U.S. patent application number 10/202830 was filed with the patent office on 2003-01-30 for methods and compositions for treating depression and other disorders using optically pure (-)-bupropion.
This patent application is currently assigned to Sepracor, Inc.. Invention is credited to Young, James W..
Application Number | 20030022942 10/202830 |
Document ID | / |
Family ID | 22110630 |
Filed Date | 2003-01-30 |
United States Patent
Application |
20030022942 |
Kind Code |
A1 |
Young, James W. |
January 30, 2003 |
Methods and compositions for treating depression and other
disorders using optically pure (-)-bupropion
Abstract
Methods and compositions are disclosed utilizing the optically
pure (-)-isomer of bupropion, which is a potent drug for treating
depression, Parkinson's disease, obesity, weight gain and other
disorders.
Inventors: |
Young, James W.; (Palo Alto,
CA) |
Correspondence
Address: |
PENNIE & EDMONDS LLP
1667 K STREET NW
SUITE 1000
WASHINGTON
DC
20006
|
Assignee: |
Sepracor, Inc.
|
Family ID: |
22110630 |
Appl. No.: |
10/202830 |
Filed: |
July 26, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10202830 |
Jul 26, 2002 |
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10076645 |
Feb 19, 2002 |
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6451860 |
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10076645 |
Feb 19, 2002 |
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09891266 |
Jun 27, 2001 |
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6369113 |
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09891266 |
Jun 27, 2001 |
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09553029 |
Apr 20, 2000 |
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6277887 |
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09553029 |
Apr 20, 2000 |
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09238812 |
Jan 28, 1999 |
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6110973 |
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60072931 |
Jan 29, 1998 |
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Current U.S.
Class: |
514/649 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/14 20180101; A61K 31/137 20130101; A61P 3/04 20180101; A61P
15/00 20180101; A61K 31/135 20130101; A61P 1/14 20180101; A61P
15/10 20180101; A61P 25/16 20180101; A61P 25/24 20180101 |
Class at
Publication: |
514/649 |
International
Class: |
A61K 031/137 |
Claims
What is claimed is:
1. A method of treating depression in a human while avoiding the
concomitant liability of adverse effects associated with
administration of racemic bupropion, which comprises administering
to a human in need of antidepressant therapy, a therapeutically
effective amount of (-)-bupropion or a pharmaceutically acceptable
salt thereof, substantially free of its (+)-stereoisomer.
2. The method of claim 1 wherein said amount is sufficient to
alleviate said depression, but insufficient to cause said adverse
effects associated with administration of racemic bupropion.
3. The method of claim 1 wherein (-)-bupropion is administered
intravenously, transdermally or orally.
4. The method of claim 3 wherein (-)-bupropion is administered
orally as a tablet or a capsule.
5. The method of claim 1 wherein the amount administered is from
about 10 mg to about 750 mg.
6. The method of claim 5 wherein the amount administered is from
about 50 mg to about 600 mg.
7. The method of claim 6 wherein the amount administered is from
about 60 mg to about 450 mg.
8. The method of claim 1 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof is greater than
approximately 90% by weight of the total amount of bupropion.
9. The method of claim 1 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer is administered together with a pharmaceutically
acceptable carrier.
10. The method according to claim 1 wherein (-)-bupropion is
administered as the hydrochloride salt.
11. The method of claim 1 wherein (-)-bupropion is administered in
a sustained or controlled release formulation.
12. A method of treating Parkinson's disease in a human while
avoiding the concomitant liability of adverse effects associated
with the administration of racemic bupropion, which comprises
administering to said human in need of treatment for Parkinson's
disease, a therapeutically effective amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer.
13. The method of claim 12 wherein said amount is sufficient to
alleviate said Parkinson's disease, but insufficient to cause said
adverse effects associated with administration of racemic
bupropion.
14. The method of claim 12 wherein (-)-bupropion is administered by
intravenously, transdermally, or orally.
15. The method of claim 14 wherein (-)-bupropion is administered
orally as a tablet or a capsule.
16. The method of claim 12 wherein the amount administered is from
about 10 mg to about 750 mg.
17. The method of claim 16 wherein the amount administered is from
about 50 mg to about 600 mg.
18. The method of claim 17 wherein the amount administered is from
about 60 mg to about 450 mg.
19. The method of claim 12 wherein the amount of (-) -bupropion or
a pharmaceutically -acceptable salt thereof is greater than
approximately 90% by weight of the total amount of bupropion.
20. The method of claim 12 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer, is administered together with a pharmaceutically
acceptable carrier.
21. The method according to claim 12 wherein (-)-bupropion is
administered as the hydrochloride salt.
22. The method of claim 12 wherein (-)-bupropion is administered in
a sustained or controlled release formulation.
23. A method for treating obesity or weight gain in a human which
comprises administering to a human in need of weight reduction or
weight control a therapeutically effective amount of (-)-bupropion
or a pharmaceutically acceptable salt thereof, substantially free
of its (+)-stereoisomer.
24. The method of claim 23 wherein said amount is sufficient to
alleviate obesity or weight gain, but insufficient to cause adverse
effects associated with administration of racemic bupropion.
25. The method of claim 23 wherein (-)-bupropion is administered by
intravenously, transdermally, or orally.
26. The method of claim 25 wherein (-)-bupropion is administered
orally as a tablet or a capsule.
27. The method of claim 23 wherein the amount administered is from
about 10 mg to about 750 mg.
28. The method of claim 27 wherein the amount administered is from
about 50 mg to about 600 mg.
29. The method of claim 28 wherein the amount administered is from
about 60 mg to about 450 mg.
30. The method of claim 23 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof is greater than
approximately 90% by weight of the total amount of bupropion.
31. The method of claim 23 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer, is administered together with a pharmaceutically
acceptable carrier.
32. The method according to claim 23 wherein (-)-bupropion is
administered as the hydrochloride salt.
33. The method of claim 23 wherein (-)-bupropion is administered in
a sustained release or controlled release formulation.
34. A method of treating a disorder selected from the group
consisting of bipolar disorders, attention-deficit disorders,
conduct disorders, psycho-sexual dysfunction, bulimia, eating
disorders and specific food craving which comprises administering
to a human suffering from said disorder a therapeutically effective
amount of (-)-bupropion, or a pharmaceutically acceptable salt
therefore, substantially free of its (+)-stereoisomer.
35. The method of claim 34 wherein (-)-bupropion is administered by
intravenously, transdermally, or orally.
36. The method of claim 35 wherein (-)-bupropion is administered
orally as a tablet or a capsule.
37. The method of claim 34 wherein the amount administered is from
about 10 mg to about 750 mg.
38. The method of claim 37 wherein the amount administered is from
about 50 mg to about 600 mg.
39. The method of claim 38 wherein the amount administered is from
about 60 mg to about 450 mg.
40. The method of claim 34 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof is greater than
approximately 90% by weight of the total amount of bupropion.
41. The method of claim 34 wherein the amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer, is administered together with a pharmaceutically
acceptable carrier.
42. The method according to claim 34 wherein (-)-bupropion is
administered as the hydrochloride salt.
43. The method of claim 34 wherein (-)-bupropion is administered in
a controlled or sustained release formulation.
44. A pharmaceutical composition which comprises a therapeutically
amount of (-)-bupropion or a pharmaceutically acceptable salt
thereof, substantially free of its (+)-stereoisomer, and a
pharmaceutically acceptable carrier.
45. The composition according to claim 44 wherein the amount is
about 10 mg to about 750 mg.
46. The composition according to claim 44 which comprises
(-)-bupropion hydrochloride.
47. The composition according to claim 46 wherein said composition
is adapted for oral administration.
48. The composition according to claim 46 adapted for intravenous
delivery.
49. The composition according to claim 46 for use in a transdermal
formulation.
50. The composition according to claim 46 for use as a transdermal
patch.
51. The composition of claim 46 wherein said composition is a solid
preparation.
52. A sustained release formulation which comprises (-)-bupropion
or a pharmaceutically acceptable salt thereof substantially free of
its (+)-stereoisomer, and a pharmaceutically acceptable
carrier.
53. The sustained release formulation of claim 52 wherein said
formulation is a tablet, capsule or gelcap.
Description
FIELD OF THE INVENTION
[0001] This invention relates to methods of treatment and
pharmaceutical compositions employing the compound
(-)-bupropion.
BACKGROUND OF THE INVENTION
2.1. Steric Relationships and Drug Action
[0002] Many organic compounds exist in optically active forms,
i.e., they have the ability to rotate the plane of plane-polarized
light. In describing an optically active compound, the prefixes D
and L or R and S are used to denote the absolute configuration of
the molecule about its chiral center(s). The prefixes (+) and (-)
or d and l are employed to designate the sign of rotation of
plane-polarized light by the compound, with (-) or l meaning that
the compound is levorotatory. A compound prefixed with (+) or d is
dextrorotatory. For a given chemical structure, these compounds,
called stereoisomers, are identical except that they are mirror
images of one another. A specific stereoisomer may also be referred
to as an enantiomer, and a mixture of such isomers is often called
an enantiomeric or racemic mixture.
[0003] Stereochemical purity is of importance in the field of
pharmaceuticals, where 16 of the 20 most prescribed drugs exhibit
chirality. A case in point is provided by the L-form of the
.beta.-adrenergic blocking agent, propranolol, which is known to be
100 times more potent than the D-enantiomer.
[0004] Furthermore, optical purity is important since certain
isomers may actually be deleterious rather than simply inert. For
example, it has been suggested that the D-enantiomer of thalidomide
was a safe and effective sedative when prescribed for the control
of morning sickness during pregnancy, while the corresponding
L-enantiomer was a potent teratogen.
[0005] Bupropion is available only as a racemic mixture called
Wellbutrin.RTM. and Wellbutrin SR.RTM. (for depression), and
Zyban.RTM. (to achieve smoking cessation). That is, bupropion is
available as a mixture of optical isomers, called enantiomers. The
racemic mixture of bupropion which is commercially available is
administered as a hydrochloride salt. In addition, European Patent
Application No. 84101070.5 published Sep. 12, 1984 discloses the
benefits of bupropion maleate over bupropion hydrochloride.
[0006] Bupropion is used primarily in the treatment of depression,
which along with mania, falls under the heading of affective
disorders. Particularly, bupropion is used in patients who do not
respond to, or cannot tolerate other antidepressants, such as the
tricyclic agents or monoamine oxidase inhibitors. Additionally, the
racemic mixture of bupropion is useful in the management of
patients with bipolar and schizo-affective disorder,
attention-deficit disorder, psycho-sexual dysfunction, bulimia and
other eating disorders, and Parkinson's disease.
[0007] Affective disorders, including major depression, and the
bipolar, manic-depressive illness, are characterized by changes in
mood as the primary clinical manifestation. Major depression is the
most common of the significant mental illnesses, and it must be
distinguished clinically from periods of normal grief, sadness and
disappointment, and the related dysphoria or demoralization
frequently associated with medical illness. Depression is
characterized by feelings of intense sadness, and despair, mental
slowing and loss of concentration, pessimistic worry, agitation,
and self-deprecation. Physical changes can also occur, including
insomnia, anorexia, and weight loss, decreased energy and libido,
and disruption of hormonal circadian rhythms. Often the condition
responds well to tricyclic or related antidepressant drugs,
monoamine oxidase inhibitors, or in resistant cases or severe
disease, to electro-convulsive shock treatment.
[0008] Mania, as well as depression, is characterized by changes in
mood as the primary symptom. Either of these two extremes of mood
may be accompanied by psychosis with disordered thought and
delusional perceptions. Psychosis may have, as a secondary symptom,
a change in mood, and it is this overlap with depression that
causes much confusion in diagnosis. Severe mood changes without
psychosis frequently occur in depression and are often accompanied
by anxiety.
[0009] Through an unknown mechanism of action, bupropion has been
demonstrated to be an effective treatment in depression in
short-term and longer duration clinical studies. The racemic
mixture of bupropion has been reported to have an antidepressant
activity equal to amitriptyline, the tricyclic antidepressant, with
fewer anticholinergic, sedative and cardiovascular side effects
than with amitriptyline.
[0010] Parkinson's disease, independent of a specific etiology, is
a chronic, progressive central nervous system disorder which
usually appears insidiously in the latter decades of life. The
disease produces a slowly increasing disability in purposeful
movement. It is characterized by four major clinical features of
tremor, bradykinesia, rigidity and a disturbance of posture. Often
patients have an accompanying dementia. In idiopathic Parkinsonism,
there is usually a loss of cells in the substantia nigra, locus
ceruleus, and other pigmented neurons of the brain, and a decrease
of dopamine content in nerve axon terminals of cells projecting
from the substantia nigra. The understanding that Parkinsonism is a
syndrome of dopamine deficiency and the discovery of levodopa as an
important drug for the treatment of the disease were the logical
culmination of a series of related basic and clinical observations,
which serves as the rationale for drug treatment.
[0011] When the racemic mixture of bupropion is used to treat
Parkinson's disease, an improvement in gait, akinesia, and postural
stability were observed, with tremor improving in those patients
experiencing the most global benefit. Concomitant depression was
alleviated in several of the patients reporting the condition.
[0012] Attention-deficit disorder ("ADD") is a common behavioral
learning disorder in children which adversely affects school
performance and family relationships. Symptoms and signs include
hyperactivity (e.q., ADDH and AD/HD, DSM-IV), impulsivity,
emotional lability, motor incoordination and some perceptual
difficulties. Treatment has included psychostimulants, which while
effective are controversial, and may cause troubling side effects
such as dysphoria, headache and growth retardation. Other drugs,
including the tricyclic antidepressants, appear to improve
attention, but may be less effective than the psychostimulants.
[0013] Bupropion has been shown to be effective in children with
attention-deficit disorder or conduct disorder thus improving the
symptoms of anxiety, hostility and uncooperativeness, antisocial
behavior, as well as eating disturbances. The drug has also
demonstrated activity in cases of psycho-sexual dysfunction and
bulimia. However, bupropion is contra-indicated in patients with a
seizure disorder, or a current or prior diagnosis of bulimia or
anorexia nervosa characterized by a disturbed sense of body image
and abnormally high anxiety about weight gain.
[0014] It has been suggested that the racemic mixture of bupropion
could be used to assist in weight loss. Treatment with bupropion is
consistently associated with a lack of weight gain. Also bupropion
reduces episodes of binge eating and purging. Although the
mechanism by which bupropion causes weight loss is uncertain, an
increase in the activity of the patient may play some part together
with subtle changes in food intake and metabolism.
[0015] The causes of excess body weight and/or obesity are complex;
however, a common denominator in the overweight person's diet is a
caloric intake which exceeds that person's body expenditures. One
method of treating a person who is overweight and/or obese is to
restrict that person's caloric intake, in combination with an
exercise regimen. This method may be limited in its effectiveness
since many overweight or obese people have developed eating and
activity patterns which are counterproductive to achieving weight
reduction. Another method to treat overweight or obese patients is
to administer appetite suppressant drugs in conjunction with a
weight reduction program. The drawback to this method is that many
appetite suppressant drugs produce undesirable adverse effects
which limit their usefulness.
[0016] The racemic mixture of bupropion, in addition to its use in
the treatment of depression and the other above-mentioned
disorders, has been shown to have a wide spectrum of action which
includes:
[0017] Treatment of the effects of ethanol (U.S. Pat. No.
4,393,078)
[0018] Treatment of Tardine Dyskinesia (U.S. Pat. No.
4,425,363)
[0019] Treatment of Minimal Brain Dysfunction (U.S. Pat. No.
4,435,449)
[0020] Treatment of amelioration of prostate hypertrophy and sexual
dysfunction (U.S. Pat. No. 4,835,147)
[0021] Treatment of psychostimulant addiction (U.S. Pat. No.
4,935,429)
[0022] Treatment of Psychosexual Dysfunction (U.S. Pat. No.
4,507,323)
[0023] Methods of Reducing Cholesterol (U.S. Pat. No.
4,438,138)
[0024] Methods of assisting weight loss (U.S. Pat. No.
4,895,845)
[0025] The racemic mixture of bupropion has been shown to have
certain advantages over other antidepressant drugs. For example,
bupropion does not inhibit monoamine oxidase, or block the reuptake
of serotonin. At therapeutic concentrations, the compound
presumably does not bind to adrenergic, dopamine, GABA, histamine,
muscarinic, serotonin, or imipramine binding sites. While its
specific neurochemical antidepressant action is unknown, it does
have a relatively weak effect on blocking the reuptake of dopamine,
and it appears to reduce norepinephrine metabolism.
[0026] While the racemic mixture of bupropion has advantages, it
also has disadvantages. Among these disadvantages are adverse
effects in addition to those described above. The most serious
adverse effect associated with the racemic mixture of bupropion is
the increased incidence of seizures. In addition, other frequently
reported adverse effects associated with the use of racemic
bupropion include nausea, vomiting, excitement, agitation, blurred
vision, restlessness, postural tremor, and some
hallucinations/confusional states with the potential for abuse.
Other adverse or side effects associated with the racemic mixture
of bupropion include but are not limited to anxiety, insomnia,
headaches and/or migraines, dry mouth, constipation, tremor,
sleeping disturbances, dermatologic problems (e.g., rashes),
neuropsychiatric signs and symptoms (e.g., delusions and paranoia),
and weight loss or gain. See, the Physician's. Desk Reference.RTM.
(1998). These effects are dose limiting in a number of patients. In
Parkinsonian patients, the adverse effects can be the particular
toxicity of the racemic mixture of bupropion, or the result of a
drug interaction (as most patients were receiving concomitant
levodopa).
[0027] Thus, it is desirable to find a compound with the advantages
of the racemic mixture of bupropion without the above-described
disadvantages.
SUMMARY OF THE INVENTION
[0028] The active compound of compositions and methods disclosed
herein is an optical isomer of the compound bupropion which is
described in U.S. Pat. Nos. 3,819,706 and 3,885,046. Chemically,
this isomer is (-)-2-(tertbutylamino)-3'-chloropropiophenone or
(-)-1-(3-chlorophenyl)-2- [(1,1-dimethyl-ethyl)amino]-1-propanone.
This isomer will hereinafter be referred to as "(-)-bupropion",
which also includes the substantially optically pure (-)-bupropion
isomer.
[0029] It has now been discovered that the optically pure
(-)-isomer of bupropion is an effective antidepressant which is
useful in treating depression in humans. In accordance with the
present invention, (-)-bupropion can be used to treat depression
while avoiding adverse effects including but not limited to
seizures, agitation, dry mouth, insomnia, headache/migraine,
nausea, dizziness, tachycardia, vomiting, constipation, and tremor
associated with the racemic mixture of bupropion. It has also been
discovered that (-)-bupropion and pharmaceutical compositions
containing optically pure (-)-bupropion are useful in treating
weight gain or obesity. Furthermore, it has been discovered that
the optically pure (-)-isomer of bupropion is useful in the
treatment of Parkinson's disease. In addition, it has been found
that the optically pure (-)-isomer of bupropion is useful in the
treatment of other disorders including but not limited to bipolar
disorders, attention-deficit disorders, conduct. disorders,
psycho-sexual dysfunction, bulimia, eating disorders and specific
food cravings.
[0030] The present invention also includes methods for treating the
above-described conditions in a human while avoiding adverse
effects that are associated with the racemic mixture of bupropion,
by administering the optically pure (-)-isomer of bupropion to said
human.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present invention encompasses a method of treating
depression in a human while avoiding the concomitant liability of
adverse effects associated with the administration of racemic.
bupropion which comprises administering to said human in need of
antidepressant therapy, an amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer, said amount being sufficient to alleviate
depression, but insufficient to cause adverse effects associated
with racemic bupropion.
[0032] The present invention also encompasses pharmaceutical
compositions for the treatment of humans which comprises a
therapeutically effective amount of (-)-bupropion or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer, and a pharmaceutically acceptable carrier.
Preferred pharmaceutical compositions are those which have a means
for controlled sustained release of the active ingredient,
(-)-bupropion.
[0033] The present invention further encompasses a method of
treating Parkinson's disease in a human while avoiding the
concomitant liability of adverse effects associated with the
administration of racemic bupropion, which comprises administering
to said human suffering from Parkinson's disease, an amount of
(-)-bupropion, or a pharmaceutically acceptable salt thereof,
substantially free of its (+)-stereoisomer, said amount being
sufficient to alleviate said condition, but insufficient to cause
adverse effects associated with administration of racemic
bupropion.
[0034] Further, the present invention encompasses a method of
treating obesity or weight gain in a human, which comprises
administering to said human in need of a reduction in weight, an
amount of (-)-bupropion or a pharmaceutically acceptable salt
thereof, substantially free of its (+)-stereoisomer, said amount
being sufficient to reduce weight or prevent weight gain, but
insufficient to cause adverse effects associated with
administration of racemic bupropion.
[0035] The present invention also encompasses a method of treating
disorders including, but not limited to, bipolar disorders,
attention-deficit disorders, conduct disorders, psycho-sexual
dysfunction, bulimia, eating disorders and specific food cravings
in humans while avoiding the concomitant liability of adverse
affects associated with the administration of racemic bupropion,
which comprises administering to a human in need of such therapy a
therapeutically effective amount of (-)-bupropion, or a
pharmaceutically acceptable salt thereof, substantially free of its
(+)-stereoisomer.
[0036] The racemic mixture of bupropion (i.e., approximately a
50:50 mixture of its two enantiomers) causes antidepressant
activity and provides therapy and/or reduction of symptoms in a
variety of conditions and disorders; however, this racemic mixture,
while offering the expectation of efficacy, causes a broad range of
adverse effects. Utilizing the optically pure (-)-isomer of
bupropion results in clearer dose-related definitions of efficacy,
diminished adverse effects, and-accordingly an improved therapeutic
index. It is therefore, more desirable to use the (-)-isomer of
bupropion for the conditions described herein.
[0037] The term "adverse effects" as used herein includes, but is
not limited to seizures, dry mouth, insomnia, dizziness,
restlessness, anxiety, agitation, headache/migraine,
nausea/vomiting, constipation, tremor, delusions, tachycardia,
hallucinations, psychotic episodes, blurred vision, confusion,
paranoia, rashes and sleep disturbances.
[0038] The term "substantially free of the (+)-stereoisomer" as
used herein means that the composition contains a greater
proportion of the (-)-isomer of bupropion in relation to the
(+)-isomer of bupropion. In a preferred embodiment the term
"substantially free of its (+)-isomer" as used herein means that
the composition contains at least 90% by weight of (-)-bupropion
and 10% by weight or less of (+)-bupropion; or more preferably
about 95% by weight of (-)-bupropion and 5% or less of its
(+)-isomer. These percentages are based on the total amount of
bupropion present in the composition. In the most preferred
embodiment the term "substantially free of the (+)-stereoisomer"
means that the composition contains approximately 99% by weight of
(-)-bupropion, and 1% or less of the (+)-bupropion. In another
preferred embodiment, the term "substantially free of its
(+)-stereoisomer" as used herein means that the composition
contains greater than 99% by weight of the (-)-isomer of bupropion,
again based on the total amount of bupropion present. The terms
"substantially optically pure (-)-isomer of bupropion," "optically
pure (-)-isomer of bupropion" and "(-)-isomer of bupropion" are
also encompassed by the above-described amounts.
[0039] The term "a method of treating depression" as used herein
means relief from the symptoms of depression which include, but are
not limited to changes in mood, feelings of intense sadness and
despair, mental slowing, loss of concentration, pessimistic worry,
agitation, and self-deprecation. Physical changes may also be
relieved, including insomnia, anorexia and weight loss, decreased
energy and libido, and the return of normal hormonal circadian
rhythms.
[0040] The term "attention deficit disorder" (ADD) and "attention
deficit disorder with hyperactivity" (ADDH), DSM-III, or attention
deficit/hyperactivity disorder (AD/HD), DSM-IV are used herein mean
in accordance with the accepted meanings.
[0041] The term "treating Parkinson's disease" as used herein means
relief from the symptoms of Parkinson's disease which include, but
are not limited to tremor, bradykinesia, rigidity, and a
disturbance of posture.
[0042] The term "treating obesity or weight gain in a human" as
used herein means reduction of weight or relief from being
overweight or gaining weight due to extensive consumption of food
and other factors including metabolism disorders.
4.1. Synthesis of Optically Pure Bupropion
[0043] The synthesis of the (-)-isomer of bupropion may start from
readily available 3-chloropropiophenone (1). Reaction of (1) with a
(2R,3R)-(+)-dialkyl tartrate such as (+)-dimethyl or diethyl
tartrate in the presence of an acid catalyst such as
methanesulfonic acid gives the chiral acetal (2) according to
Castaldi (G. Castaldi, et al., J. Org. Chem. 1987, 52: 3018).
Steroselective bromination with bromine in carbon tetrachloride, or
alternatively ethyl acetate, then produces the corresponding
bromoacetal (3) as the major product according to the
above-referenced procedure developed by Castaldi and co-workers.
The bromoacetal (3) is purified by column chromatography to yield
the optically pure bromoacetal (3) which is then hydrolyzed in the
presence of an acid to afford the bromoketone (4). Treatment of the
bromoketone (4) with tert-butylamine, followed by reaction with
anhydrous hydrogen chloride, then produces optically pure
(-)-bupropion hydrochloride (5) after recrystallization. See the
scheme below. 1
[0044] Alternatively, the optically pure isomers of bupropion can
be prepared asymmetrically according to the procedures reported by
Musso et al., "Synthesis and Evaluation of the Antidepressant
Activity of the Enantiomers of Bupropion", Chirality 5:495-500
(1993) which is incorporated herein by reference in its
entirety.
[0045] In addition to the above-described methods the stereoisomers
of bupropion may be obtained by resolutions of a mixture of
enantiomers of bupropion using conventional means such as an
optically active resolving agent; see, for example,
"Stereochemistry of Carbon Compounds", by E. L. Eliel (McGraw-Hill,
NY, 1962), and S. H. Wilen, p. 268 in "Tables of Resolving Agents
and Optical Resolutions" (E. L. Eliel, Ed., Univ. of Notre Dame
Press, Notre Dame, Ind., 1972).
[0046] The magnitude of a prophylactic or therapeutic dose of
(-)-bupropion in the acute or chronic management of disease will
vary with the severity of the condition to be treated and its route
of administration. The dose and dose frequency will also vary
according to the age, weight, condition and response of the
individual patient. In general, the recommended daily dose range
for the conditions described herein lies within the range of from
about 10 mg to about 750 mg per day, generally divided equally into
doses given three or four times a day. Preferably, a daily dose
range should be between 50 mg and 600 mg per day, usually divided
equally into a three or four times a day dosing. Most preferably, a
daily dose range should be between 60 mg and 450 mg per day,
usually divided equally into a three times or a four times a day
dosing. It may be necessary to use dosages outside these ranges in
some cases. The physician will know how to increase, decrease or
interrupt treatment based upon patient response. The various terms
described above such as "said amount being sufficient to alleviate
said depression", "said amount being sufficient to alleviate said
condition" when said condition is Parkinson's Disease, "said amount
being sufficient to reduce weight or weight gain", "said amount
being sufficient to achieve weight loss" and "therapeutically
effective amount" are encompassed by the above-described dosage
amounts and dose frequency schedule.
[0047] Any suitable route of administration may be employed for
providing the patient with an effective dosage of (-)-bupropion.
For example, oral, rectal, parenteral, transdermal, subcutaneous,
intrathecal, intramuscular and the like may be employed as
appropriate. Dosage forms include tablets, coated tablets, caplets,
capsules, troches, dispersions, sustained release formulations,
suspensions, solutions, patches and the like.
[0048] The pharmaceutical compositions of the present invention
comprise the (-)-isomer of bupropion as active ingredient or a
pharmaceutically acceptable salt thereof, and may also contain a
pharmaceutically acceptable carrier and optionally other
therapeutic ingredients. The term "pharmaceutically acceptable
salts" refers to salts prepared from pharmaceutically acceptable
non-toxic acids including inorganic acids and organic acids.
[0049] Since the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids
including inorganic and organic acids. Such acids include maleic,
acetic, benzene-sulfonic (besylate), benzoic, camphorsulfonic,
citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
Particularly preferred are hydrobromic, hydrochloric, phosphoric,
and sulfuric acids.
[0050] The pharmaceutical compositions of the present invention
include compositions suitable for oral, rectal, and parenteral
administration (including subcutaneous, intrathecal, intramuscular,
and intravenous), although the most suitable route in any given
case will depend on the nature and severity of the condition being
treated. The most preferred route of the present invention is the
oral route. They may be conveniently presented in unit dosage form
and prepared by any of the methods well-known in the art of
pharmacy.
[0051] In the case where an oral composition is employed, a
suitable dosage range for use is, e.g., from about 10 mg to about
750 mg per day, generally divided equally into a three times a day
dosing, preferably from about 50 mg to about 600 mg per day,
generally divided equally into a three times a day dosing and most
preferably-from about 60 mg to about 450 mg per day, generally
divided equally into a three times a day dosing. Patients may be
upward titrated from below to within this dose range to a
satisfactory control of symptoms as appropriate.
[0052] In practical use, (-)-bupropion can be combined as the
active ingredient in intimate admixture with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques. The carrier may take a wide variety of forms depending
on the form of preparation desired for administration, e.g., oral
or parenteral (including intravenous injections or infusions). In
preparing the compositions for oral dosage form, any of the usual
pharmaceutical media may be employed, for example, water, glycols,
oils, alcohols, flavoring agents, preservatives, coloring agents
and the like in the case of oral liquid preparations, for example,
suspensions, elixirs and solutions; or aerosols; or carriers such
as starches, sugars, microcrystalline cellulose, stabilizers,
diluents, granulating agents, lubricants, binders, fillers,
disintegrating agents and the like in the case of oral solid
preparations such as, powders, capsules and tablets, with the solid
oral preparations being preferred over the liquid preparations. The
preferred solid oral preparation is tablets. The most preferred
solid oral preparation is coated tablets. Because of their ease of
administration tablets and capsules represent the most advantageous
oral dosage unit form, in which case solid-pharmaceutical carriers
are obviously employed. If desired, tablets may be coated by
standard aqueous or nonaqueous techniques.
[0053] Pharmaceutical stabilizers may also be used to stabilize
compositions containing (-)-bupropion or salts thereof; acceptable
stabilizers including but are not limited to L-cysteine
hydrochloride, glycine hydrochloride, malic acid, sodium
metabsulfite, citric acid, tartaric acid and L-cysteine
dihydrochloride. See, e.g., U.S. Pat. No. 5,358,970 which is
incorporated herein by reference.
[0054] In addition to the common dosage forms set out above, the
compounds of the present invention may also be administered by
controlled release or sustained release means and/or delivery
devices such as those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; 3,630,200, 4,008,719, 4,687,660,
and 4,769,027, the disclosures of which are hereby incorporated by
reference. Preferred controlled release or sustained released
tablets for use with (-)-bupropion are described in U.S. Pat. No.
5,427,798 which is incorporated herein by reference.
[0055] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, cachets, or tablets or aerosol sprays, each
containing a predetermined amount of the active ingredient, as a
powder or granules or as a solution or a suspension in an aqueous
liquid, a non-aqueous liquid, an oil-in-water emulsion, or a
water-in-oil liquid emulsion. Such compositions may be prepared by
any of the methods of pharmacy but all methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more necessary ingredients. In general,
the compositions are prepared by uniformly and intimately admixing
the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation. For example, a tablet may be prepared by
compression or molding, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as powder or granules, optionally mixed with a binder, filler,
lubricant, inert diluent, and/or surface active or dispersing
agent. Molded tablets may be made by molding in a suitable machine
a mixture of the powdered compound moistened with an inert liquid
diluent. Desirably, each tablet contains from about 10 mg to about
250 mg of the active ingredient, and each cachet or capsule
contains from about 10 mg to about 250 mg of the active-ingredient.
Most preferably, the tablet, cachet or capsule contains one of four
dosages: about 50 mg, about 75 mg, about 100 mg and about 150 mg of
active ingredient.
[0056] The invention is further defined by reference to the
following examples describing in detail the preparation of the
compound and compositions of the present invention. It will be
apparent to those skilled in the art that many modifications, both
to materials and methods, may be practiced without departing from
the purpose and interest of this invention.
[0057] All temperatures are in degrees Celsius.
EXAMPLES
5.1. Example 1
Oral Formulation
[0058]
1 Coated Tablets: Formula Quantity per Tablet (mg.) (-)-bupropion
75 Lactose 125 Corn Starch 5.0 Water (per thousand Tablets) 30.0
ml* Magnesium Stearate 0.5 Corn Starch 25.0 *The water evaporates
during manufacture.
[0059] The active ingredient is blended with the lactose until a
uniform blend is formed. The smaller quantity of corn starch is
blended with a suitable quantity of water to form a corn starch
paste. This is then mixed with said uniform blend until a uniform
wet mass is formed. The remaining corn starch is added to the
resulting wet mass and mixed until uniform granules are obtained.
The granules are then screened through a suitable milling machine,
using a 1/4 inch stainless steel screen. The milled granules are
then dried in a suitable drying oven until the desired moisture
content is obtained. The dried granules are then milled through a
suitable milling machine using 1/4 mesh stainless steel screen. The
magnesium stearate is then blended and the resulting mixture is
compressed into tablets of desired shape, thickness, hardness and
disintegration. Tablets are coated by standard aqueous or
nonaqueous techniques.
5.2. Example 2
Oral Formulation
[0060]
2 Capsules: Quantity per capsule in mg. Formula A B C Active
ingredient 25 50 75 (-)-bupropion Lactose 149.5 124.5 374 Corn
Starch 25 25 50 Magnesium Stearate 0.5 0.5 1.0 Compression Weight
200.0 200.0 500.0
[0061] The active ingredient, (-)-bupropion, lactose, and corn
starch are blended until uniform; then the magnesium stearate is
blended into the resulting powder. The resulting mixture is
encapsulated into suitably sized two-piece hard gelatin
capsules.
5.3. Example 3
Oral Formulation
[0062]
3 Tablets Quantity per capsule in mg. Formula A B C Active
ingredient, 20 40 100 (-)-bupropion lactose BP 134.5 114.5 309.0
starch BP 30.0 30.0 60.0 Pregelatinized Maize 15.0 15.0 30.0 Starch
BP magnesium stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0
500.0
[0063] The active ingredient is sieved through a suitable sieve and
blended with lactose, starch, and pregelatinized maize starch.
Suitable volumes of purified water are added and the powders are
granulated. After drying, the granules are screened and blended
with the magnesium stearate. The granules are then compressed into
tablets using punches.
[0064] Tablets of other strengths may be prepared by altering the
ratio of active ingredient to lactose or the compression weight and
using punches to suit.
5.4. Example 4
[0065]
4 Sustained Release Formulation (Tablet) FORMULA QUANTITY PER
TABLET (mg) (-)-bupropion hydrochloride 100 Contramid .RTM.
crosslinked amylose 98.8 Cysteine hydrochloride 7.5 Magnesium
stearate 1.2
[0066] (-)-Bupropion Hydrochloride is formulated using
Contramid.RTM. (Labopharm, Inc, Quebec) technology. The formulation
is prepared by blending the ingredients above (dry) and compressing
into tablets. Alternatively, the ingredients can be formulated
using wet granulation technology known in the art. (See Example
1).
5.5. Example 5
[0067]
5 Sustained Release Formulation (Tablet) FORMULA QUANTITY PER
TABLET (mg) Contramid .RTM. crosslinked amylose 98.8 Cysteine
hydrochloride 7.5 (-)-bupropion hydrochloride 75 Magnesium stearate
1.2
[0068] (-)-Bupropion Hydrochloride is formulated using
Contramid.RTM. (Labopharm, Inc, Quebec), technology. The
formulation is prepared by blending the ingredients above (dry) and
compressing into tablets. Alternatively, the ingredients can be
formulated using wet granulation technology known in the art. (See
Example 1).
5.6. Example 6
[0069]
6 FORMULA QUANTITY PER TABLET (mg) (-)-bupropion hydrochloride 150
Diffutab .RTM. hydrophilic 100 polymer mixture Microcrystalline
cellulose 100 Cysteine hydrochloride 7.5 Magnesium stearate 4
[0070] (-)-Bupropion Hydrochloride is formulated using
Diffutab.RTM. (Eurand, Microencapsulation, S.A. of Switzerland)
technology. The formulation components are dry blended and directly
compressed into tablets or formulated using wet granulation
technology.
[0071] The embodiments of the present invention described above are
intended to be merely exemplary and those skilled in the art will
recognize, or be able to ascertain using no more than routine
experimentation, numerous equivalents to the specific procedures
described herein. All such equivalents are considered to be within
the scope of the present invention and are covered by the following
claims.
[0072] The contents of all references described herein are hereby
incorporated by reference.
[0073] Other embodiments are within the following claims.
* * * * *