24
hours.
[0064] In some embodiments, the allopregnanolone is provided in a
composition comprising a cyclodextrin, e.g., .beta.-cyclodextrin,
e.g., sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL. In
some embodiments, the allopregnanolone is provided at a
concentration of 0.1 to 10 mg/mL allopregnanolone. In some
embodiments, the allopregnanolone is provided at a concentration of
0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL
allopregnanolone. In some embodiments, the allopregnanolone is
provided at a concentration of 1.25 mg/mL allopregnanolone. In some
embodiments, the allopregnanolone is provided at a concentration of
2.5 mg/mL allopregnanolone. In some embodiments, the
allopregnanolone is provided at a concentration of 3.75 mg/mL
allopregnanolone. In some embodiments, the allopregnanolone is
provided at a concentration of 5 mg/mL allopregnanolone.
[0065] In some embodiments, the cyclodextrin is present in the
composition at 1-30%, 2-18%, 10-15% by weight of cyclodextrin per
volume of composition. In some embodiments, the cyclodextrin is
present in the composition at 1, 2.5, 5, 10, 12, 13, 15, 30% by
weight of cyclodextrin per volume of composition. In some
embodiments, the cyclodextrin is present in the composition at 12%
by weight of cyclodextrin per volume of composition.
[0066] In some embodiments, the cyclodextrin is present in the
composition at 1-30%, 2-18%, 10-15% by weight of cyclodextrin per
volume of composition and the allopregnanolone is provided at a
concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9,
or 10 mg/mL allopregnanolone. In some embodiments, the cyclodextrin
is present in the composition at 1, 2.5, 5, 10, 12, 13, 15, 30% by
weight of cyclodextrin per volume of composition and the
allopregnanolone is provided at a concentration of 0.1, 0.5, 1,
1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL
allopregnanolone.
[0067] In some embodiments, the cyclodextrin is present in the
composition at 12% by weight of cyclodextrin per volume of
composition and the allopregnanolone is provided at a concentration
of 5 mg/mL allopregnanolone. In some embodiments, the cyclodextrin
is present in the composition at 12% by weight of cyclodextrin per
volume of composition and the allopregnanolone is provided at a
concentration of 3.75 mg/mL allopregnanolone. In some embodiments,
the cyclodextrin is present in the composition at 12% by weight of
cyclodextrin per volume of composition and the allopregnanolone is
provided at a concentration of 2.5 mg/mL allopregnanolone. In some
embodiments, the cyclodextrin is present in the composition at 12%
by weight of cyclodextrin per volume of composition and the
allopregnanolone is provided at a concentration of 1.25 mg/mL
allopregnanolone.
[0068] In some embodiments, the method further comprises,
evaluating the subject (e.g., human subject), wherein the
evaluating comprises performing c-ECG. In some embodiments, the
method comprises, evaluating the subject (e.g., human subject),
wherein the evaluating comprises performing EEG. In some
embodiments, the method further comprises evaluating the subject
(e.g., human subject) for serum chemistry (e.g., one or more of
albumin, AST, ALT, bicarbonate, bilirubin, BUN, calcium, chloride,
creatine kinase, lipase, creatinine, magnesium, potassium, sodium,
total protein, or glucose). In some embodiments, the method further
comprises, evaluating the subject (e.g., human subject) for CBC
(e.g., one or more of RBC, hemoglobin, hematocrit, MCV, MCH, MCHC,
platelet count, WBC with differential including neutrophils,
eosinophils, basophils, lymphocytes, or monocytes. In some
embodiments, the method further comprises evaluating the subject
(e.g., human subject) for serum allopregnanolone, progesterone, and
5.alpha.-dihydrotestosterone. In some embodiments, the method
comprises comparing an observed value with a reference value.
[0069] In some embodiments, said subject (e.g., human subject) is
evaluated for a parameter described herein during said weaning
period.
[0070] In one aspect, the invention features a method of treating a
subject (e.g., human subject) having, SE, RSE, or SRSE comprising:
administering a first/load, e.g., bolus, dose concurrent with
general anesthesia, wherein administration of said first dose:
begins 2-120 hours after induction of general anesthesia; lasts for
30-90 minutes; and results in a plasma level of allopregnanolone of
100-2000 nM allopregnanolone; administering a second/maintenance
dose, wherein, the administration of said second dose begins not
longer than 1-60 minutes after the end of the second dose; lasts
for 1-6 days; and results in a plasma level of allopregnanolone of
100-2000 nM allopregnanolone; administering a third downward taper
dose, wherein, the administration of said third downward taper dose
begins not longer than 1-60 minutes after the end of the third
dose; lasts for 10-100 hours; and results in a plasma level of
allopregnanolone of 0-1500 nM allopregnanolone; wherein,
collectively, the administrations are provided in sufficient amount
to treat said subject (e.g., human subject).
[0071] In some embodiments, the method comprises administering a
first/load, e.g., bolus, dose concurrent with general anesthesia,
wherein administration of said first dose: begins 2-120 hours after
induction of general anesthesia; lasts for 60+/-15 minutes;
administering a second/maintenance dose, wherein, the
administration of said second dose begins not longer than 30
minutes after the end of the second dose; lasts for 70 to 110
hours; administering a third downward taper dose, wherein, the
administration of said third downward taper dose begins not longer
than 1-60 minutes after the end of the third dose; lasts for 10-30
hours.
[0072] In some embodiments, administering a first/load, e.g.,
bolus, dose concurrent with general anesthesia, wherein
administration of said first dose: begins 2-120 hours after
induction of general anesthesia; lasts for 60+/-15 minutes;
administering a second/maintenance dose, wherein, the
administration of said second dose begins not longer than 30
minutes after the end of the second dose; lasts for 70 to 110
hours; and administering a third downward taper dose, wherein, the
administration of said third downward taper dose begins not longer
than 1-60 minutes after the end of the third dose; lasts for 24+/-2
hours and said third downward taper dose comprises a first, second,
and third step dose.
[0073] In some embodiments, administering a first/load, e.g.,
bolus, dose concurrent with general anesthesia, wherein
administration of said first dose lasts for 60+/-15 minutes;
administering a second/maintenance dose, wherein, the
administration of said second dose begins not longer than 30
minutes after the end of the second dose; lasts for 85 to 105
hours; administering a third downward taper dose, wherein, the
administration of said third downward taper dose begins not longer
than 1-60 minutes after the end of the third dose; lasts for 10-30
hours and: the amount of allopregnanolone delivered/unit time in
said first step dose is 70 to 80% of the amount of allopregnanolone
delivered/unit time in said second/maintenance dose; the amount of
allopregnanolone delivered/unit time in said second step dose is 40
to 60% of the amount of allopregnanolone delivered/unit time in
said second/maintenance dose; and the amount of allopregnanolone
delivered/unit time in said third step dose is 20 to 30% of the
amount of allopregnanolone delivered/unit time in said
second/maintenance dose.
[0074] In some embodiments, administering a first/load, e.g.,
bolus, dose concurrent with general anesthesia, wherein
administration of said first dose lasts for 60+/-5 minutes;
administering a second/maintenance dose, wherein, the
administration of said second dose begins not longer than 30
minutes after the end of the second dose; lasts for 96+/-4 hours;
administering a third downward taper dose, wherein, the
administration of said third downward taper dose begins not longer
than 1-60 minutes after the end of the third dose; lasts for 24+/-2
hours and: the amount of allopregnanolone delivered/unit time in
said first step dose is 75% of the amount of allopregnanolone
delivered/unit time in said second/maintenance dose; the amount of
allopregnanolone delivered/unit time in said second step dose is
50% of the amount of allopregnanolone delivered/unit time in said
second/maintenance dose; and the amount of allopregnanolone
delivered/unit time in said third step dose is 25% of the amount of
allopregnanolone delivered/unit time in said second/maintenance
dose.
[0075] In some embodiments, the method further comprises
administering an amount of a composition selected from
benzodiazepines (e.g., midazolam), propofol, barbiturates, and
ketamine sufficient to place said subject (e.g., human subject)
under general anesthesia;
[0076] In one aspect, the invention features a kit comprising one
or more of: a preparation of allopregnanolone, e.g., a plurality of
preparations of allopregnanolone at a concentrations suitable for
use at the first, second, and third doses; and instructions for use
for treating a subject (e.g., human subject) having a
seizure-related disorder, e.g., status epilepticus (SE), e.g.,
super-refractory status epilepticus (SRSE).
[0077] In some embodiments, the kit further comprises a suitable
diluent (e.g., water, saline, cyclodextrin, e.g.,
.beta.-cyclodextrin, e.g., sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL).
[0078] In some embodiments, the allopregnanolone is provided at a
concentration of 0.1-10 mg/mL allopregnanolone. In some
embodiments, the allopregnanolone is provided at a concentration of
0.5-7.5 mg/mL allopregnanolone. In some embodiments, the
allopregnanolone is provided at a concentration of 1-6 mg/mL
allopregnanolone. In some embodiments, the allopregnanolone is
provided at a concentration of 5 mg/mL allopregnanolone. In some
embodiments, the allopregnanolone is provided at a concentration of
3.75 mg/mL allopregnanolone. In some embodiments, the
allopregnanolone is provided at a concentration of 2.5
allopregnanolone. In some embodiments, the allopregnanolone is
provided at a concentration of 1.25 mg/mL allopregnanolone.
[0079] In one aspect, the invention features a method of making a
series of dosages, the method comprising combining a diluent and
allopregnanolone in proportions to from dosage forms suitable for
use as the first, second and one or more step doses for said third
dose.
[0080] In one aspect, the invention features a method of adjusting
the amount of diluents and or allopregnanolone flowing into or out
of a delivery device, e.g., a catheter, reservoir, the method
comprising altering, e.g., decreasing, the flow rate of
allopregnanolone flowing into the delivery device, so as to release
in succession, two or more of a first dosage, a second dosage and
one or more step doses of the third dose.
[0081] In one aspect, the invention features a method of treating a
subject having seizure, epilepsy or status epilepticus by
administering in combination to the subject a neuroactive steroid
and a benzodiazepine or anesthetic/sedative. In some embodiments,
the method further comprises administering at least one of the
neuroactive steroid and benzodiazepine or anesthetic/sedative
parenterally (e.g., intranasally, buccally, intravenously or
intramuscularly, for example, intravenously or intramuscularly). In
some embodiments, both the neuroactive steroid and benzodiazepine
or anesthetic/sedative are administered parenterally.
[0082] In some embodiments, the neuroactive steroid and
benzodiazepine or anesthetic/sedative co-administered (e.g.,
administered simultaneously, administered concurrently). In some
embodiments, the neuroactive steroid and benzodiazepine or
anesthetic/sedative are administered sequentially. In some
embodiments, neuroactive steroid and benzodiazepine or
anesthetic/sedative are administered in a single dosage form.
[0083] When the agents described herein (e.g., the neuroactive
steroid and a benzodiazepine or anesthetic/sedative) are
administered in combination, both of the agents should be present
at dosage levels of between about 1 to 100%, and more preferably
between about 5 to 95% of the dosage normally administered in the
absence of the combination regimen. The agents may be administered
separately, as part of a multiple dose regimen. Alternatively, the
agents may be part of a single dosage form, mixed together with the
compounds of this invention in a single composition.
[0084] In some embodiments, the neuroactive steroid is a progestin
derivative, e.g., allopregnanolone. In an embodiment, the
neuroactive steroid is allopregnanolone.
[0085] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, is formulated for parenteral administration
(e.g., intranasally, buccally, intravenously or intramuscularly,
for example, intravenously or intramuscularly).
[0086] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, is administered in a composition comprising a
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex.
[0087] In some embodiments, the cyclodextrin is a
.beta.-cyclodextrin. In an embodiment, the cyclodextrin is a sulfo
butyl ether .beta.-cyclodextrin. In an embodiment, the cyclodextrin
is CAPTISOL.RTM.. In some embodiments, the cyclodextrin is a
.beta.-cyclodextrin disclosed in U.S. Pat. No. 5,874,418;
6,046,177; or 7,635,733, which are herein incorporated by
reference.
[0088] In some embodiments, the neuroactive steroid is a progestin
derivative, e.g., allopregnanolone, and the cyclodextrin is a
.beta.-cyclodextrin. In some embodiments, the neuroactive steroid
is a progestin derivative, e.g., allopregnanolone, and the
cyclodextrin is a sulfo butyl ether .beta.-cyclodextrin. In an
embodiment, the neuroactive steroid is allopregnanolone and the
cyclodextrin is CAPTISOL.RTM..
[0089] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated for parenteral administration. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition. In some embodiments, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration between 0.25-30 mg/mL, 0.5-30 mg/mL; 1-30 mg/mL; 5-30
mg/mL, 10-30 mg/mL; 15-30 mg/mL, 0.25-20 mg/mL; 0.5-20 mg/mL; 1-20
mg/mL, 0.5-20 mg/mL; 1-20 mg/mL, 5-20 mg/mL, 10-20 mg/mL, 0.25-15
mg/mL, 0.5-15 mg/mL; 0.5-10 mg/mL; 0.5-7 mg/mL; 1-15 mg/mL, 1-10
mg/mL; 1-7 mg/mL; 1-5 mg/mL; 5-15 mg/mL; 5-10 mg/mL; 10-15 mg/mL;
1-10 mg/mL; 2-8 mg/mL; 2-7 mg/mL; 3-5 mg/mL; 5-15 mg/mL; 3-7 mg/mL;
4-6 mg/mL; 7-12 mg/mL; 7-10 mg/mL; 8-9 mg/mL; 3-5 mg/mL; or 3-4
mg/mL. In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid at a concentration of 0.25 mg/mL, 0.5 mg/mL;
1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL;
4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL, 5.5 mg/mL, 6.0 mg/mL, 6.5 mg/mL,
7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL, 9.0 mg/mL, 9.5 mg/mL,
10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, or 30 mg/mL. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising the neuroactive
steroid at a concentration of 1.5 mg/mL. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration of 2.5 mg/mL. In an embodiment, the neuroactive
steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid at a concentration
of 3.5 mg/mL. In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid at a concentration of 5 mg/mL. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising the neuroactive
steroid at a concentration of 6 mg/mL. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration of 15 mg/mL.
[0090] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid at a concentration of between 0.1-50 .mu.M;
0.1-40 .mu.M; 0.1-30 .mu.M; 0.1-20 .mu.M; 0.1-15 .mu.M; 0.5-50
.mu.M; 0.5-40 .mu.M; 0.5-30 .mu.M; 0.5-20 .mu.M; 0.5-15 .mu.M; 1-50
.mu.M; 1-40 .mu.M; 1-30 .mu.M; 1-20 .mu.M; 1-15 .mu.M; 2-50 .mu.M;
2-40 .mu.M; 2-30 .mu.M; 2-20 .mu.M; 2-15 .mu.M; 0.5-15 .mu.M; 1-15
.mu.M; 2-15 .mu.M; 3-15 .mu.M; 1-20 .mu.M. In some embodiments, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration of 0.1 .mu.M; 0.5-1 .mu.M; 2 .mu.M; 4 .mu.M; 5 .mu.M;
7 .mu.M; 10 .mu.M; 15 .mu.M; 20 .mu.M; 25 .mu.M; 40 .mu.M; 50
.mu.M. In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid at a concentration of 1 .mu.M. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising the neuroactive
steroid at a concentration of 2 .mu.M. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid at a
concentration of 5 .mu.M.
[0091] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
between 25-400 mg/mL; 25-300 mg/mL; 25-200 mg/mL; 25-100 mg/mL;
25-50 mg/mL; 50-400 mg/mL; 50-300 mg/mL; 60-400 mg/mL; 60-300
mg/mL; 150-400 mg/mL; 150-300 mg/mL; 200-300 mg/mL; 200-400 mg/mL;
30-100 mg/mL; 30-300 mg/mL; 30-400 mg/mL; 45-75 mg/mL; 50-70 mg/mL;
55-65 mg/mL; or 50-60 mg/mL. In some embodiments, the neuroactive
steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., at a concentration of 25 mg/mL; 30 mg/mL; 35
mg/mL; 40 mg/mL; 45 mg/mL; 50 mg/mL; 55 mg/mL; 60 mg/mL; 65 mg/mL;
70 mg/mL; 75 mg/mL; 80 mg/mL; 85 mg/mL; 90 mg/mL, 95 mg/mL; 100
mg/mL; 150 mg/mL; 200 mg/mL; 250 mg/mL; 300 mg/mL; 350 mg/mL; or
400 mg/mL. In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 60 mg/mL.
[0092] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising between
2.5-40%, 2.5-30%, 2.5-20%, 2.5-15%, 2.5-10%, 5-40%, 5-30%, 5-20%,
5-15%, 5-10%, 6-40%, 6-30%, 6-20%, 6-10%, 6-20%, 6-30%, 10-40%,
10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10%, 3-15%,
4.5-7.5%, 4-13%, 5-7%, 5-13%, 5.5-6.5%, 7-13% by weight of the
cyclodextrin, e.g., CAPTISOL.RTM. per weight of solution.
[0093] In some embodiments, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising 2.5%,
3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%,
10%, 12%, 15%, 20%, 25%, 30%, 35% or 40% by weight of the
cyclodextrin, e.g., CAPTISOL.RTM. per weight of solution. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising 6% by weight of the
cyclodextrin, e.g., CAPTISOL.RTM. per weight of solution. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising 12% by weight of
the cyclodextrin, e.g., CAPTISOL.RTM. per weight of solution. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising 15% by weight of
the cyclodextrin, e.g., CAPTISOL.RTM. per weight of solution. In an
embodiment, the neuroactive steroid, e.g., allopregnanolone, and
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is
formulated as an aqueous composition comprising 30% by weight of
the cyclodextrin, e.g., CAPTISOL.RTM. per weight of solution.
[0094] In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid, e.g., allopregnanolone, at a concentration of
1.5 mg/mL, and the cyclodextrin, e.g., a .beta.-cyclodextrin, e.g.,
a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a
concentration of 6% by weight of the cyclodextrin, e.g.,
CAPTISOL.RTM. per weight of solution. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 10 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 6% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per weight
of solution. In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid, e.g., allopregnanolone, at a concentration of
15 mg/mL, and the cyclodextrin, e.g., a .beta.-cyclodextrin, e.g.,
a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a
concentration of 6% by weight of the cyclodextrin, e.g.,
CAPTISOL.RTM. per weight of solution.
[0095] In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid, e.g., allopregnanolone, at a concentration of
1.25 mg/mL, and the cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
at a concentration of 12% by weight of the cyclodextrin, e.g.,
CAPTISOL.RTM. per weight of solution. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 1.5 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 12% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 2.5 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 12% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 3.75 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 12% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 5 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 12% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 10 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 12% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 15 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 12% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution.
[0096] In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid, e.g., allopregnanolone, at a concentration of
1.5 mg/mL, and the cyclodextrin, e.g., a .beta.-cyclodextrin, e.g.,
a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a
concentration of 15% by weight of the cyclodextrin, e.g.,
CAPTISOL.RTM. per weight of solution. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 10 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 15% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 15 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 15% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution.
[0097] In an embodiment, the neuroactive steroid, e.g.,
allopregnanolone, and cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
complex is formulated as an aqueous composition comprising the
neuroactive steroid, e.g., allopregnanolone, at a concentration of
1.5 mg/mL, and the cyclodextrin, e.g., a .beta.-cyclodextrin, e.g.,
a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a
concentration of 30% by weight of the cyclodextrin, e.g.,
CAPTISOL.RTM. per weight of solution. In an embodiment, the
neuroactive steroid, e.g., allopregnanolone, and cyclodextrin,
e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM., complex is formulated as
an aqueous composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 10 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 30% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution. In an embodiment, the neuroactive steroid,
e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex is formulated as an aqueous
composition comprising the neuroactive steroid, e.g.,
allopregnanolone, at a concentration of 15 mg/mL, and the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., at a concentration
of 30% by weight of the cyclodextrin, e.g., CAPTISOL.RTM. per
weight of solution.
[0098] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition with a pH between
3-10, 4-9,4-8, 4-7,4-6, 4-5,5-9, 5-8,5-7, 5-6, 4.5-7.5, or 5.5-7.5.
In some embodiments, the allopregnanolone and CAPTISOL.RTM. complex
is formulated as an aqueous composition with a pH about 3, 3.5, 4,
4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In an embodiment, the
allopregnanolone and CAPTISOL.RTM. complex is formulated as an
aqueous composition with a pH about 6.
[0099] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
intravenously. In some embodiments, the allopregnanolone and
CAPTISOL.RTM. complex is formulated as an aqueous composition and
is administered intramuscularly.
[0100] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some
embodiments, the allopregnanolone and CAPTISOL.RTM. complex is
formulated as an aqueous composition and is administered between
1-10, 1-5,5-10, 1-6,2-6, 3-6, 4-5, or 1-9 consecutive days. In an
embodiment, the allopregnanolone and CAPTISOL.RTM. complex is
formulated as an aqueous composition and is administered for 5
consecutive days. In some embodiments, the duration of
administration is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some
embodiments, the duration of administration is 3-7,4-6, 4-5, or 5-6
days. In some embodiments, the duration of administration is 5
days.
[0101] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
at the same dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive
days. In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
consecutive days and then administered at a maintenance, e.g.,
infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive
days. In an embodiment, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
at a load, e.g., bolus, dose of 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL;
1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL;
4.5 mg/mL; 5.0 mg/mL, 5.5 mg/mL, 6.0 mg/mL, 6.5 mg/mL, 7.0 mg/mL,
7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL, 9.0 mg/mL, 9.5 mg/mL, 10 mg/mL, 15
mg/mL, 20 mg/mL, 25 mg/mL, or 30 mg/mL neuroactive steroid, e.g.,
allopregnanolone, for 1 day and then administered at a maintenance,
e.g., infusion, dose for 1, 2, 3, 4, 5, or 6 consecutive days of
0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL;
3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL, 5.5 mg/mL,
6.0 mg/mL, 6.5 mg/mL, 7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL,
9.0 mg/mL, 9.5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, or 30
mg/mL neuroactive steroid, e.g., allopregnanolone. In some
embodiments, a maintenance, e.g., infusion, dose described herein,
is lower than a load, e.g., bolus, dose described herein. In some
embodiments, a maintenance, e.g., infusion, dose described herein,
is the same as a load, e.g., bolus, dose described herein. In some
embodiments, the maintenance, e.g., infusion, dose is less than
0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL;
3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL, 5.5 mg/mL,
6.0 mg/mL, 6.5 mg/mL, 7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL,
9.0 mg/mL, 9.5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, or 30
mg/mL.
[0102] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
consecutive days and then administered at a maintenance, e.g.,
infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive
days and then administered at a taper dose for 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10 consecutive days. In some embodiments, the
allopregnanolone and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered at a load, e.g., bolus,
dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then
administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10 consecutive days and then administered at a
first step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.
[0103] In some embodiments, the allopregnanolone and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
consecutive days and then administered at a maintenance, e.g.,
infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive
days and then administered at a first step dose for 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 hours and then administered at a second step dose
for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. In some embodiments,
the allopregnanolone and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered at a load, e.g., bolus,
dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then
administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10 consecutive days and then administered at a
first step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then
administered at a second step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 hours and then administered at a third step dose for 1, 2, 3,
4, 5, 6, 7, 8, 9, or 10 hours.
[0104] In some embodiments the first, second, or third step dose is
less than the maintenance, e.g., infusion, dose. In some
embodiments, the second taper or third step dose is less than the
first step dose. In some embodiments, the third step dose is less
than the second step dose. In some embodiments, the first step dose
is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%,
30%, 25%, 20%, 15%, 10%, or 5% of the maintenance, e.g., infusion,
dose. In some embodiments, the first step dose is between 95-50%,
75-50%, 85-50%, 90-50%, 80-50%, or 75-100% of the maintenance,
e.g., infusion, dose. In an embodiment, the first step dose is 75%
of the maintenance, e.g., infusion, dose.
[0105] In some embodiments, the second step dose is 95%, 90%, 85%,
80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%,
15%, 10%, or 5% of the maintenance, e.g., infusion, dose. In some
embodiments, the second step dose is between 95-30%, 75-30%,
85-30%, 60-30%, 70-30%, 50-30%, or 50-40% of the maintenance, e.g.,
infusion, dose. In an embodiment, the second step dose is 50% of
the maintenance, e.g., infusion, dose.
[0106] In some embodiments, the third step dose is 95%, 90%, 85%,
80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%,
15%, 10%, or 5% of the maintenance, e.g., infusion, dose. In some
embodiments, the third step dose is between 50-5%, 40-5%, 30-5%,
25-5%, 25-10%, 25-20%, or 25-40% of the maintenance, e.g.,
infusion, dose. In an embodiment, the second step dose is 50% of
the maintenance, e.g., infusion, dose. In an embodiment, the third
step dose is 25% of the maintenance, e.g., infusion, dose.
[0107] In an embodiment, a composition comprising a neuroactive
steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., complex, comprises less than 100 ppm of a
phosphate, and the cyclodextrin, e.g., a .beta.-cyclodextrin, e.g.,
a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., has
an absorption of less than 0.2 A.U. due to a drug-degrading agent,
as determined by UV/vis spectrophotometry at a wavelength of 245 nm
to 270 nm for an aqueous solution comprising 300 mg of the
cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a sulfo butyl
ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL of solution
in a cell having a 1 cm path length.
[0108] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., has an absorption of less than 0.2 A.U. due to
a color forming agent, as determined by UV/vis spectrophotometry at
a wavelength of 320 nm to 350 nm for an aqueous solution comprising
500 mg of the cyclodextrin, e.g., a .beta.-cyclodextrin, e.g., a
sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM., per mL
of solution in a cell having a 1 cm path length.
[0109] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., further comprises: less than 20 ppm of a
sulfoalkylating agent; less than 0.5% wt. of an underivatized
cyclodextrin; less than 1% wt. of an alkali metal halide salt; and
less than 0.25% wt. of a hydrolyzed sulfoalkylating agent.
[0110] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., has an absorption of less than 0.2 A.U. due to
a drug-degrading agent, as determined by UV/vis spectrophotometry
at a wavelength of 245 nm to 270 nm for an aqueous solution
comprising 500 mg of the cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
per mL of solution in a cell having a 1 cm path length.
[0111] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., further comprises: less than 50 ppm of a
phosphate; less than 10 ppm of a sulfoalkylating agent; less than
0.2% wt. of an underivatized cyclodextrin; less than 0.5% wt. of an
alkali metal halide salt; and less than 0.1% wt. of a hydrolyzed
sulfoalkylating agent; and wherein the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., has an absorption of less than 0.2 A.U. due to
the color-forming agent, as determined by U/vis spectrophotometry
at a wavelength of 320 nm to 350 nm for an aqueous solution
comprising 500 mg of the cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
per mL of solution in a cell having a 1 cm path length.
[0112] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., further comprises: less than 10 ppm of a
phosphate; less than 2 ppm of a sulfoalkylating agent; less than
0.1% wt. of an underivatized cyclodextrin; less than 0.2% wt. of an
alkali metal halide salt; and less than 0.08% wt. of a hydrolyzed
sulfoalkylating agent; and wherein the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., has an absorption of less than 0.1 A.U. due to
the color-forming agent, as determined by UV/vis spectrophotometry
at a wavelength of 320 nm to 350 nm for an aqueous solution
comprising 500 mg of the cyclodextrin, e.g., a .beta.-cyclodextrin,
e.g., a sulfo butyl ether .beta.-cyclodextrin, e.g., CAPTISOL.RTM.,
per mL of solution in a cell having a 1 cm path length.
[0113] In some embodiments, the cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM., further comprises: less than 5 ppm of a
phosphate; less than 0.1% wt. of an alkali metal halide salt; and
less than 0.05% wt. of a hydrolyzed sulfoalkylating agent.
[0114] In some embodiments, the neuroactive steroid (e.g.,
allopregnanolone) and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered within 48 hours, 24 hours,
10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hour after a
seizure, e.g., a status epileptic seizure, e.g., a refractory
status epileptic seizure has started. In some embodiments, the
allopregnanolone and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered within 60 minutes, 45
minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after a
seizure, e.g., a status epileptic seizure, e.g., a refractory
status epileptic seizure has started. In some embodiments, the
neuroactive steroid (e.g., allopregnanolone) and CAPTISOL.RTM.
complex is formulated as an aqueous composition and is administered
after a seizure, e.g., a status epileptic seizure, e.g., a
refractory status epileptic seizure has lasted 5 minutes, 10
minutes, 15 minutes, 20 minutes, 30 minutes or 60 minutes.
[0115] In some embodiments, the neuroactive steroid (e.g.,
allopregnanolone) and CAPTISOL.RTM. complex is formulated as an
aqueous composition and is administered prior to the onset of a
seizure, e.g., a status epileptic seizure, e.g., a refractory
status epileptic seizure.
[0116] In some embodiments, the benzodiazepine is clonazepam,
lorazepam, midazolam, or diazepam.
[0117] In some embodiments, the benzodiazepine is formulated for
oral delivery. In some embodiments, the benzodiazepine is
formulated for parenteral delivery (e.g., intranasally, buccally,
intravenously or intramuscularly, for example, intravenously or
intramuscularly).
[0118] In some embodiments, the anesthetic/sedative is propofol or
a barbiturate, e.g., pentobarbital.
[0119] In some embodiments, both the neuroactive steroid and the
benzodiazepine or anesthetic/sedative are formulated for parenteral
delivery (e.g., intranasally, buccally, intravenously or
intramuscularly, for example, intravenously or
intramuscularly).
[0120] In some embodiments, the neuroactive steroid such as
allopregnanolone and benzodiazepine or anesthetic/sedative, when
administered in combination, are administered in an amount
sufficient to achieve burst suppression (e.g., a predetermined
burst suppression pattern, e.g., inter-burst intervals of between
2-30 seconds; as measured by a method of neurophysiological
monitoring, e.g., EEG, CFM). In some embodiments, the neuroactive
steroid such as allopregnanolone and benzodiazepine or
anesthetic/sedative, when administered in combination, is
administered at a dose sufficient to achieve a predetermined burst
suppression pattern, e.g., inter-burst intervals of between 2-30
seconds, 5-30 seconds, 10-30 seconds, 15-30 seconds, 1-30 seconds,
0-30 seconds, 2-20 seconds, 2-10 seconds, 5-20 seconds, 10-20
seconds, 15-25 seconds, 5-15 seconds or 5-10 seconds; as measured
by a method of neurophysiological monitoring, e.g., EEG, CFM.
BRIEF DESCRIPTION OF THE FIGURES
[0121] FIG. 1. Physical appearance of ALLO formulations with
Captisol.
[0122] FIG. 2. Plasma exposure of allopregnanolone from human SE
study. Plasma concentration profile over time of allopregnanolone
in a single male patient. The patient was dosed allopregnanolone
(ALLO) at 1.5 mg/mL in 6% hydroxypropyl-.beta.-cyclodextrin in 0.9%
sodium chloride intravenously for 5 days (120 h). The infusion rate
was 86 .mu.g/kg/h. The patient was dosed 5.6 mg/h of
allopregnanolone at 3.8 mL/h. Plasma concentration was analyzed 2
hours prior to the start of infusion and then 52, 76, 100, 124, and
148 hours post-infusion.
DETAILED DESCRIPTION OF THE INVENTION
[0123] As used herein, "administered in combination" or a combined
administration of two agents (e.g., a neuroactive steroid and a
benzodiazepine or anesthetic/sedative) means that two or more
agents are administered to a subject at the same time or within an
interval such that there is overlap of an effect of each agent on
the patient. Preferably they are administered within 15, 10, 5, or
1 minute of one another. Preferably the administrations of the
agents are spaced sufficiently close together such that a
combinatorial effect is achieved. The agents can be administered
simultaneously, for example in a combined unit dose (providing
simultaneous delivery of both agents). Alternatively, the agents
can be administered at a specified time interval, for example, an
interval of minutes, hours, days or weeks. Generally, the agents
are concurrently bioavailable, e.g., detectable, in the subject. In
an embodiment, the agents (e.g., a neuroactive steroid and a
benzodiazepine or anesthetic/sedative) are administered essentially
simultaneously, for example two unit dosages administered at the
same time, or a combined unit dosage of the two agents. In another
embodiment, the agents are delivered in separate unit dosages. The
agents can be administered in any order, or as one or more
preparations that includes two or more agents. In an embodiment, at
least one administration of one of the agents, e.g., the first
agent, is made within minutes, one, two, three, or four hours, or
even within one or two days of the other agent, e.g., the second
agent. In some cases, combinations can achieve synergistic results,
e.g., greater than additive results, e.g., at least 20, 50, 70, or
100% greater than additive.
[0124] As used herein, "concurrent" administration of a treatment
modality with a selected state, e.g., being under general
anesthesia, or while a second treatment modality is administered,
or is present at a preselected level, e.g., a therapeutic level,
means that administration of the treatment modality overlaps or
occurs at the same time as, e.g., administration of a second
treatment modality.
[0125] As used herein, an amount of a compound effective to treat a
disorder, or a "therapeutically effective amount" refers to an
amount of the compound which is effective, upon single or multiple
dose administration to a subject, in treating a cell, or in curing,
alleviating, relieving or improving a subject with a disorder
beyond that expected in the absence of such treatment.
[0126] As used herein, "general anesthesia" or "GA" is a state
produced when a subject receives medications for e.g., amnesia,
analgesia, muscle paralysis, and sedation. For example, GA is a
treatment that induces deep sleep typically used so that subjects
will not feel pain during surgery. An anesthetized patient can be
thought of as being in a reversible and controlled state of
unconsciousness. GA agents can be administered intravenously or
inhaled.
[0127] As used herein, the term "subject" is intended to include
human and non-human animals. Exemplary human subjects include a
human patient having a disorder, e.g., a disorder described herein
or a normal subject. The term "non-human animals" of the invention
includes all vertebrates, e.g., non-mammals (such as chickens,
amphibians, reptiles) and mammals, such as non-human primates,
domesticated and/or agriculturally useful animals, e.g., sheep,
dog, cat, cow, pig, etc.
Therapeutic Agents
Neuroactive Steroids
[0128] Neuroactive steroids (or neurosteroids) are natural,
synthetic, or semi-synthetic steroids that rapidly alter neuronal
excitability through interaction with neurotransmitter-gated ion
channels. Neuroactive steroids effect binding to membrane-bound
receptors such as those for inhibitory and (or) excitatory
neurotransmitters including GABA.sub.A, NMDA, and sigma
receptors.
[0129] The steroids that may be classified into functional groups
according to chemical structure and physiological activity and
include estrogenic hormones, progestational hormones, and
androgenic hormones. Of particular interest are progestational
hormones, referred to herein as "progestins" or "progestogens", and
their derivatives and bioactive metabolites. Members of this broad
family include steroid hormones disclosed in Remington's
Pharmaceutical Sciences, Gennaro et al., Mack Publishing Co. (18th
ed. 1990), 990-993. As with all other classes of steroids,
stereoisomerism is of fundamental importance with the sex hormones.
As used herein, a variety of progestins (e.g., progesterone) and
their derivatives, including both synthetic and natural products,
can be used, as well as progestin metabolites such as
progesterone.
[0130] The term "progesterone" as used herein refers to a member of
the progestin family and includes a 21 carbon steroid hormone.
Progesterone is also known as D4-pregnene-3,20-dione;
.DELTA.4-pregnene-3,20-dione; or pregn-4-ene-3,20-dione. As used
herein a "synthetic progestin" is a molecule whose structure is
related to that of progesterone, is synthetically derived, and
retains the biological activity of progesterone.
[0131] Representative synthetic progestins include, but are not
limited to, substitutions at the 17-position of the progesterone
ring to introduce a hydroxyl, acetyl, hydroxyl acetyl, aliphatic,
nitro, or heterocyclic group, modifications to produce 17.alpha.-OH
esters (e.g., 17.alpha.-hydroxyprogesterone caproate), as well as
modifications that introduce 6-methyl, 6-ene, and 6-chloro
substituents onto progesterone (e.g., medroxyprogesterone acetate,
megestrol acetate, and chlomadinone acetate), and which retains the
biological activity of progesterone. Such progestin derivatives
include 5-dehydroprogesterone, 6-dehydro-retroprogesterone
(dydrogesterone), allopregnanolone (allopregnan-3.alpha., or
3.beta.-ol-20-one), ethynodiol diacetate, hydroxyprogesterone
caproate (pregn-4-ene-3,20-dione, 17-(1-oxohexy)oxy);
levonorgestrel, norethindrone, norethindrone acetate
(19-norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-,(17.alpha.)-);
norethynodrel, norgestrel, pregnenolone, and megestrol acetate.
[0132] Useful progestins also can include allopregnone-3.alpha. or
3.beta., 20.alpha. or 20.beta.-diol (see Merck Index 258-261);
allopregnane-3.beta.,21-diol-11,20-dione;
allopregnane-3.beta.,17.alpha.-diol-20-one; 3,20-allopregnanedione,
allopregnane, 3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol;
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol;
allopregnane-3.alpha. or
3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha. or 20.beta.-triol;
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione;
allopregnane-3.beta.,11.beta.,21-triol-20-one;
allopregnane-3.beta.,17.alpha.,21-triol-20-one;
allopregnane-3.alpha. or 3.beta.-ol-20-one; pregnanediol;
3,20-pregnanedione; pregnan-3.alpha.-ol-20-one;
4-pregnene-20,21-diol-3,11-dione;
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one;
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione;
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, and pregnenolone
methyl ether. Further progestin derivatives include esters with
non-toxic organic acids such as acetic acid, benzoic acid, maleic
acid, malic acid, caproic acid, and citric acid and inorganic salts
such as hydrochloride, sulfate, nitrate, bicarbonate and carbonate
salts. Other suitable progestins include alphaxalone, alphadolone,
hydroxydione, and minaxolone.
[0133] Additional suitable neuroactive steroids are disclosed in
United States Patent Application Publication Nos. US 2011/0092473
and US 2010/0317638, and U.S. Pat. No. 5,232,917, which are
incorporated herein by reference for the neuroactive steroids
described therein.
[0134] In particular embodiments, the steroids are one or more of a
series of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnane
steroids that include the major metabolites of progesterone and
deoxycorticosterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one
(allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one
(allotetrahydroDOC), respectively. These 3 alpha-hydroxysteroids do
not interact with classical intracellular steroid receptors but
bind stereoselectively and with high affinity to receptors for the
major inhibitory neurotransmitter in the brain, gamma-amino-butyric
acid (GABA).
[0135] In certain embodiments, the neuroactive steroids are
progesterone, allopregnanolone or other progesterone analogs. In a
particular embodiment, the neuroactive steroid is allopregnanolone
or a derivative thereof. Exemplary derivatives include, but are not
limited to,
(20R)-17beta(1-hydroxy-2,3-butadienyl)-5alpha-androstane-3.alpha.alpha-ol
(HBAO). Additional derivatives are described in WO 2012/127176.
[0136] As used herein "allopregnanolone" also encompasses
pharmaceutically acceptable, pharmacologically active derivatives
including individual enantiomers (dextrogyral and levrogyral
enantiomers) and their pharmaceutically acceptable salts, mixtures
of enantiomers and their pharmaceutically acceptable salts, and
active metabolites and their pharmaceutically acceptable salts,
unless otherwise noted. It is understood that in some cases dosages
of enantiomers, derivatives, and metabolites may need to be
adjusted based on relative activity of the racemic mixture of
allopregnanolone.
[0137] The lipophilic nature of allopregnanolone can make it
different to formulate for in vivo administration. As discussed
above, allopregnanolone can be formulated with a host, such as a
cyclodextrin to improve the solubility. Alternatively, or
additionally, allopregnanolone can be modified in an attempt to
improve the solubility. For example, polar groups can be introduced
onto position 16.alpha. with the goal of increasing water
solubility, brain accessibility, and potency of neuroactive
steroids as described in Kasal et al., J. Med. Chem., 52(7),
2119-215 (2009).
[0138] In some embodiments, the compounds described herein (e.g.,
allopregnanolone), is administered to a subject under general
anesthesia.
Anesthetics and Sedatives
[0139] An anesthetic (e.g., general anesthetic) agent or sedative
is a drug that can bring about, induce, and maintain a reversible
loss of consciousness. A sedative is a substance that induces
sedation by reducing irritability or excitement in a subject.
Intravenous injections of anesthetics are generally preferred to
inhalation, intramuscular or subcutaneous injections because they
are faster, generally less painful and more reliable. Exemplary
anesthetics include propofol, etomidate, barbiturates (e.g.,
pentobarbital, methohexital, thiopentone/thiopental),
benzodiazepines (e.g., as described herein, e.g., midazolam), and
ketamine.
[0140] In some embodiments, a subject that has been administered an
anesthetic agent or anesthetic is under general anesthesia.
Benzodiazepines
[0141] A benzodiazepine is a compound having a core chemical
structure of a fusion of a benzene ring and a diazepine ring. The
first benzodiazepine, chlordiazepoxide, was discovered in 1955.
Benzodiazepines can enhance the effect of the neurotransmitter
gamma-aminobutyric acid (GABA) at the GABA.sub.A receptor, and can
result in sedative, hypnotic (sleep-inducing), anxiolytic
(anti-anxiety), anticonvulsant, or muscle relaxant properties.
Benzodiazepines are categorized as either short-, intermediate- or
long-acting. Exemplary benzodiazapines include alprazolam,
bretazenil, bromazepam, brotizolam, chloridazepoxide, cinolazepam,
clonazepam, chorazepate, clotiazepam, cloxazolam, delorazepam,
diazepam, estazolam, etizolam, ethyl loflazepate, flunitrazepam,
flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam,
lorazepam, lormetazepam, medazepam, midazolam, nimetazepam,
nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam,
premazepam, pyrazolam, quazepam, temazepam, tatrazepam, and
triazolam.
[0142] A commonly used anesthetic agent is midazolam. In some
embodiments, the benzodiazepine is midazolam.
Barbiturates
[0143] Barbiturates are drugs that have been used as CNS
depressants and used e.g., to induce mild sedation, total
anesthesia; and used as an anxiolytic, hypnotic, anticonvulsant,
analgesic. Side effects of barbiturates include addiction
potential, e.g., physical and psychological addiction. Barbiturates
may be classified as e.g., ultrashort-acting,
short/intermediate-acting, and long-acting. Exemplary barbiturates
include pentobarbital, allobarbital, amobarbital, aprobarbital,
barbital, brallobarbital.
Propofol
[0144] Propofol (2,6-diisopropylphenol) is a drug, administered
intravenously, that provides loss of awareness and can be used with
other general anesthetic agents. The main advantages are favorable
operating conditions and rapid recovery, but have disadvantages
that include a relatively high incidence of apnea and blood
pressure reductions.
[0145] As used herein "neuroactive steroid" also encompasses
pharmaceutically acceptable, pharmacologically active derivatives
of these agents (e.g., neuroactive steroids including both
individual enantiomers of neuroactive steroids (dextrogyral and
levrogyral enantiomers)) and their pharmaceutically acceptable
salts, mixtures of enantiomers and their pharmaceutically
acceptable salts, and active metabolites and their pharmaceutically
acceptable salts, unless otherwise noted. It is understood that in
some cases dosages of enantiomers, derivatives, and metabolites may
need to be adjusted based on relative activity of the racemic
mixture.
[0146] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making the acid-addition or base-addition salts
thereof. Example of pharmaceutically acceptable salts include but
are not limited to mineral or organic acid salts of basic residues
such as amines; and alkali or organic salts of acidic residues such
as carboxylic acids. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. Such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and
the salts prepared from organic acids such as acetic, propionic,
succinic, glycolic, stearic, lactic, malic, tartaric, citric,
ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,
benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethane
disulfonic, oxalic, and isethionic salts.
[0147] The pharmaceutically acceptable salts of the compounds can
be synthesized from the parent compound, which contains a basic or
acidic moiety, by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000,
p. 704.
[0148] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problems or complications commensurate with a reasonable
benefit/risk ratio.
[0149] Compounds described herein such as neuroactive steroids,
generally contain one or more chiral centers, and thus exist as one
or more stereoisomers. Such stereoisomers can be prepared and/or
isolated as a single enantiomer, a mixture of diastereomers, or a
racemic mixture.
[0150] As used herein, the term "stereoisomers" refers to compounds
made up of the same atoms having the same bond order but having
different three-dimensional arrangements of atoms which are not
interchangeable. The three-dimensional structures are called
configurations. As used herein, the term "enantiomers" refers to
two stereoisomers which are non-superimposable minor images of one
another. As used herein, the term "optical isomer" is equivalent to
the term "enantiomer". As used herein the term "diastereomer"
refers to two stereoisomers which are not minor images but also not
superimposable. The terms "racemate", "racemic mixture" or "racemic
modification" refer to a mixture of equal parts of enantiomers. The
term "chiral center" refers to a carbon atom to which four
different groups are attached. Choice of the appropriate chiral
column, eluent, and conditions necessary to effect separation of
the pair of enantiomers is well known to one of ordinary skill in
the art using standard techniques (see e.g. Jacques, J. et al.,
"Enantiomers, Racemates, and Resolutions", John Wiley and Sons,
Inc. 1981).
Dosage and Pharmacokinetics
[0151] The compositions described herein include a therapeutically
effective amount of a neuroactive steroid, such as
allopregnanolone, and a therapeutically effective amount of a
benzodiazepine or anesthetic/sedative. In some embodiments, the
neuroactive steroid and benzodiazepine or anesthetic/sedative are
co-formulated into a single composition or dosage. In some
embodiments, the neuroactive steroid and benzodiazepine or
anesthetic/sedative are administered separately. In some
embodiments, the neuroactive steroid and benzodiazepine or
anesthetic/sedative are administered sequentially. In some
embodiments, the neuroactive steroid and benzodiazepine or
anesthetic/sedative are administered separately and sequentially.
In general, at least one of the neuroactive steroid and
benzodiazepine or anesthetic/sedative is administered parenterally
(e.g., intranasally, buccally, intravenously or intramuscularly,
for example, intramuscular (IM) injection or intravenously). In
some embodiments, both the neuroactive steroid and benzodiazepine
or anesthetic/sedative is administered parenterally (e.g.,
intranasally, buccally, intravenously or intramuscularly).
[0152] In one embodiment, the neuroactive steroid and/or the
benzodiazepine or anesthetic/sedative is administered in a dose
equivalent to parenteral administration of about 0.1 ng to about
100 g per kg of body weight, about 10 ng to about 50 g per kg of
body weight, about 100 ng to about 1 g per kg of body weight, from
about 1 .mu.g to about 100 mg per kg of body weight, from about 10
.mu.g to about 10 mg per kg of body weight, from about 100 .mu.g to
about 5 mg per kg of body weight, from about 250 .mu.g to about 3
mg per kg of body weight, from about 500 .mu.g to about 2 mg per kg
of body weight, from about 1 .mu.g to about 50 mg per kg of body
weight, from about 1 .mu.g to about 50 .mu.g per kg of body weight;
and from about 1 .mu.g to about 50 .mu.g per kg of body weight.
Alternatively, the amount of neuroactive steroid and/or the
benzodiazepine or anesthetic/sedative administered to achieve a
therapeutic effective dose is about 0.1 ng, 1 ng, 10 ng, 100 ng, 1
.mu.g, 10 .mu.g, 100 .mu.g, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6
mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16
mg, 17 mg, 18 mg, 19 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg,
80 mg, 90 mg, 100 mg, 500 mg per kg of body weight or greater.
[0153] In one embodiment, the neuroactive steroid is administered
as an intravenous bolus infusion in a dose equivalent to parenteral
administration of about 0.1 ng to about 100 g per kg of body
weight, about 10 ng to about 50 g per kg of body weight, about 100
ng to about 1 g per kg of body weight, from about 1 .mu.g to about
100 mg per kg of body weight, from about 1 .mu.g to about 50 mg per
kg of body weight, from about 10 .mu.g to about 5 mg per kg of body
weight, from about 100 .mu.g to about 500 .mu.g per kg of body
weight, from about 100 .mu.g to about 40 .mu.g per kg of body
weight, from about 150 .mu.g to about 350 .mu.g per kg of body
weight, from about 25 .mu.g to about 30 .mu.g per kg of body
weight. In one embodiment, the neuroactive steroid is administered
as an intravenous bolus infusion in a dose equivalent to parenteral
administration of about 100 to about 400 .mu.g/kg. In some
embodiments, the neuroactive steroid is administered as an
intravenous bolus infusion at about 150 to about 350 .mu.g/kg. In
some embodiments, the neuroactive steroid is administered as an
intravenous bolus infusion at about 250 to about 300 .mu.g/kg. In
specific embodiments, the neuroactive steroid is administered as an
intravenous bolus infusion in a dose equivalent to about 100
.mu.g/kg, 125 .mu.g/kg, 150 .mu.g/kg, 175 .mu.g/kg, 200 .mu.g/kg,
225 .mu.g/kg, 250 .mu.g/kg, 260 .mu.g/kg, 270 .mu.g/kg, 280
.mu.g/kg, 290 .mu.g/kg, 300 .mu.g/kg, 325 .mu.g/kg, or 350
.mu.g/kg.
[0154] In one embodiment, the neuroactive steroid is administered
as an intravenous bolus infusion in a dose equivalent to parenteral
administration of about 0.1 nmoles/L to about 100 mmoles/L per kg
of body weight, about 1 nmoles/L to about 10 .mu.moles/L per kg of
body weight, about 10 nmoles/L to about 10 .mu.moles/L per kg of
body weight, about 100 nmoles/L to about 10 .mu.moles/L per kg of
body weight, about 300 nmoles/L to about 5 mmoles/L per kg of body
weight, about 500 nmoles/L to about 5 .mu.moles/L per kg of body
weight, and about 750 nmoles/L to about 1 .mu.moles/L per kg of
body weight, Alternatively, the amount of neuroactive steroid
administered to achieve a therapeutic effective dose is about 0.1
ng, 1 ng, 10 ng, 100 ng, 1 .mu.g, 10 .mu.g, 100 .mu.g, 1 mg, 1.5
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21
mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg,
40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of
body weight or greater.
[0155] In some embodiments, the neuroactive steroid and/or the
benzodiazepine or anesthetic/sedative may be administered once or
several times a day. A duration of treatment may follow, for
example, once per day for a period of about 1, 2, 3, 4, 5, 6, 7
days or more. In some embodiments, either a single dose in the form
of an individual dosage unit or several smaller dosage units or by
multiple administration of subdivided dosages at certain intervals
is administered. For instance, a dosage unit can be administered
from about 0 hours to about 1 hr, about 1 hr to about 24 hr, about
1 to about 72 hours, about 1 to about 120 hours, or about 24 hours
to at least about 120 hours post injury. Alternatively, the dosage
unit can be administered from about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
30, 40, 48, 72, 96, 120 hours or longer post injury. Subsequent
dosage units can be administered any time following the initial
administration such that a therapeutic effect is achieved. For
instance, additional dosage units can be administered to protect
the subject from the secondary wave of edema that may occur over
the first several days post-injury.
[0156] Area under the curve (AUC) refers to the area under the
curve that tracks the serum concentration (nmol/L) of neuroactive
steroid and/or the benzodiazepine or anesthetic/sedative over a
given time following the IV administration of the reference
neuroactive steroid or the benzodiazepine or anesthetic/sedative
standard. By "reference neuroactive steroid" or "benzodiazepine
standard" or "anesthetic/sedative standard" is intended the
formulation of neuroactive steroid or the benzodiazepine or
anesthetic/sedative that serves as the basis for determination of
the total hourly neuroactive steroid and/or the benzodiazepine or
anesthetic/sedative dose to be administered to a human subject with
epilepsy or status epilepticus to achieve the desired positive
effect, i.e., a positive therapeutic response that is improved with
respect to that observed without administration of neuroactive
steroid and/or the benzodiazepine or anesthetic/sedative. In an
embodiment, the dose of neuroactive steroid and/or the
benzodiazepine or anesthetic/sedative to be administered provides a
final serum level of neuroactive steroid and/or the benzodiazepine
or anesthetic/sedative of about 100 ng/mL to about 1000 ng/mL,
about 1100 ng/mL to about 1450 ng/mL, 100 ng/mL to about 250 ng/mL,
about 200 ng/mL to about 350 ng/mL, about 300 ng/mL to about 450
ng/mL, about 350 ng/mL to about 450 ng/mL, about 400 ng/mL to about
550 ng/mL, about 500 ng/mL to about 650 ng/mL, about 600 ng/mL to
about 750 ng/mL, about 700 ng/mL to about 850 ng/mL, about 800
ng/mL to about 950 ng/mL, about 900 ng/mL to about 1050 ng/mL,
about 1000 ng/mL to about 1150 ng/mL, about 100 ng/mL to about 1250
ng/mL, about 1200 ng/mL to about 1350 ng/mL, about 1300 ng/mL to
about 1500 ng/m. In specific embodiments, the serum level of
neuroactive steroid and/or the benzodiazepine or
anesthetic/sedative is about 100 ng/mL, 250 ng/mL, 300 ng/mL, 350
ng/mL, 360 ng/mL, 370 ng/mL, 380 ng/mL, 390 ng/mL, 400 ng/mL, 410
ng/mL, 420 ng/mL, 430 ng/mL, 440 ng/mL, 450 ng/mL, 500 ng/mL, 750
ng/mL, 900 ng/mL, 1200 ng/mL, 1400 ng/mL, or 1600 ng/mL.
[0157] In an embodiment, the dose of neuroactive steroid to be
administered provides a final serum level of neuroactive steroid of
about 100 nmoles/L to about 5000 nmoles/L, about 100 nmoles/L to
about 2500 nmoles/L, about 100 nmoles/L to about 1000 nmoles/L, 100
nmoles/L to about 500 nmoles/L, about 100 nmoles/L to about 250
nmoles/L, about 100 nmoles/L to about 200 nmoles/L, about 125
nmoles/L to about 175 nmoles/L. or about 140 nmoles/L to about 160
nmoles/L. In specific embodiments, the serum level of neuroactive
steroid and/or the benzodiazepine or anesthetic/sedative is about
100 nmoles/L, 125 nmoles/L, 150 nmoles/L, 175 nmoles/L, 200
nmoles/L, 250 nmoles/L, 300 nmoles/L, 350 nmoles/L, 500 nmoles/L,
750 nmoles/L, 1000 nmoles/L, 1500 nmoles/L, 2000 nmoles/L, 2500
nmoles/L, or 5000 nmoles/L.
[0158] In some embodiments, the neuroactive steroid and the
benzodiazepine or anesthetic/sedative administration includes a
time period in which the administration of the benzodiazepine
therapy or anesthetic/sedative is weaned off.
[0159] As used herein, "weaning" or "weaning dose" refers to an
administration protocol which reduces the dose of administration to
the patient and thereby produces a gradual reduction and eventual
elimination of the benzodiazepine or anesthetic/sedative, either
over a fixed period of time or a time determined empirically by a
physician's assessment based on regular monitoring of a therapeutic
response of a subject. The period of the weaned benzodiazepine or
anesthetic/sedative administration can be about 12, 24, 36, 48
hours or longer. Alternatively, the period of the weaned
benzodiazepine or anesthetic/sedative administration can range from
about 1 to 12 hours, about 12 to about 48 hours, or about 24 to
about 36 hours. In some embodiments, the period of the weaned
benzodiazepine or anesthetic/sedative administration is about 24
hours.
[0160] The weaning employed could be a "linear" weaning. For
example, a "10%" linear weaning from 500 mg would go 500, 450, 400,
350, 300, 250, 200, 150, 100, 50. Alternatively, an exponential
weaning could be employed which, if the program outlined above is
used as an example, the exponential weaning would be, e.g., 500,
450, 405, 365, 329, 296, 266, 239, etc. Accordingly, about a 5%,
10%, 15%, 20%, 25%, 30%, 35%, or 40% linear or exponential weaning
could be employed in the methods of the invention. In addition, a
linear or exponential weaning of about 1% to 5%, about 6% to 10%,
about 11% to 15%, about 16% to 20%, about 21% to 25%, about 26% to
30%, about 31% to 35%, about 36% to 40% could be employed.
[0161] In other embodiments, the neuroactive steroid and the
benzodiazepine or anesthetic/sedative administration includes a
final time period in which the administration of neuroactive
steroid is tapered off.
[0162] As used herein, "tapered administration", "tapered dose",
and "downward taper dose" refers to an administration protocol
which reduces the dose of administration to the patient and thereby
produces a gradual reduction and eventual elimination of
neuroactive steroid, either over a fixed period of time or a time
determined empirically by a physician's assessment based on regular
monitoring of a therapeutic response of a subject. The period of
the tapered neuroactive steroid administration can be about 12, 24,
36, 48 hours or longer. Alternatively, the period of the tapered
neuroactive steroid administration can range from about 1 to 12
hours, about 12 to about 48 hours, or about 24 to about 36 hours.
In some embodiments, the period of the tapered neuroactive steroid
administration is about 24 hours.
[0163] The drug taper employed could be a "linear" taper. For
example, a "10%" linear taper from 500 mg would go 500, 450, 400,
350, 300, 250, 200, 150, 100, 50. Alternatively, an exponential
taper could be employed which, if the program outlined above is
used as an example, the exponential taper would be, e.g., 500, 450,
405, 365, 329, 296, 266, 239, etc. Accordingly, about a 5%, 10%,
15%, 20%, 25%, 30%, 35%, or 40% linear or exponential taper could
be employed in the methods of the invention. In addition, a linear
or exponential taper of about 1% to 5%, about 6% to 10%, about 11%
to 15%, about 16% to 20%, about 21% to 25%, about 26% to 30%, about
31% to 35%, about 36% to 40% could be employed. In some
embodiments, the drug taper is a about 25% linear taper.
[0164] Where a subject undergoing therapy exhibits a partial
response, or a relapse following completion of the first cycle of
the therapy, subsequent courses of neuroactive steroid therapy may
be needed to achieve a partial or complete therapeutic response.
Thus, subsequent to a period of time off from a first treatment
period, which may have included a constant neuroactive steroid
dosing regimen or a two-level neuroactive steroid and/or the
benzodiazepine or anesthetic/sedative dosing regimen, a subject may
receive one or more additional treatment periods including either
constant or two-level neuroactive steroid and/or the benzodiazepine
or anesthetic/sedative dosing regimens. Such a period of time off
between treatment periods is referred to herein as a time period of
discontinuance. It is recognized that the length of the time period
of discontinuance is dependent upon the degree of subject response
(i.e., complete versus partial) achieved with any prior treatment
periods of the neuroactive steroid.
[0165] In some embodiments, the neuroactive steroid is administered
as an intravenous infusion for about 5 minutes to about 1 week;
about 30 minutes to about 24 hours, about 1 hour to about 12 hours,
about 2 hours to about 12 hours, about 4 hours to about 12 hours,
about 6 hours to about 12 hours, about 6 hours to about 10 hours;
about 5 minutes to about 1 hour, about 5 minutes to about 30
minutes; about 12 hours to about 1 week, about 24 hours to about 1
week, about 2 days to about 5 days, or about 3 days to about 5
days. In one embodiment, the neuroactive steroid is administered as
an intravenous infusion for about 5, 10, 15, 30, 45, or 60 minutes
or longer; about 1, 2, 4, 6, 8, 10, 12, 16, or 24 hours or longer;
about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or longer.
[0166] These multiple treatment sessions are referred to herein as
maintenance cycles, where each maintenance cycle includes a
completed constant or two-level neuroactive steroid or the
benzodiazapine dosing regimen. By "completed two-level
progesterone, allopregnanolone, or a synthetic progestin dosing
regimen" is intended the subject has been administered both the
first period and the second period of neuroactive steroid or the
benzodiazapine dosing. The necessity for multiple maintenance
cycles can be assessed by monitoring the physiological and
behavioral improvement of the patient. The duration between
maintenance cycles can be about 1 hr, 15 hr, 1 day, 2 day, 3 day, 4
day, 5 day, 6 day or other such time periods falling within the
range of about 1 day to about 14 days.
[0167] In some embodiments, the maintenance cycle is about 2 days.
In some embodiments, the maintenance cycle is about 3 days. In some
embodiments, the maintenance cycle is about 4 days. In some
embodiments, the maintenance cycle is about 5 days.
[0168] In some embodiments, the maintenance cycle begins from about
30 minutes to about 24 hours, about 30 minutes to about 12 hours,
about 30 minutes to about 8 hours, about 30 minutes to about 4
hours, about 30 minutes to about 2 hours, about 30 minutes to about
1 hour following the initial bolus infusion administration. In some
embodiments, the maintenance cycle begins 30 minutes, 45 minutes, 1
hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24
hours, or longer following the initial bolus infusion
administration.
[0169] In one embodiment, the maintenance cycle the neuroactive
steroid is administered as an intravenous infusion at an amount of
neuroactive steroid/unit time of about 20 to about 5000
.mu.g/kg/hr. In some embodiments, the maintenance cycle the
neuroactive steroid is administered as an intravenous infusion at
an amount of neuroactive steroid/unit time of about 20 to about
2500 .mu.g/kg/hr. In some embodiments, the maintenance cycle the
neuroactive steroid is administered as an intravenous infusion at
an amount of neuroactive steroid/unit time of about 20 to about 500
.mu.g/kg/hr. In some embodiments, the neuroactive steroid is
administered as an intravenous infusion at a rate of about 20 to
about 250 .mu.g/kg/hr. In some embodiments, the neuroactive steroid
is administered as an intravenous infusion at an amount of
neuroactive steroid/unit time of about 20 to about 200 .mu.g/kg/hr.
In some embodiments, the neuroactive steroid is administered as an
intravenous infusion at an amount of neuroactive steroid/unit time
of about 20 to about 150 .mu.g/kg/hr. In some embodiments, the
neuroactive steroid is administered as an intravenous infusion at
an amount of neuroactive steroid/unit time of about 50 to about 100
.mu.g/kg/hr. In some embodiments, the neuroactive steroid is
administered as an intravenous infusion at an amount of neuroactive
steroid/unit time of about 70 to about 100 .mu.g/kg/hr. In specific
embodiments, the neuroactive steroid is administered as an
intravenous infusion at an amount of neuroactive steroid/unit time
of about 25 .mu.g/kg/hr, 50 .mu.g/kg/hr, 75 .mu.g/kg/hr, 80
.mu.g/kg/hr, 85 .mu.g/kg/hr, 86 .mu.g/kg/hr, 87 .mu.g/kg/hr, 88
.mu.g/kg/hr, 89 .mu.g/kg/hr, 90 .mu.g/kg/hr, 100 .mu.g/kg/hr, 125
.mu.g/kg/hr, 150 .mu.g/kg/hr, or 200 .mu.g/kg/hr.
[0170] In one embodiment, the neuroactive steroid is administered
as an intravenous infusion in a dose equivalent to parenteral
administration of about 0.1 ng to about 100 g per kg of body
weight, about 10 ng to about 50 g per kg of body weight, about 100
ng to about 1 g per kg of body weight, from about 1 .mu.g to about
100 mg per kg of body weight, from about 1 .mu.g to about 50 mg per
kg of body weight, from about 10 .mu.g to about 5 mg per kg of body
weight; and from about 10014 to about 1000 .mu.g per kg of body
weight. In one embodiment, the neuroactive steroid is administered
as an intravenous infusion in a dose equivalent to parenteral
administration of about 0.1 nmoles/L to about 100 .mu.moles/L per
kg of body weight, about 1 nmoles/L to about 10 .mu.moles/L per kg
of body weight, about 10 nmoles/L to about 10 mmoles/L per kg of
body weight, about 100 nmoles/L to about 10 .mu.moles/L per kg of
body weight, about 300 nmoles/L to about 5 .mu.moles/L per kg of
body weight, about 500 nmoles/L to about 5 mmoles/L per kg of body
weight, and about 750 nmoles/L to about 5 .mu.moles/L per kg of
body weight, Alternatively, the amount of neuroactive steroid
administered to achieve a therapeutic effective dose is about 0.1
ng, 1 ng, 10 ng, 100 ng, 1 .mu.g, 10 .mu.g, 100 .mu.g, 1 mg, 1.5
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21
mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg,
40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of
body weight or greater.
[0171] As used herein, "about" means approximately plus or minus
ten percent.
Formulations
[0172] Formulations described herein include a neuroactive steroid
and/or a benzodiazepine or anesthetic/sedative in combination with
one or more pharmaceutically acceptable excipients. In some
embodiments, a formulation includes both a neuroactive steroid and
a benzodiazepine or anesthetic/sedative.
Matrix Forming Materials
[0173] Matrix forming materials are materials which form strong,
viscous gels upon hydration and provide control of drug diffusion
and release. In hydrophilic matrix systems, matrix forming
materials are uniformly incorporated throughout the tablet. Upon
contact with water, the outer tablet layer is partially hydrated,
forming a gel layer. The rate of diffusion of the drug(s) out of
the gel layer and the rate of erosion of the gel layer determine
overall tablet dissolution and drug delivery rates. Examples of
matrix forming materials include cellulose ethers that are
water-soluble such as methylcellulose, ethyl cellulose and
hydroxypropyl methylcellulose.
Solubilization of Neuroactive Steroids
[0174] Many neuroactive steroids possess limited aqueous
solubility. In order to provide formulations capable of delivering
therapeutically effective dosages, a variety of methods can be
employed to enhance the solubility and bioavailability of
neuroactive steroids. See, for example, "Water-Insoluble Drug
Formulation", 2nd Edition, edited by Rong Liu (CRC Press, Boca
Raton, Fla., 2008). Using the techniques described below, a
solubilized formulation of one or more neuroactive steroids can be
prepared. These solubilized formulations can be further
incorporated into the parenteral and non-parenteral formulations
described in sections 2 and 3.
Inclusion Complexes
[0175] The solubility of neuroactive steroids can be improved by
inclusion complexation (e.g., host-guest formulations). Inclusion
complexes are formed when a nonpolar molecule (i.e., the guest,
such as a drug with poor aqueous stability) or portion of a
molecule inserts into a nonpolar cavity of another molecule or
group of molecules (i.e., the host). If the host molecule or
molecules exhibit water good solubility, the solubility of the
host-guest complex will be greater than the solubility of the guest
alone.
[0176] Inclusion complexes containing or comprising one or more
neuroactive steroids can be formed using any suitable host molecule
or molecules. For example, the water solubility of neuroactive
steroids can be increased by inclusion complexation with
cyclodextrins. Steroid-cyclodextrin complexes are known in the art.
See, for example, U.S. Pat. No. 7,569,557 to Backensfeld, et al.,
and U.S. Patent Application Publication No. US 2006/0058262 to
Zoppetti, et al.
[0177] Dextrans are soluble polysaccharides produced by bacteria
and yeasts. They are characterized by a predominance (>95%) of a
(1-6) backbone linkages and varying proportions of a(1-2), a(1-3)
and a(1-4) linkages typically at branch points 1, 2. Dextrins are
partially hydrolyzed glucose homopolymers composed exclusively of
a(1-4) backbone linkages.
[0178] Cyclodextrins are cyclic oligosaccharides containing or
comprising six (.alpha.-cyclodextrin), seven (.beta.-cyclodextrin),
eight (.gamma.-cyclodextrin), or more .alpha.-(1,4)-linked glucose
residues. The hydroxyl groups of the cyclodextrins are oriented to
the outside of the ring while the glucosidic oxygen and two rings
of the non-exchangeable hydrogen atoms are directed towards the
interior of the cavity. As a result, cyclodextrins possess a
hydrophobic inner cavity combined with a hydrophilic exterior which
conveys water solubility. Upon combination with a hydrophobic drug,
such as a neuroactive steroid, the neuroactive steroid (i.e., the
guest) inserts into the hydrophobic interior of the cyclodextrin
(i.e., the host). The host-guest complex retains water solubility
as a consequence of the hydrophobic exterior of the cyclodextrin
ring.
[0179] Neuroactive steroid-cyclodextrin complexes can, as
solubility permits, be incorporated into any of the parenteral and
non-parenteral formulations described below. If desired, the
aqueous solubility of solid neuoractive steroid-cyclodextrin
complexes can be further enhanced by isolating the neuoractive
steroid-cyclodextrin complex as a solid via lyophilization and/or
via micronizing the solid neuoractive steroid-cyclodextrin
complex.
##STR00001##
[0180] This cyclic orientation provides a truncated cone structure
that is hydrophilic on the exterior and lipophilic on the interior.
Cyclodextrin complexes are formed when a guest molecule is
partially or fully contained in the interior of the cavity. The
parent .alpha.-, .beta.-, and .gamma.-cyclodextrins (particularly
.beta.) have limited aqueous solubility and show toxicity when
given parenterally. Therefore, the parent cyclodextrin structure
can be chemically modified to generate a parenterally safe
CD-derivative. The modifications are typically made at one or more
of the 2, 3, or 6 position hydroxyls.
[0181] Neuroactive steroid-cyclodextrin complexes are preferably
formed from a cyclodextrin selected from the group consisting of
.alpha.-cyclodextrin, .beta.-cyclodextrin, .gamma.-cyclodextrin,
and derivatives thereof. The cyclodextrin may be chemically
modified such that some or all of the primary or secondary hydroxyl
groups of the macrocycle, or both, are functionalized with a
pendant group. Suitable pendant groups include, but are not limited
to, sulfinyl, sulfonyl, phosphate, acyl, and C.sub.1-C.sub.12 alkyl
groups optionally substituted with one or more (e.g., 1, 2, 3, or
4) hydroxy, carboxy, carbonyl, acyl, oxy, oxo; or a combination
thereof. Methods of modifying these alcohol residues are known in
the art, and many cyclodextrin derivatives are commercially
available, including sulfo butyl ether .beta.-cyclodextrins
available under the trade name CAPTISOL.RTM. from Ligand
Pharmaceuticals (La Jolla, Calif.).
[0182] Examples of suitable cyclodextrins for use in neuroactive
steroid, e.g., allopregnanolone formulations, can include
cyclodextrins disclosed in U.S. Pat. Nos. 5,874,418; 6,046,177; and
7,635,733, which are herein incorporated by reference. Other
examples of suitable cyclodextrins for use in neuroactive steroid
formulations non-exclusively include .alpha.-cyclodextrin;
.beta.-cyclodextrin; .gamma.-cyclodextrin; methyl
.alpha.-cyclodextrin; methyl .beta.-cyclodextrin; methyl
.gamma.-cyclodextrin; ethyl .beta.-cyclodextrin; butyl
.alpha.-cyclodextrin; butyl .beta.-cyclodextrin; butyl
.gamma.-cyclodextrin; pentyl .gamma.-cyclodextrin; hydroxyethyl
.beta.-cyclodextrin; hydroxyethyl .gamma.-cyclodextrin;
2-hydroxypropyl .alpha.-cyclodextrin; 2-hydroxypropyl
.beta.-cyclodextrin; 2-hydroxypropyl .gamma.-cyclodextrin;
2-hydroxybutyl .beta.-cyclodextrin; acetyl .alpha.-cyclodextrin;
acetyl .beta.-cyclodextrin; acetyl .gamma.-cyclodextrin; propionyl
.beta.-cyclodextrin; butyryl .beta.-cyclodextrin; succinyl
.alpha.-cyclodextrin; succinyl .beta.-cyclodextrin; succinyl
.gamma.-cyclodextrin; benzoyl .beta.-cyclodextrin; palmityl
.beta.-cyclodextrin; toluenesulfonyl .beta.-cyclodextrin; acetyl
methyl .beta.-cyclodextrin; acetyl butyl .beta.-cyclodextrin;
glucosyl .alpha.-cyclodextrin; glucosyl .beta.-cyclodextrin;
glucosyl .gamma.-cyclodextrin; maltosyl .alpha.-cyclodextrin;
maltosyl .beta.-cyclodextrin; maltosyl .gamma.-cyclodextrin;
.alpha.-cyclodextrin carboxymethylether; .beta.-cyclodextrin
carboxymethylether; .gamma.-cyclodextrin carboxymethylether;
carboxymethylethyl .beta.-cyclodextrin; phosphate ester
.alpha.-cyclodextrin; phosphate ester .beta.-cyclodextrin;
phosphate ester .gamma.-cyclodextrin;
.beta.-trimethylammonium-2-hydroxypropyl .beta.-cyclodextrin;
sulfobutyl ether .beta.-cyclodextrin; carboxymethyl
.alpha.-cyclodextrin; carboxymethyl .beta.-cyclodextrin;
carboxymethyl .gamma.-cyclodextrin, and combinations thereof.
[0183] Preferred cyclodextrins include, but are not limited to,
alkyl cyclodextrins, hydroxy alkyl cyclodextrins, such as hydroxy
propyl .beta.-cyclodextrin, carboxy alkyl cyclodextrins and
sulfoalkyl ether cyclodextrins, such as sulfo butyl ether
.beta.-cyclodextrin.
[0184] In particular embodiments, the cyclodextrin is a alpha,
beta, or gamma cyclodextrin having a plurality of charges (e.g.,
negative or positive) on the surface. In more particular
embodiments, the cyclodextrin is a .beta.-cyclodextrin containing
or comprising a plurality of functional groups that are negatively
charged at physiological pH. Examples of such functional groups
include, but are not limited to, carboxylic acid (carboxylate)
groups, sulfonate (RSO.sub.3.sup.-), phosphonate groups,
phosphinate groups, and amino acids that are negatively charged at
physiological pH. The charged functional groups can be bound
directly to the cyclodextrins or can be linked by a spacer, such as
an alkylene chain. The number of carbon atoms in the alkylene chain
can be varied, but is generally between about 1 and 10 carbons,
preferably 1-6 carbons, more preferably 1-4 carbons. Highly
sulfated cyclodextrins are described in U.S. Pat. No.
6,316,613.
[0185] In one embodiment, the cyclodextrins is a
.beta.-cyclodextrin functionalized with a plurality of sulfobutyl
ether groups. Such a cyclodextrins is sold under the trade name
CAPTISOL.RTM.. CAPTISOL.RTM. is a polyanionic beta-cyclodextrin
derivative with a sodium sulfonate salt separated from the
lipophilic cavity by a butyl ether spacer group, or sulfobutylether
(SBE). CAPTISOL.RTM. is not a single chemical species, but
comprised of a multitude of polymeric structures of varying degrees
of substitution and positional/regional isomers dictated and
controlled to a uniform pattern by a patented manufacturing process
consistently practiced and improved to control impurities.
[0186] CAPTISOL.RTM. contains six to seven sulfobutyl ether groups
per cyclodextrin molecule. Because of the very low pKa of the
sulfonic acid groups, CAPTISOL.RTM. carries multiple negative
charges at physiologically compatible pH values. The four-carbon
butyl chain coupled with repulsion of the end group negative
charges allows for an "extension" of the cyclodextrin cavity. This
often results in stronger binding to drug candidates than can be
achieved using other modified cyclodextrins. It also provides a
potential for ionic charge interactions between the cyclodextrin
and a positively charged drug molecule. In addition, these
derivatives impart exceptional solubility and parenteral safety to
the molecule. Relative to beta-cyclodextrin, CAPTISOL.RTM. provides
higher interaction characteristics and superior water solubility in
excess of 100 grams/100 ml, a 50-fold improvement.
[0187] In other embodiments, the cyclodextrins has plurality of
functional groups that are negatively charged at physiological pH.
Suitable positively charged groups include, but are not limited to,
quaternary ammonium groups. Exemplary cyclodextrins include, but
are not limited to,
mono-6(A)-butylammonium-6(A)-deoxy-beta-cyclodextrin tosylate
(BuAM-beta-CD) and Amine- and guanidine-derivatised
.beta.-cyclodextrin (.beta.CD).
[0188] Preferably, the cyclodextrin is present in an amount of from
about 0.1% to about 40% w/w of the overall formulation, preferably
from about 5% to about 40% w/w, more preferably about 10% to about
40% w/w, most preferably about 10% to about 35% w/w. In certain
embodiments, the concentration of the cyclodextrins is from about
15% to about 35% w/w, preferably from about 20% to about 35% w/w,
more preferably about 30% to about 35% w/w. In one embodiment, the
formulation contains about 1 to about 2, preferably about 1.5 mg
neuroactive steroid (e.g., allopregnanolone) per ml of
cyclodextrin, e.g., CAPTISOL.RTM..
Ion Exchange Resins
[0189] Ion exchange resins (IER) are high molecular weight water
insoluble polymers containing or comprising fixed positively or
negatively charged functional groups in their matrix, which have an
affinity for oppositely charged counter ions. IER are solid
insoluble high molecular weight poly electrolytes that can exchange
with surrounding medium reversibly and stoichiometrically.
IER are Styrene (Di Vinyl Benzene) copolymer containing or
comprising
[0190] Acidic groups: Carboxylic or sulphonic for Cation E.R.
[0191] Basic groups: Quaternary Ammonium for Anion E.R
[0192] Based on the nature of the ionic species being interchanged,
the IE process is known as either cation exchange (CE) or anion
exchange (AE). The IE process is competitive in nature. In
practice, drug in an ionic form (usually solution) is mixed with
the appropriate IER form a complex, known as `resinate`.
[0193] The performance of resinates are governed by several
factors, such as:
1. The pH and temperature of the drug solution; 2. The molecular
weight and charge intensity of the drug and IER;
3. Geometry;
[0194] 4. Mixing speed; 5. Ionic strength of the drug solution; 6.
Degree of cross linking and particle size of the IER; 7. The nature
of solvent; and 8. Contact time between the drug species and the
IER.
[0195] In general, IER consist of spherical beads of approximately
0.5-1.2 mm in diameter. The most common type is an opaque yellow in
color, although other colors are also reported. The constitution of
each spherical particle of IER is similar to that of a homogeneous
gel. The shrinkage or expansion of the spherical volume that takes
place is based on the ionic environment in which the IER is
present.
[0196] A major drawback of controlled or sustained release systems
is dose dumping, resulting in increased risk of toxicity. Ion
exchange resins offers better drug retaining properties and
prevention of dose dumping. The polymeric (physical) and ionic
(chemical) properties of ion exchange resin will release the drugs
more uniformly than that of simple matrices (because of physical
properties only). Drug loaded onto the strong IER resinates
provides simplest form of controlled or sustained release delivery
system. Resinates can be filled directly in a capsule, suspended in
liquids, suspended in matrices or compressed into tablets. Drug
will be slowly released by ion exchange phenomenon and
absorbed.
[0197] Microencapsulation of resinates provides better control over
the drug release for oral or depo release. The absorption of the
drug from coated resinates is a consequence of the entry of the
counter ions into the coated resinates and release of drug ions
from drug resin complex by the ion exchange process and diffusion
of drug ions through the membrane into the dissolution medium.
Designed release rate at the desired level can be obtained by
optimization of coating thickness. Microencapsulation of resinates
can be achieved by air suspension coating (Wurster process),
interfacial polymerization, solvent evaporation or pan coating.
[0198] Modification of the coating of resinates for example, by
pretreatment with polyethylene glycol 400, can be used to maintain
the geometry and improve coating process. The pretreated resinates
are then coated with ethyl cellulose or any other water insoluble
polymer. The polyethylene glycol helps in controlling the swelling
rate of matrix in water, while an outer ethyl cellulose coating
modifies the diffusion pattern of ions in and out of system. A
major drawback of controlled or sustained release systems is dose
dumping, resulting in increased risk of toxicity. Ion exchange
resins offers better drug retaining properties and prevention of
dose dumping. The polymeric (physical) and ionic (chemical)
properties of ion exchange resin release the drugs more uniformly
than that of simple matrices.
[0199] Drug loaded onto the strong IER resinates provides simplest
form of controlled or sustained release delivery system. Resinates
can be filled directly in a capsule, suspended in liquids,
suspended in matrices or compressed into tablets. Drug will be
slowly released by ion exchange phenomenon and absorbed.
[0200] There are a few ion exchange resins suitable for intravenous
administration of drug. For example, Shimada, et al., in Jpn J.
Antibiot. 1985 September; 38(9):2496-502, describes a clinical
study on unmodified intravenous dried ion-exchange resin treated
human normal immunoglobulin, SM-4300 that showed efficacy with no
obvious antipyretic effect, opsonic effect or healing
impairment.
Lipid Carriers
[0201] To facilitate the administration of neuroactive steroids
possessing poor aqueous solubility, a variety of lipid carriers may
be used.
Lipid Emulsions
[0202] Neuroactive steroids can be combined suspended or dissolved
using a lipid emulsion. Lipid emulsions are known in the art. See,
for example, U.S. Pat. No. 6,361,792 to Long, et. al.; U.S. Pat.
No. 7,550,155 to Zhang, et al., and U.S. Patent Application
Publication No. US 2006/0067952. Lipid emulsions formulations
typically include one or more neuroactive steroids, an oil
component, an emulsifier, and water.
[0203] The oil component can be a monoglyceride, a diglyceride, a
triglyceride, or combinations thereof. In some cases, the oil
component includes an ester formed between one or more fatty acids
and an alcohol other than glycerol. The oil component can be, for
example, a vegetable oil such as almond oil, borage oil, black
currant seed oil, corn oil, safflower oil, soybean oil, sesame oil,
cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil,
palm oil, canola oil, or combinations thereof. Vegetable oils are
typically long-chain triglycerides formed from C.sub.14-C.sub.22
fatty acids. The oil component can also include medium chain
triglycerides formed from C8-C12 fatty acids, such as Miglyol 812,
Crodamol.RTM. GTCC-PN, or Neobees M-5 oil.
[0204] The emulsifier serves to stabilize the lipid emulsion by
preventing separation of the emulsion into individual oil and
aqueous phases. Suitable emulsifiers include, but are not limited
to, propylene glycol mono- and di-fatty acid esters,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty
acid esters, polyoxyethylene-polyoxypropylene co-polymers and block
co-polymers, salts of fatty alcohol sulphates, sorbitan fatty acid
esters, esters of polyethylene-glycol glycerol ethers, oil and wax
based emulsifiers, glycerol monostearate, glycerine sorbitan fatty
acid esters and phospholipids. In some cases the emulsifier is a
phospholipid.
[0205] In some cases, the emulsifier is a vitamin E derivative.
Suitable vitamin E derivatives include, but are not limited to,
.alpha.-tocopheryl oxalate, .alpha.-tocopheryl malonate,
.alpha.-tocopheryl succinate, .alpha.-tocopheryl glutarate,
.alpha.-tocopheryl adipate, .alpha.-tocopheryl pimelate,
.alpha.-tocopheryl suberate, .alpha.-tocopheryl azelate, and
D-.alpha.-tocopheryl polyethylene glycol 1000 succinate (vitamin E
TPGS).
[0206] Exemplary phospholipids include, phosphatidyl chlorine,
lecithin (a mixture of choline ester of phosphorylated
diacylglyceride), phosphatidylethanolamine, phosphatidylglycerol,
phosphatidic acid with about 4 to about 22 carbon atoms, and more
generally from about 10 to about 18 carbon atoms and varying
degrees of saturation. Preferably, the phospholipid is of natural
origin. Naturally occurring phospholipids include soy lecithin, egg
lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin,
sphingosine, gangliosides, and phytosphingosine, and combinations
thereof.
[0207] Suitable lipid emulsions generally contain between about 1%
and 40% w/v oil component and between about 0.1% and 7.5% w/v
emulsifier. Suitable commercially available lipid emulsions include
lipid emulsions containing or comprising soybean oil, such as
Intralipid.RTM. 10%, Intralipid.RTM.20%, and Intralipid.RTM. 30%,
as well as lipid emulsions containing or comprising a mixture of
soybean and safflower oils, such as Liposyn.RTM. II 10% and
Liposyn.RTM. II 20%.
[0208] Lipid emulsions can optionally contain one or more
additional components. For example, lipid formulations can contain
one or more non-aqueous miscible co-solvents, such as an alcohol or
glycol. In some preferred formulations, glycerol and/or propylene
glycol is present as a co-solvent.
[0209] Many lipid emulsions are capable of supporting bacterial
growth. Accordingly, in some cases, one or more components may be
added to the lipid emulsion formulation to prevent or retard
bacterial growth, for example disodium edatate, citric acid,
metabisulfate, benzyl alcohol, one or more parabens, chlorobutanol,
phenol, sorbic acid, or thimerosal.
[0210] Additionally, lipid emulsions can contain one or more agents
used to modify or stabilize the pH of the solution, including
phosphate buffers, acetate buffers, and citrate buffers.
[0211] In one embodiment, the formulation is an oil-in-water
emulsion containing or comprising a therapeutically effective
amount of one or more neuroactive steroids dissolved in a solution
containing or comprising between about 1% w/v and about 25% w/v
soybean oil, between about 0.5% and about 7.5% w/v egg yolk
phospholipid, and between about 0.5% w/v and about 5% w/v of a
miscible co-solvent.
[0212] In another embodiment, the formulation is an oil-in-water
emulsion containing or comprising a therapeutically effective
amount of one or more neuroactive steroids dissolved in a solution
containing or comprising between about 1% w/v and about 15% w/v
soybean oil, between about 1% w/v and about 15% w/v safflower oil,
between about 0.5% and about 7.5% w/v egg phosphatides, and between
0.5% w/v and about 5% w/v of a miscible co-solvent.
[0213] Lipid emulsions can be administered as described above, or
incorporated into the parenteral formulations described below.
Liposomes
[0214] One or more neuroactive steroids can be incorporated into
liposomes. As is known in the art, liposomes are generally derived
from phospholipids or other lipid substances. See, for example,
"Remington--The science and practice of pharmacy", 20th Edition,
Jennaro et. al., (Phila, Lippencott, Williams, and Wilkens,
2000).
[0215] Liposomes are generally derived from phospholipids or other
lipid substances. Liposomes are formed by mono- or multi-lamellar
hydrated liquid crystals that are dispersed in an aqueous medium.
Any nontoxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes can be used. The disclosed
compositions in liposome form can contain, in addition to one or
more neuroactive steroids, stabilizers, preservatives, excipients,
and other suitable excipients.
[0216] Examples of suitable lipids are the phospholipids and the
phosphatidylcholines (lecithins), both natural and synthetic.
Methods of forming liposomes are known in the art. See, e.g.,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York p. 33 et seq., 1976. The liposomes can be cationic
liposomes (e.g., based on DOTMA, DOPE, DC cholesterol) or anionic
liposomes. Liposomes can further comprise proteins to facilitate
targeting a particular cell, if desired. Administration of a
composition comprising a compound and a cationic liposome can be
administered to the blood afferent to a target organ or inhaled
into the respiratory tract to target cells of the respiratory
tract.
[0217] One or more neuroactive steroids can formulated using
commercially available liposome preparations such as
LIPOFECTIN.RTM., LIPOFECTAMIE.RTM. (GIBCO-BRL, Inc., Gaithersburg,
Md.), SUPERFECT.RTM. (Qiagen, Inc. Hilden, Germany) and
TRANSFECTAM.RTM. (Promega Biotec, Inc., Madison, Wis.), as well as
other liposomes developed according to procedures standard in the
art. Liposomes where the diffusion of the compound or delivery of
the compound from the liposome is designed for a specific rate or
dosage can also be used.
[0218] One or more neuroactive steroids can also be formulated
using noisomes. Noisomes are multilamellar or unilamellar vesicles
involving non-ionic surfactants. An aqueous solution of solute is
enclosed by a bilayer resulting from the organization of surfactant
macromolecules. Similar to liposomes, noisomes are used in targeted
delivery of, for example, anticancer drugs, including methotrexate,
doxorubicin, and immunoadjuvants. They are generally understood to
be different from transferosomes, vesicles prepared from
amphiphilic carbohydrate and amino group containing or comprising
polymers, e.g., chitosan.
[0219] One or more neuroactive steroids can also be delivered using
nanoerythrosomes. Nanoerythrosomes are nano-vesicles made of red
blood cells via dialysis through filters of defined pore size.
These vesicles can be loaded with one or more neuroactive
steroids.
Lipid Nanoemulsions
[0220] Lipid nanoemulsions can also be used. Lipid nanoemulsions
are known in the art. See, for example, U.S. Patent Application
Publication No. US 2007/0207173 to Chen, et al, and U.S. Patent
Application Publication No. US 2001/0045050 to Elbayoumi, et al.
Lipid nanoemulsions can be prepared by microemulsification of any
of the lipid emulsions described above using for example, a high
pressure homogenizer, or via a phase inversion temperature method
(PIT).
[0221] In preferred lipid nanoemulsions containing or comprising
neuroactive steroids, vitamin E succinate and/or Vitamin E TPGS are
included as emulsifiers.
[0222] The lipid nanoemulsion can further be lyophilized if
desired. See, for example, U.S. Patent Publication No. US
2011/0015266.
[0223] Lipid anoemulsions can be administered as described above,
or incorporated into the parenteral or non-parenteral formulations
described below.
[0224] The pre-concentrate includes an oil phase which has at least
one fatty acid oil. Fatty acid oils of the present invention
include at least one polyunsaturated fatty acid. The term
"polyunsaturated fatty acid" include those fatty acids having at
least 50 weight percent or more of polyunsaturated fatty acids.
Polyunsaturated fat can be found in grain products, fish and sea
food (herring, salmon, mackerel, halibut), soybeans, and fish oil.
Polyunsaturated fatty acids include omega-3 fatty acids and omega-6
fatty acids. Polyunsaturated fatty acids include linolic acid and
linolenic acid. Preferable polyunsaturated fatty acids include
eicosapentaenoic acid, salts of eicosapentaenoic acid,
docosahexaenoic acid, salts of docosahexaenoic acid, triglycerides
of eicosapentaenoic acid, triglycerides of docosahexaenoic acid,
ethyl esters of eicosapentaenoic acid, or ethyl esters of
docosahexaenoic acid.
[0225] Polyunsaturated fatty acids include omega-3 fatty acid oils
and medium chain triglycerides (MCT). A medium chain triglyceride
contains about 6 to 14 carbon atoms, preferably about 8 to 12
carbon atoms are suitable for use in the oil phase. Preferable
medium chain glyceride includes, for example, caprylic/capric
triglyceride such as "Migriol 810", "Migriol 812" (both trade
names, manufactured by Huls Co., Ltd., available from Mitsuba
Trading Co., Ltd.), a glyceryl tricaprylate (tricaprylin) such as
"Panasate 800" (trade name, manufactured by NOF Corporation,
Japan).
[0226] The pre-concentrate includes an emulsifier component. The
emulsifier component has one or more surfactants. Surfactants
include any molecule having both a polar head group, which
energetically prefers solvation by water, and a hydrophobic tail
that is not well solvated by water. The ratio of the oil phase to
the emulsifier component is important for the toxicity of the
nanoemulsion prepared from the pre-concentrate. Surfactants
suitable for use with the pre-concentrate and emulsion include a
variety of anionic and nonionic surfactants, as well as other
emulsifying compounds that are capable of promoting the formation
of oil-in-water emulsions; so long as they are on the GRAS
(Generally Recognized as Safe) list and are approved for human
consumption such as lecithin, solutol HS-15 (polyoxyethylene esters
of 12-hydroxystearic acid), polysorbate 80 or Cremophore EL
(polyethoxylated castor oil). See McCutcheon's Volume 1:
Emulsifiers and Detergents North American Edition, 1996
(incorporated herein by reference).
Formulations for Parenteral Administration
[0227] The compounds (e.g., allopregnanolone) described herein can
be formulated for parenteral administration. Preferred doses,
dosage forms, or modes of administration are parenteral, e.g.,
intranasally, buccally, intravenous, intramuscular, subcutaneous,
intraparenteral, bucosal, sublingual, intraocular, and topical
(e.g., intravenous or intramuscular). In another embodiment, the
informational material can include instructions to administer the
compound described herein to a suitable subject, e.g., a human,
e.g., a human having or at risk for a disorder described herein. In
some preferred embodiments, at least one of the neuroactive steroid
and benzodiazepine or anesthetic/sedative is formulated for
parenteral administration. In some embodiments, both the
neuroactive steroid and the benzodiazepine or anesthetic/sedative
are formulated for parenteral administration.
[0228] Parenteral formulations can be prepared as aqueous
compositions using techniques known in the art. Typically, such
compositions can be prepared as injectable formulations, for
example, solutions or suspensions; solid forms suitable for using
to prepare solutions or suspensions upon the addition of a
reconstitution medium prior to injection; emulsions, such as
water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and
microemulsions thereof, liposomes, or emulsomes.
[0229] In some embodiments, the parenteral formulations are
prepared as an injectable formulation, e.g., for intravenous
administration. In some embodiments, the parenteral formulation
comprises a compound (e.g., a neurosteroid as described herein,
e.g., allopregnanolone), and a cyclodextrin, e.g., a
.beta.-cyclodextrin, e.g., a sulfo butyl ether .beta.-cyclodextrin,
e.g., CAPTISOL.RTM.). In some embodiments, the parenteral
formulation comprises allopregnanolone and a sulfo butyl ether
.beta.-cyclodextrin, e.g., CAPTISOL.RTM..
[0230] The carrier can be a solvent or dispersion medium containing
or comprising, for example, water (e.g., Water for Injection, USP),
ethanol, one or more polyols (e.g., glycerol, propylene glycol, and
liquid polyethylene glycol), oils, such as vegetable oils (e.g.,
peanut oil, corn oil, sesame oil, etc.), and combinations
thereof.
[0231] The proper fluidity can be maintained, for example, by the
use of a coating, such as lecithin, by the maintenance of the
required particle size in the case of dispersion and/or by the use
of surfactants. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride.
[0232] Solutions and dispersions of the active compounds as the
free acid or base or pharmacologically acceptable salts thereof can
be prepared in water or another solvent or dispersing medium
suitably mixed with one or more pharmaceutically acceptable
excipients including, but not limited to, surfactants, dispersants,
emulsifiers, pH modifying agents, and combination thereof.
[0233] Suitable surfactants may be anionic, cationic, amphoteric or
nonionic surface active agents. Suitable anionic surfactants
include, but are not limited to, those containing or comprising
carboxylate, sulfonate and sulfate ions. Examples of anionic
surfactants include sodium, potassium, ammonium of long chain alkyl
sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene
sulfonate; dialkyl sodium sulfosuccinates, such as sodium
dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as
sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such
as sodium lauryl sulfate. Cationic surfactants include, but are not
limited to, quaternary ammonium compounds such as benzalkonium
chloride, benzethonium chloride, cetrimonium bromide, stearyl
dimethylbenzyl ammonium chloride, polyoxyethylene and coconut
amine. Examples of nonionic surfactants include ethylene glycol
monostearate, propylene glycol myristate, glyceryl monostearate,
glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose
acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene
monolaurate, polysorbates, polyoxyethylene octylphenylether,
PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene
glycol butyl ether, Poloxamer.RTM. 401, stearoyl
monoisopropanolamide, and polyoxyethylene hydrogenated tallow
amide. Examples of amphoteric surfactants include sodium
N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,
myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
[0234] The formulation can contain a preservative to prevent the
growth of microorganisms. Suitable preservatives include, but are
not limited to, parabens, chlorobutanol, phenol, sorbic acid, and
thimerosal. The formulation may also contain an antioxidant to
prevent degradation of the active agent(s).
[0235] The formulation is typically buffered to a pH of 3-8 for
parenteral administration upon reconstitution. Suitable buffers
include, but are not limited to, phosphate buffers, acetate
buffers, and citrate buffers.
[0236] Water soluble polymers are often used in formulations for
parenteral administration. Suitable water-soluble polymers include,
but are not limited to, polyvinylpyrrolidone, dextran,
carboxymethylcellulose, and polyethylene glycol.
[0237] Sterile injectable solutions can be prepared by
incorporating the active compounds in the required amount in the
appropriate solvent or dispersion medium with one or more of the
excipients listed above, as required, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating
the various sterilized active ingredients into a sterile vehicle
which contains the basic dispersion medium and the required other
ingredients from those listed above. In the case of sterile powders
for the preparation of sterile injectable solutions, the preferred
methods of preparation are vacuum-drying and freeze-drying
techniques which yield a powder of the active ingredient plus any
additional desired ingredient from a previously sterile-filtered
solution thereof. The powders can be prepared in such a manner that
the particles are porous in nature, which can increase dissolution
of the particles. Methods for making porous particles are well
known in the art.
[0238] In some embodiments, at least one of the neuroactive steroid
or the benzodiazepine or anesthetic/sedative is formulated for
intranasal, buccal, intramuscular or intravenous administration
(e.g., intramuscular or intravenous administration). In some
embodiments, both of the neuroactive steroid and the benzodiazepine
or anesthetic/sedative are formulated for intranasal, buccal,
intramuscular or intravenous administration (e.g., intramuscular or
intravenous administration).
[0239] The parenteral formulations described herein can be
formulated for controlled release including immediate release,
delayed release, extended release, pulsatile release, and
combinations thereof.
Nano- and Microparticles
[0240] For parenteral administration, the compounds, and optionally
one or more additional active agents, can be incorporated into
microparticles, nanoparticles, or combinations thereof that provide
controlled release. In embodiments wherein the formulations
contains two or more drugs, the drugs can be formulated for the
same type of controlled release (e.g., delayed, extended,
immediate, or pulsatile) or the drugs can be independently
formulated for different types of release (e.g., immediate and
delayed, immediate and extended, delayed and extended, delayed and
pulsatile, etc.).
[0241] For example, the compounds and/or one or more additional
active agents can be incorporated into polymeric microparticles
which provide controlled release of the drug(s). Release of the
drug(s) is controlled by diffusion of the drug(s) out of the
microparticles and/or degradation of the polymeric particles by
hydrolysis and/or enzymatic degradation. Suitable polymers include
ethylcellulose and other natural or synthetic cellulose
derivatives.
[0242] Polymers which are slowly soluble and form a gel in an
aqueous environment, such as hydroxypropyl methylcellulose or
polyethylene oxide may also be suitable as materials for drug
containing or comprising microparticles. Other polymers include,
but are not limited to, polyanhydrides, poly(ester anhydrides),
polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA),
poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybutyrate (PHB) and
copolymers thereof, poly-4-hydroxybutyrate (P4HB) and copolymers
thereof, polycaprolactone and copolymers thereof, and combinations
thereof.
[0243] Alternatively, the drug(s) can be incorporated into
microparticles prepared from materials which are insoluble in
aqueous solution or slowly soluble in aqueous solution, but are
capable of degrading within the GI tract by means including
enzymatic degradation, surfactant action of bile acids, and/or
mechanical erosion. As used herein, the term "slowly soluble in
water" refers to materials that are not dissolved in water within a
period of 30 minutes. Preferred examples include fats, fatty
substances, waxes, wax-like substances and mixtures thereof.
Suitable fats and fatty substances include fatty alcohols (such as
lauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty
acids and derivatives, including, but not limited to, fatty acid
esters, fatty acid glycerides (mono-, di- and tri-glycerides), and
hydrogenated fats. Specific examples include, but are not limited
to hydrogenated vegetable oil, hydrogenated cottonseed oil,
hydrogenated castor oil, hydrogenated oils available under the
trade name Sterotex.RTM., stearic acid, cocoa butter, and stearyl
alcohol. Suitable waxes and wax-like materials include natural or
synthetic waxes, hydrocarbons, and normal waxes. Specific examples
of waxes include beeswax, glycowax, castor wax, carnauba wax,
paraffins and candelilla wax. As used herein, a wax-like material
is defined as any material which is normally solid at room
temperature and has a melting point of from about 30 to 300.degree.
C.
[0244] In some cases, it may be desirable to alter the rate of
water penetration into the microparticles. To this end,
rate-controlling (wicking) agents may be formulated along with the
fats or waxes listed above. Examples of rate-controlling materials
include certain starch derivatives (e.g., waxy maltodextrin and
drum dried corn starch), cellulose derivatives (e.g.,
hydroxypropylmethyl-cellulose, hydroxypropylcellulose,
methylcellulose, and carboxymethylcellulose), alginic acid, lactose
and talc. Additionally, a pharmaceutically acceptable surfactant
(for example, lecithin) may be added to facilitate the degradation
of such microparticles.
[0245] Proteins which are water insoluble, such as zein, can also
be used as materials for the formation of drug containing or
comprising microparticles. Additionally, proteins, polysaccharides
and combinations thereof which are water soluble can be formulated
with drug into microparticles and subsequently cross-linked to form
an insoluble network. For example, cyclodextrins can be complexed
with individual drug molecules and subsequently cross-linked.
[0246] Encapsulation or incorporation of drug into carrier
materials to produce drug containing or comprising microparticles
can be achieved through known pharmaceutical formulation
techniques. In the case of formulation in fats, waxes or wax-like
materials, the carrier material is typically heated above its
melting temperature and the drug is added to form a mixture
comprising drug particles suspended in the carrier material, drug
dissolved in the carrier material, or a mixture thereof.
Microparticles can be subsequently formulated through several
methods including, but not limited to, the processes of congealing,
extrusion, spray chilling or aqueous dispersion. In a preferred
process, wax is heated above its melting temperature, drug is
added, and the molten wax-drug mixture is congealed under constant
stirring as the mixture cools. Alternatively, the molten wax-drug
mixture can be extruded and spheronized to form pellets or beads.
Detailed descriptions of these processes can be found in
"Remington--The science and practice of pharmacy", 20th Edition,
Jennaro et. al., (Phila, Lippencott, Williams, and Wilkens,
2000).
[0247] For some carrier materials it may be desirable to use a
solvent evaporation technique to produce drug containing or
comprising microparticles. In this case drug and carrier material
are co-dissolved in a mutual solvent and microparticles can
subsequently be produced by several techniques including, but not
limited to, forming an emulsion in water or other appropriate
media, spray drying or by evaporating off the solvent from the bulk
solution and milling the resulting material.
[0248] In some embodiments, drug in a particulate form is
homogeneously dispersed in a water-insoluble or slowly water
soluble material. To minimize the size of the drug particles within
the composition, the drug powder itself may be milled to generate
fine particles prior to formulation. The process of jet milling,
known in the pharmaceutical art, can be used for this purpose. In
some embodiments drug in a particulate form is homogeneously
dispersed in a wax or wax like substance by heating the wax or wax
like substance above its melting point and adding the drug
particles while stirring the mixture. In this case a
pharmaceutically acceptable surfactant may be added to the mixture
to facilitate the dispersion of the drug particles.
[0249] The particles can also be coated with one or more modified
release coatings. Solid esters of fatty acids, which are hydrolyzed
by lipases, can be spray coated onto microparticles or drug
particles. Zein is an example of a naturally water-insoluble
protein. It can be coated onto drug containing or comprising
microparticles or drug particles by spray coating or by wet
granulation techniques. In addition to naturally water-insoluble
materials, some substrates of digestive enzymes can be treated with
cross-linking procedures, resulting in the formation of non-soluble
networks. Many methods of cross-linking proteins, initiated by both
chemical and physical means, have been reported. One of the most
common methods to obtain cross-linking is the use of chemical
cross-linking agents. Examples of chemical cross-linking agents
include aldehydes (gluteraldehyde and formaldehyde), epoxy
compounds, carbodiimides, and genipin. In addition to these
cross-linking agents, oxidized and native sugars have been used to
cross-link gelatin (Cortesi, R., et al., Biomaterials 19 (1998)
1641-1649). Cross-linking can also be accomplished using enzymatic
means; for example, transglutaminase has been approved as a GRAS
substance for cross-linking seafood products. Finally,
cross-linking can be initiated by physical means such as thermal
treatment, UV irradiation and gamma irradiation.
[0250] To produce a coating layer of cross-linked protein
surrounding drug containing or comprising microparticles or drug
particles, a water soluble protein can be spray coated onto the
microparticles and subsequently cross-linked by the one of the
methods described above. Alternatively, drug containing or
comprising microparticles can be microencapsulated within protein
by coacervation-phase separation (for example, by the addition of
salts) and subsequently cross-linked. Some suitable proteins for
this purpose include gelatin, albumin, casein, and gluten.
Polysaccharides can also be cross-linked to form a water-insoluble
network. For many polysaccharides, this can be accomplished by
reaction with calcium salts or multivalent cations which cross-link
the main polymer chains. Pectin, alginate, dextran, amylose and
guar gum are subject to cross-linking in the presence of
multivalent cations. Complexes between oppositely charged
polysaccharides can also be formed; pectin and chitosan, for
example, can be complexed via electrostatic interactions.
[0251] In some embodiments, at least one of the neuroactive steroid
and/or the benzodiazepine or anesthetic/sedative is formulated for
intranasal, buccal, intramuscular or intravenous administration
(e.g., intramuscular or intravenous administration). In some
embodiments, both of the neuroactive steroid and the benzodiazepine
or anesthetic/sedative are formulated for intranasal, buccal,
intramuscular or intravenous administration (e.g., intramuscular or
intravenous administration).
[0252] The compounds described herein can be formulated for depot
injection. In a depot injection, the active agent is formulated
with one or more pharmaceutically acceptable carriers that provide
for the gradual release of active agent over a period of hours or
days after injection. The depot formulation can be administered by
any suitable means; however, the depot formulation is typically
administered via subcutaneous or intramuscular injection.
[0253] A variety of carriers may be incorporated into the depot
formulation to provide for the controlled release of the active
agent. In some cases, depot formulations contain one or more
biodegradable polymeric or oligomeric carriers. Suitable polymeric
carriers include, but are not limited to poly(lactic acid) (PLA),
poly(lactic-co-glycolic acid) (PLGA), poly(lactic
acid)-polyethyleneglycol (PLA-PEG) block copolymers,
polyanhydrides, poly(ester anhydrides), polyglycolide (PGA),
poly-3-hydroxybutyrate (PHB) and copolymers thereof,
poly-4-hydroxybutyrate (P4HB), polycaprolactone, cellulose,
hydroxypropyl methylcellulose, ethylcellulose, as well as blends,
derivatives, copolymers, and combinations thereof.
[0254] In depot formulations containing or comprising a polymeric
or oligomeric carrier, the carrier and active agent can be
formulated as a solution, an emulsion, or suspension. One or more
neuroactive steroids, and optionally one or more additional active
agents, can also be incorporated into polymeric or oligomeric
microparticles, nanoparticles, or combinations thereof.
[0255] In some cases, the formulation is fluid and designed to
solidify or gel (i.e., forming a hydrogel or organogel) upon
injection. This can result from a change in solubility of the
composition upon injection, or for example, by injecting a
pre-polymer mixed with an initiator and/or cross-linking agent. The
polymer matrix, polymer solution, or polymeric particles entrap the
active agent at the injection site. As the polymeric carrier is
gradually degraded, the active agent is released, either by
diffusion of the agent out of the matrix and/or dissipation of the
matrix as it is absorbed. The release rate of the active agent from
the injection site can be controlled by varying, for example, the
chemical composition, molecular weight, crosslink density, and
concentration of the polymeric carrier. Examples of such systems
include those described in U.S. Pat. Nos. 4,938,763, 5,480,656 and
6,113,943.
[0256] Depot formulations can also be prepared by using other
rate-controlling excipients, including hydrophobic materials,
including acceptable oils (e.g., peanut oil, corn oil, sesame oil,
cottonseed oil, etc.) and phospholipids, ion-exchange resins, and
sparingly soluble carriers.
[0257] The depot formulation can further contain a solvent or
dispersion medium containing or comprising, for example, water,
ethanol, one or more polyols (e.g., glycerol, propylene glycol, and
liquid polyethylene glycol), oils, such as vegetable oils (e.g.,
peanut oil, corn oil, sesame oil, etc.), and combinations thereof.
The proper fluidity can be maintained, for example, by the use of a
coating, such as lecithin, by the maintenance of the required
particle size in the case of dispersion and/or by the use of
surfactants. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride.
[0258] Solutions and dispersions of a neuroactive steroid or a
benzodiazepine or anesthetic/sedative as the free acid or base or
pharmacologically acceptable salts thereof can be prepared in water
or another solvent or dispersing medium suitably mixed with one or
more pharmaceutically acceptable excipients including, but not
limited to, surfactants, dispersants, emulsifiers, pH modifying
agents, and combination thereof.
[0259] Suitable surfactants may be anionic, cationic, amphoteric or
nonionic surface active agents. Suitable anionic surfactants
include, but are not limited to, those containing or comprising
carboxylate, sulfonate and sulfate ions. Examples of anionic
surfactants include sodium, potassium, ammonium of long chain alkyl
sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene
sulfonate; dialkyl sodium sulfosuccinates, such as sodium
dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as
sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such
as sodium lauryl sulfate. Cationic surfactants include, but are not
limited to, quaternary ammonium compounds such as benzalkonium
chloride, benzethonium chloride, cetrimonium bromide, stearyl
dimethylbenzyl ammonium chloride, polyoxyethylene and coconut
amine. Examples of nonionic surfactants include ethylene glycol
monostearate, propylene glycol myristate, glyceryl monostearate,
glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose
acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene
monolaurate, polysorbates, polyoxyethylene octylphenylether,
PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene
glycol butyl ether, Poloxamer.RTM. 401, stearoyl
monoisopropanolamide, and polyoxyethylene hydrogenated tallow
amide. Examples of amphoteric surfactants include sodium
N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,
myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
[0260] The formulation can contain a preservative to prevent the
growth of microorganisms. Suitable preservatives include, but are
not limited to, parabens, chlorobutanol, phenol, sorbic acid, and
thimerosal. The formulation may also contain an antioxidant to
prevent degradation of the active agent(s).
[0261] The formulation is typically buffered to a pH of 3-8 for
parenteral administration upon reconstitution. Suitable buffers
include, but are not limited to, phosphate buffers, acetate
buffers, and citrate buffers.
[0262] Water soluble polymers are often used in formulations for
parenteral administration. Suitable water-soluble polymers include,
but are not limited to, polyvinylpyrrolidone, dextran,
carboxymethylcellulose, and polyethylene glycol.
[0263] Sterile injectable solutions can be prepared by
incorporating the active compounds in the required amount in the
appropriate solvent or dispersion medium with one or more of the
excipients listed above, as required, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating
the various sterilized active ingredients into a sterile vehicle
which contains the basic dispersion medium and the required other
ingredients from those listed above. In the case of sterile powders
for the preparation of sterile injectable solutions, the preferred
methods of preparation are vacuum-drying and freeze-drying
techniques which yield a powder of the active ingredient plus any
additional desired ingredient from a previously sterile-filtered
solution thereof. The powders can be prepared in such a manner that
the particles are porous in nature, which can increase dissolution
of the particles. Methods for making porous particles are well
known in the art.
[0264] In some embodiments, at least one of the neuroactive steroid
and/or the benzodiazepine or anesthetic/sedative is formulated for
intranasal, buccal, intramuscular or intravenous administration
(e.g., intramuscular or intravenous administration). In some
embodiments, both of the neuroactive steroid and the benzodiazepine
or anesthetic/sedative are formulated for intranasal, buccal,
intramuscular or intravenous administration (e.g., intramuscular or
intravenous administration).
Combinations with Active Compounds
[0265] A composition described herein can be administered
adjunctively with other active compounds such as anesthetics or
sedatives, e.g., benzodiazepine, e.g., midazalm, propofol,
pentobarbital, and ketamine.
Methods of Use
[0266] A composition described herein, can be administered to a
subject in need thereof, to treat a disorder described herein.
Exemplary disorders include epilepsy, e.g., convulsive status
epilepticus, e.g., early status epilepticus, established status
epilepticus, refractory status epilepticus, super-refractory status
epilepticus; non-convulsive status epilepticus, e.g., generalized
status epilepticus, complex partial status epilepticus; a seizure,
e.g., acute repetitive seizures, cluster seizures.
[0267] In some embodiments, a composition described herein (e.g., a
composition comprising allopregnanolone), is administered to a
subject under general anesthesia.
Seizures and Seizure-Related Disorders
[0268] Seizures described herein can include epileptic seizures;
acute repetitive seizures; cluster seizures; continuous seizures;
unremitting seizures; prolonged seizures; recurrent seizures;
status epilepticus seizures, e.g., refractory convulsive status
epilepticus, non-convulsive status epilepticus seizures; refractory
seizures; myoclonic seizures; tonic seizures; tonic-clonic
seizures; simple partial seizures; complex partial seizures;
secondarily generalized seizures; atypical absence seizures;
absence seizures; atonic seizures; benign Rolandic seizures;
febrile seizures; emotional seizures; focal seizures; gelastic
seizures; generalized onset seizures; infantile spasms; Jacksonian
seizures; massive bilateral myoclonus seizures; multifocal
seizures; neonatal onset seizures; nocturnal seizures; occipital
lobe seizures; post traumatic seizures; subtle seizures; Sylvan
seizures; visual reflex seizures; or withdrawal seizures.
[0269] Publications cited herein and the materials for which they
are cited are specifically incorporated by reference.
Status Epilepticus (SE)
[0270] Status epilepticus (SE) encompasses a group of disorders all
involving persistent or recurring seizures. The standard of care in
the United States (US) typically involves initially treating status
epilepticus with a benzodiazepine as a first line agent for "early"
SE. A recent study showed that 26.6% of patients did not respond to
first line midazolam intramuscular (1M) treatment and 36.6% of
patients did not respond to lorazepam intravenous (IV) treatment
(Silbergleit et al, 2012).
[0271] If patients continue to have seizures after administration
of the benzodiazepine, they are treated with a second-line
anti-epileptic drug for "established" SE, which in the US is
generally fos-phenyloin IV or phenyloin IV. If patients continue to
have seizures after administration of first and second line drugs,
they are said to enter into a stage of "refractory" SE (RSE).
[0272] The generally accepted course of therapy for patients in RSE
is general anesthesia (GA) with an agent such as midazolam,
propofol, pentobarbital, or ketamine. There is no drug approved for
RSE and clinical evidence of the comparative efficacy of the
commonly used drugs is lacking (Shorvon, 2011). The goal of therapy
with these GA agents is to induce an electroencephalographic "burst
suppression" state, in an attempt to block the excitotoxic cerebral
damage believed to occur as a result of continued seizure activity
in the brain. Burst-suppression is an electroencephalography
pattern consisting of alternative periods of slow waves of high
amplitude (the burst) and periods of a flat electroencephalogram
(EEG) (the suppression); it is associated with comatose states of
various etiologies and anesthesia (Amzica & Kroeger, 2011). The
goal of a therapy is that when a patient is weaned from the general
anesthesia, the patient will no longer have clinical or
electrographic seizure activity. EEG and EEG terminology is
described in Hirsch et al., J. Clin. Neurophysiol. 2013; 30:1-27,
which reference is incorporated in its entirety.
[0273] Patients said to be in super-refractory SE (SRSE) or
super-refractory generalized SE are a subgroup of RSE patients who
have continued or recurrent seizures 24 hours or more after the
onset of anesthetic therapy; it often seen as the recurrence of
seizure activity as the patient is weaned from the anesthetic
therapy. It has been estimated that .about.15% of patients admitted
to hospitals with SE become super-refractory (Shorvon &
Ferlisi, 2011).
[0274] SE can include, e.g., convulsive status epilepticus, e.g.,
early status epilepticus, established status epilepticus,
refractory status epilepticus, super-refractory status epilepticus;
non-convulsive status epilepticus, e.g., generalized status
epilepticus, complex partial status epilepticus; generalized
periodic epileptiform discharges; and periodic lateralized
epileptiform discharges. Convulsive status epilepticus is
characterized by the presence of convulsive status epileptic
seizures, and can include early status epilepticus, established
status epilepticus, refractory status epilepticus, super-refractory
status epilepticus. Early status epilepticus is treated with a
first line therapy. Established status epilepticus is characterized
by status epileptic seizures which persist despite treatment with a
first line therapy, and a second line therapy is administered.
Refractory status epilepticus is characterized by status epileptic
seizures which persist despite treatment with a first line and a
second line therapy, and a general anesthetic is generally
administered. Super refractory status epilepticus is characterized
by status epileptic seizures which persist despite treatment with a
first line therapy, a second line therapy, and a general anesthetic
for 24 hours or more.
[0275] Non-convulsive status epilepticus can include, e.g., focal
non-convulsive status epilepticus, e.g., complex partial
non-convulsive status epilepticus, simple partial non-convulsive
status epilepticus, subtle non-convulsive status epilepticus;
generalized non-convulsive status epilepticus, e.g., late onset
absence non-convulsive status epilepticus, atypical absence
non-convulsive status epilepticus, or typical absence
non-convulsive status epilepticus.
[0276] Compositions described herein can also be administered as a
prophylactic to a subject having a CNS disorder e.g., a traumatic
brain injury, status epilepticus, e.g., convulsive status
epilepticus, e.g., early status epilepticus, established status
epilepticus, refractory status epilepticus, super-refractory status
epilepticus; non-convulsive status epilepticus, e.g., generalized
status epilepticus, complex partial status epilepticus; generalized
periodic epileptiform discharges; and periodic lateralized
epileptiform discharges; prior to the onset of a seizure.
Epilepsy
[0277] Epilepsy is a brain disorder characterized by repeated
seizures over time. Types of epilepsy can include, but are not
limited to generalized epilepsy, e.g., childhood absence epilepsy,
juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on
awakening, West syndrome, Lennox-Gastaut syndrome, partial
epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy,
benign focal epilepsy of childhood.
EXAMPLES
Example 1
Formulation of ALLO in Captisol
[0278] Four prototypes of Allopregnanolone in Captisol were made: 5
mg/mL, 7.5 mg/mL, 9 mg/mL, and 10 mg/mL of Allopregnanolone in 25%
captisol.
[0279] All formulations were high shear mixed for 1 hour then
placed on a magnetic stir plate for up to 24 hours of mixing.
[0280] 5 mg/mL--appeared clear colorless within approximately 30
min of high shear mixing. The solution was clear colorless with no
visible particulates. [0281] 7.5 mg/mL--appeared clear colorless
during the high shear mixing. When the solution was finished with
the 1 hour high shear mix, it was compared against a black
background and there was a fine haze visible. After stir plate
mixing overnight, the haze was still visible. [0282] 9 mg/mL--the
solution was hazy even after completion of the 1 hour high shear
mixing. The haze was still visible after 19 hours of mixing. [0283]
10 mg/mL--the solution was hazy even after completion of the 1 hour
high shear mixing. The haze was still visible after 16 hours of
mixing.
[0284] The haze appears as a "gradient" to the concentration of the
ALLO.
TABLE-US-00001 TABLE 1 Description of the physical appearance of
ALLO formulations with Captisol Formulation Physical Appearance 5.0
mg/ml ALLO, 25% Captisol Clear Solution 7.5 mg/ml ALLO, 25%
Captisol Very Slightly Hazy 9.0 mg/ml ALLO, 25% Captisol Slightly
Hazy 10.0 mg/ml ALLO, 25% Captisol Hazy
Example 2
Study of ALLO Injection in the Treatment of Super-Refractory Status
Epilepticus
[0285] A physician at the Massachusetts General Hospital, Boston,
Mass. treated one patient in SRSE with allopregnanolone in a
hydroxyl-propyl beta cyclodextrin formulation. The patient was a
23-year-old, previously-healthy, male, college graduate who was
started on allopregnanolone on his 92.sup.nd day of SRSE. Prior to
starting allopregnanolone, the patient had an extensive workup,
including brain biopsy, for the cause of the SE; the workup was
negative and the cause of his seizure activity was yet to be
determined.
[0286] During his hospital course, the patient had previously been
treated with propofol, midazolam, lacosamide, phenyloin,
phenobarbital, ketamine, clonazepam, levetiracetam, valproate,
pentobarbital, topiramate, steroids, pyridoxine, coq-10, lidocaine,
electroconvulsive therapy (ECT), bromides, hypothermia, a ketogenic
diet, and acupuncture. Although burst suppression was achieved with
the anesthetic agents, all attempts to wean the patient from them
met with a renewal of generalized seizure activity; this included
an attempted wean 1 week before allopregnanolone was started.
[0287] At the time that allopregnanolone was started, the patient
was still in a pentobarbital-induced coma as well as receiving
lacosamide, phenobarbital, clonazepam, and levetiracetam. The
patient was started on allopregnanolone at a continuous infusion
rate of 86 .mu.g/kg/h for 5 days, after which the allopregnanolone
was rapidly tapered and discontinued over a 24-hour period. Plasma
samples were drawn at 5 h, 29 h, 53 h, 77 h, 101 h, 125 h, 149 h,
and 173 h and are shown on FIG. 2. The plasma level rose and by Day
2 had achieved the target level of 150 nmoles/L. The pentobarbital
was tapered and discontinued over the first 36 hours of
allopregnanolone therapy. At the 36-hour time point, when patient
was entirely weaned from pentobarbital and on allopregnanolone, the
EEG had begun to normalize. The EEG continued to improve and at 72
hours the patient was awake and followed simple midline commands.
He continued to improve and was conversant, making jokes, and in a
rehabilitation facility as of April 2013. There were no adverse
events attributed to allopregnanolone.
* * * * *