Note: Descriptions are shown in the official language in which they were submitted.
W095/071103 2 1 7 0 4 8 8 PCT/US94/09581
- 1
COMPOSITIONS CONTAINING AN AMINO ACID SALT OF PROPIONIC ACID NON-STEROIDAL
ANTIINFLAMMATORY AGENT AND AT LEAST ONE OF A DECONGESTANT~ AN EXPECTORANT,
AN ANTIHISTAMINE AND AN ANTITUSSIVE
llECHCNlCAL F~ELD
s The present invention relates to compositions and methods for providing
improved tre~t~n~, management or mitig~tion of cold, cold-like and/or fiu
symptoms by q,~minictering a safe and effective amount of a composition comprising
certain amino acid salts of propionic acid non-steriodal anti-infl-q- ...n~to,y agents
along with at least one of (a) a deconge~ , (b) an expectorant, (c) an
0 ~ntihictqmine, and (d) an qntit--csive~
BACKGROUND OF THE INVENTION
The co~ llon cold, -q-lthollgh not usually a serious illness, is a highly pre-
valent, discou~- Iu~g and annoying infli~ior- The terrn ~cGI.. on cold~ is applied
to minor respiratory illnesses caused by a variety of di~e~ r~yualo~y viruses.
5 While rhinoviruses are the major known cause of common colds, nc~.~,l;~ for
appl o~ tely 30 percent of colds in adults, viruses in several other groups are also
impor~ant. While immllne responses occur, and infçctiol- vith some l~piratory
tract viruses th~.efole could be p~enled by a vaccine, dc~elop,~ of a polytypic
vaccine to cover all possible agents is ;ll~pra~lical~ Thus, the problem of controlling
20 acute upper r~sp;,~lol~ disease plesenls complex chqll~ng~s, and the long-desired
discovery of a single cure for the collu~on cold is an unrealistic c~l~e~ t;~n
Early ~mp~ol-ls may be minimql uith only mild mqlqi~., sore throat and
n_sal compl_ints. ~lth rhinovirus infection, a~ G~Ils of nasal dischal~e, nasal
co~P~lion, qnd ~.~e~-:ng usually c~ e -r.C on the first day of illness _nd progress
2s to m-q-Yimum severity by the second or third day. Along with nasal symptoms may
come sore, dry or scla~chy throat and ho~,~ess and cough. Other symptoms may
include mild bun~ing of the eyes, loss of smell and taste, a feeling of pressure or
fullness in the sinuaes or ears, headache and vocal illlpaulllelll. Fever can occur,
but is un~iouu,lon. Tnfluen~ infection generally includes fever, often of sudden30 onset and pe.a;all. g for several days, and with great severity; generalized aches and
pains; fatigue and wÇ~Icness; and chest discon~. l.
At present, only symptomatic ~ is available for the common cold.
The costs oftreating colds with over-the-counter ~.P~iC~l;or~C in the United States is
çstim~ted at an annual cost of over 1.5 billion dollars. The direct costs of llc<.l~
3s in outpatient clinics is estim~ted at almost four billion dollars. Indirect costs, based
on the amount of loss in wages because of restricted activity are subst~nti~ny
higher.
-
WO 95/07103 PCT/US94/09S81
4~ 2
Exemplary prior art forrnulations for treatment of cough, cold, cold-like
and/or flu syrnptoms and the discomfort, pain, fever and general malaise associated
therewith generally contain an analgesic (aspirin or acet~minophen) and one or more
antihistaminics, decongestants, cough suppressants, Antit~lcsives and expectorants.
s The use of non-steroidal anti-infl~mmAtory drugs to combat infl~mmAtion
and atten~Ant pain is accepted medical practice. The non-steroidals are comrnonly
employed to relieve pain and inflAmm~tion associated vith, for e ~ le, bur~itis,iLis, h~d~che and the like. Among the most commonly used drugs of the
non-narcotic ~nAl~ecic class of drugs are aspirin, ac~ ophen, ibuprofen and
0 naplo~.l. Aspirin, a~et~;nQphen and ibuprofen have heretofore been inchld~.d as
the pain reUever and fever-re~duçing component in conv~ntionAI cough/cold multi--symptom alleviating compocitiorC These co..ul~ercially "~ t~d products
generally contain in addition to aspirin, ace~ ophen or ibuprofen, one or more
:~ntih;c~z.,.;nics, decong~ s, cough-slupplessdt~ts, Antitl~-csives and e,~clo-~ls.
The oll.,llline, Iysine and a-~ine salts of ibuprofen useful for providing
relief from pain and ;~ ,....A1;0r have been disclosed in, for exarnple, U.S.
4,279,926 to BDse et al., issued July 21, 1981. A process for the prepa.~ion of
ibuprofen Iysine tablets has been ~icr,losed in EP 505,180, published March 19,
1992. The use of the S(+) form of ibuprofen has been dicrlose~ in, for e~..ple,
U.S. Patent 4,851,444 to Sunchine et al. issued July 25, 1989 and in co.. lbu,alion
with ~ntihi~ es in WO 9,205,783 to Gates et al. published April 16, 1992.
The use of napro~en as well as other of the newer non-steroidal anti-inflarn-
matory agents (i.e., ~Yclu~ g aspinn, ac~t~ -ophen and ph.onacetin) in the
prep~alion of cough/cold ph&---Pr~ltic~l co~lpGs;lions has been disclosed in, for
2s ~ .. pl, U.S. Patent 4,552,899 to !S~-~.cl.;.. ~ et al. issued November 12, 1985. The
use of some of these newer NSAID's alone to treat upper leSpllalO~ infections has
been ~iSrlos~d in "Therapeutic Utility of Napro~n in Acute Upper Respiratory
Tnr~ n ~ tirlir;c~l Double Blind Study" Ka~Asl~ogaku Zasshi 52 (5):148-
-163 (1978), HClinical Evaluation of Sl-lind~c (Clinoril~)) in the Tl~t...rA~ of Acute
30 Upper Rest,;.alo.~ Tract ~,,ilsn~tion -- Double Blind Co,ll~,~ison Wlth
Ibuprofenn, Kansenshog~hl Zasshi. Vol. 57, No. 3, pp. 260-272 (1983); "~ouble
Blind Controlled Study of Mi~ p-of~ in Acute Upper Respiratory Tract Infec~ions.Comparison with Ibuprofen" K~-ser~shogaku Zasshi. Vol. 50, No. 5, pp. 435453,
1982, HTherapeutic Effects of Fenbufen on the Common Cold. I~ulti.~.linic Double-
3s -Blind Study" Kan~--sh~gaku Zasshi. Vol. 51, No. 4, pp. 184-196, (1977);
"Clinical Evalllafiol~ of Clinoril Tablets in Acute Respiratory Tract Infec~ionsn,
K~r-~l-shogaku Zasshi. Vol. 56, No. 12, pp. 1186-1195, 1982.
WO 95/07103 2 1 7 0 4 8 8 PCT/US91/09581
The present inventors have found that selected compositions comprising
certain amino acid salts of the propionic acid NSAIDs with at least one of (a) adecongestant, (b) an expectorant (c) and antihistamine, and (d) an antitussive
provides improved l~eatl.,enl, management or mitigation of cold, cold-like and/or
s flu syrnptoms.
It is therefore an object of the present invention to provide a method for the
t~c~t~ of cough, cold, cold-like and/or ~u symptoms in a mammalian organism
in need of such h~n-f-.~ comprising adminictenng to such organism the
compositions of the present invention. Such symptoms as used herein refer to
0 coryza, nasal congestion, sinus con~,e~lion, sinus pain, upper respiratory infections,
allergic rhinitis, otitis, sinitis, etc.
SUMMARY OF THE INVENTION
The present inve.,lion relates to compositions and m~thods for providing
improved Lle~ nl management or mitig~tiQn of cold, cold-lilce and/or flu
s~rnptoms by a~lminictering a safe and effective amount of a coll,pos;lion coll~an amino acid salt of a p.opion c acid NSAID along with at least one of (a) a de-
congest~nt (b) an ~ .e~lo,~t, (c) an ~ntih~ c and (d) an ~ntitucsivc.
AU perc~ g~s and ratios used herein are by weight unless otherwise in-
dicated.
DETAILED DESCRIPIION OF THE INVEN IION
The present invention relates to compositions and metho~i5 for providing
improved Ir~ 1, m~n~g~m~nt or mitig~tion of cold, cold-like and/or flu
symptoms by ad~ i ing a safe and effective amount of a composition comprising
an amino acid salt of a propio ~ acid NSAID along with at least one of (a) a de-congest~nt (b) an e.~ or~l (c) an ~ntih~ e and (d) an ~ntihlccive.
The term ~amino acid salt" refers to salts derived from pharrn~r~ltic~l~y
ac~pl_ble organic non-toxic bases of primary, second~y, tertiary and quale.l~
amines, s~lbstituted arnines incl ing naturaUy OCCW~ g substitl-te~ ~minPC, cyclic
amines and basic ion e cch~nge resins, such as triethylamine, ll ;propylamine,
2-dimethylz.Y~ino~ anol, 2-diethylarninoethanol, Iysine, ollu~ e, a~ginine, hicti~lin~,
~e~ne, procaine, N-ethylpiperidine, h~dl~ba"~;n~ cholin~ beta ne,
ethyl~neAia.-;Qe, gluoos"-.~h-e, methylglycamine, theob1c,.luJ~e, purines, piper~7ine~
piperidine, poly~,une resins and the like.
The p.~,pionic acid derivatives of the non-steroidal anti-;..ll~..-- ~tory agents
3s which are useful in the compositions of the present invention are weU-known to
those skiUed in the art and are clis~losed in, for e-~ ~.ple, U.S. Patent 4,552,899 to
Sllnchine et al., issued Nove.llbe. 12, 1985, incorporated by refe-~,nce herein. For
WO 95/07103 PCT/US91109581
- ~ ~ 7 ~ 4
detailed disclosure of the cherrucal structure, synthesis, side effects, etc., of
non-steroidal anti-inflammatory agents, reference may be had to standard texts,
including Anti-inflam natory and Anti-Rheumatic Drugs, K. D. Rainsford, Vol. ~
CRC Press, Boca Raton, (1985), and Anti-inflamrnator,v Agents. Chernistry and
s Pharmacology 1, R. A. Scherrer, et al., .Ac~qdemic Press, New York (1974), both of
which are incorporated by reference herein.
The pr~f~,.,cd non-steroidal anti-infl~mm-q-tQry agents useful in the com-
position of the present invention include the amino acid salts of the propionic acid
derivatives such as ibuprofen, naproxen, beno~aprofcn, flu,biprvfen, ketoplofe.~,
0 fenoprofen, fenb~lfen, indoprofen, pirprofen, c~rofel-, o~apro~, pranoprofen,
Il.iroprofel~, tioxaprofcn, suprofen, alrninoprofen, and tiaprofenic. Mixtures of these
non-steroidal anti-inllz~.. ~tory agents may also be employed. Of these propionic
acid NSAIDs, ibuprofen, napro~en and ketoprofen are most pl~f~.l~.
Most pr~fel,~d for use herein is the S(+) isomer of these NSAID salts. The
s term "S(+)" as applied to the qnqlgesic agents herein is int~n~ed to encomrqcs the
d~ ivrvtato~y or S(+) isomer of the amino acid salt derivatives thereof. The
e,.~, essivn "sl~b~ ;911y free of the R(-) antipode" as used in con~unction vith the
term "S(+)~ means that the S(+) enantiomer is sufficiently free it is R(-) antipode to
exert the desired onset-hq~tene~ and enhqnced q-nq-lgesic effect. Practically
20 spe~ing this means that the active ingredient should contain at least 90% by
weight of the S(+) enantiomer and 10% or less weight R(-) enantiomer. Preferably,
the weight ratio of S(+) enantiomer to R(-) enantiomer is greater than 20:1, more
preferably greater than 97:3. Most preferably the S(+) enantiomer is 99 or more /o
by weight free of R(-) çnqntiomer, i.e., the weight ratio of S to R is appro~l5a~
2s equal to or greater than 99:1.
The safc and effective amount of the sn~ino acid salts of ibuprofen,
napro,.cn, benv. ~prvfcn, flu.l.iplofen, ketop,of~n, fenoprofen, fenbufen, indo-profen, pi~uren~ c~lofen, okapro~, pranop~oren, ....,o~,.ofen, tioxaprofen7
s~profen, ~ h~oprofen7 and tiaprofenic generally ranges from about 7.5 mg to
30 about lOOOmg, and are generally the same as their acid derivatives counterpar~s.
Useful dosage of these agents can be found in The Pl~ cians' Desk Rçference.
47th Edition (1993) and in U.S. Patent 4,552,"'~ to Çrln~hinP et al., isslled
November 12, 1985, both of which are u~col~olaled by rererence herein.
For e~ le, the safe and effective amount of the amino acid salt of
3s ibuprofen used in the compositions of the present invention generally ranges from
about 50 to about 800 mg, preferably from about 50 to about 400 mg, more
pref~.~bly from about 50 to about 200 mg and most p.eft.~bly from about 50 to
WO 95/07103 PCT/US9~/09581
~ s 21 7~88
about 100 mg. The safe and effective amount of the amino acid salt of flurbiprofen
used in the compositions of the present invention generally ranges from about 12.5
to about 300 mg, preferably from about 12.5 to about 200 mg, more preferably
from about 12.5 to about 100 mg and most preferably from about 12.5 to about 50
s mg. The safe and effective arnount of the amino acid salt of ketoprofen used in the
compositions of the present invention generaUy ranges from about 5 to about 100
mg, preferably from about 5 to about 75 mg, more preferably from about 5 to about
50 nng and most prefelably from about 5 to about 25 mg. GeneraUy, the amount of
the S(+) isomers of these agents wiU be about half of the amount of the racemic
0 mixture.
The compositions of the present invention also include at least one other
pharmacological active s~le~l~ from the foUowing class: (a) a de~ong~z-.1, (b) an
expectorant (c) an Antihi~ .;ne and (d) an Antit~esivc. The dec~nge,tAQIs useful in
the compositions of the present invention include pseudoepheA.inc, phenylpro-
5 panol~mine, phenylcplilu.e and ephed~ine, their ph&,..7ce~ltic~l1y acceptablle salts,and n~ixtures thereof. The Antitl~csives useful in the present invention include those
such as d~,~tlu~clhorphan, chloph~1;Anol, c~l,~lA~- I~n~, c~alnl~hen, noscArine,diphenhydl~,.itle, codein~, hydrocodone, hydromo~l,hone, fominob~n, their
pharmAr,enticAlly accept_ble salts, and nwctures thereof. The zntihi5~ neS useful
20 in the present invention include those such as chlo.l,h~,ntUa...lnc, ~.o...l-hcn;.~...nc,
dexchlorphel~i.~.~.,.c, d~ h~....lc, t.i~ ,lidinc, ~t~linc, doxylan~ine,
t.;~ele--nA-..h-e, cyproheptadine, hydrox~mnc, clemActine~ carbino~
phenin-lAmin~, bro..~ h~nh~,d~u~ e, pyrilamine, their ph~ P-ce~ltirqlly
acceplâble salts, as weU as the non~ Ating Anti~ lz..;l~cs which include
2s acrivastine, AHR-11325, Actemi~91e, q>~lqc~ r" c~u~u~e, eb~cl;.-r" ketotifen,
lodoxAmide, l~ralidulc, le~ocabq~ , m~uip7in~, oxatomide, setqC~inr~ ta~lline,
tem~olqctinç~ and terfenadine, their ph~l..z-r,e~ltirA11y ~ pt~le salts and mLlctures
thereo The e.~ ;lo-~ls (also known as mucolytic agents) useful in the present
invention include glyceryl guaiacolate, terpin hydrate, ~IL.uol~um chloride, N-
30 -acetylcysteine and bro.--lu~ , arnbroxol, their ph&Ace~lticqlly acceptable salts,
and mixtures thereof. All of these cc,l.,pon~,nls, as well as their acceptable dosage
ranges are described in the following: U.S. Patent 4,783,465 to S~nchine et al., is-
sued November 8, 1988, U.S. Patent 4,619,934 to ~llnchine et al., issued October28, 1986, which are incci. ~o. a~ed by refer~,nce herein.
3s ~l~,fe.ably, the phannAr~ltic~l compositions of the present invention
connprise the ~n~lg~sic agent and other pha,..lzcological active in a ratio of anal-
W O 95/07103 PCT~US9~/09581
4~ 6
gesic agent:pharmacological active of from about 200:1 to about 1:1, preferably
from about 50:1 to about 1:1 and most preferably from about 10:1 to about 1:1.
Various oral dosage forms can be used, including such solid forms as tablets,
capsules, ~ranules, lozenges and bulk powders and liquid forms such as syrups and
5 suspensions. These oral forrns comprise a safe and effective amount, usually at least
about 5% of the active component. Solid oral dosage forms preferably contain from
about 5% to about 95%, more p~f..ably from about 10 % to about 95%, and most
preferably from about 25 % to about 95% of the active ~..lpone.-t. Liquid oral
dosage forms preferably contain from about 1% to about 50% and more preferably
0 from about 1% to about 25% and most preferably from about 3% to about 10% of
the active component.
Tabletc can be con~pressed, triturated, enteric-coated, sugar-coated,
film-coated or mllltirle co.npre3sed, co~ ioi~g s~it~ble binders, lubricants, Ailu~ntc,
Aicinte2;~a~ g agents, coloring agents, flavoring agents, preservatives and flow-
ind~lçing agents. Also useful are so~ gelatin c~r~
Liquid oral dosage forms include ~lueo!ls and norl~lue~lls solutions, emul-
sions, pseudo em..lr;on~, s~cpen~;cnc, and solutionc and/or sucp~oncions recons-tituted from non-effervescent granules, co..~ ~i~ble solvents, preservatives,
emulsif~ing agents, s~ls~.A;I~g agents, ~iluentc~ s..~t~,n.,rs, taste-~ r~ g agents,
20 coloring agents, and flavoring agents. Specific ~-~...ples of phal~ ce~.tic~lly
acceplabl~ carriers and eA~-~ cnts that may be used to formulate oral dosage forms,
are des~ilil.cd in U.S. Patent 3,903,297, Robert, issued Septe...tlr 2, 1975,
incollJo.al~ by ~,fer~l~cc herein. Techniques and cG,..po~;lions for making solid
oral dosage forms are d~.ibed in Marshall, "Solid Oral Dosage Forms,~ Modern
Pl,a.. acu~tics. Vol. 7. (13anker and Rhodes, editors), 359427 (1979), incorporated
by reference herein. Techniques and co-l,pos;lions for making tablets (colllplessed
and molded), c~ps~ (hard and soft gelatin) and pills are de~.;b~d in Rçmington'sPh~l"~c~tic~l S~erc~s (Arthur Osol, editor), 1553-1593 (1980), inco.~Jo.aled
herein by r~ .encc.
In p~ the liquid oral dosage forrns, the active component is incor-
porated into an aqueous-Sascd orally acce~)l~le pl~ -^e~ti~l carrier cons;sle..lwith conv~ntion~l ph~...~-cwtic~l p, ~ticPs An ~aqueous-based orally acceptable
pharm~ce~ti~ ~l carrier" is one wherein the entire or predG~ solvent content is
water. Typical carricrs include simple ~queous solutions, syrups, dispersions and
35 suspensions, and aqueous based emulsions such as the oil-in-water type. The most
prefe,.~d carrier is a s~Spenciorl of the pharm^xutical composition in an aqueous
vehicle co.~ g a suitable su~pendi-,g agent. Suitablc suspending agents include
WO 95/07103 PCT/US9 t/09581
~ 7 21 ~04~8
Avicel RC-591 (a microcrystalline-cellulose/sodium carboxymethyl cellulose
mixture available from FMC), guar gum and the like Such suspending agents are
well known to those skilled in the art While the amount of water in the
compositions of this invention can vary over quite a wide range depending upon the
s total weight and volume of the active component and other optional non-active
ingredients, the total water content, based on the weight of the f~nal composition,
will generally range from about 20 to about 75%, and, preferably, from about 20 to
about 40%, by weight/volume.
tho~lgh water itself may make up the entire carrier, typical liquid formu-
o lations preferably contain a co-solvent, for e~ .le, propylene glycol, glycerin, sor-
bitol solution and the like, to assist solubili7~ti~n and incorporation of
water-insoluble ingre~ nts~ such as flavoring oils and the like into the ccs...pos;lion.
In general, ther~fore, the co",pos;lions of this invention p~ft;lably contain from
about 5 to about 25 volume~volume percent and, most pref.,.~bly, from about 10 to
lS about 20 volume/ volume ~rcenl, of the co-solvent.
The compositio~c of this invention may optionally contain one or more other
known therapeutic agents, particularly those ~..~ or.l~ utilized in cough/cold
prepalations~ such as, for exarnple, a s ~ol~cl~o~ tor such as terbutaline,
a.,fi.loph~lline, ep,~epLIne, isopre,1aline"~etap,oterenol, bitoterol, theoph"rlline and
20 albuterol as well as other analgesic agents such as r~~ sphell and aspirin. Ahighly prer~ d optional cc ~ronenl is c~ e Other optional inglcl;c~lls well
known to the ph~ll.zcist's art may also be inrl~dGd in ~ mtc generally known forthese ingredients, for cAample, natural or ~liLcizl ,~.~ten~,.s, flavolii1g agents,
colorants and the like to provide a palatable and ~ c~nt looking f~nal product,
2s antioxidants, for example, butylated hydroAy anisole or bul~laled l.~droA~ toluene,
and preservatives, for e~ nple methyl or propyl p&~,n or sodium ben,oate, to
prolong and çnh~nr~ shelf lilfe.
METHOD OF TREATMENT
The ~mount of the ~ha... ~r~ltir~l co"lpos;lion ~ ,(e..,d depends upon
30 the percent of active ingredients within its formula, which is a function of the
~mol~nt of the n~pl.ll.al~ derivative and any optional co",pone.lts such as a
de~ongest~nt cough s~pln~lt7 eA~lolanl and/or ~ntih.~;....;..e required per
dose, stability, release characteristics and other pharm~c~utic~l pa,~..~lers
Usually from about 1 mg/kg to about S0 mg/kg per day, preferably from
3s about 2 mg/kg to about 30 mg/kg per day and most plefe.ably from about 3 mglkg
per day to about 20 mg/kg per day of the ph~ ...~ceutical co"~pos;lion is
a~lminictered as des~,libed herein. This amount can be given in a single dose, or,
wo 95/07103 ~
. %~ 8
preferably, in multiple (two to six) doses repeatedly or sustained release dosages
over the course of treatment. Generally, each individual dosage of the pharma-
ceutical compositions of the present invention range ~om about I mg/kg to about
25 mg/kg, preferably from about 2 mgAcg to about 15 mgQcg and most preferably
s from about 3 mglkg to about 10 mg/kg. While dosages higher than the foregoing
are effective to provide relief from cough, cold-like, flu and flu-like syrnptoms, care
must be taken, as with any drug, in some individuals to prevent adverse side effec~.
The following eY~mrles illustrate emboAimentc of the subject invention
wherein both e~ ~ l and optional inglctienls are combined.
EXAMPLE I
A hard gelatin capsule composition for oral ~n~ lalion is p~e~ d by
co~.~bining the following u~gledieu1s:
Ingredient Amount
Ibuprofen Lysinate 200 mg
Pseudoephellil.e HCI 30 mg
Triturate active ingredients and q.s. with lactose to selected capsulc sizc.
~dminictration of 1 or 2 of the above cars~ s to a human in need of
..e .~ provides improved relief from cough, cold-litke~ flu and flu-like symptoms.
F.XAMPLE II
A hard gelatin capsule composition for oral ad.. ~ alion is pl~pa.~,d by
cc,lll~ , the following ingredients:
In~ienl Amount
Nap.uA~n Lysinatc 200 mg
Pse~ldoeph~ ~ HCI 30 mg
~ct~ le 5 mg
Glyce~ le 100 mg
Triturate active in~cd;c.,ls and q.s. with lactosc to s~ l~ capsule size.
~ ;n~l~alion of 1 or 2 of the above r~p~llpc to a human in need of
llc~ .l provides improved relieffrom cough, cold-like, flu and flu-likc symptoms.
EXA~LE m
A liquid ~".po~. liûn for oral a~lminictration is p~par~ by c~,..bilfing the
following ingrçAients
Il-g~ % W/V
Ketoprofcl~ Lysinate 1.00
Alcohol (95%) 25.000
Pseudoe~he~l,i,-c HCI 0.30
WO~5/07103 2 ~ 7 0 ~ PCT/USg4/09~8
Propylene Glycol 25.000
Sodium Citrate 2.000
Citric Acid 0.250
Liquid Sugar (Simple Syrup)25.000
s Glycerin 7.000
Colorants 0.008
Flavor 0.500
Water, Purified QS 100.000
The purified water (approxi-,.dtely 10% of the final batch volwne) is poured
0 into a batch co~ ine. equipped with a lightnin' mixer. The sodium citrate, citric
acid, and actives other than ibuprofen are added seqUpnt~ y and dissolved with
agitation. The ~Iyc~,.,n and liquid sugar are then colorants added. In a ~p~ate
colllail er the colorants are added to l~uliLed water (appro~ e}y 0.5% of the final
batch volume). This colorant solution is then added to the first batch conlain.,r. In
a separate COnlailL.,r the keto~.~Jren Iysinate is added to thc alcohol while stirring.
The propylene glycol, other actives and flavors are added to this alcohol premix and
the resulting ~lure is stirred until homog~n~ s and then added to the first
cont;~iner. The re~ g purified water is added to the r~Y~lting rr~ixture and
stirred.
AA~ ion of 10 ml to 20 ml (2 to 4 t~spoor.sr.ll) to a human in need of
t provides i nproved relief from cough, cold-lilce, ~u and flu-like s~lllplollls.
EXAMPLE IV
A liquid cG~ ositi~r for oral r~alion is prepa~ot by col~.bi,lillg the
following i~,gred;~lts.
2s In~cdi~ % W/V
Ibuprofen Ar~ c 1.00
Chloll,hel~an~.ne Maleate 0.02
Pseu~oep} ~ e HCI 0.30
Alcohol (95%) 25.00
Propylene Glycol 25.00
Sodium Citrate 2.00
Citric Acid 0 25
Liquid Sugar (Simple Syrup) 25 00
Glycerin 7.00
Colorants 0.008
Flavor 0.50
Water, Purified QS 100.00
WO 95/07103 PCT/US9 1/09581
~7 ~4a~ lo
The purified water (approximately 10% of the final batch volume) is poured
into a batch container equipped with a lightnin' mixer. The sodium citrate, citric
acid, pseudoephedrine HCI and chlorpheniramine maleate are added sequentially
and dissolved with agitation. The glycerin and liquid sugar are then added. ~n as separate container the colorants are added to purified water (appro~..ately 0.5% of
the final batch volume). This colorant solution is then added to the f~rst batch con-
tainer. In a separate cor.l~iner the ibuprofen ar~ e is added to the alcohol while
stirring. The propylene glycol and flavors are added to this alcohol premix and the
resulting mixture is stirred until homogeneQl~s and then added to the first cont~iner.
0 The ~g purified water is added to the resulting mixture and stirred.
l alion of 10 ml to 20 ml (2 to 4 Teasl,oor.~rul) to a human in need
of ~ ---el~l provides improved ~n~lgesic and/or anti-;~nz~ u~ effect.
EXAMPLE V
A liquid composition for oral r ~ aLiOIl iS prepal~ by ~n~bin.l~g the
following ingredients:
In~redient % WtV
S(+) Ibuprofen Lysinate 1.00
Pseudoephed.ine HCl 0.30
Chlol~hen tal,lU~e Maleate 0.02
De.~Llolllclhorphan HBr 0.15
Alcohol (95%) 25.00
Propylene Glycol 25.00
Sodium Citrate 2.00
Citric Acid 0.25
Liquid Sugar (Simple Syrup) 25.00
Glycerin 7 00
Colorants 0.008
E~lavor 0.50
Water, Purified QS 100.00
The purified water (appto,~ely 10% of the final batch volume) is poured
into a batch cor.~ er equipped with a Ugl.1,~in' mLxer. The sodium citrate, citric
acid, pseudGcphed~ e HCl and chlol~hc.~u~lune maleate are added sequentially
and dissolved with ~t~tiot The glycerin and liquid sugar are then added. In a
s~,pal~te contalncr the colorants are added to purified water (appro~ cly 0.5% of
3S the final batch volume). This colorant solutioll is then added to the first batch
conlanc[. In a ~p~tc CGnlA;~ICr the S (+) ~ profen Iysinate and dextro-
metho.~han HBr are added soquenti~lly to the alcohol while sti~ring.
wo 95/07103 PCT/US94/09581
~ 2 1 7Q488
The propylene glycol and flavors are added to this alcohol premix and the
resulting mixture is stirred until homogeneous and then added to the first container. The
remaining purified water is added to the resulting mixture and stirred.
Administration of 10 ml to 20 ml (2 to 4 teaspoonful) to a human in need of
treatment provides improved relief from cough, cold-like, flu and flu-like symptoms.
SU~SIITUTE SHEET (RULE 26)
