U.S. patent application number 10/451271 was filed with the patent office on 2004-04-01 for sustained release pharmaceutical dosage forms with minimized ph dependent dissolution profiles.
Invention is credited to Burnside, Beth A., Chang, Rong-Kun, Guo, Xiaodi.
Application Number | 20040062800 10/451271 |
Document ID | / |
Family ID | 24981155 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040062800 |
Kind Code |
A1 |
Burnside, Beth A. ; et
al. |
April 1, 2004 |
Sustained release pharmaceutical dosage forms with minimized ph
dependent dissolution profiles
Abstract
A pharmaceutical composition comprising at least one
pharmaceutically active agent that is pH dependent, at least one
non-pH dependent sustained release agent, and at least one pH
dependent agent that increases the dissolution rate of the at least
one pharmaceutically active agent at a pH in excess of 5.5. Such
compositions have minimized pH-dependent dissolution profiles or
pH-independent dissolution profiles.
Inventors: |
Burnside, Beth A.;
(Bethesda, MD) ; Chang, Rong-Kun; (Rockville,
MD) ; Guo, Xiaodi; (Coral Springs, FL) |
Correspondence
Address: |
Mary Elisa Lane
Shire Laboratories Inc
1550 East Gude Drive
Rockville
MD
20850
US
|
Family ID: |
24981155 |
Appl. No.: |
10/451271 |
Filed: |
October 21, 2003 |
PCT Filed: |
December 20, 2001 |
PCT NO: |
PCT/US01/50773 |
Current U.S.
Class: |
424/468 ;
514/211.07; 514/238.8; 514/283; 514/29 |
Current CPC
Class: |
A61K 9/2031 20130101;
A61P 25/28 20180101; A61K 9/2013 20130101; A61P 35/02 20180101;
A61P 7/00 20180101; A61K 9/2027 20130101; A61K 9/205 20130101; A61K
9/2009 20130101; A61K 9/2054 20130101 |
Class at
Publication: |
424/468 ;
514/211.07; 514/238.8; 514/283; 514/029 |
International
Class: |
A61K 031/7048; A61K
031/537; A61K 031/4745; A61K 031/553; A61K 031/554 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2000 |
US |
09741548 |
Claims
What is claimed is:
1. A pharmaceutical composition, comprising: (a) at least one
pharmaceutically active agent that is pH dependent: (b) at least
one non-pH dependent sustained release agent; and (c) at least one
pH dependent agent that increases the rate of release of said at
least one pharmaceutically active agent from the tablet at a pH in
excess of 5.5.
2. The composition of claim 1 wherein said at least one pH
dependent agent is at least one polymer that swells at a pH in
excess of 5.5.
3. The composition of claim 1 wherein said at least one pH
dependent agent is at least one enteric agent.
4. The composition of claim 1 wherein said at least one pH
dependent agent is at least one agent that increases the solubility
of said at least one pharmaceutically active agent at a pH of
greater than 5.5.
5. The composition of claim 1 wherein said at least one
pharmaceutically active agent is selected from the group consisting
of guanfacine, anagrelide, guanethidine monosulfate, quanadrel
sulfate, resirpine, propanolol, metoprolol, atenolol, timolol,
erythromycin, clonidine, chlorpheniramine, bromopheniramine,
diltiazem, and scopolamine.
6. The composition of claim 5 wherein said at least one
pharmaceutically active agent guanfacine.
7. The composition of claim 5 wherein said at least one
pharmaceutically active agent guanfacine hydrochloride.
8. The composition of claim 5 wherein said at least one
pharmaceutically active agent is anagrelide.
9. The composition of claim 5 wherein said at least one
pharmaceutically active agent is anagrelide hydrochloride.
10. The composition of claim 1 wherein said non-pH dependent
sustained release agent is selected from the group consisting of
ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride
copolymers, acrylate/methacrylate copolymers, polyethylene oxide,
hydroxypropyl methylcellulose, carageenan, alginic acid and salts
thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya
gum, acacia gum, trgacanth gum, locust bean gum, guar gum, sodium
carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax,
cetyl alcohol, hydrogenated vegetable oils, and stearyl
alcohol.
11. The composition of claim 2 wherein said at least one polymer
that swells at a pH in excess of 5.5 is selected from the group
consisting of acrylic acid copolymers, sodium alginate,
carrageenan, alginic acid, pectin, and sodium carboxymethyl
cellulose.
12. The composition of claim 3 wherein said at least one enteric
agent is selected from the group consisting of cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, polvinyl
acetate phthalate, methacrylic acid copolymers, cellulose acetate
trimellitate, hydroxypropyl methylcellulose acetate, succinate,
shellac, and zein.
13. The composition of claim 4 wherein said at least one agent that
increase the solubility of said at least one pharmaceutically
active agent at a pH greater than 5.5 is at least one organic
acid.
14. The composition of claim 13 wherein said at least one organic
acid is selected from the group consisting of citric acid, fumaric
acid, tartaric acid, adipic acid, glucono delta-lactone, and malic
acid.
15. The composition of claim I wherein said pH-dependent agent that
increases the rate of release of the at least one pharmaceutically
active agent from the tablet at a pH in excess of 5.5 is an agent
that maintains an acidic microenvironment in the composition.
16. The composition of claim 14 wherein said organic acid is
fumaric acid.
17. The composition of claim 1 and further comprising a binding
agent.
18. The composition of claim 17 wherein said binding agent is
selected from the group consisting of polyvinyl pyrrolidone,
starch, methylcellulose, hydroxypropyl methylcellulose,
carboxymethyl cellulose, sucrose solution, dextrose solution,
acacia, tragacanth, and locust bean gum.
19. The composition of claim 18 wherein said binder is
hydroxypropyl methylcellulose.
20. The composition of claim 1 wherein said pharmaceutically active
agent is present in the composition in an amount of from about 0.1
wt. % to about 70 wt. %.
21. The composition of claim 20 wherein said pharmaceutically
active agent is present in the composition in an amount of from
about 1 wt. % to about 40 wt. %.
22. The composition of claim 1 wherein said non-pH-dependent
sustained release agent is present in the composition in an amount
of from about 5 wt. % to about 50 wt. %.
23. The composition of claim 22 wherein said non-pH-dependent
sustained release agent is present in the composition in an amount
of from about 10 wt. % to about 30 wt. %.
24. The composition of claim 1 wherein said at least one
pH-dependent agent is present in the composition in an amount of
from about 0.5 wt. % to about 40 wt. %.
25. The composition of claim 24 wherein said at least one
pH-dependent agent is present in the composition in an amount of
from about 1 wt. % to about 20 wt. %.
26. The composition of claim 10 wherein said non-pH-dependent
sustained release agent is ethyl cellulose.
27. The composition of claim 10 wherein said non-pH-dependent
sustained release agent is hydroxypropyl methylcellulose.
28. The composition of claim 10 wherein said non-pH-dependent
sustained release agent is an acrylate/methacrylate copolymer.
29. The composition of claim 10 wherein said non-pH-dependent
sustained release agent is polyethylene oxide.
30. The composition of claim 11 wherein said at least one polymer
that swells at a pH in excess of 5.5 is sodium alginate.
31. The composition of claim 12 wherein said at least one enteric
agent is a methacrylic acid copolymer.
32. The composition of claim 1 wherein said composition is in the
form of a tablet.
33. The composition of claim 6 or 7 wherein said non-pH-dependent
sustained release agent is selected from the group consisting of
ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride
copolymers, acrylate/methacrylate copolymers, polyethylene oxide,
hydroxypropyl methylcellulose, carrageenan, alginic acid and salts
thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya
gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium
carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax,
cetyl alcohol, hydrogenated vegetable oils, and stearyl
alcohol.
34. The composition of claim 6 or 7 wherein said at least one
pH-dependent agent is at least one polymer that swells at a pH in
excess of 5.5.
35. The composition of claim 34 wherein said at least one polymer
that swells at a pH in excess of 5.5 is selected from the group
consisting of acrylic acid copolymers, sodium alginate,
carrageenan, alginic acid, pectin, and sodium carboxymethyl
cellulose.
36. The composition of claim 6 or 7 wherein said at least one
pH-dependent agent is at least one enteric agent.
37. The composition of claim 36 wherein said at least one enteric
agent is selected from the group consisting of cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl
acetate phthalate, methacrylic acid copolymers, cellulose acetate
trimellitate, hydroxypropyl methylcellulose acetate, succinate,
shellac, and zein.
38. The composition of claim 8 or 9 wherein said non-pH-dependent
sustained release agent is selected from the group consisting of
ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride
copolymers, acrylate/methacrylate copolymers, polyethylene oxide,
hydroxypropyl methylcellulose, carageenan, alginic acid and salts
thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya
gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium
carboxymethyl cellulose, methylcellulose, beeswax, carnauba wax,
cetyl alcohol, hydrogenated vegetable oils, and stearyl
alcohol.
39. The composition of claim 38 wherein said non-pH-dependent
sustained release agent is polyethylene oxide.
40. The composition of claim 8 or 9 wherein said at least one
pH-dependent agent is at least one enteric agent.
41. The composition of claim 40 wherein said at least one enteric
agent is selected from the group consisting of cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl
acetate phthalate, methacrylic acid copolymers, cellulose acetate
trimellitate, hydroxypropyl methylcellulose acetate, succinate,
shellac, and zein.
42. The composition of claim 41 wherein said at least one enteric
agent is a methacrylic acid copolymer.
43. The composition of claim 8 or 9 and further comprising a
bulking agent.
44. The composition of claim 43 wherein said bulking agent is
dibasic calcium phosphate.
45. The composition of claim 43 wherein said bulking agent is
microcrystalline cellulose.
46. The composition of claim 8 or 9 and further comprising a
lubricant.
47. The composition of claim 46 wherein said lubricant is glyceryl
behenate.
48. The composition of claim 46 wherein said lubricant is magnesium
stearate.
49. A pharmaceutical composition, comprising: (a) anagrelide; (b)
polyethylene oxide; (c) dibasic calcium phosphate; (d)
microcrystalline cellulose; (e) a methacrylic acid copolymer; (f)
glyceryl behenate; and (g) magnesium stearate.
50. A pharmaceutical composition, comprising: (h) Anagrelide
hydrochloride; (i) polyethylene oxide; (j) dibasic calcium
phosphate; (k) microcrystalline cellulose; (l) a methacrylic acid
copolymer; (m) glyceryl behenate; and (n) magnesium stearate.
51. A method of treating a myeloproliferative blood disorder in a
patient, comprising: administering to said patient the composition
of anyone of claims 8 to 50 in an amount effective to treat said
myeloproliferative blood disorder in said patient.
52. The method of claim 51 wherein said myeloproliferative blood
disorder is essential thrombocythemia.
53. The method of claim 51 wherein said myeloproliferative blood
disorder is chronic myelogenous leukemia.
54. The method of claim 51 wherein said myeloproliferative blood
disorder is polycythemia vera.
55. The method of claim 51 wherein said myeloproliferative blood
disorder is agnogenic myeloid metaplasia.
56. The method of claim 51 wherein the amount of the active
ingredient anagrelide is about 0.01 mg to about 15 mg.
57. The method of claim 51 wherein the amount of the active
ingredient anagrelide is about 0.1 mg to about 10 mg.
58. The method of claim 51 wherein the amount of the active
ingredient anagrelide is about 0.1 mg to about 5 mg.
59. The method of claim 51 wherein the amount of the active
ingredient anagrelide is about 0.5mg to about 2 mg.
60. A pharmaceutical composition comprising anagrelide as an active
agent and characterized in that said composition when administered
to a patient produces less of the side effects usually associated
with anagrelide.
61. The pharmaceutical composition of claim 60 wherein said side
effects are chosen from Headache, Asthenia, Somnolence, Dizziness,
Tacchycardia, Nausea, Pain Abdominal, Vomit, Infect or
Palpitations.
62. The pharmaceutical composition of claim 61 wherein said side
effects are chosen from Headache and Asthenia.
63. The pharmaceutical composition of claim 61 wherein said side
effect is Headache.
64. The pharmaceutical composition of claim 61 wherein said side
effect is Asthenia.
65. A method of reducing the likelihood of side effects associated
with the administration of anagrelide, comprising administering to
a patient a therapeutically effective amount of a composition as
defined in anyone of claims 8 to 50.
66. The method of claim 65 wherein said side effects are chosen
from Headache, Asthenia, Somnolence, Dizziness, Tacchycardia,
Nausea, Pain Abdominal, Vomit, Infect, or Palpitations.
67. The method of claim 65 wherein said side effects are chosen
from Headache and Asthenia.
68. The method of claim 65 wherein said side effect is
Headache.
69. The method of claim 65 wherein said side effect is Asthenia
70. A pharmaceutical composition, comprising: (a) guanfacine; (b)
Hydroxypropyl Methylcellulose (c) Ammonio Methacrylate Copolymer
(d) microcrystalline cellulose; (e) a methacrylic acid copolymer;
(f) glyceryl behenate; and (g) Fumaric Acid, (h) Lactose
Monohydrate (i) Povidone; and (j) Crospovidone Granulated
Blend.
71. A pharmaceutical composition comprising: (a) Guanfacine
hydrochloride; (b) Hydroxypropyl Methylcellulose (c) Ammonio
Methacrylate Copolymer (d) microcrystalline cellulose; (e) a
methacrylic acid copolymer; (f) glyceryl behenate; and (g) Fumaric
Acid, (h) Lactose Monohydrate (i) Povidone; and (j) Crospovidone
Granulated Blend.
72. A method of treating an attention deficit disorder or attention
deficit with hyperactivity disorder in a patient, comprising
administering to said patient the composition of claim 6 or 7 in an
amount effective to treat said attention deficit disorder or
attention deficit with hyperactivity disorder in said patient.
73. A method of reducing the likelihood of side effects associated
with the administration of guanfacine, comprising administering to
a patient a therapeutically effective amount of the composition of
claim 6 or 7
Description
[0001] This invention relates to pharmaceutical compositions. More
particularly, this invention relates to pharmaceutical compositions
having a pH-independent or a minimized pH-dependent dissolution
profile. In particular, such composition includes at least one
pharmaceutically active agent that has a pH dependent solubility
profile, at least one non-pH-dependent sustained release agent, and
at least one pH-dependent agent that increases the dissolution rate
of the at least one pharmaceutically active agent at a pH in excess
of 5.5. The active agent(s) has (have) a solubility profile wherein
the active agent(s) is (are) more soluble in an acidic medium than
in a basic medium.
[0002] The rate at which a drug goes into solution when it is
dissolved in a medium is proportional to the solubility of the drug
in the medium. Many drugs have different solubilities at different
pHs. These pH-dependent solubility differences lead to pH-dependent
dissolution profiles. In general, pH-dependent dissolution is an
undesirable product characteristic.
[0003] Compressed matrix tablets containing a basic drug often give
a faster dissolution profile in simulated gastric fluid, having a
pH about 1.0, than in simulated intestinal fluid (pH 6.8 to
7.4).
[0004] It is an object of the present invention to provide a
pharmaceutical composition with a minimized pH dependent or a
pH-independent dissolution profile.
[0005] In accordance with an aspect of the present invention, there
is provided a pharmaceutical composition. The composition comprises
at least one pharmaceutically active agent that is pH dependent, at
least one non-pH dependent sustained release agent, and at least
one pH-dependent agent that increases the rate of release of the at
least one pharmaceutically active agent from the tablet at a pH in
excess of 5.5, such as at least one organic acid that maintains an
acidic micro-environment in the tablet.
[0006] Pharmaceutically active agents which are pH dependent and
which may be included in the composition include, but are not
limited to, weakly basic drugs and their salts that have higher
solubilities at lower pH levels. Such drugs include, but are not
limited to, guanfacine hydrochloride, guanadrel sulfate, reserpine,
anagrelide hydrochloride, propanolol, metoprolol, atenolol,
timolol, erthyrthromycin, clonidine, chlorpheniramine,
bromopheniramine, diltiazen, and scopolamine. In general, the
pharmaceutically active agent is present in the composition in an
amount of from about 0.1 wt, % to about 70 wt. %, preferably from
about 1 wt. % to about 40 wt %. In one embodiment, the at least one
pharmaceutically active agent is guanfacine hydrochloride. In
another embodiment, the at least one pharmaceutically active agent
is anagrelide hydrocholoride. It is to be understood, however, that
the scope of the present invention is not to be limited to any
particular pharmaceutically active agent.
[0007] Non-pH-dependent sustained release agents which may be
included in the composition include, but are not limited to,
ethylcellulose, cellulose acetate, vinyl acetatelvinyl chloride
copolymers, acrylate/methacrylate copolymers, polyethylene oxide,
hydroxypropyl methylcellulose, carrageenan, alginic acid and salts
thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya
gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium
carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax,
cetyl alcohol, hydrogenated vegetable oils, and stearyl alcohol. In
general, the at least one non-pH-dependent sustained release agent
is present in the composition in an amount of from about 5 wt. % to
about 50 wt. %, preferably from about 10 wt. % to about 30 wt. %.
It is to be understood, however, that the scope of the present
invention is not to be limited to any particular non-pH-dependent
sustained release agents.
[0008] pH-dependent agents that increase the rate of release of the
at least one pharmaceutically active agent from the tablet at a pH
in excess of 5.5 include, but are not limited to, polymers that
swell at a pH in excess of 5.5, and enteric agents, and/or agents
that increase the solubility of the at least one pharmaceutically
active agent at a pH greater than 5.5, by maintaining an acidic
microenvironment in the tablet, e.g., an organic acid. The at least
one pH-dependent agent is present in the composition in an amount
of from about 0.5 wt. % to about 40 wt. %, preferably from about 1
wt. % to about 20 wt. %.
[0009] Polymers that swell at a pH in excess of 5.5 include, but
are not limited to, acrylic acid copolymers, sodium alginate,
carrageenan, alginic acid, pectin, and sodium carboxymethyl
cellulose.
[0010] Enteric agents include, but are not limited to, cellulose
acetate phthalate, hydroxypropyl methylcellulose phthalate,
polyvinyl acetate phthalate, methacrylic acid coplymers, cellulose
acetate trimellitate, hydroxypropyl methylcellulose acetate,
succinate, shellac, and zein.
[0011] Agents that increase the solubility of the at least one
pharmaceutically active agent at a pH greater than 5.5 include, but
are not limited to, organic acids. Such organic acids maintain an
acidic microenvironment in the tablet, and include, but are not
limited to, citric acid, fumaric acid, tartaric acid, adipic acid,
glucono delta-lactone, and malic acid.
[0012] The composition of the present invention may further include
other materials such as bulking agents, disintegrating agents,
anti-adherants and glidants, lubricants, and binding agents.
[0013] Bulking agents include, but are not limited to,
microcrystalline cellulose (eg., Avicel.RTM., FMC Corp.,
Emcocel.RTM., Mendell Inc.), mannitol, xylitol, dicalcium phosphate
(eg. Emcompress, Mendell Inc.) calcium sulfate (eg. Compactrol,
Mendell Inc.) starches, lactose, sucrose (Dipac, Amstar, and Nutab,
Ingredient Technology), dextrose (Emdex, Mendell, Inc.), sorbitol,
cellulose powder (Elcema, Degussa, and Solka Floc, Mendell, Inc.)
The bulking agent may be present in the composition in an amount of
from about 5 wt. % to about 90 wt. %, preferably from about 10 wt.
% to about 50 wt. %.
[0014] Disintegrating agents which may be included in the
composition include, but are not limited to, microcrystalline
cellulose, starches, crospovidone (eg. Polyplasdone XL,
International Specialty Products.), sodium starch glycolate
(Explotab, Mendell Inc.), and crosscarmellose sodium (eg.,
Ac-Di-Sol, FMC Corp.). The disintegrating agent may be present in
the composition in an amount of from about 0.5 wt. % to about 30 wt
%, preferably from about 1 wt. % to about 15 wt. %.
[0015] Antiadherants and glidants which may be employed in the
composition include, but are not limited to, talc, corn starch,
silicon dioxide, sodium lauryl sulfate, and metallic stearates. The
antiadherant or glidant may be present in the composition in an
amount of from about 0.2 wt. % to about 15 wt. %, preferably from
about 0.5 wt. % to about 5 wt. %.
[0016] Lubricants which may be employed in the composition include,
but are not limited to, magnesium stearate, calcium stearate,
sodium stearate, stearic acid, sodium stearyl fumarate,
hydrogenated cotton seed oil (sterotex), talc, and waxes, including
but not limited to, beeswax, carnuba wax, cetyl alcohol, glyceryl
stearate, glyceryl palmitate, glyceryl behenate, hydrogenated
vegetable oils, and stearyl alcohol. The lubricant may be present
in an amount of from about 0.2 wt. % to about 20 wt. %, preferably
from about 0.5 wt. % to about 5 wt. %.
[0017] Binding agents which may be employed include, but are not
limited to, polyvinyl pyrrollidone, starch, methylcellulose,
hydroxypropyl methylcellulose, carboxymethyl cellulose, sucrose
solution, dextrose solution, acacia, tragacanth and locust bean
gum. The binding agent may be present in the composition in an
amount of from about 0.2 wt. % to about 10 wt. %, preferably from
about 0.5 wt. % to about 5 wt. %.
[0018] The compositions of the present invention may be made by a
direct compression method, or by a wet granulation method. In the
direct compression method, the at least one pharmaceutically active
agent and other ingredients are sieved through a stainless steel
screen, such as a 40 mesh steel screen. The sieved materials then
are charged to a suitable blender, and blended for 10 minutes with
an intensifier bar on for 3 minutes. The blend then is compressed
into tablets on a rotary press using appropriate tooling. The
compressed tablets may be coated, if desired.
[0019] In the wet granulation method, the at least one
pharmaceutically active agent and other ingredients are granulated
with a granulating fluid (e.g., isopropyl alcohol, ethyl alcohol,
and water) in a planetary mixer, high shear mixer, or fluidized bed
granulator. Binding agents may be contained in the granulating
fluid, or may be in the dry mix. The wet granules are dried in an
oven or fluidized bed dryer, and then sieved through a suitable
screen to obtain free flowing granules. The resulting granules were
blended with a suitable lubricant and glidant, and the lubricated
granules are compressed into tablets on a rotary press using
appropriate tooling. If desired, a coating can be applied onto the
compressed tablets.
[0020] When the pharmaceutically active agent is guanfacine
hydrochloride, the composition may be employed in treating an
attention deficit disorder, or attention deficit with hyperactivity
disorder. The composition including guanfacine hydrochloride is
administered to an animal, such as a mammal, including human and
non-human primates, in an amount effective to treat the disorders
mentioned hereinabove.
[0021] The compositions of the present invention may be employed to
treat a variety of diseases or disorders.
[0022] When guanfacine hydrochloride is administered as part of a
composition in accordance with the present invention, there is a
reduction in the number of side effects associated with the
administration of guanfacine hydrochloride, or a reduction in the
likelihood of side effects associated with the administration of
guanfacine hydrochloride.
[0023] In accordance with a further aspect of the present invention
there is provided a pharmaceutical composition comprising
guafancine as an active agent and characterized in that said
composition when administered to a patient produces less of the
side effects usually associated with guafancine.
[0024] In one embodiment the side effects are chosen from Headache,
Asthenia, Somnolence, Dizziness, Tacchycardia, Nausea, Pain
Abdominal, Infect, Vomit, or Palpitations.
[0025] In a further embodiment the side effects are chosen from
Headache or Asthenia.
[0026] When the pharmaceutically active agent is anagrelide, the
composition may be employed in treating a variety of blood
disorders, including, but not limited to, myeloproliferative blood
disorders or MBDs, such as, for example, essential thrombocythemia,
or ET, chronic myelogenous leukemia, or CML, polycythemia vera, or
PV, and agnogenic myeloid metaplasia, or AMM. The composition
including anagrelide may be administered to an animal, such as a
mammal, including human and non-human primates, in an amount
effective to treat such disorders.
[0027] The active agent anagrelide may be administered to a patient
in an amount of from about 0.01 mg to 15 mg, preferably from about
0.1 mg to about 10 mg, more preferably from about 0.1 mg to about 5
mg and most preferably from about 0.5 mg to about 2 mg. In one
treatment regimen, anagrelide may be administered to a patient in
an amount of 0.5 mg four times a day, or 1 mg twice a day, for at
least one week. When anagrelide is administered as part of a
composition in accordance with the present invention, there is a
reduction in the number of side effects associated with the
administration of anagrelide, or a reduction of the likelihood of
side effects associated with the administration of anagrelide.
[0028] In accordance with a further aspect of the present invention
there is provided a pharmaceutical composition comprising
anagrelide as an active agent and characterized in that said
composition when administered to a patient produces less of the
side effects usually associated with anagrelide.
[0029] In one embodiment the side effects are chosen from Headache,
Asthenia, Somnolence, Dizziness, Tacchycardia, Nausea, Pain
Abdominal, Infect, Vomit, or Palpitations.
[0030] In a further embodiment the side effects are chosen from
Headache or Asthenia.
[0031] The invention now will be described with respect to the
following examples; however, the scope of the present invention is
not intended to be limited thereby.
EXAMPLE 1
[0032] Formulations in accordance with the present invention, as
well as control formulations, were prepared according to the direct
compression described hereinabove. In accordance with such method,
guanfacine HCl and other ingredients were sieved through a 40 mesh
steel screen. The sieved materials then were charged into a
Blendmaster blender (Patterson-Kelley Co.), and blended for 10
minutes with an intensifier bar on for 3 minutes. The blends then
are compressed into tablets on a rotary tablet press
(Stokes-Merrill Corp., Model 512) using appropriate tooling
[0033] The formulations are given in Table 1 below
1 TABLE 1 PD0052-22A PD0052-25B PD0052-28B PD0052-32B PD0052-32D
PD0052-39A Ingredient 1* 2** 1 2 1 2 1 2 1 2 1 2 Guanfacine 0.57
1.14 0.57 1.14 0.57 1.14 0.57 1.14 0.57 1.14 0.57 1.14 HCl Lactose
37.43 74.86 -- -- -- -- 45.00 90.00 65.00 130.00 -- -- -- --
ProSolv 20.00 40.00 -- -- 30.00 60.00 -- -- -- -- 29.82 59.64
Polyox WSR 40.00 80.00 40.00 80.00 -- -- 40.00 80.00 10.00 20.00
Ethocel FP -- -- -- -- 40.00 80.00 -- -- -- -- 39.82 79.64
Cellulose -- -- 50.00 100.00 -- -- -- -- -- -- -- -- acetate Sodium
-- -- -- -- 20.00 40.00 -- -- -- -- -- -- alginate Carrageenan --
-- -- -- -- -- -- -- -- -- 19.91 39.82 Carbopol -- -- -- -- -- --
-- -- 10.00 20.00 -- -- 974P Fumaric acid -- -- -- -- -- -- 5.00
10.00 -- -- -- -- Eudragit -- -- -- -- -- -- -- -- 5.00 10.00 -- --
L100-55 EDTA -- -- -- -- -- -- -- -- -- -- 0.50 1.00 Compritol --
-- 9.43 18.86 9.43 18.63 9.43 18.63 9.43 18.63 9.37 18.74 Stearic
acid 2.00 4.00 -- -- -- -- -- -- -- -- -- -- *1 = composition in %
weight **2 = composition in mg per tablet Note: PD0052-22A and
PD0052-25B contain no ionic materials in the formulations. These
two formulations serve as a control. Prosolv is a trade name for
silicified microcrystalline cellulose and marketed by Penwest Corp.
Polyox is a trade name for poly(ethyleneoxide) and marketed by
Union Carbide. Carbopol is a trade name for copolymer of acrylic
acid and marketed by BF Goodrich. Ethocel FP is a trade name for
ethyl cellulose fine powder grade and marketed by Dow Chemical.
Eudragit L100-55 is a trade name for poly(methacrylic acid, ethyl
acrylate) and marketed by Rohm GmbH. Compritol is a trade name for
glyceryl behenate and marketed by Gattefosse.
[0034] The dissolution data was determined as follows:
[0035] A Vankel dissolution tester (VanKel Industries, Edison,
N.J.) was used for all dissolution studies. The apparatus was
calibrated according to USP23. The dissolution in 0.1N hydrochloric
acid (pH 1.2) or pH 6.8 phosphate buffer was tested using the
paddle method (USP Apparatus II), employing 500 ml of dissolution
medium at a temperature of 37.degree. C. and an agitation rate of
50 rpm. Samples at specific time points were removed and filtered
through a 35 .mu.m filter. The filtered samples were kept in screw
cap glass test tubes until analysis. An HPLC system comprised of an
autosampler and a pump and a UV detector was used for sample
analysis. 50 .mu.l of the dissolution samples were injected
directly on the HPLC C18 column using a mixture of acetonitrile and
acetate buffer (20:80) as the mobile phase.
[0036] The dissolution data are given in Table 2 below.
2TABLE 2 Dissolution Data for Guanfacine Sustained Release Tablets
Time PD0052-22A PD0052-25B PD0052-28B PD0052-32B PD0052-32D
PD0052-39A (hour) 1* 2** 1 2 1 2 1 2 1 2 1 2 0.5 14.0 .+-. 0.6 7.0
.+-. 1.2 13.0 .+-. 1.5 5.0 .+-. 0.6 8.4 .+-. 2.1 10.0 .+-. 0.6 19.0
.+-. 1.2 12.0 .+-. 0.0 31.0 .+-. 1.2 11.0 .+-. 1.0 14.0 .+-. 0.6
10.0 .+-. 1.0 1.0 24.0 .+-. 1.0 12.0 .+-. 1.0 27.0 .+-. 2.0 7.0
.+-. 1.0 41.0 .+-. 1.7 20.0 .+-. 1.0 31.0 .+-. 2.6 20.0 .+-. 0.6
48.0 .+-. 1.2 19.0 .+-. 0.6 25.0 .+-. 1.0 18.0 .+-. 2.0 2.0 44.0
.+-. 0.6 19.0 .+-. 1.5 48.0 .+-. 2.5 11.0 .+-. 0.6 64.0 .+-. 2.5
36.0 .+-. 2.5 50.0 .+-. 4.2 35.0 .+-. 0.6 80.0 .+-. 5.6 31.0 .+-.
1.2 42.0 .+-. 1.0 31.0 .+-. 4.0 3.0 59.0 .+-. 0.6 26.0 .+-. 1.5
63.0 .+-. 1.7 14.0 .+-. 0.6 77.0 .+-. 2.6 49.0 .+-. 3.6 65.0 .+-.
6.1 49.0 .+-. 1.0 96.0 .+-. 5.0 46.0 .+-. 0.6 56.0 .+-. 2.6 46.0
.+-. 4.4 4.0 71.0 .+-. 6.0 31.0 .+-. 2.9 74.0 .+-. 1.5 16.0 .+-.
0.6 86.0 .+-. 3.2 59.0 .+-. 3.2 77.0 .+-. 5.5 61.0 .+-. 1.0 104
.+-. 3.5 56.0 .+-. 0.6 69.0 .+-. 3.0 56.0 .+-. 5.8 6.0 90.0 .+-.
2.0 39.0 .+-. 2.5 86.0 .+-. 1.7 19.0 .+-. 0.0 97.0 .+-. 3.5 71.0
.+-. 5.0 99.0 .+-. 4.4 87.0 .+-. 2.5 111 .+-. 4.0 74.0 .+-. 1.2
90.0 .+-. 2.6 72.0 .+-. 6.2 8.0 99.0 .+-. 1.7 46.0 .+-. 2.5 93.0
.+-. 2.1 21.0 .+-. 1.0 108 .+-. 3.8 80.0 .+-. 5.5 102 .+-. 1.2 97.0
.+-. 1.5 112 .+-. 4.0 89.0 .+-. 2.3 102 .+-. 2.3 83.0 .+-. 6.4
12.00 105.0 .+-. 61.0 .+-. 4.7 100.0 .+-. 25.0 .+-. 1.0 113 .+-.
3.6 91.0 .+-. 6.0 103 .+-. 2.3 98.0 .+-. 1.0 113 .+-. 3.8 107 .+-.
2.9 112 .+-. 0.6 96.0 .+-. 1.5 1.2 4.2 *1 = percent dissolved using
a pH 1.2 dissolution medium **2 = percent dissolved using a pH 6.8
dissolution medium Note: The data represent the mean percent
dissolved .+-. standard deviation of three replicate.
[0037] The above results show that the compositions of the present
invention have improved dissolution profiles when compared with the
control compositions.
EXAMPLE 2
[0038] Formulations in accordance with the present invention, as
well as control formulations, were prepared according to the direct
compression method described hereinabove. In accordance with such
method, guanfacine HCl and other ingredients were sieved through a
40 mesh steel screen. The sieved materials then were charged into a
Blendmaster blender (Patterson-Kelley Co.), and blended for 10
minutes with an intensifier bar on for 3 minutes. The blends then
are compressed into tablets on a rotary tablet press
(Stokes-Merrill Corp., Model 512) using appropriate tooling
[0039] The formulations are given in Table 3 below.
3TABLE 3 Weight Percentage of Components in Guanfacine MR Tablets,
1 mg, Batch Numbers 2015.00.001, 2016.00.001 and 2018.00.001
2015.00.001 2016.00.001 2018.00.001 Component (%) (%) (%)
Guanfacine HCl, USP 0.57 0.57 0.57 Hydroxypropryl 10.00 15.00 5.00
Methylcellulose (Methocel K4M Premium CR), USP/NF Methacrylic Acid
Copolymer 25.00 -- -- (Eudragit L 100-55), USP/NF Ammonio
Methacrylate -- 25.00 22.50 Copolymer (Eudragit RSPO), USP/NF
Silicified Microcrystalline 25.00 20.00 34.43 Cellulose (Prosolv HD
90) Lactose Monohydrate 24.43 24.43 20.00 Povidone Crospovidone
Granulated Blend (Ludipress) Fumaric Acid, USP/NF 5.00 10.00 5.00
Glyceryl Behenate (Compritol 10.00 5.00 12.50 888 ATO), USP/NF
Total 100.00 100.00 100.00
EXAMPLE 3
[0040] The solubility of anagrelide HCl in aqueous solutions in the
pH range of 1 to 11.4 at 25.degree. C. was determined. The
solubility-pH profile of anagrelide HCl is shown in FIG. 1. Below
pH 3, the solubility increased as the pH decreased which is
consistent with formation of a more soluble protonated form. At pH
0.96 the solubility was 236 mcg/mL. Above pH 4, the solubility was
independent of pH and remained constant (ca. 1.2 mcg/mL) up to pH
8. Above pH 8, the solubility increased with increasing pH which is
due to the ionization of the quinazoline moiety. The solubility at
pH 11.4 was 992 mcg/mL.
[0041] Formulations I through IV were formulated according to the
procedure described in Example 1, except that anagrelide HCl has
been substituted for guanfacine HCl.
[0042] The formulations are given in Table 4 below.
4 TABLE 4 Formulation I Formulation II Formulation III Formulation
IV Ingredients mg/Tablet % mg/Tablet % mg/Tablet % mg/Tablet %
Anagrelide HCl 2.44 1.22 2.44 1.22 2.44 1.22 2.44 1.22 (2.0 base)
(2.0 base) (2.0 base) (2.0 base) Polyox WSR 301 30.00 15.00 50.00
25.00 Prosolv HD 90 60.00 30.00 60.00 30.00 66.00 33.00 80.00 40.00
Fujicalin SG* 60.00 30.00 30.00 15.00 60.00 30.00 40.00 20.00
Eudragit L 100-55 20.00 10.00 30.00 15.00 24.00 12.00 20.00 10.00
Ethocel Std. 30.00 15.00 100 FP Fumaric Acid 10.00 5.00 10.00 5.00
Compritol 17.56 8.78 17.56 8.78 17.56 8.78 17.56 8.78 888 ATO
Polyox WSR N80 40.00 20.00 Formulation # PD0073-55A PD0073-57A
PD0073-64A PD0073-78A Total 200.00 100.00 200.00 100.00 200.00
100.00 200.00 100.00 *Fujicalin SG is a dibasic calcium phosphate
sold by Fuji Chemical Industry Co., Ltd.
[0043] A Vankel dissolution tester (VanKel Industries, Edison,
N.J.) was used for all dissolution studies. The apparatus was
calibrated according to USP 23. The dissolution in 0.1N
hydrochloric acid (pH 1.1) with 0.1% Tween 80 or pH 6.8 phosphate
buffer with 0.1% Tween 80 was tested using the paddle method (USP
Apparatus II), employing 900 ml of dissolution medium at a
temperature of 37.degree. C., and an agitation rate of 100 rpm.
Samples at specific time points were removed and filtered through a
70 .mu.m filter. The filtered samples were kept in screw cap glass
test tubes until analysis. An HPLC system composed of an
autosampler and a pump and a UV detector was used for sample
analysis. 20 .mu.l of the dissolution samples were injected
directly on the HPLC C18 column using a mixture of acetonitrile and
ammonium acetate buffer (36:64) as the mobile phase.
[0044] The dissolution data are given in Table 5 below.
5TABLE 5 Dissolution Data for Anagrelide Sustained Release Tablets
PD0073-55A PD0073-57A PD0073-64A PD0073-78A Time(hour) 1* 2** 1 2 1
2 1 2 0.5 N/A 4.0 .+-. 0.6 6.0 .+-. 0.0 2.0 .+-. 0.0 27.0 .+-. 2.1
5.0 .+-. 1.0 16.0 .+-. 0.6 12.0 .+-. 1.2 1.0 13.0 .+-. 0.6 6.0 .+-.
0.0 9.0 .+-. 0.6 3.0 .+-. 0.0 39.0 .+-. 3.1 11.0 .+-. 2.9 27.0 .+-.
1.5 30.0 .+-. 1.0 2.0 21.0 .+-. 0.6 10.0 .+-. 0.6 15.0 .+-. 0.6 7.0
.+-. 0.0 52.0 .+-. 4.5 31.0 .+-. 3.2 43.0 .+-. 3.6 56.0 .+-. 1.7
4.0 40.0 .+-. 2.5 22.0 .+-. 1.2 30.0 .+-. 2.3 16.0 .+-. 0.6 69.0
.+-. 5.3 58.0 .+-. 3.5 55.0 .+-. 4.4 72.0 .+-. 1.2 8.0 72.0 .+-.
5.0 57.0 .+-. 7.4 57.0 .+-. 2.0 39.0 .+-. 1.0 85.0 .+-. 2.6 73.0
.+-. 2.6 67 .+-. 5.5 78.0 .+-. 0.6 12.0 95.0 .+-. 2.9 77.0 .+-. 5.3
77.0 .+-. 2.1 62.0 .+-. 3.6 88.0 .+-. 1.0 79.0 .+-. 2.1 83 .+-. 3.6
82.0 .+-. 0.0 *1 = percent dissolved using a pH 1.1 dissolution
medium with 0.1% Tween 80. **2 = percent dissolved using a pH 6.8
dissolution medium with 0.1% Tween 80. Note: The data represent the
mean percent dissolved .+-. standard deviation of three
replicates.
EXAMPLE 4
[0045] Formulations V, VI, and VII, which are modifications of
Formulation IV of Example 2, include the following components as
shown in Table 6 below.
6 TABLE 6 Formulation V Formulation VI Formulation VII Component
mg/tablet % mg/tablet % mg/tablet % Anagrelide HCl, Monohydrate*
0.63 0.315 1.26 0.630 1.88 0.940 Polyethylene Oxide, 60 Mesh, NF
40.00 20.000 40.00 20.000 40.00 20.000 (Polyox .TM. WSR N80)
Dibasic Calcium Phosphate, Anhydrous, 39.21 19.605 37.18 18.590
38.56 19.280 USP (Fujicalin SG) Silicified High Density
Microcrystalline 80.00 40.000 80.00 40.000 80.00 40.000 Cellulose
(Prosolv HD 90), USP Methacrylic Acid Copolymer, NF 20.00 10.000
20.00 10.000 20.00 10.000 (Eudragit L 100-55) Glyceryl Behenate, NF
17.56 8.780 17.56 8.780 17.56 8.780 (Compritol 888 ATO) Magnesium
Stearate Powder, NF 2.00 1.000 2.00 1.000 2.00 1.00 (Non-Bovine)
Green PB-1763 0.60 0.300 -- -- -- -- Purple PB-1855 -- -- 2.00
1.000 -- -- Total 200.0 100.0 200.0 100.0 200.0 100.0 *includes 3%
overcharge for material loss during processing.
[0046] Formulations V, VI, and VII were prepared and processed into
tablets according to the following procedure:
[0047] Blending
[0048] 1. Weigh all the ingredients (Prosolv HD90 is divided into 3
portions).
[0049] 2. Place the ingredients in the order listed below into the
V-blender equipped with an intensifier bar:
[0050] a. Prosolv HD90 portion #1
[0051] b. Anagrelide HCl Monohydrate
[0052] c. Green PB-1763 for Formulation V; Purple PB-1855 for
Formulation VI strength; no color for Formulation VII
[0053] d. Prosolv HD90 portion #2
[0054] 3. Blend for 4 minutes in a V-blender with the intensifier
bar off. Turn the intensifier bar on and blend for 2 minutes. Turn
the intensifier bar off and blend for 4 minutes.
[0055] 4. Pass the blend through a 30-mesh screen using a Comil at
the low speed setting.
[0056] 5. Pass Prosolv HD90 portion #3 through the same Comil using
the 30-mesh screen and low speed.
[0057] 6. Place the ingredients into the larger V-blender equipped
with an intensifier bar in the following order:
[0058] a. Milled Prosolv HD90 from Step 5
[0059] b. Polyox WSR N80, 60 mesh
[0060] c. Milled blend from Step 4
[0061] d. Eudragit L100-55
[0062] e. Fujicalin SG
[0063] 7. Blend these ingredients for 4 minutes with intensifier
bar off. Turn the intensifier bar on and blend for 2 minutes. Turn
the intensifier bar off, add Compritol 888 ATO and blend for 4
minutes.
[0064] 8. Discharge this blend from the V-blender into a suitable
container.
[0065] 9. Pass Magnesium Stearate through a 30-mesh screen and
collect it in a polyethylene bag.
[0066] 10. Pass the blend from step 8 through a 30-mesh screen
using a Comil at the low speed setting and collect it in a
polyethylene bag.
[0067] 11. Transfer the milled blend from step 10 and the Magnesium
Stearate from step 9 into the V-blender used in step 7 and mix for
5 minutes with the intensifier bar off.
[0068] 12. Discharge the blend from step 11 into a polyethylene
bag.
[0069] Tableting
[0070] 1. Load the blend into the tablet press hopper.
[0071] 2. Adjust the tablet weight to 200 mg and the appropriate
tablet hardness.
[0072] 3. Compress the blend into tablets using caplet-shaped
tooling.
[0073] 4. Take tablet samples as required by departmental SOPs to
ensure product quality and to complete any process protocols of the
tableting process.
[0074] 5. Run tablets through an appropriate deduster.
[0075] 6. Collect compressed tablets in a suitable container double
lined with clean polyethylene bags.
EXAMPLE 5
[0076] Formulations 1, 2, and 3, were prepared, which had the
following components in the following amounts, as shown in Table 7
below.
7 TABLE 7 Amount, wt % Formulation Formulation Formulation
Component 1 2 3 Anagrelide HCl, Monohydrate 0.61 0.61 0.61
Polyethylene Oxide 15.00 -- 25.00 (Polyox .TM. WSR 301)
Polyethylene Oxide, 60 Mesh, -- 20.00 -- NF (Polyox .TM. WSR N80)
Dibasic Calcium Phosphate, 30.61 20.61 30.61 Anhydrous, USP
(Fujicalin SG) Silicified High Density 30.00 40.00 15.00
Microcrystalline Cellulose (Prosolv HD 90), USP Methacrylic Acid
Copolymer 10.00 10.00 15.00 (Eudragit L 100-55) Fumaric Acid 5.00
-- 5.00 Glyceryl Behenate, NF 8.78 8.78 8.78 (Compritol 888 ATO)
Total 100.0 100.0 100.0
[0077] The purpose of this example was to assess the
bioavailability of three anagrelide HCl extended release tablet
formulationsFormulation 1Formulation 2Formulation 3, compared to an
immediate release anagrelide HCl formulation (Agrylin.RTM., Lot No.
RPA 0002A), following a 1 mg dose, and to determine the safety and
tolerability of the extended release formulations in healthy
volunteers.
[0078] The extent of absorption of each drug (AUC.sub.o-t) the
maximum concentration of drug in plasma (C.sub.max), and the time
of the maximum concentration (T.sub.max) were evaluated.
[0079] The mean plasma concentrations for anagrelide following
administration of a single 1 mg dose of Agrylin.RTM., or the
anagrelide HCl extended release Formulations 1, 2, or 3, are given
in FIG. 2.
[0080] The corresponding pharmacokinetic parameters for each
formulation are given in Table 8 below.
8TABLE 8 Mean Pharmacokinetic Parameters for Anagrelide T.sub.width
AUC.sub.0-inf AUC.sub.0-t C.sub.max T.sub.max C.sub.max Treatment
(ng .multidot. hr/mL) (ng .multidot. hr/mL) (ng/mL) (hr) (hr)
Formulation 1 9.24* 8.47* 1.15* 3.41* 5.06 Formulation 2 10.32*
9.10* 1.01* 3.17* 5.99 Formulation 3 9.41* 8.48* 1.17* 3.46* 4.30
Agrylin .RTM. 14.89 14.46 5.67 1.25 2.17 Bioequivalence Formulation
1: 0.61 0.58 0.21 Ratio of test-to-ref. 90% CI 0.49-0.76 0.46-0.73
0.17-0.27 Formulation 2: 0.59 0.53 0.17 Ratio of test-to-ref. 90%
CI 0.47-0.74 0.42-0.67 0.14-0.22 Formulation 3: 0.66 0.64 0.25
Ratio of test-to-ref. 90% CI 0.52 0.50-0.81 0.20-0.32 *p < 0.05
compared to Agrylin .RTM. by Dunnett's test
[0081] All three experimental formulations exhibited extended
release characteristics for drug delivery. The extent of absorption
of anagrelide from the experimental formulations relative to
immediate-release Agrylin.RTM. (ratio of test-to-reference) was
58%, 53% and 64% for the Formulations 1, 2 and 3, respectively.
[0082] A measure of the extent of delay in release of active
pharmaceutical ingredient of the experimental formulations was the
time to reach maximum concentration (T.sub.max) values observed for
anagrelide. The T.sub.max values were approximately 2 hours later
than that observed for Agrylin.RTM., demonstrating about a 2.6-fold
delay in time to reach C.sub.max for the three extended release
formulations compared with the immediate-release Agrylin.RTM..
Furthermore, the length of time at which the anagrelide plasma
concentration remained above 1/2C.sub.max (T.sub.width
1/2C.sub.max) was approximately two- to three-fold greater for the
extended release formulations than the immediate release
formulation, demonstrating good extended release
characteristics.
[0083] No serious adverse events were reported. One subject
discontinued due to an adverse event (head cold) considered not
related to study drug. There were a total of 46 adverse events
(AEs) experienced by eleven (11) subjects. The most frequently
reported events (>5%), included asthenia, headache, somnolence,
and dizziness, and were not unexpected. These events have been
reported frequently by the target patient population at large
receiving Agrylin.RTM. for the treatment of thrombocythemia
secondary to all myeloproliferative disorders. Treatment emergent
AEs are summarized in Table 9.
9TABLE 9 Treatment Emergent AEs Preferred Term (Costart) Count % (n
= 12) Asthenia 12 26.1 Headache 9 19.6 Somnolence 6 13.0 Dizziness
5 10.9 Tachycardia 2 4.3 Infection 2 4.3 Nausea 2 4.3 Vomit 2 4.3
Pain Abd 1 2.2 Palpitations 1 2.2 Pain 1 2.2 Hem 1 2.2 Voice
alteration 1 2.2 Thirst 1 2.2 Total 46 100.0
[0084] The data would indicate that adverse events (AEs) observed
in subjects following dosage with the extended release formulation
were not as prevalent as AEs observed following the immediate
release formulation (Agrylin.RTM.). More than 50% of the reported
AEs were observed following Agrylin.RTM. administration. The number
of adverse events following administration of the new extended
release formulations were 8/46 (17%) for Formulation 1, 9/46 (20%)
for Formulation 2, and 4/46 (9%) for Formulation 3 compared to
25/46 (54%) for the marketed Agrylin.RTM.. The incidence of
subjects reporting adverse events for the new extended-release
formulations (4/12 (33%), 6/12 (50%), and 2/12 (17%) for
Formulations 1, 2, and 3, respectively) also were substantially
lower than the incidence observed in the Agrylin.RTM. group (10/12
(83%)). The number and percentage of subjects reporting adverse
events are presented in Table 10.
10TABLE 10 Treatment Emergent Adverse Events per Treatment Group
Preferred No. % Term Subjects Subjects No. AEs Drug Treatment
(Costart) Reporting Reporting Reported Formulation 1 Asthenia 3
25.0 3 (n = 12) Nausea 1 8.3 1 Pain 1 8.3 1 Somnolence 1 8.3 1
Thirst 1 8.3 1 Vomit 1 8.3 1 Formulation 2 Asthenia 3 25.0 3 (n =
12) Dizziness 2 16.7 2 Headache 2 16.7 2 Somnolence 1 8.3 1 Hem 1
8.3 1 Formulation 3 Asthenia 1 9.3 1 (n = 11) Headache 1 9.3 1
Infect 1 9.3 1 Voice 1 9.3 1 alteration Agrylin .RTM. Headache 6
50.0 6 (n = 12) Asthenia 5 41.7 5 Somnolence 3 25.0 4 Dizziness 3
25.0 3 Tacchycardia 2 16.7 2 Nausea 1 8.3 1 Pain 1 8.3 1 Abdominal
Infect 1 8.3 1 Vomit 1 8.3 1 Palpitations 1 8.3 1 Total (n = 12)
46
[0085] With respect to clinical laboratory and physical examination
findings, statistically significant (p<0.01) increases in pulse
compared with baseline were observed with Agrylin.RTM. at 2, 4, and
24 hours post dose. Significant increases were observed at 24 hours
post dose for Formulations 1 and 3. Only Agrylin.RTM. showed a
statistically significant changed from baseline for blood pressure
(i.e. at 24 hours post dose for diastolic blood pressure).
[0086] It is to be understood, however, that the scope of the
present invention is not to be limited to the specific embodiments
described above. The invention may be practiced other than as
particularly described and still be within the scope of the
accompanying claims.
* * * * *