Note: Descriptions are shown in the official language in which they were submitted.
- ~o gS/01803 ~ 1 6 6 ;7 3 0 PCT/US94/07520
TITLE OF THE INVENTION
H2 ANTAGONIST-GASTROINTEST~AL MOTILITY AGENT
COMBINATIONS
BACKGROUND OF THE INVENTION
The present invention relates to a combination of H2
antagonists selected from famotidine and pharmaceutically acceptable
salts, hydrates, stereoisomers or polymorphs thereof, with a gastro-
intestinal motility agent, and optionally an antiflatulent. The invention
further relates to pharmaceutically effective compositions which are
used to treat gastrointestinal disorders and to methods of treating and
preventing these disorders.
H2 antagonists are commonly prescribed to treat and
prevent ulcers in the walls of the stomach, duodenum or esophagus. H2
antagonists are also used to treat non-ulcerative conditions. Damage to
the mucus lining surrounding these tissues enables destructive action of
stomach acids which erodes the underlying tissue. Commonly known
H2 antagonists for the treatment of ulcers include cimetidine, ranitidine,
nizatidine, roxatidine and famotidine.
Combinations of 5-HT3 receptor antagonists with certain
H2 antagonists have been disclosed. See EP 269-452-A; EP 275-669-A.
Cisapride has the molecular formula:
OCH3 OCH3
F~ ~ H~NH2
Cl
This compound is used as a peristaltic stimulant. See A.
Reyntjens et al., Drug Div. Res., 8, 251 (1986) and Curr. Ther. Res.,
36, 1029-1070 (1984). The compound is marketed internationally
under trade names such as ACENALIN@~), PREPSULID~), RISAMOL(~),
PULSAR(~), and PROPULSIN(~). See EP application 76,530. Cisapride
stimulates gastrointestinal motility and beneficial responses have been
wo 95/01803 ~ ~ 6 6 7 3 0 PCT/US94/07520 `-
reported in treating chronic constipation, chronic dyspepsia, post-
operative gastroparesis and reflux-oesphagitis in children. See
Martindale's The Extra Pharmacopoeia, p. 1086 (1989) and references
cited therein.
There is a need to employ a combination wherein an
advantage is that the overall symptoms of gastrointestinal distress can be
effectively treated with a combination of the most powerful H2
antagonist available (famotidine) with a gastrointestinal motility agent
such as cisapride, and optionally including an anti-flatulent. The instant
combination provides a dual action approach to the treatment of
gastrointestinal disorders in that a gastrointestinal motility agent such as
cisapride offers enhanced motility while famotidine offers a systemic
effect of reduced acid production. The instant combination
simultaneously treats, relieves and/or prevents symptoms associated with
excess gastric acid secretion or evolution in the stomach and esophagus
respectively, while also promoting esophagal acid emptying with an
effective motility agent such as cisapride. Promotility agents generally
promote clearance of refluxed acid from the esophagus by increasing
the pressure of the lower esophageal sphincter. Conditions or
symptoms relieved by the promotion of gastric emptying include but are
not limited to gastric stasis, flatulence, dyspepsia, peptic ulcer and
reflux esoph~giti~.
The present invention therefore provides an effective dual
treatment of gaslloilltestinal disorders using the combination of
famotidine with a gastrointestinal motility agent such as cisapride, and
optionally with simethicone or ADG. The claimed combination is
particularly useful for treating gastrointestinal distress. Other H2
antagonists that can be used with this invention include ranitidine,
cimetidine, nizatidine and roxatidine.
DETALED DESCRIPTION OF THE INVENTION
This invention claims pharmaceutical compositions for use
in the prevention, treatment and relief of mild to moderate gastro-
intestinal distress and disorders including heartburn, indigestion, sour
2 1 6 ~
- WO 95/01803 PCT/US94/07520
stomach, overindulgence, gastroesophogeal reflux (GER), constipation,
dyspepsia and optionally flatulence. The composition comprises:
(i) an amount effective in the relief of gastrointestinal or
esophagus disorders of an H2 antagonist selected
5from a compound of the formula:
NH2~ ~z NSO2NH2
,C =Ny~NycH2scH2cH2c\
NH2 S - b NH2
and ph~rm~ceutically acceptable salts, hydrates,
stereoisomers or polymorphs thereof, and
(ii) an amount effective in the promotion of motility and
the treatment of dysfunction of the control
mech~ni~m for gastrointestinal motility and in the
treatment of symptoms such as nausea, vomiting,
anorexia, dysphagia, abdominal distension,
constipation or diarrhea, of a compound selected
from bethanechol, acylatonium (cholinergic drugs);
neostigmine (cholinesterase inhibitors);
metoclopramide, clebopride, domperidone
(dopamine antagonists); trimebutine and
acetylcholine releasing drugs including cisapride; or
a therapeutically active stereoisomer thereof
subst~nti~lly free of its other inactive or less active
stereoisomers or a pharmaceutically acceptable salt,
hydrate, or polymorph thereof, and optionally
30(iii) an amount effective in the relief of flatulence of
simethicone or alpha-D-galactosidase (ADG).
This invention is also directed to a method of preventing,
treating and relieving heartburn, indigestion, sour stomach, over-
indulgence, gastroesophogeal reflux, constipation, dyspepsia and other
wo 95~01803 2 1 6 ~ 7 ~ ~ PCT/US94/07520 --
gastrointestinal disorders, and optionally flatulence, in m~mm~
including humans, in need of treatment thereof, comprising
~lmini~tering to such org~ni~m:
(i) an amount effective in the relief of gastrointestinal or
esophagus disorders of an H2 antagonist selected
from a compound of the formula:
NH2
~ NSOzN H2
~C = Ny~NycH2scH2cH2c\
NH2 S~ NH2
and ph~rm~ceutically acceptable salts, hydrates,
stereoisomers or polymorphs thereof, and
(ii) an amount effective in the promotion of motility and
the treatment of dysfunction of the control
mech~ni~m for gastrointestinal motility and in the
treatment of symptoms such as nausea, vomiting,
anorexia, dysphagia, abdominal distension,
constipation or diarrhea, of a compound selected
from bethanechol, acylatonium (cholinergic drugs);
neostigmine (cholinesterase inhibitors);
metoclopramide, clebopride, domperidone
2s (dopamine antagonists); trimebutine and
acetylcholine releasing drugs including cisapride; or
a therapeutically active stereoisomer thereof
subst~nti~lly free of its other inactive or less active
stereoisomers or a pharmaceutically acceptable salt,
hydrate, or polymorph thereof, and optionally
(iii) an amount effective in the relief of flatulence of
simethicone or alpha-D-galactosidase.
~ ~ 6~
- WO 95/01803 PCT/US94/07520
The terms m~mm~l or m~mm~lian organism or patient are
used interchangeably herein and include but are not limited to humans,
dogs, cats, horses and cows. The preferred patients are hllm~n~.
The term treatment encompasses the complete range of
5 therapeutically positive effects associated with pharmaceutical
medication including reduction of, alleviation of and relief from the
symptoms or illness which affect the organism.
Famotidine may be purchased in bulk quantities as it is
currently available on the market, and formulated via typical
formulation processes with motility agents selected from cisapride or a
stereoisomer, salt or hydrate thereof which is suitable for tablet,
capsule, effervescent, chewable tablet, or liquid formulations of the
claimed combination. Famotidine as a prescription drug product is sold
in the United States under the trademark PEPCID(~). Janssen is a listed
15 manufacturer of cisapride. See also European Patent Application
0,076,530 published on April 13, 1983. Simethicone or alpha-D-
galactosidase (ADG) ~ntifl~tlllents may be added to the above
combination to provide maximum and broad relief of gasll~oilltestinal
disorders. Simethicone is a well-known and commercially available
antiflatulent. ADG is a commercially available enzyme preparation
used to hydrolyze indigestible sugars found in beans or bean products.
The active ingredients in the claimed combination are therefore readily
available.
Wher~ only a single stereoisomer of the gastrointestinal
motility agent is active as the therapeutically active stereoisomer, the
absence of the inactive stereoisomer of the ga~llointestinal motility
agent in the present composition avoids undesirable side effects that may
accompany ingestion and metabolism of the non-biologically active
stereoisomer. These include any toxic interactions and in addition
3 metabolic energy is saved when only one stereoisomer of the gastro-
intestinal motility agent is used in the claimed combination. The use of
the potent H2 antagonist such as famotidine combined with a gastro-
intestinal motility agent or an active stereoisomer of a gastrointestinal
motility agent provides significant dosage form advantages since less of
21 667~0
WO 95/01803 PCT/US94/07520
the H2 antagonist and the gastrointestinal motility agent is needed to
form~ te a suitable dosage form and provides for a more practical size
tablet or capsule.
The pharmaceutical compositions of the present invention
are useful in the prevention, treatment and relief of various mild to
moderate gastrointestinal disorders including indigestion, sour stomach,
overindulgence, heartburn, gastroesophageal reflux, constipation,
dyspepsia, other gastrointestinal disorders and optionally flatulence. In
particular, a gastrointestinal motility agent selected from cisapride or a
therapeutically active stereoisomer or a pharmaceutically acceptable
salt, hydrate, or polymorph thereof, combined with an H2 antagonist
selected from famotidine, a compound of the formula:
NH2, NSO2NH2
&=Ny~NyCH2SCH2CH2C\
NH2 S~ NH2
or the pharmaceutically acceptable salts, hydrates, stereoisomers or
polymorphs thereof, is useful for the prevention and treatment of
20 various ga~loilltestinal disorders such as indigestion, sour stomach,
heartburn, overindulgence, gastroesophageal reflux, constipation,
dyspepsia, and other gastrointestinal disorders. Simethicone or alpha-
D-galactosidase may be added to this preferred combination to provide
anti-flatulent relief. The lltili7~tion of the currently known biologically
25 active stereoisomers and/or salts, hydrates or polymorphs of famotidine
in combination with cisapride or its pharmacologically active
stereoisomers, salts, hydrates, or polymorphs is advantageously used to
prevent, relieve and treat mild to moderate gastrointestinal disorders.
In particular, the claimed combination is used to prevent, relieve and
30 treat the symptoms associated with gastric acid secretion while
sim--lt~neously treating the symptoms of ga~loilltestinal distress, and
optionally flatulence. Therefore, the ~nim~l, patient, or organism in
need of treatment thereof benefits from the claimed pharmaceutical
composltion.
- WO 9S/01803 2 1 6 6 7 :3 a PCT/US94/07520
H2 antagonists are well known in the treatment of ulcers
and other gastrointestinal disorders and may be used according to the
present invention in combination with a gastrointestinal motility agent
such as cisapride and optionally simethicone or ADG. H2 antagonists
used for ulcer therapy fall into four major structural classes: imidazole
derivatives; substituted furans; aminoalkylphenoxy derivatives and
guanidinothiazole compounds. Famotidine (N'-(aminosulfonyl)-3-[[[2-
[(cli~minomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide),
a member of the last named class above, is a competitive inhibitor of
o histamine H2-receptors and its primary pharmacological activity is the
inhibition -f gastric acid secretion. Famotidine suppresses both the acid
concentration and the volume of gastric acid secretion. Famotidine is
well tolerated and has minim~l side effects and thus advantageously may
be used in the present invention in combination with cisapride and
optionally simethicone or ADG. Famotidine is also the most potent and
selective H2 antagonist.
Cisapride (cis-4-amino-5-chloro-N-(1-[3-(4-fluoro-
phenoxy)propyl]-3-methoxy-4-piperidinyl)-2-methoxybenzamide) is
known to stimulate gastrointestinal motility and apparently is also
devoid of antidopa~ ergic activity. Cisapride is also known to provide
beneficial effects in a number of gastrointestinal disorders including
chronic constipation, chronic dyspepsia, improvement in stool
characteristics in patients that have cystic fibrosis, pseudoobstruction in
2s neonatal short gut, severe postoperative gastroparisis, possible
prevention of the aeration syndrome and reflux esophagitis in children.
See Martindale's The Extra Pharmacopoeia, 1086 (1989). Symptoms
associated with the dysfunction of the control mech~ni~m for motility of
the gastrointestinal tract or with abnormality of the smooth muscle
include nausea, vomiting, anorexia, dysphagia, abdominal distension,
constipation and diarrhea. Drugs known to affect the smooth muscle to
relieve the above symptoms include bethanechol, acylatonium
(cholinergic drugs); neostigmine (cholinesterase inhibitors);
metoclol,l~l~ide, clebopride, domperidone (dopamine antagonists);
trimebutine and acetylcholine releasing drugs including cisapride. The
wo 95/01803 2 ~ 66~7 ~Q PCT/US94/07520
claimed invention is also directed to combinations of famotidine with
any of the known motility drugs listed above wherein the combination is
useful to broadly relieve, treat and prevent the symptoms listed above.
Included within this invention are any diastereomers and/or
5 enantiomers of the gastrointestinal motility agent. In particular, a
therapeutically active stereoisomer of a gastrointestinal motility agent,
such as cisapride, substantially free of its other inactive or less active
stereoisomers may be employed in the instant invention. As used
herein, the phrase "a therapeutically active stereoisomer substantially
o free of its other inactive or less active stereoisomers" means that the
ratio of active stereoisomer to inactive or less active stereoisomer(s) is
at least 90:10. Where a particular therapeutically active stereoisomer is
not commercially available it may readily be prepared following
standard resolution chemistry or purification technology known in the
art. For example, high performance liquid chromatography ("HPLC")
or other suitable chromatographic or separation means may be used to
purify or isolate the active stereoisomer (enantiomer or diastereomer)
from its readily available raceniic mixture.
The claimed combination of famotidine or its
pharmaceutically effective salts, hydrates, stereoisomers or polymorphs
thereof with cisapride provides an effective combination which
simultaneously and selectively provides prevention, treatment and relief
from discomfort and injury to the stomach, esophagus, or duodenum
from excess production of gastric acid. Furthermore, famotidine in
combination with cisapride and optionally simethicone or ADG may not
interact with alcohol so that it may be ~lmini~tered prior to or during
ingestion of meals or beverages which contain alcohol and, therefore, a
patient in need of rapid treatment of gastrointestinal distress may take
the drug combination at an ~ro~.iate time which may be during a
meal in which alcohol was consumed. The combination of cisapride
with famotidine provides relief of gastroesophageal reflux while also
providing long acting relief from and treatment of gastrointestinal
disorders associated with gastric acid secretion. With the optional
- WO 95/01803 2 1 6 6 7 3 0 PCT/US94/07520
addition of simethicone or ADG, the claimed combination further
provides antiflatulent relief.
The combination of famotidine which is a highly potent H2
antagonist with cisapride, and optionally simethicone or ADG, reduces
the size and weight of all pharmaceutical delivery forms or combination
formulations and therefore improves patient compliance or tolerance.
The tablet or capsule form of this combination is more readily
swallowable by patients in need of treatment thereof.
Famotidine, or a pharmaceutically acceptable salt, hydrate
stereoisomer or polymorph thereof, is advantageously used in the
present invention in combination with cisapride and optionally with
simethicone or ADG. The amount of famotidine used in the present
invention in humans may range from 2.5 mgs/dosage to 80 mgs/dosage.
Advantageously, S to 40 mgs/dosage is ~dmini~tered in combination
with S to 40 mgs/dosage of cisapride. For example, a tablet containin~
S mgs of famotidine may be ~lmini~tered 4 times daily with an effective
amount of cisapride and suitable inert ingredients also contained within
the tablet.
When employed, the amount of simethicone per dosage
may vary depending upon the degree of antifl~hllent strength desired,
and may range from 20 to 80 mgs. Maxium strength antifl~tl~lents
~(lmini~tered in tablet form four times per day may contain 125 mgs of
simethicone per tablet. Currently marketed and available antacid/anti-
gas formulations contain, for example, 20-40 mgs/chewable tablet or
teaspoonful of liquid suspension of simethicone and 200 mgs of
al~ ---- hydroxide and 200 mgs of m~gnesium hydroxide. Two to
four tablets between meals or at bedtime or 2-4 teaspoonfuls between
meals and at be~ltimto cont~ining the above quantities are ~dmini~tered
daily. ADG is an enzyme known to assist in the hydrolysis of
indigestible sugars which are often found in beans or bean products.
The quantity of ADG utilized in the present invention depends upon the
concentration of active enzyme and upon the quantity of beans or other
source of indigestible sugars ingested. Generally, the amount of ADG
that may be employed ranges from about 675 to 31,000 GalU ("alpha-
wo 95/01803 2 ~ 6 67 3 O` PCTfUS94/07~20
- 10-
galactosidase units"), and preferably from about 675 to 2250 GalU. See
WO90/14101 orPCT/US90/02643.
The quantities of each of the active ingredients may vary
depending upon the severity of the condition and the particular
biochemistry and need of the patient or other organism in need of such
treatment. The quantities of the active ingredients may also vary
depending upon whether the active ingredients are ~lmini~tered in tablet
or liquid form or via some other suitable delivery method. A physician
or clinician or veterinarian of ordinary skill in the art may readily
determine suitable dosages of any prescription medication containing the
claimed invention. The combination claimed in the instant invention is
advantageously ~dmini.ctered orally. However, in patients with
hypersecretory conditions, intractable ulcers, or in patients who are
unable to take oral medication, the claimed combination may be
~lmini~tered intravenously in a suitable dosage within the limits
described for oral treatment.
The present composition may be ~lmini~tered in the form
of tablets, caplets, gelcaps, capsules, elixirs, syrups, chewable tablets,
lozenges, fast-dissolving wafers, effervescent formulations or
suspensions or other known and effective delivery modes. For oral
~flmini~tration, the active ingredients may be admixed with a
ph~ ceutically acceptable diluent such as lactose, sucrose, cellulose,
dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid
composition, ethyl alcohol. Acceptable emulsifying or suspending
agents such as PVP, gelatin, natural sugars, corn sweeteners, natural
and synthetic gums such as acacia, sodium cisapride, guar gum, agar,
bentonite, carboxymethylcellulose sodium, polyethylene glycol and
waxes, may also be admixed with the active components. Where
necessary, lubricants such as magnesium stearic acid talc or magnesium
stearate, and disintegrators or superdisintegrators such as starch,
sodium starch glycolate or cross-linked PVP may also be included.
Electrolytes such as dicalcium phosphate, sodium benzoate, sodium
acetate and sodium chloride may also be used.
wo 95~01803 2 1 6 6 7 3 0 PCT/US94/07520
- The active components may also be formulated in sustained
release or effervescent formulations. These formulations depending
upon whether they are sustained release or effervescent may be
employed in oral, dermal, rectal or vaginal ~lmini~trations. The
5 sustained release formulations also include layered formulations which
provide for distinct release ratio and thus may be more effective in
allowing for short and long term relief.
The following examples illustrate the compositions of the
present invention which may be readily prepared and as such are not to
o be considered as limiting the invention set forth in the claims.
EXAMPLE 1
cisapride/famotidine Tablet
cisapride 40 mg
famotidine 40 mg
PVP lS mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
EXAMPLE 2
cisapride/famotidine Tablet
cisapride 20 mg
famotidine 20 mg
PVP lS mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
wo 95/01803 2 ~ 6 6 7 3 0 PCT/US94/07520
EXAMPLE 3
cisapride/famotidine Tablet
cisapride lS mg
famotidine lS mg
PVP lS mg
Avicel PH101 40 mg
Magnesium Stearate 4 mgs
o EXAMPLE 4
cisapride/famotidine Tablet
cisapride 10 mg
famotidine 10 mg
PVP lS mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
EXAMPLE S
cisapride/famotidine Tablet
cisapride S mg
famotidine S mg
PVP lS mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
- wo gS/01803 ~ 1 6 6 7 3 0 PCT/US94/07520
- EXAMPLE 6
cisapride/famotidine Sustained Release
cisapride 40 mg
famotidine 40 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
o Methocel ElOMCR 66 mg
Methocel KlOOMLV 200 mg
EXAMPLE 7
5 cisapride/famotidine Sustained Release
cisapride 20 mg
famotidine 20 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
Methocel ElOMCR 66 mg
Methocel KlOOMLV 200 mg
EXAMPLE 8
cisapride/famotidine Solution
cisapride 10 mg
famotidine 10 mg
g.s. syrup 5 ml
WO 95/01803 2 1 6 6 7 3 0 PCT/US94/07~20
- 14 -
EXAMPLE 9
cisapride/famotidine Solution
cisapride 20 mg
famotidine 20 mg
g.s. syrup 5 ml
Simethicone or alpha-D-galactosidase may be added to each
of the above formulations or examples to provide anti-flatulent relief.
The quantity of simethicone ~lmini~tered to a patient in need of
treatment thereof may vary according to patient need, but may be, for
example, the typical known dosage range to treat flatulence (20-40 mgs
per tablet or per 5 ml liquid dosage form) or may be increased as
15 necessary. Generally, the amount of ADG that may be employed in the
above folmulations ranges from about 675 to about 2250 GalU or may
be increased as necessary. The inactive ingredients in the tablet form
may further include dextrates, m~nnitol, m~nesium stearate, Yellow
10, collodial silicon dioxide and Blue 1 or Red 27 while the liquid
20 form(s) may further include inactives such as butylparaben, carboxy-
methylcellulose sodium, flavors, hydroxypropyl methylcellulose,
microcrystalline cellulose, propylparaben, and purified water. The
previous examples are to be construed as non-limitin~ and additional
dosages and dosage forms or routes of ~(lmini~tration may be varied
25 depending upon the individual patient being treated for either the
primary (excess acid le~ding to gastrointestinal or esophageal
disturbance or ~m~ge) or secondary (infections) symptoms of
gastrointestinal disorders. In addition, known pharmaceutically
acceptable excipients or agents may be added as inactive ingredients to
30 the claimed active combination in a variety of forms including tablets,
capsules, or time-release medicaments.
