CA2149317A1 - Compositions and method for providing improved analgesic effect - Google Patents
Compositions and method for providing improved analgesic effectInfo
- Publication number
- CA2149317A1 CA2149317A1 CA002149317A CA2149317A CA2149317A1 CA 2149317 A1 CA2149317 A1 CA 2149317A1 CA 002149317 A CA002149317 A CA 002149317A CA 2149317 A CA2149317 A CA 2149317A CA 2149317 A1 CA2149317 A1 CA 2149317A1
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- Prior art keywords
- pharmaceutical composition
- ibuprofen
- composition according
- onset
- mixtures
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compositions and methods for providing improved analgesic and/or anti-inflammatory effect by administering a safe and effective amount of a composition comprising an analgesic agent substantially free of its R(-) antipode selected from the group consisting of S(+)-ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with an amount of caffeine sufficient to hasten the onset.
Description
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?
. .
. ...
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 `;~
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 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 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.
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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 :
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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~
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 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, ":
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WO 94114449 . ` PCTIUS93t~2040 ~ ~.~
~l~g31~7 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.
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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~
Claims (7)
1. A pharmaceutical composition adapted to elicit an onset-hastened and enhanced analgesic response in a mammalian organism in need of such treatment and adapted for unit dosage administration, said composition comprising:
a. an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof; and b. an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.
a. an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof; and b. an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.
2. A pharmaceutical composition according to Claim 1 comprising from 50 to 800 mg, preferably 50 to 400 mg and most preferably 50 to 200 mg S(+)-ibuprofen.
3. A pharmaceutical composition according to Claim 1 comprising from 12.5 to 300 mg, preferably from 12.5 to 100 mg and most preferably from 12.5 to 50 mg S(+)-flurbiprofen.
4. A pharmaceutical composition according to Claim 1 comprising from 5 to 75 mg, preferably from 5 to 50 mg and most preferably from 5 to 25 mg S(+)-ketoprofen.
5. A pharmaceutical composition according to any of the preceding Claims wherein said composition further comprising at least one other active component selected from the group consisting of an antihistamine, cough suppressant and expectorant and mixtures thereof.
6. A composition according to Claim 5 wherein said antihistamine is selected from the group consisting of chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.
7. A method for eliciting an onset-hastened and enhanced analgesic response in a mammalian organism in need of such treatment by administering the pharmaceutical composition of any of the preceding Claims.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99437192A | 1992-12-21 | 1992-12-21 | |
| US07/994,371 | 1992-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2149317A1 true CA2149317A1 (en) | 1994-07-07 |
Family
ID=25540587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002149317A Abandoned CA2149317A1 (en) | 1992-12-21 | 1993-12-10 | Compositions and method for providing improved analgesic effect |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0674517A1 (en) |
| JP (1) | JPH08504818A (en) |
| CN (1) | CN1094615A (en) |
| AU (1) | AU672279B2 (en) |
| BR (1) | BR9307697A (en) |
| CA (1) | CA2149317A1 (en) |
| MX (1) | MX9400038A (en) |
| PE (1) | PE56194A1 (en) |
| WO (1) | WO1994014449A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0717624A1 (en) * | 1993-09-07 | 1996-06-26 | The Procter & Gamble Company | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agents and caffeine |
| CA2227958A1 (en) * | 1995-07-28 | 1997-02-13 | Sekhar Mitra | Compositions containing analgesics and antihistamines and methods for treating respiratory disorders |
| JPH0987174A (en) * | 1995-09-26 | 1997-03-31 | Kobayashi Pharmaceut Co Ltd | Analgesic and anti-inflammatory composition |
| US6211246B1 (en) * | 1999-06-10 | 2001-04-03 | Mcneil-Ppc, Inc. | Rapidly absorbed liquid compositions |
| TWI313598B (en) | 2002-12-18 | 2009-08-21 | Wyeth Corp | Compositions of non-steroidal anti-inflammatory drugs, decongestants and anti-histamines |
| ES2358763T3 (en) * | 2006-04-28 | 2011-05-13 | Grünenthal GmbH | PHARMACEUTICAL COMBINATION THAT INCLUDES 3- (3-DIMETHYLAMINE-1-ETIL-2-METHYLPROPIL) PHENOL AND AN NSAID. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4420483A (en) * | 1982-07-22 | 1983-12-13 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising ibuprofen and methods of using same |
| US4486436A (en) * | 1982-07-22 | 1984-12-04 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
| US4851444A (en) * | 1987-07-10 | 1989-07-25 | Analgesic Associates | Onset-hastened/enhanced analgesia |
| WO1991006295A1 (en) * | 1989-11-06 | 1991-05-16 | Sepracor, Inc. | Analgesic composition containing optically pure s(+) flurbiprofen |
| AU8764191A (en) * | 1990-09-28 | 1992-04-28 | Mcneill-Ppc Inc. | Ibuprofen-antihistamine combinations |
-
1993
- 1993-12-10 WO PCT/US1993/012040 patent/WO1994014449A1/en not_active Application Discontinuation
- 1993-12-10 BR BR9307697A patent/BR9307697A/en not_active Application Discontinuation
- 1993-12-10 CA CA002149317A patent/CA2149317A1/en not_active Abandoned
- 1993-12-10 JP JP6515225A patent/JPH08504818A/en active Pending
- 1993-12-10 AU AU58993/94A patent/AU672279B2/en not_active Ceased
- 1993-12-10 EP EP94905364A patent/EP0674517A1/en not_active Withdrawn
- 1993-12-17 PE PE1993233164A patent/PE56194A1/en not_active Application Discontinuation
- 1993-12-21 CN CN93119937A patent/CN1094615A/en active Pending
-
1994
- 1994-01-03 MX MX9400038A patent/MX9400038A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU5899394A (en) | 1994-07-19 |
| AU672279B2 (en) | 1996-09-26 |
| MX9400038A (en) | 1994-07-29 |
| WO1994014449A1 (en) | 1994-07-07 |
| CN1094615A (en) | 1994-11-09 |
| BR9307697A (en) | 1999-05-25 |
| EP0674517A1 (en) | 1995-10-04 |
| JPH08504818A (en) | 1996-05-28 |
| PE56194A1 (en) | 1995-01-26 |
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