U.S. patent application number 10/611586 was filed with the patent office on 2004-05-13 for sustained release formulations for growth hormone secretagogues.
Invention is credited to Am Ende, Mary T., Curatolo, William J., Herbig, Scott M..
Application Number | 20040091530 10/611586 |
Document ID | / |
Family ID | 22859744 |
Filed Date | 2004-05-13 |
United States Patent
Application |
20040091530 |
Kind Code |
A1 |
Am Ende, Mary T. ; et
al. |
May 13, 2004 |
Sustained release formulations for growth hormone secretagogues
Abstract
The present invention relates to formulations for administering
a growth hormone secretagogue. More specifically, the present
invention relates to sustained release formulations for
administering a growth hormone secretagogue and formulations for
administering a growth hormone secretagogue that provide for a part
of the dose of the growth hormone secretagogue to be administered
using an immediate release formulation and part of the dose of the
growth hormone secretagogue to be administered using a sustained
release formulation.
Inventors: |
Am Ende, Mary T.;
(Waterford, CT) ; Curatolo, William J.; (Niantic,
CT) ; Herbig, Scott M.; (East Lyme, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
22859744 |
Appl. No.: |
10/611586 |
Filed: |
June 30, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10611586 |
Jun 30, 2003 |
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09940097 |
Aug 27, 2001 |
|
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6641840 |
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60229074 |
Aug 30, 2000 |
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Current U.S.
Class: |
424/468 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61K 9/0004 20130101; A61P 5/06 20180101; A61P 5/10 20180101; A61P
5/14 20180101; A61K 9/2054 20130101; A61K 9/2866 20130101 |
Class at
Publication: |
424/468 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. A sustained release dosage form for oral administration to a
mammal, the dosage form comprising a growth hormone secretagogue
and a pharmaceutically acceptable carrier, which dosage form
results in a maximum growth hormone secretagogue plasma
concentration, C.sub.max, which is less than 80% of the C.sub.max
that occurs when an equal dose of the growth hormone secretagogue
is orally administered using an immediate release dosage form.
2. A sustained release dosage form of claim 1 that provides total
blood growth hormone secretagogue exposure that is not
proportionately decreased as much as C.sub.max.
3. A sustained release dosage form of claim 1 wherein the growth
hormone secretagogue exhibits an elimination half-life of less than
about 6 hours.
4. A sustained release dosage form of claim 1 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide or a pharmaceutically acceptable salt or prodrug
thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,-
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-e-
thyl]-isobutyramide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxyme-
thyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2-
,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propion-
amide or a pharmaceutically acceptable salt or prodrug thereof, or
a salt of the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyr-
idin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[-
4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide.
5. A sustained release dosage form of claim 1 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate.
6. A sustained release dosage form of claim 1 wherein the dosage
form comprises a matrix tablet that remains substantially intact
during the period of sustained release; a disintegrating matrix
tablet; a matrix tablet partially coated with a polymer that
impedes the release of the growth hormone secretagogue; an osmotic
tablet; a membrane-coated swelling-core tablet; a multiparticulate;
or a combination thereof.
7. A sustained release dosage form of claim 1 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate, and which sustained release dosage form
releases about 0.007 to about 0.010 mg/hr/kg for about a 4 mg dose;
about 0.007 to about 0.014 mg/hr/kg for about a 6 mg dose; about
0.006 to about 0.019 mg/hr/kg for about an 8 mg dose; about 0.010
to about 0.029 mg/hr/kg for about a 12 mg dose; about 0.013 to
about 0.038 mg/hr/kg for about a 16 mg dose; about 0.019 to about
0.057 mg/hr/kg for about a 24 mg dose; or about 0.038 to about
0.114 mg/hr/kg for about a 48 mg dose.
8. A sustained release dosage form of claim 7 wherein the dosage
form comprises a matrix tablet that remains substantially intact
during the period of sustained release; a disintegrating matrix
tablet; a matrix tablet partially coated with a polymer that
impedes the release of the growth hormone secretagogue; an osmotic
tablet; a membrane-coated swelling-core tablet; a multiparticulate;
or a combination thereof.
9. A sustained release dosage form for oral administration to a
mammal, the dosage form comprising a growth hormone secretagogue
and a pharmaceutically acceptable carrier, which dosage form
results in a growth hormone secretagogue plasma concentration that
exceeds the minimum effective concentration for a time,
.DELTA.T.sub.T2-T1, which is greater than, by at least 30 minutes,
the .DELTA.T.sub.T2-T1 determined when an equal dose of the growth
hormone secretagogue is orally administered using an immediate
release dosage form, wherein .DELTA.T.sub.T2-T1 is the time period
for which the plasma concentration of the growth hormone
secretagogue remains above the minimum effective concentration,
with T1 being the time the plasma concentration first goes above
the minimum effective concentration and T2 being the time when the
plasma concentration goes below the minimum effective
concentration.
10. A sustained release dosage form of claim 9 wherein the growth
hormone secretagogue exhibits an elimination half-life of less than
6 hours.
11. A sustained release dosage form of claim 9 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide or a pharmaceutically acceptable salt or prodrug
thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,-
4,6,7-hexahydro-pyrazolo[4,3c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-et-
hyl]-isobutyramide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymet-
hyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,-
3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propiona-
mide or a pharmaceutically acceptable salt or prodrug thereof, or a
salt of the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyr-
idin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[-
4,3-c]pyridin-5-yl]pyridin-5-yl]-ethyl}-2-methyl-propionamide.
12. A sustained release dosage form of claim 9 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate.
13. A sustained release dosage form of claim 9 wherein the dosage
form comprises a matrix tablet that remains substantially intact
during the period of sustained release; a disintegrating matrix
tablet; a matrix tablet partially coated with a polymer that
impedes the release of the growth hormone secretagogue; an osmotic
tablet; a membrane-coated swelling-core tablet; a multiparticulate;
or a combination thereof.
14. A sustained release dosage form of claim 9 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate, and which dosage form releases about 0.009
to about 0.021 mg/hr/kg for about a 6 mg dose; about 0.006 to about
0.029 mg/hr/kg for about an 8 mg dose; about 0.010 to about 0.043
mg/hr/kg for about a 12 mg dose; about 0.013 to about 0.057
mg/hr/kg for about a 16 mg dose; about 0.019 to about 0.086
mg/hr/kg for about a 24 mg dose; or about 0.034 to about 0.343
mg/hr/kg for about a 48 mg dose.
15. A sustained release dosage form of claim 14 wherein the dosage
form comprises a matrix tablet that remains substantially intact
during the period of sustained release; a disintegrating matrix
tablet; a matrix tablet partially coated with a polymer that
impedes the release of the growth hormone secretagogue; an osmotic
tablet; a membrane-coated swelling-core tablet; a multiparticulate;
or a combination thereof.
16. A combination dosage form for oral administration of a growth
hormone secretagogue to a mammal, the dosage form comprising two
portions: 1) a portion that immediately releases an amount of a
growth hormone secretagogue; and 2) a portion that provides for
sustained release of an amount of a growth hormone secretagogue,
which dosage form results in a maximum growth hormone secretagogue
plasma concentration, C.sub.max, which is less than 80% of the
C.sub.max that occurs when an equal dose of the growth hormone
secretagogue is orally administered using an immediate release
dosage form.
17. A combination dosage form of claim 16 that provides total blood
growth hormone secretagogue exposure that is not proportionately
decreased as much as C.sub.max.
18. A combination dosage form of claim 16 wherein the growth
hormone secretagogue exhibits an elimination half-life of less than
about 6 hours.
19. A combination dosage form of claim 16 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide or a pharmaceutically acceptable salt or prodrug
thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,-
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-e-
thyl]-isobutyramide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxyme-
thyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2-
,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propion-
amide or a pharmaceutically acceptable salt or prodrug thereof, or
a salt of the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-}1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyr-
idin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[-
4,3-c]pyridin-5-yl]-ethyl}-2methyl-propionamide.
20. A combination dosage form of claim 16 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate.
21. A combination dosage form of claim 16 wherein the sustained
release portion of the dosage form comprises a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or a combination
thereof.
22. A combination dosage form of claim 16 for oral administration
of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising two portions: 1)
a portion that immediately releases an amount of a growth hormone
secretagogue; and 2) a portion that provides for sustained release
of an amount of a growth hormone secretagogue, the dosage form
having the following characteristics for each dose:
42 Total Growth Sustained Hormone Release Portion Secret- Immediate
Release (% of Total agogue Portion (% of Total Growth Hormone Time
Period of Dose Growth Hormone Secretagogue Sustained Release (mg)
Secretagogue Dose) Dose) (hours) about 4 about 5 to about 50 about
95 to about about 4 to about 6 50 about 4 about 50 to about 75
about 50 to about about 8 to about 10 25 about 4 about 75 about 25
about 12 to about 18 about 6 about 40 about 60 about 4 about 6
about 5 to about 40 about 95 to about about 6 60 about 6 about 5 to
about 75 about 95 to about about 8 to about 12 25 about 6 about 40
to about 75 about 60 to about about 14 to about 18 25 about 12
about 40 about 60 about 4 about 12 about 5 to about 40 about 95 to
about about 6 60 about 12 about 5 to about about 95 to about about
8 62.5 37.5 about 12 about 5 to about 75 about 95 to about about 12
to about 18 25 about 48 about 5 to about 75 about 95 to about about
16 25
23. A combination dosage form of claim 22 wherein the sustained
release portion of the dosage form comprises a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or a combination
thereof.
24. A combination dosage form of claim 22 wherein the immediate
release portion comprises a layer in a multilayer tablet; a coating
on a sustained release tablet or multiparticulate; a compression
coating on a sustained release tablet, or the immediate release
portion can comprise multiparticulates along with sustained release
multiparticulates.
25. A combination dosage form of claim 22 wherein the sustained
release portion comprises an osmotic tablet and the immediate
release portion comprises a compression coating.
26. A combination dosage form suitable for oral administration of a
growth hormone secretagogue to a mammal, the dosage form comprising
two portions: 1) a portion that immediately releases an amount of a
growth hormone secretagogue; and 2) a portion that provides for
sustained release of an amount of a growth hormone secretagogue,
which dosage form results in a growth hormone secretagogue plasma
concentration that exceeds the minimum effective concentration for
a time, .DELTA.T.sub.T2-T1, which is greater than, by at least 30
minutes, the .DELTA.T.sub.T2-T1 determined when an equal dose of
the growth hormone secretagogue is orally administered using an
immediate release dosage form, wherein .DELTA.T.sub.T2-T1 is the
time period for which the plasma concentration of the growth
hormone secretagogue remains above the minimum effective
concentration, with T1 being the time the plasma concentration
first goes above the minimum effective concentration and T2 being
the time when the plasma concentration goes below the minimum
effective concentration.
27. A combination dosage form of claim 26 wherein the growth
hormone secretagogue exhibits an elimination half-life of less than
6 hours.
28. A combination dosage form of claim 26 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide or a pharmaceutically acceptable salt or prodrug
thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,- 4,6,
7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo--
ethyl]-isobutyramide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxym-
ethyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)--
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propio-
namide or a pharmaceutically acceptable salt of prodrug thereof, or
a salt of the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-oxo-2-[3-oxo-3a-(-
R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyr-
azolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide.
29. A combination dosage form of claim 26 wherein the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate.
30. A combination dosage form of claim 26 wherein the sustained
release portion of the dosage form comprises a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or a combination
thereof.
31. A combination dosage form of claim 26 for oral administration
of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising two portions: 1)
a portion that immediately releases an amount of a growth hormone
secretagogue; and 2) a portion that provides for sustained release
of an amount of a growth hormone secretagogue, the dosage form
having the following characteristics for each dose:
43 Immediate Sustained Total Release Portion Release Portion Growth
(% of Total Growth (% of Total Hormone Hormone Growth Hormone Time
Period of Secretagogue Secretagogue Secretagogue Sustained Release
Dose (mg) Dose) Dose) (hours) about 6 about 5 to about about 95 to
about 4 40 about 60 about 6 about 5 to about about 95 to about 6 75
about 25 about 6 about 5 to about about 95 to about 8 62.5 about
37.5 about 6 about 5 to about about 95 to about 10 40 about 60
about 12 about 5 to about about 95 to about 4 40 about 60 about 12
about 5 to about about 95 to about 6 to 75 about 25 about 16 about
12 about 5 to about about 95 to about 18 40 about 60 about 48 about
5 to about about 95 to about 16 75 about 25
32. A combination dosage form of claim 31 wherein the sustained
release portion of the dosage form comprises a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or a combination
thereof.
33. A combination dosage form of claim 31 wherein the immediate
release portion comprises a layer in a multilayer tablet; a coating
on a sustained release tablet or multiparticulate; a compression
coating on a sustained release tablet, or the immediate release
portion can comprise multiparticulates along with sustained release
multiparticulates.
34. A combination dosage form of claim 31 wherein the sustained
release portion comprises an osmotic tablet and the immediate
release portion comprises a compression coating.
35. A sustained release dosage form of claim 1 comprising
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate and a pharmaceutically acceptable carrier, which dosage
form, when tested in a USP-2 apparatus containing 500-900 ml of
0.1N HCl or simulated gastric fluid without enzymes releases about
0.50 to about 0.67 mg/hr for about a 4 mg dose; about 0.50 to about
1.00 mg/hr for about a 6 mg dose; about 0.44 to about 1.33 mg/hr
for about an 8 mg dose, about 0.67 to about 2.00 mg/hr for about a
12 mg dose; about 0.89 to about 2.67 mg/hr for about a 16 mg dose;
about 1.33 to about 4.00 mg/hr for about a 24 mg dose; or about
2.67 to about 8.00 mg/hr for about a 48 mg dose.
36. A sustained release dosage form of claim 14 comprising
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate and a pharmaceutically acceptable carrier, which dosage
form, when tested in a USP-2 apparatus containing 500-900 ml of
0.1N HCl or simulated gastric fluid without enzymes releases about
0.60 to about 1.50 mg/hr for about a 6 mg dose, about 0.44 to about
2.00 mg/hr for about an 8 mg dose, about 0.67 to about 3.00 mg/hr
for about a 12 mg dose, about 0.89 to about 4.00 mg/hr for about a
16 mg dose, about 1.33 to about 6.00 mg/hr for about a 24 mg dose,
or about 2.40 to about 24.00 mg/hr for about a 48 mg dose.
37. A combination dosage form for orally administering
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising two portions: 1)
a portion that immediately releases an amount of a growth hormone
secretagogue; and 2) a portion that provides for sustained release
of an amount of a growth hormone secretagogue, which dosage form,
when tested in a USP-2 apparatus containing 500-900 ml of 0.1N HCl
or simulated gastric fluid without enzyme immediately releases
about 5 to about 50% of the growth hormone secretagogue immediately
and the rest over about 4 to about 6 hours for about a 4 mg total
dose; immediately releases about 50 to about 75% and the rest over
about 8 to about 10 hours for about a 4 mg total dose; immediately
releases about 75% and the rest over about 12 to about 18 hours for
about a 4 mg total dose; immediately releases about 40% and the
rest over about 4 hours for about a 6 mg total dose; immediately
releases about 5 to about 40% and the rest over about 6 hours for
about a 6 mg total dose; immediately releases about 5 to about 75%
and the rest over about 8 to about 12 hours for about a 6 mg total
dose; immediately releases about 40 to about 75% and the rest over
about 14 to about 18 hours for about a 6 mg total dose; immediately
releases about 40% and the rest over about 4 hours for about a 12
mg total dose; immediately releases about 5 to about 40% and the
rest over about 6 hours for about a 12 mg total dose; immediately
releases about 5 to about 62.5% and the rest over about 8 hours for
about a 12 mg total dose; immediately releases about to about 75%
and the rest over about 12 to about 18 hours for about a 12 mg
total dose; or immediately releases about 5 to about 75% and the
rest over about 16 hour for about a 48 mg total dose.
38. A combined dosage form of claim 37 wherein the sustained
release portion of the dosage form comprises a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or a combination
thereof.
39. A combination dosage form of claim 37 wherein the immediate
release portion comprises a layer in a multilayer tablet; a coating
on a sustained release tablet or multiparticulate; a compression
coating on a sustained release tablet, or the immediate release
portion can comprise multiparticulates along with sustained release
multiparticulates.
40. A combination dosage form of claim 37 wherein the sustained
release portion comprises an osmotic tablet and the immediate
release portion comprises a compression coating.
41. A method of increasing the plasma concentration of IGF-1 while
minimally affecting the plasma concentration of growth hormone, the
method comprising administering to a mammal in need of increased
plasma concentrations of IGF-1 a therapeutically effective amount
of a growth hormone secretagogue in a sustained release formulation
or a combination of a sustained release and immediate release
dosage form.
42. A method of claim 41 wherein the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
or a pharmaceutically acceptable salt or prodrug thereof, or a salt
of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyr-
amide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2--
[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-he-
xahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide
or a pharmaceutically acceptable salt or prodrug thereof, or a salt
of the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-diflu-
oro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-tri-
fluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-
-methyl-propionamide.
43. A method of claim 41 wherein the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate.
44. A sustained release dosage form for administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage from comprising a core
comprising: 1)
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutylramide
L-tartrate; 2) one or more osmotic agents selected from lactose,
mannitol, sorbitol, or sodium bitartrate; 3) microcrystalline
cellulose; 4) magnesium stearate; and 5) one or more acids selected
from ascorbic acid, L-aspartic acid, citric acid, fumaric acid,
succinic acid, or tartaric acid, upon which core is coated an
asymmetric membrane comprising cellulose acetate and polyethylene
glycol.
45. A combination dosage form for oral administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising two portions: A)
a portion that immediately releases an amount of a growth hormone
secretagogue; and B) a portion that provides for sustained release
of an amount of a growth hormone secretagogue, the sustained
release portion of the dosage form comprising an asymmetric
membrane coated osmotic tablet, the osmotic tablet comprising: 1)
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3--
oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymet-
hyl-2-oxo-ethyl]-isobutyramide L-tartrate; 2) one or more osmotic
agents selected from lactose, mannitol, sorbitol, or sodium
bitartrate; 3) microcrystalline cellulose; 4) magnesium stearate;
and 5) one or more acids selected from ascorbic acid, L-aspartic
acid, citric acid, fumaric acid, succinic acid, or tartaric acid;
and the asymmetric membrane comprising: cellulose acetate and
polyethylene glycol; and the immediate release portion comprising a
compression coating placed upon the asymmetric membrane coated
tablet, wherein the compression coating comprises
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahyd-
ro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobuty-
ramide L-tartrate, microcrystalline cellulose, and magnesium
stearate.
46. A sustained release dosage form for oral administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising:
44 Component Weight (mg/tablet) 2-amino-N-[2-(3a-(R)- about 3.89
benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydro-
pyrazolo[4,3-c]pyridin-5- yl)-1-(R)-benzyloxymethyl-
2-oxo-ethyl]-isobutyramide L-tartrate Mannitol about 34.00 Fumaric
acid about 12.00 Microcrystalline cellulose about 48.61 Magnesium
stearate about 1.50 Cellulose acetate about 11.90 Polyethylene
glycol about 5.10
47. A sustained release dosage form for oral administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethanol-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising:
45 Component Weight (mg/tablet) 2-amino-N-[2-(3a-(R)- about 12.97
benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydro-
pyrazolo[4,3-c]pyridin-5- yl)-1-(R)-benzyloxymethyl-
2-oxo-ethyl]-isobutyramide L-tartrate Mannitol about 113.32 Fumaric
acid about 40.00 Microcrystalline cellulose about 162.01 Magnesium
stearate about 5.00 Cellulose acetate about 33.00 Polyethylene
glycol about 22.00
48. A combination dosage form for administering a therapeutically
active compound to a mammal in need thereof, the dosage form
comprising an immediate release portion and a sustained release
portion wherein the sustained release portion comprises an osmotic
tablet, which has a membrane coating, and the immediate release
portion comprises a compression coating on the osmotic tablet.
49. A combination dosage form of claim 48 wherein the
therapeutically active compound is a growth hormone
secretagogue.
50. A combination dosage form of claim 48 wherein the
therapeutically active compound is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,-
7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl-
]-isobutyramide L-tartrate.
51. The sustained release dosage form of claim 1 wherein the dosage
form is an osmotic tablet that comprises a core that is coated with
an asymmetric membrane, the core comprising: 1) about 4 to about 10
mg of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate; 2) about 12 to about 50 wt % of the core of an acid
selected from fumaric acid, tartaric acid, succinic acid, citric
acid, L-aspartic acid, ascorbic acid, or combinations thereof; 3)
about 20 to about 63 wt % of the core of an osmotic agent selected
from mannitol, sorbitol, lactose, or combinations thereof; 4) about
22 to about 49 wt % of the core microcrysalline cellulose binder;
and 5) about 0.5 to about 1.5 wt % of the core magnesium stearate,
and the asymmetric membrane comprising cellulose acetate and
polyethylene glycol which adds about 10 to about 18 wt % to the
core for a core tablet having a weight of about 200 mg or less or
about 8 to about 17 wt % to the core tablet for core tablets having
a weight of about 300 mg.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of U.S. provisional patent
application No. 60/229,074, filed Aug. 30, 2000, which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to sustained release and combination
formulations for growth hormone secretagogues.
BACKGROUND OF THE INVENTION
[0003] Growth hormone (GH), which is secreted by the pituitary
gland, stimulates the growth of all tissues of the body that are
capable of growing. In addition, growth hormone is known to have
the following effects on metabolic processes:
[0004] 1. increased rate of protein synthesis in substantially all
cells;
[0005] 2. decreased rate of carbohydrate metabolism in cells;
and
[0006] 3. increased mobilization of free fatty acids and use of
fatty acids for energy.
[0007] A deficiency in GH production and/or secretion can result in
various diseases or conditions, such as dwarfism, profound
reduction in lean body mass and concomitant increase in total body
fat, particularly in the truncal region, decreased skeletal and
cardiac muscle mass and muscle strength that can result in
significant decreases in exercise capacity, musculoskeletal
frailty, which is typically associated with old age, congestive
heart failure, insulin resistance, bone fracture, reduction in bone
density, delayed wound healing, and osteoporosis. The
administration of exogenous growth hormone has been shown to
reverse the above-mentioned metabolic changes and has also been
shown to lower plasma low density lipoprotein (LDL) cholesterol and
improve psychological well being.
[0008] With the rapid worldwide growth of the population aged 65
years and over, aging-associated musculoskeletal frailty will
become an increasing public health problem. Frailty, in addition to
its personal impact on daily functioning and social interaction, is
associated with major health consequences such as injurious falls,
hip fractures, and nursing home admissions. Annually, in the United
States, up to 10% of frail adults over age 74 experience an
injurious fall.
[0009] The causes of the long term age-associated decline in muscle
and bone mass, which after age 40 in both men and women averages
0.5-1% per year, are unknown. A decline in synthesis/secretion of
endogenous anabolic hormones may contribute to age-associated
changes in body composition, which are characterized by decreased
muscle and bone mass and a relative increase in adiposity. For
example, in both men and women, growth hormone (GH, also termed
somatotropin) secretion declines by 50% between the ages of 30 and
70.
[0010] GH is naturally released by the body in a patterned manner
with typically large pulses during sleep and subsequent smaller
pulses of GH released later. It is also believed that growth
hormone releasing hormone [GHRH, also known as growth hormone
releasing factor (GRF)] is released from the hypothalamus in a
pulsatile or patterned manner and consequently stimulates the
release of GH in a correspondingly patterned manner.
[0011] In cases where increased levels of growth hormone are
desired, the problem has generally been approached by providing
exogenous growth hormone, typically by injection, or by
administering a compound that stimulates the secretion of growth
hormone. Typically, these compounds are peptidyl in nature and need
to be administered by injection. As an alternative approach,
compounds termed secretagogues have been developed that stimulate
the release of endogenous growth hormone. See, for example, U.S.
Pat. No. 5,723,616, WO 95/11029, WO 95/17422, WO 95/11697, and WO
94/13696.
[0012] Therapeutic intervention using the growth
hormone-Insulin-like Growth Factor-I (IGF-1) system is a developing
field, and evidence is accumulating that suggests that therapeutic
efficacy for different indications may be optimally achieved by
stimulation of GH or IGF-1 or both. For some indications such as
osteoporosis, it is believed that secretion of endogenous growth
hormone results in the subsequent release of IGF-I, and that IGF-I
elicits therapeutic effects, e.g., increased bone density. Thus, it
would be desirable to have a therapeutic formulation that
stimulates the secretion of IGF-I in a patient, but minimally
affects the secretion of growth hormone, particularly over time.
Minimizing GH levels in this situation may avoid potential adverse
sequelae of continuous GH stimulation such as in acromegaly. A
formulation that can be orally administered once per day is
preferred. Prior to the present invention, it was not known how to
prepare a therapeutic formulation containing a growth hormone
secretagogue that could be easily administered, and which
stimulated the levels of endogenous IGF-I while minimally affecting
the release of GH over time. With a sustained release dosage form,
it has been found that with steady state treatment using a growth
hormone secretagogue (i.e., after 2 or more weeks of treatment),
growth hormone plasma concentration peaks will be higher than in
the untreated patient (i.e., baseline), but lower than the growth
hormone peaks would be during the first few days of treatment.
Typically, IGF-1 would be higher at steady state than either
baseline or after the first few days of treatment.
[0013] It may also be advantageous for some indications to have an
orally administerable therapeutic formulation that provides for
both a sustained endogenous release of IGF-I and a small but
significant release of GH in order to elicit the effects of IGF-I
and non-IGF-I mediated effects of GH. Finally, it may be
advantageous in some indications such as improving muscle mass to
elevate GH while minimally elevating IGF-1.
SUMMARY OF THE INVENTION
[0014] The present invention provides sustained release dosage
forms for oral administration to a mammal, the dosage forms
comprising a growth hormone secretagogue and a pharmaceutically
acceptable carrier, which dosage forms result in a maximum growth
hormone secretagogue plasma concentration, C.sub.max, which is less
than 80% of the C.sub.max that occurs when an equal dose of the
growth hormone secretagogue is orally administered using an
immediate release dosage form.
[0015] In a preferred embodiment, the sustained release dosage
forms provide total blood growth hormone secretagogue exposure that
is not proportionately decreased as much as C.sub.max.
[0016] In another preferred embodiment of the sustained release
dosage from, the dosage form is an osmotic tablet that comprises a
core that is coated with an asymmetric membrane, the core
comprising:
[0017] 1) about 4 to about 10 mg of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo-ethyl]-isobutyramide L-tartrate;
[0018] 2) about 12 to about 50 wt % of the core of an acid selected
from fumaric acid, tartaric acid, succinic acid, citric acid,
L-aspartic acid, ascorbic acid, or combinations thereof;
[0019] 3) about 20 to about 63 wt % of the core of an osmotic agent
selected from mannitol, sorbitol, lactose, or combinations
thereof;
[0020] 4) about 22 to about 49 wt % of the core microcrysalline
cellulose binder; and
[0021] 5) about 0.5 to about 1.5 wt % of the core magnesium
stearate, and the asymmetric membrane comprising cellulose acetate
and polyethylene glycol which adds about 10 to about 18 wt % to the
core for a core tablet having a weight of about 200 mg or less or
about 8 to about 17 wt % to the core tablet for core tablets having
a weight of about 300 mg.
[0022] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue exhibits an
elimination half-life of less than about 6 hours.
[0023] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benz-
yloxymethyl-2-oxo-ethyl]-isobutyramide or a pharmaceutically
acceptable salt or prodrug thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3oxo-
-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide or a
pharmaceutically acceptable salt or prodrug thereof, or a salt of
the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-diflu-
oro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-tri-
fluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-
-methyl-propionamide.
[0024] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzy-
loxymethyl-2-oxo-ethyl]isobutyramide L-tartrate.
[0025] In another preferred embodiment of the sustained release
dosage forms, the dosage forms comprise a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or combinations
thereof.
[0026] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benz-
yloxymethyl-2-oxo-ethyl]isobutyramide L-tartrate, and which
sustained release dosage forms release about 0.007 to about 0.010
mg/hr/kg for about a 4 mg dose; about 0.007 to about 0.014 mg/hr/kg
for about a 6 mg dose; about 0.006 to about 0.019 mg/hr/kg for
about an 8 mg dose; about 0.010 to about 0.029 mg/hr/kg for about a
12 mg dose; about 0.013 to about 0.038 mg/hr/kg for about a 16 mg
dose; about 0.019 to about 0.057 mg/hr/kg for about a 24 mg dose;
or about 0.038 to about 0.114 mg/hr/kg for about a 48 mg dose.
(Mg/hr/kg means milligrams of active compound released per hour for
each kg of the patient's weight.)
[0027] In another preferred embodiment of the sustained release
dosage forms immediately above, the dosage forms comprise a matrix
tablet that remains substantially intact during the period of
sustained release; a disintegrating matrix tablet; a matrix tablet
partially coated with a polymer that impedes the release of the
growth hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or combinations
thereof.
[0028] In another preferred embodiment of the sustained release
dosage forms, one or more excipients is selected from: ascorbic
acid; L-aspartic acid; citric acid; fumaric acid; succinic acid;
tartaric acid; sodium bitartrate; microcrystalline cellulose;
microcrystalline cellulose, silicified; polyethylene glycol;
calcium stearate; or magnesium stearate.
[0029] In another preferred embodiment of the sustained release
dosage forms, the dosage forms are an osmotic tablet comprising an
osmotic agent selected from lactose; mannitol; sodium bitartrate;
or sorbitol.
[0030] The present invention also provides sustained-release dosage
forms for oral administration to a mammal, the dosage forms
comprising a growth hormone secretagogue and a pharmaceutically
acceptable carrier, which dosage forms result in a growth hormone
secretagogue plasma concentration that exceeds the minimum
effective concentration for a time, .DELTA.T.sub.T2-T1, which is
greater than, by at least 30 minutes, the .DELTA.T.sub.T2-T1
determined when an equal dose of the growth hormone secretagogue is
orally administered using an immediate release dosage form, wherein
.DELTA.T.sub.T2-T1 is the time period for which the plasma
concentration of the growth hormone secretagogue remains above the
minimum effective concentration, with T1 being the time the plasma
concentration first goes above the minimum effective concentration
and T2 being the time when the plasma concentration goes below the
minimum effective concentration.
[0031] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue exhibits an
elimination half-life of less than 6 hours.
[0032] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benz-
yloxymethyl-2-oxo-ethyl]-isobutyramide or a pharmaceutically
acceptable salt or prodrug thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-ox-
o-3a-(R)-pyridin-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-
[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide or a
pharmaceutically acceptable salt or prodrug thereof, or a salt of
the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymet-
hyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,-
3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propiona-
mide.
[0033] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benz-
yloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate.
[0034] In another preferred embodiment of the sustained release
dosage forms, the dosage forms comprise a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or combinations
thereof.
[0035] In another preferred embodiment of the sustained release
dosage forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benz-
yloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate, and which dosage
forms release about 0.009 to about 0.021 mg/hr/kg for about a 6 mg
dose; about 0.006 to about 0.029 mg/hr/kg for about an 8 mg dose;
about 0.010 to about 0.043 mg/hr/kg for about a 12 mg dose; about
0.013 to about 0.057 mg/hr/kg for about a 16 mg dose; about 0.019
to about 0.086 mg/hr/kg for about a 24 mg dose; or about 0.034 to
about 0.343 mg/hr/kg for about a 48 mg dose.
[0036] In another preferred embodiment of the sustained release
dosage forms, the dosage forms comprise a matrix tablet that
remains substantially intact during the period of sustained
release; a disintegrating matrix tablet; a matrix tablet partially
coated with a polymer that impedes the release of the growth
hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or combinations
thereof.
[0037] In another preferred embodiment of the sustained release
dosage forms, one or more excipients is selected from: ascorbic
acid; L-aspartic acid; citric acid; fumaric acid; succinic acid;
tartaric acid; sodium bitartrate; microcrystalline cellulose;
microcrystalline cellulose, silicified; polyethylene glycol;
calcium stearate; or magnesium stearate.
[0038] In another preferred embodiment of the sustained release
dosage forms, the dosage forms are an osmotic tablet comprising an
osmotic agent selected from lactose; mannitol; sodium bitartrate;
or sorbitol.
[0039] Also provided by the present invention are combination
dosage forms for oral administration of a growth hormone
secretagogue to a mammal, the dosage forms comprising two portions:
1) a portion that immediately releases an amount of a growth
hormone secretagogue; and 2) a portion that provides for sustained
release of an amount of a growth hormone secretagogue, which dosage
form results in a maximum growth hormone secretagogue plasma
concentration, C.sub.max, which is less than 80% of the C.sub.max
that occurs when an equal dose of the growth hormone secretagogue
is orally administered using an immediate release dosage form.
[0040] In a preferred embodiment, the combination dosage forms
provide total blood growth hormone secretagogue exposure that is
not proportionately decreased as much as C.sub.max.
[0041] In a preferred embodiment of the combination dosage forms,
the growth hormone secretagogue exhibits an elimination half-life
of less than about 6 hours.
[0042] In a preferred embodiment of the combination dosage forms,
the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-
-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-
-2-oxo-ethyl]-isobutyramide or a pharmaceutically acceptable salt
or prodrug thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2--
methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-ben-
zyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyr-
idin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[-
4,3-c]pyridin-5-yl]ethyl}-2-methyl-propionamide or a
pharmaceutically acceptable salt or prodrug thereof, or a salt of
the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymet-
hyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,-
3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}2-methyl-propionam-
ide.
[0043] In a preferred embodiment of the combination dosage forms,
the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-
-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-
-2-oxo-ethyl]-isobutyramide L-tartrate.
[0044] In a preferred embodiment of the combination dosage forms,
the sustained release portion of the dosage forms comprise a matrix
tablet that remains substantially intact during the period of
sustained release; a disintegrating matrix tablet; a matrix tablet
partially coated with a polymer that impedes the release of the
growth hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core, tablet; a multiparticulate; or combinations
thereof.
[0045] The present invention also provides combination dosage forms
for oral administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,-
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-e-
thyl]-isobutyramide L-tartrate to a mammal, the dosage forms
comprising two portions: 1) a portion that immediately releases an
amount of a growth hormone secretagogue; and 2) a portion that
provides for sustained release of an amount of a growth hormone
secretagogue, the dosage form having the following characteristics
for each dose:
1 Sustained Release Portion Total Growth Immediate Release (% of
Total Time Period of Hormone Portion (% of Total Growth Hormone
Sustained Secretagogue Growth Hormone Secretagogue Release Dose
(mg) Secretagogue Dose) Dose) (hours) about 4 about 5 to about 50
about 95 to about about 4 to 50 about 6 about 4 about 50 to about
75 about 50 to about about 8 to 25 about 10 about 4 about 75 about
25 about 12 to about 18 about 6 about 40 about 60 about 4 about 6
about 5 to about 40 about 95 to about about 6 60 about 6 about 5 to
about 75 about 95 to about about 8 to 25 about 12 about 6 about 40
to about 75 about 60 to about about 14 to 25 about 18 about 12
about 40 about 60 about 4 about 12 about 5 to about 40 about 95 to
about about 6 60 about 12 about 5 to about about 95 to about about
8 62.5 37.5 about 12 about 5 to about 75 about 95 to about about 12
to 25 about 18 about 48 about 5 to about 75 about 95 to about about
16 25
[0046] In a preferred embodiment of the combination dosage forms,
the sustained release portion of the dosage forms comprise a matrix
tablet that remains substantially intact during the period of
sustained release; a disintegrating matrix tablet; a matrix tablet
partially coated with a polymer that impedes the release of the
growth hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or combinations
thereof.
[0047] In a preferred embodiment of the combination dosage forms,
the immediate release portion comprises a layer in a multilayer
tablet; a coating on a sustained release tablet or
multiparticulate; a compression coating on a sustained release
tablet, or the immediate release portion can comprise
multiparticulates along with sustained release
multiparticulates.
[0048] In another preferred embodiment of the combination dosage
forms, the sustained release portion comprises an osmotic tablet
and the immediate release portion comprises a compression
coating.
[0049] Also provided by the present invention are combination
dosage forms for oral administration of a growth hormone
secretagogue to a mammal, the dosage forms comprising two portions:
1) a portion that immediately releases an amount of a growth
hormone secretagogue; and 2) a portion that provides for sustained
release of an amount of a growth hormone secretagogue, which dosage
form results in a growth hormone secretagogue plasma concentration
that exceeds the minimum effective concentration for a time,
.DELTA.T.sub.T2-T1, which is greater than, by at least 30 minutes,
the .DELTA.T.sub.T2-T1, determined when an equal dose of the growth
hormone secretagogue is orally administered using an immediate
release dosage form, wherein .DELTA.T.sub.T2-T1 is the time period
for which the plasma concentration of the growth hormone
secretagogue remains above the minimum effective concentration,
with T1 being the time the plasma concentration first goes above
the minimum effective concentration and T2 being the time when the
plasma concentration goes below the minimum effective
concentration.
[0050] In a preferred embodiment of the combination dosage forms,
the growth hormone secretagogue exhibits an elimination half-life
of less than 6 hours.
[0051] In a preferred embodiment of the combination dosage forms,
the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-
-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-
-2-oxo-ethyl]-isobutyramide or a pharmaceutically acceptable salt
or prodrug thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2--
methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-(R)-benzy-
loxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate;
2-amino-N-{1-(R)-(2,4-di-
fluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2--
trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl-
}-2-methyl-propionamide or a pharmaceutically acceptable salt or
prodrug thereof, or a salt of the prodrug; or the (L)-(+)-tartaric
acid salt of
2-amino-N{-1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyr-
idin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[-
4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide.
[0052] In another preferred embodiment of the combination dosage
forms, the growth hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymet-
hyl-2-oxo-ethyl]-isobutyramide L-tartrate.
[0053] In another preferred embodiment of the combination dosage
forms, the sustained release portion of the dosage forms comprise a
matrix tablet that remains substantially intact during the period
of sustained release; a disintegrating matrix tablet; a matrix
tablet partially coated with a polymer that impedes the release of
the growth hormone secretagogue; an osmotic tablet; a
membrane-coated swelling-core tablet; a multiparticulate; or
combinations thereof.
[0054] Also provided are combination dosage forms for oral
administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyra-
zolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage forms comprising two portions:
1) a portion that immediately releases an amount of a growth
hormone secretagogue; and 2) a portion that provides for sustained
release of an amount of a growth hormone secretagogue, the dosage
forms having the following characteristics for each dose:
2 Sustained Release Portion (% of Total Total Growth Immediate
Release Growth Time Period Hormone Portion (% of Total Hormone of
Sustained Secretagogue Growth Hormone Secretagogue Release Dose
(mg) Secretagogue Dose) Dose) (hours) about 6 about 5 to about 40
about 95 to about 4 about 60 about 6 about 5 to about 75 about 95
to about 6 about 25 about 6 about 5 to about 62.5 about 95 to about
8 about 37.5 about 6 about 5 to about 40 about 95 to about 10 about
60 about 12 about 5 to about 40 about 95 to about 4 about 60 about
12 about 5 to about 75 about 95 to about 6 to about 25 about 16
about 12 about 5 to about 40 about 95 to about 18 about 60 about 48
about 5 to about 75 about 95 to about 16 about 25
[0055] In a preferred embodiment of the combination dosage forms,
the sustained release portion of the dosage forms comprise a matrix
tablet that remains substantially intact during the period of
sustained release; a disintegrating matrix tablet; a matrix tablet
partially coated with a polymer that impedes the release of the
growth hormone secretagogue; an osmotic tablet; a membrane-coated
swelling-core tablet; a multiparticulate; or combinations
thereof.
[0056] In a preferred embodiment of the combination dosage forms,
the immediate release portion comprises a layer in a multilayer
tablet; a coating on a sustained release tablet or
multiparticulate; a compression coating on a sustained release
tablet, or the immediate release portion can comprise
multiparticulates along with sustained release
multiparticulates.
[0057] In a preferred embodiment of the combination dosage forms,
the sustained release portion comprises an osmotic tablet and the
immediate release portion comprises a compression coating.
[0058] Also provided by the present invention are sustained release
dosage forms comprising
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7--
hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]--
isobutyramide L-tartrate and a pharmaceutically acceptable carrier,
which dosage forms, when tested in a USP-2 apparatus containing
500-900 ml of 0.1 N HCl or simulated gastric fluid without enzyme
release about 0.50 to about 0.67 mg/hr for about a 4 mg dose; about
0.50 to about 1.00 mg/hr for about a 6 mg dose; about 0.44 to about
1.33 mg/hr for about an 8 mg dose, about 0.67 to about 2.00 mg/hr
for about a 12 mg dose; about 0.89 to about 2.67 mg/hr for about a
16 mg dose; about 1.33 to about 4.00 mg/hr for about a 24 mg dose;
and about 2.67 to about 8.00 mg/hr for about a 48 mg dose.
[0059] Also provided by the present invention are sustained release
dosage forms comprising
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7--
hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]--
isobutyramide L-tartrate and a pharmaceutically acceptable carrier,
which dosage forms, when tested in a USP-2 apparatus containing
500-900 ml of 0.1 N HCl or simulated gastric fluid without enzyme
release about 0.60 to about 1.50 mg/hr for about a 6 mg dose, about
0.44 to about 2.00 mg/hr for about an 8 mg dose, about 0.67 to
about 3.00 mg/hr for about a 12 mg dose, about 0.89 to about 4.00
mg/hr for about a 16 mg dose, about 1.33 to about 6.00 mg/hr for
about a 24 mg dose, and about 2.40 to about 24.00 mg/hr for about a
48 mg dose.
[0060] Also provided by the present invention are combination
dosage forms for orally administering
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3-
a,4,6,7hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo--
ethyl]-isobutyramide L-tartrate to a mammal, the dosage forms
comprising two portions: 1) a portion that immediately releases an
amount of a growth hormone secretagogue; and 2) a portion that
provides for sustained release of an amount of a growth hormone
secretagogue, which dosage form, when tested in a USP-2 apparatus
containing 500-900 ml of 0.1 N HCl or simulated gastric fluid
without enzyme immediately releases about 5 to about 50% of the
growth hormone secretagogue immediately and the rest over about 4
to about 6 hours for about a 4 mg total dose; immediately releases
about 50 to about 75% and the rest over about 8 to about 10 hours
for about a 4 mg total dose; immediately releases about 75% and the
rest over about 12 to about 18 hours for about a 4 mg total dose;
immediately releases about 40% and the rest over about 4 hours for
about a 6 mg total dose; immediately releases about 5 to about 40%
and the rest over about 6 hours for about a 6 mg total dose;
immediately releases about 5 to about 75% and the rest over about 8
to about 12 hours for about a 6 mg total dose; immediately releases
about 40 to about 75% and the rest over about 14 to about 18 hours
for about a 6 mg total dose; immediately releases about 40% and the
rest over about 4 hours for about a 12 mg total dose; immediately
releases about 5 to about 40% and the rest over about 6 hours for
about a 12 mg total dose; immediately releases about 5 to about
62.5% and the rest over about 8 hours for about a 12 mg total dose;
immediately releases about 5 to about 75% and the rest over about
12 to about 18 hours for about a 12 mg total dose; or immediately
releases about 5 to about 75% and the rest over about 16 hours for
about a 48 mg total dose.
[0061] In a preferred embodiment of the combination dosage forms,
the sustained release portion of the dosage forms comprises a
matrix tablet that remains substantially intact during the period
of sustained release; a disintegrating matrix tablet; a matrix
tablet partially coated with a polymer that impedes the release of
the growth hormone secretagogue; an osmotic tablet; a
membrane-coated swelling-core tablet; a multiparticulate; or
combinations thereof.
[0062] In another preferred embodiment of the combination dosage
forms the immediate release portion comprises a layer in a
multilayer tablet; a coating on a sustained release tablet or
multiparticulate; a compression coating on a sustained release
tablet, or the immediate release portion can comprise
multiparticulates along with sustained release
multiparticulates.
[0063] In another preferred embodiment of the combination dosage
forms, the sustained release portion comprises an osmotic tablet
and the immediate release portion comprises a compression
coating.
[0064] Also provided are methods of increasing the plasma
concentration of IGF-1 while minimally affecting the plasma
concentration of growth hormone, the methods comprising
administering to a mammal in need of increased plasma
concentrations of IGF-1 a therapeutically effective amount of a
growth hormone secretagogue using a sustained release formulation
or a combination of a sustained release and immediate release
dosage form.
[0065] In a preferred embodiment of the methods, the growth hormone
secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide or a pharmaceutically acceptable salt or prodrug
thereof, or a salt of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,-
4,6,7-hexahydro-pyrazolo[4,3c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-et-
hyl]-isobutyramide L-tartrate; 2-amino-N-{1
-(R)-(2,4-difluoro-benzyloxyme-
thyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2-
,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propion-
amide or a pharmaceutically acceptable salt or prodrug thereof, or
a salt of the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyr-
idin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[-
4,3-c]pyridin-5-yl-ethyl}-2-methyl-propionamide.
[0066] In another preferred embodiment of the methods, the growth
hormone secretagogue is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-ethyl]-isobu-
tyramide L-tartrate.
[0067] Also provided is a sustained release dosage form for
administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyra-
zolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxy-ethyl]-isobutyramide
L-tartrate to a mammal, the dosage form comprising a core
comprising:
[0068] 1)
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyr-
amide L-tartrate;
[0069] 2) one or more osmotic agents selected from lactose,
mannitol, sorbitol, or sodium bitartrate;
[0070] 3) microcrystalline cellulose;
[0071] 4) magnesium stearate; and
[0072] 5) one or more acids selected from ascorbic acid, L-aspartic
acid, citric acid, fumaric acid, succinic acid, or tartaric acid
upon which core is coated an asymmetric membrane comprising
cellulose acetate and polyethylene glycol.
[0073] Also provided by the present invention are combination
dosage forms for oral administration of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3-
,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-o-
xo-ethyl]-isobutyramide L-tartrate to a mammal, the dosage forms
comprising two portions: A) a portion that immediately releases an
amount of a growth hormone secretagogue; and B) a portion that
provides for sustained release of an amount of a growth hormone
secretagogue, the sustained release portion of the dosage form
comprising an asymmetric membrane coated osmotic tablet, the
osmotic tablet comprising:
[0074] 1)
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyr-
amide L-tartrate;
[0075] 2) one or more osmotic agents selected from lactose,
mannitol, sorbitol, or sodium bitartrate;
[0076] 3) microcrystalline cellulose;
[0077] 4) magnesium stearate; and
[0078] 5) one or more acids selected from ascorbic acid, L-aspartic
acid, citric acid, fumaric acid, succinic acid, or tartaric
acid;
[0079] and the asymmetric membrane comprising:
[0080] cellulose acetate and polyethylene glycol; and the immediate
release portion comprising a compression coating placed upon the
asymmetric membrane coated tablet, wherein the compression coating
comprises
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahyd-
ro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobuty-
ramide L-tartrate, microcrystalline cellulose, and magnesium
stearate.
[0081] Also provided is a sustained release dosage form for oral
administration of
2amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7--
hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]--
isobutyramide L-tartrate to a mammal, the dosage form
comprising:
3 Component Weight (mg/tablet) 2-amino-N-[2-(3a-(R)- about 3.89
benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydro-
pyrazolo[4,3-c]pyridin-5- yl)-1-(R)-benzyloxymethyl-
2-oxo-ethyl]-isobutyramide L-tartrate Mannitol about 34.00 Fumaric
acid about 12.00 Microcrystalline cellulose about 48.61 Magnesium
stearate about 1.50 Cellulose acetate about 11.90 Polyethylene
glycol about 5.10
[0082] Also provided is a sustained release dosage from for oral
administration of
2-amino-N-[2-(3-a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,-
7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl-
]-isobutyramide L-tartrate to a mammal, the dosage from
comprising:
4 Component Weight (mg/tablet) 2-amino-N-[2-(3a-(R)- about 12.97
benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydro-
pyrazolo[4,3-c]pyridin-5- yl)-1-(R)-benzyloxymethyl-
2-oxo-ethyl]-isobutyramide L-tartrate Mannitol about 113.32 Fumaric
acid about 40.00 Microcrystalline cellulose about 162.01 Magnesium
stearate about 5.00 Cellulose acetate about 33.00 Polyethylene
glycol about 22.00
[0083] Also provided is a combination dosage from for administering
a therapeutically active compound to a mammal in need thereof, the
dosage from comprising an immediate release portion and a sustained
release portion wherein the sustained release portion comprises an
osmotic tablet, which has a membrane coating, and the immediate
release portion comprises a compression coating on the osmotic
tablet.
[0084] In a preferred embodiment of the combination dosage from,
the therapeutically active compound is a growth hormone
secretagogue.
[0085] In another preferred embodiment of the combination dosage
form, the therapeutically active compound is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo-ethyl]-isobutyramide L-tartrate.
DETAILED DESCRIPTION OF THE INVENTION
[0086] The present invention provides sustained release dosage
forms for growth hormone secretagogues (GHSECs). The present
invention also provides dosage forms that immediately release an
amount of a GHSEC and release an amount of a GHSEC in a sustained
manner.
[0087] The term "sustained release" means that active compound or
compounds are released over a period of time. Preferably, the
amount of compound released over a period of time is relatively
constant.
[0088] The term "growth hormone secretagogue" includes the
pharmaceutically acceptable salts and prodrugs, and prodrugs of the
salts, polymorphs, hydrates, solvates, and stereoisomers of the
growth hormone secretagogue.
[0089] The terms "active compound" or "active agent" means a
compound that exerts a pharmacological effect on a patient. These
terms are intended to include salts and prodrugs of the compound
and salts of the prodrugs.
[0090] The present invention provides sustained release
formulations of a growth hormone secretagogue or a combination of
growth hormone secretagogues. The sustained release formulations of
the present invention release a GHSEC in vivo at a rate that
results in therapeutic plasma levels of the GHSEC for extended
periods of the day. Since GHSECs are typically polar molecules, it
was not known whether the permeability of the intestinal wall,
particularly the colon, would be sufficient to permit absorption
over an extended period. The GHSEC formulations of the present
invention surprisingly give plasma levels of GHSEC for extended
periods of the dosing day, and can be administered just once per
day to give adequate therapy. Furthermore, when the sustained
release formulations of the present invention are administered
daily for three or more weeks, plasma levels of IGF-I are increased
with respect to baseline levels, while GH levels are decreased or
unchanged with respect to baseline levels. In other words, over
time IGF-1 plasma levels are elevated, and GH levels are decreased
or unchanged with respect to baseline plasma levels. Thus, the
therapeutic benefits of elevated IGF-1 levels may be obtained while
minimizing any undesired effects that result from increased GH
plasma levels.
[0091] Any GHSEC can be used in the present invention. The
following patents and applications disclose GHSECs that can be used
in the present invention: PCT/US93/11038, WO 98/46569, WO 98/51687,
WO 98/58950, WO 99/08697, WO 99/09991, WO 95/13069, U.S. Pat. No.
5,492,916, U.S. Pat. No. 5,494,919, WO 95/14666, WO 94/19367, WO
94/13696, WO 94/11012, U.S. Pat. No. 5,726,319, WO 95/11029, WO
95/17422, WO 95/17423, WO 95/34311, WO 96/02530, WO 96/22996, WO
96/22997, WO 96/24580, WO 96/24587, U.S. Pat. No. 5,559,128, WO
96/32943, WO 96/33189, WO 96/15148, WO 97/00894, WO 97/07117, WO
97/06803, WO 97/11697, WO 97/15573, WO 97/22367, WO 97/23508, WO
97/22620, WO 97/22004, WO 97/21730, U.S. Pat. No. 5,663,171, WO
97/34604, WO 97/36873, WO 97/40071, WO 97/40023, WO 97/41878, WO
97/41879, WO 97/46252, WO 97/44042, WO 97/38709, WO 98/03473, WO
97/43278, U.S. Pat. No. 5,721,251, U.S. Pat. No. 5,721,250, WO
98/10653, WO 96/38471, WO 96/35713, U.S. Pat. No. 5,919,777, and
U.S. Pat. No. 5,830,433.
[0092] In addition, the following growth hormone secretagogues are
contemplated for use in the present invention: MK-0677 (Merck);
NM703 (Novo Nordisk); L-162752, and L-1 63022 (Merck); hexarelin
(Pharmacia Corporation); GPA-748, KP102, and GHRP-2 (American Home
Products); ipamorelin (Novo Nordisk); LY444711 (Eli Lilly); Geref
(Ares/Serono); GHRH (1-44) [BioNebraska]; Somatorelin (GRF 1-44)
[Fujisawa/ICN]; and ThGRF (Theratechnologies).
[0093] Preferred GHSECs that can be used in the present invention
include:
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
or a pharmaceutically acceptable salt or prodrug thereof, or a salt
of the prodrug;
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]isobutyra-
mide L-tartrate;
2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[-
3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hex-
ahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide or
a pharmaceutically acceptable salt of prodrug thereof, or a salt of
the prodrug; or the (L)-(+)-tartaric acid salt of
2-amino-N-{1-(R)-(2,4-diflu-
oro-benzyloxymethyl-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trif-
luoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2--
methyl-propionamide. The procedures for making these compounds are
disclosed in WO 97/24369 and WO 98/58947. Particularly preferred
GHSECs for use in the present invention include GHSECs that have a
plasma half-life in humans of less than about 6 hours, and
preferable of less than about 4 hours. It is also noted that the
formulation of the present invention can contain more than one
GHSEC. For example, two GHSECs can be administered in a sustained
release formulation. Similarly, two GHSECS can be administered in a
formulation that has an immediate release portion and a sustained
release portion. In one embodiment of the formulation that has an
immediate release and a sustained release portion, one GHSEC can be
used in the immediate release portion and a different GHSEC can be
used in the sustained release portion.
[0094] Dosing a GHSEC sustained release dosage form (SRDF) for
greater than three weeks resulted in elevated plasma IGF-I levels,
without significant elevation of plasma GH levels. The GHSEC SRDF
that was used to demonstrate this effect in humans resulted in at
least two major pharmacokinetic effects: the GHSEC plasma C.sub.max
was lowered, and the time duration for which the GHSEC plasma level
exceeds about 1 or about 2 ng/ml was extended when compared to an
immediate release dosage form administering the same amount of
GHSEC. The sustained release dosage forms (SRDF) of the present
invention meet either or both of the following criteria:
(1) The C.sub.max Criterion
[0095] When the GHSEC SRDF is dosed to a mammal, the resulting
maximum GHSEC plasma concentration C.sub.max is less than 80% of
the C.sub.max resulting from dosing an immediate release dosage
form (IRDF) at the same dose. An IRDF comprises a GHSEC solution,
suspension, tablet, or capsule with no incorporated mechanism for
delaying or slowing the dissolution of the active compound after
administration. It is preferred that the total active compound
exposure not be decreased as much as C.sub.max. That is, the
AUC(SRDF)/AUC(IRDF) is greater than the
C.sub.max(SRDF)/C.sub.max(IRD- F), where AUC is the area under the
plasma active compound concentration versus time plot.
(2) The .DELTA.T Criterion
[0096] When the GHSEC SRDF is dosed to a mammal, the resulting
GHSEC plasma concentration remains above the minimum therapeutic
GHSEC plasma concentration for at least 30 minutes longer than
would occur after dosing a GHSEC IRDF at the same dose. For humans
the minimum therapeutically effective GHSEC plasma concentration is
about 1 ng/ml or greater. A preferred effective GHSEC plasma
concentration is about 2 ng/ml or greater. Preferred GHSEC SRDFs of
this invention meet both the C.sub.max and .DELTA.T criteria.
[0097] Exemplary sustained release dosage forms of this invention
which meet the C.sub.max criterion, wherein the GHSEC is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo2,3,3a,4,6,7-hexahydro-pyrazolo-
[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate are those which release the above GHSEC at a rate
of:
[0098] about 0.007 to about 0.010 mg/hr/kg for about a 4 mg
dose;
[0099] about 0.007 to about 0.014 mg/hr/kg for about a 6 mg
dose;
[0100] about 0.006 to about 0.019 mg/hr/kg for about a 8 mg
dose;
[0101] about 0.010 to about 0.029 mg/hr/kg for about a 12 mg
dose;
[0102] about 0.013 to about 0.038 mg/hr/kg for about a 16 mg
dose;
[0103] about 0.019 to about 0.057 mg/hr/kg for about a 24 mg dose;
and
[0104] about 0.038 to about 0.114 mg/hr/kg for about a 48 mg
dose,
[0105] where mg refers to mg GHSEC, and kg refers to the weight of
the mammal under treatment. Preferably, the mammal is a human.
[0106] Exemplary sustained release dosage forms of this invention
which meet the .DELTA.T criterion, wherein the GHSEC is the
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate are those which release the GHSEC at a rate of:
[0107] about 0.009 to about 0.021 mg/hr/kg for about a 6 mg
dose;
[0108] about 0.006 to about 0.029 mg/hr/kg for about a 8 mg
dose;
[0109] about 0.010 to about 0.043 mg/hr/kg for about a 12 mg
dose;
[0110] about 0.013 to about 0.057 mg/hr/kg for about a 16 mg
dose;
[0111] about 0.019 to about 0.086 mg/hr/kg for about a 24 mg dose;
and
[0112] about 0.034 to about 0.343 mg/hr/kg for about a 48 mg
dose,
[0113] where mg refers to mg GHSEC, and kg refers to the weight of
the mammal under treatment. Preferably, the mammal is a human.
[0114] These release rate ranges were determined by the
pharmacokinetic modeling described in the Examples below, and
assume a desired therapeutic plasma level of 2 ng/ml. The
pharmacokinetic modeling studies utilized data from a study in
which the compound was dosed to human subjects. For some
therapeutic indications, 1 ng/ml GHSEC in plasma will be effective.
Appropriate release rates for lower doses (e.g., less than 4 mg),
for intermediate doses (e.g., 5 mg, 7 mg, 10 mg, 16 mg), or lower
therapeutic active compound plasma levels (e.g., less than 2 ng/ml)
may be determined as illustrated below in the Examples.
[0115] The present invention also relates to a combination dosage
form that comprises a sustained release portion and an immediate
release portion. Such dosage forms release a part of the GHSEC
immediately after dosing, and release another part of the GHSEC in
a sustained manner. Formulations of this type meet either or both
of the C.sub.max or .DELTA.T criteria described above. Preferred
formulations meet both criteria. Exemplary combination formulations
of the present invention that comprise a sustained release and
immediate release portion that meet the C.sub.max criterion above
for 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3--
oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymet-
hyl-2-oxo-ethyl]-isobutyramide L-tartrate include forms that
release:
[0116] about 5 to about 50% GHSEC immediately, and the rest of the
dose over about 4 to about 6 hr, for about a 4 mg dose;
[0117] about 50 to about 75% GHSEC immediately, and the rest over
about 8 to about 10 hr, for about a 4 mg dose;
[0118] about 75% GHSEC immediately, and the rest over about 12 to
about 18 hr, for about a 4 mg dose;
[0119] about 40% GHSEC immediately, and the rest over about 4 hr,
for about a 6 mg dose;
[0120] about 5 to about 40% GHSEC immediately, and the rest over
about 6 hr, for about a 6 mg dose;
[0121] about 5 to about 75% GHSEC immediately, and the rest over
about 8 to about 12 hr, for about a 6 mg dose;
[0122] about 40 to about 75% GHSEC immediately, and the rest over
about 14 to about 18 hr, for about a 6 mg dose;
[0123] about 40% GHSEC immediately, and the rest over about 4 hr,
for about a 12 mg dose;
[0124] about 5 to about 40% GHSEC immediately, and the rest over
about 6 hr, for about a 12 mg dose;
[0125] about 5 to about 62.5% GHSEC immediately, and the rest over
about 8 hr, for about a 12 mg dose;
[0126] about 5 to about 75% GHSEC immediately, and the rest over
about 12 to about 18 hr, for about a 12 mg dose; and
[0127] about 5 to about 75% GHSEC immediately, and the rest over
about 16 hr, for about a 48 mg dose.
[0128] Exemplary formulations of the present invention that have an
immediate release and a sustained release portion that meet the
.DELTA.T criterion and wherein the GHSEC is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo-ethyl]-isobutyramide L-tartrate, are those which
release:
[0129] about 5 to about 40% GHSEC immediately, and the rest over
about 4 hr, for about a 6 mg dose;
[0130] about 5 to about 75% GHSEC immediately, and the rest over
about 6 hr, for about a 6 mg dose;
[0131] about 5 to about 62.5% GHSEC immediately, and the rest over
about 8 hr, for about a 6 mg dose;
[0132] about 5 to about 40% GHSEC immediately, and the rest over
about 10 hr, for about a 6 mg dose;
[0133] about 5 to about 40% GHSEC immediately, and the rest over
about 4 hr, for about a 12 mg dose;
[0134] about 5 to about 75% GHSEC immediately, and the rest over
about 6 to about 16 hr, for about a 12 mg dose;
[0135] about 5 to about 40% GHSEC immediately, and the rest over
about 18 hr, for about a 12 mg dose; and
[0136] about 5 to about 75% GHSEC immediately, and the rest over
about 16 hr, for about a 48 mg dose.
[0137] The ranges of % immediate release component, and duration of
release of sustained release component, were determined by the
pharmacokinetic modeling described in the Examples below, and
assume a desired therapeutic plasma level of 2 ng/ml. For some
therapeutic indications, 1 ng/ml GHSEC in plasma will be effective.
Appropriate release rates for lower doses (e.g., less than 4 mg),
for intermediate doses (e.g. 5 mg, 7 mg, 10 mg, 16 mg), or for
lower therapeutic active compound plasma levels (e.g. less than 2
ng/ml) may be determined as illustrated in the Examples.
[0138] The sustained-release dosage forms useful in this invention
can be widely implemented. For purposes of discussion, not
limitation, the many embodiments hereunder can be grouped into
classes according to design and principle of operation.
[0139] The first class of sustained release dosage forms described
below is matrix systems, which include but are not limited to 1)
non-eroding matrices, tablets, multiparticulates, and
hydrogel-based systems; 2) hydrophilic eroding, dispersible or
dissolvable matrix systems, tablets and multiparticulates; and 3)
coated matrix systems. The second class comprises reservoir systems
where release of the active compound is modulated by a membrane,
such as capsules, and coated tablets or multiparticulates. The
third class comprises osmotic-based systems such as 1) coated
bilayer tablets; 2) coated homogeneous tablet cores; 3) coated
multiparticulates; and 4) osmotic capsules. The fourth class
comprises swellable systems where active compound is released by
swelling and extrusion of the core components out through a
passageway in a coating or surrounding shell or outer layer. Each
of the different types of sustained release dosage forms can be
used to administer a GHSEC in accordance with the present invention
to achieve the desired C.sub.max and/or .DELTA.T criteria that
provides for, over time, increased IGF-1 plasma levels and
decreased or normal GH plasma levels when compared with baseline
plasma levels.
[0140] A first class includes matrix systems, in which a GHSEC is
dissolved, embedded or dispersed in a matrix of another material
that serves to retard the release of the GHSEC into an aqueous
environment [e.g., the lumenal fluid of the gastrointestinal tract
(GI)]. When a GHSEC is dissolved, embedded or dispersed in a matrix
of this sort, release of the active compound takes place
principally from the surface of the matrix. Thus, the GHSEC is
released from the surface of a device which incorporates the matrix
after it diffuses through the matrix into the surrounding fluid or
when the surface of the device dissolves or erodes, exposing the
active compound. In some embodiments, both mechanisms can operate
simultaneously. The matrix systems may be large, i.e., tablet sized
(about 1 cm), or small (<0.3 cm). The system may be unitary, it
may be divided by virtue of being composed of several sub-units
(for example, several tablets which constitute a single dose) which
are administered substantially simultaneously, it may consist of
several small tablets within a capsule, or it may comprise a
plurality of particles, referred to herein as a multiparticulate. A
multiparticulate can have numerous formulation applications. For
example, a multiparticulate may be used as small beads or as powder
for filling a capsule shell, it may be compressed into a tablet, or
it may be used per se for mixing with food (for example, ice cream)
to increase palatability, or as a sachet that may be dispersed in a
liquid, such as fruit juice or water.
[0141] The multiplicity of variables affecting release of a GHSEC
from matrix devices permits abundant flexibility in the design of
devices of different materials, sizes, and release times.
[0142] Non-eroding matrix tablets that provide sustained release of
a GHSEC can be made with a GHSEC and water insoluble materials such
as waxes, cellulose, or other water insoluble polymers. Matrix
materials useful for the manufacture of these dosage forms include
microcrystalline cellulose such as Avicel.RTM. (FMC Corp.,
Philadelphia, Pa.), including grades of microcrystalline cellulose
to which binders such as hydroxypropyl methyl cellulose have been
added, waxes such as paraffin, modified vegetable oils, carnauba
wax, hydrogenated castor oil, beeswax, and the like, as well as
polymers such as cellulose, cellulose esters, cellulose ethers,
poly(vinyl chloride), poly(vinyl acetate), copolymers of vinyl
acetate and ethylene, polystyrene, and the like. Water soluble
binders or release modifying agents which can optionally be
formulated into the matrix include water-soluble polymers such as
hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose
(HPMC), methyl cellulose, poly (N-vinyl-2-pyrrolidinone) (PVP),
poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), xanthan gum,
carrageenan, and other such natural and synthetic materials. In
addition, materials that function as release-modifying agents
include water-soluble materials such as sugars or salts. Preferred
water-soluble materials include lactose, sucrose, glucose, and
mannitol, as well as HPC, HPMC, and PVP. In addition, solubilizing
acid excipients such as organic acids including but not limited to
malic acid, citric acid, erythorbic acid, ascorbic acid, adipic
acid, glutamic acid, maleic acid, aconitic acid, fumaric acid,
succinic acid, tartaric acid, and aspartic acid and solubilizing
excipients such as sodium bitartrate and cyclodextrins, can be
incorporated into matrix tablets to increase the release rate of
the GHSEC, increase the total quantity of the GHSEC released, and
potentially increase absorption and consequently the
bioavailability of the GHSEC, particularly from matrix formulations
that release the GHSEC over a period of six hours or longer.
[0143] In addition to components of the matrix system, the size of
the matrix system can affect the rate of GHSEC release; therefore,
a large matrix system such as a tablet will, in general, have a
different composition from a small one such as a multiparticulate
to achieve similar release profiles. The effect of the size of the
matrix system on the kinetics of GHSEC release follows scaling
behavior well known to those skilled in the art. By way of
illustration, the following table shows the diffusion coefficient
of a GHSEC through the matrix required to achieve a characteristic
time for release of 10 hours for matrix systems of different sizes
that release a GHSEC by a diffusive-based mechanism (rather than an
eroding or in combination with an eroding mechanism).
5 radius (cm) diffusion coefficient (cm.sup.2/sec) 0.0025 (50 .mu.m
diameter) 1.7 .times. 10.sup.-10 0.1 (2 mm diameter) 3 .times.
10.sup.-7 0.5 (1 cm diameter) 7 .times. 10.sup.-6
[0144] The above table illustrates that diffusion coefficients
necessary to achieve the target characteristic time of release can
change by orders of magnitude as the desired size of the device
changes. Matrix materials that can be used to provide a GHSEC
diffusion coefficient at the low end of the diffusion coefficient
scale are polymers such as cellulose acetate. Conversely, materials
at the upper end of the scale are materials such as polymers that
form hydrogels or a water-swollen mass when hydrated. The rate of
diffusion for any particular device can accordingly be tailored by
the material or materials selected and the structure of the
matrix.
[0145] For purposes of further illustration, to obtain a sustained
release non-eroding matrix in a particle of about 50 .mu.m in
diameter, a matrix material of a polymer such as cellulose acetate
or a similar material will likely be required, the slow diffusing
matrix material tending to offset the short distances
characteristic of small particle size. In contrast, in order to
obtain sustained release in a large (e.g., 1 cm) device, a material
which is more liquid-like (e.g., a hydrogel or water-soluble
polymer) or with greater porosity will likely be required. For
devices of an intermediate size, e.g., about 1 mm in diameter, a
matrix composition of intermediate characteristics can be
employed.
[0146] It is also noted that the effective diffusion coefficient of
a GHSEC in a matrix may be increased to the desired value by the
addition of plasticizers, pores, or pore-inducing additives, as
known in the art. Slowly hydrating materials may also be used to
effectively reduce the diffusion rates of a GHSEC, particularly at
times shortly after administration. In addition to changing the
effective diffusion coefficient, the release rate can also be
altered by the inclusion of more soluble salt forms of the GHSEC
(relative to the free base form) or excipients such as acids that
solubilize the GHSEC.
[0147] A further sustained release non-eroding matrix system
comprises a GHSEC dispersed in a hydrogel matrix. This embodiment
differs from the hydrophilic matrix tablet in that the hydrogel of
this embodiment is not a compressed tablet of soluble or erodible
granular material, but rather is a monolithic polymer network. As
is known in the art, a hydrogel is a water-swellable network
polymer. Hydrogels can be made in many geometries, such as caplets,
tablets, and multiparticulates. As an example, tablets can be
prepared by standard techniques containing 10 to 80% of a
crosslinkable polymer. Once tablets are formed the polymer can be
crosslinked via a chemical crosslinking agent such as
gluteraldehyde or via UV irradiation forming a hydrogel matrix.
Hydrogels are preferred materials for matrix devices because they
can absorb or be made to contain a large volume fraction of water,
thereby permitting diffusion of solvated active compound within the
matrix. Diffusion coefficients of active compounds in hydrogels are
characteristically high, and for highly water-swollen gels, the
diffusion coefficient of the active compound in the gel may
approach the value in pure water. This high diffusion coefficient
permits practical release rates from relatively large devices
(i.e., it is not necessary to form microparticles). Although
hydrogel devices can be prepared, loaded with a GHSEC, stored,
dispensed and dosed in the fully hydrated state, it is preferred
that they be stored, dispensed, and dosed in a dry state. In
addition to stability and convenience, dry state dosing of hydrogel
devices can provide good GHSEC release kinetics due to Case II
transport (i.e., combination of swelling of hydrogel and diffusion
of active compound out through the swollen hydrogel). Preferred
materials for forming hydrogels include hydrophilic vinyl and
acrylic polymers, polysaccharides such as calcium alginate, and
poly(ethylene oxide). Especially preferred are poly(2-hydroxyethyl
methacrylate), poly(acrylic acid), poly(methacrylic acid),
poly(N-vinyl-2-pyrolidinone), poly(vinyl alcohol) and their
copolymers with each other and with hydrophobic monomers such as
methyl methacrylate, vinyl acetate, and the like. Also preferred
are hydrophilic polyurethanes containing large poly(ethylene oxide)
blocks. Other preferred materials include hydrogels comprising
interpenetrating networks of polymers, which may be formed by
addition or by condensation polymerization, the components of which
may comprise hydrophilic and hydrophobic monomers such as those
just enumerated.
[0148] Non-eroding matrix tablets can be made by tabletting methods
common in the pharmaceutical industry. Preferred embodiments of
non-eroding matrix tablets contain about 1 to about 80% GHSEC,
about 5 to about 50% insoluble matrix materials such as cellulose,
cellulose acetate, or ethylcellulose, and optionally about 5 to
about 85% plasticizers, pore formers or solubilizing excipients,
and optionally about 0.25 to about 2% of a tabletting lubricant,
such as magnesium stearate, sodium stearyl fumarate, zinc stearate,
calcium stearate, stearic acid, polyethyleneglycol-8000, talc, or
mixtures of magnesium stearate with sodium lauryl sulfate. These
materials can be blended, granulated, and tabletted using a variety
of equipment common to the pharmaceutical industry.
[0149] A non-eroding matrix multiparticulate comprises a plurality
of GHSEC-containing particles, each particle comprising a mixture
of GHSEC with one or more excipients selected to form a matrix
capable of limiting the dissolution rate of the GHSEC into an
aqueous medium. The matrix materials useful for this embodiment are
generally water-insoluble materials such as triglycerides, waxes,
cellulose, or other water-insoluble polymers. If needed, the matrix
materials may optionally be formulated with water-soluble materials
that can be used as binders or as permeability-modifying agents.
Matrix materials useful for the manufacture of these dosage forms
include microcrystalline cellulose such as Avicel.RTM. (FMC Corp.,
Philadelphia, Pa.), including grades of microcrystalline cellulose
to which binders such as hydroxypropyl methyl cellulose have been
added, waxes such as paraffin, modified vegetable oils, carnauba
wax, hydrogenated castor oil, beeswax, and the like, as well as
synthetic polymers such as poly(vinyl chloride), poly(vinyl
acetate), copolymers of vinyl acetate and ethylene, polystyrene,
and the like. Water soluble release modifying agents that can
optionally be formulated into the matrix include water-soluble
polymers such as HPC, HPMC, methyl cellulose, PVP, PEO, PVA,
xanthan gum, carrageenan, and other such natural and synthetic
materials. In addition, materials that function as
release-modifying agents include water-soluble materials such as
sugars or salts. Preferred water-soluble materials include lactose,
sucrose, glucose, and mannitol, as well as HPC, HPMC, and PVP. In
addition, any of the solubilizing acids or excipients previously
mentioned can be incorporated into matrix multiparticulates to
increase the release rate of the GHSEC, increase the total quantity
of the GHSEC released, and potentially increase absorption and
consequently the bioavailability of the GHSEC, particularly from
matrix formulations that release the GHSEC over a period of six
hours or longer.
[0150] A preferred process for manufacturing matrix
multiparticulates is the extrusion/spheronization process. For this
process, the GHSEC is wet-massed with a binder, extruded through a
perforated plate or die, and placed on a rotating disk. The
extrudate ideally breaks into pieces, which are rounded into
spheres, spheroids, or rounded rods on the rotating plate. A
preferred process and composition for this method involves using
water to wet-mass a blend comprising about 20 to about 99% of
microcrystalline cellulose blended with, correspondingly, about 80
to about 1% GHSEC.
[0151] A preferred process for manufacturing matrix
multiparticulates is the rotary granulation process. For this
process the GHSEC and excipients such as microcrystalline cellulose
are placed in a rotor bowl in a fluid-bed processor. The active
compound and excipient are fluidized, while spraying a solution
that binds the active compound and excipients together in granules
or multiparticulates. The solution sprayed into the fluid bed can
be water or aqueous solutions or suspensions of binding agents such
as polyvinylpyrrolidone or hydroxypropylmethylcellulose. A
preferred composition for this method can comprise about 1 to about
80% GHSEC, about 10 to about 60% microcrystalline cellulose, and
about 0 to about 25% binding agent.
[0152] A further preferred process for manufacturing matrix
multiparticulates involves coating the GHSEC, matrix-forming
excipients, and if desired, release-modifying or solubilizing
excipients onto seed cores such as sugar seed cores known as
non-pareils. Such coatings can be applied by many methods known in
the pharmaceutical industry, such as spray-coating in a fluid bed
coater, spray-drying, and granulation methods such as fluid bed or
rotary granulation. Coatings can be applied from aqueous, organic
or melt solutions or suspensions.
[0153] A further preferred process for manufacturing matrix
multiparticulates is the preparation of wax granules via a
melt-congeal process. In this process, a desired amount of the
GHSEC is stirred with liquid wax to form a homogeneous mixture,
cooled and then forced through a screen to form granules.
Alternatively, the homogeneous mixture can be fed to a spinning
disc where the mixture is broken up into droplets as it is spun off
the edges of the disc. These droplets are then cooled, and solidify
before landing in a collection chamber. Preferred matrix materials
are waxy substances. Especially preferred are hydrogenated castor
oil, glyceryl behenate, microcrystalline wax, carnauba wax, and
stearyl alcohol.
[0154] A further preferred process for manufacturing matrix
multiparticulates involves using an organic solvent to aid mixing
of the GHSEC with the matrix material. This technique can be used
when it is desired to utilize a matrix material with an unsuitably
high melting point that, if the material were employed in a molten
state, would cause decomposition of the active compound or of the
matrix material, or would result in an unacceptable melt viscosity,
thereby preventing mixing of the GHSEC with the matrix material.
GHSEC and matrix material may be combined with a modest amount of
solvent to form a paste, and then forced through a screen to form
granules from which the solvent is then removed. Alternatively, the
GHSEC and matrix material may be combined with enough solvent to
completely dissolve the matrix material and the resulting solution
(which may contain solid active compound particles) spray dried to
form the particulate dosage form. This technique is preferred when
the matrix material is a high molecular weight synthetic polymer
such as a cellulose ether or cellulose ester. Solvents typically
employed for the process include acetone, ethanol, isopropanol,
ethyl acetate, and mixtures of two or more.
[0155] A further process for manufacturing matrix multiparticulates
involves using an aqueous solution or suspension of the GHSEC and
matrix forming materials. The solution or suspension can be spray
dried or sprayed or dripped into a quench bath or through a light
chamber to initiate crosslinking of matrix materials and solidify
the droplets. In this manner matrices can be made from latexes
(e.g., dispersed ethyl cellulose with a plasticizer such as oleic
acid or with a volatile water miscible solvent such as acetone or
ethanol) by spray-drying techniques. Matrices can also be made in
this manner by crosslinking a water soluble polymer or gum. For
example, sodium alginate can be crosslinked by spraying into a
solution containing soluble calcium salts, polyvinyl alcohol can be
crosslinked by spraying into a solution containing gluteraldehyde,
and di- and tri-acrylates can be crosslinked by UV irradiation.
[0156] Once formed, GHSEC matrix multiparticulates may be blended
with compressible excipients such as lactose, mannitol,
microcrystalline cellulose, dicalcium phosphate, and the like and
the blend compressed to form a tablet. Disintegrants such as sodium
starch glycolate, sodium croscarmellose, or crosslinked poly(vinyl
pyrrolidone) are also usefully employed. Tablets prepared by this
method disintegrate when placed in an aqueous medium (such as the
GI tract), thereby exposing the multiparticulate matrix, which
releases the GHSEC. GHSEC matrix multiparticulates may also be
filled into capsules, such as hard gelatin capsules.
Multiparticulates can also be directly dosed as a sachet that is
mixed with water or other suitable drink, or can be sprinkled
directly on food.
[0157] A further embodiment of a matrix system has the form of a
hydrophilic matrix tablet containing a GHSEC that eventually
dissolves or disperses in water and an amount of hydrophilic
polymer sufficient to provide a useful degree of control over the
release of GHSEC. GHSEC can be released from such matrices by
diffusion, erosion or dissolution of the matrix, or a combination
of these mechanisms. Hydrophilic polymers useful for forming a
hydrophilic matrix include HPMC, HPC, hydroxy ethyl cellulose
(HEC), PEO, PVA, polyacrylic acid, xanthan gum, carbomer,
carrageenan, and zooglan. A preferred material is HPMC. Other
similar hydrophilic polymers may also be employed. In use, the
hydrophilic material is swollen by, and eventually dissolves or
disperses in, water. The GHSEC release rate from hydrophilic matrix
formulations may be controlled by the amount and molecular weight
of hydrophilic polymer employed. In general, using a greater amount
of the hydrophilic polymer decreases the release rate, as does
using a higher molecular weight polymer. Using a lower molecular
weight polymer increases the release rate. The release rate may
also be controlled by the use of water-soluble additives such as
sugars, salts, or soluble polymers. Examples of these additives are
sugars such as lactose, sucrose, or mannitol, salts such as NaCl,
KCl, NaHCO.sub.3, and water soluble polymers such as PVP, low
molecular weight HPC or HMPC or methyl cellulose. In general,
increasing the fraction of soluble material in the formulation
increases the release rate. In addition, any of the solubilizing
acid excipients previously mentioned can be incorporated into
matrix tablets to increase the release rate of GHSEC, increase the
total quantity of GHSEC released, and potentially increase
absorption and consequently the bioavailability of GHSEC,
particularly from matrix formulations that release GHSEC over a
period of six hours or longer. A hydrophilic matrix tablet
typically comprises about 1 to about 90% by weight of the GHSEC and
about 80 to about 10% by weight of polymer.
[0158] A preferred hydrophilic matrix tablet comprises, by weight,
about 3% to about 80% GHSEC, about 5% to about 35% HPMC, about 0%
to about 55% lactose or mannitol, about 0% to about 15% PVP, about
0% to about 20% microcrystalline cellulose, and about 0.25% to
about 2% magnesium stearate.
[0159] Mixtures of polymers and/or gums can also be utilized to
make hydrophilic matrix systems. For example, homopolysaccharide
gums such as galactomannans (e.g., locust bean gum or guar gum)
mixed with heteropolysaccharide gums (e.g., xanthan gum or its
derivatives) can provide a synergistic effect that in operation
provides faster forming and more rigid matrices for the release of
active compound (See, for example, U.S. Pat. Nos. 5,455,046 and
5,512,297). Optionally, crosslinking agents such as calcium salts
can be added to improve matrix properties.
[0160] Hydrophilic matrix formulations that eventually dissolve or
disperse can also be made in the form of multiparticulates.
Hydrophilic matrix multiparticulates can be manufactured by the
techniques described previously for non-eroding matrix
multiparticulates. Preferred methods of manufacture are layering
GHSEC, a hydrophilic matrix material, and if desired release
modifying agents onto seed cores (e.g., non-pareils) via a
spray-coating process or forming multiparticulates by granulation,
such as by rotary granulation of GHSEC, hydrophilic matrix
material, and if desired, release modifying agents.
[0161] The matrix systems as a class often exhibit non-constant
release of the active compound from the matrix. This result may be
a consequence of the diffusive mechanism of active compound
release, and modifications to the geometry of the dosage form
and/or coating or partially coating the dosage form can be used to
advantage to make the release rate of the active compound more
constant as detailed below.
[0162] In a further embodiment, a GHSEC matrix tablet is coated
with an impermeable coating, and an orifice (for example, a
circular hole or a rectangular opening) is provided by which the
content of the tablet is exposed to the aqueous GI tract. These
embodiments are along the lines of those presented in U.S. Pat. No.
4,792,448 to Ranade, and as described by Hansson et al., J. Pharm.
Sci., 77 (1988) 322-324. The opening is typically of a size such
that the area of the exposed underlying GHSEC constitutes less than
about 40% of the surface area of the device, preferably less than
about 15%.
[0163] In another embodiment, a GHSEC matrix tablet is coated with
an impermeable material on part of its surface, e.g., on one or
both tablet faces, or on the tablet radial surface.
[0164] In another embodiment, a GHSEC matrix tablet is coated with
an impermeable material and an opening for active compound
transport produced by drilling a hole through the coating. The hole
may be through the coating only, or may extend as a passageway into
the tablet.
[0165] In another embodiment, a GHSEC matrix tablet is coated with
an impermeable material and a passageway for active compound
transport produced by drilling a passageway through the entire
tablet.
[0166] In another embodiment, a GHSEC matrix tablet is coated with
an impermeable material and one or more passageways for active
compound transport are produced by removing one or more strips from
the impermeable coating or by cutting one or more slits through the
coating, preferably on the radial surface or land of the
tablet.
[0167] In another embodiment, a GHSEC matrix tablet is shaped in
the form of a cone and completely coated with an impermeable
material. A passageway for active compound transport is produced by
cutting off the tip of the cone.
[0168] In another embodiment, a GHSEC matrix tablet is shaped in
the form of a hemisphere and completely coated with an impermeable
material. A passageway for active compound transport is produced by
drilling a hole in the center of the flat face of the
hemisphere.
[0169] In another embodiment, a GHSEC matrix tablet is shaped in
the form of a half-cylinder and completely coated with an
impermeable material. A passageway for GHSEC transport is produced
by cutting a slit through (or removing a strip from) the
impermeable coating along the axis of the half-cylinder along the
centerline of the flat face of the half-cylinder. Those skilled in
the art will appreciate that the geometric modifications to the
embodiments described above can be equivalently produced by more
than one method.
[0170] By "impermeable material" is meant a material having
sufficient thickness and impermeability to GHSEC such that the
majority of GHSEC is released through the passageway rather than
through the "impermeable material" during the time scale of the
intended active compound release. Such a coating can be obtained by
selecting a coating material with a sufficiently low diffusion
coefficient for GHSEC and applying it sufficiently thickly.
Materials for forming the impermeable coating of these embodiments
include substantially all materials in which the diffusion
coefficient of the GHSEC is less than about 10.sup.-7 cm.sup.2/sec.
It is noted that the preceding diffusion coefficient can be amply
sufficient to allow release of GHSEC from a matrix device, as
discussed above. However, for a device of the type now under
discussion that has been provided with a macroscopic opening or
passageway, a material with this diffusion coefficient is
effectively impermeable to GHSEC relative to GHSEC transport
through the passageway. Preferred coating materials include
film-forming polymers and waxes. Especially preferred are
thermoplastic polymers, such as poly(ethylene-co-vinyl acetate),
poly(vinyl chloride), ethylcellulose, and cellulose acetate. These
materials exhibit the desired low permeation rate of GHSEC when
applied as coatings of thickness greater than about 100 .mu.m.
[0171] A second class of GHSEC sustained-release dosage forms of
the present invention includes membrane-moderated or reservoir
systems such as membrane-coated diffusion-based capsule, tablet, or
multiparticulate. Capsules, tablets and mutiparticulates can all be
reservoir systems, such as membrane-coated diffusion-based. In this
class, a reservoir of GHSEC is surrounded by a rate-limiting
membrane. The GHSEC traverses the membrane by mass transport
mechanisms well known in the art, including but not limited to
dissolution in the membrane followed by diffusion across the
membrane or diffusion through liquid-filled pores within the
membrane. These individual reservoir system dosage forms may be
large, as in the case of a tablet containing a single large
reservoir, or multiparticulate, as in the case of a capsule
containing a plurality of reservoir particles, each individually
coated with a membrane. The coating can be non-porous, yet
permeable to GHSEC (for example, GHSEC may diffuse directly through
the membrane), or it may be porous.
[0172] Sustained release coatings as known in the art may be
employed to fabricate the membrane, especially polymer coatings,
such as a cellulose ester or ether, an acrylic polymer, or a
mixture of polymers. Preferred materials include ethyl cellulose,
cellulose acetate and cellulose acetate butyrate. The polymer may
be applied as a solution in an organic solvent or as an aqueous
dispersion or latex. The coating operation may be conducted in
standard equipment such as a fluid bed coater, a Wurster coater, or
a rotary bed coater.
[0173] If desired, the permeability of the coating may be adjusted
by blending of two or more materials. A particularly useful process
for tailoring the porosity of the coating comprises adding a
pre-determined amount of a finely-divided water-soluble material,
such as sugars or salts or water-soluble polymers to a solution or
dispersion (e.g., an aqueous latex) of the membrane-forming polymer
to be used. When the dosage form is ingested into the aqueous
medium of the GI tract, these water soluble membrane additives are
leached out of the membrane, leaving pores that facilitate release
of the active compound. The membrane coating can also be modified
by the addition of plasticizers, as known in the art.
[0174] A particularly useful variation of the process for applying
a membrane coating comprises dissolving the coating polymer in a
mixture of solvents chosen such that as the coating dries, a phase
inversion takes place in the applied coating solution, resulting in
a membrane with a porous structure. Numerous examples of this type
of coating system are given in U.S. Pat. No. 5,612,059.
[0175] The morphology of the membrane is not of critical importance
so long as the permeability characteristics enumerated herein are
met. However, specific membrane designs will have membrane
morphology constraints in order to achieve the desired
permeability. The membrane can be amorphous or crystalline. It can
have any category of morphology produced by any particular process
and can be, for example, an interfacially-polymerized membrane
(which comprises a thin rate-limiting skin on a porous support), a
porous hydrophilic membrane, a porous hydrophobic membrane, a
hydrogel membrane, an ionic membrane, and other such membrane
designs which are characterized by controlled permeability to
GHSEC.
[0176] A useful reservoir system embodiment is a capsule having a
shell comprising the material of the rate-limiting membrane,
including any of the membrane materials previously discussed, and
filled with a GHSEC active compound composition. A particular
advantage of this configuration is that the capsule may be prepared
independently of the active compound composition, thus process
conditions that would adversely affect the active compound can be
used to prepare the capsule. A preferred embodiment is a capsule
having a shell made of a porous or a permeable polymer made by a
thermal forming process. An especially preferred embodiment is a
capsule shell in the form of an asymmetric membrane; i.e., a
membrane that has a thin dense region on one surface and most of
whose thickness is constituted of a highly permeable porous
material. A preferred process for preparation of asymmetric
membrane capsules comprises a solvent exchange phase inversion,
wherein a solution of polymer, coated on a capsule-shaped mold, is
induced to phase-separate by exchanging the solvent with a miscible
non-solvent. Examples of asymmetric membranes useful in this
invention are disclosed in U.S. Pat. Nos. 5,698,220 and
5,612,059.
[0177] Tablets can also be reservoir systems. Tablet cores
containing GHSEC can be made by a variety of techniques standard in
the pharmaceutical industry. These cores can be coated with a
rate-controlling coating as described above, which allows the GHSEC
in the reservoir (tablet core) to diffuse out through the coating
at the desired rate.
[0178] Another embodiment of reservoir systems comprises a
multiparticulate wherein each particle is coated with a polymer
designed to yield sustained release of GHSEC. The multiparticulate
particles each comprise GHSEC and one or more excipients as needed
for fabrication and performance. The size of individual particles,
as previously mentioned, is generally between about 50 .mu.m and
about 3 mm, although beads of a size outside this range may also be
useful. In general, the beads comprise GHSEC and one or more
binders. As it is generally desirable to produce dosage forms that
are small and easy to swallow, beads that contain a high fraction
of GHSEC relative to excipients are preferred. Binders useful in
fabrication of these beads include microcrystalline cellulose
(e.g., Avicel.RTM., FMC Corp.), HPC, HPMC, and related materials or
combinations thereof. In general, binders that are useful in
granulation and tabletting, such as starch, pregelatinized starch,
and PVP may also be used to form multiparticulates.
[0179] Reservoir system. GHSEC multiparticulates may be prepared
using techniques known to those skilled in the art, including, but
not limited to, the techniques of extrusion and spheronization, wet
granulation, fluid bed granulation, melt-congealing, and rotary bed
granulation. In addition, the beads may also be prepared by
building the GHSEC composition (GHSEC plus excipients) up on a seed
core (such as a non-pareil seed) by an active compound-layering
technique such as powder coating or by applying the GHSEC
composition by spraying a solution or dispersion of GHSEC in an
appropriate binder solution onto seed cores in a fluidized bed such
as a Wurster coater or a rotary processor. An example of a suitable
composition and method is to spray a dispersion of a
GHSEC/hydroxypropylcellulose composition in water.
[0180] A preferred method for manufacturing the multiparticulate
cores of this embodiment is the extrusion/spheronization process,
as previously discussed for matrix multiparticulates. A preferred
process and composition for this method involves using water to
wet-mass a blend of about 5 to about 99% of microcrystalline
cellulose with correspondingly about 95 to about 1% GHSEC.
Especially preferred is the use of about 95 to about 50%
microcrystalline cellulose with correspondingly about 5 to about
50% GHSEC.
[0181] A preferred process for making multiparticulate cores of
this embodiment is the rotary-granulation process, as previously
discussed for matrix multiparticulates.
[0182] Another preferred process for making multiparticulate cores
of this embodiment is the melt-congeal process, as previously
discussed for matrix multiparticulates.
[0183] Another preferred process for making multiparticulate cores
of this embodiment is the process of coating seed cores with GHSEC
and optionally other excipients, as previously discussed for matrix
multiparticulates.
[0184] A sustained release coating as is known in the art,
especially polymer, coatings, may be employed to fabricate the
membrane, as previously discussed for reservoir systems. Suitable
and preferred polymer coating materials, equipment, and coating
methods also include those previously discussed.
[0185] The rate of GHSEC release from the coated multiparticulates
can also be controlled by factors such as the composition and
binder content of the active compound-containing core, the
thickness and permeability of the coating, and the
surface-to-volume ratio of the multiparticulates. It will be
appreciated by those skilled in the art that increasing the
thickness of the coating will decrease the release rate, whereas
increasing the permeability of the coating or the surface-to-volume
ratio of the multiparticulates will increase the release rate. If
desired, the permeability of the coating may be adjusted by
blending of two or more materials. A useful series of coatings
comprises mixtures of water-insoluble and water-soluble polymers,
for example, ethylcellulose and hydroxypropyl methylcellulose,
respectively. A particularly useful modification to the coating is
the addition of finely-divided water-soluble material, such as
sugars or salts. When placed in an aqueous medium, these water
soluble membrane additives are leached out of the membrane, leaving
pores that facilitate delivery of the active compound. The membrane
coating may also be modified by the addition of plasticizers, as is
known to those skilled in the art. A particularly useful variation
of the membrane coating utilizes a mixture of solvents chosen such
that as the coating dries, a phase inversion takes place in the
applied coating solution, resulting in a membrane with a porous
structure.
[0186] A preferred embodiment is a multiparticulate with cores
comprising about 1 to about 50% GHSEC and about 10 to about 70% of
one or more of the following: microcrystalline cellulose, lactose,
mannitol, glyceryl behenate, stearyl alcohol, microcrystalline wax,
PVP, HPC and HPMC. The individual cores are coated with either an
aqueous dispersion of ethyl cellulose, which dries to form a
continuous film, or a film of cellulose acetate containing PEG,
sorbitol or glycerol as a release-modifying agent.
[0187] A third class of GHSEC sustained-release dosage forms
includes the osmotic delivery devices or "osmotic pumps" as they
are known in the art. Osmotic pumps comprise a core containing an
osmotically effective composition surrounded by a semipermeable
membrane. The term "semipermeable" in this context means that water
can pass through the membrane, but solutes dissolved in the core
permeate through the membrane at a rate significantly slower than
water. In use, when placed in an aqueous environment, the device
imbibes water due to the osmotic activity of the core composition.
Owing to the semipermeable nature of the surrounding membrane, the
contents of the device (including the active compound and any
excipients) cannot pass through the non-porous regions of the
membrane and are driven by osmotic pressure to leave the device
through an opening or passageway pre-manufactured into the dosage
form or, alternatively, formed in situ in the GI tract as by the
bursting of intentionally-incorporated weak points in the coating
under the influence of osmotic pressure, or alternatively, formed
in situ in the GI tract by dissolution and removal of water-soluble
porosigens incorporated in the coating. The osmotically effective
composition includes water-soluble species that generate a
colloidal osmotic pressure, and water-swellable polymers. The
active compound itself (if highly water-soluble) may be an
osmotically effective component of the mixture.
2-Amino-N-[2-(3a-(R)-benz-
yl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R-
)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate, having
solubility in excess of 150 mg/ml, can provide an osmotic pressure
of about 4 atmospheres, enough to contribute some osmotic driving
force. Because this GHSEC is a base, its solubility is generally
higher at acidic pH. Therefore, the osmotic effectiveness of the
GHSEC is aided by presence of acidic buffers in the formulation.
The active compound composition may be separated from the
osmotically effective components by a movable partition or
piston.
[0188] Materials useful for forming the semipermeable membrane
include polyamides, polyesters, and cellulose derivatives.
Preferred are cellulose ethers and esters. Especially preferred are
cellulose acetate, cellulose acetate butyrate, and ethyl cellulose.
Especially useful materials include those that spontaneously form
one or more exit passageways, either during manufacturing or when
placed in an environment of use. These preferred materials comprise
porous polymers, the pores of which are formed by phase inversion
during manufacturing, as described below, or by dissolution of a
water-soluble component present in the membrane.
[0189] A class of materials that have particular utility for
forming semipermeable membranes for use in osmotic delivery devices
is that of porous hydrophobic polymers or vapor-permeable films, as
disclosed by U.S. Pat. No. 5,827,538. These materials are highly
permeable to water, but highly impermeable to solutes dissolved in
water. These materials owe their high water permeability to the
presence of numerous microscopic pores (i.e., pores that are much
larger than molecular dimensions). Despite their porosity, these
materials are impermeable to molecules in aqueous solution because
liquid water does not wet the pores. Water in the vapor phase is
easily able to pass across membranes made from these materials.
Such membranes are also known as vapor-permeable membranes.
[0190] A preferred embodiment of this class of osmotic delivery
devices consists of a coated bi-layer tablet. The coating of such a
tablet comprises a membrane permeable to water but substantially
impermeable to GHSEC and excipients contained within. The coating
contains one or more exit passageways in communication with the
GHSEC-containing layer for delivering the GHSEC. The tablet core
consists of two layers: one layer containing the GHSEC composition
(including optional osmotic agents and hydrophilic water-soluble
polymers) and another layer consisting of a water-swellable
material, with or without additional osmotic agents.
[0191] When placed in an aqueous medium, the tablet imbibes water
through the membrane, causing the GHSEC composition to form a
dispensible aqueous composition, and causing the swellable layer to
expand and push against the GHSEC composition, forcing the GHSEC
composition out of the exit passageway. The GHSEC composition can
swell aiding in forcing the GHSEC out the passageway. GHSEC can be
delivered from this type of delivery system either dissolved or
dispersed in the composition forced out of the exit passageway.
[0192] The rate of GHSEC delivery is controlled by such factors as
the permeability and thickness of the coating, the osmotic pressure
of the GHSEC-containing layer, the water activity of the swellable
layer, and the surface area of the device. Those skilled in the art
will appreciate that increasing the thickness of the coating will
reduce the release rate, whereas increasing the permeability of the
coating or the water activity of the hydrogel layer or the osmotic
pressure of the GHSEC-containing layer or the surface area of the
device will increase the release rate.
[0193] Exemplary materials that are useful to form the GHSEC
composition, in addition to the GHSEC itself, include HPMC, PEO,
and PVP, and other pharmaceutically-acceptable carriers. In
addition, osmotic agents such as sugars or salts, especially
sucrose, lactose, mannitol, or sodium bitartrate, may be added.
[0194] Materials that are useful for forming the swelling layer
include sodium carboxymethyl cellulose, poly(ethylene oxide),
poly(acrylic acid), sodium (poly-acrylate),
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
and other high molecular-weight hydrophilic materials. In addition,
osmagents such as sugars or salts may be added. Particularly useful
are poly(ethylene oxide)s having a molecular i weight from about
5,000,000 to about 7,500,000.
[0195] Materials that are useful for forming the coating are
cellulose esters, cellulose ethers, and cellulose ester-ethers.
Preferred are cellulose acetate and ethylcellulose and optionally
with PEG included as permeability modifying component.
[0196] The exit passageway must be located on the side of the
tablet containing the GHSEC composition. There may be more than one
such exit passageway. The exit passageway may be produced by
mechanical means or by laser drilling, or by creating a
difficult-to-coat region on the tablet by use of special tooling
during tablet compression or by other means. The rate of GHSEC
delivery from the device may be optimized so as to provide a method
of delivering GHSEC to a mammal for optimum therapeutic effect.
[0197] Osmotic systems can also be made with a homogeneous core
surrounded by a semipermeable membrane coating. GHSEC can be
incorporated into a tablet core that also contains other excipients
that provide sufficient osmotic driving force and optionally
solubilizing excipients such as acids. A semipermeable membrane
coating can be applied via conventional tablet-coating techniques
such as using a pan coater. An active compound-delivery passageway
can then be formed in this coating by drilling a hole in the
coating, either by use of a laser or other mechanical means.
Alternatively, the passageway may be formed by rupturing a portion
of the coating or by creating a region on the tablet that is
difficult to coat, as described above.
[0198] The core can consist of one or more pharmaceutically active
compounds, water-soluble compounds for inducing osmosis,
non-swelling solubilizing agents, non-swelling (water-soluble or
water-insoluble) wicking agents, swellable hydrophilic polymers,
binders and lubricants.
[0199] The osmotically active (water-soluble) agent is typically a
sugar alcohol such as mannitol or sorbitol, or sugars in
combination with polysaccharides such as dextrose and maltose, or a
physiologically tolerable ionic salt that is compatible with the
other components such as sodium or potassium chloride. Another
osmotic agent is urea. Examples of water-soluble compounds for
inducing osmosis are: inorganic salts such as magnesium chloride or
magnesium sulfate, lithium, sodium or potassium chloride, lithium,
sodium or potassium hydrogen or dihydrogen phosphate, salts of
organic acids such as sodium or potassium acetate, magnesium
succinate, sodium benzoate, sodium citrate or sodium ascorbate;
carbohydrates such as sorbitol or mannitol (hexite), arabinose,
dextrose, ribose or xylose (pentosene), glucose, fructose,
galactose or mannose (hexosene), sucrose, maltose or lactose
(disaccharides) or raffinose (trisaccharides); water-soluble amino
acids such as glycine, leucine, alanine or methionine, urea and the
like, and mixtures thereof. These water-soluble excipients may be
present in the core in amounts by weight of about 0.01 to about
45%, based on the total weight of the therapeutic system.
[0200] Non-swelling solubilizing agents include (a) agents that
inhibit crystal formation of the active agent or otherwise act by
complexation therewith; (b) high HLB (hydrophilic-lipophilic
balance) micelle-forming surfactants, particularly non-ionic and/or
anionic surfactants: (c) citrate esters; and combinations thereof,
particularly combinations of complexing agents and anionic
surfactants. Examples of agents that inhibit crystal formation of
the active agent or otherwise acts by complexation therewith
include polyvinylpyrrolidone, polyethyleneglycol (particularly PEG
8000), cyclodextrins and modified cyclodextrins. Examples of high
HLB, micelle forming surfactants include Tween 20, Tween 60, Tween
80, polyoxyethylene or polyethylene-containing surfactants, or
other long chain anionic surfactants, particularly sodium lauryl
sulfate. Examples of citrate ester derivatives that are preferred
are the alkyl esters, particularly triethyl citrate. Combinations
of these that are particularly preferred are polyvinylpyrrolidone
with sodium lauryl sulfate and polyethyleneglycol with sodium
lauryl sulfate.
[0201] Non-swelling wicking (wetting) agents are used to create
channels or pores in the core of the tablet. This facilitates
channeling of water through the core by physisorption. Preferred
wicking agents do not swell to any appreciable degree. These
materials can be water soluble or water insoluble materials.
Water-soluble materials suitable for acting as wicking (wetting)
agents include surface-active compounds, i.e., surfactants, e.g.,
anionic surfactants of the alkylsulfate type such as sodium,
potassium or magnesium lauryl sulfate, n-tetradecylsulfate,
n-hexadecyl sulfate or n-octadecylsulfate; of the alkyl ether
sulfate type, e.g., sodium, potassium or magnesium
n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate,
n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl sulfate; or of
the alkylsulfonate type, e.g. sodium potassium or magnesium
n-dodecanesulfonate, n-tetradecanesulfonate, n-hexadecanesulfonate
or n-octadecanesulfonate. Further suitable surfactants are nonionic
surfactants of the fatty acid polyhydoxy alcohol ester type such as
sorbitan monolaurate, sorbitan tristerate or triolate, polyethylene
glycol fatty acid ester such as polyoxyethyl stearate, polyethylene
glycol 400 stearate, polyethylene glycol 2000 stearate, preferably
polyethylene oxide/propylene oxide block copolymers of the
Pluronic.RTM. (BASF, Parsippany, N.J.) or Synperonic.RTM. (ICI
Surfactants, Everberg, Belgium) type, polyglycerol-fatty acid
esters or glyceryl-fatty acid esters. Especially suitable is sodium
lauryl sulfate. When present, these surfactants should be
preferable present from about 0.2 to about 2% based on the total
core weight. Other soluble wicking (wetting) agents include low
molecular weight polyvinyl pyrrolidone and m-pyrol.
[0202] Insoluble materials suitable for acting as wicking (welting)
agents include, but are not limited to, colloidal silicon dioxide,
kaolin, titanium dioxide, fumed silicon dioxide, alumina,
niacinamide, bentonite, magnesium aluminum silicate, polyester,
polyethylene. Particularly suitable insoluble wicking agents
include colloidal silicon dioxide.
[0203] Suitable wall materials for forming the semi-permeable wall
include microporous materials described in U.S. Pat. Nos. 3,916,899
and 3,977,404. It is possible to use acylated cellulose derivatives
(cellulose esters) which are substituted by one to three acetyl
groups or by one or two acetyl groups and a further acyl other than
acetyl, e.g., cellulose acetate, cellulose triacetate, agar
acetate, amylose acetate, beta glucan acetate, beta glucan
triacetate, ethyl cellulose, cellulose acetate ethyl carbamate,
cellulose acetate phthalate, cellulose acetate methyl carbamate,
cellulose acetate succinate, cellulose acetate dimethylaminoaceate,
cellulose acetate ethyl carbonate, cellulose acetate chloroacetate,
cellulose acetate ethyl oxalate, cellulose acetate methylsulfonate,
cellulose acetate butyl sulfonate, cellulose acetate propionate,
cellulose acetate octate, cellulose acetate laurate, cellulose
acetate p-toluenesulfonate, cellulose acetate butyrate, and other
cellulose acetate derivatives. Suitable semi-permeable membrane
materials are also triacetate of locust bean gum, methyl cellulose,
hydroxypropyl methylcellulose and polymeric epoxides, copolymers of
alkylene oxides, poly(vinyl methyl) ether polymers and alkyl
glycidyl ethers, polyglycols or polylactic acid derivatives and
further derivatives thereof. It is also possible to use mixtures of
insoluble polymers, which when coated form a semi-permeable film,
e.g. water insoluble acrylates, e.g., the copolymer of ethyl
acrylate and methyl methacrylate.
[0204] A second, water-soluble component can be added to increase
the permeability of the coating. Preferred water-soluble components
are C.sub.2-C.sub.4 alkylene glycol, preferably polyethylene
glycol.
[0205] An embodiment of GHSEC sustained release osmotic dosage
forms of this invention comprises an osmotic GHSEC-containing
tablet, which is surrounded by an asymmetric membrane, where said
asymmetric membrane possesses one or more thin dense regions in
addition to less dense porous regions. This type of membrane,
similar to those used in the reverse-osmosis industry, generally
allows higher osmotic fluxes of water than can be obtained with a
dense membrane. When applied to a active compound formulation,
e.g., a tablet, an asymmetric membrane allows high active compound
fluxes and well-controlled sustained active compound release. This
asymmetric membrane comprises a semipermeable polymeric material,
that is, a material which is permeable to water, and substantially
impermeable to salts and organic solutes such as a GHSEC.
[0206] Materials useful for forming, the semipermeable membrane
include polyamides, polyesters, and cellulose derivatives.
Preferred are cellulose ethers and esters. Especially preferred are
cellulose acetate, cellulose acetate butyrate, and ethyl cellulose.
Especially useful materials include those which spontaneously form
one or more exit passageways, either during manufacturing or when
placed in an environment of use. These preferred materials comprise
porous polymers, the pores of which are formed by phase inversion
during manufacturing, as described above, or by dissolution of a
water-soluble component present in the membrane.
[0207] The asymmetric membrane is formed by a phase-inversion
process. The coating polymer, e.g., ethylcellulose or cellulose
acetate, is dissolved in a mixed solvent system comprising a
mixture of solvents (e.g., acetone) and non-solvents (e.g., water)
for the ethylcellulose or cellulose acetate. The components of the
mixed solvent are chosen such that the solvent (e.g., acetone) is
more volatile than the non-solvent (e.g., water). When a tablet is
dipped into such a solution, removed and dried, the solvent
component of the solvent mixture evaporates more quickly than the
non-solvent. This change in solvent composition during drying
causes a phase-inversion, resulting in precipitation of the polymer
on the tablet as a porous solid with a thin dense outer region.
This outer region possesses multiple pores through which active
compound delivery can occur.
[0208] In a preferred embodiment of an asymmetric membrane-coated
tablet, the polymer/solvent/non-solvent mixture is sprayed onto a
bed of tablets in a tablet-coating apparatus such as a HCT-30
tablet coater (Vector Corporation, Marion, Iowa).
[0209] In the environment of use, e.g., the GI tract, water is
imbibed through the semipermeable asymmetric membrane into the
tablet core. As soluble material in the tablet core dissolves, an
osmotic pressure gradient across the membrane builds. When the
hydrostatic pressure within the membrane enclosed core exceeds the
pressure of the environment of use (e.g., the GI lumen), the
GHSEC-containing solution is "pumped" out of the dosage form
through preformed pores in the semipermeable membrane. The constant
osmotic pressure difference across the membrane results in a
constant well-controlled delivery of GHSEC to the use environment.
A portion of the GHSEC dissolved in the tablet also exits via
diffusion.
[0210] In this asymmetric-membrane-coated GHSEC tablet embodiment,
high solubility salts of GHSEC are preferred. Also preferred are
the inclusion of one or more solubilizing excipients, ascorbic
acid, erythorbic acid, citric acid, fumaric acid, succinic acid,
tartaric acid, sodium bitartrate, glutamic acid, aspartic acid,
partial glycerides, glycerides, glyceride derivatives, polyethylene
glycol esters, polypropylene glycol esters, polyhydric alcohol
esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylene
sorbitan esters, saccharide esters, phospholipids, polyethylene
oxide-polypropylene oxide block co-polymers, and polyethylene
glycols. Most preferred are solubilizing excipients fumaric acid,
ascorbic acid, succinic acid, and aspartic acid.
[0211] Osmotic tablets can also be made with a core tablet
containing osmogents and/or solubilizing excipients surrounded
first by a active compound containing layer and then second a
semipermeable coating. The core tablet containing osmotic agents
and/or solubilizing excipients can be made by standard tabletting
methods known in the pharmaceutical industry. The semipermeable
coating can then be applied to the layered core by many processes
known in the art such as spray-coating or dip-coating methods
described previously in these specifications. The active compound
containing layer may be applied around the core by spray-coating
methods where a solution or slurry of active compound and
excipients is coated onto the tablet core. The active compound and
excipients may also be layered around the tablet core by making a
"layered" type of configuration using a tablet press to form a
second active compound-containing layer around the tablet core.
This type of compression coating method can be used to apply a
powder coating (without solvents) around a tablet core.
[0212] Another embodiment of sustained release GHSEC osmotic dosage
forms of this invention consists of GHSEC multiparticulates coated
with an asymmetric membrane. GHSEC-containing multiparticulates are
prepared by, for example, extrusion/spheronization or fluid bed
granulation, or by coating non-pareil seeds with a mixture of GHSEC
and a water-soluble polymer, as described above. GHSEC-containing
multiparticulates are then spray-coated with a solution of a
polymer in a mixture of a solvent and a non-solvent, as described
above, to form asymmetric-membrane-coated multiparticulates. This
spray-coating operation is preferably carried out in a fluid bed
coating apparatus, e.g., a Glatt GPCG-5 fluid bed coater (Glatt Air
Techniques, Inc., Ramsey, N.J.). The polymer used for forming the
semipermeable asymmetric membrane is chosen as described above for
asymmetric-membrane coated tablets. Likewise, excipients for the
multiparticulate cores can be chosen as described above for
asymmetric-membrane coated tablets.
[0213] Osmotic capsules can be made using the same or similar
components to those described above for osmotic tablets and
multiparticulates. The capsule shell or portion of the capsule
shell can be semipermeable and made of materials described above.
The capsule can then be filled either by a powder or liquid
comprising GHSEC, excipients that provide osmotic potential, and
optionally solubilizing excipients. The capsule core can also be
made such that it has a bilayer or multilayer composition analogous
to the bilayer tablet described above.
[0214] A fourth class of GHSEC sustained release dosage forms of
this invention comprises coated swellable tablets and
multiparticulates, as described in co-pending commonly assigned
U.S. application Ser. No. 07/296,464, filed Jan. 12, 1989
(published as EP 378404 A2; Jul. 7, 1990). Coated swellable tablets
comprise a tablet core comprising GHSEC and a swelling material,
preferably a hydrophilic polymer, coated with a membrane that
contains holes or pores through which, in the aqueous use
environment, the hydrophilic polymer can extrude and carry out the
GHSEC. Alternatively, the membrane may contain polymeric or low
molecular weight water soluble porosigens which dissolve in the
aqueous use environment, providing pores through which the
hydrophilic polymer and GHSEC may extrude. Examples of porosigens
are water-soluble polymers such as hydroxypropylmethylcellulose,
and low molecular weight compounds like glycerol, sucrose, glucose,
and sodium chloride. In addition, pores may be formed in the
coating by drilling holes in the coating using a laser or other
mechanical means. In this fourth class of GHSEC sustained release
dosage forms, the membrane material may comprise any film-forming
polymer, including polymers which are water permeable or
impermeable, provided that the membrane deposited on the tablet
core is porous or contains water-soluble porosigens or possesses a
macroscopic hole for water ingress and GHSEC release.
Multiparticulates (or beads) may be similarly prepared, with a
GHSEC/swellable material core, coated by a porous or
porosigen-containing membrane. Embodiments of this fourth class of
GHSEC sustained release dosage forms may also be multilayered, as
described in EP 378 404 A2.
[0215] Sustained release formulations may also be prepared with a
portion of the dose released initially rapidly, followed by
sustained release of the remaining portion of the dose.
[0216] Formulations that release a portion of the dose as a bolus
shortly after administration and then release the remaining portion
of the dose at a sustained release rate over time, such as over 2
hours to 18 hours or longer, can be made by a variety of methods.
For example, a bilayer tablet can be formed with one layer having a
sustained release matrix and the other layer an immediate release
composition. Upon ingestion, the immediate release layer
disintegrates leaving only the matrix tablet to provide sustained
release. In another example, a drug coating can be applied over a
matrix or osmotic tablet or over sustained release
multiparticulates. The coating can be applied using typical coating
equipment standard to the pharmaceutical industry. The active
compound can either be a solution or in suspension and is typically
mixed with a water soluble polymer in the coating solution. In
addition, a combination dosage form can be made by mixing sustained
release multiparticulates and immediate release multiparticulates
in one dosage form. A preferred method of making a formulation that
has an immediate release component and a controlled-release
component is to apply a compression coating around an osmotic
tablet.
[0217] Osmotic tablets comprise a tablet core that contains active
compound and may contain excipients that have an osmotic potential
greater than the fluid in the environment of use or contain water
swellable materials. The tablet cores are surrounded by a
semipermeable coating that allows water to be imbibed into the
tablet core. In operation it is important that this semipermeable
coating remain intact, if the coating is cracked or disrupted dose
dumping could occur or the release, rate could significantly
increase. A compression coating is made by compressing a powder
granulation around a tablet core to form a outer layer or coating.
This is done in specialized tablet presses where the inner core is
place in the powder/granulation during the compression step.
Applying an immediate release active compound layer around an
osmotic tablet core can be done without cracking or disrupting the
semipermeable coating and thus, without affecting the release rate
from the osmotic tablet within the compression coating.
[0218] Compression coatings can be successfully applied with the
following parameters, the weight ratio of powder/granulation in the
compression layer to the osmotic tablet ranging from about 1 to
about 2; a tablet compression force ranging from about 5 to about
30 kP; a semipermeable osmotic coating at least 8 wt % on the
osmotic tablet cores; and active compound loading in the
compression layer ranging from about 0.1 wt % to about 40 wt %.
Compression coatings can be applied to coated osmotic tablets using
a conventional compression coating tablet press such as a Kilian
RUD Press manufactured by Kilian and Company, Inc., Horsham, Pa.
Preferred excipients for application of compression coating are
about 25 to about 98.5 wt % microcrystalline cellulose, about 0 to
about 75 wt % lactose, about 0 to about 25 wt % hydroxypropyl
methyl cellulose or polyvinyl pyrrolidone, and less than about 2%
of a lubricant such as magnesium stearate. A preferred range of
weight ratio of powder/granulation in the compression layer to the
coated osmotic tablet is about 5/4 to about 7/4. A preferred range
of tablet compression force is about 10 to about 25 kP. It is
preferred that the semipermeable coating be at least 10 wt % of the
uncoated osmotic tablet core weight.
[0219] Combination immediate release and sustained release
formulations comprising a compression coating surrounding a coated
osmotic tablet can be tested to show that the compression coating
has been successfully applied to the tablet without affecting
release rates from the coated osmotic tablet. The
compression-coated formulations can be tested in standard
dissolution tests. The release rate from the coated osmotic tablet
would be considered not changed after compression coating if the
release rates before and after compression coating are within 80%
and 125% of each other (i.e., the release rate of compression
coated osmotic tablet is within 80% to 125% of the release rate of
the osmotic tablet prior to compression coating). For example, for
the same amount of time that 50% of the active compound from the
osmotic tablet is released, active compound release from the
compression coated tablets should be within 40% and 62.5%.
[0220] A growth hormone secretagogue can be administered to a
patient as a pharmaceutically acceptable salt or as a prodrug. The
terms pharmaceutically acceptable salt or prodrug mean the salts or
prodrugs of a growth hormone secretagogue that are, within the
scope of sound medical judgment, suitable for use with patients
without undue toxicity, irritation, allergic response, and the
like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible.
[0221] The term "salts" refers to inorganic and organic salts of a
growth hormone secretagogue. Such salts can be prepared in situ
during the final isolation and purification of a compound, or by
separately reacting a purified compound with a suitable organic or
inorganic acid or base, as required, and isolating the salt thus
formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,
tosylate, besylate, esylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. These may include cations
based on the alkali and alkaline earth metals, such as sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. See, for example, S. M.
Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66:1-19
(1977).
[0222] The term "prodrug" means a compound that is transformed in
vivo to yield a growth hormone secretagogue. The transformation may
occur by various mechanisms, such as through hydrolysis in blood. A
discussion of the use of prodrugs is provided by T. Higuchi and W.
Stella, "Pro-active compounds as Novel Delivery Systems," Vol. 14
of the A. C.S. Symposium Series, and in Bioreversible Carriers in
Active compound Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
[0223] For example, if a growth hormone secretagogue contains a
carboxylic acid functional group, a prodrug can comprise an ester
formed by the replacement of the hydrogen atom of the acid group
with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0224] Similarly, if a growth hormone secretagogue comprises an
alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl- ,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxyc- arbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkan-
oyl, arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacy- l, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0225] If a growth hormone secretagogue comprises an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, or benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY wherein
Y is H, (C.sub.1-C.sub.6)alkyl or benzyl, --C(OY.sub.0)Y.sub.1
wherein Y.sub.0 is (C.sub.1-C.sub.4) alkyl and Y.sub.1 is
((C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sub.2)Y.sub.3
wherein Y.sub.2 is H or methyl and Y.sub.3 is mono-N-- or
di-N,N--(C.sub.1-C.sub.- 6)alkylamino, morpholino, piperidin-1-yl
or pyrrolidin-1-yl.
[0226] A growth hormone secretagogue may contain asymmetric or
chiral centers, and therefore, exist in different stereoisomeric
forms. It is contemplated that all stereoisomeric forms of a growth
hormone secretagogue as well as mixtures thereof, including racemic
mixtures, form part of the present invention. In addition, the
present invention contemplates all geometric and positional
isomers. For example, if a growth hormone secretagogue contains a
double bond, both the cis and trans forms, as well as mixtures, are
contemplated.
[0227] Mixtures of isomers, including stereoisomers can be
separated into their individual components on the basis of their
physical chemical differences by methods well know to those skilled
in the art, such as by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diasteromeric mixture by reaction with
an appropriate optically active compound (e.g., alcohol),
separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers.
Also, some of the compounds of this invention may be atropisomers
(e.g., substituted biaryls) and are considered as part of this
invention.
[0228] A growth hormone secretagogue may exist in unsolvated as
well as solvated forms with pharmaceutically acceptable solvents
such as water, ethanol, and the like. The present invention
contemplates and encompasses both the solvated and unsolvated
forms.
[0229] It is also possible that a growth hormone secretagogue may
exist in different tautomeric forms. All tautomers of a growth
hormone secretagogue are contemplated. For example, all of the
tautomeric forms of the imidazole moiety are included in this
invention. Also, for example, all keto-enol and/or imine-enamine
forms of a growth hormone secretagogue are included in this
invention. Those skilled in the art will recognize that any
compound names contained herein may be based on a particular
tautomer of a compound. While the name for only a particular
tautomer may be used, it is intended that all tautomers are
encompassed by the name of the particular tautomer and all
tautomers are considered part of the present invention.
[0230] The present invention also includes isotopically-labelled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Growth hormone secretagogues that contain
the aforementioned isotopes and/or other isotopes of other atoms
are within the scope of this invention. Certain
isotopically-labelled growth hormone secretagogues, for example
those into which radioactive isotopes such as .sup.3H and .sup.14C
are incorporated, are useful in active compound and/or substrate
tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detection. Further, substitution with
heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances.
[0231] The documents cited herein, including patents and patent
applications, are all, hereby incorporated by reference.
[0232] The examples presented below are intended to illustrate
particulate embodiments of the invention and are not intended to
limit the specification, including the claims, in any manner.
EXAMPLES
Example 1
Clinical Study
Study Population
[0233] This clinical study was performed in male and female
subjects between the ages of 65 and 84 years inclusive, and whose
baseline IGF-1 levels were <150 ng/ml.
Dosing Regimen
[0234] The study was a double blind, parallel group,
placebo-controlled study.
[0235] In the first leg of the study, the safety and efficacy of
2-amino-N-[2-(3a-(R)benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-
-]4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobytyramide
L-tartrate was studied in 4 groups of approximately 24 subjects at
doses of 0 mg (placebo), 1 mg tid, 3 mg tid and 3 mg am and 6 mg
pm. (All dosage forms in this part of the study were immediate
release dosage forms.)
[0236] In addition, an extension study was conducted to evaluate
the relationship between peak GH concentrations or IGF-I versus
surrogate responses such as lipid concentrations and body
composition. A sustained release (SR) formulation was also
evaluated, either alone or combined with an immediate release (IR)
formulation (24-30 patients per group). [16mg (10 SR, 6 IR) h.s. (
h.s. means at bedtime); 16 mg (10 SR, 6 IR) h.s. every third day;
16 mg SR h.s.; and placebo.] The formulations are set forth
below.
Study Active Compound Administration
[0237] In the extension study,
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo2-
,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-
-oxo-ethyl]-isobutyramide L-tartrate was supplied as 10 mg or 3 mg
sustained release tablets and 3 mg immediate release tablets, with
matching placebo tablets. Study active compound was supplied in
blisterpaks, with five tablets to be taken at time of each dosing.
Subjects were instructed to take the tablets with one glass of
water at bedtime.
Plan and Design
[0238] Return visits were scheduled at 1, 2, and 4 weeks after
baseline. A blood sample for
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7--
hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]i-
sobutyramide L-tartrate and IGF-1 levels was obtained at each
visit. The baseline and all subsequent follow-up visits were
performed at the same time of day (between approximately 8-11
am).
[0239] In addition to this schedule, subjects at selected sites in
the extension study were studied during two overnight admissions on
the first night of dosing and again on day 28 of dosing. Growth
hormone secretion and pharmacokinetic sampling was carried out.
Follow-up Period and End of Study
[0240] A follow-up evaluation was made at 1, 2, and 4 weeks. Vital
signs were obtained and the skin of the face, trunk and upper
extremities was inspected. A blood sample was obtained for
measurement of GH and IGF-1, and for measurement of plasma
concentrations of 2-amino-N-[2-(3a-(R)-benz-
yl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R-
)-benzloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate.
[0241] In addition, subjects at selected study centers were
admitted to an overnight unit on day 28 of dosing. Growth hormone
secretion profile, pharmacokinetics, and vital sign determination
were carried out.
Efficacy Endpoints
[0242] The primary efficacy endpoint was the percentage change from
baseline in IGF-1. Secondary outcomes included insulin-like growth
factor binding protein 3 (IGFBP-3), cholesterol subfractions, and
percent changes in total adipose and total lean tissue. Changes in
each of the secondary efficacy measures over time were examined
systematically either graphically or in tabular form and summarized
using appropriate descriptive statistics as is well known in the
art.
Results
[0243] In the first leg of the study, there was a dose related
increase in IGF-I, with both groups administered 9 mg daily having
similar increases of approximately 35%. IGFBP3 also increased.
There were small changes in body composition consistent with
increased GH secretion, i.e., decreased adipose tissue and
increased apparent whole body lean mass.
[0244] In the extension study, there were increases in IGF-I in
each of the 2 groups in which
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4-
,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-et-
hyl]-isobutyramide L-tartrate was dosed daily. The group randomized
to receive 2-amino-N-[2-(3aR-benzyl-2-methyl-3-oxo-2,3,3a,
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxo-eth-
yl]-isobutyramide L-tartrate every third day had a minimal average
rise of IGF-I of approximately 10%. The group receiving SR alone
had modest and sporadic GH peaks averaging less than 4 ng/ml at
baseline and 2 ng/ml after 4 weeks. The groups receiving 6 mg IR
(with 10 mg SR) had GH peaks at baseline averaging 15 ng/ml or
more, which by 4 weeks had attenuated to 4-6 ng/ml.
[0245] By a variety of analyses, there was less attenuation in the
group receiving Q 3 day
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-
-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxo-ethyl]-is-
obutyramide L-tartrate. The Q 3 day group had peak heights on
average 1.52 ng/ml greater than the QD group. Changes in body
composition were again observed and were similar in the two groups
receiving IR formulation despite large differences in the increase
of IGF-I. Increases in lean tissue approximated 0.5-0.6% with
corresponding reductions in adipose tissue.
[0246] The specific dosage forms used in the clinical study are set
forth below wherein the active compound is
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-
-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymet-
hyl-2-oxo-ethyl]isobutyramide L-tartrate.
6 1 mg immediate release tablet Component Grade of Component Weight
(mg/tablet) Active compound Pharmaceutical 1.30.sup.(a) Calcium
phosphate USP 35.08 dibasic, anhydrous Microcrystalline cellulose
NF 56.12 (Avicel .RTM. PH102; FMC Corporation, Philadelphia, PA)
Sodium starch glycolate NF 5.00 (Explotab; Penwalt, Patterson, NJ)
Magnesium stearate NF 1.50
[0247]
7 3 mg immediate release tablet Component Grade of Component Weight
(mg/tablet) Active compound Pharmaceutical 3.89.sup.(a) Calcium
phosphate USP 34.79 dibasic, anhydrous Microcrystalline cellulose
NF 54.82 (Avicel .RTM. PH102) Sodium starch glycolate NF 5.00
(Explotab) Magnesium stearate NF 1.50
[0248]
8 3 mg sustained release tablet Component Grade of Component Weight
(mg/tablet) Active compound Pharmaceutical 3.89.sup.(a) Mannitol
USP 34.00 2080, granular form Fumaric acid NF 12.00
Microcrystalline cellulose NF 48.61 Magnesium stearate NF 0.50 (1st
addition) Magnesium stearate NF 1.00 (2nd addition) Cellulose
acetate NF 11.90 (CA-398-10) Eastman Chemical, Kingsport, TN
Polyethylene glycol NF 5.10 (Carbowax PEG 3350; Union Carbide,
Charleston, WV) Purified water.sup.(b) USP (35.70) Acetone.sup.(b)
NF (117.30)
[0249]
9 10 mg sustained release tablet Component Grade of Component
Weight (mg/tablet) Active compound Pharmaceutical 12.97.sup.(a)
Mannitol USP 113.32 2080, granular form Fumaric acid NF 40.00
Microcrystalline cellulose NF 162.01 (Avicel PH102) Magnesium
stearate NF 1.67 (1st addition) Magnesium stearate NF 3.33 (2nd
addition) Cellulose acetate NF 33.00 (CA-398-10) Eastman Chemical,
Kingsport, TN Polyethylene glycol NF 22.00 (Carbowax PEG 3350)
Union Carbide, Charleston, WV Purified water.sup.(b) USP (126.50)
Acetone.sup.(b) NF (368.50) .sup.(a)Based on a theoretical active
compound substance potency of 77.1%. .sup.(b)The purified water and
acetone are volatile and are not present in the final dosage
form.
[0250] In the 3 mg and 10 mg sustained release dosage forms, the
active compound, mannitol, fumaric acid, microcrystalline
cellulose, and magnesium stearate are tablet core components.
[0251] NF is National Formulary.
[0252] USP is United States Pharmacopoeia.
Preparation of 10 mg and 3 mg Sustained Release Dosage Forms
[0253] This example illustrates a method for making formulations of
3 mg and 10 mg osmotic tablets comprising a tablet core containing
active compound surrounded by a semi-permeable asymmetric membrane
coating. The processing of the core tablet comprised (1) blending
of core components, except for magnesium stearate; (2) milling and
reblending the same components; (3) adding and blending a portion
of the magnesium stearate; (4) dry granulating; (5)
milling/screening and reblending; (6) adding and blending the
remaining portion of magnesium stearate; (7) compressing core
tablets; (8) spraying an asymmetric membrane coating on the core
tablets; and (9) drying.
[0254] In batch sizes of 6-14 kilograms,
2-amino-N-[2-(3aR-benzyl-2-methyl-
-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymet-
hyl-2-oxo-ethyl]-isobutyramide L-tartrate was blended with all
other components except magnesium stearate for 30 minutes in a
suitable sized stainless steel twin-shelled blender (16 quart to 2
cubic feet). Next, the blend was passed through a mill (Fitz model
JT or D mill fitted with #1A plate, medium speed, knives forward,
The Fitzpatrick Company, Elmhurst, Ill.) and blended again for 30
minutes. Then, magnesium stearate (1st addition) was added and
blended for 5 minutes. The partially lubricated blend was dry
granulated using a roller compactor (Freund TF-156 roller
compacter, Freund Industrial Co., Tokyo, Japan) with auger screw
feed of 10-12 rpm, pressure 25 kg/cm.sup.2, and roller speed of 12
rpm. The roller compactor was fitted with an oscillating roller
granulator screen size of 20 mesh to mill the compacted ribbons.
Next, the granulation was blended for 30 minutes before the last
portion of magnesium stearate (2nd addition) was added and
reblended for 5 minutes. Using a conventional tablet press (Kilian
LX21, Kilian and Co., Inc, Horsham, Pa.), the final blend was
compressed into tablets.
[0255] A semi-permeable membrane coating (as described in U.S. Pat.
No. 5,612,059 entitled Use of Asymmetric Membranes in Delivery
Devices) was applied to these tablets using a HCT-30
explosion-proof pan coater (Vector Corporation, Marion, Iowa)
operated at a spray rate of 20 grams per minute, an inlet
temperature of 40-45.degree. C. and air flow rate of 30 cfm
(14158.43 cm.sup.3/sec). The asymmetric membrane coating
formulations applied to the 3 mg and 10 mg core tablet released 80%
of the dose in 10-12 hours in simulated gastric fluid (sgn) at pH
about 1.2, which procedure is well known and disclosed in U.S. Pat.
No. XXIII. The coating for the 3 mg tablets consisted of cellulose
acetate/polyethylene glycol/water/acetone ratios of 7/3/21/69 (w/w)
coated to an increase in the initial weight of 17 weight %.
Likewise, for the 10 mg tablet, the coating was composed of
6/4/23/67 formulation applied to 15.5 weight %. The coated tablets
were dried in the coater for 15 minutes at an inlet temperature set
point of 60.degree. C. and dried in an oven (Gruenberg solvent tray
oven, Gruenberg Oven Company, Williamsport, Pa.) for 16 hours at
50.degree. C. before testing for dissolution performance. After
drying, the weight of the applied coating material was determined
based on a percentage of the initial core tablet weight.
Preparation of 1 mg and 3 mg Immediate Release Dosage Forms
[0256] 1. Blend calcium phosphate dibasic anhydrous,
microcystalline cellulose, and sodium starch glycolate for 5
minutes in an amber glass bottle using a Turbula mixer (WAB, Basel,
Switzerland) (20 rpm setting).
[0257] 2. Screen the excipient mixture from step 1 through a 40
mesh screen and blend for 15 minutes in an amber glass bottle using
a Turbula mixer (20 rpm setting).
[0258] 3. Add growth hormone secretagogue to the excipient mixture
from step 2 using geometric dilution. After each dilution, blend
for 10 minutes in an amber glass bottle using a Turbula mixer (20
rpm setting).
[0259] 4. Screen this active blend from step 3 through a 40 mesh
screen and blend for 10, 20 and 30 minutes in an amber glass bottle
using a Turbula mixer (20 rpm setting). Remove top, middle and
bottom samples at each time point.
[0260] 5. Add 1.0% (before granulation) magnesium stearate and
blend for 5 minutes in an amber glass bottle using a Turbula mixer
(20 rpm setting).
[0261] 6. Roller compact the blend using the TF Freund mini roller
compactor,
[0262] roll pressure: 40 kg/cm.sup.2
[0263] roll speed: 3 rpm
[0264] feed speed: 10 rpm
[0265] 7. Mill the compacts using the rotating granulator fitted
with a 30 mesh screen.
[0266] 8. Add 0.5% (after granulation) magnesium stearate to the
active granulation and blend for 5 minutes in an amber glass bottle
using a Turbula mixer (20 rpm setting).
[0267] 9. Tablet using a single station press (F-Press, Manesty
Machines, Liverpool, England).
Alternative Preparation of 1 mg and 3 mg Immediate Release Dosage
Forms
[0268] 1. Blend calcium phosphate dibasic anhydrous,
microcrystalline cellulose, and sodium starch glycolate in a
4-quart V-blender for 15 minutes.
[0269] 2. Discharge blender.
[0270] 3. Add growth hormone secretagogue and an approximately
equal volume of excipient blend from step 2 to an amber glass
bottle and blend for 15 minutes using a Turbula mixer (20 rpm
setting).
[0271] 4. Place approximately 1/2 of the excipient blend from step
2 into the V-blender.
[0272] 5. Pass active compound/excipient blend from step 3 through
a 40 mesh screen and place in V-blender. Use a mortar and pestle to
reduce the size of any agglomerates that do not pass through the
screen.
[0273] 6. Place the remaining excipient blend from step 2 into the
V-blender.
[0274] 7. Blend in the V-blender for 15 minutes.
[0275] 8. Pass the blend from step 7 through a Fitzpatrick JT mill
fitted with a #1 plate with knives forward and at medium speed (The
Fitzpatrick Company, Elmhurst, Ill.).
[0276] 9. Place the blend from step 8 in the 4-quart V-blender and
blend for 15 minutes.
[0277] 10. Add magnesium stearate (1.0% before granulation) and
blend for 5 minutes.
[0278] 11. Roller compact the blend using a Freund TF-Mini Roller
compactor,
[0279] roll pressure: 40 kg/cm.sup.2
[0280] feed speed:12 rpm
[0281] roll speed: 3 rpm
[0282] 12. Mill the compacts from step 11 using the rotating
granulator fitted with a 30 mesh screen.
[0283] 13. Place the active granulation from step 12 in the 4-quart
V-blender and blend for 10 minutes.
[0284] 14. Add 0.5% (after granulation) magnesium stearate and
blend for 15 minutes.
[0285] 15. Tablet the blend using the Kilian T100 rotary press
(Kilian and Company, Inc., Horsham, Pa.).
Example 2
Simulated Sustained Release
[0286] The ability of a simulated sustained release formulation of
a growth hormone secretagogue such as
2-amino-N-[2-(3a-(R)-benzyl-2-methyl--
3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxym-
ethyl-2-oxo-ethyl]-isobutyramide L-tartrate to induce pulsatile
release of growth hormone and increase IGF-I responses at 24 hrs
was demonstrated in young, healthy male volunteers. This dosing
regimen simulates active compound delivery by a sustained release
dosage form. The clinical study was designed as a randomized,
crossover study administering oral solutions of either a single 10
mg dose of 2-amino-N-[2-(3a-(R)-benzyl-2--
methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-ben-
zyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate as a bolus or a
single 3 mg loading dose followed by seven (7) 1 mg maintenance
doses every 2 hours for a total dose of 10 mg. Serum concentrations
of growth hormone were monitored just prior to administration of
the first dose and every 20 minutes thereafter for 24 hours. Serum
insulin-dependent growth factor-I (IGF-I) concentrations were
measured at 0, 12, and 24 hours post-first dose.
[0287] Results indicated that simulated sustained release of 10 mg
of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate generally lowered the growth hormone AUC.sub.0-24 and
C.sub.max, while the frequency and amplitude of secondary GH peaks
increased. The IGF-I serum concentration change from baseline at 24
hours was increased following the simulated sustained release
dosing compared to the bolus.
Methods
[0288] This investigation was conducted as a randomized, crossover
study of the safety, toleration, pharmacokinetics and
pharmacodynamics of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate in four fasted young, healthy, male volunteers. Each
participant received, in a randomized fashion,
2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-
-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate as either a
single 10 mg oral dose in solution or as a single 3 mg loading dose
followed by seven (7) 1 mg maintenance doses administered every two
hours. The order of treatment was defined by a randomization
schedule. Following initial administration, subjects were
readmitted to the clinical research facility approximately 14 days
later. During the second evaluation, the subject received the
treatment not used during the previous session.
[0289] Growth hormone serum concentrations were determined
following administration of the bolus or divided doses. Blood
samples, adequate to provide 0.5 ml of serum, were collected just
prior to administration of the first dose, and every 20 minutes
thereafter for 24 hours for determination of growth hormone.
Specimens were collected in tubes containing no additives, and were
maintained at room temperature until clotted. The serum was
separated from the whole blood and frozen at -20.degree. C. within
one hour of collection.
[0290] Growth hormone quantitation of the human serum samples was
conducted using luminescence measurements by means of an
Immulite.RTM. system (Diagnostic Products Corporation, Los Angeles,
Calif.). All analyses were performed using a hGH Immulite.RTM. kit
containing hGH test units (LGH 1), hGH reagent wedge (LGH 2) and
hGH adjustors (LGHL and LGHH). These kits were obtained from DPC
(Diagnostic Products Corporation, Los Angeles, Calif.). In
addition, hGH sample diluent (LGHZ), chemiluminescent substrate
module (LSUBX), probe wash module (LPWSZ) and the necessary
Immulite.RTM. accessories were obtained from DPC. For each new kit,
the Immulite.RTM. system was calibrated by running two adjuster
samples (LGHL and LGHH) obtained from the manufacturer, containing
a high and a low concentration of hGH in equine serum,
respectively. Subsequently, the signals were plotted against the
Master Curve to derive a slope and an intercept. On the basis of
these values, the Immulite.RTM. system automatically decides
whether the kit can be used for sample analysis. Samples were taken
from the -20.degree. C. freezer and thawed in a water bath at
30.degree. C. for ten minutes. Subsequently, the samples were
homogenized. An aliquot of 50 .mu.L of the serum sample and an
aliquot of a solution containing alkaline phosphatase conjugated
anti-hGH (human growth hormone) antibody were automatically
transferred into a sample cup containing an antibody coated
polypropylene bead specific for hGH. After incubation at 37.degree.
C. for 30 minutes, the unbound enzyme conjugate was removed by a
centrifugal wash, after which 200 .mu.L of a substrate solution was
added and incubated at 37.degree. C. for a further ten minutes. The
resulting luminescence was determined by means of an Immulite.RTM.
system.
[0291] IGF-I serum concentrations were determined following
administration of the bolus or divided doses. Blood samples,
adequate to provide 1.5 ml serum, were collected just prior to
administration of the first dose, and at 12 and 24 hours after
administration of the first dose, for determination of IGF-I
concentrations. Specimens were collected in tubes containing no
additives, and were maintained at room temperature until clotted.
The serum was separated from the whole blood and frozen at
-20.degree. C. within one hour of collection.
[0292] IGF-I quantitation of the human serum samples was conducted
using the "DSL-5600A Active.TM. IGF-I Coated-Tube IRMA
(immunoradiometric assay) by Extraction" Kit (Diagnostic Systems
Laboratories Inc., Webster, Tex.). All analyses were performed
using the extraction kit containing anti-IGF-I coated tubes
(plastic tubes on which the first antibody, i.e., anti-IGF-I
immunoglobulin is immobilized on the wall of the tube),
[.sup.125I]Anti-IGF-I ([.sup.125I]labelled anti-IGF-I antibodies,
which are provided in a buffer containing sodium azide and a
protein stabilizer), extraction solution, neutralizing solution,
IGF-I control and IGF-I standard samples. The lyophilized IGF-I
control and standard samples were used for the preparation of
calibration and validation samples as described. The extraction
solution consisted of a mixture of 2.0 N HCl/ethanol (12.5: 87.5,
in volume %) and the neutralizing solution contained a neutralizing
buffer and sodium azide. Lyophilized calibration and validation
samples were prepared by the addition of 1 mL of water to the
ready-to-use samples. The calibration samples were prepared at
seven levels, i.e., 4.50, 16.0, 65.0, 122, 180, 410 and 640
.mu.g.L.sup.-1. The validation samples were prepared at levels of
4.50, 65.0, 180 and 640 pg.L.sup.-1. Samples were taken from the
-20.degree. C. freezer and thawed in a water bath at 30.degree. C.
for ten minutes. Subsequently, the samples were homogenized and
centrifuged at 3200.times.g. An aliquot of 100 .mu.L of the human
serum sample was transferred into a 5 mL polypropylene tube and
incubated with 400 .mu.L of extraction solution for 30 minutes at
room temperature. After centrifugation at 5,000 r.p.m, 100 .mu.L of
the supernatant was transferred into another polypropylene tube.
Next, 500 .mu.L of neutralization solution was added. This
neutralized human serum extract was ready for use in the actual
IRMA after having vortexed it briefly. An aliquot of 50 .mu.L of
the extracted serum sample, validation or calibration sample was
transferred into an anti-IGF-I antibody coated tube, and
immediately afterwards 200 pL of [.sup.125I]anti-IGF-I antibody
solution was added. The samples were incubated for three hours at
room temperature on a multimixer at 180 r.p.m. After three hours,
all tubes were decanted and drained on adsorbent paper. Residual
droplets on the rims of the tube were removed by blotting. Next,
the tubes were washed three times with Milli-Q water (Winokur Water
Systems Corporation, Bethel, Conn.), applying the above-described
drying procedure between the washing steps. The remaining
[.sup.125I]radioactivity of all tubes was determined by counting
for five minutes using a Canberra-Packard Cobra II.TM. 5002
-counter (Canberra-Packard, Schwadorf, Austria).
Results
[0293] The results demonstrated divided dosing of
2-amino-N-[2-(3a-(R)-ben-
zyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(-
R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate lowered
the initial growth hormone peak at 1-2 hours after the first dose
compared to bolus. These findings also demonstrated an increase in
frequency and amplitude of growth hormone serum concentrations over
8-20 hours following simulated sustained release compared to bolus
dosage administration. In addition, the pulsatility of GH
concentrations increased at times typical of biological times not
as an acute response after each maintenance dose. The IGF-I serum
concentration change from baseline at 24 hours post first dose was
increased following simulated sustained release dosing compared to
bolus (Table 2-1).
10TABLE 2-1 Individual Serum Growth Hormone (GH) and IGF-I
Concentrations in Young, Healthy Male Volunteers Following Oral
Administration of 10 mg of 2-amino-N-[2-(3a-(R)-ben-
zyl-2-methyl-3-oxo-2,3,3a,
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5- -yl)-1-(R)-
benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate As A Bolus or
Simulated Sustained Release (Divided) IGF-I Change from Dosing GH
GH Baseline at 24 hrs Subject Regimen AUC.sub.0-24 C.sub.max GH
T.sub.max post dose (.mu.g/ml) 1 bolus 297 133 1 102 1 divided 313
107 1 130 2 bolus 256 125 1 98 2 divided 152 77 1 105 3 bolus 220
121 1 110 3 divided 242 82 1 123 4 bolus 292 131 0.67 98 4 divided
251 80 1 107
Example 3
Pituitary Cell Desensitization--Growth Hormone Release Assay
[0294] The ability of a growth hormone secretagogue such as GHRP-6
or
2-amino-N[-2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate to induce homologous desensitization of the growth
hormone secretion response was demonstrated in cultures of
dispersed rat pituitary cells. The experiment was designed so that
cultures were exposed to a growth hormone secretagogue for 60 min,
then growth hormone release was measured during a subsequent 15 min
exposure to the same or different growth hormone secretagogue.
Results indicate that continuous exposure to growth hormone
secretagogue rapidly desensitizes rat pituitary cells. Thus, based
on these results, it appears unlikely that sustained release growth
hormone secretagogue formulations would elicit the desired response
(i.e., stimulate the release of growth hormone).
Methods
[0295] Anterior pituitary glands from male Wistar rats (150-175 g,
Charles River, Laboratories, Wilmington, Mass.) were collected in
Hank's Balanced Salt Solution (#14170, Life Technologies,
Gaithersburg, Md.). Glands were minced with a scalpel, then
incubated with bacterial protease (Type IX, EC3.4.24.4, #P-6141,
Sigma Chemicals, Milwaukee, Wis.) at 10 U/ml to release individual
cells. Cells were pelleted by centrifugation at 200.times.g for 15
min, then suspended in culture medium and plated at a density of
6.0-6.5.times.10.sup.4 cells per 0.5 ml per well in 48-well tissue
culture plates (#3848, Costar Corporation, Cambridge, Mass.).
Culture medium consisted of D-MEM (Dulbecco's Modified Eagle
Medium) with high glucose and sodium bicarbonate (#11965)
supplemented with 10% heat-inactivated horse serum (#26050, Life
Technologies, Gaithersburg, Md.), 2.5% fetal bovine serum (#16140,
Life Technologies, Gaithersburg, Md.), 0.1 mM MEM non-essential
amino acids (#11140, Life Technologies, Gaithersburg, Md.), 100
U/ml nystatin (#15340, Life Technologies, Gaithersburg, Md.) and 50
ug/ml gentamicin sulfate (#15750, Life Technologies, Gaithersburg,
Md.). Cultures were maintained for 3-4 days in a humidified, 5%
CO.sub.2/95% air incubator at 37.degree. C. prior to performing
assays for growth hormone release.
[0296] For growth hormone release assays, cultures were
pre-equilibrated at 37.degree. C. in pre-warmed release medium for
1 h in the presence of a growth hormone secretagogue or excipient
(Pretreatment). Release medium consisted of Phenol Red-free D-MEM
without bicarbonate (#23800, Life Technologies, Gaithersburg, Md.)
supplemented with 25 mM
N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] (HEPES),
4.5 g/L glucose, 0.11 g/L sodium pyruvate, 0.584 g/L L-glutamic
acid and 0.5% bovine serum albumin (#A-7888, Sigma Chemicals,
Milwaukee, Wis.), adjusted to pH 7.4. After pretreatment, the
medium was removed and replaced with fresh pre-warmed release
medium containing a growth hormone secretagogue or excipient at 0.5
ml/well for 15 min (Treatment). Medium from the Treatment was
collected, centrifuged to remove any cells, then assayed for growth
hormone content by a conventional double-antibody radioimmunoassay
using monkey anti-growth hormone antisera (NIDDK anti-rGH-S-5) and
reference rat growth hormone standard (NIDDK-rGH-RP) from Dr. A.F.
Parlow, Harbor-UCLA Medical Center, Torrance, Calif. Immune
complexes were precipitated using goat anti-monkey immunoglobulin G
(#55418, Cappel, Durham, N.C.).
[0297] Growth hormone secretagogue solutions were prepared at 1000
times the desired concentration and diluted into pre-warmed release
medium immediately before use. Peptides such as
His-D-Trp-Ala-Trp-Ala-Trp-D-Phe-- Lys-NH2 (GHRP-6, #8061, Peninsula
Laboratories, Belmont, Calif.) and rat growth hormone releasing
factor (GHRH, #8068, Peninsula Laboratories, Belmont, Calif.) were
dissolved at 100 .mu.M in 4 mM acetic acid, 10% ethanol, 0.1 %
bovine serum albumin; other growth hormone secretagogues were
dissolved at 5 mM in dimethyl sulfoxide.
Results
[0298] The data in Table 3-1 demonstrate apparent homologous
desensitization of cellular responses to
2-amino-N-[2-(3a-(R)-benzyl-2-me-
thyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzy-
loxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate and GHRP-6 and
cross-desensitization between these two growth hormone
secretagogues. As shown in Table 3-1, rat pituitary cells showed
stimulation of growth hormone release in response to
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-
-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-
-2-oxo-ethyl]-isobutyramide L-tartrate (Compound A) after
pretreatment with GHRH but not with GHRP-6.
11TABLE 3-1 Growth Hormone Release by Rat Pituitary Cells after
Pretreatment with a Growth Hormone Secretagogue (Mean .+-. standard
deviation, n = 4) Pretreatment Treatment GH release Group 60 min 15
min ng/mL/15 min 1 none none 9.28 .+-. 1.33 2 none 100 nM GHRP-6
31.01 .+-. 8.46* 3 none 10 nM Compound A 25.17 .+-. 4.32* 4 100 nM
GHRP-6 none 9.06 .+-. 1.87 5 100 nM GHRP-6 100 nM GHRP-6 7.83 .+-.
0.98 6 100 nM GHRP-6 10 nM Compound A 7.64 .+-. 1.92 7 100 nM GHRH
none 12.67 .+-. 3.31 8 100 nM GHRH 10 nM Compound A 36.99 .+-.
2.43* *Different from Group 1 by Student's t-test, P < 0.05
Example 4
Pituitary Cell Desensitization--Intracellular Calcium Assay
[0299] The inability of somatotrophs to respond to repeated
administration of a growth hormone secretagogue by transiently
increasing their intracellular calcium concentration was
demonstrated in perfused cultures of dispersed rat pituitary cells.
Thus, it appears that sustained release formulations would not
provide the desired in vivo response. The experiment was designed
so that changes in intracellular calcium concentration could be
continuously monitored during successive exposures of the same
cells to the indicated test substances.
Methods
[0300] Rat pituitary cells were isolated as described in Example 3
and plated onto poly-D-lysine-coated glass coverslips, one
coverslip per well in 12-well plates, at a density of
3-4.times.10.sup.5 cells per well. Assays were performed 3-4 days
after plating. Cells were loaded with 5 .mu.M fura-2 AM (Molecular
Probes, Eugene, Oreg.), a calcium-sensitive fluorescent dye, by
incubation for 30 min at room temperature. Fura-2 was dissolved in
dimethylsulfoxide at 5 mM, then diluted into KRH buffer (115 mM
NaCl, 5.4 mM KCl, 1.8 mM CaCl.sub.2, 1 mM MgCl.sub.2, 0.96 mM
NaH.sub.2PO.sub.4, 25 mM HEPES, 6 mM glucose and 0.05% bovine serum
albumin, adjusted to pH 7.3).
[0301] To assay changes in intracellular calcium concentration, a
coverslip with attached cells was mounted in a perfusion chamber on
the stage of an inverted microscope (Zeiss Axiovert 135 with
epifluorescence, Geschaftsbereich Mikroscopie, Oberkochen, Germany)
and continuously superfused at room temperature. After superfusion
with KRH for 1-2 min, baseline fluorescence was recorded. Each test
substance was applied for 2 min, followed by washout with KRH prior
to stimulation with the next test substance. Up to 20 individual
cells per field were selected for recording and were excited
alternately at wavelengths of 380 nm or 340 nm (slit width 15 nm).
Fluorescence emission at 510 nm was collected at 5 sec intervals by
a low light CCD camera (Hamamatsu Photonics, Hamamatsu City,
Japan), and digitized images for the two excitation wavelengths
were analyzed using Videoprobe software (ETM Systems, Irvine,
Calif.) to determine the 340 nm/380 nm fluorescence ratio for
individual cells during each time interval. The 340 nm/380 nm
fluorescence ratio is proportional to the concentration of
intracellular calcium.
Results
[0302] The data demonstrate apparent homologous desensitization of
cellular responses to
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4-
,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-et-
hyl]isobutyramide L-tartrate and GHRP-6 and cross-desensitization
between these two growth hormone secretagogues (but no
desensitization between GHRH and
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyl-2-oxo-ethyl]isobutyramide
L-tartrate). In the experiment, cells that initially responded to
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate or GHRP-6 with a calcium flux are refractory when
re-exposed to
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyra-
zolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]isobutyramide
L-tartrate after washout with buffer, yet the same cells remained
responsive to KCl. Based on these data, it is not evident that
continuous exposure to a growth hormone secretagogue would elicit
multiple cycles of growth hormone release from pituitary cells
since the cells rapidly become refractory to this stimulus.
Example 5
Excipient Selection Based on Active Compound Solubility
Screening
[0303] The ability of selected excipients to maintain the
solubility of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate above 150 mg/ml was demonstrated in solutions of the
candidate excipient. Such excipients are useful in making osmotic
sustained release tablets. The active compound solubility screening
experiment was designed so that filtrate from saturated excipient
solutions were visually monitored for precipitation over 5 minute
intervals following addition of 50 mg/ml of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexah-
ydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobu-
tyramide L-tartrate solution. The active compound solubility
measured in this manner exceeded 150 mgA/ml (mgA is the milligrams
of active compound). Preferred excipients were selected based on
their ability to maintain
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-ixobutyr-
amide L-tartrate solubility above 150 mg/ml.
Methods
[0304] This example illustrates a method to select excipients,
including organic acids, bases, buffers, binders, lubricants,
surfactants and solubilizing agents, that have the ability to
maintain the solubility of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-(R)-ethyl]-isobutyramide
L-tartrate above 150 mg/ml. The excipients were screened by
preparing a saturated solution (unless otherwise noted) of the
candidate excipient in water at 37.degree. C. for 2 hrs, and
filtering the undissolved portion. Then, three incremental amounts
of 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo-ethyl]-isobutyramide L-tartrate at 50 mg/ml were added
to a 3 ml filtrate solution of the excipient to achieve a maximum
solubility of 150 mgA/ml. The solution was maintained at 37.degree.
C. for 5 minutes prior to making the visual observation for any
undissolved particulates. The active compound solubility was then
determined by visual observation over the range of 0-50, 50-100,
100-150, or >150 mgA/ml (Table 5-1).
Results
[0305] The results of this solubility test are listed in Table 5-1.
All of the acids evaluated successfully maintained the solubility
of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate above 150 mg/ml. The basic compounds of L-lysine and
L-arginine reduced the solubility below 50 mg/ml. The saturated
solutions of phosphate, citrate, sulfate, or chloride salts
suppressed the solubility from greater than 150 mg/ml to less than
50 mg/ml and formed a cloudy gel. However, the sodium bitartrate
buffer successfully maintained the solubility of the active
compound above 150 mgA/ml. The active compound substance solubility
was reduced by the solubilizing agent, sulfobutylether
cyclodextrin, to 100-150 mgA/ml. Sodium lauryl sulfate as a
surfactant caused
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6-
,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethy-
l]-isobutyramide L-tartrate to form a clear gel during the second
incremental addition of active compound solution. All of the
binders (microcrystalline cellulose, silicified microcrystalline
cellulose, and polyethylene glycol) and lubricants (calcium and
magnesium stearate) evaluated according to the excipient screening
test maintained the solubility of active compound substance above
150 mgA/ml.
12TABLE 5-1 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-
c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo- ethyl]-isobutyramide
L-tartrate (Compound A) solubility in saturated excipient solutions
maintained at 37.degree. C. upon three incremental additions of 50
mgA/ml Approximate Excipient COMPOUND A Excipient Concentration
(mg/ml) Solubility (mg/ml) ACIDS/BASES: 400 >150 Ascorbic acid 7
>150 L-aspartic acid 600 >150 Citric acid 10 >150 Fumaric
acid 80 >150 Succinic acid 50 (a) >150 Tartaric acid 150
L-arginine 150 <50 L-lysine 50 (a) <50, cloudy gel BUFFERS:
400 <50 Potassium phosphate monobasic Potassium chloride 360
<50, cloudy gel Sodium bitartrate 110 >150 Sodium citrate 520
<50, cloudy gel Sodium chloride 360 <50, cloudy gel Sodium
phosphate 1000 <50, cloudy gel monobasic Sodium ph osphate 290
<50, cloudy gel tribasic BINDERS: <1 (b) >150
Microcrystalline cellulose Microcrystalline <1 (c) >150
cellulose, silicified Polyethylene glycol 50 (d) >150
LUBRICANTS: <1 (e) >150 Calcium stearate Magnesium <1
>150 stearate SOLUBILIZER/SURF- 1000 100-150 ACTANTS:
Cyclodextrin, sulfobutylether Sodium lauryl 50 50-100, clear gel
sulfate (a) excipient solution prepared below saturation, at 50
mg/ml (b) Avicel PH102, FMC Corporation, Philadelphia, PA;
excipient solution prepared at 80 mg/ml (c) Prosolv SMCC50,
Mendell, Cedar Rapids, IA; excipient solution prepared at 80 mg/ml
(d) Carbowax 3350, Union Carbide Corporation, Charleston, WV. (e)
excipient solution prepared at 2 mg/mL
[0306] Preferred excipients, based on this screening test, are
organic acids. Exemplary organic acids are tartaric, citric,
ascorbic, fumaric, succinic, and L-aspartic acids. Sodium
bitartrate buffer solutions also maintained active compound
substance solubility. Some sustained release dosage forms with such
acids or buffers in the formulation can perform better than those
without such acids or buffers. This is particularly true for
osmotic-based formulations that deliver a solution of active
compound.
[0307] Preferred tablet binders for
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo-ethyl]-isobutyramide L-tartrate are microcrystalline
cellulose, silicified; microcrystalline cellulose; and polyethylene
glycol based on the screening test. Preferred lubricants for the
dosage form are calcium stearate and magnesium stearate. None of
these excipients adversely affected active compound solubility.
Example 6
Osmotic Agent Selection Based on Active Compound Solubility
Screening
[0308] The ability of selected osmotic agents (osmogens), to
maintain the solubility of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hex-
ahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-iso-
butyramide L-tartrate above 150 mg/ml was demonstrated in solutions
of the candidate osmogen. The active compound solubility screening
experiment was designed so that filtrates from saturated osmogen
solutions were visually monitored for precipitation over 5 minute
intervals following each of three incremental additions of 50 mg/ml
of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate solution. The active compound solubility measured in
this manner exceeded 150 mg/ml. Preferred excipients were selected
based on their ability to maintain
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,-
3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-ox-
o-ethyl]-isobutyramide L-tartrate solubility above 150 mg/ml.
Methods
[0309] This example illustrates a method to select the osmotic
agent for osmotic dosage forms that have the ability to maintain
the solubility of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2-methyl-3-oxo-2,3,3a,4,6,7-he-
xahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-is-
obutyramide L-tartrate above 150 mg/ml while minimizing the
potential degradation of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-he-
xahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-is-
obutyramide L-tartrate by the reducing sugar class of osmogens. The
osmogens were screened by preparing a saturated solution (unless
otherwise noted) of the candidate osmogen in water at 37.degree. C.
for 2 hours, and filtering the undissolved portion as described in
Example 5. The active compound substance solubility was then
determined by visual observation over the range of 0-50,
50-100,100-150, or >150 mgA/ml (Table 6-1).
Results
[0310] The results of the solubility test are listed in Table 6-1.
Most of the osmogens evaluated successfully maintained the
solubility of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutylramide
L-tartrate above 150 mg/ml with the exception of fructose and
xylitol.
13TABLE 6-1 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl- 3-oxo-2,3,3a
4,6,7-hexahydro-pyrazolo[4,
3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo- ethyl]-isobutyramide
L-tartrate (Compound A) solubility in saturated osmogen solutions
maintained at 37.degree. C. upon three incremental additions of 50
mgA/ml Approximate Osmogen COMPOUND A Solubility Osmogen
Concentration (mg/ml) (mg/ml) Fructose 250 (a) <50 Lactose 200
>150 Mannitol 180 >150 Sodium bitartrate 110 >150 Sorbitol
250 (a) >150 Xylitol 250 (a) <50 (a) excipient solution
prepared below saturation, at 250 mg/ml
[0311] Preferred osmogens, based on the solubility screening test,
are lactose, mannitol, sodium bitartrate and sorbitol. Further
preferred osmogens, based on the ability of (cyclic) reducing
sugars to degrade active compound substances with amines, are
mannitol, sodium bitartrate, and sorbitol. Some sustained-release
dosage forms with such osmogens in the tablet formulation can
perform better than those without such osmogens. This is
particularly true for osmotic-based formulations.
Example 7
Sustained Release Tablets
[0312] This example illustrates a process for making osmotic
tablets comprising a tablet core containing
2-amino-N-[2-(3a-(R)-benzyl-2-methyl--
3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxym-
ethyl-2-oxo-ethyl]-isobutyramide L-tartrate surrounded by a
semi-permeable asymmetric membrane coating. The processing of the
core tablet comprised (1) blending of core components as designated
in Table 7-1, except for magnesium stearate; (2) screening and
reblending the same components; (3) adding and blending magnesium
stearate; (4) compressing core tablets; (5) spraying an asymmetric
membrane coating to the core tablets; and (6) drying.
[0313] In batch sizes of 15-90 grams,
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-
-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxy-
methyl-2-oxo-ethyl]-isobutyramide L-tartrate was blended in a
suitable jar with all other components except magnesium stearate
for 10 minutes using a Turbula shaker system (Willy A. Bachofen,
Basel, Switzerland). Next, the blend was passed through a 30-35
mesh screen and blended again for 10 minutes. Then, magnesium
stearate was added and blended for 3 minutes. Using a conventional
tablet press (Manesty F-Press, Manesty Machines, Liverpool,
England), the final blend was compressed into tablets using
{fraction (5/16)} inch or 3/8 inch standard round concave (SRC)
punches for the 200 or 333.3 mg tablet weights, respectively. A
summary of the compositions manufactured by direct compression of
the formulation blend at 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyr-
amide L-tartrate per tablet is shown in Examples 7A-7K, as detailed
in Table 7-1. Significant core compositional changes included the
type and amount of acid or osmogen. The amount of binder and
lubricant were varied accordingly to obtain good tableting
properties.
[0314] A semi-permeable membrane coating (as described in U.S. Pat.
No. 5,612,059) was applied to these tablets using a HCT-30
explosion-proof pan coater (Vector Corporation, Marion, Iowa)
operated at a spray rate of 20 grams per minute, an inlet
temperature of 40-45.degree. C. and air flow rate of 30 cfm
(14158.43 cm.sup.3/sec). The coating formulation applied to
Examples 7A-7H consisted by weight of 10% cellulose acetate
(Eastman Chemical, CA-398-10, Kingsport, Tenn.), 2.5% polyethylene
glycol (PEG3350, Union Carbide Corporation, Charleston, W. Va.),
15% water, and 72.5% acetone. For Examples 7I, 7J, and 7K, the
coating formulation applied to the tablets consisted of 9/3/19/69,
6/4/23/67, and 6/4/23/67 percent by weight of cellulose acetate,
polyethylene glycol, water, and acetone, respectively (Table 7-1).
The coated tablets were dried in the coater for 10-15 minutes at an
inlet temperature set point of 60.degree. C. and/or dried in an
oven for 16 hours at 50.degree. C. before testing for dissolution
performance. After drying, the weight of the applied coating
material was determined based on a percentage of the initial core
tablet weight. These tablets contained a
2-amino-N-[2-(3a-(R)-benzyl-2-me-
thyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzy-
loxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate dose of 10
mg/tablet, and are examples of sustained release formulations.
14 TABLE 7-1 Asymmetric Core Composition Membrane Core Acid/
Coating Ex Wt Dose Solubilizer Osmogen Avicel MgSt Wt % No. (mg)
mgA Type Wt % Type Wt % Wt % Wt % (dry wt %) 7A 200 10 none --
lactose 63 30 0.5 11.5 7B 200 10 none -- mannitol 63 30 0.5 12.0 7C
200 10 tartaric 50 mannitol 20 23 0.5 12.1 7D 200 10 fumaric 20
sorbitol 50 22.5 1.0 13.8 7E 200 10 fumaric 20 mannitol 50 23 0.5
11.4 7F 200 10 fumaric 20 mannitol 50 23 0.5 22.6 7G 200 10
succinic 20 sorbitol 50 22.5 1.0 11.5 7H 200 10 none -- NaBT 62.5
30 1.0 17.1 7I 200 10 fumaric 20 mannitol 50 22 1.5 11.2 7J 333.3
10 fumaric 12 mannitol 34 48.6 1.5 14.7 7K 333.3 10 fumaric 16
mannitol 44 34.6 1.5 12.7 MgSt means magnesium stearate NaBT means
sodium bitartrate
Example 8
In Vitro Performance of Sustained Release Tablets
[0315] All sustained release asymmetric membrane tablets from
Example 7 were tested for active compound release performance using
dissolution procedures with analysis by reverse-phase high
performance liquid chromatography (RP HPLC). The sustained release
dosage forms were tested in a standard USP rotating paddle
apparatus as disclosed in United States Pharmacopeia XXIII (USP)
Dissolution Test Chapter 711, Apparatus 2. Paddles were rotated at
50 rpm (unless noted as 100 or 150 rpm) and the dissolution was
conducted in, as test medium, 900 ml of either simulated gastric
fluid without enzyme pH 1.2 (sgn) or simulated intestinal fluid
without enzyme pH 7.5 (sin) at 37.degree. C. The dissolution, or in
vitro, test medium was prepared as disclosed in USP XXIII Test
Solutions on page 2053, 1995. Simulated gastric fluid without
enzyme (sgn) was prepared by dissolving 2.0 grams of sodium
chloride in 7.0 ml of hydrochloric acid, and subsequently diluted
to 1000 ml with water to form a pH 1.2 solution. The simulated
intestinal fluid without enzyme (sin) was prepared by dissolving
6.8 grams of monobasic potassium phosphate in 250 ml of water,
mixing, and adding 190 ml of 0.2N sodium hydroxide and 400 ml of
water that was adjusted with 0.2N sodium hydroxide to a pH of 7.5
and diluted to 1000 ml with water. The sin and sgn test protocols
are well know to those skilled in the art and are set forth in the
United States Pharmacopoeia (USP).
[0316] At indicated times following test initiation (i.e.,
insertion of the dosage form into the apparatus), filtered aliquots
(typically 2 or 10 mL) from the test medium were withdrawn and
analyzed for
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate by RP HPLC as disclosed below. Dissolution results are
reported as mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-he-
xahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-is-
obutyramide L-tartrate dissolved versus time or percent of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate dissolved versus time.
[0317]
2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-p-
yrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyrami-
de L-tartrate quantification of the in vitro dissolution test
samples described above was conducted by RP HPLC as follows. An
aliquot of test solution was filtered to remove particulates. A
fixed volume of 25 .mu.l was injected onto the analytical column
(15 cm length.times.3.9 mm diameter Waters Symmetry C8 column,
Waters Company, Milford, Mass.) containing a 5 micron stationary
phase. The mobile phase was composed of perchloric acid, water, and
acetonitrile in volume percentages of 0.37/74.63/25.0. The mobile
phase was prepared by adding 5 ml of perchloric acid to 1000 ml
distilled water with stirring. Then, 750 ml of this aqueous
perchloric acid solution was volumetrically measured and added to
250 ml acetonitrile while stirring. After mixing well, the mobile
phase was degassed under reduced pressure with continuous stirring
or ultrasonic agitation for 5 minutes. The mobile phase flow rate
through the HPLC column was 2.0 ml/min with detection at 210
nm.
[0318] The results of the active compound release rate tests
performed using the procedures described above are listed in Table
8-1. Dosage forms containing an osmogen but no acid (Examples 7A is
lactose, 7B is mannitol, and 7H is sodium bitartrate) released 85%
of the dose in 16, 12 and 24 hrs, respectively. The sustained
release in vitro boundaries corresponding to the C.sub.max criteria
are about 5.56 to about 16.67%/hr and corresponding to .DELTA.T
criteria are about 5.56 to about 25%/hr for about a 10 mg dose. The
lack of an acid in the core formulation with low osmotic pressure
producing agents (lactose and sodium bitartrate of Example 7A and
7H, respectively) resulted in a failure to meet the in vitro
criteria, and therefore such formulations are not embodiments of
this invention. The addition of an acid or solubilizer to the core
tablet formulation was found to enhance the initial active compound
release rate up through 8 hours increasing in order of the acid
solubility from fumaric to succinic to tartaric acid. The increase
in acid and osmogen content in the core tablet from about 12 to
about 16% fumaric acid and about 34 to about 44% mannitol in
Examples 7J and 7K significantly increased active compound release
rates during 8-16 hours. Increasing the weight percent of coating
applied to the tablet (from about 11.4 to about 22.6% in Example 7E
and 7F, respectively) resulted in the greatest reduction in active
compound release for every in vitro time point. For the core
formulation of 7E and 7F, dosage forms coated in excess of 20 wt %
did not meet the in vitro criteria stated above, and therefore
Example 7F is not an embodiment of this invention. The active
compound release rate was not dependent on the test medium (either
SGN or SIN), or agitation rate (50, 100, and 150 rpm) typical of
osmotic-based formulations.
15TABLE 8-1 Asymmetric Membrane (AM) Coated Tablet Calc'd Pass In
Tablet In Fraction of Active Compound Release (%) At Release Vitro
Ex. Vitro Specified Time (hr) Rate Criteria No. Media 0 2 4 8 12 16
24 (%/hr) (C.sub.max, .DELTA.T) 7A sgn 0 5.6* 28.5 55.0 72.9 83.0
92.4 5.2 no, no 7B sgn 0 8.9* 39.1 68.5 85.5 91.5 97.3 7.1 yes, yes
7C sgn 0 33.6 56.6 75.5 80.1 81.8 85.4 6.7 yes, yes 7D sgn 0 38.4
60.9 81.2 88.1 91.8 95.2 10.2 yes, yes 7E sgn 0 17.0 35.0 62.3 79.4
86.3 93.1 6.6 yes, yes 7F sgn 0 3.5 13.5 34.5 52.0 66.8 77.9.sup.#
3.9 no, no 7G sgn 0 41.2 68.5 85.7 92.8 94.5 99.4 10.7 yes, yes 7H
sgn 0 7.0 16.3 35.8 52.8 64.9 84.7 3.5 no, no 7I sgn 0 18.4 34.3
62.1 82.0 94.5 96.2 6.8 yes, yes 7I sin 0 13.4 29.6 55.9 76.3 88.8
100 5.9 yes, yes 7I sin; 100 rpm 0 12.3 28.4 54.4 74.0 86.7 96.4
5.7 yes, yes 7I sin; 150 rpm 0 11.3 27.3 53.9 73.5 86.3 96.1 5.7
yes, yes 7J sgn 0 15.5 29.2 58.4 80.9 92.1 100 6.7 yes, yes 7J sin
0 13.0 23.9 49.6 71.9 86.4 96.7 5.6 yes, yes 7K sin 0 15.4 29.7
60.1 82.5 93.4 99.4 6.8 yes, yes sgn means simulated gastric fluid,
pH 1.2 sin means simulated intestinal fluid, pH 7.5 *release
measured at 1 hour instead of 2 hour .sup.#release measured at 20
hours instead of 24 hour
[0319] Preferred sustained release osmotic dosage forms of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate contain an osmotic agent producing osmotic pressures
similar to or above 38 atmospheres (mannitol, sorbitol), or contain
an organic acid such as fumaric, succinic or tartaric acid to
enhance initial release performance. Preferred coating levels for
the sustained release osmotic dosage forms are formulation and
tablet size dependent, and must be less than 20 wt % for Example 7E
and 7F. With the exception of Examples 7A, 7F, and 7H, all
formulations listed in Table 8-1 demonstrate sustained release of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,-
6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-eth-
yl]-isobutyramide L-tartrate and are embodiments of this
invention.
Example 9
Sustained Release Tablets
[0320] This example illustrates a method for making formulations of
10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate osmotic tablets comprising a tablet core containing
active compound surrounded by a semi-permeable asymmetric membrane
coating. The processing of the core tablet comprised (1) blending
of core components as designated in Table 9-1, except for magnesium
stearate; (2) milling and reblending the same components; (3)
adding and blending a portion of the magnesium stearate; (4) dry
granulating; (5) milling/screening and reblending; (6) adding and
blending the remaining portion of magnesium stearate; (7)
compressing core tablets; (8) spraying an asymmetric membrane
coating to the core tablets; and (9) drying.
[0321] In batch sizes of 2-57 kilograms,
2-amino-N-[2-(3a-(R)-benzyl-2-met-
hyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyl-
oxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate was blended with
all other components except magnesium stearate for 15 minutes in a
suitable sized stainless steel twin-shelled blender [8 quart (7.6
L) to 5 cubic feet (141.9 L)]. Next, the blend was passed through a
mill (Fitz model JT or D mill fitted with #1A plate, medium speed,
knives forward) and blended again for 30 minutes. Then, magnesium
stearate was added and blended for 5 minutes. The partially
lubricated blend was dry granulated using a roller compactor
(Freund TF-Mini or TF-156 roller compacter, Freund Industrial Co.)
with auger screw feed of 8-12 rpm, pressure 40-25 kg/cm.sup.2, and
roller speed of 5-12 rpm. The roller compactor was fitted with an
oscillating roller granulator screen size of 20-30 mesh to mill the
compacted ribbons. Next, the granulation was blended for 20 minutes
before the last portion of magnesium stearate was added and
reblended for 5 minutes.
[0322] Using a conventional tablet press (Kilian T100 or LX21,
Kilian and Co., Inc, Horsham, Pa.), the final blend was compressed
into tablets using {fraction (5/16)} or 3/8 inch standard round
concave (SRC) punches for the 200 or 333.3 mg tablet weights,
respectively. A summary of the compositions manufactured by dry
granulation of the preferred formulation blend at 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-he-
xahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]iso-
butyramide L-tartrate per tablet is shown in Example 9A-9C, as
detailed in Table 9-1. The more preferred formulation for the core
tablet is 9C.
16 TABLE 9-1 Core Composition Example Core Wt Dose Acid/Solubilizer
Osmogen Avicel MgSt No. (mg) (mgA) Type Wt % Type Wt % Wt % Wt %
9A, 9B 333.3 10 fumaric 12 mannitol 34 48.6 1.5 9C 200 10 fumaric
20 mannitol 50 22.0 1.5 MgSt means magnesium stearate
[0323] A semi-permeable membrane coating (as described in U.S. Pat.
No. 5,612,059) was applied to these tablets using a HCT-30 or
HCT-60 explosion-proof pan coater (Vector Corporation, Marion,
Iowa). The small scale coating pan, HCT-30, was operated at a spray
rate of 20 grams per minute, an inlet temperature of 40-45.degree.
C. and air flow rate of 30 cfm (14158.43 cm.sup.3/sec). The larger
coating pan, HCT-60, was operated at a spray rate of 180 grams per
minute divided between 2 guns, an inlet temperature of 55.degree.
C. and air flow rate of 300 cfm. The asymmetric membrane coating
formulations applied to the 10 mgA core tablet provided a short
duration which released 80% of the dose in 10-12 hrs and a long
duration that released 80% in 20-24 hrs. The short and long
duration coatings for the 10 mgA tablets in Example 9A and 9B
consisted of cellulose acetate/polyethylene glycol/water/acetone
ratios of 6/4/23/67 (w/w) coated to an increase in the initial
weight of 15.5 and 18.6%, respectively (Table 9-2). For the more
preferred 10 mg tablet core (9C), the short duration coating
formulation was composed of 9/3/19/69 applied to 19.5 wt % (Table
9-2). The coated tablets were dried in the coater for 15 minutes at
an inlet temperature set point of 60.degree. C. and dried in an
oven (Gruenberg solvent tray oven, Gruenberg Oven Company,
Williamsport, Pa.) for 16 hours at 50.degree. C. before testing for
dissolution performance. After drying, the weight of the applied
coating material was determined based on a percentage of the
initial core tablet weight.
17TABLE 9-2 Ex- Coating am- Core Osmotic Coating Solution Weight
ple Weight Dose CA PEG Water Acetone (dry wt No. (mg) (mgA) (wt %)
(wt %) (wt %) (wt %) %) 9A 333.3 10 6 4 23 67 15.5 9B 333.3 10 6 4
23 67 18.6 9C 200.0 10 9 3 19 69 19.5 CA means cellulose acetate
(Eastman Chemical, CA-398-10, Kingsport, TN) PEG means polyethylene
glycol (BASF, PEG3350, Union Carbide Corporation, Charleston,
WV)
Example 10
In Vitro Performance of Sustained Release Tablets
[0324] The sustained release asymmetric membrane tablets from
Example 9 were tested for active compound release performance using
dissolution procedures described in Example 8. The results of the
active compound release rate tests performed using those procedures
are listed in Table 10-1.
[0325] The sustained release in vitro boundaries corresponding to
the C.sub.max criteria are 5.56-16.67%/hr and corresponding to
.DELTA.T criteria are 5.56-25%/hr for a 10 mg dose. For the 333.3
mg tablet, increased coating level from 15.5 to 18.6% resulted in a
reduction in release rate from 5.7 to 4.1%/hr in SIN media. The
higher coating level of 18.6% in Example 9B resulted in a failure
to meet the in vitro boundaries, and therefore is not an embodiment
of this invention.
[0326] Preferred coating level is formulation and tablet size
dependent, and must be less than 18 wt % for the 333 mg tablet.
Examples 9A and 9C listed in Table 10-1 demonstrate sustained
release of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4.3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate and are embodiments of this invention.
[0327] The more preferred osmotic dosage form for the 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate asymmetric membrane coated tablet is exemplified by
Example 3C, in which the core tablet size is smaller, which allows
for use of a coating formulation with higher polymer-to-plasticizer
ratio.
18TABLE 10-1 Asymmetric Membrane (AM) Coated Tablet Calc'd Pass In
Tablet In Fraction of Active Compound Release (%) At Release Vitro
Ex. Vitro Specified Time (hr) Rate Criteria No. Media 0 2 4 8 12 16
24 (%/hr) (C.sub.max, .DELTA.T) 9A sgn 0 11.3 24.0 53.7 77.8 92.4
101 6.5 yes, yes 9A sin 0 9.8 20.4 46.8 71.1 87.5 99.9 5.7 yes, yes
9B sin 0 4.3 12.7 33.1 55.0 72.9 91.8 4.1 no, no 9C sgn 0 5.1* 34.5
63.6 81.1 91.1 97.7 6.7 yes, yes 9C sin 0 4.8* 31.7 58.8 77.3 89.1
98.1 5.9 yes, yes 9C 0.1N 0 5* 33 61 80 90 96 6.7 yes, yes HCl sgn
means simulated gastric fluid, pH 1.2 sin means simulated
intestinal fluid, pH 7.5 *means sample analyzed at 1 hour instead
of 2 hours n = 3-6 tablets
Example 11
Simulated Sustained-Release Delivery Input Rates and Doses which
Give Maximum
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-
-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyra-
mide L-tartrate Concentrations <80% of Immediate Release and
Exceed a Minimum Effective Plasma Concentration, C.sub.min, of 2
ng/ml.
[0328] This example illustrates the process for simulating active
compound delivery input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a-
,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo--
ethyl]-isobutyramide L-tartrate from sustained release dosage forms
that give maximum plasma concentrations not more than 80% of an
equivalent immediate release bolus dose and greater than a minimum
effective concentration of 2 ng/ml (C.sub.min). For some
indications, a lower plasma concentration may be adequate for
therapy. The sustained release profile is simulated as a zero-order
release through hourly pulses of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate over the specified release duration. For example, a
hypothetical sustained release (SR) formulation that delivered the
dose by zero-order for 6 hours was approximated by the pulsed
hourly administration of 1/6 of the total dose at 0, 1, 2, 3, 4,
and 5 hours. In these simulations, the two variables studied
included the dosage strengths from 4 to 48 mg and sustained release
durations from 4 to 18 hours. The resulting maximum
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2-
,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-
-oxo-ethyl]-isobutyramide L-tartrate plasma concentration simulated
for each of these sustained release dosage forms, C.sub.max,sr, are
reported in Tables 11-1 to 11-7 for dosage strengths of 4, 6, 8,
12, 16, 24, and 48 mg, respectively. These results were evaluated
according to the criteria specified above: C.sub.max,sr not more
than 80% C.sub.max,ir, and plasma concentration greater than
C.sub.min at any time. Those examples that meet both criteria, and
reported as "yes" in the tables are embodiments of this invention.
(IR refers to immediate release dosing, and SR refers to sustained
release dosing.)
Methods
[0329] A one compartment pharmacokinetic model was constructed
using the following equations (I Think, Stella, HPS, Hanover,
N.H.):
active compound_at.sub.--absn_site(t)=active
compound_at.sub.--absn_site(t- -dt)+(dosing-absorption)*dt
INIT active compound_at_absn_site=0
dosing=pulse(dose*ba,0,999)
absorption=active compound_at_absn_site*ka_hr1
active compound_in_plasma_mg(t)=active
compound_in_plasma_mg(t-dt)+(absorp- tion-elimination)*dt
INIT active compound_in_plasma_mg=0
absorption=active compound_at_absn_site*ka_hr1
elimination=elim_rate_const*active compound_in_plasma_mg
active compound_in_urine(t)=active
compound_in_urine(t-dt)+(elimination)*d- t
INIT active compound_in_urine=0
elimination=elim_rate_const*active compound_in_plasma_mg
ba=1
dose=0.3
elim_rate_const=0.693/thalf_hr
ka_hr1=1.3
plasma_conc_ugml=active compound_in_plasma_mg/Vdist_liter
thalf_hr=2.5
Vdist.sub.--liter=0.75
[0330] where ba is bioavailability (1.0), Vdist_liter is volume of
distribution in units of liters (0.75), ka_hr1 is absorption rate
constant in units of reciprocal hr (1.3), and thalf_hr is the
plasma concentration vs. time elimination half-life in units of hr
(2.5). All other equations are basic pharmacokinetic relationships
(M. Gibaldi and D. Perrier, Pharmacokinetics, 2.sup.nd Ed. "Active
Compounds And The Pharmaceutical Sciences", Editor: J. Swarbrick,
Vol. 15, 1982, NY, Marcel Dekker, Inc.).
[0331] The bioavailability, volume of distribution, half-life and
absorption rate constant were varied until the simulated plasma
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate concentrations agreed reasonably well with the average
observed plasma
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-h-
exahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate concentrations following oral
administration of 10, 3 and 0.3 mg doses to humans. These
parameters were then fixed to the values noted above for all
subsequent simulations.
[0332] The validated model was then exported to the software
Madonna for Windows (6.0, Robert I. Macey & George F. Oster,
Berkeley, Calif.) as a text file. This is a specialized program
which can perform multiple simulations using models created in I
Think and Stella. Multiple simulations of IR formulations at doses
of 4, 8, 12, 16, 18, 24 and 48 mg were completed. The maximum
plasma concentration (C.sub.max) was read from the graph. The times
at which the simulated plasma
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate concentration first exceeded 2 ng/ml (T1) and then
subsequently fell below 2 ng/ml (T2) were also read from the graph.
The difference between these two values represented the time during
which plasma
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro--
pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyram-
ide L-tartrate concentrations were >2 ng/ml
(.DELTA.T.sub.T2-T1). These values of C.sub.max and .DELTA.T.sub.ir
after IR administration were then compared to corresponding values
after simulations of SR formulations and after IR/SR hybrid
formulations. The remainder of this Example, and Examples 12-14
describe the difference in C.sub.max and .DELTA.T among these
formulations.
[0333] The model was then further modified to allow the simulation
of plasma
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro--
pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyram-
ide L-tartrate release following oral administration of
hypothetical SR formulations. The zero-order delivery by these
hypothetical formulations were approximated through hourly pulses
of 2amino-N-[2-(3a-(R)-benzyl-2-m-
ethyl-3-oxo-2,3,3a4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzy-
loxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate. For example, a
hypothetical SR formulation which delivered the dose by zero-order
for 6 hr was approximated by the pulsed hourly administration of
1/6 of the total dose at 0, 1, 2, 3, 4 and 5 hr. This was
accomplished with the addition of the following equations:
Tend=6
mr=pulse(dose/(Tend),0,1)
dosing=if time<(Tend-1)then mr else 0
[0334] where Tend is the hypothetical time when 100% of the dose
was delivered (e.g., 6 hr).
Results
[0335] The simulation results were evaluated according to the
following criteria: i) the maximum concentration following
sustained release dosing of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyra-
zolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate must be no more than 80% of L-tartrate must be no more
than 80% of an equivalent immediate release bolus; and ii) the
plasma concentration must exceed a minimum effective concentration
of 2 ng/ml at any time after dosing. Both of these criteria must be
satisfied in order for the simulated profile to exemplify an
embodiment of this invention.
[0336] The data in Tables 11-1 through 11-7 demonstrate the zero
order release rates, in mg/kg/hr, of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-
-2,3,3a,4,6,7hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl--
2-oxo-ethyl]-isobutyramide L-tartrate from sustained release dosage
forms, where kg refers to the weight of the patient. The zero order
release rate was calculated from the dosing rate for a 70 kg human.
The simulation results are illustrated in Tables 11-1 to 11-7 for
dosage strengths of 4, 6, 8, 12, 16, 24, and 48 mg,
respectively.
[0337] For the 4 mg dose, release rates of 4 to 10 hours were
simulated and evaluated according to the above specified criteria
(Table 11-1). For this case, the above model would simulate the
plasma-time profile after the oral administration of 6 hourly
pulses of 0.67 mg each. The C.sub.max simulated for a 6 hr SR
formulation of 4 mg was 2.5 ng/ml. The dosing rate per 70 kg human
for this 4 mg dose delivered over 6 hr=4 mg/6 hr/70 kg=0.010
mg/hr/kg. For the 4 mg dose, zero order release rates of 0.007 to
0.010 mg/kg/hr, or 6 to 8 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention.
19TABLE 11-1 Zero Order Release Rates Of 2-Amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,
6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-
1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate From
Sustained Release Dosage Forms That Result In No More Than 80% Of
The Maximum Plasma Concentration Produced By An Equivalent Dose Of
Immediate Release Bolus (IR Dose = 4 mg With C.sub.max = 3.5 ng/ml)
And Above C.sub.min (2 ng/ml). Zero-Order Sustained Release Release
Rate Duration C.sub.max,sr C.sub.max,sr < 80% (mg/hr/kg) (hrs)
(ng/ml) C.sub.max,ir C > C.sub.min 0.006 10 1.8 yes no 0.007 8
2.1 yes yes 0.010 6 2.5 yes yes 0.014 4 2.9 no yes
[0338] Similarly, simulations for the 6 mg dose delivered over 4 to
14 hour resulted in the values of C.sub.max listed in Table 11-2.
For the 6 mg dose, zero order release rates of 0.007 to 0.014
mg/kg/hr, or 12 to 6 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention.
20TABLE 11-2 Zero Order Release Rates Of 2-Amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,
6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-
1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate From
Sustained Release Dosage Forms That Result In No More Than 80% Of
The Maximum Plasma Concentration As An Equivalent Dose Of Immediate
Release Bolus (IR Dose = 6 mg With C.sub.max = 5.4 ng/ml) And Above
C.sub.min (2 ng/ml). Zero-Order Sustained Release Release Rate
Duration C.sub.max,sr C.sub.max,sr < 80% (mg/hr/kg) (hrs)
(ng/ml) C.sub.max,ir C > C.sub.min 0.0061 14 1.9 yes no 0.0071
12 2.3 yes yes 0.009 10 2.7 yes yes 0.011 8 3.2 yes yes 0.014 6 3.7
yes yes 0.021 4 4.4 no yes
[0339] Similarly, simulations for the 8 mg dose delivered over 4 to
20 hr resulted in the values of C.sub.max listed in Table 11-3. For
the 8 mg dose, zero order release rates of 0.0063 to 0.019
mg/kg/hr, or 18 to 6 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention.
21TABLE 11-3 Zero Order Release Rates Of 2-Amino-N-[2-(3a-(R)-
benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro- -pyrazolo-
[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-
isobutyramide L-tartrate From Sustained Release Dosage Forms That
Result In No More Than 80% Of The Maximum Plasma Concentration As
An Equivalent Dose Of Immediate Release Bolus (IR Dose = 8 mg With
C.sub.max = 7.0 ng/ml) And Above C.sub.min (2 ng/ml). Zero-Order
Sustained Release Release Rate Duration C.sub.max,sr C.sub.max,sr
< 80% (mg/hr/kg) (hrs) (ng/ml) C.sub.max,ir C > C.sub.min
0.0057 20 1.8 yes no 0.0063 18 2.2 yes yes 0.008 14 2.7 yes yes
0.011 10 3.6 yes yes 0.019 6 5.0 yes yes 0.029 4 5.9 no yes
[0340] Similarly, simulations for the 12 mg dose delivered over 4
to 18 hr resulted in the values of C.sub.max listed in Table 11-4.
For the 12 mg dose, zero order release rates of 0.010 to 0.029
mg/kg/hr, or 18 to 6 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention. In this case, some
lower release rates will also embody the invention. These lower
release rates may be determined using the simulation methodology
described in these Examples.
22TABLE 11-4 Zero Order Release Rates Of 2-Amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,
6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-
1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate From
Sustained Release Dosage Forms That Result In No More Than 80% Of
The Maximum Plasma Concentration As An Equivalent Dose Of Immediate
Release Bolus (IR Dose = 12 mg With C.sub.max = 10.8 ng/ml) And
Above C.sub.min (2 ng/ml). Zero-Order Sustained Release Release
Rate Duration C.sub.max,sr C.sub.max,sr < 80% (mg/hr/kg) (hrs)
(ng/ml) C.sub.max,ir C > C.sub.min 0.010 18 3.2 yes yes 0.012 14
4.1 yes yes 0.017 10 5.4 yes yes 0.029 6 7.5 yes yes 0.043 4 8.9 no
yes
[0341] Similarly, simulations for the 16 mg dose delivered over 4
to 18 hr resulted in the values of C.sub.max listed in Table 11-5.
For the 16 mg dose, zero order release rates of 0.013 to 0.038
mg/kg/hr, or 18 to 6 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention. In this case, some
lower release rates will also embody the invention. These lower
rates may be determined using the simulation methodology described
in these Examples.
23TABLE 11-5 Zero Order Release Rates Of 2-Amino-n-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin- 5-yl)-1-(R)-benzyloxymethy-
l-2-oxo-ethyl]- isobutyramide L-tartrate From Sustained Release
Dosage Forms That Results In No More Than 80% Of The Maximum Plasma
Concentration As An Equivalent Dose Of Immediate Release Bolus (IR
dose = 16 mg with C.sub.max = 14.0 ng/ml) and above C.sub.min (2
ng/ml). Zero-Order Sustained Release Release Rate Duration
C.sub.max,sr C.sub.max,sr < 80% (mg/hr/kg) (hrs) (ng/ml)
C.sub.max,ir C > C.sub.min 0.013 18 4.3 yes yes 0.016 14 5.4 yes
yes 0.023 10 7.2 yes yes 0.038 6 10.0 yes yes 0.057 4 11.8 no
yes
[0342] Similarly, simulations for the 24 mg dose delivered over 4
to 18 hr resulted in the values of C.sub.max listed in Table 11-6.
For the 24 mg dose, zero order release rates of at least 0.019 to
0.057 mg/kg/hr, or 18 to 6 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention. In this case, some
lower release rates will also embody the invention. These lower
rates may be determined using the simulation methodology described
in these Examples.
24TABLE 11-6 Zero Order Release Rates Of 2-Amino-n-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,
6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-
1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate From
Sustained Release Dosage Forms That Results In No More Than 80% Of
The Maximum Plasma Concentration As An Equivalent Dose Of Immediate
Release Bolus (IR dose = 24 mg with C.sub.max = 21.6 ng/ml) and
above C.sub.min (2 ng/ml). Zero-Order Sustained Release Release
Rate Duration C.sub.max,sr C.sub.max,sr < 80% (mg/hr/kg) (hrs)
(ng/ml) C.sub.max,ir C > C.sub.min 0.019 18 6.4 yes yes 0.024 14
8.1 yes yes 0.034 10 10.8 yes yes 0.057 6 15.0 yes yes 0.086 4 17.7
no yes
[0343] Similarly, simulations for the 48 mg dose delivered over 4
to 18 hr resulted in the values of C.sub.max listed in Table 11-7.
For the 48 mg dose, zero order release rates of at least 0.038 to
0.114 mg/kg/hr, or 18 to 6 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention. In this case, some
lower release rates will also embody the invention. These lower
rates may be determined using the simulation methodology described
in these Examples.
25TABLE 11-7 Zero Order Release Rates Of 2-Amino-n-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,
6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-
1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate From
Sustained Release Dosage Forms That Result In No More Than 80% Of
The Maximum Plasma Concentration As An Equivalent Dose Of Immediate
Release Bolus (IR dose = 48 mg with C.sub.max = 42.2 ng/ml) and
above C.sub.min (2 ng/ml). Zero-Order Sustained Release Release
Rate Duration C.sub.max,sr C.sub.max,sr < 80% (mg/hr/kg) (hrs)
(ng/ml) C.sub.max,ir C > C.sub.min 0.038 18 13.0 yes yes 0.049
14 16.4 yes yes 0.069 10 21.7 yes yes 0.114 6 30.0 yes yes 0.171 4
35.4 no yes
[0344] Exemplary sustained release durations of
2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-
-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate delivered
from sustained release dosage forms, based on these simulations,
are about 6 to about 8 hours for about a 4 mg dose, about 6 to
about 12 hours for about a 6 mg dose, about 6 to about 18 hours for
doses of about 8, 12, 16, 24 and 48 mg.
[0345] Exemplary in vivo input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-meth-
yl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzylo-
xymethyl-2-oxo-ethyl]isobutyramide L-tartrate delivered from
sustained release dosage forms, based on these simulations, are
about 0.007 to about 0.010 mg/hr/kg for about a 4 mg dose, about
0.007 to about 0.014 mg/hr/kg for about a 6 mg dose, about 0.006 to
about 0.019 mg/hr/kg for about an 8 mg dose, about 0.010 to about
0.029 mg/hr/kg for about a 12 mg dose, about 0.013 to about 0.038
mg/hr/kg for about a16 mg dose, about 0.019 to about 0.057mg/hr/kg
for about a 24 mg dose, and about 0.038 to about 0.114 mg/hr/kg for
about a 48 mg dose.
[0346] Exemplary zero order in vitro release rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate delivered from sustained release dosage forms, based on
these simulations, are about 0.50 to about 0.67 mg/hr for about a 4
mg dose, about 0.50 to about 1.00 mg/hr for about a 6 mg dose,
about 0.44 to about 1.33 mg/hr for about an 8 mg dose, about 0.67
to about 2.00 mg/hr for about a 12 mg dose, about 0.89 to about
2.67 mg/hr for about a 16 mg dose, about 1.33 to about 4.00 mg/hr
for about a 24 mg dose, and about 2.67 to about 8.00 mg/hr for
about a 48 mg dose, for a 70 kg patient, such as a human patient.
Exemplary release rates may be computed similarly for patients with
different weights.
Example 12
Simulated Sustained-Release Delivery Input Rates and Doses which
Maintain
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate Concentrations Above 2 ng/ml for a Length of Time Longer
than Immediate Release
[0347] This example illustrates the process for simulating active
compound delivery input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a-
,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo--
ethyl]-isobutyramide L-tartrate from sustained release dosage forms
which maintain concentrations above 2 ng/ml for a length of time
longer than an equivalent immediate release dose by at least 30
minutes. The sustained release profile is simulated as a zero-order
release through hourly pulses of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahyd-
ro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]isobutyr-
amide L-tartrate over the specified release duration. In these
simulations, the two variables studied included the dosage
strengths from 6 to 48 mg and sustained release durations from 4 to
18 hours. The resulting duration over which
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo--
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl--
2-oxo-ethyl]-isobutyramide L-tartrate plasma concentrations exceed
the C.sub.min, .DELTA.T.sub.sr, is reported in Tables 12-1 to 12-6
for dosage strengths of 6, 8, 12, 16, 24, and 48 mg, respectively.
These results were evaluated according to the criteria specified
above: .DELTA.T.sub.sr not less than 30 minutes longer than
.DELTA.T.sub.ir. The examples that meet this criteria, and reported
as `yes` in the tables are embodiments of this invention.
[0348] For some therapeutic indications, the minimum effective
2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-
[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate plasma concentration may be lower than 2 ng/ml, e.g., 1
ng/ml. The simulation methodology may be used to determine active
compound delivery rates which meet the .DELTA.T criterion for any
appropriate minimum effective concentration.
Methods
[0349] Using the same methods as described to create the
simulations for Example 11, the difference between the time at
which the simulated plasma
2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-
[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate concentration first exceeded 2 ng/ml and then
subsequently fell below 2 ng/ml (.DELTA.T.sub.sr) were tabulated
for the sustained release input rates.
Results
[0350] The simulation results were evaluated according to the
following criterion. The time during which
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-o-
xo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymeth-
yl-2-oxo-ethyl]-isobutyramide L-tartrate plasma concentrations were
above the minimum effective concentration of 2 ng/ml for the
sustained release dosage form exceeded an equivalent dose of
immediate release bolus by at least 30 minutes.
[0351] The data in Tables 12-1 through 12-6 demonstrate the zero
order release rates, in mg/kg/hr, of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-
-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-
-2-oxo-ethyl]-isobutyramide L-tartrate from sustained release
dosage forms. The zero order release rate was calculated from the
dosing rate for a 70 kg human. The simulation results are
illustrated in Tables 12-1 to 12-6 for dosage strengths of 6, 8,
12, 16, 24, and 48 mg, respectively.
[0352] For the 6 mg dose, release rates of 2 to 14 hours were
simulated and evaluated according to the above specified criteria
(Table 12-1). The .DELTA.T.sub.sr simulated for a 6 hr SR duration
was 6.5 hrs, which exceeded the .DELTA.T.sub.ir=5.6 hr by 0.9 hrs.
For the 6 mg dose, zero order release rates of 0.009 to 0.021
mg/kg/hr, or 10 to 4 hr SR durations, meet both the in vivo
criteria and are embodiments of this invention.
26TABLE 12-1 Zero order release rates of 2-amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,
3a,4,6,7-hexahydro-pyrazolo[4,3-c] pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo- ethyl]-isobutyramide L-tartrate from sustained release
dosage forms that result in plasma concentrations above 2 ng/ml for
durations exceeding an equivalent dose of immediate release bolus
by at least 30 minutes (dose = 6 mg with .DELTA.T.sub.ir = 5.6 hr
and .DELTA.T.sub.sr > 6.1 hr) and above C.sub.min (2 ng/ml).
Zero-Order Sustained Release .DELTA.T.sub.sr Release Rate Duration
C > Cmin (mg/hr/kg) (hrs) (hrs) .DELTA.T.sub.sr >
.DELTA.T.sub.ir + 0.5 0.006 14 0.7 no 0.009 10 6.9 yes 0.011 8 6.8
yes 0.014 6 6.5 yes 0.021 4 6.2 yes 0.043 2 5.9 no
[0353] For the 8 mg dose, release rates of 2 to 20 hours were
simulated and evaluated according to the above specified criteria
(Table 12-2). The zero order release rates for the 8 mg dose of
0.0063 to 0.029 mg/kg/hr, or 18 to 4 hr SR durations, meet both the
in vivo criteria and are embodiments of this invention.
27TABLE 12-2 Zero order release rates of 2-amino-N-[2-
(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-
hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1- (R)-benzyloxymethyl-2-ox-
o-ethyl]-isobutyramide L-tartrate from sustained release dosage
forms that result in plasma concentrations above 2 ng/ml for
durations exceeding an equivalent dose of immediate release bolus
by at least 30 minutes (dose = 8 mg with .DELTA.T.sub.ir = 6.8 hr
and .DELTA.T.sub.sr > 7.3 hr) and above C.sub.min (2 ng/ml).
Zero-Order Sustained Release .DELTA.T.sub.sr Release Rate Duration
C > Cmin (mg/hr/kg) (hrs) (hrs) .DELTA.T.sub.sr >
.DELTA.T.sub.ir + 0.5 0.0057 20 6 no 0.0063 18 10.4 yes 0.008 14
10.2 yes 0.011 10 9.5 yes 0.014 8 8.9 yes 0.029 4 7.4 yes 0.057 2
7.2 no
[0354] For the 12 mg dose, release rates of 4 to 18 hours were
simulated and evaluated according to the above specified criteria
(Table 12-3). The zero order release rates for the 12 mg dose of at
least 0.010 to 0.043 mg/kg/hr, or 18 to 4 hr SR durations, meet
both the in vivo criteria and are embodiments of this invention.
Some release rates and durations outside this range will also
embody the invention. These may be determined using the simulation
methodology described here.
28TABLE 12-3 Zero order release rates of 2-amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin- 5-yl)-1-(R)-benzyloxymethy-
l-2-oxo-ethyl]- isobutyramide L-tartrate from sustained release
dosage forms that result in plasma concentrations above 2 ng/ml for
durations exceeding an equivalent dose of immediate release bolus
by at least 30 minutes (dose = 12 mg with .DELTA.T.sub.ir = 8.3 hr
and .DELTA.T.sub.sr > 8.8 hr) and above C.sub.min (2 ng/ml).
Zero-Order Sustained Release .DELTA.T.sub.sr Release Rate Duration
C > Cmin (mg/hr/kg) (hrs) (hrs) .DELTA.T.sub.sr >
.DELTA.T.sub.ir + 0.5 0.010 18 16.0 yes 0.012 14 14.2 yes 0.017 10
12.0 yes 0.021 8 11.3 yes 0.043 4 9.4 yes
[0355] For the 16 mg dose, release rates of 4 to 18 hours were
simulated and evaluated according to the above specified criteria
(Table 12-4). The zero order release rates for the 16 mg dose of at
least 0.013 to 0.057 mg/kg/hr, or 18 to 4 hr SR durations, meet
both the in vivo criteria and are embodiments of this invention.
Some release rates and durations outside this range will also
embody the invention. These may be determined using the simulation
methodology described here.
29TABLE 12-4 Zero order release rates of 2-amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,
3a,4,6,7-hexahydro-pyrazolo[4,3-c] pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2- oxo-ethyl]-isobutyramide L-tartrate from sustained release
dosage forms that result in plasma concentrations above 2 ng/ml for
durations exceeding an equivalent dose of immediate release bolus
by at least 30 minutes (dose = 16 mg with .DELTA.T.sub.ir = 9.3 hr
and .DELTA.T.sub.sr > 9.8 hr) and above C.sub.min (2 ng/ml).
Zero-Order Sustained Release .DELTA.T.sub.sr Release Rate Duration
C > C.sub.min (mg/hr/kg) (hrs) (hrs) .DELTA.T.sub.sr >
.DELTA.T.sub.ir + 0.5 0.013 18 18.5 yes 0.016 14 15.9 yes 0.023 10
13.7 yes 0.029 8 12.5 yes 0.057 4 10.6 yes
[0356] For the 24 mg dose, release rates of 4 to 18 hours were
simulated and evaluated according to the above specified criteria
(Table 12-5). The zero order release rates for the 24 mg dose of at
least 0.019 to 0.086 mg/kg/hr, or 18 to 4 hr SR durations, meet
both the in vivo criteria and are embodiments of this invention.
Some release rates and durations outside this range will also
embody the invention. These may be determined using the simulation
methodology described here.
30TABLE 12-5 Zero order release rates of 2-amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,
3a,4,6,7-hexahydro-pyrazolo[4,3-c] pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo- ethyl]-isobutyramide L-tartrate from sustained release
dosage forms that result in plasma concentrations above 2 ng/ml for
durations exceeding an equivalent dose of immediate release bolus
by at least 30 minutes (dose = 24 mg with .DELTA.T.sub.ir = 10.8 hr
and .DELTA.T.sub.sr > 11.3 hr) and above C.sub.min (2 ng/ml).
Zero-Order Sustained Release .DELTA.T.sub.sr Release Rate Duration
C > C.sub.min (mg/hr/kg) (hrs) (hrs) .DELTA.T.sub.sr >
.DELTA.T.sub.ir + 0.5 0.019 18 20.9 yes 0.024 14 18.2 yes 0.034 10
15.4 yes 0.043 8 14.4 yes 0.086 4 12.3 yes
[0357] For the 48 mg dose, release rates of 2 to 20 hours were
simulated and evaluated according to the above specified criteria
(Table 12-6). The zero order release rates for the 48 mg dose of at
least 0.034 to 0.343 mg/kg/hr, or 20 to 2 hr SR durations, meet
both the in vivo criteria and are embodiments of this invention.
Some release rates and durations outside this range will also
embody the invention. These may be determined using the simulation
methodology described here.
31TABLE 12-6 Zero order release rates of 2-amino-N-
[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5- yl)-1-(R)-benzyloxymethy-
l-2-oxo-ethyl]- isobutyramide L-tartrate from sustained release
dosage forms that result in plasma concentrations above 2 ng/ml for
durations exceeding an equivalent dose of immediate release bolus
by at least 30 minutes (dose = 48 mg with .DELTA.T.sub.ir = 13.4 hr
and .DELTA.T.sub.sr > 13.9 hr) and above C.sub.min (2 ng/ml).
Zero-Order Sustained Release .DELTA.T.sub.sr Release Rate Duration
C > C.sub.min (mg/hr/kg) (hrs) (hrs) .DELTA.T.sub.sr >
.DELTA.T.sub.ir + 0.5 0.034 20 26.0 yes 0.038 18 24.4 yes 0.049 14
21.4 yes 0.069 10 18.7 yes 0.086 8 17.4 yes 0.171 4 14.9 yes 0.343
2 14.1 yes
[0358] Exemplary sustained release durations of
2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-
-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate delivered
from sustained release dosage forms, based on these simulations,
are about 4 to about 10 hours for about a 6 mg dose, about 4 to
about 18 hours for about 8, 12, 16, and 24 mg doses, and about 2 to
about 20 hours for about a 48 mg dose.
[0359] Exemplary zero order release rates of
2-amino-N-[2-(3a-(R)-benzyl-2-
-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-be-
nzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate delivered from
sustained release dosage forms, based on these simulations, are
about 0.009 to about 0.021 mg/hr/kg for about a 6 mg dose, about
0.006 to about 0.029 mg/hr/kg for about an 8 mg dose, about 0.010
to about 0.043 mg/hr/kg for about a 12 mg dose, about 0.013 to
about 0.057 mg/hr/kg for about a 16 mg dose, about 0.019 to about
0.086 mg/hr/kg for about a 24 mg dose, and about 0.034 to about
0.343 mg/hr/kg for about a 48 mg dose
[0360] Exemplary zero order in vitro release rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate delivered from sustained release dosage forms, based on
these simulations, are about 0.60 to about 1.50 mg/hr for about a 6
mg dose, about 0.44 to about 2.00 mg/hr for an 8 mg dose, about
0.67 to about 3.00 mg/hr for about a 12 mg dose, about 0.89 to
about 4.00 mg/hr for about a 16 mg dose, about 1.33 to about 6.00
mg/hr for about a 24 mg dose, and about 2.40 to about 24.00 mg/hr
for about a 48 mg dose, when computed for a 70 kg patient, such as
a human patient. Exemplary release rates may be computed similarly
for patients of different weights.
Example 13
Simulated Immediate Release Plus Sustained-Release Delivery Input
Rates and Doses which give Maximum
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2-
,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-
-oxo-ethyl]-isobutyramide L-tartrate Concentrations<80% of
Immediate Release and Exceed a Minimum Therapeutic Plasma
Concentration, C.sub.min, of 2 ng/ml.
[0361] This example illustrates the process for simulating delivery
input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydr-
o-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyr-
amide L-tartrate from immediate plus sustained release dosage forms
that give maximum plasma concentrations not more than 80% of an
equivalent immediate release bolus dose and greater than a minimum
therapeutic concentration of 2 ng/ml. For some indications, a lower
minimum plasma concentration, e.g., 1 ng/ml, may be efficacious.
The sustained release profile is simulated as a zero-order release
through hourly pulses of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate over the specified release duration. The immediate
release portion of the dose is completely input at time zero. In
these simulations, the three variables studied included the
fraction of dose delivered as an immediate release bolus from about
5.0 to about 75%, the dosage strengths from about 4 to about 48 mg,
and the sustained release durations from about 4 to about 18 hours.
The resulting maximum
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate plasma concentration simulated for each of these
immediate plus sustained release dosage forms, C.sub.max,ir+sr, are
reported in Tables 13-1 to 13-4 for dosage strengths of 4, 6, 12,
and 48 mg, respectively. These results were evaluated according to
the criteria specified above: C.sub.max,ir+sr not more than 80%
C.sub.max,ir, and plasma concentration greater than C.sub.min at
any time. Those examples that meet both criteria, and reported as
`yes` in the tables are embodiments of this invention.
Methods
[0362] Using the same methods as described to create the
simulations for example 11, the following equations were added to
the model to allow simultaneous input of both IR and SR
components:
dose=10
Tend=4
ir_fraction=0.75
ir_dose=ir_fraction*dose
mr_dose=dose*(1-ir_fraction)
ir=pulse(ba*ir_dose,0,999)
interval_dose=mr_dose/Tend
mr=pulse(interval_dose,0,1)
dosing=if time<Tend-1 then ir+mr else 0
[0363] where dose and Tend are defined above, ir_fraction is the
fraction of the total dose which was formulated as IR, ir_dose is
that IR dose, mr_dose is the remainder of the dose formulated as
SR, ir is the pulse dosing of the entire IR dose (at time=0, i.e.
immediately upon administration), interval_dose is the hourly dose
administered as an hourly pulse during the period the SR
formulation delivers, mr is the hourly pulse dosing during which
time the SR formulation delivers, dosing is the combined delivery
of the IR and SR formulations. In the above example, a 10 mg dose
is simulated with 7.5 mg as IR, and 2.5 mg as SR delivered over 4
hr.
Results
[0364] The simulation results were evaluated according to the
following criteria: i) the maximum concentration following
immediate plus sustained release dosing of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-
-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-
-isobutyramide L-tartrate must be no more than 80% of the maximum
active compound plasma concentration after dosing an immediate
release bolus at the same dose; and ii) the plasma concentration
must exceed a minimum effective concentration of 2 ng/ml at any
time after dosing. Both of these criteria must be satisfied in
order for the simulated profile, to exemplify an embodiment of this
invention, for indications requiring a 2 ng/ml minimum plasma
active compound concentration for efficacy. For some therapeutic
indications, a lower active compound plasma concentration, e.g., 1
ng/ml, may be sufficient for efficacy. The simulation methodology
can be used to determine IR/SR dosage form characteristics for such
therapeutic indications.
[0365] As described for Example 11, the maximum plasma
concentration (C.sub.max) was tabulated. Table 13-1 lists the
C.sub.max values for simulations where a 4 mg dose was delivered
from a hybrid IR/SR dosage form with varying fractions of dose
delivered by IR and SR. For the 4 mg dose in which sustained
release duration is 4 hours, the zero order sustained release rates
of 0.007 to 0.014 mg/hr/kg obtained from IR percentages of about 50
to about 5% meet both of the in vivo criteria and are embodiments
of this invention. Sustained release durations of 6, 8, 10, 12, 16
and 18 hours were also simulated according to the method described
above. For each SR release duration, the % of IR dose and SR
release rates that meet the specified criteria vary and are
detailed in Table 13-1. For the 6 hr SR duration, the SR release
rates of about 0.005 to about 0.009 mg/hr/kg obtained from IR
percentages of about 50 to about 5% meet the criteria and are
embodiments of this invention. For the 8 and 10 hr SR durations,
the zero order release rates of about 0.002-0.004 and about
0.001-0.003 mg/hr/kg obtained from IR percentages of about 75 to
about 50% meet the criteria and are embodiments of this invention.
For the 12, 16, and 18 hr SR durations, of the simulated IR
percentages, only the 75% IR dosing meet the criteria.
32TABLE 13-1 Fraction of 2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y- l)-1-
(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate dose
delivered as immediate release from a IR/SR hybrid dosage form that
results in plasma concentrations no more than 80% of the maximum
plasma concentration produced by an equivalent dose of immediate
release bolus (dose = 4 mg with C.sub.max = 3.5 ng/ml). SR Fraction
Sustained C.sub.max,ir+sr Duration of Dose Release Rate
C.sub.max,ir+sr <= 80% (hrs) as IR (mg/hr/kg) (ng/ml)
C.sub.max,ir C > C.sub.min 4 0.05 0.014 2.2 yes yes 4 0.50 0.007
2.7 yes yes 4 0.75 0.004 3.0 no yes 6 0.05 0.009 2.4 yes yes 6 0.50
0.005 2.3 yes yes 6 0.75 0.002 2.9 no yes 8 0.05 0.007 2 yes no 8
0.50 0.004 2.1 yes yes 8 0.63 0.003 2.5 yes yes 8 0.75 0.002 2.8
yes yes 10 0.05 0.005 1.7 yes no 10 0.50 0.003 2.1 yes yes 10 0.75
0.001 2.8 yes yes 12 0.05 0.005 <2.0 yes no 12 0.50 0.002 2 yes
no 12 0.75 0.001 2.8 yes yes 16 0.50 0.002 <2.0 yes no 16 0.75
0.001 2.7 yes yes 18 0.50 0.002 <2.0 yes no 18 0.75 0.001 2.7
yes yes
[0366] Table 13-2 lists the C.sub.max values for simulations where
a 6 mg dose was delivered as a hybrid IR/SR formulation. For the 6
mg dose in which sustained release duration is 4 hours, the zero
order sustained release rate of 0.013 mg/hr/kg obtained from an IR
percentage of 40% meets both of the in vivo criteria and is an
embodiment of this invention. Sustained release durations of 6, 8,
10, 12, 14, 16 and 18 hours were also simulated. For each SR
release duration, the % of IR dose and SR release rates that meet
the specified criteria vary and are detailed in Table 13-2.
[0367] For the 6 mg dose and 6 hr SR duration, the IR percentages
of 40 to 5% resulting in SR rates of 0.009-0.014 mg/kg/hr meet the
criteria and are embodiments of this invention. For the 8, 10, and
12 hr SR duration, the IR percentages of 75 to 5% result maximum
plasma levels that meet the criteria and are embodiments of this
invention. For SR durations of 14, 16, and 18 hr, the IR
percentages of 75-40% meet the specified criteria.
33TABLE 13-2 Fraction of 2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y- l)-1-
(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate dose
delivered as immediate release from a IR/SR hybrid dosage form that
results in plasma concentrations no more than 80% of the maximum
plasma concentration produced by an equivalent dose of immediate
release bolus (dose = 6 mg C.sub.max = 5.3 ng/ml). SR Fraction
Sustained C.sub.max,ir+sr Duration of Dose Release Rate
C.sub.max,ir+sr <= 80% (hrs) as IR (mg/hr/kg) (ng/ml)
C.sub.max,ir C > C.sub.min 4 0.05 0.020 4.4 no yes 4 0.40 0.013
4.1 yes yes 4 0.75 0.005 4.5 no yes 6 0.05 0.014 3.7 yes yes 6 0.40
0.009 3.3 yes yes 6 0.75 0.004 4.4 no yes 8 0.05 0.010 3.1 yes yes
8 0.25 0.008 2.7 yes yes 8 0.375 0.007 2.8 yes yes 8 0.50 0.005 3.2
yes yes 8 0.625 0.004 3.7 yes yes 8 0.75 0.003 4.2 yes yes 10 0.05
0.008 2.6 yes yes 10 0.40 0.005 2.7 yes yes 10 0.75 0.002 4.2 yes
yes 12 0.05 0.007 2.2 yes yes 12 0.40 0.004 2.6 yes yes 12 0.75
0.002 4.1 yes yes 14 0.05 0.006 1.9 yes no 14 0.40 0.004 2.5 yes
yes 14 0.75 0.002 4.1 yes yes 16 0.05 0.005 <2.0 yes no 16 0.40
0.003 2.5 yes yes 16 0.75 0.001 4.1 yes yes 18 0.05 0.005 <2.0
yes no 18 0.40 0.003 2.4 yes yes 18 0.75 0.001 4.1 yes yes
[0368] Table 13-3 lists the C.sub.max values for simulations where
a 12 mg dose was delivered as a hybrid IR/SR formulation. For the
12 mg dose in which sustained release duration is 4 hours, the zero
order sustained release rate of 0.026 mg/hr/kg obtained from an IR
percentage of 40% meets both of the in vivo criteria and is an
embodiment of this invention. Sustained release durations of 6, 8,
10, 12, 14, 16 and 18 hours were also simulated. For each SR
release duration, the % of IR dose and 3SR release rates that meet
the specified criteria vary and are detailed in Table 13-3.
34TABLE 13-3 Fraction of 2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y- l)-1-
(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate dose
delivered as immediate release from a IR/SR hybrid dosage form that
results in plasma concentrations no more than 80% of the maximum
plasma concentration produced by an equivalent dose of immediate
release bolus (dose = 12 mg C.sub.max = 10.6 ng/ml). SR Fraction
Sustained C.sub.max,ir+sr Duration of Dose Release Rate
C.sub.max,ir+sr <= 80% (hrs) as IR (mg/hr/kg) (ng/ml)
C.sub.max,ir C > C.sub.min 4 0.05 0.041 8.7 no yes 4 0.40 0.026
8.2 yes yes 4 0.75 0.011 9.0 no yes 6 0.05 0.027 7.4 yes yes 6 0.40
0.017 6.5 yes yes 6 0.75 0.007 8.7 no yes 8 0.05 0.020 6.1 yes yes
8 0.25 0.016 5.4 yes yes 8 0.375 0.013 5.6 yes yes 8 0.50 0.011 6.5
yes yes 8 0.625 0.008 7.4 yes yes 8 0.75 0.005 8.5 no yes 12 0.05
0.014 4.5 yes yes 12 0.40 0.009 5.2 yes yes 12 0.75 0.004 8.3 yes
yes 16 0.05 0.010 3.5 yes yes 16 0.40 0.006 4.9 yes yes 16 0.75
0.003 8.2 yes yes 18 0.05 0.009 3.1 yes yes 18 0.40 0.006 4.8 yes
yes 18 0.75 0.002 8.2 yes yes
[0369] Table 13-4 lists the C.sub.max values for simulations where
a 48 mg dose was delivered as a hybrid IR/SR formulation. For the
48 mg dose in which sustained release duration is 16 hours, the
zero order sustained release rates of 0.011 to 0.041 mg/hr/kg
obtained from an IR percentage of 75-5% meet both of the in vivo
criteria and are an embodiment of this invention.
35TABLE 13-4 Fraction of 2-amino-N-[2-(3a-(R)-benzy-
l-2-methyl-3-oxo-
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y- l)-1-
(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate dose
delivered as immediate release from a IR/SR hybrid dosage form that
results in plasma concentrations no more than 80% of the maximum
plasma concentration produced by an equivalent dose of immediate
release bolus (dose = 48 mg C.sub.max = 42.2 ng/ml). SR Fraction
Sustained C.sub.max,ir+sr Duration of Dose Release Rate
C.sub.max,ir+sr <= 80% (hrs) as IR (mg/hr/kg) (ng/ml)
C.sub.max,ir C > C.sub.min 16 0.05 0.041 13.8 yes yes 16 0.40
0.026 19.7 yes yes 16 0.75 0.011 32.8 yes yes
[0370] Exemplary immediate release percentages and sustained
release durations of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa-
hydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isob-
utyramide L-tartrate delivered from immediate plus sustained
release dosage forms, based on these simulations, are dependent on
dose, sustained release duration and % IR dose. For the about 4 mg
dose, exemplary IR percentages and SR durations are about 5 to
about 50% for about 4 to about 6 hr SR, about 50 to about 75% for
about 8 to about 10 hr SR and about 75% for about 12, 16, and 18 hr
SR, respectively. For the about 6 mg dose, exemplary IR percentages
and SR durations are about 40% for about 4 hr SR, about 5 to about
40% for about 6 hr SR, about 5 to about 75% for the about 8, 10,
and 12 hr SR and about 40 to about 75% for about 14, 16, and 18 hr
SR, respectively. For the about 12 mg dose, exemplary IR
percentages and SR durations are about 40% for about 4 hr SR, about
5 to about 40% for about 6 hr SR, about 5 to about 62.5% for about
8 hr SR, and about 5 to about 75% for about 12, 16, and 18 hr SR,
respectively. For the about 48 mg dose, exemplary IR percentages
for the about 16 hr SR duration is about 5 to about 75%.
[0371] Exemplary in vivo input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-meth-
yl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzylo-
xymethyl-2-oxo-ethyl]-isobutyramide L-tartrate delivered from
immediate plus sustained release dosage forms, based on these
simulations, are dependent on dose, sustained release duration and
% IR dose. For the about 4 mg dose, exemplary in vivo SR input
rates are about 0.007 to about 0.014 mg/hr/kg for the about 4 hr SR
duration, about 0.005 to about 0.009 mg/hr/kg for the about 6 hr SR
duration, about 0.002 to about 0.004 mg/hr/kg for the about 8 hr SR
duration, about 0.001 to about 0.003 mg/hr/kg for the about 10 hr
SR duration, about 0.001 mg/hr/kg for the about 12, 16, and 18 hr
SR duration. For the about 6 mg dose, exemplary in vivo SR input
rates are about 0.013 mg/hr/kg for the about 4 hr SR duration,
about 0.009 to about 0.014 mg/hr/kg for the about 6 hr SR duration,
about 0.003 to about 0.010 mg/hr/kg for the about 8 hr SR duration,
about 0.002 to about 0.008 mg/hr/kg for the about 10 hr SR
duration, about 0.002 to about 0.007 mg/hr/kg for the about 12 hr
SR duration, about 0.002 to about 0.004 mg/hr/kg for the about 14
hr SR duration, about 0.001 to about 0.003 mg/hr/kg for the about
16 and about 18 hr SR durations. For the about 12 mg dose,
exemplary in vivo SR input rates are about 0.026 mg/hr/kg for the
about 4 hr SR duration, about 0.017 to about 0.027 mg/hr/kg for the
about 6 hr SR duration, about 0.008 to about 0.020 mg/hr/kg for the
about 8 hr SR duration, about 0.004 to about 0.014 mg/hr/kg for the
about 12 hr SR duration, about 0.003 to about 0.010 mg/hr/kg for
the about 16 hr SR duration, about 0.002 to about 0.009 mg/hr/kg
for the about 18 hr SR duration. For the about 48 mg dose,
exemplary in vivo SR input rates for the about 16 hr SR duration
are about 0.011 to about 0.041 mg/hr/kg.
[0372] Exemplary zero order in vitro release rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate delivered from immediate plus sustained release dosage
forms, are dependent on dose, sustained release duration and % IR
dose. The following exemplary % IR dose and in vitro SR active
compound release rates are computed for a 70 kg patient. For the
about 4 mg dose, exemplary in vitro SR rates are about 0.050 to
about 0.95 mg/hr for the about 4 hr SR duration, about 0.33 to
about 0.63 mg/hr for the about 6 hr SR duration, about 0.13 to
about 0.25 mg/hr for the about 8 hr SR duration, about 0.10 to
about 0.20 mg/hr for the about 10 hr SR duration, about 0.08 mg/hr
for the about 12, and about 0.06 mg/hr for the about 16, and about
18 hr SR duration. For the about 6 mg dose, exemplary SR rates are
about 0.90 mg/hr/kg for the about 4 hr SR duration, about 0.60 to
about 0.95 mg/hr for the about 6 hr SR duration, about 0.19 to
about 0.71 mg/hr for the about 8 hr SR duration, about 0.15 to
about 0.57 mg/hr for the about 10 hr SR duration, about 0.13 to
about 0.48 mg/hr for the about 12 hr SR duration, about 0.11 to
about 0.26 mg/hr for the about 14 hr SR duration, about 0.09 to
about 0.23 mg/hr for the about 16 hr duration and about 0.08 to
about 0.20 mg/hr for the about 18 hr SR duration. For the about 12
mg dose, exemplary SR rates are about 1.80 mg/hr for the about 4 hr
SR duration, about 1.20 to about 1.90 mg/hr for the about 6 hr SR
duration, about 0.56 to about 1.43 mg/hr for the about 8 hr SR
duration, about 0.25 to about 0.95 mg/hr for the about 12 hr SR
duration, about 0.19 to about 0.71 mg/hr for the about 16 hr SR
duration, about 0.17 to about 0.63 mg/hr for the about 18 hr SR
duration. For the about 48 mg dose, exemplary SR rates for the
about 16 hr SR duration are about 0.75 to about 2.85 mg/hr.
[0373] Other exemplary % IR and SR release rate combinations may be
identified by utilizing the methodology in this example, for any
dose and for a patient of any weight.
Example 14
Simulated Immediate Release Plus Sustained-Release Delivery Input
Rates and Doses which Maintain
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3-
a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-
-ethyl]-isobutyramide L-tartrate Concentrations Above 2 ng/ml for a
Length of Time Longer than Immediate Release
[0374] This example illustrates the process for simulating active
compound delivery input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a-
,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo--
ethyl]-isobutyramide L-tartrate from immediate release plus
sustained release dosage forms which maintain concentrations above
2 ng/ml for a length of time longer than an equivalent immediate
release dose by at least 30 minutes. The sustained release profile
is simulated as a zero-order release through hourly pulses of
2-amino-N-[2-(3a-(R)-benzyl-2-
-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-be-
nzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate over the
specified release duration. The immediate release portion of the
dose is completely input at time zero. In these simulations, the
three variables studied included the fraction of dose delivered as
an immediate release bolus from 5.0 to 75%, the dosage strengths
from 4 to 48 mg, and the sustained release durations from 4 to 18
hours.
[0375] The resulting duration that
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3--
oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymet-
hyl-2-oxo-ethyl]-isobutyramide L-tartrate plasma concentrations
exceed the C.sub.min, .DELTA.T.sub.ir+sr, is reported in Tables
14-1 to 14-4 for dosage strengths of 4, 6, 12 and 48 mg,
respectively. These results were evaluated according to the
criteria specified above: .DELTA.T.sub.ir+sr not less than 30
minutes longer than .DELTA.T.sub.ir. The examples that satisfy this
criteria, and reported as "yes" in the tables are embodiments of
this invention.
Methods
[0376] Using the same methods to create the simulations as
described for Example 12, the difference between the time at which
the
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate plasma concentration first exceeded 2 ng/ml and then
subsequently fell below 2 ng/ml were tabulated for the immediate
plus sustained release input rates (.DELTA.T.sub.ir+sr).
Results
[0377] The simulation results were evaluated according to the
following criterion: the time duration for which
2-amino-N-[2-(3a-(R)-benzyl-2-meth-
yl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzylo-
xymethyl-2-oxo-ethyl]-isobutyramide L-tartrate plasma
concentrations were above the minimum effective plasma
concentration of 2 ng/ml for the immediate plus sustained release
dosage form exceeded the time above 2 ng/ml for an equivalent dose
of immediate release bolus by at least 30 minutes.
[0378] For the 4 mg dose, sustained release rates of 4 to 8 hours
were simulated with IR dose fractions from 5-75% (Table 14-1). The
.DELTA.T.sub.ir+sr simulated for the 4 hr SR duration with 5-50% IR
dose fraction was 1.6-4.3 hrs, which fell below the required 4.4
hrs. Therefore, the 4 mg dose delivered as an IR plus SR dosage
form with 5-75% IR and 4-8 hr SR duration do not meet the criterion
of maintaining active compound plasma concentrations at >2 ng/ml
for 30 minutes longer than an immediate release bolus dose.
However, some IR/SR combinations in the range of Table 14-1 embody
the invention because they meet the C.sub.max criterion in Example
13.
36TABLE 14-1 Fraction of 2-amino-N-[2-(3a-(R)-benzy- l-2-
methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,
3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]- isobutyramide
L-tartrate dose delivered as immediate release from a IR/SR hybrid
dosage form that results in plasma concentrations above 2 ng/ml for
durations exceeding that for an equivalent dose of immediate
release bolus by at least 30 minutes (dose = 4 mg with
.DELTA.T.sub.ir = 3.9 hr and .DELTA.T.sub.ir+sr > 4.4 hr; SR
release rate 4, 6, and 8 hr). SR Fraction of Sustained
.DELTA.T.sub.ir+sr Duration Dose Release Rate C > C.sub.min
(hrs) as IR (mg/hr/kg) (hrs) .DELTA.T.sub.ir+sr >
.DELTA.T.sub.ir + 0.5 4 0.05 0.014 1.6 no 4 0.50 0.007 4.3 no 6
0.05 0.009 3 no 6 0.50 0.005 3.8 no 8 0.50 0.004 2.1 no 8 0.63
0.003 3.1 no 8 0.75 0.002 1.5 no
[0379] Table 14-2 lists the .DELTA.T.sub.ir+sr values for
simulations where a 6 mg dose was delivered as a hybrid IR/SR
formulation. For the 6 mg dose, release rates of 4 to 12 hours were
simulated and evaluated according to the above specified criteria
(Table 14-2). The .DELTA.T.sub.ir+sr simulated for a 4 hr SR
duration with 5-40% IR was 6.3-6.5 hrs, which exceeded the
.DELTA.T.sub.ir=5.6 hr by 0.7-0.9 hrs. The corresponding zero order
sustained release rates of 0.013-0.020 mg/hr/kg satisfy the in vivo
criteria and are embodiments of this invention. For the 6 hr SR
duration with 5-75% IR, the .DELTA.T.sub.ir+sr was 6.4-7.2 hrs and
exceeded the minimum requirement of 6.1 hrs. The corresponding in
vivo sustained release rates were 0.004-0.014 mg/hr/kg. For the 8
hr SR duration with 5-62.5% IR, the .DELTA.T.sub.ir+sr was
6.7-8.1hrs and exceeded the minimum requirement of 6.1 hrs. The
corresponding in vivo sustained release rates were 0.004-0.010
mg/hr/kg. The .DELTA.T.sub.ir+sr simulated for a 10 hr SR duration
with 5-40% IR was 6.7-6.8 hrs, which exceeded the
.DELTA.T.sub.ir=5.6 hr by 1.1-1.2 hrs. The corresponding zero order
sustained release rates of 0.005-0.008 mg/hr/kg satisfy the in vivo
.DELTA.T criterion and are embodiments of this invention.
37TABLE 14-2 Fraction of 2-amino-N-[2-(3a-(R)-benzy- l-
2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-
pyrazolo[4,3-c]pyridin-5-yl)-1-(R)- benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L- tartrate dose delivered as immediate release from a
IR/SR hybrid dosage form that results in plasma concentrations
above 2 ng/ml for durations exceeding that for an equivalent dose
of immediate release bolus by at least 30 minutes (dose = 6 mg with
.DELTA.T.sub.ir = 5.6 hr and .DELTA.T.sub.ir+sr > 6.1 hr; SR
release rate 4, 6, 8, 10, and 12 hr). SR Fraction of Sustained
.DELTA.T.sub.ir+sr Duration Dose Release Rate C > C.sub.min
(hrs) as IR (mg/hr/kg) (hrs) .DELTA.T.sub.ir+sr >
.DELTA.T.sub.ir + 0.5 4 0.05 0.020 6.3 yes 4 0.40 0.013 6.5 yes 4
0.75 0.005 6.0 no 6 0.05 0.014 6.4 yes 6 0.40 0.009 7.2 yes 6 0.75
0.004 6.5 yes 8 0.05 0.010 6.7 yes 8 0.25 0.008 8 yes 8 0.375 0.007
8.1 yes 8 0.50 0.005 7.7 yes 8 0.625 0.004 6.9 yes 8 0.75 0.003 6.1
no 10 0.05 0.008 6.8 yes 10 0.40 0.005 6.7 yes 10 0.75 0.002 5.5 no
12 0.05 0.007 5.2 no 12 0.40 0.004 4.7 no 12 0.75 0.002 5.5 no
[0380] Table 14-3 lists the .DELTA.T.sub.ir+sr values for
simulations where a 12 mg dose was delivered as a hybrid IR/SR
formulation. For the 12 mg dose, release rates of 4 to 18 hours
were simulated and evaluated according to the above specified
criteria (Table 14-3). The .DELTA.T.sub.ir+sr simulated for a 4 hr
SR duration with 5-40% IR was 9.2-9.4 hrs, which exceeded the 8.8
hr requirement. The corresponding zero order sustained release
rates of 0.026-0.041 mg/hr/kg satisfy the in vivo criteria and are
embodiments of this invention. For the 6, 8, 12, and 16 hr SR
duration with 5-75% IR, the .DELTA.T.sub.ir+sr values ranged from
9.2-16.2 hrs and are embodiments of this invention. The in vivo
sustained release rates for the 6, 8, 12, and 16 hr SR duration
with 75-5% IR were 0.027-0.007, 0.020-0.005, 0.014-0.004,
0.010-0.003 mg/hr/kg, respectively. For the 18 hr SR duration with
5-40% IR, the .DELTA.T.sub.ir+sr was 16.7-17.7 hrs and exceeded the
minimum effective concentration. The corresponding in vivo
sustained release rates were 0.009-0.006 mg/hr/kg.
38TABLE 14-3 Fraction of 2-amino-N-[2-(3a-(R)-benzy- l-
2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-
pyrazolo[4,3-c]pyridin-5-yl)-1-(R)- benzyloxymethyl-2-oxo-ethyl]-i-
sobutyramide L-tartrate dose delivered as immediate release from a
IR/SR hybrid dosage form that results in plasma concentrations
above 2 ng/ml for durations exceeding that for an equivalent dose
of immediate release bolus by at least 30 minutes (dose = 12 mg
with .DELTA.T.sub.ir = 8.3 hr and .DELTA.T.sub.ir+sr > 8.8 hr;
SR release rate 4, 6, 8, 12, 16, and 18 hr). SR Fraction of
Sustained .DELTA.T.sub.ir+sr Duration Dose Release Rate C >
C.sub.min (hrs) as IR (mg/hr/kg) (hrs) .DELTA.T.sub.ir+sr >
.DELTA.T.sub.ir + 0.5 4 0.05 0.041 9.4 yes 4 0.40 0.026 9.2 yes 4
0.75 0.011 8.7 no 6 0.05 0.027 10.3 yes 6 0.40 0.017 10.2 yes 6
0.75 0.007 9.2 yes 8 0.05 0.020 11.3 yes 8 0.25 0.016 11.5 yes 8
0.375 0.013 11.2 yes 8 0.50 0.011 10.8 yes 8 0.625 0.008 10.3 yes 8
0.75 0.005 9.8 yes 12 0.05 0.014 13.6 yes 12 0.40 0.009 13.5 yes 12
0.75 0.004 10.2 yes 16 0.05 0.010 15.7 yes 16 0.40 0.006 16.2 yes
16 0.75 0.003 9.2 yes 18 0.05 0.009 16.7 yes 18 0.40 0.006 17.7 yes
18 0.75 0.002 8.7 no
[0381] Table 14-4 lists the .DELTA.T.sub.ir+sr values for
simulations where a 48 mg dose was delivered as a hybrid IR/SR
formulation. The .DELTA.T.sub.ir+sr simulated for a 16 hr SR
duration with 75-5% IR was 19.0-23.5 hrs, which exceeded the 13.9
hr requirement. The corresponding zero order sustained release
rates of 0.011-0.041 mg/hr/kg satisfy the in vivo criteria and are
embodiments of this invention.
39TABLE 14-4 Fraction of 2-amino-N-[2-(3a-(R)-benzy- l-2-
methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo
[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-
oxo-ethyl]-isobutyramide L-tartrate dose delivered as immediate
release from a IR/SR hybrid dosage form that results in plasma
concentrations above 2 ng/ml for durations exceeding that for an
equivalent dose of immediate release bolus by at least 30 minutes
(dose = 48 mg with .DELTA.T.sub.ir = 13.4 hr and .DELTA.T.sub.ir+sr
> 13.9 hr; SR release rate 16 hrs). SR Fraction of Sustained
.DELTA.T.sub.ir+sr Duration Dose Release Rate C > C.sub.min
(hrs) as IR (mg/hr/kg) (hrs) .DELTA.T.sub.ir+sr >
.DELTA.T.sub.ir + 0.5 16 0.05 0.041 23.5 yes 16 0.40 0.026 21.9 yes
16 0.75 0.011 19.0 yes
[0382] Exemplary immediate release percentages and sustained
release durations of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa-
hydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isob-
utyramide L-tartrate delivered from immediate plus sustained
release dosage forms, based on these simulations, are dependent on
dose, sustained release duration and % IR dose. For the about 6 mg
dose, exemplary IR percentages and SR durations are about 5 to
about 40% for about 4 hr SR, about 5 to about 75% for about 6 hr
SR, about 5 to about 62.5% for the about 8 hr SR, and about 5 to
about 40% for about 10 hr SR, respectively. For the about 12 mg
dose, exemplary IR percentages and SR durations are about 5 to
about 40% for about 4 hr SR, about 5 to about 75% for about 6, 8,
12, and 16 hr SR, and about 5 to about 40% for about 18 hr SR,
respectively. For the about 48 mg dose, exemplary IR percentages
for the about 16 hr SR duration is about 5 to about 75%.
[0383] Exemplary in vivo input rates of
2-amino-N-[2-(3a-(R)-benzyl-2-meth-
yl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzylo-
xymethyl-2-oxo-ethyl]-isobutyramide L-tartrate delivered from
immediate plus sustained release dosage forms, based on these
simulations, are dependent on dose, sustained release duration and
% IR dose. For the about 6 mg dose, exemplary in vivo SR input
rates are about 0.013 to about 0.020 mg/hr/kg for the about 4 hr SR
duration, about 0.004 to about 0.014 mg/hr/kg for the about 6 hr SR
duration, about 0.004 to about 0.010 mg/hr/kg for the about 8 hr SR
duration, and about 0.005 to about 0.008 mg/hr/kg for the about 10
hr SR duration. For the about 12 mg dose, exemplary in vivo SR
input rates are about 0.026 to about 0.041 mg/hr/kg for the about 4
hr SR duration, about 0.007 to about 0.027 mg/hr/kg for the about 6
hr SR duration, about 0.005 to about 0.020 mg/hr/kg for the about 8
hr SR duration, about 0.004 to about 0.014 mg/hr/kg for the about
12 hr SR duration, about 0.003 to about 0.010 mg/hr/kg for the
about 16 hr SR duration, about 0.006 to about 0.009 mg/hr/kg for
the about 18 hr SR duration. For the about 48 mg dose, exemplary in
vivo SR input rates for the about 16 hr SR duration are about 0.011
to about 0.041 mg/hr/kg.
[0384] Exemplary zero order in vitro release rates of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate delivered from sustained release dosage forms, are
dependent on dose, sustained release duration and % IR dose.
Exemplary SR rates for dosing a 70 kg human or other mammal are as
follows. For the about 6 mg dose, exemplary SR rates are about 0.90
to about 1.42 mg/hr for the about 4 hr SR duration, about 0.25 to
about 0.95 mg/hr for the about 6 hr SR duration, about 0.28 to
about 0.71 mg/hr for the about 8 hr SR duration, and about 0.36 to
about 0.57 mg/hr for the about 10 hr SR duration. For the about 12
mg dose, exemplary SR rates are about 1.80 to about 2.85 mg/hr for
the about 4 hr SR duration, about 0.50 to about 1.9 mg/hr for the
about 6 hr SR duration, about 0.38 to about 1.43 mg/hr for the
about 8 hr SR duration, about 0.25 to about 0.95mg/hr for the about
12 hr SR duration, about 0.19 to about 0.71 mg/hr for the about 16
hr SR duration, about 0.40 to about 0.63 mg/hr for the about 18 hr
SR duration. For the about 48 mg dose, exemplary SR rates for the
about 16 hr SR duration are about 0.75 to about 2.85 mg/hr.
Example 15
Immediate Plus Sustained Release Tablets
[0385] This example illustrates a process for making a combination
immediate release plus sustained release product comprised of an
active compound layer compression coated onto an osmotic
2-amino-N-[2-(3a-(R)-be-
nzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1--
(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate tablet.
The processing of the osmotic sustained release tablet was
previously described in Examples 7 and 9. The processing of the
compression coating active compound layer comprised (1) blending of
compression coating components as designated in Table 15-1, except
for magnesium stearate; (2) adding and blending magnesium stearate;
(3) placing half of the compression coating blend into the tablet
press die, leveling, and centering the asymmetric membrane (AM)
tablet on top of the powder layer, and adding the remaining half of
the compression coating blend into the tablet press die; (4)
compressing the powder active compound layer onto the asymmetric
membrane (AM) coated tablets to form a composite tablet.
[0386] In batch sizes of 500 grams,
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-
-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxyme-
thyl-2-oxo-ethyl]-isobutyramide L-tartrate was blended in a
suitable jar with all other components L-tartrate was blended in a
suitable jar with all other components except magnesium stearate
for 10 minutes using a Turbula shaker system (Willy A. Bachofen,
Basel, Switzerland). Then, magnesium stearate was added and blended
for 5 minutes. Using a conventional tablet press (Manesty F-Press,
Manesty Machines, Liverpool, England), the final blend was
compressed into tablets using {fraction (5/32)} inch standard round
concave (SRC) punches for the 350 mg compression coating layer
weight. A summary of the compositions manufactured by compression
coating of the formulation blend at 3 and 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyra-
zolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate is shown is Examples 15A-15B, as detailed in Table 15-1.
These combination immediate plus sustained release tablets
contained a sustained release 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a-
,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo--
ethyl]-isobutyramide L-tartrate AM tablet from Example 9C. The
compression coating layers consisted of a 3 or 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-me-
thyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzy-
loxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate dose. The
combination immediate plus sustained release tablets are
embodiments of this invention.
40 TABLE 15-1 Compression Coating Composition Coating Active
Example Wt compound Content Avicel MgSt (No.) (mg) (mgA) (wt %) (wt
%) (wt %) 15A 350 3 1.1 97.9 1.0 15B 350 10 3.8 95.2 1.0 Avicel
.RTM. means microcrystalline cellulose MgSt means magnesium
stearate
Example 16
In Vitro Performance of Immediate Plus Sustained Release
Tablets
[0387] The immediate plus sustained release tablets from Example 15
were tested for active compound release performance using
dissolution procedures described in Example 8 using 900 ml 0.1 N
HCl or SIN media. Additional samples were withdrawn at early time
points to monitor the immediate release portion of the dissolution
profile (i.e., 15, 30, 45, and 60 minutes). The results of the
active compound release rate tests performed using those procedures
are listed in Table 16-1.
41TABLE 16-1 Example Number - Amount Of Active Compound Release
(mgA) At Specified Time in Hours Media 0 0.25 0.50 0.75 1 2 4 8 12
16 24 9C - SIN 0 n.d. n.d. n.d. 0.5 3.2 4.6 5.9 7.7 8.9 9.8 15A -
SIN 0 2.2 2.6 2.8 3.0 3.9 5.6 8.2 10.1 11.2 12.3 15B - SIN 0 8.9
9.5 9.7 10.0 10.8 12.5 15.0 17.0 18.2 19.4 9C - HCl 0 n.d. n.d.
n.d. 0.5 1.4 3.3 6.1 8.0 9.0 9.6 15A - HCl 0 2.6 2.8 3.0 3.1 4.0
5.8 8.5 10.4 11.5 12.4 15B - HCl 0 9.1 9.9 10.2 10.4 11.5 13.4 16.1
17.9 18.9 19.7 9C consists of a 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3-
a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-
-ethyl]-isobutyramide L-tartrate AM tablet without an immediate
release active compound layer. 15A consists of a 3 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate active compound layer compression coated onto AM tablet
#9C for a total dose of 13 mgA (23% IR). 15B consists of a 10 mg
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate active compound layer compression coated onto AM tablet
#9C for a total dose of 20 mgA (50% IR). SIN means simulated
intestinal fluid without enzyme. HCl means 0.1N HCl.
[0388] The sustained release in vitro boundaries corresponding to a
16 hr SR duration dosage form, exemplified by Example 9C, are
0.19-0.71 mg/hr for both C.sub.max and .DELTA.T criteria for a
total dose between 12-48 mg and 5-75% immediate release
percentage.
[0389] Preferred immediate plus sustained release dosage forms of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazol-
o[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate contain 5-75% dose delivered as immediate release from a
16 hr SR dosage form. Examples 15A and 15B demonstrate immediate
plus sustained release of
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahy-
dro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobut-
yramide L-tartrate and are embodiments of this invention.
* * * * *