CA2170488A1 - Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussive - Google Patents
Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussiveInfo
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- CA2170488A1 CA2170488A1 CA002170488A CA2170488A CA2170488A1 CA 2170488 A1 CA2170488 A1 CA 2170488A1 CA 002170488 A CA002170488 A CA 002170488A CA 2170488 A CA2170488 A CA 2170488A CA 2170488 A1 CA2170488 A1 CA 2170488A1
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- Prior art keywords
- cold
- amino acid
- expectorant
- propionic acid
- antitussive
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- 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)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to composition and methods for providing improved treatment, management or mitigation of cold, cold-like and/or flu symptoms by administering a safe and effective amount of a composition comprising certain amino acid salts of propionic acid non-steriodal anti-inflammatory agents along with at least one of (a) a decongestant, (b) an expectorant, (c) an antihistamine and (d) an antitussive.
Description
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.
-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.
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.
-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.
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 - ~ ~ 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 ~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)
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 - ~ ~ 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 ~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)
Claims (8)
1. A composition for providing improved treatment, management or miti-gation of cold, cold-like and/or flu symptoms by administering a safe and effective amount of a composition comprising an amino acid salt of a propionic acid nonsteroidal anti-inflammatory agent along with at least one of (a) a decongestant, (b) an expectorant, (c) an antitussive and (d) an antitussive.
2. A pharmaceutical composition according to Claim 1 wherein said propionic acid derivative is selected from the group consisting of ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofen, preferably wherein said propionic acid derivative is selected from the group consisting of ibuprofen, naproxen, flurbiprofen, and ketoprofen and wherein said amino acid salt is selected from the group consisting of triethylamine, tripropylamine, 2-dimethylaminoethanol.
2-diethylaminoethanol, lysine, ornithine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purine, piperazine and piperidine and mixtures thereof.
2-diethylaminoethanol, lysine, ornithine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purine, piperazine and piperidine and mixtures thereof.
3. A pharmaceutical composition according to any of the preceding Claims wherein: said decongestant is pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof; wherein said antitussive is selected from the group consisting of dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, mixtures thereof or pharmaceutically acceptable salts thereof; wherein said expectorant is an expectorant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium chlo-ride, N-acetylcysteine, bromhexine and ambroxol, mixtures thereof or pharmaceutically acceptable salts thereof; and wherein said antihis-tamine is selected from the group consisting of chlorpheniramine, brom-pheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine.
doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bro-modiphenhydramine, pyrilamine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine ke-totifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.
doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bro-modiphenhydramine, pyrilamine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine ke-totifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition according to any of the preceding Claims which comprises the S(+) enantiomer of the amino acid salt of a propionic acid nonsteroidal anti-inflammatory agent
5. A pharmaceutical composition according to any of the preceding Claims comprising from 5 to 50 mg S(+)-ketoprofen lysinate.
6. A pharmaceutical composition according to any of Claims 1 through 4 comprising from 50 to 800 mg S(+)-ibuprofen lysinate.
7. A pharmaceutical composition according to any of Claims 1 through 4 comprising from 50 to 800 mg S(+)-naproxen lysinate.
8 A method for the treatment of cough, cold, cold-like and/or flu symptoms in a mammalian organism in need of such treatment comprising administering to such organism the composition of any of the preceding Claims.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US116,927 | 1987-11-04 | ||
| US11692793A | 1993-09-07 | 1993-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2170488A1 true CA2170488A1 (en) | 1995-03-16 |
Family
ID=22370083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002170488A Abandoned CA2170488A1 (en) | 1993-09-07 | 1994-08-24 | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussive |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0719156A1 (en) |
| JP (1) | JPH09502201A (en) |
| CN (1) | CN1130354A (en) |
| AU (1) | AU7604094A (en) |
| BR (1) | BR9407414A (en) |
| CA (1) | CA2170488A1 (en) |
| WO (1) | WO1995007103A1 (en) |
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| WO1998048839A1 (en) * | 1997-04-30 | 1998-11-05 | Warner-Lambert Company | Topical nasal antiinflammatory compositions |
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| US10016437B2 (en) | 2009-06-16 | 2018-07-10 | Infirst Healthcare Limited | Drug combinations and uses in treating a coughing condition |
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| ES2611019T3 (en) | 2009-10-26 | 2017-05-04 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
| CA2690488C (en) * | 2010-01-19 | 2013-06-11 | Accucaps Industries Limited | Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof |
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| US5164398A (en) * | 1991-04-01 | 1992-11-17 | Merck & Co., Inc. | Ibuprofen-antitussive combinations |
| JPH06506684A (en) * | 1991-04-01 | 1994-07-28 | メルク エンド カンパニー インコーポレーテッド | Ibuprofen - decongestant formulation |
-
1994
- 1994-08-24 JP JP7508695A patent/JPH09502201A/en active Pending
- 1994-08-24 CA CA002170488A patent/CA2170488A1/en not_active Abandoned
- 1994-08-24 WO PCT/US1994/009581 patent/WO1995007103A1/en not_active Application Discontinuation
- 1994-08-24 AU AU76040/94A patent/AU7604094A/en not_active Abandoned
- 1994-08-24 BR BR9407414A patent/BR9407414A/en not_active Application Discontinuation
- 1994-08-24 EP EP94926020A patent/EP0719156A1/en not_active Withdrawn
- 1994-08-24 CN CN94193312A patent/CN1130354A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995007103A1 (en) | 1995-03-16 |
| AU7604094A (en) | 1995-03-27 |
| BR9407414A (en) | 1996-11-12 |
| EP0719156A1 (en) | 1996-07-03 |
| JPH09502201A (en) | 1997-03-04 |
| CN1130354A (en) | 1996-09-04 |
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