H2 ANTAGONIST-ALGINATE-ANTACID COMBINATIONS

COMBINAISONS D'ANTACIDE, D'ALGINATE ET D'ANTAGONISTE DES RECEPTEURS DE H2

English Abstract

This invention relates to pharmaceutical composition for use in the treatment and relief of indigestion, sour stomach, heartburn and
other gastrointestinal disorders in mammals, including humans, by administering compositions comprising: (i) an amount effective in the
relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of formula (I) and its pharmaceutically
acceptable salts, hydrates, stereoisomersor polymorphs and (ii) an amount effective in relief of gastrointestinal or esophagus disorders of
at least one of the alginates and (iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a
buffering effect and generates carbon dioxide to aerate the alginate.

French Abstract

Cette invention concerne des compositions pharmaceutiques utilisables dans le traitement et le soulagement des indigestions, des aigreurs d'estomac, des brûlures d'estomac et des autres troubles gastro-intestinaux chez les mammifères, y compris l'homme. Ce traitement comprend l'administration de compositions comportant: (i) une quantité, efficace pour le soulagement des troubles gastro-intestinaux ou de l'oesophage, d'un antagoniste H2 sélectionné parmi un composé de la formule (I) et ses sels, hydrates, stéréo-isomères ou composés polymorphes pharmaceutiquement acceptables et (ii) une quantité, efficace pour le soulagement des troubles gastro-intestinaux ou de l'oesophage, d'au moins un alginate et (iii) une quantité, efficace pour le soulagement des embarras gastro-intestinaux, d'un antiacide procurant un effet régulateur et générant du dioxyde de carbone pour aérer l'alginate.

Claims

WHAT IS CLAIMED IS:
1. A pharmacetical composition for use in the
treatment of gastrointestinal disorders such as indigestion, sour stomach,
overindulgence and heartburn in a mammals, including humans
comprising:
(i) an amount effective in the relief of gastrointestinal or
espohagus disorders of an H2 antagonist selected
from a compound of the formula:
<IMG>
and its pharmaceutically acceptable salts, hydrates,
stereoisomers or polymorphs and
(ii) an amount effective in relief of gastrointestinal or
esophagus disorders of at least one of an alginate; and
(iii) an amount effective in relief of gastrointestinal
distress of an antacid wherein the antacid provides a
buffering effect and generates carbon dioxide to
aerate the alginate and optionally
(iv) an antiflatulent amount of simethicone.
2. The composition of Claim 1 comprising between 5
mg to 40 mgs of famotidine.
3. The composition of Claim 2 comprising 200-500 mgs
of an alginate selected from alginic acid or sodium alginate and 500-
1000 mgs of an antacid wherein the antacid is selected from sodium or

- 14 -
calcium carbonate salts or aluminum hydroxide or magnesium
hydroxide salts.
4. The composition according to Claim 3 comprising
(i) a tablet of 10 mgs of famotidine and
(ii) 500 mgs of alginic acid and
(iii) 500 mgs of calcium carbonate and optionally
(iv) 20-40 mgs of simethicone.
5. A method of treating gastrointestinal disorders such
as indigestion, sour stomach, overindulgence, gastroesophageal reflux
and heartburn in a mammalian organism in need of such treatment,
comprising administering to such organism:
(i) an amount effective in the relief of gastrointestinal or
esophagus disorders of an H2 antagonist selected
from a compound of the formula:
<IMG>
and its pharmaceutically acceptable salts, hydrates,
stereoisomers or polymorphs and
(ii) an amount effective in relief of gastrointestinal or
esophagus disorders of at least one of the alginates
and
(iii) an amount effective in relief of gastrointestinal
distress of an antacid wherein the antacid provides a

- 15 -
buffering effect and generates carbon dioxide to
aerate the alginate and optionally
(iv) an antiflatulent amount of simethicone.
6. A method according to Claim 5 wherein the
composition administered to a mammalian organism in need thereof
comprises:
(i) a tablet of 10 mgs of famotidine and
(ii) 500 mgs of alginic acid and
(iii) 500 mgs of calcium carbonate and optionally
(iv) 20-40 mgs of simethicone.
7. A method of reducing the size and weight of a
pharmaceutically effective amount of an alginate/antacid/H2 antagonist
combination dosage form which comprises combining
(i) an amount effective in the relief of gastrointestinal or
esophagus disorders of an H2 antagonist selected
from a compound of the formula:
<IMG>
and its pharmaceutically acceptable salts, hydrates,
stereoisomers or polymorphs and
(ii) an amount effective in relief of gastrointestinal or
esophagus disorders of at least one of the alginates
and

- 16 -
(iii) an amount effective in relief of gastrointestinal
distress of an antacid wherein the antacid provides a
buffering effect and generates carbon dioxide to
aerate the alginate and optionally
(iv) an antiflatulent amount of simethicone.
8. A method of treating gastrointestinal disorders,
overindulgence and pain before or during ingestion of a meal
accompanied by alcoholic beverages, comprising:
administration of a combination of
(i) an amount effective in the relief of gastrointestinal or
esophagus disorders of an H2 antagonist selected
from a compound of the formula:
<IMG>
and its pharmaceutically acceptable salts, hydrates,
stereoisomers or polymorphs wherein the famotidine
does not interact with ethanol from the ingestion of
the alcoholic beverage; and
(ii) an amount effective in relief of gastrointestinal or
esophagus disorders of at least one of the alginates
wherein the alginate absorbs the ethanol; and
(iii) an amount effective in relief of gastrointestinal
distress of an antacid wherein the antacid provides a
buffering effect and generates carbon dioxide to
aerate the alginate and optionally
(iv) an antiflatulent amount of simethicone.

Description

- wo 95,0l7g5 2 ~ 6 ~- 7 3 ~ PCT/US94/07519
TITLE OF T~F. ~IVENTION
H2 ANTAGONIST-ALGINATE-AN~ACID COMBINATIONS
.
BACKGROUND OF THE ~VENTION
H2 antagonisls are c~mmrnly prescAbed to treat and
prevent ulcers in the walls of the stom~rh, duo~3c~ or esophagus. H2
antagonists are alsb used to treat non-ulcerative con~lition~. Damage to
the mucus lining ~ul~v~ lin~ these tissues en~bles destructive action of
stom~rh acids which erodes the underlying tissue. ~ommonly known
H2 antagonists for the tre~tmPnt of ulcers include cim~Ptlin~.? r~niti-lin~,
nizatidine, rox~ti~line and famoti~lin~q
Combinations of ~l~in~tes with certain H2 antagonists have
been disclosed. See U.S. Pat No. 5,007,790 which discloses a solid state
drug c~--t~ g (cimetidine)/polymer (sodium ~lgin~t~); GB 2æ2772
which discloses the H2 antagonist r~niti~line and ~lginir acid. GB
2,207,865 discloses a wound h~lin~ agent co~lising H-2 antagonist
(famotidine) with carrier such as an ~ in~te wherein the composition is
used to treat wounds rather than as a gastric acid inhibitor. EP-
290,229-B discloses an H2-antagonist (cim~oti~line) plus an antacid and/or
~l~in~te. See also U.S. Pat. No. 4,996,222. It is known that with
certain H2 antagonists, an ~lgin~t~ added to treat gastroesophageal
reflux can promote oxi~l~tion of the H2 antagonist to a biological
inactive form and additional ingre~i~nts have to be added to prevent this
re~ction Combin~tion~ of antacids and ~l~in~tes have been used to
provide ~y~ omatic relief of gastroesophageal reflu~. See
Martindale's Extra Pharmacopoeia at page 1432. Combinations of H2
antagonists and antacids have been disclosed: See FR2648710,
GB2219940, EP- 294933-A, EP-286,781-A, SU 1,362,477-A, U.S.
c 4,824,664, EP 233,853 and WO 9209286 Al. There is a need,
however, to employ a drug combin~tion with the advantages of an
~lpin~te or ~l inic acid and an antacid to prevent gastroesoph~e~
reflux (GER) in cQmbin~tion with an H2 antagonist selected from
famotidine or its salts, hydrates, stereoisomers or polymorphs to treat
and prevent the discol~foll associated wi~ indigestion, sour ætQrn~Cll,

WO 95/0179~ 2 i 6 6 7 3 I PCT/US94107S19
hcall~ or other gaslr~ al disorders including GER.
Additional ~nto~ nt~ may be added to the cl~ime~l famotidine/
in~te/antacid co.~ ;on to prevent o~ t on of famotidine to a less
active metabolite.There is a need to employ a combination v~l~il~ an
5 advantage is that the overall ~y~ toms of ga~lr~ s~ l distress can be
effectively treated with a combin~tion of the most powerful H2
antagonist av~ ble with an ~lgin~t~ and an ~nt~ci~ such as a c~l,.~nate
salt or m~gn~sjllm or ~1...";..1.... hydroxide wherein the combination
simlllt~nP,ously relieves and prevents s~ln~toms associated with excess
gastric acid secretion or evolution in the stom~rh and esophagus
respectively.
The present illv~ ion th~.~role provides an effective
synergistic tre~tm~nt of ga~lr~ estin~l disorders using the combin~tion
of famotidine and its salts, hydrates, or ph~rm~cologically active
stereoisomers or polymorphs ~,vith an ~ ,in~t~ and an antacid. The
c!~ime~l combin~ti~ is particularly useful for treating gastro-
esophageal reflux disorder at ni~h*me since famotidine or the
biologically active forms of ~mot~ n~ has a long-l~*n~ effect (9
hours) thereby aiding in the prevention of he~ ~ l and other
gasL..,i,llestinal distress while the ~l~in~te aids in elimin~tin~ the rafting
effect and the ~ntar,i~l provides rapid 1, lrrelillg relief in the stomach.
Other H2 antagonists that may be employed in this illvelltion include
cimP-litine, r~niti~line, ni7~tit1inP, and roY~ti~linP.
DETA~ED DESCRIPTION OF THE INVENTION
This invention claims ~ ce~llir~l composidons for use
in the tr~tmP-nt of mild stom~h and esophagus disorders including the
prevention and l-e~t~ -t of L~lL..Ill.. The composition colrll~lises:
(i) an amPunt erre.,live in the relief of ga~o;.. ~estin~l or ''
esophagus disorders of an H2 antagonist selected
from a colllp~,ulld of the form~
*rB

WO 95/01795 . 2 1 ~ 6 7 ~ T PCTIUS94/07519
NH2` NSO2NH2
~C=Ny~N~CH2SCH2CH2C\
NH2 S - b NH2
and its ph~rm~celltic~lly accephble salts, hydrates,
stereoi~ m~.rs or polymorphs and
(ii) an amount effective in relief of gaslrol~l~esffn~l or
o esophagus disorders of at least one of an ~l~in~te and
(iii) an amount effective in relief of ga~LIo;.,~s~
distress of an arltacid wherein the ~n~cid provides a
;.~g effect and generates carbon dioxide to
aerate the ~l~in~te and optionally
(iv) an ~ntifl~tlll~.nt amount of s;~lle~ cone~
This invention is also directed to a method of preventing
20 and treating indigestion, sour stomach, he~~ "l, overindulgence,
gastroesoph~e~l reflux and other ga~lr~ estinal disorders in
m~mm~ls, inchldinp 1.~ , in need of tre~tmtont thereof, conlplising
ini~tering to such or~ni~m:
(i) an amount effective in the relief of ga~,.Jillt~stinal or
esoph~ls disorders of an H2 antagonist selected
from a compound of the formnl~.
NH2 ~NSO2NH2
~C=Ny~N~CH2SCH2CH2C\
3 o NH2 S--Y NH2
and its ph~ celltic~lly acceptable salts, hydrates,
stereoisomers or polymorphs and

wo 95,0l7g5 2 1 6 6 7 3 t PCT/US94/07519
(ii) an amount effective in relief of gasllo;..l~s(;~-~l or
eso~h~ls disorders of at least one of an ~l~in~te
(iii) an amount effective in relief of ga~ro;..~.stin~l
distress of an antacid ~11~l~ the antacid provides a
l~urre~ g effect and generates carbon dio~ide to
aerate the ~l~in~t~. and optionally
o (iv) an ~ntifl~hll~P.nt amount of simPthicone.
The te~n m~mm~l~ or m~mm~ n or~ni~m includes but is
not limited to hllm~n~, dogs, cats, horses and cows.
The term tre~SmPnt çnromr~cses the complete range of
therapelltir.~lly positive effects associated with ~.h~ ell~
me-lic~tion including reduction of, alleviation of and relief from the
s~m~oms or illness which affect the org~ n~
Famotidine may be purchq~e.~ in buLk or ot~er suitable
~l~ntitiçs as it is cu~lly available on the ma~ket and formlll~tr-3 via
typical form~ tiQn processes with ~l~n~tes selecte~3 from ~1 inir, acid
which is suitable for tablet forml~l~tion~ or ~o~ m ~l~in~tP. which is
suitable for liquid form~ tions of the cl~imP,~ combination and antacids
which are also known including calcium c~l,onate and other carbonate
salts as well as ~ -l--n and m~ npsillm hydroxides. In ~dition,
simethicone, a known ~ntifl~tl~lent~ may be added to the above
25 combination to provide ma~ and broad relief of gasll~stinal
diblulb~..res and distress. Famotidine as a prescription drug product is
sold in the United States under the tr~-iPm~rk PEPCID~).
The ph~rm~cel)hc.~l co~ ositions of the present invention
are useful in the tre~tmP,nt of various mild ga~lr~i..tes~ l disorders
including indigestion, sour stomach, overindulgence and heall~ul~. In
particular, an ~lgin~te and ~nt~cid coml~inP~ with an H2 antagonist
selected from famotidine, a coll~ound of the fo~

WO 95/01795 ;~ l 6 6 7 3 1 PCI/US94/07519
NH2~ ~NSO2NH2
~C =Ny~NycH2scH2cH2c\
NH2 s_b NH2
or its rh~rm^^~ c~lly acceptable salts, hydrates, stereoisomers or
polymorphs is useful for the prevention and tr~ of various
ga~lloi~ stinal disorders such as indigestion,- sour stom~rh, or
h~ . The llhli7~tion of the ~ lly known biologically active
o forms and/or salts or hydrates of famotidine in combination with an
~1 in~te selected from ~1 inic acid or sodinm ~l~in~te or other
ph~rm~ceutically acceptable ~ tç salts or hydrates and an antacid is
advantageously used to treat mild ga~lruilltestinal disorders.
SimP,thirone or another anti-fl~ lent such as alpha-galactosid~ee (ADG)
15 may be added to this ~l~f~ d co~nbin~tion to provide anti-fl~t~ t
relief. In particular, the cl~imed combin~tion is used to treat the
~y~ ullle associated with ~t ic acid secretion while simlllt~neously
treating the Sylll~tOlllS of gastroesoph~ge~l reflux and fl~t~llenr~. The
- ~nim~l, p~ti~nt, or org~niem in need of tre~ -nt thereof the,e~o~e
20 bençfite from the Gl~ime~l ph~rm - elltic~l compositi~n-
H2 antagonists are well known in the tre~nent of ulcers
and other ga~llo;nlestin~l disorders and may be used, according to the
present inv~ntion, in combination with an ~lgin~te and an antacid and
optional anti-fl~ t H2 antagonists used for ulcer ~lel~y fall into
25 four major structural cl~ses imi~l~701e denvalives; s~lbsl ;l~e~l furans,
~mino~lkylrh.ono~y de~ivalives and ~li...;.l;l.othiazole compounds.
Famotidine (N-(~minoslllfonyl)-3-[[[2-[~i~...;.-nln~thylene)~minQ]4-
thiazolyl]methyl]thio] yloy~ mi~le)~ a m~mber of the latter class,
is a colllye~iliv-e inhibitor of hist~min~ H2-rec~tol;, and its primary
3 0 y~ cQlogical activity is the inhibition of gastric acid secretion.
Famotidine su~l~sses both the acid co--cæ-~ alion and the volume of
gastric acid secretion. Famotidine is well tolerated and has ~I;t~it~ side
effects and thus advantageously may be used in the present invention in
combin~tion with an ~1 in~te and an antacid. Famotidine is also the
most potent and selective H2 antagonist.

WO 95tO1795 2 1 6 6 7 3 t PCT/US94/07519
The combination of famotidine or its ph~ celltie~lly
effective salts, hydrates, ~lereoi~omPrs or polymorphs with an antacid
and an ~l~in~te and optionally simP-thirone provides a combin~tir~n
which simnlt~neously and selectively provides relief from and
prevention of disco nfoll and injury to the stom~h, esophagus, or
dllo~lenllm from excess production of gastric acid. I;,llll.P-I...ore,
famotidine in combination with an ~l~in~te and an antacid may not
interact with ~lr,ohol so that it may be ~lmini~tered prior to or during
ingestion of meals or beverages which Cû~ lcQhol and, thef~fol~, a
p~tiPnt in need of rapid tre~tment of ga~ l distress may take
the drug combination at an &~pf~ll&te time which may be during a
meal in which alcohol was c~ ecl The combin~ti~ n of an alginate
and antacid with famotidine provides relief of gastroesoph~ge~l reflux
while also providing long acting relief from and tre~tmP-nt of
ga~ 'estin~l disorders associ~te~l with gastric acid secretion. The
~nt~rid ~ min;~tered in the cl~imP~ comkinqtion provides both a
l~urrt~ g effect and sim~11t~nPously generates c~l,ull dioxide to aerate
the ~ n~te raft formed from the ~1 in~te The raft has a lower density
after this aeration effect and floats on the stom~r~ co~ s;
A ~l~"~eulically active stereoisomer or polymorph of
famotidine may be employed sllbst~nti~lly free of other stereoisomeric
forms of polymorphs, sllbst~nti~lly free should be taken to mean at least
90% of one ~ tinct stereoisomer or polymorph.
The combin~tion of famotidine which is a highly potent H2
antagonist with an ~l~in~te and an ~nt~cid re-lllces the size and weight of
all pl-~fm~r,eutical delivery forms or combination form~ tions and
lllelefole i~ wes p~ti~ t compliance or tolerance. The tablet or
capsule form of this co~ tion is more readily swallowable by
p~tirnt~ in need of tre~tmpnt thereof.
F~moti-line or its ~rm~r,elltiG~lly acceptable salts,
hydrates, stereoisomers or polymorphs is adv~nt~eously used in the
present invention in combination with ~l~inir acid or sodium ~1 in~te
and calcium c~l~ . Of course, other suitable and known antacids
such as the ~1--...;..--.~. hydroxide or m~esillm hydroxide salts or

WO 95/0179~ ~ 1 6 6 7 3 1 PCTtUS94/07519
~ ,s or com~in~tions thereof may be used in the cl~imP(l
form~ tion. For example, a one to one ratio of m~gnP,,cium hydroxide
to ~11... ~ hydroxide salts may be ntili7~jcl in the p~,se-ll invention.
The ~mount of famotidine used in the ~ t invention in hllm~nc may
range from 2.5 mg/day to 80 mg/day. Adv~nt~g-P,ously, 2.5 to 40
mgs/day is ~llrnini~tered in co~l,;- .~l ;c!n with 200-500 mgs/day mg of an
~l~n~te and 250-750 mgs/day of calcium carbonate. The qll~ntitieS of
each of the active ingre-lientc may vary depen~1in~ upon the severity of
the con~lition and the particular biocl~f ~ and need of the p~tipnt or
other or~ni.cm in need of tre~tn~-nt thereof. A physician or clinician
or veterinarian of ordinary skill in ~e art may readily detel~ine
suitable dosages of any prescription mP~lic~tiQn C~ 'E the cl~ime~l
invPntion- The combination cl~imPi-l in the ;..~ invention is
advantageously ~rlmini~ctered orally. The antacid employed herein may
15 be selec~ed from any of the co~ -~ially available or known antacids
or com~in~tions thereof such as ~l.. ;.. ~ hydro~cide, calcium
c~bollate, m~3yl~s~ l hydroxide or so~ m bicarbonate. The
simP-thicone optionally employed herein is also available con~lelically
and the ~t1mini~tered oral dosage may range in hllm~n~ from 10-1,000
mgs/day. This ~mollnt varies depen~lin~ upon the severity of the
con~ition and typical dosages are described in the Physicians Desk
Reference at pages 1155-56 (1992). ADG may be employed as an anti-
fl~ in doses of 290 to 31,000 ('J~ tosidase ~ ;o~l Units
(GaIU) particularly 675 to 2250 GaIU.
The present composition may be ~ministered to a p~l;.ont
in need of ~e~ ..t thereof in ~e form of tablets, caplets, gelcaps,
capsules, elixirs, lozenges, wafers, effervescent formnl~tioll.c, chewable
tablets, syrups, or s~lepeneioI c or via other known and effective delivery
methods. For oral ~lminictr~tion~ the acfive ingredients may be
30 ~-lmise~ with a ph~ celltir~lly acceptable dilnPnt such as lactose,
sucrose, cellulose, dicalcium phosph~te, c~l~illm slllf~te, ..~,..ilol, and,
in a liquid composit-io~ ethyl alcohol. Acceptable e-ml~leifying or
sllepen-lin~ agents such as PVP, gelatin, natural sugars, com swe~teners,
natural and synthetic gums such as ~ ci~, sodium ~1 in~te, guar gum,

wOgS/0l79!i 2 1 ~7 ~ PCT/US94/07519
agar, I~.to~ e, ca,l~ymethylcellulose so~ m) polyethylene glycol r
and waxes, may also be qtlmixe~l with the active cG~ Jo~?~ . Where
n~ce~ssqry~ lubricants such as m-q~sillm stearic acid talc or mqgn~sillm
st~qr-qte, and ~ inte~atol~ or supe~;~intçg~dtol~ such as starch, sodium
starch glycolate or cross-linked PVP may also be in~ etl~ Electrolytes
such as lic--q-lcillm ~os~ e, so~lillm ~ c~te, sodium qcet~q~te and
so~ m chloride may also be used. The inactive ingreflients may also
include m~psillm or ~ ;n~ tricilirqt~, sodium or potq..~sillm salts
including c~l,o late salts, -q~ .. hydroxide gel, lqr,tose, sorbitol,
as~al~lle or sodium sqcrh~ri~
The active comrQn~-nts may also be form~ ted in sust~in
release or effervescent forml~lqtio~ . The sust-q-in~ release
form~ tions also include layered formnl-qtiQn~ which provide for
tinct release ratios and thus may be more er~c~ive in allowing for
short and long term relief.
The following eY-qmrles illustrate tbe compositions of the
~.~se.ll invention which may be readily ~pa~d and as such are not to
be considered as limiting the lll./e~lion set forth in the claims.
EXAMPLE 1
al~in~t~lantacid/famotidine Tablet
~lginic acid 500 mg
famotidine 40 mg
PVP 15 mg
Avicel PHlOl 40 mg
.e~ St~ate 4 mg
c~lcillm c~l~ale 500 mg
m~ lm tri~ c~te 25 mg
soflillm bic~l,o~ e 170 mg
~l.. ;... hydroxide gel 100 mg

WO 95/~17~5 2 1 ~ 6 7 } ~ ~/US94107519
EXAMPLE 2
t~/antacid/f~mc)tidine Tablet
~lpinir acid 500 mg
famotidine 20 mg
PVP 15 mg
Avicel PH101 40 mg
.jllm Stearate 4 mg
0 C~lcjnm c~l~l~ate 500 mg
EXAMp~ .F. 3
in~te/antacid/f~motidine Tablet
~lpiniG acid 500 mg
famotidine 15 mg
PVP 15 mg
Avicel PH101 40 mg
2 Ma~siul~ Stearate 4 mg
calcium c~l,ol.ate 500 mg
- EXAMPLE 4
25 al~inate/antacid/famotidine Tablet
~l inicacid g
famotidine 10 mg
PVP 15 mg
3 Avicel PH101 . 40 mg
~gneSjllm Stearate 4 mg
c.~lci~m c~o-~ate 500 mg

wo 95/0l7g5 2 1 6 ~ 7 3 1 PCT/USg4l075lg
- 10-
EXA~IP! .F. 5
~in~tt~./antacid/famotidine Tablet
~1 iniC acid 500mg
famotidine 5 mg
PVP 1~ mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
calcium c~l~ollat~ 500 mg
EXAMPLE 6
15 ~l~in~te/antacid/f~m~ tidine Sustained Release
~1 inir.acid 600mg
famotidine 40 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
Me~hocel ElOMCR 66 mg
Meth~cel KlOOMLV 200 mg
calcinm c~l~ale 600 mg
EXAMP! P 7
~l~inate/famotidine/antacid Sus~lled Release
~1 inicacid 600mg
famotidine 20 mg
PVP 30 mg
AvicelPH101 80 mg
M~esil~mStearate 8 mg

WO 95/017g5 2 1 6 6 7 3 1PCT/US94/07S19
MethooelElOMCR 66 mg
Methocel KlOOMLV 200 mg
calcium c&ll~nale 600 mg
EXAl~IPLE 8
in~tP/antacidtfamotidine Solut;on
sodium ~ n~te 500 mg
o famotidine 10 mg
g.s. syrup 5 ml
c~ -m c~l,o~le 500mg
EXAMP~.F, g
al~inate/~nt~id~f~motidine Solution
sodium ~l~in~te 500 mg
famotidine 20 mg
g.s. syrup 5 ml
c~lcillm carbonate 500 mg
Simethirone may be added to each of the above
form~ hions or examples to provide anti-fl~hllent relief. The ~u~lily
Of ~imethic ?ne ~lminictered to a p~ti~nt in need of tre~tm~-*t thereof is
25 the typical known dosage range to treat fl~tnlPnre. The dose may be,
for example 2~40 mgs of ~imethiconP per 5 mls of a liquid form
cl~ime~ c~ mbin~tion or per chewable tablet wherein the other active
ingre~ P-nt~ inrl~ P famoti~line (20~0 mgs), m~eSi~lm hydroxide (200
mg), ~ll.. li.. ~. hydroxide (dried gel, 200 mg). The inactive
30 ingreflient~ in the tablet form may fur~her include dextrates, m~nnitol,
m~ ea.ate, Yellow 10, collodial silicondioxide andBlue 1 or
Red 27 while the liquid form(s) may ru~ r incl~fle inactives such as
butylparaben, c&lbo~ymethylcel11-lose sodium, flavors, hyd~ypr~yl
methylcellulose, microcryst~lline cellulose, propylparaben, and purified

wo gS/01795 2 1 6 6 7 3 ~ PCT~S94/07519
- 12-
water. Tbe previous examples are to be construed as non-limi*ng and
~di*on~l dosages and ~los~ge forms or routes of ~ nini~tration may be
varied lepen~1in upon tbe individual ~ t being treated for ei~er the
primary (e~cess acid I~P~r1;n~ to ga~ estinal or esophap~e~l
dislu~ lce or tl~m~ge) or secondary (infections) sylllptoms of
gasllu~lestinal disorders. ~ ~d~lition, known ~ "~e~?l*r~lly
acceptab}e exci~k,~s or agents may be added as inactive ingre~lipnt~ to
the cl~ime~ active combination in a variety of forms including tablets,
capsules, or time-release me~lic~m~nts

Representative Drawing