U.S. patent application number 10/997836 was filed with the patent office on 2005-08-11 for carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods.
Invention is credited to Castan, Catherine, Crowley, Patrick J., Guimberteau, Florence, Meyrueix, Remi, Oh, Chooh K., Soula, Gerard.
Application Number | 20050175695 10/997836 |
Document ID | / |
Family ID | 34636531 |
Filed Date | 2005-08-11 |
United States Patent
Application |
20050175695 |
Kind Code |
A1 |
Castan, Catherine ; et
al. |
August 11, 2005 |
Carvedilol free base, salts, anhydrous forms or solvates thereof,
corresponding pharmaceutical compositions, controlled release
formulations, and treatment or delivery methods
Abstract
The present invention also relates to carvedilol free base,
carvedilol salts, anhydrous forms, or solvates thereof,
corresponding pharmaceutical compositions or controlled release
formulations, and delivery or dosing methods of carvedilol forms to
the lower gastrointestingal tract or methods to treat
cardiovascular diseases, which may include, but are not limited to
hypertension, congestive heart failure, atherosclerosis, and
angina. The present invention relates to controlled release
formulations, which comprise various carvedilol forms, which may
include, but are not limited to a carvedilol free base or
corresponding carvedilol salts, anhydrous forms or solvates
thereof.
Inventors: |
Castan, Catherine;
(Venissieux, FR) ; Crowley, Patrick J.;
(Collegeville, PA) ; Guimberteau, Florence;
(Venissieux, FR) ; Meyrueix, Remi; (Venissieux,
FR) ; Oh, Chooh K.; (Collegeville, PA) ;
Soula, Gerard; (Venissieux, FR) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Porperty - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Family ID: |
34636531 |
Appl. No.: |
10/997836 |
Filed: |
November 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60524991 |
Nov 25, 2003 |
|
|
|
60605680 |
Aug 30, 2004 |
|
|
|
Current U.S.
Class: |
424/468 ;
514/411 |
Current CPC
Class: |
A61K 9/1658 20130101;
A61P 9/12 20180101; A61K 9/1635 20130101; A61K 9/1641 20130101;
A61P 9/10 20180101; A61P 9/04 20180101; A61K 31/403 20130101; A61K
9/2077 20130101 |
Class at
Publication: |
424/468 ;
514/411 |
International
Class: |
A61K 031/403; A61K
009/22 |
Claims
What is claimed is:
1. A controlled release formulation, comprising: a solubility
enhanced carvedilol free base or carvedilol salt, solvate or
anhydrous form thereof; wherein the controlled release formulation
following oral dosage exhibits a substantially biphasic plasma
profile with a first plasma concentration peak level within within
14 hours of ingestion and a second plasma concentration peak level
within 5-10 hours after ingestion.
2. The controlled release formulation according to claim 1, wherein
the oral dosage is administered at night.
3. The controlled release formulation according to claim 1, wherein
the solubility enhanced carvedilol free base or carvedilol salt,
solvate or anhydrous form thereof is an acid addition salt of
carvedilol free base.
4. The controlled release formulation according to claim 3, wherein
the acid addition salt of carvedilol free base is an acid addition
salt formed from a mineral acid or an organic acid.
5. The controlled release formulation according to claim 4, wherein
the mineral acid is selected from hydrobromic acid, hydrochloric
acid, phosphoric or sulphuric acid, and the organic acid is
selected from methansulphuric acid, tartaric acid, maleic acid,
acetic acid, citric acid, benzoic acid and the like.
6. The controlled release formulation according to claim 1, wherein
the solubility enhanced carvedilol salt, solvate or anhydrous form
is selected from the group consisting of carvedilol mandelate,
carvedilol lactate, carvedilol maleate, carvedilol sulfate,
carvedilol glutarate, carvedilol mesylate, carvedilol phosphate,
carvedilol citrate, carvedilol hydrogen bromide, carvedilol
oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide,
carvedilol benzoate, or corresponding solvates thereof.
7. The controlled release formulation according to claim 6, wherein
the solubility enhanced carvedilol salt, solvate or anhydrous form
thereof is carvedilol phosphate.
8. The controlled release formulation according to claim 1, wherein
the formulation is in an oral dosage form.
9. The controlled release formulation according to claim 8, wherein
the oral dosage form is a capsule dosage form.
10. The controlled release formulation according to claim 9,
wherein the capsule dosage form is comprised of a mixture of two or
more populations of coated pellets of different sizes with
different associated immediate or controlled release
characteristics.
11. A microparticle composition or formulation, which comprises: a
mixture of rapidly releasing and controlled-release microparticles;
wherein the mixture contains carvedilol free base or a carvedilol
salt, solvate or anhydrous form thereof; wherein each rapidly
releasing microparticle has a core unit formed by applying a
mixture of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof and materials selected from at
least one nitrogen containing polymer, a plasticizer or
pharmaceutically acceptable excipients onto a cellulose
microparticle or pharmaceutically acceptable material; and wherein
each core of the rapidly releasing and controlled-release
microparticles further are layered or coated with an additional
controlled release layer formed from pharmaceutically acceptable
excipients.
12. A microparticle composition or formulation of claim 11, wherein
the controlled release layer is formed from a mixture of the
pharmaceutically acceptable excipients selected from a film former,
a plasticiser or other pharmaceutically acceptable excipients.
13. A microparticle composition or formulation, which comprises: a
mixture of: [a] rapidly-releasing microparticles containing
carvedilol free base, or a carvedilol salt, solvate or anhydrous
form thereof; and [b] at least two types of controlled-release
microparticles containing a carvedilol free base or a carvedilol
salt, solvate or anhydrous form thereof; wherein the rapidly
releasing microparticles contain a first dosage amount of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof different than each of the dosage amounts of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in at least two different types of delayed
or controlled-release microparticles; and wherein rapid release of
the first dosage amount of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in
the rapidly releasing microparticles is followed by a serial or
sequential time-triggered and pH-triggered release of each of the
different dosage amounts of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in
each of the at least two different types of controlled release
microparticles.
14. The microparticle composition or formulation of claim 13,
wherein the serial or sequential pH triggered release of each of
the different dosage amounts of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in
each of the at least two different types of controlled release
microparticles occurs at a pH of about 5.5 to a pH of about a
pH>6.4.
15. The microparticle composition or formulation of claim 13,
wherein a first maximum plasma drug level following rapid release
of the first dosage amount of the carvedilol free base, or the
carvedilol salt, solvate, or anhydrous form thereof contained in
the rapidly releasing microparticles occur at a time between about
1 hour to about 3 hour following dosage of the microparticle
composition or formulation.
16. The microparticle composition or formulation of claim 13,
wherein a second maximum plasma drug level following the serial or
sequential time-triggered release of each of the different dosage
amounts of the carvedilol free base or carvedilol salt, solvate, or
anhydrous form thereof contained in each of the at least two
different types of controlled release microparticles occur at a
time between about 5 hours to about 10 hours following dosage of
the microparticle composition or formulation.
17. The microparticle composition or formulation of claim 11,
wherein each of the first and second maximum plasma levels
following the time and pH triggered release of each of the
different dosage amounts of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in
the rapidly releasing microparticles and each of the at least two
different types of controlled release microparticles results in a
controlled release of the total dosage amount of the carvedilol
free base or the carvedilol salt, solvate, or anhydrous form
thereof contained in the microparticle composition or
formulation.
18. The microparticle composition or formulation of claim 17
wherein the first maximum plasma levels following the time and pH
triggered release of each of the different dosage amounts of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in the rapidly releasing microparticles is
about 10% to about 15% of the total dosage amount of carvedilol
free base, carvedilol salt, solvate, or anhydrous form thereof
contained in the microparticle composition or formulation.
19. The microparticle composition or formulation of claim 18,
wherein the first maximum plasma levels following the time and pH
triggered release of each of the different dosage amounts of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in the rapidly releasing microparticles is
about 12.5% of the total dosage amount of carvedilol free base,
carvedilol salt, solvate, or anhydrous form thereof contained in
the microparticle composition or formulation
20. The microparticle composition or formulation of claim 17,
wherein the second maximum plasma levels following the time and pH
triggered release of each of the different dosage amounts of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in each of the at least two different types
of controlled release microparticles results in a controlled
release of between about 85% to about 90% the total dosage amount
of the carvedilol free base or the carvedilol salt, solvate, or
anhydrous form thereof contained in the microparticle composition
or formulation
21. The microparticle composition or formulation of claim 13,
wherein a controlled release of the total dosage amount of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in the microparticle composition or
formulation occurs in a gastrointestinal tract system.
22. A microparticle formulation for once-a-day therapy, which
comprises: a mixture of: [a] rapidly releasing microparticles
containing carvedilol free base or a carvedilol salt, solvate, or
anhydrous form thereof; and [b] at least two types of
controlled-release microparticles containing carvedilol free base
or a carvedilol salt, solvate, or anhydrous form thereof; wherein
the rapidly releasing microparticles contain a first dosage amount
of the carvedilol free base or the carvedilol salt, solvate, or
anhydrous form thereof different from each dosage amount contained
in each of the at least two different types of delayed or
controlled-release microparticles; wherein the rapidly releasing
microparticles exhibit rapid release of the first dosage amount of
the carvedilol free base or the carvedilol salt, solvate, or
anhydrous form thereof and the at least two different types of
controlled release microparticles exhibit a pH-dependent, a time
dependent or a pH-dependent and time-dependent, a triggered serial
or sequential sustained prolonged release or controlled release for
each of the dosage amounts of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in
the at least two different types of controlled release
microparticles.
23. A microparticle composition or formulation, which comprises:
[a] a rapidly releasing microparticle type containing carvedilol
free base or a carvedilol salt, solvate, or anhydrous form thereof;
wherein each rapidly releasing microparticle type is comprised of a
rapidly releasing microparticle core unit formed from a mixture of
the carvedilol free base or the carvedilol, salt, solvate, or
anhydrous form thereof in combination with one or more
nitrogen-containing pharmaceutical polymers and a plasticizer or
other pharmaceutically acceptable excipients; [b] at least two
different controlled-release microparticle types each containing
carvedilol free base or a carvedilol salt, solvate, or anhydrous
form thereof; wherein each of the at least two different
controlled-release microparticles is comprised of a drug-containing
microparticle core unit as defined in [a] above and is further
coated with a controlled release layer(s) formed from a
film-forming polymer, a plasticizing agent or other
pharmaceutically acceptable excipients; wherein each of the rapidly
releasing microparticle type contains the carvedilol free base or
the carvedilol salt, solvate, or anhydrous form thereof dosage
amount different from the carvedilol free base or the carvedilol
salt, solvate, or anhydrous form thereof dosage amounts contained
in each of the at least two different controlled release
microparticle types; wherein each of the rapidly releasing and at
least two different controlled release microparticles are mixed
together with materials selected from the group consisting of a
surface active, a lubricating agent, an anti-agglomerating agent or
other pharmaceutically acceptable excipients.
24. A controlled-release microparticle formulation, which comprises
a microparticle ratio mixture formed from: [1] a first rapidly
releasingmicroparticle population, [2] a first controlled release
microparticle population; and [3] a second controlled release
microparticle population; wherein each first rapidly releasing
microparticle population is formed from a rapid releasing
microparticle comprised of a combination of carvedilol free base or
a carvedilol salt, solvate, or anhydrous form thereof, one or more
nitrogen-containing polymers, a plasticizer and, other
pharmaceutically acceptable excipients; wherein each first
controlled release microparticle population and each second
controlled release microparticle population is comprised of a
controlled-release microparticle unit comprised of an active drug
loaded core comprised of a combination of a carvedilol free base or
a carvedilol salt, solvate, or anhydrous form thereof, one or more
nitrogen-containing polymers, a plasticizer or pharmaceutically
acceptable excipients; wherein the active drug loaded core of each
first controlled release microcapsule and each second controlled
release microcapsule is layered with a controlled release layer of
film forming polymer(s), or mixtures of film forming polymers
thereof, and a plasticizer agent or pharmaceutically acceptable
excipients; wherein each first rapidly releasing microparticle
unit, first controlled release microparticle unit and second
controlled release microparticle unit each contain a different
dosage amount of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof.
25. The controlled-release microparticle formulation of claim 24,
wherein the first rapidly releasing microparticle population
contains at least 5% and no more than 20% of a total dosage of the
carvedilol free base or the carvedilol salt, solvate or anhydrous
form thereof.
26. The controlled-release microparticle formulation of claim 25,
wherein the first rapidly releasing microparticle population
contains at least 10% and no more than 15% of the total dosage of
the carvedilol free base or the carvedilol salt, solvate or
anhydrous form thereof.
27. The controlled-release microparticle formulation of claim 24,
wherein the first controlled-release microparticle population
contains at least 25% and no more than 50% of a total dosage of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof.
28. The controlled-release microparticle formulation of claim 24,
wherein the second controlled-release microparticle population
contains at least 40% and no more than 60% of a total dosage of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof.
29. The controlled-release microparticle formulation of claim 24,
wherein each first rapidly releasing microparticle unit, first
controlled release microparticle unit and second controlled release
microparticle unit has a particle size of between 50 .mu.m and 1000
.mu.m.
30. The controlled-release microparticle formulation of claim 24,
wherein the microparticle formulation is an oral dosage form.
31. The controlled-release microparticle formulation of claim 30,
wherein the oral dosage form is administered at night.
32. The controlled release formulation according to claim 24,
wherein the carvedilol salt, solvate or anhydrous form thereof is
an acid addition salt of carvedilol free base.
33. The controlled release formulation according to claim 32,
wherein the acid addition salt of carvedilol free base is formed
from a mineral acid or an organic acid.
34. The controlled release formulation according to claim 33,
wherein the mineral acid is selected from hydrobromic acid,
hydrochloric acid, phosphoric or sulphuric acid, and the organic
acid is selected from methansulphuric acid, tartaric acid, maleic
acid, acetic acid, citric acid, benzoic acid and the like.
35. The controlled release formulation according to claim 24,
wherein the carvedilol salt, solvate or anhydrous form thereof is
selected from the group consisting of carvedilol mandelate,
carvedilol lactate, carvedilol maleate, carvedilol sulfate,
carvedilol glutarate, carvedilol mesylate, carvedilol phosphate,
carvedilol citrate, carvedilol hydrogen bromide, carvedilol
oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide,
carvedilol benzoate, and corresponding solvates thereof.
36. The controlled release formulation according to claim 35,.
wherein the carvedilol salt, solvate or anhydrous form thereof is
carvedilol phosphate.
37. The controlled release formulation according to claim 35,
wherein the carvedilol salt, solvate or anhydrous form is selected
from the group consisting of carvedilol hydrogen phosphate,
carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate
hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol
dihydrogen phosphate methanol solvate, carvedilol hydrobromide
monohydrate, carvedilol hydrobromide dioxane solvate, carvedilol
hydrobromide 1-pentanol solvate, carvedilol hydrobromide
2-methyl-1-propanol solvate, carvedilol hydrobromide
trifluoroethanol solvate, carvedilol hydrobromide 2-propanol
solvate, carvedilol hydrobromide n-propanol solvate #1, carvedilol
hydrobromide n-propanol solvate #2, carvedilol hydrobromide
anhydrous forms or anhydrous forms, carvedilol hydrobromide ethanol
solvate, carvedilol hydrobromide dioxane solvate, carvedilol
monocitrate monohydrate, carvedilol mandelate, carvedilol lactate,
carvedilol hydrochloride, carvedilol maleate, carvedilol sulfate,
carvedilol glutarate, or corresponding anhydrous forms, solvates
thereof.
38. The controlled release formulation according to claim 37,
wherein the carvedilol salt, solvate or anhydrous form thereof is
selected from the group consisting of carvedilol hydrogen
phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen
phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate,
carvedilol dihydrogen phosphate methanol solvate.
39. The controlled release formulation according to claim 38,
wherein the carvedilol salt, solvate or anhydrous form thereof is
carvedilol dihydrogen phosphate hemihydrate.
40. A controlled-release microparticle composition or formulation,
which comprises: a tri-component controlled-release microparticle
composition or formulation product formed from: [1] a first rapidly
releasing microparticle population comprised of rapidly releasing
microparticles; wherein each rapidly releasing microparticle
contains a layer comprised of carvedilol free base or a carvedilol,
salt, solvate, or anhydrous form thereof, at least one nitrogen
containing polymer and a plasticizer or other pharmaceutically
acceptable excipients applied to a cellulose sphere or a cellulose
core; and [2] a first controlled release microparticle population
comprised of first controlled release microparticless; wherein each
first controlled release microparticle contains a layer comprised
of carvedilol free base or a carvedilol salt, solvate, or anhydrous
form thereof, at least one nitrogen containing polymer and a
plasticizer or pharmaceutically acceptable excipients applied to a
cellulose sphere or a cellulose core; wherein each first controlled
release microparticle is coated with at least one release
controlling coating layer(s) formed from a film forming polymer and
a plasticizing agent or other pharmaceutically acceptable materials
to form each first controlled release microparticle; and wherein
each first controlled release granule triggers a release of the
carvedilol free base, or the carvedilol salt, solvate, or anhydrous
form thereof at a pH of about 5.5; [3] a second controlled release
microparticle population comprised of second controlled release
microparticle granules; wherein each second controlled release
microparticle contains a layer comprised of carvedilol free base or
a carvedilol salt, solvate, or anhydrous form thereof, at least one
nitrogen containing polymer and a plasticizer and pharmaceutically
acceptable excipients applied to a cellulose sphere or a cellulose
core; wherein each second controlled release microparticle is
coated with at least one release controlling coating layer(s)
formed from a film forming polymer, or mixtures thereof and a
plasticizing agent to form each second controlled release
microparticle; and wherein each second controlled release granule
triggers a release of the carvedilol free base, or the carvedilol
salt, solvate, or anhydrous form thereof at a pH of about
pH>6.4; and wherein each rapidly releasing population, first
controlled release population and second controlled release
population further are admixed with pharmaceutically acceptable
adjuvants, carriers or excipients to form the tri-component
controlled-release microparticle-containing dosage form.
41. A controlled-release microparticle composition or formulation,
comprises: a tri-component controlled-release microparticle
composition, formulation or dosage product formed from: [1] a first
rapidly releasing microparticle population comprised of
microparticle rapidly releasing granules; wherein each rapidly
releasing microcapsule population is comprised of microparticle
rapidly releasing granules each of which contain a layer comprised
of carvedilol free base, or a carvedilol salt, solvate, or
anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or core or other pharmaceutically
acceptable core; and [2] a first controlled release microparticle
population comprised of first controlled release. microparticle
granules; wherein each first controlled release population is
comprised of first controlled release microparticle granules each
of which contain a layer comprised of carvedilol free base or a
carvedilol salt, solvate, or anhydrous form thereof, at least one
nitrogen containing polymer and a plasticizer or other
pharmaceutically acceptable excipients applied to a cellulose
sphere or core or other pharmaceutically acceptable core; wherein
each first controlled release microparticle is coated with at least
one release controlling coating layer(s) formed from a film forming
polymer and a plasticizing agent to form each first controlled
release microparticle; and wherein each first controlled release
granule triggers a release of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof at a pH of
about 5.5. [3] a second controlled release microparticle population
comprised of second controlled release microparticle granules;
wherein each second controlled release population is comprised of
second controlled release microparticle granules each of which
contain a layer comprised of carvedilol free base or a carvedilol
salt, solvate, or anhydrous form thereof, at least one nitrogen
containing polymer and a plasticizer or pharmaceutically acceptable
excipients applied to a cellulose sphere or core or
pharmaceutically acceptable core; wherein each second controlled
release microparticle is coated with at least one release
controlling coating layer(s) formed from a film forming polymer and
a plasticizing agent to form each second controlled release
microparticle; and wherein each second controlled release granule
triggers a release of the carvedilol free base or the carvedilol
salt, solvate, or anhydrous form thereof at a pH of about
pH>6.4; and wherein each rapidly releasing population, first
controlled release population and second controlled release
population are admixed with pharmaceutically acceptable adjuvants,
carriers or excipients to form the tri-component controlled-release
microparticle composition or formulation product.
42. A controlled-release microparticle composition, formulation or
dosage form, which comprises: a tri-component controlled-release
microparticle composition or formulation product formed from: [1] a
first rapidly releasing microparticle population comprised of
microparticle rapidly releasing granules; wherein each
microparticle rapidly releasing granule contains a layer comprised
of a carvedilol phosphate salt, solvate, or anhydrous form thereof,
at least one nitrogen containing polymer and a plasticizer or other
pharmaceutically acceptable excipients applied to a cellulose
sphere or pharmaceutically acceptable core; and [2] a first
controlled release microparticle population comprised of first
controlled release microparticle granules; wherein each first
controlled release microparticle granule contains a layer comprised
of a carvedilol phosphate salt, solvate, or anhydrous form thereof,
at least one nitrogen containing polymer and a plasticizer or other
pharmaceutically acceptable excipients applied to a cellulose
sphere or pharmaceutically acceptable core; wherein each first
controlled release microparticle is coated with at least one
release controlling coating layer(s) formed from a film forming
polymer and a plasticizing agent to form each first controlled
release microparticle; and wherein each first controlled release
granule triggers a release of the carvedilol phosphate, salt,
solvate, or anhydrous form thereof at a pH of about 5.5; [3] a
second controlled release microparticle population comprised of
second controlled release microparticle granules; wherein each
second controlled release microparticle granule contains a layer
comprised of a carvedilol phosphate salt, solvate, or anhydrous
form thereof, at least one nitrogen containing polymer and a
plasticizer or other pharmaceutically acceptable excipients applied
to a cellulose sphere or pharmaceutically acceptable core; wherein
each second controlled release microparticle is coated with at
least one release controlling coating layer(s) formed from a film
forming polymer and a plasticizing agent to form each second
controlled release microparticle; and wherein each second
controlled release granule triggers a release of the carvedilol
phosphate salt, solvate, or anhydrous form thereof at a pH of about
pH>6.4; and wherein each rapidly releasing population, first
controlled release population and second controlled release
population are admixed with pharmaceutically acceptable adjuvants,
carriers or excipients to form the tri-component controlled-release
microparticle composition, formulation or dosage form.
43. The controlled release formulation according to claim 42,
wherein each rapidly releasing population, first controlled release
population and second controlled release population are in a 1:3:4
active drug content ratio.
44. The controlled release formulation according to claim 42,
wherein the carvedilol phosphate salt, solvate or anhydrous form is
selected from the group consisting of carvedilol hydrogen
phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen
phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate,
carvedilol dihydrogen phosphate methanol solvate.
45. The controlled release formulation according to claim 43,
wherein the carvedilol phosphate salt, solvate or anhydrous form is
carvedilol dihydrogen phosphate hemihydrate.
46. The controlled release formulation according to claim 42,
wherein: each microparticle rapidly releasing granule contains a
carvedilol phosphate salt, solvate, or anhydrous form thereof
contained in a dosage amount of 1.25 mg to 10 mg; and each first
controlled release microparticle granule contains a carvedilol
phosphate salt, solvate, or anhydrous form thereof contained in a
dosage amount of about 10 mg to about 80 mg.
47. The controlled release formulation according to claim 42,
wherein a total dosage amount of the carvedilol phosphate salt,
solvate, or anhydrous form thereof dosage amount contained in a sum
of each first rapidly releasing microparticle granule, a first
controlled release microparticle granule and a second controlled
release microparticle granule is the sum of the total dosage amount
between about 10 mg to about 80 mg.
48. The controlled release formulation according to claim 42,
wherein each first controlled release microparticle granule and
second controlled release microparticle granules further contain
swelling agents selected from crosslinked polyvinylpyrrolidones,
crosslinked carboxyalkylcelluloses, hydrophilic polymers of high
molar mass, hydroxyalkylcelluloses, carboxyalkylcellulose, modified
starch, starch, cellulose, sodium alginate, potassium polacriline,
or corresponding blends thereof.
49. The controlled release formulation according to claim 48,
wherein each first controlled release microparticle granule and
second controlled release microparticle granules, wherein: the
crosslinked polyvinylpyrrolidones are selected from polyplasdone or
crospovidone; the crosslinked carboxyalkylcelluloses are selected
from crosslinked carboxymethylcellulose or crosslinked sodium
croscarmellose; the hydrophilic polymers of high molar mass of
greater than or equal to 100000 Dalton are selected from:
polyvinylpyrrolidone, polyalkylene oxides selected from
polyethylene oxide or polypropylne oxide; hydroxyalkylcelluloses
selected from hydroxypropylcellulose or
hydroxypropylmethylcellulose; carboxyalkylcellulose selected from
carboxymethylcellulose; modified starch selected from sodium
glycolate; starch selected from corn, wheat, rice, or potato;
cellulose in a powder form or microcrystalline form; sodium
alginate; potassium polacriline; and corresponding blends
thereof.
50. The controlled release formulation according to claim 49,
wherein the swelling agent is selected from: the crosslinked
polyvinylpyrrolidones selected from polyplasdone or crospovidone;
or the crosslinked carboxyalkylcelluloses selected from crosslinked
carboxymethylcellulose or crosslinked sodium croscarmellose.
51. The controlled release formulation according to claim 42,
wherein the nitrogen-containing polymer in each first controlled
release microparticle granule and second controlled release
microparticle granule is a swelling agent.
52. The controlled release formulation according to claim 52,
wherein the nitrogen containing polymers are selected from
polyvinyl pyrrolidone (povidone or PVP), or cross-linked polyvinyl
pyrrolidone (cross-linked povidone).
53. The controlled release formulation according to claim 42,
wherein the nitrogen containing polymer in each first controlled
release microparticle granule and in each second controlled release
microparticle granule is a combination of polyvinyl pyrrolidone
(povidone or PVP), or cross-linked polyvinyl pyrrolidone
(cross-linked povidone).
54. The controlled release formulation according to claim 48,
wherein in each of the first microparticle rapidly releasing
granules, the first controlled release microparticle granules and
the second controlled release microparticle granules, the
plasticizer or the other pharmaceutically acceptable excipients
selected from surface-active or lubricating agents are selected
from castor oil, diethyl phthalate, triethyl citrate, salicylic
acid, magnesium stearate, sodium oleate or polyoxyethylenated
sorbitan laurate.
55. The controlled release formulation according to claim 42,
wherein at least one release controlling layer is formed from at
least one film forming polymer and a plasticizing agent in a ratio
from about 60% (w/w) to about 40% (w/w).
56. The controlled release formulation according to claim 42,
wherein the film forming polymer in at least one release
controlling coating layer(s) of each first controlled release
microparticle is selected from a polymethylmethacrylate polymer
selected from Eudragit L, Eudragit RL, Eudragit RS, other Eudragit
NE polymers, Acrycoat S100, or Acrycoat L 100D.
57. The controlled release formulation according to claim 42,
wherein the plasticizing agent in at least one release controlling
coating layer(s) of each first controlled release microparticle is
selected from a hydrogenated vegetable oil, propan 2-ol or
propylene glycol, diethyl phthalate or other pharmaceutically
acceptable materials.
58. A microparticle composition or formulation, which comprises: a
mixture of: [a] rapidly releasing microparticles containing a
carvedilol free base or a carvedilol salt, solvate, or anhydrous
form thereof; and [b] at least two types of controlled-release
microparticles containing carvedilol free base or a carvedilol
salt, solvate, or anhydrous form thereof; wherein the rapidly
releasing microparticles contain a first dosage amount of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof different than each of the dosage amounts contained in
at least two different types of delayed or controlled-release
microparticles; and wherein the rapidly releasing microparticles
exhibit different serial or sequential release for the first dosage
amount of carvedilol free base or the carvedilol salt, solvate, or
anhydrous form thereof than the dosage amounts contained in the at
least two different types of controlled release microparticles.
59. The microparticle composition or formulation according to claim
56, wherein the different serial or sequential release of the
rapidly releasing microparticles and at least two types of
controlled release microparticles are defined by a mean plasma
level representing a total carvedilol dosage amount as shown by a
substantially biphasic profile; wherein a total carvedilol dosage
amount is the sum of the first and second dosage amounts; wherein
the rapidly releasing microparticles comprising the carvedilol free
base or the carvedilol salt, solvate or anhydrous form thereof
provide a peak plasma level at about 1 to 3 hours after dosing and
each of the at least two types of delayed-controlled release
microparticles release the carvedilol free base or the carvedilol
salt, solvate or anhydrous form thereof provide a second peak
plasma level between 5 to 10 hours after dosing.
60. The microparticle composition or formulation according to claim
56, wherein the serial or sequential release of the total
carvedilol dosage amount from the rapidly releasing microparticles
and at least two types of controlled release microparticles provide
prolonged plasma levels as characterized by a substantially
biphasic profile and residual drug plasma levels 24 hours after
dosing comparable to a conventional carvedilol free base dosage
dosed twice daily at 12 hour intervals for a total 24 hour
period.
61. A controlled-release microparticle formulation for once-a-day
administration, which comprises: a microparticle mixture ratio
formed from an rapidly releasing microparticle population, a first
delayed release microparticle population; and a second delayed
release microparticle population; wherein each of the
microparticles in each population contain carvedilol free base,
salt, solvate, or anhydrous form thereof in a different dosage
amount adapted to provide controlled release of the different
dosages contained in each microparticle populations to achieve
comparable total plasma or total time concentrations (Area Under
Curve) and plasma levels at C24 hours comparable to a
conventional(rapidly releasing) carvedilol composition dosed twice
daily at 12 hour intervals.; wherein each of the first, second, and
third dosage form has a different release profile, said
microparticle product reaching a first peak plasma concentration
level between about 1 hour to about 3 hours after dosing the
controlled-release microparticle formulation and a second peak
plasma concentration level between about 5 hours to about 10 hours
after dosing the controlled-release microparticle formulation.
62. The controlled release microparticle formulation of claim 59,
wherein the release profile is a substantially biphasic profile
shown by: first release microparticles exhibiting a release rate of
the carvedilol free base or carvedilol salt, solvate, or anhydrous
form thereof providing a first peak plasma concentration level
between 1 to 3 hours after dosing the microparticle composition or
formulation; and each of the at least two types of controlled
release microparticles exhibiting a release rate of the carvedilol
free base or the carvedilol salt, solvate, or anhydrous form
thereof providing a second peak plasma concentration level between
5 to 10 hours after dosing the microparticle composition or
formulation exhibiting a combined higher peak plasma concentration
level than for the first release microparticles; wherein the first
peak plasma concentration level and the second peak plasma
concentration level are in a ratio of about 0.5:1.0; and wherein a
total of peak plasma concentration levels contributed by either the
first release microparticles or each of the two types of delayed
controlled release microparticles are substantially comparable to
Cmax levels for an rapidly releasing carvedilol free base
composition dosed twice daily at 12 hour intervals.
63. The controlled release microparticle formulation according to
claim 60, wherein the the first peak plasma concentration level
with a first T.sub.max pulse occurs within 1-3 hours of ingestion
and the second peak plasma concentration level with a second
T.sub.max pulse occurs within 5-10 hours after ingestion.
64. A controlled release microparticle dosage product, comprising:
a first immediate-release dosage form; a second delayed release
dosage form; and a third delayed release dosage form, wherein each
of said first, second and third dosage forms comprise carvediloll
free base or a carvedilol salt, solvate or anhydrous form thereof
and a pharmaceutically acceptable carrier(s), said three dosage
forms having different release profiles, said microparticle dosage
product reaching a first peak plasma level from about 1 to about 3
hours and a second peak plasma level from about 5 hours to about 10
hours.
65. The controlled release microparticle dosage product of claim
62, wherein the first immediate-release dosage form; the second
delayed release dosage form; and the third delayed release dosage
form includes a total dosage of the carvedilol free base or the
carvedilol salt, solvate or anhydrous form thereof that is
effective for a twenty four hour period.
66. A method of treating cardiovascular diseases, which comprises
administering to a subject in need thereof an effective amount of
the controlled release formulation according to claim 1.
67. The method of treating cardiovascular diseases of claim 64,
wherein cardiovascular diseases are selected from the group
consisting of hypertension, atherosclerosis, congestive heart
failure and angina.
68. A method of treating hypertension, atherosclerosis, congestive
heart failure or angina, which comprises administering to a subject
in need thereof an effective amount of the controlled release
formulation according to claim 21.
69. A method of treating hypertension, atherosclerosis, congestive
heart failure or angina, which comprises administering to a subject
in need thereof an effective amount of the controlled release
formulation according to claim 22.
70. A method of treating hypertension, atherosclerosis, congestive
heart failure or angina, which comprises administering to a subject
in need thereof an effective amount of the controlled release
formulation according to claim 23.
71. A method of treating hypertension, atherosclerosis, congestive
heart failure or angina, which comprises administering to a subject
in need thereof an effective amount of the controlled release
formulation according to claim 39.
72. A method of treating hypertension, atherosclerosis, congestive
heart failure or angina, which comprises administering to a subject
in need thereof an effective amount of the controlled release
formulation according to claim 40.
73. A method of treating hypertension, atherosclerosis, congestive
heart failure or angina, which comprises administering to a subject
in need thereof an effective amount of the controlled release
formulation according to claim 41.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to carvedilol free base,
carvedilol salts, anhydrous forms, or solvates thereof,
corresponding pharmaceutical compositions or controlled release
formulations, delivery methods of carvedilol forms to the
gastrointestingal tract or methods to treat cardiovascular
diseases, which may include, but are not limited to hypertension,
congestive heart failure, atherosclerosis, and angina.
[0002] The present invention relates to controlled release
formulations, which comprise various cavedilol forms, which may
include, but are not limited to carvedilol free base and
corresponding carvedilol salts, anhydrous forms or solvates
thereof.
BACKGROUND OF THE INVENTION
[0003] Carvedilol
[0004] The compound,
1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]-am-
ino]-2-propanol is known as Carvedilol. Carvedilol is depicted by
the following chemical structure: 1
[0005] Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to
Wiedemann et al. (i.e., assigned to Boehringer Mannheim, GmbH,
Mannheim-Waldhof, Fed. Rep. of Germany), which was issued on Mar.
5, 1985.
[0006] Currently, carvedilol is synthesized as free base for
incorporation in medication that is available commercially. The
aforementioned free base form of carvedilol is a racemic mixture of
R(+) and S(-) enantiomers, where non-selective
.beta.-adrenoreceptor blocking activity is exhibited by the S(-)
enantiomer and .alpha.-adrenergic blocking activity is exhibited by
both R(+) and S(-) enantiomers. Those unique features or
characteristics associated with such a racemic carvedilol mixture
contributes to two complementary pharmacologic actions: i.e., mixed
venous and arterial vasodilation and non-cardioselective,
beta-adrenergic blockade.
[0007] Carvedilol is used for treatment of hypertension, congestive
heart failure, and angina.
[0008] The currently commercially available carvedilol product is a
conventional, tablet prescribed as a twice-a-day (BID) medication
in the United States. The commercially available carvedilol
formulation is in an immediate release or rapidly releasing
carvedilol in its free base form, where the nature or the chemical
and physical formulation properties are such that by the time the
carvedilol leaves the stomach, it is either in solution or it is in
the form of a suspension of fine particles, i.e. a form from which
carvedilol can be readily absorbed.
[0009] Carvedilol contains an .alpha.-hydroxyl secondary amine
functional group, which has a pKa of 7.8. Carvedilol exhibits
predictable solubility behaviour in neutral or alkaline media, i.e.
above a pH of 9.0, the solubility of carvedilol is relatively low
(<1 .mu.g/mL). The solubility of carvedilol increases with
decreasing pH and reaches a plateau near pH=5, i.e. where
saturation solubility is about 23 .mu.g/mL at pH=7 and about 100
.mu.g/mL at pH=5 at room temperature. At lower pH values (i.e., at
a pH of 1 to 4 in various buffer systems), solubility of carvedilol
is limited by the solubility of its protonated form or its
corresponding salt formed in-situ. For example, a hydrochloride
salt of carvedilol generated in situ an acidic medium, which
simulates gastric fluid, is less soluble in such medium.
[0010] In addition, the presence of the .alpha.-hydroxyl secondary
amine group in the carvedilol chemical structure confers a
propensity upon the compound to chemically react with excipients
normally included in a dosage form to aid manufacture, maintain
quality, or enhances dissolution rate. For example, the
.alpha.-hydroxyl secondary amine group of carvedilol can react with
aldehydes or ester functional groups through nucleophilic
reactions. Common chemical functional group residues associated
with conventionally used excipients, include ester, aldehyde or
other chemical residue functional groups. This often results in
marginal or unacceptable chemical stability upon storage.
[0011] Pharmaceutical Compositions/Formulations and
Controlled-Release Technology
[0012] In the medical treatment of mammals, a desire to maintain a
constant concentration of a pharmaceutical composition within the
blood stream of human or animal patient, is dependent upon regular
administration of such a composition, such as in an oral tablet or
capsule form. Regularity of oral administration of various drug
dosage forms is important as a typical pharmaceutical composition
form is released immediately upon dissolution in a recipients
stomach. Thus, any interruption in a patient's tablet supply
regimen causes a consequent drug or pharmaceutical concentration
reduction in the patient's blood.
[0013] Therefore, for ease of patient use, it is often desirable to
maintain a controlled concentration of an pharmaceutical active
drug agent or composition at a predetermined site for an extended
period of time.
[0014] The use of controlled release technology allows for release
of a pharmaceutical composition at a constant rate at a desired
concentration into a patient's system over many hours. For example,
if a controlled release tablet contains a sufficient drug or
composition amount to maintain a desired concentration for twelve
or more hours, there would be no need for a patient to take tablets
frequently and would reduce interrupting a patient's drug
regime.
[0015] As conventionally known in the art, many different examples
have been developed to accomplish such results.
[0016] For example, U.S. Pat. No. 3,845,770 to Theeuwes et al.
teaches a device that provides a controlled release via a core
tablet including an active agent coated with a semipermeable
membrane permeable only to a fluid present in the environment of
use (i.e., water), where the active agent or another component of
the core tablet exhibits osmotic activity and the rate of release
is dependent upon the permeability of the semipermeable
membrane.
[0017] U.S. Pat. No. 4,624,847 to Ayer et al. describes an osmotic
dispensing device, where a drug mixed with an osmopolymer and/or
osmagent is in a compartment surrounded by a semipermeable wall
with an osmotic passageway to the compartment. Other patents
describing various osmotic dispensing devices include: U.S. Pat.
No. 4,519,801 to Edgren; U.S. Pat. No. 4,111,203 to Theeuwes; U.S.
Pat. No. 4,777,049 to Magruder et al.; U.S. Pat. No. 4,612,008 to
Wong et al.; U.S. Pat. No. 4,610,686 to Ayer et al.; U.S. Pat. No.
4,036,227 to Zaffaroni et al.; U.S. Pat. No. 4,553,973 to Edgren;
U.S. Pat. No. 4,077,407 to Theeuwes et al.; and U.S. Pat. No.
4,609,374 to Ayer.
[0018] U.S. Pat. No. 4,218,433 to Kooichi et al. describes a tablet
with a water insoluble coating and a water soluble component that
releases an active component at a constant rate due to an
indentation formed on its surface.
[0019] U.S. Pat. No. 4,687,660 to Baker et al. describes an osmotic
dispensing device without a preformed single passageway to release
water-soluble drugs, where based upon an osmotic gradient formed
from water insoluble film coated core containing a drug is combined
with excipient and an osmotic enhancing agent.
[0020] U.S. Pat. No. 4,816,262 to McMullen relates to a controlled
release disc-like configured tablet with a centrally extending
cylindrical hole that allows for zero order or constant release of
the active agent.
[0021] Devices with an impermeable coating covering various
portions of the device include: U.S. Pat. No. 4,814,183 to Zentner
relates to a controlled release device with a charged resin core
encased in a water insoluble semi-permeable material that is
impermeable to core components, but permeable to the passage of an
external fluid in the environment of use. U.S. Pat. No. 4,814,182
to Graham et al. describes a controlled release device which
comprises an active ingredient/hydrogel mixture with at least one
surface of the device having a coating impermeable to aqueous
media. U.S. Pat. No. 4,792,448 to Ranade relates to a cylindrical
tablet or bolus with a impermeable coated core having an active
ingredient blended with inert excipients and formed into a
cylindrical tablet preferably having a flat cylindrical side and a
convex top and bottom.
[0022] Moreover, numerous prior art references also describe
producing alternate sustained-release systems, with the aim of
providing medicinal forms, which may be taken once a day, to
prolong the action of a medicinal product. (see, for example,
Formes Pharmaceutiques Nouvelles, Buri, Puisieux, Doelker et
Benoit, Lavoisier 1985, pages 175-227).
[0023] These include monolithic systems, where dose to be
administered is in the form of a solid object, such as a tablet. DE
Pat. Appn. No. 39 43 242 (FR No. 2 670 112) discloses "matrix" type
granules, which comprise active particles ("AP") and inert
excipent(s), useful for making tablets. Such granules, which are
distinct from microcapsules, consist of a multitude of particles
included in a roughly spherical matrix comprising a cellulosic
polymer, a vinylic or acrylic polymer, a plasticizer and a
lubricating agent.
[0024] U.S. Pat. No. 4,461,759 to Dunn describes a oral solid
dosage coated tablet, which includes active particles ("AP")
protected from harmful effects of stomach acidity that are released
at a constant rate in the gastrointestinal tract.
[0025] U.S. Pat. No. 5,028,434 to Barclay et al. and Inter.l'
Appin. No. WO 91/16885 describes a monolithic tablet form using a
microporous film coating that allows controlled release of active
particles via osmotic pressure.
[0026] Other literature examples of microparticulate pharmaceutical
systems giving a sustained release of active particles ("AP" or
"AP's") include: U.S. Pat. No. 5,286,497 to Hendrickson et al.,
which relates to a once a day controlled release diltiazem
formulation, which contains a blend of rapid release bead and
delayed release coated diltiazem beads with different dissolution
rates.
[0027] Consequently, the short residence time in the small
intestine poses a considerable problem to those skilled in the art
interested in developing sustained-absorption medicinal products
intended for oral administration. The medicinal product
administered orally is, in effect, subject to the natural transit
of the gastrointestinal tract, thereby limiting its residence time.
Now, the small intestine is the preferred location for systemic
absorption and it represents the ideal site for making APs
available. Thus, it is easy to appreciate the value of a
pharmaceutical form having an increased residence time in the small
intestine, in view of the sustained in vivo absorption of an AP,
beyond normal transit time in the small intestine.
[0028] Many studies have been performed regarding the time for
gastrointestinal transit. These studies show that the duration of
gastric transit is very variable, in particular as a function of
feeding, and that it is between a few minutes and a few hours. On
the other hand, the duration of transit in the small intestine is
particularly constant and, more precisely, is 3 hours plus or minus
one hour (see for example S. S. Davis: Assessment of
gastrointestinal transit and drug absorption, in Noval drug
delivery and its therapeutic application, Ed L. F. Prescott-W. S.
Nimmo, 1989, J. Wiley & Son, page 89-101).
[0029] In light of the foregoing, novel carvedilol salt, solvate,
or anhydrous forms thereof, corresponding pharmaceutical
compositions or controlled release formulations containing
carvedilol free base or novel carvedilol salt, solvate, or
anhydrous forms thereof, with greater aqueous solubility, chemical
stability, prolonged residence time, absorption in the
gastrointestingal tract, especially such as in the small intestine,
etc. would offer many potential benefits for provision of medicinal
products containing the drug carvedilol.
[0030] Examples of such benefits would include products with the
ability to achieve desired or prolonged drug levels in a systemic
system by sustaining absorption along the gastrointestinal tract of
mammals (i.e., such as humans), particularly in regions of neutral
pH, where a drug, such as carvedilol, has minimal solubility.
[0031] Surprisingly, it has now been shown that novel forms of
carvedilol salts, anhydrous forms or solvates thereof, which may
isolated as, but not limited to crystalline or other solid forms,
exhibit much higher aqueous solubility than the corresponding free
base or other prepared carvedilol salts, which may include, but are
not limited to crystalline forms or other solid forms.
[0032] Such carvedilol salts, anhydrous forms or solvates thereof,
which may include, but are not limited to crystalline forms or
other solid forms, also have potential to improve the stability of
carvedilol in pharmaceutical compositions or controlled-release
formulations due to the fact that the secondary amine functional
group attached to the carvedilol core structure, a moiety pivotal
to degradation processes, is protonated as a salt.
[0033] Such carvedilol salts, anhydrous forms or solvates thereof,
which may include, but are not limited to crystalline forms or
other solid forms, in pharmaceutical compositions or
controlled-release formulations also have potential to lead to
prolonged residence, absorption time, and/or good tolerance levels
in the gastrointestinal tract, such as the small intestine, colon,
etc.
[0034] In light of the above, a need exists to develop carvedilol
free base or different carvedilol salts, anhydrous forms or
solvates forms thereof, different corresponding compositions or
controlled release formulations, respectively, which have greater
aqueous solubility, chemical stability, good tolerance levels,
sustained or prolonged drug or absorption properties or transit
levels (i.e., such as in neutral gastrointestinal tract pH regions,
etc.).
[0035] There also exists a need to develop methods of delivery of
carvedilol (such as carvedilol free base or as a carvedilol salt,
solvate or anhydrous form thereof) to the gastrointestinal tract or
methods of treatment for cardiovascular diseases or associated
disorders, which may include, but are not limited to hypertension,
congestive heart failure, atherosclerosis or angina, etc., which
comprises administration of the such carvedilol free base,
carvedilol salt, anhydrous forms or solvate forms thereof,
corresponding pharmaceutical compositions, or controlled release
dosage formulations.
[0036] The present invention is directed to overcoming these and
other problems encountered in the art.
SUMMARY OF THE INVENTION
[0037] The present invention relates to carvedilol free base,
carvedilol salts, anhydrous forms, or solvates thereof,
corresponding pharmaceutical compositions or controlled release
formulations, and delivery methods of carvedilol forms to the
gastrointestingal tract or methods to treat cardiovascular
diseases, which may include, but are not limited to hypertension,
congestive heart failure, atherosclerosis, and angina.
[0038] The present invention generally relates to control release
formulations, which comprise various cavedilol forms, which may
include, but are not limited to carvedilol free base and
corresponding carvedilol salts, anhydrous forms or solvates
thereof.
[0039] In particular, the present invention relates to a controlled
release formulation, which comprises at least one of these
components: [a]carvedilol free base; or [b] a solubility enhanced
carvedilol salt, solvate or anhydrous form; where the
aforementioned controlled release formulation following oral dosage
exhibits a substantially biphasic plasma profile with a first
plasma concentration peak level and a first T.sub.max pulse
occurring within 1-4 hours of ingestion and a second a plasma
concentration peak level and second T.sub.max pulse occurring
within 5-8 hours after ingestion.
BRIEF DESCRIPTION OF THE FIGURES
[0040] Carvedilol Phosphate Salts
[0041] FIG. 1 is an x-ray powder diffractogram for carvedilol
dihydrogen phosphate hemihydrate (Form I).
[0042] FIG. 2 shows the thermal analysis results for carvedilol
dihydrogen phosphate hemihydrate (Form I).
[0043] FIG. 3 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate hemihydrate (Form I).
[0044] FIG. 4 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate hemihydrate in the 4000-2000 cm.sup.-1 region of the
spectrum (Form I).
[0045] FIG. 5 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate hemihydrate in the 2000-400 cm.sup.-1 region of the
spectrum (Form I).
[0046] FIG. 6 is an FT-IR spectrum for carvedilol dihydrogen
phosphate hemihydrate (Form I).
[0047] FIG. 7 is an FT-IR spectrum for carvedilol dihydrogen
phosphate hemihydrate in the 4000-2000 cm.sup.-1 region of the
spectrum (Form I).
[0048] FIG. 8 is an FT-IR spectrum for carvedilol dihydrogen
phosphate hemihydrate in the 2000-500 cm.sup.-1 region of the
spectrum (Form I).
[0049] FIG. 9 is an x-ray powder diffractogram for carvedilol
dihydrogen phosphate dihydrate (Form II).
[0050] FIG. 10 shows the thermal analysis results for carvedilol
dihydrogen phosphate dihydrate (Form II).
[0051] FIG. 11 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate dihydrate (Form II).
[0052] FIG. 12 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate dihydrate in the 4000-2000 cm.sup.-1 region of the
spectrum (Form II).
[0053] FIG. 13 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate dihydrate in the 2000-400 cm.sup.-1 region of the
spectrum (Form II).
[0054] FIG. 14 is an FT-IR spectrum for carvedilol dihydrogen
phosphate dihydrate (Form II).
[0055] FIG. 15 is an FT-IR spectrum for carvedilol dihydrogen
phosphate dihydrate in the 4000-2000 cm.sup.-1 region of the
spectrum (Form II).
[0056] FIG. 16 is an FT-IR spectrum for carvedilol dihydrogen
phosphate dihydrate in the 2000-500 cm.sup.-1 region of the
spectrum (Form II).
[0057] FIG. 17 shows the thermal analysis results for carvedilol
dihydrogen phosphate methanol solvate (Form III).
[0058] FIG. 18 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate methanol solvate (Form III).
[0059] FIG. 19 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate methanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum (Form III).
[0060] FIG. 20 is an FT-Raman spectrum for carvedilol dihydrogen
phosphate methanol solvate in the 2000-400 cm.sup.-1 region of the
spectrum (Form III).
[0061] FIG. 21 is an FT-IR spectrum for carvedilol dihydrogen
phosphate methanol solvate (Form III).
[0062] FIG. 22 is an FT-IR spectrum for carvedilol dihydrogen
phosphate methanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum (Form III).
[0063] FIG. 23 is an FT-IR spectrum for carvedilol dihydrogen
phosphate methanol solvate in the 2000-500 cm.sup.-1 region of the
spectrum (Form III).
[0064] FIG. 24 is an x-ray powder diffractogram for carvedilol
dihydrogen phosphate methanol solvate (Form III).
[0065] FIG. 25 is an x-ray powder diffractogram for carvedilol
dihydrogen phosphate dihydrate (Form IV).
[0066] FIG. 26 is a solid state .sup.13C NMR for carvedilol
dihydrogen phosphate dihydrate (Form I).
[0067] FIG. 27 is a solid state .sup.31P NMR for carvedilol
dihydrogen phosphate dihydrate (Form I).
[0068] FIG. 28 is an x-ray powder diffractogram for carvedilol
dihydrogen phosphate (Form V).
[0069] FIG. 29 is an x-ray powder diffractogram for carvedilol
hydrogen phosphate (Form VI).
[0070] Carvedilol HBr Salts
[0071] FIG. 30 is an x-ray powder diffractogram for carvedilol
hydrobromide monohydrate.
[0072] FIG. 31 is a differential scanning calorimetry thermogram
for carvedilol hydrobromide monohydrate.
[0073] FIG. 32 is an FT-Raman spectrum for carvedilol hydrobromide
monohydrate.
[0074] FIG. 33 is an FT-Raman spectrum for carvedilol hydrobromide
monohydrate in the 4000-2000 cm.sup.-1 region of the spectrum.
[0075] FIG. 34 is an FT-Raman spectrum for carvedilol hydrobromide
monohydrate in the 2000-400 cm.sup.-1 region of the spectrum.
[0076] FIG. 35 is an FT-IR spectrum for carvedilol hydrobromide
monohydrate.
[0077] FIG. 36 is an FT-IR spectrum for carvedilol hydrobromide
monohydrate in the 4000-2000 cm.sup.-1 region of the spectrum.
[0078] FIG. 37 is an FT-IR spectrum for carvedilol hydrobromide
monohydrate in the 2000-500 cm.sup.-1 region of the spectrum.
[0079] FIG. 38 is a view of a single molecule of carvedilol
hydrobromide monohydrate. The hydroxyl group and the water molecule
are disordered.
[0080] FIG. 39 are views of molecules of carvedilol hydrobromide
monohydrate showing the N--H . . . Br . . . H--N interactions. The
top view focuses on Br1 and the bottom view focuses on Br2. The
interaction between the carvedilol cation and the bromine anion is
unusual. Each carvedilol molecule makes two chemically different
contacts to the bromine anions. Each bromine anion sits on a
crystallographic special position (that is, on a crystallographic
two-fold axis) which means that there are two half bromine anions
interacting with each carvedilol cation.
[0081] FIG. 40 is a differential scanning calorimetry thermogram
for carvedilol hydrobromide dioxane solvate.
[0082] FIG. 41 is an FT-Raman spectrum for carvedilol hydrobromide
dioxane solvate.
[0083] FIG. 42 is an FT-Raman spectrum for carvedilol hydrobromide
dioxane solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0084] FIG. 43 is an FT-Raman spectrum for carvedilol hydrobromide
dioxane solvate in the 2000-400 cm.sup.-1 region of the
spectrum.
[0085] FIG. 44 is an FT-IR spectrum for carvedilol hydrobromide
dioxane solvate.
[0086] FIG. 45 is an FT-IR spectrum for carvedilol hydrobromide
dioxane solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0087] FIG. 46 is an FT-IR spectrum for carvedilol hydrobromide
dioxane solvate in the 2000-500 cm.sup.-1 region of the
spectrum.
[0088] FIG. 47 is a differential scanning calorimetry thermogram
for carvedilol hydrobromide 1-pentanol solvate.
[0089] FIG. 48 is an FT-Raman spectrum for carvedilol hydrobromide
1-pentanol solvate.
[0090] FIG. 49 is an FT-Raman spectrum for carvedilol hydrobromide
1-pentanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0091] FIG. 50 is an FT-Raman spectrum for carvedilol hydrobromide
1 pentanol solvate in the 2000-400 cm.sup.-1 region of the
spectrum.
[0092] FIG. 51 is an FT-IR spectrum for carvedilol hydrobromide
1-pentanol solvate.
[0093] FIG. 52 is an FT-IR spectrum for carvedilol hydrobromide
1-pentanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0094] FIG. 53 is an FT-IR spectrum for carvedilol hydrobromide
1-pentanol solvate in the 2000-500 cm.sup.-1 region of the
spectrum.
[0095] FIG. 54 is a differential scanning calorimetry thermogram
for carvedilol hydrobromide 2-methyl-1-propanol solvate.
[0096] FIG. 55 is an FT-Raman spectrum for carvedilol hydrobromide
2-methyl-1-propanol solvate.
[0097] FIG. 56 is an FT-Raman spectrum for carvedilol hydrobromide
2-methyl-1-propanol solvate in the 4000-2000 cm.sup.-1 region of
the spectrum.
[0098] FIG. 57 is an FT-Raman spectrum for carvedilol hydrobromide
2-methyl-1-propanol solvate in the 2000-400 cm.sup.-1 region of the
spectrum.
[0099] FIG. 58 is an FT-IR spectrum for carvedilol hydrobromide
2-methyl-1-propanol solvate.
[0100] FIG. 59 is an FT-IR spectrum for carvedilol hydrobromide
2-methyl-1-propanol solvate in the 4000-2000 cm.sup.-1 region of
the spectrum.
[0101] FIG. 60 is an FT-IR spectrum for carvedilol hydrobromide
2-methyl-1-propanol solvate in the 2000-500 cm.sup.-1 region of the
spectrum.
[0102] FIG. 61 is a differential scanning calorimetry thermogram
for carvedilol hydrobromide trifluoroethanol solvate.
[0103] FIG. 62 is an FT-Raman spectrum for carvedilol hydrobromide
trifluoroethanol solvate.
[0104] FIG. 63 is an FT-Raman spectrum for carvedilol hydrobromide
trifluoroethanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0105] FIG. 64 is an FT-Raman spectrum for carvedilol hydrobromide
trifluoroethanol solvate in the 2000-400 cm.sup.-1 region of the
spectrum.
[0106] FIG. 65 is an FT-IR spectrum for carvedilol hydrobromide
trifluoroethanol solvate.
[0107] FIG. 66 is an FT-IR spectrum for carvedilol hydrobromide
trifluoroethanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0108] FIG. 67 is an FT-IR spectrum for carvedilol hydrobromide
trifluoroethanol solvate in the 2000-500 cm.sup.-1 region of the
spectrum.
[0109] FIG. 68 is a differential scanning calorimetry thermogram
for carvedilol hydrobromide 2-propanol solvate.
[0110] FIG. 69 is an FT-Raman spectrum for carvedilol hydrobromide
2-propanol solvate.
[0111] FIG. 70 is an FT-Raman spectrum for carvedilol hydrobromide
2-propanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0112] FIG. 71 is an FT-Raman spectrum for carvedilol hydrobromide
2-propanol solvate in the 2000-400 cm.sup.-1 region of the
spectrum.
[0113] FIG. 72 is an FT-IR spectrum for carvedilol hydrobromide
2-propanol solvate.
[0114] FIG. 73 is an FT-IR spectrum for carvedilol hydrobromide
2-propanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0115] FIG. 74 is an FT-IR spectrum for carvedilol hydrobromide
2-propanol solvate in the 2000-500 cm.sup.-1 region of the
spectrum.
[0116] FIG. 75 is an x-ray powder diffractogram for carvedilol
hydrobromide n-propanol solvate #1.
[0117] FIG. 76 shows the thermal analysis results for carvedilol
hydrobromide n-propanol solvate #1.
[0118] FIG. 77 is an FT-Raman spectrum for carvedilol hydrobromide
n-propanol solvate #1.
[0119] FIG. 78 is an FT-Raman spectrum for carvedilol hydrobromide
n-propanol solvate #1 in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0120] FIG. 79 is an FT-Raman spectrum for carvedilol hydrobromide
n-propanol solvate #1 in the 2000-400 cm.sup.-1 region of the
spectrum.
[0121] FIG. 80 is an FT-IR spectrum for carvedilol hydrobromide
n-propanol solvate #1.
[0122] FIG. 81 is an FT-IR spectrum for carvedilol hydrobromide
n-propanol solvate #1 in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0123] FIG. 82 is an FT-IR spectrum for carvedilol hydrobromide
n-propanol solvate #1 in the 2000-500 cm.sup.-1 region of the
spectrum.
[0124] FIG. 83 is an x-ray powder diffractogram for carvedilol
hydrobromide n-propanol solvate #2.
[0125] FIG. 84 shows the thermal analysis results for carvedilol
hydrobromide n-propanol solvate #2.
[0126] FIG. 85 is an FT-Raman spectrum for carvedilol hydrobromide
n-propanol solvate #2.
[0127] FIG. 86 is an FT-Raman spectrum for carvedilol hydrobromide
n-propanol solvate #2 in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0128] FIG. 87 is an FT-Raman spectrum for carvedilol hydrobromide
n-propanol solvate #2 in the 2000-400 cm.sup.-1 region of the
spectrum.
[0129] FIG. 88 is an FT-IR spectrum for carvedilol hydrobromide
n-propanol solvate #2.
[0130] FIG. 89 is an FT-IR spectrum for carvedilol hydrobromide
n-propanol solvate #2 in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0131] FIG. 90 is an FT-IR spectrum for carvedilol hydrobromide
n-propanol solvate #2 in the 2000-500 cm.sup.-1 region of the
spectrum.
[0132] FIG. 91 is an x-ray powder diffractogram for carvedilol
hydrobromide anhydrous forms.
[0133] FIG. 92 shows the thermal analysis results for carvedilol
hydrobromide anhydrous forms.
[0134] FIG. 93 is an FT-Raman spectrum for carvedilol hydrobromide
anhydrous forms.
[0135] FIG. 94 is an FT-Raman spectrum for carvedilol hydrobromide
anhydrous forms in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0136] FIG. 95 is an FT-Raman spectrum for carvedilol hydrobromide
anhydrous forms in the 2000-400 cm.sup.-1 region of the
spectrum.
[0137] FIG. 96 is an FT-IR spectrum for carvedilol hydrobromide
anhydrous forms.
[0138] FIG. 97 is an FT-IR spectrum for carvedilol hydrobromide
anhydrous forms in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0139] FIG. 98 is an FT-IR spectrum for carvedilol hydrobromide
anhydrous forms in the 2000-500 cm.sup.-1 region of the
spectrum.
[0140] FIG. 99 is an x-ray powder diffractogram for carvedilol
hydrobromide ethanol solvate.
[0141] FIG. 100 shows the thermal analysis results for carvedilol
hydrobromide ethanol solvate.
[0142] FIG. 101 is an FT-Raman spectrum for carvedilol hydrobromide
ethanol solvate.
[0143] FIG. 102 is an FT-Raman spectrum for carvedilol hydrobromide
ethanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0144] FIG. 103 is an FT-Raman spectrum for carvedilol hydrobromide
ethanol solvate in the 2000-400 cm.sup.-1 region of the
spectrum.
[0145] FIG. 104 is an FT-IR spectrum for carvedilol hydrobromide
ethanol solvate.
[0146] FIG. 105 is an FT-IR spectrum for carvedilol hydrobromide
ethanol solvate in the 4000-2000 cm.sup.-1 region of the
spectrum.
[0147] FIG. 106 is an FT-IR spectrum for carvedilol hydrobromide
ethanol solvate in the 2000-500 cm.sup.-1 region of the
spectrum.
[0148] FIG. 107 is an x-ray powder diffractogram for carvedilol
hydrobromide dioxane solvate.
[0149] FIG. 108 is an x-ray powder diffractogram for carvedilol
hydrobromide 1-pentanol solvate.
[0150] FIG. 109 is an x-ray powder diffractogram for carvedilol
hydrobromide 2-methyl-1-propanol solvate.
[0151] FIG. 110 is an x-ray powder diffractogram for carvedilol
hydrobromide trifluoroethanol solvate.
[0152] FIG. 111 is an x-ray powder diffractogram for carvedilol
hydrobromide 2-propanol solvate.
[0153] Carvedilol Citrate Salts FIG. 112 is a FT-IR spectrum of
carvedilol monocitrate salt.
[0154] FIG. 113 depicts XRPD patterns of two different batches of
Carvedilol monocitrate salt.
[0155] Carvedilol Mandelate Salts
[0156] FIG. 114 is a FT-IR spectrum of carvedilol mandelate
salt.
[0157] FIG. 115 is a FT-Raman spectrum of carvedilol mandelate
salt.
[0158] Carvedilol Lactate Salts
[0159] FIG. 116 is a FT-IR spectrum of carvedilol lactate salt.
[0160] FIG. 117 is a FT-Raman spectrum of carvedilol lacatate
salt.
[0161] Carvedilol Maleate Salts
[0162] FIG. 118 is a FT-IR spectrum of carvedilol maleate salt.
[0163] FIG. 119 is a FT-Raman spectrum of carvedilol maleate
salt.
[0164] Carvedilol Sulfate Salts
[0165] FIG. 120 is a FT-IR spectrum of carvedilol sulfate salt.
[0166] FIG. 121 is a FT-Raman spectrum of carvedilol sulfate
salt.
[0167] Carvedilol Glutarate Salts
[0168] FIG. 122 is a FT-IR spectrum of carvedilol glutarate
salt.
[0169] FIG. 123 is a FT-Raman spectrum of carvedilol glutarate
salt.
[0170] Carvedilol Benzoate Salts
[0171] FIG. 124 is a FT-IR spectrum of carvedilol benzoate
salt.
[0172] FIG. 125 is a FT-Raman spectrum of carvedilol benzoate
salt.
[0173] Drug Solubility Enhancement in GI tract
[0174] FIG. 126 depicts a pH-solubility profile for carvedilol.
[0175] FIG. 127 depicts mean plasma profiles in beagle dogs
following intra-colonic administration of a carvedilol solution
containing captisol or carvedilol in aqueous suspension.
[0176] FIG. 128 depicts dissolution/solubility profile of
carvedilol phosphate in pH=7.1 tris buffer.
[0177] FIG. 129 depicts mean plasma profiles in beagle dogs
following oral administration of the formulations listed in Table
4.
[0178] FIG. 130 depicts mean plasma profiles following oral
administration of companion capsules filled with four formulations
at 10 mg strength to beagle dogs.
[0179] Pharmacodynamic Profiles
[0180] FIG. 131 depicts a plasma profile from capsules formulated
according to Example 29 (B).
[0181] FIG. 132 depicts depicts a mean plasma profiles of subjects)
for the formulation described in Example 33, Table 23.
[0182] FIG. 133 depicts a representative individual plasma
profile.
[0183] FIG. 134 depicts a comparison between a test product profile
(mean values as in FIG. 133) vs. a profile for a conventional
(immediate release) product dosed twice daily.
DETAILED DESCRIPTION OF THE INVENTION
[0184] In general, the present invention relates to carvedilol free
base or carvedilol salt, anhydrous form, or solvate thereof,
corresponding pharmaceutical compositions or controlled release
dosage forms or formulations, and delivery methods of carvedilol
forms to the gastrointestingal tract or methods to treat
cardiovascular diseases, which may include, but are not limited to
hypertension, congestive heart failure, atherosclerosis, and
angina.
[0185] The present invention relates to control release
formulations, which comprise various cavedilol forms, which may
include, but are not limited to carvedilol free base or
corresponding carvedilol salts, anhydrous forms or solvates
thereof.
[0186] The present invention generally relates to a controlled
release formulation, which comprises at least one of these
components: [a] carvedilol free base; or [b] a solubility enhanced
carvedilol salt, solvate or anhydrous forms; where the
aforementioned controlled release formulation following oral dosage
exhibits a substantially biphasic plasma profile which exhibits a
first plasma concentration peak level and a first T.sub.max pulse
within 1-4 hours of ingestion and a second a plasma concentration
peak level and second T.sub.max pulse within 5-8 hours after
ingestion.
[0187] In a general embodiment, the present invention relates to a
controlled release formulation, which comprises:
[0188] a solubility enhanced carvedilol salt, solvate or anhydrous
forms;
[0189] where the controlled release formulation following oral
dosage exhibits a substantially biphasic plasma profile with a
first plasma concentration peak level and a first T.sub.max pulse
within 1-4 hours of ingestion and a second plasma concentration
peak level and a second T.sub.max pulse within 5-10 hours after
ingestion. In an embodiment of the present invention a first
T.sub.max pulse may occur within 1-3 hours of ingestion and the
second T.sub.max pulse may occur within 5-10 hours after
ingestion.
[0190] In yet another general embodiment, the present invention
relates to a controlled release formulation, comprising at least
one of these components:
[0191] [a] carvedilol free base; or
[0192] [b] a solubility enhanced carvedilol salt, solvate or
anhydrous forms;
[0193] where the controlled release formulation is a capsule dosage
form is comprised of a pellet or microparticle mixture of immediate
release coated pellet populations or controlled release coated
pellet populations of differing sizes; or
[0194] where the controlled release formulation is a capsule dosage
form is comprised of a pellet or microparticle mixture of immediate
release coated pellet populations and controlled release coated
pellet populations; or
[0195] where the controlled release formulation following oral
dosage at night exhibits a substantially biphasic plasma peak
concentration profile which exhibits a first pharmacokinetic plasma
concentration peak level and a first T.sub.max pulse within 1-4
hours of ingestion and a second plasma concentration peak level and
a second T.sub.max pulse within 5-8 hours after ingestion.
[0196] Carvedilol Salts, Anhydrous Forms, or Solvates Thereof
[0197] In general, the present invention relates to carvedilol free
base or carvedilol salts, anhydrous forms or solvates thereof.
[0198] In particular, the present invention relates to carvedilol
free base or a novel crystalline salt, anhydrous forms, or solvate
form thereof, which may include, but are not limited to crystalline
or other solid forms, such as a salt form of
1-(carbazol-4-yloxy-3-[[2-(o-methoxyp-
henoxy)ethyl]amino]-2-propanol).
[0199] Carvedilol free base or all carvedilol salt, anhydrous or
solvate compound forms thereof suitable for use in the present
invention, which include starting materials (i.e., such as
carvedilol), intermediates or products, etc., are prepared as
described herein, or by the application or adaptation of known
methods, which may be methods used heretofore or described in the
literature.
[0200] Carvedilol is disclosed and claimed in U.S. Pat. No.
4,503,067 to Wiedemann et al. ("U.S. '067 patent"). Reference
should be made to U.S. '067 patent for its full disclosure, which
include methods of preparing or using the carvedilol compound. The
entire disclosure of the U.S. '067 patent is incorporated hereby by
reference in its entirety.
[0201] U.S. Pat. No. 6,515,010 to Franchini et al. discloses a
novel salt form of carvedilol, namely carvedilol methanesulfonate
salt form, pharmaceutical compositions containing carvedilol
methanesulfonate and the use of the aforementioned compound in the
treatment of hypertension, congestive heart failure, and angina,
which is hereby incorporated by reference in its entirety.
[0202] The present invention relates to a carvedilol compound,
which is carvedilol free base or a novel salt, solvate or anhydrous
form of carvedilol, which may include, but is not limited to a
crystalline salt or other solid form.
[0203] In accordance with the present invention, it has been
unexpectedly found that carvedilol compounds may be isolated
readily, but are not limited to crystalline forms or other solid
forms, which display much higher solubility when compared to the
free base form of carvedilol.
[0204] The present invention is related to pharmaceutically
acceptable acid addition salts of carvedilol free base or
corresponding forms.
[0205] Such pharmaceutically acceptable acid addition salts of
carvedilol free base or corresponding forms thereof are formed by
reaction with appropriate organic acids or mineral acids, which may
include, but are not limited to formation by such methods described
herein or conventionally known in the chemical arts.
[0206] For example, such acid addition salts may be formed via the
following conventional chemical reactions or methods:
[0207] reaction of carvedilol free base with a suitable organic
acid or mineral acid in an aqueous miscible organic solvent with
isolation of the formed acid addition salt by removing the organic
solvent by conventional art known techniques; or
[0208] reaction of carvedilol free base with a suitable organic
acid or mineral acid in an aqueous immiscible organic solvent where
the formed acid addition salt is separated directly or isolated by
removing the solvent by conventional art known techniques, such as
by filtration.
[0209] For example, an acid addition salt of carvedilol free base
or carvedilol salt, solvate or anhydrous form thereof is an acid
addition salt formed from mineral acids or organic acids.
[0210] Representative examples of such suitable organic or mineral
acids may include, but are not limited to maleic acid, fumaric
acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid,
bismethylenesalicyclic acid, methane sulphonic or sulfonic acid,
acetic acid, propionic acid, tartaric acid, salicyclic acid, citric
acid, gluconic acid, aspartic acid, stearic acid, palmitic acid,
itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid,
benzene sulfonic acid or sulphonic acid, hydrochloric acid,
hydrobromic acid, sulfuric acid or sulphuric acid,
cyclohexylsulfamic acid, phosphoric acid, nitric acid and the
like.
[0211] In accordance with the present invention, mineral acids may
be selected from, but are not limited to hydrobromic acid,
hydrochloric acid, phosphoric acid, sulfuric acid or sulphuric
acid, and the like; and organic acids may be selected from, but not
limited to methansulphuric acid, tartaric acid, maleic acid, acetic
acid, citric acid, benzoic acid and the like.
[0212] As indicated above, the present invention further relates to
carvedilol salt forms, which may include, but are not limited to
novel crystalline salt or other solid forms of carvedilol
mandelate, carvedilol lactate, carvedilol maleate, carvedilol
sulfate, carvedilol glutarate, carvedilol mesylate, carvedilol
phosphate, carvedilol citrate, carvedilol hydrogen bromide,
carvedilol oxalate, carvedilol hydrogen chloride, carvedilol
hydrogen bromide, carvedilol benzoate, or corresponding solvates
thereof.
[0213] More particularly, the present invention relates to
carvedilol salt forms, which may include, but are not limited to
carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate,
carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen
phosphate dihydrate, carvedilol dihydrogen phosphate methanol
solvate, carvedilol hydrobromide monohydrate, carvedilol
hydrobromide dioxane solvate, carvedilol hydrobromide 1-pentanol
solvate, carvedilol hydrobromide 2-methyl-1-propanol solvate,
carvedilol hydrobromide trifluoroethanol solvate, carvedilol
hydrobromide 2-propanol solvate, carvedilol hydrobromide n-propanol
solvate #1, carvedilol hydrobromide n-propanol solvate #2,
carvedilol hydrobromide anhydrous forms or anhydrous forms,
carvedilol hydrobromide ethanol solvate, carvedilol hydrobromide
dioxane solvate, carvedilol monocitrate monohydrate, carvedilol
mandelate, carvedilol lactate, carvedilol hydrochloride, carvedilol
maleate, carvedilol sulfate, carvedilol glutarate, or corresponding
anhydrous forms, solvates thereof.
[0214] In accordance with the present invention, other salts or
solvates of carvedilol of the present invention may be isolated,
but not limited to different solid or crystalline forms. Moreover,
a specific identified species of such carvedilol salts (or a
specific identified corresponding solvate species) also may be
isolated in various different crystalline or solid forms, which may
include anhydrous forms or solvate forms. For example, suitable
solvates of carvedilol phosphate as defined in the present
invention, include, but are not limited to carvedilol dihydrogen
phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate
(i.e., which include Forms II and IV, respectively), carvedilol
dihydrogen phosphate methanol solvate, and carvedilol hydrogen
phosphate.
[0215] In light of this, carvedilol salt forms of the present
invention (i.e., which may include different polymorphs, ahydrous
forms, solvates, or hydrates thereof) may exhibit characteristic
polymorphism. As conventionally understood in the art, polymorphism
is defined as an ability of a compound to crystallize as more than
one distinct crystalline or "polymorphic" species. A polymorph is
defined as a solid crystalline phase of a compound with at least
two different arrangements or polymorphic forms of that compound
molecule in the solid state.
[0216] Polymorphic forms of any given compound, including those of
the present invention, are defined by the same chemical formula or
composition and are as distinct in chemical structure as
crystalline structures of two different chemical compounds. Such
compounds may differ in packing, geometrical arrangement of
respective crystalline lattices, etc.
[0217] In light of the foregoing, chemical and/or physical
properties or characteristics vary with each distinct polymorphic
form, which may include variations in solubility, melting point,
density, hardness, crystal shape, optical and electrical
properties, vapor pressure, stability, etc.
[0218] Solvates and/or hydrates of crystalline carvedilol salt
forms of the present invention also may be formed when solvent
molecules are incorporated into the crystalline lattice structure
of the compound molecule during the crystallization process. For
example, solvate forms of the present invention may incorporate
nonaqueous solvents such as methanol and the like as described
herein below. Hydrate forms are solvate forms, which incorporate
water as a solvent into a crystalline lattice.
[0219] In general, FIGS. 1-125 depict spectroscopic and other
characterizing data for different, specific, and distinct
carvedilol salt, anhydrous forms, or solvate forms thereof, which
may include, but are not limited to crystalline or other solid
forms. For example, carvedilol dihydrogen phosphate, may be
isolated as two different and distinct crystalline forms, Forms II
and IV, respectively represented and substantially shown FIGS. 9 to
6 (for Form II) and FIG. 25 (for Form IV), which represent
spectroscopic and/or other characterizing data.
[0220] It is recognized that the compounds of the present invention
may exist in forms as stereoisomers, regioisomers, or
diastereiomers. These compounds may contain one or more asymmetric
carbon atoms and may exist in racemic and optically active forms.
For example, carvedilol may exist as racemic mixture of R(+) and
S(-) enantiomers, or in separate respectively optical forms, i.e.,
existing separately as either the R(+) enantiomer form or in the
S(+) enantiomer form. All of these individual compounds, isomers,
and mixtures thereof are included within the scope of the present
invention.
[0221] Carvedilol salts of the present invention may be prepared by
various techniques, such as those exemplified below.
[0222] For example, crystalline carvedilol dihydrogen phosphate
hemihydrate of the instant invention can be prepared by
crystallization from an acetone-water solvent system containing
carvedilol and H.sub.3PO.sub.4. Also suitable solvates of
carvedilol phosphate salts of present invention may be prepared by
preparing a slurrying a carvedilol phosphate salt, such as a
carvedilol dihydrogen salt, in a solvent, such as methanol.
[0223] In another example, crystalline carvedilol hydrobromide
monohydrate of the present invention can be prepared by
crystallization from an acetone-water solvent system containing
carvedilol and hydrobromic acid. Also, suitable solvates of
carvedilol hydrobromide salts may be made by preparing a slurry of
the carvedilol hydrobromide salt in a solvent (i.e., such as
dioxane, 1-pentanol, 2-methyl-1-propanol, trifluoroethanol,
2-propanol and n-propanol. In particular, solvates of carvedilol
hydrobromide as defined in the present invention, include, but are
not limited to carvedilol hydrobromide 1-pentanol solvate,
carvedilol hydrobromide 2-methyl-1-pentanol solvate, carvedilol
hydrobromide trifluoroethanol solvate, carvedilol hydrobromide
2-propanol solvate, carvedilol hydrobromide n-propanol solvate #1,
carvedilol hydrobromide n-propanol solvate #2, carvedilol
hydrobromide ethanol solvate, carvedilol hydrobromide anhydrous
forms), and/or dissolving the carvedilol hydrobromide salt in the
aforementioned solvents and allowing the salt to crystallize out.
Carvedilol hydrobromide anhydrous forms can be prepared by
dissolving carvedilol in a solvent, such as dichloromethane,
acetonitrile or isopropyl acetate, followed by the addition of
anhydrous HBr (HBr in acetic acid or gaseous HBr).
[0224] In yet another example, the crystalline carvedilol citrate
salt of the instant invention can be prepared by making an aqueous
citric acid solution saturated with carvedilol, either by lowering
the temperature of the solution, or slowly evaporating water from
the solution. In addition, it can be prepared by crystallization
from an acetone-water solvent system containing carvedilol and
citric acid.
[0225] A particularly useful and surprising characteristic of the
crystalline form of carvedilol citrate salt stems from the fact
that citric acid is a prochiral molecule. Consequently, a 1 to 1
ratio of racemic diasteromers are present in the crystalline
carvedilol citrate salt lattice. This avoids generation of yet more
optically active forms that could potentially complicate stability,
dissolution rates, in vivo absorption metabolism and possibly
pharmacologic effects.
[0226] According to the instant invention, the various salt forms
of carvedilol and/or corresponding solvates thereof are
distinguished from each other using different characterization or
identification techniques. Such techniques, include solid state
.sup.13C Nuclear Magnetic Resonance (NMR), .sup.31P Nuclear
Magnetic Resonance (NMR), Infrared (IR), Raman, X-ray powder
diffraction, etc. and/or other techniques, such as Differential
Scanning Calorimetry (DSC) (i.e., which measures the amount of
energy (heat) absorbed or released by a sample as it is heated,
cooled or held at constant temperature).
[0227] In general, the aforementioned solid state NMR techniques
are non-destructive techniques to yield spectra, which depict an
NMR peak for each magnetically non-equivalent carbon site the
solid-state For example, in identification of compounds of the
present invention, .sup.13C NMR spectrum of a powdered
microcrystalline organic molecules reflect that the number of peaks
observed for a given sample will depend on the number of chemically
unique carbons per molecule and the number of non-equivalent
molecules per unit cell. Peak positions (chemical shifts) of carbon
atoms reflect the chemical environment of the carbon in much the
same manner as in solution-state .sup.13C NMR. Although peaks can
overlap, each peak is in principle assignable to a single type of
carbon. Therefore, an approximate count of the number of carbon
sites observed yields useful information about the crystalline
phase of a small organic molecule.
[0228] Based upon the foregoing, the same principles apply to
phosphorus, which has additional advantages due to high sensitivity
of the .sup.31P nucleus.
[0229] Polymorphism also can be studied by comparison of .sup.13C
and .sup.31P spectra. In the case of amorphous material, broadened
peak shapes are usually observed, reflecting the range of
environments experienced by the .sup.13C or .sup.31P sites in
amorphous material types.
[0230] Specifically, carvedilol salts, anhydrous forms or solvates
thereof, which may include novel crystalline forms are
characterized substantially by spectroscopic data as described
below and depicted in FIGS. 1-125.
[0231] Examples of spectroscopic data associated with specific
carvedilol salt, anhydrous forms or solvate forms are described
below.
[0232] For example, crystalline carvedilol dihydrogen phosphate
hemihydrate (see, Example 1: Form I) is identified by an x-ray
diffraction pattern as shown substantially in FIG. 1, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,
7.0.+-.0.2 (2.theta.), 11.4.+-.0.2 (2.theta.), 15.9.+-.0.2
(2.theta.), 18.8.+-.0.2 (2.theta.), 20.6.+-.0.2 (28), 22.8.+-.0.2
(2.theta.), and 25.4.+-.0.2 (2.theta.).
[0233] Crystalline carvedilol dihydrogen phosphate dihydrate (see,
Example 2: Form II) is identified by an x-ray diffraction pattern
as shown substantially in FIG. 9, which depicts characteristic
peaks in degrees two-theta (2.theta.): i.e., 6.5.+-.0.2 (2.theta.),
7.1.+-.0.2 (2.theta.), 13.5.+-.0.2 (2.theta.), 14.0.+-.0.2
(2.theta.), 17.8.+-.0.2 (2.theta.), 18.9.+-.0.2 (2.theta.), and
21.0.+-.0.2 (2.theta.).
[0234] Crystalline carvedilol dihydrogen phosphate methanol solvate
(see, Example 3: Form III) is identified by an x-ray diffraction
pattern as shown substantially in FIG. 24, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,
6.9.+-.0.2 (2.theta.), 7.2.+-.0.2 (2.theta.), 13.5.+-.0.2
(2.theta.), 14.1.+-.0.2 (2.theta.), 17.8.+-.0.2 (28), and
34.0.+-.0.2 (2.theta.).
[0235] Crystalline carvedilol dihydrogen phosphate dihydrate (see,
Example 4: Form IV) is identified by an x-ray diffraction pattern
as shown substantially in FIG. 24, which depicts characteristic
peaks in degrees two-theta (2.theta.): i.e., 6.4.+-.0.2 (2.theta.),
9.6.+-.0.2 (2.theta.), 16.0.+-.0.2 (2.theta.), 18.4.+-.0.2
(2.theta.), 20.7.+-.0.2 (2.theta.), and 24.5.+-.0.2 (2.theta.).
[0236] Crystalline carvedilol dihydrogen phosphate preparation
(see, Example 5: Form V) is identified by an x-ray diffraction
pattern as shown substantially in FIG. 28, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,
13.2.+-.0.2 (2.theta.), 15.8.+-.0.2 (2.theta.), 16.3.+-.0.2
(2.theta.), 21.2.+-.0.2 (2.theta.), 23.7.+-.0.2 (2.theta.), and
26.0.+-.0.2 (2.theta.).
[0237] Crystalline carvedilol hydrogen phosphate preparation (see,
Example 6: Form VI) is identified by an x-ray diffraction pattern
as shown substantially in FIG. 29, which depicts characteristic
peaks in degrees two-theta (2E): i.e., 5.5.+-.0.2 (2.theta.),
12.3.+-.0.2 (2.theta.), 15.3.+-.0.2 (2.theta.), 19.5.+-.0.2
(2.theta.), 21.6.+-.0.2 (2.theta.), and 24.9.+-.0.2 (2.theta.).
[0238] Crystalline carvedilol hydrobromide monohydrate (see,
Example 8: Form 1) is identified by an x-ray diffraction pattern as
shown substantially in FIG. 1, which depicts characteristic peaks
in degrees two-theta (2.theta.): i.e., 6.5.+-.0.2 (2.theta.),
10.3.+-.0.2 (2.theta.), 15.7.+-.0.2 (2.theta.), 16.3.+-.0.2
(2.theta.), 19.8.+-.0.2 (2E), 20.1.+-.0.2 (2.theta.), 21.9.+-.0.2
(2.theta.), 25.2.+-.0.2 (2.theta.), and 30.6.+-.0.2 (2.theta.).
[0239] Crystalline carvedilol hydrobromide dioxane solvate (see,
Example 9: Form 2) also is identified by an x-ray diffraction
pattern as shown substantially in FIG. 78, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,
7.7.+-.0.2 (2.theta.), 8.4.+-.0.2 (2.theta.), 15.6.+-.0.2
(2.theta.), 17.0.+-.0.2 (2.theta.), 18.7.+-.0.2 (2.theta.),
19.5.+-.0.2 (2.theta.), 21.4.+-.0.2 (2.theta.), 23.7.+-.0.2
(2.theta.), and 27.9.+-.0.2 (2.theta.).
[0240] Crystalline carvedilol hydrobromide 1-pentanol solvate (see,
Example 10: Form 3) also is identified by an x-ray diffraction
pattern as shown substantially in FIG. 79, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,
77.5.+-.0.2 (2.theta.), 7.8.+-.0.2 (2.theta.), 15.2.+-.0.2
(2.theta.), 18.9.+-.0.2 (2.theta.), 22.1.+-.0.2 (2.theta.), and
31.4.+-.0.2 (2.theta.).
[0241] Crystalline carvedilol hydrobromide 2-methyl-1-propanol
solvate (see, Example 11: Form 4) also is identified by an x-ray
diffraction pattern as shown substantially in FIG. 80, which
depicts characteristic peaks in degrees two-theta (2.theta.): i.e.,
7.8.+-.0.2 (2.theta.), 8.1.+-.0.2 (2.theta.), 16.3.+-.0.2
(2.theta.), 18.8.+-.0.2 (2.theta.), 21.8.+-.0.2 (2.theta.), and
28.5.+-.0.2 (2.theta.).
[0242] Crystalline carvedilol hydrobromide trifluoroethanol solvate
(see, Example 12: Form 5) also is identified by an x-ray
diffraction pattern as shown substantially in FIG. 81, which
depicts characteristic peaks in degrees two-theta (2.theta.):
i.e.,. 7.7.+-.0.2 (2.theta.), 8.4.+-.0.2 (2.theta.), 15.6.+-.0.2
(2.theta.), 16.9.+-.0.2 (2.theta.), 18.9.+-.0.2 (2.theta.),
21.8.+-.0.2 (2.theta.), 23.8.+-.0.2 (2.theta.), 23.7.+-.0.2
(2.theta.), and 32.7.+-.0.2 (2.theta.).
[0243] Crystalline carvedilol hydrobromide 2-propanol solvate (see,
Example 13: Form 6) also is identified by an x-ray diffraction
pattern as shown substantially in FIG. 82, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,.
7.9.+-.0.2 (2.theta.), 8.3.+-.0.2 (2.theta.), 18.8.+-.0.2
(2.theta.), 21.7.+-.0.2 (2.theta.), 23.2.+-.0.2 (2.theta.),
23.6.+-.0.2 (2.theta.), and 32.1.+-.0.2 (2.theta.).
[0244] Crystalline carvedilol hydrobromide n-propanol solvate #1
(see, Example 14: Form 7) also is identified by an x-ray
diffraction pattern as shown substantially in FIG. 46, which
depicts characteristic peaks in degrees two-theta (2.theta.): i.e.,
7.9.+-.0.2 (2.theta.), 8.5.+-.0.2 (2.theta.), 17.0.+-.0.2
(2.theta.), 18.8.+-.0.2 (2.theta.), 21.6.+-.0.2 (2.theta.),
23.1.+-.0.2 (2.theta.), 23.6.+-.0.2 (2.theta.), and 21.2.+-.0.2
(2.theta.).
[0245] Crystalline carvedilol hydrobromide n-propanol solvate #2
(see, Example 15: Form 8) also is identified by an x-ray
diffraction pattern as shown substantially in FIG. 54, which
depicts characteristic peaks in degrees two-theta (2.theta.): i.e.,
8.0.+-.0.2 (2.theta.), 18.8.+-.0.2 (2.theta.), 21.6.+-.0.2
(2.theta.), 23.1.+-.0.2 (2.theta.), 25.9.+-.0.2 (2.theta.),
27.2.+-.0.2 (2.theta.), 30.6.+-.0.2-(2.theta.), and 32.2.+-.0.2
(2.theta.).
[0246] Crystalline carvedilol hydrobromide anhydrous forms (see,
Example 16: Form 9) also is identified by an x-ray diffraction
pattern as shown substantially in FIG. 62, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,.
6.6.+-.0.2 (2.theta.), 16.1.+-.0.2 (2.theta.), 17.3.+-.0.2
(2.theta.), 21.2.+-.0.2 (2.theta.), 22.1.+-.0.2 (2.theta.),
24.1.+-.0.2 (2.theta.), and 27.9.+-.0.2 (2.theta.).
[0247] Crystalline carvedilol hydrobromide ethanol solvate (see,
Example 17: Form 10) also is identified by an x-ray diffraction
pattern as shown substantially in FIG. 70, which depicts
characteristic peaks in degrees two-theta (2.theta.): i.e.,
8.1.+-.0.2 (2.theta.), 8.6.+-.0.2 (2.theta.), 13.2.+-.0.2
(2.theta.), 17.4.+-.0.2 (2.theta.), 18.6.+-.0.2 (2.theta.),
21.8.+-.0.2 (2.theta.), 23.2.+-.0.2 (2.theta.), 23.7.+-.0.2
(2.theta.), and 27.4.+-.0.2 (2.theta.).
[0248] Crystalline carvedilol hydrobromide monohydrate further is
identified by an infrared spectrum as shown substantially in FIG.
6.
[0249] Carvedilol hydrobromide anhydrous forms also an infrared
spectrum, which comprises characteristic absorption, bands
expressed in wave numbers as shown substantially in FIG. 67.
[0250] Crystalline carvedilol hydrobromide monohydrate is
identified also by a Raman spectrum as shown substantially in FIG.
3.
[0251] Carvedilol hydrobromide anhydrous forms also a Raman
spectrum which comprises characteristic peaks as shown
substantially in FIG. 64.
[0252] Crystalline carvedilol benzoate (see, Example 22) is
identified by an FT-IR spectrum pattern as shown substantially in
FIG. 124, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 672 cm.sup.-1, 718 cm.sup.-1, 754 cm.sup.-1, 767
cm.sup.-1, 1022 cm.sup.-1, 1041 cm.sup.-1, 1106 cm.sup.-1, 1260
cm.sup.-1, 1498 cm.sup.-1, 1582 cm.sup.-1, 1604 cm.sup.-1, 1626
cm.sup.-1, 2932 cm.sup.-1, 3184 cm.sup.-1, and 3428 cm.sup.-1.
Also, crystalline carvedilol benzoate (see, Example 22) is
identified by an FT-Raman spectrum pattern as shown substantially
in FIG. 125, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 108 cm.sup.-1, 244 cm.sup.-1, 424 cm.sup.-1, 538
cm.sup.-1, 549 cm.sup.-1, 728 cm.sup.-1, 1001 cm.sup.-1, 1015
cm.sup.-1, 1128 cm.sup.-1, 1286 cm.sup.-1, 1598 cm.sup.-1, 1626
cm.sup.-1, 2934 cm.sup.-1, 3058 cm.sup.-1, and 3072 cm.sup.-1.
[0253] Crystalline carvedilol mandelate (see, Example 23) is
identified by an FT-IR spectrum pattern as shown substantially in
FIG. 114, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 699 cm.sup.-1, 723 cm.sup.-1, 752 cm.sup.-1, 784
cm.sup.-1, 1053 cm.sup.-1, 1583 cm.sup.-1, 1631 cm.sup.-1, 3189
cm.sup.-1, 3246 cm.sup.-1, and 3396 cm.sup.-1. Also crystalline
carvedilol mandelate (see, Example 23) is identified by an FT-Raman
spectrum pattern as shown substantially in FIG. 115, which depicts
characteristic peaks in wavenumbers (cm.sup.-1): i.e., 233
cm.sup.-1, 252 cm.sup.-1, 322 cm.sup.-1, 359 cm.sup.-1, 423
cm.sup.-1, 744 cm.sup.-1, 1002 cm.sup.-1, 1286 cm.sup.-1, 1631
cm.sup.-1, 3052 cm.sup.-1, 3063 cm.sup.-1, and 3077 cm.sup.-1.
[0254] Crystalline carvedilol lactate (see, Example 24) is
identified by an FT-IR spectrum pattern as shown substantially in
FIG. 116, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 720 cm.sup.-1, 753 cm.sup.-1, 785 cm.sup.-1,
1097 cm.sup.-1, 1124 cm.sup.-1, 1253 cm.sup.-1, 1584 cm.sup.-1, and
3396 cm.sup.-1. Also, crystalline carvedilol lactate (see, Example
24) is identified by an FT-Raman spectrum pattern as shown
substantially in FIG. 117, which depicts characteristic peaks in
wavenumbers (cm.sup.-1): i.e., 321 cm.sup.-1, 422 cm.sup.-1, 549
cm.sup.-1, 765 cm.sup.-1, 1015 cm.sup.-1, 1284 cm.sup.-1, 1626
cm.sup.-1, 3066 cm.sup.-1, and 3078 cm.sup.-1.
[0255] Crystalline carvedilol sulfate (see, Example 25) is
identified by an FT-IR spectrum pattern as shown substantially in
FIG. 120, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 727 cm.sup.-1, 743 cm.sup.-1, 787 cm.sup.-1,
1026 cm.sup.-1, 1089 cm.sup.-1, 1251cm.sup.-1, 1215 cm.sup.-1, 1586
cm.sup.-1, 1604 cm.sup.-1, and 3230 cm.sup.-1. Also, crystalline
carvedilol sulfate (see, Example 25) also is identified by an
FT-Raman spectrum pattern as shown substantially in FIG. 121, which
depicts characteristic peaks in wavenumbers (cm.sup.-1): i.e., 242
cm.sup.-1, 318 cm.sup.-1, 423 cm.sup.-1, 549 cm.sup.-1, 1014
cm.sup.-1, 1214 cm.sup.-1, 1282 cm.sup.-1, 1627 cm.sup.-1, 2969
cm.sup.-1, and 3066 cm.sup.-1.
[0256] Crystalline carvedilol maleate (see, Example 26) is
identified by an FT-IR spectrum pattern as shown substantially in
FIG. 118, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 725 cm.sup.-1, 741 cm.sup.-1, 756 cm.sup.-1, 786
cm.sup.1, 1024 cm.sup.-1, 1109 cm.sup.1, 1215 cm.sup.-1, 1586
cm.sup.-1, and 3481 cm.sup.-1. Also, crystalline carvedilol maleate
(see, Example 26) also is identified by an FT-Raman spectrum
pattern as shown substantially in FIG. 119, which depicts
characteristic peaks in wavenumbers (cm.sup.-1): i.e., 249
cm.sup.-1, 324 cm.sup.-1, 423 cm.sup.-1, 549 cm.sup.-1, 751
cm.sup.-1, 1012 cm.sup.-1, 1216 cm.sup.-1, 1286 cm.sup.-1, 1629
cm.sup.-1, and 3070 cm.sup.-1.
[0257] Crystalline carvedilol glutarate (see, Example 27) is
identified by an FT-IR spectrum pattern as shown substantially in
FIG. 122, which depicts characteristic peaks in wavenumbers
(cm.sup.-1): i.e., 724 cm.sup.-1, 743 cm.sup.-1, 786 cm.sup.-1,
1024 cm.sup.1, 1044 cm.sup.-1, 1089 cm.sup.1, 1251 cm.sup.1, 1586
cm.sup.-1, 1604 cm.sup.-1, and 3229 cm.sup.-1. Also, crystalline
carvedilol glutarate (see, Example 27) is identified by an FT-Raman
spectrum pattern as shown substantially in FIG. 123, which depicts
characteristic peaks in wavenumbers (cm.sup.-1): i.e., 141
cm.sup.-1, 246 cm.sup.-1, 322 cm.sup.-1, 423 cm.sup.-1, 551
cm.sup.-1, 749 cm.sup.-1, 1011 cm.sup.-1, 1213 cm.sup.-1, 1284
cm.sup.-1, 1628 cm.sup.-1, 2934 cm.sup.-1, and 3073 cm.sup.-1.
[0258] Pharmaceutical Compositions, Controlled-Release
Formulations, Dosage Regimens and Dosage Forms
[0259] In general, the present invention also relates to different
dosage forms, pharmaceutical compositions and/or controlled-release
formulations, which may contain carvedilol free base or a
carvedilol salt, solvate, or anhydrous forms thereof as described
herein.
[0260] In general, for medications to be optimally effective it is
important that administration complies with the stipulated dosage
regimen. Poor compliance can compromise safety and efficacy.
Compliance is usually a problem with medications for chronic
asymptomatic ilnesses and where patients are elderly and/or
infirm.
[0261] As previously discussed, carvedilol is known as an effective
medication for treating hypertension, congestive heart failure,
atherosclerosis, and other cardiovascular conditions. Its unique
mode of action is a consequence of it being a mixture of R and S
isomers with complimentary pharmacological effects. Vasodilation
and reduced peripheral resistance are a consequence of the alpha
blockade associated with the R isomer. Blood pressure reduction is
ascribed to the beta blockade contributed by both R and S
isomers.
[0262] Currently, carvedilol is administered to treat
cardiovascular diseases to a subject in need thereof and is usually
administered twice daily. Cardiovascular diseases treatable by
methods of the present invention, include, but are not limited to
hypertension, congestive heart failure, atherosclerosis, angina,
etc.
[0263] However, for chronic diseases such as cardiovascular
diseases, a once-daily dosage regimen is desirable, to enhance
patient compliance and reduce "pill burden". Medication that is
dosed once daily facilitates greater compliance with the dosage
regimen. This applies especially to chronic asymptomatic illnesses.
It follows that medication for a condition like hypertension,
atherosclerosis and/or some other cardiac conditions is most
effective, from a safety and efficacy perspective if dosed once
daily.
[0264] In many cases the pharmacokinetics or pharmacodynamics of a
drug are such that once a day dosage, using conventional dosage
forms provides adequate therapy.
[0265] With some drugs it may be necessary to formulate a dosage
form that releases the drug over an extended period, to provide
sustained plasma levels that evince the desired duration of action.
Such modified release dosage forms are invariably designed to
provide plasma levels that do not fluctuate significantly over
time.
[0266] It is well established that there is a strong relationship
between frequency of dosage and compliance. Medication that is
dosed once daily is considered best from a convenience and
compliance perspective than when more frequent doses are necessary.
Thus, medication for a chronic and "silent" condition like
hypertension, and other cardiac conditions is most effective, from
a safety and efficacy perspective if dosed once daily.
[0267] The pharmacokinetics or pharmacodynamics of a drug may be
such that once-a-day dosage, using conventional dosage forms
provides adequate therapy. However, with some drugs it may be
necessary to formulate so that the dosage form releases the drug
over an extended period, in order to sustain plasma levels to
provide the desired duration of action. Such modified release
dosage forms are traditionally designed to provide plasma levels of
drug that do not fluctuate significantly over time.
[0268] However, a medication providing constant plasma levels may
not always be optimal for treating hypertension, atherosclerosis or
related conditions. Blood pressure is influenced by cirdadian
rhythm. It rises in the morning on awakening (so-called "morning
surge"), is maximum during daytime activities and falls at night,
particularly between around midnight to 3 am (see, Anar. Y. A,
White. W. B; Drugs (1998) 55 (5) 631-643; Chronotherapeutics for
Cardiovascular Disease). "Morning-surge may be a factor in the
higher incidence of cardiovascular incidents like stroke, acute
myocardial infarction and angina pectoris that occur in the early
morning.
[0269] Blood pressure also can remain elevated at night in some
hypertensives, particularly the elderly. These have been termed
"non-dippers' and such a condition is associated with increased
cardiovascular morbidity (see, Kario. K, Matsuo. T, Kobayashi. H,
Imiya. M, Matsuo. M, Shimida. K; Hypertension (1996) 27 (1)
130-135. Nocturnal Fall of Blood Pressure and Silent
Cerebrovascular Damage in Elderly Hypertensive Patients).
[0270] Drug absorption following oral dosage requires that drug
first dissolves in the gastro-intestinal milieu. In most cases such
dissolution is primarily a function of drug solubility. If
solubility is affected by pH it is likely that absorption will vary
in different regions of the gastro intestinal tract, because pH
varies from acidic in the stomach to more neutral values in the
intestine.
[0271] Such pH-dependent solubility can complicate dosage form
design when drug absorption needs to be prolonged, delayed or
otherwise controlled, to evince a sustained or delayed action
effect. Variations in solubility can lead to variable dissolution,
absorption and consequent therapeutic effect.
[0272] A case can therefore be made that plasma levels ought be
optimal at times of high risk, provided that there is an
association between plasma level and pharmacodynamic effect. In
general, cardiovascular medication has been designed with such
requirements in mind (see, White. W. H, Andes. R. J, Macintyre. J.
M, Black. H. R, Sica. D. A; The American Journal of Cardiology
(1995) 76, 375-380. Nocturnal Dosing of a Novel Delivery System of
Verapamil for Systemic Hypertension). For example, the beta
blockade-associated effect on blood pressure is proportional to
dose (see, De May. C. D, Breithaupt. K, Schloos. J, Neugebauer. G,
Palm. D, Belz. G. G; Clinical Pharmacology & Therapeutics
((1994) 55, (3) 329-337. Dose-Effect and Pharmacokinetic and
Pharmacodynamic Relationships of Beta-Adrenergic Receptor Blocking
Properties of Various Doses of Carvedilol in Healthy Humans).
[0273] It would be beneficial therefore, in cases where there is
good association between plasma level and clinical response, that
optimal levels of drug be present before and during times of high
risk so that the cardiovascular system is stabilized and not
vulnerable to dramatic change, or that levels of the
pharmacological agent are not sub therapeutic. Some recent
cardiovascular medications have been designed to provide for "early
morning cover" (White. W. H, Andes. R. J, MacIntyre. J. M, Black.
H. R, Sica. D. A; The American Journal of Cardiology (1995) 76
375-380. Nocturnal Dosing of a Novel Delivery System of Verapamil
for Systemic Hypertension.) but none appear to be available that
provide cover for the "non-dipping" period as well as protecting
against morning surge.
[0274] The beta blockade-associated effect on blood pressure is
proportional to dose (De May. C. D, Breithaupt. K, Schloos. J,
Neugebauer. G, Palm. D, Belz. G. G; Clinical Pharmacology &
Therapeutics ((1994) 55 (3)329-337. Dose-Effect and Pharmacokinetic
and Pharmacodynamic Relationships of Beta-Adrenergic Receptor
Blocking Properties of Various Doses of Carvedilol in Healthy
Humans.
[0275] Hence, therapy is likely to be more effective if adequate
plasma levels are provided before and during times of greatest
risk. Thus, a dosage form taken at night (bedtime), that delivers
drug in two phases viz during the midnight-3 am period and prior to
and during "morning surge" activities ought provide optimum
pharmacological-based therapy. At the same time it is important
that adequate levels are maintained throughout the full dosage
period, to provide reliable and stable control.
[0276] A further advantage of an optimally designed dosage form
concerns rate of release of drug from the unit immediately after
ingestion. Alpha blockade evinces a vasodilation effect and
associated reduction of peripheral resistance. If drug plasma
levels rise too rapidly this can lead to postural hypotension and
risk of falling over. More gradual rise in plasma levels would,
conceivably make for a safer medication.
[0277] With the above considerations, it will be evident that an
optimally designed, once daily dosage form of carvedilol, taken at
night should have the following features:
[0278] release drug at a slower rate following ingestion so that
plasma buildup is gradual, thereby avoiding rapid fall in blood
pressure and minimizing risk of orthostatic hypotension-related
adverse events;
[0279] provide adequate plasma levels of drug about 1-3 hours after
dosing, with subsequent falloff as time progresses;
[0280] provide a "later or second peak", about 5-10 hours after
dosing with gradual reduction of plasma levels thereafter; and
[0281] provide that plasma levels that do not fall below the
minimum level for effectiveness such that plasma levels after 24
hours should be comparable to those obtained when dosing twice
daily dosage (as current commercial COREG.RTM. medication in the
United States).
[0282] Moreover, a profile associated with such a once daily dosage
of carvedilol, would exhibit a first peak at about 1 hours to about
3 hours, which should be lower than the later or second peak as
physiological activity is at a minimum during sleep so control
requires less drug.
[0283] In contrast, plasma levels in the morning ought to reflect
the greater activity and associated cardiovascular stress at this
time.
[0284] Such a profile is consistent with current thinking that
medications for cardiovascular conditions, that provide near
constant drug concentrations over time may not be optimally
designed. Because of circadian variations in blood pressure it may
be more appropriate to provide high concentrations of drug at times
of greatest need. Furthermore, blood pressure lowering should not
be excessive during night time, so as to reduce potential for
night-time hypotension and ischaemic stroke (Smith David. G. H:
American Journal of Hypertension: (2001) 14 296S-301S. Pharmacology
of Cardiovascular Therapeutic Agents).
[0285] The physico chemical properties, and pharmacokinetics of
carvedilol make it difficult to design the kind of delivery system
described above, for the following reasons:
[0286] both R and S isomer carvedilol forms are cleared relatively
rapidly from the systemic circulation (alpha elimination phase is
about 1.5 hours); and
[0287] plasma levels are depleted rapidly and substantially
following attainment of peak plasma concentrations.
[0288] The pH-aqueous solubility of the free base form of
carvedilol is such (FIG. 126) that absorption is likely to be low,
or even non-existent from the neutral regions of the gastro
intestinal tract. A drug needs to be in solution if it is to pass
from the intestine to systemic circulation and it is generally
accepted that, where aqueous solubility is less than about 5 mg/ml,
absorption following oral dosage can be problematical (Ritschel W.
A. Arzneim Forsch (1975), 25, p. 853)). At the pH values
encountered in the distal small intestine and colon, solubility of
carvedilol free base does not exceed 0.1 mg (100 mcg) per ml).
[0289] Such a solubility profile makes it difficult to design a
dosage form to sustain absorption for long periods by providing
slow release of drug from the dosage form as it transits the gastro
intestinal tract. At pH values in the middle and lower parts of the
small intestine solubility is likely to be insufficient to enable
sufficient drug to dissolve to provide adequate absorption flux.
This constraint could theoretically be surmounted if it were
possible to design a unit that remained in the stomach or upper
small intestine, such that drug was released to an environment more
conducive to dissolution and absorption. However, the maximum
period that a dosage form is retained in the fed stomach is about
three hours. This time period possibly might be prolonged if a high
fat content meal were consumed at the time of dosage. However, this
is probably impractical for "before bedtime" dosage, especially
where in any case such a diet is inadvisable for patients with
cardiovascular disease.
[0290] Thus, it will be obvious to a person skilled in the art that
the rapid systemic clearance combined with poor solubility at
neutral pH of carvedilol constrain possibilities for designing a
unit to provide prolonged absorption and sustained plasma levels.
In effect there are formidable, if not insurmountable challenges in
the design of a unit incorporating delayed and time-specific
release features as well as providing adequate plasma levels over a
once-a day dosing period. The absence of any commercially available
modified release dosage form of carvedilol, designed for optimal
chronotherapeutic effect supports this view.
[0291] However, the dose response and time course of carvedilol in
the body is such that a conventional dosage form, releasing all the
drug immediately on ingestion does not provide once-a-day
therapy.
[0292] Release from the dosage form needs to be slowed down so that
absorption and subsequent systemic residence is prolonged. This
however requires that release and dissolution occurs along the GI
tract, not just in the stomach.
[0293] Hence, it would be expected that therapy would be more
effective if peak plasma levels were provided times of greatest
risk.
[0294] In such a context a carvedilol based dosage form that is
taken at night (at bedtime), that delivers drug in two phases to
cover the midnight-3 am period, and the early morning surge ought
provide optimum therapy, while maintaining a once-daily dosage
regimen.
[0295] However, the properties of carvedilol drug substance, as
well as its pharmacokinetics make it difficult to design such a
delivery system, for the following reasons:
[0296] [1] absorption from the lower gastro intestinal tract is
less efficient than from the stomach. This is probably related to
the very low solubility of carvedilol at neutral pH, making it
difficult to design a dosage form to sustain absorption for long
periods. The maximum period that a dosage form is retained in the
fed stomach is around three hours; or
[0297] [2] the relatively rapid clearance (alpha elimination phase)
means that plasma levels are reduced rapidly and substantially
following attainment of the peak plasma concentration.
[0298] These considerations, taken together teach that the
provision of a dosage form, delivering carvedilol at times of
maximum patient risk, and potential optimum benefit is difficult if
not impossible.
[0299] Nevertheless, it has now, surprisingly been shown that, when
a carvedilol salt, solvate or anhydrous forms thereof is utilized,
and, when such a carvedilol salt, solvate or anhydrous forms
thereof is formulated using appropriate modified release
technology, plasma profiles are obtained in human volunteers which
are aligned with what knowledge of chronobiology suggests may be
optimally beneficial in hypertension, atherosclerosis, congestive
heart failure or other cardiovascular disorders. Formulations of
the present invention may also include carvedilol free base.
[0300] Therefore, solubility of carvedilol free base or various
carvedilol salts, or solvates as those described herein may
facilitate provision or development of a dosage form, such as a
controlled-release formulation, from which the drug substance
becomes available for bioabsorption throughout the gastrointestinal
tract (i.e., in particular the lower small intestine and colon).
See Example 28 herein and corresponding discussion at pages 111-116
of the instant specification.
[0301] Parts of the gastrointestinal tract are defined to include
generally the stomach (i.e. which includes the antrum and pylorus
bowel), small intestine (i.e., which has three parts: the duodenum,
jejunum, illeum), large intestine (i.e., which has three parts: the
cecum, colon, rectum), liver, gall bladder and pancreas.
[0302] In light of the foregoing, the present invention relates to
an embodiment where a compound, pharmaceutical composition, or
controlled-release formulation or dosage form is presented as a
unit dose taken or administered from 1 to 2 times daily, most
especially taken or adminstered once daily to achieve the desired
effect.
[0303] Importantly, the chemical or physical properties of
carvedilol forms described herein, which include, but are not
limited to the above-identified carvedilol free base or carvedilol
salts, anhydrous forms or solvates thereof indicate that those
forms may be particularly suitable for inclusion in medicinal
agents, pharmaceutical compositions, controlled release
formulations or dosage forms, etc.
[0304] Treatment regimen for the administration of compounds,
pharmaceutical compositions, or controlled-release formulations or
dosage forms of the present invention also may be determined
readily by those with ordinary skill in art. The quantity of the
compound, pharmaceutical composition, or controlled-release
formulation or dosage form of the present invention administered
may vary over a wide range to provide in a unit dosage in an
effective amount based upon the body weight of the patient per day
to achieve the desired effect and as based upon the mode of
administration.
[0305] The scope of the present invention includes all compounds,
pharmaceutical compositions, or controlled-release formulations or
dosage forms, which is contained in an amount effective to achieve
its intended purpose. While individual needs vary, determination of
optimal ranges of effective amounts of each component is within the
skill of the art.
[0306] In accordance with a pharmaceutical composition, dosage form
or controlled release formulation of the present invention as
described herein (i.e., which include any of the specific
embodiment described for various delivery systems or technologies
applicable with the present invention), a specific embodiment may
include carvedilol free base or carvedilol free base, which may be,
but is not limited to, be in a combination with a solubility
enhanced carvedilol salt, solvate or anhydrous form(s) thereof.
[0307] General definitions suitable to define aspects of the
present invention are set forth below.
[0308] As used in the present invention, the term controlled
release generally is defined as a formulation that achieves slow or
controlled release of a drug over an extended period of time.
[0309] In the controlled or modified release formulations of the
present invention, a portion of the carvedilol free base, salt,
solvate or anhydrous form thereof in a formulation is made
available as a rapidly releasing, immediate release or or priming
dose and where the remainder portion is released in a controlled,
delayed or sustained release fashion.
[0310] Conventional art known examples of such controlled release
systems may include, but are not limited to a matrix tablet or bead
formulation, and/or a barrier film coated tablet or bead/pellet
formulation.
[0311] The term delayed release is defined as any formulation,
where release of the drug is delayed for certain time or minimum
under acidic conditions but rapid above a certain pH depending on
use of pharmaceutically acceptable coating materials or excipients,
such the type of polymer used for a barrier film coat. Conventional
art known examples of such delayed release systems may include, but
are not limited to timed-release tablets and capsules and
enteric-coated tablets and beads.
[0312] For the purposes of the present application the term
"extended release" means contained in a matrix, or combined with
excipients, which delay the release of and thereby prolong the
duration of action of the active constituent.
[0313] Further, "long acting" means having a longer time of
elimination (t one-half or t.sub.1/2) from the plasma compartment
than other drugs of the same class.
[0314] The term pulsatile release is meant any multi-unit tablet or
capsule formulation where in individual mini-tablets or
particulates/pellets/beads are polymer barrier film coated, that
utilizes intermittent pulsatile dosings of an active drug from one
or more units as a function of time. Such controlled or modified
release formulations of the present inventions are formulated in a
manner such that release modes such as described above result in
release of the active drug form of a carvedilol free base, or a
carvedilol salt, solvate or anhydrous form thereof is predominantly
affected after administration during passage in the
gastrointestinal tract, especially passage through the stomach,
small and large intestine and the colon.
[0315] General examples of controlled release, pulsatile release
and delayed release formulations which are suitable for
incorporating compounds of the present invention described in such
references as follows, respectively which are hereby incorporated
by reference in their entirety: Sustained Release Medications,
Chemical Technology, Review No. 177, Ed. J. C. Johnson, Noyes Data
Corporation (1980); Controlled Drug Delivery, Fundamentals and
Applications, 2nd Edition, Eds. J. R. Robinson, V. H. L. Lee,
Mercel Dekkes Inc., New York (1987); Remington's Pharmaceutical
Sciences, 16th Edition, Ed. A. Osol, Mack Publishing Company
(1980); and/or Solubility Considerations and Design of Controlled
Release Dosage Forms, by G. M. Venkatesh, Polymer Preprint, Volume
40, pp 322, 1999 (American Chemical Society).
[0316] In accordance with a pharmaceutical composition, dosage form
or controlled release formulation of the present invention as
described herein (i.e., which include any of the specific
embodiment described for various delivery systems or technologies
applicable with the present invention), a specific embodiment may
include a pharmaceutically acceptable acid addition salts of
carvedilol free base or corresponding forms as described herein.
Such pharmaceutically acceptable salts of carvedilol free base or
corresponding forms are formed with appropriate organic or mineral
acids, which may include, but are not limited to formation by
methods known in the art.
[0317] Representative examples of such suitable organic or mineral
acids may include, but are not limited to maleic acid, fumaric
acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid,
bismethylenesalicyclic acid, methane sulphonic or sulfonic acid,
acetic acid, propionic acid, tartaric acid, salicyclic acid, citric
acid, gluconic acid, aspartic acid, stearic acid, palmitic acid,
itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid,
benzene sulfonic acid or sulphonic acid, hydrochloric acid,
hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid,
phosphoric acid, nitric acid and the like.
[0318] In accordance with the present invention, mineral acids may
be selected from, but are not limited to hydrobromic acid,
hydrochloric acid, phosphoric acid, sulfuric acid or sulphuric
acid, and the like; and organic acids may be selected from, but not
limited to methansulphuric acid, tartaric acid, maleic acid, acetic
acid, citric acid, benzoic acid and the like.
[0319] Also in accordance with a pharmaceutical composition, dosage
form or controlled release formulation of the present invention as
described herein (i.e., which include any of the specific
embodiment described for various delivery systems or technologies
applicable with the present invention), a specific embodiment may
include a solubility enhanced carvedilol salt, solvate or anhydrous
forms form or forms selected from the group consisting of a novel
crystalline salt or other solid forms of carvedilol mandelate,
carvedilol lactate, carvedilol maleate, carvedilol sulfate,
carvedilol glutarate, carvedilol mesylate, carvedilol phosphate,
carvedilol citrate, carvedilol hydrogen bromide, carvedilol
oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide,
carvedilol benzoate, or corresponding solvates thereof with any of
the characteristics noted herein, in association with one or more
non-toxic pharmaceutically acceptable carriers or diluents thereof,
and if desired, other active ingredients.
[0320] Further in accordance with a pharmaceutical composition,
dosage form or controlled release formulation of the present
invention as described herein (i.e., which include any of the
specific embodiment described for various delivery systems or
technologies applicable with the present invention), a specific
embodiment may include, but are not limited to novel crystalline
salt or other solid forms of carvedilol hydrogen phosphate,
carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate
hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol
dihydrogen phosphate methanol solvate, carvedilol hydrobromide
monohydrate, carvedilol hydrobromide dioxane solvate, carvedilol
hydrobromide 1-pentanol solvate, carvedilol hydrobromide
2-methyl-1-propanol solvate, carvedilol hydrobromide
trifluoroethanol solvate, carvedilol hydrobromide 2-propanol
solvate, carvedilol hydrobromide n-propanol solvate #1, carvedilol
hydrobromide n-propanol solvate #2, carvedilol hydrobromide
anhydrous forms or anhydrous forms, carvedilol hydrobromide ethanol
solvate, carvedilol hydrobromide dioxane solvate, carvedilol
monocitrate monohydrate, carvedilol mandelate, carvedilol lactate,
carvedilol hydrochloride, carvedilol maleate, carvedilol sulfate,
carvedilol glutarate, or corresponding anhydrous forms, solvates
thereof.
[0321] Also suitable for use in any of the pharmaceutical
compositions, dosage forms or controlled release formulations of
the present invention are solubility enhanced carvedilol salt,
solvate or anhydrous forms thereof, which may include, but are not
limited to novel crystalline salt or other solid forms, selected
from the group consisting of carvedilol hydrogen phosphate,
carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate
hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol
dihydrogen phosphate methanol solvate.
[0322] In particular, in accordance with a pharmaceutical
composition, dosage form or controlled release formulation of the
present invention as described herein (i.e., which include any of
the specific embodiment described for various delivery systems or
technologies applicable with the present invention), a specific
embodiment may include a carvedilol salt, solvate, or anhydrous
forms thereof, such as a carvedilol phosphate salt, which may
include, but is not limited to or selected from the group
consisting of a carvedilol dihydrogen phosphate hemihydrate (Form
I), carvedilol dihydrogen phosphate dihydrate (Form II), carvedilol
dihydrogen phosphate methanol solvate (Form III), carvedilol
dihydrogen phosphate dihydrate (Form IV), carvedilol dihydrogen
phosphate (Form V) and carvedilol hydrogen phosphate (Form VI), and
the like.
[0323] Also, suitable for use in any of the pharmaceutical
compositions, dosage forms or controlled release formulations of
the present invention is carvedilol dihydrogen phosphate
hemihydrate or carvedilol phosphate anhydrous.
[0324] Depending upon the treatment being effected, the compounds,
or compositions of the present invention can be administered
orally, intraperitoneally, or topically, etc. Preferably, the
composition is adapted for oral administration.
[0325] In general, pharmaceutical compositions of the present
invention are prepared using conventional materials and techniques,
such as mixing, blending and the like.
[0326] In accordance with the present invention, compounds or
pharmaceutical composition can also include, but are not limited
to, suitable adjuvants, carriers, excipients, or stabilizers, etc.
and can be in solid or liquid form such as, tablets, capsules,
powders, solutions, suspensions, or emulsions, etc.
[0327] Typically, the composition will contain a carvedilol free
base or carvedilol salt, solvate or anhydrous form thereof compound
of the present invention, such as a salt of carvedilol or active
compound(s), together with the adjuvants, carriers or excipients.
For example, a pharmaceutical composition of the present invention
may comprise, but is not limited to an effective amount of a salt
of carvedilol (i.e., such as carvedilol dihydrogen phosphate salts)
or corresponding solvates (i.e., as identified herein) thereof,
with any of the characteristics noted herein, in association with
one or more non-toxic pharmaceutically acceptable carriers or
diluents thereof, and if desired, other active ingredients.
[0328] These active compounds may also be administered
parenterally. Solutions or suspensions of these active compounds
for use in such parental administrations can be prepared in water
suitably mixed with a surfactant such as
hydroxypropylcellulose.
[0329] Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, and mixtures thereof in oils. Illustrative
oils are those of petroleum, animal, vegetable, or synthetic
origin, for example, peanut oil, soybean oil, or mineral oil, etc.
In general, water, saline, aqueous dextrose and related sugar
solution, and glycols such as, propylene glycol or polyethylene
glycol, etc., are preferred liquid carriers, particularly for
injectable solutions. Under ordinary conditions of storage and use,
these preparations contain a preservative to prevent the growth of
microorganisms.
[0330] In accordance with the present invention, solid unit dosage
forms can be conventional types known in the art. The solid form
can be a capsule and the like, such as an ordinary gelatin type
containing the compounds of the present invention and a carrier,
for example, lubricants and inert fillers such as, lactose,
sucrose, or cornstarch, etc. In another embodiment, these compounds
are tableted with conventional tablet bases such as lactose,
sucrose, or cornstarch in combination with binders like acacia,
cornstarch, or gelatin, disintegrating agents, such as cornstarch,
potato starch, or alginic acid, and a lubricant, like stearic acid
or magnesium stearate, etc.
[0331] The tablets, capsules, and the like can also contain a
binder, such as gum tragacanth, acacia, corn starch, or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose,
lactose, or saccharin, etc. When the dosage unit form is a capsule,
it can contain, in addition to materials of the above type, a
liquid carrier such as a fatty oil.
[0332] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
can be coated with shellac, sugar, or both, etc. A syrup can
contain, in addition to active ingredient, sucrose as a sweetening
agent, methyl and propylparabens as preservatives, a dye, and
flavoring such as cherry or orange flavor, etc.
[0333] For oral therapeutic administration, these active compounds
can be incorporated with excipients and used in the form of
tablets, capsules, elixirs, suspensions, syrups, and the like.
[0334] The percentage of the compound in compositions can, of
course, be varied as the amount of active carvedilol free base or
carvedilol salt, solvate or anhydrous form thereof in such
therapeutically useful compositions is such that a suitable dosage
will be obtained.
[0335] Typically in accordance with the present invention, the oral
maintenance dose is between about 25 mg and about 70 mg, preferably
given once daily. In accordance with the present invention, the
preferred unit dosage forms include tablets or capsules.
[0336] It will be appreciated that the actual preferred dosages of
the compounds being used in the compositions of this invention will
vary according to the particular composition formulated, the mode
of administration, the particular site of administration and the
host being treated.
[0337] In particular, dosing in humans for treatment of diseases
according to the present invention should not ordinarily or
normally exceed a dosage range of from about 5 mg to about 75 mg of
carvedilol free base or an equivalent amount of a carvedilol salt,
solvate or anhydrous form thereof. As one of ordinary skill in the
art will readily comprehend, the patient should be started on a low
dosage regimen of a compound of the present invention and monitored
for well-known symptoms of intolerance, e.g., fainting, to such
compound. Once the patient is found to tolerate such compound
amount, the patient should be brought slowly and incrementally up
to the maintenance dose. The preferred course of treatment is to
start the patient on a dosage regimen of either approximately or
about 8 mg to about 16 mg, given once daily, for approximately two
weeks. The choice of initial dosage most appropriate for the
particular patient is determined by the practitioner using
well-known medical principles, including, but not limited to, body
weight. In the event that the patient exhibits medically acceptable
tolerance of a compound, corresponding composition or formulation
of the present invention for two weeks, the dosage is doubled at
the end of the two weeks and the patient is maintained at the new,
higher dosage for two more weeks, and observed for signs of
intolerance. This course is continued until the patient is brought
to a maintenance dose. The preferred maintenance dose for
carvedilol free base or an equivalent amount of a carvedilol salt,
solvate or anhydrous form thereof is about 32.5 mg to about 65 mg
given once daily for patients having a body weight of up to 85 kg.
For patients having a body weight of over 85 kg, the maintenance
dose is about 65 mg if given once daily.
[0338] The active compounds of the present invention may be orally
administered, for example, with an inert diluent, or with an
assimilable edible carrier, or they can be enclosed in hard or soft
shell capsules, or they can be compressed into tablets, or they can
be incorporated directly with the food of the diet, etc.
[0339] In addition, compounds or pharmaceutical compositions of the
present invention may incorporated into controlled or modified
release forms, which may incorporate the use of or modification of
various controlled release development processes, which may
include, but are not limited to technologies such as those
conventionally known in the art.
[0340] Specific examples of technologies related or used in the
formation of pharmaceutical compositions, controlled-release
formulations or dosage forms of the present invention are described
below.
[0341] General Formulation Technologies
[0342] Delivery systems suitable for use in accordance with the
present invention, may include, but are not limited to materials as
described generally in this section.
[0343] The term "active agent" is defined for purposes of the
present invention as any chemical substance or composition of the
present invention, such as carvedilol free base, or a carvedilol
salt, anhydrous form, or solvate thereof, which can be delivered
from the device into an environment of use to obtain a desired
result. When the active agent is a biologically active drug, such
as carvedilol free base, or a carvedilol salt, anhydrous forms, or
solvate thereof, or corresponding pharmaceutical composition of the
present invention, which is taken orally and the external fluid is
gastric fluid, it is preferred that the drug exhibits a between the
solubility defined in the United States Pharmacopeia (USP) XXI,
page 7 as "freely soluble" (i.e., 1-10 parts solvent per 1 part
solute) and "sparingly soluble" (i.e., 30-1000 parts solvent per 1
part solute).
[0344] The dosage form, which includes a device or delivery system
associated with the present invention can be used in conjunction
with a wide range of drugs (i.e., which includes carvedilol free
base, or a carvedilol salt, anhydrous forms, or solvate thereof)
and is especially well-suited for drugs having a wide therapeutic
window, since precise dosing is not very critical for the same. The
therapeutic window is commonly defined as the difference between
the minimum effective blood concentration and the maximum effective
blood concentration and the toxic concentration of the drug.
[0345] Depending upon the solubility and the amount of active agent
to be included in the core, any generally accepted soluble or
insoluble inert pharmaceutical filler (diluent) material may be
used to bulk up the core or to solubilize the active agent.
[0346] Suitable materials for use in the present invention,
include, but are not limited to sucrose, dextrose, lactose,
fructose, xylitol, mannitol, sorbitol, dicalcium phosphate, calcium
sulfate, calcium carbonate, starches, cellulose, polyethylene
glycols, polyvinylpyrollidones, polyvinyl alcohols, sodium or
potassium carboxmethylcelluloses, gelatins, mixtures of any of the
above, and the like.
[0347] In addition, it is possible to directly compress an active
agent with a small amount of lubricant when the active agent is
soluble in the external fluid and is included in such an amount to
provide a suitably sized core.
[0348] Lubricant may be mixed with the active agent and excipients
prior to compression into a solid core. Any generally accepted
pharmaceutical lubricant may be used, which may include, but are
not limited to calcium or magnesium soaps and the like.
[0349] Active agents can be formulated with a small amount of a
binder material such as, for example, gelatin or
polyvinylpyrollidone (i.e. 94%-99.75% of the core comprises the
active agent). In such cases, the components of the core may be
subjected to wet granulation. For example, highly soluble
pharmaceutically active compounds such as potassium chloride may be
directly compressed into an acceptable core with the inclusion of
0.25 percent magnesium stearate without being in admixture with an
excipient.
[0350] The particular excipient chosen is dependent in part upon
the solubility of the active agent in the environmental fluid. The
ratio of active agent to excipient is based in part upon relative
solubility of the active agent in the external fluid and the
desired rate of release. If the active agent is relatively soluble,
it may be desirable to slow down the eroding of the core by using a
relatively insoluble excipient such as dicalcium phosphate.
[0351] Representative materials suitable for use in the present
invention as a coating include those materials commonly considered
to be insoluble in the art, which may include, but are not limited
to materials, such as ethyl cellulose, acrylate polymers,
polyamides (nylons), polymethacrylates, polyalkenes (polyethylene,
polypropylene), bio-degradable polymers (including homo- or
hetero-polymers of polyhydroxy butyric or valeric acids and homo or
hetero-polymers of polylactic, polyglycolic, polybutyric,
polyvaleric, and polycaprolactic acids), waxes, natural oils, other
hydrophobic insoluble materials such as polydimethylsiloxane,
hydrophilic materials such as cross-linked sodium carboxymethyl
cellulose and cross-linked sodium or uncross-linked carboxy-methyl
starch and the like. Many other polymers considered to be
relatively insoluble as conventionally used in the art also would
be useful in the present invention.
[0352] It is also possible to use relatively thick coatings of
materials in the present invention, which are considered in the art
to be relatively soluble in, environmental fluid, which may
include, but are not limited to materials, such as
polyvinylpyrrolidone, cellulose ethers including
hydroxypropylmethylcellulose, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethyl
cellulose, sodium carboxymethyl starch, enteric materials (such as
cellulose acetate phthallate, polyvinylalcohol phthallate, shellac,
zein, hydroxypropylmethyl cellulose phthallate, cellulose acetate
trimaleate, etc) and the like.
[0353] In certain embodiments of the present invention, it may be
advantageous to include one or more release modifying agents which
aids in the release of the active agent from a suitable device of
the present invention in the environment of use.
[0354] For example, the inclusion of a surfactant or an
effervescent base may be helpful in certain cases to overcome
surface tension effects, etc. Other releasing modifying agents may
include osmagents (i.e., which osmotically deliver the active agent
from the device by providing an osmotic pressure gradient against
the external fluid and are particularly useful when the active
agent has limited solubility in the environment of use), swelling
agents (i.e., which may include, but are not limited to hydrophilic
pharmaceutically acceptable compounds with various swelling rates
in water) or other pharmaceutically acceptable agents (i.e.,
provided in an amount sufficient to facilitate the entry of the
environmental fluid without causing the disruption of the
impermeable coating).
[0355] Alternatively, release modifying agents, such as hydrophobic
materials and insoluble polymers, may be used to slow the release
of active agent from the device or release modifying agents may be
used in conjunction with the present invention to include ion
exchange resins.
[0356] Surfactants useful as release modifying agents in the
present invention can be anionic, cationic, nonionic, or
amphoteric. Examples of such surfactants or release modifying
agents, may include, but are not limited to sodium lauryl sulfate,
sodium dodecyl sulfate, sorbitan esters, polysorbates, pluronics,
potassium laurate, and the like.
[0357] Effervescent bases useful as release modifying agents in the
present invention, may include, but are not limited to sodium
glycine carbonate, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium bicarbonate, and the
like.
[0358] Osmagents useful as release modifying agents in the present
invention may include, but are not limited to sodium chloride,
calcium chloride, calcium lactate, sodium sulfate, lactose,
glucose, sucrose, mannitol, urea, and many other organic and
inorganic compounds known in the art and the like.
[0359] Examples of suitable swelling agents for use in the present
invention may include, but are not limited to, crosslinked
polyvinylpyrrolidones (for example, such as polyplasdone,
crospovidone and the like), crosslinked carboxyalkylcelluloses,
crosslinked carboxymethylcellulose (for example, such as
crosslinked sodium croscarmellose and the like), hydrophilic
polymers of high molar mass (i.e., which may be, but are not
limited to being greater than or equal to 100,000 Dalton) which may
include, but are not limited to: polyvinylpyrrolidone(s),
polyalkylene oxides (for example, such as polyethylene oxide or
polypropylene oxide and the like), hydroxyalkylcelluloses (for
example, such as hydroxypropylcellulose,
hydroxypropylmethylcellulose and the like), carboxyalkylcellulose
(for example, carboxymethylcellulose and the like), modified starch
(for example, sodium glycolate and the like), starch or natural
starch (for example, such as corn, wheat, rice, potato and the
like), cellulose (for example, which may be, but not limited to
being in powder form or microcrystalline form), sodium alginate,
potassium polacriline, and corresponding blends or mixtures
thereof.
[0360] For example, a swelling agent for use in the present
invention may be selected from, but not limited to, the following
sub-set or group of compounds or materials: crosslinked
polyvinylpyrrolidone (for example, polyplasdone, crospovidone and
the like), crosslinked carboxyalkylcelluloses, such as crosslinked
carboxymethylcellulose (for example, crosslinked sodium
croscarmellose and the like), etc.
[0361] Examples of other suitable pharmaceutically acceptable
agents for use in the present invention, include synthetic gums,
which further may include, but are not limited to
hydroxypropylmethylcelluloses (HPMC) hydroxypropyl cellulose,
carboxymethyl cellulose, and natural gums such as xanthan gum,
locust bean gum, acacia, tragacanth, guar gum, carrageenan, and
propylene glycol alginate, and the like.
[0362] Examples of suitable hydrophobic materials useful as release
modifying agents in the present invention, include vegetable oils,
which may include, but are not limited to hydrogenated cottonseed
oil, hydrogenated castor oil, and the like. An example of insoluble
polymers includes ethyl cellulose, etc.
[0363] A device may be designed such that the rate of release of
the active agent varies with time which may be used to achieve a
chronotherapeutic effect not normally possible with some
conventional art-known sustained release devices.
[0364] Microparticle or Microcapsule Type Technology Section
[0365] In light of the foregoing an example of a delivery system
suitable for use in the present invention is described by a
microparticle or microcapsule technology system, which may be
include, but is not limited to a capsule that contains two or more
populations of pellets, coated to provide earlier and later
release. The early-release pellets may be coated with a polymer
that delays release by pH, hydration or other effect. The
later-releasing pellets may be coated with a polymer that dissolves
at higher pH than the polymer coating the units providing early
release.
[0366] Such a delivery system is exemplified by U.S. Pat. No.
5,004,614 to Autant et al., which is hereby incorporated by
reference in its entirety.
[0367] In particular, U.S. Pat. No. 6,022,562 to Autant et al.
discloses microcapsules used for oral administration of medicinal
or nutritional active principles or particles (AP) and a process
for making such microcapsules, which are smaller than or equal to
1000 .mu.m in size, where such microcapsules are particles coated
with a coating material (i.e., formed from a mixture of a
film-forming polymer derivative, a hydrophobic plasticizer, a
functional agent and a nitrogen-containing polymer) and are
characterized by an ability to remain in the small intestine for a
long time period (at least 5 hours) and allows, during the
residence, release and absorption of the active principle.
[0368] In light of the foregoing, the present invention relates to
microparticulate systems for the delayed and controlled release or
modified release of carvedilol free base, salt, anhydrous or
solvate forms thereof, which are active principle particles ("AP")
according to the present invention designed for oral
administration.
[0369] In general, carvedilol free base, salt, anhydrous or solvate
forms thereof, which are active principle particles ("AP")
according to the present invention, are coated by spraying with
such a combination forming the coating film, as a dispersion or a
suspension in an organic solvent or a mixture of organic
solvents.
[0370] In another aspect of the present invention, the coating
process is within the scope of micro-encapsulation techniques,
which are summarized or exemplified in an article by C. Duverney
and J. P. Benoit in "L'actualite chimique" Dec. 1986 and cf. book
entitled "Novel drug delivery and its therapeutic application" L.
F. Prescott & W. S. Nimmo, Ed. John Wiley & Sons, which is
hereby incorporated by reference in its entirety).
[0371] The technique is characterized as microencapsulation by film
formation, which results in the formation of "reservoir" systems
versus matrix systems.
[0372] Essential parameters of the present invention relate to
residence time and in vivo absorption of microcapsules containing
carvedilol free base, salt, anhydrous or solvate forms thereof,
which are active principle particles in the gastrointestinal tract,
such in the small intestine. The residence time in the small
intestine of microcapsules, administered orally, as well as the in
vivo absorption may by determined by measurement of the plasma
concentration of carvedilol free base, salt, anhydrous or solvate
forms thereof, which are active principle particles according to
the present invention, which has a short half-life in the body of a
mammal, i.e., which is not absorbed in the gastrointestinal tract
components, such as the colon.
[0373] One of the important parameters of the present invention
relates to microcapsule particle size. Desired particle size is
determined by screening, which may be, but is not limited to be
microcapsules between 100 microns and 500 microns in size.
[0374] Another important component of the present invention relates
to the coating film or composition associated or applied to the
microparticles. This coating composition is formed from a
non-arbitrary choice of four compounds with unique functionalities
and characteristics that combine to achieve the desired effects
associated with delivery systems of the present invention. For
example, ethylcellulose and cellulose acetate may be combined to a
film-forming polymer P1 and may be soluble in at least one organic
solvent of boiling point between 35.degree. C. and 120.degree. C.
Polyvinylpyrrolidone and/or polyacrylamide representing P2 are
polymers soluble in at least one solvent for P1.
[0375] Suitable plasticizer, surface-active and/or lubricating
agents for use in the present invention may include, but are not
limited to castor oil, and/or diethyl phthalate, and/or triethyl
citrate and/or salicylic acid, and magnesium stearate, and/or
sodium oleate and/or polyoxyethylenated sorbitan laurate and the
like.
[0376] As example of a coating composition suitable for use in the
present invention may comprise, but is not limited to:
ethylcellulose (P1)/polyvinylpyrrolidone (P2)/castor oil
(plasticizer)/magnesium stearate (lubricating agent), which may be
present respectively in the following specific relative
percentages: 60%-80%/5%-10%/5%-10%/2%-8% (i.e., where such
percentages are defined by weight % relative to the total
components of each coating composition).
[0377] Moreover, it is possible to add other conventionally art
known adjuvants to a coating composition of the present invention,
which may include, but are not limited to pigments, fillers and the
like.
[0378] In order to prevent the caking problems associated with
coated particles that constitute microcapsule or coated
compositions of the present invention, at least one
anti-agglomerating agent may be included. Suitable
anti-agglomerating agents, may include, but are not limited to
talc, colloidal silica or of a mixture of the two and the like,
which may be in amounts of from 0.5% by weight to 5% by weight,
preferably from 1.5% by weight to 3% by weight.
[0379] A general process for making coated microparticle containing
compositions of the present invention may include, but are not
limited to the following steps: [a]selecting, or in case of need
making, microparticles of carvedilol free base, salt, anhydrous or
solvate forms thereof, which are active principle particles ("AP")
according to the present invention, with a particle size of between
50 and 1000 microns, preferably of between 100 and 750 microns and,
more preferably, of between 100 and 500 microns; [b] preparing the
coating composition by mixing together a polymer P1, a polymer P2,
the plasticizer and the surface-active and/or lubricating agent in
a solvent system; [c] applying the coating composition/solvent
system mixture to particles of carvedilol free base, salt,
anhydrous or solvate forms thereof, which are active principle
particles according to the present invention; [d] drying the
microcapsules thus obtained; and [e] optionally, mixing these
microcapsules with at least one antiagglomerating agent.
[0380] Suitable solvents suitable for use in the composition of
such a solvent system may include, but are not limited to, ketones,
esters, chlorinated solvents, alcohols, which are preferably
aliphatic, alkanes or mixtures thereof and the like. Specific
solvent examples, may include, but are not limited to
C.sub.1-C.sub.6 compound solvents, such as acetone, methyl ethyl
ketone, methanol, ethanol, isopropanol, cyclohexane and methylene
chloride and the like.
[0381] In order to go into greater detail into the coating
methodology which may be used in accordance with the invention, it
may be pointed out that the coating composition/solvent system
mixture is applied by spraying onto the particles of carvedilol
free base, salt, anhydrous or solvate forms thereof, which are
active principle particles according to the present invention, set
in motion, preferably by mechanical stirring or by
fluidization.
[0382] In order to obtain microcapsules according to the invention,
it is necessary to encapsulate particles of carvedilol free base,
salt, anhydrous or solvate forms thereof, which are active
principle particles ("AP") according to the present invention, of
size between 50 microns and 1000 microns. For example, such
particles of carvedilol free base, salt, anhydrous or solvate forms
thereof, which are active principle particles according to the
present invention are between 100 microns and 750 microns; or
between 100 microns and 500 microns.
[0383] The active principle particles of carvedilol free base,
salt, anhydrous or solvate forms thereof, of desired particle size
and necessary for the production of microcapsules according to the
invention, may be crystals of pure carvedilol free base, salt,
anhydrous or solvate forms thereof, which have undergone a
pretreatment by one of the conventional techniques of the art such
as, for example, granulation in the presence of a small amount of
at least one standard binder and/or of an agent modifying the
intrinsic solubility feature of the carvedilol free base, salt,
anhydrous or solvate forms thereof, which are active principle
particles according to the present invention.
[0384] According to an embodiment of the present invention, the
content of carvedilol free base, salt, anhydrous or solvate forms
thereof, which are active principle particles according to the
present invention, before coating is between 75% and 100% by
weight, preferably between 95% and 100% by weight. The amount of
coating agent in the microcapsules may represent from 5% to 40% of
the weight of the coated microcapsules. The actual density of the
microcapsules according to the invention is not critical, but may
be between 1.0 grams per cubic centimeter and 1.35 grams per cubic
centimeter.
[0385] In accordance with the present invention, a embodiment of
the process for the micro-encapsulation of particles of carvedilol
free base, salt, anhydrous or solvate forms thereof, which are
active principle particles according to the present invention, may
include, but are not limited to the following steps: [a.sub.1]
preparation of a mixture, which comprises from 70% by weight to 80%
by weight of a film-forming polymer P1 and 5% by weight to 10% by
weight of a plasticizer for 5% by weight to 10% by weight of a
nitrogen-containing polymer P2 in solution, either in an
acetone/alkanol mixture such that the acetone/alkanol volume ratio
is between 50/50 and 70/30, or in a solvent, which may be chosen
from, but not limited to cyclohexane, toluene, carbon
tetrachloride, chloroform and methylene chloride and the like;
[a.sub.2] placing in suspension a solution prepared in the step
[a.sub.1], of 2% by weight to 8% by weight of surface-active; [b]
lubricating and/or spraying of the resulting mixture onto
microparticles of active principle, in a fluidized bed; [c] drying
of microcapsules after spraying in a fluidized bed and/or in the
oven; and/or [d] mixing of obtained or formed microcapsules with
0.5 by weight to 3% by weight of anti-adhesion agent, on the basis
of 100% of final product obtained after mixing.
[0386] As described herein the microcapsules obtained by a example
process as outlined above, may be used for manufacture of novel
pharmaceutical or nutritional preparations of carvedilol free base,
salt, anhydrous or solvate forms thereof, which are active
principle particles according to the present invention, having
optimized therapeutic or nutritional performance, which may be
provided specifically in the form of tablets that can
advantageously be crumbled, or powders or gelatin capsules.
[0387] Thus, the present invention relates to new galenic systems,
which may be defined by the following forms: tablets, powders,
gelatin capsules, which contain microcapsules of the present
invention.
[0388] The microcapsules of the present invention are well
tolerated by the human body, in particular at the gastric
level.
[0389] The present invention also relates to these novel
microparticle containing pharmaceutical preparations or
compositions, which may be administered orally, preferably by
single daily doses.
[0390] It also may be advantageous to mix within the same gelatin
capsule, the same tablet or the same powder materials, at least two
types of microcapsules which have release kinetics that are
different, but are within the characteristic scope of the
invention.
[0391] In accordance with the present invention, such microcapsules
also may be mixed with a certain amount of other active principle
particles ("AP") immediately available to the body.
[0392] The present invention also relates to the use of
microcapsules as vehicles for at least one medicinal and/or
nutritional active principle particle (AP) capable of residing in
the small intestine for a prolonged period, where such
microcapsules: .DELTA. being designed for oral administration
(i.e., e.g., which may be able to reside in the small intestine for
at least about 5 hours, preferably at least about 7 hours and, even
more preferably, for a period of between 8 and 24 hours, to allow
the release of the active principles ("AP") in the small intestine
for at least part of their residence time), .DELTA. and consisting
of particles of active principles ("AP") each coated with at least
one coating film of specific composition and having a particle size
of between 50 .mu.m and 1000 .mu.m, preferably of between 100 and
750 .mu.m and, even more preferably, of between 100 .mu.m and 500
.mu.m.
[0393] PCT International Application WO 03/030878 to Flamel
Technologies, which is incorporated by reference in its entirety,
also discloses a microparticulate system based upon oral
administration for delayed and controlled release of active
principles, where the in vivo absorption window is limited to parts
of the gastrointestinal tract.
[0394] The WO 03/030878 Application is aimed at providing a system
for reliably releasing active principles through a double time
dependent and pH-dependent mechanism.
[0395] In light of the foregoing, the present invention also
relates microparticulate systems for the delayed and
controlled-release or modified release of carvedilol free base,
salt, anhydrous or solvate forms thereof, which are active
principle particles ("AP") according to the present invention, such
as a multiple microcapsule galenic oral formulation designed for
therapeutic efficacy, such that release of active principles is
controlled by a double release triggering mechanism, involving time
triggering and pH-triggering.
[0396] In particular, the present invention relates to a
microparticulate galenic (i.e., tablets, powders, gelatin capsules,
which contain microcapsules of the present invention) formulation
with delayed and controlled-release for which the
controlled-release phase is triggered in a specific way due to a
double mechanism: "time-dependent" release triggered after a
certain amount of time in the stomach, and "pH-dependent" release
triggered by a change in pH when the particles enter into the small
intestine and which starts without a latency period.
[0397] The microparticles of this invention are microcapsules
containing at least one carvedilol free base, salt, anhydrous or
solvate forms thereof, which are active principle particles
according to the present invention, with granulometry such as
between 100 microns and 1,200 microns individually covered with a
film coating allowing the delayed and controlled-release of the
active principle.
[0398] Modified-release or delayed and controlled-release systems
containing active principles are useful when it is desirable, for
chronobiological reasons, for such active principles to be
"bioabsorbed" at a specific time of day so that it is in phase with
the circadian cycle. This approach is appropriate for the treatment
of cancer, hypertension, atherosclerosis, administration of
anti-inflammatory drugs or regulation of glycemia in the treatment
of diabetes.
[0399] For example, it may be advantageous for an active carvedilol
free base, salt, anhydrous or solvate forms thereof to be
bioabsorbed very early in the morning in order to ensure
therapeutic coverage when the patient awakens without requiring
early awakening. To achieve this, the galenic system ingested by
the patient in the evening after a meal, should allow the
delayed-release of the active principle.
[0400] In the case of a modified, delayed or controlled release
formulation, it is therefore crucial to have a complete guarantee
of release and absorption of the active principle by a patient at a
specific moment in order to achieve the therapeutic effect.
However, it must be pointed out that the delayed-release forms
cannot definitely ensure the release of the active principle in a
prescribed amount of time. For example, achievement of accurate
timed release of carvedilol free base, salt, anhydrous or solvate
forms thereof, which are active principle particles according to
the present invention, are important especially for patients
undergoing cardiovascular disease or diabetes treatments.
[0401] In fact, traditionally, delayed-release forms are obtained
by coating the active principle with a layer of enteric polymer.
This type of enteric coating is known to present reduced
permeability in the acid pH conditions in the stomach and dissolves
when the pH increases to a value close to what exists in the small
intestine, thus releasing the active principle. However, the intra
and inter-individual variability of gastric pH conditions and of
gastric emptying duration do not allow the definite release of the
active principle after a specific amount of time.
[0402] The purely "time-dependent" delayed-release systems for
which release of the active principle is triggered after it spends
a specific amount of time in the gastrointestinal tract, are not
satisfactory either. In fact, due to the intra and inter-individual
variability of gastric residence time, release of the active
principle may occur after the latter has passed its absorption
window, which is located for a majority of active principle's in
the upper part. of the gastro-intestinal tract. Bio-absorption may
thus be very low, even non-existent.
[0403] In this context, it would be particularly advantageous to
have a delayed and controlled-release formulation of the active
principle, which ensures active principle release based upon the
aforementioned double triggering release of such active principles:
i.e., "time-dependent" release triggered after a controlled amount
of time in the stomach, without pH change, and "pH-dependent"
release triggered by an increase in the pH when the galenic
formulation penetrates into the intestine. These two triggering
factors for release of carvedilol free base, salt, anhydrous or
solvate forms thereof, which are active principle particles
according to the present invention, occurring in serial fashion
would make formulations of the present invention very safe to use.
The release of the active principle would be guaranteed, after a
pre-regulated latency time, even if the pH variation did not
intervene as a triggering factor (i.e., even if such a galenic
formulation did not pass from the stomach into the intestine).
[0404] In order to minimize the inter-individual variability of the
absorption of the principle particle of carvedilol free base, salt,
anhydrous or solvate forms thereof, which are active principle
particles according to the present invention, it is necessary to
adjust the latency time preceding the release of the carvedilol
free base, salt, anhydrous or solvate forms thereof active
principle particle in the stomach by taking into consideration the
physiological conditions of the gastrointestinal tract in humans.
According to the well-known results of Davis et al., J. of
Controlled-Release, 2, 27-38 (1985), the residence time in the
stomach of a preparation varies greatly, on the order of 0.5 to 10
hours. It would therefore be advantageous to have a galenic
formulation releasing the active principle in the stomach after a
given constant latency time, within this 0.5 hours to 10 hours
interval, so that the drug's action time is the same from one
individual to another, or even from one day to the next for the
same individual.
[0405] In addition, in order to optimize the bioavailability of the
active principles whose absorption is limited mainly to the upper
portions of the gastro-intestinal tract, it would be advantageous
for the "pH-dependent" release in the intestine to occur without
latency time because otherwise the active principle will not be
released within its absorption window and the patient will
consequently not be treated.
[0406] Another unique interesting factor of such a system would be
to allow us to achieve, by mixing with an immediate-release galenic
formulation of active principle carvedilol free base, salt,
anhydrous or solvate forms thereof, or by mixing with another
delayed- and controlled-release galenic formulation of active
principle carvedilol free base, salt, anhydrous or solvate forms
thereof, release profiles presenting several waves of active
principle carvedilol free base, salt, anhydrous or solvate forms
thereof release (i.e., which represents a single active principle
or several identical or different active principles) or ensuring
with appropriate adjustment of the various fractions a constant
plasma concentration level of active principle.
[0407] Suitable delayed and controlled-release formulations of the
present invention may be comprised of, but not limited to a large
number of microcapsules with a diameter of less than 2000 microns.
In fact, for such a formulation, the dose of active principles to
be administered is distributed among, a great number of
microcapsules (typically 10,000 for a dose of 500 mg).
[0408] In accordance with the present invention, the following
intrinsic advantages result from the use of such delayed and
controlled-release formulations: [1] prolonged residence time of
microcapsules in regions of the gastrointestinal tract, which
ensures an increase in the amount of time the active principle
carvedilol free base, salt, anhydrous or solvate forms thereof
spends within absorption windows to maximize active principle
bioavailability; [2] implementation of a mixture of microcapsules
with various immediate and/or modified, delayed or
controlled-release profiles allows release profiles to be achieved
that present several waves of release to ensure a constant plasma
concentration level of active principle carvedilol free base, salt,
anhydrous or solvate forms thereof by adequate adjustment of
various fractions; [3] sensitivity to variability of gastric
emptying is less, because the emptying, which occurs here with a
large number of particles, is statistically more reproducible; [4]
contact of the tissues with a high dose of active principle
carvedilol free base, salt, anhydrous or solvate forms thereof is
avoided: "dose dumping", where each microcapsule contains only a
very reduced dose of the active principle carvedilol free base,
salt, anhydrous or solvate forms thereof and risk of deterioration
of tissues by a local superconcentration of aggressive active
principle carvedilol free base, salt, anhydrous or solvate forms
thereof is eliminated.; [5] possibility to form
"multi-microcapsular" systems, i.e., to combine several galenic
forms (immediate-release and/or delayed-release and/or
prolonged-release) containing one or several active principle forms
of carvedilol free base, salt, anhydrous or solvate forms thereof;
[6] possibility to present these microcapsules in a packet, capsule
or tablet form (i.e., as in cases where active principle dose is
high (500 mg or more), monolithic formulations are too large to be
easily swallowed, such that it is important for a microparticulate
formulation to ensure delayed and controlled-release of an active
principle carvedilol free base, salt, anhydrous or solvate forms
thereof that one skilled in the art can put into the form of
splittable tablets or packets.; and [7] desirability for film
coating around microcapsules to not be very thick.
[0409] In particular, it would be important to have an oral
microparticulate galenic formulation with delayed and
controlled-release of AP carvedilol free base, salt, anhydrous or
solvate forms thereof, simultaneously having the following
properties: where active principles release may be triggered, by
time-dependent release when duration of particulates in the stomach
exceeds 5 hours; and by pH variation-dependent release, also called
"pH-dependent", which starts without latency time when the system
penetrates into the intestine and the pH increases.
[0410] Importantly, these two triggering factors affect release of
active principle carvedilol free base, salt, anhydrous or solvate
forms thereof occurring in serial fashion to guarantee release of
the active principle after a pre-regulated latency time, even if
the pH variation is not involved as a triggering factor. It is
composed of a large number of microcapsules of coated active
principle carvedilol free base, salt, anhydrous or solvate forms
thereof small in size; and/or mass fraction in excipients of
coating is limited.
[0411] Further in accordance with the present invention is the use
of suitable swelling agents in compositions or controlled-release
formulations as described herein.
[0412] As used in the present invention, the term "swelling agent"
may include, but is not limited to at least one pharmaceutically
acceptable hydrophilic compound, having a swelling rate or swelling
amount in water at about 25.degree. C. that is: greater than or
equal to at least 10% by weight (wt/wt), greater than or equal to
at least 15% by weight (wt/wt), or greater than or equal to at
least 20% by weight (wt/wt).
[0413] According to an advantageous or remarkable characteristic of
the present invention, a swelling agent is selected from among
swelling agents with chemical, physical or pharmaceutically
acceptable characteristics which make possible for microcapsules of
the present invention to release at least 50% by weight (wt/wt) of
the active principle carvedilol free base or carvedilol salt,
anhydrous or solvate thereof, after at least 16 hours at about a pH
of 1.4 and after a latency phase or lag time of less than or equal
to about 7 hours, or after a latency phase or lag time of less than
or equal to about 5 hours or after a latency period or lag time of
between about 1 hour to 1.5 hours in an in vitro dissolution test
performed according to guidelines as specified in the European
Pharmacopoeia, 4.sup.th Edition, entitled: "Dissolution Test of
Solid Oral Forms": a type II dissolutest performed in SINK
conditions kept at 37.degree. C. and stirred or agitated at 100
rpm.
[0414] According to the present invention, it is possible to adjust
the rate of release at about a pH of 1.4 of the active principle
carvedilol free base or carvedilol salt, anhydrous or solvate
thereof, from the microcapsules described herein, by carefully
selecting the concentration (Cd) of the swelling agent particles in
the microcapsules.
[0415] When a swelling agent is included into a microparticle form
of the present invention, the mean diameter (Td) of a swelling
agent particle is selected from particle sizes with ranges of at
least between 5 micrometers (.mu.m) to 200 micrometers (.mu.m), or
of at least between 10 micrometers (.mu.m) to 50 micrometers
(.mu.m).
[0416] In light of the above and in an embodiment of the present
invention, the concentration (Cd) of the swelling agent is selected
from to include, but is not limited to be in the following ranges
of percentage by weight (in wt %) relative to the total mass of the
microcapsules of the present invention as follows:
[0417] 3<=Cd<=40;
[0418] 4<=Cd <=30; or
[0419] 5<=Cd <=25.
[0420] In one embodiment swelling agents for use in the present
invention may include, but are not limited to, crosslinked
polyvinylpyrrolidones (for example, such as polyplasdone,
crospovidone and the like), crosslinked carboxyalkylcelluloses,
such as crosslinked carboxymethylcellulose (for example, such as
crosslinked sodium croscarmellose and the like), hydrophilic
polymers of high molar mass (for example, i.e., which may be, but
not limited to being greater than or equal to 100000 Dalton) which
may include, but are not limited to: polyvinylpyrrolidone,
polyalkylene oxides (for example, such as polyethylene oxide or
polypropylene oxide and the like), hydroxyalkylcelluloses (for
example, such as hydroxypropylcellulose,
hydroxypropylmethylcellulose and the like), carboxyalkylcellulose
(for example, carboxymethylcellulose and the like), modified starch
(for example, sodium glycolate and the like), starch (for example,
such as corn, wheat, rice, potato and the like), cellulose (for
example, which may be, but not limited to being in powder form or
microcrystalline), sodium alginate, potassium polacriline, and
corresponding blends thereof.
[0421] In another embodiment, a swelling agent for use in the
present invention may be chosen from, but not limited to, the
following sub-set of compounds: crosslinked polyvinylpyrrolidone
(e;g; polyplasdone or crospovidone), crosslinked
carboxyalkylcelluloses (such as the crosslinked
carboxymethylcellulose (e;g; crosslinked sodium croscarmellose),
and the like.
[0422] In another embodiment, a suitable swelling agent for use in
the present invention may also a nitrogen containing polymer, which
may include but is not limited to polyvinylpyrrolidone, crosslinked
polyvinylpyrrolidone and the like.
[0423] Also in accordance with the present invention, to reduce the
possibility of active principle carvedilol free base, salt,
anhydrous or solvate forms thereof being insufficiently wetted by
water and therefore tending to aggregate, it is proposed in an
advantageous variant of the present invention is to make sure that
a formulation or pharmaceutically acceptable composition of the
present invention may include, but is not limited to including at
least one wetting agent, selected from, but not limited to the
following group of products: anionic surfactants (for example, such
as those in the sub-group of the alkaline or alkaline-earth salts
of fatty acids, stearic acid, oleic acid and the like) and/or
non-ionic surfactants (for example, which may include, but are not
limited to polyoxyethylenated oils (for example, such as
polyoxyethylenated hydrogenated castor oil and the like),
polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated
sorbitan esters, polyoxyethylenated castor oil derivatives,
stearates (for example, such as calcium, magnesium, aluminum, zinc
stearate and the like), stearyl fumarates (for example, such as
sodium stearyl fumarate and the like), glycerol behenate, or
mixtures thereof.
[0424] In accordance with the present invention, mixtures of the
following components in general form the basis of a
controlled-release microparticle composition of the present
invention:
[0425] i) Microparticle pellets or granules, which comprise an
active carvedilol free base or a carvedilol salt, solvate or
anhydrous form thereof formulated to release the drug relatively
quickly, but not immediately, as there may be a time delay in
release;
[0426] ii) pellets, granules or microparticles may be prepared by
granulating the drug with a hydrophilic polymer such as cellulose
ethers, which may include, but is not limited to methyl cellulose,
hydroxypropyl methylcellulose, polyvinyl pyrrolidone and the like.
Alternatively, the drug may be applied to a base granule in an
aqueous slurry with hydrophilic polymers, followed by subsequent
drying to provide an embedded drug/matrix pellet;
[0427] iii) pellets, granules or microparticles also may be coated
with or containing the drug embedded in a polymer, which prevents
release at the more acid pH values encountered in the
gastrointestinal tract, but which effect ready release of drug,
after a defined time has elapsed or when the pellet, granule or
microparticle unit is in an environment of more neutral pH.
Examples of suitable coating or release modifying materials, may
include, but are not limited to methacrylic acid polymers, shellac
or cellulose acetate phthalate or mixtures thereof and the like;
or
[0428] iv) pellets, granules or microparticles coated with or
containing embedded drug as described in [iii], but which release
drug at higher pH, such as a pH of about 6.5 to a pH of about 7.5,
prepared using identical or similar coating materials as in [iii]
such that coating material ratios may be varied.
[0429] In light of the foregoing, the early releasing component
would be formulated to start releasing drug shortly after dosing
(i.e., when a pellet, granule or microcapsule unit enters the
stomach) to provide a "pulse", peaking at about 1 hour to about 3
hours. At a later time, the more slowly releasing formulated
components release drug in parts of the small intestine, where the
associated polymer coat or matrix is soluble.
[0430] The overall dose of drug and ratios of the different
pellets, granules or microparticles can be determined by studies in
human volunteers to examine plasma levels for at least 24 hours
after dosage.
[0431] A general representative process for forming a controlled
release formulation of the present invention, may be, but is not
limited to a process where:
[0432] [1] rapidly releasing microparticle units are formed by
applying a aqueous or other suitable liquid dispersion, which
contains a carvedilol free base, salt, solvate, or anhydrous form
thereof and at least one nitrogen-containing polymer and,
optionally other pharmaceutically acceptable agents, onto cellulose
or similar pharmaceutically acceptable core microparticle, which
are subsequently heated in environment where moisture is removed,
leaving the aforementioned desired material solids embedded or
layered on the core microparticles;
[0433] [2] delayed or controlled release microparticle core
particles are formed by applying a aqueous or other suitable liquid
dispersion, which contains a carvedilol free base, salt, solvate,
or anhydrous form thereof and at least one nitrogen-containing
polymer and, optionally other pharmaceutically acceptable agents,
onto cellulose or similar pharmaceutically acceptable core
microparticle, subsequently which are heated in environment where
moisture is removed, leaving the aforementioned desired material
solids embedded or layered on the core microparticles. A delaying
or drug release-modifying coat is further applied to the each of
the aforementioned heated core microparticles, where such a coat is
comprised of at least one film-forming polymer, a plasticiser, a
surface active agent and, optionally other pharmaceutically
acceptable excipients know to those skilled in the art. The
delaying or drug release-modifying coat components may be dissolved
or dispersed in an aqueous or suitable non-aqueous solvent, the
coat being applied in a warm environment such that the solvent is
removed by evaporation;
[0434] [3] where each of the rapidly releasing microparticle units
or delayed or controlled release microparticle core particles are
held such that the coated particles are in a warm environment to
ensure that each applied coat or coat layer is satisfactorily
formed;
[0435] [4] where one or more rapidly releasing or delayed
controlled release microparticle units are mixed together; or
[0436] where one or more rapidly releasing or delayed controlled
release populations respectively are formed from the each type of
the above-identified microparticle units with a mixture formed from
each one or more rapidly releasing population and each of the
different controlled release populations.
[0437] [5] where each mixture type as identified in [4] are filled
into a appropriate delivery form, such as a capsule.
[0438] In light of the foregoing technologies, it may be possible
to develop stable pharmaceutical compositions or controlled release
or modified dosage forms, containing such carvedilol free base or
carvedilol salts, solvates, or anhydrous forms thereof of the
present invention, which may be used in combination therapies with
other for once-per-day dosage, delayed release or pulsatile release
to optimize therapy by matching pharmacokinetic performance (i.e.,
which relates to the time-dependent changes of plasma drug
concentration and the time dependent changes of the total amount of
drug in a body following various routes of administration) with
pharmacodynamic requirements (i.e., which relates to the
biochemical and physiologic effects of drugs and their mechanisms
of action).
[0439] As previously indicated herein, it would be expected that
therapy would be more effective if peak plasma levels were provided
times of greatest risk. In such a context a carvedilol based dosage
form that is taken at night (at bedtime), that delivers drug in two
phases to cover the midnight-3 am period, and the early morning
surge ought provide optimum therapy, while maintaining a once-daily
dosage regimen.
[0440] A controlled-release microparticle composition, dosage form
or formulation of the present invention, may be comprised of, but
is not limited to rapidly releasing microparticles or different
types controlled release microparticles (such as first or second
controlled release microparticles) or respective corresponding
populations thereof, where each type of the aforementioned
microparticles may include, but is not limited to a carvedilol free
base or a carvedilol salt, solvate or anhydrous form thereof.
[0441] As described herein, each of the aforementioned
microparticles also may contain, but are not limited to an active
drug ingredient selected from the group consisting of salt forms of
carvedilol mandelate, carvedilol lactate, carvedilol maleate,
carvedilol sulfate, carvedilol glutarate, carvedilol mesylate,
carvedilol phosphate, carvedilol citrate, carvedilol hydrogen
bromide, carvedilol oxalate, carvedilol hydrogen chloride,
carvedilol hydrogen bromide, carvedilol benzoate, and corresponding
solvates thereof.
[0442] Further such specific microparticle types of the present
invention may include, but are not limited to an active drug
ingredient selected from carvedilol hydrogen phosphate, carvedilol
dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate,
carvedilol dihydrogen phosphate dihydrate, carvedilol dihydrogen
phosphate methanol solvate, carvedilol hydrobromide monohydrate,
carvedilol hydrobromide dioxane solvate, carvedilol hydrobromide
1-pentanol solvate, carvedilol hydrobromide 2-methyl-1-propanol
solvate, carvedilol hydrobromide trifluoroethanol solvate,
carvedilol hydrobromide 2-propanol solvate, carvedilol hydrobromide
n-propanol solvate #1, carvedilol hydrobromide n-propanol solvate
#2, carvedilol hydrobromide anhydrous forms or anhydrous forms,
carvedilol hydrobromide ethanol solvate, carvedilol hydrobromide
dioxane solvate, carvedilol monocitrate monohydrate, carvedilol
mandelate, carvedilol lactate, carvedilol hydrochloride, carvedilol
maleate, carvedilol sulfate, carvedilol glutarate, or corresponding
anhydrous forms, solvates thereof.
[0443] Also such specific microparticle types of the present
invention may include, but are not limited to an active drug
ingredient selected from carvedilol hydrogen phosphate, carvedilol
dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate,
carvedilol dihydrogen phosphate dihydrate. In a specific
embodiment, the active drug is selected from a carvedilol phosphate
anhydrous form or carvedilol dihydrogen phosphate hemihydrate.
[0444] Therefore, in a specific embodiment of the present
invention, such units, dosage forms, pharmaceutical compositions or
controlled-release formulations of the present invention are
formulated or prepared so that drug is released in "pulses",
separated in time such that the first "peak" or T.sub.max occurs
within 1-4 hours of dosage, preferably the first "peak" or
T.sub.max occurs 1-2 hours of dosage or preferably the first "peak"
or T.sub.max occurs within 2-4 hours of dosage, with the second
"peak" or T.sub.max occurring 5-10 hours later or preferably the
second "peak" or T.sub.max occurring 5-8 hours later.
[0445] In accordance with the present invention, the pulses as
described above may refer to a peak, plasma peak concentration
level, "a first peak" or "a first peak plasma concentration level",
a "second peak" or a "second peak plasma concentration level",
etc.
[0446] In particular, such a pharmaceutical composition or
controlled-release formulation of the present invention following
oral dosage would be depicted by a unique substantially biphasic
pharmacokinetic/pharmacodynamic plasma profile, which exhibits a
first T.sub.max pulse and a plasma concentration peak level within
1-4 hours of ingestion and a second T.sub.max pulse and a plasma
concentration peak level within, 5-10 hours after ingestion.
[0447] In accordance with the present invention, a substantially
biphasic plasma profile corresponding to a controlled release
composition, dosage form or formulation of the present invention is
represented by a graphical profile representation depicting a
plasma profile curve, where a higher second plasma peak
concentration level may or may not be substantially or
significantly higher than a lower or first plasma peak
concentration level as the substantially biphasic nature of the
profile curve may be obscured as mean plasma level value variations
may vary based upon intrinsic intersubject variation or
variability.
[0448] In another specific embodiment, such a pharmaceutical
composition or controlled-release formulation of the present
invention following oral dosage would be depicted by a unique
substantially biphasic pharmacokinetic/pharmacodynamic plasma
profile, which exhibits a first T.sub.max pulse and a plasma
concentration peak level within 2-4 hours of ingestion and a second
T.sub.max pulse and a plasma concentration peak level within, 5-8
hours after ingestion.
[0449] In a specific embodiment, the aforementioned oral dosage or
administration associated with a pharmaceutical composition or
controlled-release formulation of the present invention, preferably
occurs at night.
[0450] It is important that release from the first "pulse" or
T.sub.max occurs gradually, so that subsequent absorption is
gradual, thereby avoiding a rapid fall in blood pressure. This
would minimize the risk of orthostatic hypotension-related adverse
events.
[0451] Such a profile can be obtained by formulating a drug
suitable for use in the present invention with differential
release, capitalizing on a combination of approaches to operate
sequentially. It may be, for instance that a capsule may be
formulated into pellets, capsules or microparticles which may be,
but are not limited to coatings with different release-modifying
components, such pellets being contained in capsule dosage forms
such that release characteristics are affected or influenced by
factors such as gastrointestinal pH, or time, to provide
differentiated absorption profiles.
EMBODIMENTS
[0452] In light of the foregoing discussion, the present invention
relates to and is exemplified by, but not limited to the following
embodiments present below, which include corresponding
pharmaceutical compositions, different controlled release
formulations, respectively comprised or formed from the following
components, such as carvedilol free base, carvedilol salts,
anhydrous forms or solvates thereof, and which also may include,
but are not limited to the various components (i.e., such as
conventionally known, adjuvants, carriers, diluents, excipients,
agents, plasticizers, polymers, etc. as described herein) which may
be in or formed into different dosage forms (i.e., which may
include, but are not limited to, tablets, capsules and the like) as
described herein.
[0453] In a general or first embodiment, the present invention
relates to a controlled release formulation, which comprises:
[0454] a solubility enhanced carvedilol free base or a carvedilol
salt, solvate or anhydrous forms thereof;
[0455] where the controlled release formulation following oral
dosage exhibits a substantially biphasic plasma profile with a
first plasma concentration peak level and a first T.sub.max pulse
within 1-4 hours of ingestion and a second plasma concentration
peak level and a second T.sub.max pulse within 5-10 hours after
ingestion. In an embodiment of the present invention a first
T.sub.max pulse may occur within 2-4 hours of ingestion and the
second T.sub.max pulse may occur within 5-8 hours after
ingestion.
[0456] In accordance with the present invention and the
aforementioned general or other embodiments, a specific embodiment
relates to a formulation in an oral dosage form. Such an oral
dosage form may be in a capsule dosage form. A capsule dosage form
of the present invention may be comprised of, but not limited to a
mixture of two or more populations of coated pellets of different
sizes with different associated immediate or controlled release
characteristics.
[0457] In another or second embodiment, the present invention also
relates to a controlled release formulation, comprising at least
one of the following components:
[0458] [a]carvedilol free base; and [b] a solubility enhanced
carvedilol salt, solvate or anhydrous forms; or
[0459] [a]carvedilol free base; or [b] a solubility enhanced
carvedilol salt, solvate or anhydrous forms;
[0460] where the controlled release formulation following oral
dosage exhibits a substantially biphasic plasma profile which
exhibits a first plasma concentration peak level and a first
T.sub.max pulse within 1-4 hours of ingestion and a second plasma
concentration peak level and a second T.sub.max pulse within 5-8
hours after ingestion.
[0461] In yet another or third embodiment, the present invention
also relates to a controlled release formulation, comprising at
least one of these components:
[0462] [a]carvedilol free base; and [b] a solubility enhanced
carvedilol salt, solvate or anhydrous forms; or
[0463] [a]carvedilol free base; or [b] a solubility enhanced
carvedilol salt, solvate or anhydrous forms;
[0464] where the controlled release formulation is a capsule dosage
form is comprised of a pellet or microparticle mixture of immediate
release coated pellets or microparticles or controlled release
coated pellets or microparticles of differing sizes; and
[0465] where the controlled release formulation following oral
dosage at night exhibits a substantially biphasic plasma peak
concentration profile which exhibits a first pharmacokinetic plasma
concentration peak level and a first T.sub.max pulse within 1-4
hours of ingestion and a second plasma concentration peak level and
a second T.sub.max pulse within 5-8 hours after ingestion.
[0466] In accordance with the present invention and the
aforementioned third or other embodiments, a capsule dosage form of
the present invention, may be, but is not limited to being a soft
gelatin capsule or hard gelatin capsule. Such a pellet or
microparticle mixture may consist of two or more different pellet
or microparticle population types characterized by different pellet
sizes and/or different immediate-release and/or modified-release
characteristics. Moreover, different pellet or microparticle sizes
and/or different immediate-release and/or modified-release
characteristics are achieved by layering of active principle(s) and
pharmaceutically acceptable components. The coated
immediate-release pellets or microparticles, or modified-release
pellets or microparticles, respectively, may be, but not limited to
being coated with a polymer. The coated pellets consist of two or
more different population types, with one population defined as
immediate release pellets or microparticles and another population
defined as modified release pellets or microparticles. More
particularly, the capsule dosage form may be filled with differing
ratios of immediate release pellets or microparticles and modified
release pellets or microparticles blended together to a form a
pharmaceutically acceptable amount or dosage. The capsule dosage
form also may be filled with differing ratios of immediate release
pellets or microparticles and modified release pellets or
microparticles. In particular, immediate release pellets or
microparticles and modified release pellets or microparticles may
be in a ratio range from about 30% to about 70%, preferably the
immediate release pellets and modified release pellets are in a
ratio from about 40% to about 60%.
[0467] In yet another or fourth embodiment, the present invention
also relates to a controlled release formulation, which
comprises:
[0468] a solubility enhanced carvedilol free base or a carvedilol
salt, solvate or anhydrous forms;
[0469] where the controlled release formulation is a capsule dosage
form is comprised of a mixture of two or more populations of coated
pellets or microparticles of differing sizes with differing release
characteristics; and
[0470] where the controlled release formulation following oral
dosage exhibits a substantially biphasic plasma peak concentration
profile which exhibits a first pharmacokinetic plasma concentration
peak level and first T.sub.max pulse within 1-4 hours of ingestion
and a second plasma concentration peak level and a second T.sub.max
pulse within 5-8 hours after ingestion.
[0471] In yet another or fifth embodiment, the present invention
also relates to a controlled release formulation or a
pharmaceutical form, which comprises:
[0472] several microcapsules for the modified or controlled release
of carvedilol free base or a carvedilol salt, anhydrous or solvate
form thereof,
[0473] wherein at least one part of the microparticles are
individually composed of a microparticle comprised of or loaded
with the carvedilol free base or the carvedilol salt, anhydrous or
solvate form thereof; or such microparticles are loaded with low or
a poorly soluble carvedilol free base or a carvedilol salt,
anhydrous or solvate form thereof; and
[0474] coated by at least one coating layer ensuring the controlled
or modified release of the carvedilol free base or a carvedilol
salt, anhydrous or solvate form thereof,
[0475] where these microcapsules are characterized by:
[0476] (a) carvedilol free base or a carvedilol salt, anhydrous or
solvate form thereof release governed by two different triggering
mechanisms, one being based on a variation in pH and the other
allowing the release of the carvedilol free base or a carvedilol
salt, anhydrous or solvate form thereof after a predetermined
residence time in the stomach,
[0477] (b) the dissolution behavior in vitro (determined as
indicated in the European Pharmacopeia, 4th edition, under the
title: "Dissolution test for solid oral forms": type II dissolutest
performed under SINK conditions, maintained at 37.degree. C. and
agitated at 100 rpm) such that:
[0478] at a constant pH of 1.4, the dissolution profile includes a
latency phase with a duration less than or equal to 7 hours,
preferably less than or equal to 5 hours and more preferably
between 1 and 5 hours; and
[0479] the change from about a pH of 1.4 to about a pH of 6.8,
during the latency phase, results in a release phase that starts
without a latency period; and
[0480] (c) at least one part of these microcapsules contains at
least one swelling agent.
[0481] In yet another or sixth embodiment, the present invention
also relates to a controlled release formulation, comprising at
least one of these components:
[0482] [a]carvedilol free base; and [b] a solubility enhanced
carvedilol salt, solvate or anhydrous forms; or [a]carvedilol free
base; or [b] a solubility enhanced carvedilol salt, solvate or
anhydrous forms;
[0483] where the controlled release formulation is a capsule dosage
form is comprised of a mixture of two or more populations of coated
pellets or microparticles of differing sizes and differing release
characteristics; and
[0484] where the controlled release formulation following oral
dosage at night exhibits a substantially biphasic plasma peak
concentration profile which exhibits a first pharmacokinetic plasma
concentration peak level and a first T.sub.max pulse within 1-4
hours of ingestion and a second plasma concentration peak level and
a second T.sub.max pulse within 5-8 hours after ingestion.
[0485] In accordance with the present invention, and which may be
relevant to the aforementioned fourth, fifth, sixth or other
embodiments, each of the two or more populations of the mixture
coated pellets or microparticles are characterized by different
release-modifying components or characteristics based upon
gastrointestinal environment, pH, or time. The mixture of two or
more populations of coated pellets or microparticles is comprised
of a first set of controlled release pellets or microparticles and
a second set of controlled release pellets or microparticles,
wherein the first set of controlled release pellets or
microparticles provides earlier release of its chemical and
physical properties than the second set of controlled release
pellets. In particular, such a first set of controlled release
pellets or microparticles may be, but is not limited to being
coated with a pH sensitive polymer that delays active component
release by pH or hydration effects. The second set of controlled
release pellets or microparticles, may be, but is not limited to,
being coated with a pH sensitive polymer that dissolves at a higher
pH than the polymer which coats the first set of release pellets or
microparticles.
[0486] In yet another or seventh embodiment, the present invention
relates to a microparticle composition or formulation, which
comprises:
[0487] a mixture of:
[0488] [a] rapidly-releasing microparticles containing carvedilol
free base, or a carvedilol salt, solvate, or anhydrous form
thereof; and
[0489] [b] at least two types of controlled-release microparticles
containing carvedilol free base or a carvedilol salt, solvate, or
anhydrous form thereof;
[0490] where the rapidly releasing microparticles contain a first
dosage amount of the carvedilol free base or a first dosage amount
of the carvedilolsalt, solvate, or anhydrous form thereof different
than each of the dosage amounts of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in at
least two different types of delayed or controlled-release
microparticles; and
[0491] where rapid release of the first dosage amount of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in the rapidly releasing microparticles is
followed by a serial or sequential time-triggered and pH-triggered
release of each of the different dosage amounts of the carvedilol
free base or the carvedilol salt, solvate, or anhydrous form
thereof contained in each of the at least two different types of
controlled release microparticles.
[0492] In accordance with the present invention and seventh or
other embodiments, the serial or sequential pH triggered release of
each of the different dosage amounts of the carvedilol free base or
the carvedilol salt, solvate, or anhydrous form thereof contained
in each of the at least two different types of controlled release
microparticles occurs at a pH of about 5.5 to a pH of about a
pH>6.4. In such an embodiment, a first maximum plasma drug level
following rapid release of the first dosage amount of the
carvedilol free base, or the carvedilol salt, solvate, or anhydrous
form thereof contained in the rapidly releasing microparticles
occur at a time between about 1 hour to about 3 hour following
dosage of the microparticle composition or formulation; and a
second maximum plasma drug level following the serial or sequential
time-triggered release of each of the different dosage amounts of
the carvedilol free base or the carvedilol salt, solvate, or
anhydrous form thereof contained in each of the at least two
different types of controlled release microparticles occur at a
time between about 5 hours to about 10 hours following dosage of
the microparticle composition or formulation.
[0493] Also in accordance with a microparticle composition or
formulation of the present invention, each of the first and second
maximum plasma levels in such an embodiment following the time and
pH triggered release of each of the different dosage amounts of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof contained in the rapidly releasing microparticles and
each of the at least two different types of controlled release
microparticles results in a controlled release of the total dosage
amount of the carvedilol free base or the carvedilol salt, solvate,
or anhydrous form thereof contained in the microparticle
composition or formulation.
[0494] In addition, the first maximum plasma levels following the
time and pH triggered release of each of the different dosage
amounts of the the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof contained in the rapidly
releasing microparticles results in about 10% to about 15%, such as
12.5% of the total dosage amount of carvedilolfree base or
carvedilol salt, solvate, or anhydrous form thereof contained in
the microparticle composition or formulation.
[0495] In addition, the second maximum plasma levels following the
time and pH triggered release of each of the different dosage
amounts of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof contained in each of the at
least two different types of controlled release microparticles
results in a controlled release of between about 85% to about 90%,
such as 87.5% the total dosage amount of the carvedilol salt,
solvate, or anhydrous form thereof contained in the microparticle
composition or formulation he microparticle composition or
formulation of claim 1, where a controlled release of the total
dosage amount of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof contained in the microparticle
composition or formulation occurs in a gastrointestinal tract
system.
[0496] In yet another or eighth embodiment, a microparticle
formulation for once-a-day therapy of the present invention relates
to a mixture of:
[0497] [a] rapidly releasing microparticles containing carvedilol
free base or a carvedilol salt, solvate, or anhydrous form thereof;
and
[0498] [b] at least two types of controlled-release microparticles
containing carvedilol free base or a carvedilol salt, solvate, or
anhydrous form thereof;
[0499] where the rapidly releasing microparticles contain a first
dosage amount of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof different from each dosage
amount contained in each of the at least two different types of
delayed or controlled-release microparticles;
[0500] where the rapidly releasing microparticles exhibit rapid
release of the first dosage amount of the carvedilol free base or
the carvedilol salt, solvate, or anhydrous form thereof and the at
least two different types of controlled release microparticles
exhibit a pH-dependent and time-dependent triggered serial or
sequential sustained prolonged release or controlled release for
each of the dosage amounts of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form thereof contained in
the at least two different types of controlled release
microparticles.
[0501] In yet another or ninth embodiment a microparticle
composition or formulation of the present invention relates to
a:
[0502] [a] a rapidly releasing microparticle type containing
carvedilol free base or a carvedilol salt, solvate, or anhydrous
form thereof;
[0503] where each rapidly releasing microparticle type is comprised
of a rapidly releasing microparticle core unit formed from a
mixture of the carvedilol free base or the carvedilol, salt,
solvate, or anhydrous form thereof in combination with one or more
nitrogen-containing pharmaceutical polymers and a plasticizer and
optionally other pharmaceutically acceptable excipients; and
[0504] [b] at least two different controlled-release microparticle
types each containing carvedilol free base or a carvedilol salt,
solvate, or anhydrous form thereof;
[0505] where each of the at least two different controlled-release
microparticles is comprised of a drug-containing microparticle core
unit as defined in [a]above and is further coated with a controlled
release layer(s) formed from a film-forming polymer, a plasticizing
agent and optionally other pharmaceutically acceptable
excipients;
[0506] where each of the rapidly releasing microparticle type
contains carvedilol free or a carvedilol salt, solvate, or
anhydrous dosage amount different from the carvedilol free base or
the carvedilol salt, solvate, or anhydrous dosage amounts contained
in each of the at least two different controlled release
microparticle types;
[0507] where each of the rapidly releasing and at least two
different controlled release microparticles are mixed together with
materials selected from the group consisting of a surface active, a
lubricating agent, an anti-agglomerating agent or other
pharmaceutically acceptable excipients.
[0508] In accordance with the present invention, the ninth or other
embodiments, a controlled release formulation, composition or
dosage form of the present invention may include, but is not
limited to containing a swelling agent as defined herein or other
pharmaceutically acceptable adjuvants, carriers or excipients. In
particular, such a suitable swelling agent, which may be selected
from, but not limited to crosslinked polyvinylpyrrolidones (i.e.,
which may be selected from, but not limited to polyplasdone or
crospovidone); or crosslinked carboxyalkylcelluloses (i.e., which
may be selected from, but not limited to crosslinked
carboxymethylcellulose or crosslinked sodium croscarmellose). In
one embodiment of the present invention, a nitrogen-containing
polymer in each first controlled release microparticle granule and
second controlled release microparticle granule is a swelling agent
as defined herein. In further embodiments of the present invention,
such nitrogen containing polymers may be selected from, but not
limited to polyvinyl pyrrolidone (also conventionally known as
povidone or PVP), or cross-linked polyvinyl pyrrolidone (also
conventionally known as cross-linked povidone). A nitrogen
containing polymer in each first controlled release microparticle
granule and in each second controlled release microparticle granule
of the present invention, also may be, but is not limited to being
a combination of polyvinyl pyrrolidone (povidone or PVP), or
cross-linked polyvinyl pyrrolidone (cross-linked povidone).
[0509] In yet another or tenth embodiment, a microparticle
composition or formulation of the present invention relates to:
[0510] a mixture of rapidly releasing or controlled-release
microparticles containing carvedilol free base or a carvedilol
salt, solvate or anhydrous form thereof;
[0511] where each rapidly releasing microparticle has a core unit
formed by applying a mixture of the carvedilol free base or the
carvedilol salt, solvate, or anhydrous form and materials selected
from at least one nitrogen containing polymer, a plasticizer or
pharmaceutically acceptable excipients onto a cellulose
microparticle or similar pharmaceutically acceptable material.
[0512] where core each of the rapidly releasing or
controlled-release microparticles further are layered or coated
with an additional controlled release layer formed from
pharmaceutically acceptable excipients.
[0513] In accordance with the present invention and ninth or other
embodiments, a microparticle composition or formulation may
include, but is not limited to a controlled release layer formed
from a mixture of the pharmaceutically acceptable excipients
selected from a film former, a plasticiser or other
pharmaceutically acceptable excipients.
[0514] In yet another or eleventh embodiment, the present invention
relates to a controlled-release microparticle formulation, which
comprises a microparticle ratio mixture formed from:
[0515] [1] a first rapidly releasing microparticle population,
[0516] [2] a first controlled release microparticle population;
and
[0517] [3] a second controlled release microparticle
population;
[0518] where each first rapidly releasing microparticle population
is formed from a rapid releasing microparticle comprised of a
combination of carvedilol free base or a carvedilol salt, solvate,
or anhydrous form thereof, one or more nitrogen-containing
polymers, a plasticizer and, other pharmaceutically acceptable
excipients;
[0519] where each first controlled release microparticle population
and each second controlled release microparticle population is
comprised of a controlled-release microparticle unit comprised of
an active drug loaded core comprised of a combination of carvedilol
free base or a carvedilol salt, solvate, or anhydrous form thereof,
one or more nitrogen-containing polymers, a plasticizer or
pharmaceutically acceptable excipients;
[0520] where the active drug loaded core of each first controlled
release microcapsule and each second controlled release
microcapsule is layered with a controlled release layer of film
forming polymer(s), or mixtures of film forming polymers thereof, a
and a plasticizer agent or pharmaceutically acceptable
excipients;
[0521] where each first rapidly releasing microparticle unit, first
controlled release microparticle unit and second controlled release
microparticle unit each contain a different dosage amount of the
carvedilol salt, solvate, or anhydrous form thereof.
[0522] In accordance with the present invention, a
controlled-release microparticle formulation may have, but is not
limited to a first rapidly releasing microparticle population
contains at least 5% and no more than 20% of the total dosage of
the carvedilol free base or the carvedilol salt, solvate or
anhydrous form thereof. Further, the first rapidly releasing
microparticle population may contain, but is not limited to at
least 10% and no more than 15% of the total dosage of the
carvedilol free base or the carvedilol salt, solvate or anhydrous
form thereof. The first controlled-release microparticle population
also may contain, but is not limited to at least 25% and no more
than 50% of the total dosage of the carvedilol salt, solvate, or
anhydrous form thereof. The controlled-release microparticle
formulation also may have, but is not limited to a second
controlled-release microparticle population, which contains at
least 40% and no more than 60% of the total dosage of the
carvedilol salt, solvate, or anhydrous form thereof.
[0523] In yet another or twelfth embodiment, the present invention
relates to a controlled-release microparticle composition or
formulation, which comprises:
[0524] a tri-component controlled-release microparticle composition
or formulation product formed from:
[0525] [1] a first rapidly releasing microparticle population
comprised of rapidly releasing microparticles rapidly
releasing;
[0526] where each rapidly releasing microparticle contains a layer
comprised of carvedilol free base or a carvedilol, salt, solvate,
or anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or a cellulose core; and
[0527] [2] a first controlled release microparticle population
comprised of first controlled release microparticless;
[0528] where each first controlled release microparticle contains a
layer comprised of carvedilol free base or a carvedilol salt,
solvate, or anhydrous form thereof, at least one nitrogen
containing polymer and a plasticizer or other pharmaceutically
acceptable excipients applied to a cellulose sphere or a cellulose
core;
[0529] where each first controlled release microparticle is coated
with at least one release controlling coating layer(s) formed from
a film forming polymer and a plasticizing agent or other
pharmaceutically acceptable materials to form each first controlled
release microparticle; and
[0530] where each first controlled release granule triggers a
release of the carvedilol free base, or the carvedilol salt,
solvate, or anhydrous form thereof at a pH of about 5.5;
[0531] [3] a second controlled release microparticle population
comprised of second controlled release microparticle granules;
[0532] where each second controlled release microparticle contains
a layer comprised of carvedilol free base or a carvedilol salt,
solvate, or anhydrous form thereof, at least one nitrogen
containing polymer and a plasticizer and pharmaceutically
acceptable excipients applied to a cellulose sphere or a cellulose
core;
[0533] where each second controlled release microparticle is coated
with at least one release controlling coating layer(s) formed from
a film forming polymer, or mixtures thereof and a plasticizing
agent to form each second controlled release microparticle; and
[0534] where each second controlled release granule triggers a
release of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof at a pH of about pH>6.4;
and
[0535] where each rapidly releasing population, first controlled
release population and second controlled release population further
are admixed with pharmaceutically acceptable adjuvants, carriers or
excipients to form the tri-component controlled-release
microparticle-containing dosage form.
[0536] In yet another or thirteenth embodiment of the present
invention, a controlled-release microparticle composition or
formulation, comprises:
[0537] a tri-component controlled-release microparticle
composition, formulation or dosage product formed from:
[0538] [1] a first rapidly releasing microparticle population
comprised of microparticle rapidly releasing granules;
[0539] where each rapidly releasing microcapsule population is
comprised of microparticle rapidly releasing granules each of which
contain a layer comprised of a carvedilol free base, salt, solvate,
or anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or core or other pharmaceutically
acceptable core; and
[0540] [2] a first controlled release microparticle population
comprised of first controlled release microparticle granules;
[0541] where each first controlled release population is comprised
of first controlled release microparticle granules each of which
contain a layer comprised of carvedilol free base, salt, solvate,
or anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or core or other pharmaceutically
acceptable core;
[0542] where each first controlled release microparticle is coated
with at least one release controlling coating layer(s) formed from
a film forming polymer and a plasticizing agent to form each first
controlled release microparticle; and
[0543] where each first controlled release granule triggers a
release of the carvedilol free salt, solvate, or anhydrous form
thereof at a pH of about 5.5.
[0544] [3] a second controlled release microparticle population
comprised of second controlled release microparticle granules;
[0545] where each second controlled release population is comprised
of second controlled release microparticle granules each of which
contain a layer comprised of a carvedilol free base, salt, solvate,
or anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or pharmaceutically acceptable excipients applied
to a cellulose sphere or core or pharmaceutically acceptable
core;
[0546] where each second controlled release microparticle is coated
with at least one release controlling coating layer(s) formed from
a film forming polymer and a plasticizing agent to form each second
controlled release microparticle; and
[0547] where each second controlled release granule triggers a
release of the carvedilol free base, salt, solvate, or anhydrous
form thereof at a pH of about pH>6.4; and
[0548] where each rapidly releasing population, first controlled
release population and second controlled release population are
admixed with pharmaceutically acceptable adjuvants, carriers or
excipients to form the tri-component controlled-release
microparticle composition or formulation product.
[0549] In yet another or fourteenth embodiment, the present
invention relates to a controlled-release microparticle
composition, formulation or dosage form, which comprises:
[0550] a tri-component controlled-release microparticle composition
or formulation product formed from:
[0551] [1] a first rapidly releasing microparticle population
comprised of microparticle rapidly releasing granules;
[0552] where each microparticle rapidly releasing granule contains
a layer comprised of a carvedilol phosphate salt, solvate, or
anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or pharmaceutically acceptable core;
and
[0553] [2] a first controlled release microparticle population
comprised of first controlled release microparticle granules;
[0554] where each first controlled release microparticle granule
contains a layer comprised of a carvedilol phosphate salt, solvate,
or anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or pharmaceutically acceptable
core;
[0555] where each first controlled release microparticle is coated
with at least one release controlling coating layer(s) formed from
a film forming polymer and a plasticizing agent to form each first
controlled release microparticle; and
[0556] where each first controlled release granule triggers a
release of the carvedilol phosphate, salt, solvate, or anhydrous
form thereof at a pH of about 5.5;
[0557] [3] a second controlled release microparticle population
comprised of second controlled release microparticle granules;
[0558] where each second controlled release microparticle granule
contains a layer comprised of a carvedilol phosphate salt, solvate,
or anhydrous form thereof, at least one nitrogen containing polymer
and a plasticizer or other pharmaceutically acceptable excipients
applied to a cellulose sphere or pharmaceutically acceptable
core;
[0559] where each second controlled release microparticle is coated
with at least one release controlling coating layer(s) formed from
a film forming polymer and a plasticizing agent to form each second
controlled release microparticle; and
[0560] where each second controlled release granule triggers a
release of the carvedilol phosphate salt, solvate, or anhydrous
form thereof at a pH of about pH>6.4; and
[0561] where each rapidly releasing population, first controlled
release population and second controlled release population are
admixed with pharmaceutically acceptable adjuvants, carriers or
excipients to form the tri-component controlled-release
microparticle composition, formulation or dosage form.
[0562] In accordance with the present invention and which may be
relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle formulation of the present invention may be, but is
not limited to microparticles having a particle size of between 50
and 1000 .mu.m, preferably of between 100 .mu.m and 750 .mu.m and,
even more preferably, of between 150 .mu.m and 500 .mu.m.
[0563] Also in accordance with the present invention and which may
be relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation of the present invention
may also include, but not be limited to:
[0564] where each microparticle rapidly releasing granule with a
mean microparticle diameter size in a range from about 150 .mu.m to
500 .mu.m, such as 150 .mu.m to 300 .mu.m;
[0565] where each first controlled release microparticle granule
with a mean microparticle diameter size in a range from about 200
.mu.m to about 500 .mu.m;
[0566] where each second controlled release microparticle granule
may with a mean microparticle diameter size in a range from about
150 .mu.m to about 400 .mu.m, which may include mean microparticle
diameter ranges from about 250 .mu.m to about 360 .mu.m or from
about 270 .mu.m to about 360 .mu.m.
[0567] In accordance with the present invention and which may be
relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation may also include, but is
not limited to:
[0568] where each microparticle rapidly releasing granule contains
a carvedilol salt, solvate, or anhydrous form thereof contained in
a dosage amount of 1.25 mg to 10 mg;
[0569] where each first controlled release microparticle granule
containing a carvedilol salt, solvate, or anhydrous form thereof
contained in a dosage amount of about 10 mg to about 80 mg, such as
for example where, such a dosage amount may range from about 3.75
mg to about 30 mg; or where each second controlled release
microparticle granules contains a carvedilol salt, solvate, and/or
anhydrous form thereof in a dosage amount range of about 5 mg to
about 40 mg.
[0570] Also in accordance with the present invention and which may
be relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation of the present invention
may include, but is not limited to a total dosage amount of the
carvedilol free base or the carvedilol salt, solvate, or anhydrous
form thereof dosage amount contained in a sum of each first rapidly
releasing microparticle granule, a first controlled release
microparticle granule and a second controlled release microparticle
granule is the sum of the total dosage amount between about 10 mg
to about 80 mg.
[0571] In accordance with the present invention and which may be
relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation of the present invention
also may contain, but is not limited to at least one release
controlling layer formed from at least one polymethylmethacrylate
polymer(s) and a plasticizing agent, which may be, but is not
limited to a ratio from about 60% (w/w) to about 40% (w/w).
[0572] In accordance with the present invention and which may be
relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation may include, but is not
limited to containing a film forming polymer in at least one
release controlling coating layer(s) of each first controlled
release microparticle, which may be, but is not limited to a
polymethylmethacrylate polymer selected from Eudragit L, Eudragit
RL, Eudragit RS and other Eudragit NE polymers (i.e., such as
commercially available polymers as supplied by the Rohm Pharma
group), Acrycoat S100, Acrycoat L 100D and the like.
[0573] In accordance with the present invention and which may be
relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation of the present invention,
may contain, but is not limited to containing a plasticizing agent
in at least one release controlling coating layer(s) of each first
controlled release microparticle, where such a plasticizing agent
is selected, but is not limited to a hydrogenated vegetable oil,
propan 2-ol or propylene glycol, diethyl phthalate or other
pharmaceutically acceptable materials. Suitable plasticizers may
include, but are not limited to hyrogenated vegetable oil,
hydrogenated cottonseed oil, hydrogenated castor oil and the
like.
[0574] In accordance with the present invention and which may be
relevant, but not limited to the tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments, a controlled-release
microparticle composition or formulation may contain, but is not
limited to a different carvedilol free base salt, solvate or
anhydrous form thereof dosage amounts contained in each rapidly
releasing population, first controlled release population and
second controlled release population are in a 1:3:4 active drug
content ratio. A controlled-release microparticle composition or
formulation of the present invention, may also exhibit, but is not
limited to a where a serial or sequential release of each of the
different dosage amounts of the carvedilol free base or the
carvedilol salt, solvate or anhydrous form thereof contained in
each immediate-release population, first controlled release
population and second controlled release population.
[0575] In yet another or fifteenth embodiment, the present
invention relates to a modified-release microparticle formulation,
which comprises:
[0576] a microparticle mixture ratio formed from:
[0577] a rapidly releasing microparticle population, a first
delayed release microparticle population and a second delayed
release microparticle population;
[0578] wherein each microparticle population contains a different
microparticle type with a different dosage amount of carvedilol
free base, or a carvedilol salt, solvate, or anhydrous form
thereof;
[0579] wherein a rapid release or a controlled release of the
different dosages contained in each of the microparticle
populations achieves total plasma levels or total time
concentrations (Area Under Curve) at C24 hours comparable to a
conventional rapidly or immediately releasing carvedilol free base
composition dosed twice daily at 12 hour intervals;
[0580] wherein each of microparticle populations exhibits a
different release profile where a first peak plasma concentration
level and a first Tmax pulse is reached between about 1 hour to
about 3 hours and a second peak plasma concentration level and a
second Tmax pulse is reached between about 5 hours to about 10
hours after dosing the controlled-release microparticle
formulation.
[0581] In yet another or sixteenth embodiment, the present
invention relates to a modified-release microparticle formulation,
which comprises:
[0582] a mixture of:
[0583] [a]rapidly releasing microparticles containing a carvedilol
free base or a carvedilol salt, solvate, or anhydrous form thereof;
and
[0584] [b] at least two types of controlled-release microparticles
containing carvedilol free base or a carvedilol salt, solvate, or
anhydrous form thereof;
[0585] where the rapidly releasing microparticles contain a first
dosage amount of the carvedilol free base or the carvedilol salt,
solvate, or anhydrous form thereof different than each of the
dosage amounts contained in at least two different types of delayed
or controlled-release microparticles; and
[0586] where the rapidly releasing microparticles exhibit different
serial or sequential release for the first dosage amount of
carvedilol free base or carvedilol salt, solvate, or anhydrous form
thereof than the dosage amounts contained in the at least two
different types of controlled release microparticles.
[0587] In accordance with the present invention, each different
serial or sequential release of the rapidly releasing
microparticles and at least two types of controlled release
microparticles are defined by a mean plasma level representing a
total carvedilol dosage amount as shown by a substantially biphasic
profile; where the total carvedilol dosage amount is the sum of the
first and second dosage amounts; where the rapidly releasing
microparticles comprising release the carvedilol free base or the
carvedilol salt, solvate or anhydrous form thereof to provide a
peak plasma level at between 1 to 3 hours after dosing and each of
the at least two types of delayed-controlled release microparticles
release the carvedilol salt, solvate or anhydrous form thereof to
provide a second peak plasma level between 5 to 10 hours after
dosing.
[0588] Further, the serial or sequential release of the total
carvedilol dosage amount from the rapidly releasing microparticles
and at least two types of controlled release microparticles provide
prolonged plasma levels as characterized by a substantially
biphasic profile and residual drug plasma levels 24 hours after
dosing comparable to a conventional carvedilol free base dosage
dosed twice daily at 12 hour intervals for a total 24 hour
period;
[0589] where the serial or sequential release of the rapidly
releasing microparticles and at least two types of controlled
release microparticles provide plasma levels of drug characterised
by a substantially biphasic profile, with the rapidly releasing
microparticles contributing a first peak plasma level of drug
between 1 to 3 hours after dosing and the delayed-controlled
release microparticles contributing a second peak plasma level of
drug between 5 to 10 hours after dosing.
[0590] In yet another or seventeenth embodiment, the present
invention relates to a controlled-release microparticle formulation
for once-a-day administration, which comprises:
[0591] a microparticle mixture ratio formed from an rapidly
releasing microparticle population, a first delayed release
microparticle population; and a second delayed release
microparticle population;
[0592] where each of the microparticles in each population contain
carvedilol free base, salt, solvate, or anhydrous form thereof in a
different dosage amount adapted to provide controlled release of
the different dosages contained in each microparticle populations
to achieve comparable total plasma or total time concentrations
(Area Under Curve) and plasma levels at C24 hours comparable to a
conventional(rapidly releasing) carvedilol composition dosed twice
daily at 12 hour intervals.;
[0593] where each of the first, second, and third dosage form has a
different release profile, said microparticle product reaching a
first Plasma peak concentration level between 1 to 3 hours after
dosing the controlled-release microparticle formulation and a
second C max between 5 to 10 hours after dosing the
controlled-release microparticle formulation.
[0594] In accordance with the present invention, each release
profile is a substantially biphasic profile shown by:first release
microparticles exhibiting a release rate of the carvedilol free
base or carvedilol salt, solvate, or anhydrous form providing a
first plasma peak concentration level between 1 to 3 hours after
dosing the microparticle composition or formulation; each of the at
least two types of controlled release microparticles exhibiting a
release rate of the carvedilol salt, solvate, or anhydrous form
providing a second Plasma peak concentration level between 5 to 10
hours after dosing the microparticle composition or formulation
exhibiting a combined higher plasma peak concentration level peak
level than for the first release microparticles;
[0595] where the first peak plasma concentration level and the
second Plasma peak concentration level are in a ratio of about
0.5:1.0;
[0596] where the peak plasma concentration levels contributed by
either the first release microparticles or each of the two types of
delayed controlled release microparticles are substantially
comparable to peak plasma concentration level levels for an rapidly
releasing carvedilol free base composition dosed twice daily at 12
hour intervals.
[0597] In accordance with the present invention, a substantially
biphasic profile is shown by: an immediate-release microparticles
exhibiting a release rate of the carvedilol free base, salt,
solvate, or anhydrous form that provide a first peak plasma
concentration between 1 to 3 hours after dosing the microparticle
composition or formulation; and each of the at least two types of
delayed-controlled release microparticles exhibiting a release rate
of the carvedilol free base, salt, solvate, or anhydrous form that
provide a second peak plasma concentration between 5 to 10 hours
after dosing the microparticle composition or formulation.
[0598] In yet another or eighteenth embodiment, the present
invention relates to a controlled release microparticle dosage
product, which comprises:
[0599] a first immediate-release dosage form;
[0600] a second delayed release dosage form; and
[0601] a third delayed release dosage form,
[0602] where each of said first, second and third dosage forms
comprise a carvedilol free base, salt, solvate or anhydrous form
thereof and a pharmaceutically acceptable carrier(s), said three
dosage forms having different release profiles, said microparticle
dosage product reaching a first peak plasma concentration level
from about one to about three hours and a second peak plasma
concentration level from about five hours to about ten hours.
[0603] In accordance with the present invention, each rapidly
releasing dosage form contains at least 10% and no more than 15% of
the total dosage of carvedilol free base, salt, solvate or
anhydrous form thereof; each second delayed release dosage form
contains at least 30% and no more than 50% of the total dosage of
carvedilol free base, salt, solvate or anhydrous form thereof; and
each third delayed release dosage form contains at least 40% and no
more than 60% of the total dosage of carvedilol free base, salt,
solvate or anhydrous form thereof. In addition, each first
immediate-release dosage form; each second delayed release dosage
form; and each third delayed release dosage form includes a total
dosage of the carvedilol free base, salt, solvate or anhydrous form
thereof that is effective for a twenty four hour period.
[0604] In yet another or ninteenth embodiment, the present
invention relates to a microparticle composition or formulation,
which comprises:
[0605] [a] a rapidly releasing microparticle population containing
carvedilol free base or a carvedilol salt, solvate, or anhydrous
form thereof;
[0606] where each rapidly releasing microparticle population is
comprised of a rapidly releasing microparticle core unit formed
from a mixture of the carvedilol free base or the carvedilol, salt,
solvate, or anhydrous form thereof in combination with one or more
nitrogen-containing pharmaceutical polymers and a plasticizer or
other pharmaceutically acceptable excipients;
[0607] [b] at least two different controlled-release microparticle
populations each containing carvedilol free base or a carvedilol
salt, solvate, or anhydrous form thereof;
[0608] where each of the at least two different controlled-release
microparticle populations is comprised of a microparticle core unit
formed from a mixture of the carvedilol free base or the
carvedilol, salt, solvate, or anhydrous form thereof in combination
with one or more nitrogen-containing pharmaceutical polymers and a
plasticizer or other pharmaceutically acceptable excipients;
and
[0609] where the microparticle core unit is further coated with a
controlled release layer(s) formed from a film-forming polymer, a
plasticizing agent and optionally other pharmaceutically acceptable
excipients that controls aqueous drug medium release and exhibits a
pH-dependent and time-dependent triggered serial or sequential
release for each of the dosage amounts of carvedilol free base or
carvedilol salt, solvate, or anhydrous form thereof contained in
the at least two different types of controlled release
microparticles;
[0610] where each of the rapidly releasing and at least two
different controlled release microparticle populations are mixed
together with additional materials selected from a surface active,
a lubricating agent, an anti-agglomerating agent or other
pharmaceutically acceptable excipients;
[0611] where each of the rapidly releasing microparticle core units
contain a different dosage amount of carvedilol free base or a
carvedilol salt, solvate, or anhydrous form thereof than the dosage
amounts of carvedilol free base or carvedilol salt, solvate, or
anhydrous dosage amounts contained in each of the at least two
different controlled release microparticle units;
[0612] where each of the controlled release microparticle
populations has a different release profile with a first peak
plasma concentration level between about 1 to about 3 hours and a
second peak plasma concentration level between about 5 to about 10
hours after dosing the controlled-release microparticle formulation
to achieve total plasma levels or total time concentrations (Area
Under Curve) at C24 hours comparable to a conventional rapidly or
immediately releasing carvedilol free base composition dosed twice
daily at 12 hour intervals.
[0613] Methods of Treatment and Combination Therapies
[0614] The compounds, pharmaceutical compositions, controlled
release formulations or dosage forms prepared according to the
present invention can be used to treat warm-blooded animals, such
as mammals, which include humans.
[0615] The present invention relates to methods of treating
cardiovascular diseases, which may include, but is not limited to
hypertension, congestive heart failure, atherosclerosis, or angina,
which comprises administering to a subject in need thereof an
effective amount of carvedilol free base or a carvedilol salt,
anhydrous forms, or solvate thereof as defined herein, a
pharmaceutical composition, or controlled release formulation as
described herein.
[0616] For example, the present invention further relates to a
method of treating hypertension, congestive heart failure,
atherosclerosis and angina, which comprises administering to a
subject in need thereof an effective amount of a carvedilol
phosphate salt (which may include, but are not limited to novel
crystalline or other solid forms), anhydrous forms, or solvates
thereof, a pharmaceutical composition or controlled release
formulation (i.e., which contains such salts or solvates of
carvedilol phosphate), etc.
[0617] In a specific embodiment, the present invention relates to a
method of treating hypertension, which comprises administering to a
subject in need thereof an effective amount of a carvedilol
phosphate salt (which may include, but are not limited to novel
crystalline or other solid forms), anhydrous forms, or solvates
thereof, a pharmaceutical composition or controlled release
formulation (i.e., which contains such salts or solvates of
carvedilol phosphate), etc.
[0618] In another specific embodiment, the present invention
relates to a method of treating atherosclerosis, which comprises
administering to a subject in need thereof an effective amount of a
carvedilol phosphate salt (which may include, but are not limited
to novel crystalline or other solid forms), anhydrous forms, or
solvates thereof, a pharmaceutical composition or controlled
release formulation (i.e., which contains such salts or solvates of
carvedilol phosphate), etc.
[0619] The present invention also relates to a method of delivering
carvedilol to gastrointestinal tract of a subject in need thereof,
which comprises administering an effective amount of a carvedilol
salt, anhydrous forms, or solvate thereof, which may be in, but not
limited to being in combination with carvedilol free base,
corresponding pharmaceutical compositions or control-release
formulations or dosage forms as described herein.
[0620] In a specific embodiment, the present invention relates to a
method of delivering carvedilol to the gastrointestinal tract,
which comprises administering an effective amount of a carvedilol
salt, anhydrous forms, or solvate thereof, which may be in, but not
limited to being in combination with carvedilol free base,
corresponding pharmaceutical compositions or control-release
formulations or dosage forms as described herein.
[0621] In another embodiment, the present invention relates to a
method of orally dosing a modified release composition, dosage form
or formulation as described herein, which comprises progressive
release of a drug amount of carvedilol free base or a carvedilol
salt, solvate or anhydrous form thereof from each microcapsule of
the modified release composition, dosage form or formulation, which
are absorped as the microparticles transit the GI tract to provide
sustained and controlled release levels of the drug amount for
maintenance of prolonged plasma levels.
[0622] The present invention also relates to a method of dosing a
carvedilol dosage unit, which may include, but is not limited to a
carvedilol free base or a carvedilol salt, solvate or anhydrous
form thereof, to a patient in need thereof, which comprises
administering to a subject in need thereof an effective amount of a
controlled release composition, dosage form or formulation of the
present invention, where release of the carvedilol dosage unit
transits through a lower gastrointestinal tract.
[0623] In accordance with any of the methods of administration of
the present invention, the term a "therapeutically effective
amount", as used herein, generally includes within its meaning a
non-toxic but sufficient amount of the particular drug to which it
is referring to provide the desired therapeutic effect. The exact
amount required will vary from subject to subject depending on
factors such as the patient's general health, the patient's age,
etc.
[0624] Also, the present invention relates to combination therapy
methods for treatment of cardiovascular disorders to a subject in
need thereof, which comprises a compound or controlled release
composition, dosage form or formulation as described herein in a
synergistic combination with other drug agents, which may, but not
limited to a group selected from the group consisting of calcium
channel blockers, beta blockers, diuretics, ACE inhibitors,
Angiotensin II receptor antagonists, statin agents and or the like,
or pharmaceutically acceptable adjuvant(s), carrier(s), diluent(s),
or excipient(s).
[0625] In particular, compounds or controlled release composition,
dosage forms or formulations of the present invention may be
employed alone or in combination with each other or other suitable
therapeutic agents useful in treatment of the aforementioned
cardiovascular disorders, which may include, but are not limited to
hypertension, congestive heart failure, atherosclerosis, angina and
the like.
[0626] Examples of suitable calcium channel blocker agents (both
L-type and T-type) for use in combination with compounds or a
controlled release composition, dosage form or formulation of the
present invention, may include, but are not limited to diltiazem,
verapamil, nifedipine, amlodipine, mybefradil or any other calcium
channel blocker and the like.
[0627] Suitable beta-blockers for use in combination with compounds
or a controlled release composition, dosage form or formulation of
the present invention, may include, but are not limited to
atenolol, metoprolol, and the like.
[0628] Suitable statin agents, such as HMG-COA reductase
inhibitors, for use in combination with compounds or a controlled
release composition, dosage form or formulation of the present
invention, may include, but are not limited to lovastatin,
simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin
or any other suitable statin agent and the like.
[0629] Suitable adrenoreceptor agents for use in combination with
compounds or a controlled release composition, dosage form or
formulation of the present invention, may include, but are not
limited to may include metoprolol (toprol-XL), metoprol succinate,
metoprol tartrate or any other suitable adrenoreceptor agents and
the like, Suitable ACE inhibitors for use in combination with
compounds or a controlled release composition, dosage form or
formulation of the present invention, may include, but are not
limited to alacepril, benazepril, captopril, ceronapril,
cilazepril, cilazopril, delapril, enalapril, enalaprilat,
fosinopril, imidapril, libenzapril, lisinopril, moexipril,
monopril, moveltipril, pentopril, perindopril, quinapril, ramipril,
spirapril, temocapril, teprotide, trandolapril, zofenopril or any
other suitable ACE inhibitor and the like.
[0630] Suitable diuretics for use in combination with compounds or
a controlled release formulation of the present invention, may
include, but are not limited to acetazolamide, flumethiazide,
hydroflumethiazide, bendroflumethiazide, brinzolamide,
dichlorphenamide, dorzolamide, methazolamide, azosemide,
bumetamide, ethacrynic acid, etozolin, frusemide, piretamide,
torasemide, isosorbide, mannitol, amiloride, canrenoate potassium,
canrenone, spironolactone, triamterene, althiazide, bemetizide,
bendrofluazide, benzthiazide, buthiazide, chlorothiazide,
chlorthalidone, clopamide, cyclopenthiazide, cyclothiazide,
epithiazide, hydrochlorothiazide, hydroflumethiazide, indapamide,
mebutizide, mefruside, methylclothiazide, meticrane, metolazone,
polythiazide, quinethazone, teclothiazide, trichlormethiazide,
tripamide, xipamide, furosemide, musolimine, triamtrenene,
amiloride, and spironolactone or other suitable diuretics and the
like.
[0631] Suitable angiotensin II receptor antagonists for use in
combination with compounds or a controlled release formulation of
the present invention, may include, but are not limited to
losartan, irbesartan, valsartan or any other angiotensin II
receptor antagonist and the like.
[0632] Active drug or therapeutic agents or compounds, such as
those described above may be prepared according to processes or
methods taught by either the present disclosure or processes or
methods known to those of skill in the art.
[0633] Active drug or therapeutic agents, when employed in
combination with the compounds, controlled release compositions,
dosage forms or formulations of the present invention, may be used
or administered, for example, in dosage amounts indicated in the
Physicians' Desk Reference (PDR) or as otherwise determined by one
of ordinary skill in the art.
[0634] In the context of this specification, the term
"simultaneously" when referring to simultaneous administration of
the relevant drugs means at exactly the same time, as would be the
case, for example in embodiments where the drugs are combined in a
single preparation. In other embodiments, "simultaneously" can mean
one drug taken a short duration after another, wherein "a short
duration" means a duration which allows the drugs to have their
intended synergistic effect.
[0635] In light of the foregoing, the present invention also
relates to a combination therapy, which may be a comprised of a
simultaneous or co-administration, or serial administration of a
combination of compounds, controlled release compositions, dosage
forms or formulations of the present invention with other active
drug or therapeutic agents, such as described above, and where such
administration also is determined by one of ordinary skill in the
art. As previously indicated active drug compounds, controlled
release compositions, dosage forms or formulations of the present
invention, may include, but are not limited to a carvedilol free
base or a carvedilol salt, solvate or anhydrous form thereof.
[0636] In addition, the present invention also relates to a
combination therapy for the treatment or prevention of
cardiovascular diseases as described herein, which is comprised of
a composition, dosage form or formulation formed from a synergistic
combination or mixture of compounds, controlled release
compositions, dosage forms or formulations of the present invention
and another active drug or therapeutic agent or agents as those
described above and optionally which comprises pharmaceutically
acceptable carrier, diluent or adjuvent. In such an aforementioned
combination composition, dosage form or formulation of the present
invention, each of the active drug components are contained in
therapeutically effective and synergistic dosage amounts.
[0637] In yet another embodiment, the present invention further
relates to a combination therapy for the treatment of
cardiovascular diseases, such as diseases described herein, which
comprises administering a synergistic combination of:
[0638] [1] a therapeutically effective amount of a carvedilol free
base or a carvedilol salt, solvate or anhydrous form thereof;
or
[0639] a corresponding controlled release composition, dosage form
or formulation thereof which comprises a therapeutically effective
amount of a carvedilol free base or a carvedilol salt, solvate or
anhydrous form thereof; and
[0640] [2] a therapeutically effective amount of another active
drug or therapeutic agent selected from the group consisting of at
least one calcium channel blockers, beta blockers, diuretics, ACE
inhibitors, Angiotensin II receptor antagonists, statin agents and
or the like, any other drugs suitable for the treatment of
cardiovascular diseases, or combinations thereof; and
[0641] further comprises pharmaceutically acceptable carriers,
diluents or adjuvants.
[0642] Conventional administration methods as described in examples
and throughout this application above may be suitable for such use
in methods of treatment or delivery methods of various forms of the
present invention, including any combination therapy methods.
[0643] The Examples set forth below are illustrative of the present
invention and are not intended to limit, in any way, the scope of
the present invention.
EXAMPLES
[0644] Carvedilol Salt, Solvate, or Anhydrous forms Examples
[0645] Carvedilol Phosphate Examples
Example 1
Form I Carvedilol Dihydrogen Phosphate Hemihydrate Preparation
[0646] A suitable reactor is charged with acetone. The acetone
solution is sequentially charged with carvedilol and water. Upon
addition of the water, the slurry dissolves quickly. To the
solution is added aqueous H.sub.3PO.sub.4. The reaction mixture is
stirred at room temperature and carvedilol dihydrogen phosphate
seeds are added in one portion. The solid precipitate formed is
stirred, then filtered and the collected cake is washed with
aqueous acetone. The cake is dried under vacuum to a constant
weight. The cake is weighed and stored in a polyethylene
container.
Example 2
Form II Carvedilol Dihydrogen Phosphate Dihydrate Preparation
[0647] Form I is slurried in acetone/water mixture between 10 and
30.degree. C. for several days.
Example 3
Form III Carvedilol Dihydrogen phosphate Methanol Solvate
Preparation
[0648] Form I is slurried in methanol between 10 and 30.degree. C.
for several days.
Example 4
Form IV--Carvedilol Dihydrogen Phosphate Dihydrate Preparation
[0649] Carvedilol dihydrogen dihydrogen phosphate is dissolved in
an acetone/water mixture. The acetone is removed by distillation. A
solid crystallizes during acetone removal and is filtered and
dried.
Example 5
Form V--Carvedilol Dihydrogen Phosphate Preparation
[0650] Carvedilol dihydrogen phosphate hemihydrate (Form I) was
suspended in water, and the suspension was placed on a mechanical
shaker at room temperature. After 48 hours of shaking, the solid
was isolated from suspension by filtration, then dried in a
desiccator under vacuum for a few days.
Example 6
Form VI--Carvedilol Hydrogen Phosphate Preparation
[0651] A suitable reactor is charged with acetone. The acetone
solution is sequentially charged with SK&F 105517 and water.
Upon addition of the water, the slurry dissolves quickly. To the
solution is added aqueous H.sub.3PO.sub.4 (at 1/2 the molar
quantity of Carvedilol). The reaction mixture is stirred and
allowed to crystallize. The solid precipitate formed is stirred and
cooled, then filtered and the collected cake is washed with aqueous
acetone.
Example 7
.sup.13C and .sup.31P Solid State NMR Data Analysis of Carvedilol
Dihydrogen Phosphate
[0652] A sample of carvedilol dihydrogen phosphate was analyzed by
solid-state .sup.13C NMR and .sup.31P NMR (i.e., to probe solid
compound form structure).
[0653] Carvedilol dihydrogen phosphate (Parent MW=406.5; Salt
MW=504.5) has the following structure and numbering scheme: 2
[0654] Experimental Details and .sup.13C and .sup.31P Analysis
[0655] The solid state .sup.13C NMR methods used to analyze
compounds of the present invention produce a qualitative picture of
the types of carbon sites within the solid material. Because of
variable polarization transfer rates and the need for sideband
suppression, the peak intensities are not quantitative (much like
the case in solution-state .sup.13C NMR).
[0656] However, the .sup.31P spectra are inherently
quantitative.
[0657] For the .sup.13C analysis, approximately 100 mg of sample
was packed into a 7-mm O.D. magic-angle spinning rotor and spun at
5 kHz. The .sup.13C spectrum of the sample was recorded using a
CP-TOSS pulse sequence (cross-polarization with total suppression
of sidebands). An edited spectrum containing only quaternary and
methyl carbons was then obtained using an CP-TOSS sequence with NQS
(non-quaternary suppression). The .sup.13C spectra are referenced
externally to tetramethylsilane via a sample of solid
hexamethylbenzene.
[0658] For .sup.31P Solid State NMR, approximately 40 mg of sample
was packed into a 4-mm O.D. rotor and spun at 10 kHz. Both CP-MAS
and single-pulse MAS.sup.31P pulse sequences were used with .sup.1H
decoupling. The .sup.31P data are externally referenced to 85%
phosphoric acid by a secondary solid-state reference
(triphenylphosphine oxide). The Bruker AMX2-360 spectrometer used
for this work operates at .sup.13C, .sup.31P and .sup.1H
frequencies of 90.556, 145.782 and 360.097 MHz, respectively. All
spectra were obtained at 298 K.
[0659] Results and Discussion
[0660] The highly sensitive .sup.13C and .sup.31P Solid State NMR
identification methods were used for the analysis and
characterization of a polymorphic form of Carvedilol phosphate,
which confirms its chemical structure in the solid-state.
[0661] The form of Carvedilol dihydrogen phosphate is defined by
these spectra, where both .sup.13C and .sup.31P spectra show clear
and distinct differences.
[0662] In particular, FIG. 26 shows the .sup.13C CP-TOSS spectrum
of carevedilol dihydrogen phosphate. An assignment of the numerous
.sup.13C resonances in FIG. 1 can be made by chemical shift
assignment, the NQS spectrum and comparisons with solution-state
.sup.13C assignments. At least two non-equivalent molecules per
unit cell are observed in this form of Carvedilol phosphate.
[0663] FIG. 27 shows the .sup.31P MAS spectrum of carvedilol
dihydrogen phosphate. A single phosphorus signal is observed at 4.7
ppm, which is characteristic of phosphate salts.
[0664] Carvedilol Hydrogen Bromide Examples
Example 8
[0665] Form 1. Carvedilol HBr Monohydrate.
[0666] A suitable reactor is charged with acetone. The acetone
solution is sequentially charged with carvedilol, water and 48%
aqueous HBr. On addition of the water, the acetone slurry becomes a
solution. The reaction mixture is stirred at room temperature. A
solid precipitates during the course of the stir. The precipitate
is filtered and the collected cake is washed with acetone. The cake
is dried under vacuum to a constant weight. The cake is weighed and
stored in a polyethylene container.
[0667] The single crystal x-ray data for carvedilol hydrobromide
monohydrate is provided below.
1TABLE 1 Sample and Crystal Data for Carvedilol Hydrobromide
Monohydrate. Crystallization solvents Acetone, water
Crystallization method Slow cooling Empirical formula
C.sub.24H.sub.29BrN.sub.2O.sub.5 Formula weight 505.40 Temperature
150(2) K Wavelength 0.71073 .ANG. Crystal size 0.18 .times. 0.14
.times. 0.08 mm Crystal habit Clear colorless prism Crystal system
Monoclinic Space group C2/c Unit cell dimensions a = 18.0356(3)
.ANG. .alpha. = 90.degree. b = 20.8385(5) .ANG. .beta. =
103.5680(10).degree. c = 12.9342(3) .ANG. .gamma. = 90.degree.
Volume 4725.46(18) .ANG..sup.3 Z 8 Density (calculated) 1.421
Mg/m.sup.3 Absorption coefficient 1.777 mm.sup.-1 F(000) 2096
[0668]
2TABLE 2 Data collection and structure refinement for Carvedilol
Hydrobromide Monohydrate. Diffractometer KappaCCD Radiation source
Fine-focus sealed tube, MoK.sub..alpha. Data collection method CCD;
rotation images; thick slices Theta range for data collection 3.42
to 23.27.degree. Index ranges 0 .ltoreq. h .ltoreq. 20, 0 .ltoreq.
k .ltoreq. 23, -14 .ltoreq. l .ltoreq. 13 Reflections collected
30823 Independent reflections 3404 [R(int) = 0.042] Coverage of
independent 99.7% reflections Variation in check reflections N/A
Absorption correction Symmetry-related measurements Max. and min.
transmission 0.8709 and 0.7404 Structure solution technique Direct
methods Structure solution program SHELXTL V5.10 UNIX (Bruker,
1997) Refinement technique Full-matrix least-squares on F.sup.2
Refinement program SHELXTL V5.10 UNIX (Bruker, 1997) Function
minimized .SIGMA. w(F.sub.o.sup.2 - F.sub.c.sup.2).sup.2
Data/restraints/parameters 3404/11/336 Goodness-of-fit on F.sup.2
1.020 .DELTA./.sigma..sub.max 0.000 Final R indices 3071 data; I
> 2.sigma.(I) R1 = 0.0353, wR2 = 0.0797 all data R1 = 0.0405,
wR2 = 0.0829 Weighting scheme w = 1/[.sigma..sup.2(F.sub.o.sup.2) +
[(0.0304P).sup.2 + 14.1564P] where P = [MAX(F.sub.o.sup.2, 0) +
2F.sub.c.sup.2]/3 Largest diff. peak and hole 0.786 and -0.914
e..ANG..sup.-3 Refinement summary: Ordered Non-H atoms, XYZ Freely
refined Ordered Non-H atoms, U Anisotropic H atoms (on carbon), XYZ
Idealized positions riding on attached atom H atoms (on carbon), U
Appropriate constant times Ueq of attached atom H atoms (on
heteroatoms), Freely refined XYZ H atoms (on heteroatoms), U
Refined Isotropically Disordered atoms, OCC See Table 10 Disordered
atoms, XYZ Refined with distance restraints Disordered atoms, U
Anisotropic
[0669]
3TABLE 3 Atomic Coordinates and Equivalent Isotropic Atomic
Displacement Parameters (.ANG..sup.2) for Carvedilol Hydrobromide
Monohydrate. U(eq) is defined as one third of the trace of the
orthogonalized U.sub.ij tensor. x/a y/b z/c U(eq) Br1 0.5000
0.22079(2) -0.2500 0.04329(15) Br2 0.0000 0.40821(2) -0.2500
0.04510(16) O1 0.19543(10) 0.37037(10) -0.00168(15) 0.0328(5) O2
0.08660(19) 0.48508(15) 0.1085(2) 0.0312(7) O2' 0.0825(3) 0.4816(3)
-0.0328(4) 0.0311(13) O3 -0.19428(10) 0.39492(10) -0.01310(15)
0.0347(5) O4 -0.24723(12) 0.46974(11) 0.11008(16) 0.0404(5) O99A
-0.0880(5) 0.4236(3) 0.1967(7) 0.0430(19) O99B -0.0833(5) 0.4514(4)
0.1784(7) 0.0431(19) N1 0.34092(16) 0.25072(13) -0.1793(2)
0.0390(7) N2 -0.03151(14) 0.39706(13) -0.0026(2) 0.0314(6) C1
0.26859(15) 0.35551(14) -0.0070(2) 0.0301(7) C2 0.33380(16)
0.38188(15) 0.0568(2) 0.0339(7) C3 0.40553(17) 0.36537(16)
0.0409(3) 0.0402(8) C4 0.41433(17) 0.32249(16) -0.0364(3) 0.0401(8)
C5 0.34850(16) 0.29538(15) -0.0986(2) 0.0343(7) C6 0.26499(17)
0.23737(14) -0.2202(2) 0.0343(7) C7 0.23145(19) 0.19604(15)
-0.3022(2) 0.0401(8) C8 0.15313(19) 0.19096(15) -0.3275(2)
0.0412(8) C9 0.10866(18) 0.22594(14) -0.2721(2) 0.0364(7) C10
0.14185(17) 0.26731(14) -0.1910(2) 0.0323(7) C11 0.22085(16)
0.27356(13) -0.1639(2) 0.0300(7) C12 0.27490(16) 0.31103(13)
-0.0855(2) 0.0294(6) C13 0.18523(16) 0.41746(14) 0.0740(2)
0.0301(7) C14 0.10181(16) 0.43671(13) 0.0452(2) 0.0305(7) C15
0.05016(15) 0.37919(14) 0.0363(2) 0.0289(6) C16 -0.08143(16)
0.33991(14) -0.0272(2) 0.0361(7) C17 -0.16200(16) 0.35626(16)
-0.0833(2) 0.0380(7) C18 -0.27156(15) 0.40680(14) -0.0445(2)
0.0300(6) C19 -0.30049(16) 0.44705(14) 0.0236(2) 0.0316(7) C20
-0.37754(18) 0.46060(16) 0.0007(3) 0.0409(8) C21 -0.42545(18)
0.43467(17) -0.0895(3) 0.0499(9) C22 -0.39733(18) 0.39593(17)
-0.1567(3) 0.0504(9) C23 -0.31949(17) 0.38199(15) -0.1342(3)
0.0388(7) C24 -0.2743(2) 0.50999(17) 0.1833(3) 0.0482(9)
[0670]
4TABLE 4 Selected Bond Lengths (.ANG.) for Carvedilol Hydrobromide
Monohydrate. O1-C1 1.373(3) O1-C13 1.428(3) O2-C14 1.366(4) O2'-C14
1.360(6) O3-C18 1.380(3) O3-C17 1.435(3) O4-C19 1.376(4) O4-C24
1.433(4) N1-C6 1.376(4) N1-C5 1.381(4) N2-C16 1.482(4) N2-C15
1.488(4) C1-C2 1.382(4) C1-C12 1.399(4) C2-C3 1.399(4) C3-C4
1.378(5) C4-C5 1.388(4) C5-C12 1.415(4) C6-C7 1.389(4) C6-C11
1.416(4) C7-C8 1.377(5) C8-C9 1.399(4) C9-C10 1.381(4) C10-C11
1.391(4) C11-C12 1.458(4) C13-C14 1.517(4) C14-C15 1.506(4) C16-C17
1.503(4) C18-C23 1.374(4) C18-C19 1.403(4) C19-C20 1.380(4) C20-C21
1.388(5) C21-C22 1.368(5) C22-C23 1.396(4)
[0671]
5TABLE 5 Selected bond angles (.degree.) for Carvedilol
Hydrobromide Monohydrate. C1--O1--C13 118.0(2) C18--O3--C17
116.5(2) C19--O4--C24 117.2(2) C6--N1--C5 109.9(3) C16--N2--C15
112.0(2) O1--C1--C2 125.0(3) O1--C1--C12 115.4(2) C2--C1--C12
119.6(3) C1--C2--C3 120.1(3) C4--C3--C2 122.3(3) C3--C4--C5
117.1(3) N1--C5--C4 129.2(3) N1--C5--C12 108.5(3) C4--C5--C12
122.4(3) N1--C6--C7 129.4(3) N1--C6--C11 108.9(3) C7--C6--C11
121.7(3) C8--C7--C6 117.9(3) C7--C8--C9 121.1(3) C10--C9--C8
121.0(3) C9--C10--C11 119.1(3) C10--C11--C6 119.1(3) C10--C11--C12
134.7(3) C6--C11--C12 106.2(3) C1--C12--C5 118.6(3) C1--C12--C11
134.8(3) C5--C12--C11 106.6(3) O1--C13--C14 107.0(2) O2'--C14--O2
83.4(3) O2'--C14--C15 116.4(3) O2--C14--C15 115.2(3) O2'--C14--C13
115.6(3) O2--C14--C13 112.0(3) C15--C14--C13 111.6(2) N2--C15--C14
111.8(2) N2--C16--C17 113.0(3) O3--C17--C16 108.1(2) C23--C18--O3
125.0(3) C23--C18--C19 120.1(3) O3--C18--C19 114.9(2) O4--C19--C20
125.4(3) O4--C19--C18 115.1(2) C20--C19--C18 119.4(3) C19--C20--C21
119.8(3) C22--C21--C20 120.9(3) C21--C22--C23 119.7(3)
C18--C23--C22 120.0(3)
[0672]
6TABLE 6 Hydrogen Bonds and Short C--H . . . X Contacts for
Carvedilol Hydrobromide Monohydrate (.ANG. and .degree.). D-H . . .
A d(D-H) d(H . . . A) d(D . . . A) <(DHA) N1-H1N . . . Br1
0.76(3) 2.53(4) 3.269(3) 166(3) N2-H2NA . . . O99A 0.83(4) 2.29(4)
3.037(10) 149(3) N2-H2NA . . . O99B 0.83(4) 2.13(4) 2.943(10)
165(4) N2-H2NB . . . O2#1 0.89(5) 2.17(4) 2.873(4) 135(4) O2'-H2O'.
. . Br2 0.67(5) 2.65(7) 3.237(6) 149(12) O99A-H99A . . . Br1#2
0.94(3) 2.49(4) 3.395(8) 163(6) O99B-H99B . . . Br2#1 0.94(3)
2.38(3) 3.320(8) 173(6) C15-H15A . . . O1 0.99 2.38 2.783(3) 103.2
C15-H15B . . . Br1#2 0.99 2.85 3.738(3) 149.3 C16-H16A . . . Br1#2
0.99 2.88 3.760(3) 148.2 Symmetry transformations used to generate
equivalent atoms: #1 -x, -y + 1, -z #2 -x + 1/2, -y + 1/2, -z
[0673]
7TABLE 7 Selected torsion angles (.degree.) for Carvedilol
Hydrobromide Monohydrate. C13--O1--C1--C2 1.2(4) C13--O1--C1--C12
-177.5(2) O1--C1--C2--C3 -177.0(3) C12--C1--C2--C3 1.7(4)
C1--C2--C3--C4 -0.8(5) C2--C3--C4--C5 -0.5(5) C6--N1--C5--C4
-179.7(3) C6--N1--C5--C12 0.8(3) C3--C4--C5--N1 -178.6(3)
C3--C4--C5--C12 0.8(4) C5--N1--C6--C7 179.4(3) C5--N1--C6--C11
-0.9(3) N1--C6--C7--C8 179.5(3) C11--C6--C7--C8 -0.1(4)
C6--C7--C8--C9 -0.4(5) C7--C8--C9--C10 0.8(5) C8--C9--C10--C11
-0.6(4) C9--C10--C11--C6 0.0(4) C9--C10--C11--C12 -179.9(3)
N1--C6--C11--C10 -179.4(3) C7--C6--C11--C10 0.3(4) N1--C6--C11--C12
0.6(3) C7--C6--C11--C12 -179.7(3) O1--C1--C12--C5 177.4(2)
C2--C1--C12--C5 -1.4(4) O1--C1--C12--C11 -2.4(5) C2--C1--C12--C11
178.8(3) N1--C5--C12--C1 179.6(2) C4--C5--C12--C1 0.1(4)
N1--C5--C12--C11 -0.5(3) C4--C5--C12--C11 180.0(3)
C10--C11--C12--C1 -0.3(6) C6--C11--C12--C1 179.8(3)
C10--C11--C12--C5 179.9(3) C6--C11--C12--C5 -0.1(3)
C1--O1--C13--C14 166.1(2) O1--C13--C14--O2' -82.6(4)
O1--C13--C14--O2 -175.8(2) O1--C13--C14--C15 53.4(3)
C16--N2--C15--C14 171.3(2) O2'--C14--C15--N2 -38.6(4)
O2--C14--C15--N2 56.6(3) C13--C14--C15--N2 -174.2(2)
C15--N2--C16--C17 -170.5(2) C18--O3--C17--C16 -170.7(2)
N2--C16--C17--O3 -63.3(3) C17--O3--C18--C23 3.3(4)
C17--O3--C18--C19 -177.3(3) C24--O4--C19--C20 1.0(4)
C24--O4--C19--C18 -178.7(3) C23--C18--C19--O4 -179.2(3)
O3--C18--C19--O4 1.4(4) C23--C18--C19--C20 1.0(4) O3--C18--C19--C20
-178.3(3) O4--C19--C20--C21 179.9(3) C18--C19--C20--C21 -0.4(5)
C19--C20--C21--C22 -0.3(5) C20--C21--C22--C23 0.3(6)
O3--C18--C23--C22 178.2(3) C19--C18--C23--C22 -1.1(5)
C21--C22--C23--C18 0.4(5)
[0674]
8TABLE 8 Anisotropic Atomic Displacement Parameters (.ANG..sup.2)
for Carvedilol Hydrobromide Monohydrate. The anisotropic atomic
displacement factor exponent takes the form: -2.pi..sup.2
[h.sup.2a.sup.*2U.sub.11 + . . . + 2hka* b* U.sub.12] U.sub.11
U.sub.22 U.sub.33 U.sub.23 U.sub.13 U.sub.12 Br1 0.0484(3)
0.0447(3) 0.0464(3) 0.000 0.0306(2) 0.000 Br2 0.0707(3) 0.0413(3)
0.0234(2) 0.000 0.0111(2) 0.000 O1 0.0272(11) 0.0408(12) 0.0323(11)
0.0067(9) 0.0108(9) -0.0009(9) O2 0.0416(18) 0.0306(18) 0.0215(17)
-0.0006(14) 0.0077(15) 0.0059(14) O2' 0.038(3) 0.028(3) 0.031(3)
0.001(3) 0.014(3) 0.000(3) O3 0.0254(11) 0.0473(13) 0.0308(11)
-0.0091(9) 0.0058(9) -0.0001(9) O4 0.0400(12) 0.0500(14) 0.0323(11)
-0.0076(10) 0.0108(10) 0.0019(10) O99A 0.042(3) 0.044(5) 0.040(4)
-0.004(4) 0.004(3) 0.002(4) O99B 0.033(3) 0.061(6) 0.035(4)
-0.004(4) 0.007(2) -0.010(4) N1 0.0384(17) 0.0449(17) 0.0393(16)
0.0053(13) 0.0203(14) 0.0112(13) N2 0.0270(13) 0.0341(15)
0.0332(15) 0.0015(13) 0.0075(12) 0.0033(11) C1 0.0283(16)
0.0324(16) 0.0321(16) 0.0078(13) 0.0124(13) 0.0005(12) C2
0.0321(17) 0.0381(17) 0.0327(16) 0.0056(13) 0.0100(13) -0.0014(13)
C3 0.0301(17) 0.048(2) 0.0412(18) 0.0104(16) 0.0051(14) -0.0044(14)
C4 0.0290(17) 0.0471(19) 0.0470(19) 0.0133(16) 0.0148(15)
0.0064(14) C5 0.0324(17) 0.0390(17) 0.0343(16) 0.0113(14)
0.0132(14) 0.0065(14) C6 0.0391(18) 0.0334(17) 0.0339(17)
0.0099(14) 0.0161(14) 0.0088(14) C7 0.056(2) 0.0324(17) 0.0362(18)
0.0011(14) 0.0204(16) 0.0098(15) C8 0.055(2) 0.0337(18) 0.0357(18)
-0.0020(14) 0.0119(16) 0.0003(15) C9 0.0411(18) 0.0344(17)
0.0348(17) 0.0030(14) 0.0111(14) -0.0009(14) C10 0.0362(17)
0.0321(16) 0.0323(16) 0.0038(13) 0.0155(14) 0.0022(13) C11
0.0377(17) 0.0275(15) 0.0277(15) 0.0079(12) 0.0136(13) 0.0040(13)
C12 0.0305(16) 0.0309(16) 0.0295(15) 0.0085(13) 0.0122(13)
0.0017(12) C13 0.0311(16) 0.0331(16) 0.0265(15) -0.0019(12)
0.0078(12) -0.0021(12) C14 0.0325(16) 0.0307(16) 0.0290(16)
0.0010(13) 0.0083(13) 0.0015(13) C15 0.0263(15) 0.0327(16)
0.0289(15) 0.0031(12) 0.0090(12) 0.0043(12) C16 0.0322(16)
0.0347(17) 0.0390(18) -0.0078(14) 0.0036(14) 0.0016(13) C17
0.0298(16) 0.0477(19) 0.0342(17) -0.0106(15) 0.0031(13) 0.0023(14)
C18 0.0246(15) 0.0317(16) 0.0337(16) 0.0031(13) 0.0069(13)
-0.0014(12) C19 0.0299(16) 0.0352(17) 0.0313(16) 0.0063(13)
0.0103(13) -0.0031(13) C20 0.0379(18) 0.0382(18) 0.051(2)
0.0048(15) 0.0194(16) 0.0033(15) C21 0.0245(17) 0.050(2) 0.073(3)
0.0038(19) 0.0059(17) 0.0012(15) C22 0.0326(18) 0.053(2) 0.057(2)
-0.0075(18) -0.0052(16) -0.0012(16) C23 0.0317(17) 0.0407(18)
0.0407(18) -0.0045(14) 0.0021(14) -0.0004(14) C24 0.065(2) 0.050(2)
0.0325(18) -0.0027(15) 0.0176(17) 0.0098(17)
[0675]
9TABLE 9 Hydrogen Atom Coordinates and Isotropic Atomic
Displacement Parameters (.ANG..sup.2) for Carvedilol Hydrobromide
Monohydrate. x/a y/b z/c U H2O 0.086(3) 0.471(3) 0.155(4) 0.047
H2O' 0.082(6) 0.465(5) -0.077(6) 0.047 H99A -0.073(4) 0.3802(19)
0.201(6) 0.064 H99B -0.060(4) 0.490(2) 0.205(6) 0.065 H99
-0.1344(19) 0.4409(13) 0.157(3) 0.065 H1N 0.373(2) 0.2411(16)
-0.205(3) 0.039(10) H2NA -0.043(2) 0.4188(18) 0.045(3) 0.058(12)
H2NB -0.036(2) 0.422(2) -0.060(4) 0.077(14) H2A 0.3299 0.4112
0.1114 0.041 H3A 0.4497 0.3844 0.0850 0.048 H4A 0.4633 0.3119
-0.0468 0.048 H7A 0.2616 0.1720 -0.3395 0.048 H8A 0.1289 0.1632
-0.3836 0.049 H9A 0.0548 0.2212 -0.2906 0.044 H10A 0.1112 0.2912
-0.1543 0.039 H13A 0.2180 0.4552 0.0713 0.036 H13B 0.1990 0.3994
0.1468 0.036 H14 0.0925 0.4552 -0.0281 0.037 H14' 0.0943 0.4596
0.1099 0.037 H15A 0.0642 0.3477 -0.0132 0.035 H15B 0.0576 0.3585
0.1069 0.035 H16A -0.0819 0.3172 0.0400 0.043 H16B -0.0599 0.3103
-0.0723 0.043 H17A -0.1625 0.3802 -0.1496 0.046 H17B -0.1922 0.3165
-0.1021 0.046 H20A -0.3977 0.4876 0.0466 0.049 H21A -0.4785 0.4439
-0.1048 0.060 H22A -0.4306 0.3786 -0.2183 0.060 H23A -0.2996 0.3553
-0.1809 0.047 H24A -0.2310 0.5242 0.2397 0.072 H24B -0.3101 0.4858
0.2148 0.072 H24C -0.3002 0.5475 0.1455 0.072
[0676]
10TABLE 10 Site Occupation Factors that Deviate from Unity for
Carvedilol Hydrobromide Monohydrate. Atom sof Atom sof Atom sof Br1
1 Br2 1 O1 1 O2 0.65 H2O 0.65 O2' 0.35 H2O' 0.35 O99A 0.50 H99A
0.50 O99B 0.50 H99B 0.50 H99 1 H14 0.65 H14' 0.35
Example 9
[0677] Form 2. Carvedilol HBr (Dioxane Solvate)
[0678] Form 1 is slurried in dioxane between 0 and 40.degree. C.
for 2 days. The product is filtered and mildly dried.
Example 10
[0679] Form 3. Carvedilol HBr (1-pentanol Solvate)
[0680] Form 1 is slurried in 1-pentanol between 0.degree. C. and
40.degree. C. for 2 days. The product is filtered and mildly
dried.
Example 11
[0681] Form 4. Carvedilol HBr (2-Methyl-1-Propanol Solvate)
[0682] Form 1 is slurried in 2-Methyl-1-Propanol between 0.degree.
C. and 40.degree. C. for 2 days. The product is filtered and mildly
dried.
Example 12
[0683] Form 5. Carvedilol HBr (Trifluoroethanol Solvate)
[0684] Form 1 is slurried in trifluoroethanol between 0.degree. C.
and 40.degree. C. for 2 days. The product is filtered and mildly
dried.
Example 13
[0685] Form 6. Carvedilol HBr (2-propanol Solvate)
[0686] Form 1 is slurried in 2-propanol between 0.degree. C. and
40.degree. C. for 2 days. The product is filtered and mildly
dried.
Example 14
[0687] Form 7. Carvedilol HBr (n-propanol Solvate #1)
[0688] Carvedilol free base is dissolved in n-propanol/water
(95:5), and stoichiometric hydrobromic acid is added. The solution
is cooled, and crystallization ensues. The product is filtered,
washed with process solvent, and dried.
Example 15
[0689] Form 8. Carvedilol HBr (n-propanol Solvate #2)
[0690] Carvedilol HBr monohydrate (Form 1) is dissolved in
n-propanol at ambient temperature. The n-propanol is slowly
evaporated off, giving a white solid.
Example 16
[0691] Form 9. Carvedilol HBr (Anhydrous Forms and Solvent
Free)
[0692] Carvedilol free base is dissolved in a solvent
(dichloromethane, isopropyl acetate, and acetonitrile have been
used) and anhydrous forms HBr is added (HBr in acetic acid or
gaseous HBr). The solution is cooled, and crystallization ensues.
The product is filtered, washed with process solvent, and
dried.
Example 17
[0693] Form 10. Carvedilol HBr (Ethanol Solvate)
[0694] Carvedilol free base is dissolved in ethanol, and anhydrous
forms HBr is added (HBr in acetic acid). The solution is cooled,
and crystallization ensues. The product is filtered, washed with
process solvent, and dried.
Example 18
[0695] Carvedilol Monocitrate Monohydrate Preparation
[0696] In a 150 mL glass beaker, 100 gram of 20% w/w citric acid
solution was prepared and 2.2 gram of carvedilol was added. The
solution became slightly brownish after 15 minutes stirring, with
only a little solid sticking on the bottom of the beaker. The
beaker was then placed in a fume hood for evaporation. After
staying in the hood overnight, large single crystals appeared in
the beaker. The solid crystals were isolated and dried in a
desiccator under vacuum. Similarly single crystals of citrate salt
could be obtained by slow evaporation of carvedilol/citric acid
solutions (containing citric acid 5%, 10% or 20% w/w) in Petri
dishes (150 mm diameter) placed in a desiccator connected to a
house vacuum.
Example 19
[0697] Carvedilol Monocitrate Monohydrate Preparation
[0698] A 250 mL three-necked flask equipped with stirrer bar,
thermometer, and an addition funnel is charged with acetone (20 mL,
2.5 volumes). The solution is sequentially charged with carvedilol
(8 g, 19.7 mmol), and 2 M citric acid solution (40 mL, 5 volumes).
Upon addition of the citric acid solution, the slurry dissolves
quickly. The solution is filtered through a Buchner funnel fitted
with Whatman filter paper and the solution is returned to a 250 mL
flask fitted with a stirrer. To the light brown solution is added
water (20 mL, 2.5 volumes). No exotherm is noted. The reaction
mixture becomes cloudy but disappears upon stirring (heating up to
40.degree. C. maybe needed to remove cloudiness). The mixture is
stirred at room temperature and when judged clear is charged with
carvedilol monocitrate monohydrate seeds (80 mgs) in one portion.
An immediate cloudiness is observed (solid starts to precipitate
out over 12-24 hours). The precipitate formed is stirred for 24-48
hours and is filtered through a Buchner funnel fitted with Whatman
filter paper and the collected cake is washed with water
(2.times.16 mL). The cake is dried in the oven under house vacuum
at 50.degree. C. to a constant weight. The cake (7.95 g, 67%) is
weighed and stored in a polyethylene container.
Example 20
[0699] Carvedilol Monocitrate Monohydrate Preparation
[0700] A suitable reactor is charged with acetone. The solution is
sequentially charged with carvedilol, and aqueous citric acid
solution. Upon addition of the citric acid solution, the slurry
dissolves quickly. To the solution is added water. The mixture is
stirred at room temperature and is charged with carvedilol seeds in
one portion. The precipitate formed is stirred for a period of
time, filtered and the collected cake is washed with water. The
cake is dried under vacuum to a constant weight and stored in a
polyethylene container.
Example 21
[0701] Characterization of Carvedilol Monocitrate Monohydrate
Preparation
[0702] The HPLC assay and .sup.1H-NMR revealed that the molar ratio
of carvedilol and citric acid in carvedilol citrate salt prepared
was approximately 1:1. The characterization by several other
techniques are listed below:
[0703] Scanning Electron Microscopy (SEM)
[0704] The SEM used for the study was a Hitachi S-3500N. SEM was
performed using an acceleration voltage of 5 kV. The samples were
gold sputtered.
[0705] The carvedilol monocitrate salt consists of crystals with
plate-shape, and various sizes depending on the preparation method.
Crystals as large as 1 mm width and length were observed.
[0706] Differential Scanning Calorimetry (DSC)
[0707] DSC measurements were performed with a MDSC 2920 (TA
Instruments, Inc.). Approximately 5 mg of the sample was placed in
an open aluminum pan. The sample was scanned at 10.degree. C./min.
An endothermic event was observed with an onset temperature near
82-83.degree. C. The heat of fusion was calculated as 63
kJ/mol.
[0708] Fourier Transform Infrared Spectroscopy (FT-IR)
[0709] Approximately 2 mg of sample was diluted with 300 mg of
dried potassium bromide (KBr). The mixture was ground with a mortar
and pestle, then transferred to a die that is placed under high
pressure for 3 minutes. The instrument was a PerkinElmer Spectrum
GX FTIR instrument. Forty scans were collected at 4 cm.sup.-1
resolution. The typical FT-IR spectrum of carvedilol monocitrate
salt is shown in FIG. 1. The characteristic peaks in the 1800 to
600 cm.sup.-1 region are found at about 1727, 1709, 1636, 1625,
1604, 1586, 1508, 1475, 1454, 1443, 1396, 1346, 1332, 1305, 1256,
1221, 1129, 1096, 1077, 1054, 1021, 1008, 984, 939, 919, 902, 826,
787, 755, 749, 729, 676, 664, 611 cm.sup.-1.
[0710] X-Ray Powder Diffraction (XRPD)
[0711] XRPD patterns were collected using a Philips X'Pert Pro
Diffractometer. Approximately 30 mg of sample was gently flattened
on a silicon sample holder and scanned from 2-35 degrees two-theta,
at 0.02 degrees two-theta per step and a step time of 2.5 seconds.
The sample was rotated at 25 rpm. The XRPD patterns of two
different batches of Carvedilol monocitrate salt are shown in FIG.
2.
[0712] Solubility in Water
[0713] Glass vials containing water and excess amount of carvedilol
salts were shaken by a mechanical shaker at ambient conditions.
Aliquots were taken out at various time-point, filtered through
0.45 .mu.m Acrodisc GHP filter. The pH of the filtered solutions
was measured and suitable dilution was performed prior to UV-Vis
analysis of carvedilol concentration.
[0714] The solubility of carvedilol monocitrate salt in water at
room temperature was determined. The drug concentrations and pH
values at different time-points are presented in Table 11. This
crystalline form of carvedilol monocitrate salt exhibited high
solubility in water (1.63 mg/mL at 1 hour and 1.02 mg/mL at 48
hour).
11TABLE 11 Aqueous Solubility (expressed as mg of carvedilol free
base/mL of solution) over time at 25.degree. C. for Carvedilol Free
Base and Its Monocitrate Salt. Carvedilol Carvedilol Mono-Citrate
Time, hr Free Base Salt 1 0.0098 1.63 (pH = 3.5) 4 1.47 (pH = 3.4)
24 0.0116 1.07 (pH = 3.0) 48 1.02 (pH = 3.0)
[0715] Carvedilol monocitrate salt has two free carboxylic acid
groups in one unit salt, which contributes the low pH value (near
pH 3) observed for monocitrate salt when dissolved in water. This
may potentially lead to improved formulations by providing a low pH
microenvironment within the formulation as it traverses the GI
tract. This may provide an environment at a molecular level that is
more conductive to dissolution, particularly in the lower GI tract,
where the pH of the environment is near neutral pH and the
intrinsic solubility of the drug substance is limited. Such a
microenvironmental pH should lead to greater dissolution rate
because of higher solubility in the solid/liquid interface, leading
to improved absorption of drug in the lower GI tract thereby
sustaining overall absorption and, in consequence providing
prolonged blood levels and allowing less frequent dosing.
Therefore, a once-per-day carvedilol formulation may be possible by
incorporating carvedilol monocitrate salt. Such a unit is more
convenient for patients and result in higher patient compliance
with the dosage regimen and hence a better therapeutic effect.
[0716] Crystalline Structure of Carvedilol Monocitrate Salt
[0717] The crystalline structure of carvedilol citrate salt was
determined by Single Crystal X-Ray Diffraction analysis on the
large crystals formed by evaporation. The result indicated that the
salt form was a carvedilol monocitrate, where the molar ratio of
carvedilol and citric acid was 1:1. Surprisingly, the hydroxyl of
carvedilol is disordered in the crystalline packing. In other
words, the monocitrate salt has both R(+) and S(-) carvedilol
enantiomers at 1:1 molar ratio, and the two enantiomers are
randomly distributed, without any specific order.
[0718] This crystalline packing habit is very unusual for a salt
formed between a chiral compound and a chiral counter-ion
(monocitrate). Typically, chiral counter-ion tends to differentiate
the two stereoisomers of the compound when forming crystals.
However, in the case of the monocitrate salt, there seems to be
enough space in the crystal packing to allow the carbonyl group of
the terminal carboxylic acid group of citrate to form equivalent
hydrogen bond with the hydroxyl from either the R(+) or the S(-)
carvedilol stereoisomer.
[0719] This avoids generation of yet more optically active forms
that could potentially complicate stability, dissolution rates and
possibly in vivo absorption and pharmacologic effects.
[0720] The above data demonstrates that a novel crystalline form of
carvedilol monocitrate monohydrate can be prepared with a unique
crystalline packing habit, which exhibits high aqueous solubility
and can provide a low pH microenvironment for enhanced
dissolution.
Example 22
[0721] Crystalline Carvedilol Benzoate Preparation
[0722] A suitable reactor is charged with acetone. The solution is
sequentially charged with carvedilol (4.1 grams, 0.1 moles), and
benzoic acid solution. Upon addition of the benzoic acid (1.4
grams, 0.011 moles) solution, all material dissolves into the
solution. To the stirred solution is added tert-butyl methyl ether
(60 ml). The precipitate formed is stirred for a period of time,
filtered and the collected cake is washed with water. The cake is
dried under vacuum to a constant weight and stored in a
polyethylene container.
Example 23
[0723] Crystalline Carvedilol Mandelate Preparation
[0724] A suitable reactor is charged with acetone (38 mL). The
acetone solution is sequentially charged with carvedilol (11.08
grams) and water (8 mL) Upon addition of the water, the slurry
dissolves completely with heating. To the solution, 1 N Mandelic
acid in methanol (1 Equiv. 27.3 mL.) is added. The resulting
mixture is stirred at the range between 17.degree. C. and
35.degree. C., and the solid precipitate is formed over 10 hours to
24 hours. Later, the mixture filtered and the cake is washed with a
mixture of acetone and water (10 to 1) at 3 volumes or 33 mL. The
cake is then dried under vacuum to a constant weight. The final
weight is 8.34 g, 54,5% yield.
Example 24
[0725] Crystalline Carvedilol Lactate Preparation
[0726] A suitable reactor is charged with acetone (50 mL). The
acetone solution is sequentially charged with carvedilol (15.0
grams) and water (7 mL). Upon addition of the water, the slurry
dissolves completely with heating. To the solution is added 1 N
aqueous D, L-Lactic acid (1 equiv., 36.9 mL). The reaction mixture
is stirred at between 17.degree. C. and 35.degree. C. and seeded in
one portion. The solid precipitate is formed over 10 hours to 24
hours. Later, the mixture is filtered and the cake is washed with a
mixture of acetone and water (10 to 1) at 2 volume or 30 mL. The
cake is dried under vacuum to a constant weight. The final weight
is 9.16 grams.
Example 25
[0727] Crystalline Carvedilol Sulfate Preparation
[0728] A suitable reactor is charged with acetone (38 mL). The
acetone solution is sequentially charged with carvedilol (10.25
grams) and water (6 mL). Upon addition of the water, the slurry
dissolves completely with heating. To the solution, 1 N aqueous
sulfuric acid (1 equiv., 25.2 mL) is added. The reaction mixture is
stirred at between 17.degree. C. and 35.degree. C. and the solid
precipitate is formed over 10 hours to 24 hours. Later, the mixture
is filtered and the cake is washed with a mixture of acetone and
water at 2 volumes or 20.5 mL. The cake is then added a mixture of
acetone and water (10 to 1) for ripening between 20.degree.
C.-35.degree. C. over 24 hours to 48 hours. The slurry is filtered
and the cake is dried under vacuum to a constant weight. The final
weight is 5.48 grams.
Example 26
[0729] Crystalline Carvedilol Maleate Preparation
[0730] A suitable reactor is charged with acetone (56 mL). The
acetone solution is sequentially charged with carvedilol (15.0
grams) and water (8 mL). Upon addition of the water, the slurry
dissolves completely with heating. To the solution is added 1 M of
aqueous Maleic acid (1 Equiv. 36.9 mL.) The reaction mixture is
stirred at between 17.degree. C. and 35.degree. C. The solid
precipitate is formed over 10 hours to 24 hours. Later, the mixture
is filtered and the cake is washed with a mixture of acetone and
water (10 to 1) at 3 volume or 45.0 mL. The cake is dried under
vacuum to a constant weight. The final weight is 14.08 grams.
Example 27
[0731] Crystalline Carvedilol Glutarate Preparation
[0732] A suitable reactor is charged with 2 grams of carvedilol and
a mixture of acetone and water (in a 7 to 1 ratio) at 8 mL. The
contents were warmed to 35.degree. C. to 40.degree. C. to a clear
solution. 1 N D,L-Glutaric acid in water (1 equivalent. 4.9 mL.) is
added to the solution. The resulting mixture is stirred at the
temperature between 17.degree. C. and 35.degree. C. until the solid
precipitate is formed over 10 hours to 24 hours. Subsequently, the
mixture filtered and the cake is washed with a mixture of acetone
and water (in a 10 to 1) at about 5 mL. The cake is then dried
under vacuum to a constant weight. The final weight is 1.35
grams.
Example 28
[0733] Solubility Enhancement in the GI tract
[0734] Background:
[0735] Drug absorption following oral dosage requires that drug
first dissolves in the gastrointestinal milieu. In most cases such
dissolution is primarily a function of drug solubility. If
solubility is affected by pH it is likely that absorption will vary
in different regions of the gastro intestinal tract, because pH
varies from acidic in the stomach to more neutral values in the
intestine.
[0736] Such pH-dependent solubility can complicate dosage form
design when drug absorption needs to be prolonged, delayed or
otherwise controlled, to evince a sustained or delayed action
effect. Variations in solubility can lead to variable dissolution,
absorption and subsequent therapeutic effect.
[0737] Carvedilol is a drug used to treat hypertension and
congestive heart failure, being usually administered twice daily.
For chronic diseases such as these a once-daily dosage regimen is
desirable, to enhance patient compliance and reduce "pill burden".
However, the dose response and time course of carvedilol in the
body is such that a conventional dosage form, releasing all the
drug immediately on ingestion does not provide once-a-day therapy.
Release from the dosage form needs to be slowed down so that
absorption and subsequent systemic residence is prolonged. This
however requires that release and dissolution occurs along the GI
tract, not just in the stomach.
[0738] The pH-dependent solubility of the currently used form of
carvedilol (free base) is such that, while gastric solubility is
adequate, solubility is much poorer at pH values encountered in the
small intestine and beyond (see, FIG. 126), which depicts a
pH-solubility profile for carvedilol.
[0739] Consequently, while drug dissolution rate and extent from an
immediate release dosage form is likely to be acceptable (such
dissolution occurring in the stomach) it could be inadequate in
regions beyond the stomach, with absorption compromised as a
consequence.
[0740] However, when drug is administered as a solution (in
cyclodextrin in this example), directly to the colon it can be seen
that absorption is significantly improved (FIG. 128, which depicts
mean plasma profiles in beagle dogs following intra-colonic
administration of a carvedilol solution containing Captisol or
carvedilol in aqueous suspension.). All this information suggests
that absorption throughout the GI tract could be significant,
provided that drug can be solubilized.
[0741] Moreover, solubilization may mean that drug stability is
compromised. The secondary amino group of carvedilol is prone to
chemically react with excipients normally included in a dosage form
to aid manufacture, maintain quality or enhance dissolution rate.
For example, this type of amine groups can react with aldehydes or
ester functional groups through nucleophilic reactions. Many
excipients have ester functional groups. Furthermore, aldehydes and
other such residues are common residues in excipients. This often
results in marginal or unacceptable chemical stability of
conventionally formulated carvedilol dosage forms, where drug is
simply blended with excipients before being compressed to tablets.
As drug-excipient interactions are likely to be even faster in the
solvated state it follows that solubilization does not provide
facile resolution of dissolution-limited absorption challenges.
This is illustrated in Table 12. Solutions of carvedilol in oleic
acid degraded rapidly. Other approaches to solubilization evince
the same effect. Thus solubilization might enhance absorption but
is not a practical approach because of the destabilizing
effect.
12TABLE 12 Drug content (mg/g) in carvedilol/Oleic acid solution
during storage. Initial 1 month at 25.degree. C. 3 months at
25.degree. C. 7.788% w/w carvedilol 76.6 71.3 64.3 solution in
Oleic acid
[0742] It has now been unexpectedly shown that salts of carvedilol
afford significant improvement in absorption from the lower GI
tract in dogs over that seen when carvedilol base is used. There is
no reason to believe that this surprising effect does not also
apply to humans and it may be feasible as a consequence to design
dosage forms that enable drug to be absorbed as the unit traverses
the gastrointestinal tract. This ought provide more gradual
absorption and prolonged plasma profiles that facilitate once-a-day
dosage.
[0743] The better absorption may be partially due to the better
solubilities of salts of carvedilol. It can be seen from the data
in Table 13 that citrate, hydrobromide and phosphate salts have
much better aqueous solubility than the free base.
13TABLE 13 Aqueous Solubility (expressed as mg of Carvedilol free
base/mL of solution) at 25.degree. C. for Carvedilol free base and
three salts. Time Free Base Citrate salt Phosphate salt HBr salt 1
hr -- 1.64 (pH = 3.3) 2.35 (pH = 3.0) 0.62 (pH = 6.1) 4 hr -- 1.74
(pH = 3.2) 2.25 (pH = 3.0) 0.61 (pH = 6.3) 24 hr 0.024 1.46 (pH =
3.2) 2.21 (pH = 3.0) 0.61 (pH = 6.2) (pH = 7.0)
[0744] Ostensibly, it can be claimed that these acidic salts simply
generate low pH when dissolved in water (Table 13), leading to
solubility enhancement (because of the pH/solubility relationship
shown in FIG. 126). However, it is also possible that any
pH-lowering effect contributed by the modest amounts of drug (that
would be included in a dosage form to provide a therapeutic effect)
would be readily swamped in the in vivo situation, with pH soon
reverting to that of the general intestinal milieu. Consequently,
any short term solubilization would be quickly negatived. However,
it has been surprisingly shown that when pH is adjusted to neutral,
the solubilities of salts remain higher than free base for a
significant period, rather than equilibrating rapidly. Such
prolonged solubility could be crucial in vivo, allowing dissolution
and absorption to occur more readily at neutral pH than for free
base (FIG. 128, which depicts dissolution/solubility profile of
carvedilol phosphate in pH=7.1 Tris buffer (for comparison,
carvedilol free base has a solubility of -20-30 ug/mL at this
pH).
[0745] Furthermore, it has been shown that, if carvedilol salts are
dissolved in solubilizing agents, stability is much better than
when free base is used in the same system (Table 14). Thus, if
solubilizing agents were to be required in the formulation, to
provide even greater solubility enhancement, salts would be
preferred to the base because of such better stability.
14TABLE 14 Chemical stability data of carvedilol/Vitamin E TPGS
granulation containing carvedilol free base or carvedilol HBr salt.
Assay/Impurity after 1 month's storage at 40.degree. C./75% RH
(open vials) % of initial Total Impurities Formulation level* (%
peak area) Carvedilol free base granulation 81.5* 7.77 containing
Vitamin E TPGS (Lot 200412-144) Carvedilol HBr salt granulation
89.9* 0.15 containing Vitamin E TPGS (Lot 200746-102) *Lower % of
nominal due to additional moisture in the system.
[0746] The foregoing facts and considerations suggest but do not
provide conclusive proof that forms of carvedilol with superior
solubility, whether effected by using a solvent to dissolve
carvedilol base, or by using a carvedilol salt have better
potential than conventionally formulated base for prolonged
absorption along the GI tract. To provide stronger evidence that
solubilization enhances absorption, formulations containing
carvedilol base, formulated in a conventional manner, and also
fully solvated by dissolving in n-methyl pyrrolidone were dosed to
beagle dogs in units that were activated to make drug available
after the dosage unit had passed the pyloric sphincter separating
the stomach from the duodenum. Intestinal absorption efficiency was
determined by monitoring plasma levels of carvedilol following such
dosage. Results are provided in Table 5 and FIG. 128 (which depicts
mean plasma profiles in beagle dogs following oral administration
of the formulations listed in Table 15).
15TABLE 15 Pharmacokinetic values following dosage of 10 mg
carvedilol (base) to three fasted beagle dogs. Solubility in pH 6.8
Phosphate Buffer AUC (0-t) Over 4-hour C.sub.max T.sub.max (ug
.multidot. Formulation Period (ug/mL) (ng/mL) (min) min/mL)
Carvedilol 86-120 31.32 .+-. 3.43 15.sup.b., 30 4.03 .+-. 1.34
Pharmasolve .RTM. (n = 3) 45.sup.a (n = 3) (n = 3) Granulation
Carvedilol Vitamin 108-94 16.26 .+-. 1.20 30, 120, 2.75 .+-. 0.55
ETPGS Granulation (n = 3) 45.sup.a (n = 3) (n = 3) Carvedilol in
29-36 13.08, 12.74, 45, 30, 2.14, 1.19, conventional granules
2.89.sup.a (n = 3) 120.sup.a (n = 3) 0.60.sup.a (n = 3) .sup.a=
values listed individually due to large variability; animals always
listed in the same order. AUC(0-t) refers to the area from time 0
to the last quantifiable concentration. .sup.b= Pharmasolve .RTM.
capsule was leaking slightly before firing in-vivo.
[0747] It can be seen that, when drug was fully dissolved
absorption was rapid and high, contrasting with lower
concentrations in dogs that were dosed intraduodenally with base in
a conventional solid dosage unit. These findings indicated that
bioavailability from carvedilol base in the small intestine is
constrained by its low solubility at neutral pH. When units are
introduced to the stomach the low gastric pH can be expected to
facilitate dissolution and absorption but this will not be the case
in the more neutral small intestine or beyond. A further dog study
utilized salts of carvedilol, formulated using conventional
(non-solubilizing) excipients. The mode of dosage was the same as
for the first dog study, the formulations being delivered such that
drug did not become available until units were beyond the gastric
milieu. Results are provided in Table 16 and FIG. 130 (which
depicts mean plasma profiles following oral administration of
Companion capsules filled with four formulations at 10 mg strength
to Beagle dogs).
16TABLE 16 Pharmacokinetic analysis of 10 mg dose formulations in
three fasted beagle dogs from study. AUC (0-t).sup.a AUC (0-inf)
Formulation C.sub.max (ng/mL) T.sub.max (min) (ug .multidot.
min/mL) (ug .multidot. min/mL) Carvedilol HBr Salt 12.9 .+-. 7.11
45 .+-. 15 2.22 .+-. 1.37 2.35 .+-. 1.46 granules Carvedilol 61.8,
28.4 45, 60 6.69, 4.56 6.75, 4.90 Phosphate Salt Granules.sup.b
Carvedilol Citrate 30.4 .+-. 16.9 45 .+-. 15 4.41 .+-. 2.43 4.66
.+-. 2.54 Salt Granules Carvedilol Base 13.08, 12.74, 45, 30, 120
2.14, 1.19, 0.60 -- Granulesx.sup.c 2.89 .sup.aAUC(0-t) refers to
the area from time 0 to the last quantifiable concentration .sup.bn
= 2 only, due to malfunction of one InteliSite .RTM. Companion
capsule; animals always listed in the same order .sup.cdata from
dog study DI01251; values listed individually due to large
variability; animals always listed in the same order.
[0748] The findings from the second dog study, illustrated
graphically in FIG. 130 conclusively showed that drug, administered
in salt form was rapidly and more completely absorbed than the free
base form.
Example 29
[0749] The present invention relates to dosage forms of carvedilol
to match drug delivery with pharmacodynamic requirements.
[0750] Accordingly the present invention provides a unit dose
composition that comprises:
Example B
[0751] A second controlled release component, providing a peak
plasma level about 5-8 hours post-dose. FIG. 132 is a plasma
profile from capsules formulated according to the Example].
[0752] Units, formulated as described in two examples described
above have been evaluated for their biopharmaceutical profiles in
human subjects and provide the requisite substantially biphasic
pulsed profiles.
[0753] It can be seen that both types of dosage form provided
distinctive substantially biphasic profiles, and timecourses
aligned with those defined in earlier discussions.
Example 30
[0754] Dosage Forms Utilized in PK Studies
[0755] Dosage forms comprised capsules containing a mixture of
beads (pellets) to provide rapid and delayed release components.
The delayed release effect was provided by a pH or time-mediated
mechanism. Rapid release was attained by having no release barrier
in one population of pellets.
17TABLE 21 Capsule composition 1. Immediate Release pellets
Carvedilol Free base* Cellulose microspheres (Cellsphere CP-303
Polyvinyl Pyrollidone (PVP) Modified Release Pellets Carvedilol
Phosphate Cellulose microspheres (Cellsphere CP-303 Polyvinyl
pyrollidone (PVP) Cross Linked PVP (Plasdone) Cremophor RH 40
Methacrylic acid polymer (Eudragit L100-55) Hydrogenated vegetable
oil.
[0756] Manufacture
[0757] Immediate-Release Pellets:
[0758] An aqueous suspension of drug and PVP was sprayed on to
fluidized cellulose pellets in a stream of warm air.
[0759] Modified Release Pellets:
[0760] A mixture of drug, PVP, Cremophor RH40 and cross linked PVP
was sprayed on fluidized cellulose microspheres to provide a layer
of drug on the pellets. The fluidized pellets were then coated,
using either a suspension of Methacrylic acid polymer (Eudragit
L100-55) and hydrogenated vegetable oil in isopropyl alcohol,
providing an acid-insoluble coat, or a coat comprising
ethylcellulose, dibutyl sebacate and PVP to retard release of drug
from the pellet over time.
[0761] The level of coat applied was varied in different batches to
determine the impact on in vivo absorption.
[0762] Pellets were filled in to capsules in differing ratios of
immediate and delayed release forms to determine the impact on
plasma profiles. Details are shown in Table 22.
18 TABLE 22 Ratio IR to DR Formulation Coat Type level on pellet in
capsule (%) B ethylcellulose 9% 30/70 D " 12% " E Eudragit 18% " F
" 22% " G " 25% 40/60
[0763] A Phase 1 volunteer study was performed to determine the
impact of various formula variants on in vivo performance.
Example 31
[0764] A controlled release composition, dosage form or formulation
of the present invention is formed from mixtures of the following
components:
[0765] [1] pellets, granules or microparticles, which comprise an
active carvedilol free base or a carvedilol salt, solvate or
anhydrous form thereof formulated to release the drug relatively
quickly, but not immediately, as there may be a time delay in
release;
[0766] [2] pellets, granules or microparticles may be prepared by
granulating the drug with a hydrophilic polymer such as cellulose
ethers, which may include, but is not limited to methyl cellulose,
hydroxypropyl methylcellulose, polyvinyl pyrrolidone and the like.
Alternatively, the drug may be applied to a base granule in an
aqueous slurry with hydrophilic polymers, followed by subsequent
drying to provide an embedded drug/matrix pellet;
[0767] [3] pellets, granules or microparticles also may be coated
with or containing the drug embedded in a polymer, which prevents
release at the more acid pH values encountered in the
gastrointestinal tract, but which effect ready release of drug,
after a defined time has elapsed or when the pellet, granule or
microparticle unit is in an environment of more neutral pH.
Examples of suitable coating or release modifying materials, may
include, but are not limited to methacrylic acid polymers, shellac
or cellulose acetate phthalate or mixtures thereof and the like;
or
[0768] [4] pellets, granules or microparticles coated with or
containing embedded drug as described in [3], but which release
drug at higher pH, such as a pH of about 6.5 to a pH of about 7.5,
prepared using identical or similar coating materials as in [3]
such that coating material ratios may be varied.
[0769] In light of the foregoing, the early releasing component
would be formulated to start releasing drug shortly after dosing
(i.e., when a pellet, granule or microcapsule unit enters the
stomach) to provide a "pulse", peaking at about 1 hour to about 3
hours. At a later time, the more slowly releasing formulated
components release drug in parts of the small intestine, where the
associated polymer coat or matrix is soluble.
[0770] The overall dose of drug and ratios of the different
pellets, granules or microparticles can be determined by studies in
human volunteers to examine plasma levels for at least 24 hours
after dosage.
[0771] Examples of formulations and modes of preparation as
described above are exemplified below:
[0772] (i) Early Releasing Pellets
19 carvedilol phosphate hemihydrate 10 mg* polyvinyl pyrrolidone
(PVP) 2 mg* *quantities refer to levels contained in the final
dosage form. The active ingredient content is expressed as the
equivalent of anhydrous phosphate salt. The amounts of the
non-active ingredients are approximate.
[0773] Early releasing pellets, granules or microparticles are
prepared by spraying a liquid aqueous suspension of the drug and
PVP onto cellulose pellets, fluidized in a stream of warmed air.
The solvent is removed during fluidization, providing free flowing
beads, which may contain, but is not limited to containing 15-30%
of drug, although other drug loading levels also are
acceptable.
[0774] (ii) Delayed Release Pellets--Type I
20 carvedilol phosphate hemihydrate 30 mg* cross linked PVP
(Polyplasdone XL10) 30 mg* PVP 20 mg* polyoxylated hydrogenated
castor oil 2 mg* (Cremophor RH40) *quantities refer to levels
contained in the final dosage form. The active ingredient content
is expressed as the equivalent of anhydrous phosphate salt. The
amounts of the non-active ingredients are approximate.
[0775] Delayed release pellets, granules or microparticles--Type I
are prepared by spraying a liquid suspension of above-identified
components onto cellulose pellets, fluidized in a stream of warmed
air. The solvent is removed during fluidization providing free
flowing beads, which may contain, but is not limited to 10-50% of
drug (although other drug inclusion levels are also acceptable).
Such pellets, granules or microparticles are then coated, using
conventional fluidization and spraying technology, with a
suspension containing methacrylic acid co polymer (Eudragit L100
55) and hydrogenated cottonseed oil (Lubritab) in a suitable ratio
that is determined by monitoring release rate in vitro.
[0776] (iii) Delayed Release Pellets--Type II
21 carvedilol phosphate hemihydrate 40 mg* cross linked PVP 12 mg*
PVP 12 mg* Polyoxylated hydrogenated castor oil 3 mg* (Cremophor
RH40) *quantities refer to levels contained in the final dosage
form. The active ingredient content is expressed as the equivalent
of anhydrous phosphate salt. The amounts of the non-active
ingredients are approximate.
[0777] Delayed release pellets, granules or microparticles--Type II
are prepared by spraying a liquid suspension of the
above-identified components onto cellulose pellets, fluidized in a
stream of warmed air. The solvent is removed during fluidization
providing free flowing beads, which may contain, but is not limited
to 10-20% of drug (although other drug inclusion levels are also
acceptable). The pellets, granules or microparticles are then
coated, using identical technology to above with a suspension,
comprising a mixture of methacrylic acid copolymers viz Eudragit L
55 (25%) and Eudragit S 100 (35%) and Lubritab (40%)
[0778] (iv) Capsule Formation
[0779] Mixtures of the three types of pellets, granules or
microgranule types as identified above either are blended and
filled into capsules or filled directly into capsules to provide
the requisite overall dosage.
[0780] It will be obvious to those skilled in the art that
differing levels of each type of pellet, granule or microparticle
or corresponding populations may be employed to provide different
doses and ratios of each of the differently releasing pellet,
granule or microparticle units to provide the requisite
drug-plasma-time profiles.
Example 32
[0781] Biopharmaceutical Performance of Units Prepared According to
Example 32
[0782] In accordance with the present invention, capsules were
formulated according to descriptions as in Example 32, where each
capsule contain a total dose of 80 mg carvedilol phosphate
(anhydrous equivalent) divided according to Table 23 below.
22 TABLE 23 Dose (Carvedilol pfb Pellet type equivalent) early
releasing pellets 7.5 mg delayed release pellets I 22.5 mg delayed
release pellets II 30.0 mg
[0783] Capsules of the present invention were evaluated in a study
in after administration to human volunteers to determine plasma
profiles. Volunteers were administered one capsule, after food.
Plasma samples were withdrawn at regular intervals over a several
hour period (i.e., such as a 24 hour period), for determination of
drug content, thereby enabling profiles to be constructed. To
provide comparative data in the present study, one conventional,
immediate release dosage form (commercial Corege Tablet) containing
25 mg of drug, was dosed twice, at an interval of 12 hours (giving
a total dose of 50 mg).
[0784] FIG. 133 shows mean plasma profiles of subjects for a
formulation of the present invention described in Table 23.
[0785] As mean values tend to obscure profiles to some extent
(because of intrinsic intersubject variation) a representative
profile from a single subject is shown in FIG. 134 to illustrate
more clearly the substantially biphasic nature of a plasma profile
from the formulation described in Example 32/Table 23.
[0786] FIG. 135 compares the profiles for the test product (mean
values as in FIG. 133) with those obtained form the conventional
(immediate release) product dosed twice daily. It is noteworthy
that the test product has comparable plasma levels to the
conventional product at the 24-hour timepoint, indicating that
efficacy will or should be maintained for a once-daily dosage
interval.
[0787] In summary, mean and individual profiles of the present
invention exemplify or indicate that a single dose of a test
controlled release formulation delivered a plasma profile
incorporate the following characteristics:
[0788] a more gradual release of drug at the early stages than the
conventional or current commercially available COREG.RTM.
product;
[0789] a first plasma concentration peak about 1 hour to about-3
hours after dosage of a formulation of the present invention and a
second plasma concentration peak after about 5 hours to 10 hours
after dosage of a formulation of the present invention; and
[0790] levels at 24 hours that were comparable to those obtained
after twice daily dosage of the current commercial product
COREG.RTM..
[0791] Thus, data from dosage to humans show that the required
plasma level profile is attainable with this dosage form.
[0792] It is to be understood that the invention is not limited to
the embodiments illustrated hereinabove and the right is reserved
to the illustrated embodiments and all modifications coming within
the scope of the following claims.
[0793] The various references to journals, patents, and other
publications which are cited herein comprise the state of the art
and are incorporated herein by reference as though fully set
forth.
* * * * *