U.S. patent application number 15/985390 was filed with the patent office on 2018-11-22 for modified release pharmaceutical compositions of huperzine and methods of using the same.
The applicant listed for this patent is BISCAYNE NEUROTHERAPEUTICS, INC.. Invention is credited to Stephen D. COLLINS, Peter GOLDSTEIN, Joshua T. JOHNSTONE.
Application Number | 20180333365 15/985390 |
Document ID | / |
Family ID | 64270169 |
Filed Date | 2018-11-22 |
United States Patent
Application |
20180333365 |
Kind Code |
A1 |
COLLINS; Stephen D. ; et
al. |
November 22, 2018 |
MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF HUPERZINE AND
METHODS OF USING THE SAME
Abstract
The present application discloses pharmaceutical compositions
for modified release of huperzine. The pharmaceutical compositions
and methods described herein, allow for dosing of huperzine at
higher therapeutic thresholds, while avoiding rapid serum peak
plasma levels, thereby avoiding the adverse nausea and vomiting
associated with the immediate release pharmaceutical compositions.
Methods of treating neurological disorders and/or seizure disorders
with the modified release compositions is also described.
Inventors: |
COLLINS; Stephen D.; (Lake
Forest, IL) ; GOLDSTEIN; Peter; (Hollywood, FL)
; JOHNSTONE; Joshua T.; (Apex, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BISCAYNE NEUROTHERAPEUTICS, INC. |
Miami |
FL |
US |
|
|
Family ID: |
64270169 |
Appl. No.: |
15/985390 |
Filed: |
May 21, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62508554 |
May 19, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/48 20130101; A61K
47/38 20130101; A61K 31/435 20130101; A61K 9/5078 20130101; A61P
25/08 20180101; A61K 9/5042 20130101; A61K 47/32 20130101 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/435 20060101 A61K031/435; A61K 47/32 20060101
A61K047/32; A61K 47/38 20060101 A61K047/38 |
Claims
1. A pharmaceutical composition for oral delivery comprising: a.
about 74 weight % to about 86 weight % of a sugar sphere core
wherein the sugar sphere core has a particle size of about 500-710
.mu.m; b. a huperzine layer coating the sugar sphere, wherein the
huperzine layer comprises about 0.95% to about 1 weight % huperzine
or a pharmaceutically acceptable salt of huperzine that is
equivalent to about 0.95% to about 1 weight % huperzine, and one or
more excipients, wherein the total amount of excipients is about 5
weight % to about 9 weight %; and c. about 7 weight % to about 16
weight % of a plasticized ethyl cellulose polymer layer coating the
huperzine layer, wherein the huperzine layer contains a
therapeutically-effective amount of huperzine.
2. The pharmaceutical composition of claim 1 wherein the huperzine
is huperzine A or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition of claim 1, further comprising a
seal coat layer coating the huperzine layer between the huperzine
layer and the plasticized ethyl cellulose polymer layer.
4. The pharmaceutical composition of claim 1, wherein the one or
more excipients is selected from hydroxypropyl methylcellulose, and
polyvinylpryrrolidone or combinations thereof.
5. The pharmaceutical composition of claim 1, wherein the one or
more excipients is selected from low viscosity hydroxypropyl
methylcellulose, and polyvinylpryrrolidone K30 or combinations
thereof.
6. The pharmaceutical composition of claim 1 wherein one or more
excipients is a combination of about 5 weight % to about 7 weight %
hydroxypropyl methylcellulose and about 0.5 weight % to about 1.5
weight % polyvinylpryrrolidone.
7. The pharmaceutical composition of claim 1 wherein the
plasticized ethyl cellulose is SurRelease.RTM. Type B NF E.
8. The pharmaceutical composition of claim 1 wherein the huperzine
is huperzine A; one or more excipients is a combination of low
viscosity hydroxypropyl methylcellulose and polyvinylpyrrolidone
K30; and the plasticized ethyl cellulose is SurRelease.RTM. Type B
NF E.
9. The pharmaceutical composition of claim 1, comprising about 80
weight % to about 86 weight % of the sugar sphere.
10. The pharmaceutical composition of claim 1, wherein the
plasticized ethyl cellulose polymer layer is about 7 weight % to
about 12 weight %.
11. The pharmaceutical composition of claim 1 comprising: a. about
79 weight % to about 84 weight % of the sugar sphere core; b. a
huperzine layer coating the sugar sphere, wherein the huperzine
layer comprises about 0.95 weight % to about 1 weight % huperzine
A, or a pharmaceutically acceptable salt of huperzine A that is
equivalent to about 0.95 weight % to about 1 weight % of huperzine
A; about 6 weight % hydroxypropyl methylcellulose, and about 0.95
weight % to about 1 weight % polyvinylpryrrolidone; and c. about 8
weight % to about 13 weight % of a plasticized ethyl cellulose
polymer layer coating the huperzine layer, wherein the huperzine
layer contains a therapeutically-effective amount of huperzine
A.
12. The pharmaceutical composition of claim 1 comprising: a. about
80 weight % to about 83 weight % of a sugar sphere core wherein the
sugar sphere core has a particle size of about 500-710 .mu.m; b. a
huperzine layer coating the sugar sphere, wherein the huperzine
layer comprises about 0.95 weight % to about 1 weight % huperzine
A, about 5 weight % to about 6 weight % hydroxypropyl
methylcellulose, and about 0.95 weight % to about 1 weight %
polyvinylpryrrolidone; and c. about 8 weight % to about 12 weight %
of a plasticized ethyl cellulose polymer layer coating the
huperzine layer, wherein the huperzine layer contains a
therapeutically-effective amount of huperzine A.
13. The pharmaceutical composition of claim 1 comprising: a. about
81 weight % to about 82 weight % of a sugar sphere core wherein the
sugar sphere core has a particle size of about 500-710 .mu.m; b. a
huperzine layer coating the sugar sphere, wherein the huperzine
layer comprises about 0.95 weight % to about 1 weight % huperzine
A, about 5 weight % to about 6 weight % hydroxypropyl
methylcellulose, and about 0.95 weight % to about 1 weight %
polyvinylpryrrolidone; and c. about 10 weight % to about 11 weight
% of a plasticized ethyl cellulose polymer layer coating the
huperzine layer, wherein the huperzine layer contains a
therapeutically-effective amount of huperzine A.
14. The pharmaceutical composition of claim 1 comprising: a. about
82 weight % to about 83 weight % of a sugar sphere core wherein the
sugar sphere core has a particle size of about 500-710 .mu.m; b. a
huperzine layer coating the sugar sphere, wherein the huperzine
layer comprises about 0.95 weight % to about 1 weight % huperzine
A, about 6 weight % hydroxypropyl methylcellulose, and about 0.95
weight % to about 1 weight % polyvinylpryrrolidone; and c. about 9
weight % to about 10 weight % of a plasticized ethyl cellulose
polymer layer coating the huperzine layer, wherein the huperzine
layer contains a therapeutically-effective amount of huperzine
A.
15. The pharmaceutical composition of claim 2 comprising: a. about
76 weight % to about 76 weight % of a sugar sphere core wherein the
sugar sphere core has a particle size of about 500-710 .mu.m; b. a
huperzine layer coating the sugar sphere, wherein the huperzine
layer comprises about 0.9 weight % to about 1 weight % huperzine A,
about 5 weight % to about 6 weight % hydroxypropyl methylcellulose,
and 0.9 weight % to about 1 weight % polyvinylpryrrolidone; c. a
seal coat layer coating the huperzine layer, comprising about 1
weight % to about 2 weight % hydroxypropylmethyl cellulose; and d.
about 15 weight % to about 16 weight % of a plasticized ethyl
cellulose polymer layer coating the seal coat layer, wherein the
huperzine layer contains a therapeutically-effective amount of
huperzine A.
16. The pharmaceutical composition of claim 1 wherein the
pharmaceutical composition is in a capsule.
17. A pharmaceutical composition comprising huperzine A,
characterized by a C.sub.max of huperzine in plasma of about 4
ng/mL to about 8 ng/mL, a T.sub.max of about 4 hours to about 8
hours and a t.sub.1/2 of about 8 hours to about 12 hours upon oral
administration of a therapeutically effective dose of the
pharmaceutical composition to a human subject.
18. The pharmaceutical composition of claim 17 wherein the
C.sub.max is about 4 ng/mL to about 6 ng/mL, T.sub.max is about 4
hours to about 8 hours and the t.sub.1/2 is about 10 hours to about
12 hours.
19. The pharmaceutical composition of claim 17 wherein the
C.sub.max is about 6 ng/mL, the T.sub.max is about 4 hours and the
t.sub.1/2 is about 8.3 hours.
20. A pharmaceutical composition comprising a
therapeutically-effective amount of huperzine, characterized by a
T.sub.max of about 4 to about 8 hours and a C.sub.max that is
reduced by about 25% to about 50% when compared with a C.sub.max of
an immediate release huperzine pharmaceutical composition
administered at an equivalent dose.
21. The pharmaceutical composition of claim 20 wherein the
C.sub.max is reduced by about 50%.
22. The pharmaceutical composition of claim 1 that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 36% to about 46% of the huperzine is
released after 2 hours, about 61% to about 77% of the huperzine is
released after 4 hours, about 84% to about 97% of the huperzine is
released after 8 hours and not less than about 89% of the huperzine
is released after 12 hours.
23. The pharmaceutical composition of claim 1 that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 36% of the huperzine is released after 2
hours, about 63% of the huperzine is released after 4 hours, about
84% of the huperzine is released after 8 hours and not less than
about 89% of the huperzine is released after 12 hours.
24. The pharmaceutical composition of claim 1 that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 46% of the huperzine is released after 2
hours, about 77% of the huperzine is released after 4 hours, about
97% of the huperzine is released after 8 hours and not less than
about 99% of the huperzine is released after 12 hours.
25. The pharmaceutical composition of claim 1 that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 43% of the huperzine is released after 2
hours, about 68% of the huperzine is released after 4 hours, about
88% of the huperzine is released after 8 hours and not less than
about 96% of the huperzine is released after 12 hours.
26. The pharmaceutical composition of claim 1 that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 38% of the huperzine is released after 2
hours, about 61% of the huperzine is released after 4 hours, about
84% of the huperzine is released after 8 hours and not less than
about 94% of the huperzine is released after 12 hours.
27. A method of treating a disorder selected from a neurological
disorder or a seizure disorder, comprising administering to a
patient in need thereof, a pharmaceutical composition according to
claim 1.
28. The method of claim 27 wherein the seizure disorder is selected
from epilepsy and complex partial seizure.
29. The method of claim 27 wherein the pharmaceutical composition
is administered twice a day.
30. The method of claim 27 wherein said administering comprises a.
administering one or more titration doses of the pharmaceutical
composition followed by b. administering a maintenance dose of the
pharmaceutical composition wherein the maintenance dose is a
therapeutically effective dose.
31. The method of claim 27, wherein the patient experiences a
better side effect profile, comprising administering a first dosing
regimen of at least one dosing regimen selected from a. to h. and
administering a second dosing regimen of at least one dosing
regimen selected from a. to i., provided the second dosing regimen
ascends from the first dosing regimen and further provided the last
dosing regimen is the maintenance dose and therefore will be
administered for as long as the patient is in need of treatment
thereof: a. optionally administering a dose of about 0.25 mg of
huperzine A, once every about 12 hours for at least two days and up
to two weeks; b. optionally administering a dose of about 0.5 mg of
huperzine A, once every about 12 hours for at least two days and up
to two weeks; c. optionally administering a dose of about 0.75 mg
of huperzine A, once every about 12 hours for at least two days and
up to two weeks; d. optionally administering a dose of about 1 mg
of huperzine A, once every about 12 hours for at least two days and
up to two weeks; e. optionally administering a dose of about 1.25
mg of huperzine A, once every about 12 hours for at least two days
and up to two weeks; f. optionally administering a dose of about
1.5 mg of huperzine A, once every about 12 hours for at least two
days and up to two weeks; g. optionally administering a dose of
about 1.75 mg of huperzine A, once every about 12 hours for at
least two days and up to two weeks; h. optionally administering a
dose of about 2 mg of huperzine A, once every about 12 hours for at
least two days and up to two weeks; i. optionally administering a
dose of about 2.5 mg of huperzine A, once every about 12 hours for
at least two days; wherein the huperzine A of a.-i. is administered
in the pharmaceutical composition of claim 1.
32. The method of claim 31, comprising: a. administering a dose of
about 0.25 mg of huperzine A, once every about 12 hours for two
days to two weeks; b. administering a dose of about 0.5 mg of
huperzine A, once every about 12 hours for two days to two weeks;
c. administering a dose of about 0.75 mg of huperzine A, once every
about 12 hours for two days to two weeks; d. administering a dose
of about 1 mg of huperzine A, once every about 12 hours for at
least two days.
33. The method of claim 32, wherein step d is administered for as
long as the patient is in need of treatment.
34. The method of claim 32, further comprising after step d: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for as long as the patient is in need thereof.
35. The method of claim 32, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for as long
as the patient is in need thereof.
36. The method of claim 32, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for 2 days to
2 weeks; g. administering a dose of about 1.75 mg of huperzine A
once every about 12 hours for as long as the patient is in need
thereof.
37. The method of claim 32, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for 2 days to
2 weeks; g. administering a dose of about 1.75 mg of huperzine A
once every about 12 hours for 2 days to 2 weeks; h. administering a
dose of about 2.0 mg of huperzine A once every about 12 hours for
as long as the patient is in need thereof.
38. The method of claim 32, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for 2 days to
2 weeks; g. administering a dose of about 1.75 mg of huperzine A
once every about 12 hours for 2 days to 2 weeks; h. administering a
dose of about 2.0 mg of huperzine A once every about 12 hours for 2
days to 2 weeks; i. administering a dose of about 2.5 mg of
huperzine A once every about 12 hours for as long as the patient is
in need thereof.
39. A method of treating a disorder selected from the group
consisting of a neurological disorder and a seizure disorder, in a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering one or more titration
doses of huperzine A, followed by administering a therapeutically
effective dose of huperzine A; wherein the huperzine A is
administered in a modified release pharmaceutical composition.
40. The method of claim 39 wherein the modified release
pharmaceutical composition comprises a dissolvable core; an active
huperzine A layer coating the dissolvable core; and a polymer
coating, coating the huperzine A layer; wherein the huperzine A
layer comprises a therapeutically-effective amount of
huperzine.
41. A method of treating a disorder selected from the group
consisting of a neurological disorder and a seizure disorder, in a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering a first dosing
regimen of at least one dosing regimen selected from a. to h. (as
described below) and administering a second dosing regimen of at
least one dosing regimen selected from a. to i. (as described
below), provided the second dosing regimen ascends from the first
dosing regimen and further provided the last dosing regimen is the
maintenance dose and therefore will be administered for as long as
the patient is in need of treatment thereof a. administering a dose
of about 0.25 mg of huperzine A, once every about 12 hours at least
two days and up to two weeks; b. administering a dose of about 0.5
mg of huperzine A, once every about 12 hours for at least two days
and up to two weeks; c. administering a dose of about 0.75 mg of
huperzine A, once every about 12 hours for at least two days and up
to two weeks; d. administering a dose of about 1 mg of huperzine A,
once every about 12 hours for at least two days and up to two
weeks; e. administering a dose of about 1.25 mg of huperzine A,
once every about 12 hours for at least two days and up to two
weeks; f. administering a dose of about 1.5 mg of huperzine A, once
every about 12 hours for at least two days and up to two weeks; g.
administering a dose of about 1.75 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; h.
administering a dose of about 2 mg of huperzine A, once every about
12 hours for at least two days and up to two weeks; i.
administering a dose of about 2.5 mg of huperzine A, once every
about 12 hours for at least two days; wherein the huperzine A of
a.-i. is administered in a modified release pharmaceutical
composition.
42. The method of claim 41 comprising: a. administering a dose of
about 0.25 mg of huperzine A, once every about 12 hours for two
days to two weeks; b. administering a dose of about 0.5 mg of
huperzine A, once every about 12 hours for two days to two weeks;
c. administering a dose of about 0.75 mg of huperzine A, once every
about 12 hours for two days to two weeks; d. administering a dose
of about 1 mg of huperzine A, once every about 12 hours for at
least two days
43. The method of claim 42, wherein step d. is administered for as
long as the patient is in need of treatment.
44. The method of claim 42, further comprising after step d: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for as long as the patient is in need thereof.
45. The method of claim 42, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for as long
as the patient is in need thereof.
46. The method of claim 42, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for 2 days to
2 weeks; g. administering a dose of about 1.75 mg of huperzine A
once every about 12 hours for as long as the patient is in need
thereof.
47. The method of claim 42, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for 2 days to
2 weeks; g. administering a dose of about 1.75 mg of huperzine A
once every about 12 hours for 2 days to 2 weeks; h. administering a
dose of about 2 mg of huperzine A once every about 12 hours for as
long as the patient is in need thereof.
48. The method of claim 42, further comprising after step d.: e.
administering a dose of about 1.25 mg of huperzine A once every
about 12 hours for 2 days to 2 weeks; f. administering a dose of
about 1.5 mg of huperzine A once every about 12 hours for 2 days to
2 weeks; g. administering a dose of about 1.75 mg of huperzine A
once every about 12 hours for 2 days to 2 weeks; h. administering a
dose of about 2 mg of huperzine A once every about 12 hours for 2
days to 2 weeks; i. administering a dose of about 2.5 mg of
huperzine A once every about 12 hours for as long as the patient is
in need thereof.
49. A method of treating a disorder selected from the group
consisting of a neurological disorder and a seizure disorder, to a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering a modified release
pharmaceutical composition of huperzine A, wherein the modified
release pharmaceutical composition of huperzine A is characterized
by a C.sub.ss of huperzine A in plasma selected from the group
consisting of: about 0.52 to about 0.82 ng/mL at a 0.25 mg dose;
about 1.91 to about 2.99 ng/mL at a 0.50 mg dose; about 3.56 to
about 5.55 ng/mL at a 0.75 mg dose; about 5.58 to about 8.72 ng/mL
at a 1 mg dose; about 8.22 to about 12.84 ng/mL at a 1.25 mg dose;
about 9.02 to about 14.09 ng/mL at a 1.5 mg dose; about 10.04 to
about 15.69 ng/mL at a 1.75 mg dose; about 16 to about 25 ng/mL at
a 2.0 mg dose; and about 18.48 to about 28.88 ng/mL at a 2.5 mg
dose.
50. A method of treating a disorder selected from the group
consisting of a neurological disorder and a seizure disorder, to a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering a modified release
pharmaceutical composition of huperzine A, wherein the modified
release pharmaceutical composition of huperzine A is characterized
by a C.sub.ss of huperzine A in plasma of at least 8 ng/mL when
administered at a therapeutically effective dose.
51. A method of treating a disorder selected from the group
consisting of a neurological disorder and a seizure disorder, to a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering a modified release
pharmaceutical composition of huperzine A, wherein the modified
release pharmaceutical composition of huperzine A is characterized
by a C.sub.max of huperzine in plasma of about 0.76 ng/mL to about
1.19 ng/mL, a T.sub.max of about 4 hour to about 6.25 hours and an
AUC.sub.0-8 of about 4.18 to about 6.53 upon oral administration of
a therapeutically effective dose of the pharmaceutical composition
to a human patient.
52. A method of treating a disorder selected from the group
consisting of a neurological disorder and a seizure disorder, to a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering a modified release
pharmaceutical composition of huperzine A, wherein the modified
release pharmaceutical composition of huperzine A is characterized
by a C.sub.max of huperzine in plasma of about 2.51 ng/mL to about
3.93 ng/mL, a T.sub.max of about 4 hour to about 6.25 hours and an
AUC.sub.0-8 of about 13.76 to about 21.5 upon oral administration
of a therapeutically effective dose of the pharmaceutical
composition to a human patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit of and priority to
U.S. Provisional No. 62/508,554 entitled "EXTENDED RELEASE
FORMULATIONS OF HUPERZINE AND METHODS OF USING THE SAME," filed May
19, 2017, the contents of which is hereby incorporated by reference
in its entirety.
SUMMARY OF THE INVENTION
[0002] Huperzine A is a naturally occurring sesquiterpene alkaloid
compound found in the firmoss Huperzia serrata. It is a potent
inhibitor of acetylcholinesterase. In several countries, Huperzine
A is sold as a dietary supplement for memory support. In China,
huperzine A is State Food and Drug Administration (SFDA) approved
for the treatment of dementia.
[0003] Huperzine A has been administered to healthy volunteers and
patients in numerous trials, many in China, demonstrating
acceptable safety and tolerability as well as efficacy in
Alzheimer's disease, benign senescent forgetfulness, vascular
dementia, myasthenia gravis, schizophrenia, and cocaine dependence.
The dosages used in these trials were between 0.01 and 0.8 mg/day
via oral administration or intramuscular injection. While these
studies showed a favorable safety profile, in some studies,
transient dose related nausea occurred at the higher dose
levels.
[0004] Applicants conducted a dose escalation study in patients
with drug-resistant epilepsy, to investigate the safety and
tolerability of immediate release pharmaceutical compositions of
huperzine A. In this study, patients experienced serious adverse
events (nausea and vomiting), many within the first 31 hours, most
probably due to the rapid serum exposure of the immediate release
pharmaceutical composition. (vide infra).
[0005] There are no available published data on the efficacy of
huperzine A in patients with epilepsy in the medical or patent
literature. Nonclinical data in rodent models show that huperzine A
has very high efficacy as an anticonvulsant, with mechanisms of
action that are markedly different from available anti-epileptic
drugs (AEDs). Applicants however, have predicted that higher doses
of huperzine than previously administered in clinical trials, will
be needed to achieve efficacy in treating seizure disorders in
patients (vide infra).
[0006] While huperzine A could potentially provide additional
beneficial effects in the areas of neurological disorders, seizure
disorders, memory and language impairment, immediate release
pharmaceutical compositions of huperzine A are inadequate for
treating disorders where higher therapeutic thresholds are needed
due to dose-related adverse events, especially in patients with
chronic conditions. Immediate release pharmaceutical compositions
also have the added drawback of requiring dosing 4 to 6 times daily
due to the fast t.sub.1/2 associated with these pharmaceutical
compositions. Dosing 4 to 6 times daily is unacceptable in many
patient populations, for example, those related to memory loss or
seizures, as compliance becomes a major issue for these patients.
Nonclinical studies suggest that higher doses than those used
previously, such as up to 5 mg/day, may be safe if delivered with a
pharmaceutical composition that reduces high peak-trough serum
levels.
[0007] A slow release pill containing Huperzine A has been reported
by Zhou et al. in Chinese patent application CN101081217, however,
these pharmaceutical compositions fail to significantly reduce peak
plasma concentrations compared with immediate release
pharmaceutical compositions and also fail to extend the t.sub.max.
As a result, these pharmaceutical compositions would not overcome
the serious adverse events associated with rapid, high peak serum
concentrations and would require dosing 4-6 times a day, thus
offering no advantage over immediate release pharmaceutical
compositions.
[0008] The present invention allows for the plasma exposure
necessary for achieving efficacy while maintaining a desirable
safety profile not attainable with previously known pharmaceutical
compositions of huperzine.
[0009] Embodiments of the present invention relate to
pharmaceutical compositions for oral delivery of huperzine that may
be used to treat various neurological disorders and diseases, for
example, pain, Alzheimer's disease, and seizure disorders. The
modified release pharmaceutical compositions of huperzine described
herein, allow for optimal efficacy of huperzine with either reduced
duration, severity and/or risk of the serious adverse events
associated with immediate release pharmaceutical compositions that
are either dose limiting or completely prevent the continued use of
huperzine.
[0010] Embodiments of the invention are directed to a
pharmaceutical composition for oral delivery comprising: (a) about
74 to 86 weight % of a sugar sphere core wherein the sugar sphere
core has a particle size of about 500-710 .mu.m; (b) a huperzine
layer coating the sugar sphere, wherein the huperzine layer
comprises about 0.95 weight % to about 1 weight % huperzine or a
pharmaceutically acceptable salt of huperzine that is equivalent to
about 0.95 weight % to about 1 weight % huperzine, and one or more
excipients, wherein the total amount of excipients is about 5
weight % to about 9 weight %; and (c) about 7 weight % to 16 weight
% of an plasticized ethyl cellulose polymer layer coating the
huperzine layer, wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine. In some embodiments
the huperzine is huperzine A or a pharmaceutically acceptable salt
thereof.
[0011] Some embodiments of the invention are directed to a
pharmaceutical composition comprising: (a) about 80 weight % to
about 83 weight % of a sugar sphere core wherein the sugar sphere
core has a particle size of about 500-710 .mu.m; (b) a huperzine
layer coating the sugar sphere, wherein the huperzine layer
comprises about 0.95 weight % to about 1 weight % huperzine A or a
pharmaceutically acceptable salt of huperzine A that is equivalent
to about 0.95 weight % to about 1 weight % huperzine A, about 5
weight % to about 6 weight % hydroxypropyl methylcellulose, and
about 0.95 weight % to about 1 weight % polyvinylpryrrolidone; and
(c) about 8 weight % to about 12 weight % of a plasticized ethyl
cellulose polymer layer coating the huperzine layer, wherein the
huperzine layer comprises a therapeutically-effective amount of
huperzine A.
[0012] Some embodiments of the present inventions are directed to a
pharmaceutical composition characterized by a C.sub.max of
huperzine A in plasma of about 4 ng/mL to about 8 ng/mL, a
T.sub.max of about 4 hours to about 8 hours and a t.sub.1/2 of
about 8 hours to about 12 hours, upon oral administration of a
therapeutically effective dose of the composition to a human
subject. In one embodiment the C.sub.max is about 4 ng/mL to about
6 ng/mL, T.sub.max is about 4 hours to about 8 hours and the
t.sub.1/2 is about 10 hours to about 12 hours. In one embodiment
the C.sub.max is about 6 ng/mL, the T.sub.max is about 4 hours and
the t.sub.1/2 is about 8.3 hours.
[0013] Some embodiments of the invention are to a pharmaceutical
composition comprising a therapeutically-effective amount of
huperzine A, characterized by a T.sub.max of about 4 hours to about
8 hours and a C.sub.max that is reduced by about 25% to about 75%
when compared with a C.sub.max of an immediate release huperzine
pharmaceutical composition administered at an equivalent dose. In
some embodiments the C.sub.max is reduced by 50% when compared with
a C.sub.max of an immediate release huperzine pharmaceutical
composition administered at an equivalent dose.
[0014] Some embodiments of the present invention are directed to a
pharmaceutical composition that exhibits the following dissolution
profile when tested according to USP 1 type apparatus at 50
revolutions per minute in 50 mM phosphate (pH 6.8) at 37.degree.
C.: about 36% to about 46% of the huperzine is released after 2
hours, about 61% to about 77% of the huperzine is released after 4
hours, about 84% to about 97% of the huperzine is released after 8
hours and not less than about 89% of the huperzine is released
after 12 hours.
[0015] Some embodiment of the invention describe a method of
treating a neurological disorder and/or seizure disorders
comprising administering a pharmaceutical composition according to
any embodiment described herein. In some embodiments, the
composition is administered once daily or twice daily. In some
embodiments, the composition is administered for at least 1 day, at
least 2 days, at least 3 days, at least 4 days, at least 5 days, at
least 6 days, at least 7 days, at least 8 days, at least 9 days, at
least 10 day, at least 11 days, at least 12 days, at least 13 days,
at least 14 days, at least 1 month, at least 2 months, at least 3
months, at least 4 months, at least 5 months, at least 6 months or
for so long as the subject is in need of treatment. In some
embodiments, the composition is administered in a titration
regimen, wherein the dose of huperzine is increased in increments
of 0.25 mg or 0.5 mg every two days or up to two weeks. In some
embodiments the seizure disorder is epilepsy or complex partial
seizures.
[0016] Some embodiment of the invention describe a method of
treating a disorder selected from the group consisting of a
neurological disorder and a seizure disorder, in a patient in need
thereof, wherein the patient experiences a better side effect
profile, comprising administering one or more titration doses of
huperzine A, followed by administering a maintenance dose of
huperzine A; wherein the huperzine A is administered in a modified
release pharmaceutical 1 composition of huperzine A. In some
embodiments the modified release pharmaceutical is a modified
release pharmaceutical according to any embodiment described
herein.
[0017] Some embodiments of the invention describe a method of
treating a neurological disorder and/or a seizure disorder, in a
patient in need thereof, wherein the patient experiences a better
side effect profile, comprising administering a first dosing
regimen of at least one dosing regimen selected from a. to h. (as
further described below) and administering a second dosing regimen
of at least one dosing regimen selected from a. to i. (as further
described below), provided the second dosing regimen ascends from
the first dosing regimen and further provided the last dosing
regimen is the maintenance dose and therefore will be administered
for as long as the patient is in need of treatment thereof: [0018]
a. administering a dose of about 0.25 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; [0019] b.
administering a dose of about 0.5 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; [0020] c.
administering a dose of about 0.75 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; [0021] d.
administering a dose of about 1 mg of huperzine A, once every about
12 hours for at least two days and up to two weeks; [0022] e.
administering a dose of about 1.25 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; [0023] f.
administering a dose of about 1.5 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; [0024] g.
administering a dose of about 1.75 mg of huperzine A, once every
about 12 hours for at least two days and up to two weeks; [0025] h.
administering a dose of about 2 mg of huperzine A, once every about
12 hours for at least two days and up to two weeks; [0026] i.
administering a dose of about 2.5 mg of huperzine A, once every
about 12 hours for at least two days; wherein the huperzine A of
a.-i. is administered in a modified release pharmaceutical
composition of huperzine A. In some embodiments the modified
release pharmaceutical composition is a pharmaceutical composition
according to any embodiment described herein.
[0027] Some embodiments describe a method of treating a disorder
selected from the group consisting of a neurological disorder
and/or a seizure disorder, to a patient in need thereof, wherein
the patient experiences a better side effect profile, comprising
administering a modified release pharmaceutical composition of
huperzine A, wherein the modified release pharmaceutical
composition of huperzine A is characterized by a C.sub.ss of
huperzine A in plasma selected from the group consisting of: about
0.52 to about 0.82 ng/mL at a 0.25 mg dose; about 1.91 to about
2.99 ng/mL at a 0.50 mg dose; about 3.56 to about 5.55 ng/mL at a
0.75 mg dose; about 5.58 to about 8.72 ng/mL at a 1 mg dose; about
8.22 to about 12.84 ng/mL at a 1.25 mg dose; about 9.02 to about
14.09 ng/mL at a 1.5 mg dose; about 10.04 to about 15.69 ng/mL at a
1.75 mg dose; about 16 to about 25 ng/mL at a 2.0 mg dose; and
about 18.48 to about 28.88 ng/mL at a 2.5 mg dose. In some
embodiments, the modified release pharmaceutical composition is
according to any embodiment described herein.
[0028] Some embodiments describe a method of treating a disorder
selected from the group consisting of a neurological disorder
and/or a seizure disorder, in a patient in need thereof, wherein
the patient experiences a better side effect profile, comprising
administering a modified release pharmaceutical composition of
huperzine A, wherein the modified release pharmaceutical
composition of huperzine A is characterized by a C.sub.ss of
huperzine A in plasma of at least 8 ng/mL when administered at a
therapeutically effective dose
[0029] Some embodiments describe a method of treating a disorder
selected from the group consisting of a neurological disorder and a
seizure disorder, to a patient in need thereof, wherein the patient
experiences a better side effect profile, comprising administering
a modified release pharmaceutical composition of huperzine A,
wherein the modified release pharmaceutical composition of
huperzine A is characterized by a C.sub.max of huperzine in plasma
of about 0.76 ng/mL to about 1.19 ng/mL, a T.sub.max of about 4
hour to about 6.25 hours and an AUC.sub.0-8 of about 4.18 .mu.gh/L
to about 6.53 .mu.gh/L upon oral administration of a
therapeutically effective dose of the pharmaceutical composition to
a human subject.
[0030] Some embodiments describe a method of treating a disorder
selected from the group consisting of a neurological disorder and a
seizure disorder, to a patient in need thereof, wherein the patient
experiences a better side effect profile, comprising administering
a modified release pharmaceutical composition of huperzine A,
wherein the modified release pharmaceutical composition of
huperzine A is characterized by a C.sub.max of huperzine in plasma
of about 2.51 ng/mL to about 3.93 ng/mL, a T.sub.max of about 4
hour to about 6.25 hours and an AUC.sub.0-8 of about 13.76 to about
21.5 upon oral administration of a therapeutically effective dose
of the pharmaceutical composition to a human subject.
DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 shows the modeled plasma levels of huperzine A
following immediate release dosing for an example titration
schedule of 2 mg twice a day.
[0032] FIG. 2 shows the modeled plasma levels of huperzine A
modified release pharmaceutical composition 4A based on a titration
schedule of 0.5 mg huperzine A twice a day for days 1-2; 1 mg
huperzine A twice a day for days 3-4; 1.5 mg huperzine twice a day
for days 5-6 and 2 mg twice a day for days 7-11
[0033] FIG. 3 is a schematic of the compositions of the invention.
The white inner circle is the sugar sphere, the middle circle is
the huperzine layer and the outer circle is the plasticized ethyl
cellulose polymer.
[0034] FIG. 4 shows the in vitro dissolution profile of
pharmaceutical composition 1A (solid line with small circle),
composition 1B (dashed line with small square), composition 2A
(solid line with small triangle), composition 2B (dashed line with
small triangle), composition 2C (solid line with small triangle),
composition 3A (solid line with large circle), composition 3B
(dashed line with large square), composition 3C (dashed line with
large point up triangle), composition 4A (solid line with large,
point down triangle), composition 4B (dashed line with small
diamond), composition 4C (solid line with asterisk).
[0035] FIG. 5 shows the in vitro dissolution profile of composition
4D (solid line with upward pointing triangle), composition 4E
(solid line with small diamond), composition 4A (large square with
dashed line), composition 4F-1 (solid line with small triangle
pointing downward), composition 4F-2 (solid line with circle).
[0036] FIG. 6 shows the in vivo plasma concentration in dogs at a
dose of 0.49 mg/kg for pharmaceutical composition 4A (solid line
with point down triangle) and pharmaceutical composition 2C (solid
line with point up triangle).
[0037] FIG. 7 shows in vivo plasma concentration in humans over
time taken during dose titration of 0.25 mg (solid small circle),
0.5 mg (large circle), 0.75 mg (solid large square), 1 mg (large
square), 1.25 mg (small solid triangle), 1.50 mg (small triangle),
1.75 mg (small solid diamond), 2.0 (small diamond) and 2.5 mg (box
with X) of pharmaceutical composition 4D.
[0038] FIG. 8 is the in vivo plasma concentration (C.sub.ss) in
humans at various doses for pharmaceutical composition 4D.
[0039] FIG. 9 shows the in vivo plasma concentration for three
human patients (circle, triangle and square) and the average plasma
concentration (dashed diamond line) taken during dose titration of
0.25 mg, 0.5 mg, 0.75 mg, 1.25 mg.
DETAILED DESCRIPTION
Definitions
[0040] This invention is not limited to the particular processes,
compositions, or methodologies described, as these may vary. The
terminology used in the description is for the purpose of
describing the particular versions or embodiments only, and is not
intended to limit the scope of the present invention. Unless
defined otherwise, all technical and scientific terms used herein
have the same meanings as commonly understood by one of ordinary
skill in the art. All publications mentioned herein are
incorporated by reference in their entirety. Nothing herein is to
be construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention.
[0041] It must also be noted that as used herein and in the
appended claims, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "symptom" is a reference to one
or more symptoms and equivalents thereof known to those skilled in
the art, and so forth.
[0042] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
Therefore, about 50 mL means in the range of 45 mL-55 mL.
[0043] The term "administering" or "administration" and the like,
refers to providing the compositions of the invention (e.g. a
composition according to any embodiment described herein) to a
subject in need of treatment. Preferably the subject is a mammal,
more preferably a human. The present invention comprises
administering a pharmaceutical composition according to any
embodiment described herein, alone or in conjunction with another
therapeutic agent. When a composition according to any embodiment
described herein, is administered in conjunction with another
therapeutic agent, the pharmaceutical composition and the other
therapeutic agent can be administered at the same time or different
times.
[0044] "Serious adverse event" as used herein refers to any adverse
event that (a) causes the subject discomfort and interrupts the
subject's usual activities, (b) causes considerable interference
with the subject's usual activities, and may be incapacitating or
life threatening, (c) is life threatening to the subject, (d)
results in dose limiting toxicity or (e) requires additional
medication to combat the adverse event, or combinations thereof.
For example, if the subject experiences nausea and/or vomiting upon
administration of a huperzine pharmaceutical composition that
requires the administration of an antiemetic in order to continue
to take the huperzine pharmaceutical composition, the subject has a
serious adverse event.
[0045] "Amyloid-related disorders" as used herein, include diseases
associated with the accumulation of amyloid which can either be
restricted to one organ, "localized amyloidosis", or spread to
several organs, "systemic amyloidosis". Secondary amyloidosis may
be associated with chronic infection (such as tuberculosis) or
chronic inflammation (such as rheumatoid arthritis), including a
familial form of secondary amyloidosis which is also seen in
Familial Mediterranean Fever (FMF) and another type of systemic
amyloidosis found in long-term hemodialysis patients. Localized
forms of amyloidosis include, without limitation, type II diabetes
and any related disorders thereof, neurodegenerative diseases such
as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob
disease, Alzheimer's disease, senile systemic amyloidosis (SSA),
Cerebral Amyloid Angiopathy, Parkinson's disease, and prion protein
related disorders (e.g. prion-related encephalopathies), and
rheumatoid arthritis.
[0046] The phrase "better side effect profile" means that the side
effect(s) or serious adverse event(s) experienced by the patient or
group of patients upon treatment with the modified release
pharmaceutical composition of huperzine (1) occur at a lower
incidence, (2) occur for a shorter duration, and/or (3) occur with
a lesser severity; when compared to immediate release
pharmaceutical compositions of an equivalent dose of huperzine.
[0047] The term "C.sub.max" is the peak plasma concentration of a
drug after administration to a subject.
[0048] The term "dose" as used herein refers to the quantity of
active compound, for example huperzine or huperzine A absent any
inactive ingredients or salts.
[0049] As used herein, the term "effective amount" means the amount
of a drug or pharmaceutical agent, or the amount of a combination
of drugs or pharmaceutical agents that will elicit the biological
or medical response of a tissue, system, animal or human that is
being sought, for instance, by a researcher or clinician.
[0050] As used herein, the term "epilepsy" refers to a disorder of
the brain characterized by an enduring predisposition to generate
epileptic seizures and by the neurobiologic, cognitive,
psychological, and social consequences of this condition. An
epileptic seizure is a transient occurrence of signs and/or
symptoms due to abnormal excessive or synchronous neuronal activity
in the brain.
[0051] It will be understood by one of skill in the art that the
term "plasticized ethylcellulose" is also known by non-proprietary
names, for example, "plasticized ethyl cellulose"; synonyms and
several brand names, for example, SuRelease.RTM..
[0052] It will be understood by one of skill in the art that the
term "hydroxyproyl methylcellulose" is also known by many
non-proprietary names, for example, "HPMC", "hypromellose",
"hydroxypropylmethylcellulose", "hypromellosum", and
"hypromellose"; synonyms; and several branded names, for example,
Methocel.TM..
[0053] The term "huperzine" means huperzine A, huperzine B, or
huperzine C, or their pharmaceutically accepted salts or solvates
thereof, unless otherwise defined in a particular embodiment.
Huperzine A is
(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7]trid-
eca-2(7),3,10-trien-5-one. Huperzine B is
(4aR,5R,10bR)-2,3,4,4a,5,6-hexahydro-12-methyl-1H-5,10b-propeno-1,7-phena-
nthrolin-8(7H)-one. Huperzine C is
(1R,9S,13R)-1-amino-13-ethenyl-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-
-2(7),3,10-trien-5-one.
##STR00001##
Preferably, huperzine is huperzine A in any embodiment described
herein.
[0054] The term "maintenance dose" as described herein refers to a
dose of huperzine that administered to maintain a desired level of
the medication in the blood. In some embodiments the maintenance
dose is the therapeutically effect amount.
[0055] The term "modified release pharmaceutical composition of
huperzine" refers to any oral pharmaceutical composition of
huperzine wherein the huperzine-release characteristics of time,
course and/or location are chosen to accomplish therapeutic or
convenience objectives not offered by immediate release
huperzine.
[0056] The term "neurological disorder" includes, but is not
limited to, seizure disorders, an amyloid-related disorder such as
Alzheimer's disease and the amyloid-disorders described herein,
psychiatric disorders such as Tourette's syndrome, posttraumatic
stress disorder (PTSD), panic and anxiety disorders,
obsessive-compulsive disorder, and schizophrenia, developmental
disorders such as fragile X syndrome and autism, pain, drug
addictions such as alcoholism, neurodegenerative diseases such as
Parkinson's disease and Huntington's disease, as well as stroke and
ischemic brain injury, amyotrophic lateral sclerosis, and epilepsy.
"Neurological disorder" also includes any disorder, symptom, or
effect associated with or relating to exposure to a neurotoxin,
including but not limited to neurotoxins such as chemical warfare
agents.
[0057] The term "patient" or "subject" are used interchangeably and
is used throughout the specification within context to describe an
animal, generally a mammal and preferably a human, to whom
treatment, including prophylactic treatment (prophylaxis), with the
pharmaceutical compositions according to any embodiment described
herein. For treatment of those infections, conditions or disease
states which are specific for a specific animal such as a human
patient, the term patient refers to that specific animal.
[0058] By "pharmaceutically-acceptable" it is meant that the
carrier, diluent or excipient must be compatible with the other
ingredients of the pharmaceutical composition and not deleterious
to the recipient thereof.
[0059] The term "pharmaceutically acceptable salt of huperzine that
is equivalent to about 1 weight % huperzine" refers to a
pharmaceutically acceptable salt of huperzine that would provide
about 1 weight % of huperzine free base if the salt was converted
to huperzine. Similarly the terms "pharmaceutically acceptable salt
that is equivalent to about 0.5 weight % to about 1.5 weight %
huperzine", "pharmaceutically acceptable salt that is equivalent to
about 0.9 weight % to about 1 weight % huperzine",
"pharmaceutically acceptable salt that is equivalent to about 0.95
weight % to about 1 weight % huperzine" and the like refer to a
pharmaceutically acceptable salt of huperzine that would provide
about 0.5 weight % to about 1.5 weight %, about 0.9 weight % to
about 1 weight %, about 0.95 weight % to about 1 weight %,
huperzine free base respectively, if the salt was converted to
huperzine. For example 6 grams of huperzine A is needed to provide
1 weight % of a 600 g pharmaceutical composition, but 6.89 g of the
HCl salt of huperzine A is needed to provide 1 weight % huperzine
A.
[0060] It will be understood by one of skill in the art that the
term "polyvinylpyrrolidone" is also known by several
non-proprietary names, for example, "PVP" "polyvinyl pyrrolidone",
"povidone", and "polyvidone". It will also be understood that
polyvinylpyrrolidones are referred to by their k number which
indicates the mean molecular weight of the polyvinylpyrrolidone.
Examples of polyvinylpyrrolidones include, but is not limited to
polyvinylpyrrolidone K30, polyvinylpyrrolidone K10,
polyvinylpyrrolidone K360, polyvinylpyrrolidone K40.
[0061] As used herein, the term "seizure disorder" means any
condition in which one or more seizures is a symptom. As used
herein, a seizure may be due to unusual electrical activity in the
brain or may be a non-epileptic seizure, which is not accompanied
by abnormal electrical activity in the brain. A seizure may be
caused by, for example, but not limited to, psychological issues,
psychological stress, trauma, hypoglycemia, low blood sodium,
fever, alcohol use, or drug use or unknown causes. Types of
seizures and seizure disorders include, but are not limited to,
epilepsy (including intractable epilepsy), generalized seizures,
primary generalized seizures, absence seizures, myoclonic seizures,
partial seizures, complex partial seizures with or without
generalization (for example, focal impaired awareness seizures
(FIAS)), Lennox-Gastaut Syndrome, Dravet Syndrome and Generalized
Epilepsy with Febrile Seizures plus (GEFS+). In some embodiments,
the seizure disorder is epilepsy.
[0062] As used herein, the term "therapeutic" means an agent
utilized to treat, combat, ameliorate, prevent, or improve an
unwanted condition or disease of a patient. In part, embodiments of
the present invention are directed to the treatment of
neurodegenerative disorders including seizure disorders such as
epilepsy.
[0063] The term "therapeutically effective amount" means any amount
which results in improved treatment, healing, prevention, or
amelioration of a disease, disorder, or side effect, or a decrease
in the rate of advancement of a disease or disorder. The term also
includes within its scope amounts effective to enhance normal
physiological function.
[0064] The term "t.sub.1/2" is the time it takes for the peak
plasma concentration to reach half of its original value after
administration to a subject.
[0065] By "t.sub.max" it is meant the time to reach C.sub.max after
administration to a subject.
[0066] The terms "treat," "treated," or "treating" as used herein
refers to both therapeutic treatment and prophylactic or
preventative measures, wherein the object is to prevent or slow
down (lessen) an undesired physiological condition, disorder or
disease, or to obtain beneficial or desired clinical results. For
the purposes of this invention, beneficial or desired clinical
results include, but are not limited to, alleviation of symptoms;
diminishment of the extent of the condition, disorder or disease;
stabilization (i.e., not worsening) of the state of the condition,
disorder or disease; delay in onset or slowing of the progression
of the condition, disorder or disease; amelioration of the
condition, disorder or disease state; and remission (whether
partial or total), whether detectable or undetectable, or
enhancement or improvement of the condition, disorder or disease.
Treatment includes eliciting a clinically significant response
without excessive levels of side effects. Treatment also includes
prolonging survival as compared to expected survival if not
receiving treatment.
[0067] In some embodiments, the compounds and methods disclosed
herein can be utilized with or on a subject in need of such
treatment, which can also be referred to as "in need thereof." As
used herein, the phrase "in need thereof" means that the subject
has been identified as having a need for the particular method or
treatment and that the treatment has been given to the subject for
that particular purpose.
[0068] Generally speaking, the term "tissue" refers to any
aggregation of similarly specialized cells which are united in the
performance of a particular function.
[0069] The embodiments set forth herein are described in terms of
"comprising", however any embodiment described herein may also be
described in terms of "consists of" or "consisting of", meaning
that the pharmaceutical composition or method includes only the
elements, steps, or ingredients specifically recited in the
particular claimed embodiment or claim and each of the embodiments
described herein, may also be described in terms of "consisting
essentially of" or "consists essentially of", meaning that the
pharmaceutical composition or method includes only the specified
materials or steps and those that do not materially affect the
basic and novel characteristics of the claimed invention.
[0070] Pharmaceutical Compositions
[0071] Embodiments of the present invention relate to modified
release, oral, pharmaceutical compositions of huperzine, and more
particularly to huperzine A. Applicants have discovered modified
release pharmaceutical compositions of huperzine that provide
therapeutically effective plasma concentrations of huperzine, with
twice daily dosing, and overcome the rapid high serum peak levels
associated with the serious adverse (and dosing limiting) side
effects of huperzine.
[0072] To illustrate the advantages of a modified release
pharmaceutical composition of huperzine A in treating, for example,
seizure disorders, applicant used non clinical animal data,
applicant generated pharmacokinetics in dogs (vide infra),
allometric scaling, and modeling to determine that a therapeutic
threshold (C.sub.max) of about 16.5 ng/mL (2 mg dose) of huperzine
A in serum is predicted to achieve efficacy in treating subjects
with seizure disorders. However, a dose escalation study conducted
by the applicant (unpublished), indicated that high serum peak
levels greater than about 5 ng/mL especially within the first 31
hours have a high probability of resulting in nausea and vomiting.
In the study, 7 out of 8 subjects experienced nausea and/or
vomiting within the first 31 hrs. These subjects had an average
time to initial nausea of 17.7 hours, and displayed huperzine
plasma levels of 4.8 ng/mL on average. The one subject that did not
experience nausea did not reach plasma levels of over 5 ng/mL until
42 hours after initial dosing. These findings would indicate that
there is a time-concentration relationship, where achieving plasma
exposures between 4-5 ng/mL within the first 31 hours may result in
drug-related adverse events. Prior to Applicant's immediate release
dose escalation study, it was unknown what plasma concentration
threshold to stay below in order to obtain a better side effect
profile. Dosing of about 2 mg immediate release huperzine A twice a
day therefore is predicted to cause early, high serum peaks
associated with nausea and vomiting. Additionally, peak to trough
serum exposures are predicted to fluctuate below the therapeutic
threshold. Furthermore, a single missed dose of huperzine is
predicted to not only put the subject below the therapeutic
threshold, but also expose the subject to rapid, high peak serum
concentration upon resuming the immediate release dose, thus
potentially resulting in nausea and vomiting each time a dose is
missed (FIG. 1). This makes the immediate release pharmaceutical
composition unfavorable and potentially dangerous as a therapeutic
option. In contrast, the modified release pharmaceutical
compositions developed by the applicant and administered as
described herein, achieved the therapeutic threshold and unlike
immediate release pharmaceutical compositions, keep serum exposure
levels below the 5 ng/mL threshold initially, thereby avoiding the
adverse nausea and vomiting associated with the immediate release
pharmaceutical compositions. In addition, if, after reaching the
therapeutic level, a subject misses a dose, the plasma
concentration will not fall so low that the serious adverse events
will occur (FIG. 2).
[0073] Applicant has discovered oral pharmaceutical modified
release pharmaceutical compositions of huperzine that offer
unexpected properties over other oral pharmaceutical compositions
of huperzine. These pharmaceutical compositions allow for higher
therapeutic thresholds to be obtained without the side effects
associated with high serum peak levels and also allow for twice
daily dosing.
[0074] In embodiments, orally administerable, modified release
pharmaceutical compositions of huperzine of the present invention
comprise a dissolvable core; a huperzine layer coating the
dissolvable core; and a polymer coating, coating the huperzine
layer; wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine.
[0075] In some embodiments of the invention, the dissolvable core
is a fully dissolvable core. In further embodiments, the core is a
sugar sphere. In some embodiments, the sugar sphere comprises
sucrose and starch. In some embodiments, the sucrose is at least
62% by weight sucrose. In further embodiments, the sugar spheres
are Suglets.RTM. sugar spheres. In some embodiments, the sugar
spheres are of a particle size of about 250 .mu.m to about 1700
.mu.m. In some embodiments, the sugar spheres are selected from a
particle size of about 250 .mu.m to about 355 .mu.m, about 500
.mu.m to about 600 .mu.m, about 600 .mu.m to about 710 .mu.m, about
710 .mu.m to about 850 .mu.m, about 850 .mu.m to about 1000 .mu.m,
about 850 .mu.m to about 1180 .mu.m, about 1000 .mu.m to about 1180
.mu.m, about 1000 .mu.m to about 1400 .mu.m, about 1400 .mu.m to
about 1700 .mu.m and combinations thereof. In further embodiments,
the sugar spheres are selected from a particle size of about 500
.mu.m to about 600 .mu.m, or about 600 .mu.m to about 710 .mu.m. In
some embodiments, the sugar spheres are selected from a particle
size of about 500 .mu.m to about 710 .mu.m. In some embodiments,
the sugar spheres are Suglets.RTM. PF006.
[0076] In further embodiments, the sugar sphere comprises about 74
weight % to about 86 weight % of the pharmaceutical composition. In
some embodiments, the sugar sphere comprises about 79 weight % to
about 84 weight % of the pharmaceutical composition. In some
embodiments, the sugar sphere comprises about 80 weight % to about
86 weight % of the pharmaceutical composition. In some embodiments
the sugar sphere comprises about 80 weight % to about 83 weight %
of the pharmaceutical composition. In some embodiments the sugar
sphere comprises about 81 weight % to about 83 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises about 81 weight % to about 82.8 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises 81.5 weight % to 83.0 weight %. In some embodiments the
sugar sphere comprises about 79.1 weight % to about 80 weight % of
the pharmaceutical composition. In some embodiments the sugar
sphere comprises about 80 weight % to about 81 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises about 81 weight % to about 82 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises about 81 weight % to about 81.9 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises about 81.9 weight % to about 82.8 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises about 82 weight % to about 83 weight % of the
pharmaceutical composition. In some embodiments the sugar sphere
comprises about 82.8 weight % to about 83.7 weight % of the
pharmaceutical composition.
[0077] In some embodiments the weight percent of sugar sphere in
the pharmaceutical composition is between a lower limit of about 74
weight %, about 75 weight %, about 76 weight %, about 77 weight %,
78 about weight %, about 79 weight %, about 80 weight %, about 81
weight %, about 82 weight %, about 83 weight %, about 84 weight %,
about 85 weight %, and about 86 weight % and an upper limit of
about 86 weight %, about 85 weight %, about 84 weight %, 83 weight
%, 82 weight %, 81 weight %, 80 weight %, 79 weight %, 78 weight %,
77 weight %, 76 weight %, 75 weight %, and 74 weight %.
[0078] In some embodiments the weight percent of sugar sphere in
the pharmaceutical composition is about 74 weight %, about 75
weight %, about 76 weight %, about 77 weight %, about 78 weight %,
about 79 weight %, about 80 weight %, about 81 weight %, about 82
weight %, about 83 weight %, about 84 weight %, about 85 weight %,
or about 86 weight %.
[0079] In some embodiments of the invention, the huperzine layer
comprises huperzine A or pharmaceutically acceptable salts thereof.
In some embodiments the huperzine A is a huperzia serrata extract.
In some embodiments the huperzia serrata extract is about 99%
huperzine A.
[0080] In some embodiments, the weight percent of huperzine in the
pharmaceutical composition comprises about 0.5 weight % to about
1.5 weight % huperzine or a pharmaceutically acceptable salt of
huperzine that is equivalent to 0.5 weight % to about 1.5 weight %
huperzine. In some embodiments, the weight percent of huperzine in
the pharmaceutical composition comprises about 0.9 weight % to
about 1 weight % huperzine or a pharmaceutically acceptable salt of
huperzine that is equivalent to 0.9 weight % to about 1 weight %
huperzine. In some embodiments, the weight percent of huperzine in
the pharmaceutical composition comprises about 0.95 weight % to
about 1 weight % huperzine or a pharmaceutically acceptable salt of
huperzine that is equivalent to 0.95 weight % to about 1 weight %
huperzine. In some embodiments, the weight percent of huperzine in
the pharmaceutical composition comprises about 1 weight % huperzine
or a pharmaceutically acceptable salt that is equivalent to about 1
weight % huperzine. In some embodiments the weight percent of
huperzine in the pharmaceutical composition comprises between a
lower limit of about 0.5 weight %, about 0.6 weight %, about 0.7
weight %, about 0.8 weight %, 0.9 about weight %, about 1 weight %,
about 1.1 weight %, about 1.2 weight %, about 1.3 weight %, about
1.4 weight %, and about 1.5 weight % and an upper limit of about
1.5 weight %, about 1.4 weight %, about 1.3 weight %, 1.2 weight %,
1.1 weight %, 1 weight %, 0.9 weight %, 0.8 weight %, 0.7 weight %,
0.6 weight, and 0.5 weight % of huperzine or a pharmaceutically
acceptable salt of huperzine that is equivalent to a lower limit of
about 0.5 weight %, about 0.6 weight %, about 0.7 weight %, about
0.8 weight %, 0.9 about weight %, about 1 weight %, about 1.1
weight %, about 1.2 weight %, about 1.3 weight %, about 1.4 weight
%, and about 1.5 weight % and an upper limit of about 1.5 weight %,
about 1.4 weight %, about 1.3 weight %, 1.2 weight %, 1.1 weight %,
1 weight %, 0.9 weight %, 0.8 weight %, 0.7 weight %, 0.6 weight,
and 0.5 weight % of huperzine. In some embodiments the weight
percent of huperzine in the pharmaceutical composition comprises
0.5 weight %, about 0.6 weight %, about 0.7 weight %, about 0.8
weight %, 0.9 about weight %, about 1 weight %, about 1.1 weight %,
about 1.2 weight %, about 1.3 weight %, about 1.4 weight %, and
about 1.5 weight % or a pharmaceutically acceptable salt of
huperzine that is equivalent to 0.5 weight %, about 0.6 weight %,
about 0.7 weight %, about 0.8 weight %, 0.9 about weight %, about 1
weight %, about 1.1 weight %, about 1.2 weight %, about 1.3 weight
%, about 1.4 weight %, and about 1.5 weight % of huperzine. In
further embodiments, the huperzine layer comprises a
therapeutically-effective amount of huperzine.
[0081] In some embodiments, the huperzine layer further comprises
one or more excipients. In some embodiments, the total amount of
excipients is about 5 weight % to about 10 weight % of the
pharmaceutical composition. In some embodiments the total amount of
excipients is about 5 weight % to about 9 weight % of the
pharmaceutical composition. In some embodiments the total amount of
excipients is about 5 weight % to about 7 weight % of the
pharmaceutical composition. In some embodiments the total amount of
excipients in the huperzine layer is selected from about 5 weight
%, about 6 weight %, about 7 weight %, about 8 weight %, about 9
weight %, or about 10% weight %, of the pharmaceutical composition.
In some embodiments, the excipients are selected from hydroxypropyl
methylcellulose or polyvinylpyrrolidone and combinations
thereof.
[0082] In some embodiments, the hydroxypropyl methylcellulose is a
low viscosity or very low viscosity hydroxypropyl methylcellulose,
such as, for example Methocel.TM. hydroxyproply methycelluloses. In
further embodiments, the hydroxypropyl methylcellulose is Methocel
VLV or the like. In some embodiments, the amount of hydroxypropyl
methylcellulose in the huperizine layer is about 6 weight % to
about 7 weight % of the composition. In some embodiments, the
amount of hydroxypropyl methylcellulose in the huperizine layer is
about 5 weight % to about 6 weight % of the composition. In some
embodiments, the amount of hydroxypropyl methylcellulose in the
huperizine layer is about 6 weight %. In some embodiments, the
amount of hydroxypropyl methylcellulose in the huperizine layer is
about 5 weight %. In further embodiments, the hydroxypropyl
methylcellulose is Methocel VLV and the amount of Methocel VLV in
the huperizine layer is about 6.1 weight % of the composition.
[0083] In some embodiments of the invention, the
polyvinylpyrrolidone is any polyvinylpyrrolidone appropriate for
use in an oral pharmaceutical composition. In further embodiments,
the polyvinyl pyrrolidone is polyvinylpyrrolidone K30. In some
embodiments, the amount of polyvinylpyrrolidone in the huperzine
layer is about 0.5 weight % to about 1.5 weight % of the
composition. In some embodiments, the polyvinylpyrrolidone in the
huperzine layer is about 0.95 weight % to about 1 weight % of the
composition. In some embodiments, the polyvinylpyrrolidone in the
huperzine layer is about 0.90 weight % to about 1 weight % of the
composition. In some embodiments, the polyvinylpyrrolidone in the
huperzine layer is about 1 weight % of the composition. In further
embodiments the polyvinylpyrrolidone is polyvinylpyrrolidone K30
and the amount of polyvinylpyrrolidone K30 in the huperzine layer
is about 1 weight % of the composition.
[0084] In some embodiments the one or more excipients in the
huperzine layer is a combination of hydroxypropyl methylcellulose
and polyvinylpyrrolidone. In some embodiments the one or more
excipients in the huperzine layer is of about 5 weight % to about 7
weight % hydroxypropyl methylcellulose and about 0.5 weight % to
about 1.5 weight % polyvinylpryrrolidone. In some embodiments the
one or more excipients in the huperzine layer is about 6 weight %
hydroxypropyl methylcellulose and about 1 weight %
polyvinylpryrrolidone.
[0085] In some embodiments of the invention, the polymer coating is
a poly acrylamide polymer or ethylcellulose polymer layer coating
the huperzine layer. In some embodiments the polymer coating is a
non-polyacrylamide polymer coating the huperzine layer. In some
embodiments the polymer coating is an a plasticized ethylcellulose
polymer layer coating the huperzine layer. In further embodiments
the plasticized ethylcellulose is a SuRelease.RTM. ethylcellulose.
In some embodiments the plasticized ethylcellulose is
SurRelease.RTM. Type B NF E.
[0086] In some embodiments the plasticized ethylcellulose polymer
comprises about 7 weight % to about 16 weight % of the composition.
In some embodiments the plasticized ethylcellulose polymer
comprises about 8 weight % to about 13 weight % of the composition.
In some embodiments the plasticized ethylcellulose polymer
comprises about 7 weight % to about 12 weight % of the composition.
In some embodiments the plasticized ethylcellulose polymer
comprises about 8 weight % to about 12 weight % of the composition.
In some embodiments the plasticized ethylcellulose polymer
comprises about 9 weight % to about 11 weight % of the composition.
In some embodiments the plasticized ethylcellulose polymer
comprises about 9 weight % to about 10 weight % of the composition.
In some embodiments the plasticized ethyl cellulose polymer
comprises about 8.3 weight % to about 9.2 weight % of the
pharmaceutical composition. In some embodiments the plasticized
ethyl cellulose polymer comprises about 9.2 weight % to about 10.1
weight % of the pharmaceutical composition. In some embodiments the
plasticized ethyl cellulose polymer comprises about 10.1 weight %
to about 11 weight % of the pharmaceutical composition. In some
embodiments the plasticized ethyl cellulose polymer comprises about
11 weight % to about 12 weight % of the pharmaceutical composition.
In some embodiments the plasticized ethyl cellulose polymer
comprises about 12 weight % to about 12.9 weight % of the
pharmaceutical composition. In some embodiments the plasticized
ethyl cellulose polymer comprises about 15 weight % to about 16
weight % of the pharmaceutical composition.
[0087] In some embodiments, the weight percent of plasticized
ethylcellulose polymer in the composition is between a lower limit
of 7 weight %, 8 weight %, 9 weight %, 10 weight %, 11 weight %, 12
weight %, 13 weight %, 14 weight %, 15 weight %; and 16 weight %
and an upper limit of 16 weight %, 15 weight %, 14 weight %; 13
weight %, 12 weight %, 11 weight %, 10 weight %, 9 weight %, 8
weight % and 7 weight %.
[0088] In some embodiments, the pharmaceutical composition
comprises: [0089] a) a dissolvable core according to any embodiment
described herein for dissolvable cores; [0090] b) a huperzine layer
comprising huperzine or a pharmaceutically acceptable salt of
huperzine, according to any embodiment described herein for the
huperzine layer, coating the dissolvable core; and [0091] c) a
polymer coating, coating the huperzine layer, according to any
embodiment described herein.
[0092] In some embodiments of the invention the pharmaceutical
composition for oral delivery comprises: (a) about 74 weight % to
about 86 weight % of a sugar sphere core wherein the sugar sphere
core has a particle size of about 500-710 .mu.m; (b) a huperzine
layer coating the sugar sphere, wherein the huperzine layer
comprises about 0.95% to about 1 weight % huperzine or a
pharmaceutically acceptable salt of huperzine that is equivalent to
about 0.95% to about 1 weight % huperzine, and one or more
excipients, wherein the total amount of excipients is about 5
weight % to about 9 weight %, (c) about 7 weight % to about 16
weight % of a plasticized ethyl cellulose polymer layer coating the
huperzine layer, wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine. In further
embodiments, the huperzine is huperzine A. In further embodiments
the one or more excipients is a combination of hydroxypropyl
methylcellulose and polyvinylpyrrolidone. In further embodiments
the one or more excipients is a combination of about 6 weight %
hydroxypropyl methylcellulose and about 1 weight %
polyvinylpyrrolidone. In some embodiments the hydroxypropyl
methylcellulose is a low viscosity hydroxypropyl methylcellulose,
the polyvinylpyrrolidone is a polyvinylpyrrolidone K30 and the
plasticized ethyl cellulose is SurRelease.RTM. Type B NF E.
[0093] In some embodiments of the invention the pharmaceutical
composition comprises: (a) about 79 weight % to about 84 weight %
of a sugar sphere core wherein the sugar sphere core has a particle
size of about 500-710 .mu.m; (b) a huperzine layer coating the
sugar sphere, wherein the huperzine layer comprises about 0.95
weight % to about 1 weight % huperzine or a pharmaceutically
acceptable salt of huperzine that is equivalent to about 0.95
weight % to about 1 weight % of huperzine, about 6 weight %
hydroxypropyl methylcellulose, and 0.95% to about 1 weight %
polyvinylpryrrolidone; and (c) about 8 weight % to about 13 weight
% of a plasticized ethyl cellulose polymer layer coating the
huperzine layer, wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine. In further
embodiments, the huperzine is huperzine A. In further embodiments,
the huperzine is huperzine A, the hydroxypropyl methylcellulose is
a low viscosity hydroxypropyl methylcellulose, the
polyvinylpyrrolidone is a polyvinylpyrrolidone K30 and the
plasticized ethyl cellulose is SurRelease.RTM. Type B NF E., the
hydroxypropyl methylcellulose is a low viscosity hydroxypropyl
methylcellulose, the polyvinylpyrrolidone is a polyvinylpyrrolidone
K30 and the plasticized ethyl cellulose is SurRelease.RTM. Type B
NF E.
[0094] In some embodiments of the invention the pharmaceutical
composition comprises: (a) about 80 weight % to about 83 weight %
of a sugar sphere core wherein the sugar sphere core has a particle
size of about 500-710 .mu.m; (b) a huperzine layer coating the
sugar sphere, wherein the huperzine layer about 0.95 weight % to
about 1 weight % huperzine or a pharmaceutically acceptable salt of
huperzine that is equivalent to about 0.95 weight % to about 1
weight % huperzine, about 5 weight % to about 6 weight %
hydroxypropyl methylcellulose, and about 0.95 weight % to about 1
weight % polyvinylpryrrolidone; and (c) about 8 weight % to about
12 weight % of a plasticized ethyl cellulose polymer layer coating
the huperzine layer, wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine. In further
embodiments, the huperzine is huperzine A, the hydroxypropyl
methylcellulose is a low viscosity hydroxypropyl methylcellulose,
the polyvinylpyrrolidone is a polyvinylpyrrolidone K30 and the
plasticized ethyl cellulose is SurRelease.RTM. Type B NF E.
[0095] In some embodiments of the invention the pharmaceutical
composition comprises: (a) about 81 weight % to about 82 weight %
of a sugar sphere core wherein the sugar sphere core has a particle
size of about 500-710 .mu.m; (b) a huperzine layer coating the
sugar sphere, wherein the huperzine layer comprises about 0.95
weight % to about 1 weight % huperzine or a pharmaceutically
acceptable salt of huperzine that is equivalent to about 0.95
weight % to about 1 weight % of huperzine, about 5 weight % to
about 6 weight % hydroxypropyl methylcellulose, and about 0.95
weight % to about 1 weight % polyvinylpryrrolidone; and (c) about
10 weight % to about 11 weight % of a plasticized ethyl cellulose
polymer layer coating the huperzine layer, wherein the huperzine
layer comprises a therapeutically-effective amount of huperzine. In
further embodiments, the huperzine is huperzine A, the
hydroxypropyl methylcellulose is a low viscosity hydroxypropyl
methylcellulose, the polyvinylpyrrolidone is a polyvinylpyrrolidone
K30 and the plasticized ethyl cellulose is SurRelease.RTM. Type B
NF E.
[0096] In some embodiments of the invention the pharmaceutical
composition comprises: (a) about 81.5 weight % of a sugar sphere
core wherein the sugar sphere core has a particle size of about
500-710 .mu.m; (b) a huperzine layer coating the sugar sphere,
wherein the huperzine layer comprises about 1 weight % huperzine or
a pharmaceutically acceptable salt of huperzine that is equivalent
to 1 weight % of huperzine, about 5.9 weight % hydroxypropyl
methylcellulose, and about 1 weight % polyvinylpryrrolidone; and
(c) about 10.7 weight % of a plasticized ethyl cellulose polymer
layer coating the huperzine layer, wherein the huperzine layer
comprises a therapeutically-effective amount of huperzine. In
further embodiments, the huperzine is huperzine A, the
hydroxypropyl methylcellulose is a low viscosity hydroxypropyl
methylcellulose, the polyvinylpyrrolidone is a polyvinylpyrrolidone
K30 and the plasticized ethyl cellulose is SurRelease.RTM. Type B
NF E.
[0097] In some embodiments of the invention the pharmaceutical
composition comprises: (a) about 82 weight % to about 83 weight %
of a sugar sphere core wherein the sugar sphere core has a particle
size of about 500-710 .mu.m; (b) a huperzine layer coating the
sugar sphere, wherein the huperzine layer comprises about 0.95
weight % to about 1 weight % huperzine or a pharmaceutically
acceptable salt of huperzine that is equivalent to about 0.95
weight % to about 1 weight % of huperzine, about 5 weight % to
about 6 weight % hydroxypropyl methylcellulose, and about 0.95
weight % to about 1 weight % polyvinylpryrrolidone; and (c) about 9
weight % to about 10 weight % of a plasticized ethyl cellulose
polymer layer coating the huperzine layer, wherein the huperzine
layer comprises a therapeutically-effective amount of huperzine. In
further embodiments, the huperzine is huperzine A, the
hydroxypropyl methylcellulose is a low viscosity hydroxypropyl
methylcellulose, the polyvinylpyrrolidone is a polyvinylpyrrolidone
K30 and the plasticized ethyl cellulose is SurRelease.RTM. Type B
NF E.
[0098] In some embodiments of the invention the pharmaceutical
comprises: (a) about 83 weight % of a sugar sphere core wherein the
sugar sphere core has a particle size of about 500-710 .mu.m; (b) a
huperzine layer coating the sugar sphere, wherein the huperzine
layer comprises about 1 weight % huperzine or a pharmaceutically
acceptable salt of huperzine that is equivalent to 1 weight % of
huperzine, about 6 weight % hydroxypropyl methylcellulose, and
about 1 weight % polyvinylpryrrolidone; and (c) about 9 weight % of
a plasticized ethyl cellulose polymer layer coating the huperzine
layer, wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine. In further
embodiments, the huperzine is huperzine A, the hydroxypropyl
methylcellulose is a low viscosity hydroxypropyl methylcellulose,
the polyvinylpyrrolidone is a polyvinylpyrrolidone K30 and the
plasticized ethyl cellulose is SurRelease.RTM. Type B NF E.
[0099] In some embodiments of the invention the pharmaceutical
composition further comprises a seal coat layer in between the
huperzine layer and the plasticized ethyl cellulose layer.
[0100] Some embodiments describe a pharmaceutical composition
comprising: (a) about 75 weight % to about 76 weight % of a sugar
sphere core wherein the sugar sphere core has a particle size of
about 500-710 .mu.m; (b) a huperzine layer coating the sugar
sphere, wherein the huperzine layer comprises about 0.9 weight % to
about 1 weight % huperzine or a pharmaceutically acceptable salt of
huperzine that is equivalent to about 0.9 weight % to about 1
weight % of huperzine, about 5 weight % to about 6 weight %
hydroxypropyl methylcellulose, and about 0.9 weight % to about 1
weight % polyvinylpryrrolidone; (c) a seal coat layer coating the
huperzine layer, comprising about 1 weight % to about 2 weight %
hydroxypropylmethyl cellulose; and (d) about 15 weight % to about
16 weight % of a plasticized ethyl cellulose polymer layer coating
the huperzine layer, wherein the huperzine layer comprises a
therapeutically-effective amount of huperzine. In further
embodiments, the huperzine is huperzine A, the hydroxypropyl
methylcellulose is a low viscosity hydroxypropyl methylcellulose,
the polyvinylpyrrolidone is a polyvinylpyrrolidone K30 and the
plasticized ethyl cellulose is SurRelease.RTM. Type B NF E.
[0101] Embodiments of the present invention comprise a
pharmaceutical composition according to any embodiment described
herein, characterized by a C.sub.max of huperzine in plasma of
about 4 ng/mL to about 8 ng/mL, a T.sub.max of about 4 hour to
about 8 hours and a t.sub.1/2 of about 8 hours to about 12 hours,
upon oral administration of a therapeutically effective dose of the
pharmaceutical composition to a human subject. In one embodiment
the C.sub.max is about 4 ng/mL to about 6 ng/mL, T.sub.max is about
4 hours to about 8 hours and the t.sub.1/2 is about 10 hours to
about 12 hours. In one embodiment the C.sub.max is about 6 ng/mL,
the T.sub.max is about 4 hours and the t.sub.1/2 is about 8.3
hours.
[0102] Further embodiments of the invention encompass
pharmaceutical composition according to any embodiment described
herein, comprising a therapeutically-effective amount of huperzine,
characterized by a T.sub.max of about 4 to about 8 hours and a
C.sub.max that is reduced by about 25% to about 75% when compared
with a C.sub.max of an immediate release huperzine pharmaceutical
composition administered at an equivalent dose. In some embodiments
the C.sub.max is reduced by 50% when compared with a C.sub.max of
an immediate release huperzine pharmaceutical composition.
[0103] Some embodiments describe a pharmaceutical compositions
according to any embodiment described herein, that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 36% to about 46% of the huperzine is
released after 2 hours, about 61% to about 77% of the huperzine is
released after 4 hours, about 84% to about 97% of the huperzine is
released after 8 hours and not less than about 89% of the huperzine
is released after 12 hours.
[0104] Some embodiments describe a pharmaceutical compositions
according to any embodiment described herein, that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 36% of the huperzine is released after 2
hours, about 63% of the huperzine is released after 4 hours about
84% of the huperzine is released after 8 hours and not less than
about 89% of the huperzine is released after 12 hours.
[0105] Some embodiments describe a pharmaceutical compositions
according to any embodiment described herein, that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 46% of the huperzine is released after 2
hours, about 77% of the huperzine is released after 4 hours about
97% of the huperzine is released after 8 hours and not less than
about 99% of the huperzine is released after 12 hours.
[0106] Some embodiments describe a pharmaceutical compositions
according to any embodiment described herein, that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 43% of the huperzine is released after 2
hours, about 68% of the huperzine is released after 4 hours about
88% of the huperzine is released after 8 hours and not less than
about 96% of the huperzine is released after 12 hours.
[0107] Some embodiments describe a pharmaceutical compositions
according to any embodiment described herein, that exhibits the
following dissolution profile when tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C.: about 38% of the huperzine is released after 2
hours, about 61% of the huperzine is released after 4 hours about
84% of the huperzine is released after 8 hours and not less than
about 94% of the huperzine is released after 12 hours.
[0108] Pharmaceutical compositions characterized by a plasma
concentration of below 5 ng/mL maintained within the first 31
hours, upon oral administration of the pharmaceutical composition
to a human subject are another embodiment of some embodiments of
the invention.
[0109] In any embodiments described herein, the huperzine is
huperzine A or pharmaceutically acceptable salts thereof. In any
embodiments, the huperzine A is a huperzia serrata extract. In any
embodiments, the huperzia serrata extract is about 99% huperzine
A.
[0110] In any embodiments described herein, the pharmaceutical
composition is for oral delivery. In embodiments, the
pharmaceutical compositions of the invention are formulated for
oral administration and can be, for example, in the form of
tablets, sprinkles, capsules and pills. In one embodiment, the
pharmaceutical compositions according to any embodiment described
herein, are formulated for oral administration in the form of
capsules. In some embodiments, the pharmaceutical compositions
according to any embodiment described herein, are formulated for
oral administration in the form of tablets. The compositions of the
inventions can contain additional non-toxic pharmaceutically
acceptable carriers and/or diluents and/or adjuvants and/or
excipients. The use of such media and agents for pharmaceutically
active substances is well known in the art and includes tablet
binders, lubricants, flavoring agents, preservatives, wetting
agents, emulsifying agents, and dispersing agents.
[0111] As illustrated below and in the examples that follow,
applicant has shown that the pharmaceutical compositions described
in any of the embodiments described herein, have unexpected and
unpredictable properties.
[0112] Applicant prepared a number of pharmaceutical compositions
comprising an inert core layer, a huperzine layer coating the core
layer and a polymer layer coating the huperzine layer as shown in
Table 1.
TABLE-US-00001 TABLE 1 Seat coat layer Weight % Core type/Size*
Huperzine Layer** of each Weight % of Weight % of each component
Polymer layer Composition total component in total in total Weight
% of total No. composition composition composition composition 1A
76.10 5.48 HPMC 4.88 Eudragit RL 30 D MCC 0.91 PVP 4.88 Eudragit RS
30 D 500-710 .mu.m 0.91 huperzine A 1.97 Triethyl citrate 4.88 Talc
1B 76.10 5.48 HPMC 4.88 Eudragit RL 30 D MCC 0.91 PVP 4.88 Eudragit
RS 30 D 500-710 .mu.m 0.91huperzine A 1.97 Triethyl citrate 4.88
Talc Eudragit, cured 2A 82.95 5.97 HPMC 9.09 SuRelease MCC 1 PVP
255-500 .mu.m 1 huperzine A 2B 79.34 5.71 HPMC 13.04 SuRelease MCC
0.95 PVP 255-500 .mu.m 0.95 huperzine A 2C 76.03 5.47 HPMC 16.67
SuRelease MCC 0.91 PVP 255-500 .mu.m 0.91 huperzine A 3A 82.95 5.97
HPMC 9.09 SuRelease MCC 1 PVP 500-710 .mu.m 1 huperzine A 3B 79.34
5.71 HPMC 13.04 SuRelease MCC 0.95 PVP 500-710 .mu.m 0.95 huperzine
A 3C 76.03 5.47 HPMC 16.67 SuRelease MCC 0.91 PVP 500-710 .mu.m
0.91 huperzine A 4A 82.95 5.97 HPMC 9.09 Sugar spheres 1 PVP
SuRelease 500-710 .mu.m 1 Huperzine A 4B 79.34 5.71 HPMC 13.04
Sugar spheres 0.95 PVP SuRelease 500-710 .mu.m 0.95 Huperzine A 4D
82.95 5.97 HPMC 9.09 Sugar spheres 1 PVP SuRelease 500-710 .mu.m 1
Huperzine A 4C 91.24 6.57 HPMC 0% Sugar spheres 1.09 PVP 500-710
.mu.m 1.09 Huperzine A 4E 75.81 5.46 HPMC 1.66 HPMC 15.35 SuRelease
Sugar spheres 0.91 PVP 500-710 .mu.m 0.91 Huperzine A 4F-1 81.47
5.87 HPMC 10.71 SuRelease Sugar spheres 0.98 PVP 500-710 .mu.m 0.98
Huperzine A 4F-2 81.47 5.87 HPMC 10.71 SuRelease Sugar spheres 0.98
PVP 500-710 .mu.m 0.98 Huperzine A *MCC = Microcrystalline
cellulose spheres **HPMC = hydroxypropylmethyl cellulose; PVP =
polyvinylpyrrolidone
[0113] As illustrated in FIG. 4, compositions 1A and 1B had
dissolution profiles that were so fast that they were more similar
to immediate release pharmaceutical compositions than modified
release pharmaceutical compositions, releasing 88-92% of the
huperzine in about 30 minutes. This result is unexpected since
microcrystalline cellulose spheres are known to one of skill in the
art as suitable cores for extended/modified release of
pharmaceuticals. Moreover, the MCC compositions 1A and 1B contained
a Eudragit layer coating the huperzine layer. Eudragit would have
been predicted to slow the rate of dissolution even further.
Furthermore, given the dissolution profile of compositions 1 and 2,
one of skill in the art would not have expected compositions
comprising sugar spheres to offer advantages over the MCC spheres.
Because sugar spheres are water soluble, one of skill in the art
would expect the dissolution profile of a sugar sphere composition
to be faster than compositions with the water insoluble MCC
spheres. While the MCC compositions 2A, 2B, 2C, 3A, 3B, and 3C had
longer release profiles, they either had an initial release that
was too fast (rapid release), or they released too slowly. The
sugar sphere compositions 4A, 4B, 4D, 4E, 4F-1, and 4F-2 and
particularly 4D, 4F-1, and 4F-2, however, unexpectedly had a slow
initial rate of dissolution and released about 85-90% (or higher)
of huperzine after 12 hours, making them ideal for modified release
pharmaceutical compositions of huperzine (See FIG. 5 and Table
2).
TABLE-US-00002 TABLE 2 Time (min) 4A 4B 4D 4E 4F-1 4F-2 0 0.0 0 0 0
0 0 30 4.5 1.4 10 4.9 12 12 60 16.5 7.0 22 12.1 23 22 120 35.8 24.5
46 25.8 43 38 180 51.7 37.2 65 37.9 58 51 240 63.2 47.8 77 48.3 68
61 300 70.5 57.7 86 56.5 75 69 360 76.6 64.6 92 63.6 81 75 420 81.8
69.9 95 69.6 85 80 480 84.0 77.9 97 74.6 88 84 600 87.2 80.1 100 82
92 90 720 89.3 83.5 101 87.4 96 94
[0114] Some embodiments describe a pharmaceutical composition
according to any embodiment described herein, that exhibit a
dissolution profile as defined in Table 2. In some embodiments, the
dissolution profile has an F2 of greater than 50%, when compared to
any of compositions 4A, 4D, 4F-1 and 4F-2. It will be understood by
one of skill in the art that F2 is a factor that assesses the
similarity of 2 dissolution curves and is represented by the
formula
F2=50.times.log {[1+(1/n).SIGMA.(R-T) 2] -0.5.times.100}
where n is the number of time points being assessed, R=reference
value at a given time, T=test value at equivalent time.
[0115] A pharmacokinetic study in dogs further illustrates the
advantages of composition 4A, for example over the MCC compositions
(See FIG. 6). The following pharmacokinetic parameters were
observed in the study (See Table 3 and Example 2).
TABLE-US-00003 TABLE 3 Immediate Release* Composition 4A
Composition 2C C.sub.max ng/ml 12.7 6.0 4.2 T.sub.max (hours) 1.25
4.0 2.0 T.sub.1/2 (hours) 5.71 8.32 5.54 *based on values from Chu
D, Liu W, Li Y, Li P, Gu J, Liu K. Pharmacokinetics of huperzine A
in dogs following single intravenous and oral administrations.
Planta Med. 2006 May; 72(6): 552-5, **calculated based on
equivalent dosing
[0116] As illustrated in Table 3 and in FIG. 6, the MCC composition
2C, releases huperzine, however, the release and subsequent
absorption of huperzine isn't fast enough to keep up with the
clearance of the drug from the body, yielding only a minor
prolongation of t1/2 to 2 hours from 1.25 hours. Therefore,
patients would have to receive huperzine in composition 2C four to
six times daily, thus offering little advantage over immediate
release pharmaceutical compositions. Composition 4A however, had a
pharmacokinetic profile ideal for twice daily doing, demonstrating
higher overall absorption, without clearing from the body too
quickly.
[0117] A phase 1b clinical trial in humans, further illustrated
that composition 4D had a favorable pharmacokinetic profile that
showed a dramatic reduction of serious adverse events compared with
the immediate release preparation, demonstrated twice a day dosing
and demonstrated achievable drug plasma levels predicted to provide
significant protection in patients that require higher doses of
huperzine, for example, patients with seizure disorders (See
Example 3).
Methods of Treatment
[0118] The pharmaceutical compositions according to any embodiment
described herein, are useful in treating neurological disorders
and/or seizure disorders to a patient in need thereof. They can be
administered therapeutically to treat, prevent, or slow the rate of
onset of neuronal dysfunctions. Some embodiments describe methods
of treating neurological disorders and/or seizure disorders. Some
embodiments describe methods of treating neurological disorders
selected from amyloid-related disorder such as Alzheimer's disease
and the amyloid-disorders described herein, psychiatric disorders
such as Tourette's syndrome, posttraumatic stress disorder (PTSD),
panic and anxiety disorders, obsessive-compulsive disorder, and
schizophrenia, developmental disorders such as fragile X syndrome
and autism, pain, drug addictions such as alcoholism,
neurodegenerative diseases such as Parkinson's disease and
Huntington's disease, as well as stroke and ischemic brain injury,
amyotrophic lateral sclerosis, epilepsy, and any disorder, symptom,
or effect associated with or relating to exposure to a neurotoxin,
including but not limited to neurotoxins such as chemical warfare,
with a pharmaceutical composition according to any embodiment
described herein.
[0119] In embodiments, the present invention provides methods of
treating seizures or seizure disorders selected from epilepsy
(including intractable epilepsy), generalized seizures, primary
generalized seizures, absence seizures, myoclonic seizures, partial
seizures, complex partial seizures with or without generalization
(for example, focal impaired awareness seizures (FIAS)),
Lennox-Gastaut Syndrome, Dravet Syndrome and Generalized Epilepsy
with Febrile Seizures plus (GEFS+). In some embodiments, the
seizure disorder is epilepsy.
[0120] The pharmaceutical compositions according to any embodiment
described herein, can be administered therapeutically to treat,
prevent, or slow the rate of onset of neuronal dysfunctions, such
as epilepsy and seizures, or prophylactically to either protect
against further seizures associated with epilepsy or to avoid or
forestall the onset of seizures associated with other disorders.
For example, the pharmaceutical compositions according to any
embodiment described herein, can be administered prophylactically
to slow or halt the progression of seizures and epilepsy in a
patient who has had a stroke and has a risk of developing seizure
as a result of the stroke.
[0121] Further embodiments describe methods of treating epilepsy,
intractable epilepsy and FIAS, comprising administering to a
patient in need thereof, a pharmaceutical composition according to
any embodiment described herein.
[0122] In some embodiments the pharmaceutical compositions of the
invention is administered at a dose to reduce seizures by at least
10% with a better side effect profile. Preferably, the reduction is
20%, 50%, 75% or eliminates seizure episodes. For example, the
pharmaceutical compositions according to any embodiment described
herein, prevents the development of or completely eliminates
seizures.
[0123] In further embodiments, the present invention provides
methods of treating any disorder, symptom, or effect associated
with or relating to exposure to a neurotoxin, including but not
limited to neurotoxins such as chemical warfare, comprising
administering to a patient in need thereof, a pharmaceutical
composition according to any embodiment described herein.
[0124] In some embodiments, the dose of huperzine in the
pharmaceutical compositions of the invention preferably does not
exceed 10 mg/day. In some embodiments, the dose preferably does not
exceed 6.5 mg/day. In some embodiments, the dose is between a lower
limit of about 0.01 mg/day, about 0.05 mg/day, about 0.1 mg/day,
about 0.25 mg/day, about 0.5 mg/day, about 0.75 mg/day, about 0.8
mg/day, about 1 mg/day, about 1.1 mg/day, about 1.25 mg/day, about
1.5 mg/day, about 1.75 mg/day, about 2 mg/day, about 2.2 mg/day,
about 2.25 mg/day, about 2.5 mg/day, about 3.0 mg/day, about 3.5
mg/day, about 4.0 mg/day, about 4.5 mg/day, about 5.0 mg/day, about
5.5 mg/day, about 6.0 mg/day and about 6.5 mg/day; and an upper
limit of about 6.5 mg/day, about 6.0 mg/day, about 5.5 mg/day,
about 5 mg/day, about 4.5 mg/day, about 4.0 mg/day, about 3.5
mg/day, about 3.0 mg/day, about 2.5 mg/day, about 2.25 mg/day,
about 2.2 mg/day, about 2 mg/day, about 1.75 mg/day, about 1.5
mg/day, about 1.25 mg/day, about 1.1 mg/day, about 1 mg/day, about
0.75 mg/day, about 0.8 mg/day, about 0.5 mg/day, about 0.25 mg/day,
about 0.1 mg/day, about 0.05 mg/day and about 0.01 mg/day. In some
embodiments the dose is about 0.01 mg/day to about 0.8 mg/day. In
further embodiments the dose is about 0.25 mg/day to about 5
mg/day. In some embodiments the dose is about 0.25 mg/day to about
0.5 mg/day. In some embodiments the dose is about 0.5 mg/day to
about 0.75 mg/day. In some embodiments the dose is about 0.75
mg/day to about 1 mg/day. In some embodiments the dose is about 1
mg/day to about 1.25 mg/day. In some embodiments the dose is about
1.25 mg/day to about 1.5 mg/day. In some embodiments the dose is
about 1.5 mg/day to about 1.75 mg/day. In some embodiments the dose
is about 1.75 mg/day to about 2.0 mg/day. In some embodiments the
dose is about 2.0 mg/day to about 2.25 mg/day. In some embodiments
the dose is about 2.25 mg/day to about 2.5 mg/day. In some
embodiments the dose is about 2.5 mg/day to about 2.75 mg/day. In
some embodiments the dose is about 2.75 mg/day to about 3.0 mg/day.
In some embodiments the dose is about 3.0 mg/day to about 3.25
mg/day. In some embodiments the dose is about 3.25 mg/day to about
3.50 mg/day. In some embodiments the dose is about 3.50 mg/day to
about 3.75 mg/day. In some embodiments the dose is about 3.75
mg/day to about 4.0 mg/day. In some embodiments the dose is about
4.0 mg/day to about 4.25 mg/day. In some embodiments the dose is
about 4.25 mg/day to about 4.5 mg/day. In some embodiments the dose
is about 4.5 mg/day to about 4.75 mg/day. In some embodiments the
dose is about 4.75 mg/day to about 5 mg/day. In some embodiments
the dose is about 1 mg/day to about 5 mg/day. In some embodiments
the dose is about 0.5 mg/day to about 5 mg/day. In some embodiments
the dose is about 0.5 mg/day to about 2.2 mg/day. In some
embodiments, the dose is about 5 mg/day. In some embodiments the
dose is about 0.5 mg/day, about 1 mg/day, about 1.1 mg/day mg/day,
about 1.5 mg/day, about 2.0 mg/day, about 2.50 mg/day, about 3.0
mg/day, about 3.5 mg/day or about 3.6 mg/day. In some embodiments
the daily dose according to any embodiment described herein, is
administered twice a day. In some embodiments the dose is about
0.25 mg twice a day to about 2.5 mg twice a day. In some
embodiments the dose is about 0.25 mg twice a day, about 0.5 mg
twice a day, about 0.75 mg twice a day, about 1.0 mg twice a day,
about 1.1 mg twice a day, about 1.25 mg twice a day, 1.5 mg twice a
day, 1.75 mg twice a day, 1.8 mg twice a day, 2.0 mg twice a day,
2.25 mg twice a day, or 2.5 mg twice a day.
[0125] In some embodiments, doses of about 0.05 mg/day to about 7
mg/day, about 05 mg/day to about 5 mg/day, about 0.05 mg/day to
about 0.8 mg/day, about 0.05 mg/day to about 0.4 mg/day, about 0.05
mg/day to about 0.02 mg/day, or 0.05 mg/day to about 0.01 mg/day
may also used. In some embodiments these doses may be used to treat
any neurological disorder. In some embodiments these doses may be
used to treat symptoms or effects associated with or relating to
exposure to neurotoxins such as chemical warfare agents.
[0126] In some embodiments the present disclosure provides a method
of treating a neurological and/or seizure disorder comprising
administering to a patient in need thereof, one or more titration
doses of an modified release pharmaceutical composition of
huperzine, followed by a maintenance dose of an oral modified
release pharmaceutical composition of huperzine, wherein the
patient experiences a better side effect profile. In some
embodiments, the modified release pharmaceutical composition of
huperzine administered in the titration dose is the same modified
release pharmaceutical composition of huperzine administered in the
maintenance dose. In further embodiments, the modified release
pharmaceutical composition of huperzine administered in the
titration dose is different than the modified release
pharmaceutical composition of huperzine administered in the
maintenance dose. In further embodiments the huperzine is huperzine
A. In some embodiments the modified release pharmaceutical
composition of huperzine comprises a dissolvable core; an active
huperzine A layer coating the dissolvable core; and a polymer
coating, coating the huperzine A layer. In further embodiments, the
modified release huperzine pharmaceutical composition is a
pharmaceutical composition according to any embodiment described
herein. In some embodiments, the modified release pharmaceutical
composition of huperzine is a pharmaceutical composition according
to any embodiment described herein, and is the same pharmaceutical
composition in the titration dose and the maintenance dose. In some
embodiments, the oral modified release pharmaceutical composition
of huperzine is a pharmaceutical composition comprising huperzine A
according to any embodiment described herein, and is the same
pharmaceutical composition comprising huperzine A in the titration
dose and the maintenance dose. In some embodiments, the dose is
titrated from a low dose to high dose over several days to several
weeks until a maintenance dose is reached.
[0127] Some embodiments describe a method of treating a
neurological disorder and/or a seizure disorder, in a patient in
need thereof, wherein the patient experiences a better side effect
profile, comprising administering a first dosing regimen of at
least one dosing regimen selected from a. to h. (as further
described below) and administering a second dosing regimen of at
least one dosing regimen selected from a. to i. (as further
described below), provided the second dosing regimen ascends from
the first dosing regimen and further provided the last dosing
regimen is the maintenance dose and therefore will be administered
for as long as the patient is in need of treatment thereof: [0128]
a. administering a dose of about 0.01 mg to about 0.25 mg of
huperzine, once every about 12 hours for at least two days and up
to two weeks; [0129] b. administering a dose of about 0.26 mg to
about 0.5 mg of huperzine, once every about 12 hours for at least
two days and up to two weeks; [0130] c. administering a dose of
about 0.51 mg to about 0.75 mg of huperzine, once every about 12
hours for at least two days and up to two weeks; [0131] d.
administering a dose of about 0.76 mg to about 1 mg of huperzine,
once every about 12 hours for at least two days and up to two
weeks; [0132] e. administering a dose of about 1.1 mg to about 1.25
mg of huperzine, once every about 12 hours for at least two days
and up to two weeks; [0133] f. administering a dose of about 1.26
mg to about 1.5 mg of huperzine, once every about 12 hours for at
least two days and up to two weeks; [0134] g. administering a dose
of about 1.51 mg to about 1.75 mg of huperzine, once every about 12
hours for at least two days and up to two weeks; [0135] h.
administering a dose of about 1.76 mg to about 2 mg of huperzine,
once every about 12 hours for at least two days and up to two
weeks; and [0136] i. administering a dose of about 2.1 mg to about
2.5 mg of huperzine, once every about 12 hours for at least two
days; wherein the huperzine of a.-i. is administered in a modified
release pharmaceutical composition. In further embodiments the
modified release pharmaceutical composition is a pharmaceutical
composition according to any embodiment described herein. In
further embodiments each dose prior to the maintenance dose is
administered for 2 days to two weeks.
[0137] Some embodiments describe a method of treating a
neurological disorder and/or a seizure disorder, in a patient in
need thereof, wherein the patient experiences a better side effect
profile, comprising administering a first dosing regimen of at
least one dosing regimen selected from a. to h. (as further
described below) and administering a second dosing regimen of at
least one dosing regimen selected from a. to i. (as further
described below), provided the second dosing regimen ascends from
the first dosing regimen and further provided the last dosing
regimen is the maintenance dose and therefore will be administered
for as long as the patient is in need of treatment thereof: [0138]
a. administering a dose of about 0.25 mg of huperzine, once every
about 12 hours for at least two days and up to two weeks; [0139] b.
administering a dose of about 0.5 mg of huperzine, once every about
12 hours for at least two days and up to two weeks; [0140] c.
administering a dose of about 0.75 mg of huperzine, once every
about 12 hours for at least two days and up to two weeks; [0141] d.
administering a dose of about 1 mg of huperzine, once every about
12 hours for at least two days and up to two weeks; [0142] e.
administering a dose of about 1.25 mg of huperzine, once every
about 12 hours for at least two days and up to two weeks; [0143] f.
administering a dose of about 1.5 mg of huperzine, once every about
12 hours for at least two days and up to two weeks; [0144] g.
administering a dose of about 1.75 mg of huperzine, once every
about 12 hours for at least two days and up to two weeks; [0145] h.
administering a dose of about 2 mg of huperzine, once every about
12 hours for at least two days and up to two weeks; [0146] i.
administering a dose of about 2.5 mg of huperzine, once every about
12 hours for at least two days; wherein the huperzine of a.-i. is
administered in a modified release pharmaceutical composition. In
further embodiments the modified release pharmaceutical composition
is a pharmaceutical composition according to any embodiment
described herein. In further embodiments each dose prior to the
maintenance dose is administered for 2 days to two weeks. It will
be understood that any combination of at least one dosing regimen
selected from a. to h. and at least one dosing regimen selected
from a. to i., allows for any combination of dosing regimens and
thus describes a minimum of two dosing regimens (1 initial dose
lower than the maintenance dose and 1 maintenance dose) and a
maximum of 9 dosing regimens (ascending dosing regimens a. through
h and maintenance dose i.).
[0147] In some embodiments the method comprises administering any
dosing regimen selected from the following (wherein the last
designated dose is the maintenance dose):
TABLE-US-00004 a to i; a to h; a to g; a to f; a to e; a to d; a,
b, c; a, b; a, c to i; a, c to h; a, c to g; a, c to f; a, c to e;
a, c, d; a, b, d to i; a, b, d to h; a, b, d to g; a, b, d to f; a,
b, d, e; a, b, d; a to c, e to i; a to c, e to h; a to c, e to g; a
to c, e, f; a to c, e; a to d, f to i; a to d, f to h; a to d, f to
g; a to d, f; a to e, g to i; a to e, g, h; a to e, g; a to f, h,
i; a to f, h; a to g, I; b to i; b to h; b to g; b to f; b to e; b
to d; b, d to i; b, d to h; b, d to g; b, d to f; b, d, e; b, d; b,
c, e to i; b, c, e to h; b, c, e to g; b, c, e, f; b, c, e; b, c; b
to d, f to i; b to d, f to h; b to d, f, g; b to d, f; b to e, g to
i; b to e, g, h; b to e, g; b to f, h, i; b to f, h; b to g, I; c
to i; c to h; c to g; c to f; c to e; c, d; c, e to i; c, e to h;
c, e to g; c, e, f; c, e; c, d, f to i; c, d, f to h; c, d, f, g;
c, d, f; c to e, g to i; b to e, g, h; c to e, g; c to f, h, i; c
to f, h; c to g, i
[0148] In some embodiments, the method comprises
[0149] a. administering a dose of about 0.25 mg of huperzine A,
once every about 12 hours for two days to two weeks;
[0150] b. administering a dose of about 0.5 mg of huperzine A, once
every about 12 hours for two days to two weeks;
[0151] c. administering a dose of about 0.75 mg of huperzine A,
once every about 12 hours for two days to two weeks; and
[0152] d. administering a dose of about 1 mg of huperzine A, once
every about 12 hours for at least two days.
[0153] In some embodiments step d. is administered for as long as
the patient is in need of treatment.
[0154] In some embodiments, the method further comprises after step
d.:
[0155] e. administering a dose of about 1.25 mg of huperzine A once
every about 12 hours for as long as the patient is in need
thereof.
[0156] In some embodiments, the method further comprises after step
d.:
[0157] e. administering a dose of about 1.25 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0158] f. administering a dose of about 1.5 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0159] In some embodiments, the method further comprises after step
d.:
[0160] e. administering a dose of about 1.25 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0161] f. administering a dose of about 1.5 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0162] g. administering a dose of about 1.75 mg of huperzine A once
every about 12 hours for as long as the patient is in need
thereof.
[0163] In some embodiments, the method further comprises after step
d.:
[0164] e. administering a dose of about 1.25 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0165] f. administering a dose of about 1.5 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0166] g. administering a dose of about 1.75 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0167] h. administering a dose of about 2 mg of huperzine A once
every about 12 hours for as long as the patient is in need
thereof.
[0168] In some embodiments, the method further comprises after step
d.:
[0169] e. administering a dose of about 1.25 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0170] f. administering a dose of about 1.5 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0171] g. administering a dose of about 1.75 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0172] h. administering a dose of about 2 mg of huperzine A once
every about 12 hours for 2 days to 2 weeks;
[0173] i. administering a dose of about 2.5 mg of huperzine A once
every about 12 hours for as long as the patient is in need
thereof.
[0174] Some embodiments of the present disclosure are directed to a
method of treating a neurological disorder and/or a seizure
disorder, in a patient in need thereof, wherein the patient
experiences a better side effect profile, comprising administering
a modified release pharmaceutical composition of huperzine, wherein
the modified release pharmaceutical composition of huperzine is
characterized by a C.sub.ss of huperzine in plasma selected
from
TABLE-US-00005 Dose (mg) Css (ng/mL) 0.25 about 0.52 to about 0.82
0.50 about 1.91 to about 2.99 0.75 about 3.56 to about 5.55 1.0
about 5.58 to about 8.72 1.25 about 8.22 to about 12.84 1.50 about
9.02 to about 14.09 1.75 about 10.04 to about 15.69 2.0 about 16 to
about 25 2.5 about 18.48 to about 28.88
[0175] In some embodiments the Css of huperzine in plasma is
selected from
TABLE-US-00006 Dose (mg) Css (ng/mL) 0.25 0.59 to about 0.72 0.50
2.15 to about 2.63 0.75 4.0 to about 4.89 1.0 6.28 to about 7.68
1.25 9.24 to about 11.30 1.50 10.14 to about 12.4 1.75 11.3 to
about 13.8 2.0 18 to about 22 2.5 20.79 to about 25.41
[0176] In some embodiments the Css of huperzine in plasma is
selected from
TABLE-US-00007 Dose (mg) Css (ng/mL) 0.25 about 0.652 0.50 about
2.391 0.75 about 4.445 1.0 about 6.978 1.25 about 10.27 1.50 about
11.27 1.75 about 12.55 2.0 about 20 2.5 about 23.1
In further embodiments the modified release pharmaceutical
composition is a pharmaceutical composition according to any
embodiment described herein.
[0177] Some embodiments describe a method of treating a
neurological disorder and/or seizure disorder, to a patient in need
thereof, wherein the patient experiences a better side effect
profile, comprising administering a modified release pharmaceutical
composition of huperzine A, wherein the modified release
pharmaceutical composition of huperzine is characterized by a Css
of huperzine in plasma of about 0.6 ng/mL to about 12 ng/mL when
administered at a therapeutically effective dose. In some
embodiments the Css of huperzine in plasma is about 2 ng/mL to
about 12 ng/mL when administered at a therapeutically effective
dose. In some embodiments the Css of huperzine in plasma is about 4
ng/mL to about 12 ng/mL when administered at a therapeutically
effective dose. In some embodiments the Css of huperzine in plasma
is about 6 ng/mL to about 12 ng/mL when administered at a
therapeutically effective dose. In some embodiments the Css of
huperzine in plasma is about 4 ng/mL to about 10 ng/mL when
administered at a therapeutically effective dose. In some
embodiments the Css of huperzine in plasma is about 4 ng/mL to
about 8 ng/mL when administered at a therapeutically effective
dose. In some embodiments the Css of huperzine in plasma is about
6.4 ng/mL to about 10 ng/mL when administered at a therapeutically
effective dose. In some embodiments the Css of huperzine in plasma
is about 8 ng/mL when administered at a therapeutically effective
dose. In some embodiments the Css of huperzine in plasma is at
least 8 ng/mL when administered at a therapeutically effective
dose. In further embodiments the modified release pharmaceutical
composition is a pharmaceutical composition according to any
embodiment described herein.
[0178] Some embodiments of the present disclosure are directed to a
method of treating a neurological or seizure disorder comprising
administering to a patient in need thereof, a modified release
pharmaceutical composition of huperzine, wherein the pharmaceutical
composition has a pharmacokinetic profile as defined in Table 4
upon oral administration of a therapeutically effective dose of the
pharmaceutical composition to a human subject. In some embodiments
the modified release pharmaceutical composition of huperzine is a
pharmaceutical composition according to any embodiment described
herein. In some embodiments the modified huperzine pharmaceutical
composition is pharmaceutical composition 4D.
TABLE-US-00008 TABLE 4 Dose C.sub.max ng/ml T.sub.max (h)
AUC.sub.0-8 .mu.g h/L 0.25 mg about 0.76 to about 1.19 about 4 to
about 4.18 to about 6.25 about 6.53 0.5 mg about 2.51 to about 3.93
about 4 to about 13.76 to about 6.25 about 21.5
In some embodiments the pharmacokinetic profile is as defined in
Table 5 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00009 TABLE 5 Dose C.sub.max ng/ml T.sub.max (h)
AUC.sub.0-8 .mu.g h/L 0.25 mg about 0.86 to about 1.05 about 4.5 to
about 4.7 to about 5.5 about 5.74 0.5 mg about 2.83 to about 3.46
about 4.5 to about 15.48 to about 5.5 about 18.9
In some embodiments the pharmacokinetic profile is as defined in
Table 6 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00010 TABLE 6 Dose C.sub.max ng/ml T.sub.max (h)
AUC.sub.0-8 .mu.g h/L 0.25 mg about 0.95 about 5 about 5.22 0.5 mg
about 3.14 about 5 about 17.2
[0179] Some embodiments of the present disclosure are directed to a
method of treating a neurological or seizure disorder comprising
administering to a patient in need thereof, a modified release
pharmaceutical composition of huperzine, wherein the pharmaceutical
composition has a pharmacokinetic profile as defined in Table 7
upon oral administration of a therapeutically effective dose of the
pharmaceutical composition to a human subject. In some embodiments
the modified release pharmaceutical composition of huperzine is a
pharmaceutical composition according to any embodiment described
herein. In some embodiments the modified huperzine pharmaceutical
composition is pharmaceutical composition 4E.
TABLE-US-00011 TABLE 7 Dose C.sub.max ng/ml T.sub.max (h)
AUC.sub.0-8 .mu.g h/L 0.5 mg about 1.90 to about 4.8 to about 12.12
to about 2.96 about 7.5 about 18.94
In some embodiments the pharmacokinetic profile is as defined in
Table 8 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00012 TABLE 8 Dose C.sub.max ng/ml T.sub.max (h)
AUC.sub.0-8 .mu.g h/L 0.5 mg about 2.13 to about 5.4 to about 13.64
to about 2.61 about 6.6 about 16.67
In some embodiments the pharmacokinetic profile is as defined in
Table 9 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00013 TABLE 9 Dose C.sub.max ng/ml T.sub.max (h)
AUC.sub.0-8 .mu.g h/L 0.5 mg about 2.37 about 6 about 15.15
[0180] Some embodiments of the present disclosure are directed to a
method of treating a neurological and/or seizure disorder
comprising administering to a patient in need thereof, a modified
release pharmaceutical composition of huperzine, wherein the
pharmaceutical composition has a pharmacokinetic profile as defined
in Table 10 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject. In some
embodiments the modified release pharmaceutical composition of
huperzine is a pharmaceutical composition according to any
embodiment described herein. In some embodiments the modified
huperzine pharmaceutical composition is pharmaceutical composition
4D.
TABLE-US-00014 TABLE 10 Dose of Time huperzine (h) Plasma
concentration ng/ml 0.25 mg 0.5 about 0.17 to about 0.26 2 about
0.30 to about 0.48 4 about 0.76 to about 1.19 6 about 0.66 to about
1.0 8 about 0.6 to about 0.94 0.5 mg 0 about 0.62 to about 0.96 0.5
about 0.68 to about 1.05 2 about 1.68 to about 2.63 4 about 2.38 to
about 3.71 6 about 2.51 to about 3.93 8 about 1.76 to about 2.75
0.75 mg 0 about 1.78 to about 2.78 0.5 about 1.96 to about 3.06 2
about 3.54 to about 5.54 4 about 4.4 to about 6.88 6 about 3.76 to
about 5.88 8 about 3.53 to about 5.51 1.0 mg 0 about 3.28 to about
5.13 0.5 about 3.34 to about 5.21 2 about 6.2 to about 9.7 4 about
6.06 to about 9.48 6 about 6.41 to about 10.01 8 about 5.13 to
about 8.01 1.25 mg 0 about 4.6 to about 7.19 0.5 about 4.52 to
about 7.06 2 about 5.88 to about 9.19 4 about 10.03 to about 15.68
6 about 10.85 to about 16.95 8 about 8.37 to about 13.08 1.5 mg 0
About 6.17 to about 9.64 0.5 about 5.70 to about 8.91 2 about 8.4
to about 13.13 4 about 10.65 to about 16.62 6 about 10 to about
15.63 8 about 8.88 to about 13.88 1.75 mg 0 about 7.77 to about
12.14 0.5 about 6.78 to about 10.6 2 about 8.37 to about 13.08 4
about 11.92 to about 18.63 6 about 10.89 to about 17.01 8 about
11.1 to about 17.34 2.0 mg 0 about 9.84 to about 15.38 0.5 about
10.88 to about 17 2 about 15.44 to about 24.13 4 about 18.72 to
about 29.25 6 about 16.96 to about 26.5 8 about 16.08 to about
25.13 2.5 mg 0 about 13.6 to about 21.25 0.5 about 16.08 to about
25.13 2 about 17.68 to about 27.63 4 about 21.36 to about 33.37 6
about 19.84 to about 31 8 about 14.89 to about 23.25
In some embodiments the pharmacokinetic profile is as defined in
Table 11 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00015 TABLE 11 Dose of Time huperzine (h) Plasma
concentration ng/ml 0.25 mg 0.5 about 0.19 to about 0.23 2 about
0.34 to about 0.42 4 about 0.86 to about 1.05 6 about 0.74to about
0.90 8 about 0.68 to about 0.83 0.5 mg 0 about 0.69 to about 0.85
0.5 about 0.77 to about 0.94 2 about 1.89 to about 2.31 4 about
2.67 to about 3.27 6 about 2.83 to about 3.45 8 about 1.98 to about
2.42 0.75 mg 0 about 2 to about 2.45 0.5 about 2.21 to about 2.70 2
about 3.99 to about 4.87 4 about 4.95 to about 6.05 6 about 4.23 to
about 5.17 8 about 3.97 to about 4.85 1.0 mg 0 about 3.69 to about
4.51 0.5 about 3.75 to about 4.59 2 about 6.98 to about 8.54 4
about 6.82 to about 8.34 6 about 7.21 to about 8.81 8 about 5.77 to
about 7.05 1.25 mg 0 about 5.18 to about 6.33 0.5 about 5.09 to
about 6.22 2 about 6.62 to about 8.09 4 about 11.29 to about 13.79
6 about 12.20 to about 14.92 8 about 9.41 to about 11.51 1.5 mg 0
about 6.94 to about 8.48 0.5 about 6.42 to about 7.84 2 about 9.45
to about 11.55 4 about 11.97 to about 14.63 6 about 11.25 to about
13.75 8 about 9.99 to about 12.21 1.75 mg 0 about 8.74 to about
10.68 0.5 about 7.63 to about 9.33 2 About 9.41 to about 11.51 4
about 13.41 to about 16.39 6 about 12.25 to about 14.97 8 about
12.48 to about 15.26 2.0 mg 0 about 11.07 to about 13.53 0.5 about
12.24 to about 14.96 2 about 17.37 to about 21.23 4 about 21.06 to
about 25.74 6 about 19.08 to about 23.32 8 about 18.09 to about
22.11 2.5 mg 0 about 15.3 to about 18.7 0.5 about 18.09 to about
22.11 2 about 19.89 to about 24.31 4 about 24.03 to about 29.37 6
about 22.32 to about 27.28 8 about 16.74 to about 20.46
In some embodiments the pharmacokinetic profile is as defined in
Table 12 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00016 TABLE 12 Dose of Time Plasma huperzine (h)
concentration ng/ml 0.25 mg 0.5 about 0.21 2 about 0.38 4 about
0.95 6 about 0.82 8 about 0.75 0.5 mg 0 about 0.77 0.5 about 0.85 2
about 2.10 4 about 2.97 6 about 3.14 8 about 2.20 0.75 mg 0 about
2.22 0.5 about 2.45 2 about 4.43 4 about 5.5 6 about 4.70 8 about
4.41 1.0 mg 0 about 4.1 0.5 about 4.17 2 about 7.76 4 about 7.58 6
about 8.01 8 about 6.41 1.25 mg 0 about 5.75 0.5 about 5.65 2 about
7.35 4 about 12.54 6 about 13.56 8 about 10.46 1.5 mg 0 about 7.71
0.5 about 7.13 2 about 10.5 4 about 13.3 6 about 12.5 8 about 11.1
1.75 mg 0 about 9.71 0.5 about 8.48 2 about 10.46 4 about 14.9 6
about 13.61 8 about 13.87 2.0 mg 0 about 12.3 0.5 about 13.6 2
about 19.3 4 about 23.4 6 about 21.2 8 about 20.1 2.5 mg 0 about
17.0 0.5 about 20.1 2 about 22.1 4 about 26.7 6 about 24.8 8 about
18.6
[0181] Some embodiments of the present disclosure are directed to a
method of treating a neurological and/or seizure disorder
comprising administering to a patient in need thereof, a modified
release pharmaceutical composition of huperzine, wherein the
pharmaceutical composition has a pharmacokinetic profile as defined
in Table 13 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject. In some
embodiments the modified release pharmaceutical composition of
huperzine is a pharmaceutical composition according to any
embodiment described herein. In some embodiments the modified
huperzine pharmaceutical composition is pharmaceutical composition
4E.
TABLE-US-00017 TABLE 13 Dose of Time Plasma huperzine (h)
concentration ng/ml 0.5 mg 0.5 about 0.78 to about 1.23 2 about
1.24 to about 1.94 4 about 1.81 to about 2.83 6 about 1.90 to about
2.96 8 about 1.66 to about 2.59 1.0 mg 0.5 about 2.96 to about 4.63
2 about 4.52 to about 7.06 4 about 6.44 to about 10.06 6 about 5 to
about 7.81 8 about 3.95 to about 6.18
In some embodiments the pharmacokinetic profile is as defined in
Table 14 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00018 TABLE 14 Dose of Time huperzine (h) Plasma
concentration ng/ml 0.5 mg 0.5 about 0.88 to about 1.08 2 about
1.39 to about 1.71 4 about 2.03 to about 2.49 6 about 2.13 to about
2.61 8 about 1.86 to about 2.28 1.0 mg 0.5 about 3.33 to about 4.07
2 about 5.09 to about 6.22 4 about 7.25 to about 8.86 6 about 5.63
to about 6.88 8 about 4.45 to about 5.43
In some embodiments the pharmacokinetic profile is as defined in
Table 15 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject.
TABLE-US-00019 TABLE 15 Dose of Time huperzine (h) Plasma
concentration ng/ml 0.5 mg 0.5 about 0.98 2 about 1.55 4 about 2.26
6 about 2.37 8 about 2.07 1.0 mg 0.5 about 3.70 2 about 5.65 4
about 8.05 6 about 6.25 8 about 4.94
[0182] Some embodiments of the present disclosure are directed to a
method of treating a neurological or seizure disorder comprising
administering to a patient in need thereof, a modified release
pharmaceutical composition of huperzine, wherein the pharmaceutical
composition has a pharmacokinetic profile as defined in Table 16
upon oral administration of a therapeutically effective dose of the
pharmaceutical composition to a human subject. In some embodiments
the modified release pharmaceutical composition of huperzine is a
pharmaceutical composition according to any embodiment described
herein. In some embodiments the modified huperzine pharmaceutical
composition is pharmaceutical composition 4F-1.
TABLE-US-00020 TABLE 16 Dose Plasma concentration (mg) (ng/mL) 0.25
about 1.36 to about 2.13 0.50 about 2.02 to about 3.15 0.75 about
4.45 to about 6.95 1.25 about 3.82 to about 5.96
[0183] Some embodiments of the present disclosure are directed to a
method of treating a neurological or seizure disorder comprising
administering to a patient in need thereof, a modified release
pharmaceutical composition of huperzine, wherein the pharmaceutical
composition has a pharmacokinetic profile as defined in Table 17
upon oral administration of a therapeutically effective dose of the
pharmaceutical composition to a human subject. In some embodiments
the modified release pharmaceutical composition of huperzine is a
pharmaceutical composition according to any embodiment described
herein. In some embodiments the modified huperzine pharmaceutical
composition is pharmaceutical composition 4F-1.
TABLE-US-00021 TABLE 17 Dose Plasma concentration (mg) (ng/mL) 0.25
about 1.53 to about 1.87 0.50 about 2.27 to about 2.77 0.75 about
5.00 to about 6.12 1.25 about 4.29 to about 5.25
[0184] Some embodiments of the present disclosure are directed to a
method of treating a neurological and/or seizure disorder
comprising administering to a patient in need thereof, a modified
release pharmaceutical composition of huperzine, wherein the
pharmaceutical composition has a pharmacokinetic profile as defined
in Table 18 upon oral administration of a therapeutically effective
dose of the pharmaceutical composition to a human subject. In some
embodiments the modified release pharmaceutical composition of
huperzine is a pharmaceutical composition according to any
embodiment described herein. In some embodiments the modified
huperzine pharmaceutical composition is pharmaceutical composition
4F-1.
TABLE-US-00022 TABLE 18 Dose Plasma concentration (mg) (ng/mL) 0.25
about 1.7 0.50 about 2.52 0.75 about 5.56 1.25 about 4.77
[0185] The pharmaceutical compositions of the present invention can
be administered in a combination with other therapeutic agent(s).
The choice of therapeutic agents that can be co-administered with
the composition of the invention will depend, in part, on the
condition being treated. For example, the compounds of the
invention can be administered in combination with other agents,
such as acetaminophen, acetazolamide, alprazolam, armodafinil,
benzodiazepines, brivaracetam, busprirone, cannabinoids,
carbamazepine, carisoprodol, chlordiazepoxide, chloroxazone,
clobazam, clonazepam, clorazepate, cyclobenzaprine, diazepam,
divalproex, erenumab-aooe, eslicarbazine, ethosuximide, ezogabine,
felbamate, flunarizine, fosphenytoin, gabapentin, hydroxyzine,
ibuprofen, lacosamide, lamotrigine, levetiracetam, lorazepam,
metaxalone, methocarbamolimipramine, methsuximide, modafinil,
naproxen, nitrazepam, oxcarbazepine, perampanel, phenobarbital,
phenytoin, pregabalin, primidone, propranolol, rufinamide,
stiripental, tiagabine, topiramate, valproic acid, vigabatrin, and
zonisamide or combinations thereof, used to treat other symptoms
and side effects commonly associated with epilepsy or seizures,
such as fainting, fatigue, muscle spasms, auras, amnesia, anxiety,
depression, headaches, sleepiness, or staring spells.
[0186] Such other therapeutic agent(s) may be administered prior
to, simultaneously with or following the administration of
huperzine pharmaceutical composition according to any embodiment
described herein.
EXAMPLES
[0187] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Therefore, the spirit and
scope of the appended claims should not be limited to the
description and the preferred versions contained within this
specification. Various embodiments of the present invention will be
illustrated with reference to the following non-limiting examples.
The following examples are for illustrative purposes only and are
not to be construed as limiting the invention in any manner.
Example 1: In Vitro Dissolution Testing
[0188] The compositions were tested according to USP 1 type
apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8)
at 37.degree. C. Results are shown in FIG. 4.
Example 2: Pharmacokinetic Study in Dogs
[0189] A Study Objective
[0190] The objective of this study was to determine the plasma
pharmacokinetics of modified release huperzine Composition 4A in
male beagle dogs. The huperzine A was monitored in plasma for up to
24 hours.
[0191] Vehicle and Pharmaceutical Composition Preparation
[0192] Animals were dosed at a nominal dose of 5.45 mg/kg modified
release huperzine A (composition 4A, equivalent to 0.049 mg/kg
huperzine A)
[0193] Animal Specifications
[0194] Three, non-naive, male, beagle dogs (Marshall Bioresources,
Beijing, China) weighing .gtoreq.6 kg were used in the study.
Animals underwent a physical examination for general health by a
staff veterinarian prior to assignment to the study. The animals
were acclimated to the testing facility prior to the study.
[0195] Environmental Conditions
[0196] Animals were housed in room(s) that were controlled and
monitored for relative humidity (targeted mean range 40% to 70%)
and temperature (targeted mean range 18.degree. to 26.degree. C.)
with 10 to 20 air changes/hour. The room(s) were on a 12-hour
light/dark cycle except when interruptions were necessitated by
study activities.
[0197] Housing
[0198] Animals were individually housed in stainless-steel mesh
cages during in-life that were in accordance with the National
Research Council "Guide for the Care and Use of Laboratory
Animals."
[0199] Diet and Feeding
[0200] Animals were fed twice daily. The dogs were fed
approximately 220 grams of Certified Dog Diet daily (Beijing Vital
Keao Feed Co., Ltd. Beijing, P. R. China). These amounts could be
adjusted as necessary based on food consumption of the group or an
individual body weight changes of the group or an individual and/or
changes in the certified diet.
[0201] Drinking Water
[0202] RO (reverses osmosis) water was made available to all
animals, ad libitum.
[0203] Environmental Enrichment
[0204] Enrichment toys were provided.
[0205] Administration of Dose Pharmaceutical Composition
[0206] The modified release huperzine A composition 4A was
administered orally via capsule delivery.
[0207] Dose Administration:
[0208] a. The technician pulled the lower jaw down with his/her
other hand and placed the capsule far back in the throat. The
capsule was then pushed past the pharynx by using a thumb or index
finger. b. The capsule could be moistened with water to facilitate
dosing, and water could be used to facilitate swallowing of
capsules, if necessary. c. After administering the dose, swallowing
could be induced, if needed, by gently stroking the dog's throat or
tapping the dog under the chin. d. Immediately following capsule
administration, water was given to the mouth of the animals at the
dose volume of about 10 mL/animal to help capsule swallowing. e.
After administration, the animal's mouth was inspected to ensure
that the dose has been swallowed.
[0209] Observations and Examinations
[0210] Twice daily, cage-side observations for general health and
appearance were done.
[0211] On dosing day, the animals were observed before and after
each sample collection time point. General condition, behavior,
activity, excretion, respiration or other unusual observations
noted throughout the study were recorded in the raw data.
[0212] Body Weight
[0213] All animals were weighed on the dosing day prior to dosing
to determine the dose volume to be administered.
[0214] Data Analysis and Reporting
[0215] Plasma concentration versus time data was analyzed by
non-compartmental approaches using the WinNonlin software program
(version 6.3, Pharsight, Mountain View, Calif.). C.sub.max,
T.sub.max,
[0216] Clearance, T.sub.1/2, AUC.sub.0-t, AUC.sub.0-inf,
MRT.sub.0-t, MRT.sub.0-inf, and graphs of plasma concentration
versus time profile were reported for each analyte. The results of
the study are summarized in FIG. 5.
Example 3: Evaluation of the Bioavailability, Safety and
Tolerability of Modified Release Huperzine a Following Multiple
Dose Administrations in Healthy Subjects
[0217] A single center, on-site/outpatient, dose escalation study
was conducted with oral pharmaceutical composition 4D. The subjects
were dosed twice daily (BID) in 4 cohorts of 2 subjects each
(Pharmaceutical composition 4D) and 2 cohorts of 3 subjects total
(Pharmaceutical composition 4E) to assess plasma levels, safety,
and allow necessary dosing alterations to occur prior to dosing any
subsequent subjects. The study was conducted in an on-site setting
at dose initiation and at times of dose escalation to evaluate
safety, and for specimen collection for routine laboratory and
pharmacokinetic analysis. Subjects were discharged and compliance
of BID dosing was monitored via twice daily phone calls by site
staff. The initial dose was 0.5 mg BID with a dose escalation every
2-3 days until a maximum tolerated dose was observed or a maximum
of 2.5 mg BID dose was obtained. Initial dose and rate of
escalation was able to be altered at the discretion of the site
staff to ensure safety of the subjects.
[0218] Study Endpoints: Plasma concentration data was used for
bioavailability assessment. The derived pharmacokinetic parameters
include: area under the curve (AUC), maximum serum concentration
(C.sub.max), and time of C.sub.max (T.sub.max).
[0219] The safety and tolerability parameters were assessed based
on the occurrence of adverse events as well as the results of
study-specified vital signs, neurological and physical
examinations, ECG evaluations, and clinical laboratory studies.
[0220] Dosing schedule was as follows:
Cohorts 1 & 2 (Pharmaceutical Composition 4D):
TABLE-US-00023 [0221] Days 1, 2 Days 3, 4 Days 5, 6, 7 Days 8, 9
Days 10, 11 0.5 mg BID 1 mg BID 1.5 mg BID 2.0 mg BID 2.5 mg
BID
Cohort 3 (Pharmaceutical Composition 4D):
TABLE-US-00024 [0222] Days Days Days Days Days Days 1, 2 3, 4 5, 6,
7 8, 9 10, 11 12, 13, 14 0.25 mg 0.5 mg 1 mg 1.5 mg 2 mg 2.5 mg BID
BID BID BID BID BID
Cohort 4 (Pharmaceutical Composition 4D):
TABLE-US-00025 [0223] Days Days Days Days Days Days Days Day 1, 2
3, 4 5, 6, 7 8, 9 10, 11 12, 13, 14 15, 16 17, 18 0.25 0.5 mg 0.75
mg 1 mg 1.25 mg 1.5 mg 1.75 mg 2.0 mg mg BID BID BID BID BID BID
BID BID
Cohort 5 and 6 (Pharmaceutical Composition 4E):
TABLE-US-00026 [0224] Days Days Days Days Days Days Days Day 1, 2
3, 4 5, 6, 7 8, 9 10, 11 12, 13, 14 15, 16 17, 18 0.25 0.5 mg 0.75
mg 1 mg 1.25 mg 1.5 mg 1.75 mg 2.0 mg mg BID BID BID BID BID BID
BID BID
[0225] Plasma levels taken on dose titration inpatient days
throughout the study for cohorts 1-4 are shown in FIG. 7. Plasma
draws occurred throughout the dose titration schedule to assess
total plasma concentrations. Time=0 represents pre-dose baseline on
the titration day corresponding to the dosing schedule. Means
reflect all data obtained for 8 subjects. The initial dosing
schedule was altered for cohorts 3 and 4 to accommodate a slower
titration (0.25 mg dose increments).
[0226] A graph of the average plasma levels taken on inpatient days
throughout the study at particular doses is shown in FIG. 8.
Pharmacokinetic modeling predicts average plasma level (Css) of 8.4
ng/mL to achieve 100% seizure protection in 50% of patients (dosing
equivalent of about 1.1-1.25 mg BID.
[0227] The compositions in the study yielded favorable
pharmacokinetic profiles, demonstrated twice a day dosing and
demonstrated a dramatic reduction in adverse events when compared
to immediate release preparation, even with double the dose
previously used. Pharmacokinetic modeling accurately predicted
dose-exposure relationships for the entire dose titration.
[0228] Adverse events were mild and transient. Testing showed that
approximately double the dose predicted for significant seizure
control was attainable; yielding much higher, stable plasma levels
of huperzine A given on a twice/day schedule, and achieved drug
plasma levels predicted to provide significant seizure protection
in patients with adult and childhood intractable epilepsies.
Example 4: Evaluation of Safety and Efficacy of Modified Release
Pharmaceutical Compositions of Huperzine for the Treatment of Adult
Focal Impaired Awareness Seizures (FIAS)
[0229] The purpose of this study is to examine safety signals and
demonstrate seizure reduction in adults with FIAS treated with
modified release pharmaceutical compositions of huperzine as an
add-on therapy in an in-patient and out-patient study with the
pharmaceutical composition according to any embodiment described
herein. In some embodiments the pharmaceutical composition is 4F1
or 4F-2.
[0230] Dose administration for each participant will begin at 0.25
mg BID escalating sequentially every 4 days to a maximum tolerated
dose or target dose of 1.75 mg BID Participants who are unable to
tolerate a dose during dose escalation will have their dose reduced
to the prior tolerable dose; if unable to tolerate lower doses,
participants will be withdrawn from the study.
Planned Number of Participants:
[0231] Sixteen participants will be enrolled into and complete the
study.
Study Design:
[0232] This study is a single center, multi-site, open-label,
add-on study in otherwise healthy participants with frequent Focal
Impaired Awareness Seizures.
[0233] Pre-qualified, eligible participants age 18 and older that
have signed an informed consent will be enrolled into the study.
The study will consist of a 96-hour baseline continuous VEM period,
a one-month out-patient dose escalation treatment period, followed
by a second 96-hour continuous VEM treatment period.
[0234] On Day 1 of the baseline period (after completion of
physical and neurological exams, vital signs, electrocardiogram
(ECG), blood sample for CBC and chemistry, urine sample collection
for standard urinalysis including creatinine and electrolytes)
daily seizure counting will begin and will be collected via VEM
with standard lead placement. Participants will remain on stable
anticonvulsant treatment regimen as determined by their treating
physician. Upon completion of the baseline period (5 days
in-patient VEM), participants who experienced at least 5 focal
impaired awareness seizures will be immediately enrolled into
treatment. They will begin dose escalation of modified release
pharmaceutical composition of huperzine to either the target dose
of 1.75 mg BID or a maximum tolerated dose. The modified release
pharmaceutical composition of huperzine will be titrated over 28
days, escalating every 4 days. Upon reaching the target dose or
maximum tolerated dose, participants will maintain that dose for
the balance of the out-patient titration period, after which they
will begin a 96-hour in-patient VEM treatment period. A daily
seizure diary will be kept for the duration of the out-patient
titration period where participants or caregivers will notate
seizure type and time of day. Participants who are unable to attain
target dose of 1.75 mg BID will be dose reduced to a prior
tolerable dose. If unable to tolerate lower doses, participants may
be withdrawn from the study. Participants will be dosed 2 times
daily (every 12 hrs) with the modified release pharmaceutical
composition of huperzine, administration occurring in the morning
and evening. Participants will have the modified release
pharmaceutical composition of huperzine discontinued at the final
day of in-patient VEM unless they elect to participate in the
open-label extension period, during which they will continue to
record seizure diaries and will have safety assessments on a
regular basis.
[0235] Blood samples for pharmacology will be drawn on selected
out- and in-patient study days. Adverse events (AE) and use of
concurrent medications will be recorded throughout the study.
[0236] All participants who receive at least one dose of modified
release pharmaceutical composition of huperzine will be included in
safety analyses that includes vital signs, clinical laboratory
testing, physical and neurological examinations, electrocardiograms
and adverse event monitoring.
Endpoint:
[0237] Primary Efficacy Variables: Reduction in average daily
seizure count between baseline (pre-treatment) and evaluation (on
treatment) VEM periods.
[0238] Secondary Efficacy Variables: [0239] Percent reduction in
average daily seizure count from the baseline VEM period compared
to the evaluation VEM period (on treatment) [0240] Percent
reduction in average number of seizures from the baseline period
(screening/retrospective diary) compared to the last week of the
titration treatment period [0241] Percent of participants
considered treatment responders defined as those with a
.gtoreq.25%, .gtoreq.50%, .gtoreq.75% reduction in seizures from
the baseline VEM period compared to the VEM treatment evaluation
period [0242] Percent of reduction of average number of seizures
vs. baseline/retrospective diary at 1, 3, 6, 12 months during the
extension period [0243] Proportion of subjects with 100% seizure
reduction [0244] Proportion of subjects requiring rescue medication
at different dosages
Pharmacology:
[0245] Plasma concentration data will be used determine a dose,
serum level and seizure effect relationship.
[0246] Urine samples will undergo standard urinalysis, test drug
elimination and presence of potential metabolites.
[0247] To date three patients have received 2-3 dose titrations as
described in FIG. 9 and Table 19.
TABLE-US-00027 TABLE 1 Plasma Time Dose concentration post Patient
(mg) (ng/mL) dose (h) 1001 0.25 1.7 2.43 0.75 4.02 3 1.25 4.77 4
1002 0.5 3.13 5.25 0.75 9.07 5.25 2001 0.5 1.9 5.25 0.75 3.58 5
Example 5: General Procedure for the Preparation of Pharmaceutical
Compositions
[0248] The pharmaceutical compositions described herein can
generally be prepared as follows:
[0249] Utilizing a fluid bed coating equipment (or similar coated
particle manufacturing equipment), use standard procedures and
operating conditions to manufacture coated particles. These
procedures include:
[0250] Prepare of solutions for manufacturing the modified release
particles, e.g. solutions containing huperzine, binders,
anti-caking agents, etc.
[0251] Load uncoated cores into fluid bed
[0252] Adjust all operating parameters nozzles, pressures, to
appropriate ranges for the appropriate batch size and equipment
being utilized
[0253] Process coated pellets to remove agglomerates or fine
particles outside of the desired particle size distribution.
[0254] An exemplary process comprises:
[0255] 1. Solution Preparation [0256] a. Heat up predetermined
amount of distilled water to 70 degrees centigrade. [0257] b.
Dissolve huperzine into anhydrous ethanol by stirring. [0258] c.
Add HPMC into the heated water with continuous stirring when
needed. [0259] d. Add another partitioned amount of distilled water
into the above solution; keep stirring until the powders are fully
dissolved. [0260] e. Add PVP into HPMC solution and equally make it
dissolve by continuous stirring. [0261] f. Combine HMPC/PVP
solution with the huperzine ethanol solution. Flush the vessel
using distilled water and carefully pour into the solution until
the final weight is targeted and keep stirring for another 5
min.
[0262] 2. Drug Layer Coating [0263] a. sucrose spheres of the
desired size were transferred into a fluidized bed processor and
the aforesaid huperzine solution of 1f. was coated onto the sucrose
spheres at the product temp of 35.about.45 C.
[0264] 3. Sustained Release Layer Coating [0265] a. Plasticized
ethyl cellulose solution that had been prepared ahead was coated
onto the resultant huperzine loaded sugar spheres using the same
product temp range above till the theoretical weight gain achieved
was achieved.
* * * * *