Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO 94/14449 ~1 4 9 317 PCT/USs3/12n40
Co~poslt~ons conta~nlng caffelne and S(+)-~buprofen or S(+)-flurb1profen or
S(~)-ketoprofen. ~`
. .
. ...
TECHNICAl, FIEL~ " '
5The present invention relates to compos~tions and methods for
providtng improved analgesic and/or antt-lnflammatory effect by
administering a safe and effective amount of a composltion compr1sing
an analgestc agent substanttally free or of tts R(-) antipode se~ected
from the group conststtng of S(+)-tbuprofen, S(+) flurbiprofen and
S(+) ketoprofen, pharmaceuttcally-acceptable salts thereof, and
mixtures thereof along with an amount of caffetne sufficient to has~en :~
the onset.
BA~KGROUN~ OF THE~INVENT~ON
Inflammationt or the ~tnflammatory response~, is the result of '
lS complex interconnected physiological events, inciuding increased ~`
vascular permeabiltty, flutd accumulattons, and the migrat~on of a
-changing populat~on of inflammatory cells~into the inflamed area. The
clinical manifestations of lnflammat~ton ~include swelltng (edemaj, j`
increased local temperature, erythema, and patn. The inflammatary
response can be tr1ggered by any of a num:ber of causative factors,~
includtng certain bacteria, rad~ation, hypersensittvity to chemical
agents, arthrttts-llke condittons, and the ltke. The inflammatorg
response is generally believed to be a primary defense mechanism ~n
the body, but, unchecked, can become excess1ve and can result in
25 functional impairment. ~ ,~
The use of non-steroidal ant1-inflammatory, anti-pyrettc and
analgesic drugs,~especially thè salicylates~,~ which include aspirtn and~
açpirin derivatives,~ ~to combat inflammation~ and atten~Jant pain ts
accepted medtcal praftice. ~he non-steroidals are commonly employed~ I 30 to relieve pain and in~lammatton associated~with, for example, burslt-
is, arthritts, and the like.
hile paiD~ 5 incapable of precise definitlon due to its bas1~al~
ly subject1ve nature, i`t can generally~be said~;that the ter~ refers to~
feel1ngs o~ d1stress or suffer1ng caused by st1mulat10n of~spec1al1~ed
~5 ner~e endtngs.~A~gr~at variety o~f drugs~have~been developed to reduce
~pa1n tn man and~other an1mals; some directed to el1minattng pain at
its source, and~others~d1rected to block1~ng~the percept10n of pa1n by
.;
WO 94/149 ~ ~.`^ . PCT/US93112040 ~.
~14931?
-2-
the brain. A~ong the latter group of dru~s that are designed to bloc~ -
the sensatton of paln~ are the analgesics, which generally re7ieve
pain without causing unconsciousness~ Analgesics can be further
classified into two main categories: opioid analgesics, including
morphine, codeine, levorphanol, and the morphine-like analgesics
meperidine, and methadone; and antipyretic analgesics, such as
aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, and '~
indomethacin. ~ ~ "
Although the precise pharmacolog1cal actton of these analgesics
I0 is uncertatn, there are certain effects whtch read~ly distinguish the
opioid analgesics from the antipyretics. In~particular, the; antipyre- r"~
tics are weak analgesics, with much of their ef~ect in the peripheral
nervous system, so that behavioral changes~ do not usually occur.
Generally, these analgestcs relieve only pain ortginating from~mus- '''
15 cles, joints, tendons and fasciae, and~ are ineffe'ctive against deep
visceral pain. However, the opioid~analgesics are quite effective
against all types of pain,~with broad-based' actton in the central ~'.'
nervous system. Aside from potent analgesta, the~opioids, also known Il"'
as narcottcs, often produce effects on mood and other behavioral
20 changes. Perhaps the most notable side effect of opioid analgesics ts L~'
the fact that their repeated use is assoclated with tolerance, as well~ ;'
as psychtc and phys~cal dependence.
Ibuprofen, or ~+)~ 2-(p-isobutylphenyl)propionic acid, is
well-known as a nonsteroidal ant~-inflammatory ~drug hav1ng analgestc; 'i
25 and anttpyretic activity. Ib~profen is curre~ntly marketed by~ L"~""'
~prescriptton in the United States generically, as ;well as~ under ~'
t`radenames such;~as Mot~rln-, which i~s~ avallable ln 400, 600 and~ 800 mg '~"
tablets for oral administration. ~Ibuprofen~has recently~al~so become~
available in this country in non-prescription strength (200~ ~g); under~
30 ' a variety of tlradenames, including Advil and Nuprin~, as well as in
~` generic form.~ For the treatment~of mild~t moderate pa~in, 400 mg
every 4 to 6~ hours,~ not to exeeed~ 3200 ~mg~ daily,~ is gener~1~ly
; recommended~for~Motrin. The 1~ower~dose~over-the-count~er~prod~cts~are
~; gener~lly recommended for minor aches~and;~pa~ins, ~o be used oral~ly ~at;~
the 200 to 400~;~;mg leve1, ~every 4~to 6 hours,~not to~exceed~1200~mg;~
dailg unless~directed by~a physic~an.
Flurb1profen,~ or ~*)~[I,l'~-biphenyl]-~4-acet1c~acid;, ;~
WO 94/14449 ~ 1 l 9 3 1 7 ` PCT/US93112040 `;~
-3-
2~fluoro-alphamethyl, is also well-known as a nonsteroidal anti- `~
inflammatory drug having analgesic and antipyretic activity.
Flurbiprofen is currently marketed by ~prescription in the United
States under the tradename Ansaid~,~ which~ts available in SO and 100
mg tablets for oral administration.
Ketoprofen, or (-~) 2-t3-~ben~oylphenyl)propionic acid,~ another `-wel~-known nonsteroidal ant~1nflammatory drug having analgesic and ~ ~`
antipyret k activity is currently marketed by prescription in the ''United States under the tradename Orud~s~ wh1ch~is av~ilable in 25, i'~"~
10 SO and 75 mg capsules for oral admin1stration.~For~the treatment of ~$
mild to moderate pain,~25'-50 mg every~6~to 8 bours,~ not to exceed 300~
mg daily, is generall`y~ recommended for Orùd~s~ See Phrsician's Desk ~.;
- Reference, 46th~ed1tion, ~1992,;~publ~jsher Edward R.~ Barnhart, Medical
Economics Company, Inc., Oradell, N.~. 07649,~pp.'235I-54, 2319-20 and
lS 2488-90, the dsisclosure of wh1ch is~ncorporated herein.
As apparent`fro- their chemical~nomenclature, these analges1c
agents are racemic m~xtures. ~It ~s only~the~racemtc mlxture of`~these
`agents wh1ch h~ave in~fact~ever~been~marketed.~ There have,~ however,
been some studi~es ~of~the individual ~S(~ and~R(-) enantiomer~ o`f
~ 20 ibuprofen. In the~body,~ some of the~R~(-J;~enanttomer is converted~to
the S( ) enantiomer~ which is the~ phar aeol~ogically active;form of
ibuprofen.
The use ~of~ the ~racèmlc ~ ixture~of ~ibuprQfen~ together~ w1th~
caffeine has been;~d~sclosed 1n, for~examp~l~e,~in U.~S.~Patent 4,~64,376
to~ Sunshine et~al~.~ i5~s~ued~August,~7,~I984.~ ~The use of ibuprofen,~ as
well as other~of ~the~newer;non-steroidal~ant1-infl-mmatory~a~enCs~
(i.e., excludl~ng~ asp~i;rin~ acetaminophen~ a~nd ~ phenaceti~n) in; the~
pre~parat10n of~coug~h/cold~;pharmaceuti~cal ~composi~tions ~ containlng~
; sympathomimetic ~amines,~ has been di~sclosed in,~ for example, U.S.
Patent 4,552,8g9 to~Sunshine et ;al. issued November 12, 1985
The~`use of the~S(~)~ form of l~buprofen~has been~disc~losed~in,~ for~
example;, U.S.~Patent 4~,~85~ 444~to~5unsh~ine et~al.~ilssued~July 25,~1989
;and~n comb~nat`i~on~wlth~antihistad nes ln~O~9~,205,783~;to Gates et al.
publtshed~Aprt1~ 16,~ 992.;~
35 ' Surprisingly,~ the~;present~;inYen~ors~;have; ~found~that;~selected~
composi~ttons ;comp sing~S~(+) ibuprofen` in~combination~ith caffeine~
provides furthèr improved~analges~c~and/or~ant1-~inflammatory~effect~
W0 94/14~49 2 14g 3 17~ PCT/U593/12040
s~ ~ - 4 -
SUMZ~ARY QF THE INVE~TION
The present invention relates to a method of eliciting a sus-
tained, enhanced analgèsio response in a human or lower animal in need
of such treatment, comprising administering to such human or lower
animal a safe and effectiYe amount~ of a composltion coZmlprising:
a. an analgesicall~y and antt-tnflammatory effective amount of
an an~lgesic agent substantially free or of its RZ~
antipode selected~ from the ~group~ consisting of S(+)
ibuprofen, S(+) flurbtprofen ~and ~ St+) ketoprofen,
phanraceutlcally-acceptable salt thereof,~ and mixtures
thereof; and
b. an amount of~;caffei'ne sufflcient~to hasten the onset of and
- enhance the analgesic response.
All percentages and ratios uséd herein are by weight unless
otherwise indicated.
DETAI~ED ~ESCRIPrIOH OF JHE~INV~ENTIQN
The present invention relates to~a method of eliciting~a sust~in~
ed, enhanced analgesic response in a~human or lower an~mal~in need~of
s~ch treatment, comprising administering to such human~or lower anim~
a safe and efferZ~tive amount of~ a~ compositton comprising an
analgesicatly and antt-infldmmdtory~effective amount of an~;and1ges~c
agent substantially free or;of its~R(-) ~anttpode sel~ected from the~
group consisttng~ of ~S(+) tbuprofen, S(~)~' n urbiprofen and~ St+)
ketoprofen, pharmaceùt;icalty-acceptab1e salt thereof, and mixtures
~25 ~ thereof, and an~amount~of caffeine~sufficient to hasten;the onset of
and enhance the~ana19esic response.
The ~tenm ~5(+)~ as applied to the analges~ic ~agents~ herein~is~
~ntended to encompass- not onl~y the~ dextrorotatory or` S(+)~isomer~of~ p
these agents but also aZny pharmaceutically ~acceptable, analgesically
effecttve salt thereof.~ The;express'ion'~substanttaliy~ree of the~
R(-) anttpopde~as~ used tn conjunct~ton~with the; termZ ~S(+)~ means~
that~the 5(~)~enantiomer l~5 suffic1~ent~1y~ree~of its R~-) ant1pode~to
exert ~the;- dèsi~red'~ onset-hastened ~and;~enhanced a~na~ges~i~c ;effect.
' Practtcally~ speaking,~ thfs~ means that the~acttYe~ ingredient~ shoZuld
35~ contain'at least 90%~by~we1ght of~the S(+)~ena;nttomer and~ % or~less~
welght ~R~-) en~anttomer.~ Preferab1y,~th;e~ we1ght rat10 ~of~ S(f)
enantio~Zer to~R(~ enant~iomer 1s;greater~than;~20~ more ~preferabtY
~ w o 94/14449 2 ~ 4 9 3i:7 PCT/U593/12040
greater than 97:~. Most preferably the S~+) enantiomer is 99 or more
X by we~gh~ free of R(-) enantiomer, i.e.~ the weight ratio of S to R
is approximately e~ual to or greater than 99:I. i
The safe and effective amount of S(+) ibuprofen used in the
compositions of the present invention generally ranges from about SQ
to about 800 mg, preferably from about 50 to about 400 mg, more
preferably from about S0 to about 200 mg and most preferably from
about 50 to about I00 mg. The safe and effèctive amount of S(+)
flurbiprofen used in the compos1ttons 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 I2.5 to about
I00 mg and most preferably from about 12.5 to about 50 mg. The safe
and effective amount of S~+) ketoprofen used in the compositions of
the present invention generally ranges from about S to about I00 mg,
I5 preferably from about 5 to about 75 m~, more prefer!ably from about 5
to about 50 mg and most`preferably from about 5 to about 25 mg. ~The amount of caffeine used tn the compositions of the present ~:
invention generally ranges from about 20 to about 200 mg, preferably 1~,7'
from about 32 to about 2Q0 mg, more preferably from about~32 to about
I50 mg and most preferably from about 32 to about I00 mg.
The term ~pharmaceuttcally acceptable salts~ refers to salts
prepared from phsrmaceutically accept~ble non-toxic bases including ` j~
inorganic bases and organic bases. Salts derived from nonorganic
bases include sodium, potassium, lithium, ammonia, calcium, magnesium,
ferrous, zinc, manganous, aluminum, ~ferrlc, manganic salts and the
like. Salts derived from pharmaceutically acceptable organic non-
; toxic bases include salts of primary, secondary, tertiary and quater-
nary amines, substituted amines inoluding naturally occurring substi-
tuted amines, cyclic amines and basic ion exchange resins, ~such as ~ ~`triethylamine, tripropylamine,~2-dimethylaminoethanol, 2-diethylamino-
ethanal, lysine,~arginine, histidine~, caffeine, p~ocaine, N~-ethylpip~
eridine, hydrabamine, choline, beta~ine,~ ethylenediamine, glucosamine, ~-
methylglycamine, theobromine, purinesj piperazine, piperidine, poly-
amine resins and the li~ke.
Preferably, the phanmaceutical c~mposltions of ~ the present l
invention comprise the S(+~ enantiomer and caffeine in a ratio o~ S(+) l;enantiomer:caffeine of from about IO:I to -bout I:I0, preferably from~ ~}
: ,,
j
wo 94/1444g 21 ~ 7 ~ - PCT~US93/l2040
-6-
about 5:l to about l:5 and most preferably from about 2:l to about
1:5.
Various oral dosage forms can be used, including such solid forms
as tablets, gelcaps capsules, granules, lozenges and bulk powders and ;'
liquid forms such as syrups and suspensions. These oral forms com-
prise a safe an~ effectiYe amount, usually at least about 5% of the 1;
active component. Solid oral dosa~e forms preferably contain from ~-
about 5% to about g5%, more preferably fro- about l0% to about 95%t
and most preferably from about 25% to about 95X of the active compo- ;'`
nent. Ltquid oral dosage forms preferably contaln from about 1% to
about 50~t and more preferably from about 1% to about 25% and most
preferably ~rom about 3%~to about 10% of the active compo'nent. ~''
~ablets can be compressed, tablet trtturates, enteric-coated, ~"
sugar-coated, film-coated or multiple compressed, containing suitable '~
binders, lubrican~s, diluents, disintegrating agents, coloring agents,
Slavoring agents, preservattves and flow-inducing agents. "
L~qu1d oral dosage fonms include aqueous and nonaqueous solu-
tions, emulsions, suspensions, and solutions~ and~or suspensions
reconstituted from non-effervescent granules, containing suitable ~
20 solvents, preservat1ves, emulsifying agents, suspending ~agentst ~!,
diluents, sweeteners, taste-masking agents, coloring agents, and
flavoring agents. SpeciSic examples ~of pharmaceutically acceptable
carrters and excipients that may ~be used to formulate oral dosage
forms, are described in U.S. Patent 3,903,2g7, Robert, issued' Sep-~
tember 2, 1975, incorporated by reference~herein. Techniques and~ -`
compositions for making solid oral dosage forms are described in
Marshall, ~Solid Oral Dosage Fonms,~ Mod'ern Phanmaceutics, ~ ,
`(Banker and Rhodes, editors), 359-427 (1979), incorporated by refer~
ence herein. Techniques and composittons for making tablëts~
' 30 (compressed and molded), capsules ~hard and soft gelatin~ and p~lls
are described in ~ L~ Phanmaceutical Sciences~(Arthur Osol,
editor), 1553-1593 (1989~, incorporated herein by reference.
In preparing~the ltquid~oral dosage;forms,~ the actlve~component
is incorporated~1nto an aqueous-based ora~lly~acceptable~ph~armaceut1cal
'~5 carrier consistent ~with conYentional pharmaceutical pract1ees~. An
'aqueaus-based orat~y~acceptable ;phar~aceutical carrier~ is one~
~` `wherein the entire or predomtnant ~solvent content is water. Typical ~ 0
WO 94/14449 2~ 1 4 9 3 l PCTN593/120qO
carriers include simple aqueous soiutions, syrups, dispersions and
suspensions, and aqueous based emulsions such as the oil-in-water
type. The most preferred carrier ~s a suspension of the pharma-
ceutical composition in an aqueous vehicle containing a suitable
suspending agent. Suitable suspending agents include Avicel RC-S91 (a `
microcrystalline cellulose/sodium carboxymethyl cellulose mixture
ava~lable from FM~), guar gum~and the 11ke. ~Such suspending agents
are well known to those skilled ~n thè art. ~hile the a~ount of water
in the compositions of th~s invention can vary over~quite a wide range
depending upon the total weight and volume of~the act~ve component and
other optional non-actiYe~ingred1ents, the total water content, based
on the weight of the~final composit10n,~ will~:generally range from 2
about 20 to about 75%, and, preferably, fro~ about 20 to about 40X, by
weight/volume.
Although water itself may make ~up the entire carrier, typical
liquid formulations ;preferably contain a co-solvent, for example, ~'
propylene glycol, glycerin, sorbitol~solution and the like, to assist
solubilization and incorporation of water-insoluble ingredients, such
as flavoring oils and the like into the composition. In general,
20 therefore, the compositlons of thts invention preferably contain from
about 5 to about 25 volume/volume percént and, most preferably, fro~
about 10 to about 20 volume/ volume per~ent, of the co-solvent.
rhe compositions of this invention ma~ optionally contatn one or
more other known therapeutic agents, particularly those commonly
25 utilized in cough~cold preparations, such~as, for exàmple, a cough
suppressant such as~dextroDethorphan, chlophedianol, carbetapentane,
caramiphen, noscapine, diphenhydramine, ~ codeine, hydrocodone,
hydromorphone, fominoben, their pharmaceutically-acceptable salts; an~
expectorant or mucolyt k such ~as glyceryl guaiacolate, terpin,
ammonium chloride,~ N-acetylcysteine and ~bromhexine, ambroxol, their
pharmaceutically acceptable salts; and an antihista~ne such as
chlorpheniramine ~ ~ brompheniramine,~ ~ dexchiorpheniram1ne,
dexbrompheniramine, triprol~dine,~ dox~la~ine, tripelenna~tne,~
cyproheptadine,~ carbinoxa~ine, bromodiphenhydramine, phenindam1ne,
~5 pyrilamine, azatadlne, their pharmaceutically acceptable salts, as
well as the non-sedating ant1histam1nes ~hich inc~ude acr1vastine,
AHR-11325, pheni~ndam~ine, astemizo~1e,~aze1astine, cetirizine, ebastine,
":
: . : : .~
i~ ~ ' ! ` " :
WO 94114449 . ` PCTIUS93t~2040 ~ ~.~
~l~g31~7
-8-
ketotlfen, lodoxamide, loratidine, levocabastine, mequitazine,
oxatomide, setastine, tazifylline, teme~astine, and terfenadine, their
pharmaceutically acceptabte salts all of these components, as well
as their acceptable dosage ranges are described in the following
U S Patent 4,~83,465 to Sunshine et al , issued November 8, 1988,
U S Patent 4,619,934 to Sunshine et al , issued October 28, 1986,
which are incorporated by reference herein Also useful~are broncho-
dilators such as theophyll~ne and albuterol as well as other analgesic
agents such as acetaminophen and asp1rin ~ A highly preferred opttonal
component ts caffeine, which ~s preferably~present at a level of from
about l0% to about 50%
Other optional ingredients weli known to~the pharmacist s art may
also be included in amounts generally known ~for these ingredients,~for
example, natural or art1fic1al sweeteners, flavoring agents, colorants
and the like to provide a palatable and pleasant looking final prod-
uct, ant10xidants, for example, butylated~hydroxy anisole or~butylated
hydroxy toluene, and preservatlYes, `for example, methyl or propyl
paraben or sodium~benzoate, to prolong and enhance shelf life
:~ MET~OO OF T~REATM~I ;`
The amount of the phanm-ceut~cal ;composit10n ~administered depends
upon the percent of actlve ingred1ents wlthin its fonmula, which is a
functlon of the;amount of the ibuprofen and caffeine and any opttonal
components such as a decon~estant, expectorant and~or antih~stamine
requ1red per dose, Stdbillty~ ~ release characteristics and other~
pharmaceut1cal parameters
Usually from abou~t 1 mg/kg to about 50 mg/kg per day,~preferably
from about 2 mg/kg to~about 30 mg/kg~per day~and most preferably from
about 3 mg~kg per-day to about~20 mg/kg per :dar of the pharmac~utical~
compositlon is administered as~ described herein This amount can be ~`
0 given in a single dose,~or, preferably,~ ln multtple (two to s~x) doses
repeatedly or sus~talned release dosages~over~the course ~of treatment
Generally, each~indivldual~dosdge~ of ~the;phdrmdceut1cal ~compos1t10ns
of the present~invention~range from; about 1 mg/kg to about~25 mg/kg~
preferably from ~about ~2 mg/kg ta about lS~g/kg~and most preferably ~ !~
35 from about ~mg/kg~ to ~about lO~mg/kg~ ~Typlca)~ unit dosage~forms~for ; r``'`
oral ~dministrat1~on generally comprise from~about 50 mg to~about ~2000
mg~, preferably from dbout IOO~mg ~o ~bou~600 mg and most prefer-bly~
WO 94/14449 2 1 ~ 9.3.1i7. ~ PCT/US93112040
_ 9
from about lO0 mg to about 400 mg of the ibuprofen and from about 2S
mg to aboùt 200 mg, preferably from about 50 mg to about 200 mg and
most preferably from about 50 mg to about lO0 mg of caffeine. While
dosages htgher than the foregoing are effective to provide analgesic
5 relief, care must be taken, as w1th any drug, in some individuals to
prevent adverse slde effects. `
The follow~ng exàmples tllustrate embodiments of the subject
inventton wherein both essent~al and opttonal ingredients are com-
bined.
AMPL~ I ,
A hard ge?attn capsule composition for ora1 administration isprepared by combtning the followtng tngredtents:
Inqredient em~gn~ ``- S~+) Ibuprofen lO0 mg
Caffetne lO0 mg
Trtturate acttve ingredtents and q.s. with lactose to selected
capsule stze.
Admtntstration of l or 2 of the above capsules to a human in need
of treatment provides improved analgesic and/or anti-inflammatory
effect.
.
AMPLE ~l
A hard gelatin capsule compositton f~or oral administratton ts
prepared by combtning the~ollowing tngredients:
Tnqredtent ount
S(+J Flurbiprofen 50 mg
Astemtzole 5 my
Caffetne 50 mg
Glyceryl guaiacolate ~ lO0 mg
Trlturate acttve tngredtents and q.s. with tactose to selecte~ i-capsule stze.
Administration of l or 2 of the above capsules to a human in need
of treatment provides improved analgeslc; and/or anti-inflammatory
effect.
, .
~ ~
;
.;
.
. .
WO 94/14449 ~14 9 3 i7 PCTIU593112040 1~ ~-
-lo- !
EXAMPl ~
A liquid composition for oral administration is prepared by
combining the following ingredients:
Ingredi~ % W~V
S(+) Ibuprofen 1.00
Caffeine 1.00
Alcohol ~95Z) ~25.000
Propylene 61ycol ~ 25.000
Sodtum Cltrate 2.00Q
Cttrlc Actd 0.250
Liquid Sugar (Simple SyrupJ 25.00
Glycerin ~ ~ 7-000
Colorants ~ 0.008
Flavor ~ 0.500
~ater, Purified ~S 100.000
The purified water (approximately 10% of the final batch vol~ume)
is poured tnto a batch container equipped with a lightnin' mixer. The
sodium citrate, cttric ~acid and Caffeine are added sequenttally and
dissolved with agitation. The glycerin ~and liquîd sugar are then
color~nts added. In a separate contalner the colorants are added to
purifted water (approximately 0.5% of the final batch volume). Thts
colorant solution is then added to th~ first batch container. In a t~
seperate contatner the ibuprofen is added to the alcohol while st~r-
ring. The propylene glycol and flavors are added to thts alc~hol
premix and the resulttng mixt~re is stirred until homogeneous and then
added to the first conta~ner. The ~remalning purified water is added
to the resulting mixture and stirred.
Admtntstration of 10 ml to 20 m7 (2 to 4~ teaspoonsful)~ to a human
in need of treatment provides `impro~ed analgesic andjor
anti-inflammatory effect.
t ~-
' : : , ~,y .
~Y,.,i/,s W094/14449 214931rt PCT/IJ593/12040
~L~ .
A liquid composition for oral administration is prepared by
combining the following ingredients:
Inq~ient %
S~+) Ibuprofen I.00
Caffeine 1.00
Chlorpheniramine Maleate 0.02
Pseudoephedrine HCl ~ 0.30
Alcohol (95Z) 25.00
Propylene Glycol ~ 25 00
Sodium C~trate 2.00
Cttrtc Actd 0.2S
Liquid Sugar (Simple Syrup) 25.00 ~-
&lycerin 7.00 ~`
lS Colorants 0.008
Flavor 0-50
~ater Purtfied ~QS I00.00
The purifted water (approximately lOX of the final batch volume)
is poured tnto a batch container equipped~with a lightnin mixer. The
sodlum cttrate citr1c actt pseudoephedrine HCL and chlorpheniramine
maleate are added sequentialty and dissolved w~th ag1tation. The
glycerin and liqu~id sugar are then adde~. ln a seperate container~the
colorants are added to pur1fied water (approxtmately 0.5% of the ftnal
batch Yolume). This colorant solution is then added to the ftrst
batch contatner. In a separate container the ibuprofen is added to
the alcohol while St~rring. The propylene~ glycol and fla~rs are~ -
added to this a1cohol premix and the resutting mixture is stirred
unttl homogeneous and then added to the first container. The
remaining purified water is added to the resulting mixture and
30 stirred. ``
Administration of lO ml to 20~ml~2 to 4~ Teaspoonsful) to a human~
in need of treatment provides improYed analgesic ind/or
antt-tnflammatory effect.
- ~
~ ~ 35
:: : : ~ i
:
. .
: ` . .
;; , : ~ ~i . `
w o 94t14449 ~ PcTruss3ll2o4o ~ ¦
2 1 4 9 3 17 - 12- ` "
EXAMPLE V '
A liquid composition for oral administration is prepared by
combintng the following ingre~ients: '
Inqrçdient : % W~
S(+) Ibuprofen ~ 1.00 ~
Caffetne 1.00 ~ ``'
Pseudoephedrine HCl 0.30
Chlorpheniramine Maleate 0.02 ':
Dextromethorphan HBr ~ ~0.15
Alcohol (9SX) 25.00
Propylene Glycol 25.00
Sodtum Cttrate ~ 2.0Q
Cttrlc Actd ~; 0.25 Li
Liquid Sugar (Simple Syrup) Z5.OD
`15 Glycerin ~.oo `
Colorants ~ 0.008
Fla~or ' ~ ~ 0.50
~ater Purified' QS lOO.OO
The purified water (approximately 10% of the final i~atch ~olume)
is poured into a batch conta1ner equipped wtth a lightntn' m~xer. The
sodium citrate citric acid pseudoephedrine HCl ;and chlorpheniramine "'~
maleate are added sequentially and dlssolved with agitatton. The
glycerln and liquid sugar are then added. In a seperate container the ~
colorants are added to~purifted~water (approximately~0.5%~of the final ~ ``
25~ batch volume). This colorant solution ts then added to the ftrst '~'
batch contatner.~ In a~separate container the ibuprofen ~and dextro~
; ~ methorphan HBr are added sequentlally to the alcohol while;stirr~ng.
:The propylene glycol~and flavors are~added to this~alciohol preimlx~
and the resultinq mixture is stirred until `homogeneous and then added
30 to the firsticontainer. The rema~ning purif~ed water is added to the ~ ''~""
resulting mlxture~and stirred.
Administratl~on~of 10 ml to 20~ml (2~to~4;'teaspoonsful) to; a human
in~ need of~ treatment ~ provides~' improv~d~ analgesic ~ and/or
nt~-~nrl~mm~t~ry e~ect.
L~
