Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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GASTROINTESTINAL COMPOSITIONS COMPRISING GABA DERIVATIVES
This Continuation-ln-Pan application claims priority to the utility
application filed on July 10, 2002
by Express Mail No. EL819323526US.
FIELD OF THE INVENTION
The invention relates to compositions and methods for treating and/or
preventing lower
gastrointestinal (G1) disorders in mammalian patients, more particularly for
alleviating and/or
preventing the lower GI symptoms associated with such disorders.
BACKGROUND OF THE INVENTION
The primary function of the gastrointestinal tract is the absorption of
ingested nutrients.
This is achieved when transit along the esophagus and gastrointestinal tract
is at a rate which
facilitates optimal digestion and absorption of water and electrolytes.
abnormal patterns in
gastrointestinal motility result in number of disorders ranging from diffuse
esophageal spasm (an
esophageal obstructive disorder characterized by dysphagia), achalasia (an
obstructive disorder in
which the lower esophageal sphincter fails to relax adequately resulting in
dysphagia) and
noncardiac chest pain to functional bowel disorders such as the irritable
bowel syndrome (IBS), non-
ulcer dyspepsia, and idiopathic-constipation.- - ---- - ----
IBS is particularly disturbing since it involves chronic episodes of diarrhea
and/or
constipation for which there is no identifiable organic cause. The disorder
appears to result from
faulty regulation in both the gastrointestinal and nervous systems.
Where drug therapy is indicated, the therapy includes prokinetic agents for
constipation;
anticholinergics, antispasmodics such as trimebutine, tricylic and serotonin
reuptake inhibitor
antidepressants, and sedatives for cramping pain; and opiates (such as
loperamide and
diphenoxylate) and cholestyramine for diarrhea. However, such therapy has
proven to have limited,
if any, efficacy.
Clearly, therefore, a significant unmet need remains for an efficacious and
comprehensive
treatment of patients afflicted with such lower GI disorders, including
alleviation of such lower Gl
symptoms as chronic diarrhea, constipation and cramps.
The present inventors have found that gastrointestinal compositions comprising
a gamma
aminobutyric acid analogs in combination with amino-ether and/or ester oxides
provide a more
comprehensive reduction in IBS symptoms as compared to previous drug
therapies.
Accordingly, an aspect of the present invention is to provide gastrointestinal
compositions.
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Another aspect of the present invention is to provide gastrointestinal
compositions which
prevent, reduce or alleviate the symptoms associated with IBS.
A further aspect of the present invention is to provide gastrointestinal
compositions
comprising gamma-aminobutyric acid analogs in combination with amino-ether
and/or ester oxides.
SUMMARY OF THE INVENTION
The present invention relates to compositions for treating or preventing
gastrointestinal
disorders, comprising:
a) a GABA analog of the formula selected from the group consisting of:
H2N--CHz--C H2COzR,
(CHz)~
R3 Rz
H2NCHCCH2COOH
R~
and mixtures thereof; and
b) an amino-ether and/or -ester oxide having the formula:
~a
~~2)n
R I~-W~"12)m-Q-' ~CH~p-RS
( ~ Hl)9
N
R2 R3
in which: R, is a lower alkyl, Rz and R3 which are the same or different are
hydrogen or lower alkyl, R4 is a phenyl or phenoxy nucleus optionally
monosubstituted to trisubstituted by substituents which are identical or
different,
halogen or lower alkoxy, RS is a phenyl radical optionally monosubstituted to
trisubstituted by substituents which are the same or different, halogen, lower
alkyl,
lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, Q is -0- or
-COO-,
n is equal to zero, I or 2, m and q are, independently of one another, equal
to zero or
to l, p is an integer ranging from 0 to 9.
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Methods of treating or preventing gastrointestinal disorders using the above
compositions are also disclosed.
S DETAILED DESCRIPTION OF THE INVENTION
All percentages and ratios used herein are by weight of the total composition
and all
measurements made are at 25° C., unless otherwise designated.
The compositions of the present invention can comprise, consist essentially
of, or consist of,
the essential as well as optional ingredients and components described herein.
As used herein,
"consisting essentially of means that the composition or component may include
additional
ingredients, but only if the-additional-ingredients--do not materially alter
the basic and novel
characteristics of the claimed compositions or methods.
All publications cited herein are hereby incorporated by reference in their
entirety.
As used herein, a "pharmaceutically acceptable" component is one that is
suitable for use
with humans and/or animals without undue adverse side effects (such as
toxicity, irntation, and
allergic response) commensurate with a reasonable benefit/risk ratio.
By "safe and effective amount" is meant an amount of a compound or composition
which is
high enough to positively modify the condition being treated, but low enough
to avoid serious side
effects at a reasonable benefit/risk ratio within the scope of sound medical
judgement. The safe and
effective amount may vary with the age and physical condition of the person
being treated, the
severity of the condition, the specific ingredients employed, and like
factors.
The phrase "gastrointestinal disorder", as used herein, means a disorder of
the
gastrointestinal tract, including the small and large intestines and the
rectum, and/or symptoms
usually attributed to a dysfunction of one or more of these organs, such as
diarrhea, constipation
and/or abdominal and lower abdominal cramping or pain. It is understood that
gastro intestinal
disorders include both disorders for which an organic cause (e.g. infection by
a parasite) is known
and disorders for which no organic cause can be ascertained, such as IBS.
Gastrointestinal
disorders, therefore, include, but are not limited to, irritable bowel
syndrome, functional diarrhea,
ulcerative colitis, collagenous colitis, microscopic colitis, lymphocytic
colitis, inflammatory bowel
disease, Crohn's disease, and infectious diarrhea such as diarrhea associated
with amebiasis,
giardiasis, a viral infection, cytomegalovirus infection, or a pathogenic
bacterial infection. The
bacterial infection may, for example, be an infection by a bacterium selected
from the group
consisting of a bacterium of the genus Escherichia, an Escherichia coli
0157:H7 bacterium, a
bacterium of the genus Salmonella, a bacterium of the genus Shigella, a
bacterium of the genus
Campylobacter, a bacterium of the species Campylobacter jejuni, and a
bacterium of the genus
Yersinia
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The gastrointestinal compositions of the present invention, including the
essential and
optional components thereof, are described in detail hereinafter.
Gamma-Aminobutyric Acid Analogs
The compositions and methods of this invention utilize a safe and effective
amount of a
gamma-aminobutyric acid (GABA) analogs. A GAGA analog is any compound derived
from or
based upon ganuna-anvnobutyric acid. The compounds are readily available,
either commercially,
or by synthetic methodology well known to those skilled in the art of organic
chemistry. GABA
analogs used in the present invention are cyclic amino acids of Formula 1.
HzN--CHz--C--CHZCOzR,
C 2)n
wherein R, is hydrogen or lower alkyl and n is an integer of from 4 to 6, and
the pharmaceutically
acceptable salts thereof. An especially useful embodiment utilizes a compound
of Formula I where
R, is hydrogen and n is 5, which compound is 1-(aminomethyl)-cyclohexane
acetic acid, known
generically as gabapentin. Also useful herein are GABA analogs of Formula I
wherein the cyclic
ring is substituted, for example with alkyl groups such as methyl or ethyl.
Typical compounds include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-
aminomethyl-3-methylcyclopentyl)acetic acid, and (1-aminomethyl-3,4-
dimethylcyclopentyl)acetic
acid. Compounds and embodiments of Formula I are described in more detail in
U.S. Patent
4,024,175; herein incorporated by reference in its entirety. Also useful in
the present invention are
GABA analogs of Formula Il.
R~ RZ
H2NCHCCH2COOH a
R~
or a pharmaceutically acceptable salt thereof, wherein R, is a straight or
branched alkyl of from 1 to
6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms; RZ is
hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl. Diastereomers and enantiomers of
compounds of Formula II
can be utilized in the invention. An especially useful embodiment employs a
compound of Formula
II where RZ and R3 are both hydrogen, and R, is -(CHz)o-2-iCaH9 as an (R),
(S), or (R,S) isomer.
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3-( 1-aminoethyl)-5-methylhexanoic acid, 3-aminomethyl-5-methyl-hexanoic acid,
and (S)-
3-(aminomethyl)-5-methylhexanoic acid (now known generically as pregabalin, as
well as CI-1008)
are also useful herein. Compounds and embodiments represented by Formula Il
can be found in
U.S. Patent 5,563,175, which is also incorporated herein by reference in its
entirety.
5
The percentage of the active ingredient in the foregoing compositions can be
varied within
wide limits, but for practical purposes it is preferably present in a
concentration of at least 10% in a
solid composition and at least 2% in a primary liquid composition. The most
satisfactory
compositions are those in which a much higher proportion of the active
ingredient is present, for
example, from 10% to 90%_by weight._
The amount of GABA- analog in the composition will generally be from about 1
to about
300 mg per kg, preferably from about 5 to about 200 mg per kg, more preferably
from about 10 to
about 100 mg per kg of subject body weight. Typical doses will be from about
10 to about 5000 mg,
preferably from about 20 to about 800mg, per day for an adult subject of
normal weight. It is
expected that common doses that might be administered could be from 100 mg
three times a day up
to 600 mg four times a day. Useful intravenous dose is between about 5 and
about 50 mg. (The
intravenous dosage is within the dosing range used in treatment of
gastrointestinal diseases such as
ulcers and IBS,-or as_would_be_dictated .by the needs of the patient as
described by the physician.) A
more complete description of acceptable GABA analog effective amounts thereof
for use in unit
dose compositions of the present invention can be found in US Patents
6,127,418 and 6,117,908,
both of which are herein incorporated by reference in their entirety.
Amino-Ether And/Or Ester Oxides
The compositions and methods of the present invention also comprise a safe and
effective
amount of an amino-ether and/or -ester oxide. Amino-ether and/or -ester oxides
according to the
invention conform to the formula:
R4
1
~ i NZ)n
R 1- i -(CHZ)m-Q-(CI-i~p-RS
~~~9
N
RZ R3
in which: R, is a lower alkyl, RZ and R3 which are the same or different are
hydrogen or lower alkyl,
R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted
by substituents which
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are identical or different, halogen or lower alkoxy, RS is a phenyl radical
optionally
monosubstituted to trisubstituted by substituents which are the same or
different, halogen, lower
alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, Q is
-O- or -COO-, n is equal
to zero, I or 2, m and q are, independently of one another, equal to zero or
to l, p is an integer
ranging from 0 to 9.
By lower radical are meant radicals having from I to 10 carbon atoms,
preferably 1 to 6
carbon atoms, especially 1 to 4 carbon atoms in a straight or branched chain.
If RS is alkyl, it is preferably methyl. If the amino-ether oxides are
halogenated, they are
preferably brominated or chlorinated.
The invention also embraces the acid addition salts of amino-ether oxides,
notably those of
nvneral acids, such as halohydrates, sulphates, phosphates, or organic acids
such as maleates,
citrates, malates, tartrates, methanesulphonates, camphosulphonates,
benzoates, etc.
The invention further covers both racemic and optionally active forms which
can be
separated, particularly by forming salts with optically active acids.
Examples of suitable amino-ether and/or -ester oxides include trimebutine
(3,4,5-
trimethoxybenzoic acid 2-(dimethylamino)-2-phenylbutyl ester), fedotozine ((R)-
a-ethyl-N,N-
dimethyl-a-[[(3,4,5-trimethoxyphenyl) methoxy]methyl] benzenemethanamine) and
mixtures
thereof.
Trimebutine is available under the tradenames I\9odulon (Canada), Debridat
(Italy),
Cerekinon (Japan), and Polibutin (Spain). A more detailed description of
Fedotozine can be found
in U.S. Patent 4,301,163 to Torossian et al. (1981) and U.S. Patent 5,245,080
to Aubard et al.
( 1993), both of which are herein incorporated by reference in their entirety.
Fedotozine has been administered effectively at dosages of up to 210mg daily,
preferably 30
to 70 mg three times daily, and up to 100mg intravenously daily. Trimebutine
has been effectively
administered orally at up to 600mg/day, preferably up to 200 milligrams 3
times daily, or
intramuscularly/intravenously at up to 100 milligrams every 12 hours. While
mindful of individual
patient parameters and symptom severity, the amino-ether and/or ester oxides
are preferably
administered orally at 1-75 mg/kg, preferably 2-50 mg/kg and most preferably
at 5-20 mg/kg.
The compositions of the present invention can additionally contain:
A. Anti-Inflammatory Agents
A safe and effective amount of an anti-inflammatory agent may be added to the
compositions of the subject invention. The exact amount of anti-inflammatory
agent to be used in
the compositions will depend on the particular anti-inflammatory agent
utilized since such agents
vary widely in potency. A more complete description of the various NSAlITs,
including acceptable
analgesically effective amounts thereof for use in unit dose compositions of
the present invention
also appears in applicants co-pending U.S. application Ser. Nos. 474,358,
filed Mar. 11, 1983, and
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now U.S. Pat. No. 4,486,436, and 578,288, filed Feb. 8, 1984, now U.S. Pat.
No. 4,522,826 the
entire disclosures of which are incorporated herein by reference.
Steroidal anti-inflammatory agents, including but not limited to,
corticosteroids such as
hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,
dexamethasone-phosphate,
beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone
diacetate, diflucortolone
valerate, lluadrenolone, f7uclorolone acetonide. fludrocortisone, f7umethasone
pivalate, f7uosinolone
acetonide, fluocinonide, f7ucoriine butylesters, f7uocortolone, fluprednidene
(fluprednylidene)
acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone
butyrate,
methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone,
flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone
diacetate, fluradrenolone
acetonide; - medrysone,- amcinafel,-amcinafide, - belamethasone and the
balance of its esters,
chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone,
dichlorisone, diflurprednate,
flucloronide, f7unisolide, fluoromethalone, fluperolone, fluprednisolone,
hydrocortisone valerate,
hydrocortisone cyclopentylpropionate, hydrocortamate, ~ meprednisone,
paramethasone,
prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and
miXtures thereof may be
used. Mixtures of the above steroidal anti-inflammatory agents can also be
used. The preferred
steroidal anti-inflammatory for use is hydrocortisone.
----- - --A -second-class of anti-inflammatory-agents which is-useful in the
compositions includes the
nonsteroidal anti-inflammatory agents. The variety of compounds encompassed by
this group are
well-known to those skilled in the art. For detailed disclosure of the
chemical structure, synthesis,
side effects, etc. of non-steroidal anti-inflammatory agents, reference may be
had to standard texts,
including Anti-inflammatory and Anti-Rheumatic Drugs, K. D. Rainsford, Vol. I-
III, CRC Press,
Boca Raton, (1985), and Anti-inflammatory Agents, Chemistry and Pharmacology
1, R. A. Scherrer,
et al., Academic Press, New York (1974), each incorporated herein by
reference. .
Specific non-steroidal anti-inflammatory agents useful in the composition
invention include,
but are not limited to:
1) the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-
14,304;
2) the salicylates, such as aspirin, disalcid, benorylate, trilisate,
safapryn, solprin,
diflunisal, and fendosal;
3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin,
sulindac,
tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac,
zomepirac,
clindanac, oxepinac, felbinac, and ketorolac;
4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and
tolfenamic
acids;
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5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen,
flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen,
carprofen,
oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and
tiaprofenic;
and
6) the p~7azoles, such as phenvlbutazone, oxyphenbutazone, feprazone,
azapropazone, and
trimethazone.
Mixtures of these non-steroidal anti-inflammatory agents may also be employed,
as well as
the pharmologically acceptable salts and esters of these agents. For example,
etofenamate, a
flufenamic acid derivative, is particularly useful for topical application. Of
the nonsteroidal anti-
inflammatory agents, ibuprofen, naproxen, flufenamic acid, etofenamate,
aspirin, mefenamic acid,
-meclofenamic acid, piroxicam and-felbinac-are preferred; ibuprofen, naproxen,
etofenamate, aspirin
and flufenamic acid are most-preferred. ~---
Finally, so-called "natural" anti-inflanvnatory agents are useful in methods
of the subject
invention. Such agents may suitably be obtained as an extract by suitable
physical and/or chemical
isolation from natural sources (e.g., plants, fungi, by-products of
microorganisms). For example,
candelilla wax, alpha bisabolol, aloe vera, Manjistha (extracted from plants
in the genus Rubia,
particularly Rubia Cordifolia), and Guggal (extracted from plants in the genus
Commiphora,
particularly Commiphora Mukul), kola extract, chamomile, and sea whip extract,
may be used.
Additional anti-inflammatory agents useful herein include compounds of the
Licorice (the plant
genus/species Glycyrrhiza glabra) family, including glycyrrhetic acid,
glycyrrhizic acid, and
derivatives thereof (e.g., salts and esters). Suitable salts of the foregoing
compounds include metal
and ammonium salts. Suitable esters include Cz -C24 saturated or unsaturated
esters of the acids,
preferably C,o -C24, more preferably C,6 -Cz4. Specific examples of the
foregoing include oil soluble
licorice extract, the glycyrrhizic and glycyrrhetic acids themselves,
monoammonium glycyrrhizinate,
monopotassium glycyrrhizinate, dipotassium glycyrrhizinate, 1-beta-
glycyrrhetic acid, stearyl
glycyrrhetinate, and 3-stearyloxy-glycyrrhetinic acid, and disodium 3-
succinyloxy-beta-
glycyrrhetinate. Stearyl glycyrrhetinate is preferred.
Mixtures of any of the above anti-inflammatory agents can also be used.
B. Laxatives
A safe and effective amount of a laxative may be added to the compositions of
the subject
invention. The exact amount of laxative to be used in the compositions will
depend on the particular
laxative utilized since such agents vary widely in potency. A more omplete
descr7ption of the
various laxatives, including acceptable laxative effective amounts thereof for
use in unit dose
compositions of the present invention can be found in US patent 5,516,524;
herein incorporated by
reference in its entirety; as well as the Handbook of Nonprescription Drugs,
12th Ed., Chapter 12,
pp. 279-290 (American Pharmaceutical Association, Washington, D.C.; 2000); and
Drug Facts and
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Comparisons (54th Ed. 2000), pp. 1166-1177; the cited pages of which are
herein incorporated by
reference.
Laxatives useful herein include. but are not limited to, hydrophilic
derivatives of cellulose
(such methylcellulose and carboxymethylcellulose sodium), malt soup extract,
polyacrylic resins
(preferably hydrophilic forms such as polycarbophil and calcium
polycarbophil), plantago seeds,
psyllium husk, dioctyl calcium sulfosuccinate, dioctyl potassium
sulfosuccinate, dioctyl sodium
sulfosuccinate, mineral oil, magnesium citrate, magnesium hydroxide, magnesium
sulfate, dibasic
sodium phosphate, monobasic sodium phosphate. sodium biphosphate, glycerin,
anthraquinones or
anthracene laxatives (such as aloe, cascara sagrada, danthron, senna, aloin,
casanthranol , frangula,
and rhubarb), diphenylmethanes (such as bisacodyl and phenolphthalein), and
castor oil. Mixtures
---of the-above laxatives can also be-used.- - -- --- ----- . - --- - -
. _ -C~~-ntidiarrheals- _.___-_ - _ - -_ .__ . .
A safe and effective amount of an antidiarrheal may be added to the
compositions of the
subject invention. The exact amount of the antidiarrheal to be used in the
compositions will depend
on the particular antidiarrheal utilized since such agents vary widely in
potency. A more complete
description of the various antidiarrheals, including acceptable antidiarrheal
effective amounts thereof
for use in unit dose compositions of the present invention can be found in the
Handbook of
Nonprescription Dru&s, 12th Ed., Chapter 13, pp. 312-316 (American
Pharmaceutical Association,
Washington, D.C.;-2000); and Drug-Facts--and Comparisons (54th Ed. 2000), pp.
1178-1182; the
cited pages of which are herein incorporated by reference.
Antidiarrheals useful herein include, but are not limited to, natural or
synthetic opiates (such
as difenoxin, diphenoxylate, pargoric, opium tincture, and loperamide),
anticholinergics (such as
belladonna alkoloids - atropine hyoscyamine, and hyosine), acetyltannic acid,
albumin tannate,
alkofanone, aluminum salicylates, catechin, , lidamidine, mebiguine, trillium,
and uzarin. Mixtures
of the above antidiarrheals can also be used.
D. Antiu)cerative
A safe and effective amount of an antiulcerative may be added to the
compositions of the
subject invention. The exact amount of the antiulcerative to be used in the
compositions will depend
on the particular antiulcerative utilized since such agents vary widely in
potency. A more complete
description of the various antiulceratives, including acceptable
antiulcerative effective amounts
thereof for use in unit dose compositions of the present invention can be
found in the Drug Facts and
Comparisons (54th Ed. 2000), pp. 1131-1139; the cited pages of which are
herein incorporated by
reference.
Antiulcerative useful in the present invention include, but are not limited
to, aceglutamide
aluminum complex, E-acetamidocaproic acid zinc salt, acetoxolone, arbaprostil,
benexate
hydrochloride, bismuth subcitrate sol (dried), carbenoxolone, cetraxate,
cimetidine, enprostil,
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esaprazole, famotidine, flaxilide, gefarnate, guaiazulene, irsogladine,
nizatidine, omeprazole,
ornoprostil, Y-oryzanol, pifarnine, pirenzepine, plaunotol, ranitidine,
rioprostil, rosaprostol, rotraxate,
roxatidine acetate, sofalcone, spizofurone, sucralfate, teprenone,
trimoprostil, thrithiozine, troxipide,
and zolimidine. Mixtures of the above antiulcerative can also be used.
5 E. Antibiotics.
A safe and effective amount of an antibiotic may be added to the compositions
of the subject
invention. The exact amount of the antibiotic to be used in the compositions
will depend on the
particular antibiotic utilized since such agents vary widely in potency. A
complete description of the
various antibiotics, including acceptable antibiotic effective amounts thereof
for use in unit dose
10 compositions of the present invention can be found in the Drug Facts and
Comparisons (54th Ed.
2000);-pp. 1217-1354; the=cited-pages-of which are-herein incorporated by
reference. -
- A wide -variety of antibiotics may be used according to the invention,
including for example
nitroimidazole antibiotics (e.g. tinidazole or metronidazole), tetracyclines
(e.g. tetracyclin,
doxycyclin and minocyclin), pencillins (e.g. amoxycillin, ampicillin and
mezlocillin),
cephalosporins (e.g. cefachlor, cefadroxil, cephradine, cefuroxime, cefuroxime
axetil, cephalexin,
cefpodoxime proxetil, ceflazidime and ceftriaxone), carbopenems (e.g. imipenem
and meropenem),
amino-glycosides (e.g. paromonycin), macrolide antibiotics (e.g. erythromycin,
clarithromycin and
azithromycin), lincosamide antibiotics (e.g. clindamycin), 4-quinolones (e.g.
ofloxacin,
ciprofloxacin, pefloxacin and norfloxacin), rifamycins (e.g. rifampicin),
nitrofurantoin and
derivatives of 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2Ø0.3.8Jundec-2-
ene-2-carboxylic acid
and mixtures thereof as well as those described in US Patent 5,719,197 to
Kanios et al. ( 1998),
published European Patent Specification No. 0416953 and published
International Patent
Specification No. W092/03437, each of which are herein incorporated by
reference in its entirety.
F. Gastric Secretion Inhibitors
A safe and effective amount of a gastric secretion inhibitor may be added to
the
compositions of the subject invention. Suitable gastric secretion inhibitors
include, but are not
limited to, enterogastrone and octreotide. The exact amount of gastric
secretion inhibitors to be used
in the compositions will depend on the particular gastric secretion inhibitor
utilized since such
agents vary widely in potency. A more complete description of the various
Gastric Secretion
Inhibitors, including acceptable a Gastric Secretion Inhibitor effective
amounts thereof for use in
unit dose compositions of the present invention can be found in the Drug Facts
and Comparisons
(54th Ed. 2000), pp. 352-354; the cited pages of which are herein incorporated
by reference.
Mixtures of the above gastric secretion inhibitors can also be used.
G. Peristaltic Stimulants
A safe and effective amount of a peristaltic stimulant may be added to the
compositions of
the subject invention. Suitable peristaltic stimulants include, but are not
limited to, dexpanthenol,
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metoclopromide, cisapride, and domperidone. The exact amount of peristalitc
stimulants to be
used in the compositions will depend on the particular peristalitc stimulant
utilized since such agents
vary widely in potency. A more complete description of the various,
Peristaltic Stimulants including
acceptable Peristaltic Stimulant effective amounts thereof for use in unit
dose compositions of the
present invention can be found in the Drug Facts and Comparisons (54th Ed.
2000), pp. 1 I 88-1193;
the cited pages of which are herein incorporated by reference. Mixtures of the
above peristalitc
stimulants can also be used.
H. Serotonin (SHT3) Receptor Antagonist
A safe and effective amount of a serotonin (SHT3) receptor antagonist may be
added to the
compositions of the subject invention. Suitable serotonin (SHT3) receptor
antagonists include, but
are not limited .to, cilansetron, dolasetron, ondansetron and alosetron. The
exact amount of serotonin
(SNT3)-receptor antagonists to be used in the compositions will depend on the
particular serotonin
(SHT3) receptor antagonist utilized since such agents vary widely in potency.
A more complete
description of the various serotonin (SHT3) receptor antagonists, including
acceptable effective
amounts thereof for use in unit dose compositions of the present invention can
be found in US patent
6,235,745, herein incorporated by reference and the Drug Facts and Comparisons
(54th Ed. 2000),
pp. 869-872 and KU47; the cited pages of which are herein incorporated by
reference. Mixtures of
the above serotonin (SHT3) receptor antagonists can also be used.
L- Serotonin (5HT4) Receptor agonist ----- -
A safe and effective amount of a serotonin (SHT4) receptor agonist may be
added to the
compositions of the subject invention. Suitable serotonin (SHT4) receptor
agonists include, but are
not limited to tegaserod, renzapride and prucalopride. The exact amount of
serotonin (SHT4)
receptor agonists to be used in the compositions will depend on the particular
serotonin (SHT4)
receptor agonist utilized since such agents vary widely in potency. Tegaserod
is a partial serotonin
(SHT4) receptor agonist which accelerates orocecal transit (without effect on
gastic emptying) and
tends to enhance colonic transit. l2mg/day of tegaserod is taught to result in
effective relief of
irntable bowel syndrome symptoms. Prucalopride is a full serotonin (SHT4)
receptor agonist which
accelerates gastric, small bowel and colonic transit in functional
constipation. Up to 4mg/day,
particularly 2-4mg/day, of prucalopride is taught to result in effective
relief of untoward bowel
symptoms. Renzapride possesses both serotonin (SHT4) receptor agonist and
serotonin (SHT3)
receptor antagonist activity, providing increased gastric emptying and reduced
gastrintestinal transit
time. Mixtures of the above serotonin (SHT4) receptor agonists can also be
used. Mixtures of any of
the above-mentioned pharmaceutical compounds can also be used.
J. Selective Serotonin Reuptake lnhibitors
A safe and effective amount of a selective serotonin reuptake inhibitor may be
added to the
compositions of the subject invention. Suitable selective serotonin reuptake
inhibitors include, but
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12
are not limited to, fluoxetine, fluvoxamine, paroxetine, and sertraline. The
exact amount of
selective serotonin reuptake inhibitors to be used in the compositions will
depend on the particular
selective serotonin reuptake inhibitor utilized since such agents vary widely
in potency. A more
complete description of the various selective serotonin reuptake inhibitors,
including acceptable
effective amounts thereof for use in unit dose compositions of the present
invention can be found in
the Drug Facts and Comparisons (54th Ed. 2000), pp. 918-928; the cited pages
of which are herein
incorporated by reference. Mixtures of the above selective serotonin reuptake
inhibitors can also be
used.
Further dosage information concerning the disclosed actives is summarized in
the table below:
Generic Name Suitable StrengthsUsual Adult Dosage
and
_._ _,___--__.-- _Dosage Forms _.__ _ ____..
(Brand
_ . _ __ _ .. Names _ .._
-
Bulk-Foaming
Laxatives
Calcium polycarbophil625-mg tablets 1~ g/day as polycarbophil
that
provide 500 mg in divided doses
of
- polycarbophil
Kons 1 Fiber
Methylcellulose 2 g/Tbsp oral 4-6 g/day in divided
powder doses
Citrucel
Psyllium 3.4 .g/tsp or 2.5-30 g/day in
3.4 gf1'bsp divided
_ _ . _ _oral powder; doses _ __ _ _...
1-7g wafer
_-_-_. -__ . . _ . (Metamucil
_.__ _
Antidiarrheals
(opiate
and anticholinergic
a ents
Diphenoxylate 2.5-mg tablets; 2.5-5 mg four times
2.5 daily
mg/5 mL oral as needed for diarrhea
liquid
Lomotil
Loperamide 2-mg tablets 2-4 mg up to four
and times
capsules; 1 mg/5daily as needed.
mL
oral li uid (Imodium
Dicyclomine 10-mg capsules; 10-20 mg three or
20-mg four
tablets; 10 mg/5times daily
mL
s B ent 1
Nyoscyamine 0.125-mg tablets;0.15-0.3 mg up to
0.125 four
mg/mL; 0.125 times daily
mg/5
mL elixir Levsin
Tincture of bellormaTincture with 0.6-1 mL three or
0.3 four
mg/mL alkaloids times daily
of
belladonna leaf
Peristaltic Stimulants
Cisapride 10-, 20-mg tablets;5-10 mg three times
5 daily
mg/mL oral suspension
Pro ulsid
Metoclopramide 5-, 10-mg tablets;
5
m 5 mLoral li
uid
Selective Serotonin
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13
Reu take Inhibitors
Fluoxetine 20-mg capsules;
20
mg/5 mL oral
solution
(Prozac
Fluvoxamine SO-, 100-mg tablets
(Luvox
Paroxetine 10 mg/5 mL oral
suspension; 10-,
20-,
30-, 40-mg tablets
(Paxil
Sertraline 25-, 50-, 100-mg
tablets
(Zoloft
Serotonin (SHT3)
Rece for Anta onist
Alosetron 1-m tablets (Lotronex1 m twice dail
-Granisetron =-_-_-----1-m -tablets -- -
- ------__- (K ril --
-Ondansetron.- -.- 4-, 8-mg tablets4 mg three.times
_ __ - _ .. - daily
(Zofran
Gastric Secretion
Inhibitors
Octreotide _-_-_ 50, 100, 200,
500, 1000
~g/mL sterile
solution
for s.c. or i.v.
injection
(Sandostatin);10-,
20-,
30-mg sterile
suspensionfor
i.m.
injection (Sandostatin
L,AR Depot)
Garners
In accordance with the practices of the present invention, the
gastrointestinal compositions
may be administered in admixture with suitable pharmaceutical diluents,
carriers or other excipients
(collectively referred to as "carrier" materials) suitably selected with
respect to the intended route of
administration and conventional pharmaceutical practices. The gastrointestinal
compositions of the
present invention are typically mixed with a pharmaceutically acceptable
Garner. This carrier can be
a solid or liquid and the type is generally chosen based on the type of
administration being used.
The actives can be coadministered in the form of a tablet or capsule,
liposome, as an agglomerated
powder or in a liquid form. Capsule or tablets can be easily formulated and
can be made easy to
swallow or chew; other solid forms include granules, and bulk powders. Tablets
may contain
suitable binders, lubricants, diluents, disintegrating agents, coloring
agents, flavoring agents, flow-
inducing agents, and melting agents. Examples of suitable liquid dosage forms
include solutions or
suspensions in water, pharmaceutically acceptable fats and oils, alcohols or
other organic solvents,
including esters, emulsions, syrups or elixirs, suspensions, solutions and/or
suspensions reconstituted
from non-effervescent granules and effervescent preparations reconstituted
from effervescent
granules. Such liquid dosage forms may contain, for example, suitable
solvents, preservatives,
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14
emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and
melting agents. Oral
dosage forms optionally contain flavorants and coloring agents.
Examples of suitable tablet or capsule form ingredients, include but are not
limited, to oral
non-toxic pharmaceutically acceptable inert carrier such as lactose, starch,
sucrose, cellulose,
magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and the
like. Moreover, when
desired or necessary, suitable binders, lubricants, disintegrating agents and
coloring agents can also
be incorporated in the mixture. Suitable binders include starch, gelatin,
natural sugars, corn
sweeteners, natural and synthetic gums such as acacia, sodium alginate,
carboxymethylcellulose,
polyethylene glycol and waxes. Among the lubricants there may be mentioned for
use in these
dosage forms, boric acid, sodiumbenzoate, sodium acetate, sodium chloride,
etc. Disintegrators
include, without limitation, starch; methylcellulose; agar, bentonite, guar
gum, etc.
- ---Of course, additionally, the compositions of the present -invention may
be formulated in
sustained release form to provide the rate controlled release of any one or
more of the components to
optimize the therapeutic effects, i.e., analgesia, skeletal muscle relaxation,
etc. while minimizing
undesirable side effects. Suitable dosage forms for sustained release include
layered tablets
containing layers of varying disintegration rates or controlled release
polymeric matrices
impregnated with the active components and shaped in tablet form or capsules
containing such
impregnated or encapsulated porous polymeric matrices.
Similarly, injectable dosage units may be utilized to accomplish intravenous,
intramuscular
or subcutaneous administration and, for such parenteral administration,
suitable sterile aqueous or
non-aqueous solutions or suspensions, optionally containing appropriate
solutes to effectuate
isotonicity, will be employed.
Specific examples of pharmaceutical acceptable carriers and excipients that
may be used to
formulate oral dosage forms of the present invention are described in U.S.
Pat. No. 3,903,297 to
Robert, issued Sep. 2, 1975, herein incorporated by reference in its entirety.
Techniques and
compositions for making dosage forms useful in the present invention are
described in the following
references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,
Editors, 1979);
Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel,
Introduction to
Pharmaceutical Dosage Forms 2nd Edition (1976), each of which are herein
incorporated by
reference in its entirety.
The gastrointestinal compositions of the present invention may also be
formulated and
administered by other methods known for administering gastrointestinal
actives. For example, the
composition may be adapted for topical administration in the form of rectal
preparations such as a
rectal cream, gel, ointment, or suppository.
Method of Treatment
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The method of treatment can be any suitable method which is effective in the
treatment of
the particular type of lower gastrointestinal disorder that is being treated.
Treatment may be oral,
rectal, parenteral, intravenous administration or injection. The method of
applying an effective
5 amount also varies depending on the lower gastrointestinal disorder being
treated. It is believed that
oral treatment by tablet, capsule or liquid will be the preferred method of
administering the
compounds to warm blooded mammals.
The method of treating viral infections may also be by rectal, parenteral, or
intravenous
administration. The actual time and dosage will depend on the type of the
lower gastrointestinal
10 disorder being treated and the desired blood levels.
--In-accordance with the practices of the-present invention, the
gastrointestinal compositions
may be administered in admixture with suitable pharmaceutical diluents,
carriers or other excipients
(collectively referred to as "carrier" materials) suitably selected with
respect to the intended route of
administration and conventional pharmaceutical practices. The gastrointestinal
compositions of the
15 present invention are typically mixed with a pharmaceutically acceptable
carrier. This Garner can be
a solid or liquid and the type is generally chosen based on the type of
administration being used.
The actives can be coadministered in the form of a tablet or capsule,
liposome, as an agglomerated
powder or in a liquid form. Capsule or tablets can be easily formulated and
can be made easy to
swallow or chew; other solid forms include granules, and bulk powders. Tablets
may contain
suitable binders, lubricants, diluents, disintegrating agents, coloring
agents, flavoring agents, flow-
inducing agents, and melting agents. Examples of suitable liquid dosage forms
include solutions or
suspensions in water, pharmaceutically acceptable fats and oils, alcohols or
other organic solvents,
including esters, emulsions, syrups or elixirs, suspensions, solutions and/or
suspensions reconstituted
from non-effervescent granules and effervescent preparations reconstituted
from effervescent
granules. Such liquid dosage forms may contain, for example, suitable
solvents, preservatives,
emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and
melting agents. Oral
dosage forms optionally contain flavorants and coloring agents.
Examples of suitable tablet or capsule form ingredients, include but are not
limited, to oral
non-toxic pharmaceutically acceptable inert carrier such as lactose, starch,
sucrose, cellulose,
magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and the
like. Moreover, when
desired or necessary, suitable binders, lubricants, disintegrating agents and
coloring agents can also
be incorporated in the mixture. Suitable binders include starch, gelatin,
natural sugars, corn
sweeteners, natural and synthetic gums such as acacia, sodium alginate,
carboxymethylcellulose,
polyethylene glycol and waxes. Among the lubricants there may be mentioned for
use in these
dosage forms, boric acid, sodiumbenzoate, sodium acetate, sodium chloride,
etc. Disintegrators
include, without limitation, starch, methylcellulose, agar, bentonite, guar
gum, etc.
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16
Of course, additionally, the compositions of the present invention may be
formulated in
sustained release form to provide the rate controlled release of any one or
more of the components to
optimize the therapeutic effects, i.e., analgesia, skeletal muscle relaxation,
etc. while minimizing
undesirable side effects. Suitable dosage forms for sustained release include
layered tablets
containing layers of varying disintegration rates or controlled release
polymeric matrices
impregnated with the active components and shaped in tablet form or capsules
containing such
impregnated or encapsulated porous polymeric matrices.
Similarly, injectable dosage units may be utilized to accomplish intravenous,
intramuscular
or subcutaneous administration and, for such parenteral administration,
suitable sterile aqueous or
non-aqueous solutions or suspensions, optionally containing appropriate
solutes to effectuate
isotonicity;-will be employed._ .. - -
- Specific-examples of pharmaceutical_acceptable carriers and excipients that
may be used to
formulate oral dosage forms of the present invention are described in U.S.
Pat. No. 3,903,297 to
Robert, issued Sep. 2, 1975, herein incorporated by reference in its entirety.
Techniques and
compositions for making dosage forms useful in the present invention are
described in the following
references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,
Editors, 1979);
Lieberman et al., Pharmaceutical Dosage Forms: Tablets ( 1981 ); and Ansel,
Introduction to
Pharmaceutical Dosage Forms 2nd Edition (1976), each of which are herein
incorporated by
reference in its entirety.
The gastrointestinal compositions of the present invention may also be
formulated and
administered by other methods known for administering gastrointestinal
actives. For example, the
composition may be adapted for topical administration in the form of rectal
preparations such as a
rectal cream, gel, ointment, or suppository.
Method of Treatment
The method of treatment can be any suitable method which is effective in the
treatment of
the particular type of lower gastrointestinal disorder that is being treated.
Treatment may be oral,
rectal, parenteral, intravenous administration or injection. The method of
applying an effective
amount also varies depending on the lower gastrointestinal disorder being
treated. It is believed that
oral treatment by tablet, capsule or liquid will be the preferred method of
administering the
compounds to warm blooded mammals.
The method of treating lower gastrointestinal disorders may also be by rectal,
parenteral, or
intravenous administration. The actual time and dosage will depend on the type
of the lower
gastrointestinal disorder being treated and the desired blood levels.
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17
EXAMPLES
The compositions in the following illustrate specific embodiments of the
gastrointestinal
compositions of the present invention, but are not intended to be limiting
thereof. Other
modifications can be undertaken by the skilled artisan without departing from
the spirit and scope of
this invention.
All exemplified compositions can be prepared by conventional formulation and
mixing
techniques. Component amounts are listed as weight percents and exclude minor
materials such as
diluents, filler, and so forth. The listed formulations, therefore, comprise
the listed components and
any minor materials associated with such components.
Example I
The following is an example of a gelatin capsule composition of the present
invention. The
capsule is formed by combining and mixing the ingredients of each column using
conventional
technology and transferring the mixture to an appropriate sized hard gelatin
capsule (e.g., #2 size)
for oral administration.
IS
In edient %/w/w
Gaba entin20.000_
Trimebutine20.000
-- - - --- ~~- - -- --- Lactose 5.000-
NF
Tricalcium55.000
Phos hate
Lactose NF - Lactose Monohydrate, Amresco lnc.
zTricalcium Phosphate - American International Chemical Inc.
Example II
The following is an example of a rectal ointment of the present invention.
In edient %w/w
Gaba entin 2.500
Trimebutine 5.000
White Wax 5.000
NF'
Petrolatum 87.500
USPZ
100.000
Beeswax, Bleached supplied trahl &
by S Pitsch
lnc.
zWhite Petrolatum supplied
by Witco Corporation
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18
In a suitable vessel equipped with a heat source and a cover or lid for
sealing the
vessel, the white wax and petrolatum are added and heated with mixing to a
melt temperature of
between 85 - 90oC C using a suitable turbine blade agitator. The Gabapentin
and Trimebutine are
slowly added to the molten petrolatum mixture. The mixture is cooled to a
temperature of about 60
degrees C and then poured into a suitable container.
The rectal ointment is applied in an appropriate amount (e.g., two to four
grams) to the rectal
area .
Example III
-- -- - The following-is an example of an sterile liquid composition of the
present invention.
In edients %w/v
Gaba entin 2.500
Trimebutine1.500
Methyl 0.020
Paraban'
-Water for q.s
In'ection
USP
Supplied by Chem,
Universal Inc.
Preserv-A-
In a suitable vessel, equipped with a suitable turbine agitator, the water for
injection is added.
While providing moderate agitation, the remaining ingredients are then added
and mixed with the
water. The mixture is stirred until a homogenous, clear solution is formed.
The solution is filtered,
aseptically, through a 0.22 micron filter into a sterile container suitable
for vial filling. The solution
is then aseptically transferred to appropriately sized sterile vials and
sealed.
The injectable is administered hypodermically.
Example IV
The following is an example of an oral solution of the present invention. The
solution is
formed by combining and mixing the ingredients of each column using
conventional technology and
transferring the mixture to an appropriate containers (e.g., HDPE or brown
glass). The oral solution
is administered orally at dosage amounts of about Sml.
In edients %w/v
Gaba entin 0.025
~rimebutin 0.020
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Famotidine 0.002
Alcohol USP 20.000
(190'
Purified Water 89.955
USP
'Ethanol 190 USP, Grain Processing Corporation
