CA2227958A1 - Compositions containing analgesics and antihistamines and methods for treating respiratory disorders - Google Patents
Compositions containing analgesics and antihistamines and methods for treating respiratory disorders Download PDFInfo
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- CA2227958A1 CA2227958A1 CA002227958A CA2227958A CA2227958A1 CA 2227958 A1 CA2227958 A1 CA 2227958A1 CA 002227958 A CA002227958 A CA 002227958A CA 2227958 A CA2227958 A CA 2227958A CA 2227958 A1 CA2227958 A1 CA 2227958A1
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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
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition comprising an analgesic agent along with certain pyrrolidine and piperidine ether antihistaminic agents.
Description
W O 97/04808 PCT~US96/12249 COMPOSITIONS CONTAINING ANALGESICS AND ANTIHISTAMINES AND METHODS FOR
TREATING RESPIRATORY DISORDERS
The present ulvelllioll relates to comrositionc and mRthoAs for providing ul~ vt;d ~ l, mz~n~g~m~nt or mitig~tiOlt of cold, cold-lilce, allergy, sinus and/or flu ~ c by aA~ t~ g a safe and ~fIe~ e amount of a comrosi~ion comrricin~ an ~n~lgRQ;c agent along with certain pyrrolidine and piperidine ether 5 ~ntihi~;;c agents.
R~CKGROUND OF 1~ INVENI~ON
The commnn cold, ~1th~l~h not usually a serious illness, is a highly pre-valent, ~i~co...ro.Ling and al~nojLl~g ~ tion The term "cQmmnn cold" is applied to minor respiratory i~ F5s~g caused by a variety of d;~e~ JU~IOl~ viruses.
20 While .l.inovu,lses are the major known cause of cc~ n colds, rccv~ for appl. Y;-..~I~ly 30 percent of colds in adults, viruses in several other groups are also i.llpol~ . While i~ c ~ nc~s occur, and infRction with some ~e~u~
tract viruses therefore could be pl~ nled by a vaccine, development of a polytypic vaccine to cover all possible agents is impractical. Thus, the problem of controlling 2s acute upper l~s~u~tol~ disease p-~3enls co~ ch~ n~Rs~ and the long-desired disco~e.y of a single cure for the co on cold is an ~l~li~Lic e ec~ n Early symrtQmc may be minim~l with only mild m~ sore throat and nasal co...~ With rhinovirus ;..r. c~;on ~.~plo...~ of nasal discl~ , nasal col~gc,l;on, and S--F, ~ g usually co~ F-~ce on the first day of illness and progress to .. ~;.. ,.. s~ ~.ily by the second or third day. Along with nasal Sy~ptO-~e may come sore, dry or scr~chy throat and ho~a~ness and cough. Other ~r...ptO-..c mayinclude mild burning of the eyes, loss of smell and taste, a feeling of pressure or fullness in the sinuses or ears, h~ rh~ and vocal ;"-P~;"--F~-I Fever can occur,but is ..i~-on~ n Tnflll~n7~ infPc~ion generally inrllldes fever, often of sudden 3s onset and ~,.a;alillg for several days, and with great s~.ily; generalized aches and pains; fatigue and we~knF~; and chest ~I;CGOn~
At present, only i~y~ O~ iC L~ is available for the CG~ OIl cold.
The costs of llcaL.~ colds with over-the-counter meAir~ti~nc in the United States is 1 ed at an annual cost of over 1.5 billion dollars. The direct costs of h ~,n~ ~-f -~in outr~ti~?nt clinics is ~ ed at almost four billion dollars. ~direct costs, based s on the amount of loss in wages bec~ -~e of r~ct irted activity are ~-.l,s~ y higher.
FYf~ y prior art forrmll~tinnc for L14~ 'f~l of cough, cold, cold-lilce, allergy, sinus and/or flu ;~ylllplon~s and the ~iccor-r~"L, pain, fever and general malaise ~ccor;~tetl thcl.,~.~iLll generally contain an ~n~l~cic (aspirin or 0 acet~minl phen) and one or more ~ntil~ c~ ;c~, decol~riP~Ie, cough sup-pl~ssa~ ntitllCcives and ~ e~lo,a ~ls.
The use of non-steroidal anti~ n~ lo,y drugs to combat il~n~ linn and A~ l pain is q,cepte~ r.li~Al practice. The non-~L~loidals are CQI~ Ollly employed to relieve pain and ;.. n~.. ~;On ~csori~ted with, for ~ lr, bursitis, 5 arthritis, h.~a~ h.o and the lilce. Among the most cQ----.-~ ly used drugs of the non-narcotic ~n~lge~io class of drugs are aspirin, ~:e~ ~h~n, il,uylurell, ketoprofen, dirl~f~n~r, and ~ n ~d their salts (e.g., lysine, &.~.-..c, sodium and pul~ ). Aspi~ cel~ .oph~, and ibuprofen have he.~Lororc been includ-ed as the pain reliever and fever- educ: ~g component in convention~l cough/cold20 multi~y~ lo~n allc~isLu.~ 'OC:l;rmc These co~ f ~,idlly .-~A~,ted products generally contain in rd~;tinn to aspirin, ~.ce~ ophen or il,up.orfn, one or more~ntihictAminicc, ~econgr~ lQ., cough-~ul,plc~s&-L~ ;ves and ~ e.lQI~-L~.
The present u~ve~Lci~ have found that srle~l~d compositionc co~ g an ~n~1ge~iG agent along with certain pyrrolidine and pir~ri~inA ether Anti~
25 agents provides u..~-o~- d Ir~A~ f .~r m~n~g~m~nt or mitigPtinn of cold, cold-lilce, allergy, sinus and/or flu ~plQ~ n~ ing nasal c~ f l;nn It is ~cre;rolf an object ofthe present invention to provide a method for the Ll ~ l of cough, cold, cold-like, allergy, sinus and/or flu ~.-~ o...Q in a mam-malian ~-x~s-n in need of such hf~ C~nlrrici~g r~ lf~ P. to such 30 o~ .sul the compositinnS of the present illv~rLion. Such ~ u~Q as used hereinrefer to co~u~ nasal Co~f~l;o~ sinus cQn~f~l;nn~ S~nUQ pai~ upper l~u~lo.
infectionc, otitis, ~ ;s, etc.
SI~IARY OF 1~ INVENI~ON
The present invention relates to coll-pGs;Lions and mf~thods for providing 35 i~ -uv~d l c~ m~n~gfmfnt or mitigPtinn of cold, cold-l~ce, allergy, ~inusand/or flu ~InpLoll~Q by ~ t~ g a safe and e~c ~L~.e amount of a c~ ro.:l;on con~ C~ ssF~ ly of an AnAlg~os;c agent along with certain pyrrolidine and piperidine ether ~ntihi~li....;..;c agents.
All percPntag~s and ratios used herein are by weight unless otherwise in-dir,At~(l 5DFTAT~ Fn I)ESC~TPTION OF THE INVF~IION
The present invention relates to CCJ~ OS;~ C and m~tho~ls for providing plo~cd l~ l management or miti~tion of cold, cold-like, allergy, sinus and/or flu ~ll~Lon~ by ~ a safe and ~Li'._ amount of a composition CQ~ ç~..,..l;~lly of an analgesic agent along with certain pyrrolidine and 0 pi~c.idine ethers.
AnAI~~c;~- Pl,a, ...Acc~l;cal Actives Useful AnAl~çc;c ph~.,l.Ac~.l;r,Al actives in the CO~ G~ I;OI~c of the present invention include aspirin and ~.c~ ophen as well as the non-steroidal anti-in-n~ 0, y drugs (NSAIDS) sF~ led from the following c ~l e~,o, ies propionic acid5 deliva~ , acetic acid dc~i~aLi~ , fenAm;c acid derivatives; ~ " ..~lc~l,o~ylic acid deliv~Liv~ and t)xi~9mC All of these NSAIDS are fully ~l~s~ ed in the U.S.
Patent 4,985,459 to .S~ ch;~r et al., issued January 15, 1991, incol~ul~tcd by refer-ence herein. For det~iled dicrlos~re of the chemicAl structure, synthesis, side e~
fects, etc., of non-steroidal anti-;~ o~y agents, r~,f..~nce may be had to 20 ~ld~d texts, inr~ ng Anti-i~nA~ to~y and Anti-l~h~ ;c Drugs. K. D.
RA lsru~d, Vol. I-m, CRC Press, Boca Raton, (1985), and Anti-i.~lld~ o As~entc Che ..:s~ and PL~.---acologY. 1, R A Scherrer, et al., ~ omiç Press, New York (1974), both of which are ~I~co-l.o.aled by l~fel..dlce herein.
Useful dosage of these agents can be found in The I'l.ys;c;~u-s' Desk Refer-25ence. 47th Edition (1993) and in U.S. Patent 4,552,899 to ,S,~s~ e et al. issued No~..ber 12, 1985, both of which are incorporated by r~r.;.w~ce herein.
FY~nlp~ of p-~f~ .d ~n~ oQ;ç phA~..ulçeutic~l actives useful in the present invention in~ludlo, but are not limited to, ~c~ ophen, acetylsalicylic acid, ibupro-fen, f~ u~ r~ r~.lûplûre.~ nul~ lofe~ int~ lo~l~fe~ dp~ , their 30 ph~...~çe~lti~lly ~ceF~ salts, e-~ ;o...- -~ thereof, and .l~lul~g thereof.
~cet~minophen, ;buprorcn and naplo~ are especially pl~,f...~d for use in the co..l~os;lions of the present i.-~ ;on.
The term "ph~....~çe~ ly acceptable salts" refers to salts p.ep~ed from ph~rm~ce~ltiç~lly acc~l~blc non-toxic bases inc~ ir~ O.~ llC bases and organic 3s bases. Salts derived from nono-~nic bases include so~ m~ pOl~c~ ~.-- lithium, A.l....~l~;s. c~lri~lm, ~ , ferrous, zinc, ~ v~nnv~ .." ferric, ...~ ic salts and the like. Salts derived from ph~....~çc.,l;r~lly ~c~eptal 'e organic non-toxic bases include salts of ~ uy, secon~lAAry, tertiary and ~ amines, ,~.1. ,l;l uledamines incl~lclinp naturally occ--~ c s~,b~ u~ed amines, cyclic amines and basic ion eYch~n~e resins, such as triethylamine, hil~lo~~ ule, 2-d~ elh~lA~ ntll~A~lol~ 2-diethylaminoethAAnol Iysine, ~u~ c, hictirlinP" çAAffcine, procaine, N e Ll~l~ipt;lidine, hydrA~AAminP" choline, betaine, ethylrl~rA;A----~-r, glllcos~minP, methyl~ly.,~u.,c, theo-I.rol-~e, purinps~ pipe.2~.e, pirPrj~inP~ polyamine resins and the lilce.
Most p,~ d for use herein is ~r-~ ph~ and the S(+) isomer of the NSAIDs and their salts. The term AS(+)" as applied to the ~nAAl~P~A;c agents herein is intPn~ed to f"eQr"rACs the d~hulolalo,y or S(+) isomer of the amino acid salt 0 d~i~ali~c,s thereo~ The e,.l"ession "s~llJstA~ ;AIIy free ofthe R(-) ~ -odc" as used in col~j~m.,~;on with the term "S(+)~ means that the S(+) e~ ;o~r~ is sl~ffi~iPntly free of its R(-) antipode to exert the desired onset-h~t~ ~cd and Pl~h~re~ ~n~lgç5;e effect. Practically sre~ing this means that the active i"~di~l should contain atleast 90% by weight of the S(+) onAAntiomPr and 10% or less weight R(-) cnAAntinmP-. Fltir~.~ bly, the weight ratio of S(+) en~ntinn~r to R(-) Pn~ntinmPr is greater than 20:1, more ~.refef~l~ greater than 97:3. Most pl~,r~ably the S(+) ~nAntinmPr iS 99 or more % by weight ~ee of R(-) enAntiomer~ i.e., the weight ratio of S to R is appru~ ly equal to or greater than 99: 1.
For PYAmrle the safe and el~_li~_ amount of ibu~lor~ .~ used in the compo-20 sitions of the present invention generally ranges from about 50 to about 800 mg, p~t;r~ bly from about 50 to about 400 mg and more pl.f~ bly from about 50 to about 200 mg. The safe and ~,Lre~;L~ amount of n&l)ro"~ll used in the compo-sitions of the present .~ ..Loll generally ranges from about 50 to about 660 mg,plere~ably from about 100 to about 330 mg and more plefe.~ly from about 150 to 2s about 220 mg. The safe and ~.Lr~~, amount of ~ult,.l)ror~.l used in the com~rositiQnQ of the present invention generally ranges from about 12.5 to about300 mg, preferably from about 12.5 to about 200 mg, more p~f~..ably from about 12.5 to about 100 mg and most ~l~r~ly from about 12.5 to about 50 mg. The safe and err~li~ amount of ~opi~,r . used in the cc--~po~ nnQ of the present invention generally range_ from about 5 to about 100 mg, pl~f~l~ from about 5 to about 7~ mg, more pl~f~ bly from about 5 to about 50 mg and most preferably from about 5 to about 25 mg. Generally, the amount of the S(~ o.... - ~ of theseagents will be about half of the amount of the racemic n~lule.
Useful dosage of these agents can be found in The Physicians' Desk Refier-3~ ~n~~, 47th Edition (1993) and in U.S. Patent 4,552,899 to ~SI~n~hine et al., issued No~_...ber 12, 1985, both of which are inco-~ol~Led by l~rer~ce herein.
PyITolidine and ~ipc.idine ether ~ ;c agents W O 97/04808 PCT~US96/12249 s -The pyrrolidine and piperidine ethers are of the formula:
(CH2)m H3 ~ CH~)n Rl~ _O ~H2~H2--H& CH
~ I
~ R2 wh~,.e~ Rl is a radical sF~ ed from the group cnn~ of Lydlu~,e.~, h~logPn lower allyl con~ Q from 1 to 4 carbon atoms and lower alkoxy cc,~ln;~ from 1 S to 4 carbon atoms, R2 is a radical sFlPcled from the group con~ 8 of lower alkyl co..ln;~ 1 to 4 carbon atoms, m is an integer from 0, 1, 2 and 3 and n is an integer from 1 to 2, with the proviso that m I n must be at least 2. Salts of these cG~I-poul~ds are also useful.
These co...l~o~n~ls have ~nt~ e~n-..:~lc plu~ l;es and are more fully des~ -ed 0in U.S. Patent 3,097,212 to Jucker et al., issued July 9, 1963, incol~ol~Lcd bycfelence herein.
Pl~rell~,d for use herein are N-methyl-2-[2'(a-methyl-p-chloro-be.~l.yd oxy)ethyl]-pyrrolidine and N-methyl-2-[2'(a-methyl-p-bromo-be.~lly~yl-oxy)ethyl]pyrrolidine. Most pref~l~d for use herein is N-methyl-2-[2'(a-methyl-p-chloro-15be.~ll~rdlyl-oxy)ethyl]-pyrrolidine which is co~ -nnly hlown as r~ C~ e rull~ale and sold as Tavist~ by Sandoz ph~ ce~ti~ ~Ic The safe and e~t,~ amount of these pyrrolidine and piperidine ethers gen-erally ranges from about 0.1 to about 10 mg, preferably from about 0.3 to about 3 mg, more preferably from about 0.5 to about 2 mg and most pl~,~el.,bly from about 200.67 to about 1.34 mg.
~dditional Phann~ce~ltic~l Actives The comroeitinne of the present invention can also include at least one other ph~ cological active s~le~,led from the following class: (a) a decon~f,~ (b) an e.lo.~l (c) an ~ditinn~l ~ntihi~ e and (d) an ~ . The decon-2sg~Sin~le useful in the co.~ o;~ I;nnc of the present i~ on include pse~doeph~d-rine, phellylplop~nnl~mine~ phenylephrine and eph~A-;..e, their ph~.,ncelltir~lly ac ceptable salts, and ~ Ul~S thereof. The ~ntihlc~ives useful in the present i~lvel~lio include those such as d~~ clho~h&ll~ chlophe~ nol~ cdll,c~A~
c&l~ ;ph~n, nosrarin~ rh- I~I~ydl~ul~lc~ codeirl~ h)/Loco~one, hydl(JlllGlphol~e, 30 fominnben their phA~ c~ ;r~lly-~ccept~bl~ salts, and ~ Ul~,S thereof. The atl~1ition~l ~ntih.~ n~ s usefiul in the present invention include those such as chlor-phe~ e, l~r~....I hP~ Iil,e, ~IPY~ h~,.~ilalllil~ d~l~ln~hl~l~le, tripro-lidine, A7AtA~linp~ du~yla~nil~e, tnrPlF ~n~ r, cyprohPpP.~1inP., Lyd~uAy~e, car-bint~Y~min~, ~hr.~ .F~ brom~ irh~ y~ ; r~ their ~ n~
cally acceptable salts, as well as the non sedA~ g Ant~ s which include U,l~ ;nP, AE~ 11325, ~A ~ A7~t~A~;nP~ ~,ft~CI;n~" C~ r, e1~AC~ r, k~Q,;r..~, lo~oyAm;~lp~ loratidine, levoc~b~ e"~r~ o, o~lu~ dP s~A~tinG~
ta_ifylline, ~ ,rt~ r and terfPnAdinp~ their pllA~ 9~ tir~lly arUC~ h1e salts and ~LUreS thereo~ The ~-l-eclo~ls (also known as mucolytic agents) usefill in the present invention include ~.,~ ;ACO15lP terpin hydrate, ~.. nl~:.. chloride, 0 N-acetyl~iy~ e and blo ~ k ~ e, &I~ u.~Ol, their ph~ c~ Ally $~ t-~le salts,and ~ les thereof. All of these ~pOI~ ~s, ae well as their P-C~L ~IF dosage ranges are described in the following: U.S. Patent 4,783,465 to ,~llnehine et al., is-sued Nu~ llber 8, 1988, U.S. Patent 4,619,934 to ~ e~ t et al., issued ~ctob 28, 1986, which are illco~G~Ic1 by r~,f~ ce herein.
~ itio~l agents which are found useful in the present co~ nc are a-~oni~tc such as those ~ osed in U.S. Patent 5,478,858, issu_d De~ bPr 26, 1995, illCO-~dtC~ herein by ~ ce in its e~
Various oral dosage forms can be used, in~ Aing such solid forms as tablets, caplets, c~rs~lPe, ~les, 10-P ~A~S and bulk powders and liquid forms such as syr-ups and s-~t-~ onC Controlled release dosage forms which provide a controlled release of these active(s) are slso useful. These oral forms co~ .~ a safe snd err~ e ~lnm~nt, usually at lesst sbout 5% of the sctive cQ-~.pon~ .1c Solid oraldossge forms l,lefe.~l" contain ftom about 5% to about 95%, more ~-,re~
from about 10% to about 95%, and most p~r~ from about 25% to sbout 95%
2s ofthe active C0~ 4l~ lc Liquid oral dossge fonns p~f~l~ contain from about 1% to about 50% snd more p~t:r~,~ably from about 1% to about 25% and most plerel~ly from about 3% to about 10% of the active compone.lLs.
Tablets can be collll)~essed, lliLwaled, enteric-coated, sugar-coated, film-coated or multiple co~llplc~sed, co-~ln;~ g snit~le binders, 1~ , Ail~lpntc~
d~ Ling agents, c~lcrin~ agents, n~v(,l~,g agents, preSe~vaLi~,s and flow-in~ rir~g agents. Also useful are soft gelatin cArsl~les Liquid oral dosage forms include aqueous and non~ Pollc so1~ltinne, emul-sions, pseudo çml~lQ;~nc, s .~p~1~Q clle., and sol~ltion~ andlor 5 '~1 ., onQ recons-tituted from non c~ sc~,n~ granules, co.-~ g s~lit~b!~ sol~ ls, ple~ ra emuls~ing agents, SU~1L1;1I~ agents, l1illlentC, s~ t~ , taste~ QI.ug agents, cclnring agents, and ll~o~ing agents. Specific ~ r~s of ph~ ccu~;~Ally ac-ceptAble car~iers and excipients that may be used to ~~ e oral dosage forms, .
W 097/04808 PCT~US96/12249 are decrrihed in U.S. Patent 3,903,297, Robert, issued SPptPmbP~2,1975, incorpo-rated by rerel~nce herein. Te~hn;qu~Ps and comroeitione for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Phar-maceutics. Vol. 7. ~anker and Rhodes, editors), 359-427 (1979), ~lcOl~lalcd by 5 rcfe.~llce herein. Techn;q~ e and comrQeitinne for making tablets (c~ lesbed and molded), c~rs~llPe (hard and soft gelatin) and pills are d~Psr~ihed in ~2e-~ ol~'s ~h~n~ce~ltic~l Sciences (A~thur Osol, editor), 1553-1593 (1980), LcOl~olalcd herein by lercl~lce.
An ~rlitinn~l agent found useful in the present comrositinne is C~rr. ,.r.
o ~ff~ine has been found to lessen the sed~ effect of the pyrrolidine and piperidine ethers. The level of c;~ rre;--c use is generally from about 20 mg to about 500 mg, ~Jlercl~bly from about 50 mg to about 200 mg, most preferably from about65 mg to about l00 mg.
In p.cp~.llg the liquid oral dosage forms, the active c~ po~ l is incor-5 porated into an n~lueo~l~based orally ~ecept~h'e ph~ ceutiC~ rier C~with c~ e-~l;on~l ph ~~ cevtir~l practices. An "aqlleo~lc-based orally acce~ b'e ph~ r,e~ltir~l carrier" is one wllcr~ the entire or predo---;~ solvent content is water. Typical carriers include simple ~q~leo-~e sol~ltinnQ~, syrups, disp~.~;olls and ~u~pC~l~ nl~ and ~q~leollC based eml~lQ;nne such as the oil-in-water type. The most 20 prerc;ll~ d carrier is a ~ iSyrln~ of the ph~ r,e~ltir~l colllpGs;lion in an aqueous vehicle co--l~ g a suitable ,..,~ agent. ,S~ ble ~,~5~ agents include Avicel RC-59l (a miclu~ lalline-c~ os~/sodium C~UbUAY~ hYI celllllose mix-ture available from FMC), guar gum and the lilce. Such s~p- ~~ R agents are wellknown to those skilled in the art. While the amount of water in the co~po;. I;onc of 25 this invention can vary over quite a wide range ~lep~ g upon the total weight and volume of the active ~ onr ~1 and other optional non-active h~ d;e..l~, the total water cQntent based on the weight of the final CO...pGS liG~ will generally range from about 20 to about 75%, and, pl~tre.ably, from about 20 to about 40%, by weight/volume.
Althnugh water itself may malce up tne entire carrier, typical liquid formu-lations pl~r~lably contain a co-solvent, for ~oY~mrl~, propylene glycol, glyc~;.in, sor-bitol so1utinn and the l~e, to assist so1~lkili7~tiQn and incorporation of water-insQl11h1c ingredients, such as navo-ing oils and the like into the CG~.lposiliol~.
In general, therero-e, the co~ o~ ~;onc of this invention preferably contain from 3s about 5 to about 2~ volume/volume percent and, most p~r~.ably, from about l0 to about 25 volumeJ volume percent, of the co-solvent.
..
W O 97/04808 PCT~US96/12249 Other optional ingre-lie ~1~ well known to the ph~....n :~('s art may also be inrl~lde(~ in ~ ou ~ generally kno~-vn for these i Igre l:t ~1~, for exasnple, natural or artificial ~ tW~ , navo-ing agents, colorants and the l;lce to provide a p~l~t~ble and ple ~ ~t looking final product, ~ntir~-xir1~nt~, for; .~ le, l~ulylaled Lydlo~ ani-s sole or l~ulylalcd Ly~l10~ tQI l~nP~ and l~r~se. valiv-es, for example, methyl or propyl paraben or sodium bPn7o~tP, to prolong and Pnh~nce shelf life A highly prer~ d optional component is r~n~i~u~
METHOD OF TREATMENT
The amount of the phsrm~ce~tir~l co...posilion ~ .;n ~l~r ,d d~t ~.~15 upon 0 the percent of sctive ingredients within its ro~ ula~ which is a fi~nCtion of the amount of the n~phth~lPnP, dc-ivali~, and any optional CQ~ul~Qn~ such as a de-col~st~nt cough suppr~ 3s<~ll, e.~pe-ilo,~-l and/or ~ c l~luilel per dose,stability, release chara~ ,5 and other pharm~celltir~l pa,~~
Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from 5 about 2 mgfkg to about 30 mgfkg per day and most p.~,E~l~bly from about 3 mgfkg per day to about 20 mgfkg per day of the P!~z ~ c~ ~;c~l comro~itinn is ~rlmini~tered as ~Irs~ ~ ;ked herein. This amount can be given in a single dose, or, preferably, in multiple (two to SL~) doses repe~le~ly or s~ ed release do~gfs over the course of ll~nl~P-~l Generally, each individual dosage of the ph~ ti~l com-20 positi(mc of the present invention range from about 1 n glkg to about 2~ mg/kg, pl~r~ably from about 2 mg/kg to about 15 mgfkg and most pr~f~lably from about 3 mgfkg to about 10 mgfkg. While dos~ges higher than the roregoL.g are effective to provide relief from cough, cold-like, flu, flu-like and allergic rhinitis ~..~plo~ , care must be taken, as with any drug, in some individuals to prevent adverse side effects.
~s The following eY~nlpl~- illustrate emho~ .. f~ of the subject invention ~l.~re~- both eecenti~l and optional ingredients are co~ rd FXAMPLE I
A hard gelatin capsule cO~ Gc l;on for oral s ~ aLion is prepd~ed by cc......ki~ g the following ingredients:
Tn~redient Amount It~ul)~Or~l~ 200.00 mg Cl~m~tinP fumarate 0.67 mg Pseudoeph~A~ine HCI 30.00 mg Triturate active ingredients and q.s. with lactose to 3Pl~';led capsule size.
3~ ~min;ctration of one or two the above c~psvl~s every four to twelve hours to a human in need of he~ P-Il provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis ~...l-lo,nc FXAMPLE II
A hard CO~ ssed caplet comrociti~n for oral n~ lion is p~cp~ed by cQmhining the follouing ingredients:
T~ Amount Il up~of~.- 300.00 mg Cl~m~tinP rul~ e0.67 mg IIyd,oxyy,~opyl methyleP~ ose 300.00 mg 0 Corn starch 150.00 mg Pre~ tini7ed starch40.00mg Silicon ~lio~ e7 c~ 1loid~l 1.50 mg Stearic acid TP fine powder 2.00 mg Sodium lauryl sulfate0.50 mg ~ ion of two caplets every twelve hours to a human in need of provides ull~ ed relief from cough, cold-like, flu-lilce and allergic rhinitis ~y"-l,lwus.
E~AMPLE m A hard co~"p,~ s~ed tablet c~..po~;l;on for oral ar1-~ alion is ~,~p~ed by 20 co..hi~ g the following in~edients:
Tl~gfcdi~uL Amount Na,~,o~e. sodium 220.00mg Cl~ ru,~le 1.34 mg M~-PS- ~--. sl~ 2.00 mg 2s Povidone 10.00 mg Talc 12.00 mg Microcrystalline ce~ nse45.00 mg ~ 1....n ~ lion of one of the above tablets every twelve hours to a human in need of ~ ...f ~ provides u~pl~v~;d relief from cough, cold-lilce, flu, flu-like and 30 allergic rhinitis ~..~
EXAMPLE IV
A liquid co",~o~Lol- for oral ~ lion is prl ~u~d by CQlll~ the following ill~edic.,ls.
In~ e.li~,.,l % W/V
Na~.ox~n sodium 2.2000 Alcohol (95%) 25.0000 ~l~m~qine rull~ale 0.0134 W O 97/04808 PCT~US96/12249 Propylene Glycol25.0000 Sodium Citrate 2.0000 Citric Acid 0.2S00 Liquid Sugar (Simple Syrup) 25.0000 Glycerin 7.0000 Colorants 0.0080 Flavor 0.5000 Water, Purified QS100.0000 The purified water (aP1).U~ el,~r 10% of the ~nal batch volume) is poured 0 into a batch co..lAi~v~ c.luipped with a lightnin' mixer. The sodium citrate, citric acid, and actives other than n ap~o~e.l sodium are added SC~1U~ r.l;AIIy and dissolved with ~ it~tion The gl~ and liquid sugar are then added. ~ a sep~le contAinp~ the colorants are added to p l-ifiPd water (ap~ el~ 0.5% of the final batch volume). This colorant sol~tion is then added to the first batch C~ r. In 5 a s~al~le contAinpr the napro~e.l sodium is added to the alcohol while sti~rin~
The propylene glycol and fiavors are added to this alcohol premLlc and the res~lting iAlur~ is stirred until ho...og. ~F.~UQ and then added to the first cQntAinpr. The .,.Ai,l;"g purified water is added to the resllltin~ mixture and stirred.
l.alion of 10 ml to 20 ml (2 to 4 teA~roon~fi~l) every twelve hours to 20 a human in need of lr"Al~--k--~ provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis ~.-.l-lO~
EXA~LE V
A liquid co~pos~ n for oral ~dmini~tration is p.t;p_ed by co~.l,;..;i~ the following ingredients:
2s In~ t.lie~,l % W/V
Il u~ f.,~ 2.0000 ~IPmA~tin-P, ru.. ,~e 0.0067 Alcohol (95~/0) 25.0000 Propylene Glycol 25.0000 Sodium Citrate 2.0000 Citric Acid 0.2500 Liquid Sugar (Simple Syrup)25.0000 Glycerin 7.0000 Colorants 0.0080 3s Flavor 0.5000 Water, Purified QS 100.0000 W O 97/04808 PCT~US96/12249 The purified water (appro~ ly 10% of the final batch volume) is poured into a batch CO~ P~r ~uipped with a lightnin' mixer. The sodium citrate, citric acid, ~ ACl;-~e ru~l~ale are added seq~l~ntiAIIy and dissolved with ~yt~tion Theglyeeli~l _nd liquid sugar are then added. In a S~ &ale CO~ the colorants are 5 added to purified water (app-o~ 0.5% of the final batch volume). This colorant sQI~lfion is then added to the first batch CO~ -. ~ a s~alale CO~
the il~up~ren is added to the alcohol while stirring. The propylene glycol and flavors are added to this alcohol premix and the reslllting ll~lUie iS stirred until homnge~eulls and then added to the first CQ~ . The r.c...~ pl~rifie~l water is~0 added to the l- ;,.~ g l~lule and stirred.
ion of 10 ml to 20 ml (2 to 4 teAcpoonefill) every four to twelve hours to a human in need of h~ nl provides ~ Jro~,d relief from cough, cold-like, flu, flu-lilce and aUergic rhinitis s~ ~l.plo..ls.
EXAMPLE VI
A liquid co.. ~po~ n for oral ~rlminietration is prep~ed by cc .. bi~ g the following ingredients:
Tl,~.edi~
S(+) Il~ul~lur~.~ Lysinate2.000 r'l~.mActin~ r"".l .Ale o oos D~l~u~e~l~orphan HBr 0.300 Alcohol (95%) 25.000 Propylene Glycol 25.000 ~o~1illm Citrate 2.000 Citric Acid 0.250 2s Liquid Sugar (Simple Syrup)25.000 Glycerin 7.000 Colorants 0.008 Flavor 0.500 Water, Purified QS 100.000 The purified water (app-~y 10% of the final batch volume) is poured into a batch CO~ I e~ ;l.pcd with a ligl-ll~; mixer. The sodium citrate, citric acid and C1el~ C ru~ aLe are added seq~lentiAlly and dissolved with a~it~t;~n The ~,c.in and liquid sugar are then added. In a sep~le co--lA-~-~r the colorants are added to purified water (applo~ y 0.5% of the final batch volume). This 35 colorant sol~tion is then added to the first batch COI~ U In a sepal~le CO~
the S (+) il,~lp.urell Iysinate and deAL-u...- ll~ ~Rr are added sequ~nti~ y to the a!cohol while stirring.
W O 97/04808 PCT~US96/12249 12 The propylene glycol and fiavors are added to this alcohol premix and the res~-lting mixture is stirred until hom~gF ~eO-Ie and then added to the first co.
The ~ , purified water is added to the, ~ g ~ lur, and stirred.
~rlminietration of 20 ml (4 te~epoonefi~l) every eight to twelve hours to a 5 human in need of ll~ol ~Pnl provides i.~-oved relief from cough, cold-like, flu, flu-like and aller~gic rhinitis ~...l.tc~ e
TREATING RESPIRATORY DISORDERS
The present ulvelllioll relates to comrositionc and mRthoAs for providing ul~ vt;d ~ l, mz~n~g~m~nt or mitig~tiOlt of cold, cold-lilce, allergy, sinus and/or flu ~ c by aA~ t~ g a safe and ~fIe~ e amount of a comrosi~ion comrricin~ an ~n~lgRQ;c agent along with certain pyrrolidine and piperidine ether 5 ~ntihi~;;c agents.
R~CKGROUND OF 1~ INVENI~ON
The commnn cold, ~1th~l~h not usually a serious illness, is a highly pre-valent, ~i~co...ro.Ling and al~nojLl~g ~ tion The term "cQmmnn cold" is applied to minor respiratory i~ F5s~g caused by a variety of d;~e~ JU~IOl~ viruses.
20 While .l.inovu,lses are the major known cause of cc~ n colds, rccv~ for appl. Y;-..~I~ly 30 percent of colds in adults, viruses in several other groups are also i.llpol~ . While i~ c ~ nc~s occur, and infRction with some ~e~u~
tract viruses therefore could be pl~ nled by a vaccine, development of a polytypic vaccine to cover all possible agents is impractical. Thus, the problem of controlling 2s acute upper l~s~u~tol~ disease p-~3enls co~ ch~ n~Rs~ and the long-desired disco~e.y of a single cure for the co on cold is an ~l~li~Lic e ec~ n Early symrtQmc may be minim~l with only mild m~ sore throat and nasal co...~ With rhinovirus ;..r. c~;on ~.~plo...~ of nasal discl~ , nasal col~gc,l;on, and S--F, ~ g usually co~ F-~ce on the first day of illness and progress to .. ~;.. ,.. s~ ~.ily by the second or third day. Along with nasal Sy~ptO-~e may come sore, dry or scr~chy throat and ho~a~ness and cough. Other ~r...ptO-..c mayinclude mild burning of the eyes, loss of smell and taste, a feeling of pressure or fullness in the sinuses or ears, h~ rh~ and vocal ;"-P~;"--F~-I Fever can occur,but is ..i~-on~ n Tnflll~n7~ infPc~ion generally inrllldes fever, often of sudden 3s onset and ~,.a;alillg for several days, and with great s~.ily; generalized aches and pains; fatigue and we~knF~; and chest ~I;CGOn~
At present, only i~y~ O~ iC L~ is available for the CG~ OIl cold.
The costs of llcaL.~ colds with over-the-counter meAir~ti~nc in the United States is 1 ed at an annual cost of over 1.5 billion dollars. The direct costs of h ~,n~ ~-f -~in outr~ti~?nt clinics is ~ ed at almost four billion dollars. ~direct costs, based s on the amount of loss in wages bec~ -~e of r~ct irted activity are ~-.l,s~ y higher.
FYf~ y prior art forrmll~tinnc for L14~ 'f~l of cough, cold, cold-lilce, allergy, sinus and/or flu ;~ylllplon~s and the ~iccor-r~"L, pain, fever and general malaise ~ccor;~tetl thcl.,~.~iLll generally contain an ~n~l~cic (aspirin or 0 acet~minl phen) and one or more ~ntil~ c~ ;c~, decol~riP~Ie, cough sup-pl~ssa~ ntitllCcives and ~ e~lo,a ~ls.
The use of non-steroidal anti~ n~ lo,y drugs to combat il~n~ linn and A~ l pain is q,cepte~ r.li~Al practice. The non-~L~loidals are CQI~ Ollly employed to relieve pain and ;.. n~.. ~;On ~csori~ted with, for ~ lr, bursitis, 5 arthritis, h.~a~ h.o and the lilce. Among the most cQ----.-~ ly used drugs of the non-narcotic ~n~lge~io class of drugs are aspirin, ~:e~ ~h~n, il,uylurell, ketoprofen, dirl~f~n~r, and ~ n ~d their salts (e.g., lysine, &.~.-..c, sodium and pul~ ). Aspi~ cel~ .oph~, and ibuprofen have he.~Lororc been includ-ed as the pain reliever and fever- educ: ~g component in convention~l cough/cold20 multi~y~ lo~n allc~isLu.~ 'OC:l;rmc These co~ f ~,idlly .-~A~,ted products generally contain in rd~;tinn to aspirin, ~.ce~ ophen or il,up.orfn, one or more~ntihictAminicc, ~econgr~ lQ., cough-~ul,plc~s&-L~ ;ves and ~ e.lQI~-L~.
The present u~ve~Lci~ have found that srle~l~d compositionc co~ g an ~n~1ge~iG agent along with certain pyrrolidine and pir~ri~inA ether Anti~
25 agents provides u..~-o~- d Ir~A~ f .~r m~n~g~m~nt or mitigPtinn of cold, cold-lilce, allergy, sinus and/or flu ~plQ~ n~ ing nasal c~ f l;nn It is ~cre;rolf an object ofthe present invention to provide a method for the Ll ~ l of cough, cold, cold-like, allergy, sinus and/or flu ~.-~ o...Q in a mam-malian ~-x~s-n in need of such hf~ C~nlrrici~g r~ lf~ P. to such 30 o~ .sul the compositinnS of the present illv~rLion. Such ~ u~Q as used hereinrefer to co~u~ nasal Co~f~l;o~ sinus cQn~f~l;nn~ S~nUQ pai~ upper l~u~lo.
infectionc, otitis, ~ ;s, etc.
SI~IARY OF 1~ INVENI~ON
The present invention relates to coll-pGs;Lions and mf~thods for providing 35 i~ -uv~d l c~ m~n~gfmfnt or mitigPtinn of cold, cold-l~ce, allergy, ~inusand/or flu ~InpLoll~Q by ~ t~ g a safe and e~c ~L~.e amount of a c~ ro.:l;on con~ C~ ssF~ ly of an AnAlg~os;c agent along with certain pyrrolidine and piperidine ether ~ntihi~li....;..;c agents.
All percPntag~s and ratios used herein are by weight unless otherwise in-dir,At~(l 5DFTAT~ Fn I)ESC~TPTION OF THE INVF~IION
The present invention relates to CCJ~ OS;~ C and m~tho~ls for providing plo~cd l~ l management or miti~tion of cold, cold-like, allergy, sinus and/or flu ~ll~Lon~ by ~ a safe and ~Li'._ amount of a composition CQ~ ç~..,..l;~lly of an analgesic agent along with certain pyrrolidine and 0 pi~c.idine ethers.
AnAI~~c;~- Pl,a, ...Acc~l;cal Actives Useful AnAl~çc;c ph~.,l.Ac~.l;r,Al actives in the CO~ G~ I;OI~c of the present invention include aspirin and ~.c~ ophen as well as the non-steroidal anti-in-n~ 0, y drugs (NSAIDS) sF~ led from the following c ~l e~,o, ies propionic acid5 deliva~ , acetic acid dc~i~aLi~ , fenAm;c acid derivatives; ~ " ..~lc~l,o~ylic acid deliv~Liv~ and t)xi~9mC All of these NSAIDS are fully ~l~s~ ed in the U.S.
Patent 4,985,459 to .S~ ch;~r et al., issued January 15, 1991, incol~ul~tcd by refer-ence herein. For det~iled dicrlos~re of the chemicAl structure, synthesis, side e~
fects, etc., of non-steroidal anti-;~ o~y agents, r~,f..~nce may be had to 20 ~ld~d texts, inr~ ng Anti-i~nA~ to~y and Anti-l~h~ ;c Drugs. K. D.
RA lsru~d, Vol. I-m, CRC Press, Boca Raton, (1985), and Anti-i.~lld~ o As~entc Che ..:s~ and PL~.---acologY. 1, R A Scherrer, et al., ~ omiç Press, New York (1974), both of which are ~I~co-l.o.aled by l~fel..dlce herein.
Useful dosage of these agents can be found in The I'l.ys;c;~u-s' Desk Refer-25ence. 47th Edition (1993) and in U.S. Patent 4,552,899 to ,S,~s~ e et al. issued No~..ber 12, 1985, both of which are incorporated by r~r.;.w~ce herein.
FY~nlp~ of p-~f~ .d ~n~ oQ;ç phA~..ulçeutic~l actives useful in the present invention in~ludlo, but are not limited to, ~c~ ophen, acetylsalicylic acid, ibupro-fen, f~ u~ r~ r~.lûplûre.~ nul~ lofe~ int~ lo~l~fe~ dp~ , their 30 ph~...~çe~lti~lly ~ceF~ salts, e-~ ;o...- -~ thereof, and .l~lul~g thereof.
~cet~minophen, ;buprorcn and naplo~ are especially pl~,f...~d for use in the co..l~os;lions of the present i.-~ ;on.
The term "ph~....~çe~ ly acceptable salts" refers to salts p.ep~ed from ph~rm~ce~ltiç~lly acc~l~blc non-toxic bases inc~ ir~ O.~ llC bases and organic 3s bases. Salts derived from nono-~nic bases include so~ m~ pOl~c~ ~.-- lithium, A.l....~l~;s. c~lri~lm, ~ , ferrous, zinc, ~ v~nnv~ .." ferric, ...~ ic salts and the like. Salts derived from ph~....~çc.,l;r~lly ~c~eptal 'e organic non-toxic bases include salts of ~ uy, secon~lAAry, tertiary and ~ amines, ,~.1. ,l;l uledamines incl~lclinp naturally occ--~ c s~,b~ u~ed amines, cyclic amines and basic ion eYch~n~e resins, such as triethylamine, hil~lo~~ ule, 2-d~ elh~lA~ ntll~A~lol~ 2-diethylaminoethAAnol Iysine, ~u~ c, hictirlinP" çAAffcine, procaine, N e Ll~l~ipt;lidine, hydrA~AAminP" choline, betaine, ethylrl~rA;A----~-r, glllcos~minP, methyl~ly.,~u.,c, theo-I.rol-~e, purinps~ pipe.2~.e, pirPrj~inP~ polyamine resins and the lilce.
Most p,~ d for use herein is ~r-~ ph~ and the S(+) isomer of the NSAIDs and their salts. The term AS(+)" as applied to the ~nAAl~P~A;c agents herein is intPn~ed to f"eQr"rACs the d~hulolalo,y or S(+) isomer of the amino acid salt 0 d~i~ali~c,s thereo~ The e,.l"ession "s~llJstA~ ;AIIy free ofthe R(-) ~ -odc" as used in col~j~m.,~;on with the term "S(+)~ means that the S(+) e~ ;o~r~ is sl~ffi~iPntly free of its R(-) antipode to exert the desired onset-h~t~ ~cd and Pl~h~re~ ~n~lgç5;e effect. Practically sre~ing this means that the active i"~di~l should contain atleast 90% by weight of the S(+) onAAntiomPr and 10% or less weight R(-) cnAAntinmP-. Fltir~.~ bly, the weight ratio of S(+) en~ntinn~r to R(-) Pn~ntinmPr is greater than 20:1, more ~.refef~l~ greater than 97:3. Most pl~,r~ably the S(+) ~nAntinmPr iS 99 or more % by weight ~ee of R(-) enAntiomer~ i.e., the weight ratio of S to R is appru~ ly equal to or greater than 99: 1.
For PYAmrle the safe and el~_li~_ amount of ibu~lor~ .~ used in the compo-20 sitions of the present invention generally ranges from about 50 to about 800 mg, p~t;r~ bly from about 50 to about 400 mg and more pl.f~ bly from about 50 to about 200 mg. The safe and ~,Lre~;L~ amount of n&l)ro"~ll used in the compo-sitions of the present .~ ..Loll generally ranges from about 50 to about 660 mg,plere~ably from about 100 to about 330 mg and more plefe.~ly from about 150 to 2s about 220 mg. The safe and ~.Lr~~, amount of ~ult,.l)ror~.l used in the com~rositiQnQ of the present invention generally ranges from about 12.5 to about300 mg, preferably from about 12.5 to about 200 mg, more p~f~..ably from about 12.5 to about 100 mg and most ~l~r~ly from about 12.5 to about 50 mg. The safe and err~li~ amount of ~opi~,r . used in the cc--~po~ nnQ of the present invention generally range_ from about 5 to about 100 mg, pl~f~l~ from about 5 to about 7~ mg, more pl~f~ bly from about 5 to about 50 mg and most preferably from about 5 to about 25 mg. Generally, the amount of the S(~ o.... - ~ of theseagents will be about half of the amount of the racemic n~lule.
Useful dosage of these agents can be found in The Physicians' Desk Refier-3~ ~n~~, 47th Edition (1993) and in U.S. Patent 4,552,899 to ~SI~n~hine et al., issued No~_...ber 12, 1985, both of which are inco-~ol~Led by l~rer~ce herein.
PyITolidine and ~ipc.idine ether ~ ;c agents W O 97/04808 PCT~US96/12249 s -The pyrrolidine and piperidine ethers are of the formula:
(CH2)m H3 ~ CH~)n Rl~ _O ~H2~H2--H& CH
~ I
~ R2 wh~,.e~ Rl is a radical sF~ ed from the group cnn~ of Lydlu~,e.~, h~logPn lower allyl con~ Q from 1 to 4 carbon atoms and lower alkoxy cc,~ln;~ from 1 S to 4 carbon atoms, R2 is a radical sFlPcled from the group con~ 8 of lower alkyl co..ln;~ 1 to 4 carbon atoms, m is an integer from 0, 1, 2 and 3 and n is an integer from 1 to 2, with the proviso that m I n must be at least 2. Salts of these cG~I-poul~ds are also useful.
These co...l~o~n~ls have ~nt~ e~n-..:~lc plu~ l;es and are more fully des~ -ed 0in U.S. Patent 3,097,212 to Jucker et al., issued July 9, 1963, incol~ol~Lcd bycfelence herein.
Pl~rell~,d for use herein are N-methyl-2-[2'(a-methyl-p-chloro-be.~l.yd oxy)ethyl]-pyrrolidine and N-methyl-2-[2'(a-methyl-p-bromo-be.~lly~yl-oxy)ethyl]pyrrolidine. Most pref~l~d for use herein is N-methyl-2-[2'(a-methyl-p-chloro-15be.~ll~rdlyl-oxy)ethyl]-pyrrolidine which is co~ -nnly hlown as r~ C~ e rull~ale and sold as Tavist~ by Sandoz ph~ ce~ti~ ~Ic The safe and e~t,~ amount of these pyrrolidine and piperidine ethers gen-erally ranges from about 0.1 to about 10 mg, preferably from about 0.3 to about 3 mg, more preferably from about 0.5 to about 2 mg and most pl~,~el.,bly from about 200.67 to about 1.34 mg.
~dditional Phann~ce~ltic~l Actives The comroeitinne of the present invention can also include at least one other ph~ cological active s~le~,led from the following class: (a) a decon~f,~ (b) an e.lo.~l (c) an ~ditinn~l ~ntihi~ e and (d) an ~ . The decon-2sg~Sin~le useful in the co.~ o;~ I;nnc of the present i~ on include pse~doeph~d-rine, phellylplop~nnl~mine~ phenylephrine and eph~A-;..e, their ph~.,ncelltir~lly ac ceptable salts, and ~ Ul~S thereof. The ~ntihlc~ives useful in the present i~lvel~lio include those such as d~~ clho~h&ll~ chlophe~ nol~ cdll,c~A~
c&l~ ;ph~n, nosrarin~ rh- I~I~ydl~ul~lc~ codeirl~ h)/Loco~one, hydl(JlllGlphol~e, 30 fominnben their phA~ c~ ;r~lly-~ccept~bl~ salts, and ~ Ul~,S thereof. The atl~1ition~l ~ntih.~ n~ s usefiul in the present invention include those such as chlor-phe~ e, l~r~....I hP~ Iil,e, ~IPY~ h~,.~ilalllil~ d~l~ln~hl~l~le, tripro-lidine, A7AtA~linp~ du~yla~nil~e, tnrPlF ~n~ r, cyprohPpP.~1inP., Lyd~uAy~e, car-bint~Y~min~, ~hr.~ .F~ brom~ irh~ y~ ; r~ their ~ n~
cally acceptable salts, as well as the non sedA~ g Ant~ s which include U,l~ ;nP, AE~ 11325, ~A ~ A7~t~A~;nP~ ~,ft~CI;n~" C~ r, e1~AC~ r, k~Q,;r..~, lo~oyAm;~lp~ loratidine, levoc~b~ e"~r~ o, o~lu~ dP s~A~tinG~
ta_ifylline, ~ ,rt~ r and terfPnAdinp~ their pllA~ 9~ tir~lly arUC~ h1e salts and ~LUreS thereo~ The ~-l-eclo~ls (also known as mucolytic agents) usefill in the present invention include ~.,~ ;ACO15lP terpin hydrate, ~.. nl~:.. chloride, 0 N-acetyl~iy~ e and blo ~ k ~ e, &I~ u.~Ol, their ph~ c~ Ally $~ t-~le salts,and ~ les thereof. All of these ~pOI~ ~s, ae well as their P-C~L ~IF dosage ranges are described in the following: U.S. Patent 4,783,465 to ,~llnehine et al., is-sued Nu~ llber 8, 1988, U.S. Patent 4,619,934 to ~ e~ t et al., issued ~ctob 28, 1986, which are illco~G~Ic1 by r~,f~ ce herein.
~ itio~l agents which are found useful in the present co~ nc are a-~oni~tc such as those ~ osed in U.S. Patent 5,478,858, issu_d De~ bPr 26, 1995, illCO-~dtC~ herein by ~ ce in its e~
Various oral dosage forms can be used, in~ Aing such solid forms as tablets, caplets, c~rs~lPe, ~les, 10-P ~A~S and bulk powders and liquid forms such as syr-ups and s-~t-~ onC Controlled release dosage forms which provide a controlled release of these active(s) are slso useful. These oral forms co~ .~ a safe snd err~ e ~lnm~nt, usually at lesst sbout 5% of the sctive cQ-~.pon~ .1c Solid oraldossge forms l,lefe.~l" contain ftom about 5% to about 95%, more ~-,re~
from about 10% to about 95%, and most p~r~ from about 25% to sbout 95%
2s ofthe active C0~ 4l~ lc Liquid oral dossge fonns p~f~l~ contain from about 1% to about 50% snd more p~t:r~,~ably from about 1% to about 25% and most plerel~ly from about 3% to about 10% of the active compone.lLs.
Tablets can be collll)~essed, lliLwaled, enteric-coated, sugar-coated, film-coated or multiple co~llplc~sed, co-~ln;~ g snit~le binders, 1~ , Ail~lpntc~
d~ Ling agents, c~lcrin~ agents, n~v(,l~,g agents, preSe~vaLi~,s and flow-in~ rir~g agents. Also useful are soft gelatin cArsl~les Liquid oral dosage forms include aqueous and non~ Pollc so1~ltinne, emul-sions, pseudo çml~lQ;~nc, s .~p~1~Q clle., and sol~ltion~ andlor 5 '~1 ., onQ recons-tituted from non c~ sc~,n~ granules, co.-~ g s~lit~b!~ sol~ ls, ple~ ra emuls~ing agents, SU~1L1;1I~ agents, l1illlentC, s~ t~ , taste~ QI.ug agents, cclnring agents, and ll~o~ing agents. Specific ~ r~s of ph~ ccu~;~Ally ac-ceptAble car~iers and excipients that may be used to ~~ e oral dosage forms, .
W 097/04808 PCT~US96/12249 are decrrihed in U.S. Patent 3,903,297, Robert, issued SPptPmbP~2,1975, incorpo-rated by rerel~nce herein. Te~hn;qu~Ps and comroeitione for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Phar-maceutics. Vol. 7. ~anker and Rhodes, editors), 359-427 (1979), ~lcOl~lalcd by 5 rcfe.~llce herein. Techn;q~ e and comrQeitinne for making tablets (c~ lesbed and molded), c~rs~llPe (hard and soft gelatin) and pills are d~Psr~ihed in ~2e-~ ol~'s ~h~n~ce~ltic~l Sciences (A~thur Osol, editor), 1553-1593 (1980), LcOl~olalcd herein by lercl~lce.
An ~rlitinn~l agent found useful in the present comrositinne is C~rr. ,.r.
o ~ff~ine has been found to lessen the sed~ effect of the pyrrolidine and piperidine ethers. The level of c;~ rre;--c use is generally from about 20 mg to about 500 mg, ~Jlercl~bly from about 50 mg to about 200 mg, most preferably from about65 mg to about l00 mg.
In p.cp~.llg the liquid oral dosage forms, the active c~ po~ l is incor-5 porated into an n~lueo~l~based orally ~ecept~h'e ph~ ceutiC~ rier C~with c~ e-~l;on~l ph ~~ cevtir~l practices. An "aqlleo~lc-based orally acce~ b'e ph~ r,e~ltir~l carrier" is one wllcr~ the entire or predo---;~ solvent content is water. Typical carriers include simple ~q~leo-~e sol~ltinnQ~, syrups, disp~.~;olls and ~u~pC~l~ nl~ and ~q~leollC based eml~lQ;nne such as the oil-in-water type. The most 20 prerc;ll~ d carrier is a ~ iSyrln~ of the ph~ r,e~ltir~l colllpGs;lion in an aqueous vehicle co--l~ g a suitable ,..,~ agent. ,S~ ble ~,~5~ agents include Avicel RC-59l (a miclu~ lalline-c~ os~/sodium C~UbUAY~ hYI celllllose mix-ture available from FMC), guar gum and the lilce. Such s~p- ~~ R agents are wellknown to those skilled in the art. While the amount of water in the co~po;. I;onc of 25 this invention can vary over quite a wide range ~lep~ g upon the total weight and volume of the active ~ onr ~1 and other optional non-active h~ d;e..l~, the total water cQntent based on the weight of the final CO...pGS liG~ will generally range from about 20 to about 75%, and, pl~tre.ably, from about 20 to about 40%, by weight/volume.
Althnugh water itself may malce up tne entire carrier, typical liquid formu-lations pl~r~lably contain a co-solvent, for ~oY~mrl~, propylene glycol, glyc~;.in, sor-bitol so1utinn and the l~e, to assist so1~lkili7~tiQn and incorporation of water-insQl11h1c ingredients, such as navo-ing oils and the like into the CG~.lposiliol~.
In general, therero-e, the co~ o~ ~;onc of this invention preferably contain from 3s about 5 to about 2~ volume/volume percent and, most p~r~.ably, from about l0 to about 25 volumeJ volume percent, of the co-solvent.
..
W O 97/04808 PCT~US96/12249 Other optional ingre-lie ~1~ well known to the ph~....n :~('s art may also be inrl~lde(~ in ~ ou ~ generally kno~-vn for these i Igre l:t ~1~, for exasnple, natural or artificial ~ tW~ , navo-ing agents, colorants and the l;lce to provide a p~l~t~ble and ple ~ ~t looking final product, ~ntir~-xir1~nt~, for; .~ le, l~ulylaled Lydlo~ ani-s sole or l~ulylalcd Ly~l10~ tQI l~nP~ and l~r~se. valiv-es, for example, methyl or propyl paraben or sodium bPn7o~tP, to prolong and Pnh~nce shelf life A highly prer~ d optional component is r~n~i~u~
METHOD OF TREATMENT
The amount of the phsrm~ce~tir~l co...posilion ~ .;n ~l~r ,d d~t ~.~15 upon 0 the percent of sctive ingredients within its ro~ ula~ which is a fi~nCtion of the amount of the n~phth~lPnP, dc-ivali~, and any optional CQ~ul~Qn~ such as a de-col~st~nt cough suppr~ 3s<~ll, e.~pe-ilo,~-l and/or ~ c l~luilel per dose,stability, release chara~ ,5 and other pharm~celltir~l pa,~~
Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from 5 about 2 mgfkg to about 30 mgfkg per day and most p.~,E~l~bly from about 3 mgfkg per day to about 20 mgfkg per day of the P!~z ~ c~ ~;c~l comro~itinn is ~rlmini~tered as ~Irs~ ~ ;ked herein. This amount can be given in a single dose, or, preferably, in multiple (two to SL~) doses repe~le~ly or s~ ed release do~gfs over the course of ll~nl~P-~l Generally, each individual dosage of the ph~ ti~l com-20 positi(mc of the present invention range from about 1 n glkg to about 2~ mg/kg, pl~r~ably from about 2 mg/kg to about 15 mgfkg and most pr~f~lably from about 3 mgfkg to about 10 mgfkg. While dos~ges higher than the roregoL.g are effective to provide relief from cough, cold-like, flu, flu-like and allergic rhinitis ~..~plo~ , care must be taken, as with any drug, in some individuals to prevent adverse side effects.
~s The following eY~nlpl~- illustrate emho~ .. f~ of the subject invention ~l.~re~- both eecenti~l and optional ingredients are co~ rd FXAMPLE I
A hard gelatin capsule cO~ Gc l;on for oral s ~ aLion is prepd~ed by cc......ki~ g the following ingredients:
Tn~redient Amount It~ul)~Or~l~ 200.00 mg Cl~m~tinP fumarate 0.67 mg Pseudoeph~A~ine HCI 30.00 mg Triturate active ingredients and q.s. with lactose to 3Pl~';led capsule size.
3~ ~min;ctration of one or two the above c~psvl~s every four to twelve hours to a human in need of he~ P-Il provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis ~...l-lo,nc FXAMPLE II
A hard CO~ ssed caplet comrociti~n for oral n~ lion is p~cp~ed by cQmhining the follouing ingredients:
T~ Amount Il up~of~.- 300.00 mg Cl~m~tinP rul~ e0.67 mg IIyd,oxyy,~opyl methyleP~ ose 300.00 mg 0 Corn starch 150.00 mg Pre~ tini7ed starch40.00mg Silicon ~lio~ e7 c~ 1loid~l 1.50 mg Stearic acid TP fine powder 2.00 mg Sodium lauryl sulfate0.50 mg ~ ion of two caplets every twelve hours to a human in need of provides ull~ ed relief from cough, cold-like, flu-lilce and allergic rhinitis ~y"-l,lwus.
E~AMPLE m A hard co~"p,~ s~ed tablet c~..po~;l;on for oral ar1-~ alion is ~,~p~ed by 20 co..hi~ g the following in~edients:
Tl~gfcdi~uL Amount Na,~,o~e. sodium 220.00mg Cl~ ru,~le 1.34 mg M~-PS- ~--. sl~ 2.00 mg 2s Povidone 10.00 mg Talc 12.00 mg Microcrystalline ce~ nse45.00 mg ~ 1....n ~ lion of one of the above tablets every twelve hours to a human in need of ~ ...f ~ provides u~pl~v~;d relief from cough, cold-lilce, flu, flu-like and 30 allergic rhinitis ~..~
EXAMPLE IV
A liquid co",~o~Lol- for oral ~ lion is prl ~u~d by CQlll~ the following ill~edic.,ls.
In~ e.li~,.,l % W/V
Na~.ox~n sodium 2.2000 Alcohol (95%) 25.0000 ~l~m~qine rull~ale 0.0134 W O 97/04808 PCT~US96/12249 Propylene Glycol25.0000 Sodium Citrate 2.0000 Citric Acid 0.2S00 Liquid Sugar (Simple Syrup) 25.0000 Glycerin 7.0000 Colorants 0.0080 Flavor 0.5000 Water, Purified QS100.0000 The purified water (aP1).U~ el,~r 10% of the ~nal batch volume) is poured 0 into a batch co..lAi~v~ c.luipped with a lightnin' mixer. The sodium citrate, citric acid, and actives other than n ap~o~e.l sodium are added SC~1U~ r.l;AIIy and dissolved with ~ it~tion The gl~ and liquid sugar are then added. ~ a sep~le contAinp~ the colorants are added to p l-ifiPd water (ap~ el~ 0.5% of the final batch volume). This colorant sol~tion is then added to the first batch C~ r. In 5 a s~al~le contAinpr the napro~e.l sodium is added to the alcohol while sti~rin~
The propylene glycol and fiavors are added to this alcohol premLlc and the res~lting iAlur~ is stirred until ho...og. ~F.~UQ and then added to the first cQntAinpr. The .,.Ai,l;"g purified water is added to the resllltin~ mixture and stirred.
l.alion of 10 ml to 20 ml (2 to 4 teA~roon~fi~l) every twelve hours to 20 a human in need of lr"Al~--k--~ provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis ~.-.l-lO~
EXA~LE V
A liquid co~pos~ n for oral ~dmini~tration is p.t;p_ed by co~.l,;..;i~ the following ingredients:
2s In~ t.lie~,l % W/V
Il u~ f.,~ 2.0000 ~IPmA~tin-P, ru.. ,~e 0.0067 Alcohol (95~/0) 25.0000 Propylene Glycol 25.0000 Sodium Citrate 2.0000 Citric Acid 0.2500 Liquid Sugar (Simple Syrup)25.0000 Glycerin 7.0000 Colorants 0.0080 3s Flavor 0.5000 Water, Purified QS 100.0000 W O 97/04808 PCT~US96/12249 The purified water (appro~ ly 10% of the final batch volume) is poured into a batch CO~ P~r ~uipped with a lightnin' mixer. The sodium citrate, citric acid, ~ ACl;-~e ru~l~ale are added seq~l~ntiAIIy and dissolved with ~yt~tion Theglyeeli~l _nd liquid sugar are then added. In a S~ &ale CO~ the colorants are 5 added to purified water (app-o~ 0.5% of the final batch volume). This colorant sQI~lfion is then added to the first batch CO~ -. ~ a s~alale CO~
the il~up~ren is added to the alcohol while stirring. The propylene glycol and flavors are added to this alcohol premix and the reslllting ll~lUie iS stirred until homnge~eulls and then added to the first CQ~ . The r.c...~ pl~rifie~l water is~0 added to the l- ;,.~ g l~lule and stirred.
ion of 10 ml to 20 ml (2 to 4 teAcpoonefill) every four to twelve hours to a human in need of h~ nl provides ~ Jro~,d relief from cough, cold-like, flu, flu-lilce and aUergic rhinitis s~ ~l.plo..ls.
EXAMPLE VI
A liquid co.. ~po~ n for oral ~rlminietration is prep~ed by cc .. bi~ g the following ingredients:
Tl,~.edi~
S(+) Il~ul~lur~.~ Lysinate2.000 r'l~.mActin~ r"".l .Ale o oos D~l~u~e~l~orphan HBr 0.300 Alcohol (95%) 25.000 Propylene Glycol 25.000 ~o~1illm Citrate 2.000 Citric Acid 0.250 2s Liquid Sugar (Simple Syrup)25.000 Glycerin 7.000 Colorants 0.008 Flavor 0.500 Water, Purified QS 100.000 The purified water (app-~y 10% of the final batch volume) is poured into a batch CO~ I e~ ;l.pcd with a ligl-ll~; mixer. The sodium citrate, citric acid and C1el~ C ru~ aLe are added seq~lentiAlly and dissolved with a~it~t;~n The ~,c.in and liquid sugar are then added. In a sep~le co--lA-~-~r the colorants are added to purified water (applo~ y 0.5% of the final batch volume). This 35 colorant sol~tion is then added to the first batch COI~ U In a sepal~le CO~
the S (+) il,~lp.urell Iysinate and deAL-u...- ll~ ~Rr are added sequ~nti~ y to the a!cohol while stirring.
W O 97/04808 PCT~US96/12249 12 The propylene glycol and fiavors are added to this alcohol premix and the res~-lting mixture is stirred until hom~gF ~eO-Ie and then added to the first co.
The ~ , purified water is added to the, ~ g ~ lur, and stirred.
~rlminietration of 20 ml (4 te~epoonefi~l) every eight to twelve hours to a 5 human in need of ll~ol ~Pnl provides i.~-oved relief from cough, cold-like, flu, flu-like and aller~gic rhinitis ~...l.tc~ e
Claims (14)
1. A composition for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition consisting essentially of:
(a) an analgesic pharmaceutical active; and (b) a pyrrolidine or piperidine ether antihistaminic agent of the formula:
wherein R1 is a radical selected from the group consisting of hydrogen, halogen,lower alkyl containing from 1 to 4 carbon atoms and lower alkoxy containing from 1 to 4 carbon atoms, R2 is a radical selected from the group consisting of lower alkyl containing 1 to 4 carbon atoms, m is an integer from 0, 1, 2 and 3 and n is an integer from 1 to 2, with the proviso that m+n must be at least 2.
(a) an analgesic pharmaceutical active; and (b) a pyrrolidine or piperidine ether antihistaminic agent of the formula:
wherein R1 is a radical selected from the group consisting of hydrogen, halogen,lower alkyl containing from 1 to 4 carbon atoms and lower alkoxy containing from 1 to 4 carbon atoms, R2 is a radical selected from the group consisting of lower alkyl containing 1 to 4 carbon atoms, m is an integer from 0, 1, 2 and 3 and n is an integer from 1 to 2, with the proviso that m+n must be at least 2.
2. A pharmaceutical composition according to Claim 1 wherein said antihistaminic agent is selected from the group consisting of N-methyl-2-[2'(.alpha.-methyl-p-chloro-benzhydryl-oxy)ethyl]-pyrrolidine and N-methyl-2-[2'(.alpha.-methyl-p-bromo-benzhydryl-oxy)ethyl]-pyrrolidine and salts thereof.
3. A pharmaceutical composition according to either of Claims 1 or 2 wherein said propionic acid derivative is selected from the group consisting of ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenburen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen and diclofenac.
4. A pharmaceutical composition according to any of the above Claims wherein said propionic acid derivative is selected from the group consisting of ibuprofen, naproxen,flurbiprofen, and ketoprofen.
5. A pharmaceutical composition according to any of the above Claims wherein said antithistaminic agent is N-methyl-2-[2'(.alpha.-methyl-p-chloro-benzhydryl-oxy)ethyl]-pyrrolidine.
6. A pharmaceutical composition according to any of the above Claims wherein said propionic acid derivative is the amino acid salt and is selected from the group consisting of triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, ornithine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamide, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purine, piperazine and piperidine and mixtures thereof.
7. A pharmaceutical composition according to any of the above Claims which also contains an additional pharmaceutical active selected from the group consisting of decongestants , expectorants, additional antihistamines and antitussives.
8. A pharmaceutical composition according to any of the above Claims wherein said decongestant is pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof.
9. A pharmaceutical composition according to any of the above Claims 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.
10. A pharmaceutical composition according to any of the above Claims wherein said expectorant is an expectorant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine, bromhexine and ambroxol, mixtures thereof or pharmaceutically acceptable salts thereof.
11. A pharmaceutical composition according to any of the above Claims wherein said additional antihistamine is selected from the group consisting of chlorphe-~ alllinc, bromphe-lil al,line, dexchlorphenil al~une~
dcAl),o-,lpl~e,lilaln-ne, triprolidine, doxylamine, tripele~-nh~ e cypro-heptadine, call;.~ -e, bromodiphenhydl~l.ille, pyril~mine, acrivastine, AED~-l 1325, pho-i~ ,....;..e, ~ e~ ~7~t~line~ tine, ce~ e, eb~etine~ k~loLiren~ lodoxamide, loratidine, levw~ ctin~, ll,e4~ r, o~lollllde, s~ r" taif~lline, te--~r~ ;..ç, and terfen~rline, mixtures thereof or ph~rm~ce~tic~lly acc~L~ le salts thereof.
dcAl),o-,lpl~e,lilaln-ne, triprolidine, doxylamine, tripele~-nh~ e cypro-heptadine, call;.~ -e, bromodiphenhydl~l.ille, pyril~mine, acrivastine, AED~-l 1325, pho-i~ ,....;..e, ~ e~ ~7~t~line~ tine, ce~ e, eb~etine~ k~loLiren~ lodoxamide, loratidine, levw~ ctin~, ll,e4~ r, o~lollllde, s~ r" taif~lline, te--~r~ ;..ç, and terfen~rline, mixtures thereof or ph~rm~ce~tic~lly acc~L~ le salts thereof.
12. A ph~rm~c~ ti~l composition acco,diilg to any of the above Claims which comprises the S(+) en~ntiom~r of the propionic acid non~leloidal anti-;--llh------~lory agent.
13. A pharm~ceutic~l composition accoldi~g to any of the above Claims wheleill said S(+) enantiomer is s~lected from the group con~ ing of S(+)-k~,Loplor~ll Iysinate, S(+)-il,.~plor~.~ Iysinate, and S(+)-napru Iysinate.
14. A pharm~ce~ltic~l composition accor.ling to any of the above Claims which in addition col~lains an a-agonist compound.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50877595A | 1995-07-28 | 1995-07-28 | |
| US61152896A | 1996-03-05 | 1996-03-05 | |
| US08/508,775 | 1996-03-05 | ||
| US08/611,528 | 1996-03-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2227958A1 true CA2227958A1 (en) | 1997-02-13 |
Family
ID=27056302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002227958A Abandoned CA2227958A1 (en) | 1995-07-28 | 1996-07-25 | Compositions containing analgesics and antihistamines and methods for treating respiratory disorders |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0841947A1 (en) |
| JP (1) | JPH11510168A (en) |
| AR (1) | AR003470A1 (en) |
| AU (1) | AU6599196A (en) |
| CA (1) | CA2227958A1 (en) |
| CO (1) | CO4750820A1 (en) |
| PE (1) | PE12098A1 (en) |
| WO (1) | WO1997004808A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5648358A (en) * | 1996-03-05 | 1997-07-15 | Mitra; Sekhar | Compositions and methods for treating respiratory disorders |
| US5770618A (en) * | 1996-11-13 | 1998-06-23 | Nastech Pharmaceutical Company, Inc. | Method for increasing the solubility of clemastine and pharmaceutical compositions prepared therefrom |
| HUP9700654A2 (en) | 1997-03-26 | 1999-09-28 | Dezső Korbonits | Antitussive compositions containing theobromine |
| JP2001517626A (en) * | 1997-09-19 | 2001-10-09 | ザ、プロクター、エンド、ギャンブル、カンパニー | Compositions and methods for treating respiratory disorders |
| DE60232445D1 (en) | 2001-06-28 | 2009-07-09 | Ucb Farchim Sa | CETIRIC AND PSEUDOEPHEDRINE-CONTAINING TABLET |
| BR0212232A (en) * | 2001-09-04 | 2004-10-05 | Boehringer Ingelheim Int | Antiinfluenza agent |
| CL2003002653A1 (en) * | 2002-12-18 | 2005-04-22 | Wyeth Corp | PHARMACEUTICAL COMPOSITION THAT INCLUDES (A) AN NON-STEROID ANTI-INFLAMMATORY (NSAID), PREFERREDLY IBUPROFEN, (B) A DECONGESTIONANT, PREFERENTIALLY PSEUDOEFEDRINE AND (C) AN ANTIHISTAMINIC, PREFERENTLY CHLORINE; METHOD FOR YOUR PREPARATION |
| FR2865648B1 (en) * | 2004-02-03 | 2006-06-30 | Philippe Perovitch | METHOD FOR DIFFUSION OF INSOLUBLE MOLECULES IN AQUEOUS MEDIUM AND COMPOSITION IMPLEMENTING SAID METHOD |
| RU2286770C2 (en) * | 2004-11-22 | 2006-11-10 | Закрытое акционерное общество "Научно-производственное объединение "Антивирал" (ЗАО "НПО "Антивирал") | Anti-influenza agent |
| JP5598108B2 (en) * | 2009-07-09 | 2014-10-01 | ライオン株式会社 | Solid composition for internal use |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59222406A (en) * | 1983-06-01 | 1984-12-14 | Teijin Ltd | Pharmaceutical preparation for remedying periodontosis and its preparation |
| US4552899A (en) * | 1984-04-09 | 1985-11-12 | Analgesic Associates | Cough/cold mixtures comprising non-steroidal anti-inflammatory drugs |
| WO1992005783A1 (en) * | 1990-09-28 | 1992-04-16 | Merck & Co., Inc. | Ibuprofen-antihistamine combinations |
| DE69229880T2 (en) * | 1991-11-19 | 2000-05-04 | Univ Virginia | COMBINED VIRUSTATIC ANTIMEDIATOR TREATMENT (COVAM) OF ORDINARY COOLS |
| GB9222849D0 (en) * | 1992-10-31 | 1992-12-16 | Smithkline Beecham Plc | Novel use of pharmaceutical compositions |
| EP0674517A1 (en) * | 1992-12-21 | 1995-10-04 | The Procter & Gamble Company | Compositions containing caffeine and s(+)-ibuprofen or s(+)-flurbiprofen or s(+)-ketoprofen |
-
1996
- 1996-07-25 CA CA002227958A patent/CA2227958A1/en not_active Abandoned
- 1996-07-25 EP EP96925495A patent/EP0841947A1/en not_active Withdrawn
- 1996-07-25 WO PCT/US1996/012249 patent/WO1997004808A1/en not_active Application Discontinuation
- 1996-07-25 JP JP9507747A patent/JPH11510168A/en active Pending
- 1996-07-25 AU AU65991/96A patent/AU6599196A/en not_active Abandoned
- 1996-07-26 PE PE1996000570A patent/PE12098A1/en not_active Application Discontinuation
- 1996-07-26 AR ARP960103779A patent/AR003470A1/en unknown
- 1996-07-29 CO CO96039940A patent/CO4750820A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997004808A1 (en) | 1997-02-13 |
| AU6599196A (en) | 1997-02-26 |
| PE12098A1 (en) | 1998-04-19 |
| JPH11510168A (en) | 1999-09-07 |
| EP0841947A1 (en) | 1998-05-20 |
| CO4750820A1 (en) | 1999-03-31 |
| AR003470A1 (en) | 1998-08-05 |
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