Note: Descriptions are shown in the official language in which they were submitted.
2~ 12'~8~ ~
WOs3/00075 PcT/uss2/os377
--1--
METHODS AND COMPOSITIONS ~OR TREATING
EMESIS, NAUSEA AND OTHER DISORDERS
USING OP~TICALLY PURE Sf-l ON~Y~E~B~
:...~ .-,
This application is a continuation-in-part of
copending application serial no. 07/721,723, filed June
26, 1~91.
17 BA~CKGROUND OF THE INVE~
This invention relates to novel composi~ions of .~
matter containing optically pure s(-) ondansetron. These ~ :
novel compositions have potent antiemetic activity and are ~-
10 useful in ameliorating the nausea and vomiting otherwise
induced by cancer chemotherapeutic agents and higher dose ;;~
radiotherapeutic tr~atme~t pr~cedures while avoiding
~~ adverse effects including but not limited to headache~
constipation and increases in transaminase levels, which
15 are associated with the admînistration of the racemic
mixture of ondansetron. Additionally, these novel
compositions of matter containing optically pure S(~
ondansetron are useful in treating behavioral disorders
such as mood anxiety and schizophrenia, and such other
conditions as may relate to S(-) ondan~etron's a~tivity as
a compatitive antagonist of serotonin receptor subtype 5-
HT3, including but not limited to disorders of
~astrointestinal motility, depression, migraine, alcohol,
nicotine or drug (benzodiazepine ~t al.) withdrawal, while
avoiding adverse eff~cts associated with the
administration of the racemic mixture of ondansetron. ~`
Furthermore, these novel compositions of matter containing
optically pure 5~-) ondansetron are useful in treating
, cognitive disorders such as dementia and age-associated
memory impairment, while avoiding the adverse ef~ects ~-
associated with the admînistration of the racemic mixture
of ondansetron. Also disclosed are methodæ for trea~ing
the above described conditions in a human while avoiding
35 the adver~e effects that are associated with the racemic ~ i
~.;
',:
~,
W093/~0075 ~ PCT/US92/053' ~ ~
mixture of ondansetron, by administering the S~-) isomer :-
of o~dansetron to said human. -
The ac~ive compound of this compositi~n, and meth~d
is an optical isomer of the compound, ondansetron which is ~:
5 described in United States Patent No~ 4,695,578.
Chemically, the active compound is the S(-) isomer of
l,2,3,9-tetrahydro-9-methyl-3-~t2-methyl-lH-imidazol-l-yl)
methyl]-4H-carbazol-4-one. This isomer will hereinafter
be referred to as S~-) ondansetron.
'' ` " '
l.l. Steric Relationships and_Dru~_Action
Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane o~
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. ~ compound prefixed
with (+) or d is dex~rorotatory. 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 ~
25 as an enantiomer, and a mixture of such isomers is often ~ i
called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field
of pharmaceuticals, where 12 of the 20 most prescribed
drugs exhibit chirality. A case in point is provided by ~
30 the L-form of the ~-adrener~ic blocking agent, ~;
propranolol, which is known to be lO0 times more potent ~ -
than the D-enantiomer.
~urthermore, optical purity is important since ~`
certain iæomers may actually be deleterious rather than
simply inert. For example, it has been suggested that the
W093~00075 2 ~ 1 ~ `1 8 8 PCT/US92/05377
-3-
D-enantiomer of thalidomide was a safe and effective
sedati~e when prescribed for the control of morning ~ -
sickness during pregnancy, and that the corresponding
L-enantiomer, a potent teratogen.
Ondansetron, which is the subject of the present
invention, is available commercially only as the l:l
racemic mixture; i.e., it is a mixture of optical isomers, ~`~
called enantiomers. The racemic mixture of ondansetron is
a dihydrate, that is administered as a hydrochloride salt.
The enantiomers of ondansetron are disclosed in Butler et
al., Br. J. Pharmacol., 94, pg. 397-412 (1988)~ This
reference states that the R and S isomers of ondansetron
were approximately equipotent as 5-HT antagonists on rat
~~ vagus nerve. Fu~thermore, the reference alleges that the
15 racemic mixture caused concentration-dependent parallel ~
rightward displacement of the 2-methyl -5-HT concentration ~;
response curve when exposed to the longitudinal smooth
muscle of the guinea-pig ileum, and that the R isomer was
more potent than the S isomer when administered -~;
competitively against 2-methyl-5-HT.
The racemic mixture of ondansetron is an antagonist
of the 5-hydroxytryptamine (5-HT3 or serotonin) receptor.
The role of serotonin, and thus the pharmacology of
ondansetron has been broadly i~plicated in a variety of ~
25 conditions for many years ~see, Phillis, J.W., The --
Pharmacology of Synapses, Pergamon Press, Monograph 43,
~970; Frazer, A. et al. Annual Rev. of Pharmacology and
Therapeutics 30, 307-348, l990). Thus, research has
focused on locating the production and storage sites of ~-~
30 serotonin as well as the location of serotonin receptors `;
in the human body in order to determine the connection ~-
between these sites and various disease states or
conditions.
In this regard, it was discovered that a major site
35 of p~oduction and storage of serotonin is the ~-
, .
WO 93/00075 PCI`/US92/053'
enterochromaffin cell of the gastrointestinal mucosa. It
was also di~co~ered that serotonin has a powerful
stimulating action on intestinal motility by stimulating
intestinal smooth muscle, speéding intestinal transit, and
5 decreasing absorption time, as in diarrhea. This
stimulating action i5 also assQciated with nausea an~
vomitinq .
Thus, researchers studied diseases and treatment o~
diseases where the above described effects were
10 manifested. One such treatment is chemo-and radio-therapy
of cancer using chemotherapeutic and hiqh dose
radiotherapeut~c agents~ Chemo-and radio-therapy may
induce nausea and vomiting by the release of serotonin
from damaged enterochromaffin cells in the
gastrointestinal tract. Release of the neurotransmitter
serotonin, stimulates both afferent vagal nerve fibers
(thus initiating the vomiting reflex) and serotonin
receptors in the chemoreceptor trigger zone of the area
postrema region of the brain.
one of the first agents used to prevent the nausea
and vomiting associated with emetogenic cancer
chemotherapy was metoclopramide. This compound is an
antagonist of central and peripheral dopamine receptors,
and at hiqh doses it also antagonizes serotonin receptors.
Because it had this combined effect, researchers began to
search for a more specific and safer serotonin 5-HT3
antagonist to use to treat nausea and vomiting associated
with chemo-and radio-therapy of cancer. This led to the
development of ondansetron. -
Ondansetron is a competitive antaqonist at ;
serotonin 5-HT3 receptor subtypes in both t~e
gast~ointestinal tract and the brain, where it blocks both
sites of serotonin-induced emesis. With respect to its
anti-emetic potential, ondansetron appears to o~fer a dual
mode of action through antaqonism of serotonin at
w093J00075 2 ~ 1 2 ~ PCT/US92/05377
-5- :~
peripheral vagal nerve afferents, and antagonism of
serotonin within the central nervous system, at or near
the chemoreceptor trigqer zone.
Consequently, ondansetron may produce a significant
5 reduction, or a complete inhibition of nausea and vomiting
in the majority of patients subsequently treated with
cancer chemotherapeutics of moderate or high emetic
potential. Similarly, the compound prevented radiation
induced nausea and emesis. Further, ondansetron appears
to have an effect on gastrointestinal motility slowing the
transit of material through portions of the tract. This
decrease in motility may be beneficial in those patients
undergoing the chemotherapy for cancer where diarrhea can
provide an additional debilitating burden.
Ondansetron's use as an antiemetic by either the
intravenous or oral routes is disclosed in U.S. Patent
No~'s 4,753,789 and 4,929,632. Furthermore, various
researchers h~ve tested the use of the racemic mixture of ~-
ondansetron to prevent nausea and vomiting caused by
anticancer chemotherapy. See, Green et al., Car.cer
~ , 24:137-139 (1989); Cubeddu et al.,
New Eng~ . J. _Med~, Vol. 322; No. 12, pg. 810-815 (1990); :~
De Mulder et al., Ann. Int. Med., Vol. 113: No. 11, pg. :;;
834-840 (1990); Marty, Eur. J. Cancer Clin. Oncol., Vol.
25, Suppl. 1, pg. 541-545 (1989); Khojasteh et al., Can~
, Vol. 66, No. 6, pg. 1101-1105 (1990); Schmoll, Eur
Ca~cer ~lin._Onc~l., Vol. 25, Suppl. 1, pg. 535-539
(1989); Grunberger et al., J. ~lin. Oncol., Vol. 7, No. 8, ~
pg. 1137-1141 (1989); Kris et al., J. Clin. Oncol., Vol. ~;
6, no. 4, pg. 659-662 (1988). ;
Thus, in the context of adjunctive therapy for
cancer treatment, ondansetron appears to be an effective
antiemetic, although- its dose-response relationships
remain to be clarified. The drug offers a moderate `~
potency, a half-life of some three hours, and t~e
: .'
W093/0~075 ~ P~T/US92/0s37
-6- :
potential fGr prophylactic/therapeutic activity. Dosing ~
1-2 hours prior to cancer therapy or at the initiation of -~-
therapy can be accomplished by continuous infusion, or
repeated oral or intravenous administrations. (see Smith, -
5 R.N., Safety o~ Ondansetron, European J. of cancer and
Clinical Oncology, 25 Suppl.1 547-50, 1989; and Smyth,
J.F. ibid., 5s5-57, 1989).
As stated previously, stimulation of serotonin
receptors has been postulated to be involved in a variety
of disease states and conditions. Thus, it has been
proposed that antagonizing serotonin receptors will assist
in treating these conditions.
It has been proposed that the racemic mixture of
'- ondansetron i8 useful in the treatment of anxiety
15 disorders. Anxiety disorder has its etiology in both
psychologic and physiologic factors, and it has been
suggested that a genetic inf luence exîsts. Emotional
stres~ can precipitate anxiety neurosis which represents
the individual's fear of losing control of such emotional
drives as aggression or dependency needs, and losing
control of one's resulting actions. Physiologically,
anxiety is associated with autonomi~ nervous system
discharge, and related neurohumoral processes. In acute
anxiety attacks, lasting from a few minutes to an hour,
the individual experiences a subjective sense of terror,
for no evident reason, and perhaps a haunting dread of
catastrophe. Chronic anxiety displays less int~nse
symptoms o~ longer duration, characterized by uneasiness,
n~rvousness, nagging uncertainty about future events,
headache, fatigue and subacute autonomic symptoms. The
use of the r~cemic mixture o~ ondansetron to treat anxiety
disorders is disclosed in U.S. Patent No. 4,695,578.
It has ~150 been proposed that the racemic mixture `~
o~ ondansetron is useful to treat psychotic disorders such
as schizophrenia. (See U.S. Patent No. 4,695,578).
WO 93/00075 2 1 ~ PCl/US92~0~i377
-7- : .
. ,
Schizophrenic disorders are complex mental disorders which
tend toward chronicity, and which impair functioning, and
are characterized by psychotic symptoms of disturbed
thinking, feeling and general behavior. Clear, goal
5 directed thought becomes difficult, while blunting and ~;~
inappropriate affect become the most characteristic
emotional changes. Auditory hallucinations can be common,
and delusions of persecution are frequent, as are threats
of violence, and minor aggressive outbursts. Disturbances
10 of movement can range from significant over-activity and
excitement to retarda~?on an~ stupor. Treatment has often -~
included tranquilizer and other antipsychotic dru~s, `
administered orally or by long acting depot injections (to
offset problems of patient compliance).
The racemic mixture of ondansetron has also been
proposed to be useful in the treatment of depression (see
U.S. Patent No. 4,835,173). Depression, an affective ~`
disorder, is characterized by changes in mood, as a
primary clinical feature. The most common of the ;~
significant mental illnesses, depression 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 the disruption of circadian
30 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. Nevertheless, the
treatment of depression would benefit fro~ new therapy.
W .~ ~ J`~
w093/0007~ PcT/uss
--8--
It has al50 been proposed that the racemic mixture
of ondansetron is useful to treat migraine (se U.S.
Patent No. 4,695,57~). Migraine is of unknown cause,
although evidence suggests a functional disturbance of the
cranial circulation. The condition is a paroxysmal
disorder, characterized by recurrent attacks of headache,
which can be associated with visual and gastrointest~nal
disturbancès. Migraine headaches may be preceded by a
short period of depression, irritability, restlessness or
anorexia.
U.S. Patent No. 4,847,281 discloses the use of the `;~
racemic mixture of ondansetron to treat substance abuse~
Disorders of substance use or abuse often involve both
~- psychologic and physical dependence, accompanied by the
development of tolerance (the need to increase the dose
progressively so as to produce the effect originaily
achieved by smaller amounts), and manifested by a
withdrawal or abstinence syndrome.
Alcohol withdrawal syndrome represents a continuum
Of symptoms including tremor, weakness, sweatinq and
gastrointestinal symptoms usually beginning some hours
after cessation of intake. Druqs which alter the
serotonin system can modulate the alcohol consumption in
humans. Some mutual, but incomplete cross-tolerance
exists between alcohol and other drugs including the
benzodiazepines, the sedative-hypnotic, and the anxiolytic
muscle r~laxant group. While benzodiazepine withdrawal
symptoms are often considered moderate, in withdrawal,
often anxiety returns, with dysphoria irritability,
sweating, headache and sleep abnormalities. Nicotine
withdrawal syndrome following cessati~n of tobacco use, ~^
varies significantly amon~ subjects in intensity, and
specific signs and symptoms. Apart from the craving for
tobacco products, which begins within 24 hours of
cessat~on and then subsides over a period of some days,
'Jt~
W093/0007~ PCT/US92/05377
_9_
other symptoms include, but are not limited to,
irritability, anxiety, increased appetite and the
gastrointPstinal symptoms, and inability to c~ncentrate.
In addition, the racemic mixture of ondansetron
5 could be useful in the treatment of cognitive disorders.
Cognitive disorders include but are not limited to
dementia and age-associated memory impairment.
Dementia can occur at any age. It is a ~ ~
structurally caused permanent or progressive decline in ~:;
1~ several dimensions of intellectual function that
interferes substantially with individual normal social or
economic activi,ty.
One particular type of dementia is Alzheimers~type
~- dementia. Alzheimers-type of dementia is thought to be ~-
due to a degenerative process, with a large loss of cells
from the cerebral cortex and other brain areas.
Acetylcholine-transmitting neurons and their target nerve ;
cells are particularly affected. The brain shows marked ~-~
atrophy with wide sulci and dilated ventricles. Senile
20 plaques and neurofibrillary tangles are present. Memory
loss is the most prominent early symptom. Disturbances of
arousal do not occur early in the course. Alzheimer's
presenile and senile onset dementias are similar in both
clinical and pathologic features, with the former commonly
beginning in the 5th and 6th decades and the latter in the
7th and 8th de~ades. The dementia usually progresses
steadily, becoming well advanced in 2 to 3 years. Some
cases of dementia occurring in the presenile period are
hard to classify and are sometimes labelled idiopathic or
simple presenile dementia.
The signs and symptoms of dementia in particular
Alzheimers-type dementia, include depression, paranoia, -~`
anxiety or any of several other psychologic symptoms. The ~`
most common clinical picture is slow disintegration of
35 personality and intellect due to impaired insight and ~;
~ ~,
W093/00075 ~ 2 ~ PCT~US~2/~53~
--10
judgment and loss of affect. Memory impairment increases, ;
beginning with problems recalling recent events or finding
names. The impairment varies greatly from time to time
and often from moment t~ moment~ Dementia generally is an ;
5 insidious, slowly progressive, untreatable condition.
However, the rate of progression varies widely and depends
on the cause.
Another type of cognitive disorder is ~
age-associated memory impairment (AAMI). AAMI is used to `
10 describe healthy non-demented people who have experienced
memory loss over the course of the person's life. Most v
commonly it is used to describe adults over the age of 50
who have experienced memory loss over the course of adult ;
life. It has been estimated that between 25% and 50% of
15 people over the age of 65 have this disorder.
While the racemic mixture of ondansetron offers
efficacy in treating a variety of diseased states and
conditions, its use is associated with adverse effects `
(principally headache and constipation) which increase
20 with the dose of the racem c mixture of ondansetron
administered.
Thus it would be particularly desirable to find a
compound with the advantages of ondansetron which would
not have the aforementioned disadvantages.
2. SU~ARY OF THE INVENTION
It has now been discovered that the optically pure ;~
S(-) isomer of ondansetron is an~ effective anti-emetic
agent, useful as an adjunctive therapy in cancer treatment -~
30 Ito ameliorate nausea and vomiting induced by chemo- or
radio-therapeutics, while decreasing the usual adverse -~
effects including, but not limited to, headache, -
constipation and increases in transa~inase levels which ~`
are associated with the racemic mixture of ondansetron.
35 It has also been discovered that the optically pure S(-)
~'' '''
w093/00075 ~ 8 8 PCT/US92J05377
isomer of ondansetron is a useful agent to treat such
behavioral disorders as mood anxiety and schizophrenia,
and such other conditions as may relate to the
compositionls activity as a competitive antagonist at
5 serotonin receptor subtype 5-HT3, such as disorders of ~-
gastrointestinal motility, depression, migraine, and as a `~;~
therapeutic aid in alcohol, nicotine, and benzodiazepine -`~
withdrawal, while decreasing the usual adverse effects ~-
associated with the racemic mixture of ondansetron.
Furthermore, it has also now been discovered that ;-
the optically pure S(-) isomer of ondansetron is useful in --:
treating cognitive disorders such as dementia and ~`
age-associ~ted memory impairment, while decreasing the
adverse effects associated with the racemic mixture of
ondansetron.
The present invention also includes novel
compositions of matter, containing optically pure S(-)
ondansetron which are useful and effective as antiemetic
adjunctive therapy in cancer treatment by chemo-or
radio-therapeutics, and as agents for the aforementioned
disorders. These novel compositions also avoid, or reduce
the above described adverse effects associated with the
administration of the racemic mixture of ondansetron.
Thus, with the S(-) isomer of ondansetron, clearer dose
definitions of efficacy vis a vis adverse effects, may be
achieved. `
~-`. ':
3. DET~ILED_DESCRIPTION_O~_~HE INV~NTION ~
The present invention encompasses a method of ~;
eliciting an antiemetic effect while avoiding the
concomitant liability of adverse effects which comprises ;
administering to a human in need of such antiemetic
therapy an amount sufficient to alleviate nausea and ~`~
vomiting, but insufficient to cause said adverse effects,
~. . .
WO 93/00075 ~ ~ t 2 ~ ~ 8 P~r/US92/053-
--12--
of S (-) ondansetron, or a pharmaceutically acceptable salt
thereof, substantially free of its R (+) stereoisomer.
The present invention also encompasses an
antiemetic composition for the treatment of a human in
5 need of antiemetic therapy, which comprises an amount
sufficient to alleviate nausea and vomiting but
insufficient to cause adverse effects, of s(-)
ondansetron, or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer.
The present invention further encompasses a method ;
of treating behavioral disorders such as mood anxiety or
schizophrenia in a human while avoiding the concomitant
liability of adverse effectsr which comprises
~-~ administering to said human in need of such therapy, an
is amount sufficient to alleviate said condition, but
insufficient to cause said adverse effects, of S(~
ondansetron, or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer.
In addition, the present invention encompasses a
composition for the treatment of a human with behavior
disorders such as m~od anxiety or schizophrenia, which
comprises an amount sufficient to alleviate behavioral
disorders such as mood anxiety or schizophrenia, but
insufficient to cause adverse effects, of S(-)
ondansetron, or a pharmaceutically acceptable salt
thereof, substantial~y free of its R(+) stereoisomer.
Also included in the present invention is a method
of treating a condition caused by disturbance of neuronal
5-HT function while avoiding the concomitant liability of `~
adverse effects, which comprises administerinq to a human
in need of such therapy an amount sufficient to alleviate
said condition but insufficient to cause said adverse ~;
effects, of S(-) ondansetron, or a pharmaceutically
acceptable salt thereof, substantially free of its Rt+)
stereoisomer. Conditions caused by a disturbance of
2i~ ~488 ~::W093/00075 PCT/US92/05377
-13-
neuronal 5-HT function include but are not limited to, -
disorders of gastrointestinal motility, depression,
migraine, and alcohol, nicotine, or drug (benzodiazepine
et al.) withdrawal.
A further aspect of the present invention is a
composition for treating a condition caused by disturbance
o~ neuronal 5-HT function, which comprises an amount
sufficient to alleviate said condition but insufficient to
cause adverse effects, of S(-) ondansetron, or a
1O pharmaceutically acceptable salt thereof, substantially
free of its R(+) stereoisomer.
Furthermore, the present invention includes a
method of treating cognitive disorders such as dementia or
age-associated memory impairment, while avoiding the
15 ~oncomitant liability of adverse effects, which comprises ~
administering to a human in need of such therapy an amount ~:
sufficient to alleviate said cognitive disorder but
insufficient to cause said adverse effects, of S~-)
ondansetron, or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer.
A further aspect of the present invention is a
composition for treating cognitive disorders such as
dementia or age-associated memory impairment, whlch
comprises an amount sufficient ~o alleviate said
~s condition, but insufficient to cause adverse effects, of
S(-) ondansetron, or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer~
The available racemic mixture of ondansetron (i.e.
a 1:1 racemic mixture of stereoisomers) causes antiemetic
activity, and provides therapy and a reduction of symptoms
in a variety of conditions and disorders; howe~er this
racemic mixture, while offering the expectation of
efficacy, causes adverse effects. Utilizing the S(~
isomer of ondansetron alone results in dose related
definitions of effioacy, diminished adverse effects, and
W093/00075 2~ 1248~ PCI/USg2/053- .......................................... :
-14- ~ -
accordingly, an improved th~rapeutic index. It is ... ;;~
therefore, more desirable to use the S(-) isomer of .
ondansetron. . ::~
The term ~adverse effects~ includes, but is not ;.-~
5 limited to headache, constipation, fatigue, sedation,
lethargy, drowsiness, dry mouth, diarrhea and transient
increases in transaminase levels. Increases in the serum :.. .. ~.
activity of certain hapatocellular enzymes is also ~.
included within the term "adverse effects". ~::
The term "substantially free of its R(+) ~:.
stereoisomer" as used herein means that the composition
contains a greater proportion of the S(-) isomer of
ondansetron in relation to the R(+) isomer of ondansetron.
~-~ In one embodiment the term "substantially free of its R(+) ..
stereoisomer" as used herein means that the composition
contains at least 90 % by weight of S(-) ondansetron, and ~.
lO % by weight or less of R(+) ondansetron~ In the most
preferred embodiment the term "substantially free of the .~.~
R(+) stereoisomer" means that the composition contains at .~:.
20 least 99 % by weight S~-) ondansetron, and l % or less of ~ -
R(+) ondansetron. .
The term, "eliciting an antiemetic effect" as used :~
herein means providing relief from the symptoms of nausea
and vomiting induced spontaneously or associated with ::~
emetogenic cancer chemotherapy or irradiation therapy~
The term, "behavioral disorders such as mood
anxiety~ and schizophrenia" as used herein means relief `.~-
from the symptoms which include, but are not limited to! a ~
subjective sense of terror, a dread of catastrophe, :.. -;.
uneasiness, nervousness uncertainty, headache, fatigue,
disturbed thinking, inappropriate affect, auditory .;
hallucinations, aggressive outbursts and the like.
The term, "a condition caused by disturbance of :.
neuronal 5-HT function" includes but is not limited to
35 disorders of gastrointestinal motility, depression, .. ~
,.~.....
~: '
~ w093~0007s 2 1 ~ ~ 4 8 8 PCT/US92/05377
-15-
migraine and alcohol, nicotine or drug (benzodiazepine et
al.) withdrawal. This includes relief from the symptoms
which include, but are not limited to, diarrhea and
related symptoms , as decreased absorption time, etc.,
5 intense sadness, despair, mental slowing, loss of
concentration, worry, agitation, headache, irritability, '~
restlessness, anorexia, sweating, sleep abnorma~ities, and
the like.
The term "treating cognitive disorders" as used
10 herein means providing relief from the symptoms of
cognitive disorders including but not limited to memory
loss, disintegra~ion of personality and intellect, ;
d'epression, paranoia, anxiety and other psychologic
. symptoms. '
The preparation of the mixture of enantiomers,
(e.g., racemic mixture) of ondansetron is disclosed in
U.S. Patent No. 4,695,578. The S(-) isomer of '~
ondansetron, may be obtained by resolution of the mixture
of enantiomers of ondansetron using conventional means
such as an optically active resolving acid; see, for
example, "Stereochemistry of Carbon Compounds", by E.L.
Eliel (McGraw Hill 1962) and Lochmuller C.H.'et al., J.
Ch~o~ g~ , 1975, Vol. 113, No. 3, Pg. 283-302.
The magnitude of a prophylactic or therapeutic dose
o~ S(-) ondansetron in the acute or chronic management of
disease will vary with the severity of the condition to be
treated, and the route of administration. The dose, and
perhaps dose frequency, will also vary according to the
age, body weight, and response of the individual patient.
30 In general, the total, daily dose ranges, for the ~`~
conditions described herein, from about 0.01 mg to about
35 mg administered in divided doses orally, or by a slow
intravenous injection or infusion. In cases of moderate
to highly emetogenic chemotherapy, it may be expected
that, an initial loading dose of between about 2 mg to
WO93/00075 2~ t 'L ~ 8~ PC~/US92/053' ~
--16--
about 10 mg given by slow intravenous injection or
infusion over 15-30 minutes, immediately before the -
emetogenic chemotherapy, ahd followed by about 2 mg to
about 8 mg given orally every eight hours for periods up
5 to four to five days will elicit therapy and provide for a
reduction of symptoms. In cases of radiotherapy, and as
an oral therap~utic for the other conditions described
herein, generally doses of between about 2 mg to about
8 mg orally e~ery eight hours, should provide benefit to
adult patients. In the case of using S(-) ondansetron to
treat cognitive disorders such as dementia and
age-associated memory impairment, the total daily dosage
ranges may be from about o.ool mg to about 35 mg in
.- divided doses orally or by a slow intravenous injection or
infusion. Children generally will benefit from doses that
are generally some 25-S0 percent those of the adult for a
given condit~on, while geriatric patients generally
tolerate adult doses. It may be neoessary to use dosages
outside these ranges in some conditions.
The term, "an amount sufficient to alleviate the ~`
nausea and vomiting but insufficient to cause said adverse
effects" is encompassed by the abo~e described dosage
amounts and dose frequency schedule. In addition, the
term "an amount sufficient to alleviate said condition but
insufficient to cause said adverse effects" wherein said
conditions include but are not limited to behavioral
disorders such as mood anxiety and schizophrenia as well
as disturbances of neuronal 5-HT function including, but
not limited to, disorders of gastrointestinal motility,
depression, migraine and alcohol, nicotine or drug
tbenzodiazepine et al.) withdrawal are also encompassed by
the above described amounts. The term "an amount
sufficient to alleviate said condition but insuffi ient to
cause said adverse effects" wherei~ said condit~on
includes cognitive disorders such as dementia and
W093/00075 2 ~ 1 2 4 8 8 PCT/US92/05377
age-associated memory impairment, is also encompassed by
the above-described amounts.
A~y suitable route of administration may be
employed for providing the patient with an effecti~e
dosage of Sl-) ondansetron. For example, oral, rectal,
parenteral, transdermal, subcutaneous, intramuscular, and
the like may be employed. Dosage forms include tablets,
troches, dispersions, suspensions, solutions, capsules,
patches, and the like.
The pharmaceutical compositions of the present
invention comprise S(-) ondansetron as active ingredie~t,
or a pharma~eutically 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.
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 acetic, benzene-sulfonic,
benzoic camphorsulfonic, citric! ethenesulfonic, fumaric,
gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic,
nitric, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric acid, p-toluenesulfonic, and the like.
Particularly preferred are hydrobromic, hydrochloric r
phosphoric and sulfuric acids.
The compositions include compositions suitable for
30l oral, rectal or other mucosal routes, transdermal,
parenteral (including subcutaneous, 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 routes of the
present invention include both intravenous injections, and
W093/00075 2 i 1 2 4 8 ~ PCT/US92/053,
-18-
infusions and 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.
In the case where an oral composltion is employed,
a suitable dosage range for use is, e.g., from about 5 mg
to about 35 mg total daily dose, administered as equally
divided doses, three times a day. Pref~rably, a dose
range of between about 10 mg to about 30 mg per day,
administered as equally divided doses, three times a day,
and most preferably from between about 12 mg to about 24
mg per day, administered as equally divided doses, three ~-~
times a day. Patients ~ay ~e upwardly titrated within
this dose range to enable the satisfactory control of
symptoms. In the case where an oral composition is
employed to treat cognitive disorders such as dementia and
age-associated memory impairment, a suitable dosage range
for use is from about 0.001 mg to about 35 mg total daily
dose administered as equally divided doses from one to
three times a day. Preferably a dose range of between
about 0.001 mg to about 20 mg per day administered as
equally divided doses one to three times a day and most
preferably from between 0.001 mg to about 10 mg per day
~dministered as equally divided doses, one to t,hree times
a day.
In the case where an intravenous injection or
infusion composition is employed, a suitable dosage range
for us~ is, e.g. from about 0.01 mg to about 32 mg total
daily dose, presented as a loading slow intravenous
injection of about 2 mg to about 8 mg over 15-30 minutes,
followed by an intravenous infusion of about 0.5!mg to
about 1.0 mg/bour for up to 24 hours. These regimens may
be followed by oral doses of between about 1~5 mg to about
8.0 mg every eight hours for periods up to five days.
In practical use, S(-) ondansetron can be combined
as the active ingredient in intimate admixture with a
21~2~88
w093/00075 PCT/US92/05377
--lg--
pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may
take a wide variety of forms depending on the ~orm of
preparation desired for administration, e.g. oral or
parenteral (including ntravenous injections or
infusions). In preparing the compositions for oral dosage
form, any of the usual pharmaceutical media may be
employed, e.g., water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents, and the like in
the ca~e of oral liquid preparations, e.g., suspensions,
solutions, and elixirs; or aerosols; or carriers such as
starches, sugars, micro-crystalline cellulose, diluents,
granulating agents, lubricants, binders, disintegrating
agents, and the like in the case of oral solid
preparations e.g., powders, capsules, and tablets, with
the solid oral preparations being preferred over the
liquid preparations. The most preferred solid oral
preparation is tablets.
Because of their ease of administration, tablets
and capsu~es represent ~e most advantageous oral dosage
unit form, in which case solid pharmaceutical carriers are
employed. If desired, tablets may be coated by standard
aqueous or nonaqueous techniques.
In addition to the common dosage forms set out
above,the compounds of the present invention may also be
administered by controlled release means and/or delivery
devices such as those described in U.S. Patent Nos.:
3,845,7~0; 3,916,899; 3,536,809; 3,598,123; and 4,008,719,
the disclosures of which are hereby incorporated by
reference.
. .
Another preferred route of administration,
particularly to avoid problems associated with emesis, is ~-
transdermal delivery, for example, via an abdominal skin
patch.
8 ~
W093/0007~ PCT/US92/0~3,
--~0-- :
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
a~ueous liquid, a non-aqueous liquid, an oil-in-water
emulsion, or a water-in-oil ~iquid 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, shapinq 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, lubricant, inert
diluent, surface active or dispersing agent. Molded
tahlets 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 2.0 mg to about 8~0 mg of the active inqredient, and
each cachet or capsule contains from about 2.0 mg to abo~t
30l 8.0 mg. of the active i~gredient~ Most preferably, the
tablet/ cachet or capsule contains either one of three ~
~osages: 2.0 mg, 4.0 mq and 8.0 mg (as scored tablets, -
the preferable dose form) of active ingredient.
Furthermore, each tablet or capsule can contain from about
O.OOl mg to about lO.0 mg o~ the active ingredient.
wo 93/nnn7s 2 1 1 2 4 8 ~ PCT/US92/~377 ~
However, the amount of active ingredient found in ~he
composition may vary depending on the amount of active
ingredient to be administered to the patient. ^:~
The invention is furthér defined by reference to
the following examples describing in detail, the
preparation of the compound, and the 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.
All temperatures are in degrees Celsius.
~r- 4. EXAMPLES
4.1. EXAMPLE 1 :
A pharmacological study to determine the relative
potency and specificity of optically pure S(-) ondansetron
and racemic ondansetron as competitive antagonists at
20 serotonin receptor subtype 5-HT3 rresent in ~
gastrointestinal, brain, and othe~ tissues. ;;
The optically pure and racemic compounds may be
evaluated as a function of their molar concentration, for
their relative abilities to inhibit the binding of 3H-s-HT
in such selected preparations as nerves of guinea pig
ileum and preparations of brain tissue from several
species including rats and humans. The availability of 3
H-5-HT as a radioligand with relatively high specific
activity, the development of other selective~5-HT3
antagonists, and the additional agonist, ~ ! ~
2-methyl-5-hydroxy-tryptamine (2-methyl-5-HT) provide the
pharmacologic tools for the characterization of the 5-HT3
receptor, and the evaluation of S(-), and racemic
ondansetron. (see Frazer, A~, et al., Annu. Rev.
Pharmacol. Toxicol. 30, 307-348, l990). It has been
'2~1 2~88
W093/00075 PCT/US92/053 :
-22-
suggested, (Bradley, P.B et al., Neuropharmacology 25,
563-576, 1986) as part of the evolving characterization of
serotonin receptor subtypes, that responses mediated by ~-
HT3 receptors: be reduced by selective antagonists, not be
inhibited by selective antagonists of other subtypes of
serotonin receptors, and be mimicked by 2-methyl 5-HT at
concentrations comparable to that of serotonin.
Accordingly, the comparative ability of S(-3 and
racemic ondansetron, to inhibit the binding of 3H-5-HT and
the agonist, 3H-2-methyl 5-HT, not to be inhibited as a
radioligand for 5-HT3 receptors by selective antagonists of
other subtypes and to be inhibited from selective binding
. as a function of concentration, by other 5-HT3 selective ::
antagonists of possibly greater potency inc~uding
zacopride, ICS 205-930, and granisetron, will serve a
characterization of potency and specificity at 5-HT3
receptors.
30~ ~:
~li2~
WO 93/00075 P~/US92/0~377
--23-- :
4 .2 . EXAMPLE 2:
ORAL FORMULATION
Tablet: :
. ~:
Formula Quantity per Tablet
in mg ;
A B c
Active Ingredient
S(-) ondansetron 2.0 4.0 8.0
Lactose BP 1~1.5 149.5 145.5
Starch ~P 30.0 30.0 30.0
~~ Pregelatinized Maize Starch BP 15.0 15.0 15.0
Magnesium Stearate BP 1.5 1.5 1.5
Compression Weight 200.0 200.0 200.0
- - - ';.
The active ingredient, is sieved through a suitable
sieve and blended with lactose, starch, and pregeatinised
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 7 mm diameter punches.
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. ~;
~'
Wo 93/~0075 2 i 1 2 ~ 8 ~ P~r/US92/053~ ~
--24--
4 . 3 . EXAMPLE 3
ORAL FOR~TION .
Capsules:
Formula mg/capsule
,
A B C
Active Ingredient
S(-) ondansetron 2.0 4.0 8.0 ::
10Starch 1500 97.0 95.0 91.0
Magnesium Stearate BP 1.0 1.0 1.0
Compression Weight 100.0 100.0 100.0 :
,,-~ , - ' ,
The active ingredient is sieved and blended with
the excipients. The mix is f illed into size No. 2 hard -~
gelatin capsules using suitable machinery. Other doses
may be prepared by altering the f ill weight an if
necessary changing the capsule size to suit.
WO 93/0007~ 2 ~ ~ 2 ~1 ~ S PCI /US92/05377 .: :
-25~
4 . 4 . EXAMPLE 4
INTRAYENOUS FORMULATIQN ~ .
5 ~ormula ~g/ml
,
Active Ingredient ~ -
S(-) ondansetron 400
Dilute Hydrochloric Acid BP to pH 3.5 .
10 Sodium Chloride Injection BP 1 ml ~
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